Practical Cu-catalyzed amination of functionalized heteroaryl halides

Article abstract of DOI:10.1016/j.tetlet.2006.06.119

The amination of a variety of highly functionalized heterocyclic bromides has been accomplished using a CuI/proline catalyst system. The current study significantly expanded the scope of the reaction by using examples relevant to drug discovery programs a

Full text of DOI:10.1016/j.tetlet.2006.06.119

Tetrahedron Letters 47 (2006) 6011–6016
Practical Cu-catalyzed amination of functionalized
heteroaryl halides
Vince S. C. Yeha,* and Paul E. Wiedemanb,*
aAbbott Laboratories, Metabolic Disease Research, 100 Abbott Park Road, Dept. R4MC, AP10-3, Abbott Park, IL 60064-6113, USA
bAbbott Laboratories, Advanced Technology, 100 Abbott Park Road, Dept. R4CP, AP9B, Abbott Park, IL 60064-6113, USA
Received 15 June 2006; revised 21 June 2006; accepted 22 June 2006
Available online 10 July 2006
Abstract—The amination of a variety of highly functionalized heterocyclic bromides has been accomplished using a CuI/proline
catalyst system. The current study significantly expanded the scope of the reaction by using examples relevant to drug discovery
programs and has demonstrated reaction rate acceleration using microwave heating.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Metal catalyzed C–N bond formation reactions of aro-
matic compounds have made tremendous advances in
the past decade.1 Landmark innovations from the Har-
twig2 and Buchwald3 groups have continued to inspire
researchers to discover milder and more selective condi-
tions for a diverse array of substrates. Heteroaromatic
amines are ubiquitous in biologically active molecules.4
Historically, this class of compounds has been prepared
using either nucleophilic aromatic substitution reactions
or potentially dangerous and sometimes unselective
nitration chemistry. The use of metal catalyzed C–N
bond formation reactions allows chemists to view vari-
ous heteroaryl halides, which are widely commercially
available, as viable synthons.
variety of state of the art ligands for both Pd and Cu.6
Selected results are summarized in Table 1. It quickly
became apparent that the CuI/proline method reported
by Ma7 consistently outperformed all the other
methods.
To optimize this reaction, we examined the conditions in
more detail, and the selected examples are summarized
in Table 2. A number of N,O-bidentate ligands were
tested along with other condition changes such as cata-
lyst amounts and different bases. The time of reaction
was held constant using a timer to turn off the heating
source.
The conversion of each reaction was analyzed by LC/
MS. For most of the reactions, four main products were
observed: the desired product; starting material; debro-
mination product; and product derived from ligand addi-
tion. Among the amino acid ligands tested, pipecolinic
acid and azetidine-2 carboxylic acid gave comparable
conversions (entry 2 vs 3). Reactions with dimethylgly-
cine and N-methyl proline were slower, giving slightly
lower yields as compared to proline (entries 1 and 7)
but gave no ligand addition product. Proline proved to
be the optimal ligand in terms of rate and yield. The reac-
tion can be pushed to completion by doubling the cata-
lyst amount (Table 2 entry 8 vs Table 1 entry 5). We
found that the reaction can be accelerated by microwave
heating, which significantly reduces the reaction time
(entry 8 vs 9).8 We attempted to overcome the slower rate
of reaction with dimethylglycine or N-methyl proline by
heating the reactions in the microwave reactor at higher
Over the course of several drug discovery programs, we
found a need to prepare a variety of N-substituted nico-
tinamides such as 1a (Table 1) for SAR studies. After
surveying the literature on C–N coupling methods for
heteroaryl compounds,5 we noticed that there were very
few examples of heteroaromatic substrates containing
unprotected amide NH groups. Moreover, it does not
appear that there is a general metal/ligand combination
that is amenable to parallel synthesis of diverse classes
of heterohalides and amines.
We used the coupling of 1 and morpholine as a test case
and examined a number of literature methods using a
*
Corresponding authors. Tel.: +1 847 937 5567; fax: +1 847 938
1674; e-mail addresses: vince.yeh@abbott.com; paul.e.wiedeman@
abbott.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.119

6012
V. S. C. Yeh, P. E. Wiedeman / Tetrahedron Letters 47 (2006) 6011–6016
Table 1. Metal catalyzed amination of 1
O
NH
O
O
O
Br
N
M/L
Base
N
N
H
H
N
N
1
1a
Entry
1a
Catalyst, conditionsb
Ligand
% conversion (dp/sm/de-Br)c
30/45/25
Pd2(dba)3 (5%), K3PO4, toluene
Pd2(dba)3 (5%), K3PO4, toluene
x-Phosd (20%)
2a
q-Phose (20%)
25/60/15
5/50/45
NHMe
3a
CuI (10%), K3PO4, toluene
(30%)
NHMe
O
4a
5
CuI (10%), K3PO4, DMF
CuI (10%), K2CO3, DMSO
(30%)
10/70/20
NEt2
OH
Proline (20%)
50/40/5/5f
a See Ref. 6.
b Base (3 equiv), 110 ꢁC.
c Conversions were determined based on LC/MS results. dp = desired product, sm = starting material, de-Br = debrominated product.
d x-Phos: 2-dicyclohexylphosphino-20,40,60-triisopropyl-1,10-biphenyl.
e q-Phos: pentaphenylferrocenyl di-tert-butylphosphine.
f Product derived from ligand addition.
Table 2. Optimization of Cu catalyzed amination
O
NH
O
O
O
Br
N
CuI/L
N
N
H
H
Base
1
N
N
Entry
1
Reaction conditionsa
Ligand
% conversion (dp/sm/de-Br/ligand adduct)b
45/50/5/0
O
A
N
OH
2
A
30/35/20/15
N
H
CO2H
CO2H
3
4
5
A
A
A
30/30/25/15
10/20/50/20
5/95/0/0
N
H
NMe2
OH
N
CO2H
NHMe
6
A
15/70/5/10
OH
7
8
9
10c
A
B
C
C
N-Methyl proline
Proline
Proline
40/50/10/0
80/0/5/15
75/0/15/10
75/0/15/10
Proline
a Condition A: 1 (0.2 mmol), morpholine (1.5 equiv), CuI (10%), ligand (20%), K2CO3 (3 equiv), DMSO (1 mL), 120 ꢁC, 15 h. Condition B: 1
(0.2 mmol), morpholine (2.0 equiv), CuI (20%), ligand (40%), K2CO3 (3 equiv), DMSO (1 mL), 120 ꢁC, 15 h. Condition C: 1 (0.2 mmol), mor-
pholine (2.0 equiv), CuI (20%), ligand (40%), K2CO3 (3 equiv), DMSO (1 mL), microwave heating at 140 ꢁC, 30 min.
b Conversion based on LC/MS.
c Reaction performed on 1 mmol scale.
temperatures (>170 ꢁC), but an increased amount of
the debromination product was noticed. Among the
common inorganic bases surveyed, K3PO4 and Na2CO3
gave poorer yields, and Cs2CO3 gave comparable results

V. S. C. Yeh, P. E. Wiedeman / Tetrahedron Letters 47 (2006) 6011–6016
Table 3. C–N formation of heteroaryl bromides with aliphatic primary amines
6013
Entry
Het-Br
Product
Yield isolated/HPLC (%)
O
H
O
O
1a
1
1
50/65
56/70
N
N
Br
N
H
H
N
N
O
H
N
N
Br
2b
N
H
H
N
O
N
N
Br
CN
CN
H
N
CN
3a
2
2
70/90
33/50
N
N
H
N
CN
Br
4b
O
O
N
N
H
N
Br
O
5b
3
55/75
O
N
N
H
N
N
N
H
O
O
H
N
Br
6b
4
5
60/80
70/80
NH2
NH2
N
O
O
7b
N
O
O
Br
N
H
N
N
N
H
N
S
N
H
S
O
8b
5
6
70/80
65/80
N
Br
H
N
N
H
N
H
S
S
O
O
N
O
O
9a
H
H
N
N
N
Br
Br
BnHN
BnHN
O
O
10a
7
65/75
N
N
SO2Ph
SO2Ph
a Reaction performed on 0.2 mmol scale using condition 1.
b Reaction performed on 0.33 mmol scale using condition 2.
to K2CO3. DMSO was the preferred solvent not only
because it gave consistently good reaction yields, but it
was also highly compatible with our high-throughput
reversed-phase HPLC purification systems.9 The isolated
yields using either condition B or C are generally between
60% and 70%, and the reaction has been scaled (1 mmol)
with reproducible results (entry 10).
amates (6), 5-membered heterocycles (5), 6-membered
heterocycles (1–4), and indoles (7). Table 3 shows the
results from primary amines. Reactions generally gave
good conversion and acceptable isolated yields using
either conventional heating (condition 1) or microwave
heating (condition 2).
Good conversion was achieved on substrate 3 which is
a potential metal chelator (entry 5). Multifunctional
oxazolidinone 6 (entry 9) underwent coupling without
the need for an additional protecting group on the
amide nitrogen. This result is noticeably different from
previous work using this type of substrate and Pd
as catalyst where amide NH protection is required.5e
In addition to 1, we demonstrated the utility of the Cu/
proline amination system on various highly functional-
ized heterocyclic bromides and amine nucleophiles. We
tested the reaction on substrates with functional groups
commonly encountered in medicinal chemistry such as
cyanides (2), primary and secondary amides (3–6), carb-

6014
V. S. C. Yeh, P. E. Wiedeman / Tetrahedron Letters 47 (2006) 6011–6016
Table 4. C–N formation of heteroaryl bromides with cyclic aliphatic secondary amines
Entry
1a
Het-Br
Product
Yield isolated/HPLC (%)
42/60
O
1
Br
N
O
N
H
N
N
H
N
N
O
Br
CN
N
CN
2a
2
3
65/90
58/70
N
N
N
O
Br
O
N
3b
O
N
N
H
N
H
O
O
N
O
Br
4b
4
5
52/80
65/75
NH2
NH2
N
N
O
O
O
O
N
5a
Br
N
N
N
H
N
H
S
S
F
O
6b
5
6
50/85
72/85
N
N
N
Br
N
N
H
N
S
H
S
O
N
O
N
O
O
H
7a
6b
H
N
N
N
O
Br
Br
O
O
O
N
8a
7
8
66/70
N
N
SO2Ph
SO2Ph
CONHPh
Br
9c
No product
N
H
a Reaction performed on 0.2 mmol scale using condition 1.
b Reaction performed on 0.33 mmol scale using condition 2.
c Reaction performed using condition 1 and morpholine as amine nucleophile.
Control reaction of thiazole substrate 5 without Cu gave
<10% coupled product. Lower isolated yields were
either due to water solubility of the products which were
lost during extractive work up or material loss on HPLC
purification.9 Side product from ligand addition was less
than 5% when primary amines are used as nucleophiles.
structurally simpler 5-bromoindole did not work in
our hands.
We also attempted using acyclic secondary amines as
nucleophiles, but the reactions invariably failed or at
best formed less than 20% of the desired product.
Table 4 summarizes the results from C–N coupling of
heteroaryl bromides with cyclic aliphatic secondary
amines. Similar to primary amines, the yields were good,
but the rate of reaction is slower than primary amines.
Compound 6b (entry 7) is structurally similar to the
commercially marketed antibiotic Linezolid10 which
was synthesized via a multi-step sequence using tradi-
tional nucleophilic aromatic substitution. With the cur-
rent method, one would have greater access to structural
analogues for SAR studies through C–N coupling on
unprotected substrates such as 6. Indoles with an unpro-
tected heterocyclic NH such as 8 (entry 9) or the
Table 5 shows the results of coupling reactions with
pyrazole as the nucleophile. The reactivity of pyrazole
is similar to that of secondary amines, and generally
good yields were obtained.
Aniline and other aromatic amines such as 2-amino-
thiazole are poor nucleophiles for this reaction. Low
conversions were observed and significant debromina-
tion occurred in all the examples. Specifically, when bro-
mides 1, 6, and 7 were reacted with aniline, product
yields were 20%, 38%, and 25%, respectively. No prod-
uct was recovered from the reaction with bromide 5.

V. S. C. Yeh, P. E. Wiedeman / Tetrahedron Letters 47 (2006) 6011–6016
Table 5. C–N formation of heteroaryl bromides with pyrazole
6015
Entry
Het-Br
Product
Yield isolated/HPLC (%)
O
O
1a
1
72/80
Br
N
N
N
N
H
H
N
N
Br
CN
O
N
N
CN
2b
2
5
30/80
65/75
N
N
O
3a
N
N
Br
N
N
N
N
H
H
S
S
O
O
N
O
O
H
4a
6
7
70/80
68/75
H
N
N
N
N
Br
Br
O
O
N
N
N
5a
N
N
SO2Ph
SO2Ph
a Reaction performed on 0.2 mmol scale using condition 1.
b Reaction performed on 0.33 mmol scale using condition 2.
In conclusion, we have demonstrated the expanded
scope and utility of CuI/proline catalyzed amination
reactions on functionalized heterocyclic bromides with
various types of amine nucleophiles often encountered
in a drug discovery program. The current method is per-
formed using a mild base that is compatible with many
functional groups, and the polar solvent medium used in
the reaction greatly facilitates the purification of prod-
ucts especially when reversed-phase HPLC is used.
Although the catalyst loading is relatively high, both
the metal and the ligand are inexpensive and readily
available. Unlike many of the Pd catalyzed reactions
which use non-polar phosphine ligands, amino acid
ligands are easily separated from the product mixture
through simple aqueous workup. Finally, we have also
revealed some of the limitations of the current catalyst
system when aryl amines and acyclic secondary amines
are used as nucleophiles. We hope that our current re-
sults will stimulate further research and lead to improve-
ments to this crucial bond forming reaction.
versed phase HPLC using 0.1% TFA in water and
CH3CN as eluent. The desired fractions were evapo-
rated in a SpeedVac, and the purified products were sub-
jected to 1H NMR, 13C NMR, HRMS, and IR analyses.
Condition 2. Heteroaryl bromide (0.33 mmol), CuI
(13 mg, 0.067 mmol), proline (15.5 mg, 0.134 mmol),
K2CO3 (140 mg, 1.00 mmol) and amine (0.673 mmol)
were combined in a microwave tube fitted with a sep-
tum. The tube was evacuated and then filled with nitro-
gen several times. DMSO (1.5 mL) was added, and the
septum was replaced with a crimped septum cap. The
reaction mixture was heated in a microwave at 140 ꢁC
for 30 min. The reaction mixture was partitioned be-
tween EtOAc (10 mL) and water (10 mL). The aqueous
phase was extracted again with EtOAc (2 mL). The
combined organic washes were dried (Na2SO4) and con-
centrated in vacuo. The crude material was purified by
flash chromatography (Biotage 40S, 50% EtOAc/hexane
then EtOAc). The purified product was subjected to the
standard characterizations as described above.
Experimental
Acknowledgments
Condition 1. Heteroaryl bromide (0.2 mmol), CuI
(7.6 mg, 0.04 mmol), proline (9.2 mg, 0.08 mmol), and
K2CO3 (83 mg, 0.6 mmol) were placed in a 5 mL micro-
wave tube capped with a rubber septum. The tube was
placed under vacuum and refilled with argon three
times. Amine (0.4 mmol) and degassed DMSO (1 mL)
were added to the tube and the rubber septa was quickly
replaced with a microwave tube cap. The reaction was
heated in an oil bath at 120 ꢁC for 15 h before it was
cooled, diluted with EtOAc, and filtered through a pad
of Celite. The EtOAc was removed on a rotary evapora-
tor. The residual DMSO solution was diluted with 1 mL
of MeOH, and the solution was purified through re-
The authors thank the staff of Abbott Structural Chem-
istry Department for obtaining the spectral data and
Drs. John Lynch and Bruce Szczepankiewicz for proof-
reading the manuscript.
Supplementary data
Detailed experimental procedures and 1H and 13C NMR
spectra of the synthesized compounds. Supplementary
data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2006.06.119.

6016
V. S. C. Yeh, P. E. Wiedeman / Tetrahedron Letters 47 (2006) 6011–6016
Hartwig, J. F. J. Org. Chem. 2002, 67, 5553; (c) Antilla,
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˚
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