1,3-Diaza-1,3-butadienes. Synthesis and conversion into pyrimidines by [4π + 2π] cycloaddition with electron deficient acetylenes. Synthetic utility of 2-(trichloromethyl)pyrimidines

Article abstract of DOI:10.1021/jo952106w

Methods have been devised to generate 1H-1,3-diaza-1,3-butadienes bearing a leaving group at position-4 in latent, masked, and unprotected forms. A hallmark of these azadienes is that they undergo thermal [4π ± 2π] cycloaddition reactions with electron deficient acetylenes to give adducts which are aromatized to pyrimidine derivatives under the reaction conditions. Thus, 1-(methoxycarbonyl)-3-acylamidines 17 on heating in solution are converted in situ into the 1,3-diaza-1,3-dienes 18 and/or 19 which react with dimethyl acetylenedicarboxylate (DMAD) to produce the pyrimidines 26. The 1-Boc-1,3-diaza-1,3-dienes 24 are masked forms of the 1H-dienes inasmuch as they react with DMAD under relatively mild conditions to give the dihydropyrimidine adducts 25, which are easily detectable by ¹H NMR spectroscopy, and which aromatize to pyrimidines 20 at higher temperatures. The 4-methylthio compounds 31 and 33, and the 2-(trichloromethyl) compounds 37, are isolable, relatively stable, 1H-1,3-diaza-1,3-butadienes. These easily prepared compounds react with electron deficient acetylenes under mild conditions to provide the pyrimidines 20, 34, and 38, respectively, in fair to excellent yields. The 2-(trichloromethyl)pyrimidines 38 are very useful precursors of a wide variety of other 2-substituted pyrimidines 46-52.

Full text of DOI:10.1021/jo952106w

2470
J . Org. Chem. 1996, 61, 2470-2483
1,3-Dia za -1,3-bu ta d ien es. Syn th esis a n d Con ver sion in to
P yr im id in es by [4π + 2π] Cycloa d d ition w ith Electr on Deficien t
Acetylen es. Syn th etic Utility of 2-(Tr ich lor om eth yl)p yr im id in es1
Angel Guzma´n, Moise´s Romero,2 and Francisco X. Talama´s
Syntex, S. A. de C. V., Divisio´n de Investigacio´n, Apartado Postal 272 (CIVAC), 62500 J iutepec,
Morelos, Mexico
Rene Villena
Universidad Nacional Auto´noma de Me´xico, Ciudad Universitaria, 04510 Coyoaca´n,
Me´xico, D. F., Mexico
Robert Greenhouse and J oseph M. Muchowski*
Syntex Research, Institute of Organic Chemistry, 3401 Hillview Avenue, Palo Alto, California 94304
Received November 28, 1995X
Methods have been devised to generate 1H-1,3-diaza-1,3-butadienes bearing a leaving group at
position-4 in latent, masked, and unprotected forms. A hallmark of these azadienes is that they
undergo thermal [4π + 2π] cycloaddition reactions with electron deficient acetylenes to give adducts
which are aromatized to pyrimidine derivatives under the reaction conditions. Thus, 1-(methoxy-
carbonyl)-3-acylamidines 17 on heating in solution are converted in situ into the 1,3-diaza-1,3-
dienes 18 and/or 19 which react with dimethyl acetylenedicarboxylate (DMAD) to produce the
pyrimidines 20. The 1-Boc-1,3-diaza-1,3-dienes 24 are masked forms of the 1H-dienes inasmuch
as they react with DMAD under relatively mild conditions to give the dihydropyrimidine adducts
1
25, which are easily detectable by H NMR spectroscopy, and which aromatize to pyrimidines 26
at higher temperatures. The 4-methylthio compounds 31 and 33, and the 2-(trichloromethyl)
compounds 37, are isolable, relatively stable, 1H-1,3-diaza-1,3-butadienes. These easily prepared
compounds react with electron deficient acetylenes under mild conditions to provide the pyrimidines
20, 34, and 38, respectively, in fair to excellent yields. The 2-(trichloromethyl)pyrimidines 38 are
very useful precursors of a wide variety of other 2-substituted pyrimidines 46-52.
In tr od u ction
ultraviolet spectroscopic data.7,8 Tolmacheva et al.9 have
synthesized a series of structural analogs of 9 from
perfluorinated aliphatic amidines and perfluorinated
aliphatic nitriles. Since 1976, there has been sporadic
interest in the synthesis and reactions, especially the
cycloaddition reactions,10,11 of 1,3-diaza-1,3-butadienes.
It has been stated10 that the paucity of studies in this
area is a consequence of the inherent instability of the
simpler members of this series of compounds. The
references cited above, as well as the work described
herein, demonstrate that this supposition is invalid.
Indeed, quite a variety of 1,3-diaza-1,3-butadienes, with
or without a substituent at position-1 can be prepared,
and they have acceptable stability provided that the
carbon bearing substituents are appropriately chosen.
We became interested in the generation of 1-unsub-
stituted-1,3-diaza-1,3-butadienes with a leaving group at
position-4 since it was expected that such compounds
The first 1,3-diaza-1,3-butadiene 3 was described by
Pinner3,4 in 1889 who synthesized it from benzamidine
(1) and benzaldehyde (2) (Scheme 1). An analogous
product is obtained from salicylaldehyde,5 but non-
aromatic aldehydes lead to different products.4 In 1907,
Ley and Mu¨ller6 prepared the triphenyl compound 5 from
N-phenylbenzimidoyl chloride 4 and benzamidine. In
two notable publications7,8 issued from the Boots Pure
Drug Co. (Nottingham, England), the method of Ley and
Mu¨ller was expanded7 to include the synthesis of the fully
substituted compounds 6, and then a new process was
devised8 by which a series of 1,3-diaryl compounds 9,
without substituents on the nitrogen termini, were
prepared from N-thiobenzoylbenzamidines 7 and aryl
benzamidines 8. The conjugated diene forms of 5 and 9,
at least as the hydrochloride salts, were supported by
(9) Tolmacheva, G. M.; Krukovskii, S. P.; Berman, E. L.; Ponama-
renko, E. L. Izv. Akad. Nauk SSSR Ser. Khim. 1976, 1963; Chem.
Abstr. 1977, 86, 88663c.
X Abstract published in Advance ACS Abstracts, March 15, 1996.
(1) Contribution No. 934 from the Syntex Institute of Organic
Chemistry.
(2) The majority of the research described herein was carried out
by M. Romero in partial fulfillment of the requirements for the degree
of Doctorado en Qu´ımica Orga´nica in the Facultad de Qu´ımica,
Universidad Nacional Auto´noma de Me´xico, Me´xico, D. F., 1995.
Current address: Facultad de Qu´ımica, Universidad Auto´noma del
Estado de Me´xico, Paseo Colo´n/Paseo Tollocan, Toluca Me´xico 5000.
(3) Pinner, A. Chem. Ber. 1889, 22, 1600.
(10) Boger, D. C.; Weinreb, S. M. In Hetero Diels-Alder Methodology
in Organic Synthesis; Academic Press: San Diego, 1987; pp 272-274.
(11) (a) Crook, S.; Sykes, P. J . Chem. Soc., Perkin Trans. 1 1977,
1791. (b) Mazumdar, S. N.; Ibnasud, I.; Mahajan, M. P. Tetrahedron
Lett. 1986, 27, 5875. (c) Mazumdar, S. N.; Sharma, M.; Mahajan, M.
P. Tetrahedron Lett. 1987, 28, 2641. (d) Luthardt, P.; Wu¨rthwein, E.-
W. Tetrahedron Lett. 1988, 29, 921. (e) Barluenga, J .; Toma´s, M.;
Ballesteros, A.; Lo´pez, L. A. Tetrahedron Lett. 1989, 30, 4573. (f)
Ibnasud, I.; Malar, E. J . P.; Sundaram, N. Tetrahedron Lett. 1990, 31,
7357. (g) Mazumdar, S. N.; Mahajan, M. P. Tetrahedron 1991, 47, 1473.
(h) Sain, B.; Singh, S. P.; Sandhu, J . S. Tetrahedron Lett. 1991, 32,
5151. Tetrahedron 1992, 48, 4567. (i) Mazumdar, S. N.; Mukherjee,
S.; Sharma, A. K.; Sengupta, D.; Mahajan, M. P. Tetrahedron 1994,
50, 7579.
(4) Pinner, A. Chem. Ber. 1890, 23, 2923.
(5) Kunckell, F.; Bauer, R. Chem. Ber. 1901, 34, 3029.
(6) Ley, H.; Mu¨ller, F. Chem. Ber. 1907, 40, 2950.
(7) Cooper, F. C.; Partridge, M. W.; Short, W. F. J . Chem. Soc. 1951,
391.
(8) Peak, D. A. J . Chem. Soc. 1952, 215.
0022-3263/96/1961-2470$12.00/0 © 1996 American Chemical Society

Cycloaddition of 1,3-Diaza-1,3-butadienes with Acetylenes
J . Org. Chem., Vol. 61, No. 7, 1996 2471
Sch em e 1
Resu lts a n d Discu ssion
I. Gen er a tion of La ten t a n d Ma sk ed N-Un su b-
stitu ted -1,3-d ia za -1,3-bu ta d ien es. Our initial studies
were based on the erroneous assumption that all N-un-
substituted-1,3-diaza-1,3-butadienes would be too un-
stable to be readily isolable under ambient conditions.
Therefore the synthesis of various protected forms of
these entities was undertaken on the expectation that
the in situ generation of the deprotected forms in the
presence of an excess of an activated acetylene would
produce pyrimidine derivatives.
a . F r om N-Acyla ted Am id in es a n d Meth yl Ch lo-
r ofor m a te. Since amides are O-alkylated by powerful
alkylating agents such as dimethyl sulfate,14 it was
thought that N-acylamidines might react in an analogous
manner. This supposition was incorrect. For example,
N-benzoylacetamidine (15e, Scheme 3) gave a crystalline
methosulfate salt of the N-methylated compound 16. The
1H NMR spectrum of the free base was not consistent
with that expected for the O-methylated diene 19e. In
addition, this substance did not react with DMAD.
Imidates are also known to be produced from amides
and chloroformates by spontaneous loss of carbon dioxide
from the unstable O-acylated primary product.15 Reac-
tion of equimolar amounts of N-(4-methylbenzoyl)benz-
amidine (15b) and methyl chloroformate, in the presence
of a base, gave a crystalline product, which initially was
taken to be the O-acylated diazadiene 18b, based on the
formation of the diphenylpyrimidine derivative 20b (43%,
Table 1) with excess 12a at 150 °C in o-dichlorobenzene.
A single crystal X-ray analysis16 showed, however, that
methoxycarbonylation of 15b had occurred on the basic
nitrogen atom to produce 17b. This conclusion is obvious
from a comparison of the much longer bond of the
methoxycarbonyl N1-C8 system (1.395 Å, see Figure 1)
vs that of the p-toluoyl N2-C8 bond system (1.271 Å).
Nevertheless, to account for the formation of the pyrim-
idine 20b, it is reasonable to propose that the O-acylated
compound 18b is in equilibrium with 17b at 150 °C in
o-dichlorobenzene. Either 18b itself or 19b derived there
from by loss of CO2, should undergo [4π + 2π] cyclo-
addition with 12a . The diaryl-1,3,5-oxadiazinone (21b)
is probably not involved in the genesis of 20b. This was
established by the observation that heating a mixture of
the known17 diphenyl-1,3,5-oxadiazinone (21a) and DMAD
in o-dichlorobenzene produced no 20a . In addition,
heating an o-dichlorobenzene solution of 17a did not
generate any 21a . In both cases unidentified mixtures
were obtained.
Sch em e 2
would undergo [4π + 2π] cycloaddition reactions with
activated acetylenes, such as dimethyl acetylenedicar-
boxylate (12a , DMAD) to produce pyrimidine derivatives
(Scheme 2).12 This article describes the full details of our
studies on the synthesis of stable 1-unsubstituted-1,3-
diaza-1,3-butadienes, their cycloaddition reactions with
activated acetylenes, and some reactions of the pyrimi-
dine derivatives obtained in this way.13 In addition, we
describe several methods of generating latent forms of
such 1-unsubstituted 1,3-diaza-1,3-butadienes and trap-
ping studies of these dienes with activated acetylenes.
An example of such a strategy was described by Ibnasud
et al.11f while our work was in progress.
The N-(methoxycarbonyl)benzamidines 17a ,c,d also
reacted with DMAD to give the expected pyrimidine
derivatives 20a ,c,d (Table 1). It is interesting that in
the solid state, N-(methoxycarbonyl)-N′-acetylbenz-
amidine (17c) exists as tautomeric form 22 in which the
methoxycarbonyl group is situated on the CN double
bond. This is very clear from the X-ray structure (Figure
2)16 which shows that the bond length (1.393 Å) of the
(14) Pielartzik, H.; Irmisch-Pielartzik, B.; Eicher, T. In Houben-Weyl,
Methoden der Organischen Chimie; G. Theime: Stuttgart, 1985; Teil
I, Vol. E5, pp 813-815.
(15) Snytham, F. H.; Greth, W. E.; Langerman, N. R. J . Org. Chem.
1968, 34, 292. Mohashi, E.; Gordon, E. M. Synth. Commun. 1984, 14,
1159.
(16) The authors have deposited atomic coordinates for this struc-
ture with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
(12) In principle, a 1,3-diaza-1,3-butadiene bearing at least one
hydrogen at position-4 and a leaving group at position-1 should also
lead to pyrimidines with activated acetylenes. 1,4-Bis(dimethylamino)-
2-phenyl-1,3-butadiene was synthesized for this purpose and found to
not undergo cycloaddition with DMAD under a wide variety of neutral
and acidic (Brφnsted, Lewis) conditions (R. Greenhouse. Unpublished
observations).
(13) For
a preliminary communication on these aspects of our
studies, see: Guzma´n, A.; Romero, M.; Talama´s, F. X.; Muchowski, J .
M. Tetrahedron Lett. 1992, 33, 3449.
(17) Matsuda, I.; Itoh, K.; Ishii, Y. J . Chem. Soc. (C) 1971, 1870.

2472 J . Org. Chem., Vol. 61, No. 7, 1996
Guzma´n et al.
Sch em e 3
Ta ble 1. Syn th esis of P yr m id in e Der iva tives 20, 26, a n d
34 fr om 17, 24, 31, a n d 33 a n d Acetylen ic Ester s 12a a n d
12b
would require an unfavorable boatlike transition state
with the methoxycarbonyl and dimethylamino substitu-
ents axially disposed. Furthermore, it was not obvious
to us how the constituents of the reaction mixture could
effect oxidation of 25a by an intermolecular process. Our
suspicions concerning the facile formation of 25a were
confirmed upon repetition of the cycloaddition process
under the reported conditions. Compound 25a exhibited
pronounced and prolonged stability in boiling benzene
with less than 10% of 26a being formed after 24 h. The
concept of using stable 1-acyl derivatives as a formal
source of 1-unsubstituted-1,3-diazadienes nevertheless
has considerable merit. In this context, the known
thermal fragmentation of N-tert-butoxycarbonyl com-
pounds to isobutylene, carbon dioxide, and the NH
compound18 suggested the 1-tert-Boc derivatives of 24 as
logical equivalents of the N-unsubstituted congeners.
Therefore, tert-Boc-benzamidine (23b) was converted into
the corresponding diazadiene 24b by heating with DMF
dimethylacetal in THF at reflux temperature. Heating
a toluene solution of this compound with an excess of
DMAD or ethyl propiolate (12b) in toluene at 100-110
°C, provided the pyrimidines 20d and 26c, respectively,
in about 40% yields (Table 1). Similarly the 1-tert-Boc
diazadienes 24c, 24d , and 27 led to the dimethyl pyrim-
idine-4,5-dicarboxylates 26d , 26e, and 20c, respectively.
An experiment which highlights the greatly differing
consequences of N-tert-Boc vs N-(methoxycarbonyl) pro-
tection of the diazadienes was conducted in an NMR
spectrometer probe in deuterated 1,1,2,2-tetrachloro-
ethane. Thus, both 24b and 24e were completely con-
verted into the cycloadducts 25b and 25f after 1 h at 75
°C (3 equiv of DMAD) as indicated by the disappearance
of the singlet absorptions for the NMe2 and vinyl func-
tions at ca. δ 3.8 and 8.5 and the appearance of a new
NMe2 resonance at ca. δ 3.2. After 1 h at 100 °C more
than 70% of 25b had been transformed into the pyrimi-
dine 20d and isobutylene (1H NMR absorptions of δ 1.85
and 5.3.19,20 In the absence of DMAD, the azadiene 24b
is stable under these conditions). In contrast, the meth-
oxycarbonyl derivatives 25f was essentially unchanged
diazadiene
or precursor
acetylene
product
% yield
17a
17b
17c
17d
24b
24b
24c
24d
27
12a
12a
12a
12a
12a
12b
12a
12a
12a
12a
12a
12a
12a
12b
20a
20b
20c
20d
20d
26c
26d
26e
20c
20d
20a
20e
34a
34b
43
53
48
21a
44
42b
46
42
45
28
44c
92
31a
31b
33
7-11d
65
33
26
a
One pot reaction without isolation of 15d or 17d . b Sealed tube
reaction (120 °C). c Yield based on 24b; compound 28 was gener-
ated and used without purification. One-pot reaction without
d
isolation of 29, 30, or 31.
methoxycarbonyl N2-C7 system is much greater than
that of the acetyl N1-C7 bond system (1.280 Å). This
structure difference may be a reflection of a greater
degree of conjugation in 17b vs 17c, but in solution 22
must tautomerize to 17c enroute to 20c.
In startling contrast to 17c (22), N-(methoxycarbonyl)-
N′-benzoylacetamidine (17e) does not produce the cor-
responding pyrimidine (20e) on reaction with DMAD.
Whereas 17a -d require heating to effect reaction with
DMAD, 17e reacts rapidly with this acetylene even at
-10 °C, but a complex mixture containing no 20e is
produced. We are unable to rationalize the greatly
differing reactivity and reaction course of 17e vs 17a -d
with DMAD.
b . F r om 1-(ter t-Bu t oxyca r b on yl)-4-(d im et h yl-
a m in o)-1,3-d ia za -1,3-bu ta d ien es. During the course
of our studies, Ibnasud et al.11f reported that 1-(meth-
oxycarbonyl)-2-(methylthio)-4-(dimethylamino)-1,3-diaza-
1,3-butadiene (24a , Scheme 4) readily reacted with
DMAD in benzene (80 °C) to produce the 2-(methylthio)-
pyrimidine derivative 26a (72%) via the isolable inter-
mediate dihydro compound 25a . This stratagem circum-
vented the instability problem thought to be associated
with 1-unsubstituted-1,3-diaza-1,3-butadienes. It seemed
to us, however, that the aromatization of 25a had taken
place with remarkable ease given the mild reaction
conditions. The intramolecular loss of trimethylurethane
(18) Green, T. W.; Wuts, P. G. M. In Protective Groups in Organic
Synthesis, 2nd ed.; J . Wiley & Sons Inc.: New York, 1991; pp 327-
330.
(19) In CCl4 at 31 °C, isobutylene has absorptions at δ 1.68 and 4.63.
Rumens, F. H. A.; Lomas, J . S.; Tiflon, B.; Coupry, C.; Lumbroso-Bader,
N. Org. Magn. Reson. 1982, 19, 35.
(20) It is noteworthy that the Boc-azadiene 24b is recovered
unchanged after heating in xylenes for 6 h in the absence of DMAD.

Cycloaddition of 1,3-Diaza-1,3-butadienes with Acetylenes
J . Org. Chem., Vol. 61, No. 7, 1996 2473
F igu r e 1. Computer-generated stereoview of N-(methoxycarbonyl)-N′-(4-methylbenzoyl)benzamidine (17b).
F igu r e 2. Computer-generated stereoview of N-(methoxycarbonyl)-N′-acetylbenzamidine [17c(22)].
Sch em e 4
after 2 h at 100 °C. After 24 h at 100 °C, 25f had
completely decomposed, but only a minor amount of 20d
was present in the product mixture.
resulted in no observable reaction. On warming the
solution to room temperature, a mildly exothermic reac-
tion ensued resulting in the formation of the previously
described pyrimidine derivative 20d (Table 1). This
process clearly merits further study.
II. Gen er a tion of “Sta ble” N-Un su bstitu ted -1,3-
d ia za -1,3-b u t a d ien es. (a ) F r om N-Th ioa cyla t ed
Am id in es a n d Meth yl Iod id e. Thioamides are readily
alkylated on sulfur21 and N-thioacylamidines should react
analogously. In fact, N-thiobenzoylbenzamidine (29a ,
Scheme 5), and methyl iodide gave a crystalline salt 30a
Another potential advantage of the Boc-substituted
diazadienes is that it should be possible to cleave the
protecting group under mildly acidic conditions to pro-
duce stable salts of the 1H-dienes (see above). Indeed, a
solution of 24b in dichloromethane containing excess
trifluoroacetic acid was rapidly (<2 h at 15 °C) trans-
formed into a polar material, which was undoubtedly the
trifluoroacetic acid salt 28 of the diene. Addition of
excess triethylamine to a dichloromethane solution of the
crude product (obtained by removal of the solvent and
excess acid in vacuo) containing excess DMAD at 0 °C
(21) Smith, P. A. S. In The Chemistry of Open Chain Nitrogen
Compounds; W. A. Benjamin Inc.: New York, 1965; Vol. 1, p 163.

2474 J . Org. Chem., Vol. 61, No. 7, 1996
Guzma´n et al.
Sch em e 5
Sch em e 7
Sch em e 6
formed, albeit in much lower yields, but that the diaza-
dienes derived therefrom are much less stable than 33
and decompose as they are generated.24 The generation
of alkyl analogs of 33 at low temperatures under more
carefully controlled conditions nevertheless merits fur-
ther study.
from which the somewhat unstable diene 31a was
liberated with triethylamine. Heating a toluene solution
of crude 31a with excess DMAD gave 20a in over 90%
yield (Table 1). The application of this process to
N-thiobenzoylacetamidine (29b) was much less success-
ful. Liberation of 29b from its HCl salt with aqueous
sodium bicarbonate and reaction of this unstable sub-
stance with methyl iodide gave a mixture of 30b and
S-methylthiobenziminium iodide. Treatment of this
mixture with triethylamine gave a mixture containing
the even less stable diene 31b, which on subsequent
reaction with DMAD as for 31a , produced the pyrimidine
derivative 20e in low yield.
b. By Dim eth yla tion of th e Am id in e-Ca r bon
Disu lfid e Ad d u cts. Amidines form zwitterionic adducts
with carbon disulfide, and these salts, like those derived
from amines,22 should undergo sequential mono-23 and
di-S-alkylation to generate 4,4-di-S-alkyl-1,3-diaza-1,3-
butadienes as the ultimate products.24 Indeed, sequential
addition of carbon disulfide and methyl iodide to equi-
molar amounts of benzamidine and n-butyllithium pro-
duced the methyl dithio derivatives 32 (Scheme 6) as one
of the products. When this process was carried out in a
two-phase ether:water system, using sodium hydroxide
as the base, 32 was obtained in nearly quantitative yield.
Compound 32 could be S-methylated a second time under
aqueous or anhydrous conditions to give the 1,3-diaza-
1,3-diene 33 as an acid soluble (stable hydrochloride)
solid indefinitely stable at -10 °C. The entire reaction
sequence could be effected in one pot without isolation
of intermediates to produce 33 in 42% (aqueous, phase
transfer) -73% (anhydrous) overall yields. Cycloaddition
of 33 with DMAD and ethyl propiolate gave the expected
pyrimidine derivatives 34a and 34b, respectively (Table
1).
c. F r om Tr ich lor oa ceta m id in e a n d Am id e Ace-
ta ls. The facile generation of 2-phenyl-1,3-diaza-1H-1,3-
butadiene as its stable trifluoroacetic acid salt (28)
suggested that it might be possible to prepare congeners
of 28 directly from amidines or their salts and amide
acetals. We have not yet found conditions to effect this
condensation reaction in a general way, using either the
amidines or various salts thereof. The very readily
available trichloroacetamidine (35)26 is, however, an
exception. Heating a THF solution of this amidine with
a slight excess of the amide acetals 36a -c produced the
1,3-diaza-1H-1,3-butadienes 37a -c (Scheme 7) as oils
(90-100% yields) which have prolonged stability at -10
°C. These dienes react rapidly at room temperature with
DMAD to give the 2-(trichloromethyl)pyrimidines 38a ,e,g
in high yields (see Table 2) accompanied by the dimeth-
ylamine-acetylene adduct27 39a . Analogous reactions
occurred with propiolic aldehyde (12d ) at room temper-
ature and with ethyl propiolate and methyl phenyl-
propynoate (12c) under more vigorous conditions (see
Table 2).
Only one cycloaddition reaction with an activated olefin
has so far been examined. An attempt to generate
2-(trichloromethyl)pyrimidine (41, Scheme 8) from 37a
(24) Eul and Gattow23 reported that the carbon disulfide:acetamidine
adduct reacted with methyl iodide to produce, among other products,
MeC(NH2)NCS2Me, MeSCSNH2, and 2-(methylthio)-4,6-dimethyl-1,3,5-
triazine. The last two products are consistent with the formation of
the 1,3-diaza-1,3-butadiene MeC(NH)NC(SMe)2 as an intermediate.
On the basis of the results described herein, this diene is expected to
fragment to MeSCSNH2 and acetonitrile, and the latter on [4π + 2π]
cycloaddition with the diazadiene would give rise to the observed
triazine. This type of cycloaddition has been observed at least in one
instance.25
Preliminary experiments with alkylamidines, such as
n-nonanamidine or phenylacetamidine, indicate that the
mono-S-methyldithiocarbonyl analogs of 32 are readily
(25) Burger, K.; Penninger, S. Synthesis 1978, 524.
(26) Dachlauer, K. Ger. Patent 671,785, 1939; Chem. Abst. 1939,
33, 6345.1 Albert, A.; Paal, B. Chem. Ind. (London) 1974, 874.
Trichloroacetamidine is a much weaker base (pKa ) 6.5) than acet-
amidine (pKa ) 12.4; Albert, A.; Paal, B. Ibid.).
(27) Such addition products were also obtained in the cycloaddition
reactions of the diazadienes 23, 31, and 33.
(22) Chabrier, P.; Nachmias, G. Bull. Soc. Chim. Fr. 1950, D43-
D65.
(23) Eul, W.; Gattow, G. Z. Anorg. Allg. Chem. 1987, 545, 125.

Cycloaddition of 1,3-Diaza-1,3-butadienes with Acetylenes
J . Org. Chem., Vol. 61, No. 7, 1996 2475
Ta ble 2. Rea ction of 2-Tr ich lor om eth yl-4-d im eth yla m in o-1,3-d ia za -1,3-bu ta d ien es 37 w ith Electr on Deficien t
Acetylen es 12a ,b
moles of 12 per
mole of 37
CC sol system
hex:EtOAc
R1
R2
R3
temp (°C)
time (h)
prod
% yield
mp (°C)c
H
H
H
H
Me
Me
Ph
Ph
Ph
Ph
MeOOC
H
Ph
H
MeOOC
H
MeOOC
H
OMe
OEt
OMe
H
OMe
OEt
OMe
OEt
OMe
H
4
4
2
1
4
4
4
4
rt
0.5
24
30
0.5
0.5
1
0.5
3
4
4:1
4:1
9:1
85:15
9:1
9:1
85:15
9:1
9:1
9:1
38a
38b
38c
38d
38e
38f
38g
38h
38i
98
75
51
66
76
65
73
56
40
43
65-66
58-60
70
101
rt
68-69
75-76
rt
68-69
80d
rt
83-84
111-112
49-50
80
101
rt
Ph
H
2.7
1.3
165-166
1
38j
99-100e
a
b
In toluene solution except where indicated otherwise. The dimethylamine-acetylene adduct 39 was also isolated in all cases.
c Crystallized from hexane-dichloromethane mixtures unless stated otherwise. Benzene as solvent. e Crystallized from hexane-ethyl
acetate.
d
Sch em e 8
Sch em e 9
and phenyl vinyl sulfoxide (40) (toluene/101 °C) failed
and produced 2-(trichloromethyl)-4-(dimethylamino)-
1,3,5-triazine (45) as the only isolable product (20%). This
compound is suggested to arise as a consequence of a
partial fragmentation of 37a to N,N-dimethylformami-
dine (42) and trichloroacetonitrile. Cycloaddition of
trichloroacetonitrile with the diazadiene 37a would
produce the dihydrotriazine 43a , which upon tautomer-
ization to 43b, and sequential 1,5-hydrogen shift and loss
of chloroform would produce 45. Consistent with this
mechanistic proposal is that the 1,3-diaza-1,3-diene 37a
is formed (ca. 50% yield) from a mixture of trichloro-
acetonitrile and N,N-dimethylformamidine, and the tri-
azine 45 is obtained from a mixture of the diazadiene
37a and trichloroacetonitrile (83% yield).

2476 J . Org. Chem., Vol. 61, No. 7, 1996
Guzma´n et al.
% yield
Ta ble 3. 2-(Tr ich lor om eth yl)p yr im id in e 38a a n d 38b a s a Sou r ce of Oth er P yr im id in e Der iva tivesa
CC sol system
hex:EtOAc
CC sol system
hex:EtOAc
stg mat.
product(s)
% yield
stg mat.
product(s)
38a
38a
38a
38a
38a
38b
38a
38a
38b
47b
47b
48a
47b
47b
47b
48a
46a , 46b
46b, 46c
46c
47a
47b
48a
47c
47b, 49a
48a , 49b
47d
47e
48b
50a
50b
50c
51a
4:1
4:1
4:1
4:1
4:1
9:1
4:1
4:1
9:1
1:1
1:1
1:1
71,b 24
62, 14
72
48a
47b
47b
47c
50a
50b
50c
51a
51b
47c
48b
50f
47g
50a
51b
50d
50e
46c
46d
46e
46f
52a
52b
50f
51c
47g
47h
47i
4:1
4:1
4:1
4:1
4:1
4:1
9:1
9:1
9:1
7:3
4:1
1:1
4:1
9:1
82
71
71
82
62
72
85
87
80
93
92
59f
87
86
66
97c
100d
90
5, 64
23, 70
76
92e
95
72
85
71
68
4:1
85:15
85:15
9:1
a
b
All compounds, except those indicated, were oils. Solid compounds were crystallized from CH2Cl2-hexane mixtures. Mp 83-84 °C.
c Mp 65-66 °C. Mp 58-59 °C. e Mp 103-104 °C. f Mp 143-144 °C.
d
It is noteworthy that the fragmentation of 37a to N,N-
dimethylformamidine and trichloroacetonitrile is not an
unique process. This type of cleavage reaction occurs to
a greater or lessor extent with all of the 1H-1,3-diaza-
1,3-butadienes described in this study.
presence of p-dinitrobenzene.28 It is probable that the
process involves the formation and protonation of a series
of anions generated by the attack of thiophenolate on
chlorine resulting in the rapid production of 49a as the
immediate precursor of 47b. It is possible that carbenes
might be intermediates in the formation of 49a , but no
evidence for or against such species was sought.
Because of the availability of the sulfides 47b and 48a ,
the oxidation thereof to the sulfoxides 47d and 48b and
the sulfone 47e was effected using m-chloroperbenzoic
acid. These compounds, and the sulfides from which they
were derived, were sufficiently acidic to the deprotonated
by sodium hydride in DMF at room temperature. Al-
though the alkylation of all of these anions was readily
accomplished, only that of the sulfide-derived anions was
studied preparatively. Thus, monoalkylation with n-
propyl iodide or ethyl bromoacetate to 50a , 50b, and 51a ,
as well as dimethylation with methyl iodide to 50c and
51c, were effected efficiently. Furthermore, the mono-
and dialkylation of the sulfide 47b in the Michael sense
with methyl acrylate catalyzed by Triton B produced
compounds 50d and 50e uneventfully.
Several of the above sulfides, including 47c, were
reductively desulfurized with Raney nickel to the 2-alkyl-
pyrimidines 46c-f and 52a ,b (Note transesterification in
these two cases).
The sulfoxides 47d and 48b were converted into the
Pummerer products 50f and 51c by hot acetic anhydride.
We were unable to generate the aldehyde 47f from 50f
under a variety of conditions, but the oxime 47g could
be obtained under acidic conditions, and this compound
was dehydrated to the nitrile 47h with polyphosphate
ester.
III. 2-(Tr ich lor om eth yl)p yr im id in es a s P r ecu r -
sor s of Oth er 2-Su bstitu ted P yr im id in es. The tri-
chloromethyl group in 38 is quite reactive and these
compounds serve as a source of a wide variety of other
2-substituted pyrimidines. Thus, catalytic hydrogenoly-
sis of 38a at atmospheric pressure (Pd-CaCO3/Et3N) is
easily controlled to produce the 2-(dichloromethyl) and
the 2-(chloromethyl) compounds 46a and 46b selectively,
or the 2-methyl derivatives 46c exclusively (Scheme 9,
Table 3). Reaction of 38a with an equimolar amount of
methanolic sodium methoxide also took place at room
temperature to give the 2-methoxy compound 47a , pos-
sibly by the loss of trichloromethide ion. In sharp
contrast, excess sodium thiophenolate or sodium ethane-
thiolate (3 equiv) reacted rapidly to give the sulfides 47b
and 47c exclusively in near quantitative yields. Ethyl
2-(trichloromethyl)pyrimidine-5-carboxylate (38b) was
converted into the corresponding (phenylthio)methyl
compound 48a in the same manner. The efficient forma-
tion of the sulfides 47b and 48a at least requires the
presence of free thiophenol, since under otherwise identi-
cal conditions, the bis(phenylthio) compounds 49a and
49b are the major products. These compounds presum-
ably are derived from the corresponding anions by
protonolysis on workup. The bis(phenylthio) compound
49a was instantly converted into the sulfide 47b by an
equimolar amount of the 1:1 thiophenol-sodium thio-
phenolate mixture in THF at room temperature, and it
was demonstrated to be the penultimate intermediate in
the formation of the sulfide. When the reaction was
effected at -78 °C, both 49a and 47b were present in
significant amounts (TLC) by 5 min, but 49a was by far
the major species. By 10 min the 49a :47b ratio had
decreased to unity, and then it remained approximately
constant, at least up to 30 min. When this mixture was
left to warm to room temperature, 49a disappeared
completely in favor of 47b. We no longer believe that
the formation of the sulfides occurs by a radical process.13
The reaction shows no induction period; even at -78 °C,
it proceeds at the same rate in the dark or under
laboratory light and is not affected in any way by the
The sulfide 50a was selectively oxidized to the sulfoxide
46g. Thermolysis of 46g in toluene at reflux temperature
gave the trans disubstituted olefin 47i.
Su m m a r y
Methodology has been developed to prepare 1H-1,3-
diaza-1,3-butadienes in latent (17), masked (24), and
unprotected (31, 33, and 37) forms. For example, the
1-(methoxycarbonyl)-3-acylamidines 17 undergo thermal
(28) Kornblum, N.; Michel, R. E.; Kerber, R. C. J . Am. Chem. Soc.
1966, 88, 5660. Kornblum, N.; Davies, T. M.; Earl, G. W.; Holy, K. L.;
Kerber, R. C.; Musser, M. T.; Snow, D. H. J . Am. Chem. Soc. 1967, 89,
725.

Cycloaddition of 1,3-Diaza-1,3-butadienes with Acetylenes
J . Org. Chem., Vol. 61, No. 7, 1996 2477
(0.55 mL, 0.4 g, 4.0 mmol) was stirred at room temperature
for 0.5 h. The solid was removed by filtration and washed with
ethyl acetate, and the filtrate was washed with water, dried
over sodium sulfate, and evaporated in vacuo. After drying
in high vacuum compound 16 was obtained as a clear oil in
quantitative yield: IR 3472, 1595, 1580 cm-1; 1H NMR δ 2.21
(s, 3H), 3.03 (s, 3H), 7.31-7.55 (m, 3H), 8.12-8.35 (m, 2H);
13C NMR δ 21.76, 30.64, 128.50, 128.51, 129.69, 138.38, 172.75,
180.37. Anal. Calcd for C10H11N2O: C, 68.16; H, 6.86; N,
15.90. Found: C, 68.49; H, 6.83; N, 15.74.
Syn t h esis of t h e N-(Met h oxyca r b on yl)-N′-a cyla m i-
d in es 17. Methyl chloroformate (10.2 mmol) was added slowly
at room temperature to a stirred solution of the N-acylamidine
(15, 10 mmol) in anhydrous dichloromethane (10 mL) contain-
ing anhydrous pyridine (10.2 mmol) maintained in a nitrogen
atmosphere. The reaction mixture was stirred for an ad-
ditional 1-2 h, it was then diluted with dichloromethane (50
mL), and the mixture was washed with water. The organic
phase was combined with a dichloromethane extract of the
aqueous phase, dried (Na2SO4), and evaporated in vacuo. The
crude product was then subjected to column chromatographic
purification on silica gel using a hexane-ethyl acetate mixture
to elute the product.
conversion into the 1,3-diaza-1,3-dienes 18 and/or 19
which can be trapped with DMAD to produce the pyr-
imidines 20. The 1-Boc-1,3-diaza-1,3-dienes 24 are
masked forms of the corresponding 1H-dienes. They
react with DMAD under mild conditions to give the
adducts 25, which under more vigorous conditions are
aromatized to the pyrimidines 26 by loss of Me2NH, CO2,
and isobutylene. The readily preparable 1H-1,3-diaza-
1,3-dienes 31, 33, and 37 all react with electron deficient
acetylenes under mild conditions to produce the pyrim-
idines 20, 34, and 38, respectively. The (trichlorometh-
yl)pyrimidines 38 are versatile precursors of numerous
other 2-substituted pyrimidines 46-52.
Finally, the facile generation of the relatively stable
1H-1,3-diaza-1,3-butadienes 31, 33, and 37 now makes
it possible to undertake a detailed study of other reac-
tions and properties of these compounds.
Exp er im en ta l Section
The 1H NMR were measured on 90 or 200 MHz instruments
in CDCl3 solution (except where stated otherwise) and are
reported in δ (ppm) from internal tetramethylsilane. 13C NMR
spectra were also recorded in CDCl3 solution. High resolution
mass spectra were obtained on samples which were judged to
be at least of 90% purity by TLC and 1H NMR spectroscopy.
The IR spectra were measured in CHCl3 solution unless
specified otherwise. The melting points are not corrected.
The following compounds were prepared by the literature
methods cited: N-benzoylbenzamidine (15a ),3 N-acetylbenz-
amidine (15c),29 N-benzoylacetamidine (15e),30 1-(ethoxycar-
bonyl)formamidine hydrobromide,31 1,1-bis(ethoxycarbonyl)-
formamidine hydrochloride,31 N-thiobenzoylbenzamidine (29a ),8
hydrochloride salt of N-thiobenzoylacetamidine (29b),32 hy-
drochloride salt of N,N-dimethylformamidine (42).33
N-(Met h oxyca r b on yl)-N′-b en zoylben za m id in e (17a ).
Hexane-ethyl acetate (4:1) eluted the product as a solid in
72% yield. After crystallization from hexane-dichloromethane
it had mp 79-80 °C; IR (KBr) 3120, 1753, 1634 cm-1; 1H NMR
δ 3.78 (s, 3H), 7.41-7.66 (m, 6H), 7.71-7.82 (m, 2H), 8.08-
8.26 (m, 2H); mass spectrum m/ z 282 (32, M+), 223 (15), 205
(13), 105 (100), 77 (39). Anal. Calcd for C16H14N2O3: C, 68.08;
H, 5.00; N, 9.92. Found: C, 67.92; H, 4.95; N, 9.76.
N-(Met h oxyca r b on yl)-N′-(4-m et h ylb en zoyl)b en za m i-
d in e (17b). Hexane-ethyl acetate (85:15) eluted the product
as a solid (80% yield) which after crystallization from hexane-
dichloromethane had mp 120-122 °C; IR (KBr) 3202, 1762,
1624 cm-1; 1H NMR δ 2.43 (s, 3H), 3.77 (s, 3H), 7.29 (d, 2H, J
) 8.0 Hz), 7.41-7.61 (m, 2H), 7.77 (d, 2H, J ) 8.0 Hz), 7.89-
8.18 (m, 2H); mass spectrum m/ z 296 (16, M+), 119 (100), 91
(32). Anal. Calcd for C17H16N2O3: C, 68.90; H, 5.44; N, 9.45.
Found: C, 68.05; H, 5.48; N, 9.41.
N-(Meth oxycar bon yl)-N′-acetylben zam idin e (17c). Elut-
ed from the column with hexane-ethyl acetate (4:1) as a solid
in 86% yield. After crystallization from hexane-dichloro-
methane it had mp 118-119 °C; IR (KBr) 3251, 1720, 1676
cm-1; 1H NMR δ 2.29 (s, 3H), 3.77 (s, 3H), 7.38-7.62 (m, 5H),
9.11-9.72 (bs, 1H); mass spectrum m/ z 219 (98, M+ - 1), 205
(100), 147 (65), 104 (56). Anal. Calcd for C11 H12N2O3: C,
59.99; H, 5.49; N, 12.72. Found: C, 59.87; H, 5.36; N, 12.67.
The spectroscopic data not found in the Experimental
Section is located in Table 4 of the supporting information.
N-(4-Meth ylben zoyl)ben za m id in e (15b). This compound
was prepared from benzamidine hydrochloride and 4-methyl-
benzoyl chloride using the method described by Chua et al.30
for the preparation of N-benzoylacetamidine (15e). After
crystallization of the crude product from hexane-ethyl acetate
pure 15b was obtained in 78% yield as a solid: mp 101-102
1
°C; IR 3460, 3215, 1590, 1562, 1553 cm-1; H NMR δ 2.42 (s,
3H), 7.26 (d, 2H, J ) 8.0 Hz), 7.47-7.65 (m, 3H), 8.05-8.14
(m, 2H), 8.29 (d, 2H, J ) 8.0 Hz); mass spectrum m/ z 238
(30, M+), 119 (100), 91 (40). Anal. Calcd for C15H14N2O: 0.125
H2O: C, 74.89; H, 5.97; N, 11.65. Found: C, 74.76; H, 5.83;
N, 11.64.
N-(Met h oxyca r b on yl)-N′-b en zoyla cet a m id in e (17e).
Prepared in the general manner except that triethylamine was
used instead of pyridine. Chromatographic purification of this
material was not necessary. The pure material, obtained in
75% yield after crystallization from hexane-dichloromethane,
1-Meth yl-3-ben zoyla ceta m id in e (16). A solution of N-
benzoylacetamidine (15e, 1.0 g, 6.2 mmol) in dimethyl sulfate
(3 mL) was stirred at room temperature for 15 h. The reaction
mixture was washed with hexane to remove the excess
dimethyl sulfate, and the solid residue was washed with ether.
Crystallization of this solid from methanol gave the metho-
sulfate salt of 16 as a solid (1.5 g, 89% yield) with mp 174-
175 °C; IR (KBr) 3260, 3142, 1693, 1662, 1550, 1544 cm-1; 1H
NMR (DMSO d6) δ 2.57 (s, 3H), 3.24 (s, 3H), 3.43 (s, 3H), 7.54-
7.83 (m, 3H), 7.98-8.13 (m, 2H); mass spectrum m/ z 176 (35;
M+, free base), 175 (100), 105 (78), 99 (50). Anal. Calcd for
C10H12N2O‚HSO4Me: C, 45.82; H, 5.59; N, 9.71. Found: C,
45.80; H, 5.59; N, 9.72.
1
had mp 50-52 °C; IR (KBr) 3371, 3182, 1761, 1657 cm-1; H
NMR δ 2.63 (s, 3H), 3.80 (s, 3H), 7.32-7.62 (m, 3H), 7.90-
8.25 (m, 2H); mass spectrum m/ z 220 (20, M+), 219 (35), 105
(100). Anal. Calcd for C11H12N2O3: C, 59.99; H, 5.49; N, 12.72.
Found: C, 60.00; H, 5.64; N, 12.82.
Syn th esis of Dim eth yl 2-P h en ylp yr im id in e-4,5-d ica r -
b oxyla t es (20a -c) b y Th er m olysis of N-(Met h oxyca r -
bon yl)-N′-a cylben za m id in es (17a -c) in th e P r esen ce of
Dim eth yl Acetylen ed ica r boxyla te. A solution of 17 (1
equiv) and DMAD (2 equiv) in anhydrous o-dichlorobenzene
(5-10 mL/mmol 17) was heated at 150 °C (N2
atmosphere)
for 24-28 h. The solution was absorbed onto a column of silica
gel, and the solvent was eluted with hexane. The product was
then eluted from the column with the appropriate hexane-
ethyl acetate mixture. See Table 1 for product yields.
A suspension of the above salt (0.580 g, 2.0 mmol) in
anhydrous THF (10 mL) containing anhydrous triethylamine
(29) Cherkasov, V. N.; Dashevskaya, T. A. Ukr. Khim. Zh. 1973,
39, 1155; Chem. Abstr. 1974, 80, 47616x.
(30) Chua, S.-W.; Cook, M. J .; Katritzky, A. R. J . Chem. Soc., Perkin
Trans. 2 1974, 546.
(31) Schaefer, F. C. J . Org. Chem. 1962, 27, 3608.
(32) Goerdeler, J .; Porrmann, H. Chem. Ber. 1961, 94, 2856.
(33) Matterstock, K.; J ensen, H. Ger. Patent 1,168,896, 1964; Chem.
Abstr. 1964, 61, 6991f. J entzsch, W.; Seefedler, M. Chem. Ber. 1965,
98, 1342.
Dim et h yl 2,6-Dip h en ylp yr im id in e-4,5-d ica r b oxyla t e
(20a ). Eluted from the column with hexane-ethyl acetate (9:
1) to give the product as a solid, which, after crystallization
from hexane-dichloromethane, had mp 144-145 °C; IR 1728
cm-1 13C NMR δ 53.00, 53.48, 123.02, 128.64, 128.91, 130.66,
;
131.75, 136.12, 136.99, 154.94, 164.62, 164.94, 165.40, 167.37;
mass spectrum m/ z 348 (70, M+), 333 (100), 273 (34), 232 (95).

2478 J . Org. Chem., Vol. 61, No. 7, 1996
Guzma´n et al.
Anal. Calcd for C20H16N2O: C 68.95; H, 4.63; N, 8.04.
Found: C, 68.87; N, 4.58; N, 8.02.
3471, 3407, 1724, 1667, 1632 cm-1
;
1H NMR δ 1.27 (t, 3H),
1.40 (2, 9H), 4.20 (q, 2H), 8.16-8.82 (bs, 2H); mass spectrum
m/ z 217 (100, M+), 135 (25). Anal. Calcd for C9H16N2O4: C,
49.98; H, 7.45; N, 12.95. Found: C, 50.08; H, 7.33; N, 12.94.
Dim eth yl 2-P h en yl-6-(4-m eth ylp h en yl)p yr im id in e-4,5-
d ica r boxyla te (20b). Eluted from the column with hexane-
ethyl acetate (95:5) to give a solid, which after crystalliztion
from hexane-dichloromethane, had mp 134-135 °C. Anal.
Calcd for C21H18N2O4: C, 69.60; H, 5.00; N, 7.73. Found: C,
69.57; H, 5.01; N, 7.64.
Dim eth yl 2-P h en yl-6-m eth ylp yr im id in e-4,5-d ica r box-
yla te (20c). Eluted from the column with hexane-ethyl
acetate (9:1) as a solid, which after crystallization from
hexane-dichloromethane, had mp 88-89 °C; 13C NMR δ 23.78,
53.51, 53.85, 123.31, 129.14, 129.37, 132.18, 136.56, 155.39,
165.12, 165.76 (2), 167.12, 167.96; mass spectrum m/ z 286 (50,
M+), 256 (20), 227 (15), 198 (30), 170 (100). Anal. Calcd for
C15H14N2O4: C, 62.93; H, 4.92; N, 9.78. Found: C, 62.85; H,
4.95; N, 9.73.
N-(ter t-Bu toxyca r bon yl)-2-(d ieth oxym eth yl)for m a m i-
d in e (23d ). 2-(Diethoxymethyl)formamidine hydrochloride
was converted into the corresponding N-(tert-butoxycarbonyl)
compound 23d in the same manner as described for the
synthesis of 23c. After crystallization from hexane-dichloro-
methane pure 23d was obtained in 97% yield and had mp 75-
77 °C; IR 3476, 3329, 1737, 1663, 1625 cm-1 13C NMR δ 14.92,
;
27.98, 63.10, 100.12, 163.84, 167.85; mass spectrum m/ z 247
(22, MH+), 191 (100), 147 (50), 103 (62). Anal. Calcd for
C11H22N2O4: C, 53.63; H, 9.00; N, 11.37. Found: C, 53.41; H,
9.08; N, 11.42.
N-(Meth oxyca r bon yl)ben za m id in e (23e). This com-
pound was prepared in the same manner as described for
compound 23b except that methyl chloroformate was used as
the acylating agent. After crystallization of the crude product
from hexane-dichloromethane pure 23e was obtained in 85%
yield and had mp 95-98 °C; IR 3498, 3311, 1659, 1613, 1579
cm-1; mass spectrum m/ z 178 (50, M+), 163 (18), 147 (100),
120 (45), 104 (60), 77 (40). Anal. Calcd for C9H10N2O2: C,
60.65; H, 5.65; N, 15.72. Found: C, 60.59; H, 5.70; N, 15.76.
Syn th esis of th e 1-(Alkoxycar bon yl)-4-(dim eth ylam in o)-
1,3-d ia za -1,3-bu ta d ien es (24). A solution of the N-(alkoxyl-
carbonyl)amidine 23 (1 equiv) in anhydrous THF (1-7 mL/
mmol 23) containing dimethylformamide dimethyl acetal (1.1-
1.5 equiv) was heated at reflux temperature for 2-5 h. The
solution was then diluted with ethyl acetate, and it was
washed with saturated NaCl solution, dried (Na2SO4), and
evaporated in vacuo.
Dim eth yl 2-P h en ylp yr im id in e-4,5-d ica r boxyla te (20d )
w ith ou t Isola tion of (17d ). Because of the pronounced
tendency of N-formylbenzamidine (15d ) to be converted into
2,4-diphenyl-s-triazine under formylation conditions,34 this
substance was generated and used directly for the synthesis
of 20d without isolation of either 15d or 17d . Thus, 50 wt %
aqueous sodium hydroxide (1.6 mL) was added dropwise at 0
°C to a stirred suspension of benzamidine hydrochloride (1.56
g, 10 mmol) in acetone (50 mL), and after 5 min freshly
prepared formic acid anhydride (10 mmol) was added. The
reaction mixture was stirred for an additional 2 h at 0 °C. The
presence of diphenyl-s-triazine at this stage was confirmed by
TLC (silica gel). An additional quantity of 50% sodium
hydroxide (0.8 mL) was added followed by dropwise addition
of methyl chloroformate (0.8 mL, 0.98 g, 10 mmol). After a
further 2 h at 0 °C, ethyl acetate (50 mL) was added to the
reaction mixture, and the organic phase was separated,
washed with saturated NaCl solution, and dried (Na2SO4).
Evaporation of the solvent in vacuo gave a residue which was
dissolved in o-dichlorobenzene (10 mL), DMAD (1.2 mL, 1.39
g, 9.8 mmol) was added, and the solution was then heated at
100 °C in a nitrogen atmosphere for 15 h. The solution was
then worked up as described above for 20a -c. Compound 20d
was eluted from the column as a solid, which after crystal-
lization from hexane-dichloromethane, had mp 115-116 °C;
1-(ter t-Bu toxyca r bon yl)-2-p h en yl-4-(d im eth yla m in o)-
1,3-d ia za -1,3-bu ta d ien e (24b). Obtained in quantitative
yield as an oil: IR 1695, 1636, 1590, 1572 cm-1; H NMR δ
1
1.43 (s, 9H), 3.01 (s, 3H), 3.05 (s, 3H), 7.32-7.36 (m, 3H), 7.77-
7.82 (m, 2H), 7.92 (s, 1H); 13C NMR δ 28.52, 35.12, 41.15, 80.75,
128.42, 129.15, 131.07, 137.00, 156.13, 162.69; 166.24; mass
spectrum m/ z 275 (10, M+), 202 (13), 176 (60), 57 (100). Anal.
Calcd for C15 H21N3O2: C, 65.43; H, 7.69; N, 15.26. Found:
C, 65.56; H, 7.74; N, 15.59.
1-(t er t -Bu t oxyca r b on yl)-2-(e t h oxyca r b on yl)-4-(d i-
m eth yla m in o)-1,3-d ia za -1,3-bu ta d ien e (24c). Obtained in
1
IR (KBr) 1733, 1569, 1540 cm-1; H NMR δ 3.96 (s, 3H), 4.04
(s, 3H), 7.46-7.55 (m, 3H), 8.50-8.54 (m, 2H), 9.32 (s, 1H);
13C NMR δ 53.47; 53.77, 118.93, 129.55, 129.74, 132.82, 136.20,
159.98, 160.11, 164.08, 166.22, 167.35; mass spectrum m/ z 272
(55, M+), 241 (15), 213 (30), 184 (45), 156 (100). Anal. Calcd
for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29. Found: C, 61.57;
H, 4.33; N, 10.19.
quantitative yield as an oil: IR 1736, 1668, 1154, 1531 cm-1
;
1H NMR δ 1.33 (t, 3H), 1.51 (s, 9H), 3.06 (s, 3H), 3.10 (s, 3H),
4.26 (q, 2H), 8.35 (s, 1H); 13C NMR δ 13.83, 28.01, 41.21, 62.09,
80.71, 158.01, 163.41, 166.10, 168.29; FAB HRMS calcd for
C22H22N3O4 272.1610, found 272.1618 (MH+).
1-(t er t -Bu t oxyca r b on yl)-2-(d ie t h oxym e t h yl)-4-(d i-
m eth yla m in o)-1,3-d ia za -1,3-bu ta d ien e (24d ). Obtained in
N-(ter t-Bu toxyca r bon yl)ben za m id in e (23b). A solution
of sodium hydroxide (1.0 g, 25 mmol) in water (20 mL) was
added dropwise at 0 °C to a stirred suspension of benzamidine
hydrochloride (1.56 g, 10 mmol) in THF (20 mL), and di-tert-
butyl dicarbonate (2.2 g, 10 mmol) was added immediately
thereafter. After 1 h at 0 °C, ethyl acetate was added, and
the organic phase was separated, washed with saturated NaCl
solution, dried (Na2SO4), and evaporated in vacuo. Crystal-
lization of the solid residue from hexane-dichloromethane
gave pure 23b (2.0 g, 91% yield) mp 102-103 °C; IR 3497,
quantitative yield as an oil: IR 1704, 1583 cm-1; H NMR δ
1
1.24 (t, 6H), 1.52 (s, 9H), 3.02 (s, 3H), 3.06 (s, 3H), 3.58-3.78
(m, 4H), 4.98 (s, 1H), 8.41 (s, 1H); 13C NMR δ 15.08, 28.04,
40.74, 63.24, 80.18, 102.65, 157.48, 161.90, 162.35. Anal.
Calcd for C14H27N3O4: C, 55.79; H, 9.03, N, 13.94. Found: C,
55.70; H, 9.34; N, 13.88.
1-(Meth oxyca r bon yl)-2-p h en yl-4-(d im eth yla m in o)-1,3-
d ia za -1,3-bu ta d ien e (24e). Obtained in quantitative yield
as an oil: IR 1702, 1633, 1589, 1570 cm-1; 1H NMR δ 3.06 (s,
3H), 3.10 (s, 3H), 3.77 (s, 3H), 7.32-7.48 (m, 3H), 7.75-7.91
(m, 2H), 7.96 (s, 1H); 13C NMR δ 34.78, 40.76, 52.83, 128.05,
128.62, 130.79, 136.28, 156.14, 163.63, 166.97; mass spectrum
m/ z 233 (18, M+), 201 (100), 118 (30), 104 (35); FAB HRMS
calcd for C12H16N3O2 234.1243, found 234.1231 (MH+).
1-(ter t-Bu toxyca r bon yl)-2-p h en yl-4-(d im eth yla m in o)-
1,3-d ia za -1,3-p en ta d ien e (27). A solution of the N-acylated
amidine 23b (0.440 g, 2 mmol) in dry THF (10 mL) containing
N,N-dimethylacetamide dimethyl acetal (0.6 mL, 0.55 g, 4
mmol) was heated at reflux temperature for 5 h. The crude
product was obtained in quantitative yield as a solid, which
on crystallization from hexane-ethyl acetate had mp 99-100
°C; IR 1702, 1620, 1576 cm-1; 1H NMR δ 1.52 (s, 9H), 1.96 (s,
3H), 3.07 (s, 6H), 7.31-7.42 (m, 3H), 7.82-8.01 (m, 2H); 13C
NMR δ 18.18, 28.05, 38.06, 79.71, 127.91, 128.51, 130.95,
136.05, 157.62, 162.58, 164.53; mass spectrum m/ z 289 (3,
3310, 1611, 1578 cm-1 13C NMR δ 28.07, 79.51, 127.11, 128.39,
;
131.69, 134.84, 163.86, 167.31; mass spectrum m/ z 220 (5,
M+), 165 (100), 147 (45), 104 (45). Anal. Calcd for
C12H16N2O2: C, 65.43; H, 7.32; N, 12.72. Found: C, 65.45; H,
7.40; N, 12.77.
N-(ter t-Bu toxyca r bon yl)-1-(eth oxyca r bon yl)for m a m i-
d in e (23c). Triethylamine (0.72 mL, 0.52 g, 5.2 mmol) was
added dropwise to stirred suspension of 1-(ethoxycarbonyl)-
formamidine hydrobromide (0.985 g, 5.0 mmol) in anhydrous
THF (15 mL) containing 4-(dimethylamino)pyridine (0.06 g,
0.5 mmol) and di-tert-butyl dicarbonate (1.10 g, 5.0 mmol) at
room temperature (N2 atmosphere). After 2 h the reaction
mixture was worked up as described for 23b above giving the
product as a somewhat unstable oil in quantitative yield: IR
(34) Bredereck, H.; Effenberger, F.; Hofmann, A. Chem. Ber. 1963,
96, 3265.

Cycloaddition of 1,3-Diaza-1,3-butadienes with Acetylenes
J . Org. Chem., Vol. 61, No. 7, 1996 2479
M+), 216 (21), 57 (100). Anal. Calcd for C16H23N3O2: 0.2
H2O: C, 65.59; H, 8.05; N, 14.34. Found: C, 65.85; H, 8.09;
N, 14.18.
Triethylamine (0.5 mL, 0.36 g, 3.6 mmol) was added to a
suspension of 30a (0.690 g, 1.81 mmol) in ethyl acetate (20
mL) with stirring. The solution was then washed with
saturated NaCl solution, dried over sodium sulfate, and
evaporated in vacuo giving 31a as a somewhat unstable solid
in quantitative yield: 1H NMR δ 2.66 (s, 3H), 7.57 (m, 6H),
8.06 (m, 2H), 8.40 (m, 2H), 8.81 (m, 4H). This material was
used without purification for the synthesis of 20a .
Syn th esis of Dim eth yl 2,6-Dip h en ylp yr im id in e-4,5-
d ica r boxyla te (20a ) fr om 31a a n d DMAD. A solution of
the diazadiene 31a (0.460 g, 1.81 mmol) in toluene (20 mL)
containing DMAD (0.5 mL, 0.58 g, 4.1 mmol) was heated at
reflux temperature (N2 atmosphere) for 4 h. The solvent was
removed in vacuo, and the residue was purified by column
chromatophraphy on silica gel using hexane-ethyl acetate to
elute solid 20a (0.580 g, 92%) identical in all respects to that
obtained by the methods described above.
Syn th esis of P yr im id in e Der iva tives fr om 1-(ter t-
Bu toxycar bon yl)-1,3-diaza-1,3-dien es 24 an d 27 an d Acet-
ylen ic Ester s. A solution of the diazadiene (1 equiv) in
toluene (1-5 mL/mmol diene) containing the acetylenic ester
(4 mol/mol diene) was heated at reflux temperature in a
nitrogen atmosphere for 24-48 h. The solvent was removed
in vacuo, and the residue was purified by column chromatog-
raphy on silica gel using a hexane-ethyl acetate or hexane-
acetone mixtures to elute the product (Table 1 for yields).
Eth yl 2-P h en ylp yr im id in e-5-ca r boxyla te (26c). This
reaction was carried out in a sealed tube at 120 °C for 24 h.
The product was eluted from the column with hexane-ethyl
acetate (9:1) as a solid, which after crystallization from
hexane-dichloromethane, had mp 95-97 °C; IR 1723, 1589
cm-1; 1H NMR δ 1.42 (t, 3H), 4.44 (q, 2H), 7.49-7.53 (m, 3H),
8.49-8.53 (m, 2H), 9.30 (s, 2H); 13C NMR δ 61.61, 121.00,
128.67, 128.91, 131.74, 136.59, 158.35 (2), 163.94, 167.00; mass
spectrum m/ z 228 (95, M+), 200 (35), 183 (98), 103 (100). Anal.
Calcd for C13H12N2O2: C, 68.41; H, 5.30; N, 12.27. Found: C,
68.18; H, 5.28, N, 12.04.
Syn th esis of Dim eth yl 2-Meth yl-6-p h en ylp yr im id in e-
4,5-d ica r boxyla te (20e) w ith ou t Isola tion of In ter m ed i-
a tes 29b, 30b, a n d 31b. N-Thiobenzoylacetamidine hydro-
chloride (5.7 g, 26.5 mmol) was stirred with a mixture of
saturated NaHCO3 solution (50 mL) and ethyl acetate (50 mL).
After 5 min, the organic phase was separated, dried (Na2SO4),
and evaporated in vacuo to give crude 29b. A solution of crude
29b (0.400 g, 2.24 mmol) in anhydrous acetone (5 mL)
containing methyl iodide (0.15 mL, 0.36 g, 2.5 mmol) was
stirred at room temperature (N2 atmosphere) for 15 h. The
solvent was removed in vacuo, and the solid residue was
washed with ether and dried in vacuo giving a mixture of 30b
and S-methylthiobenzimidate hydriodide (0.32 g). This mix-
ture was suspended in ethyl acetate (10 mL) containing
triethylamine (0.55 mL, 0.4 g, 4 mmol) and stirred at room
temperature for 10 min. The mixture was washed with
saturated NaCl solution, and the organic phase was dried
(Na2SO4) and evaporated in vacuo giving an oily mixture of
31b and S-methylthiobenzimidate. The crude mixture of
methyl thiobenzimidate and the diazadiene 31b in anhydrous
toluene (5 mL/mmol mixture) containing DMAD (4 mmol/mmol
crude 31b) was heated at reflux temperature (N2 atmosphere)
for 18 h. The solvent was removed in vacuo, and the residue
was subjected to column chromatograhy on silica gel using
hexane-ethyl acetate (85:15) to elute 20e as a solid (7-11%)
which, after crystallization from hexane-dichloromethane,
Dim eth yl 2-(Eth oxyca r bon yl)p yr im id in e-4,5-d ica r box-
yla te (26d ). Eluted from the column with hexane-ethyl
acetate (7:3) as a solid which, after crystallization from
hexane-ethyl acetate, had mp 112-114 °C; mass spectrum
m/ z 237 (25, M+ - OMe), 196 (100), 164 (60), 152 (40), 59
(65). Anal. Calcd for C11H12N2O6: C, 49.25; H, 4.51; N, 10.45.
Found: C, 49.43; H, 4.60; N, 10.38.
Dim eth yl 2-(Dieth oxym eth yl)p yr im id in e-4,5-d ica r box-
yla te (26e). Eluted from the column with hexane-acetone
(9:1) as an oil; 1H NMR δ 1.27 (t, 6H), 3.66-3.82 (m, 4H), 3.94
(s, 3H), 4.02 (s, 3H), 5.63 (s, 1H), 9.34 (s, 1H); mass spectrum
m/ z 267 (10, M+ - OMe), 254 (15), 225 (70), 193 (90), 193
(90), 137 (40), 103 (100). Anal. Calcd for C13H18N2O6: C,
52.34; H, 6.08; N, 9.39. Found: C, 52.21; H, 6.47; N, 9.53.
Syn th esis of Dim eth yl 2-P h en ylp yr im id in e-4,5-d ica r -
b oxyla t e (20d ) fr om 2-P h en yl-4-(d im et h yla m in o)-1,3-
d ia za -1,3-bu ta d ien iu m Tr iflu or oa ceta te (28). Trifluoro-
acetic acid (10 mL) was added to a stirred solution of the Boc
diene 24b (1.00 g, 3.6 mmol) in dichloromethane (20 mL) at 0
°C. Stirring at 0-15 °C was continued for 2 h, and then the
solvent was removed in vacuo at room temperature. The
residue 28 was dissolved in dichloromethane (30 mL) and
cooled to 0 °C (N2 atmosphere). DMAD (4 mL) was added to
the stirred solution, and then a solution of triethylamine (1.1
mL, 0.8 g, 8 mmol) in dichloromethane (30 mL) was added
dropwise. The solution was allowed to reach room tempera-
ture, and a further quantity of triethylamine (1.0 mL, 0.73 g,
7.3 mmol) was added. The solution turned yellow in color and
an exothermic reaction commenced. The reaction mixture was
placed in an ice-water bath until the reaction subsided, and
then it was left at room temperature for 1 h. The solvent was
removed in vacuo, and the residue was subjected to column
chromatographic purification on silica gel using hexane-ethyl
acetate (88:12) to elute the solid product (0.438 g, 44% yield)
which was identical in all respects to compound 20d prepared
by the methods described above.
Syn th esis of 2,4-Dip h en yl-4-(m eth ylth io)-1,3-d ia za -1,3-
bu ta d ien iu m Iod id e (30a ) a n d 2,4-Dip h en yl-4-(m eth -
ylth io)-1,3-d ia za -1,3-bu ta d ien e (31a ). A solution of N-
thiobenzoylbenzamidine (29a , 0.480 g, 2.0 mmol) in anhydrous
acetone (5 mL) containing methyl iodide (0.13 mL, 0.3 g, 2
mmol) was stirred at room temperature in a nitrogen atmo-
sphere for 15 h. The solvent was removed in vacuo, and the
crystalline residue was washed with ether and dried in vacuo.
Crystalline 30a (0.520 g, 91% yield) thus obtained, on recrys-
tallization from dichloromethane-ether, had mp 155-156 °C
dec; 1H NMR (DMSO-d6) δ 2.73 (s, 3H), 7.52-7.66 (m, 8H),
8.02-8.06 (d, 2H, J ) 7.7 Hz); 13C NMR (DMSO-d6) δ 16.05,
127.32, 127.55, 129.37, 129.60, 129.88, 133.32, 133.72, 135.84,
172.17, 179.16; mass spectrum m/ z 254 (8, M+, free base), 253
(40), 239 (58), 104 (100), 77 (37). Anal. Calcd for C15H14N2S:
HI: C, 47.13; H, 3.95; N, 7.32. Found: C, 47.00; H, 4.03; N,
7.32.
1
had mp 75-77 °C; IR (KBr) 1739, 1717, 1554 cm-1; H NMR
δ 2.90 (s, 3H), 3.80 (s, 3H), 4.03 (s, 3H), 7.47-7.52 (m, 3H),
7.66-7.71 (m, 2H); mass spectrum m/ z 286 (44, M+), 271 (100),
255 (24), 170 (78). Anal. Calcd for C15H14N2O4: C, 62.93; H,
4.92; N, 9.78. Found: C, 62.85; H, 4.95; N, 9.73.
N-[(Meth ylth io)th ioca r bon yl]ben za m id in e (32). (a ) n -
Bu tyllith iu m a s Ba se. n-Butyllithium (38 mL of a 2.5 M
solution in THF, 95.0 mmol) was added dropwise to a solution
of benzamidine (13.1 g, 109.2 mmol) in anhydrous THF (375
mL, freshly distilled from sodium benzophenone ketyl) at -20
°C (N2 atmosphere) over a 5 min period. After a further 5 min,
carbon disulfide (5.2 mL, 6.4 g, 84.1 mmol) was added and the
temperature was allowed to reach 0 °C. Methyl iodide (5.65
mL, 13.1 g, 92.3 mmol) was added all at once to the clear yellow
solution, and the reaction temperature was allowed to rise to
ambient temperature. After 0.5 h, the reaction was quenched
with saturated NH4Cl solution, ether was added, and the
organic phase was separated and combined with an ether
extract of the aqueous phase. The combined organic phases
were dried (Na2SO4) and evaporated in vacuo. The residue
was purified by column chromatrography on silica gel, and the
product was eluted with hexane-ethyl acetate (9:1 f 4:1) to
give 32 as a yellow solid (5.45 g, 31% yield based on CS2) which,
after crystallization from hexane-ether, had mp 97-98 °C;
IR (KBr) 3420, 1597, 1578 cm-1; 1H NMR (300) δ 2.60 (s, 3H),
7.43-7.48 (m, 2H), 7.52-7.58 (m, 1H), 7.89-7.93 (m, 2H); 13
C
NMR δ 19.03, 127.56 (2), 128.90 (2), 132.60, 134.35, 161.60,
218.79; mass spectrum m/ z 210 (15, M+), 163 (100), 104 (43).
Anal. Calcd for C9H10N2S2: C, 51.39; H, 4.79; N, 13.32.
Found: C, 51.30; H, 4.75; N, 13.35.
(b) Sod iu m Hyd r oxid e a s Ba se in a Tw o-P h a se Eth er -
Wa ter Solven t System . Benzamidine hydrochloride hydrate
(15.0 g, 85.9 mmol) was suspended in ether (500 mL) and

2480 J . Org. Chem., Vol. 61, No. 7, 1996
Guzma´n et al.
saturated aqueous bicarbonate solution (100 mL) was added
all at once. The amidine hydrochloride dissolved. To the
stirred two-phase mixture were added carbon disulfide (20 mL,
24.6 g, 323 mmol), methyl iodide (20 mL, 45.6 g, 321 mmol),
and sodium hydroxide (15 g, 375 mmol) sequentially. After
4.5 h the bright yellow ether phase was separated from the
colorless aqueous layer. It was dried (Mg SO4) and evaporated
in vacuo to give 32 as a solid (17.7 g, 98% yield) identical in
all respects to that prepared by method a.
2-P h en yl-4,4-b is(m et h ylt h io)-1,3-d ia za -1,3-b u t a d ien e
(33). (a ) F r om Com p ou n d 32. n-Butyllithium [2.0 mL of a
2.5 M solution in THF (5.0 mmol)] was added to a stirred
solution of compound 32 (1.00 g, 4.75 mmol) in anhydrous THF
(20 mL, distilled from sodium benzophenone ketyl) at -20 °C
(N2 atmosphere). After 5 min, methyl iodide (0.4 mL, 0.91 g,
6.4 mmol) was added and the solution was stirred for 20 min.
The reaction mixture was quenched with saturated NH4Cl
solution, ether was added, and the organic phase was sepa-
rated, dried (Na2SO4), and evaporated in vacuo to give an oil,
in quantitative yield, which was a solid in the refrigerator:
1H NMR (300) δ 2.50 (s, 6H), 7.38-7.45 (m, 3H), 7.83-7.85
(m, 2H); 13C NMR δ 15.11, 127.55, 128.34, 130.98, 134.25,
165.33, 169.14; HRMS calcd for C10H11N2S2 223.0364, found
223.0361 (M - H)+, HRMS calcd for C9H9N2S2 209.0207, found
209.0204 (M - Me)+.
14.21, 61.46, 118.68, 128.55 (2), 131.65, 136.76, 158.01, 164.33,
172.70. Anal. Calcd for C14H14N2O2S: C, 61.29; H, 5.14; N,
10.21. Found: C, 61.36; H, 5.15; N, 10.28.
Syn t h esis of t h e 2-(Tr ich lor om et h yl)-4-(d im et h yl-
a m in o)-1,3-d ia za -1,3-d ien es (37). A solution of trichloro-
acetamidine (1 equiv) in anhydrous THF (2.5 mL/mmol 35)
containing the appropriate amide acetal (1 equiv) was heated
at 40-50 °C (N2 atmosphere) for 2-3 h. Excess ethyl acetate
was added, and the solution was washed with saturated NaCl
solution, dried (Na2SO4), and evaporated in vacuo.
2-(Tr ich lor om eth yl)-4-(d im eth yla m in o)-1,3-d ia za -1,3-
bu ta d ien e (37a ). Obtained in quantitative yield as an oil
which, though unstable at room temperature, can be stored
at -10 °C for prolonged periods with only minor decomposition;
IR 3316, 1634, 1587 cm-1; 1H NMR δ 3.06 (s, 3H), 3.08 (s, 3H),
8.20 (bs, 1H), 8.30 (s, 1H); 13C NMR δ 35.42, 41.35, 97.61,
157.93, 168.74. A satisfactory elemental analysis could not
be obtained due to contamination with varying amounts of the
amidine 42 and the triazine 45. Anal. Calcd for C5H8Cl3N3:
C, 27.74; H, 3.72; N, 19.41. Found: C, 27.27; H, 3.22; N, 20.01.
2-(Tr ich lor om eth yl)-4-(d im eth yla m in o)-1,3-d ia za -1,3-
p en ta d ien e (37b). Obtained in 91% yield as an oil: 13C NMR
δ 15.71, 38.28, 38.75, 98.14, 160.78, 167.24. Anal. Calcd for
C6H10Cl3N3: C, 31.26; H, 4.37; N, 18.23. Found: C, 31.22; H,
4.57; N, 18.52.
The hydrochloride salt was obtained by adding a slight
excess of ethereal 1 N hydrogen chloride to an ether solution
of 33. The mixture was evaporated to dryness, and the residue
was crystallized from ethyl acetate-methanol to give material
with mp 162-165 °C dec; 13C NMR δ 17.01 (2), 126.76, 129.47
(2), 130.07 (2), 135.38, 171.25, 179.92. Anal. Calcd for
C10H12N2S2‚HCl: C, 46.05; H, 5.02; N, 10.74. Found: C, 45.97;
H, 5.05; N, 10.68.
2-(Tr ich lor om eth yl)-4-(d im eth yla m in o)-4-p h en yl-1,3-
d ia za -1,3-bu ta d ien e (37c). Obtained in 96% yield as an oil:
1H NMR δ 3.11 (s, 3H), 3.22 (s, 3H), 2.72-7.35 (m, 3H), 7.96-
8.10 (m, 2H). It was not possible to obtain an analytically pure
sample of this compound because it was always contaminated
with N,N-dimethylbenzamide (ca 5%) derived from hydrolysis
of the amide acetal 36c. It was therefore used without further
purification.
(b) F r om Ben za m id in e in a On e-P ot Rea ction . n-
Butyllithium [(56.7 mL of a 1.49 M solution in THF (84.5
mmol)] was added at 0 °C to a stirred solution of benzamidine
(10.2 g, 84.7 mmol) in freshly distilled anhydrous THF (250
mL, N2 atmosphere). Precipitation of a white solid occurred.
Carbon disulfide (5.1 mL, 6.27 g, 82.4 mm) was added with
stirring, giving a red-brown solution, and then methyl iodide
(5.3 mL, 12.0 g, 84.6 mmol) was added. After 10 min, a further
quantity of n-butyllithium solution (56.7 mL) was added
followed by more methyl iodide (10.0 mL, 22.8 g, 161 mmol),
and the reaction mixture was stirred for 0.5 h. The reaction
mixture was worked up as described in a to give a solid (13.5
g, 73% based on CS2) identical in all respects to compound 33
obtained as described above.
Syn th esis of 2-(Tr ich lor om eth yl)-4-(d im eth yla m in o)-
1,3-d ia za -1,3-bu ta d ien e (37a ) fr om Tr ich lor oa ceton itr ile
a n d N,N-Dim eth ylfor m a m id in e (42). 1,3-Diazabicyclo-
[5.4.0]undec-7-ene (0.75 mL, 0.76 g, 5.0 mmol) was added to a
stirred suspension of N,N-dimethylformamidine hydrochloride
(0.553 g, 5.1 mmol) in anhydrous THF (10 mL) containing
trichloroacetonitrile (0.5 mL, 0.72 g, 5.0 mmol) at room
temperature (N2 atmosphere). After stirring for 2 h, the
reaction mixture was diluted with ethyl acetate, water was
added, and the organic phase was separated. The organic
phase was washed with saturated NaCl solution, dried
(Na2SO4), and evaporated in vacuo to give 37a as an oil (0.563
g, 52% yield) identical in all respects to material obtained as
described above.
Dim et h yl 2-P h en yl-6-(m et h ylt h io)p yr im id in e-4,5-d i-
ca r boxyla te (34a ). A solution of the diazadiene 33 (0.67 g,
2.99 mmol) in neat DMAD (2.5 mL) was heated at 55 °C for 1
h. The mixture thus produced was subjected to column
chromatography on silica gel using hexane-dichloromethane
to elute the product (0.62 g, 65% yield) which on crystallization
from hexane had mp 140-141 °C; IR (KBr) 1757, 1725, 1528
Syn th esis of 2-(Tr ich lor om eth yl)p yr im id in es 38 by
Cycloa d d ition of Dia za d ien es 37 a n d Electr on Acety-
len es 12. A solution of the diazadiene 37 in anhydrous toluene
or benzene (3-8 mL/mmol 37) containing the activated
acetylene 12 (1-4 molar equiv/mol of 37; see Table 2), in a
nitrogen atmosphere, was maintained at the temperature and
for the time indicated in Table 2. The solvent was removed
in vacuo and the pure pyrimidine was obtained by column
chromatography on silica using a hexane-ethyl acetate mix-
ture (see Table 2) as the eluant. Crystalline pyrimidines were
recrystallized from the solvent mixtures indicated in Table 2.
Dim et h yl 2-(Tr ich lor om et h yl)p yr im id in e-4,5-d ica r -
cm-1 13C NMR δ 13.75, 52.83, 53.14, 128.57 (2), 129.07 (2),
;
131.98, 156.40, 163.67, 164.77, 165.66, 172.45. Anal. Calcd
for C15H14N2O4S: C, 56.59; H, 4.43; N, 8.80. Found: C, 56.31;
H, 4.48; N, 8.54.
Eth yl 2-P h en yl-4-(m eth ylth io)p yr im id in e-5-ca r boxyl-
a te (34b). A solution of the diene 33 (freshly prepared from
the hydrochloride salt (1.00 g, 3.83 mmol) by partitioning it
between ether and saturated NaHCO3 solution, followed by
drying (MgSO4) and evaporation of the ether in vacuo) in
toluene (10 mL) was added dropwise to a solution of ethyl
propiolate (2.0 mL, 1.94 g, 20 mmol) in toluene (20 mL) at
reflux temperature (N2 atmosphere). The solution was heated
at reflux temperature for 1.5 h after the addition was com-
pleted. At this time an additional 10 mmol of ethyl propiolate
was added and 1 h thereafter the cooled solution was evapo-
rated in vacuo. The residue was purified by flash column
chromatography on silica gel using hexane-dichloromethante
(4:1 to 2:1 to 1:1) to elute the solid ester 34b (0.33 g, 31% yield)
which on crystallization from hexane gave pure 34b (0.27 g,
1
boxyla te (38a ): IR 1742, 1572 cm-1; H NMR δ 4.01 (s, 3H),
4.06 (s, 3H), 9.41 (s, 1H); 13C NMR δ 54.28, 54.42, 95.89,
122.00, 160.27, 160.79; 163.13, 164.19. Anal. Calcd for
C9H7Cl3N2O4: C, 34.47; H, 2.25; Cl, 33.92; N, 8.93. Found:
C, 34.58; H, 2.23; Cl, 33.99; H, 8.86.
E t h yl 2-(Tr ich lor om et h yl)p yr im id in e-5-ca r b oxyla t e
(38b): IR 1733, 1588 cm-1 1H NMR δ 1.43 (t, 3H), 4.48 (q,
;
2H), 9.40 (s, 2H); 13C NMR δ 14.60, 62.81, 96.44, 124.47, 159.38
(2), 162.94, 168.39. Anal. Calcd for C8H7Cl3N2O2: C, 35.65;
H, 2.61; Cl, 39.46; N, 10.39. Found: C, 35.44; H, 2.71; Cl,
39.62; N, 10.44.
Met h yl 2-(Tr ich lor om et h yl)-4-p h en ylp yr im id in e-5-
ca r boxyla te (38c): IR 1736, 1600, 1567 cm-1 13C NMR δ
;
26% yield): mp 79-80 °C; IR (KBr) 1709, 1557, 1512 cm-1
;
53.15, 96.12, 123.97, 128.73, 129.37, 131.41, 136.09, 159.43,
166.07, 166.16, 166.21; HRMS calcd for C13H935Cl3N2O2
329.9730, found 329.9738.
1H NMR (300) δ 1.43 (t, 3H), 2.68 (s, 3H), 4.43 (q, 2H), 7.48-
7.55 (m, 3H), 8.50-8.55 (m, 2H), 9.08 (s, 1H); 13C NMR δ 13.53,

Cycloaddition of 1,3-Diaza-1,3-butadienes with Acetylenes
J . Org. Chem., Vol. 61, No. 7, 1996 2481
2-(Tr ich lor om eth yl)pyr im idin e-5-car boxaldeh yde (38d):
suspended 5% Pd/CaCO3 (0.315 g) was hydrogenated at room
temperature and atmospheric pressure for 3 h. The reaction
mixture was then worked up as described above for 46a giving
dimethyl 2-methylpyrimidine-4,5-dicarboxylate as an oil: IR
1
IR 1726, 1567, 1534 cm-1; H NMR δ 9.35 (s, 2H), 10.21 (s,
1H); 13C NMR δ 96.02, 128.21, 159.49, 168.90, 188.05. Anal.
Calcd for C6H3Cl3N2O:0.33 CH2Cl2: C, 29.88; H, 1.46; Cl, 47.17.
Found: C, 30.09; H, 1.30; Cl, 47.43.
Dim et h yl 2-(Tr ich lor om et h yl)-6-m et h ylp yr im id in e-
4,5-d ica r boxyla te (38e). Anal. Calcd for C10H9Cl3N2O4: C,
36.66; H, 2.76; Cl, 32.42; N, 8.55. Found: C, 36.92; H, 2.72;
Cl, 32.30; N, 8.58.
1
1738, 1574, 1534 cm-1; H NMR δ 2.80 (s, 3H), 3.91 (s, 3H),
3.97 (s, 3H), 9.14 (s, 1H); 13C NMR δ 26.69, 53.48, 53.82,
119.10, 159.51, 160.26, 164.06, 165.85, 172.09. Anal. Calcd
for C9H10N2O4: C, 51.43; H, 4.80; N, 13.33. Found: C, 51.43;
H, 4.84; N, 13.16.
Eth yl 2-(Tr ich lor om eth yl)-4-m eth ylp yr im id in e-5-ca r -
Dim eth yl 2-Meth oxypyr im idin e-4,5-dicar boxylate (47a).
A solution of 38a (0.313 g, 1.0 mmol) in anhydrous methanol
(5 mL) containing sodium methoxide [prepared from sodium
(0.023 g, 1.0 mmol)] was stirred at room temperature (N2) for
5 h. Sufficient acetic acid was then added to give a neutral
solution, and the solvent was removed in vacuo. After
purification of the crude product by column chromatography,
pure 47a was obtained as an oil: 13C NMR δ 53.25, 53.74,
56.60, 115.00, 162.78, 163.03, 163.71, 165.88, 167.22. Anal.
Calcd for C9H10N2O5: C, 47.78; H, 4.45; N, 12.38. Found: C,
47.72; H, 4.42; N, 12.28.
Syn th esis of 2-[(P h en ylth io)m eth yl]p yr im id in es fr om
2-(Tr ich lor om eth yl)p yr im id in es. Thiophenol (6.6 equiv)
was added to a suspension of sodium hydride (3.3 equiv,
prepared from a 50% suspension of NaH in mineral oil; washed
free of mineral oil with dry hexane) in anhydrous THF (1-3
mL/mmol pyrimidine derivative) in a nitrogen atmosphere.
After ca. 10 min the (trichloromethyl)pyrimidine 38a or 38b
(1 equiv) was added, and the reaction mixture was stirred at
room temperature for 15 min. Sufficient acetic acid was then
added to give a neutral solution and then a large volume of
ehtyl acetate was added. The solution was washed succes-
sively with water and saturated NaCl solution, and it was
dried (Na2SO4) and evaporated in vacuo. The product was
then obtained from the residue by column chromatography on
silica gel.
Dim eth yl 2-[(P h en ylth io)m eth yl]p yr im id in e-4,5-d ica r -
boxyla te (47b): 13C NMR δ 41.46, 53.14, 53.40, 119.35, 126.91,
128.96, 130.32, 134.64, 159.10, 159.42, 163.33, 165.04, 170.85;
mass spectrum m/ z 318 (100, M+), 303 (20), 386 (15), 226 (15),
200 (40). Anal. Calcd for C15H14N2O4S: C, 56.59; H, 4.43; N,
8.79; S, 10.07. Found: C, 56.51; H, 4.39; N, 8.69; S, 10.09.
E t h yl 2-[(P h en ylt h io)m et h yl]p yr im id in e-5-ca r b ox-
yla te (48a ): 13C NMR δ 14.14, 41.41, 61.77, 122.02, 128.56,
128.83, 129.57, 134.97, 163.48, 171.00; mass spectrum m/ z 274
(100, M+), 259 (25), 241 (22), 213 (45). Anal. Calcd for
C14H14N2O2S: C, 61.29; H, 5.14; N, 10.21; S, 11.68. Found:
C, 61.20; H, 5.12; N, 10.13; S, 11.96.
Dim eth yl 2-[(Eth ylth io)m eth yl]p yr im id in e-4,5-d ica r -
boxyla te (47c). A suspension of sodium hydride in mineral
oil (50%, 0.173 g, 3.6 mmol) was washed free of the carrier
with dry hexane (N2) and layered with anhydrous THF (15
mL), and ethanethiol (0.25 mL, 0.205 g, 3.3 mmol) dissolved
in anhydrous THF (2 mL) was added. The reaction mixture
was stirred at room temperature for 1 h and then worked up
as described for 47b and 48a above: 13C NMR δ 14.47, 26.48,
38.70, 53.57, 53.84, 119.64, 159.65, 159.93, 163.85, 165.64,
172.39; mass spectrum m/ z 270 (12, M+), 239 (10), 210 (100),
178 (45), 150 (90). Anal. Calcd for C11H14N2O4S: C, 48.87;
H, 5.22; N, 10.36; S, 11.86. Found: C, 48.90; H, 5.26; N, 9.99;
S, 11.62.
Syn th esis of th e [Bis(p h en ylth io)m eth yl]p yr im id in es
fr om th e (Tr ich lor om eth yl)p yr im id in es. The appropriate
(trichloromethyl)pyrimidine (1 equiv) was added to a solution
of sodium thiophenolate (3.3 equiv, prepared as described
above from equimolar quantitites of sodium hydride and
thiophenol) in anhydrous THF (5.25 mL/mmol (trichloro-
methyl)pyrimidine). The reaction mixture was stirred at room
temperature (N2 atmosphere) for 15 min and then worked up
as described above to give a mixture of the bis(phenylthio)
(major) and mono(phenylthio) (minor) compounds which was
separated by column chromatography on silica gel.
1
boxyla te (38f): H NMR δ 1.42 (t, 3H), 2.92 (s, 3H), 4.44 (q,
2H), 9.25 (s, 1H); 13C NMR δ 14.68, 25.01, 62.63, 96.58, 123.82,
160.00, 164.29, 166.66, 170.80. Anal. Calcd for C9H9-
Cl3N2O2: C, 38.12; H, 3.19; Cl, 37.51; N, 9.88. Found: C,
38.42; H, 3.27; Cl, 37.28; N, 9.68.
Dim et h yl 2-(Tr ich lor om et h yl)-6-p h en ylp yr im id in e-
4,5-d ica r boxyla te (38g). Anal. Calcd for C15H11Cl3N2O4: C,
46.23; H, 2.84; Cl, 27.30; N, 7.19. Found: C, 46.30; H, 2.87;
Cl, 27.01; N, 7.14.
Eth yl 2-(Tr ich lor om eth yl)-4-p h en ylp yr im id in e-5-ca r -
boxyla te (38h ): 13C NMR δ 14.21, 62.91, 96.22, 129.04, 129.79,
131.66, 136.62, 159.75, 166.12, 166.37, 166.59; HRMS calcd
for C14H1135Cl3N2O2 343.9886, found 343.9886.
Meth yl 2-(Tr ich lor om eth yl)-4,6-d ip h en ylp yr im id in e-
5-ca r boxyla te (38i). Anal. Calcd for C19H13Cl3N2O2: C,
55.97; H, 3.21; Cl, 26.08; N, 6.87. Found: C, 55.90; H, 3.09;
Cl, 26.27; N, 6.92.
2-(Tr ich lor om e t h yl)-4-p h e n ylp yr im id in e -5-ca r b ox-
a ld eh yd e (38j): 13C NMR δ 96.03, 125.55, 129.28, 130.79,
132.03, 133.89, 159.24, 166.99, 168.45, 188.97; FAB HRMS
calcd for C12H935Cl3N2O 300.9702, found 300.9707 (MH+).
Syn t h esis of 2-(N,N-Dim et h yla m in o)-4-(t r ich lor o-
m eth yl)-1,3,5-tr ia zin e (45) fr om Tr ich lor oa ceton itr ile
a n d Dia za d ien e (37a ). A solution of the diazadiene 37a
(0.2165 g, 1.0 mmol) in toluene (2 mL) containing trichloro-
acetonitrile (0.22 ml, 0.289 g, 2.0 mmol) was left at room
temperature for 4 h. The solvent was removed in vacuo, and
the residue was purified by column chromatography on silica
gel using hexane-ethyl acetate (9:1) to elute the product (0.195
g, 83% yield) as a solid. Crystallization of this material from
hexane-dichloromethane gave pure 45 with mp 71-73 °C; 1H
NMR δ 3.28 (s, 3H), 3.30 (s, 3H), 8.70 (s, 1H); 13C NMR δ 36.97,
37.12, 96.60, 164.89, 167.22, 172.72. Anal. Calcd for C6H7-
Cl3N4: C, 29.84; H, 2.92; Cl, 44.03. Found: C, 29.90; H, 2.86;
Cl, 43.81.
Dim eth yl 2-(Dich lor om eth yl)p yr im id in e-4,5-d ica r box-
yla te (46a ). A solution of the (trichloromethyl)pyrimidine 38a
(0.470 g, 1.5 mmol) in ethyl acetate (10 mL) containing
triethylamine (0.66 mL, 0.455 g, 4.5 mmol) and suspended 5%
Pd/CaCO3 (0.250 g) was hydrogenated at atmospheric pressure
at room temperature until 1 mmol of hydrogen had been
absorbed. The mixture was filtered through Celite, the filter
cake was washed with ethyl acetate, and the filtrate was
washed with water, dried (Na2SO4), and evaporated in vacuo.
The residue was separated by column chromatography on
silica gel using hexane-ethyl acetate to give the dichloro
compound 46a (0.300 g) and the monochloro compound 46b
(0.090 g). See Table 3 for column chromatographic solvent
systems, product yields, mps, etc. Pure 46a was a solid: 13C
NMR δ 53.95, 54.12, 70.18, 121.95, 159.93, 160.90, 163.13,
164.85, 167.92. Anal. Calcd for C9H8Cl2N2O4: C, 38.73; H,
2.88; Cl, 25.40; N, 10.03. Found: C, 38.73; H, 2.83; Cl, 25.14;
N, 9.99.
For data for 46b see below.
Dim et h yl 2-(Ch lor om et h yl)p yr im id in e-4,5-d ica r b ox-
yla te (46b). This compound was prepared in the same
manner as described for 46a except that the hydrogenolysis
was conducted until 2 molar equiv of hydrogen had been
absorbed. Chromatographic separation gave 46c (see below)
as the minor product and 46b as the major product: 13C NMR
δ 46.50, 53.80, 54.02, 120.86, 159.75, 160.28, 163.57, 165.28,
168.93. Anal. Calcd for C9H9ClN2O4: C, 44.18; H, 3.70; Cl,
14.49; N, 11.45. Found: C, 44.25; H, 3.70; Cl, 14.17; N, 11.15.
Dim eth yl 2-Meth ylp yr im id in e-4,5-d ica r boxyla te (46c).
A solution of 38a (0.630 g, 2 mmol) in methanol (50 mL)
containing triethylamine (2.0 mL, 1.82 g, 18 mmol) and
Dim eth yl 2-[Bis(p h en ylth io)m eth yl]p yr im id in e-4,5-d i-
ca r boxyla te (49a ): 13C NMR δ 53.33, 53.51, 62.91, 119.60,
128.64, 129.17, 133.01, 133.47, 159.27, 159.70, 163.27, 164.92,
171.09; mass spectrum m/ z 426 (15, M+), 317 (100), 284 (55).

2482 J . Org. Chem., Vol. 61, No. 7, 1996
Guzma´n et al.
Anal. Calcd for C21H18N2O4S2: C, 59.13; H, 4.25; N, 6.56; S,
15.03. Found: C, 59.03; H, 4.29; N, 6.48; S, 14.75.
14.91, 20.67, 36.11, 54.91, 61.73, 121.93, 127.20, 128.76,
131.92, 134.25, 158.20 (2), 163.65, 174.41; mass spectrum m/ e
316 (55, M+), 283 (100), 274 (60), 207 (42), 179 (65). Anal.
Calcd for C17H20N2O2S: C, 64.52; H, 6.37; N, 8.85; S, 10.11.
Found: C, 64.50; H, 6.34; N, 8.83; S, 10.14.
Eth yl 2-[1-(P h en ylth io)-1-m eth yleth yl]p yr im id in e-5-
ca r boxyla te (51b). From methyl iodide (4 equiv): 13C NMR
δ 14.46, 28.05, 54.35, 61.94, 121.67, 128.67, 129.26, 132.15,
137.02, 157.89 (2), 164.08, 176.85; mass spectrum m/ z 302 (25,
M+), 257 (5), 193 (100), 165 (58). Anal. Calcd for
C16H18N2O2S: C, 63.54; H, 5.99; N, 9.26; S, 10.60. Found: C,
63.49; H, 6.10; N, 9.19; S, 10.68.
Mich a el Ad d ition of Su lfid e 47b to Meth yl Acr yla te.
A solution of 47b (1 equiv) in anhydrous acetonitrile (2.5 mL/
mmol 47b) containing ethyl acrylate (1 or 2 equiv) and Triton
B (100 µL/mmol 47b) was stirred at room temperature (N2
atmosphere) for 3 h. The reaction was quenched with acetic
acid and diluted with ethyl acetate, and then saturated NaCl
solution was added. The organic phase was separated, dried
(Na2SO4), and evaporated in vacuo, and the product was
recovered from the residue by column chromatography on silica
gel.
Dim eth yl 2-[1-(P h en ylth io)-3-(m eth oxyca r bon yl)p r o-
p yl]p yr im id in e-4,5-d ica r boxyla te (50d ): 13C NMR δ 28.52,
31.65, 51.85, 53.22, 53.41, 54.51, 119.27, 128.07, 129.05,
133.19, 132.97, 159.29, 159.45, 163.43, 165.22, 173.05, 173.21;
mass spectrum m/ z 404 (100, M+), 373 (38), 331 (43). Anal.
Calcd for C19H20N2O6S: C, 56.42; H, 4.98; N, 6.92; S, 7.92.
Found: C, 56.52; H, 4.97; N, 6.84; S, 7.78.
Eth yl 2-[Bis(p h en ylth io)m eth yl]p yr im id in e-5-ca r box-
yla te (49b): 13C NMR δ 14.02, 61.75, 62.52, 122.13, 128.10,
128.10, 128.79, 132.31, 132.66, 132.78, 133.06, 157.26 (2),
163.13, 171.15; mass spectrum m/ z 382 (10, M+), 273 (100),
240 (70), 212 (42). Anal. Calcd for C20H18N2O2S2: C, 62.80;
H, 4.74; N, 7.32; S, 16.26. Found: C, 62.57; H, 4.53; N, 7.16;
S, 16.20.
Oxid a tion of th e [(P h en ylth io)m eth yl]p yr im id in e to
t h e Cor r esp on d in g Su lfoxid es or Su lfon es. m-Chloro-
perbenzoic acid (80%, 1 or 2 equiv) was added to a stirred
solution of the sulfide (1 molar equiv) in anhydrous dichloro-
methane (3-5 mL/mmol sulfide) at 0 °C (N2 atmosphere), and
agitation was continued for 0.5 h. The solution was diluted
with dichloromethane, extracted with saturated aqueous
NaHCO3 solution, and dried (Na2SO4). The solvent was
removed in vacuo, and the residue was subjected to column
chromatographic separation on silica gel to give the product.
Dim eth yl 2-[(P h en ylsu lfin yl)m eth yl]p yr im id in e-4,5-
d ica r boxyla te (47d ): 13C NMR δ 53.08, 53.21, 66.07, 119.78,
123.96, 129.14, 131.47, 142.77, 158.96, 159.20, 162.98, 164.45
(2); mass spectrum m/ z 334 (70, M+), 303 (20), 286 (100), 125
(55). Anal. Calcd for C15H14N2O5S: C, 53.88; H, 4.22; N, 8.38;
S, 9.59. Found: C, 53.98; H, 4.28; N, 8.26; S, 9.38.
Dim eth yl 2-[(P h en ylsu lfon yl)m eth yl]p yr im id in e-4,5-
d ica r boxyla te (47e): 13C NMR δ 53.47, 53.51, 65.51, 120.51,
128.68, 129.30, 134.26, 138.51, 159.23, 159.63, 162.51, 163.14,
164.54; mass spectrum m/ z 319 (15, M+ - MeO), 285 (100),
168 (15). Anal. Calcd for C15H14N2O6S: C, 51.42; H, 4.02; N,
7.99; S, 9.14. Found: C, 51.21; H, 4.00; N, 8.00; S, 9.13.
Eth yl 2-[(P h en ylsu lfin yl)m eth yl]p yr im id in e-5-ca r box-
Dim eth yl 4-(P h en ylth io)-4-[3,4-(bism eth oxyca r bon yl)-
1
p yr im id in -2-yl]h ep ta n e-1,7-d ioa te (50e): H NMR δ 2.44
(m, 8H), 3.66 (s, 6H), 3.96 (s, 3H), 3.97 (s, 3H), 7.06-7.39 (m,
5H), 9.17 (s, 1H); mass spectrum m/ z 490 (18, M+), 459 (20),
381 (100), 349 (85), 275 (50). Anal. Calcd for C23H26N2O8S:
C, 56.31; H, 5.34; N, 5.71; S, 6.53. Found: C, 56.20; H, 5.25;
N, 5.88; S, 6.32.
1
yla te (48b): H NMR δ 1.43 (t, 3H), 4.33-4.57 (m, 4H), 9.22
(s, 2H); mass spectrum m/ z 290 (38, M+), 242 (100), 213 (22),
125 (95). Anal. Calcd for C14H14N2O3S: C, 57.91; H, 4.85; N,
9.65; S, 11.04. Found: C, 57.61; H, 4.90; N, 9.47; S, 10.92.
Alk yla tion of th e [(P h en ylth io)m eth yl]p yr im id in es
w ith Alk yl Ha lid es. To a stirred suspension of sodium
hydride (1 or 3 equiv, from 50% suspension in mineral oil
which had been washed with dry hexane) in anhydrous DMF
(5-7.5 mL/mmol sulfides) was added the sulfide (1 equiv) at
room temperature (N2 atmosphere). After stirring for about
10 min, the alkyl halide (see below for molar equivalents used)
was added and stirring was continued for 4-15 h. The
reaction was quenched by the addition of saturated aqueous
NH4Cl, and the product was extracted into ethyl acetate. The
extract was washed with water and dried (Na2SO4), the solvent
was removed in vacuo, and the product was separated from
the residual mixture by column chromatography on silica gel.
Dim eth yl 2-[1-(P h en ylth io)bu tyl]p yr im id in e-4,5-d ica r -
boxyla te (50a ). From n-propyl iodide (1 equiv): 1H NMR δ
0.92 (t, 3H), 1.21-1.62 (m, 2H), 1.83-2.29 (m, 2H), 3.94 (s,
3H), 3.99 (s, 3H), 4.50 (t, 1H), 7.20-7.33 (m, 5H), 9.18 (s, 1H);
13C NMR δ 13.89, 20.86, 35.93, 53.22, 53.44, 55.06, 119.15,
127.77, 129.00, 132.72, 133.83, 159.24, 159.44, 163.59, 165.38,
174.29; mass spectrum m/ z 360 (74, M+), 327 (100), 251 (32),
191 (33). Anal. Calcd for C18H20N2O4S: C, 59.98; H, 5.59; N,
7.77. Found: C, 59.46; H, 5.64; N, 7.39.
Red u ctive Desu lfu r iza tion of P yr im id in es w ith Ra n ey
Nick el. Raney nickel (1-1.5 g/mmol pyrimidine) was added
portionwise to a solution of the pyrimidine derivative in
methanol (10 mL/mmol pyrimidine) at reflux temperature. The
mixture was then stirred at reflux temperature for 0.5 -1 h,
the mixture was filtered through Celite, the filter cake was
washed with methanol, and the filtrate was evaporated in
vacuo. The product was isolated from the residue by column
chromatography on silica gel.
Dim eth yl 2-n -Bu tylpyr im idin e-4,5-dicar boxylate (46d):
13C NMR δ 13.77, 22.42, 30.48, 39.29, 52.92, 53.26, 118.57,
158.95, 163.64, 165.51, 175.02; HRMS calcd for C12H16N2O4
252.1110, found 252.1114.
Dim eth yl 2-[2-(Eth oxyca r bon yl)eth yl]p yr im id in e-4,5-
d ica r boxyla te (46e): 13C NMR δ 14.08, 31.25, 33.78, 52.94,
53.21, 60.49, 118.84, 158.84, 158.94, 163.48, 165.31, 172.36,
172.73; mass spectrum m/ z 296 (38, M+), 265 (35), 251 (78),
223 (100), 191 (62). Anal. Calcd for C13H16N2O6: C, 52.96;
H, 5.44; N, 9.45. Found: C, 52.73; H, 5.42; N, 9.28.
Dim et h yl 2-Isop r op ylp yr im id in e-4,5-d ica r b oxyla t e
(46f): IR 1737, 1574 cm-1; 1H NMR δ 1.38 (d, 6H), 3.33 (sept,
1H), 3.96 (s, 3H), 4.03 (s, 3H), 9.22 (s, 1H); 13C NMR δ 21.41
(2), 37.88, 52.95, 53.28, 118.50, 159.03 (2), 163.66, 165.70,
178.91; mass spectrum m/ z 238 (38, M+), 223 (100), 206 (90),
120 (70). Anal. Calcd for C11H14N2O4: C, 55.45; H, 5.92; N,
11.75. Found: C, 55.79; H, 5.45; N, 11.35.
Meth yl 2-n -Bu tylp yr im id in e-5-ca r boxyla te (52a ). Es-
ter interchange took place in this desulfurization: 1H NMR δ
0.95 (t, 3H), 1.41 (m, 2H), 1.82 (m, 2H), 3.03 (t, 2H), 3.97 (s,
3H), 9.19 (s, 1H); mass spectrum m/ z 194 (10, M+), 165 (25),
152 (100), 121 (18). Anal. Calcd for C10H14N2O2: C, 61.84;
H, 7.26; N, 14.42. Found: C, 61.89; H, 7.26; N, 13.97.
Meth yl 2-Isopr opylpyr im idin e-5-car boxylate (52b). Es-
ter interchange occurred in this desulfurization reaction: 1H
NMR δ 1.38 (d, 6H), 3.31 (sept, 1H), 3.98 (s, 3H), 9.21 (s, 2H);
13C NMR δ 21.49 (2), 37.92, 52.48, 121.26, 158.09 (2), 164.45,
179.14; mass spectrum m/ z 180 (22, M+), 165 (100), 152 (22).
Anal. Calcd for C9H12N2O2: C, 59.98; H, 6.71; N, 15.54.
Found: C, 60.11; H, 6.83; N, 15.27.
Dim eth yl 2-[1-(P h en ylth io)-2-(eth oxyca r bon yl)eth yl]-
p yr im id in e-4,5-d ica r b oxyla t e (50b ). From ethyl bromo-
1
acetate (1 equiv): IR 1734, 1571, 1549 cm-1; H NMR δ 1.16
(t, 3H), 3.05 (dd, J ) 6.0, 16.0 Hz, 1H), 3.34 (dd, J ) 10.0,
16.0 Hz, 1H), 3.94 (s, 3H), 3.98 (s, 3H), 4.06 (q, 2H), 4.88 (dd,
J ) 6.0, 10.0 Hz, 1H), 7.23-7.36 (m, 5H), 9.16 (s, 1H); mass
spectrum m/ z 404 (100, M+), 331 (30), 249 (18). Anal. Calcd
for C19H20N2O6S: C, 56.42; H, 4.98; N, 6.92; S, 7.92. Found:
C, 56.25; H. 5.01; N, 6.83; S, 7.70.
Dim eth yl 2-[1-(P h en ylth io)-1-m eth yleth yl]p yr im id in e-
4,5-d ica r boxyla te (50c). From methyl iodide (8 equiv): 13C
NMR δ 27.45 (2), 52.98, 53.11, 53.89, 118.06, 128.48, 129.14,
131.35, 136.94, 158.64, 158.80, 163.48, 165.41, 176.19; mass
spectrum m/ z 346 (40, M+), 237 (100), 205 (45), 177 (60). Anal.
Calcd for C17H18N2O4S: C, 58.19; H, 5.31; N, 7.98. Found: C,
58.37; H, 5.22; N, 7.90.
E t h yl 2-[1-(P h en ylt h io)b u t yl]p yr im id in e-5-ca r b ox-
yla te (51a ). From n-propyl iodide (1 equiv): 13C NMR δ 13.67,

Cycloaddition of 1,3-Diaza-1,3-butadienes with Acetylenes
J . Org. Chem., Vol. 61, No. 7, 1996 2483
P u m m er er Rea ction w ith Su lfoxid es 47d a n d 48b. A
solution of the sulfoxide in acetic anhydride (5 mL/mmol
sulfoxide) was heated at 100 °C (N2 atmosphere) for 1-2 h.
The solvent was removed in vacuo, and the product was
obtained from the residue by column chromatography on silica
gel.
for 18 h. The chloroform was removed in vacuo, the residue
was partitioned between ethyl acetate and water, and the
organic phase was washed with saturated NaCl solution, dried
(Na2SO4), and evaporated in vacuo. The product was obtained
from the residue by column chromatography on silica gel: IR
2252, 1744, 1564, 1547 cm-1 13C NMR δ 53.85, 53.90, 114.48,
;
123.62, 146.18, 159.34, 159.98, 162.05, 163.33; mass spectrum
m/ z 221 (15, M+), 191 (100), 163 (20). Anal. Calcd for
C9H7N3O4: C, 48.82; H, 3.19; N, 18.99. Found: C, 48.71; H,
3.21; N, 19.01.
Dim eth yl 2-[1-Acetoxy-1-(p h en ylth io)m eth yl]p yr im i-
d in e-4,5-d ica r boxyla te (50f): IR 1740, 1572 cm-1; 1H NMR
δ 2.21 (s, 3H), 3.97 (s, 3H), 4.02 (s, 3H), 7.10 (s, 1H), 7.30-
7.52 (m, 5H), 9.18 (s, 1H); 13C NMR δ 21.14, 53.42, 53.57, 81.93,
120.25, 129.26, 129.34, 130.44, 134.62, 159.51, 163.21, 164.93,
167.92, 169.92; mass spectrum m/ z 376 (10, M+), 267 (10), 225
(100), 193 (50). Anal. Calcd for C17H16N2O6S: C, 54.25; H,
4.28; N, 7.44; S, 8.51. Found: C, 54.16; H, 4.32; N, 7.35; S,
8.58.
Eth yl 2-[1-Acetoxy-2-(p h en ylth io)m eth yl]p yr im id in e-
5-ca r boxyla te (51c): IR 1731, 1587 cm-1; 1H NMR δ 1.41 (t,
3H), 2.20 (s, 3H), 4.43 (q, 2H), 7.10 (s, 1H), 7.30-7.49 (m, 5H),
9.20 (s, 2H); 13C NMR δ 14.40, 21.20, 62.21, 82.21, 123.03,
129.24, 130.70, 134.45, 158.62, 163.41, 168.22, 170.09; mass
spectrum m/ z 332 (15, M+), 181 (100), 153 (15), 110 (22). Anal.
Calcd for C16H16N2O4S: C, 57.81; H, 4.85; N, 8.43; S, 9.64.
Found: C, 57.76; H, 4.86; N, 8.19; S, 9.70.
Oxim e of Dim eth yl 2-F or m ylp yr im id in e-4,5-d ica r box-
yla te (47g). A solution of compound 50f (0.376 g, 1.0 mmol)
in formic acid (5 mL containing hydroxylamine hydrochloride
(0.140 g, 2.0 mmol) was heated at reflux temperature (N2
atmosphere) for 5 h. The solvent was removed in vacuo, and
the product was obtained from the residue by column chro-
matography on silica gel: 13C NMR δ 52.75, 52.90, 128.09,
147.03, 158.90, 159.10, 162.76, 162.83, 164.57; mass spectrum
m/ z 239 (30, M+), 209 (99), 207 (100), 179 (70). Anal. Calcd
for C9H9N3O5: C, 45.19; H, 3.79; N, 17.56. Found: C, 44.96;
H, 3.76; N, 17.31.
Dim eth yl 2-(tr a n s-bu ten -1-yl)p yr im id in e-4,5-d ica r box-
yla te (47i). A solution of compound 50a (0.300 g, 0.83 mmol)
in anhydrous dichloromethane (5 mL) was cooled to 0 °C (N2
atmosphere) and 80% m-chloroperbenzoic acid (0.180 g, 0.83
mmol) was added with stirring. After 15 min the reaction
mixture was worked up as described above for the synthesis
of 47d ,e, etc. The crude sulfoxide 46g was dissolved in dry
toluene and heated at 100 °C for 1 h. The solvent was removed
in vacuo, and the residue was purified by column chromatog-
raphy on silica gel: 1H NMR δ 1.55 (t, 3H), 2.38 (q, 2H), 3.94
(s, 3H), 4.02 (s, 3H), 6.63 (dt, 1H, J ) 15.5 Hz, 2.0 Hz), 7.48
(dt, 1H, J ) 15.5 Hz, 6.5 Hz), 9.18 (s, 1H); 13C NMR δ 12.51,
26.03, 52.94, 53.31, 117.84, 127.60, 148.88, 159.24, 159.37,
163.67, 165.71, 167.15; mass spectrum m/ z 250 (60, M+), 235
(28), 190 (35), 160 (38), 132 (100). Anal. Calcd for
C12H14N2O4: C, 57.59; H, 5.64; N, 11.20. Found: C, 57.02; H,
5.68; N, 10.75.
Ack n ow led gm en t. The authors are very grateful to
Drs. Aaron B. Miller and Daniel L. Severance for
generating the stereoscopic views of compounds 17b and
17c (22c).
Su p p or tin g In for m a tion Ava ila ble: Miscellaneous spec-
troscopic data for 20a -c, 23b,d ,e, 26d ,e, 30, 33, 34a ,b, 37b,
38c,e-g,i,j, 46a ,b,d ,e, 47a -e,g,i, 48a ,b, 49a ,b, 50a ,c-e, 51a ,b,
and 52a (6 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.
Dim eth yl 2-Cya n op yr im id in e-4,5-d ica r boxyla te (47h ).
The above oxime (0.100 g, 0.41 mmol) was dissolved in a
chloroform solution of polyphosphate ester (10 mL)35 and the
solution was heated at reflux temperature (N2 atmosphere)
(35) Cava, M. P.; Lakshmikanthan, M. V.; Mitchell, M. J . J . Org.
Chem. 1969, 34, 2665.
J O952106W