Copper-catalyzed N-arylation of hindered substrates under mild conditions

Article abstract of DOI:10.1002/adsc.200800730

A mild, efficient method utilizing a copper-diamine catalyst at room temperature is reported for the coupling of hindered imidazoles with unsubstituted, orthzo-substituted, and bis-ortho-substi-tuted boronic acids in good to excellent yields. Aryl halides

Full text of DOI:10.1002/adsc.200800730

FULL PAPERS
DOI: 10.1002/adsc.200800730
Copper-Catalyzed N-Arylation of Hindered Substrates Under
Mild Conditions
Michael T. Wentzel,a J. Brian Hewgley,a Rajesh M. Kamble,a Philip D. Wall,a
and Marisa C. Kozlowskia,*
a
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania
19104, USA
Fax : (+1)-215-573-7156; phone: (+1)-215-898-3048; e-mail: marisa@sas.upenn.edu
Received: November 24, 2008; Revised: March 4, 2009; Published online: April 6, 2009
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A mild, efficient method utilizing a halides do not reaction under these conditions per-
copper-diamine catalyst at room temperature is re- mitting sequential N-arylation reactions.
ported for the coupling of hindered imidazoles with
unsubstituted, ortho-substituted, and bis-ortho-substi- Keywords: N-arylation; boronic acids; copper cataly-
tuted boronic acids in good to excellent yields. Aryl sis; nitrogen heterocycles
À
Introduction
zoles and benzimidazoles, C N biaryls with substitu-
tion at up to two ortho-positions could be achieved
N-Arylation has received much attention due to the using Cu2O, Cs2CO3, polyethylene glycol, and a phen-
use of arylated heterocycles in agricultural and phar-
anthroline ligand at 110–1508C.[14] Related reports
ACHTUNGTRENNUNG
À
maceutical chemistry. Successful C N coupling meth- have appeared recently for N-aryl heterocycles, but
ods[1] have employed palladium, nickel[2] and copper[3] high temperatures (125–1708C) were requried and
À
catalysts in the coupling of amines with aryl halides; there were no cases leading to C N bonds with more
however, mild methods are scarce. These reactions than two ortho-substituents.[15] In all of these reports,
À
typically require stoichiometric quantities of base and there were no cases leading to C N bonds with more
elevated reaction temperatures. Alternative ap- than two ortho-substituents.
proaches have been developed using aryllead,[4]
While the more reactive boronic acid precursors
-tins,[5] -bismuths,[6] -silanes,[7] and -boronic acids[8] as permit N-arylations of heterocycles to proceed at
À
transmetallating reagents. A reactivity pattern for het- lower temperatures, the formation of the hindered C
erocycles in N-arylation reactions has begun to be N biaryls remains a challenge.[16] For example, Yu and
seen based on nucleophilicity, complexing ability of co-workers developed a method to couple ortho-sub-
catalyst, and acidity. Heterocycles with fewer nitro- stituted boronic acids with imidazole using catalytic
gens are more reactive: carbazole>imidazole> CuCl in MeOH at reflux. However, this method was
indole~pyrrole> triazole@tetrazole.[9]
only effective for mono-ortho-substituted boronic
In general, these methods are limited to sterically acids and imidazole.[17] Furthermore, Alcade and co-
unhindered N-arylation when nitrogen heterocycles workers reported that benzimidazole underwent poor
are employed.[10] However, a few reports for hindered coupling with arylboronic acids using catalytic copper
cases have surfaced. Buchwald and co-workers have conditions.[12c]
successfully coupled 2-substituted indoles, pyrroles,
imidazoles, and benzimidazoles with aryl halides
using using copper-diamine catalysts at elevated tem- Results and Discussion
peratures (110–1508C)[11] Related reports have ap-
peared recently for futher N-aryl heterocycles, but Together, these results highlight the limits of current
high temperatures (110–1708C) were required.[12] The methods, namely, the synthesis of a biaryl C N bond
À
same catalyst system was also effective in coupling with more than two ortho-substituents. Therefore, we
ortho-substituted aryl halides with unsubstituted were motivated to develop a method aimed at this
indole[11] and 2-substituted pyrroles.[13] With imida- product category. Herein, we report our efforts result-
Adv. Synth. Catal. 2009, 351, 931 – 937
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Michael T. Wentzel et al.
FULL PAPERS
Table 1. Survey of copper salts with TMEDA in the reaction
ing in the coupling of benzimidazoles and 2-substitut-
ed imidazoles with mono- and bis-ortho-substituted
boronic acids under mild conditions (catalytic copper
at room temperature).
from Scheme 1.[a]
Entry Copper source
Cu oxidation
state
Conversion
[%][b]
Boronic acids were selected as the N-arylation cou-
pling partners since they are more reactive than the
corresponding halides but remain stable and easy to
handle. While most copper-based N-arylation meth-
ods with arylboronic acids require stoichiometric
quantities of the metal, Lam and Buchwald have re-
ported a catalytic arylation of amines using 10 mol%
1
2
3
4
5
6
7
8
9
10
Cu
Cu
CuBr2
Cu(OAc)2
CuSO4
CuCl2
Cu
CuCl
CuI
CuBr
N
II
100
99
37
2
2
1
99
76
67
30
II
II
II
II
I
I
I
I
Cu
lation of imidazoles catalytic when CuClOH-
ACHTUNGTRENNUNG
(OAc)2.[18] Collman was also able to render the ary-
ACHTUNGTRENNUNG(TMEDA) was used (TMEDA=tetramethylethylene-
diamine).[19]
[a]
Conditions: 20 mol% ligand and Cu salt, 0.16 mmol of
imidazole, 0.32 mmol of ArB(OH)2 in 2 mL of 3:2
CH3CN:CH2Cl2 under O2 atmosphere at room tempera-
ture for 16 h.
Determined by GC using 4-phenoxylbiphenyl as a stan-
dard.
Our studies commenced with hindered substrates
1a and 2a, a combination which does not react under
the conditions reported by Lam[18a] or Collman.[19a] We
discovered that 20 mol% of the CuOTf-TMEDA
complex under the conditions outlined in Scheme 1
furnished the product 3aa in 90% isolated yield.
[b]
Table 2. Survey of solvent with Cu
ACHTNUGTNER(NUGN NO3)2·2.5H2O and
TMEDA in the reaction from Scheme 1.[a]
Entry
Solvent
Conversion [%][b]
1
2
3
4
5
6
1:1 CH3CN: MeOH
MeOH
CH3CN
3:2 CH3CN:CH2Cl2
EtOAc
CH2Cl2
81
72
61
60
5
Scheme 1. Mild copper-catalyzed N-arylation.
1
[a]
Conditions: 20 mol% ligand and Cu salt, 0.16 mmol of
imidazole, 0.32 mmol of ArB(OH)2 in 2 mL of solvent
under O2 atmosphere at room temperature for 1.5 h.
Determined by GC using 4-phenoxylbiphenyl as a stan-
dard.
With this result in hand, a variety of copper salt
complexes with TMEDA were surveyed (Table 1).
Copper(I) and copper(II) triflate gave yields similar
[b]
to CuACHTUNGTRENNUNG(NO3)2 2.5H2O. The latter was utilized for fur-
ther studies (Table 2) as it is inexpensive, readily ob-
tained, and stable [copper(I) species oxidize and an-
hydrous copper(II) salts hydrate upon storage].
Table 3. Effect of the TMEDA ratio with 20 mol%
Cu(NO3)2·2.5H2O in MeOH on the reaction from
Scheme 1.[a]
Under identical conditions,
a 1:1 mixture of
AHCTUNGTRENNUNG
MeOH:CH3CN gave 81% conversion (Table 1
entry 5) whereas MeOH alone provided a slightly
lower 72% conversion. All other solvent combina-
tions were less optimal.
Entry
TMEDA (mol%)
Conversion [%][b]
3:2 CH3CN:CH2Cl2
MeOH
The amount of TMEDA relative to the copper spe-
cies was studied in two solvent systems. In a mixture
of 3:2 CH3CN:CH2Cl2, the TMEDA:Cu ratio has a
large effect on the conversion. Using an excess of
TMEDA with respect to the copper salt proved to be
the most beneficial beneficial (Table 3, entry 5). On
the other hand, the TMEDA:Cu ratio does not effect
the conversion strongly when MeOH was used as the
solvent (Table 3). These results point to a coordina-
tion role for the MeOH which solubilizes and acti-
vates the copper species to a large extent. In the ab-
1
2
3
4
5
0
5
10
20
50
21
14
10
76
92
72
80
99
88
94
[a]
Conditions: 20 mol% Cu salt, 0.16 mmol of imidazole,
0.32 mmol of ArB(OH)2 in 2 mL of CH3CN:CH2Cl2 or
MeOH under O2 atmosphere at room temperature for
16 h.
Determined by GC using 4-phenoxylbiphenyl as a stan-
dard.
[b]
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Copper-Catalyzed N-Arylation of Hindered Substrates Under Mild Conditions
FULL PAPERS
sence of MeOH, a much larger amount of diamine
(TMEDA) is needed for the same effect; there may
also be competition between TMEDA coordination
and substrate coordination. A screen of other di-
ACHTUNGTRENNUNGamines showed that 1,2-dimethylethylenediamine and
1,3-dimethylpropylenediamine were just as effective.
However, 1,2-ethylenediamine provided no reaction
and more hindered diamines compromised reactivity.
For simplicity, MeOH alone was used as the solvent
Scheme 2. Conditions: 10–50 mol% CuACHTUNRTGNE(UNG NO3)2·2.5H2O, 10–
50 mol% TMEDA, under O2 in MeOH.
in the next series of studies to maxmize the solubility which allowed consistent results without reoptimiza-
of the polar imidazoles that would be employed. In tion, was used for the remaining substrates.
addition,
a
1:1 TMEDA:Cu
G
With benzimidazole, couplings to unhindered bor-
could be employed, minimizing the amount of di- onic acid substrates by far and large proceeded very
A
well (Table 4). From the series of para-substituted
GC monitoring (Figure 1). Using 1 mol% of the cata-
lyst, 74% conversion was observed after 23 h and pro-
Table 4. Unhindered couplings (Scheme 2) using 10 mol%
CuACTHNUTRGNEUNG
(NO3)2-TMEDA catalyst.[a]
Entry
1
2
Product 3
Yield [%][b]
99
1
1a
2b
3ab
3ac
3ad
2
3
1a
1a
2c
83
99
2d
4
1a
1a
2e
2f
3ae
3af
59
84
Figure 1. Effect of the CuACHTNUGTRENUNG(NO3)2-TMEDA catalyst loading
on the reaction from Scheme 1. Conditions: 0.16 mmol of
imidazole, 0.32 mmol of ArB(OH)2 in 2 mL of MeOH under
O2 atmosphere at room temperature. Conversion deter-
mined by GC using 4-phenoxylbiphenyl as a standard.
5
[a]
Conditions: 0.16 mmol of imidazole, 0.32 mmol of
ArB(OH)2 in 2 mL of MeOH under O2 atmosphere at
room temperature for 24 h.
gressed to 90% after 48 h. With 1.5 mol% catalyst,
very good conversion (90%) was observed after 23 h
and little further progress was observed afterward.
[b]
Isolated yield after chromatography.
With 2 mol% of the catalyst, very good conversions phenylboronic acids, no electronic effect was readily
occurred rapidly (91% after 12 h) that increased to apparent. Pleasingly, sensitive substrates could be em-
98% after 48 h.
ployed including those containing aldehyde (entry 3)
With optimal conditions [1:1 CuACHTNUGTERNGN(NU NO3)2:TMEDA) and iodide (entry 5) groups. The latter (product 3af)
in MeOH under O2 at ambient temperature] estab- is especially noteworthy as it would not be accessible
lished, series of substrates were screened via a benzimidazole/aryl halide coupling. The iodo
a
(Scheme 2). With other hindered substrates (2-tolyl- group also provides a means for further cross-cou-
boronic acid), the standard conditions using a 2 mol% pling chemistries.
catalyst loading gave variable results. Apparently, the
To illustrate the utility of the idodide species, a se-
substrates also contribute to the equilibrium phenom- quential bis-N-arylation was undertaken (Scheme 3).
ena observed in Table 3. As such, 10 mol% catalyst, In this three-component coupling, the iodoarylboronic
Adv. Synth. Catal. 2009, 351, 931 – 937
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Michael T. Wentzel et al.
FULL PAPERS
Table 5. Hindered couplings (Scheme 2) using CuACHTUNGTRENNUNG(NO3)2-
TMEDA catalyst.[a]
Entry 1
2
Product 3
Catalyst
[mol%]
Yield
[%][b]
1
2
3
4
1a 2g
1a 2h
1a 2i
1a 2j
3ag 10
97
Scheme 3. Sequential bis-N-arylation.
3ah 10
3ai 10
3aj 30
95
acid first undergoes chemoselective N-arylation with
benzimidazole at the boronic acid position using the
catalyst system described herein. Next, the conditions
of Buchwald and co-workers[20] were applied to gener-
82
À
ate a second C N bond from the iodide and acet-
amide.
99[c]
Next, more hindered boronic acids and imidazoles
were examined leading to a variety of products with
two ortho-groups (Table 5). With benzimidazole (en-
tries 1–4), a selection of ortho-substituted boronic
acids could be coupled quite well. The reactions of 2-
phenylimidazole (entries 5–7) proved particularly dif-
ficult requiring higher catalyst loadings (30–
50 mol%). On the other hand, 2-methylimidazole (en-
tries 8 and 9) was quite tractable providing the prod-
ucts in high yield at 10 mol% loading. Finally, the
very challenging 2-methylbenzimidazole (two ortho
substituents on the imidazole portion) was also cou-
pled effectively to phenylboronic acid (entry 10).
Finally, substrates were examined leading to even
more hindered products (Table 6). The results leading
to products with three ortho-groups (entries 1–4)
highlight the utility of this method. During this study,
one substrate (2,3-dimethoxyphenylboronic acid, 2m)
produced unexpected product 5 upon attempted cou-
pling with benzimidazole (Scheme 4). Either the
product of initial N-arylation undergoes a rapid hy-
dration and subsequent O-arylation (path a) or 2,6-di-
methoxyphenol is somehow formed and undergoes
imine addition (path b) to the N-arylation product. Fi-
nally, a survey of the less reactive 2-methylimidazole
with ortho-phenylboronic acids (entries 5–7) showed
that high yields can be obtained simply and rapidly.
5
6
1b 2b
1b 2h
3bb 30
3bh 30
71[f]
71[f]
7
1b 2g
3bg 50
70[d,e]
8
9
1c 2b
1c 2c
3cb 10
3cc 10
99
86[c]
10
1d 2b
3db 10
82
[a]
Conditions: 0.16 mmol of imidazole, 0.32 mmol of
ArB(OH)2 in 2 mL of MeOH under O2 atmosphere at
room temperature for 24 h.
Isolated yield after chromatography.
Further 0.16 mmol of ArB(OH)2 added after 24 h and
quenched after 48 h total.
ArB(OH)2 added in two 0.24 mmol portions, the second
after 3 h.
Heated to 658C.
ArB(OH)2 added in two 0.24 mmol portions, the second
after 24 h, reaction quenched after 48 h total.
[b]
[c]
[d]
[e]
[f]
Conclusions
In conclusion, an effective catalyst system has been
À
developed to form hindered C N biaryls. The method
has been illustrated in the cross-coupling of imida-
zoles and arylboronic acids. For most cases, the reac- TMEDA catalyst in MeOH under O2. Further studies
tion conditions are very mild proceeding at ambient to examine the utility with other N-coupling partners
temperature with a simple catalyst system: CuACHTNUGTRNEG(UN NO3)2- are underway.
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Adv. Synth. Catal. 2009, 351, 931 – 937

Copper-Catalyzed N-Arylation of Hindered Substrates Under Mild Conditions
Table 6. Very hindered couplings (Scheme 2) using
FULL PAPERS
Cu
ACHTUNGTRENNUNG
Entry 1
2
Catalyst
[mol%]
Yield
[%][b]
1
2
1a 2a
1a 2k
3aa 10
98
3ak 50
48[c,e]
3
4
1c 2a
1c 2l
3ca 10
3cl 30
65
Scheme 4. Unusual coupling. Conditions: 0.16 mmol of imi-
dazole, 0.32 mmol of ArB(OH)2 in 2 mL of MeOH under
O2 atmosphere at room temperature. Further 0.16 mmol of
ArB(OH)2 added after 24 h and reaction quenched after
48 h total.
90[c,e]
formed under a positive flow of oxygen. Analytical thin
layer chromatography (TLC) was performed on EM Re-
agents 0.25 mm silica gel 60-F plates. Visualization was ac-
complished with UV light or KMnO4 stain. Chromatography
was performed using a forced flow of the indicated solvent
system on EM Reagents silica gel 60 (230–400 mesh).[22]
1H NMR spectra were recorded on Bruker AM-500
(500 MHz), AM-360 (360 MHz), AM-250 (250 MHz), or
AM-200 (200 MHz) spectrometers. Chemical shifts are re-
ported in ppm from tetramethylsilane (0 ppm) or from the
solvent resonance (CDCl3 7.26 ppm). Data are reported as
follows: chemical shift, multiplicity (s=singlet, d=doublet,
t=triplet, q=quartet, br=broad, m=multiplet), coupling
constants, and number of protons. Decoupled 13C NMR
spectra were recorded on a Bruker AM-500 (125 MHz)
spectrometer. IR spectra were taken on a ASI ReactIR
1000 equipped with an Si-Comp probe. High resolution
mass spectra were performed by Dr. Kohli at the Mass Spec-
trometry Laboratory at the University of Pennsylvania.
5
6
1c 2g
1c 2h
1c 2j
3cg 30
3ch 30
3cj 30
99
99[f]
99[f]
7
[a]
Conditions: 0.16 mmol of imidazole, 0.32 mmol of
ArB(OH)2 in 2 mL of MeOH under O2 atmosphere at
room temperature for 24 h.
Isolated yield after chromatography.
Further 0.16 mmol of ArB(OH)2 added after 24 h and re-
action quenched after 48 h total.
ArB(OH)2 added in two 0.24 mmol portions, the second
after 3 h.
Heated to 658C.
ArB(OH)2 added in two 0.24 mmol portions, the second
after 24 h, quenched after 48 h total.
[b]
[c]
[d]
[e]
[f]
Typical Procedure A: 1-(4-Iodophenyl)-1H-benzo[d]-
imidazole (3af)
Here, the individual catalyst components were added direct-
ly to the reagents. The imidazole (0.16 mmol) and the bor-
onic acid (0.32 mmol) were added to a 2 dram vial with a
septum. Distilled MeOH (to achieve a final volume of
Experimental Section
2 mL), a stock solution of CuACTHNUTRGNEUNG(NO3)2 in MeOH (0.16M,
General Considerations
volume used based on mol% required), and a stock solution
of TMEDA in MeOH (0.16M, volume used based on mol%
required) were added to the vial while under 1 atm of O2.
The solution was stirred for 24 h at ambient temperature.
After addition of H2O (1 mL), the mixture was extracted
with CH2Cl2 (3ꢁ2 mL). The combined organic extracts were
dried with MgSO4 and concentrated. Chromatography (1%
MeOH/CH2Cl2) afforded the N-arylation product as a
yellow film; yield: 84%; Rf =0.68 (10% MeOH/CH2Cl2);
Unless stated all reactions were carried out in oven-dried
glassware. TMEDA (N,N,N’,N’-tetramethylethylenediamine)
was distilled from CaH2. CuACHTUNGRTNEUNG(NO3)2·2.5H2O was purchased
from Fisher and was used as received. All imidazoles are
commercially available, as were the boronic acids except for
2-methoxy-1-napthylboronic acid which was synthesized ac-
cording to a literature[21] procedure. Distilled HPLC grade
methanol was used for all reactions. All reactions were per-
Adv. Synth. Catal. 2009, 351, 931 – 937
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Michael T. Wentzel et al.
FULL PAPERS
1H NMR (500 MHz, CDCl3): d=8.07 (s, 1H), 7.88 (m, 2H), References
7.49 (m, 1H), 7.33 (m, 2H), 7.27 (m, 2H); 13C NMR
(125 MHz, CDCl3): d=144.2, 142.0, 139.3 (2C), 136.2, 125.8
(2C), 124.1, 123.2, 120.9, 110.4 (2C), 92.8; IR (film): n=
3084, 3057, 1613, 1586, 1498, 1455, 1289, 1231 cmÀ1; HR-MS
(ES): m/z=320.9878, calcd. for C13H9IN2 (M+): 319.9808.
[1] For a general review: M. Kienle, S. R. Dubbaka, K.
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Typical Procedure B: 1-o-Tolyl-1H-benzo[d]imidazole
(3ag)
Here, the catalyst solution was generated shortly before ad-
dition of the reagents. No practical difference was observed
between this protocol and that described above in Typical
Procedure A. A 0.16M TMEDA (3.38 mmol, volume used
based on mol% required) methanolic stock solution was
added to a 0.053M cupric nitrate (3.38 mmol, volume used
based on mol% required) methanolic stock solution in a
5 mL vial. After stirring at ambient temperature for 15 min,
the mixture was diluted with MeOH to a final volume of
2 mL. The imidazole (0.16 mmol) and boronic acid
(0.32 mmol) were added as solids and the mixture placed
under a positive flow of oxygen at room temperature. After
24 h, H2O (1 mL) was added and the resultant mixture was
extracted with CH2Cl2 (3ꢁ2 mL). The combined organic ex-
tracts were dried with MgSO4 and concentrated. Chroma-
tography (EtOAc/hexanes) afforded the N-arylation product
as a yellow film; yield: 97%; Rf =0.68 (10% MeOH/
[4] P. Lꢂpez-Alvarado, C. AvendaÇo, J. C. Menꢃndez, J.
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1
CH2Cl2); H NMR (500 MHz, CDCl3): d=7.96 (s, 1H), 7.88
(d, J=8.0 Hz, 1H), 7.42 (m, 2H), 7.43–7.26 (m, 4H), 7.13
(d, J=7.9 Hz, 1H), 2.09 (s, 3H); 13C NMR (125 MHz,
CDCl3): d=143.3, 142.9, 135.3, 134.7, 131.5, 129.3, 127.6,
127.1, 123.5, 122.4 (2C), 120.4, 110.4, 17.5; IR (film): n=
3057, 2922, 1613, 1502, 1459, 1231 cmÀ1; HR-MS (ES): m/z=
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GC Reaction Monitoring
4-Phenoxybiphenyl was used as an internal standard for GC
analysis of reactions. At regular intervals, aliquots (~100 mL)
were removed. To the respective aliquot were added H2O
and CH2Cl2. The solution was then shaken and the organic
phase was filtered through SiO2 (10% MeOH/CH2Cl2). Gas
chromatography (GC) analyses of reaction progress were
conducted with an Agilent 6850 gas chromatograph with a
flame ionization detector equipped with an HP-1 column
(Agilent): length=30 m, ID=0.32 mm, film=0.25 mm,
flow=2 mLminÀ1, 1658C to 1808C, pressure 27.29 psi; carri-
er gas: N2; injector=1858C; detector 2508C. Retention
times; product: 4.41 min, 4-phenoxybiphenyl (internal stan-
dard): 12.4 min.
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À
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Acknowledgements
We are grateful to the NSF (CHE-0616885) for financial sup-
port.
936
asc.wiley-vch.de
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 931 – 937

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