Copper-diamine-catalyzed N-arylation of pyrroles, pyrazoles, indazoles, imidazoles, and triazoles

Article abstract of DOI:10.1021/jo049658b

This paper details the copper-catalyzed N-arylation of π-excessive nitrogen heterocycles. The coupling of either aryl iodides or aryl bromides with common nitrogen heterocycles (pyrroles, pyrazoles, indazoles, imidazoles, and triazoles) was successfully performed in good yield with catalysts derived from diamine ligands and CuI. General conditions were found that tolerate functional groups such as aldehydes, ketones, alcohols, primary amines, and nitriles on the aryl halide or heterocycle. Hindered aryl halides or heterocycles were also found to be suitable substrates using the conditions reported herein.

Full text of DOI:10.1021/jo049658b

Cop p er -Dia m in e-Ca ta lyzed N-Ar yla tion of P yr r oles, P yr a zoles,
In d a zoles, Im id a zoles, a n d Tr ia zoles
J on C. Antilla, J eremy M. Baskin, Timothy E. Barder, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received March 1, 2004
This paper details the copper-catalyzed N-arylation of π-excessive nitrogen heterocycles. The
coupling of either aryl iodides or aryl bromides with common nitrogen heterocycles (pyrroles,
pyrazoles, indazoles, imidazoles, and triazoles) was successfully performed in good yield with
catalysts derived from diamine ligands and CuI. General conditions were found that tolerate
functional groups such as aldehydes, ketones, alcohols, primary amines, and nitriles on the aryl
halide or heterocycle. Hindered aryl halides or heterocycles were also found to be suitable substrates
using the conditions reported herein.
In tr od u ction
in terms of generality have lessened the utility of the
method.4 We have previously reported a general method
for the N-arylation of amides and of nitrogen heterocycles
catalyzed by copper-diamine complexes.5 The use of
diamine ligands for copper has resulted in numerous new
coupling reactions being developed in our laboratory6 and
in those of others.7 Herein, we report a general process
for the cross-coupling of a variety of nitrogen heterocycles
with aryl iodides or aryl bromides. This paper does not
present results for the arylation of indoles as our work
with this important class of nitrogen hetereocycles was
described in detail in an earlier report.6c
Nitrogen-containing heterocycles are subunits found
in numerous natural products and in many biologically
active pharmaceuticals.1 It is therefore important that
general methods to synthesize or to modify such com-
pounds are developed. One such reaction is the cross-
coupling of N-H containing heterocycles with aryl halides
to form the respective N-arylated heterocycle (Ullmann
coupling). To date, there have been numerous copper-
mediated or copper-catalyzed methods published to allow
for such a transformation.2 However, these reports, while
significant contributions, generally suffer from important
limitations such as high reaction temperatures (often 140
°C or higher) and poor substrate generality. Another
limitation has been that, to date, no single method has
found success with each of the major classes of nitrogen
heterocycles (imidazoles, pyrroles, pyrazoles, etc.). Re-
cently, the use of C-H bond functionalization via pal-
ladium and ruthenium catalysis has been applied to the
arylation of several azoles.3 These methods provide access
to a wide range of azole derivatives; however, high
temperatures (130-150 °C) are necessary. Palladium-
catalyzed cross-coupling of N-H heterocycles with aryl
halides has been moderately successful, but limitations
Resu lts a n d Discu ssion
In our initial communication utilizing diamines as
ligands for copper catalysis, a number of N-H heterocycles
were reported to undergo coupling with aryl iodides in
dioxane as a solvent.5 In a subsequent, more detailed
exploration of the coupling of aryl halides with indoles,6c
it became apparent that N,N′-dimethyl-substituted ligands
(2 and 3) were superior to the parent ligands (Figure 1).
This was at least partly due to the fact that competitive
N-arylation of the ligand was suppressed because of the
increase in steric hindrance at the nitrogen center. It was
(4) (a) Mann, G.; Hartwig, J . F.; Driver, M. S.; Fernandez-Rivas, C.
J . Am. Chem. Soc. 1998, 120, 827. (b) Hartwig, J . F.; Kawatsura, M.;
Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J . Org. Chem.
1999, 64, 5575. (c) Old, D. W.; Harris, M. C.; Buchwald, S. L. Org.
Lett. 2000, 2, 1403.
(5) Klapars, A.; Antilla J . C.; Huang, X.; Buchwald, S. L. J . Am.
Chem. Soc. 2001, 123, 7727.
(1) (a) Craig, P. N. In Comprehensive Medicinal Chemistry; Drayton,
C. J ., Ed.; Pergamon Press: New York, 1991; Vol. 8. (b) Southon, I.
W.; Buckingham, J . In Dictionary of Alkaloids; Saxton, J . E., Ed.;
Chapman and Hall: London, 1989. (c) Negwer, M. In Organic-Chemical
Drugs and their Synonyms: (An International Survey), 7th ed.;
Akademie Verlag GmbH: Berlin, 1994.
(2) (a) Harbert, C. A.; Plattner, J . J .; Welch, W. M.; Weissman, A.;
Koe, B. K. J . Med. Chem. 1980, 23, 635. (b) Lexy, H.; Kauffmann, T.
Chem. Ber. 1980, 113, 2755. (c) Unangst, P. C.; Connor, D. T.; Stabler,
S. R.; Weikert, R. J . J . Heterocycl. Chem. 1987, 24, 811. (d) Kato, Y.;
Conn, M. M.; Rebek, J ., J r. J . Am. Chem. Soc. 1994, 116, 3279. (e)
Murakami, Y.; Watnabe, T.; Hagiwara, T.; Akiyama, Y.; Ishii, H. Chem.
Pharm. Bull. 1995, 43, 1281. (f) Mederski, W. W. K. R.; Lefort, M.;
Germann, M.; Kux, D. Tetrahedron 1999, 55, 12757. (g) Collman, J .
P.; Zhong, M. Org. Lett. 2000, 2, 1233.
(6) (a) Zanon, J .; Klapars, A. Buchwald, S. L. J . Am. Chem. Soc.
2003, 125, 2890. (b) Klapars, A.; Buchwald S. L. J . Am. Chem. Soc.
2002, 124, 14844. (c) Antilla, J . C.; Klapars, A.; Buchwald, S. L. J .
Am. Chem. Soc. 2002, 124, 11684. (d) Klapars, A.; Huang X.; Buchwald
S. L. J . Am. Chem. Soc. 2002, 124, 7421. (e) Wolter, M.; Klapars, A.;
Buchwald, S. L. Org. Lett. 2001, 3803.
(7) (a) Wang X.; Porco, J . A., J r. J . Am. Chem. Soc. 2003, 125, 6040.
(b) Padwa, A.; Crawford, K. R.; Rashatasakhon, P.; Rose, M. J . Org.
Chem. 2003, 68, 2609. (c) Fredrick, M. O.; Mulder, J . A.; Tracey, M.
R.; Hsung, R. P.; Huang, J .; Kurtz, K. C. M.; Shen, L.; Douglas, C. J .
J . Am. Chem. Soc. 2003, 125, 2368.
(3) (a) Sezen, B.; Sames, D. J . Am. Chem. Soc. 2003, 125, 5274. (b)
Sezen, B.; Sames, D. J . Am. Chem. Soc. 2003, 125, 10580.
10.1021/jo049658b CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/10/2004
5578
J . Org. Chem. 2004, 69, 5578-5587

Copper-Diamine-Catalyzed N-Arylation of Pyrroles
TABLE 1. Cop p er -Dia m in e-Ca ta lyzed N-Ar yla tion of P yr r oles
a
b
d
Reaction performed with 2.0 equiv of ArBr. With 20% ligand 3. c With 20% ligand 3 and neat in aryl iodide (no solvent). Reaction
performed neat in aryl iodide (no solvent).
quantity of catalyst, nor reaction time. Instead, this
procedure is meant to be a starting point or guideline
for chemists interested in pursuing the reaction of a new
combination of substrates.
Table 1 shows that para (entries 1 and 2), meta (entries
6 and 8), or ortho (entries 3, 4 and 11, 12) substitution
on the aryl halide is tolerated under these reaction
conditions. A variety of functional groups, including
esters, primary amines, aldehydes, and ketones can be
present on either the pyrrole or aryl halide. Several
examples of 2-substituted (entries 5-8, 11, and 12) and
trisubstituted pyrroles (entries 9 and 10) were also shown
to be good substrates. Particularly noteworthy is the use
of the sterically hindered substrate combinations shown
in entries 10-12. It was found that in three instances
(entries 7, 10, and 12) the use of the aryl iodide (3 equiv)
as the solvent was required in order for the reaction to
proceed to completion. In two cases, entries 9-10, 3 was
shown to be a good ligand for this coupling. In the other
examples, diamine 2 gave superior results. It is important
to note that both 2 (Strem) and 3 (Aldrich) are com-
mercially available. The method, while more tolerant of
steric hindrance than its predecessors, still slows signifi-
cantly with increased substitution on either substrate.
For example, the coupling of 2,5-dimethylpyrrole with
iodobenzene only proceeded to 20% conversion of pyrrole
even under conditions where the aryl halide was used
as the solvent (4 equiv of PhI). Moreover, 2,6-disubsti-
tuted aryl iodides were not successfully coupled to pyrrole
itself.
F IGURE 1. Ligands for C-N bond formation.
also found that changing to a less polar solvent like
toluene led to improved reaction rates. We have found
that these conditions are also applicable, with generality,
to the N-arylation of pyrroles, pyrazoles, and indazoles.
The conditions for the arylation of triazoles required the
use of a more polar solvent (DMF), most likely because
of the insolubility of the triazoles in toluene. General
conditions for the arylation of imidazoles utilizing ligand
2 resulted in a moderate improvement upon our previous
publication that utilized 1,10-phenanthroline (4) as a
ligand to afford such couplings.8
The arylation of a wide range of pyrrole substrates
utilizing aryl iodides or aryl bromides was accomplished
through the application of a general reaction procedure
that use5 K3PO4 as a base, 5 mol % CuI, 20 mol % ligand
2, and toluene as the solvent. Although we have found
that ligand 2 is the most effective, these reactions can
be conducted with less costly ligands 1 and 3, albeit with
generally lower yields. It is important to note that this
represents a general procedure and each individual
reaction was not optimized in terms of temperature,
(8) Kiyomori, A.; Marcoux, J .-F.; Buchwald, S. L. Tetrahedron Lett.
1999, 40, 2657.
J . Org. Chem, Vol. 69, No. 17, 2004 5579

Antilla et al.
TABLE 2. Cop p er -Dia m in e-Ca ta lyzed N-Ar yla tion of P yr a zoles
a
b
With 10 mol % of ligand 2. Reaction run neat in aryl halide (2-4 equiv) with no additional solvent added. c Reaction run at 80 °C.
Extending this chemistry to include pyrazoles as
substrates proved to be quite successful. It was found that
the ideal base for the coupling of pyrazole was K2CO3,
rather than K3PO4. Presumably, this is due to the more
acidic pyrazole N-H. Again, a number of aryl bromides
where found to be quite reactive under the general
reaction conditions (entries 1-5, 9, and 11 in Table 2)
shown below. As with pyrroles, a variety of functional
groups were tolerated under the reaction conditions.
Hindered substrate combinations (entries 6 and 11-13)
required 2-4 equiv of the aryl halide as the solvent to
allow for complete conversion of the pyrazole.
Several interesting features are apparent from the
results in Table 2. First, the reaction works well with
electron-neutral and electron-deficient pyrazoles. Sec-
ond, the reaction is efficient even for very electron-rich
aryl halides (e.g., entries 4 and 5). Third, the reaction of
“unsymmetrical” pyrazoles produced products in which
the less hindered nitrogen was selectively arylated
(entries 5 and 10). This is as would be expected on the
basis of literature precedent for alkylation and arylation
processes involving substituted pyrazoles.9
F IGURE 2. Equilibration of the copper-indazole complex.
arylation product was observed (>20/1). It was found that
changing the solvent from dioxane to toluene, together
with the use of ligand 2, increased the rate of the
reaction. This rate enhancement allowed for the use of
aryl bromide substrates. However, a dramatic lowering
of regioselectivity was observed when using aryl bromides
(compare entries 1-6, Table 3) as substrates. Only in the
case of 3-chloroindazole was a high level of regioselec-
tivity for N-1 coupling observed with an aryl bromide
(entry 7). A possible explanation for this dramatic change
in regioselectivity could be due to the fact that oxidative
addition with aryl bromides is much slower than that of
aryl iodides. We believe that indazole first reacts to form
a (diamine)Cu(indazole) intermediate, A1 (Figure 2).
Kinetically, A1 is preferred over A2; however, these
complexes are in equilibrium. When aryl iodides are
employed as substrates, oxidative addition to A1 occurs
In our initial studies, we found that the reaction of aryl
halides with indazole was readily accomplished using CuI
and ligand 1;5 excellent regioselectivity for the N-1
(9) J oule, J . A.; Mills, K. In Heterocyclic Chemistry; Blackwell
Science Ltd: Oxford, 2000.
5580 J . Org. Chem., Vol. 69, No. 17, 2004

Copper-Diamine-Catalyzed N-Arylation of Pyrroles
TABLE 3. Cop p er -Dia m in e-Ca ta lyzed N-Ar yla tion of In d a zoles
TABLE 4. Cop p er -Ca ta lyzed N-Ar yla tion of Im id a zoles
a
b
With 5 mol % of CuI, 10 mol % of 4, and 2 M dioxane. With 10 mol % of CuI, 20 mol % of 4, and 2 DMF. c With 5 mol % of CuI, 20
d
mol % of 2, and 2 M DMF. Only one regioisomer was detected as determined by GC/MS on a sample of the crude reaction mixture.
e With 5 mol % of CuI, 20 mol % of 2, and 2 M DMF in 70 °C.
faster than the A1/A2 equilibration, thereby forming
predominately the N-1 substituted product after reduc-
tive elimination. For reactions with aryl bromides, the
rate of the A1/A2 equilibration is competitive compared
to the rate of oxidative addition and a mixture of products
is observed.
sufficient activity so that these substrates were reactive
(entries 3 and 4). The reaction was found to proceed more
efficiently with DMF as a solvent and also required the
use of Cs2CO3 as the base. Additionally, we were pleased
to find that purine could also be arylated using these
reaction conditions (entry 5).
It was found to be difficult to improve upon previous
conditions for the copper-catalyzed N-arylation of imid-
azoles.8 Our previous conditions using dioxane, ligand 1,
and Cs2CO3 provided a high yield of the arylated imid-
azole (entries 1-2, Table 4).5 However, these conditions
provided incomplete conversion of starting materials
when applied to the arylation of 4-methyl- or 4-phenyl-
imidazole. The copper catalyst derived from 2 provided
Arylation of triazole substrates could also be achieved
using copper-diamine catalysts. To optimize this process,
a series of experiments were performed that revealed that
DMF (solvent) and K3PO4 (base) were optimal for obtain-
ing complete conversion of starting materials. The use
of other bases such as K2CO3 and Cs2CO3 was also
suitable for reactions of some of the triazoles screened.
Both 2 (entries 1-3, 5, and 6, Table 5) and 3 (entry 4)
J . Org. Chem, Vol. 69, No. 17, 2004 5581

Antilla et al.
TABLE 5. Cop p er -Dia m in e Ca ta lyzed N-Ar yla tion of Tr ia zoles
a
b
With 10 mol % of ligand 3. >25:1 Regioselective for the N-1 isomer.
SCHEME 1. Ha lid e Exch a n ge/Ar yla tion Sequ en ce
were capable ligands for the arylation of triazoles. The
arylation of benzotriazole (entries 5 and 6) occurred
almost exclusively at the N-1 position; the use of aryl bro-
mides as substrates resulted in low conversion to product.
The arylation of 1,2,3-triazole proved to be problematic
as competitive N-1/N-2 arylation resulted, giving mix-
tures slightly favoring the formation of the N-1 isomer.
A general problem encountered in the development of
this methodology was the slower rate of reaction with
aryl bromides relative to aryl iodides. Another issue that
surfaced was the poor regioselectivity found in indazole
arylation when using aryl bromides as substrates. These
two problems were circumvented by first performing our
previously published Cu-catalyzed halide exchange6b
followed by reaction with the appropriate nitrogen het-
erocycle in a two-step/one-pot sequence (Scheme 1).
Equation 1 shows that, starting from the aryl bromide,
one can achieve high regioselectivity for the arylation of
indazole. Equation 2 shows that by using this procedure
the problem of a particularly slow substrate combination
(4-bromotoluene with 2-acetylpyrrole) can be overcome
by performing the reaction via the more reactive iodide
that can be generated in an in situ fashion.
Con clu sion
In summary, we have shown that the Cu-catalyzed
N-arylation of common nitrogen heterocycles, taken with
our previous work on indole arylation, is a broadly
applicable method. A general reaction protocol for each
class of heterocycles was determined, and represents a
good starting point for future studies with particular
substrates of interest. This work should find wide ap-
plication among synthetic and medicinal chemists in
industry and academics. While we have made consider-
able inroads, future work is needed to further generalize
this type of heterocycle arylation. In particular, the
development of new catalysts that allow for C-N bond
formation to take place with more highly hindered
substrate combinations is desirable.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All reactions were carried out
in resealable Schlenk or test tubes and run under an atmo-
sphere of dry argon or nitrogen. Toluene was purchased from
J . T. Baker in CYCLE-TAINER solvent delivery kegs, was
vigorously purged with argon for 2 h, and was further purified
5582 J . Org. Chem., Vol. 69, No. 17, 2004

Copper-Diamine-Catalyzed N-Arylation of Pyrroles
by passing through two packed columns of neutral alumina
and copper(II) oxide under argon pressure. K3PO4 was pur-
chased from Fluka and used without further purification. It
is important that the base is powdered and free-flowing.
Copper(I) iodide was purchased from Strem (98% purity, off-
white) and was a fine powder. Aryl halides and nitrogen
heterocycles were purchased from commercial sources and
used without further purification. trans-N,N′-Dimethyl-1,2-
cyclohexanediamine was prepared as previously described6c
and is commercially available. Flash column chromatography
was performed using Merck silica gel (230-400 mesh). IR
spectra were recorded for all previously unknown compounds
mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20 mmol,
20 mol %) in toluene (0.5 mL). Column chromatography (50:1
hexanes/ethyl acetate) provided 0.140 g (89% yield) of the title
compound as a colorless oil. The 1H NMR spectrum was in
accord with that reported in the literature.12
2-Acetyl-1-p h en ylp yr r ole (En tr y 5). Following the gen-
eral procedure, 2-acetylpyrrole (0.109 g, 1.00 mmol) was
coupled with iodobenzene (134 µL, 1.20 mmol) using K3PO4
(0.446 g, 2.1 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (16 µL,
0.10 mmol, 10 mol %) in toluene (1 mL). Column chromatog-
raphy (9:1 hexanes/ethyl acetate) provided 0.176 g (95% yield)
of the title compound as a colorless oil that solidified upon
standing at 4 °C to give a white solid, mp 52-54 °C (chloro-
form) [lit.13 52-53 °C (pet. ether)]. The 1H NMR spectrum was
in accord with that reported in the literature.13
1
(neat, thin film). H NMR and 13C NMR was recorded at 400
MHz instrument with chemical shifts reported relative to
tetramethylsilane (TMS). Gas chromatographic analysis was
performed on an instrument with an FID or MS detector using
a capillary column. All yields reported represent an average
of at least two independent runs. Previously unknown com-
pounds were synthesized, purified, and analyzed from a single
run; yields are the average yield of the two experiments.
Unknown compounds were characterized by 1H and 13C NMR,
IR, and GC. They were further characterized by elemental
analysis. For compounds that did not return a satisfactory
elemental analysis, 1-(3′-Pyridinyl)ethyl-4-pyrazolecarbox-
ylate, 3,5-dimethyl-1-phenylpyrazole, 1-(3′-aminomethyl-
phenyl)-2,4-triazole), and (1-(4′-methylphenyl)-2-acetylpyrrole,
copies of their 1H and 13C NMR spectra are included in the
Supporting Information. Compounds described in the litera-
1-(3-Meth oxyp h en yl)-2-eth ylp yr r ole (En tr y 6). Follow-
ing the general procedure, 2-ethylpyrrole (0.106 g, 1.0 mmol,
based on 90% tech material) was coupled with 3-iodoanisole
(143 µL, 1.20 mmol) using K3PO4 (0.446 g, 2.1 mmol), CuI
(0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20 mmol, 20 mol %) in
toluene (0.5 mL). Column chromatography (50:1 hexanes/ethyl
acetate) provided 0.172 g (85% yield) of the title compound as
1
a colorless oil. H NMR (400 MHz, CDCl3): δ 7.28 (t, 1H, J )
8.0 Hz), 6.85 (m, 3H), 6.73 (m, 1H), 6.21 (t, 1H, J ) 3.1 Hz),
6.06 (m, 1H), 3.77 (s, 3H), 2.56 (q, 2H, J ) 7.6 Hz), 1.15 (t,
3H, J ) 7.5 Hz). 13C NMR (100 MHz, CDCl3): δ 159.9, 141.4,
135.4, 130.0, 129.6, 121.3, 118.2, 112.5, 111.7, 111.0, 107.8,
106.0, 55.2, 20.0, 13.2. IR (neat, cm-1): 2968, 1606, 1495, 1336,
1241, 1221, 1047, 843, 780, 698. Anal. Calcd for C13H15NO:
C, 77.58; H, 7.51. Found: C, 77.82; H, 7.44.
1
ture were characterized by comparing their H NMR, melting
point (mp), and GC/MS to the previously reported data; their
purity was confirmed by GC and 1H NMR.
1-P h en ylp yr r ole-2-ca r boxa ld eh yd e (En tr y 7). Following
the general procedure, pyrrole-2-carboxaldehyde (0.095 g, 1.0
mmol) was coupled with iodobenzene (336 µL, 3.00 mmol)
using K3PO4 (0.446 g, 2.1 mmol), CuI (0.0095 g, 0.050 mmol),
and 2 (32 µL, 0.20 mmol, 20 mol %) in toluene (0.5 mL).
Column chromatography (9:1 hexanes/ethyl acetate) provided
0.154 g (89% yield) of the title compound as a yellow oil. The
1H NMR spectrum was in accord with that reported in the
literature.14
1-(3-Ca r boxym eth yl)-2-cya n op yr r ole (En tr y 8). Follow-
ing the general procedure, pyrrole-2-carbonitrile (85 µL, 1.0
mmol) was coupled with ethyl-3-iodobenzoate (293 µL, 1.20
mmol) using K3PO4 (0.446 g, 2.1 mmol), CuI (0.0095 g, 0.050
mmol), and 2 (32 µL, 0.20 mmol, 20 mol %) in toluene (1 mL).
Column chromatography (5:1 hexanes/ethyl acetate) provided
0.204 g (85% yield) of the title compound as a colorless oil that
solidified to give a white solid upon drying. Mp: 69-70 °C
(chloroform). 1H NMR (400 MHz, CDCl3): δ 8.10 (m, 2H), 7.67
(m, 1H), 7.58 (t, 1H, J ) 8.1 Hz), 7.12 (dd, 1H, J ) 1.6, 2.6
Hz), 7.00 (dd, 1H, J ) 1.5, 3.9 Hz), 6.37 (dd, 1H, J ) 2.9, 3.9
Hz), 4.41 (q, 2H, J ) 7.2 Hz), 1.41 (t, 3H, J ) 7.2 Hz). 13C
NMR (100 MHz, CDCl3): δ 165.0, 138.1, 132.1, 129.6, 129.1,
128.1, 126.9, 125.0, 122.3, 113.3, 110.8, 104.0, 61.3, 14.1. IR
(neat, cm-1): 3124, 2983, 2219, 1721, 1590, 1492, 1460, 1262,
1174, 757, 689. Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03.
Found: C, 70.21; H, 5.10.
See the Supporting Information for a general procedure for
the N-arylation of nitrogen heterocycles.
1-(4-Dim eth yla m in o)p yr r ole (En tr y 1). Following the
general procedure, pyrrole (69 µL, 1.0 mmol) was coupled with
4-bromo-N,N′-dimethylaminoaniline (0.240 g, 1.20 mmol) using
K3PO4 (0.446 g, 2.1 mmol), CuI (0.0095 g, 0.050 mmol), and 2
(32 µL, 0.20 mmol, 20 mol %) in toluene (1 mL). Column
chromatography (5:1 hexanes/ethyl acetate) provided 0.175 g
(94% yield) of the title compound as a white solid, mp 152-
153 °C (chloroform) [lit.10 150-151 °C (no solvent given)]. The
1H NMR spectrum was in accord with that reported in the
literature.10
1-(4-P r op iop h en on e)p yr r ole (En tr y 2). Following the
general procedure, pyrrole (69 µL, 1.0 mmol) was coupled with
4′-bromopropiophenone (0.277 g, 1.20 mmol) using K3PO4
(0.446 g, 2.1 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL,
0.20 mmol, 20 mol %) in toluene (1 mL). Column chromatog-
raphy (3:1 hexanes/ethyl acetate) provided 0.180 g (90% yield)
of the title compound as a white solid. Mp: 123-125 °C
1
(chloroform). H NMR (400 MHz, CDCl3): δ 8.04 (d, 2H, J )
8.7 Hz), 7.45 (d, 2H, J ) 8.7 Hz), 6.17 (t, 2H, J ) 2.2 Hz), 6.38
(t, 2H, J ) 2.2 Hz), 3.01 (q, 2H, J ) 7.2 Hz), 1.24 (t, 3H, J )
7.2 Hz). 13C NMR (100 MHz, CDCl3): δ 199.4, 143.8, 133.7,
129.7, 119.3, 119.0, 111.5, 31.6, 8.2. IR (neat, cm-1): 3140,
1686, 1607, 1333, 1194, 843, 796, 737, 608. Anal. Calcd for
3-Acetyl-2,4-d im eth yl-1-p h en ylp yr r ole (En tr y 9). Fol-
lowing the general procedure, 3-acetyl-2,4-dimethylpyrrole
(0.137 g, 1.00 mmol) was coupled with iodobenzene (134 µL,
1.20 mmol) using K3PO4 (0.446 g, 2.1 mmol), CuI (0.0095 g,
0.050 mmol), and 3 (22 µL, 0.20 mmol, 20 mol %) in toluene
(0.5 mL). Column chromatography (5:1 hexanes/ethyl acetate)
provided 0.202 g (95% yield) of the title compound as a white
solid. Mp: 80-81 °C (chloroform). 1H NMR (400 MHz,
CDCl3): δ 7.44 (m, 2H), 7.39 (m, 1H), 7.23 (m, 2H), 6.47 (s,
1H), 2.42 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 195.5, 138.8, 135.9, 129.1, 127.8, 126.2, 122.4, 120.7,
C
13H13NO: C, 78.36; H, 6.57. Found: C, 78.25; H, 6.59.
1-(2-Am in op h en yl)p yr r ole (En tr y 3). Following the gen-
eral procedure, pyrrole (69 µL, 1.0 mmol) was coupled with
2-bromoaniline (0.206 g, 1.20 mmol) using K3PO4 (0.446 g, 2.1
mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20 mmol,
20 mol %) in toluene (1 mL). Column chromatography (9:1
hexanes/ethyl acetate) provided 0.130 g (82% yield) of the title
compound as a white solid, mp 96-97 °C (chloroform) [lit.11
96-98 °C (no solvent given)]. The 1H NMR spectrum was in
accord with that reported in the literature.11
1-(2-Meth ylp h en yl)p yr r ole (En tr y 4). Following the gen-
eral procedure, pyrrole (69 µL, 1.0 mmol) was coupled with
2-bromotoluene (240 µL, 2.00 mmol) using K3PO4 (0.446 g, 2.1
(12) Faigl, F.; Schlosser, M. Tetrahedron 1993, 49, 10271.
(13) Cheeseman, G. W. H.; Hawi, A. A. J . Heterocycl. Chem. 1983,
20, 585.
(10) J ones, R. A. Aust. J . Chem. 1966, 19, 289.
(11) Aldrich Chemical Spectra, FT-NMR 1(3), 4B.
(14) Ewen, J . A.; Elder, M. J .; J ones, R. L.; Rheingold, A. L.; Liable-
Sands, L. M.; Sommer, R. D. J . Am. Chem. Soc. 2001, 123, 4763.
J . Org. Chem, Vol. 69, No. 17, 2004 5583

Antilla et al.
119.7, 31.1, 13.4, 12.8. IR (neat, cm-1): 3050, 2946, 1638, 1495,
1413, 1210, 944, 773, 750, 702. Anal. Calcd for C14H15NO: C,
78.84; H, 7.09. Found: C, 78.66; H, 7.04.
tography (9:1 hexanes/ethyl acetate) provided 0.196 g (98%
yield) of the title compound as a white solid. Mp: 90-91 °C
(chloroform). 1H NMR (400 MHz, CDCl3): δ 8.07 (m, 2H), 8.02
(d, 1H, J ) 2.3 Hz), 7.79 (m, 3H), 6.51 (s, 1H), 3.02 (q, 2H, J
) 7.2 Hz), 1.23 (t, 3H, J ) 7.2 Hz). 13C NMR (100 MHz,
CDCl3): δ 199.5, 143.0, 141.9, 134.4, 129.6, 126.8, 118.3, 108.5,
31.7, 8.2. IR (neat, cm-1): 3132, 2972, 1681, 1604, 1413, 1201,
1047, 932, 850, 801, 747. Anal. Calcd for C12H12N2O: C, 71.98;
H, 6.04. Found: C, 71.83; H, 6.11.
1-(3′-P yr id in e)eth yl-4-p yr a zoleca r boxyla te (En tr y 3).
Following the general procedure, ethyl-4-pyrazolecarboxylate
(0.140 g, 1.00 mmol) was coupled with 3-bromopyridine (116
µL, 1.20 mmol) using K2CO3 (0.290 g, 2.1 mmol), CuI (0.0095
g, 0.050 mmol), and 2 (32 µL, 0.20 mmol, 20 mol %) in toluene
(1 mL). Column chromatography (1:1 hexanes/ethyl acetate
for two rows and then ethyl acetate to elute) provided 0.186 g
(86% yield) of the title compound as a white solid. Mp: 87-89
°C (chloroform). 1H NMR (400 MHz, CDCl3): δ 9.04 (s, 1H),
8.62 (d, 1H, J ) 4.3 Hz), 8.52 (s, 1H), 8.15 (s, 1H), 8.08 (d, 1H,
J ) 8.1 Hz), 7.45 (dd, 1H, J ) 4.7, 8.1 Hz), 4.35 (q, 2H, J )
7.1 Hz), 1.38 (t, 3H, J ) 7.1 Hz). 13C NMR (100 MHz, CDCl3):
δ 162.3, 148.4, 142.6, 140.7, 135.6, 130.0, 126.7, 123.8, 117.5,
60.4, 14.17. IR (neat, cm-1): 3123, 2978, 1706, 1561, 1275,
1258, 1140, 949, 766.
2,4-Dim eth yl-1-p h en yl-3-ca r boxyeth ylp yr r ole (En tr y
10). Following the general procedure, 2,4-dimethyl-5-carboxy-
ethylpyrrole (0.167 g, 1.00 mmol) was coupled with iodoben-
zene (336 µL, 3.00 mmol) using K3PO4 (0.446 g, 2.1 mmol),
CuI (0.0095 g, 0.050 mmol), and 3 (22 µL, 0.20 mmol, 20 mol
%) with no additional solvent. Column chromatography (19:1
hexanes/ethyl acetate) provided 0.215 g (89% yield) of the title
compound as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.40
(m, 3H), 7.16 (m, 2H), 5.91 (s, 1H), 4.03 (q, 2H, J ) 7.1 Hz),
2.38 (s, 3H), 1.95 (s, 3H), 1.04 (t, 3H, J ) 7.1 Hz). 13C NMR
(100 MHz, CDCl3): δ 161.2, 140.2, 135.9, 130.1, 128.5, 127.7,
127.6, 120.5, 111.0, 59.0, 13.9, 13.7, 12.7. IR (neat, cm-1): 3065,
2980, 2927, 1950, 1882, 1698, 1498, 1273, 1182, 1090, 762, 698,
637. Anal. Calcd for C15H17NO2: C, 74.04; H, 7.04. Found: C,
74.14; H, 7.16.
1-(2′-Meth oxyp h en yl)eth ylp yr r ole-2-ca r boxyla te (En -
tr y 11). Following the general procedure, ethylpyrrole-2-
carboxylate (0.139 g, 1.00 mmol) was coupled with 2-iodo-
anisole (156 µL, 1.20 mmol) using K3PO4 (0.446 g, 2.1 mmol),
CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20 mmol, 20 mol
%) in toluene (0.5 mL). The crude reaction mixture was
dissolved in ethyl acetate (∼3 mL), and 15 mL of hexanes was
added to this solution. The resulting turbid solution was placed
in a freezer at -20 °C for 16 h. Filtration and concentration
under reduced pressure provided 0.243 g (99%) of the title
compound as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ
7.32 (td, 1H, J ) 1.7, 8.0 Hz), 7.19 (dd, 1H, J ) 1.7, 7.6 Hz),
7.07 (dd, 1H, J ) 1.8, 3.9 Hz), 6.95 (m, 2H), 6.81 (dd, 1H, J )
1.9, 2.4 Hz), 6.27 (dd, 1H, J ) 2.6, 3.9 Hz), 4.11 (q, 2H, J )
7.1 Hz), 3.68 (s, 3H), 1.14 (t, 3H, J ) 7.1 Hz). 13C NMR (100
MHz, CDCl3): δ 160.8, 160.2, 154.5, 129.6, 128.9, 127.4, 124.2,
120.0, 117.3, 111.2, 108.6, 59.4, 55.3, 13.9. IR (neat, cm-1):
2980, 2839, 1711, 1508, 1417, 1268, 1109, 1025, 751. Anal.
Calcd for C14H15NO3: C, 68.56; H, 6.16. Found: C, 68.45; H,
6.27.
1-(2′-Meth ylp h en yl)eth ylp yr r ole-2-ca r boxyla te (En tr y
12). Following the general procedure, ethyl pyrrole-2-carbox-
ylate (0.139 g, 1.00 mmol) was coupled with 2-iodotoluene (510
µL, 4.00 mmol) using K2CO3 (0.290 g, 2.1 mmol), CuI (0.0095
g, 0.050 mmol), and 2 (32 µL, 0.20 mmol, 20 mol %) with no
additional solvent. Column chromatography (19:1 hexanes/
ethyl acetate) provided 0.202 g (88% yield) of the title
compound as a colorless oil. 1H NMR (400 MHz, CDCl3):
δ 7.28 (m, 3H), 7.18 (m, 1H), 7.10 (m, 1H), 6.79 (dd, 1H,
J ) 1.8, 2.5 Hz), 6.25 (m, 1H), 4.02 (dq, 2H, J ) 1.8, 7.1 Hz),
2.00 (s, 3H), 1.14 (t, 3H, J ) 7.1 Hz). 13C NMR (100 MHz,
CDCl3): δ 160.2, 140.0, 135.5, 130.1, 128.8, 128.3, 127.1, 126.0,
123.9, 117.6, 108.9, 59.6, 17.0, 14.0. IR (neat, cm-1): 2981,
1712, 1499, 1417, 1266, 1324, 1111, 1023, 741. Anal. Calcd
for C14H15NO2: C, 73.34; H, 6.59. Found: C, 73.08; H, 6.57.
1-(P h en yl-2-m eth a n ol)p yr a zole (En tr y 1). Following the
general procedure, pyrazole (0.068 g, 1.0 mmol) was coupled
with 2-bromobenzyl alcohol (0.187 g, 1.00 mmol) using K2CO3
(0.290 g, 2.1 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (16 µL,
0.10 mmol, 10 mol %) in toluene (0.5 mL). Column chroma-
tography (3:1 hexanes:ethyl acetate) provided 0.132 g (76%
yield) of the title compound as a colorless oil. 1H NMR (400
MHz, CDCl3): δ 7.77 (m, 1H), 7.69 (m, 1H), 7.48 (m, 1H), 7.30
(m, 3H), 6.46 (m, 1H), 5.33 (t, 1H, J ) 7.0 Hz), 4.40 (d, 2H, J
) 7.00 Hz). 13C NMR (100 MHz, CDCl3): δ 140.4, 139.4, 135.2,
131.4, 130.0, 128.6, 128.0, 123.6, 106.9, 62.2. IR (neat, cm-1):
3364, 2878, 1519, 1456, 1397, 1329, 1203, 1051, 1022, 943, 761.
Anal. Calcd for C10H10N2O: C, 68.95; H, 5.79. Found: C, 68.59;
H, 5.81.
1-(2′-Am in op h en yl)p yr a zole (En tr y 4). Following the
general procedure, pyrazole (0.068 g, 1.0 mmol) was coupled
with 2-bromoaniline (0.206 g, 1.20 mmol) using K2CO3 (0.290
g, 2.1 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20
mmol, 20 mol %) in toluene (1 mL). Column chromatography
(1:1 hexanes/ethyl acetate) provided 0.144 g (90% yield) of the
1
title compound as a yellow oil. The H NMR spectrum was in
accord with that reported in the literature.15
1-(4′-Hyd r oxyp h en yl)-3-m eth ylp yr a zole (En tr y 5). Fol-
lowing the general procedure, 3-methylpyrazole (81 µL, 1.00
mmol) was coupled with 4-bromophenol (0.208 g, 1.20 mmol)
using K2CO3 (0.290 g, 2.1 mmol), CuI (0.0095 g, 0.050 mmol),
and 2 (32 µL, 0.20 mmol, 20 mol %) in toluene (1 mL). Column
chromatography (3:1 hexanes/ethyl acetate) provided 0.138 g
(79% yield) of the title compound as a white solid. Mp: 92-93
1
°C (chloroform). H NMR (400 MHz, CDCl3): δ 7.85 (d, 1H, J
) 2.3 Hz), 7.42 (m, 2H), 6.85 (m, 2H), 6.23 (d, 1H, J ) 2.3 Hz),
4.99 (bs, 1H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
157.7, 151.2, 134.2, 130.1, 122.5, 117.0, 108.0, 13.5. IR (neat,
cm-1): 3423, 1642, 1455, 1374, 1275, 1237, 1053, 833, 768.
Anal. Calcd for C10H10N2O: C, 68.95; H, 5.79. Found: C, 68.59;
H, 5.78.
1-(2′-Meth ylp h en yl)p yr a zole (En tr y 6). Following the
general procedure, pyrazole (0.068 g, 1.0 mmol) was coupled
with 2-bromotoluene (1 mL, 8.31 mmol) using K2CO3 (0.290
g, 2.1 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20
mmol, 20 mol %) with no additional solvent. Column chroma-
tography (19:1 hexanes/ethyl acetate and then 4:1 hexanes/
ethyl acetate to elute product) provided 0.142 g (90% yield) of
the title compound as a colorless oil. The 1H NMR spectrum
was in accord with that reported in the literature.16
1-P h en ylp yr a zole (En tr y 7). Following the general pro-
cedure, pyrazole (0.068 g, 1.0 mmol) was coupled with iodo-
benzene (134 µL, 8.31 mmol) using K2CO3 (0.290 g, 2.1 mmol),
CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20 mmol, 20 mol
%) in toluene (1 mL) at 80 °C for 24 h. Column chromatography
(19:1 hexanes/ethyl acetate) provided 0.134 g (93% yield) of
the title compound as a colorless oil. The 1H NMR spectrum
was in accord with that reported in the literature.17
1-(4”-Ch lor o-3′-ca r boxym eth ylp h en yl)p yr a zole (En tr y
8). Following the general procedure, pyrazole (0.034 g, 0.50
mmol) was coupled with 3-carboxymethyl-4-choloro-1-iodo-
benzene (0.178 g, 0.0600 mmol) using K2CO3 (0.145 g, 1.05
1-(4′-P r op iop h en on e)p yr a zole (En tr y 2). Following the
general procedure, pyrazole (0.068 g, 1.00 mmol) was coupled
with 4′-bromopropiophenone (0.277 g, 1.20 mmol) using K2CO3
(0.290 g, 2.1 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL,
0.20 mmol, 20 mol %) with toluene (1 mL). Column chroma-
(15) Hoz, A.; Diaz-Ortiz, A.; Elguero, J .; Martinez, L. J .; Moreno,
A.; Sanchez-Migallon, A. Tetrahedron 2001, 57, 4397.
(16) Grimmett, M. R.; Hartshorn, S. R.; Schofield, K.; Weston, J . B.
J . Chem. Soc., Perkin Trans. 2 1972, 1654.
(17) Aldrich Chemical Spectra, FT-NMR 1(3), 68A.
5584 J . Org. Chem., Vol. 69, No. 17, 2004

Copper-Diamine-Catalyzed N-Arylation of Pyrroles
mmol), CuI (0.0048 g, 0.025 mmol), and 2 (16 µL, 0.10 mmol,
10 mol %) in toluene (0.5 mL). Column chromatography (9:1
hexanes/ethyl acetate) provided 0.104 g (88% yield) of the title
(0.096 g, 1.0 mmol) was coupled with 3-iodobenzylamine (266
µL, 2.00 mmol) using K2CO3 (0.290 g, 2.10 mmol), CuI (0.0095
g, 0.050 mmol), and 2 (32 µL, 0.20 mmol, 20 mol %) with no
added solvent. Column chromatography (50:1 CH2Cl2/MeOH
solution saturated with ammonia) provided 0.137 g (68% yield)
of the title compound as a yellow oil. 1H NMR (400 MHz,
CDCl3): δ 7.39 (m, 2H), 7.27 (m, 2H), 5.97 (s, 1H), 3.89 (s,
2H), 2.61 (s, 2H), 2.28 (s, 3H), 2.27 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 148.7, 144.3, 139.9, 139.1, 128.7, 125.6, 123.3, 122.6,
106.7, 45.9, 13.2, 12.1. IR (neat, cm-1): 3362, 2924, 1593, 1557,
1495, 1367, 1323, 1133, 1025, 979, 906, 794, 701. Anal. Calcd
for C12H15N3: C, 71.61; H, 7.51. Found: C, 71.51; H, 7.23.
1
compound as a white solid. Mp: 101-102 °C (chloroform). H
NMR (400 MHz, CDCl3): δ 8.17 (d, 1H, J ) 2.7 Hz), 7.94 (d,
1H, J ) 2.5 Hz), 7.75 (m, 2H), 7.50 (d, 1H, J ) 8.7 Hz), 6.48
(m, 1H), 3.95 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 165.1,
141.6, 138.4, 132.0, 131.0, 130.5, 126.6, 122.5, 121.3, 108.3,
52.6. IR (neat, cm-1): 3131, 3147, 2955, 1724, 1582, 1481, 1345,
1233, 1058, 944, 828, 742. Anal. Calcd for C11H9N2O2Cl: C,
55.83; H, 3.83. Found: C, 56.04; H, 3.93.
1-(Eth yl-4′-ben zoa te)eth ylp yr a zole-4-ca r boxyla te (En -
t r y 9). Following the general procedure, ethyl 4-pyrazole-
carboxylate (0.140 g, 1.00 mmol) was coupled with ethyl
4-bromobenzoate (196 µL, 1.20 mmol) using K2CO3 (0.290 g,
2.10 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20
mmol, 20 mol %) in toluene (1 mL). Column chromatography
(9:1 hexanes/ethyl acetate) provided 0.226 g (78% yield) of the
title compound as a white solid. Mp: 135-136 °C (chloroform).
1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 8.15 (m, 3H), 7.81
(d, 2H, J ) 8.7 Hz), 4.38 (m, 4H), 1.40 (m, 6H). 13C NMR (100
MHz, CDCl3): δ 165.5, 162.4, 142.6, 142.3, 131.1, 130.0, 129.1,
118.7, 117.5, 61.2, 60.5, 14.3, 14.2. IR (neat, cm-1): 3135, 2981,
1715, 1610, 1563, 1413, 1283, 1107, 1030, 949, 858, 767. Anal.
Calcd for C15H16N2O4: C, 62.49; H, 5.59. Found: C, 62.73; H,
5.68.
1-P h en yl-3-(t r iflu or om et h yl)et h ylp yr a zole-4-ca r b ox-
yla te (En tr y 10). Following the general procedure, ethyl-3-
(triflouromethyl)-pyrazole-4-carboxylate (0.208 g, 1.00 mmol)
was coupled with iodobenzene (134 µL, 1.20 mmol) using
K2CO3 (0.290 g, 2.10 mmol), CuI (0.0095 g, 0.050 mmol), and
2 (32 µL, 0.20 mmol, 20 mol %) in toluene (0.5 mL). Column
chromatography (9:1 hexanes/ethyl acetate) provided 0.223 g
(78% yield) of the title compound as a white solid. Mp: 91-93
°C (chloroform). 1H NMR (400 MHz, CDCl3): δ 8.47 (s, 1H),
7.70 (m, 2H), 7.48 (m, 2H), 7.40 (m, 1H), 4.35 (q, 2H, J ) 7.1
Hz), 1.37 (t, 3H, J ) 7.1 Hz). 13C NMR (100 MHz, CDCl3): δ
160.6, 138.5, 132.8, 129.7, 128.4, 121.7, 119.9, 119.0, 114.7,
61.0, 14.0. IR (neat, cm-1): 3136, 2992, 1732, 1551, 1490, 1303,
2,5-Dip h en yl-3-a m in op yr a zole (En tr y 14). Following the
general procedure, 3-amino-5-phenylpyrazole (0.159 g, 1.00
mmol) was coupled with iodobenzene (112 µL, 1.00 mmol)
using K2CO3 (0.290 g, 2.10 mmol), CuI (0.0095 g, 0.050 mmol),
and 2 (32 µL, 0.20 mmol, 20 mol %) in toluene (0.5 mL).
Column chromatography (1:1 hexanes/ethyl acetate) provided
0.212 g (90% yield) of the title compound as a pale brown solid.
1
Mp: 129-130 °C (chloroform). H NMR (400 MHz, CDCl3): δ
7.80 (m, 2H), 7.59 (m, 2H), 7.47 (m, 2H), 7.35 (m, 4H), 5.88 (s,
1H), 3.82 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 151.4, 145.8,
138.5, 133.4, 129.4, 128.4, 127.7, 127.4, 125.5, 124.0, 88.0. IR
(neat, cm-1): 3060, 1624, 1598, 1561, 1480, 1505, 1456, 1070,
954, 758, 698, 653. Anal. Calcd for C15H13N3: C, 76.57; H, 5.57.
Found: C, 76.48; H, 5.54. The regiochemistry of the product
(i.e., arylation at N-1 vs N-2) was determined via NOE
difference experiments. See the Supporting Information for
details.
1-(4′-Meth ylp h en yl)in d a zole (En tr y 1). Following the
general procedure, indazole (0.118 g, 1.00 mmol) was coupled
with 4-iodotoluene (0.262 g, 1.20 mmol) using K3PO4 (0.446 g,
2.1 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20
mmol, 20 mol %) in toluene (1 mL). Column chromatography
(19:1 hexanes/ethyl acetate) provided 0.178 g (85% yield) of
the title compound as a white solid. Mp: 62-64 °C (chloroform)
1
[lit.18 mp 63-65 °C (no solvent given)]. The H NMR spectrum
was in accord with that reported in the literature.18
1-(3′-Meth oxyp h en yl)in d a zole (En tr y 3): Following the
general procedure, indazole (0.118 g, 1.00 mmol) was coupled
with 3-iodoanisole (0.281, 1.20 mmol) using K3PO4 (0.446 g,
2.10 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20
mmol, 20 mol %) in toluene (1 mL). Column chromatography
(19:1 hexanes/ethyl acetate) provided 0.204 g (91% yield) of
the title compound as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ 8.19 (s, 1H), 7.77 (m, 2H), 7.41 (m, 2H), 7.30 (m,
2H), 7.21 (m, 1H), 6.88 (m, 1H), 3.85 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 160.4, 141.2, 138.6, 135.3, 130.0, 127.1, 125.2,
121.5, 121.2, 114.6, 112.5, 110.5, 108.2, 55.4. IR (neat, cm-1):
3063, 2960, 2836, 1607, 1497, 1419, 1244, 1163, 909, 844, 744,
691. Anal. Calcd for C14H12N2O: C, 74.98; H, 5.39. Found: C,
74.83; H, 5.55.
1-(2′-Am in op h en yl)in d a zole (En tr y 5). Following the
general procedure, indazole (0.118 g, 1.00 mmol) was coupled
with 2-iodoaniline (0.263 g, 1.20 mmol) using K3PO4 (0.446 g,
2.1 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20
mmol, 20 mol %) in toluene (1 mL). Column chromatography
(5:1 hexanes/ethyl acetate) provided 0.180 g (80% yield) of the
title compound as an orange oil. The 1H NMR spectrum was
in accord with that reported in the literature.19
1220, 1148, 1068, 1049, 909, 743. Anal. Calcd for C13H11
-
N2O2F3: C, 54.93; H, 3.90. Found: C, 55.02; H, 3.89. The
regiochemistry of the product (i.e., arylation at N-1 vs N-2)
was determined via X-ray crystallography. See the Supporting
Information for details.
1-(2′-Br om op h en yl)eth ylp yr a zole-4-ca r boxyla te (En -
tr y 11). Following the general procedure, ethylpyrazole-4-
carboxylate (0.140 g, 1.00 mmol) was coupled with 2-bromo-
toluene (361 µL, 3.00 mmol) using K2CO3 (0.290 g, 2.10 mmol),
CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20 mmol, 20 mol
%) with no added solvent. Column chromatography (9:1
hexanes/ethyl acetate) provided 0.180 g (78% yield) of the title
compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ
8.09 (d, 2H, J ) 6.6 Hz), 7.30 (m, 4H), 4.33 (q, 2H, J ) 7.1
Hz), 2.24 (s, 3H), 1.36 (t, 3H, J ) 7.1 Hz). 13C NMR (100 MHz,
CDCl3): δ 162.8, 141.5, 139.0, 133.7, 133.6, 131.3, 129.0, 126.6,
125.9, 115.8, 60.2, 17.8, 14.3. IR (neat, cm-1): 3129, 2981, 1717,
1556, 1505, 1406, 1247, 1140, 1030, 955, 764. Anal. Calcd for
C
13H14N2O2: C, 67.81; H, 6.13. Found: C, 67.76; H, 6.18.
3,5-Dim eth yl-1-p h en ylp yr a zole (En tr y 12). Following
the general procedure, 3,5-dimethylpyrazole (0.096 g, 1.0
mmol) was coupled with iodobenzene (225 µL, 2.00 mmol)
using K2CO3 (0.290 g, 2.10 mmol), CuI (0.0095 g, 0.050 mmol),
and 2 (32 µL, 0.20 mmol, 20 mol %) with no added solvent.
Column chromatography (3:1 hexanes/ethyl acetate) provided
0.171 g (91% yield) of the title compound as a colorless oil. 1H
NMR (400 MHz, CDCl3): δ 7.42 (m, 4H), 7.31 (m, 1H), 5.98
(s, 1H), 2.29 (s, 3H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 148.7, 139.7, 139.1, 128.8, 127.0, 124.5, 106.7, 13.3, 12.2. IR
(neat, cm-1): 2922, 1598, 1557, 1504, 1419, 1381, 1366, 1132,
1026, 779, 755, 696.
3-Ch lor o-1-(4′-m eth ylp h en yl)-n d a zole (En tr y 7). Fol-
lowing the general procedure, 3-chloroindazole (0.153 g, 1.00
mmol) was coupled with 4-bromotoluene (148 µL, 1.20 mmol)
using K3PO4 (0.446 g, 2.10 mmol), CuI (0.0095 g, 0.050 mmol),
and 2 (32 µL, 0.20 mmol, 20 mol %) in toluene (1 mL). Column
chromatography (50:1 hexanes/ethyl acetate) provided 0.206
g (85% yield) of the title compound as a white solid. Mp: 51-
52 °C (chloroform). 1H NMR (400 MHz, CDCl3): δ 7.70 (d, 1H,
(18) Lopez-Alvarado, P.; Avendano, C.; Menendez, J . C. J . Org.
Chem. 1995, 60, 5678.
(19) Tsuge, O.; Samura, H. J . Heterocycl. Chem. 1971, 707.
3,5-Dim eth yl-1-(3′-a m in om eth ylp h en yl)p yr a zole (En -
tr y 13). Following the general procedure, 3,5-dimethylpyrazole
J . Org. Chem, Vol. 69, No. 17, 2004 5585

Antilla et al.
J ) 8.2 Hz), 7.62 (d, 1H, J ) 8.6 Hz), 7.52 (m, 2H), 7.41 (m,
1H), 7.28 (d, 2H, J ) 8.2 Hz), 7.22 (m, 1H), 2.35 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 139.9, 137.0, 136.8, 135.4, 130.0,
128.1, 122.5, 122.1, 121.9, 119.9, 110.7, 21.0. IR (neat, cm-1):
3040, 2922, 1613, 1517, 1465, 1337, 1213, 1040, 819, 743. Anal.
Calcd for C14H11N2Cl: C, 69.28; H, 4.57. Found: C, 69.50; H,
4.73.
1-(3,5-Dim eth ylp h en yl)im id a zole (En tr y 1). Prepared as
previously described.5 Column chromatography provided 0.158
g (92% yield) of the title compound as a white solid. The 1H
NMR spectrum was in accord with that reported in the
literature.5
[lit.24 mp 95-96 °C (no solvent given)]. The 1H NMR spectrum
was in accord with that reported in the literature.24
1-(4′-Acetylp h en yl)-2,4-tr ia zole (En tr y 3). Following the
general procedure, 1,2,4-triazole (0.069 g, 1.00 mmol) was
coupled with 4′-iodoacetophenone (0.295 g, 1.20 mmol) using
K3PO4 (0.425 g, 2.0 mmol), CuI (0.0095 g, 0.050 mmol), and 2
(16 µL, 0.10 mmol, 10 mol %) in DMF (1 mL). Column
chromatography (1:1 hexanes/ethyl acetate) provided 0.147 g
(79% yield) of the title compound as a white solid. Mp: 151.5-
152.5 °C (chloroform) [lit.25 mp 150-151 °C (no solvent given)].
The 1H NMR spectrum was in accord with that reported in
the literature.25
1-(3′-Am in om eth ylp h en yl)-2,4-tr ia zole (En tr y 4). Fol-
lowing the general procedure, 1,2,4-triazole (0.069 g, 1.00
mmol) was coupled with 3-iodobenzylamine (133 µL, 1.00
mmol) using K3PO4 (0.425 g, 2.10 mmol), CuI (0.0095 g, 0.050
mmol), and 3 (11 µL, 0.10 mmol, 10 mol %) in DMF (1 mL).
Column chromatography (100:1 CH2Cl2/MeOH solution satu-
rated with ammonia, then 25:1 to elute product) provided 0.138
g (79% yield) of the title compound as a yellow oil. 1H NMR
(400 MHz, CDCl3): δ 8.58 (s, 1H), 8.07 (s, 1H), 7.67 (s, 1H),
7.50 (m, 3H), 3.94 (s, 2H), 1.57 (s, 2H). 13C NMR (100 MHz,
CDCl3): δ 152.0, 145.0, 140.5, 136.7, 129.4, 126.4, 118.3, 117.8,
45.7. IR (neat, cm-1): 3348, 3098, 2917, 1594, 1510, 1279, 1145,
994, 790, 674.
1-P h en ylben zotr ia zole (En tr y 5). Following the general
procedure, benzotriazole (0.119 g, 1.00 mmol) was coupled with
iodobenzene (134 µL, 1.20 mmol) using K3PO4 (0.425 g, 2.0
mmol), CuI (0.0095 g, 0.050 mmol), and 2 (16 µL, 0.10 mmol,
10 mol %) in DMF (1 mL). Column chromatography (1:1
hexanes/ethyl acetate) provided 0.175 g (90% yield) of the title
compound as a white solid. Mp: 85-87 °C (chloroform) (lit.26
mp 85-86 °C). The 1H NMR spectrum was in accord with that
reported in the literature.26
1-(4′-Acetylp h en yl)ben zotr ia zole (En tr y 6). Following
the general procedure, benzotriazole (0.119 g, 1.00 mmol) was
coupled with 4′-iodoacetophenone (0.295 g, 1.20 mmol) using
K3PO4 (0.425 g, 2.0 mmol), CuI (0.0095 g, 0.050 mmol), and 2
(16 µL, 0.10 mmol, 10 mol %) in DMF (1 mL). Column
chromatography (1:1 hexanes/ethyl acetate) provided 0.149 g
(63% yield) of the title compound as a white solid. Mp: 151-
152 °C (chloroform) [lit.27 mp 152-153 °C (no solvent given)].
The 1H NMR spectrum was in accord with that reported in
the literature.27
Gen er a l P r oced u r e for Ha lid e Exch a n ge/Ar yla tion
Seq u en ce a n d Ch a r a ct er iza t ion of P r od u ct s. 1-(4′-
Meth ylp h en yl)-2-a cetylp yr r ole. To a screw cap resealable
test tube with stir bar were added CuI (0.019 g, 0.10 mmol)
and NaI (0.300 g, 2.00 mmol). A rubber septum was attached,
and the tube was evacuated and then back-filled with argon
and repeated. To this tube was then added 4-bromotoluene
(123 µL, 1.20 mmol), 3 (22 µL, 0.20 mmol, 20 mol %), and
toluene (1 mL) by syringe. A screw cap was fitted, and the
tube was immerged into a preheated oil bath (caution: build-
up of pressure possible; use a safety shield) at 110 °C for 24 h
with magnetic stirring. The tube was temporarily removed
from the oil bath and cooled at ambient temperature for 15
min, and then 2-acetylpyrrole (0.109 g, 1.00 mmol) and K3PO4
(0.446 g, 2.10 mmol) were quickly added and the tube was re-
capped and again placed in the oil bath for an additional 24
h. The reaction mixture was removed from heating, allowed
to attain ambient temperature, diluted with ethyl acetate (2-3
mL), filtered through a plug of silica gel, and eluted with
additional ethyl acetate (10-20 mL). The filtrate was concen-
trated, and the resulting residue was purified by silica gel
column chromatography (2 × 25 cm of silica, 9:1 hexanes/ethyl
1-(3,5-Dim eth ylp h en yl)ben zim id a zole (En tr y 2). Pre-
pared as previously described.5 Column chromatography (1:1
hexanes/ethyl acetate) provided 0.205 g (92% yield) of the title
compound as a white solid. The 1H NMR spectrum was in
accord with that reported in the literature.5
1-P h en yl-4-m eth ylim id a zole (En tr y 3). Following the
general procedure, 4-methylimidazole (0.082 g, 1.00 mmol) was
coupled with iodobenzene (134 µL, 1.20 mmol) using Cs2CO3
(0.684 g, 2.1 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL,
0.20 mmol, 20 mol %) in DMF (0.5 mL). Column chromatog-
raphy (10:1 hexanes/ethyl acetate) provided 0.122 g (77% yield)
of the title compound as a white solid. Mp: 61-63 °C
(chloroform) [lit.20 mp 59.5-60.5 °C (ether)]. The 1H NMR
spectrum was in accord with that reported in the literature.20
Only one regioisomer was detected by GC/MS from the crude
reaction mixture.
1,4-Dip h en ylim id a zole (En tr y 4). Following the general
procedure, 4-phenylimidazole (0.144 g, 1.00 mmol) was coupled
with iodobenzene (134 µL, 1.20 mmol) using Cs2CO3 (0.652 g,
2.0 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20
mmol, 20 mol %) in DMF (0.5 mL). Column chromatography
(2:1 hexanes/ethyl acetate) provided 0.194 g (88% yield) of the
title compound as a white solid. Mp: 98-99 °C (chloroform)
1
[lit.21 mp 96-98 °C (no solvent given)]. The H NMR spectrum
was in accord with that reported in the literature.21 Only one
regioisomer was detected by GC/MS from the crude reaction
mixture.
9-P h en ylp u r in e (En tr y 5). Following the general proce-
dure, purine (0.120 g, 1.00 mmol) was coupled with iodo-
benzene (2225 µL, 2.00 mmol) using Cs2CO3 (0.684 g, 2.1
mmol), CuI (0.0095 g, 0.050 mmol), and 2 (32 µL, 0.20 mmol,
20 mol %) in DMF (0.5 mL). Column chromatography (1:2
hexanes/ethyl acetate) provided 0.136 g (69% yield) of the title
compound as a colorless oil. The 1H NMR spectrum was in
accord with that reported in the literature.22
1-P h en yl-2,4-tr ia zole (En tr y 1). Following the general
procedure, 1,2,4-triazole (0.069 g, 1.00 mmol) was coupled with
iodobenzene (134 µL, 1.20 mmol) using K3PO4 (0.425 g, 2.0
mmol), CuI (0.0095 g, 0.050 mmol), and 2 (16 µL, 0.10 mmol,
10 mol %) in DMF (1 mL). Column chromatography (3:1
hexanes/ethyl acetate) provided 0.135 g (93% yield) of the title
compound as a colorless oil that solidified to a light yellow solid
after drying under vacuum. Mp: 44-44.5 °C (chloroform) (lit.23
mp 44-45 °C). The 1H NMR spectrum was in accord with that
reported in the literature.23
1-(4′-Meth oxyp h en yl)-2,4-tr ia zole (En tr y 2). Following
the general procedure, 1,2,4-triazole (0.069 g, 1.00 mmol) was
coupled with 4-iodoanisole (0.281 g, 1.20 mmol) using K3PO4
(0.425 g, 2.0 mmol), CuI (0.0095 g, 0.050 mmol), and 2 (16 µL,
0.10 mmol, 10 mol %) in DMF (1 mL). Column chromatography
(1:1 hexanes/ethyl acetate) provided 0.138 g (79% yield) of the
title compound as a white solid. Mp: 96-97 °C (chloroform)
(20) Pavik, J . W.; Connors, R. E.; Burns, D. S.; Kurzweil, E. M. J .
Am. Chem. Soc. 1993, 115, 7645.
(21) Dodson, R. J .; Ross F. J . Am. Chem. Soc. 1950, 72, 1478.
(22) Higashino, T.; Sato, S.; Miyashita, A.; Katori, T. Chem. Pharm.
Bull. 1987, 35 (12), 4803.
(23) Micetich, R. G.; Spevak, P.; Hall, T. W.; Bains, B. K. Heterocycles
1985, 23 (7), 1645.
(24) Hu, K.; Niyazymbetov, M. E.; Evans, D. H. Tetrahedron Lett.
1995, 36, 7027.
(25) Lin, M. Aust. J . Chem. 1977, 30, 629.
(26) Begtrup, M.; Elguero, J .; Faure, R.; Camps, P. Estopa, C. Magn.
Reson. Chem. 1988, 26, 134.
(27) Reynolds, J . J . Org. Chem. 1964, 29, 3733.
5586 J . Org. Chem., Vol. 69, No. 17, 2004

Copper-Diamine-Catalyzed N-Arylation of Pyrroles
acetate) to provided 0.147 g (74% yield) of the title compound
as a colorless oil. H NMR (400 MHz, CDCl3): δ 7.17 (m, 2H),
7.12 (m, 2H), 7.09 (m, 1H), 6.89 (m, 1H), 6.23 (m, 1H), 2.37 (s,
3H), 2.36 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 186.8, 138.1,
137.2, 131.3, 130.9, 129.0, 125.6, 120.1, 108.8, 27.0, 20.9. IR
(neat, cm-1): 3034, 2923, 1664, 1516, 1408, 1347, 1268, 1111,
935, 821, 741.
thank Mr. Eric Strieter for insightful discussions. J .C.A.
was supported as a postdoctoral trainee of the Na-
tional Cancer Institute (Training Grant NCI No. CI
T32CA09112). J .M.B. thanks the MIT Undergraduate
Research Opportunities Program for financial support.
1
1
Su p p or tin g In for m a tion Ava ila ble: Required H and 13C
NMR spectra for unknown compounds, X-ray crystallography
data, and NOE difference spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM 58160) for support of this work.
We are grateful to Pfizer, Merck, Lundbeck, and Rhodia
Pharmaceutical Solutions for additional funds. We also
J O049658B
J . Org. Chem, Vol. 69, No. 17, 2004 5587