Dipolar cycloaddition reactions of dihydropyrimidine-fused mesomeric betaines. An approach toward conformationally restricted dihydropyrimidine derivatives

Article abstract of DOI:10.1021/jo970121q

The bimolecular and intramolecular cycloaddition potential of various 4-aryldihydropyrimidine-fused mesomeric betaines was investigated. Dihydropyrimidine-fused isothiomunchnones and isomunchnones were found to undergo 1,3-dipolar cycloaddition reactions with electron-deficient dipolarophiles such as DMAD, methyl propiolate, methyl vinyl ketone, or N-methylmaleimide. In contrast, cross-conjugated mesomeric thiazinium betaines underwent 1,4-dipolar cycloaddition reaction with electron-rich dipolarophiles such as ynamines or ketene acetals. In general, these cycloadditions show a high degree of regioselectivity, facial selectivity, and exo/endo diastereoselectivity. Intramolecular variations of the above processes involving o-alkenylaryl-tethered dihydropyrimidine-fused isomunchnones lead to polycyclic dihydropyrimidine analogs that closely mimic the proposed receptor-bound conformation of dihydropyridine calcium channel modulators. These cycloadducts are the result of an endo-addition of the π-bond to the carbonyl ylide dipole embedded in the isomunchnone system. The relative stereochemistry of these cycloadducts was established by single-crystal X-ray analysis.

Full text of DOI:10.1021/jo970121q

J . Org. Chem. 1997, 62, 3109-3118
3109
Dip ola r Cycloa d d ition Rea ction s of Dih yd r op yr im id in e-F u sed
Mesom er ic Beta in es. An Ap p r oa ch tow a r d Con for m a tion a lly
Restr icted Dih yd r op yr im id in e Der iva tives1
C. Oliver Kappe*
Institute of Organic Chemistry, Karl-Franzens-University Graz, A-8010 Graz, Austria
Karl Peters and Eva-Maria Peters
Max-Planck-Institut fu¨r Festko¨rperforschung, Heisenbergstrasse 1, D-70506 Stuttgart, Germany
Received J anuary 22, 1997X
The bimolecular and intramolecular cycloaddition potential of various 4-aryldihydropyrimidine-
fused mesomeric betaines was investigated. Dihydropyrimidine-fused isothiomu¨nchnones and
isomu¨nchnones were found to undergo 1,3-dipolar cycloaddition reactions with electron-deficient
dipolarophiles such as DMAD, methyl propiolate, methyl vinyl ketone, or N-methylmaleimide. In
contrast, cross-conjugated mesomeric thiazinium betaines underwent 1,4-dipolar cycloaddition
reaction with electron-rich dipolarophiles such as ynamines or ketene acetals. In general, these
cycloadditions show a high degree of regioselectivity, facial selectivity, and exo/endo diastereose-
lectivity. Intramolecular variations of the above processes involving o-alkenylaryl-tethered
dihydropyrimidine-fused isomu¨nchnones lead to polycyclic dihydropyrimidine analogs that closely
mimic the proposed receptor-bound conformation of dihydropyridine calcium channel modulators.
These cycloadducts are the result of an endo-addition of the π-bond to the carbonyl ylide dipole
embedded in the isomu¨nchnone system. The relative stereochemistry of these cycloadducts was
established by single-crystal X-ray analysis.
In tr od u ction
4-Aryl-1,4-dihydropyridines of the nifedipine type
(DHPs, e.g., 1) were first introduced into clinical medicine
in 1975 and are still the most potent group of calcium
channel modulators available for the treatment of car-
diovascular diseases.2 Dihydropyrimidines of type 2
(DHPMs) show a very similar pharmacological profile,
and in recent years, several lead compounds were devel-
oped (e.g., 3) that are equal in potency and duration of
antihypertensive activity to classical and second-genera-
tion dihydropyridine drugs.3,4
detailed structure-activity profile for a series of DHPM
derivatives was reported, leading to a general binding-
site model for DHP/DHPM calcium channel modulators.6
The stereochemical relationship between the aryl group
and the dihydropyrimidine ring was found to be one of
the factors having a pronounced effect on the biological
activity.5,6 It was proposed that in the receptor-bound
conformation the substituted aryl ring is positioned
axially, perpendicular to, and bisecting the boatlike
dihydropyridine/dihydropyrimidine ring, with the 4-aryl
substituent X adopting a synperiplanar (relative to C4-
H) orientation.6
Despite many studies on the structure-function rela-
tionships of this type of calcium channel modulators,
there still remains debate on the exact stereochemical/
conformational requirements for activity.5 In 1995, a
* To whom correspondence should be addressed. Fax: (43)-(316)-
3809840. E-mail: kappeco@balu.kfunigraz.ac.at.
X Abstract published in Advance ACS Abstracts, April 15, 1997.
(1) Synthesis and Reactions of Biginelli Compounds. 7. Part 6:
Kappe, C. O.; Fabian, W. M. F.; Semones, M. A. Tetrahedron 1997,
53, 2803-2816.
(2) (a) J anis, R. A.; Silver, P. J .; Triggle, D. J . Adv. Drug. Res. 1987,
16, 309. (b) Bossert, F.; Vater, W. Med. Res. Rev. 1989, 9, 291-324.
(3) (a) 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.; Satah, F.; Morita,
M.; Noguchi, T. J . Med. Chem. 1989, 32, 2399-2406. (b) Atwal, K.;
Rovnyak, G. C.; Schwartz, J .; Moreland, S.; Hedberg, A.; Gougoutas,
J . Z.; Malley, M. F.; Floyd, D. M. J . Med. Chem. 1990, 33, 1510-1515.
(c) 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, 2629-2635. (d) 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, 806-811. (e) Rovnyak, G. C.;
Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.; Gougoutas, J .
Z.; O’Reilly, B. C.; Schwartz, J .; Malley, M. F. J . Med. Chem. 1992,
35, 3254-3263. (f) Grover, G. J .; Dzwonczyk, S.; McMullen, D. M.;
Normadinam, C. S.; Sleph, P. G.; Moreland, S. J . J . Cardiovasc.
Pharmacol. 1995, 26, 289-294. (g) Negwer, M. Organic-Chemical
Drugs and their Synonyms; Akademie Verlag: Berlin, 1994; p 2558.
(4) (a) Atwal, K. S.; Moreland, S. Bioorg. Med. Chem. Lett. 1991, 1,
291-294. (b) Alajarin, R.; Vaquero, J . J .; Alvarez-Builla, J .; Fau de
Casa-J uana, M.; Sunkel, C.; Priego, J . G.; Gomez-Sal, P.; Torres, R.
Bioorg. Med. Chem. 1994, 2, 323-329.
(5) For a recent review, see: Goldman, S.; Stoltefuss, J . Angew.
Chem. 1991, 103, 1587-1605; Angew. Chem., Int. Ed. Engl. 1991, 30,
1559-1578 and references therein.
(6) For a more detailed discussion, see: Rovnyak, G. C.; Kimball,
S. D.; Beyer, B.; Cucinotta, G.; DiMarco, J . D.; Gougoutas, J .; Hedberg,
A.; Malley, M.; McCarthy, J . P.; Zhang, R.; Moreland, S. J . Med. Chem.
1995, 38, 119-129. For a commentary, see: Triggle, D. J .; Padmanab-
han, S. Chemtracts: Org. Chem. 1995, 8, 191-196.
S0022-3263(97)00121-7 CCC: $14.00 © 1997 American Chemical Society

3110 J . Org. Chem., Vol. 62, No. 10, 1997
Kappe et al.
Sch em e 1
stereocenter in the dipole and (ii) the application of the
intramolecular variation of this methodology toward the
construction of conformationally restricted dihydropyri-
midine derivatives.
Resu lts a n d Discu ssion
Whereas dihydropyridines of the nifedipine type (DHPs)
are generally prepared by the well-known Hantzsch
synthesis,12 the aza-analogs 2 (DHPMs) are readily
available through the Biginelli dihydropyrimidine syn-
thesis (Scheme 1)13 or other related methods.13,14 These
dihydropyrimidine derivatives are inherently asymmetric
and have the advantage that the (thio)amide moiety
embedded in the dihydropyrimidine ring allows a selec-
tive functionalization of the biologically less important
“right-hand side” of the molecule (see above),13 a process
that is more troublesome in the dihydropyridine series.15
We began by first exploring the intermolecular cy-
cloaddition properties of a series of dihydropyrimidine-
fused betaines in order to establish the general viability
of dipolar cycloaddition reactions in this series of fused
mesoionics. Our studies commenced with the synthesis
of dihydropyrimidine-fused isothiomu¨nchnone 8 (Scheme
2). The required dihydropyrimidine-2-thione 7 was
readily available by condensation of benzaldehyde, ethyl
acetoacetate, and N-methylthiourea under standard Bigi-
nelli conditions.16 Thioisomu¨nchnone 8 was obtained as
a stable, orange-red solid by sequential addition of
R-bromophenylacetyl chloride and triethylamine to a
solution of 7 in chloroform, following a protocol developed
by Potts et al.17,18 Thioisomu¨nchnone 8 reacted smoothly
with dimethyl acetylenedicarboxylate (DMAD) and meth-
yl propiolate at ca. 100 °C in toluene to produce pyri-
dopyrimidines 10a ,b in high yields. The intermediate
primary cycloadducts 9a ,b could not be isolated and
underwent clean extrusion of sulfur (9 f 10). In the
reaction with methyl propiolate complete regioselectivity
was observed, no trace of the other isomer being observed.
The position of the methyl ester group in 10b was
established unequivocally by determination of long-range
1H-13C connectivities through an HMBC NMR experi-
ment,19 which confirms the expected and well-prece-
dented regiochemistry of this bimolecular 1,3-dipolar
cycloaddition.20,21 Recent semiempirical calculations on
the FMO interactions in the cycloaddition of related
Herein we describe synthetic methodology leading
toward novel types of conformationally restricted dihy-
dropyrimidine derivatives of type 5 that closely mimic
the recently proposed receptor-bound conformation of
DHP/DHPM calcium channel modulators (see above).
Our strategy toward these polycyclic dihydropyrimidines
is outlined in Scheme 1 and involves an intramolecular
1,3-dipolar cycloaddition reaction of an o-alkenylaryl-
tethered dihydropyrimidine-fused mesomeric betaine as
the key step (6 f 5). In recent years, mesomeric beatines
of this general type, i.e., isomu¨nchnones (1,3-oxazolium-
4-olates)7,8 and isothiomu¨nchnones (1,3-thiazolium-4-
olates),7,9 have proven to be very useful intermediates in
a variety of synthetic applications.7-9 The carbonyl ylide
or thiocarbonyl ylide dipoles, respectively, incorporated
in these mesoionics have been demonstrated to undergo
both bimolecular and intramolecular cycloaddition reac-
tions with relative ease.7-9 There are also a number of
examples involving bimolecular and intramolecular 1,4-
dipolar cycloaddition reactions of related six-membered
analogs, i.e., of cross-conjugated heteroaromatic 1,3-
thiazinium betaines.10,11
In the present paper, we investigate the dipolar cy-
cloaddition chemistry of dihydropyrimidine-fused five-
and six-membered mesomeric betaines. Of particular
interest to us are (i) stereochemical aspects in these
cycloaddition reactions relating to the presence of a
(12) For reviews of the Hantzsch synthesis and related reactions,
see: (a) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 269-289. (b)
Stout, D. M.; Meyers, A. J . Chem. Rev. 1982, 82, 223-243. (c) Eisner,
U.; Kuthan, J . Chem. Rev. 1972, 72, 1-42.
(13) For a review of the Biginelli-condensation, see: Kappe, C. O.
Tetrahedron 1993, 49, 6937-6963.
(14) (a) O’Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 1185-
1188. (b) Atwal, K. S.; O’Reilley, B. C.; Gougoutas, J . Z.; Malley, M.
F. Heterocycles 1987, 26, 1189-1192. (c) Atwal, K. S.; Rovnyak, G.
C.; O’Reilly, B. C.; Schwartz, J . J . Org. Chem. 1989, 54, 5898-5907.
(15) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 291-314.
(16) Kappe, C. O.; Roschger, P. J . Heterocycl. Chem. 1989, 26, 55-
64.
(7) For reviews of the cycloaddition chemistry of isomu¨nchnones and
isothiomu¨nchnones, see: (a) Osterhout, M. H.; Nadler, W. R.; Padwa,
A. Synthesis 1994, 123-141. (b) Newton, C. G.; Ramsden, C. A.
Tetrahedron 1982, 38, 2965-3011. (c) Ollis, W. D.; Ramsden, C. A.
Adv. Heterocycl. Chem. 1976, 19, 1-122.
(8) (a) Padwa, A.; Austin, D. J .; Price, A. T.; Weingarten, M. D.
Tetrahedron 1996, 52, 3247-3260. (b) Padwa, A.; Hertzog, D. L.;
Nadler, W. R.; Osterhout, M. H.; Price, A. T. J . Org. Chem. 1994, 59,
1418-1427 and references cited therein.
(9) (a) Avalos, M.; Babiano, R.; Cabanillas, A.; Cintas, P.; Higes, F.
J .; J imenez, J . L.; Palacios, J . C. J . Org. Chem. 1996, 61, 3738-3748.
(b) Padwa, A.; Kinder, F. R.; Nadler, W. R.; Zhi, L. Heterocycles 1993,
35, 367-383 and references cited therein.
(17) Potts, K. T.; Chen, S. J .; Kane, J .; Marshall, J . L. J . Org. Chem.
1977, 42, 1633-1638.
(18) Potts, K. T.; Houghton, E.; Singh, U. P. J . Org. Chem. 1974,
39, 3627-3631.
(10) For reviews and classifications of this type of heteroaromatic
betaines, see: (a) Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A.
Tetrahedron 1985, 41, 2239-2329. (b) Friedrichsen, W.; Bo¨ttcher, A.;
Kappe, T. Heterocycles 1982, 19, 1082-1148.
(11) For more recent examples, see: Padwa, A.; Coats, S. J .;
Semones, M. Tetrahedron 1995, 51, 6651-6668 and references therein.
(19) Heteronuclear multiple-bond correlation (HMBC), see: Bax, A.;
Summers, M. F. J . Am. Chem. Soc. 1986, 108, 2093-2094. 2-D NMR
spectra of 10b and 17 are presented in the Supporting Information.
(20) (a) Fischer, U.; Mo¨hler, H.; Schneider, F.; Widmer, U. Helv.
Chim. Acta 1990, 73, 763-781. (b) Potts, K. T.; Bordeaux, K. G.;
Kuehnling, W. R.; Salsbury, R. L. J . Org. Chem. 1985, 50, 1666-1676.

Dihydropyrimidine Calcium Channel Modulators
J . Org. Chem., Vol. 62, No. 10, 1997 3111
Sch em e 2
be expected if facial and exo/endo diastereoselectivities
are considered. According to recent computational stud-
ies on the conformation of 4-aryldihydropyrimidines of
type 2,1 the dihydropyrimidine ring is not planar but
adopts a boatlike conformation, with the 4-aryl substitu-
ent in axial position. This geometric arrangement has
also been found to exist in the solid state for bicyclic
derivatives related to 8.16 Due to the steric effect of the
comparatively bulky axial phenyl group, attack of the
dipolarophile anti to the phenyl substituent (i.e., from
the less hindered “bottom-face” of the molecule) should
be strongly favoured.
The relative stereochemistry of 11 was established by
an X-ray analysis22 confirming that the isolated cycload-
duct is the result of an “anti/exo-addition” of the dipo-
larophile to the isothiomu¨nchnone. Due to the complex-
ity of the crude 1H-NMR spectrum, the presence of minor
amounts of other diastereoisomers (<5%) cannot be
excluded with certainty. Cycloadduct 11 is relatively
stable; however, on prolonged standing of a chloroform
solution at room temperature or in the presence of silica
gel, slow conversion into 12 takes place.7,23
In order to compare the cycloaddition behavior of the
“masked” 1,3-dipole 8 with a related 1,4-dipolar system,
we have prepared the fused 1,3-thiazinium betaines
13a ,b. These cross-conjugated heteroaromatic betaines10
were readily prepared by cyclocondensation of thioamide
7 with (chlorocarbonyl)phenylketene24 or methylmalonyl
dichloride,25 respectively (Scheme 3). Both betaines are
bright yellow, thermally stable solids that can be stored
for long periods of time at room temperature. Whereas
mono- and bicyclic thiazinium betaines in general are
known to participate readily in 1,4-dipolar cycloaddition
reactions,10,11 betaines 13a ,b proved to be inert against
electron-deficient dipolarophiles such as N-methylmale-
imide or DMAD even under forcing conditions. The
supression of 1,4-dipolar character in 2-amino-substitut-
ed mesomeric 1,3-thiazinium betaines has been noted
previously24,26 and may be due to unfavorable FMO
interactions.11a
On the other hand, 13a ,b did undergo 1,4-dipolar
cycloaddition with electron-rich dipolarophiles such as
1-(diethylamino)-1-propyne (8 h, rt) and 1,1-diethoxy-
ethene (2 h, 110 °C), although the yields of isolated
cycloadducts 15a ,b and 17 were moderate. In both cases,
the primary cycloadducts (14, 16) were not isolable and
did undergo spontaneous extrusion of carbonyl sulfide10,11
to furnish pyridopyrimidines 15 and 17 as the final
products. According to recent semiempirical calcula-
2-amino-substituted isothiomu¨nchnones with electron-
deficient alkenes9a further support the here observed
regiochemistry and allow the classification of this type
of cycloaddition as HOMOdipol - LUMOdipolarophile-con-
trolled (Sustmann type I)21 addition.
The reaction of thioisomu¨nchnone 8 with olefinic
dipolarophiles such as N-methylmaleimide is more com-
plex. Treatment of dipole 8 with N-methylmaleimide in
toluene at 110 °C for 20 min resulted in the formation of
cycloadduct 11 in 63% isolated yield. Investigation of the
crude reaction mixture by 1H-NMR revealed the presence
of a number of minor byproducts that could, however,
not be separated or identified (with the exception of 12,
see below). Variations in the reaction conditions, i.e.,
performing the reaction at room temperature over a
longer period of time or changing the solvent, did not
raise the yield of 11 or reduce the number of byproducts.
Due to the presence of the stereocenter at C-5 of the
dipole, four diastereoisomeric cycloadducts can a priori
(22) The authors have deposited atomic coordinates for structures
11, 21, 23, and 27a ,b with the Cambridge Crystallographic Data
Centre. The coordinates can be obtained, on request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, UK.
(23) Potts, K. T.; Choudhury, D. R. J . Org. Chem. 1978, 43, 2697-
2700.
(24) Potts, K. T.; Ehlinger, R.; Nichols, W. M. J . Org. Chem. 1975,
40, 2596-2600.
(25) Kappe, T.; Golser, W. Synthesis 1972, 312-314.
(26) Potts, K. T.; Ehlinger, R.; Kanemasa, S. J . Org. Chem. 1980,
45, 2474-2479.
(21) (a) Sustmann, R. Tetrahedron Lett. 1971, 2717-2720. (b)
Sustmann, R.; Trill, H. Angew. Chem., Int. Ed. Engl. 1972, 11, 838-
840.

3112 J . Org. Chem., Vol. 62, No. 10, 1997
Kappe et al.
Sch em e 3
Sch em e 4
Isomu¨nchnones contain a masked carbonyl ylide dipole
and have been shown to be considerably more reactive
than their sulfur analogs.7,8 In general, these mesoionic
systems are prepared in situ by cyclization of suitable
diazo imides via metallo carbenoid intermediates.7,8 In
the dihydropyrimidine series, the required diazo imide
precursor 19 was readily prepared in high overall yield
by N-malonylacylation8 of 8 with methyl malonyl chlo-
ride, followed by standard diazo-transfer reaction with
mesyl azide.28 Decomposition of diazo imide 19 with a
catalytic amount of Rh2(OAc)4 in refluxing benzene in the
presence of a slight excess of N-methylmaleimide gave
cycloadduct 21 in 80% isolated yield. The relative
stereochemistry of 21 was proven by an X-ray analysis22
and is analogous to the stereochemistry observed for 11
(Scheme 2). Surprisingly, when the rhodium-catalyzed
decomposition of 19 was carried out in the absence of a
dipolarophile, isomu¨nchnone 20 precipitated from the hot
benzene solution as a colorless solid in 88% yield and
analytical purity! This carbonyl ylide dipole proved to
be remarkably stable and could even by recrystallized
from methanol. Although isomu¨nchnones bearing aryl
substituents at the C-2 and C-5 positions have been
isolated and reported as being stable in the open air for
weeks,29 the comparable stability of “aminoisomu¨nch-
none” 20 is notable.30 The stability of isomu¨nchnone 20
allowed us to investigate the cycloaddition step 20 f 21
in more detail. 1H-NMR monitoring of this reactin in
CDCl3 at 25 °C demonstrated the ease of the 1,3-dipolar
tions,11a cycloadditions of thiazinium betaines with elec-
tron-rich π-systems are LUMOdipol - HOMOdipolarophile
(Sustmann type III)21 controlled. The observed regio-
chemistry here is in full accord with FMO theory27 and
related cycloadditions.11a In addition, the structure of
cycloadduct 17 was confirmed by determination of long-
range 1H-13C connectivities through an HMBC NMR
experiment.19
It should be noted that the reaction of isothiomu¨nch-
none 8 with 1-(diethylamino)-1-propyne (i.e., with an
electron-rich dipolarophile) did not produce any isolable
cycloaddition products. Therefore, the cycloaddition
reactions of isothiomu¨nchnone 8 and thiazinium betaines
13 nicely supplement each other, the former undergoing
cycloaddition with electron-deficient π-systems and the
latter undergoing cycloaddition with electron-rich π-sys-
tems.
We next turned our attention to dihydropyrimidine-
fused isomu¨nchnone dipoles of type 20 (Scheme 4).
(28) Taber, D. F.; Ruckle, R. E., J r.; Hennesy, M. J . Org. Chem. 1986,
51, 4077-4078.
(29) Hamaguchi, M.; Ibata, T. Tetrahedron Lett. 1974, 4475-4478.
(27) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: New York, 1976.

Dihydropyrimidine Calcium Channel Modulators
J . Org. Chem., Vol. 62, No. 10, 1997 3113
Sch em e 5
cycloaddition (complete consumption of dipol 20 within
20 min) and the essentially clean formation of dia-
stereoisomer 21 as the only cycloaddition product (82%
isolated yield).
When methyl vinyl ketone was employed as dipolaro-
phile, similar results were obtained leading to high yields
of pyridopyrimidine 23 from isomu¨nchnone 20 (88%) or
directly from diazo compound 19 via in situ generated
20 (71%). The primary cycloadduct 22 was not isolated
and underwent facile rearrangement to alcohol 23,
presumably through nitrogen lone-pair-assisted opening
of the oxygen bridge followed by proton loss from the
resulting acyl iminium intermediate.31 Here, eight pos-
sible diastereoisomeric primary cycloadducts are possible
if one considers regioselectivity, facial selectivity (syn/
anti), and exo/endo diastereoselectivity, although the
information about exo/endo selectivity is “lost” during the
rearrangement of 22 to 23. The relative stereochemistry
of alcohol 23 was established unequivocally by an X-ray
crystal analysis22 and is consistent with the mechanistic
concept discussed above. Attack of the dipolarophile
occurs anti to the phenyl group, which places the oxygen
bridge syn to the phenyl ring in cycloadduct 22. This
stereochemical arrangement is then conserved during the
ring-opening step 22 f 23. The regiochemical outcome
of the 1,3-dipolar cycloaddition again is consistent with
FMO theory27 and not without precedent in iso-
mu¨nchnone chemistry.31 According to semiempirical
calculations,31 such cycloadditions are HOMOdipol
-
LUMOdipolarophile (Sustmann type I)21 controlled.
A critical comparison of the results obtained in the
bimolecular cycloaddition reactions of the various di-
hydropyrimidine-fused mesomeric betaines described
above (Schemes 2-4) led us to select the isomu¨nchnone
dipole as a model system for the planned intramolecular
cycloaddition reactions (Scheme 1). The relative ease of
dipole generation, the high reactivity of the dipole itself,
and the high yields and selectivities observed in the
cycloaddition reactions make this mesoionic system an
obvious choice.
In order to construct the desired conformationally
restricted polycyclic DHPM systems, an intramolecular
variation of the bimolecular cycloaddition protocol de-
scribed above was developed (Scheme 5). This was
readily achieved by incorporating an alkenyl tether into
the ortho-position of the aryl moiety in the DHPM
framework. The required starting materials 24a ,b were
obtained by classical Biginelli condensation of ethyl
acetoacetate, with N-methylurea, and 2-vinylbenzalde-
hyde (or 2-allylbenzaldehyde, respectively). N-Malonyl-
acylation,8 followed by standard diazo-transfer,28 pro-
duced the corresponding diazo precursors 25a ,b in high
yield. Treatment of diazo imides 25a ,b with a catalytic
amount of Rh2(OAc)4 in refluxing benzene produced
directly the desired pentacyclic dihydropyrimidine de-
rivatives 27a ,b in high yields. In this tandem-cycliza-
tion-cycloaddition sequence8 the initially generated
transient isomu¨nchnone dipole 26 adds spontaneously
across the unactivated π-bond of the olefinic tether in a
regio- and stereospecific manner. Analysis of the crude
reaction mixtures for both homologs (n ) 0, n ) 1) by
1H-NMR (200 MHz) confirmed that 27a and 27b, respec-
tively, were the only isomers formed (within the detection
limit of 1H-NMR spectroscopy). The stereospecificity and
relative ease of these intramolecular cycloadditions are
readily explained by considering molecular models (Dre-
iding) of the transition states involved.32 The pseudoaxial
orientation of the aryl substituent allows for an extremely
favorable alignment of the double bond relative to the
dipole, placing the π-bond in close proximity above the
dipole.33 For n ) 0, only an endo approach of the π-bond
with the terminal end of the olefin directed toward the
negative center of the dipole is possible (endo A). Transi-
tion states according to types B-D leading to exo isomers
and/or different regioisomers cannot be modeled at all
or place a too high steric demand on the transition state.
For n ) 1, the endo A approach again is the most
favorable, although an endo B and even an exo C
approach cannot be totally excluded. The structures of
both cycloadducts were unequivocally established by an
X-ray crystallographic analysis (Figure 1; additional
(30) To the best of our knowledge, 20 is the first non-aryl-substituted
stable isomu¨nchnone reported. A crystalline sample of 20 could be
kept in the open air for 2 months without any sign of decomposition
(1H-NMR). For previous examples of the generation of aminoiso-
mu¨nchnones as transient intermediates, see: Doyle, M. P.; Pieters,
R. J .; Taunton, J .; Pho, H. Q.; Padwa, A.; Hertzog, D. L.; Precedo, L.
J . Org. Chem. 1991, 56, 820-829. Kappe, C. O. Tetrahedron Lett.
1997, 38, in press.
(32) Potts, K. T.; Dery, M. O.; J uzukonis, W. H. J . Org. Chem. 1989,
54, 1077-1088.
(33) The conformation necessary for an intramolecular cycloaddition
requires the tether on the aryl substituent close to antiperiplanar
arrangement with C4-H (i.e., above the dihydropyrimidine ring).
According to recent ab initio and semiempirical calculations,1 this type
of DHPM conformation is only slightly higher in energy than the lowest
energy conformation with synperiplanar orientation of an o-aryl
substituent (i.e., away from the dihydropyrimidine ring).
(31) Padwa, A.; Hertzog, D. L. Tetrahedron 1993, 49, 2589-2560.

3114 J . Org. Chem., Vol. 62, No. 10, 1997
Kappe et al.
Sch em e 6
F igu r e 1. Solid-state structure of 27a .
X-ray plots of 27a and 27b are presented in the Sup-
porting Information),22 confirming that both cycloadducts
result from an endo A type transition state.
equilibrium mixture (1:1) of C-2 epimers (see the Experi-
mental Section). Apparently, a facile and thermally
allowed 1,5-sigmatropic hydrogen shift in oxazolopyri-
midiniumolate 30 leads to a collapse of the dipole before
cycloaddition (30 f 32) can take place. Since it has been
suggested that 4(5H)-oxazolones can undergo 1,3-dipolar
cycloaddition reaction via tautomerization to an iso-
mu¨nchnone dipole,34 we have tried to effect the desired
cycloaddition reaction by subjecting 31 to a number of
different experimental conditions (polar solvents, heat,
acid catalysis). However, no evidence for an intra-
molecular cycloaddition from 31 could be obtained.
Therefore, a protecting group strategy as outlined in
Scheme 1 for the preparation of biologically active DHPM
derivatives of type 6 (Scheme 1) is essential.
In conclusion, we have demonstrated that dihydro-
pyrimidine-fused mesomeric betaines (i.e., 8, 13, 20) serve
as useful intermediates for the preparation of bicyclic
dihydropyrimidine derivatives. In effect, these cyclo-
additions constitute a two-step annulation sequence of
dihydropyrimidines providing a novel entry into bicyclic
DHPM analogs. In the model studies described herein,
a high degree of regioselectivity, facial selectivity, and
exo/endo diastereoselectivity was observed. In its in-
tramolecular variation, the described isomu¨nchnone cy-
cloaddition sequence leads to a rigid, polycyclic DHPM
skeleton, which closely resembles the recently proposed
receptor-bound conformation of dihydropyridine calcium
channel modulators. The ease of generation of the key
dipolar intermediates makes this an attractive method
for the preparation of pharmacologially interesting DHPM
The solid-state structure of 27a demonstrates that the
geometry of this conformationally restricted DHPM
derivative is very similar to the receptor-bound confor-
mation proposed in the recent binding-site model for
DHP/DHPM calcium channel modulators (see above).5,6
The aryl group is “tied” into the axial position and is
perpendicular to and (nearly) bisecting the boatlike
dihydropyrimidine ring. Any additional substituent on
the aromatic ring (i.e., Z in 6) would be forced into the
synperiplanar orientation relative to C4-H. Importantly,
by using this cycloaddition protocol all manipulations on
the DHPM system are occuring on the nonessential
“right-hand” side of the molecule, thereby not interfering
with the receptor-sensitive groups on the “left-hand” side
(see above).
Polycycles 27 above differ significantly from the pro-
posed calcium channel modulator targets of type 5
regarding the absence of the enamidic NH on the dihy-
dropyrimidine. Thus, we have investigated the potential
cycloaddition reactivity of fused isomu¨nchnone 30 with
an N-H functionality next to the dipole. Biginelli
condensation of ethyl acetoacetate with urea and 2-
vinylbenzaldehyde provided dihydropyrimidine 28 (74%
yield), which was converted smoothly into diazo imide
29 by sequential N-malonylacylation and diazo transfer
(Scheme 6). Decomposition of 29 in benzene in the
presence of a catalytic amount of Rh2(OAc)4, i.e., under
identical conditions as described above for the N-protect-
ed analog 25a , did not provide any product derived from
an intramolecular cycloaddition reaction. Instead, oxa-
zolopyrimidine 31 was obtained in 91% yield as an
(34) Potts, K. T.; Marshall, J . L. J . Org. Chem. 1979, 44, 626-628.

Dihydropyrimidine Calcium Channel Modulators
J . Org. Chem., Vol. 62, No. 10, 1997 3115
4-ca r boxyla te (11). A mixture of 102 mg (0.25 mmol) of
isothiomu¨nchnone 8, 35 mg (0.32 mmol) of N-methylmaleim-
ide, and 5 mL of toluene was heated under reflux for 20 min.
After the solvent was removed under reduced pressure, the
remaining oil was crystallized by addition of a small amount
of cold ethanol to give 81 mg (63%) of cycloadduct 11 as a
colorless solid: mp 215 °C (1-propanol); IR (KBr) 1776, 1704,
1690, 1593 cm-1; 1H-NMR (CDCl3) δ 1.25 (t, 3H, J ) 7.5 Hz),
2.70 (s, 3H), 2.97 (s, 3H), 3.26 (s, 3H), 3.77 and 4.00 (2 d, 2H,
J ) 7.0 Hz each), 4.12 (q, 2H, J ) 7.5 Hz), 5.68 (s, 1H), 7.17-
7.40 (m, 10H); 13C-NMR (CDCl3) δ 14.2, 17.1, 25.2, 36.6, 51.0,
54.1, 54.7, 60.1, 70.9, 90.4, 105.7, 127.2, 127.3, 128.1 (2
carbons), 128.5, 129.0, 129.9, 141.7, 155.2, 165.9, 169.8, 172.0,
172.4. Anal. Calcd for C28H27N3O5S: C, 64.97; H, 5.26; N,
8.12. Found: C, 64.69; H, 5.33; N, 8.01.
derivatives. The application and further development of
this methodology for the preparation of properly func-
tionalized DHPM calcium channel modulators is under
investigation.
Exp er im en ta l Section
Melting points are uncorrected. 1H- and 13C-NMR spectra
were obtained from 200 or 360 MHz instruments. HMBC-
NMR measurements were performed on a 360 MHz spectrom-
eter. IR spectra were recorded on dispersive or FT instru-
ments. Flash chromatography was performed with silica gel
60, 40-63 µm, using mixtures of hexane and ethyl acetate as
eluent. For further details, see ref 1.
Methylene chloride, benzene, and toluene were distilled and
dried over 4 Å molecular sieves. Triethylamine (TEA) was
distilled from solid KOH before use. All reactions were carried
out in a dry N2 atmosphere to minimize contact with moisture.
6-[(E t h yloxy)ca r b on yl]-7,8-d im e t h yl-2,5-d ip h e n yl-
5H,8H-[1,3]th ia zolo[3,2-a ]p yr im id in -4-iu m -3-ola te (8). A
solution of 701 mg (3.00 mmol) of R-bromophenylacetyl chlo-
ride35 in 10 mL of alcohol-free CHCl3 was added dropwise to a
solution of 870 mg (3.00 mmol) of pyrimidine 716 in 10 mL of
CHCl3. After the solution was stirred at rt for 5 min, a solution
of 606 mg (6.00 mmol) of TEA in 5 mL of CHCl3 was added
dropwise, and the resulting red solution was stirred for an
additional 5 min before the mixture was washed twice with
ice-water. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure to give 1.05 g (86%) of
pure 8 as an orange-red solid: mp 230-232 °C (acetone); IR
Eth yl 1,2,9-Tr im eth yl-6,8,10-tr ioxo-4,7-d ip h en yl-1,4,6,-
8,9,10-h exah ydr opyr r olo[3′4′:3,4]pyr ido[1,2-a ]-pyr im idin e-
3-ca r boxyla te (12). A mixture of 52 mg (0.10 mmol) of
cycloadduct 11, 1.0 g of silica gel 60, and 5 mL of CH2Cl2 was
stirred at rt for 1-2 weeks. After all starting material was
consumed (TLC), the mixture was filtered and the solvent
removed under reduced pressure. The crude product was
purified by flash chromatography to give 48 mg (ca. 100%) of
tricyclus 12 as a greenish solid: mp 228-231 °C; IR (KBr)
1
1753, 1701, 1660, 1561 cm-1; H-NMR (CDCl3) δ 1.31 (t, 3H,
J ) 7.5 Hz), 3.06 (s, 3H), 3.61 (s, 3H), 4.25 (q, 2H, J ) 7.5 Hz),
7.24-7.44 (m, 11H); 13C-NMR (CDCl3) δ 14.2, 16.2, 24.2, 40.5,
52.0, 61.0, 91.6, 104.9, 110.6, 124.4, 126.4, 127.6, 128.3, 128.7,
128.8, 130.4, 120.9, 136.8, 138.8, 144.4, 151.1, 161.8, 164.6,
165.4. Anal. Calcd for C28H25N3O5: C, 69.55; H, 5.27; N, 8.69.
Found: C, 69.27; H, 5.23; N, 8.55.
1
(KBr) 1706, 1653, 1588, 1533 cm-1; H-NMR (CDCl3) δ 1.23
7-(E t h oxyca r b on yl)-8,9-d im et h yl-4-oxo-3,6-d ip h en yl-
4H,6H,9H-p yr im ido[2,1-b][1,3]th ia zin -5-iu m -2-ola te (13a ).
To a solution of 1.16 g (4.00 mmol) of pyrimidine 7 in 10 mL
of alcohol-free CHCl3 was added 812 mg (4.50 mmol) of distilled
phenyl(chlorocarbonyl)ketene.36 After the solution was stirred
for 1 h at rt, the solvent was removed under reduced pressure
to give 1.25 g (72%) of betaine 13a as a yellow solid: mp 202-
(t, 3H, J ) 7.5 Hz), 2.62 (s, 3H), 3.27 (s, 3H), 4.14 (q, 2H, J )
7.5 Hz), 6.58 (s, 1H), 6.96-7.70 (m, 10H); 13C-NMR (CDCl3) δ
14.0, 15.0, 34.5, 53.9, 60.8, 85.1, 105.0, 122.2, 122.9, 127.3,
128.3, 128.5, 128.6, 134.3, 139.8, 145.5, 151.0, 153.9, 164.8;
MS m/e 407, 406 (M+, base). Anal. Calcd for C23H22N2O3S:
C, 67.96; H, 5.46; N, 6.89. Found: C, 67.63; H, 5.47; N, 6.66.
3-Eth yl 8,9-Dim eth yl 1,2-Dim eth yl-6-oxo-4,7-d ip h en yl-
1,6-d ih yd r o-4H-p yr id o[1,2-a ]p yr im id in e-3,8,9-tr ica r box-
yla te (10a ). A mixture of 406 mg (1.00 mmol) of isothio-
mu¨nchnone 8, 185 mg (1.30 mmol) of distilled dimethyl
acetylenedicarboxylate (DMAD), and 10 mL of toluene was
heated under reflux for 20 min. After the solvent was removed
under reduced pressure, the crude product was purified by
flash chromatography to yield 423 mg (82%) of cycloadduct
10a as a colorless solid: mp 170-172 °C (cyclohexane); IR
203 °C (MeCN); IR (KBr) 1711, 1685, 1652, 1611, 1500 cm-1
;
1H-NMR (CDCl3) δ 1.27 (t, 3H, J ) 7.5 Hz), 2.61 (s, 3H), 3.33
(s, 3H), 4.24 (q, 2H, J ) 7.5 Hz), 7.19-7.51 (m, 10H), 7.61 (s,
1H); 13C-NMR (CDCl3) δ 14.0, 15.4, 35.2, 51.7, 61.7, 99.5, 111.0,
126.3, 127.8, 128.9, 129.0, 130.9, 134.3, 137.1, 145.9, 159.6,
163.9, 164.2, 165.3; MS m/e 435 (M + 1), 406 (base). Anal.
Calcd for C24H22N2O4S: C, 66.34; H, 5.10; N, 6.45. Found: C,
66.35; H, 5.09; N, 6.36.
7-(E t h oxyca r b on yl)-4-oxo-6-p h e n yl-3,8,9-t r im e t h yl-
4H,6H,9H-pyr im ido[2,1-b][1,3]th iazin -5-iu m -2-olate (13b).
To a mixture of 290 mg (1 mmol) of pyrimidine 7 in 5 mL of
CH2Cl2 was added dropwise at 0 °C 232 mg (1.5 mmol) of
methyl malonyl dichloride. The resulting yellow solution was
stirred for 12 h at rt. The reaction mixture was diluted with
30 mL of CH2Cl2 and washed with saturated NaHCO3 and
brine. The organic layer was dried over Na2SO4 and the
solvent removed under reduced pressure. The crude product
was purified by flash chromatography to give 335 mg (90%) of
betaine 13b as a yellow solid: mp 157-162 °C; IR (KBr) 1702,
1654, 1605, 1504 cm-1; 1H-NMR (CDCl3) δ 1.31 (t, 3H, J ) 7.5
Hz), 2.02 (s, 3H), 2.65 (s, 3H), 3.38 (s, 3H), 4.28 (q, 2H, J )
7.5 Hz), 7.14-7.32 (m, 5H), 7.62 (s, 1H); 13C-NMR (CDCl3) δ
11.0, 14.0, 15.4, 35.2, 51.6, 61.6, 93.6, 110.8, 126.2, 128.7, 129.0,
137.2, 145.0, 159.8, 163.7, 163.9, 165.1. Anal. Calcd for
C19H20N2O4S: C, 61.27; H, 5.41; N, 7.52. Found: C, 61.19; H,
5.47; N, 7.43.
1
(KBr) 1752, 1721, 1702, 1655, 1520 cm-1; H-NMR (CDCl3) δ
1.30 (t, 3H, J ) 7.5 Hz), 2.56 (s, 3H), 3.12 (s, 3H), 3.55 (s, 3H),
3.81 (s, 3H), 4.24 (q, 2H, J ) 7.5 Hz), 7.17-7.35 (m, 11H); 13C-
NMR (CDCl3) δ 14.2, 15.9, 38.6, 51.6, 52.2, 52.5, 60.8, 93.9,
110.4, 122.5, 126.1, 127.9, 128.0, 128.6, 129.7, 133.9, 138.8,
143.1, 147.4, 152.1, 159.8, 164.6, 164.7, 166.9; MS m/e 516 (M+,
base). Anal. Calcd for C29H28N2O7: C, 67.37; H, 5.46; N, 5.42.
Found: C, 67.66; H, 5.43; N, 5.34.
3-Eth yl 9-Meth yl 1,2-Dim eth yl-6-oxo-4,7-d ip h en yl-1,6-
d ih yd r o-4H -p yr id o[1,2-a ]p yr im id in e-3,9-d ica r b oxyla t e
(10b). A mixture of 406 mg (1.00 mmol) of isothiomu¨nchnone
8, 228 mg (3.00 mmol) of distilled methyl propiolate, and 10
mL of toluene was heated at 90-100 °C for 30 min. After the
solvent was removed under reduced pressure, the crude
product was purified by flash chromatography to yield 394 mg
(86%) of cycloadduct 10b as a colorless solid: mp 212-215 °C
(1-propanol); IR (KBr) 1711sh, 1704, 1650, 1519 cm-1; 1H-NMR
(CDCl3) δ 1.34 (t, 3H, J ) 7.5 Hz), 2.57 (s, 3H), 3.15 (s, 3H),
3.86 (s, 3H), 4.28 (q, 2H, J ) 7.5 Hz), 7.18-7.42 (m, 9H), 7.72
(m, 2H), 8.07 (s, 1H); 13C-NMR (CDCl3) δ 14.3, 16.2, 39.6, 51.2,
52.0, 60.8, 95.9, 110.5, 122.9, 126.1, 127.4, 127.7, 128.1, 128.3,
128.5, 136.1, 139.5, 139.8, 148.3, 152.4, 159.9, 164.6, 164.9.
Anal. Calcd for C27H26N2O5: C, 70.72; H, 5.72; N, 6.11.
Found: C, 70.61; H, 5.70; N, 6.06.
E t h yl 8-(Diet h yla m in o)-1,2,9-t r im et h yl-6-oxo-4,7-d i-
p h en yl-1,6-d ih yd r o-4H -p yr id o[1,2-a ]p yr im id in e-3-ca r -
boxyla te (15a ). A mixture of 217 mg (0.50 mmol) of betaine
13a , 167 mg (1.50 mmol) of 1-(diethylamino)-1-propyne,37 and
5 mL of CH2Cl2 was kept at rt for 8 h. The solvent and excess
reagent were removed under reduced pressure, and the
remaining residue was purified by flash chromatography to
Eth yl 2,3,11-Tr im eth yl-7,10,12-tr ioxo-5,8-d ip h en yl-14-
th ia -2,6,11-tr ia za tetr a cyclo[6.5.1.01,6.09,13]tetr a d ec-3-en e-
(36) Nakanishi, S.; Butler, K. Org. Prep. Proced. Int. 1975, 7, 155-
158.
(35) Harpp, D. N.; Bao, L. Q.; Black, C. J .; Gleason, J . G.; Smith, R.
A. J . Org. Chem. 1975, 23, 3420-3426.
(37) Brandsma, L. Preperative Acetylene Chemistry; Elsevier: Am-
sterdam, 1971; p 146.

3116 J . Org. Chem., Vol. 62, No. 10, 1997
Kappe et al.
give 78 mg (32%) of cycloadduct 15a as a colorless solid: mp
amount of Rh2(OAc)4 (ca. 5 mg) was heated under reflux for
30-60 min. After all starting material had been consumed
(TLC), the solution was cooled and kept at rt for 1 h. The
precipitated solid was filtered to give 655 mg (88%) of analyti-
cally pure isomu¨nchnone 20: mp 235 °C dec; IR (KBr) 1719,
1
144-146 °C; IR (KBr) 1675, 1630, 1565, 1510 cm-1; H-NMR
(CDCl3) δ 0.96 (t, 6H, J ) 7.5 Hz), 1.30 (t, 3H, J ) 7.5 Hz),
2.04 (s, 3H), 2.56 (s, 3H), 2.68-2.88 (m, 4H), 3.22 (s, 3H), 4.12
(m, 2H), 7.12-7.39 (m, 6H). Anal. Calcd for C30H35N3O3: C,
74.20; H, 7.26; N, 8.65. Found: C, 73.97; H, 7.39; N, 8.51.
E t h yl 8-(Diet h yla m in o)-1,2,7,9-t et r a m et h yl-6-oxo-4-
p h en yl-1,6-d ih yd r o-4H-p yr id o-[1,2-a ]p yr im id in e-3-ca r -
boxyla te (15b). This cycloadduct was prepared in analogy
to 15a described above using betaine 13b: yield 74 mg (35%)
of 15b as a colorless solid; mp 137-139 °C; IR (KBr) 1670,
1630, 1570, 1510 cm-1; 1H-NMR (CDCl3) δ 1.05 (t, 6H, J ) 7.5
Hz), 1.32 (t, 3H, J ) 7.5 Hz), 2.01 (s, 3H), 2.08 (s, 3H), 2.49 (s,
3H), 3.11 (s, 3H), 3.00-3.32 (m, 4H), 4.22 (q, 2H, J ) 7.5 Hz),
7.15-7.28; 13C-NMR (CDCl3) δ 14.1, 14.3, 14.4, 15.9, 16.8, 39.6,
45.9, 50.9, 60.3, 100.2, 110.0, 114.8, 126.2, 127.2, 129.4, 141.6,
1
1682, 1669, 1584, 1544 cm-1; H-NMR (CDCl3) δ 1.13 (t, 3H,
J ) 7.5 Hz), 2.66 (s, 3H), 3.52 (s, 3H), 3.78 (s, 3H), 4.10 (q,
2H, J ) 7.5 Hz), 6.35 (s, 1H), 7.30-7.43 (m, 1H); 13C-NMR
(CDCl3) δ 13.9, 14.9, 31.0, 50.8, 53.1, 61.3, 106.5, 116.7, 127.6,
128.9, 129.2, 137.9, 144.3, 147.2, 150.8, 159.8, 164.0. Anal.
Calcd for C19H20N2O6: C, 61.28; H, 5.41; N, 7.52. Found: C,
61.09; H, 5.42; N, 7.41.
4-Eth yl 8-Meth yl 2,3,11-tr im eth yl-7,10,12-tr ioxo-5-ph en -
yl-14-oxa -2,6,11-t r ia za t et r a cyclo[6.5.1.01,6.09,13]t et r a d ec-
3-en e-4,8-d ica r boxyla te (21). (a ) F r om Dia zo Com p ou n d
19. A solution of 300 mg (0.75 mmol) of diazo compound 19
and 89 mg (0.80 mmol) of N-methylmaleimide in 10 mL of
benzene containing a catalytic amount of Rh2(OAc)4 was
heated at reflux for 1 h (TLC). After the solvent was removed
under reduced pressure, the crude product was purified by
flash chromatography to give 290 mg (80%) of cycloadduct 21
as a colorless solid, mp 190 °C.
142.7, 154.7, 159.3, 161.5, 165.9. Anal. Calcd for C25H33
-
N3O3: C, 70.89; H, 7.85; N, 9.92. Found: C, 70.91; H, 7.99;
N, 9.78.
Eth yl 8-Eth oxy-1,2,7-tr im eth yl-6-oxo-4-p h en yl- 1,6-d i-
h yd r o-4H-p yr id o[1,2-a ]p yr im id in e-3-ca r boxyla te (17). A
mixture of 186 mg (0.50 mmol) of betaine 13b, 290 mg (2.50
mmol) of 1,1-diethoxyethene, and 5 mL of toluene was heated
under reflux for 2 h. After removal of the solvent under
reduced pressure, the crude oil was purified by flash chroma-
tography to provide 60 mg (31%) of cycloadduct 17 as a
colorless solid: mp 190-192 °C (ethyl acetate); IR (KBr) 1700,
1638, 1530, 1258 cm-1; 1H-NMR (CDCl3) δ 1.31 (t, 3H, J ) 7.5
Hz) 1.43 (t, 3H, J ) 7.5 Hz), 2.00 (s, 3H), 2.58 (s, 3H), 3.24 (s,
3H), 4.08 (q, 2H, J ) 7.5 Hz), 4.22 (m, 2H), 5.46 (s, 1H), 7.19
(s, 5H), 7.29 (s, 1H); 13C-NMR (CDCl3) δ 8.9, 14.3, 14.8, 15.9,
34.2, 49.9, 60.3, 64.0, 78.1, 103.5, 105.5, 126.3, 127.3, 128.3,
(b) F r om Isom u1 n ch n on e 20. A solution of 186 mg (0.50
mmol) of isomu¨nchnone 20 and 67 mg (0.60 mmol) of N-
methylmaleimide in 4 mL of CH2Cl2 was stirred at rt for 20
min. After the solvent was removed under reduced pressure,
the crude product was titurated with a small amount of cold
ethanol to give 198 mg (82%) of cycloadduct 21 as a colorless
solid: mp 190 °C (ethanol), identical in all respects with the
product prepared above; IR (KBr) 1770, 1750, 1705, 1590 cm-1
;
1H-NMR (CDCl3) δ 1.18 (t, 3H, J ) 7.5 Hz), 2.66 (s, 3H), 3.03
(s, 3H), 3.09 (s, 3H), 3.67 (m, 2H), 3.94 (s, 3H), 4.05 (q, 2H, J
) 7.5 Hz), 5.58 (s, 1H), 7.19-7.36 (m, 5H); 13C-NMR (CDCl3)
δ 14.0, 16.4, 25.5, 30.5, 48.6, 49.7, 53.3, 54.2, 60.0, 84.9, 99.6,
103.1, 127.6, 127.7, 128.1, 140.3, 153.3, 161.9, 164.2, 165.7,
171.5, 171.9. Anal. Calcd for C24H25N3O8: C, 59.62; H, 5.21;
N, 8.69. Found: C, 59.57; H, 5.22; N, 8.56.
140.6, 144.1, 150.2, 161.5, 163.8, 165.6. Anal. Calcd for C22
-
H26N2O4: C, 69.09; H, 6.85; N, 7.32. Found: C, 69.02; H, 6.80;
N, 7.28.
Eth yl 3-[2-Dia zo-2-[(m eth yloxy)ca r bon yl]a cetyl]-1,6-
d im et h yl-2-oxo-4-p h en yl-1,2,3,4-t et r a h yd r o-5-p yr im id i-
n eca r boxyla te (19). A mixture of 822 mg (3.00 mmol) of
pyrimidine 18, 680 mg (5.00 mmol) of distilled methyl malonyl
chloride, and 30 mL of benzene was heated at reflux for 30
min. After all starting material had been consumed (TLC),
the solution was cooled to ambient temperature and washed
twice with saturated NaHCO3 and brine. The solvent was
removed under reduced pressure and the crude product
titurated with ether to give 1.07 g (95%) of ethyl 1,6-dimethyl-
3-[2-[(methyloxy)carbonyl]acetyl]-2-oxo-4-phenyl-1,2,3,4-tet-
rahydro-5-pyrimidinecarboxylate as a colorless solid: mp 143-
3-Eth yl 7-Meth yl 9-Acetyl-7-h yd r oxy-1,2-d im eth yl-6-
oxo-4-p h en yl-1,6,7,8-tetr a h yd r o-4H-p yr id o[1,2-a ]p yr im i-
d in e-3,7-d ica r boxyla te (23). (a ) F r om Dia zo Com p ou n d
19. A solution of 300 mg (0.75 mmol) of diazo compound 19
and 105 mg (1.5 mmol) of distilled methyl vinyl ketone in 10
mL of benzene containing a catalytic amount of Rh2(OAc)4 was
heated at reflux for 6 h (TLC). After the solvent and excess
reagent were removed under reduced pressure, the crude
product was purified by flash chromatography to give 235 mg
(71%) of cycloadduct 23 as pale yellow solid, mp 125-127 °C.
(b) F r om Isom u1 n ch n on e 20. A mixture of 189 mg (0.50
mmol) of isomu¨nchnone 20, 105 mg (1.50 mmol) of distilled
methyl vinyl ketone, and 2 mL of benzene was heated at reflux
for 40 min. The solvent and excess reagent were removed
under reduced pressure, and the crude product was purified
by flash chromatography to give 195 mg (88%) of cycloadduct
23, identical in all respects with the product prepared above:
mp 125-127 °C; IR (KBr) 3400, 1740, 1716, 1709, 1637, 1540
cm-1; 1H-NMR (CDCl3) δ 1.30 (t, 3H, J ) 7.5 Hz), 2.24 (s, 3H),
2.50 (s, 3H), 2.83 and 3.31 (2 d, 2H, J ) 14.5 Hz), 2.88 (s, 3H),
3.71 (s, 3H), 4.22-4.28 (m, 2H), 4.38 (br s, 1H), 6.83 (s, 1H),
7.16-7.33 (m, 5H); 13C-NMR (CDCl3) δ 14.0, 17.0, 28.9, 32.0,
40.1, 50.2, 52.9, 60.7, 75.8, 90.1, 112.6, 125.8, 127.8, 128.6,
138.5, 146.4, 151.7, 164.7, 168.8, 169.4, 192.9. Anal. Calcd
for C23H26N2O7: C, 62.43; H, 5.92; N, 6.33. Found: C, 62.39;
H, 5.92; N, 6.27.
145 °C (ethanol); IR (KBr) 1743, 1704, 1693, 1631, 1379 cm-1
;
1H-NMR (CDCl3) δ 1.26 (t, 3H, J ) 7.5 Hz), 2.55 (s, 3H), 3.15
(s, 3H), 3.73 (s, 3H), 3.92 (s, 2H), 4.21 (q, 2H, J ) 7.5 Hz),
6.77 (s, 1H), 7.23-7.30 (m, 5H); 13C-NMR (CDCl3) δ 14.1, 16.0,
31.2, 44.9, 51.1, 52.2, 60.6, 108.9, 126.1, 127.8, 128.5, 138.5,
148.6, 152.2, 165.0, 166.8, 167.6. Anal. Calcd for C19H22
-
N2O6: C, 60.95; H, 5.92; H, 7.48. Found: C, 60.84; H, 5.99;
N, 7.54.
A mixture of 748 mg (2.00 mmol) of the above 1,3-dicarbonyl
compound, 290 mg (2.40 mmol) of MesN3, 485 mg (4.80 mmol)
of TEA, and 20 mL of dry CH2Cl2 was stirred at rt for 24-48
h. After all starting material had been consumed (1H-NMR),
the reaction mixture was washed with ice-cold 5% KOH and
brine. The organic layer was dried over Na2SO4 and the
solvent removed under reduced pressure. The crude diazo
compound was purified by flash chromatography to give 720
mg (90%) of 19 (86% based on 18) as a pale yellow oil that
slowly crystallized on prolonged standing: mp 115 °C dec; IR
Eth yl 1,6-Dim eth yl-2-oxo-4-(2′-vin ylp h en yl)-1,2,3,4-tet-
r a h yd r o-5-p yr im id in eca r boxyla te (24a ). A mixture of 660
mg (5.00 mmol) of 2-vinylbenzaldehyde,38 975 mg (7.50 mmol)
of ethyl acetoacetate, 480 mg (6.50 mmol) of N-methylurea, 5
mL of MeOH, and two drops of concd HCl was stirred at 50-
55 °C for 10 h. One drop of concd HCl was added every 2 h.
After the mixture was allowed to stand at 0 °C overnight, the
precipitate was filtered to give 1.13 g (71%) of pyrimidine
24a : mp 153-155 °C (ethanol); IR (KBr) 3220, 3090, 1710,
1685, 1638, 1418 cm-1; 1H-NMR (CDCl3) δ 1.03 (t, 3H, J ) 7.5
1
(KBr) 2145, 1707, 1686, 1643, 1338 cm-1, H-NMR (CDCl3) δ
1.27 (t, 3H, J ) 7.5 Hz), 2.60 (s, 3H), 3.17 (s, 3H), 3.77 (s, 3H),
4.21 (q, 2H, J ) 7.5 Hz), 6.23 (s, 1H), 7.27-7.30 (m, 5H); 13C-
NMR (CDCl3) δ 14.2, 16.2, 30.9, 52.3, 54.0, 60.7, 73.4, 109.7,
126.3, 127.8, 128.5, 138.8, 149.1, 152.0, 161.3, 162.8, 165.1.
Anal. Calcd for C19H20N4O6: C, 57.00; H, 5.04; N, 13.99.
Found: C, 56.93; H, 5.10; N, 13.90.
6-[(E t h yloxy)ca r b on yl]-7,8-d im et h yl-2-[(m et h yloxy)-
ca r bon yl]-5-p h en yl-5H,8H-[1,3]oxa zolo[3,2-a ]p yr im id in -
4-iu m -3-ola te (20). A solution of 800 mg (2.00 mmol) of diazo
compound 19 in 40 mL of benzene containing a catalytic
(38) Dale, W. J .; Starr, L.; Strobel, C. W. J . Org. Chem. 1961, 26,
2225-2227.

Dihydropyrimidine Calcium Channel Modulators
J . Org. Chem., Vol. 62, No. 10, 1997 3117
Hz), 2.59 (s, 3H), 3.23 (s, 3H), 3.99 (q, 2H, J ) 7.5 Hz), 5.40
(dd, 1H, J ) 11.0, 1.5 Hz), 5.43 (br s, 1H), 5.63 (dd, 1H, J )
16.0, 1.5 Hz), 5.69 (d, 1H, J ) 2.0 Hz), 7.04-7.42 (m, 5H); 13C-
NMR (CDCl3) δ 14.1, 16.6, 30.2, 50.3, 60.1, 102.9, 118.2, 126.3,
127.1, 128.1, 128.5, 134.0, 136.2, 139.8, 150.1, 153.2, 165.0.
Anal. Calcd for C17H20N2O3: C, 67.98; H, 6.71; N, 9.33.
Found: C, 68.08; H, 6.66; N, 9.24.
Eth yl 4-(2′-Allylp h en yl)-1,6-d im eth yl-2-oxo-1,2,3,4-tet-
r a h yd r o-5-p yr im id in eca r boxyla te (24b). This pyrimidine
was prepared in analogy to 24a (see above), employing
2-allylbenzaldehyde39 as the aldehyde component: yield 62%;
mp 146-147 °C (methanol); IR (KBr) 3220, 3090, 1710, 1680,
1635, 1480 cm-1; 1H-NMR (CDCl3) δ 1.05 (t, 3H, J ) 7.5 Hz),
2.58 (s, 3H), 3.25 (s, 3H), 3.28-3.43 and 3.55-3.78 (2 m, 2H),
3.98 (q, 2H, J ) 7.5 Hz), 4.92-5.19 (m, 2H), 5.40 (br s, 1H),
5.60 (d, 1H, J ) 2.0 Hz), 5.96-6.16 (m, 1H), 7.10-7.24 (m,
4H); 13C-NMR (CDCl3) δ 13.9, 16.5, 30.1, 37.2, 50.1, 60.0, 103.5,
116.2, 127.1, 127.5, 127.9, 130.3, 136.1, 138.6, 141.2, 149.7,
152.8, 165.8. Anal. Calcd for C18H22N2O3: C, 68.77; H, 7.05;
N, 8.91. Found: C, 68.71; H, 7.27; N, 8.78.
Eth yl 3-[2-Dia zo-2-[(m eth yloxy)ca r bon yl]a cetyl]-1,6-
d im et h yl-2-oxo-4-(2′-vin ylp h en yl)-1,2,3,4-t et r a h yd r o-5-
p yr im id in eca r boxyla te (25a ). A mixture of 900 mg (3.00
mmol) of pyrimidine 24a , 680 mg (5.00 mmol) of distilled
methyl malonyl chloride, and 30 mL of benzene was heated
at reflux for 30 min. After all starting material had been
consumed (TLC), the solution was cooled to ambient temper-
ature and washed twice with saturated NaHCO3 and brine.
The solvent was removed under reduced pressure and the
crude product titurated with ether to give 1.03 g (86%) of ethyl
1,6-dimethyl-3-[2-[(methyloxy)carbonyl]acetyl]-2-oxo-4-(2′-
vinylphenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate as a
colorless solid: mp 111-113 °C (methanol); IR (KBr) 1737,
1694sh, 1690, 1631, 1331 cm-1; 1H-NMR (CDCl3) δ 1.21 (t, 3H,
J ) 7.5 Hz), 2.54 (s, 3H), 3.29 (s, 3H), 3.66 (s, 3H), 3.77 and
4.00 (2 d, 2H, J ) 16.5 Hz), 4.04-4.19 (m, 2H), 5.36 (dd, 1H,
J ) 12.0, 1.5 Hz), 5.62 (dd, 1H, J ) 17.0, 1,5 Hz), 6.88 (s, 1H),
7.06-7.60 (m, 5H); 13C-NMR (CDCl3) δ 14.1, 16.3, 31.2, 45.0,
49.3, 52.2, 60.7, 110.2, 116.0, 126.3, 126.8, 128.1, 128.5, 135.3,
136.3, 137.1, 147.0, 152.2, 164.8, 166.7, 167.7. Anal. Calcd
for C21H24N2O6: C, 62.99; H, 6.04; H, 7.00. Found: C, 62.92;
H, 6.06; N, 7.00.
A mixture of 800 mg (2.00 mmol) of the above 1,3-dicarbonyl
compound, 290 mg (2.40 mmol) of MesN3, 485 mg (4.80 mmol)
of TEA, and 20 mL of CH2Cl2 was stirred at rt for 24-48 h.
After all starting material had been consumed (1H-NMR), the
diazo-transfer reaction mixture was washed with ice-cold 5%
aqueous KOH and brine. The organic layer was dried over
Na2SO4 and the solvent removed under reduced pressure. The
crude diazo compound was purified by flash chromatography
to give 809 mg (95%) of 25a (82% based on 24a ) as a pale
yellow foam: IR (neat) 2134, 1715, 1696, 1651, 1331 cm-1; 1H-
NMR (CDCl3) δ 1.21 (t, 3H, J ) 7.5 Hz), 2.56 (s, 3H), 3.34 (s,
3H), 3.76 (s, 3H), 4.02-4.21 (m, 2H), 5.38 (dd, 1H, J ) 12.0,
1.5 Hz), 5.66 (dd, 1H, J ) 17.0, 1.5 Hz), 6.35 (s, 1H), 7.09-
7.67 (m, 5H); 13C-NMR (CDCl3) δ 14.1, 16.4, 30.9, 51.8, 52.2,
60.5, 71.8, 110.5, 115.8, 126.0, 126.6, 128.3, 128.4, 135.0, 136.4,
110.6, 116.0, 126.4, 126.5, 128.4, 130.3, 135.9, 137.4, 138.9,
147.5, 152.3, 164.9, 166.2, 167.7. Anal. Calcd for C22H26
-
N2O6: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.86; H, 6.45;
N, 6.78.
A sample of 828 mg (2.00 mmol) of the above 1,3-dicarbonyl
compound was transformed into the diazo derivative as
described above for 25a to yield 800 mg (91%) of 25b (74%
based on 24b) as a pale yellow oil: IR (neat) 2140, 1720, 1700,
1650, 1340 cm-1
; 1H-NMR (CDCl3) δ 1.24 (t, 3H, J ) 7.5 Hz),
2.57 (s, 3H), 3.34 (s, 3H), 3.76 (s, 3H), 3.79-3.96 (m, 2H), 4.08-
4.22 (m, 2H), 5.12-5.24 (m, 2H), 5.93-6.15 (m, 1H), 7.09-
7.20 (m, 4H);
13C-NMR (CDCl3) δ 14.2, 16.6, 31.0, 35.7, 51.7,
52.3, 60.7, 71.4, 110.9, 116.4, 126.2, 126.8, 128.3, 129.6, 137.4,
138.4, 147.3, 151.8, 161.5, 162.8, 165.0. Anal. Calcd for C22
-
H24N4O6: C, 59.99; H, 5.49; N, 12.72. Found: C, 60.12; H,
5.48; N, 12.53.
4-E t h yl 14-Met h yl 2,3-Dim et h yl-15-oxo-17-oxa -2,16-
diazapen tacyclo[12.2.1.01,12.05,16.06,11]h eptadeca-3,6(11),7,9-
tetr a en e-4,14-d ica r boxyla te (27a ). A solution of 213 mg
(0.50 mmol) of diazo compound 24a in 5 mL of benzene
containing a catalytic amount (ca. 5 mg) of Rh2(OAc)4 was
heated under reflux for 30 min. After all starting material
was consumed (TLC), the solvent was removed under reduced
pressure and the crude product purified by flash chromatog-
raphy to yield 183 mg (92%) of 27a as a colorless solid: mp
170-171 °C; IR (KBr) 1759, 1736, 1680, 1569, 1444 cm-1; 1H-
NMR (CDCl3) δ 1.40 (t, 3H, J ) 7.5 Hz), 1.95 (dd, 1H, J )
12.5, 3.0 Hz), 2.43 (s, 3H), 2.80 (dd, 1H, J ) 12.5, 10.5 Hz),
3.08 (s, 3H), 3.76 (dd, 1H, J ) 10.5, 3.0 Hz), 4.20-4.33 (m,
2H), 6.05 (s, 1H), 7.10-7.22 (m, 3H), 7.46-7.49 (m, 1H); 13C-
NMR (CDCl3) δ 14.5, 15.7, 29.9, 39.5, 44.9, 50.1, 53.0, 59.6,
86.2, 97.8, 99.7, 126.5, 127.5, 127.8, 130.0, 132.2, 136.6, 152.9,
164.4, 165.8, 167.3. Anal. Calcd for C21H22N2O6: C, 63.31;
H, 5.57; N, 7.03. Found: C, 63.29; H, 5.58; N, 6.92.
4-E t h yl 15-Met h yl 2,3-Dim et h yl-16-oxo-18-oxa -2,17-
d ia za p en ta cyclo[13.2.1.01,13.05,17.06,11]octa d eca -3,6(11),7,9-
tetr a en e-4,15-d ica r boxyla te (27b). This polycycle was pre-
pared in a similar manner as described above for 27a from
diazo compound 24b: yield 88% of 27b as a colorless solid;
mp 222-224 °C; IR (KBr) 1765, 1730, 1690, 1570, 1450 cm-1
;
1H-NMR (CDCl3) δ 1.23 (t, 3H, J ) 7.5 Hz), 1.49 (dd, 1H, J )
13.0, 5.0 Hz), 2.38 (dd, 1H, J ) 13.0, 9.5 Hz), 2.57 (s, 3H),
2.71-2.82 (m, 2H), 3.14 (3H), 3.15-3.28 (m, 1H), 3.82 (s, 3H),
3.92-4.17 (m, 2H), 5.73 (s, 1H), 6.97-7.51 (m, 4H); 13C-NMR
(CDCl3) δ 14.2, 16.2, 29.7, 31.1, 32.0, 38.9, 53.0, 54.3, 59.7,
85.6, 95.7, 98.8, 126.4, 127.7, 132.1, 132.4, 133.3, 138.7, 152.5,
165.1, 166.5, 166.6. Anal. Calcd for C22H24N2O6: C, 64.07;
H, 5.87; N, 6.79. Found: C, 64.22; H, 5.96; N, 6.77.
E t h yl 6-Met h yl-2-oxo-4-(2′-vin ylp h en yl)-1,2,3,4-t et r a -
h yd r o-5-p yr im id in eca r boxyla te (28). A mixture of 660 mg
(5.00 mmol) of 2-vinylbenzaldehyde,38 975 mg (7.50 mmol) of
ethyl acetoacetate, 390 mg (6.50 mmol) of urea, 5 mL of MeOH,
and two drops of concd HCl was stirred at 50-55 °C for 10 h.
One drop of concd HCl was added every 2 h. After the mixture
was allowed to stand at rt overnight, the precipitate was
filtered to give 1.06 g (74%) of pyrimidine 28 as a colorless
solid: mp 211-213 °C (ethanol); IR (KBr) 3350, 3220, 3100,
1690, 1640, 1455 cm-1; 1H-NMR (DMSO-d6) δ 0.97 (t, 3H, J )
7.5 Hz), 2.30 (s, 3H), 3.86 (q, 2H, J ) 7.5 Hz), 5.36 (dd, 1H, J
) 11.0, 1.5 Hz), 5.53 (d, 1H, J ) 2.5 Hz), 5.67 (dd, 1H, J )
17.0, 1.5 Hz), 7.21-7.51 (m, 5H), 7.65 (br s, 1H), 9.21 (br s,
1H); 13C-NMR (CDCl3) δ 13.9, 17.7, 50.3, 59.1, 99.3, 116.6,
125.9, 127.1, 127.6, 128.4, 134.5, 135.3, 142.2, 148.5, 151.5,
165.2. Anal. Calcd for C16H18N2O3: C, 67.12; H, 6.34; N, 9.78.
Found: C, 66.93; H, 6.30; N, 9.79.
Eth yl 3-[2-Diazo-2-[(m eth yloxy)car bon yl]acetyl]-6-m eth -
yl-2-oxo-4-(2′-vin ylp h en yl)-1,2,3,4-tetr a h yd r o-5-p yr im id i-
n eca r boxyla te (29). This 1,3-dicarbonyl compound was
prepared from pyrimidine 28 and methyl malonyl chloride in
an analogous manner as described above for 25a : yield 89%
of ethyl 6-methyl-3-[2-[(methyloxy)carbonyl]acetyl]-2-oxo-4-(2′-
vinylphenyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate as a
colorless solid; mp 160-162 °C (ethanol); IR (KBr) 3230, 3140,
1755, 1720, 1710sh, 1695, 1640 cm-1; 1H-NMR (CDCl3) δ 1.20
(t, 3H, J ) 7.5 Hz), 2.38 (s, 3H), 3.63 (s, 3H), 3.82 and 4.04 (2
d, 2H, J ) 16.0 Hz), 4.08 (m, 2H), 5.39 (dd, 1H, J ) 11.0, 1.5
137.2, 147.1, 151.6, 161.4, 163.1, 164.8. Anal. Calcd for C21
-
H22N4O6: C, 59.15; H, 5.26; N, 13.14. Found: C, 59.08; H,
5.21; N, 13.00.
Eth yl 4-(2′-Allylp h en yl)-3-[2-d ia zo-2-[(m eth yloxy)ca r -
b on yl]a cet yl]-1,6-d im et h yl-2-oxo-1,2,3,4-t et r a h yd r o-5-
p yr im id in eca r boxyla te (25b). A 942 mg (3.00 mmol) por-
tion of pyrimidine 24b was N-malonylacetylated in a similar
manner as described above for 24a to give 1.00 g (81%) of ethyl
4-(2′-allylphenyl)-1,6-dimethyl-3-[2-[(methyloxy)carbonyl]acetyl]-
2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate as a colorless
solid: mp 106-108 °C (methanol); IR (KBr) 1745, 1710, 1690,
1640, 1335 cm-1; 1H-NMR (CDCl3) δ 1.22 (t, 3H, J ) 7.5 Hz),
2.57 (s, 3H), 3.28 (s, 3H), 3.67 (s, 3H), 3.68-3.75 (m, 2H), 3.74
and 3.99 (2 d, 2H, J ) 16.5 Hz), 4.01-4.24 (m, 2H), 5.00-5.14
(m, 2H), 5.89-6.10 (m, 1H), 6.89 (s, 1H), 7.05-7.22 (m, 4H);
13C-NMR (CDCl3) δ 14.1, 16.3, 31.2, 36.1, 44.7, 48.8, 52.2, 60.7,
(39) Hartman, G. D.; Halczenko, W.; Phillips, B. T. J . Org. Chem.
1985, 50, 2427-2431.

3118 J . Org. Chem., Vol. 62, No. 10, 1997
Kappe et al.
Hz), 5.67 (dd, 1H, J ) 17.0, 1.5 Hz), 6.79 (s, 1H), 7.19-7.74
(m, 5H), 8.54 (br s); 13C-NMR (CDCl3) δ 14.2, 17.6, 46.1, 51.8,
52.2, 60.5, 106.5, 115.6, 126.2, 126.9, 128.3, 128.4, 135.2, 136.5,
5.66 (dd, 1H, J ) 17.0, 1.5 Hz), 6.35 (s, 1H), and 7.22-7.51
(m, 5H); 1:1 mixture of epimers, the signals at 5.10 and 5.14
disappeared on addition of D2O; 13C-NMR (CDCl3) δ 13.8, 22.8,
51.8/52.2, 53.3/53.5, 59.7/59.9, 76.2/76.3, 107.1/107.2, 116.7/
117.1, 125.6/125.8, 128.0/128.3, 128.4/128.5, 128.6/128.7, 133.8/
134.2, 136.3/136.6, 137.0/137.1, 152.8/152.9, 155.1, 162.5/162.8,
163.7/164.1, 164.3/164.4; 1:1 mixture of epimers. Anal. Calcd
for C20H20N2O6: C, 62.49; H, 5.24; N, 7.29. Found: C, 62.55;
H, 5.12; N, 7.20.
Addition of an excess of triethylamine to a solution of 31 in
CH2Cl2 and rapid workup of the resulting yellow solution with
excess aqueous NH4Cl produced a single epimer of 31 (>90%
purity): 1H-NMR (CDCl3) δ 1.09 (t, 3H, J ) 7.5 Hz), 2.47 (s,
3H), 3.68 (s, 3H), 4.02 (q, 2H, J ) 7.5 Hz), 5.14 (s, 1H), 5.42
(dd, 1H, J ) 11.0, 1.5 Hz), 5.66 (dd, 1H, J ) 17.0, 1.5 Hz),
6.35 (s, 1H), and 7.22-7.51 (m, 5H); complete equilibration of
epimers took place within 30 min in CDCl3 at rt.
138.3, 143.4, 152.2, 164.5, 166.8, 167.5. Anal. Calcd for C20
-
H22N2O6: C, 62.17; H, 5.74; N, 7.25. Found: C, 62.05; H, 5.71;
N, 7.09.
A sample of the above 1,3-dicarbonyl compound was trans-
formed into diazo compound 29 employing the standard
procedure given above for 25a . The crude diazo compound was
purified by flash chromatography to give 88% of 29 (78% based
on 28) as a pale yellow oil that crystallized on standing: mp
134 °C dec; IR (KBr) 3230, 3130, 2140, 1740sh, 1720sh, 1705,
1660, 1645sh cm-1 1H-NMR (CDCl3) δ 1.19 (t, 3H, J ) 7.5
,
Hz), 2.39 (s, 3H), 3.78 (s, 3H), 4.09 (m, 2H), 5.39 (dd, 1H, J )
11.0, 1.5 Hz), 5.69 (dd, 1H, J ) 17.0, 1.5 Hz), 6.36 (s, 1H),
7.21-7.66 (m, 5H), 7.78 (br s, 1H); 13C-NMR (CDCl3), δ 14.2,
17.8, 52.4, 53.8, 60.4, 72.7, 106.6, 115.8, 126.2, 126.7, 128.4,
128.5, 134.9, 136.2, 138.7, 144.0, 151.7, 161.4, 163.2, 164.6.
Anal. Calcd for C20H20N4O6: C, 58.25; H, 4.89; N, 13.59.
Found: C, 58.44; H, 4.86; N, 13.40.
Ack n ow led gm en t. This work was supported by the
Austrian Academy of Sciences (Austrian Programme for
Advanced Research and Technology, APART 319) and
the Austrian Science Foundation (FWF, Project P-11994-
CHE).
6-Eth yl 2-Meth yl 7-Meth yl-3-oxo-5-(2′vin ylp h en yl)-2,3-
d ih yd r o-5H-[1,3]oxa zolo[3,2-a ]p yr im id in e-2,6-d ica r boxy-
la te (31). A solution of 824 mg (2.00 mmol) of diazo compound
29 in 40 mL of dry benzene containing a catalytic amount of
Rh2(OAc)4 (ca. 5 mg) was heated under reflux for 2 h. After
all starting material had been consumed (TLC), the solution
was cooled and the solvent removed under reduced pressure.
The crude product was titurated with ether to yield 699 mg
(91%) of oxazolopyrimidine 31 as a colorless solid: mp 178-
Su p p or tin g In for m a tion Ava ila ble: 2D-HMBC spectra
of compounds 10b and 17 and ORTEP representations of X-ray
structures for compounds 11, 21, 23, and 27a ,b (8 pages) . This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
180 °C (ethanol); IR (KBr) 1785, 1760, 1695, 1655, 1570 cm-1
;
1H-NMR (CDCl3) δ 1.08 and 1.09 (2 t, 3H, J ) 7.5 Hz), 2.47
and 2.49 (2 s, 3H), 3.68 and 3.87 (2 s, 3H), 4.02 (q, 2H, J ) 7.5
Hz), 5.10 and 5.14 (2 s, 1H), 5.42 (dd, 1H, J ) 11.0, 1.5 Hz),
J O970121Q