Vous êtes sur la page 1sur 4

A Reexamination of the Mechanismof the Biginelli

Dihydropyrimidine Synthesis. Support for an N-AcyliminiumIon


Intermediate
1
C. Ol i ver Kappe*
I nstituteof Organic Chemistry, Karl-Franzens-University Graz, A-8010 Graz, Austria
Received J une4, 1997
X
The mechansi m of the three-component Bi gi nel l i di hydropyri mi di ne synthesi s was rei nvesti gated
usi ng
1
H and
13
C NMR spectroscopy. Condensati on of benzal dehyde, ethyl acetoacetate, and urea
(or N-methyl urea) i n CD
3
OH accordi ng to the procedure descri bed by Bi gi nel l i produced the expected
6-methyl -2-oxo-4-phenyl -1,2,3,4-tetrahydropyri mi di ne-5-carboxyl ates. Accordi ng to NMR measure-
ments, there i s no evi dence that the fi rst step i n the Bi gi nel l i reacti on i s an aci d-catal yzed al dol
reacti on of ethyl acetoacetate and benzal dehyde l eadi ng to a carbeni um i on i ntermedi ate, as has
been suggested previ ousl y. I n contrast, al l experi mental evi dence poi nts to a mechani sm i nvol vi ng
an N-acyl i mi ni um i on as the key i ntermedi ate, formed by aci d-catal yzed condensati on of benzal -
dehyde and urea (or N-methyl urea). I ntercepti on of thi s i mi ni um i on by ethyl acetoacetate produces
open-chai n urei des whi ch subsequentl y cycl i ze to the Bi gi nel l i di hydropyri mi di nes.
I n 1893 Bi gi nel l i reported the fi rst synthesi s of di hy-
dropyri mi di nes of type 4by a si mpl e one-pot condensa-
ti on reacti on of ethyl acetoacetate (1), benzal dehyde (2),
and urea (3a).
2
I n the fol l owi ng decades the ori gi nal
cycl ocondensati on reacti on has been extended wi del y to
i ncl ude vari ati ons i n al l three components, al l owi ng
access to a l arge number of mul ti functi onal i zed di hydro-
pyri mi di ne deri vati ves.
3
Largel y i gnored for many years,
the Bi gi nel l i reacti on has recentl y attracted a great deal
of attenti on, and several i mproved procedures for the
preparati on of di hydropyri mi di nes of type 4 have been
reported wi thi n the past few years.
3-5
Vari ous sol i d-
phase modi fi cati ons of the Bi gi nel l i reacti on sui tabl e for
combi natori al chemi stry have al so been descri bed.
6
The present i nterest i n Bi gi nel l i compounds 4 i s
mai nl y due to thei r cl ose structural rel ati onshi p to the
cl i ni cal l y i mportant di hydropyri di ne cal ci um channel
modul ators of the ni fedi pi ne-type.
7
Properl y functi onal -
i zed di hydropyri mi di nes of type 4 show a very si mi l ar
pharmacol ogi cal profi l e to cl assi cal di hydropyri di ne drugs
and several l ead compounds wi th excel l ent cal ci um
channel modul atory acti vi ty have been i denti fi ed.
8
I n
addi ti on, several mari ne al kal oi ds wi th i nteresti ng bi o-
l ogi cal acti vi ti es contai ni ng the di hydropyri mi di ne-5-
carboxyl ate core have been i sol ated.
9-11
Most notabl y
among these are the crambi ne
9
and batzel l adi ne al ka-
l oi ds
10
and the more compl ex pentacycl i c al kal oi d pti l o-
mycal i n A,
11
whi ch was recentl y synthesi zed empl oyi ng
a tethered Bi gi nel l i condensati on as one of the key
steps.
12
Despi te the i mportance and current i nterest i n di hy-
dropyri mi di nes of type 4, the mechani sm of the cl assi cal
three-component Bi gi nel l i condensati on has not been
el uci dated wi th certai nty and remai ns di sputed.
3
Earl y
work by Fol kers and Johnson suggested that N,N-
benzyl i denebi surea (15a, see bel ow), i.e. the pri mary
bi mol ecul ar condensati on product of benzal dehyde (2)
and urea (3a), i s the fi rst i ntermedi ate i n thi s reacti on.
13
Later, Sweet and Fi sseki s have proposed a di fferent
mechani sm postul ati ng that carbeni um i on 6(see bel ow),
produced by an aci d-catal yzed al dol reacti on of benzal -
dehyde (2) wi th ethyl acetoacetate (1), i s the key i nter-
medi ate and i s formed i n the fi rst and l i mi ti ng step of
the Bi gi nel l i reacti on.
14
To deci de whi ch of the two
fundamental l y di fferent mechani sti c proposal s i s correct
* To whom correspondence shoul d be addressed. Fax: (43)-(316)-
3809840. E-mai l : kappeco@bal u.kfuni graz.ac.at.
X
Abstract publ i shed i n Advance ACS Abstracts, October 1, 1997.
(1) Synthesi s and Reacti ons of Bi gi nel l i Compounds. 9. For part 8,
see: Kl ei derni gg, O. P.; Kappe, C. O. Tetrahedron: Asymmetry 1997,
8, 2057-2067.
(2) Bi gi nel l i , P. Gazz. Chim. I tal. 1893, 23, 360-416.
(3) For a revi ew of the Bi gi nel l i -condensati on, see: Kappe, C. O.
Tetrahedron 1993, 49, 6937-6963.
(4) Kappe, C. O.; Peters. K.; Peters, E.-M. J . Org. Chem. 1997, 62,
2786-2797. Kappe, C. O.; Fabi an, W. M. F.; Semones, M. A. Tetrahe-
dron 1997, 53, 2803-2816.
(5) ORei l l y, B. C.; Atwal , K. S. Heterocycles 1987, 26, 1185-1188.
Atwal , K. S.; Rovnyak, G. C.; ORei l l y, B. C.; Schwartz, J. J . Org. Chem.
1989, 54, 5898-5907. Gupta, R.; Gupta, A. K.; Paul , S.; Kachroo, P.
L. I nd. J . Chem. 1995, 34B, 151-152. Sar, C. P.; Hankovszky, O. H.;
Jerkovi ch, G.; Pal l agi , I .; Hi deg, K. ACH-Models Chem. 1994, 131,
363-376.
(6) Wi pf, P.; Cunni ngham, A. Tetrahedron Lett. 1995, 36, 7819-
7822. Studer, A.; Jeger, P.; Wi pf, P.; Curran, D. P. J . Org. Chem. 1997,
62, 2917-2924. Robi nett, L. D.; Yager, K. M.; Phel an, J. C. 211th
Nati onal Meeti ng of the Ameri can Chemi cal Soci ety, New Orl eans,
1996; Ameri can Chemi cal Soci ety: Washi ngton, DC, 1996; ORGN 122.
(7) Gol dman, S.; Stol tefuss, J. Angew. Chem., I nt. Ed. Engl. 1991,
30, 1559-1578.
(8) Atwal , K. S.; Swanson, B. N.; Unger, S. E.; Fl oyd, D. M.;
Morel and, S.; Hedberg, A.; ORei l l y, B. C. J . Med. Chem. 1991, 34,
806-811. Rovnyak, G. C.; Atwal , K. S.; Hedberg, A.; Ki mbal l , S. D.;
Morel and, S.; Gougoutas, J. Z.; ORei l l y, B. C.; Schwartz, J.; Mal l ey,
M. F. J . Med. Chem. 1992, 35, 3254-3263.
(9) Sni der, B. B.; Shi , Z. J . Org. Chem. 1993, 58, 3828-3839, and
references therei n.
(10) Pati l , A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer,
A. J.; DeBrosse, C.; Mai , S.; Truneh, A.; Faul kner, D. J.; Carte, B.;
Breen, A. L.; Hertzberg, R. P.; Johnson, R. K.; Westl ey, J. W.; Potts,
B. C. M. J . Org. Chem. 1995, 60, 1182-1188.
(11) Kashman, Y.; Hi rsh, S.; McConnel , O. J.; Ohtani , I .; Takenori ,
K.; Kaki sawa, H. J . Am. Chem. Soc. 1989, 111, 8925-8926. Ohtani ,
I .; Kusumi , T.; Kaki sawa, H.; Kashman, Y.; Hi rsh, S. J . Am. Chem.
Soc. 1992, 114, 8472-8479.
(12) Overman, L. E.; Rabi nowi tz, M. H. J . Org. Chem. 1993, 58,
3235-3237. Overman, L. E.; Rabi nowi tz, M. H.; Renhowe, P. A. J . Am.
Chem. Soc. 1995, 117, 2657-2658.
(13) Fol kers, K.; Johnson, T. B. J . Am. Chem. Soc. 1933, 55, 3784-
3791.
7201 J . Org. Chem. 1997, 62, 7201-7204
S0022-3263(97)01010-4 CCC: $14.00 1997 Ameri can Chemi cal Soci ety
we have carri ed out a detai l ed rei nvesti gati on of the
mechani sm of the Bi gi nel l i condensati on usi ng
1
H and
13
C NMR spectroscopy to i denti fy possi bl e i ntermedi ates.
To be abl e to moni tor al l reacti ons by
1
H and
13
C NMR
spectroscopy, CD
3
OH was used as sol vent i n the NMR
experi ments whi ch were carri ed out at room temperature
i n the presence of a catal yti c amount of HCl (see
Supporti ng I nformati on).
13,15
As al ready suggested by
Fol kers and Johnson,
13
i t i s very l i kel y that thi s three-
component condensati on proceeds vi a one of the three
possi bl e bi mol ecul ar reacti on pathways from the urea/
al dehyde/acetoacetate system. We have rei nvesti gated
these pathways, whi ch are di scussed bel ow.
The carbeni um i on mechani sm was proposed by
Sweet and Fi sseki s,
14
who i nvesti gated the reacti on i n
1973 and suggested that an aci d-catal yzed al dol conden-
sati on i s the fi rst and l i mi ti ng step of the Bi gi nel l i
condensati on. I t was proposed that under aci d catal ysi s
benzal dehyde (2) and ethyl acetoacetate (1) woul d react
i n an al dol -type fashi on to produce the correspondi ng
al dol 5, whi ch dehydrates i n the presence of aci d to the
resonance-stabi l i zed carbeni um i on 6.
14,16
I ntercepti on
of cati on 6 by urea (3a) or N-methyl urea (3b) then
produces urei des 7, whi ch ul ti matel y cycl i ze to the
Bi gi nel l i products 4.
14
The mai n argument for the
proposed mechani sm made by the authors
14
rel ates to the
fact that aci d-catal yzed treatment of i ndependentl y
prepared enone 8wi th N-methyl urea (3b) al so produced
pyri mi di ne 4b, al bei t i n moderate yi el d.
14
Accordi ng to
Sweet and Fi sseki s, protonati on of enone 8regenerates
the carbeni um i on i ntermedi ate 6,
16
whi ch then can react
wi th urea (3a) or N-methyl urea (3b) as descri bed above
(6f 7f 4).
14
I t was al so consi dered i mportant that i n
the reacti on of enone 8wi th N-methyl urea (3b) onl y the
N1-methyl deri vati ve 4b was produced and not the N3-
substi tuted i somer 12b (see bel ow), whi ch corresponds
to the regi ochemi cal outcome observed i n the three-
component Bi gi nel l i reacti on of ethyl acetoacetate (1),
benzal dehyde (2), and N-methyl urea (3b).
3,17
Accordi ng to the experi mental data descri bed herei n,
a mechani sm i nvol vi ng carbeni um i on 6 as the key
i ntermedi ate i n the Bi gi nel l i reacti on seems unl i kel y. We
have attempted to observe the aci d-catal yzed al dol reac-
ti on of benzal dehyde (2) wi th ethyl acetoacetate (1)
proposed by Sweet and Fi sseki s
14
under typi cal Bi gi nel l i
reacti on condi ti ons. Al though al dol reacti ons are most
often catal yzed by base, the possi bi l i ty of an aci d-
catal yzed al dol reacti on of benzal dehyde wi th a 1,3-
di carbonyl component such as ethyl acetoacetate can not
be a pri ori excl uded.
18
However, i t i s wel l -known that
i n the case of aci d catal ysi s the reacti on products of the
al dol reacti on are i n most cases the R,-unsaturated
carbonyl compounds (i.e. 8) and not the -hydroxycar-
bonyl (al dol ) products (i.e. 5).
18
Upon moni tori ng the
reacti on of benzal dehyde (2) and ethyl acetoacetate (1)
i n CD
3
OH/HCl by
1
H and
13
C NMR spectroscopy, no
evi dence for an al dol reacti on or any other reacti on
between the two components at room temperature coul d
be obtai ned (see Supporti ng I nformati on). The fact that
benzal dehyde (2) and ethyl acetoacetate (1) do not react
under condi ti ons where the Bi gi nel l i condensati on i tsel f
proceeds smoothl y (see bel ow) rul es out the carbeni um
i on mechani sm, where such a reacti on i s proposed to be
the fi rst step.
The possi bi l i ty of a carbeni um i on i ntermedi ate of type
6i n the Bi gi nel l i condensati on seems even more unl i kel y
i f one consi ders the case where thi ourea i s substi tuted
for urea. Both thi ourea (9a)
17
and N-methyl thi ourea
(9b)
19
are known to produce the expected di hydropyri m-
i di ne-2-thi ones (Bi gi nel l i compounds) when reacted
wi th benzal dehyde (2) and ethyl acetoacetate (1) under
standard Bi gi nel l i condi ti ons.
3,17,19
I n contrast, treatment
of enone 8 wi th thi ourea (9a) or N-methyl thi ourea (9b)
under aci d catal ysi s, i.e. under condi ti ons where accord-
i ng to Sweet and Fi sseki s carbeni um i on 6i s generated,
14
furni shed excl usi vel y the i someri c 2-ami no-1,3-thi azi nes
10a,b i n excel l ent yi el ds.
The structures of thi azi nes 10 were establ i shed by
spectroscopi c methods (see the Experi mental Secti on)
and, for 10a, by compari son wi th authenti c materi al .
19,20
I n contrast to the reacti on of enone 8 wi th N-methyl -
urea,
14
where reacti on ti mes of 2 weeks and onl y moder-
ate yi el ds of pyri mi di ne 4b have been encountered, the
reacti on ti mes wi th thi oureas 9 are much shorter (3-5
h), whi ch can be rati onal i zed by the consi derabl e hi gher
nucl eophi l i ci ty of sul fur. The fact that i n the three-
component Bi gi nel l i reacti on usi ng thi oureas the thi azi ne
products 10 are not observed makes a carbeni um i on
i ntermedi ate of type 6 unl i kel y.
The so-cal l ed urei docrotonate mechani sm was al -
ready consi dered by Fol kers and Johnson
13
but was rul ed
out as a mechani sti c pathway si nce the bi mol ecul ar
condensati on product of ethyl acetoacetate (1) and urea
(3a), i.e. urei docrotonate 11a,
21
was shown to rapi dl y
(14) Sweet, F.; Fi sseki s, J. D. J . Am. Chem. Soc. 1973, 95, 8741-
8749.
(15) Fol kers, K.; Harwood, H. J.; Johnson, T. B. J . Am. Chem. Soc.
1932, 54, 3751-3758.
(16) A more modern descri pti on of the carbeni um i on i ntermedi ate
woul d be the tautomeri c O-protonated enone.
18
(17) Fol kers, K.; Johnson, T. B. J . Am. Chem. Soc. 1933, 55, 2886-
2893.
(18) Heathcock, C. H. ComprehensiveOrganic Synthesis; Trost, B.
M., Fl emi ng, I ., Eds.; Pergamon Press: Oxford; 1991; Vol . 2, p 133-
179. Ni el son, A. T.; Houl i han, W. Org. React. (N.Y.) 1968, 16, 1-438.
(19) Kappe, C. O.; Roschger, P. J . Heterocycl. Chem. 1989, 26, 55-
64.
(20) For an anal ogous cycl ocondensati on usi ng N-benzyl thi ourea,
the structure of the thi azi ne product was confi rmed by X-ray anal y-
si s: Atwal , K S.; ORei l l ey, B. C.; Gougoutas, J. Z.; Mal l ey, M. F.
Heterocycles 1987, 26, 1189-1192.
7202 J . Org. Chem., Vol. 62, No. 21, 1997 Kappe
hydrol yze under the typi cal Bi gi nel l i reacti on condi ti ons
(EtOH, HCl ).
13
Si nce the fact that urei docrotonate 11a
i s sensi ti ve to hydrol ysi s does not excl ude thi s i ntermedi -
ate for the Bi gi nel l i reacti on, we have rei nvesti gated thi s
pathway (i ncl udi ng the N-methyl anal ogue 11b
22
). The
i ndependentl y prepared
21,22
enami des 11a,bwere shown
to rapi dl y hydrol i ze i n CD
3
OH when catal yti c amounts
of aci d (and water) were present (see the Supporti ng
I nformati on). Whi l e urei docrotonates 11a,bcan be pre-
pared from 1 and 3a,b under stri ctl y anhydrous condi -
ti ons, i.e. by al l owi ng a mi xture of 1and 3to react i n a
desi ccator over concentrated H
2
SO
4
for several days,
21,22
i t i s evi dent that under Bi gi nel l i reacti on condi ti ons the
equi l i bri um i s far on the acetoacetate/urea si de.
Another argument agai nst the i nvol vment of an urei -
docrotonate i ntermedi ate rel ates to the fact that N-
methyl urea (3b) reacts wi th ethyl acetoacetate (1) to
furni sh excl usi vel y regi oi somer 11bbeari ng the N-methyl
substi tuent at the termi nal ami no group.
22
The forma-
ti on of a Bi gi nel l i di hydropyri mi di ne i n a 5 + 1 cycl o-
condensati on manner from 11band benzal dehyde woul d
be expected to l ead to the N3-substi tuted Bi gi nel l i
product 12b,
19
whi ch i s observed nei ther i n the three-
component Bi gi nel l i reacti on (see above)
3,14,17
nor from
the reacti on of urei de 11b wi th benzal dehyde under
Bi gi nel l i condi ti ons. I n both cases the i someri c di hydro-
pyri mi di ne 4b i s formed as the excl usi ve regi oi somer,
whi ch further supports Fol kers and Johnsons
13
proposi -
ti on that the Bi gi nel l i reacti on does not proceed through
an urei docrotonate i ntermedi ate of type 11 and that
i mmedi ate hydrol ysi s of 11takes pl ace i f the reacti on i s
started from such urei docrotonates.
Fi nal l y, we have consi dered the ori gi nal mechani sti c
proposal made by Fol kers and Johnson,
13
who suggested
that the fi rst step i n the three-component Bi gi nel l i
condensati on i s the reacti on of benzal dehyde (2) wi th
urea (3a). When benzal dehyde (2) and urea (3a, 2 mol
equi v) were reacted under typi cal Bi gi nel l i condi ti ons
(CH
3
OH/HCl ) at room temperature, the anti ci pated
condensati on product bi surei de 15a
23
started to preci pi -
tate from the sol uti on wi thi n 15-20 mi n. Bi surei de 15a
was al so formed when equi mol ar amounts of the two
components were empl oyed, and the anal ogous condensa-
ti on product (15b)
24
was produced when N-methyl urea
(3b) was used i nstead of urea (3a). However, when these
reacti ons were carri ed out in the presence of ethyl
acetoacetate(1) under otherwi se i denti cal reacti on condi -
ti ons, bi surei des 15a,b were not formed, but di hydropy-
ri mi di nes 4a,b started to preci pi tate sl owl y from the
reacti on mi xture wi thi n 1-2 h (compl ete conversi on took
2-3 days).
On the basi s of these experi mental resul ts, we propose
the fol l owi ng mechani sti c concept. Addi ti on of ureas 3a
or 3b to benzal dehyde (2) l eads to N-(1-hydroxybenzyl )-
ureas of type 13 vi a standard nucl eophi l i c addi ti on.
Al though thi s i s l i kel y to be an equi l i bri um reacti on,
hemi ami nal s 13 are expected to undergo rapi d dehy-
drati on i n the presence of aci d to a carbeni um i on whi ch
may be formul ated as a hi ghl y reacti ve N-acyl i mi ni um
speci es, i.e. 14. I n the absence of the 1,3-di carbonyl
compound a second equi val ent of urea 3a,b i s added to
furni sh bi surei des 15a,b, whi ch due to thei r l ow sol ubi l -
i ty
23,24
preci pi tate from the reacti on mi xture. However,
i f ethyl acetoacetate (1) i s present i n the reacti on
medi um, i mi ni um i on 14 i s i ntercepted by the 1,3-
di carbonyl compound, possi bl y through i ts enol tautomer,
to furni sh i ntermedi ates 7a,b, whi ch then cycl i ze to the
Bi gi nel l i compounds 4a,b. Moni tori ng the formati on of
bi surei des 15a,b from 2and 3a,b by
1
H NMR (CD
3
OH,
HCl ) di d not al l ow the observati on of any i ntermedi ates,
e.g. 13, i n thi s process. We assume that the fi rst addi ti on
step (2f13) i s the rate-determi ni ng (sl ow) step and that
both the subsequent aci d-catal yzed dehydrati on (13 f
14) and the addi ti on of a second equi val ent of urea to
the i mi ni um i on (14 f 15) are fast steps, therefore not
al l owi ng 13 to accumul ate. Thi s seems al so to be true
for the Bi gi nel l i reacti on i tsel f: under typi cal Bi gi nel l i
condi ti ons, no i ntermedi ates i n the reacti on of ethyl
acetoacetate (1), benzal dehyde (2), and N-methyl urea
(3b) coul d be observed by
1
H or
13
C NMR spectroscopy.
After about 30 mi n, si gnal s due to the fi nal product (4b)
started to appear i n the
1
H NMR that were easi l y
i denti fi ed, as these si gnal s are ni cel y separated from the
peaks due to starti ng materi al s (see Tabl e S1 i n the
Supporti ng I nformati on). As the reacti on proceeded,
these peaks became more promi nent and after ca. 18 h
50% conversi on was achi eved. At thi s poi nt 4b started
to preci pi tate from the NMR sol uti on and the experi ment
was termi nated.
I n concl usi on, we have shown that the ori gi nal mecha-
ni sti c proposal put forward by Fol kers and Johnson i n
1933,
13
i nvol vi ng an al dehyde-urea condensati on product
as key i ntermedi ate i n the Bi gi nel l i condensati on i s
essenti al l y correct. The fi rst step i n thi s mechani sm
evi dentl y i nvol ves the aci d-catal yzed formati on of an
N-acyl i mi ni um i on precursor of type 14from an al dehyde
and urea component. I n the case of ami des and carbam-
ates, thi s reacti on pathway i s wel l -establ i shed,
25
and at
l east one exampl e exi sts for ureas.
26
The second step (14
f 7) can be regarded as an addi ti on of a -nucl eophi l e,
i.e. the enol tautomer of acetoacetate 1 to the el ectron-
defi ci ent N-acyl i mi ni um speci es 14. Addi ti ons of -nu-
cl eophi l es to i mi ni um speci es are very wel l -known and
(21) Donl eavy, J. J.; Ki se, M. A. Org. Synth. 1943, Collect. Vol. I I ,
422-423.
(22) Senda, S.; Suzui , A. Chem. Pharm. Bull. 1958, 6, 476-479.
Hl ousek, J.; Machacek, V.; Sterba, V. Sb. Ved. Pr., Vys. Sk. Chemicko-
technol. Pardubice1978, 39, 11-25 (Chem. Abstr. 1979, 91, 174663n).
(23) Schi ff, H. Ann. 1869, 151, 186-213. Ludy, E. Monatsh. Chem.
1889, 10, 295-316. Baki baev, A. A.; Ti gni bi di na, L. G.; Fi l i monov, V.
D.; Gorshkova, V. K.; Sarati kov, A. S. Khim. Farm. Zh. 1991, 25, 31-
35. Baki baev, A. A. Zh. Org. Khim. 1994, 11, 1686-1687.
(24) Schi ff, H. Ann. 1896, 291, 367-377. See al so Koyano, K.;
McArthur, C. R. Can. J . Chem. 1973, 51, 333-337.
Support for an N-Acyl i mi ni um I on I ntermedi ate J . Org. Chem., Vol. 62, No. 21, 1997 7203
have proven to be val uabl e syntheti c transformati ons i n
target-ori ented synthesi s.
25
I mportantl y, several ex-
ampl es of thi s type of reacti on i nvol vi ng 1,3-di carbonyl
compounds and urea-deri ved N-acyl i mi ni um i ons yi el di ng
di hydropyri mi di nes of type 4are reported i n the l i tera-
ture,
26
provi di ng addi ti onal support for thi s mechani sm.
Experimental Section
General Methods. Consul t ref 4. Detai l s of al l NMR
measurements are presented i n the Supporti ng I nformati on
al ong wi th Tabl es S1 and S2.
Reagents. Benzal dehyde (2) and ethyl acetoacetate (1)
were freshl y di sti l l ed under vacuo and stored under argon. The
fol l owi ng compounds were prepared accordi ng to l i terature
procedures: enone 8,
14
urei docrotonate 11a,b,
21,22
and bi s-
urei des 15a,b.
23,24
The preparati on of 15a,b i s gi ven i n the
Supporti ng I nformati on).
Ethyl 2-Amino-4-methyl-6-phenyl-6H-1,3-thiazine-5-
carboxylate (10a). A sol uti on of enone 8(2.18 g, 10 mmol )
and thi ourea 9a(0.76 g, 10 mmol ) i n MeOH (10 mL) contai ni ng
concentrated HCl (1 mL) was heated at refl ux for 3-5 h. After
al l starti ng materi al had been consumed (TLC), the mi xture
was concentrated i n vacuo. The crude product (10aHCl ) was
di ssol ved i n H2O (30 mL) and treated wi th i ce-col d 2 N NaOH
(6 mL) to yi el d 2.31 g (84%) of thi azi ne 10aas a col orl ess sol i d,
mp 120-122 C (CHCl 3/hexane) (l i t.
23
mp 120-122 C). Thi s
product was i denti cal (TLC, I R,
1
H NMR) wi th an authenti c
sampl e prepared accordi ng to ref 19
Ethyl 4-Methyl-2-(methylamino)-6-phenyl-6H-1,3-thia-
zine-5-carboxylate (10b). Thi s compound was prepared i n
an anal ogous fashi on as decri bed above for 10a, usi ng N-
methyl thi ourea (9b) i nstead of thi ourea (9a) to yi el d 2.29 g
(79%) of 10bas col orl ess sol i d: mp 128-131 C; I R (KBr) 3340,
3220, 1690, 1670 cm-1;
1
H NMR (DMSO-d6) 1.14 (t, J ) 7.0
Hz, 3H), 2.45 (s, 3H), 2.82 (3H), 4.04 (q, J ) 7.0 Hz, 2H), 5.33
(s, 1H), 7.15-7.27 (m, 5H), 7.84 (br s, 1H);
13
C NMR (DMSO-
d6) 14.2, 24.5, 28.8, 41.6, 59.5, 101.1, 126.5, 127.1, 128.4,
142.7, 153.5, 158.6, 166.5. Anal . Cal cd for C15H18N2O2S: C,
62.04; H, 6.25; N, 9.65. Found: C, 62.14; H, 6.34; N, 9.58.
Ethyl 1,6-Dimethyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (4b) from Ureidocrotonate
11b. A mi xture of urei docrotonate 11b(1.86 g, 10 mmol ) and
benzal dehyde (2) (1.06 g, 10 mmol ) i n MeOH (40 mL) contai n-
i ng 1 drop of concentrated HCl was heated under refl ux for 3
h. The sol uti on was kept at -20 C for several hours to yi el d
1.97 g (72%) of pyri mi di ne 4b, mp 176-178 C (l i t.
14,17
mp
176-178 C). The crude
1
H NMR spectrum of the concen-
trated reacti on mi xture showed no evi dence for the presence
of the i someri c pyri mi di ne 12b.
19
For
1
H and
13
C NMR data,
see Tabl es S1 and S2.
Ethyl 6-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropy-
rimidine-5-carboxylate (4a). A mi xture of ethyl acetoac-
etate (1) (1.30 g, 10 mmol ), benzal dehyde (2) (1.06 g, 10 mmol ),
urea (3a) (0.60 g, 10 mmol ), and MeOH (5 mL) contai ni ng 1-2
drops of concentrated HCl was sti rred at rt. After 2 h product
began to preci pi tate from the sol uti on, and after 3 d of sti rri ng
at rt the preci pi tated sol i d was fi l trated to yi el d 1.98 g (76%)
of pyri mi di ne 4a: mp 206-207 C (l i t.
15
mp 202-204 C, l i t.
14
mp 207-208 C);
1
H NMR (DMSO-d6) 1.14 (t, J ) 7.0 Hz,
3H), 2.26 (s, 3H), 3.91 (q, J ) 7.0 Hz, 2H), 5.12 (d, J ) 4.5 Hz,
1H), 7.30 (s, 5H), 7.67 (d, J ) 4.5 Hz, 1H), 9.09 (br s, 1H).
Ethyl 1,6-Dimethyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (4b). Thi s pyri mi di ne was pre-
pared i n an anal ogous fashi on as decri bed above for 4a, usi ng
N-methyl urea (3b) i nstead of urea (3a) to yi el d 2.05 g (79%)
of 4b as col orl ess sol i d, mp 176-178 C. Thi s materi al was
i denti cal (mp, I R,
1
H NMR) wi th a sampl e prepared from 11b
and 2 descri bed above.
Acknowledgment. Thi s work was supported by the
Austri an Academy of Sci ences (Austri an Programme for
Advanced Research and Technol ogy, APART 319) and
the Austri an Sci ence Fund (FWF, Project P-11994-
CHE).
SupportingInformation Available: Experi mental pro-
cedures for 15a,b, detai l s of
1
H and
13
C NMR measurements,
Tabl es S1 and S2 (5 pages). Thi s materi al i s contai ned i n
l i brari es on mi crofi che, i mmedi atel y fol l ows thi s arti cl e i n the
mi crofi l m versi on versi on of the journal , and can be ordered
fr om the ACS; see any cur r ent masthead for or der i ng
i nformati on.
JO971010U
(25) Overman, L. E.; Ri cca, D. J. ComprehensiveOrganicSynthesis;
Trost, B. M.; Fl emi ng, I .; Eds.; Pergamon Press: Oxford; Vol . 2, 1991;
p 1007-1046. Hi emstra, H.; Speckamp, W. N. ComprehensiveOrganic
Synthesis; Trost, B. M.; Fl emi ng, I .; Eds.; Pergamon Press: Oxford;
Vol . 2, 1991; p 1047-1082, and references therei n.
(26) Okamoto, K. T.; Cl ardy, J. Tetrahedron Lett. 1984, 25, 2937-
2940. Di jki nk, J.; Deghati , P. Y. F.; Hi emstra, H. 11th I UPAC
Conferenceon Organic Synthesis, Amsterdam, June 30-Jul y 4, 1996,
Book of Abstracts p 379.
7204 J . Org. Chem., Vol. 62, No. 21, 1997 Kappe

Vous aimerez peut-être aussi