Cu-catalyzed N-alkynylation of imidazoles, benzimidazoles, indazoles, and pyrazoles using PEG as solvent medium

Article abstract of DOI:10.1021/jo902466f

(Chemical Equation Presented) A facile and efficient Cu(I)-catalyzed cross-coupling method is reported for the preparation of N-alkynyl or N-bromoalkenyl heteroarenes from bromoalkynes. Generally superior yields and functional group tolerance were obtained with microwave (MW) irradiation using imidazole, benzimidazole, pyrazole, and indazole substrates and poly(ethylene glycol) 400 (PEG400) as an additive. We speculate that PEG400 acts as both a Cu(I)-stabilizing ligand as well as a phase transfer solvent.

Full text of DOI:10.1021/jo902466f

pubs.acs.org/joc
Previous preparative methods of N-alkynylheteroarenes
Cu-Catalyzed N-Alkynylation of Imidazoles,
Benzimidazoles, Indazoles, and Pyrazoles Using PEG
as Solvent Medium
have included the coupling of alkynyl iodonium species,1,2
elimination of haloenamines,1 nucleophilic substitution of
metal amides, and isomerization of propargyl amines; how-
ever, these methods suffer from step and atom inefficiency
and have limited functional group tolerance. We have re-
cently become interested in utilizing N-alkynylheteroarenes
as useful synthons in the combinatorial preparation of novel
heterocyclic scaffolds. We envisaged that the recent deve-
lopments in copper-catalyzed cross-couplings pioneered by
groups such as Evano,6 Buchwald,7 Hsung,8 Kerwin,9 and
others10 could provide an efficient means to prepare such
scaffolds from bromoalkynes and the appropriate N-con-
taining heterocycle. In this communication, we report a
simple and facile method for the synthesis of N-alkynylhe-
teroarenes incorporating the imidazole, benzimidazole,
pyrazole, and indazole heterocyclic cores.
Glenn A. Burley,* David L. Davies,* Gerry A. Griffith,
Michael Lee, and Kuldip Singh
Department of Chemistry, University of Leicester, University
Road, Leicester LE1 7RH, United Kingdom
gab13@le.ac.uk
Received November 19, 2009
Initial attempts to couple benzimidazole (1) with the
bromoalkyne (2) provided moderate yields of N-alkynylhe-
teroarene when Hsung’s copper(II) (entry 1, Table 1)8 or
Buchwald’s copper(I) protocols were applied (entry 2,
Table 1).7a,b,11 Direct cross-coupling of triisopropylsilylace-
tylene with benzimidazole using Stahl’s conditions also
proved unsuccessful (results not shown).12 Buchwald and
others have reported increases in yields and reproducibility
of palladium- and copper-catalyzed cross-couplings when
poly(ethylene glycol) (PEG) additives were used.7d,13 PEG
can act as a highly efficient phase transfer solvent by
providing a compatible reaction bridge between the hydro-
phobic organic components (1 and 2) and the hydrophilic
base (Cs2CO3). When poly(ethylene glycol) 400 (molecular
weight 400, PEG400) was added to the reaction mixture and
heated by conventional means (entry 5, Table 1), we ob-
served similar yields of 3; however, microwave irradiation
resulted in a marked increase in isolated yield of 3 (entry 6,
Table 1). These reactions were particularly facile with reac-
tion times reduced from 24 h to 30 min (entry 7, Table 1)
when microwave heating was applied. Interestingly we dis-
covered that the presence of Cu(I)-stabilizing ligands such as
A facile and efficient Cu(I)-catalyzed cross-coupling
method is reported for the preparation of N-alkynyl
or N-bromoalkenyl heteroarenes from bromoalkynes.
Generally superior yields and functional group tolerance
were obtained with microwave (MW) irradiation using
imidazole, benzimidazole, pyrazole, and indazole sub-
strates and poly(ethylene glycol) 400 (PEG400) as an
additive. We speculate that PEG400 acts as both a Cu(I)-
stabilizing ligand as well as a phase transfer solvent.
Aromatic ynamines or N-alkynylheteroarenes are func-
tional groups where the aromatic nitrogen atom is directly
linked to an alkyne.1 As a consequence of this, N-alkynylhe-
teroarenes are useful yet under-utilized intermediates in
5
organic synthesis2-4 and medicinal chemistry; the under-
(6) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem., Int.
Ed. 2009, 48, 4381.
lying reason is the dearth of mild and general preparative
methods of their formation. In addition, understanding the
structure-reactivity relationship of these functional groups
is also limited, as highlighted by the small number (less than
20) of crystal structures present in the literature. Therefore
mild and efficient routes toward their formation could
provide access to new chemical reactivity particularly toward
the synthesis of valuable heterocycles. In addition further
structural studies may give insight into the effect of sub-
stituents on reactivity.
(7) (a) Altman, R. A.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem.
2008, 73, 5167. (b) Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org.
Chem. 2007, 72, 6190. (c) Altman, R. A.; Buchwald, S. L. Org. Lett. 2007, 9,
643. (d) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779.
(8) (a) Yao, P. Y.; Zhang, Y.; Hsung, R. P.; Zhao, K. Org. Lett. 2008, 10,
4275. (b) Zhang, X. J.; Zhang, Y. S.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.;
Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L. C.; Tracey,
M. R. J. Org. Chem. 2006, 71, 4170. (c) Zhang, Y.; Hsung, R. P.; Tracey, M. R.;
Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6 (7), 1151–1154.
(9) Laroche, C.; Li, J.; Freyer, M. W.; Kerwin, S. M. J. Org. Chem. 2008,
73, 6462.
(10) (a) Gao, Y. X.; Wang, G.; Chen, L.; Xu, P. X.; Zhao, Y. F.; Zhou,
Y. B.; Han, L. B. J. Am. Chem. Soc. 2009, 131, 7956. (b) Evano, G.; Toumi,
M.; Coste, A. Chem. Commun. 2009, 4166. (c) de Parrodi, C. A.; Walsh, P. J.
Angew. Chem., Int. Ed. 2009, 48, 4679.
(11) Strieter, E. R.; Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009,
131, 78.
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(2) Ishihara, T.; Mantani, T.; Konno, T.; Yamanaka, H. Tetrahedron
2006, 62, 3783.
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(5) (a) Xu, Z. Q.; Joshi, R. V.; Zemlicka, J. Tetrahedron 1995, 51, 67.
(b) Joshi, R. V.; Xu, Z. Q.; Ksebati, M. B.; Kessel, D.; Corbett, T. H.; Drach,
J. C.; Zemlicka, J. J. Chem. Soc., Perkin Trans. 1 1994, 1089.
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Published on Web 01/04/2010
DOI: 10.1021/jo902466f
r
2010 American Chemical Society

Burley et al.
JOCNote
TABLE 1. Screening of Solvent, Ligand and Heating Conditions for the
N-Alkynylation of Benzimidazole with the Bromoalkyne (2)
TABLE 2. Microwave-Promoted Copper-Catalyzed Cross-Coupling
of Bromoalkynes (2, 4 and 5) with Imidazoles and Benzimidazoles
entry
solvent (1.0 M)
L (10 mol %)
base
yield of 3 (%)a
1
2
3
4
5
6
7
8
9
10
toluene
DMF
Phen
Phen
AcC
AcC
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
K2CO3
22a
43b
12b
51b
53c
72d
74d
72d
64d
57d
DMSO
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
AcC
DiOMePhen
aAll reactions conducted with 1 (1.0 equiv), 2 (1.2 equiv), 36 h, 90 °C
unless stated otherwise. bCuSO4 5H2O (5 mol %). cCuI (5 mol %),
3
PEG400 (200 mg). dCuI (5 mol %), PEG400, 90 °C, 30 min, MW
(125 W).
Phen, AcC, or DiOMePhen was not essential for high yields
of 3, which is indicative of the PEG-400 additive not only
acting as a phase transfer solvent but also participating as a
Cu-stabilizing ligand. When applied to the N-alkynylation of
imidazole, the isolated yield (88%) was superior using these
conditions compared to previous conditions that yielded
53% of N-alkynylheteroarene product.9
With a set of reaction conditions in hand, we screened a
series of imidazole and benzimidazoles against bromo-
alkynes 2, 4, and 5, which resulted in the formation of either
N-alkynylheteroarene or N-alkenylbromoheteroarene pro-
ducts (Table 2). Bulky bromoalkynes such as 2 exclusively
formed N-alkynylheteroarenes, whereas bromoalkyne 4
formed predominantly N-alkynylheteroarene products with
nonhindered imidazole and benzimidazole substrates.
Under microwave irradiation conditions, cross-couplings
using 2 as the coupling partner generally afforded superior
yields over reactions using the less sterically hindered bromo-
alkynes 4 and 5. In these cases the lower yields are also
associated with the formation of the corresponding debromi-
nated alkyne in addition to small quantities of homocoupled
bisalkyne products.
For imidazole substrates (entries 1-9, Table 2) we
generally observed good yields, although the imidazole sub-
strates (entries 1-3, Table 2) were found to be a little
unstable, resulting in decomposition upon standing in the
reaction mixture after 72 h. Sterically hindered imidazole
substrates and alkyne 2 give good or moderate yields of
N-alkynylheteroarene (entries 4 and 7, Table 2). However,
with less bulky alkynes 4 and 5 no reaction occurs with
2-methylimidazole (entries 5 and 6, Table 2) as the substrate.
For 4,5-diphenylimidazole the bromoalkene is formed
exclusively (entries 8 and 9, Table 2) in moderate yields.
When 2-methylbenzimidazole was used, a moderate yield
of the N-alkynylheteroarene derived from the coupling of the
aHetereocycle (1.0 equiv), bromoalkyne (1.2 equiv), CuI (5 mol %),
PEG400 (200 mg), Cs2CO3 (1.2 equiv), MW (125 W), 80 °C, 90 min.
c
bGC-MS yield. Afforded a regioisomeric mixture (3:1 ratio) of two
bromoalkenes. dAfforded a complex mixture of homocoupled bisalkyne
as well as a regioisomeric mixture of both N-alkynylheteroarene and
bromoalkenes. NR = no reaction.
bulky bromoalkyne 2 was observed (entry 22, Table 2),
similar to the 2-methylimidazole substrate (entry 7, Table 2),
whereas 4 and 5 both afford exclusively the bromoalkene
products in good yields (entries 23 and 24, Table 2).
NOE studies of the resultant bromoalkene products
determined the alkene stereochemistry to be Z. This was
J. Org. Chem. Vol. 75, No. 3, 2010 981

Burley et al.
JOCNote
SCHEME 1. Influence of Bromide on Product Distribution
confirmed by an absence of an NOE between the methyl and
the alkenyl methine protons. However, strong NOEs were
observed between the alkenyl proton and several of the
protons derived from the bromoalkyne precursor (see Sup-
porting Information).
Although Kerwin et al. observed bromoalkene forma-
tion with the same reported stereochemistry,9 uniquely
under these conditions the N-alkynylheteroarene was
found to be the major product with the bromoalkene
formed as a minor product. The formation of the bromo-
alkene is quite sensitive to the steric bulk of the hetero-
arene. With the more sterically bulky alkyne substituents
(TIPS and Ph, entries 10 and 11, Table 2), no bromoalkene
was formed, whereas with TBDMS-protected 2-hydroxy-
ethyl (entry 12, Table 2) a 5:1 ratio of alkynylheteroarene/
bromoalkene was observed. However, we observed a trend
of increasing bromoalkene formation as the steric bulk of
the heteroarene increases (compare entry 14 and 11), and
this can even become the major product (entry 15, Table 2).
This suggests that attack of the nitrogen nucleophile is
slower and bromoalkene formation can then compete
with N-alkynylation. We have checked that bromoalkene
formation does not occur from the N-alkynylheteroarene
product, but more detailed studies are necessary to eluci-
date the mechanism of formation of the bromoalkene.14
However, the addition of a bromide source [(Bu)4NBr]
with the other reagents results in increased bromoalkene
formation (for example, Scheme 1). Omission of a copper
source affords no change in product distribution, which
suggests that this process is indeed copper-mediated. It is
likely that bromoalkene formation proceeds via π-activa-
tion of the alkyne species rather than an oxidative addi-
tion process as we assume is occurring in the case of
N-alkynylhetereoarene formation.15
FIGURE 1. X-ray structures of (a) 7 and (b) 8.
In 7 there is evidence of delocalization in the benzimida-
˚
zole ring with N(1);C(1) distance of 1.362(8) A being
˚
intermediate between N(1);C(2) 1.410(8) A and N(2);
˚
C(1) 1.306(8) A as expected. The N(1);C(8) bond is also
˚
shorter than a conventional single bond at 1.342(10) A. The
alkyne triple bond length though is relatively unaffected at
˚
1.199(11)A, which may be indicative of the limited inter-
action of the lone pair of nitrogen (N1) with the alkyne
π-system because the former is tied into the aromatic system.
The phenyl ring and benzimidazole ring are almost coplanar;
the torsion angles C(11)-C(10)-N(1)-C(2) and C(15)-C-
(10)-N(1)-C(1) are 5.4° and 5.6°, respectively. This is
consistent with a crystal structure of an imidazole-derived
N-alkynylheteroarene recently published by Kerwin.17 This
is in contrast to a phenyl-substituted amidoalkyne where the
phenyl and amido substituents are at an angle of 79.9°.18
There is no evidence of π-stacking, but H(3) of one molecule
is hydrogen-bonded to N(2) of another. Compound 8 forms
dimers through H-bonding between N(1) and H(1). In
addition N(1) is H-bonded to the alkyne hydrogen H(9)
of another molecule, forming a two-dimensional layer of
dimers.
These Cu-catalyzed cross-coupling conditions were also
suitable for the novel preparation of N-alkynylated pyrazole
and indazole substrates (Table 3). N-Alkynylated pyrazoles
have only been transiently observed by the rearrangement of
alkynamides to the corresponding pyrazolo N-alkynylhetero-
areneusing flashvacuum photolysis,19 which providedus with
the motivation to develop more convenient methods of their
formation. The preparation of N-alkynylated pyrazole or
indazole products was observed to be superior with micro-
wave-assisted heating, albeit in the presence of 2.0 equiv of
bromoalkyne. Previous reports of copper-catalyzed N-aryla-
tionsusing indazoles typically produced minoramounts of the
N2 isomer; however, in our hands we observed N1-coupled
products almost exclusively using either microwave-assisted or
conventional heating protocols.7b NOE experiments confirmed
the stereochemistry of the bromoalkene to be Z, again consis-
tent with the imidazole/benzimidazole series. Of particular
The regioselectivity of the reaction was found to be low
for nonliganded reactions when nonsymmetrical benzi-
midazoles 5-chloro-1H-benzo[d ]imidazole (entries 25-27,
Table 2) and azabenzimidazoles (entries 16-18, Table 2)
were used. N-Alkynylated purines, however, were formed in
only trace quantities (entries 19-21, Table 2).
We determined the structures of two benzimidazole deri-
vatives, 7 and 8 (Figure 1).16
(14) To a microwave tube were added solid CuI (0.05 mmol, 9.00 mg),
compound 6 (34 mg, 0.14 mmol), Bu4NBr (90 mg, 0.28 mmol), and Cs2CO3
(54 mg, 0.17 mmol). A solution of PEG400 (50 mg) in dioxane (0.5 mL) was
added, and the reaction mixture evacuated and back filled with argon. The
reaction mixture was then heated under microwave irradiation (125 W) at
85 °C for 60 min. GC-MS analysis observed only starting material present in
the crude mixture.
(17) Li, J.; Kaoud, T. S.; Laroche, C.; Dalby, K. N.; Kerwin, S. M. Bioorg.
Med. Chem. Lett. 2009, 19 (22), 6293–6297.
(15) For a recent example of π-activation of an alkyne by copper, see:
Laroche, C.; Kerwin, S. M. J. Org. Chem. 2009, 74, 9229–9232.
(16) The United Kingdom Chemical Database Service; Fletcher, D. A.;
McMeeking, R. F.; Parkin, D. J. Chem. Inf. Comp. Sci. 1996, 36, 746.
(18) Tracey, M. R.; Zhang, Y. S.; Frederick, M. O.; Mulder, J. A.; Hsung,
R. P. Org. Lett. 2004, 6, 2209.
(19) Brown, R. F. C.; Eastwood, F. W.; Fallon, G. D.; Lee, S. C.;
McGeary, R. P. Aust. J. Chem. 1994, 47, 991.
982 J. Org. Chem. Vol. 75, No. 3, 2010

Burley et al.
JOCNote
N-alkynylation to other heterocycles and investigating their
reactivity.
TABLE 3. Copper-Catalyzed Cross-Coupling of Bromoalkynes (2, 4, 5)
with Pyrazoles and Indazoles
Experimental Section
General Procedure for the Copper-Catalyzed N-Alkynylation
of Bromoalkynes with Aromatic Nitrogen Nucleophiles under
Microwave Irradiation (1.0 mmol scale). To a microwave tube
were added solid CuI (0.05 mmol, 9.00 mg), the aromatic
N-heterocycle (1.0 mmol), and Cs2CO3 (1.2 mmol, 392 mg).
The reaction flask was capped, evacuated, and backfilled
with nitrogen three times. In a separate flask, a solution of
dry dioxane (1 mL) containing poly(ethylene glycol) 400
(PEG400, 200 mg) and the bromoalkyne (1.10 mmol) was
evacuated and backfilled with nitrogen gas three times. The
solution was then added to the reaction vessel and irradiated
(125 W) at 70 °C for 30-90 min. The reaction mixture was
then diluted with diethyl ether (100 mL), filtered through a
pad of Celite, and concentrated in vacuo. Flash column
chromatography (SiO2) eluting with a gradient of ethyl ace-
tate/hexane (1:20f1:10) provided the N-alkynylated hetereo-
cycle.
Procedure for the Formation of 1-Ethynyl-5,6-dimethyl-1H-
benzo[d ]imidazole (8). To a solution of 5,6-dimethyl-1-((triiso-
propylsilyl)ethynyl)-1H-benzo[d ]imidazole (640 mg, 1.96 mmol)
in THF was added tetrabutylammonium fluoride (2.40 mL,
1.0 M, 2.36 mol) under a nitrogen atmosphere. The reaction
mixture was stirred at rt under a nitrogen atmosphere for
30 min, followed by concentration in vacuo. Flash column
chromatography (SiO2) eluting with a gradient of ethyl acetate/
hexane (1:10 f 1:5) provided 8 as a pale yellow crystalline solid
(208 mg, 62%). Analytically pure crystals suitable for X-ray
analysis were obtained by crystallization from a diethyl ether/
hexane mixture (5:95) to form colorless plates. 1H NMR
(CDCl3, 500 MHz): δ 2.33 (s, 3H, Ar-CH3), 2.34 (s, 3H, Ar-
CH3), 3.27 (s, 1H, CCH), 7.27 (s, 1H, Ar-H), 7.53 (s, 1H, Ar-H),
7.94 (s, 1H, Ar-H). 13C NMR (CDCl3, 125.76 MHz): δ 20.2 (1C,
Ar-CH3), 20.4 (1C, Ar-CH3), 61.7 (1C, CCH), 70.7 (1C, Ar-
CCH), 110.9 (1C, ArC), 120.7 (1C, ArC), 132.7 (1C, ArC), 133.0
(1C, ArC), 134.2 (1C, ArC), 140.2 (1C, ArC), 142.8 (1C, ArC).
HRMS (EI, þve) calcd for C11H10N2 170.08440 [M]þ, found
170.08407.
aHetereocycle (1.0 equiv), bromoalkyne (2.0 equiv), CuI (5 mol %),
PEG400 (200 mg), 90 min, MW (125 W), 80 °C. bGC yield as compound
degrades after purification. cPresent as an inseparable 1:1.5 [N-alkynyl-
heteroarene/bromoalkene] mixture by column chromatography. Analy-
tically pure sample obtained by HPLC. NR = no reaction.
note is the regioselective N-alkynylation of 6-aminoindazole
(entry 10, Table 3). Bromoalkyne 2 exclusively afforded the
N-alkynylated product at N1 with very little N2 and N6 coupled
products observed according to GC-MS. Additionally this
reaction only proceeded with the sterically hindered bromoalk-
yne 2 with no product obtained with the bromoalkyne sub-
strates 4 and 5.
In summary, we have described here a simple and cost-
effective method of N-alkynylation of N-containing hetero-
cycles. The reaction utilizes inexpensive starting materials
and affords either N-alkynylated or N-bromoalkenylated
products in generally good yield. The use of the PEG additive
and microwave-based heating is key to the good yields
and short reaction times. Future studies will endeavor to
investigate broadening the scope and regioselectivity of
Acknowledgment. We wish to acknowledge the use of the
EPSRC’s Chemical Database Service at Daresbury.14 G.A.
B. [Advanced Fellowship] thanks the EPSRC for financial
support [EP/E055095/1].
Supporting Information Available: Procedures for the pre-
paration of bromoalkynes (2, 4, 5) and their use in the prepara-
tion of N-alkynes and N-bromoalkenes; characterization data
and 1H and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 3, 2010 983