N-functionalized benzotriazole-1-carboximidoyl chlorides: Synthetic equivalents for isocyanide dichlorides

Article abstract of DOI:10.1021/jo001685o

Readily prepared N-functionalized benzotriazole-1-carboximidoyl chlorides are proposed as stable and novel isocyanide dichloride synthetic equivalents. Subsequent condensations of these new intermediates afford polysubstituted guanidines, S-aryl isothiour

Full text of DOI:10.1021/jo001685o

2854
J . Org. Chem. 2001, 66, 2854-2857
N-F u n ction a lized Ben zotr ia zole-1-ca r boxim id oyl Ch lor id es:
Syn th etic Equ iva len ts for Isocya n id e Dich lor id es
Alan R. Katritzky,* Boris Rogovoy, Cedric Klein, Henry Insuasty, Vladimir Vvedensky, and
Braulio Insuasty‡
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida
32611-7200, and Centro de Compuestos Heteroc´ıclicos, Departamento de Quı´mica, Universidad del Valle,
A.A. 25360, Cali, Colombia
katritzky@chem.ufl.edu
Received November 30, 2000
Readily prepared N-functionalized benzotriazole-1-carboximidoyl chlorides are proposed as stable
and novel isocyanide dichloride synthetic equivalents. Subsequent condensations of these new
intermediates afford polysubstituted guanidines, S-aryl isothioureas, and 2-aminoquinazolin-4-
thiones.
In tr od u ction
Resu lts a n d Discu ssion
Isocyanide dichlorides,1 including N-acyl2 and N-sul-
fonyl3 derivatives, undergo nucleophilic substitution with
various nucleophiles to provide access to carbodiimides,
guanidines, chloroformamidines, thioesters, isoureas,
isothioureas, carbonimidates, and five- and six-membered
heterocycles.1 Preparative routes to isocyanide dichlo-
rides4 include (i) the reaction of isothiocyanates with
chlorine,5 (ii) the reaction of isocyanates with phosphorus
pentachloride,5a (iii) the addition of chlorine to isocya-
nides,6,7 (iv) the reaction of monosubstituted formanilides
with a mixture of thionyl chloride and sulfuryl chloride,7
(v) the addition of dichlorocarbenes to azides8 or azabi-
cyclobutanes,9 and (vi) the reaction of trisubstituted ureas
with carbon tetrachloride in the presence of triphenyl
phosphine or with phosphorus pentachloride.10 While
many isocyanide dichlorides can be made in satisfactory
yields by these methods, these compounds are often
strongly corrosive, toxic, and sensitive toward hydroly-
sis,4,11 properties that decrease their convenience for
possible applications.
A one-step reaction of easily available N-chlorobenzo-
triazole (1)13 with isonitriles 2a -f in chloroform at room
temperature conveniently affords N-functionalized ben-
zotriazole-1-carboximidoyl chlorides as approximately
equimolar mixtures of the Bt1 (3a -f) and Bt2 (4a -f)
isomers (Scheme 1). Benzyl, benzotriazolylmethyl, tosyl-
methyl, and aryl isonitriles 2 all afford almost quantita-
tive total yields of the expected adducts 3a -f and 4a -f.
For analytical purposes, we isolated some of the indi-
vidual isomers by extraction and recrystallization (3a -d
and 4b,d ) or column chromatography (3e, 4e). Thus, in
1
the H NMR spectrum of crude material obtained in the
reaction of [(p-methylphenyl)sulfonylmethyl]isonitrile (2b)
with compound 1, the Me and CH2 signals for isomers
3b and 4b appeared as singlets with the same integral
intensity at 2.46, 2.45, and 5.16, 5.19 ppm, respectively.
Complex superposition of the aromatic signals is observed
at 7.30-8.20 ppm. In the spectra of individual isomers
3b and 4b, characteristic patterns for the four non-
equivalent protons of the Bt1 moiety showed at 7.52-
8.13 ppm, and two typical multiplets of the AA′BB′ spin
system of Bt2 group showed at 7.48-7.51 and 7.90-7.93
ppm, respectively. In contrast with isocyanide dichlorides,
compounds 3a -f and 4a -f are high melting crystalline
compounds, stable on storage, insensitive to air and
moisture, nonvolatile, and odorless.
For further synthetic transformations, the mixtures of
3a -f with the corresponding 4a -f were used without
separation for the sequential displacement of the chlorine
atom and the benzotriazole moiety to prepare polysub-
stituted guanidines 10, S-arylisothioureas 11, and 2-ami-
noquinazoline-4-thiones 13.
Thus, N-functionalized 1H-benzotriazole-1-carboximi-
doyl chlorides 3a -f and 2H-benzotriazole-2-carboximi-
doyl chlorides 4a -f condensed with primary and second-
ary aliphatic and primary aromatic amines, in the
presence of triethylamine in dry methylene chloride, to
afford the corresponding N,N′-functionalized 1H-benzo-
triazole-1-carboximidamides 6a -j and 2H-benzotriazole-
2-carboximidamides 7a -j in overall yields of 45-92%.
Our earlier investigations have shown that the re-
placement of the halogen atom in such synthons as
R-chloroalkyl ethers and R-chloroalkylamines by a ben-
zotriazole moiety provides stable and nontoxic synthetic
equivalents.12 We now describe the synthesis of novel
N-functionalized benzotriazole-1-carboximidoyl chlorides
and their use as stable isocyanide dichloride synthetic
equivalents.
* Corresponding author.
‡ Universidad del Valle.
(1) Ku¨hle, E. Angew. Chem., Int. Ed. Engl. 1969, 8, 20.
(2) Descours, D.; Festal, D. Synthesis 1983, 12, 1033.
(3) Mercha´n, F. L.; Gar´ın, J .; Tejero, T. Synthesis 1982, 11, 984.
(4) Ku¨hle, E.; Anders, B.; Zumach, G. Angew. Chem., Int. Ed. Engl.
1967, 6, 649.
(5) (a) Grabenko, A. D.; Danchenko, M. N.; Pel’kis, P. S. J . Org.
Chem. USSR (Engl. Transl.) 1969, 5, 53. (b) Knapp, S.; Patel, D. V.
Tetrahedron Lett. 1982, 23, 3539.
(6) Klich, M.; Teutsch, G. Tetrahedron 1986, 42, 2677.
(7) Ku¨hle, E. Angew. Chem., Int. Ed. Engl. 1962, 1, 647.
(8) Szo¨nyi, F.; Cambon, A. Tetrahedron Lett. 1992, 33, 2339.
(9) Mloston, G.; Galindo, A.; Bartnik, R.; Marchand, A. P.; Rajagopal,
D. J . Heterocycl. Chem. 1996, 33, 93.
(10) Appel, R.; Warning, K.; Ziehn, K.-D. Chem. Ber. 1974, 107, 698.
(11) The Sigma-Aldrich Library of Chemical Safety Data; Lenga,
R. E., Ed.; Sigma-Aldrich Corp.: Milwaukee, WI, 1988; Vol. 2, p 2788.
(12) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. V. Chem.
Rev. 1998, 98, 409.
(13) Hughes, T. V.; Hammond, S. D.; Cava, M. P. J . Org. Chem.
1998, 63, 401.
10.1021/jo001685o CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/28/2001

Functionalized Benzotriazole-1-carboximidoyl Chlorides
J . Org. Chem., Vol. 66, No. 8, 2001 2855
mations. However, the individual Bt1 isomers (6b,c,e-
j) and/or Bt2 isomers (7a ,b,d ,f-h ) were isolated for
analytical purposes.
Sch em e 1
In both the 1H and 13C NMR spectra, the signals of
the N(CH2-)2 and N(CH2CH2-) groups in compounds
6b,f-h , and 7b,d ,f-j appeared as broad singlets due to
hindered rotation around amide-type C-N bonds. N,N′-
Disubstituted carboximidamides 6c,e,i, and 7a are po-
tentially tautomeric. Nevertheless, N-(4-nitrophenyl)-
and N-[(4-methylphenyl)sulfonyl]methyl derivatives 6c,e,
and 7a demonstrate well-resolved 1H and 13C NMR
spectra of the single tautomeric form, as depicted in
Scheme 2. For the N-(4-methylphenyl)-N′-propyl-substi-
tuted compound 6i, a strong broadening of the signals of
the N′CH2- group and CH-7 fragment of the benzotria-
zole moiety is observed in both the 1H and 13C NMR
spectra. It may indicate fast (on the NMR time scale)
exchange of the proton between NH and N′H positions.
A benzotriazole moiety can in many ways be compared
to a halogen substituent.12 Compounds 3a -f and 4a -f
provide models for the investigation of the relative
reactivity of a Bt group and chlorine. Thus, condensation
of compound 3d with isobutylamine during 4 h gave a
mixture of compounds 6,7e (60%) and 9e (40%). Increas-
ing the reaction time for up to 72 h gave products 6e and
7e in almost quantitative yield. This suggests that the
displacement of the Bt group is as fast as that of the
chlorine atom, but that the chloro intermediates 8 are
less stable thermodynamically than the benzotriazole-
substituted analogues 6 and 7, which become the major
products after establishment of the equilibrium. It is
surprising that mixtures of compounds 6 + 7 and
compound 8 were formed competitively since a halogen
is a much better leaving group than benzotriazole.14a
Thus, acylbenzotriazoles14b and R-benzotriazolyl ketones14c
are usually less reactive than the corresponding acyl
chlorides and R-chloro ketones. However, the present
result suggests that when chlorine and benzotriazole are
connected to the same carbon center, a benzotriazole
moiety has a lability comparable with that of a chlorine
atom; implications of this conclusion are under investiga-
tion.
Sch em e 2
Ta ble 1. P r ep a r a tion of
Ben zotr ia zole-1-ca r boxim id a m id es 6 a n d 7
reaction
time,
h
yield
of
6 + 7,
yield
9
R1
R2
i-butyl
R3
6 + 7 of 9
a
b
c
d
e
-
f
g
h
i
4
4
72
78
4
72
15
1
30
1
TsCH2
BtCH2
H
62
0a
32
0a
0a
40
0a
0a
0a
0a
0a
0a
65
57
allyl
allyl 45
4-NO2C6H4 4-CH3OC6H4
TsCH2 (CH2)2O(CH2)2
4-NO2C6H4 i-butyl
H
65
78
60
89
81
80
H
-
Early syntheses of guanidines from isocyanide dichlo-
rides1 were performed with an excess of the amine and
led exclusively to symmetrically substituted products.
Syntheses of unsymmetrical guanidines from isocyanide
dichlorides by sequential displacement of two chlorine
atoms were reported only for N-acyl or N-tosyl deriva-
tives.15
-
-
4-CH3C6H4 (CH2)2O(CH2)2
4-CH3C6H4 (CH2)4
4-CH3C6H4 ethyl
4-CH3C6H4 n-propyl
ethyl 78
H
70
92
0a
j
k
l
2
4
3
3-NO2C6H4
BtCH2
C6H5CH2
(CH2)2O(CH2)2
i-butyl
H
(CH2)2O(CH2)2
0a
a
Compound was not isolated.
Reactions of the mixtures of benzotriazole-carboximi-
damides 6c,e and 7c,e with amines in refluxing THF
during 2-3 d lead to unsymmetrical tetrasubstituted
guanidines 10a ,b in 68-69% yields (Scheme 3). Sharp
The preparation of compounds 6,7b and 6,7e was ac-
companied by the formation of the disubstituted 9b or
trisubstituted urea 9e, which apparently was formed by
the hydrolysis of nonisolated chloroformamidines 8b,e
during workup. Ureas 9k ,l were the sole products iso-
lated from 3,4k and 3,4l (Scheme 2, Table 1 ). Benzot-
riazole-substituted carboximidoyl chlorides 3,4d and 3,4f,
activated by a nitro group in the N-phenyl moiety, gave
the best yields of carboximidamides 6,7e and 6,7j (89 and
92% respectively). In contrast, N-benzyl and N-(benzot-
riazol-1-yl)methyl carboximidoyl chlorides 3,4a ,c either
gave lower yields of desired compounds (6,7b, 45%), or
did not form compounds at all (6,7k ,l) (Table 1). N,N′-
Functionalized 1H-benzotriazole-1-carboximidamides 6a-j
and 2H-benzotriazole-2-carboximidamides 7a -j were
used without separation of isomers for further transfor-
and well-resolved signals of the compound 10a (R2
)
1
i-Bu) in both H and 13C NMR spectra indicate that 10a
exists in solution (CDCl3, rt) exclusively as the -NH-i-
Bu tautomer. The NH proton signal is observed as a
(14) (a) Richard, J . P.; Nagorski, R, W.; Rudich, S.; Amyes, T. L.;
Katritzky, A. R.; Wells, A. P. J . Org. Chem. 1995, 60, 5989. (b)
Katritzky, A. R.; Pleynet, D. P. M.; Yang, B. J . Org. Chem. 1997, 62,
4155. (c) Katritzky, A. R.; Tymoshenko, D. O.; Monteux, D.; Vvedensky,
V.; Nikonov, G.; Cooper, C. B.; Deshpande, M. J . Org. Chem. 2000,
65, 8059.
(15) (a) Neidlein, R.; Haussmann, W. Tetrahedron Lett. 1966, 20,
2217. (b) Ivanova, Zh. M.; Kirsanova, N. A.; Stukalo, E. A.; Derkach,
G. I. J . Org. Chem. USSR (Engl. Transl.) 1967, 3, 460; Chem. Abstr.
1967, 2869u.

2856 J . Org. Chem., Vol. 66, No. 8, 2001
Katritzky et al.
Sch em e 3
Sch em e 4
broad singlet at 4.10 ppm. In contrast, two different NH
signals at 5.58 and 5.95 ppm (integral ratio 7:3) are
observed under the same conditions for compound 10b
(R2 ) 4-methoxyphenyl). Aromatic, morpholine, and MeO
groups appear as a single set of relatively (compared to
compound 10a ) broad signals. Perhaps, this compound
exists as a mixture of 4-MeO-C6H4-NH- tautomer 10b
and 4-NO2C6H4-NH- tautomer 10′b in the molar ratio
7:3, respectively. We estimated the parameters of this
tautomeric system by using AM1 semiempirical calcula-
tions. The results obtained (∆∆G10b-10′b ) -0.34 kcal/mol
or 10b:10′b ) 60:40) are in good agreement with the
experimental data.
Sch em e 5
Isothioureas are known as specific inhibitors of induc-
ible nitric oxide synthase,16a-d and S-alkyl isothioureas
are useful synthons in organic chemistry.16e However,
there were no general synthetic procedures described
previously for the preparation of S-aryl-N,N,N′-substi-
tuted isothioureas.
to the tautomeric nature of these compounds. However,
S-methylation of the crude products 13a -c with methyl
iodide in the presence of sodium hydride in DMF gave
compounds 14a -c in overall 50-70% yields (Scheme 5).
2-Amino-4-(methylthio)quinazolines 14a -c were com-
Reactions of mixtures of compounds 6f-j and 7f-j with
aryl thiols at room temperature in dry THF during 15-
36 h readily afford S-aryl isothioureas 11a -f in 80-88%
1
pletely characterized by H and 13C NMR spectroscopy
1
yields (Scheme 4). According to the H NMR (rt, CDCl3)
spectrum, a potentially tautomeric compound 11c (R1 )
4-Me-C6H4, R2 ) n-Pr, R3 ) H, R4 ) 4-Cl-C6H4) exists
exclusively in the NH-Pr form.
and elemental analyses.
Con clu sion s
Reactions of compounds 6f-h and 7f-h with potas-
sium thiocyanate, leading to 2-aminoquinazolin-4-thiones
13a -c, demonstrate the synthetic equivalency of 6f-h ,
7f-h , and the analogous chloroformamidines.17 This
reaction required a 2-fold excess of potassium thiocyanate
and zinc bromide as a catalyst. A complete conversion of
the starting materials in refluxing 1,2-dimethoxyethane
according to TLC control needed about 7-8 h to give
crude compounds 13a -c in good yields. We suggest that
the cyclization process takes place via nonisolated inter-
mediates 12a -c, which undergo cyclization in situ to give
the 2-aminoquinazoline derivatives 13a -c. Analysis of
The preparation of N-functionalized benzotriazole-
substituted carboximidoyl chlorides 3a -f and 4a -f as
stable and easily accessible synthetic equivalents to
isocyanide dichlorides has been described. These deriva-
tives are sequentially condensed with amines, aryl thiols,
and potassium thiocyanate to afford entries to polysub-
stituted guanidines 10, S-aryl isothioureas 11, and
2-aminoquinazoline-4-thiones 13, respectively.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined with
a capillary melting point apparatus equipped with a digital
thermometer and are uncorrected. 1H and 13C NMR spectra
were recorded on a 300 MHz NMR spectrometer (300 and 75
MHz respectively) using CDCl3 as a solvent. Tetrahydrofuran
(THF) was distilled under nitrogen, immediately before use,
from sodium/benzophenone. Column chromatography was
conducted with silica gel 230-400 mesh. All the other reagents
were of reagent grade and were used without purification.
Thermodynamic properties of compounds 10b and 10′b were
calculated by Mopac 6 using method AM1.
1
1,3-quinazoline-4-thiones 13a -c by H NMR (DMSO-d6
and CDCl3) showed a complex superposition of broad
signals in both the aliphatic and aromatic regions due
(16) (a) Zhang, J .; McCarthy, T. J .; Moore, W. M.; Currie, M. G.;
Welch, M. J . J . Med. Chem. 1996, 39, 5110. (b) Wei, L. H.; Arabolos,
N.; Ignarro, L. J . Nitric Oxide 1998, 2, 155. (c) Cooper, G. R.;
Mialkowski, K.; Wolff, D. J . Arch. Biochem. Biophys. 2000, 375, 183.
(d) Southan, G. J .; Gauld, D.; Lubeskie, A.; Zingarelli, B.; Cuzzocrea,
S.; Salzman, A. L.; Szabo, C.; Wolff, D. J . Biochem. Pharmacol. 1997,
54, 409. (e)Comprehensive Organic Functional Group Transformations;
Kirby, G. W., Ed.; Pergamon Press: 1995; Vol. 4, pp 973, 980.
(17) Ried, W.; Merkel, W. J ustus Liebigs Ann. Chem. 1973, 122.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
3 a n d 4. A solution of 1-chlorobenzotriazole (765 mg, 5 mmol)

Functionalized Benzotriazole-1-carboximidoyl Chlorides
J . Org. Chem., Vol. 66, No. 8, 2001 2857
in chloroform (30 mL) was slowly added to a solution of an
isonitrile 2 (5 mmol) in chloroform (30 mL) with stirring at
room temperature. After the complete conversion of the
starting materials, the crude mixtures of compounds 3a -f (Bt1
isomers) and 4a -f (Bt2 isomers) were used for the preparation
of derivatives 6a -j and 7a -j without separation. Since Bt1
isomer is more soluble in organic solvents, it can be separated
from Bt2 isomer by extraction with an appropriate solvent
followed by recrystallization from the same solvent. Separation
of isomer of 3e was performed by column chromatography
(ethyl ether/pentane, 2/8).
N-(4-Nitr op h en yl)-1H-ben zotr ia zole-1-ca r boxim id oyl
Ch lor id e (3d ). This compound was isolated from acetone as
light yellow needles: mp 218-220 °C; 1H NMR δ 6.76 (d, J )
8.8 Hz, 2H), 7.66 (t, J ) 7.7 Hz, 1H), 7.78 (t, J ) 7.7 Hz, 1H),
8.12 (d, J ) 8.8 Hz, 2H), 8.21 (d, J ) 8.4 Hz, 1H), 8.39 (d, J )
8.4 Hz, 1H); 13C NMR δ 113.5, 119.8, 120.2, 124.3, 126.5, 129.6,
130.3, 142.6, 144.9, 145.6, 149.5. Anal. Calcd for C13H8-
ClN5O2: C, 51.76; H, 2.67. Found: C, 51.76; H, 2.58.
ca r boxim id a m id e (10′b). This mixture was isolated as yellow
prisms from ethanol: mp 176-178 °C; H NMR δ 3.34-3.37
(m, 4H), 3.66 (br s, 4H), 3.77 (s, 3H), 5.58 (br s, 0.7H), 5.95 (br
s, 0.3H), 6.82 (d, J ) 8.4 Hz, 2H), 6.91-6.94 (m, 4H), 8.04 (d,
J ) 8.2 Hz, 2H); 13C NMR δ 46.9, 55.4, 66.2, 114.7, 121.0,
122.3, 125.3, 133.9, 141.9, 152.1, 155.9, 157.0. Anal. Calcd for
1
C
18H20N4O4: N, 15.72. Found: N, 16.02.
P r oced u r e for th e Syn th esis of Isoth iou r ea s 11. A
mixture of compounds 6f-j and 7f-j (0.85 mmol) was dis-
solved in dry THF (10 mL) under argon. An appropriate
thiophenol (0.85 mmol) in THF (5 mL) was added slowly to
the stirred mixture and was allowed to react for 15-48 h at
room temperature. After the complete conversion of the
starting materials (TLC control), the solvent was removed
under reduced pressure, and the crude product obtained was
purified by column chromatography with a mixture of ethyl
acetate/hexanes as an eluent.
4-Ch lor op h en yl-N-(4-m eth ylp h en yl)-4-m or p h olin eca r -
bim id oth ioa te (11b). The compound was purified by column
chromatography with ethyl acetate/pentane as eluent. The
light yellow oil, obtained after evaporation of the solvents, was
crystallized during 2 days to give off-white prisms: mp 67-
68 °C; 1H NMR δ 2.28 (s, 3H), 3.54 (br s, 8H), 6.63 (d, J ) 8.1
Hz, 2H), 6.99 (d, J ) 8.1 Hz, 2H), 7.12 (d, J ) 8.7 Hz, 2H),
7.18 (d, J ) 8.7 Hz, 2H); 13C NMR δ 20.8, 48.3, 66.3, 121.4,
128.9, 129.0, 131.5, 132.2, 132.6, 133.1, 147.1, 152.8. Anal.
Calcd for C18H19ClN2OS: C, 62.33; H, 5.52; N, 8.08. Found:
C, 62.51; H, 5.71; N, 8.16.
N-(4-Nitr op h en yl)-2H-ben zotr ia zole-2-ca r boxim id oyl
Ch lor id e (4d ). This compound was separated from 3d by
washing with cold acetone. Yellow microcrystals were obtained
1
after evaporation of the solvent: mp 213-214 °C; H NMR δ
7.39 (d, J ) 7.8 Hz, 2H), 7.56-7.58 (m, 2H), 7.95-7.97 (m,
2H), 8.38 (d, J ) 7.8 Hz, 2H); 13C NMR δ 119.3, 121.4, 114.3,
121.8, 125.2, 130.2, 146.0, 150.0. Anal. Calcd for C13H8-
ClN5O2: C, 51.76; H, 2.67; N, 23.21. Found: C, 51.55; H, 2.71;
N, 23.01.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
6 a n d 7. A mixture of an amine (1.37 mmol) and triethylamine
(1.37 mmol) was added to a suspension of N-functionalized
benzotriazole-carboximidoyl chlorides 3 and 4 and was allowed
to react for 72 h. The reaction mixture was then washed with
water and dried over MgSO4. Magnesium sulfate was filtered
off, and the filtrate was concentrated under reduced pressure.
The residue obtained was separated by column chromatogra-
phy on silica gel to afford compounds 6 and 7 in approximately
equimolar amounts. Analytical samples of these compounds
were also purified by recrystallization.
N-[1H-Ben zotr ia zol-1-yl(m or p h olin o)m eth ylid en e]-4-
m eth yla n ilin e (6f). This compound was isolated as white
prisms from ethyl acetate/hexanes: mp 141-142 °C; 1H NMR
δ 2.06 (s, 3H), 3.38 (br s, 4H), 3.82 (br s, 4H), 6.43 (d, J ) 8.5
Hz, 2H), 6.72 (d, J ) 8.2 Hz, 2H), 7.30-7.38 (m, 3H), 7.98 (d,
J ) 8.7 Hz, 1H); 13C NMR δ 20.6, 46.7, 66.3, 110.4, 119.9,
120.1, 124.5, 128.6, 129.2, 132.0, 132.4, 141.9, 143.9, 144.8.
Anal. Calcd for C18H19N5O: C, 67.27; H, 5.96; N, 21.79.
Found: C, 67.09; H, 6.09; N, 21.79.
N-[2H-Ben zotr ia zol-2-yl(m or p h olin o)m eth ylid en e]-4-
m eth yla n ilin e (7f). This compound was isolated as yellow
prisms from ethyl acetate/hexanes: mp 155-156 °C; 1H NMR
δ 2.11 (s, 3H), 3.29 (br s, 4H), 3.79-3.82 (m, 4H), 6.49 (d, J )
9.0 Hz, 2H), 6.78 (d, J ) 9.0 Hz, 2H), 7.37-7.40 (m, 2H), 7.81-
7.84 (m, 2H); 13C NMR δ 20.7, 46.5, 66.2, 118.8, 121.0, 127.7,
129.1, 132.4, 143.7, 143.8, 143.9. Anal. Calcd for C18H19N5O:
C, 67.27; H, 5.96; N, 21.79. Found: C, 67.43; H, 5.83; N, 21.95.
N-Isobu tyl-N′-(4-n itr op h en yl)u r ea (9e). This compound
was isolated as yellow prisms from ethanol: mp 195-196 °C;
1H NMR δ 0.93 (d, J ) 6.8 Hz, 6H), 1.83-1.75 (m, 1H), 3.06
(t, J ) 6.2 Hz, 2H), 6.12 (t, J ) 5.4 Hz, 1H), 7.55 (d, J ) 9.2
Hz, 2H), 8.01 (d, J ) 9.2 Hz, 2H), 8.78 (br s, 1H); 13C NMR δ
19.7, 28.4, 46.8, 116.5, 124.7, 140.7, 146.5, 154.8. Anal. Calcd
for C11H15N3O3: C, 55.69; H, 6.37; N, 17.71. Found: C, 55.79;
H, 6.68; N, 17.94.
P r oced u r e for P r ep a r a tion of Com p ou n d s 10. A mix-
ture of compounds 6c,e + 7c,e (1 mmol) and morpholine (90
mg, 1.03 mmol) were dissolved in THF (15 mL). The reaction
was allowed to occur in refluxing THF for 96 h. The reaction
was monitored by TLC until the disappearance of the starting
materials 6c, e + 7c, e was noted. The THF was then removed
under reduced pressure and the residue was purified by flash
chromotography ((i) ethyl acetate/hexane 1/1, (ii) ethyl alcohol).
Ta u tom er ic Mixtu r e of N-(4-Meth oxyp h en yl)-N′-(4-
n itr op h en yl)-4-m or p h olin eca r boxim id a m id e (10b) a n d
N-(4-Meth oxyp h en yl)-N′-(4-n itr op h en yl)-4-m or p h olin e-
P r oced u r e for th e Syn th esis of 6-Meth yl-4-m eth ylth io-
2-am in oqu in azolin es 14a-c. Potassium thiocyanate (2 equiv,
dry powder) and zinc bromide (1.1 equiv, dry powder) were
added to a solution of the mixture of compounds 6f-h + 7f-h
(1 equiv) in 1,2-dimethoxyethane (70 mL) under argon atmo-
sphere. The reaction mixture was kept at reflux for 6-8 h until
the complete conversion of the starting materials 6f-h + 7f-h
(TLC control). A dark yellow suspension was obtained and
cooled to room temperature, and then water (100 mL) was
added. The product was extracted four times with methylene
chloride (1 × 350 mL and 3 × 50 mL), the organic extracts
were dried over MgSO4, and the solvent was removed to
dryness under reduced pressure to give a crude compound
13a -c. Compound 13a -c (1 equiv) was dissolved in DMF (2
mL) at room temperature, and then a slight excess of sodium
hydride (1.2 equiv) was added and the reaction mixture was
stirred for 10-15 min before the addition of a solution of
methyl iodide (1.2 equiv). The stirring was continued for 1 h
at room temperature. The product 14a -c was precipitated
with ice water, filtered off, washed with water, dried in vacuo,
and purified by column chromatography.
6-Meth yl-4-(m eth ylth io)-2-m or ph olin oqu in azolin e (14a)
The compound was purified by column chromatography with
ethyl ether/pentane as eluent, and yellow prisms were obtained
after evaporation of the solvents: mp 128-129 °C; 1H NMR δ
2.42 (s, 3H), 2.61 (s, 3H), 3.79-3.82 (m, 4H) 3.91-3.94 (m,
4H), 7.44 (s, 2H), 7.61 (s, 1H); 13C NMR δ 12.5, 21.2, 44.5, 66.9,
118.7, 122.8, 125.8, 131.9, 135.6, 148.6, 157.2, 171.0. Anal.
Calcd for C14H17N3OS: C, 61.06; H, 6.22; N, 15.26. Found: C,
61.01; H, 6.33; N, 15.22.
Ack n ow led gm en t. We thank Dr. Christophe Chas-
saing and Dr. Randy Duran for the help and discussions
regarding this work. Financial support provided by the
NSF US/France REU program (CHE9732161, with
funds from the French Ministry of Research), the
Scientific Mission of the French Embassy, the Univer-
sity Louis Pasteur in Strasbourg, and the Colombian
Institute for Science and Technology Development
(COLCIENCIAS).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR,
and CHN analysis data for compounds 3a-c,e, 4b,e,f, 6b,c,e,g-
j, 7a ,b,d ,g,h , 9b,k ,l, 10a , 11a ,c-f, and 14b,c. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O001685O