Synthesis of 2-thio- and 2-oxoimidazoles via cascade addition- cycloisomerization reactions of propargylcyanamides

Article abstract of DOI:10.1021/jo902326d

(Chemical Equation Presented) A methodology to generate 2-thio- and 2-oxoimidazoles through an addition-cyclization-isomerization reaction of propargylcyanamides with thiol and alcohol nucleophiles is described. In general, the reaction sequence allows for the rapid formation of highly substituted 2-thio- and 2-oxoimidazoles in good to excellent yields.

Full text of DOI:10.1021/jo902326d

pubs.acs.org/joc
Synthesis of 2-Thio- and 2-Oxoimidazoles via
Cascade Addition-Cycloisomerization Reactions
of Propargylcyanamides
Robert L. Giles, Richard A. Nkansah, and Ryan E. Looper*
Department of Chemistry, University of Utah, 315 South
1400 East, Salt lake City, Utah 84112
FIGURE 1. Medicinally relevant 2-thio- and 2-oxoimidazoles.
r.looper@utah.edu
dized electrophiles and can give mixtures of S/O and N
alkylated products.
Received October 30, 2009
Our interest in the chemistry and biology of 2-aminoimi-
dazoles10 prompted us to develop a one-pot addition-
hydroamination-isomerization sequence to access these
related heterocycles.11 This approach generates highly
substituted 2-aminoimidazoles in just three steps by the
addition of secondary amines to propargylcyanamides, as
shown in Scheme 1. This reaction required the addition of a
metal catalyst and it was eventually found that La(III)
promotes the reaction effectively.
A methodology to generate 2-thio- and 2-oxoimidazoles
through an addition-cyclization-isomerization reaction
of propargylcyanamides with thiol and alcohol nucleo-
philes is described. In general, the reaction sequence
allows for the rapid formation of highly substituted
2-thio- and 2-oxoimidazoles in good to excellent yields.
SCHEME 1. Addition-Hydroamination-Isomerization
Sequence
Both 2-thio- and 2-oxoimidazoles represent medicinally
important heterocyclic scaffolds. These target substructures
are central to compounds possessing inhibitory activity
against HIV-1 reverse transcriptase,1 p38 MAP kinase,2 as
well as histamine-H3 antagonists3 (Figure 1). They have also
been documented as key pharmacophores in agents for the
treatment of thrombosis,4 inflammation, and asthma.5 The
preparation of these heterocycles is usually accomplished by
nucleophilic substitution of activated 2-sulfonyl-,6 2-nitro-,7
or 2-haloimidazoles8 or by the alkylation of imidazo-
lethiones.9 The substitution approach is often lengthy
requiring multiple protecting group and oxidation manipu-
lations, while alkylation is generally restricted to sp3 hybri-
We felt that the success of this methodology might be
expanded to incorporate the addition of sulfur and oxy-
gen nucleophiles to propargylcyanamides to rapidly synthe-
size 2-thio- and 2-oxoimidazoles.12 This approach would
obviate the need to prepare an activated imidazole for
nucleophilic substitution. It would also allow for S/O build-
ing blocks to be introduced as nucleophiles, thus com-
plementing imidazolethione alkylation. In particular it
would broaden substituent diversity with the inclusion of
an S/O substituent bearing an adjacent sp2 hybridized
carbon atom.
One of the key aspects to this chemistry is the rapid pre-
paration of the propargylcyanamide precursors (Table 1).
The propargylcyanamides (2a-d) used in this study were
prepared in two steps by a iminium-acetylide three-compo-
nent coupling (3-CC) to give the propargylamines 1a-d.13
Cleavage of the tertiary amine with cyanogen bromide
gave the propargylcyanamides 2a-d with cleavage of the
(1) (a) Loksha, Y. M.; Ei-Barbary, A. A.; El-Baadawi, M. A.; Nielsen, C.;
Pedersen, E. B. Bioorg. Med. Chem. 2005, 13, 4209. (b) Loksha, Y. M.;
El-Baadawi, M. A.; Ei-Barbary, A. A.; Pedersen, E. B.; Nielsen, C. Arch.
Pharm. Pharm. Med. Chem. 2003, 336, 175.
(2) Laufer, S. A.; Hauser, D. R. J.; Domeyer, D. M.; Kinkel, K.; Liedtke,
A. J. J. Med. Chem. 2008, 51, 4122.
(3) Jablonowski, J. A.; Ly, K. S.; Bogenstaetter, M.; Dvorak, C. A.;
Boggs, J. D.; Dvorak, L. K.; Lord, B.; Miller, K. L.; Mazur, C.; Wilson, S. J.;
Lovenberg, T. W.; Carruthers, N. I. Bioorg. Med. Chem. Lett. 2009, 19, 203.
(4) Nishi, T.; Uno, T.; Koga, Y.; Chu, G. N. Patent EP 240015, 1987.
(5) Fenske, D. C.; Kuo, E. A.; Tully, W. R. U.S. Patent 4,810,828, 1989.
(6) Jarosinski, M. A.; Anderson, W. K. J. Org. Chem. 1991, 56, 4058.
(7) Goldamn, P.; Wuest, J. D. J. Am. Chem. Soc. 1981, 103, 6224.
(8) Heras, M.; Ventura, M.; Linden, A.; Villalgordo, J. M. Synthesis 1999,
1613.
(10) Sullivan, J. D.; Giles, R. L.; Looper, R. E. Curr. Bioact. Compd. 2009,
5, 39.
(11) Giles, R. L.; Sullivan, J. D.; Steiner, A. M.; Looper, R. E. Angew.
Chem., Int. Ed. 2009, 48, 3116.
(12) A conceptually related sequence has been reported for the addi-
tion of H2S to allenylthioureas to generate imidazolethiones: Devan, B.;
Rajagopalan, K. Tetrahedron Lett. 1994, 35, 1585.
(9) For representative examples see: (a) Tweit, R. C.; Kreider, E. M.; Muir,
R. D. J. Med. Chem. 1973, 16, 1161. (b) Anderson, W. K.; Bhattacharjee, D.;
Houston, D. M. J. Med. Chem. 1989, 32, 119. (c) Theoclitou, M.-E.; Delaet,
N. G. J.; Robinson, L. A. J. Comb. Chem. 2002, 4, 315.
(13) (a) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002,
41, 2535. (b) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew.
Chem., Int. Ed. 2003, 42, 5763. (c) Aschwanden, P.; Stephenson, C. R. J.;
Carreira, E. M. Org. Lett. 2006, 8, 2437.
DOI: 10.1021/jo902326d
r
Published on Web 12/02/2009
J. Org. Chem. 2010, 75, 261–264 261
2009 American Chemical Society

Giles et al.
JOCNote
TABLE 1. Synthesis of Propargylcyanamides
TABLE 2. Scheme 2 Synthesis of 2-Thioimidazoles
intermediate cyanoammonium salt at the activated benzylic
position of the PMB group.14
We initially investigated the addition of neutral thiols to
initiate the addition-cyclization-isomerization sequence.
While we observed formation of 3a after heating a solution
of the propargylcyanamide 2a with ethanethiol, only ∼5% of
the propargylcyanamide had been converted to the desired
2-thioimidazole after 24 h at 150 °C. The poor electrophilic
nature of N,N-dialkylcyanamides suggested that a Lewis
acid catalyst or an anionic species would be required to effect
addition to the cyanamide.15,16 In contrast to the addition of
amines to propargylcyanamides, La(III) did not catalyze
product formation.11 This was worrisome as we had pre-
viously noted that the propargylcyanamides undergo iso-
merization to the allenecyanamides under basic conditions,
resulting in decomposition/polymerization. Thus it was
questionable if thiolate anions (pKa ≈ 8-11)17 would be
capable of isomerizing the propargylcyanamides. Fortu-
nately, the addition of 5 equiv of Hunig’s base in the reaction
mixture led to complete consumption of the propargylcya-
namide after only 12 h at 120 °C to give 2-ethylthioimidazole
3a in 67% yield (Table 2, entry 1). Treatment of the other
cyanamides under the same conditions gave comparative
results (entries 2-4). Benzylic thiols also gave the 2-thioimi-
dazoles in moderate to good yields (Table 2, entries 5-8).
Thiophenols are also competent partners in this reaction
sequence (Table 2, entries 9-12) and react chemoselectively
in the presence of phenols (Table 2, entries 13-16).
however, we found that the use of dithiols in the presence of
1.5 equiv of cyanamide per thiol was capable of producing bis-
2-thioimidazoles 7a and 7b in good yields (Scheme 2).
Since we had noted that isopropanol was a noncompetitive
solvent for the La(III) catalyzed addition of amines to
cyanamides, it was not surprising to observe that they were
not competent nucleophiles in the addition-cycloisomeriza-
tion sequence under neutral conditions.11 Also, we had
previously observed that sterically hindered alkoxides
(KOtBu in THF) quantitatively isomerized propargylcyana-
mides to the allenecyanamides in ∼10 min at 0 °C. Due to
the increased basicity of alkoxides relative to thiolates,
which could favor isomerization over addition to the cyana-
mide, we were pessimistic that phenoxides or alkoxides
For experimental convenience we were using an excess of
thiol in the addition-cyclization-isomerization sequence;
(14) von Braun, J. Chem. Ber. 1900, 33, 1438.
(15) Snider, B. B.; O’Hare, S. M. Tetrahedron Lett. 2001, 42, 2455.
(16) Dalby, K. N.; Jencks, W. P J. Chem. Soc., Perkin Trans. 2 1997, 1555.
(17) (a) Pascal, I.; Tarbell, D. S. J. Am. Chem. Soc. 1957, 79, 6015.
(b) Kreevoy, M. M.; Harper, E. T.; Duvall, R. E.; Wilgus, H. S. III; Ditsch, L.
T. J. Am. Chem. Soc. 1960, 82, 4899.
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SCHEME 2. Synthesis of Bis-2-thioimidazoles
Studies to elucidate this mechanistic difference are currently
underway and will be reported in due course.
Experimental Section
Typical Procedure for the Preparation of Propargylamines.
N,N-Bis(4-methoxybenzyl)-3-(4-methoxyphenyl)prop-2-yn-
1-amine (1a). To a 100 mL round-bottomed flask containing a
magnetic stir bar was added bis(4-methoxybenzyl)amine
(PMB2NH) (3.73 g, 14.5 mmol, 1.0 equiv), 37% aqueous solu-
tion of formaldehyde (6.54 g, 6.00 mL, 80.6 mmol, 5.6 equiv),
4-methoxyphenyl acetylene (2.02 g, 15.3 mmol, 1.06 equiv),
CuBr (0.209 g, 1.45 mmol, 0.1 equiv), and MeCN (45 mL).
The reaction mixture was allowed to stir at room temperature
for 24 h. The reaction mixture was filtered through a plug of
Celite before the solvent was removed under reduced pressure.
Purification of the material was accomplished by flash column
chromatography on a 5.7 ꢀ 15 cm column, eluting with 20%
ethyl acetate/hexanes. The product containing fractions were
combined and then concentrated under reduced pressure to give
propargylamine 1a (5.77 g, 98% yield) as a light yellow oil. Rf
0.49 (35% ethyl acetate /hexanes). 1H NMR (CDCl3, 500 MHz):
δ 7.45 (ddd, J = 9.5, 2.5, 2.0 Hz 2H), 7.35 (ddd, J = 8.4, 2.9, 1.8
Hz 4H), 6.90-6.86 (m, 6H), 3.81 (s, 6H), 3.83 (s, 3H), 3.80 (s,
6H), 3.67 (s, 2H), 3.43 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ
159.6, 159.0, 133.4, 131.3, 130.5, 115.8, 114.2, 113.9, 85.8, 83.2,
57.1, 55.6, 55.5, 42.0. 13C DEPT NMR (CDCl3, 125 MHz): δ
CH3: (2 ꢀ 55.4); CH2: 57.0, 41.8; CH1: 133.3, 132.3, 131.1, 114.0,
113.8; CH0: 158.9, 85.8, 83.2. IR (neat): 2933, 2834, 1607, 1509,
1463, 1291, 1246, 1172, 1106, 1034, 832, 668 cm-1. HRMS (ESI)
calcd for C26H28NO3 m/z (M þ H) 402.2069, obsd 402.2055.
Typical Procedure for the Preparation of Propargylcyan-
amides. N-(4-Methoxybenzyl)-N-(3-(4-methoxyphenyl)prop-2-yn-
1-yl)cyanamide (2a). To a 250 mL round-bottomed flask contain-
ing a magnetic stir bar was added propargylamine 1a (5.030 g, 12.5
mmol, 1.0 equiv), 3 M solution of CNBr in CH2Cl2 (8.40 mL, 25.1
mmol, 2.0 equiv), K2CO3 (3.916 g, 28.33 mmol, 2.3 equiv), and
dioxane (125 mL). The reaction mixture was allowed to stir at rt
for 24 h before being quenched with a saturated aqueous solution
of NaHCO3 (25 mL). The reaction mixture was diluted in CH2Cl2
(100 mL) and water (50 mL) and the layers were separated. The
aqueous phase was extracted with CH2Cl2 (2 ꢀ 25 mL). The
organic extract was then dried over Na2SO4, filtered, and concen-
trated under reduced pressure. Purification of the material was
accomplished by flash column chromatography on a 5.7 ꢀ 15 cm
column, eluting with 20% ethyl acetate/hexanes. The product
containing fractions were combined and then concentrated under
reduced pressure to give cyanamide 2a (3.608 g, 94% yield) as a
would be competent nucleophiles in this chemistry. Contrary
to our assumptions, treatment of cyanamide 2a with phe-
nol in the presence of K2CO3 successfully delivered the
2-phenoxyimidazole (8a) in 77% yield (Table 3, entry 1).
Toluene proved to be the best solvent for temperature con-
siderations.
TABLE 3. Synthesis of 2-Oxoimidazoles
We then pressed our nucleophile choice to alkoxides and
were quite surprised to see that MeOH and Huning’s base
gave the methoxyimidazole 8d in 72% yield (Table 3, entry 4).
The use of K2CO3 worked equally as well to promote the
reaction (entry 5). We were quite surprised to see that iPrOH,
the solvent choice for the La(III) catalyzed amine addition-
hydroamination-isomerization manifold, delivered the
2-isopropoxyimidazole 8e in 67% yield with the addition
of K2CO3 (entry 6).
In conclusion we have developed optimal conditions for
the addition of both alkyl and aryl thiols and alcohols to
propargylcyanamides. Subsequent cycloisomerization deli-
vers the 2-thio- or 2-oxoimidazoles in good yields. The fact
that equimolar KOtBu decomposes the substrates but cata-
lytically generated nucleophiles (e.g., K2CO3/iPrOH) are
competent partners suggests that thio- or oxo-nucleophiles
with a pKa < ∼18 should be tolerated under these condi-
tions. Interestingly La(III) does not influence the reaction of
thio- or oxo-nucleophiles with propargylcyanamides, sug-
gesting a unique catalytic role for La(III) in the addition-
hydroamination-isomerization sequence with amines.
1
light yellow oil. Rf 0.40 (35% ethyl acetate/hexanes). H NMR
(CDCl3, 500 MHz): δ7.40 (d, J = 9.0 Hz, 2H), 7.31 (d, J= 9.0 Hz,
2H), 6.91 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 4.26 (s,
2H), 3.92 (s, 2H), 3.81 (s, 3H), 3.80 (s, 3H). 13C NMR (CDCl3, 125
MHz): δ 160.3, 160.2, 133.6, 130.7, 126.0, 117.7, 114.5, 114.4,
114.3, 114.2, 87.2, 80.1, 55.6, 55.5, 54.3, 41.1. 13C DEPT NMR
(CDCl3, 125 MHz): δ CH3: 55.6, 55.5; CH2: 54.3, 41.1; CH1: 133.6,
130.7, 114.5, 114.3; CH0: 160.3, 160.2, 126.0, 117.7, 114.5, 114.4,
87.2, 80.1. IR (neat): 2931, 2836, 1721, 1643, 1612, 1585, 1512,
1491, 1453, 1407, 1359, 1302, 1247, 1223, 1175, 1145, 1107, 1078,
1034, 905 822, 758, 696 cm-1. HRMS (ESI) calcd for m/z
C19H18N2NaO2 (M þ Na) 329.1266, obsd 329.1263.
Typical Procedure for the Preparation of 2-Thioimidazoles.
Preparation of 2-(Ethylthio)-1,4-bis(4-methoxybenzyl)-1H-imi-
dazole (3a). To a 15 mL high-pressure tube containing a
magnetic stir bar was added cyanamide 2a (0.107 g, 0.347 mmol,
1.0 equiv), ethanethiol (0.216 g, 260 μL, 3.47 mmol, 10.0 equiv),
N,N-diisopropylethylamine (0.674 g, 910 μL, 5.21 mmol, 15.0
equiv), and isopropanol (2 mL). The high-pressure tube was
then sealed and placed in a preheated 120 °C oil bath. After 24 h
J. Org. Chem. Vol. 75, No. 1, 2010 263

Giles et al.
JOCNote
at 120 °C, the high pressure was removed from the oil bath,
which was then left to cool to rt. The crude reaction mixture was
diluted in CH2Cl2 (50 mL) and water (50 mL) and the layers
separated. The aqueous phase was extracted with CH2Cl2 (2 ꢀ
25 mL). The organic extract was then dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification
of the material was accomplished by flash column chromato-
graphy on a 2.5 ꢀ 15 cm column, eluting with 35% ethyl acetate/
hexanes (w/3% triethylamine). The product containing frac-
tions were combined and then concentrated under reduced
pressure to give 2-thioimidazole 3a (0.086 g, 67% yield) as a
light yellow oil. Rf 0.24 (35% ethyl acetate/hexanes). 1H NMR
(CDCl3, 500 MHz): δ 7.13 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8
Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 6.42
(s, 1H), 4.96 (s, 2H), 3.80 (s, 2H), 3.73 (s, 6H), 2.94 (q, J = 7.6
Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3, 125 MHz):
δ 159.3, 158.0, 143.5, 140.5, 132.2, 130.0, 128.9, 128.7, 118.3,
114.3, 113.8 (2 ꢀ 55.4), 49.7, 34.4, 29.5, 15.7. DEPT 13C NMR
(CDCl3, 125 MHz): δ CH3: (2 ꢀ 55.4), 15.7; CH2: 49.7, 34.4,
29.5; CH1: 130.0, 128.7, 118.3, 114.3, 113.8; CH0: 159.3, 158.0,
143.5, 140.5, 132.2, 128.9. IR (neat): 2931, 2834, 1612, 1584,
1512, 1453, 1300, 1247, 1176, 1106, 1034, 794 cm-1. HRMS
(ESI) calcd for C21H24N2O2S m/z (M þ H) 369.1637, obsd
369.1641.
Typical Procedure for the Preparation of 2-Oxoimida-
zoles. 1,4-Bis(4-methoxybenzyl)-2-phenoxy-1H-imidazole (8a).
In a 15 mL high-pressure tube containing a magnetic stir bar
was added cyanamide 2a (0.120 g, 0.392 mmol, 1.0 equiv),
phenol (0.111 g, 0.1.18 mmol, 3.0 equiv), K2CO3 (0.271 g, 1.96
mmol, 5.0 equiv), and toluene (1.5 mL). The high-pressure tube
was then sealed and placed in a preheated 150 °C oil bath. After
24 h at 150 °C, the high pressure was removed from the oil bath,
which was then left to cool to rt. The crude reaction mixture was
diluted in CH2Cl2 (50 mL) and water (50 mL) and the layers
separated. The aqueous phase was extracted with CH2Cl2 (2 ꢀ
25 mL). The organic extract was then dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification
of the material was accomplished by flash column chromato-
graphy on a 2.5 ꢀ 15 cm column, eluting with 350 mL of
25% ethyl acetate/hexanes (w/1% triethylamine). The product
containing fractions were combined and then concentrated
under reduced pressure to give 2-oxoimidazole 8a (0.121 g,
77% yield) as a light yellow oil. Rf 0.43 (40% ethyl acetate/
hexane w/1% triethylamine). 1H NMR (CDCl3, 500 MHz):
δ 7.32 (dd, J = 7.3, 8.8 Hz, 2H), 7.20-7.14 (m, 4H),
7.13-7.07 (m, 3H), 6.84-6.81 (m, 4H), 6.13 (s, 1H), 4.82
(s, 2H), 3.77 (s, 3H), 3.77 (s, 3H), 3.76 (s, 2H). 13C NMR
(CDCl3, 125 MHz): δ 159.4, 158.1, 155.7, 148.8, 137.9, 132.1,
130.1, 129.8, 129.1, 128.7, 124.1, 118.1, 114.3, 113.9, 112.3, 55.4,
55.4, 47.8, 34.7. 13C DEPT NMR (CDCl3, 125 MHz): δ CH3:
55.4, 55.4; CH2: 47.8, 34.7; CH1: 130.1, 129.8, 129.1, 124.1,
118.1, 114.3, 113.9, 112.3 . IR (neat): 2933, 2834, 1611, 1587,
1509, 1476, 1299, 1240, 1204, 1174, 1030, 807, 755, 687 cm-1
.
HRMS (ESI) calcd for C25H25N2O3 m/z (M þ H) 401.1865,
obsd 401.1860.
Acknowledgment. We are grateful to the Donors of the
American Chemical Society Petroleum Research Fund for
partial support of this research. We are also grateful for
financial support from the University of Utah Research
foundation. We thank Mr. John Sullivan for the preparation
of substrate 2a.
Supporting Information Available: Experimental details and
1H, 13C, and 13C DEPT NMR spectra for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
264 J. Org. Chem. Vol. 75, No. 1, 2010