Coupling reactions of bromoalkynes with imidazoles mediated by copper salts: Synthesis of novel N-alkynylimidazoles

Article abstract of DOI:10.1021/jo801118q

(Chemical Equation Presented) A cross-coupling reaction of imidazoles with bromoalkynes in the presence of a catalytic amount of CuI is reported. This protocol allows an access to novel N-(1-alkynyl)imidazoles in moderate to good yields.

Full text of DOI:10.1021/jo801118q

Coupling Reactions of Bromoalkynes with
Imidazoles Mediated by Copper Salts: Synthesis
of Novel N-Alkynylimidazoles
Christophe Laroche, Jing Li, Matthew W. Freyer, and
Sean M. Kerwin*
DiVision of Medicinal Chemistry, College of Pharmacy,
The UniVersity of Texas at Austin, Austin, Texas 78712
skerwin@mail.utexas.edu
FIGURE 1. Ligands used in this work.
ReceiVed May 22, 2008
groups,6 or coupling with alkynyl iodonium salts7 all suffer
limitations in scope.
One class of N-alkynylheteroarenes that has received recent
attention are the 1,2-dialkynylimidazoles, which have been
studied as aza analogues of diradical-generating enediynes.8
Unfortunately, the synthesis of such N-alkynylimidazole moi-
eties via alkynyliodonium salt chemistry gives poor yields and
presents a limited scope.8 Recent advances in copper-catalyzed
amination of aryl halides, including N-arylations of imidazole9
and diverse N-alkynylation reactions of sulfonamides,10–13
amides,11,13 ureas,11–13 indoles,11–13 or carbamates11–13 mediated
by copper complexes inspired the work described here, which
has led to the first copper-catalyzed alkynylation of imidazoles
by alkynyl halides.
Initial attempts to couple imidazole with bromophenylacety-
lene employed conditions similar to Hsung’s protocol11 for
N-alkynylations of amides using 1,10-phenanthroline (Figure
1) as ligand and CuSO4 ·5H2O as copper source, and Sato’s
protocol10,14 for N-alkynylation of sulfonamides using N,N′-
dimethylethylenediamine (Figure 1) as ligand and CuI as copper
source yielded only traces of the expected N-alkynylimidazole.
In contrast, by using 2-acetylcyclohexanone (AcC, Figure 1)
A cross-coupling reaction of imidazoles with bromoalkynes
in the presence of a catalytic amount of CuI is reported. This
protocol allows an access to novel N-(1-alkynyl)imidazoles
in moderate to good yields.
N-Alkynylheteroarenes are an interesting variation on ynamines
and share with ynamides the increased stability engendered by
delocalization of the nitrogen lone pair.1 Despite a few reports
of interesting biological2 and photoconductive3 properties, this
entire class of molecules remains largely unexplored. This may
be explained by the lack of a general and mild synthetic route
to these compounds. Current methods involving elimination
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Singh, S. K. Heterocycles 2004, 63, 1455–1475. For reviews of ynamide
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Shen, L.; Slafer, B. W.; Zhang, Y. Sci. Synth. 2005, 21, 404. (b) Zificsak, C. A.;
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2004, 8, 1404–1408. (c) Nadipuram, A. K.; Kerwin, S. M. Tetrahedron 2006,
62, 3798–3808.
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40, 2657–2660. (b) Cristau, H.-J.; Cellier, P. P.; Spindler, J-F.; Taillefer, M.
Chem. Eur. J. 2004, 10, 5607–5622. (c) Yang, M.; Liu, F. J. Org. Chem. 2007,
72, 8969–8971. For reviews on arylamination, see: (d) Ley, S. V.; Thomas, A. W.
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6462 J. Org. Chem. 2008, 73, 6462–6465
10.1021/jo801118q CCC: $40.75 2008 American Chemical Society
Published on Web 07/23/2008

TABLE 1. Solvent and Temperature Effects on the Imidazole
Alkynylation Reactiona
TABLE 2. Condition Optimization of the Imidazole Alkynylation
Reactiona
ligand (L)b
“Cu”
yieldc (%)
entry
solvent
T (°C)
yieldb (%)
entry
X
base
1
2
3
4
5
6
7
8
DMF
DMF
toluene
toluene
toluene
THF
THF
DME
DME
DMSO
DMSO
dioxane
dioxane
dioxane
rtc
50
rtc
50
26
40
0
1
2
3
4
5
6
7
8
Br
I16
Cl17
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
AcC
AcC
AcC
AcC
AcC
AcC
AcC
None
i-BuC
acac
Phen
AcC
AcC
AcC
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuCN
CuSO4
52
2
15
6
1
30
9
10
26
2
39
12
23
43
18
39
41
36
8
110 (reflux)
K2CO3
rtc
t-BuOK
LHMDS
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
50
rtc
9
50
9
10
11
12
13
14
rtc
10
11
12
13
14
50
7
rtc
57
44
39
50
52
49
101 (reflux)
a Reactions carried out on 1 mmole scale in 2 mL of solvent under
argon. b Isolated yield after column chromatography. c Room tempera-
ture, approximately 20 °C.
a Reactions carried out on 1 mmole scale in 2 mL of solvent under
argon. b See Figure 1 for the structures of the ligands. c Yields of isola-
ted products after chromatographic purification.
as ligand and CuI as the copper source15 in DMF at room
temperature, the N-alkynylimidazole was formed in moderate
yield. A screen of various solvent and temperature conditions
(Table 1) demonstrates that with the exception of toluene, all
of the solvents examined provided at least low yields of the
N-alkynylimidazole at room temperature. With the exception
of reactions run in DMSO, an increase in reaction temperature
from room temperature to 50 °C leads to an increase in yield;
however, for toluene and dioxane, a further increase in tem-
perature to reflux is detrimental. Under reflux conditions, as in
DMSO at 50 °C, fast disappearance of the bromoalkyne is
accompanied by the formation of the homocoupling product.
Thus, dioxane appears to be the optimal solvent for this
transformation, and DMSO is a possible alternative at room
temperature.
After optimizing the solvent, a second set of reactions were
carried out to ascertain the effects of different bases, copper
sources, ligands, and haloalkyne partners (Table 2). On the basis
of the reaction with three different halo(phenyl)acetylenes, only
bromoacetylenes undergo coupling in good yield (entry 1-3).
Cesium carbonate appears to be the base of choice for this
coupling reaction. Here, this system presents a different reactiv-
ity than the alkynylation reactions developed by Hsung11 or
Sato10 where K3PO4 and K2CO3 are, in both cases, bases of
choice for the transformation.16 These results are not consistent
with a problem of base strength but can be explained by superior
solubility of Cs2CO3 in dioxane at 50 °C.
2-acetylcyclohexanone ligand by acetylacetate (acac) or 2-isobu-
tyrylcyclohexanone (i-BuC) leads to a decrease in yield, in
contrast to the case for the copper-mediated aryl amination
reported by Buchwald,15 in which i-BuC is the superior ligand.
Additionally, 1,10-phenanthroline (Phen, entry 11), though
suitable for numerous alkynylation reactions and imidazole
arylations, is ineffective under our reaction conditions. The
coupling shows little influence on the source of copper; either
copper(I) or copper(II) species can be used.
A variety of imidazole and bromoacetylene coupling partners
were examined. In order to avoid problems with less reactive
reagent pairs, the consumption of bromoalkyne by TLC was
monitored after the reaction mixtures were stirred for 14 h at
50 °C, and if necessary, the mixtures were then heated under
reflux for 4 h. The coupling reactions of unsubstituted imidazole
and benzimidazole were successfully achieved in good to
moderate yield with aryl, alkyl, and silylated bromoalkynes
(Table 3, entries 1-3, 6-8). In the case of the tert-butyldim-
ethylsilyl-protected bromopropargyl alcohol (entry 4), the low
yield of N-alkynylimidazole could be explained by the formation
of a side product, the bromoalkene 16 (Figure 2) in 20% yield.18
This direct nucleophilic addition of the imidazole anion to the
bromoalkyne is not observed for the more hindered, dimethyl-
substituted propargylic alcohol coupling partner (entry 5).
In the case of 4-phenylimidazole, coupling with bromophe-
nylacetylene affords a 9:1 mixture of regioisomeric N-alky-
nylimidazoles 9a,b. The regiochemistry of the major isomer 9a
was established as 1,4 by conversion to the haloalkene 17
Without added ligand, the reaction proceeds, but only in 10%
yield (Table 2, entry 8). We surmise that imidazole itself can
serve as ligand, similar to what is observed in copper-mediated
arylation reactions.17 However, without any copper catalyst
present, no reaction is observed (in DMF). Replacing the
1
(Figure 2), the structure of which was established by H NOE
analysis (Supporting Information). In the case of other bro-
moacetylenes (Table 3, entries 10 and 11), the regioselectivity
is excellent and only the 1,4-regioisomers were observed. This
(15) (a) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742–
8743. (b) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3490–3491.
(17) (a) Liangbo Zhu, L.; Guo, P.; Li, G.; Lan, J.; Xie, R.; You, J. J. Org.
Chem. 2007, 72, 8535–8538. (b) Sperotto, E.; de Vries, J. G.; van Klinka,
G. P. M.; van Koten, G. Tetrahedron Lett. 2007, 48, 7366–7370.
(16) We noticed that during the solvent screening (Table 1) the reactions
with K3PO4 or Cs2CO3 afforded the product with the same yield at room
temperature in DMF (26% in both cases) and that these reactions were not very
sensitive to the equivalents of base added; see the Supporting Information.
(18) The alkene stereochemistry of 15 was elucidated by 1H nuclear
Overhauser enhancement experiments (see the Supporting Information).
J. Org. Chem. Vol. 73, No. 16, 2008 6463

TABLE 3. Preparation of N-Alkynylimidazoles 1-15a
fluorophenyl)-5-(4-pyridyl)-1H-imidazole20 affords low yields
of a mixture of regioisomeric N-alkynylimidazoles (entry 14).
In contrast, the related 4-(4-fluorophenyl)imidazole affords the
coupling product in good yield and regioselectivity (entry 15).
There are a few observations concerning the proposed
mechanism of this coupling reaction. Imidazole and imidazolate
are good ligands for both copper(I) and copper(II), and in the
case of bridging imidazolate, polymorphic, aggregated com-
plexes are possible.21 It is noteworthy that the coupling reaction
showed little sensitivity to the oxidation state of the copper
source used (Table 2, entries 11-14) or the presence or
exclusion of air (Supporting Information). Although a catalyti-
cally active copper-imidazole species can carry out the coupling
in the absence of added ligand (Table 2, entry 8), the efficiency
is low, which may arise from catalytically inactive complexes/
aggregates. The role of the added ligand may be to promote
disaggregation of these imidazole(imidazaolate)/copper com-
plexes and to increase the electron density of the resulting
ligand-associated copper complex in order to aid the oxidative
addition of the haloalkyne. In this respect, the anionic ligands
derived from diketones are strongly electron-donating, so that
when they bind to the copper, the oxidative addition reaction is
more likely to occur. The increase in coupling yields with
increasing reaction temperature that is observed could be partly
due to disruption of the copper-imidazole complexes. Solvent
polarity could play a similar role; DMSO which enables
coupling reaction at room temperature (Table 1, entry 10) is
able to bind to the copper22 and may compete with the ligand
imidazole to prevent the aggregation. Finally, the nature of the
imidazole partner affects the stability and aggregation state of
any complex with copper, which may in part explain why the
reactions of 2- and 4-methylimidazole do not work as well as
the unsubstituted imidazole (Table 3, entries 12-13).
In conclusion, a copper-catalyzed coupling reaction between
imidazoles or benzimidazole and bromoalkynes has been
developed to afford N-alkynyl derivatives which is both more
efficient and of wider scope compared to previous routes to these
compounds. This transformation allows access to numerous new
N-alkynylimidazoles and benzimidazoles, which may display
interesting chemical and biological propertires and are potential
starting materials in the synthesis of aza-enediyne derivatives.
a Except where noted otherwise, all reactions were carried out on a 1
mmol scale in 2 mL of dioxane under argon at 50 °C for 14 h followed by
h
under reflux. b Isolated yields after column chromatography.
Experimental Section
4
c Reaction carried out at 50 °C overnight. d Ratio of 1,4- to 1,5-regio-
isomeric products a and b, respectively. e None of the 1,5-regioisomeric
product was observed.
General Procedure for the Synthesis of 1-(2-Phenylethynyl)-
1H-imidazole 1. A reaction flask under argon was charged with
Cs2CO3 (652 mg, 2 mmol), CuI (10 mg, 0.05 mmol), and imidazole
(68 mg, 1 mmol) and backfilled with argon. Dry 1,4-dioxane (2
mL) was added followed by the bromophenylacetylene (0.237 mL,
2 mmol), the 2-acetylcyclohexanone (0.026 mL, 0.2 mmol), and 4
Å molecular sieves (75-115 mg). The mixture was heated to 50
°C in an oil bath for 14 h and then heated to reflux for 4 h. The
reaction mixture was cooled to room temperature, quenched with
5 mL of a saturated NH4Cl solution, and extracted with CH2Cl2 (3
× 20 mL). The combined organic layers were evaporated and
FIGURE 2. Structures of the N-(halovinyl)imidazoles.
regiocontrol could be explained by a combination of steric and
electronic effects due to a favorable annular tautomerism.19
The coupling reactions of 2- and 4-methylimidazole afforded
N-alkynylimidazoles as well but in low yield and in the case of
4-methylimidazole with poor regioselectivity (Table 3, entries
12-13). Similarly, the coupling of the challenging 4-(4-
(20) Sisko, J.; Kassick, A. J.; Melliger, M.; Filan, J. J.; Allen, A.; Olsen,
M. A. J. Org. Chem. 2000, 65, 1516–1524.
(21) (a) Bauman, J. E.; Wang, J. C. Inorg. Chem. 1964, 3, 368–373. (b)
Kitagawa, S.; Munakata, M. Bull. Chem. Soc. Jpn. 1986, 59, 2743–2750. (c)
Swiatek-Tran, B; Kolodziej, H. A Czech. J. Phys. 2004, 54, 547–550. (d) Huang,
X.-C.; Zhang, J.-P.; Chen, X.-M. Cryst. Growth Des. 2006, 6, 1194–1198.
(22) (a) Ahrland, S. Pure Appl. Chem. 1990, 62 (11), 2077–2082. (b)
Lefebvre, J.; Batchelor, R. J.; Leznoff, D. B. J. Am. Chem. Soc. 2004, 126,
16117–16125.
(19) Claramunt, R. M.; Santa Maria, M. D.; Infantes, L.; Cano, F. H.; Elguero,
J. J. Chem. Soc., Perkin Trans. 2 2002, 564–568.
(23) Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory Chemi-
cals;Butterworth Hanemann: Oxford, 1996; Chapter 4.
6464 J. Org. Chem. Vol. 73, No. 16, 2008

subjected to flash chromatography (0-25% EtOAc/hexane) to
afford 1 (87 mg, 52% yield) as a white solid: mp 42.1-43.3 °C;
1H NMR (400 MHz, CDCl3) δ 7.82 (1H, s), 7.53-7.48 (2H, m),
7.39-7.34 (3H, m), 7.20 (1H, s), 7.09(1H, s); 13C NMR (100 MHz,
CDCl3) δ 140.0, 131.7 (2C), 129.3, 129.0, 128.5 (2C), 121.7, 121.0,
was heated at 80 °C for 3 days and then cooled to room temperature,
quenched with a saturated solution of Na2CO3, and extracted with
CH2Cl2. The combined organic layers were subjected to flash
chromatography (0-20% EtOAc/hexane) to afford 8 mg of 17 (3%)
as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.95 (1H, s),
7.84-7.79 (2H, m), 7.69-7.65 (2H, m), 7.57 (1H, s), 7.47-7.35
(5H, m), 7.34-7.27 (1H, m), 6.88 (1H, s); 13C NMR (100 MHz,
CDCl3) δ 142.9, 136.6, 133.0, 132.3, 129.2 (2C), 128.9, 128.7 (2C),
128.6 (2C), 127.5, 125.1 (2C), 123.3, 120.8, 114.1; IR (neat) 2926,
2854, 1718, 1637, 1489, 1446, 1381, 1239, 1184, 1068, 1043, 900
cm-1; MS (CI) (m/z) 281 (M + 1, 100); HRMS calcd for
C17H14N2Cl (M + H+) 281.0846, found 281.0843.
78.1, 70.3; IR (KBr) 2263, 1478, 1309, 1165, 1067, 1013 cm-1
;
MS (CI) (m/z) 337 (2M + 1, 15), 169 (M + 1, 100); HRMS calcd
for C11H9N2 (M + H+) 169.0766, found 169.0769.
1-(Z-2-Bromo-1-(tert-butyldimethylsilanyloxymethyl)vinyl)-
1H-imidazole 16. Following the general procedure above (flash
chromatography; 0-10% EtOAc/hexane), 47 mg of 15 (15%) was
1
obtained as a colorless oil: H NMR (400 MHz, CDCl3) δ 7.67
(1H, s), 7.25 (1H, s), 7.07 (1H, s), 6.52 (1H, t, J ) 1.4 Hz), 4.31
(2H, d, J ) 1.4 Hz), 0.88 (9H, s), 0.05 (6H, s); 13C NMR (100
MHz, CDCl3) δ 139.5 (br), 136.8 (br), 129.3 (br), 118.3 (br), 102.8,
65.1, 25.6 (3C), 18.1, -5.6 (2C); IR (neat) 2954, 2931, 2888, 2857,
1646, 1486, 1382, 1314, 1256, 1140, 1084 cm-1; MS (CI) (m/z)
635 (2M + 1, 35), 317 (M + 1, 100); HRMS calcd for
C12H22BrN2OSi (M + H+) 317.0685, found 317.0683.
Acknowledgment. We are grateful to the Robert Welch
Foundation (F-1298) and the Texas Advanced Research Program
(3658-003) for financial support of this research.
Supporting Information Available: General procedure for
1
bromoalkyne preparation, characterization data, and H NMR
1-(Z-2-Chloro-2-phenylvinyl)-4-phenyl-1H-imidazole 17. A
reaction flask under argon was charged with 9a (89 mg, 0.36 mmol)
and backfilled with argon. DMF (15 mL) was added followed by
concd HCl (0.121 mL, approximately 1.46 mmol). The reaction
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO801118Q
J. Org. Chem. Vol. 73, No. 16, 2008 6465