A reexamination of the mechanism of the Biginelli dihydropyrimidine synthesis. Support for an N-acyliminium ion intermediate

Article abstract of DOI:10.1021/jo971010u

The mechanism of three-component Biginelli dihydropyrimidine synthesis was reinvestigated using ¹H and ¹³C NMR spectroscopy. Condensation of benzaldehyde, ethyl acetoacetate, and urea (or N-methylurea) in CD₃OH according t

Full text of DOI:10.1021/jo971010u

J . Org. Chem. 1997, 62, 7201-7204
7201
A Reexa m in a tion of th e Mech a n ism of th e Bigin elli
Dih yd r op yr im id in e Syn th esis. Su p p or t for a n N-Acylim in iu m Ion
In ter m ed ia te1
C. Oliver Kappe*
Institute of Organic Chemistry, Karl-Franzens-University Graz, A-8010 Graz, Austria
Received J une 4, 1997X
The mechansim of the three-component Biginelli dihydropyrimidine synthesis was reinvestigated
1
using H and 13C NMR spectroscopy. Condensation of benzaldehyde, ethyl acetoacetate, and urea
(or N-methylurea) in CD3OH according to the procedure described by Biginelli produced the expected
6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates. According to NMR measure-
ments, there is no evidence that the first step in the Biginelli reaction is an acid-catalyzed aldol
reaction of ethyl acetoacetate and benzaldehyde leading to a carbenium ion intermediate, as has
been suggested previously. In contrast, all experimental evidence points to a mechanism involving
an N-acyliminium ion as the key intermediate, formed by acid-catalyzed condensation of benzal-
dehyde and urea (or N-methylurea). Interception of this iminium ion by ethyl acetoacetate produces
open-chain ureides which subsequently cyclize to the Biginelli dihydropyrimidines.
In 1893 Biginelli reported the first synthesis of dihy-
dropyrimidines of type 4 by a simple one-pot condensa-
tion reaction of ethyl acetoacetate (1), benzaldehyde (2),
and urea (3a ).2 In the following decades the original
cyclocondensation reaction has been extended widely to
include variations in all three components, allowing
access to a large number of multifunctionalized dihydro-
pyrimidine derivatives.3 Largely ignored for many years,
the Biginelli reaction has recently attracted a great deal
of attention, and several improved procedures for the
preparation of dihydropyrimidines of type 4 have been
reported within the past few years.3-5 Various solid-
phase modifications of the Biginelli reaction suitable for
combinatorial chemistry have also been described.6
ized dihydropyrimidines of type 4 show a very similar
pharmacological profile to classical dihydropyridine drugs
and several lead compounds with excellent calcium
channel modulatory activity have been identified.8 In
addition, several marine alkaloids with interesting bio-
logical activities containing the dihydropyrimidine-5-
carboxylate core have been isolated.9-11 Most notably
among these are the crambine9 and batzelladine alka-
loids10 and the more complex pentacyclic alkaloid ptilo-
mycalin A,11 which was recently synthesized employing
a “tethered Biginelli condensation” as one of the key
steps.12
Despite the importance and current interest in dihy-
dropyrimidines of type 4, the mechanism of the classical
three-component Biginelli condensation has not been
elucidated with certainty and remains disputed.3 Early
work by Folkers and J ohnson suggested that N,N′′-
benzylidenebisurea (15a , see below), i.e. the primary
bimolecular condensation product of benzaldehyde (2)
and urea (3a ), is the first intermediate in this reaction.13
Later, Sweet and Fissekis have proposed a different
mechanism postulating that carbenium ion 6 (see below),
produced by an acid-catalyzed aldol reaction of benzal-
dehyde (2) with ethyl acetoacetate (1), is the key inter-
mediate and is formed in the first and limiting step of
the Biginelli reaction.14 To decide which of the two
fundamentally different mechanistic proposals is correct
The present interest in “Biginelli compounds” 4 is
mainly due to their close structural relationship to the
clinically important dihydropyridine calcium channel
modulators of the nifedipine-type.7 Properly functional-
* To whom correspondence should be addressed. Fax: (43)-(316)-
3809840. E-mail: kappeco@balu.kfunigraz.ac.at.
(7) Goldman, S.; Stoltefuss, J . Angew. Chem., Int. Ed. Engl. 1991,
30, 1559-1578.
(8) 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. 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.
(9) Snider, B. B.; Shi, Z. J . Org. Chem. 1993, 58, 3828-3839, and
references therein.
(10) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer,
A. J .; DeBrosse, C.; Mai, S.; Truneh, A.; Faulkner, D. J .; Carte, B.;
Breen, A. L.; Hertzberg, R. P.; J ohnson, R. K.; Westley, J . W.; Potts,
B. C. M. J . Org. Chem. 1995, 60, 1182-1188.
(11) Kashman, Y.; Hirsh, S.; McConnel, O. J .; Ohtani, I.; Takenori,
K.; Kakisawa, H. J . Am. Chem. Soc. 1989, 111, 8925-8926. Ohtani,
I.; Kusumi, T.; Kakisawa, H.; Kashman, Y.; Hirsh, S. J . Am. Chem.
Soc. 1992, 114, 8472-8479.
X Abstract published in Advance ACS Abstracts, October 1, 1997.
(1) Synthesis and Reactions of Biginelli Compounds. 9. For part 8,
see: Kleidernigg, O. P.; Kappe, C. O. Tetrahedron: Asymmetry 1997,
8, 2057-2067.
(2) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360-416.
(3) For a review of the Biginelli-condensation, 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.; Fabian, W. M. F.; Semones, M. A. Tetrahe-
dron 1997, 53, 2803-2816.
(5) O’Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 1185-1188.
Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J . J . Org. Chem.
1989, 54, 5898-5907. Gupta, R.; Gupta, A. K.; Paul, S.; Kachroo, P.
L. Ind. J . Chem. 1995, 34B, 151-152. Sa´r, C. P.; Hankovszky, O. H.;
J erkovich, G.; Pallagi, I.; Hideg, K. ACH-Models Chem. 1994, 131,
363-376.
(6) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36, 7819-
7822. Studer, A.; J eger, P.; Wipf, P.; Curran, D. P. J . Org. Chem. 1997,
62, 2917-2924. Robinett, L. D.; Yager, K. M.; Phelan, J . C. 211th
National Meeting of the American Chemical Society, New Orleans,
1996; American Chemical Society: Washington, DC, 1996; ORGN 122.
(12) Overman, L. E.; Rabinowitz, M. H. J . Org. Chem. 1993, 58,
3235-3237. Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J . Am.
Chem. Soc. 1995, 117, 2657-2658.
(13) Folkers, K.; J ohnson, T. B. J . Am. Chem. Soc. 1933, 55, 3784-
3791.
S0022-3263(97)01010-4 CCC: $14.00 © 1997 American Chemical Society

7202 J . Org. Chem., Vol. 62, No. 21, 1997
Kappe
we have carried out a detailed reinvestigation of the
tion of benzaldehyde (2) with ethyl acetoacetate (1)
proposed by Sweet and Fissekis14 under typical Biginelli
reaction conditions. Although aldol reactions are most
often catalyzed by base, the possibility of an acid-
catalyzed aldol reaction of benzaldehyde with a 1,3-
dicarbonyl component such as ethyl acetoacetate can not
be a priori excluded.18 However, it is well-known that
in the case of acid catalysis the reaction products of the
aldol reaction are in most cases the R,â-unsaturated
carbonyl compounds (i.e. 8) and not the â-hydroxycar-
bonyl (aldol) products (i.e. 5).18 Upon monitoring the
reaction of benzaldehyde (2) and ethyl acetoacetate (1)
in CD3OH/HCl by 1H and 13C NMR spectroscopy, no
evidence for an aldol reaction or any other reaction
between the two components at room temperature could
be obtained (see Supporting Information). The fact that
benzaldehyde (2) and ethyl acetoacetate (1) do not react
under conditions where the Biginelli condensation itself
proceeds smoothly (see below) rules out the carbenium
ion mechanism, where such a reaction is proposed to be
the first step.
The possibility of a carbenium ion intermediate of type
6 in the Biginelli condensation seems even more unlikely
if one considers the case where thiourea is substituted
for urea. Both thiourea (9a )17 and N-methylthiourea
(9b)19 are known to produce the expected dihydropyrim-
idine-2-thiones (“Biginelli compounds”) when reacted
with benzaldehyde (2) and ethyl acetoacetate (1) under
standard Biginelli conditions.3,17,19 In contrast, treatment
of enone 8 with thiourea (9a ) or N-methylthiourea (9b)
under acid catalysis, i.e. under conditions where accord-
ing to Sweet and Fissekis carbenium ion 6 is generated,14
furnished exclusively the isomeric 2-amino-1,3-thiazines
10a ,b in excellent yields.
1
mechanism of the Biginelli condensation using H and
13C NMR spectroscopy to identify possible intermediates.
1
To be able to monitor all reactions by H and 13C NMR
spectroscopy, CD3OH was used as solvent in the NMR
experiments which were carried out at room temperature
in the presence of a catalytic amount of HCl (see
Supporting Information).13,15 As already suggested by
Folkers and J ohnson,13 it is very likely that this three-
component condensation proceeds via one of the three
possible bimolecular reaction pathways from the urea/
aldehyde/acetoacetate system. We have reinvestigated
these pathways, which are discussed below.
The “carbenium ion mechanism” was proposed by
Sweet and Fissekis,14 who investigated the reaction in
1973 and suggested that an acid-catalyzed aldol conden-
sation is the first and limiting step of the Biginelli
condensation. It was proposed that under acid catalysis
benzaldehyde (2) and ethyl acetoacetate (1) would react
in an aldol-type fashion to produce the corresponding
aldol 5, which dehydrates in the presence of acid to the
resonance-stabilized carbenium ion 6.14,16 Interception
of cation 6 by urea (3a ) or N-methylurea (3b) then
produces ureides 7, which ultimately cyclize to the
Biginelli products 4.14 The main argument for the
proposed mechanism made by the authors14 relates to the
fact that acid-catalyzed treatment of independently
prepared enone 8 with N-methylurea (3b) also produced
pyrimidine 4b, albeit in moderate yield.14 According to
Sweet and Fissekis, protonation of enone 8 regenerates
the carbenium ion intermediate 6,16 which then can react
with urea (3a ) or N-methylurea (3b) as described above
(6 f 7 f 4).14 It was also considered important that in
the reaction of enone 8 with N-methylurea (3b) only the
N1-methyl derivative 4b was produced and not the N3-
substituted isomer 12b (see below), which corresponds
to the regiochemical outcome observed in the three-
component Biginelli reaction of ethyl acetoacetate (1),
benzaldehyde (2), and N-methylurea (3b).3,17
The structures of thiazines 10 were established by
spectroscopic methods (see the Experimental Section)
and, for 10a , by comparison with authentic material.19,20
In contrast to the reaction of enone 8 with N-methyl-
urea,14 where reaction times of 2 weeks and only moder-
ate yields of pyrimidine 4b have been encountered, the
reaction times with thioureas 9 are much shorter (3-5
h), which can be rationalized by the considerable higher
nucleophilicity of sulfur. The fact that in the three-
component Biginelli reaction using thioureas the thiazine
products 10 are not observed makes a carbenium ion
intermediate of type 6 unlikely.
The so-called “ureidocrotonate mechanism” was al-
ready considered by Folkers and J ohnson13 but was ruled
out as a mechanistic pathway since the bimolecular
condensation product of ethyl acetoacetate (1) and urea
(3a ), i.e. ureidocrotonate 11a ,21 was shown to rapidly
According to the experimental data described herein,
a mechanism involving carbenium ion 6 as the key
intermediate in the Biginelli reaction seems unlikely. We
have attempted to observe the acid-catalyzed aldol reac-
(18) Heathcock, C. H. Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford; 1991; Vol. 2, p 133-
179. Nielson, A. T.; Houlihan, 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 analogous cyclocondensation using N-benzylthiourea,
the structure of the thiazine product was confirmed by X-ray analy-
sis: Atwal, K S.; O’Reilley, B. C.; Gougoutas, J . Z.; Malley, M. F.
Heterocycles 1987, 26, 1189-1192.
(14) Sweet, F.; Fissekis, J . D. J . Am. Chem. Soc. 1973, 95, 8741-
8749.
(15) Folkers, K.; Harwood, H. J .; J ohnson, T. B. J . Am. Chem. Soc.
1932, 54, 3751-3758.
(16) A more modern description of the carbenium ion intermediate
would be the tautomeric O-protonated enone.18
(17) Folkers, K.; J ohnson, T. B. J . Am. Chem. Soc. 1933, 55, 2886-
2893.

Support for an N-Acyliminium Ion Intermediate
J . Org. Chem., Vol. 62, No. 21, 1997 7203
hydrolyze under the typical Biginelli reaction conditions
(EtOH, HCl).13 Since the fact that ureidocrotonate 11a
is sensitive to hydrolysis does not exclude this intermedi-
ate for the Biginelli reaction, we have reinvestigated this
pathway (including the N-methyl analogue 11b22). The
independently prepared21,22 enamides 11a ,b were shown
to rapidly hydrolize in CD3OH when catalytic amounts
of acid (and water) were present (see the Supporting
Information). While ureidocrotonates 11a ,b can be pre-
pared from 1 and 3a ,b under strictly anhydrous condi-
tions, i.e. by allowing a mixture of 1 and 3 to react in a
desiccator over concentrated H2SO4 for several days,21,22
it is evident that under Biginelli reaction conditions the
equilibrium is far on the acetoacetate/urea side.
On the basis of these experimental results, we propose
the following mechanistic concept. Addition of ureas 3a
or 3b to benzaldehyde (2) leads to N-(1-hydroxybenzyl)-
ureas of type 13 via standard nucleophilic addition.
Although this is likely to be an equilibrium reaction,
“hemiaminals” 13 are expected to undergo rapid dehy-
dration in the presence of acid to a carbenium ion which
may be formulated as a highly reactive N-acyliminium
species, i.e. 14. In the absence of the 1,3-dicarbonyl
compound a second equivalent of urea 3a ,b is added to
furnish bisureides 15a ,b, which due to their low solubil-
ity23,24 precipitate from the reaction mixture. However,
if ethyl acetoacetate (1) is present in the reaction
medium, iminium ion 14 is intercepted by the 1,3-
dicarbonyl compound, possibly through its enol tautomer,
to furnish intermediates 7a ,b, which then cyclize to the
Biginelli compounds 4a ,b. Monitoring the formation of
Another argument against the involvment of an urei-
docrotonate intermediate relates to the fact that N-
methylurea (3b) reacts with ethyl acetoacetate (1) to
furnish exclusively regioisomer 11b bearing the N-methyl
substituent at the terminal amino group.22 The forma-
tion of a Biginelli dihydropyrimidine in a 5 + 1 cyclo-
condensation manner from 11b and benzaldehyde would
be expected to lead to the N3-substituted Biginelli
product 12b,19 which is observed neither in the three-
component Biginelli reaction (see above)3,14,17 nor from
the reaction of ureide 11b with benzaldehyde under
Biginelli conditions. In both cases the isomeric dihydro-
pyrimidine 4b is formed as the exclusive regioisomer,
which further supports Folkers and J ohnson’s13 proposi-
tion that the Biginelli reaction does not proceed through
an ureidocrotonate intermediate of type 11 and that
immediate hydrolysis of 11 takes place if the reaction is
started from such ureidocrotonates.
Finally, we have considered the original mechanistic
proposal made by Folkers and J ohnson,13 who suggested
that the first step in the three-component Biginelli
condensation is the reaction of benzaldehyde (2) with
urea (3a ). When benzaldehyde (2) and urea (3a , 2 mol
equiv) were reacted under typical Biginelli conditions
(CH3OH/HCl) at room temperature, the anticipated
condensation product bisureide 15a 23 started to precipi-
tate from the solution within 15-20 min. Bisureide 15a
was also formed when equimolar amounts of the two
components were employed, and the analogous condensa-
tion product (15b)24 was produced when N-methylurea
(3b) was used instead of urea (3a ). However, when these
reactions were carried out in the presence of ethyl
acetoacetate (1) under otherwise identical reaction condi-
tions, bisureides 15a ,b were not formed, but dihydropy-
rimidines 4a ,b started to precipitate slowly from the
reaction mixture within 1-2 h (complete conversion took
2-3 days).
1
bisureides 15a ,b from 2 and 3a ,b by H NMR (CD3OH,
HCl) did not allow the observation of any intermediates,
e.g. 13, in this process. We assume that the first addition
step (2 f 13) is the rate-determining (slow) step and that
both the subsequent acid-catalyzed dehydration (13 f
14) and the addition of a second equivalent of urea to
the iminium ion (14 f 15) are fast steps, therefore not
allowing 13 to accumulate. This seems also to be true
for the Biginelli reaction itself: under typical Biginelli
conditions, no intermediates in the reaction of ethyl
acetoacetate (1), benzaldehyde (2), and N-methylurea
1
(3b) could be observed by H or 13C NMR spectroscopy.
After about 30 min, signals due to the final product (4b)
started to appear in the 1H NMR that were easily
identified, as these signals are nicely separated from the
peaks due to starting materials (see Table S1 in the
Supporting Information). As the reaction proceeded,
these peaks became more prominent and after ca. 18 h
50% conversion was achieved. At this point 4b started
to precipitate from the NMR solution and the experiment
was terminated.
In conclusion, we have shown that the original mecha-
nistic proposal put forward by Folkers and J ohnson in
1933,13 involving an aldehyde-urea condensation product
as key intermediate in the Biginelli condensation is
essentially correct. The first step in this mechanism
evidently involves the acid-catalyzed formation of an
N-acyliminium ion precursor of type 14 from an aldehyde
and urea component. In the case of amides and carbam-
ates, this reaction pathway is well-established,25 and at
least one example exists for ureas.26 The second step (14
f 7) can be regarded as an addition of a π-nucleophile,
i.e. the enol tautomer of acetoacetate 1 to the electron-
deficient N-acyliminium species 14. Additions of π-nu-
cleophiles to iminium species are very well-known and
(21) Donleavy, J . J .; Kise, M. A. Org. Synth. 1943, Collect. Vol. II,
422-423.
(22) Senda, S.; Suzui, A. Chem. Pharm. Bull. 1958, 6, 476-479.
Hlousek, J .; Machacek, V.; Sterba, V. Sb. Ved. Pr., Vys. Sk. Chemicko-
technol. Pardubice 1978, 39, 11-25 (Chem. Abstr. 1979, 91, 174663n).
(23) Schiff, H. Ann. 1869, 151, 186-213. Lu¨dy, E. Monatsh. Chem.
1889, 10, 295-316. Bakibaev, A. A.; Tignibidina, L. G.; Filimonov, V.
D.; Gorshkova, V. K.; Saratikov, A. S. Khim. Farm. Zh. 1991, 25, 31-
35. Bakibaev, A. A. Zh. Org. Khim. 1994, 11, 1686-1687.
(24) Schiff, H. Ann. 1896, 291, 367-377. See also Koyano, K.;
McArthur, C. R. Can. J . Chem. 1973, 51, 333-337.

7204 J . Org. Chem., Vol. 62, No. 21, 1997
Kappe
142.7, 153.5, 158.6, 166.5. Anal. Calcd for C15H18N2O2S: C,
62.04; H, 6.25; N, 9.65. Found: C, 62.14; H, 6.34; N, 9.58.
Eth yl 1,6-Dim eth yl-2-oxo-4-p h en yl-1,2,3,4-tetr a h yd r o-
p yr im id in e-5-ca r b oxyla t e (4b) fr om Ur eid ocr ot on a t e
11b. A mixture of ureidocrotonate 11b (1.86 g, 10 mmol) and
benzaldehyde (2) (1.06 g, 10 mmol) in MeOH (40 mL) contain-
ing 1 drop of concentrated HCl was heated under reflux for 3
h. The solution was kept at -20 °C for several hours to yield
1.97 g (72%) of pyrimidine 4b, mp 176-178 °C (lit.14,17 mp
176-178 °C). The crude 1H NMR spectrum of the concen-
trated reaction mixture showed no evidence for the presence
of the isomeric pyrimidine 12b.19 For 1H and 13C NMR data,
see Tables S1 and S2.
have proven to be valuable synthetic transformations in
target-oriented synthesis.25 Importantly, several ex-
amples of this type of reaction involving 1,3-dicarbonyl
compounds and urea-derived N-acyliminium ions yielding
dihydropyrimidines of type 4 are reported in the litera-
ture,26 providing additional support for this mechanism.
Exp er im en ta l Section
Gen er a l Meth od s. Consult ref 4. Details of all NMR
measurements are presented in the Supporting Information
along with Tables S1 and S2.
Rea gen ts. Benzaldehyde (2) and ethyl acetoacetate (1)
were freshly distilled under vacuo and stored under argon. The
following compounds were prepared according to literature
procedures: enone 8,14 ureidocrotonate 11a ,b,21,22 and bis-
ureides 15a ,b.23,24 The preparation of 15a ,b is given in the
Supporting Information).
E t h yl 6-Met h yl-2-oxo-4-p h en yl-1,2,3,4-t et r a h yd r op y-
r im id in e-5-ca r boxyla te (4a ). A mixture of ethyl acetoac-
etate (1) (1.30 g, 10 mmol), benzaldehyde (2) (1.06 g, 10 mmol),
urea (3a ) (0.60 g, 10 mmol), and MeOH (5 mL) containing 1-2
drops of concentrated HCl was stirred at rt. After 2 h product
began to precipitate from the solution, and after 3 d of stirring
at rt the precipitated solid was filtrated to yield 1.98 g (76%)
of pyrimidine 4a : mp 206-207 °C (lit.15 mp 202-204 °C, lit.14
E t h yl 2-Am in o-4-m et h yl-6-p h en yl-6H -1,3-t h ia zin e-5-
ca r boxyla te (10a ). A solution of enone 8 (2.18 g, 10 mmol)
and thiourea 9a (0.76 g, 10 mmol) in MeOH (10 mL) containing
concentrated HCl (1 mL) was heated at reflux for 3-5 h. After
all starting material had been consumed (TLC), the mixture
was concentrated in vacuo. The crude product (10a ‚HCl) was
dissolved in H2O (30 mL) and treated with ice-cold 2 N NaOH
(6 mL) to yield 2.31 g (84%) of thiazine 10a as a colorless solid,
mp 120-122 °C (CHCl3/hexane) (lit.23 mp 120-122 °C). This
1
mp 207-208 °C); H NMR (DMSO-d6) δ 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).
Eth yl 1,6-Dim eth yl-2-oxo-4-p h en yl-1,2,3,4-tetr a h yd r o-
p yr im id in e-5-ca r boxyla te (4b). This pyrimidine was pre-
pared in an analogous fashion as decribed above for 4a , using
N-methylurea (3b) instead of urea (3a ) to yield 2.05 g (79%)
of 4b as colorless solid, mp 176-178 °C. This material was
identical (mp, IR, 1H NMR) with a sample prepared from 11b
and 2 described above.
1
product was identical (TLC, IR, H NMR) with an authentic
sample prepared according to ref 19
Eth yl 4-Meth yl-2-(m eth yla m in o)-6-p h en yl-6H-1,3-th ia -
zin e-5-ca r boxyla te (10b). This compound was prepared in
an analogous fashion as decribed above for 10a, using N-
methylthiourea (9b) instead of thiourea (9a ) to yield 2.29 g
(79%) of 10b as colorless solid: mp 128-131 °C; IR (KBr) 3340,
3220, 1690, 1670 cm-1; 1H NMR (DMSO-d6) δ 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); 13C NMR (DMSO-
d6) δ 14.2, 24.5, 28.8, 41.6, 59.5, 101.1, 126.5, 127.1, 128.4,
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 Fund (FWF, Project P-11994-
CHE).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for 15a ,b, details of 1H and 13C NMR measurements,
Tables S1 and S2 (5 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version version of the journal, and can be ordered
from the ACS; see any current masthead for ordering
information.
(25) Overman, L. E.; Ricca, D. J . Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I.; Eds.; Pergamon Press: Oxford; Vol. 2, 1991;
p 1007-1046. Hiemstra, H.; Speckamp, W. N. Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I.; Eds.; Pergamon Press: Oxford;
Vol. 2, 1991; p 1047-1082, and references therein.
(26) Okamoto, K. T.; Clardy, J . Tetrahedron Lett. 1984, 25, 2937-
2940. Dijkink, J .; Deghati, P. Y. F.; Hiemstra, H. 11th IUPAC
Conference on Organic Synthesis, Amsterdam, J une 30-J uly 4, 1996,
Book of Abstracts p 379.
J O971010U