Synthesis of heterocycles by intramolecular nucleophilic substitution at an electron-deficient sp2 nitrogen atom

Article abstract of DOI:10.1002/ejoc.200901520

2-Aryl(arylsulfonyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ones and 3-arylimino-6,7-dihydroimidazo[2,1-c]-[1,2,4]thiadlazoles have been synthesized by intramolecular nucleophilic substitution reactions at the electron-deficient sp²

Full text of DOI:10.1002/ejoc.200901520

FULL PAPER
DOI: 10.1002/ejoc.200901520
Synthesis of Heterocycles by Intramolecular Nucleophilic Substitution at an
Electron-Deficient sp2 Nitrogen Atom
Jarosław Saczewski*[a] and Maria Gdaniec[b]
˛
Keywords: Nucleophilic addition / Amination / Nucleophilic substitution / Nitrogen heterocycles / Transition states
2-Aryl(arylsulfonyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]tri-
azol-3(5H)-ones and 3-arylimino-6,7-dihydroimidazo[2,1-c]-
[1,2,4]thiadiazoles have been synthesized by intramolecular
nucleophilic substitution reactions at the electron-deficient
sp2 nitrogen atom of 2-(hydroxyimino)imidazolidine O-sulf-
onate. The displacement of the sulfate leaving group by both
nitrogen and sulfur anionic nucleophiles proceeds exother-
mically by in-plane SN2σ nucleophilic substitution.
applied to the formation of C–N bonds by an intermo-
lecular SN2-type reaction with organometallic reagents, the
O-amination of alcohols and the preparation of a wide
range of heterocycles (cyclic or spiro imines) by the Mizo-
roki–Heck, that is, amino-Heck, reaction. On the other
hand, oxime derivatives C and D served as convenient sub-
strates for the preparation of primary amines upon treat-
ment with Grignard reagents and subsequent hydrolysis of
the intermediary formed imines under acidic conditions.
Introduction
Electrophilic amination is a long-established reaction in
organic synthesis applied to the formation of C–N, N–N,
O–N, S–N, S=N or P=N bonds.[1–9] In this process an elec-
tronegatively substituted nitrogen compound serves as the
electrophilic [NH2+] equivalent (a1 synthon) for the reaction
with carbon, nitrogen, oxygen, sulfur or phosphorus nu-
cleophiles.[10–17] Although there are many synthetic meth-
ods reported in the literature for the formation of [R2N+]
synthons susceptible to nucleophilic attack, examples of in-
tramolecular electrophilic amination reactions are rare. In
this context, it is worth mentioning Sheradsky and Yusupo-
va’s synthesis of pyrrolidines[17a] and the recently described
base-mediated 1,3-elimination of sulfuric acid from N-
hydroxyguanidine O-sulfonic acids A (Scheme 1) leading to
(alkylimino)diaziridines.[18]
Figure 1. Compounds with electron-deficient sp2-hybridized nitro-
gen atoms.
In contrast, there have only been a few reports on N–N,
O–N and S–N bond formation at the electron-deficient ox-
ime nitrogen.[19,22–24] Examples include the tandem nucleo-
philic addition–electrophilic amination reactions of cyclic
hydroxyguanidine derivative 2 (Scheme 2) with aldehydes,
carbon disulfide or Eschenmoser salts leading to novel bicy-
clic heterocycles with O–N, S–N or N–N bonds, respec-
tively.[25,26] Note that an analogous reaction of 2 with
phenyl isothiocyanate was not that straightforward. Indeed,
it led to the initial formation of a nucleophilic addition
product with a thioureido structure. However, this interme-
diate reacted with a second equivalent of isothiocyanate
followed by cyclodesulfurization to give 3-phenyl-2-phen-
ylimino-2,6,7,8-tetrahydroimidazo[1,2-a][1,3,5]triazine-
4(3H)-thione.[25]
Scheme 1. Reactivity of N-hydroxyguanidine O-sulfonic acids (A).
A conceptually interesting approach to electrophilic am-
ination is based on nucleophilic substitution at the sp2 N
atom of ketone oximes B[19,20] or derivatives of 1,3-diox-
olan-2-one oxime C[21] and imidazolidin-2-one oxime D[22]
(Figure 1). The amination with oximes A was successfully
[a] Department of Chemical Technology of Drugs, Medical Uni-
versity of Gdan´sk,
Al. Gen. J. Hallera 107, 80-416 Gdan´sk, Poland
Fax: +48-583493257
E-mail: js@gumed.edu.pl
[b] Faculty of Chemistry, A. Mickiewicz University,
60-780 Poznan´, Poland
To the best of our knowledge, thus far no report has
dealt with the electrophilic amination of ambident amido
anions by compounds bearing an electron-deficient sp2-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901520.
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Scheme 2. Reactivity of triethylaminium 2-(hydroxyimino)imid-
azolidine O-sulfonate (2).
Scheme 3. Preparation of 6,7-dihydro-2H-imidazo[2,1-c][1,2,4]tri-
azol-3(5H)-ones (5a,b).
hybridized nitrogen atom. Therefore, in this paper, we wish
to describe the domino nucleophilic addition–electrophilic
amination reaction of 2-iminoimidazolidine 2 with aryl and
arylsulfonyl isocyanates with a view to obtaining imid-
azo[2,1-c][1,2,4]triazol-3(5H)-one derivatives that, by anal-
ogy to the well-known imidazo[2,1-c][1,2,4]triazoles and imid-
azo[2,1-c][1,2,4]triazin-4-ones,[27,28] may exhibit antibacte-
rial and antiproliferative activities. Moreover, the newly pre-
pared compounds, which are cyclic analogues of amidino-
arylsulfonylureas, may behave as neuropeptide Y receptor
(NPY) antagonists useful for the treatment of anxiety, obes-
ity, hypertension and/or the regulation of coronary tone.[29]
This synthetic strategy is based on the unique properties of
2, which can be generated from betaine 1 by treatment with
Et3N and represents a cyclic guanidine derivative bearing a
strong electron-withdrawing sulfate substituent at the exo-
cyclic nitrogen atom N2. As described previously, the endo-
cyclic nitrogen atoms N1 and N3 in 2 behave as nucleo-
philes, whereas the exocyclic N2 can react either with
nucleophilic[25,26] or electrophilic[30,31] reagents.
To improve the efficiency of the above chemical pro-
cesses, a one-pot synthesis was performed in which the sub-
strate 2 was subjected to successive reactions with aryl iso-
cyanates and aqueous NaOH. In this manner compounds
5a and 5b were obtained in 71 and 68% yields, respectively
(see the Exp. Sect.).
It should be emphasized that the amidate anion is am-
bident in nature and hence intramolecular electrophilic am-
ination could occur at either the nitrogen or the oxygen
atom of E/F. However, no O-amination product of type G
(Scheme 3) was found in the reaction mixture. The struc-
tures of the N-amination products were confirmed by ele-
mental analysis and IR and NMR spectroscopy of 5a,b as
well as by single-crystal X-ray analysis of compound 5a
(Figure 2).
Results and Discussion
As shown in Scheme 3, the reaction of triethylaminium
2-(hydroxyimino)imidazolidine O-sulfonate (2) with com-
mercially available p-tolyl isocyanate (3a) in DMF at an ele-
vated temperature led to the formation of the nucleophilic
addition product 4a, which was separated from the reaction
Figure 2. X-ray structure of 5a (only the ordered molecule is
shown).
The next logical step in the development of this chemis-
mixture in its pure form in 75% yield. Then, upon treat- try was to study a similar reaction sequence by using aryl-
ment of an aqueous solution of the triethylaminium salt 4 sulfonyl isocyanates. As depicted in Scheme 4, for the
with 10% NaOH at room temperature, an almost instan- above-mentioned purposes we used both the commercially
taneous reaction occurred to furnish 2-(4-methylphenyl)- available p-tolylsulfonyl isocyanate (6) and 4-(dimeth-
6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-one (5a) ylamino)pyridinium arylsulfonyl carbamoylides 7a–f, eas-
in 90% yield as a result of facile N–N bond formation. ily-handled and indefinitely bench-top-stable under air sub-
From the above findings it may be inferred that the neutral stitutes of arylsulfonyl isocyanates prepared in our
ureide functionality is not susceptible to electrophilic amin- laboratories.[32,33] Thus, heating 2 with p-tolylsulfonyl isocy-
ation by the sp2-hybridized nitrogen and that a strong base anate (6) in the presence of Et3N and an analogous reaction
was necessary to generate the ambident ureido anion E, with the arylsulfonyl carbamoylides furnished 2-(arylsulf-
which was immediately N-aminated with simultaneous ex- onyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-
2–
trusion of the SO4 leaving group.
ones 8a–f in isolated yields of 23–69%. In this case the in-
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Heterocycles by Intramolecular Nucleophilic Substitution
termediary addition products H were not isolated from the
reaction mixture. Apparently, the sulfonylureas H, which
are stronger NH acids than the ureas 4 (pKa ≈ 3–4 vs. 13–
14[34]), suffered deprotonation in the presence of triethyl-
amine or DMAP to give ambident anions of type H which,
by analogy to 4, underwent regioselective N-amination to
give the final bicyclic products 8.
Scheme 5. Reactivity of 6,7-dihydro-2H-imidazo[2,1-c][1,2,4]tri-
azol-3(5H)-one (8b).
Having succeeded in the preparation of the desired imid-
azotriazolone derivatives 5 and 8, we turned our attention
to the less active aryl isothiocyanates. As stated in the Intro-
duction, the previously described reaction of 2 with phenyl
isothiocyanate carried out at room temperature consumed
3 mol-equiv. of isothiocyanate and afforded 3-phenyl-2-
phenylimino-2,6,7,8-tetrahydroimidazo[1,2-a][1,3,5]triazine-
4(3H)-thione.[25] We have now found that the same reaction
performed in DMF at 40 °C for 12 h led to the formation of
the desired S-amination product 12a (Scheme 6). A similar
result was observed by using 4-chlorophenyl isothiocyanate,
which gave 12c, the structure of which was confirmed un-
ambiguously by single-crystal X-ray analysis (Figure 4).
The less active 4-methylphenyl isothiocyanate gave 7-un-
substituted 6,7-dihydro-5H-imidazo[2,1-c][1,2,4]thiadiazole
(11). The use of 2 equiv. of isothiocyanates with 12a,c pre-
vented the formation of a mixture of 11 and 12.
Scheme 4. Preparation of 2-arylsulfonyl-6,7-dihydro-2H-imid-
azo[2,1-c][1,2,4]triazol-3(5H)-ones (8a–f).
Again, the structures of compounds 8 bearing a N–N
bond were confirmed by elemental analysis, IR and NMR
spectroscopy as well as by X-ray diffraction analysis of 8c
(Figure 3). Note that the previously described approaches
to the synthesis of similarly fused 1,2,4-triazole hetero-
cyclic rings comprise the condensation reactions of 2-
hydrazono-imidazolidines[27,28] or 2-hydrazono-hexahydro-
pyrimidines.[35]
Scheme 6. Preparation of 6,7-dihydroimidazo[2,1-c][1,2,4]thiadi-
azoles 11b and 12a–c.
Figure 3. X-ray structure of 8c.
Figure 4. X-ray structure of 12c.
To explore the reactivity of 2-(arylsulfonyl)-6,7-dihydro-
2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ones of type 8 and to
prove their chemical stability, we successfully prepared the
acetyl and benzyl derivatives 9 and 10 (Scheme 5).
Computational Studies
It is generally accepted that the alkylation of neutral
amides usually proceeds at the oxygen atom with N-substi-
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J. Saczewski, M. Gdaniec
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tution arising from a subsequent rearrangement,[36] whereas
the corresponding ambident anions, generated by the treat-
ment of amides with strong bases, react with alkylating
agents to give N-substituted products.[37,38] A similar reac-
tion of amide anions with electrophilic carbenes leads to the
formation of both N-substituted amides and O-substituted
imidates.[39]
However, from a mechanistic point of view it should be
noted that the electrophilic amination of anions of type E,
H and J may be regarded as an intramolecular nucleophilic
substitution at the sp2-hybridized nitrogen atom. Several re-
ports have been published on such processes including those
of Narasaka and co-workers who found that substitution at
the nitrogen atom of O-protonated oximes may occur easily
in an SN2 manner.[40] Moreover, based on the knowledge of
heterocyclic chemistry, the well-known Boulton–Katritzky
rearrangement can formally be written as an intramolecular
nucleophilic substitution that proceeds according to a uni-
molecular one-step mechanism,[41–44] which, in turn, bears
a resemblance to the recently investigated vinylic SN2 reac-
tions at carbon atoms.[45–51]
Scheme 7. Intramolecular nucleophilic substitution (SN2) reaction
by two different mechanisms.
As shown in Figure 5 and Table 1, the cyclization reac-
tions of dianions E, H and J to the bicyclic compounds 5,
On the basis of this knowledge, substitution of the sulfate 8 and 11, respectively, gave only the planar in-plane SN2σ
leaving group by the amidate anion at the sp2-hybridized transition states TSE, TSH and TSJ, all of which have suffi-
N2 nitrogen atom in 2 may proceed either by an SN2π ciently low activation energies (∆G‡ = 11.09, 23.74 and
mechanism (out-of-plane nucleophilic attack) by interacting 15.32 kcal/mol, respectively) to undergo substitution reac-
with the π* orbital of the imino group or by an SN2σ tions under mild reaction conditions. The displacement of
mechanism (in-plane attack) in which the nucleophile inter- the sulfate anion occurs in a nearly linear manner (N–N2–
acts with the σ* orbital of the imino nitrogen of the N–O O ranges from 169.8 to 170.7° and S–N2–O 163.9°). The
bond (Scheme 7). To gain a mechanistic insight into these p(π) atomic orbitals perpendicular to the imidazoline ring
processes, theoretical studies of the transition states were of the exocyclic C=N2 bond are not involved in any bond-
undertaken (see the Exp. Sect. for computational details).
building or -breaking processes of σ bonds. The “looseness”
Figure 5. N–N, S–N and N–O atom distances and N–N–O and S–N–O bond angles calculated for the dianions E, H and J and the
transition states TSE, TSH and TSJ by the B3LYP 6-31+G* method.
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Heterocycles by Intramolecular Nucleophilic Substitution
ium 2-(hydroxyimino)imidazolidine O-sulfonate[25] (2) and the 4-
of these transition states correlates with the activation bar-
riers, that is, the higher the barrier for the concerted SN2
reaction, the larger the stretching of the N2–O bond in the
transition-state structures.
(dimethylamino)pyridinium N-(arylsulfonyl)carbamoylides[32,33]
7
were prepared according to literature procedures.
Triethylaminium 1-(4-Methylphenylcarbamoyl)imidazolidin-2-ylid-
eneaminosulfate (4a): 2-Hydroxyamino-4,5-dihydroimidazolium O-
sulfonate (1; 0.9 g, 5 mmol) and triethylamine (1.4 mL, 10 mmol)
were added to DMF (4 mL). The suspension was stirred at room
temperature for 3 min until a clear solution of the triethylaminium
2-(hydroxyimino)imidazolidine O-sulfonate salt (2) was formed. 4-
Methylphenyl isocyanate (3a; 0.7 mL, 5.5 mmol) was introduced
and the reaction mixture was kept at 80 °C for 0.5 h. Then the
solution was cooled to 0 °C and the precipitated product 4a was
filtered and washed with acetone; yield 1.55 g (75%); m.p. 182–
Table 1. Electronic energy and Gibbs free-energy profiles
(298.15 K) for the intramolecular SN2 reactions calculated by the
B3LYP 6-31+G* method using SM8[55] with H2O (5) and DMF (8,
11a) solvation models.[a]
2–
Energy
E
TSE
5
5 + SO4
Ee
–1380.70988
0
–1380.55066
0
–1380.69326 –681.35760
10.43
–1380.53298 –681.19858
11.09
–1380.79159
–51.27
–1380.64552
–59.52
∆Ee
Go
1
184 °C. H NMR (200 MHz, [D6]DMSO): δ = 1.15 (t, J = 7.3 Hz,
∆G
9 H, CH3), 2.25 (s, 3 H, CH3), 3.07 (q, J = 7.3, 6 H, CH2), 3.34 (t,
J = 7.7 Hz, 2 H, CH2), 3.82 (t, J = 7.7 Hz, 2 H, CH2), 7.11 (d, J
= 8.4 Hz, 2 H, CH), 7.19 (s, 1 H, NH), 7.34 (d, J = 8.4 Hz, 1 H,
CH), 8.80 (br. s, 1 H, NH), 10.96 (s, 1 H, NH) ppm. 13C NMR
(50 MHz, [D6]DMSO): δ = 8.9, 20.7, 39.7, 44.0, 46.1, 118.7, 129.6,
2–
Energy
H
TSH
8
8 + SO4
Ee
–1929.28494
0
–1929.11748
0
–1929.24747 –1229.94481 –1929.29895
23.52 –8.79
–1929.07965 –1229.78236 –1929.14879
∆Ee
Go
∆G
23.74
–19.64
131.8, 136.6, 150.1, 154.0 ppm. IR (KBr): ν = 3377, 3028, 2733,
˜
2–
1701, 1650, 1611, 1557, 1488, 1434, 1318, 1275, 1210, 1051 cm–1.
C17H29ClN5O5S (415.51): calcd. C 49.14, H 7.03, N 16.85; found
C 48.80, H 7.22, N 16.82.
Energy
J
TSJ
11a
11a + SO4
Ee
–1703.63582
0
–1703.47746
0
–1703.61125 –1004.32236 –1703.67649
15.42 –25.53
–1703.45305 –1004.16961 –1703.53604
15.32 –36.76
∆Ee
Go
General Procedure for the Synthesis of 2-Aryl-6,7-dihydro-2H-
imidazo[2,1-c][1,2,4]triazol-3(5H)-ones (5): 2-Hydroxyamino-4,5-di-
hydroimidazolium O-sulfonate (1; 0.9 g, 5 mmol) and triethylamine
(1.4 mL, 10 mmol) were added to DMF (4 mL). The suspension
was stirred at room temperature for 3 min until a clear solution
of the triethylaminium 2-(hydroxyimino)imidazolidine O-sulfonate
salt (2) was formed. The corresponding isocyanate (3; 0.7 mL,
5.5 mmol) was introduced and the reaction mixture was kept at
80 °C for 0.5 h. Then the reaction mixture was quenched with 5%
NaOH (10 mL) and the precipitated product 5 was filtered and
washed with water and acetone. Compound 5a was also obtained in
90% yield by treatment of triethylaminium salt 4a with 5% NaOH
solution.
∆G
[a] Electronic energies and Gibbs free-energies are given in Har-
trees. The relative energies (∆Ee and ∆G) are given in kcal/mol.
All the investigated reactions are exothermic with ∆G
ranging from –19.64 to –59.52 kcal/mol (Table 1). The reac-
tion of the aryl amidate anion E has the lowest barrier and
is considerably more exothermic than the corresponding
reaction of the aryl thioamidate J and especially the aryl-
sulfonyl amidate anion H.
2-(4-Methylphenyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-
3(5H)-one (5a): Yield 0.76 g (71 %); m.p. 200–203 °C. 1H NMR
(200 MHz, [D6]DMSO): δ = 2.26 (s, 3 H, CH3), 3.85 (s, 4 H, CH2),
6.91 (s, 1 H, NH), 7.15 (d, J = 8.6 Hz, 1 H, CH), 7.65 (d, J =
Conclusions
The synthetically useful intramolecular nucleophilic sub-
stitution at an electron-deficient sp2 nitrogen atom de-
scribed herein represents a facile route to 2-aryl(arylsulf- 8.6 Hz, 1 H, CH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 20.6,
40.2, 47.9, 117.0, 129.4, 132.3, 137.1, 148.9, 154.9 ppm. IR (KBr):
onyl)imidazo[2,1-c][1,2,4]triazol-3-ones 5 and 8 or 3-imino-
imidazo[2,1-c][1,2,4]thiadiazoles 11, which may find poten-
tial pharmaceutical use as antibacterial and antiprolifera-
tive agents or neuropeptide Y receptor (NPY) antagonists.
Of the possible reaction mechanisms, the SN2σ pathway is
feasible. This behaviour adds to the attractiveness of HN–
C=N–O-containing azoles and may lead to a number of
possible applications in heterocyclic synthesis.
ν = 3236, 2899, 1697, 1615, 1512, 1368, 1294, 819 cm–1. C H N O
˜
11 12
4
(216.24): calcd. C 61.10, H 5.59, N 25.91; found C 60.98, H 5.82,
N 25.77.
2-[3-(Trifluoromethyl)phenyl]-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]-
1
triazol-3(5H)-one (5b): Yield 0.92 g (68%); m.p. 159–165 °C. H
NMR (200 MHz, [D6]DMSO): δ = 3.89 (s, 4 H, CH2), 7.11 (s, 1
H, NH), 7.41 (d, J = 7.8 Hz, 1 H, CH), 7.61 (t, J = 7.8 Hz, 1 H,
CH), 8.06 (d, J = 7.8 Hz, 1 H, CH), 8.11 (s, 1 H, CH) ppm. 13C
NMR (50 MHz, [D6]DMSO): δ = 40.3, 47.9, 112.6 (q, J = 4 Hz),
119.4 (q, J = 4 Hz), 120.1, 130.4, 139.9, 149.1, 155.4 ppm. IR
Experimental Section
(KBr): ν = 3335, 2985, 2907, 1725, 1670, 1516, 1494, 1466, 1368,
˜
1320, 1166, 1119 cm–1. C11H9F3N4O (270.21): calcd. C 48.89, H
3.36, N 20.73; found C 48.87, H 3.40, N 20.56.
General: Melting points were determined with a Boëtius melting
point apparatus. The IR spectra were recorded with a Thermo Sci-
entific Nicolet FTIR spectrometer using a mixture of the com-
pound and KBr. 1H and 13C NMR spectra were recorded with a
General Procedure for the Synthesis of 2-(Arylsulfonyl)-6,7-dihydro-
2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ones (8): 2-Hydroxyamino-
Varian Gemini 200 or Varian Unity Plus 500 spectrometer. The 4,5-dihydroimidazolium O-sulfonate (1; 0.9 g, 5 mmol) and trieth-
chemical shifts were measured relative to the residual solvent sig- ylamine (1.4 mL, 10 mmol) were added to DMF (4 mL). The sus-
nals at 2.50 or 7.26 ppm and 39.50 or 77 ppm, respectively. All
reagents were used directly as obtained commercially. 2-Hy-
droxyamino-4,5-dihydroimidazolium O-sulfonate (1), triethylamin-
pension was stirred at room temperature for 3 min until a clear
solution of the triethylaminium 2-(hydroxyimino)imidazolidine O-
sulfonate salt (2) was formed. Subsequently, the corresponding car-
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bamoylide 7 was added and the reaction mixture was heated at
100 °C with stirring for 5 min. When the carbamoylide had dis-
solved the heating and stirring were stopped and the solution was
left at room temperature for 12 h. Then the solvent was evaporated
under reduced pressure and the resulting residue was treated with
methanol. The precipitated product 8 was washed with methanol
followed by water and dried in vacuo. Compound 8b was also ob-
tained by using 4-methylbenzenesulfonyl isocyanate as a substrate.
IR (KBr): ν = 3349, 3092, 1748, 1660, 1559, 1500, 1402, 1371, 1282,
˜
1179 cm–1. C9H8ClN5O3S (301.71): calcd. C 35.83, H 2.67, N 23.21;
found C 35.66, H 2.82, N 23.17.
7-Acetyl-2-(4-methylphenylsulfonyl)-6,7-dihydro-2H-imidazo[2,1-c]-
[1,2,4]triazol-3(5H)-one (9): 2-(4-Methylphenylsulfonyl)-6,7-dihy-
dro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-one (8b; 0.2 g,
0.714 mmol) was dissolved in pyridine (1 mL). The reaction mix-
ture was cooled to 0 °C and acetyl chloride (0.25 mL, 3.5 mmol)
was added dropwise with stirring. After 30 min the reaction mix-
ture was quenched with water (1 mL) and evaporated under re-
duced pressure. The residue was dissolved in dichloromethane, fil-
tered and purified on silica with the use of a chromatotron (ethyl
acetate); yield 0.08 g (34.8 %); m.p. 230–232 °C. 1H NMR
(200 MHz, CDCl3): δ = 2.44 (s, 3 H, CH3), 2.48 (s, 3 H, CH3), 3.88
(t, J = 7.4 Hz, 2 H, CH2), 4.33 (t, J = 7.4 Hz, 2 H, CH2), 7.36 (d,
J = 8.4 Hz, 2 H, CH), 7.94 (d, J = 8.4 Hz, 2 H, CH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 22.2, 24.1, 38.6, 49.3, 128.6, 130.5,
2-(Phenylsulfonyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-
3(5H)-one (8a): Yield 0.82 (62 %); m.p. 246–252 °C. 1H NMR
(200 MHz, [D6]DMSO): δ = 3.73 (s, 4 H, CH2), 7.22 (s, 1 H, NH),
7.60–7.88 (m, 5 H, CH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ =
39.7, 47.3, 127.3, 129.6, 134.4, 137.1, 148.8, 156.2 ppm. IR (KBr): ν
˜
= 3366, 2910, 1755, 1662, 1500, 1488, 1450, 1366, 1287, 1185, 1169,
1116, 1027, 880 cm–1. C10H10N4O3S (266.28): calcd. C 45.11, H
3.79, N 21.04; found C 44.93, H 3.97, N 20.86.
2-(4-Methylphenylsulfonyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]tri-
azol-3(5H)-one (8b): Yield from ylide: 0.87 g (62%); yield from iso-
cyanate: 0.93 g (66%); m.p. 262–268 °C. 1H NMR (200 MHz, [D6]-
DMSO): δ = 2.35 (s, 3 H, CH3), 3.82 (s, 4 H, CH2), 7.23 (s, 1 H,
NH), 7.42 (d, J = 8.4 Hz, 1 H, CH), 7.73 (d, J = 8.4 Hz, 1 H,
CH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 21.1, 39.7, 47.3,
134.8, 146.3, 148.3, 148.8, 168.1 ppm. IR (KBr): ν = 2929, 1756,
˜
1706, 1651, 1504, 1457, 1372, 1303, 1178 cm–1. C13H14N4O4S
(322.34): calcd. C 48.44, H 4.38, N 17.38; found C 48.41, H 4.33,
N 17.26.
7-Benzyl-2-(4-methylphenylsulfonyl)-6,7-dihydro-2H-imidazo[2,1-c]-
[1,2,4]triazol-3(5H)-one (10): 2-(4-Methylphenylsulfonyl)-6,7-di-
hydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-one (8b; 0.2 g,
0.714 mmol) was dissolved in DMSO (4 mL) and powdered NaOH
(0.06 g, 1.5 mmol) was added with stirring. Subsequently benzyl
bromide (0.128 mL, 1.07 mmol) was introduced dropwise. After 6 h
of stirring the reaction mixture was quenched with water (20 mL)
and extracted with dichloromethane (3ϫ10 mL). The combined
organic layers were dried with anhydrous sodium sulfate, filtered
and evaporated under reduced pressure. The residue was dissolved
in dichloromethane and purified on silica with the use of a chro-
matotron (ethyl acetate); yield 0.06 g (23.1%); m.p. 134–136 °C. 1H
NMR (200 MHz, CDCl3): δ = 2.46 (s, 3 H, CH3), 3.63 (t, J =
7.3 Hz, 1 H, CH2), 3.75 (t, J = 7.3 Hz, 1 H, CH2), 4.37 (s, 2 H,
CH2), 7.24–7.26 (m, 2 H, CH), 7.33–7.35 (m, 3 H, CH), 7.36 (d, J
= 8.3 Hz, 2 H, CH), 7.98 (d, J = 8.3 Hz, 2 H, CH) ppm. 13C NMR
(50 MHz, CDCl3): δ = 22.2, 39.8, 49.6, 51.6. 128.6, 128.8, 128.9,
127.3, 130.0, 134.2, 145.1, 148.8, 156.1 ppm. IR (KBr): ν = 3377,
˜
2913, 1748, 1669, 1498, 1459, 1365, 1289, 1188, 1171, 1116,
815 cm–1. C11H12N4O3S (280.30): calcd. C 47.13, H 4.32, N 19.99;
found C 46.96, H 4.54, N 19.79.
2-(4-Chlorophenylsulfonyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]tri-
azol-3(5H)-one (8c): Yield 1.04 g (69%); m.p. 264–269 °C. 1H NMR
(500 MHz, [D6]DMSO): δ = 3.74–3.76 (m, 4 H, CH2), 7.28 (s, 1 H,
NH), 7.74 (d, J = 8.3 Hz, 1 H, CH), 7.86 (d, J = 8.3 Hz, 1 H,
CH) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 39.7, 47.3, 129.2,
129.8, 135.7, 139.4, 148.8, 156.4 ppm. IR (KBr): ν = 3365, 3091,
˜
2911, 1741, 1622, 1503, 1475, 1380, 1288, 1187, 1012, 832,
757 cm–1. C10H9ClN4O3S (300.72): calcd. C 39.94, H 3.02, N 18.63;
found C 39.71, H 3.30, N 18.48.
2-(4-Nitrophenylsulfonyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]tri-
azol-3(5H)-one (8d): Yield 0.69 g (44%); m.p. 247–248 °C. 1HNMR
(200 MHz, [D6]DMSO): δ = 3.75 (s, 4 H, CH2), 7.34 (s, 1 H, NH),
8.12 (d, J = 7.8 Hz, 2 H, CH), 8.46 (d, J = 7.8 Hz, 2 H, CH) ppm.
13C NMR (50 MHz, [D6]DMSO): δ = 40.1, 47.6, 125.2, 129.3,
129.4, 130.2, 135.1, 135.3, 145.6, 149.5, 154.9 ppm. IR (KBr): ν =
˜
3057, 2959, 1761, 1648, 1507, 1376, 1189, 1175 cm–1. C18H18N4O3S
(370.43): calcd. C 58.36, H 4.90, N 15.12; found C 58.11, H 5.13,
N 14.98.
142.2, 148.9, 151.0, 156.9 ppm. IR (KBr): ν = 3238, 2984, 2906,
˜
1766, 1686, 1531, 1372, 1349, 1297, 1183, 1126, 740 cm–1
.
N-(6,7-Dihydroimidazo[2,1-c][1,2,4]thiadiazol-3(5H)-ylidene)-4-meth-
ylaniline (11b): 2-Hydroxyamino-4,5-dihydroimidazolium O-sulfo-
nate (1; 0.9 g, 5 mmol) and triethylamine (0.8 mL, 5.7 mmol) were
added to DMF (10 mL). The suspension was stirred at room tem-
perature for 3 min until a clear solution of the triethylaminium 2-
(hydroxyimino)imidazolidine O-sulfonate salt (2) was formed. Sub-
sequently, p-tolyl isothiocyanate (0.75 g, 5 mmol) was added and
the reaction mixture was heated at 40 °C with stirring for 12 h.
Then the solvent was evaporated under reduced pressure and the
resulting residue was treated with methanol. The precipitated prod-
uct 11b was washed with 5% NaOH solution and water. The crude
product was crystallized from DMF and dried in vacuo; yield
C10H9N5O5S (311.27): calcd. C 38.59, H 2.91, N 22.50; found C
38.14, H 3.20, N 22.19.
2-(2,4,6-Triisopropylphenylsulfonyl)-6,7-dihydro-2H-imidazo[2,1-c]-
[1,2,4]triazol-3(5H)-one (8e): Yield 0.45 g (23%); m.p. 180–182 °C.
1H NMR (200 MHz, [D6]DMSO): δ = 1.15 (d, J = 6.8 Hz, 12 H,
CH3), 1.21 (d, J = 6.8 Hz, 6 H, CH3), 2.93 (sept, J = 6.8 Hz, 1 H,
CH), 3.79 (s, 4 H, CH2), 4.22 (sept, J = 6.8 Hz, 2 H, CH), 7.19 (s,
1 H, NH), 7.29 (s, 2 H, CH) ppm. 13C NMR (50 MHz, [D6]-
DMSO): δ = 23.6, 24.7, 28.9, 33.7, 40.1, 47.8, 124.2, 131.5, 148.2,
151.4, 154.2, 155.8 ppm. IR (KBr): ν = 3262, 3057, 2957, 2867,
˜
1763, 1673, 1602, 1503, 1383, 1293, 1112 cm–1. C10H9N5O5S
(392.52): calcd. C 58.14, H 7.19, N 14.27; found C 58.03, H 7.35,
N 14.01.
1
0.23 g (18%); m.p. 208–209 °C (DMF). H NMR (200 MHz, [D6]-
DMSO): δ = 2.25 (s, 3 H, CH3), 3.89 (s, 4 H, CH2), 6.80 (d, J =
2-(4-Chloropyridin-3-ylsulfonyl)-6,7-dihydro-2H-imidazo[2,1-c]- 8.0 Hz, 2 H, CH2), 7.10 (d, J = 8.0 Hz, 2 H, CH), 7.33 (s, 1 H,
[1,2,4]triazol-3(5H)-one (8f): Yield 0.51 g (34%); m.p. 228 °C (dec.).
1H NMR (200 MHz, [D6]DMSO): δ = 3.82 (s, 4 H, CH2), 7.31 (s,
1 H, NH), 7.88 (d, J = 5.4 Hz, 1 H, CH), 8.85 (d, J = 5.4 Hz, 1 H,
NH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 20.7, 41.6, 47.0,
120.8, 130.0, 132.26, 147.36, 157.5, 158.7 ppm. IR (KBr): ν = 3189,
˜
1648, 1627, 1599, 1483 cm–1. MS (EI): m/z = 232 (100) [M]+.
CH), 9.01 (s, 1 H, CH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ C11H12N4S (232.30): calcd. C 56.87, H 5.21, N 24.12; found C
= 39.8, 47.4, 126.8, 131.6, 141.8, 147.8, 151.3, 155.7, 156.2 ppm.
56.58, H 5.30, N 23.95.
2392
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2387–2394

Heterocycles by Intramolecular Nucleophilic Substitution
N-Phenyl-3-(phenylimino)-5,6-dihydro-7H-imidazo[2,1-c][1,2,4]thia- 100.569(4), γ = 92.532(4)°, V = 592.94(5) Å3, Z = 2, dx = 1.684 g/
diazole-7-carbothioamide (12a): Hydroxyamino-4,5-dihydroimid-
azolium O-sulfonate (1; 0.9 g, 5 mmol) and triethylamine (0.8 mL,
cm3, T = 294 K. Data were collected by using a crystal with dimen-
sions 0.5ϫ0.15ϫ0.10 mm. Final R indices for 1890 reflections
5.7 mmol) were added to DMF (10 mL). The suspension was with IϾ2σ(I) and 172 refined parameters are R1 = 0.0299 and wR2
stirred at room temperature for 3 min until a clear solution of the
triethylaminium 2-(hydroxyimino)imidazolidine O-sulfonate salt
(2) was formed. Subsequently phenyl isothiocyanate (1.2 mL,
10 mmol) was added and the reaction mixture was heated at 40 °C
with stirring for 12 h. Then the solvent was evaporated under re-
duced pressure and the resulting residue was treated with methanol.
The precipitated product 12a was washed with a 5% NaOH solu-
tion and water. The crude product was crystallized from DMF and
dried in vacuo; yield 0.9 g (51 %); m.p. 188–189 °C (DMF). 1H
NMR (200 MHz, CDCl3): δ = 4.20 (t, J = 7.8 Hz, 2 H, CH2), 4.88
(t, J = 7.8 Hz, 2 H, CH2), 7.08 (d, J = 7.8 Hz, 2 H, CH), 7.20 (t,
J = 7.3 Hz, 1 H, CH), 7.28–7.30 (m, 2 H, CH), 7.38–7.44 (m, 3 H,
CH), 7.59 (d, J = 7.3 Hz, 2 H, CH), 11.17 (s, 1 H, NH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 39.3, 53.5, 121.0, 124.9, 125.0, 126.0,
= 0.0809 (R1 = 0.0416 and wR2 = 0.0867 for all 2412 data).[54]
Crystal Data for C17H13Cl2N5S2 (12c): Monoclinic, space group
P21/c, a = 10.5880(6), b = 14.5965(7), c = 11.5524(6) Å, β =
101.268(5)°, V = 1750.98(16) Å3, Z = 4, dx = 1.602 g/cm3, T =
193 K. Data were collected by using a crystal with dimensions
0.4ϫ0.3ϫ0.05 mm. The final R indices for 2956 reflections with
IϾ2σ(I) and 249 refined parameters are R1 = 0.0325 and wR2
=
0.0877 (R1 = 0.0410 and wR2 = 0.0920 for all 3554 data).[54]
Computational Methods: All the calculations presented in this pa-
per were carried out with the Spartan 08 program package pro-
vided by Wavefunction, Inc.[56] The geometries were fully optimized
in vacuo by using the DFT B3LYP method with the diffuse func-
tions 6-31+G* basis set. Frequency calculations were performed
for all structures to prove the energy minima. The geometries of
the transition states found showed single imaginary frequencies
pertaining to N–N or N–S bond formation and N–O bond break-
age. The SN2σ reaction energy profiles were derived from calcula-
tions at the DFT B3LYP/6-31+G* level of theory with application
of the water (formation of 5) and DMF (formation of 8 and 11a)
SM8[55] solvation models. The Gibbs free energies were obtained
from electronic energies corrected with zero-point vibrational ener-
gies (ZPE), thermal energies involving a temperature increase from
0 to 298.15 K and entropies. The relative energies were obtained by
subtracting the energy of the lowest-energy structures (dianions)
from the energies of all the other geometries and converting these
differences into kcal/mol.
129.2, 129.9, 138.3, 148.7, 150.9, 156.3, 176.3 ppm. IR (KBr): ν =
˜
1616, 1583, 1570, 1480, 1433 cm–1. MS (EI): m/z = 353 (100)
[M]+, 218 (99.5) [M – PhNCS]+, 135 (25.8). C17H15N5S2 (353.46):
calcd. C 57.77, H 4.28, N 19.81; found C 57.68, H 4.29, N 19.66.
N-(4-Chlorophenyl)-3-(4-chlorophenylimino)-7H-imidazo[2,1-c]-
[1,2,4]thiadiazole-7-carbothioamide (12c): Hydroxyamino-4,5-dihy-
droimidazolium O-sulfonate (1; 0.9 g, 5 mmol) and triethylamine
(0.8 mL, 5.7 mmol) were added to DMF (10 mL). The suspension
was stirred at room temperature for 3 min until a clear solution
of the triethylaminium 2-(hydroxyimino)imidazolidine O-sulfonate
salt (2) was formed. Subsequently, 4-chlorophenyl isothiocyanate
(1.7 g, 10 mmol) was added and the reaction mixture was heated at
40 °C with stirring for 12 h. Then the solvent was evaporated under
reduced pressure and the resulting residue was treated with meth-
anol. The precipitated product 12c was washed with a 5% NaOH
solution and water. The crude product was crystallized from DMF
and dried in vacuo; yield 0.41 g (19%); m.p. 208–209 °C (DMF).
1H NMR (200 MHz, [D6]DMSO): δ = 3.98–4.06 (m, 2 H, CH2),
4.64–4.72 (m, 2 H, CH2), 6.98–7.04 (m, 2 H, CH), 7.41–7.52 (m, 4
H, CH), 7.59–7.65 (m, 2 H, CH), 11.12 (s, 1 H, NH) ppm. 13C
NMR (50 MHz, [D6]DMSO): δ = 40.1, 54.2, 122.6, 126.6, 128.1,
Supporting Information (see also the footnote on the first page of
this article): B3LYP 6-31+G* geometries and imaginary fre-
quencies for TSE, TSH and TSJ transition-state stationary points.
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Eur. J. Org. Chem. 2010, 2387–2394
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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J. Saczewski, M. Gdaniec
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Published Online: March 9, 2010
2394
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Eur. J. Org. Chem. 2010, 2387–2394