Exploring the synthetic utility of 1-alkynylimidazoles: Regiocontrolled cyclization to diverse imidazoazines and imidazoazoles

Article abstract of DOI:10.1016/j.tet.2014.04.099

Regiocontrolled cyclizations involving alkynes have utility in the formation of diverse heterocyclic systems. Here we report the participation of model 1-alkynylimidazoles in intramolecular hydroalkoxylation and hydroamination reactions leading to diverse imidazoazine and imidazoazole ring systems. In many cases, the preference for 5-exo-dig or 6-endo-dig cyclization can be controlled by variations in reaction conditions. This work establishes 1-alkynylimidazoles as versatile intermediates in the synthesis of a wide variety of fused-imidazole heterocycles.

Full text of DOI:10.1016/j.tet.2014.04.099

Tetrahedron xxx (2014) 1e6
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exploring the synthetic utility of 1-alkynylimidazoles:
regiocontrolled cyclization to diverse imidazoazines and
imidazoazoles
*
Christophe Laroche, Bradford Gilbreath, Sean M. Kerwin
Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Regiocontrolled cyclizations involving alkynes have utility in the formation of diverse heterocyclic sys-
tems. Here we report the participation of model 1-alkynylimidazoles in intramolecular hydro-
alkoxylation and hydroamination reactions leading to diverse imidazoazine and imidazoazole ring
systems. In many cases, the preference for 5-exo-dig or 6-endo-dig cyclization can be controlled by
variations in reaction conditions. This work establishes 1-alkynylimidazoles as versatile intermediates in
the synthesis of a wide variety of fused-imidazole heterocycles.
Received 3 April 2014
Received in revised form 28 April 2014
Accepted 30 April 2014
Available online xxx
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
reasoned that these 1-alkynylimidazoles could in turn serve as
versatile intermediates in the preparation of a wide range of
N-Fused heterocycles incorporating an imidazole ring are ver-
satile chemo-types for both drug discovery and chemical biology.1,2
These N-fused-imidazole heterocycles appear as cores of natural
products, such as nagstatin3 and cypridine luciferin4 (Fig. 1), as well
as in many pharmaceutical agents, such as the hypnotic zolpidem,5
the kinase inhibitor SKF 86002,6 and others7 (Fig. 1). Paradoxically,
despite the demonstrated biological activity associated with these
fused-imidazole heterocycles, certain members of this class are
virtually unexplored, such as the 1H,3H-imidazo[1,5-c]oxazole
system8 (Fig. 1). Thus, the development of new synthetic routes
to these heterocycles may both aid the preparation of well-
established core structures and provide entry to the still
unexplored regions of this biologically promising chemical space.
As such, this remains a very active area of research.9e15
The synthesis of imidazole-fused heterocycles generally in-
volves one of two strategies: elaboration of the imidazole cycle
starting from a functionalized heterocycle, or formation of the
fused-heterocycle via the cyclization of an imidazole derivative.9,11
While both strategies offer advantages and limitations, the later
approach has the potential to afford a wide range of imidazole-
fused heterocycles from a common imidazole intermediate.
Recently, copper-catalyzed coupling reactions between imidaz-
oles and bromoalkynes or their surrogates have emerged as a direct,
convenient, and efficient route to 1-alkynylimidazoles.16e19 We
imidazole-fused heterocycles through cyclizations involving the
1-alkynyl substituent.20 One important consideration in this ap-
proach is the ability to control the regiochemistry of these cycliza-
tions. We have previously shown that 1-alkynylimidazoles bearing
a carbinol substituent at the 2-position undergo regiocontrolled
intramolecular hydroalkoxylation.21 Under base-catalysis, 1-alkynyl-
2-hydroxymethylimidazoles, such as 1 undergo selective 5-exo-dig
cyclization to afford 5,7-dihydro-5-methyleneimidazo[1,2-c]oxa-
zoles 2 (Scheme 1). In contrast, under Au-catalysis 1 undergoes ex-
clusive 6-endo-dig cyclization to afford 8H-imidazo[2,1-c][1,4]
oxazines 3 (Scheme 1).
Here we describe studies that examine the generality of this
regiocontrol in the intramolecular hydroalkoxylation and hydro-
amination reactions of model 1-alkynylimidazoles. In addition,
a range of regiospecific alternative cyclizations of 2-carboxaldehyde
substituted 1-alkynylimidazoles are also described. Overall, these
studies demonstrate the synthetic versatility of 1-alkynylimidazoles
in the rapid and regiocontrolled preparation of a wide range of
well-established and novel bicyclic imidazole heterocycles.
2. Results and discussion
We first examined if the reagent-controlled regioselective
hydroalkoxylation cyclization of 2-substituted 1-alkynylimidazoles
(Scheme 1) also holds when the carbinol moiety is located at
5-position of the 1-alkynylimidazole. In order to access the required
carbinol, we employed the sequential metalationefunctionalization
of the 4-phenyl-substituted 1-alkynylimidazole 4 (Scheme 2). In one
* Corresponding author. E-mail addresses: skerwin@mail.utexas.edu, skerwin@
austin.utexas.edu (S.M. Kerwin).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.099
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C. Laroche et al. / Tetrahedron xxx (2014) 1e6
Fig. 1. Examples of N-fused-imidazole heterocycles.
Scheme 1. Reagent-controlled regioselective hydroalkoxylation cyclization of 2-
carbinol substituted 1-alkynylimidazoles.21
Scheme 3. Regiocontrolled cyclization of 5-carbinol-functionalized 1-alkynylimidazole 5.
changes in geometry of the attacking hydroxyl group and the
1-alkynyl between isomers 1 and 5 do not affect the origin or
magnitude of the reagent-controlled regioselectivity.
We next explored the regioselectivity of the intramolecular
hydroamination reactions of 1-alkynylimidazoles. We prepared the
precursor 2-substituted sulfonamide by deprotonation of the
1-alkynylimidazole 816 followed by addition of (E)-benzylidene-
benzenesulfonamide to afford sulfonamide 9 in 86% yield. Compound
9 was then subjected to various cyclization conditions (Table 1).
Cyclization of 9 did not occur in the presence of AuCl3 even with
prolonged reaction times and only starting material was recovered
(Table 1, entry 1). This was somewhat surprising in light of the
results shown in Schemes 1 and 3, but may be due to preferential
coordination of the Au species with the sulfonamide moiety of 9.
Under base catalysis with K3PO4 at room temperature, the desired
products were obtained as a 1:1 mixture of chromatographically
separable 5-exo-dig and 6-endo-dig products (Table 1, entry 2). The
structure of the 6-endo-dig cyclization product 11 was confirmed by
single crystal X-ray analysis (see Supplementary data), while that of
the 5-exo-dig cyclization product 10 was assigned in analogy to the
5-exo-dig cyclization product 2, which was also determined by
single crystal X-ray analysis.21 While the lack of regiocontrol under
these conditions was disappointing, the ratio 10/11 was highly
dependent on the reaction temperature, ranging from 5:1 at 5 ꢁC in
CH3CN (Table 1, entry 3) to 1:2 at reflux (Table 1, entry 4).
Scheme 2. Preparation of 5-carbinol-functionalized 1-alkynylimidazole.
pot,1-alkynylimidazole 4 was deprotonated with n-BuLi at ꢀ78 ꢁC to
afford the 2-lithio species,20 which was trapped with trimethylsilyl
chloride. A second addition of base followed by trapping of the
resulting 5-lithio species with benzaldehyde afforded the desired
carbinol 5 in good yield after acidic work-up (Scheme 2).
Treating 1-alkynylimidazole 5 under the same conditions as
employed for the regioselective 5-exo-dig cyclization of 1 (5 mol %
K3PO4 in CH3CN under reflux) afforded the 5-exo-dig cyclization
product 6 in 80% yield after chromatography (Scheme 3). In con-
trast, treatment of 5 with 2 mol % AuCl3 afforded exclusively the
6-endo-dig cyclization product 7, which was isolated in 92% yield
after chromatography (Scheme 3). The structures of 6 and 7 were
assigned based on their 1H and 13C NMR spectra in comparison with
that of 2 and 3, respectively. Thus, the reagent-controlled regiose-
lective cyclization of 5-substituted 1-alkynylimidazole 5 mirrors
that of the 2-substituted isomer 1. This indicates that the subtle
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C. Laroche et al. / Tetrahedron xxx (2014) 1e6
3
Table 1
Regiocontrolled intramolecular hydroamination of 1-alkynylimidazole 9
Entry
1
Conditions
Combined yielda (%)
0
Ratio (10/11)
Purified yield (Compound)b
nac
AuCl3 (2mol %)
CH3CN reflux
d
2
3
4
K3PO4 (5 mol %)
CH3CN at rt
K3PO4 (5 mol %)
CH3CN at 5 ꢁC
K3PO4 (5 mol %)
CH3CN at reflux
90
90
90
5:1
1:1
1:2
75% (10)
ndd
60% (11)
a
Combined yield of 10 and 11.
Purified yield of major isomer.
Not applicable.
b
c
d
Not determined.
Interestingly, this reaction temperature-dependent regioselectivity
does not appear to simply reflect kinetic versus thermodynamic
control, as re-subjecting purified 10 or 11 to the reaction conditions
did not afford the expected mixture of isomers. Still, synthetically
useful yields of either isomer could be obtained (Table 1, entries 2
and 4). Other attempts to enhance the cyclization mode selectivity
by using higher boiling point solvent (toluene) and other transition
metals (Pd, Ag, Cu) have been explored with no success.
products 12 and 13 were obtained in 92% combined yield as a 12:1
mixture, affording chromatographically isolated 5-exo-dig product
12 in 85% yield (Scheme 4).
Finally, we explored the use of 2-carbaldehyde 1-
alkynylimidazoles as precursors to a variety of imidazo-fused het-
erocycles. The aldehyde 15, prepared from 8 by deprotonation and
trapping with DMF,21 undergoes cyclization to the imidazolopyr-
azine 16 when treated with ammonia in MeOH/THF in the presence
of catalytic Cu(OTf)2 (Scheme 5). Similarly, in the presence of cat-
alytic Cu(OTf)2 in ethanol,15 is cleanly converted to the cyclic acetal
17. Aldehyde 15 undergoes cyclization in the absence of metal
catalyst when treated with hydroxylamine hydrochloride in DMF to
afford the imidazolopyrazine N-oxide 18. No products of 5-exo-dig
cyclization were observed in any of these cyclizations. Thus, under
the influence of catalytic Cu2þ (i.e.,15/16 and 15/17) or when the
nucleophilic group involved in the cyclization is an sp2-nitrogen
(i.e., 15/18), only products of 6-endo-dig cyclization are observed.
In conclusion, we have shown that 1-alkynylimidazole de-
rivatives represent versatile building blocks for the construction of
an array of N-fused-imidazole heterocycles. The regiocontrol of
both intramolecular hydroalkoxylation and hydroamination re-
actions can be accomplished simply through reagent- or
temperature-control, affording synthetically useful yields of either
products of 5-exo-dig or 6-endo-dig cyclization. In contrast,
We next explored the scope of this intramolecular hydro-
amination route to other fused imidazole systems. Deprotonation
of 8 followed by trapping with di-(tert-butyl)azodicarboxylate
afforded the hydrazine 12 in 79% yield (Scheme 4). Compound 12
was then subjected to cyclization in the presence of K3PO4 (5 mol %)
in CH3CN at various temperatures. The reaction did not proceed at
5 ꢁC nor at room temperature. In acetonitrile at reflux, the expected
products were obtained in 95% combined yield as a 1:4 mixture of
the 5-exo-dig cyclization product 12 and the 6-endo-dig product 13.
By increasing the temperature ever further by running the reaction
in toluene under reflux, a 90% yield of the pure 6-endo-dig cycli-
zation product 13 could be obtained (Scheme 4). We reasoned that
the inability to obtain reaction products at temperatures lower than
refluxing acetonitrile might be due to the higher pKa of 11 com-
pared to the sulfonamide 8. Upon performing the cyclization re-
t
action of 11 with catalytic NaOtBu in BuOH at 5 ꢁC, the expected
Scheme 4. Regiocontrolled cyclization of 2-hydrazinyl-functionalized 1-alkynylimidazole.
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4
C. Laroche et al. / Tetrahedron xxx (2014) 1e6
(Mþ1, 100%), 333 (Mꢀ18, 76%); HRMS calcd for C24H19N2O (MþHþ)
351.1497, found 351.1495.
3.1.2. (Z)-3-Benzylidene-1,3-dihydro-1,7-diphenylimidazo[1,5-c]ox-
azole (6). A round bottom flask was charged with K3PO4 (3 mg,
0.014 mmol). To this was added, by syringe, a solution of phenyl(4-
phenyl-1-(2-phenylethynyl)-1H-imidazol-5-yl)methanol
(5)
(100 mg, 0.285 mmol) in 10 mL of CH3CN. The reaction was held at
reflux for 10 h, cooled to room temperature, diluted with 10 mL
H2O, and extracted with CH2Cl2 (3ꢂ15 mL). The organic extracts
were combined, dried over Na2SO4, and evaporated by reduced
pressure yielding a light yellow oil, which was purified by flash
chromatography (0e6% EtOAc in hexanes). Purification afforded
(Z)-3-benzylidene-1,3-dihydro-1,7-diphenylimidazo[1,5-c]oxazole
(6) (86 mg, 87%) as a white crystalline solid. Rf 0.44 (10% EtOAc in
Scheme 5. Exclusive 6-endo-dig cyclizations of 2-carbaldehyde-functionalized 1-
alkynylimidazole.
hexane); Mp 190e191 ꢁC; 1H NMR
m), 7.32e7.13 (6H, m), 6.71 (1H, s), 5.63 (1H, s); 13C NMR
d
7.94 (1H, s), 7.54e7.39 (9H,
142.8,
d
exclusive 6-endo-dig cyclization is observed for 2-carboxaldehyde-
substituted 1-alkynylimidazole 14, providing rapid access to known
and novel imidazole heterocycles.
135.3, 133.7, 133.2, 132.4, 130.1, 129.2 (2C), 128.6 (2C), 128.5 (2C),
128.3 (2C), 128.2, 127.3 (2C), 127.0, 126.0, 125.8, 125.5 (2C), 85.37,
82.37; IR (KBr) 1702, 1598, 1462, 1418, 1268, 1152, 1054, 950,
696 cmꢀ1; MS 351 (Mþ1, 100%), 119 (Mꢀ232, 39%), 233 (Mꢀ118,
38%), 352 (Mþ2, 34%); HRMS calcd for
C
24H19N2O (MþHþ)
351.1497, found 351.1496.
3. Experimental section
3.1. General
3.1.3. 1,6,8-Triphenyl-8H-imidazo[5,1-c][1,4]oxazine (7). To a round
bottom flask was added by syringe a solution of AuCl3 (0.6 mL of
0.01 M in CH3CN, 0.006 mmol) followed by the addition of a solu-
tion of phenyl(4-phenyl-1-(2-phenylethynyl)-1H-imidazol-5-yl)
methanol (5) (101 mg, 0.29 mmol) in 10 mL of CH3CN and the
resulting solution was degassed by sparging with argon. The re-
action was heated under reflux for 10 h, cooled to room tempera-
ture, diluted with H2O (10 mL), and extracted with CH2Cl2
(3ꢂ15 mL). The organic extracts were combined, dried over Na2SO4,
and evaporated by reduced pressure yielding a light yellow oil,
which was purified by flash chromatography (0e2% EtOAc in hex-
anes). Purification afforded 1,6,8-triphenyl-8H-imidazo[5,1-c][1,4]
oxazine (7) (92 mg, 91%) as a white crystalline solid. Rf 0.53 (10%
All reactions were performed under an atmosphere of argon in
either oven- or flame-dried glassware. Immediately prior to use, THF
was distilled from Na/benzophenone, whereas CH3CN and toluene
ꢀ
were distilled from CaH2. Ethanol and DMF were dried over 4 A
molecularsieves. Unless otherwisenoted,all materialswereobtained
from commercial suppliers and were used without further purifica-
tion. FlashchromatographywasperformedwithEMReagentsilicagel
(230e400 mesh) using the mobile phase indicated. Melting points
(open capillary) are uncorrected. 1H and 13C NMR spectra were de-
termined in CDCl3 on a spectrometer operating at 400 and 100 MHz,
respectively, except where noted, and are reported in parts per mil-
lion using solvent as internal standard. All mass spectra were ob-
tained in the positive mode by CI using methane as the ionizing gas.
EtOAc in hexane); Mp 142e143 ꢁC; 1H NMR
(4H, m), 7.37e7.22 (11H, m), 7.10 (1H, s), 6.83 (1H, s); 13C NMR
141.7, 137.5, 136.3, 133.8, 132.9, 132.5, 129.1, 129.0, 128.7 (2C), 128.6
d 7.78 (1H, s), 7.6e7.51
d
(2C), 128.5 (2C), 127.7 (2C), 126.9, 126.2 (2C), 124.4 (2C), 118.2, 101.5,
74.2; IR (KBr) 1683, 1615, 1492, 1457, 1402, 1285, 1219, 743,
691 cmꢀ1; MS 351 (Mþ1, 100%), 352 (Mþ2, 19%), 350 (M, 5%) 245
(Mꢀ105, 4%); HRMS calcd for C24H19N2O (MþHþ) 351.1497, found
351.1497.
3.1.1. Phenyl(4-phenyl-1-(2-phenylethynyl)-1H-imidazol-5-yl)meth-
anol (5). A stirred solution of 4-phenyl-1-(2-phenylethynyl)-1H-
imidazole (4)16 (324 mg, 1.32 mmol) in 20 mL of THF was cooled to
ꢀ78 ꢁC. The following successive additions to the reaction solution
were carried out while maintaining the reaction temperature at
ꢀ78 ꢁC. n-BuLi (2 M in hexanes, 0.66 mL, 1.32 mmol) was added by
syringe and the reaction stirred for 20 min. TMSCl (0.17 mL,
1.327 mmol) was added by syringe and the reaction stirred for
45 min. A second equivalent of n-BuLi (2 M in hexanes, 0.66 mL,
1.32 mmol) was added and the reaction stirred for 30 min. Benz-
aldehyde (0.162 mL, 1.592 mmol) was added by syringe and the
reaction allowed to stir for 30 min. Aqueous 1 M HCl (10 mL) was
added by syringe and the reaction was allowed to reach room
temperature. The reaction mixture was extracted with EtOAc
(3ꢂ20 mL). The combined organic extracts were dried over Na2SO4,
and the solvents were removed by reduced pressure giving a light
yellow oil, which was purified by flash chromatography (0e5%
EtOAc in hexanes). Purification afforded 390 mg (84%) of phenyl(4-
phenyl-1-(2-phenylethynyl)-1H-imidazol-5-yl)methanol (5) as
a white crystalline solid. Rf 0.6 (25% EtOAc in hexane); Mp
3.1.4. N-(Phenyl(1-(phenylethynyl)-1H-imidazol-2-yl)methyl)benze-
nesulfonamide (9). A round bottom flask was charged with 1-
(phenylethynyl)-1H-imidazole (8)16 (84 mg, 0.5 mmol). The solu-
tion was brought to ꢀ78 ꢁC and n-BuLi (0.2 mL, 0.5 mmol) was
added. The reaction mixture was stirred at ꢀ78 ꢁC for 30 min fol-
lowed by the addition of N-benzylidenebenzenesulfonamide
(123 mg, 0.5 mmol). The reaction was allowed to reach ꢀ60 ꢁC then
quenched with 1 M HCl (2 mL), diluted with 10 mL H2O, and
extracted with CH2Cl2 (3ꢂ15 mL). The combined organic extracts
were dried over Na2SO4 and evaporated by reduced pressure
yielding a white solid that was purified by flash chromatography
(50% EtOAc in hexanes). Purification afforded (9) (178 mg, 86%) as
a white solid. Rf 0.2 (50% EtOAc in hexane); Mp 177e178 ꢁC; 1H
NMR (300 MHz, CDCl3)
d 7.68e7.62 (2H, m), 7.44e7.36 (6H, m),
155e157 ꢁC; 1H NMR
(11H, m), 7.19e7.14 (2H, m), 6.36 (1H, s), 3.15 (1H, s, OH); 13C NMR
140.7, 140.4, 133.1, 131.3 (2C), 130.2, 128.8, 128.5 (2C), 128.4 (2C),
d 7.80 (1H, s), 7.67e7.61 (2H, m), 7.46e7.25
7.32e7.24 (2H, m), 7.24e7.18 (5H, m), 6.95 (1H, d, J¼1.5 Hz), 6.88
(1H, d, J¼1.5 Hz), 6.43 (1H, br s, NH), 5.95 (1H, d, J¼8.2 Hz); 13C NMR
(75 MHz, CDCl3)
d 149.4, 140.1, 137.2, 132.1, 131.6 (2C), 129.2, 128.6
d
(2C), 128.6 (4C), 128.3, 128.2, 127.4 (2C), 126.8 (2C), 121.6, 120.5,
76.5, 74.2, 53.7; IR (KBr) 3061, 2868, 2257, 1481, 1428, 1333, 1169,
128.3 (2C), 128.1 (2C), 127.8, 127.5, 126.0 (2C), 120.9, 77.2, 73.7, 66.5;
IR (KBr) 3172, 1741, 1597, 1410, 1236, 1204, 1038, 962, 770; MS 351
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C. Laroche et al. / Tetrahedron xxx (2014) 1e6
5
1090, 1063, 948 cmꢀ1; MS 827 (2Mþ1, 4%), 414 (Mþ1, 100%); HRMS
calcd for C24H20N3O2S (MþHþ) 414.1276, found 414.1282.
1441, 1394, 1325, 1248, 1153, 1081, 757 cmꢀ1; MS 399 (Mþ1, 100%);
HRMS calcd for C21H27N4O4 (MþHþ) 399.2032, found 399.2035.
3.1.5. (E)-5-Benzylidene-6-(phenylsulfonyl)-7-phenyl-6,8-dihydro-
5H-imidazo[1,5-a]imidazole (10). A two-neck round bottom flask
was charged with N-(phenyl(1-(phenylethynyl)-1H-imidazol-2-yl)
methyl)benzenesulfonamide (9) (103 mg, 0.25 mmol). To this was
added, by syringe, CH3CN (10 mL). The solution was brought to 0 ꢁC,
then K3PO4 (2.65 mg, 0.0125 mmol) was added. The reaction was
held at 0 ꢁC for 10 h then at 4 ꢁC for 24 h, diluted with H2O (10 mL),
and extracted with CH2Cl2 (3ꢂ15 mL). The organic extracts were
combined, dried over Na2SO4, and evaporated by reduced pressure
yielding an orange solid that was purified by flash chromatography
(50% EtOAc in hexanes). Purification afforded (E)-5-benzylidene-6-
(phenylsulfonyl)-7-phenyl-6,8-dihydro-5H-imidazo[1,5-a]imidaz-
ole (10) (77 mg, 75%) as an orange solid. Rf 0.2 (40% EtOAc in hex-
3.1.8. (Z)-Di-tert-butyl
azole-1,2(3H)-dicarboxylate
ethynyl)-1H-imidazol-2-yl)hydrazine-1,2-dicarboxylate
3-benzylidene-1H-imidazo[2,1-c][1,2,4]tri-
(13). Di-tert-butyl 1-(1-(phenyl-
(12)
(79.7 mg, 0.2 mmol) was dissolved in t-BuOH. To this solution was
added NaOtBu (1 mg, 0.01 mmol) and the reaction stirred at room
temperature for 30 min. The reaction was diluted with H2O (5 mL)
and extracted with CH2Cl2 (3ꢂ15 mL). The organic extracts were
combined, dried over Na2SO4, and evaporated by reduced pressure
yielding a white solid that was purified by flash chromatography
(50% EtOAc in hexanes). Purification afforded (Z)-di-tert-butyl 3-
benzylidene-1H-imidazo[2,1-c][1,2,4]triazole-1,2(3H)-dicarbox-
ylate (13) (68 mg, 85%) as a white solid. Rf 0.25 (50% EtOAc in
hexane); Mp 150e153 ꢁC; 1H NMR
d 7.50e7.46 (2H, m), 7.33e7.27
ane); Mp 154e156 ꢁC; 1H NMR
d
7.78e7.74 (2H, m), 7.69e7.65 (2H,
(2H, m), 7.23e7.17 (1H, m), 7.04 (1H, d, J¼1.6 Hz), 6.99 (1H, d,
m), 7.57e7.46 (3H, m), 7.44e7.32 (7H, m), 7.29e7.24 (1H, m), 6.98
J¼1.6 Hz), 6.02 (1H, s), 1.62 (9H, s), 1.25 (9H, s); 13C NMR
d 151.2,
(1H, d, J¼1.4 Hz), 6.94 (1H, d, J¼1.4 Hz), 6.32 (1H, s), 6.04 (1H, s); 13
C
149.7, 145.8, 134.0, 133.9, 130.3, 128.2, 128.1, 127.1, 108.3, 99.9, 84.9,
84.8, 29.9 (3C), 27.4 (2C); IR (KBr) 1775,1751, 1689, 1579, 1446, 1396,
1372, 1301, 1138, 969, 836, 754 cmꢀ1; MS 399 (Mþ1, 44%), 199
(Mꢀ199, 46%), 243 (Mꢀ155, 34%); HRMS calcd for C21H27N4O4
(MþHþ) 399.2032, found 399.2032.
NMR
d 149.84, 135.7, 135.4, 135.2, 134.1, 132.8, 130.4, 129.2 (4C),
129.0 (2C), 128.7, 128.2 (2C), 128.0, 127.5 (2C), 126.8 (2C), 110.2,
107.6, 63.4; IR (KBr) 3155, 1673, 1541, 1472, 1449, 1413, 1396, 1285,
1170, 1093, 986 cmꢀ1; MS 414 (Mþ1, 100%); HRMS calcd for
C
24H20N3O2S (MþHþ) 414.1276, found 414.1274. Elem. Anal. Calcd
for C24H20N3O2S: C, 69.71; H, 4.63; N, 10.16. Found: C, 69.39; H,
4.63; N, 10.07.
3.1.9. Di-tert-butyl 3-phenylimidazo[2,1-c][1,2,4]triazine-1,2-
dicarboxylate (14). A two-neck, round bottom flask was charged
with di-tert-butyl 1-(1-(phenylethynyl)-1H-imidazol-2-yl)hydra-
zine-1,2-dicarboxylate (12) (20 mg, 0.05 mmol). To this was added, by
syringe, toluene (10 mL) then K3PO4 (0.053 mg, 0.0025 mmol). The
solution was held at reflux for 14 h then diluted with 5 mL H2O and
extracted with CH2Cl2 (3ꢂ15 mL). The organic extracts were com-
bined, dried over Na2SO4, and evaporated by reduced pressure
yielding awhite solid that was purified by flash chromatography (50%
EtOAc in hexanes). Purification afforded di-tert-butyl 3-
phenylimidazo[2,1-c][1,2,4]triazine-1,2-dicarboxylate (14) (18 mg,
90%)asawhitesolid.Rf 0.2(50%EtOAcinhexane);Mp202e205ꢁC;1H
3.1.6. 6,8-Diphenyl-7-(phenylsulfonyl)-7,8-dihydroimidazo[1,2-a]
pyrazine (11). A two-neck round bottom flask was charged with N-
(phenyl(1-(phenylethynyl)-1H-imidazol-2-yl)methyl)benzene-
sulfonamide (9) (103 mg, 0.25 mmol). To this was added, by syringe,
CH3CN (10 mL) then K3PO4 (2.65 mg, 0.0125 mmol). The reaction
was heated under reflux for 1 h, diluted with H2O (10 mL), and
extracted with CH2Cl2 (3ꢂ15 mL). The organic extracts were com-
bined, dried over Na2SO4, and evaporated by reduced pressure
yielding a light yellow solid, which was purified by flash chroma-
tography (50% EtOAc in hexanes). Purification afforded 6,8-
diphenyl-7-(phenylsulfonyl)-7,8-dihydroimidazo[1,2-a]pyrazine
(11) (62 mg, 60%) as a white crystalline solid. Rf 0.17 (40% EtOAc in
NMR
d
7.65e7.62 (2H, m), 7.43e7.33 (3H, m), 7.02 (1H, d, J¼1.6 Hz),
6.99 (1H, d, J¼1.6 Hz), 6.92 (1H, s), 1.58 (9H, s), 1.25 (9H, s); 13C NMR
d
151.5, 151.1, 139.8, 133.4, 131.2, 128.7, 128.6, 127.8, 125.4, 113.7, 111.8,
hexane); Mp 153e155 ꢁC; 1H NMR
d
7.59e7.55 (2H, m), 7.46e7.38
84.0, 83.3, 28.0, 27.6; IR (KBr) 3133, 2979,1738,1550,1495,1433,1370,
(3H, m), 7.37e7.27 (8H, m), 7.17e7.12 (2H, m), 6.93 (1H, d, J¼1.5 Hz),
1305,1153,1120, 840, 757 cmꢀ1; MS 399 (Mþ1,100%); HRMS calcd for
6.82 (1H, s), 6.78 (1H, s), 6.62 (1H, d, J¼1.5 Hz); 13C NMR
d
140.8,
C
21H27N4O4 (MþHþ) 399.2032, found 399.2032.
136.3, 135.9, 134.9, 133.0, 129.4, 129.0, 128.6 (2C), 128.5, 128.4 (4C),
127.8, 127.2 (2C), 127.1 (2C), 126.5 (2C), 116.2, 115.1, 57.4; IR (KBr)
3067, 1491, 1450, 1433, 1360, 1172, 1089, 980 cmꢀ1; MS 414 (Mþ1,
100%); HRMS calcd for C24H20N3O2S (MþHþ) 414.1276, found
414.1276.
3.1.10. 6-Phenylimidazo[1,2-a]pyrazine (16). A round bottom flask
was charged with Cu(OTf)2 (14 mg, 0.038 mmol) to which a solution
of
1-(2-phenylethynyl)-1H-imidazole-2-carbaldehyde
(15)21
(150 mg, 0.765 mmol) in 10 mL THF was added by syringe fol-
lowed by the addition of a 2 M solution of ammonia in methanol
(0.42 mL, 0.842 mmol). The mixture was heated under reflux for
12 h, allowed to cool to room temperature, diluted with H2O
(10 mL), and extracted with EtOAc (3ꢂ20 mL). The organic extracts
were combined, dried over Na2SO4, and the solvents removed un-
der reduced pressure. The residual yellow oil was purified by flash
chromatography (0e25% EtOAc in hexanes) to afford 6-
phenylimidazo[1,2-a]pyrazine (16) (114 mg, 76%) as a colorless
crystalline solid. Rf 0.32 (75% EtOAc in hexane); Mp¼107e108 ꢁC;
3.1.7. Di-tert-butyl
1-(1-(phenylethynyl)-1H-imidazol-2-yl)hydra-
zine-1,2-dicarboxylate (12). A round bottom flask was charged with
1-(phenylethynyl)-1H-imidazole (8)16 (840 mg, 5 mmol). To this
was added, by syringe, THF (30 mL). The solution was brought to
ꢀ78 ꢁC and n-BuLi (2.0 mL, 5 mmol) was added. The reaction
mixture was stirred at ꢀ78 ꢁC for 30 min followed by the addition
of di-(tert-butyl)azodicarboxylate (1.26 g, 5.5 mmol). The reaction
mixture was stirred at ꢀ78 ꢁC for 1 h then quenched with 1 M HCl
(10 mL), and extracted with CH2Cl2 (3ꢂ15 mL). The organic extracts
were combined, dried over Na2SO4, and evaporated by reduced
pressure yielding a white solid that was purified by flash chroma-
tography (20% EtOAc in hexanes). Purification afforded di-tert-butyl
1-(1-(phenylethynyl)-1H-imidazol-2-yl)hydrazine-1,2-
1H NMR
d
9.12 (1H, d, J¼1.6 Hz), 8.38 (1H, d, J¼1.6 Hz), 7.87e7.84
(2H, m), 7.75 (1H, s), 7.67 (1H, s), 7.44e7.34 (3H, m); 13C NMR
143.2, 140.0, 139.8, 136.3, 136.0, 129.0 (2C), 128.8, 126.3 (2C), 115.0,
d
113.9; IR (KBr) 1521, 1485, 1459, 1439, 1325, 1317, 1144, 917, 778,
691; MS 196 (Mþ1, 100%), 195 (M, 12%), 194 (Mꢀ1, 1%); HRMS calcd
for C12H10N3 (MþHþ) 196.0875, found 196.0878.
dicarboxylate (12) (1.51 g 76%) as a white solid. Rf 0.2 (20% EtOAc in
hexane); Mp 72e75 ꢁC; 1H NMR
d 7.54e7.48 (3H, m), 7.37e7.33 (3H,
m), 7.09 (1H, d, J¼1.7 Hz), 6.97 (1H, d, J¼1.7 Hz), 1.46 (18H, s); 13C
3.1.11. 8-Ethoxy-6-phenyl-8H-imidazo[2,1-c][1,4]oxazine
(17). A
NMR
d
154.4, 152.4, 144.4, 131.5 (2C), 128.7, 128.3 (2C), 126.9, 121.3,
round bottom flask was charged with Cu(OTf)2 (9 mg, 0.025 mmol)to
121.1, 83.5, 81.4, 28.1, 27.8; IR (KBr) 3179, 2979, 2265, 1737, 1553,
which 1-(2-phenylethynyl)-1H-imidazole-2-carbaldehyde (15)21
Please cite this article in press as: Laroche, C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.099

6
C. Laroche et al. / Tetrahedron xxx (2014) 1e6
(100 mg, 0.51 mmol) in ethanol (10 mL) was added by syringe. The
reaction was held at reflux for 4 h then allowed to cool to room
temperature. H2O (10 mL) was added, the mixture extracted with
CH2Cl2 (3ꢂ15 mL), the organic extracts were combined and dried
over Na2SO4, and the solvents removed under reduced pressure. The
residual yellow oil was purified by flash chromatography (0e25%
EtOAc in hexanes) to afford 8-ethoxy-6-phenyl-8H-imidazo[2,1-c]
[1,4]oxazine (17) (120 mg, 97%) as a white crystalline solid. Rf 0.51
Supplementary data
1H and 13C NMR spectra for all new compounds and details for
the crystal structure of 11. Supplementary data associated with
this article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2014.04.099. These data include MOL files and
InChiKeys of the most important compounds described in this
article.
(25% EtOAc in hexane); Mp¼86e87 ꢁC; 1H NMR
d 7.63e7.61 (2H, m),
7.41e7.34 (3H, m), 7.14 (1H, d, J¼1.1 Hz), 7.09 (1H, s), 7.02 (1H, d,
J¼1.3 Hz), 6.36 (1H, s), 4.05 (1H, quint, J¼11.9, 9.4 Hz), 3.87 (1H, quint,
J¼11.9, 9.4 Hz), 1.25 (3H, t, J¼7.1 Hz); 13C NMR
d 141.0, 137.4, 132.3,
References and notes
129.6, 129.0, 128.7 (2C), 124.4 (2C), 115.4, 102.0, 94.6, 64.4, 15.2; IR
(KBr) 3410, 3121, 2990, 2446, 1684, 1497, 1454, 1308, 1202, 1088, 1018,
970; MS 243 (Mþ1,100%),197 (Mꢀ46, 38%),165 (Mꢀ78, 23%); HRMS
calcd for C14H15N2O2 (MþHþ) 243.1134, found 243.1137.
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(37 mg, 71%) as a yellow oil. 1H NMR
d 8.75 (1H, s), 8.08 (1H, s), 7.73
(1H, d, J¼1.4 Hz), 7.65e7.59 (3H, m), 7.48e7.44 (3H, m); 13C NMR
d
160.6, 156.8, 156.7, 149.4, 149.3, 148.4, 147.9, 147.2, 139.7, 133.1; IR
(neat) 3380, 3081, 3059, 3025, 2924, 2850, 1694, 1600, 1492, 1450,
755, 698 cmꢀ1; MS 212 (Mþ1, 90%), 196 (Mꢀ15, 100%); HRMS calcd
for C12H10N3O (MþHþ) 212.0824, found 212.0823.
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Acknowledgements
We are grateful to the Robert Welch Foundation (F-1298) and
TI3D for financial support of this research.
Please cite this article in press as: Laroche, C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.099