Pd-catalyzed amination in a polar medium: Rate enhancement, convenient product isolation, and tandem Suzuki cross-coupling

Article abstract of DOI:10.1016/j.tetlet.2005.02.095

A catalytic system utilizing a polar medium for the Pd-catalyzed amination reaction is described. This system utilizes Pd[P(t-Bu)₃]₂ and a weak base and displays a modest rate enhancement compared to similar existing protocols. Significant functional group tolerance is observed in both amine and aryl halide, including carboxylates, carbamates, nitriles, amides, and esters. Product isolation after filtration and automated reverse-phase chromatography readily permits parallel synthetic approaches if desired.

Full text of DOI:10.1016/j.tetlet.2005.02.095

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2571–2575
Pd-catalyzed amination in a polar medium:
rate enhancement, convenient product isolation,
and tandem Suzuki cross-coupling
Shaun R. Stauffer* and Melissa A. Steinbeiser
Department of Medicinal Chemistry, Merck Research Laboratories WP14-3, West Point, PA 19486, USA
Received 21 December 2004; revised 16 February 2005; accepted 16 February 2005
Abstract—A catalytic system utilizing a polar medium for the Pd-catalyzed amination reaction is described. This system utilizes
Pd[P(t-Bu)3]2 and a weak base and displays a modest rate enhancement compared to similar existing protocols. Significant func-
tional group tolerance is observed in both amine and aryl halide, including carboxylates, carbamates, nitriles, amides, and esters.
Product isolation after filtration and automated reverse-phase chromatography readily permits parallel synthetic approaches if
desired.
Ó 2005 Elsevier Ltd. All rights reserved.
The palladium-catalyzed amination reaction has become
an integral and valuable transformation within the phar-
maceutical industry. Ongoing advances1,2 for this pro-
cess since the original landmark contributions utilizing
amines with aryl bromides and iodides reported by
Louie and Hartwig3 and Wolfe and Buchwald4 continue
to allow milder conditions and the use of more diverse
substrates. More specifically, catalytic conditions
employing alkylmono-phosphines5–7 or heterocyclic car-
bene ligands,8,9 many now widely available, allow the
amination of aryl chlorides. More recently ligand and
reaction conditions have been optimized which greatly
increase the scope for the amination of aryl tosylates10
and allow room temperature coupling of unactivated
aryl tosylates.11
of the commercially available Pd[P(t-Bu)3]2 (1) pre-cata-
lyst in conjunction with a weak base and polar medium
was highly effective toward the palladium mediated cou-
plings of aryl bromides and aryl chlorides with amines.
The use of a polar medium in combination with a weak
base and a sterically hindered phosphine was recently
studied in detail using a high-throughput screening
assay.15 Although yields of coupled product using aque-
ous DMA and K3PO4 were not as high as those in less
polar solvent mixtures, product yields using sterically
hindered alkyl mono-phosphines were moderate. This
observation, in addition to a recent study by Roy and
Hartwig11 demonstrating a rare medium rate enhance-
ment for the oxidative addition of aryl tosylates, encour-
aged us to further evaluate the use of a polar medium-
mild base combination in order to develop an optimal
protocol for rapid parallel synthesis and purification.
Current C–N bond-forming methods which tolerate
functionalized substrates typically utilize ether, t-BuOH,
arene, or biphasic solvent systems which are incompat-
ible with direct reverse-phase purification methods.10,12–14
As part of a medicinal chemistry effort to develop cat-
alytic amination conditions more suitable for both polar
substrates and parallel synthetic strategies amenable to
direct reverse-phase purification we found that the use
A number of reaction parameters were investigated uti-
lizing morpholine and 4-bromoanisole as coupling part-
ners; beginning with a brief re-evaluation of the effect of
catalyst structure on product yield. Initial studies were
conducted with 2.0 equiv anhydrous powdered K3PO4
as base and DMF as solvent at elevated temperatures
and included 1, the Pd(I)-dimer [P(t-Bu)3PdBr]2, rac-BI-
NAP, Xantphos, biphenyl-2-yl(di-tert-butyl)-phosphine,
and a number of commercially available SolviasÕ Josi-
phos ligands using one or more Pd sources. In short,
Keywords: Amination reaction; Palladium; Tandem cross-couplings.
*
Corresponding author. Tel.: +1 215 652 3631; fax: +1 215 652
3971; e-mail: shaun_stauffer@merck.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.095

2572
S. R. Stauffer, M. A. Steinbeiser / Tetrahedron Letters 46 (2005) 2571–2575
the results of these studies revealed that 1 was superior
to all other ligand–metal combinations tested (>80%
conversion versus <15% for all others). More significant
and somewhat unexpected, was the observation that
DMA and DMF were consistently the solvents that gave
reaction rates 2-fold faster than those conducted in
arene or ether solvents which are traditionally preferred
for the Buchwald–Hartwig amination. Indeed, time–
course experiments conducted in parallel (Fig. 1) com-
paring DMA versus toluene showed the relative rates
for product formation under the optimal conditions
were faster in DMA. After 5 h complete conversion oc-
curred in DMA, whereas in toluene starting material re-
mained even after 20 h. A second experiment comparing
DMA and toluene was conducted with 4-chlorotoluene
and morpholine (Fig. 1). Once again the rate of product
formation was significantly faster in the more polar
medium indicating the rate enhancement was not limited
to aryl bromides.
>90% when using 4-bromotoluene. In contrast to previ-
ous studies5 simple acyclic secondary amines were poor
substrates (entry 6) and simple primary amines gave low
to moderate yields of coupled products (entries 4 and
11). Remarkably, for couplings with primary amines
no diarylated material was detected when using
1.5 equiv of amine. In the case of morpholine and 4-
bromoanisole (entry 8) the reaction occurred within
1 h using 2.5 mol% of 1. The yield of the product from
the coupling of morpholine and 2-bromoanisole, a steri-
cally and electronically demanding aryl bromide, oc-
curred in only 11% yield. However, both aniline and
2,6-dimethylaniline underwent coupling with 2-bromo-
anisole smoothly giving >80% conversion and good iso-
lated yields (entries 10 and 12).
In a few cases (entries 1, 4, 6, 8, and 11) the isolated
yields via reverse-phase purification were unexpectedly
low due to poor retention characteristics for those par-
ticular low molecular weight compounds.18 In these
instances the reactions were repeated on a 1 mmol scale
and the product was purified on silica gel by flash
chromatography.
In addition to K3PO4, Cs2CO3 is also effective as a base;
however, Cs2CO3 tended to generate heterogeneous
solutions that were more difficult to filter prior to re-
verse-phase purification. Attempts to use either biphasic
or monophasic aqueous DMF with carbonate or phos-
phate solutions proved ineffective and tended to gener-
ate arene. The use of [HP(t-Bu)3][BF4]16 in
combination with either Pd(OAc)2, PdCl2, or Pd2dba3
in the place of 1 gave comparable yields of (4-
methylphenyl)morpholine.
The use of K3PO4 in arene or ether solvents has previ-
ously been shown to permit base-sensitive functionality
to be tolerant in the amination reaction;5,19 despite this
advance in substrate scope carboxyl groups and amides
have until recently remained problematic.20 By using 1
and K3PO4 in DMA in the coupling reaction of
4-amino-acetanilide with 4-bromotoluene (entry 7,
Table 1) product was obtained in 58% isolated yield.
Table 1 summarizes the results from reactions using a
variety of aryl bromide substrates under our optimized
conditions, which consisted of 2.5 mol% of 1 as catalyst,
K3PO4 as base, and DMA as solvent.17 The examples
shown were performed in parallel. The crude reactions
were simply filtered using a nylon or glass frit and the
resulting eluent purified directly by reverse-phase chro-
matography. A number of trends in Table 1 with regard
to substrate scope are similar to those reported for this
catalyst using toluene and NaO-tBu.5 For example, ani-
lines and cyclic secondary amines were among the more
effective amine substrate partners and gave conversions
Table 2 summarizes examples which contain additional
functionality and polarity. In addition to the secondary
amide as exemplified in Table 1, carbamate (entry 1),
ester (entries 2–7), and carboxylate functionalities (entry
5) are tolerant to these conditions and give isolated
products in yields ranging from 35% to 62%. Interest-
ingly, the use of a primary alkyl amine bearing a b-t-
butylester (entry 3) was moderately effective in the cou-
pling with p-bromobenzonitrile21 to give, in 57% iso-
lated yield, the N-arylated product, which is
a
useful intermediate toward the synthesis of N-arylated
b-lactams.
100
80
60
40
20
0
A variety of activated heteroaromatic halides were evalu-
ated and found to generate products with varying lev-
els of success. For example, 2,6-dichloropyridine (entry
4) coupled with 3-ethoxycarboxyl-piperidine to give
pure product in 55% isolated yield. Reaction with 2-
chloropyrazine (entry 7) gave a low yield of isolated
product. Lastly, unprotected 6-bromopurine (entry 6),
when exposed to the polar amination conditions gave
coupled product in moderate isolated yield.
The rate enhancement in a polar medium using a weak
base led us to propose that perhaps other cross-cou-
plings conducive to a polar medium might permit a
selective tandem amination–cross-coupling. Such a pro-
cess would offer an efficient means to access modular
compounds using a single catalyst in a one pot fashion.
Preliminary efforts toward utilizing the differential aryl
0
5
10
15
20
Time (h)
Figure 1. Comparison of DMA (red) versus toluene (blue) as solvent
in the coupling of 4-bromoanisole and morpholine (80 °C, m) and
4-chlorotoluene and morpholine (100 °C, d): 2.5 mol% 1, 2 equiv
K3PO4, 1.0 M substrate concentration.

S. R. Stauffer, M. A. Steinbeiser / Tetrahedron Letters 46 (2005) 2571–2575
Table 1. Amination of aryl bromides using 1 and polar mediaa
2573
Pd[P(t-Bu)3]2
ArX
ArNRR'
NHRR'
1.5 eq.
2 eq K3PO4
DMA
1.0 eq
100 oC, 16-24h
Entry
1
Aryl bromide
Amine
Product
Yield (% )
67b
Br
Me
O
NH
O
N
Me
2
3
4
PhNH2
68
PhHN
Me
PhNHMe
59
PhMeN
Me
n-OctylNH2
36b
(n-Octyl)HN
Me
Me
Me
H
NH2
N
Me
5
70
Me
Me
6
7
(n-Bu)2NH
28b
58
(n-Bu)2N
Me
NH2
O
H
N
Me
Ar
N
H
8
95b
11
MeO
Br
O
O
NH
NH
O
O
N
OMe
Br
N
9
OMe
MeO
PhHN
MeO
10
11
12
PhNH2
55
(n-Octyl)HN
MeO
n-OctylNH2
63b
73
Me
Me
H
N
NH2
OMe
Me
Me
a Performed at 2.5 mol% 1, see Ref. 17 for further details. Isolated yields average of two runs; products >95% pure as judged by 1H NMR
spectroscopy and HPLC.
b Performed on 1.0 mmol scale and purified by SiO2 chromatography.
halide reactivity in a one-pot tandem amination–Suzuki
cross-coupling using 1-bromo-3-chlorobenzene were
successful giving the meta substituted biphenyl 2 in
30% isolated yield after RP-HPLC (Scheme 1). Upon
completion of the initial amination step as evident
by LC–MS, boronic acid was added and the reaction
continued until disappearance of the intermediary
product.22
Mechanistically we suggest the observed rate enhance-
ment could perhaps involve solvent coordination at
events early in the catalytic cycle leading to an increased

2574
S. R. Stauffer, M. A. Steinbeiser / Tetrahedron Letters 46 (2005) 2571–2575
Table 2. Amination of functionalized substrates using 1a,17
Pd[P(t-Bu)3]2
ArX
ArNRR'
NHRR'
1.5 eq.
2 eq K3PO4
DMA
1.0 eq
100 oC, 16-24h
Entry
1
Aryl bromide
Amine
Product
Yield (%)
50
NC
Br
BocN
NH
BocN
N
CN
NH
N
CN
2
3
62
57
EtO2C
EtO2C
NH2
HN
N
CN
t-BuO2C
t-BuO2C
NH
4
5
55
35
N
N
Cl
N
Cl
EtO2C
EtO2C
EtO2C
Cl
CO2H
CO2H
N
Cl
N
N
Cl
Cl
Br
N
NH
N
N
6
7
55
35
N
N
N
N
H
N
EtO2C
EtO2C
N
N
N
N
Cl
a Isolated yields average of two runs; products >95% pure as judged by 1H NMR spectroscopy and HPLC.
O
X
L
Pd
L
R'RN
Y
Y
Br
N
1) Pd[P(t-Bu)3]2 (1)
L
Pd
L
Pd
S
+
O
NH
2 eq K3PO4
DMA, 100 oC, 16h
2) p-CH3C6H4B(OH)2
20h
3a
3b
Cl
2 (30%)
Ar
NRR'
Ar
L
S
LPd
Pd
Scheme 1. One-pot tandem amination–Suzuki coupling.
X
6
4
X-
concentration of either the active catalyst 3a, or a sol-
vent coordinated complex 3b, both of which could par-
ticipate in the subsequent oxidative addition step (Fig.
2). This proposal is consistent with studies involving
P(t-Bu)3 as a supporting ligand5,23–25 which have dem-
onstrated that factors, such as pre-catalyst source and
ligand stoichiometry, can significantly alter the reaction
rate by effecting the concentration of the active palla-
dium-mono-phosphane adduct. Additionally, the ob-
served rate increase could be related to a Ôbase effectÕ,
which has recently been suggested for a BINAP–toluene
Ar
NHRR'
L
S
Pd
KX
Base
5
Figure 2. Potential pathways for amination in polar medium.
system studied by Maes and co-workers26 and Dom-
misse and co-workers.14 These studies imply that the sol-
vent is enhancing or increasing a proposed interphase
pathway via the generation of 6. This later proposal is

S. R. Stauffer, M. A. Steinbeiser / Tetrahedron Letters 46 (2005) 2571–2575
2575
7. Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999,
38, 2413.
also consistent with the observation that finely ground
K3PO4 gives better yields than unground phosphate.
8. Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.;
Hartwig, J. F. Org. Lett. 2000, 2, 1423.
9. Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1,
1307.
10. Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
6653.
11. Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
8704.
12. Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett.
2002, 4, 2885.
13. Kuwano, R.; Utsunomiya, M.; Hartwig, J. F. J. Org.
Chem. 2002, 67, 6479.
`
14. Jonkers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.;
Dommisse, R. Tetrahedron 2001, 57, 7027.
15. Stauffer, S. R.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
6977.
In summary, we have developed a mild and convenient
method for the synthesis of functionalized amines using
a polar medium which allows products to be purified in
a rapid fashion using reverse-phase chromatography. In
addition, the polar amination conditions demonstrate
the potential for a novel tandem amination–Suzuki
cross-coupling. The relative enhancement in catalyst
activity for 1 by simply modifying the medium is signif-
icant from the standpoint of implications for future
high-throughput catalysis screening efforts and our cur-
rent understanding of existing protocols and substrate
scope for other cross-couplings utilizing 1. Applications
of these modified conditions toward other such pro-
cesses in addition to the use of microwave technology
as a means to shorten reaction times and expand sub-
strate scope are currently under investigation.
16. Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
17. Representative procedure: A screw cap vial was charged
with aryl halide (0.25 mmol), amine (0.38 mmol), Pd[P(t-
Bu)3]2 (0.01 mmol) and K3PO4 (0.50 mmol). The vial was
sealed with a Teflon-lined enclosure, put under an argon
atmosphere and 0.3 mL degassed DMA added via syringe.
The vial was vortexed briefly and placed in a pre-heated
100 °C oil bath. After stirring overnight the reaction was
Acknowledgements
We thank Joan Murphy for high resolution mass deter-
minations and Dr. Neil Beare and Dr. Christopher Krug
for useful discussions.
diluted with DMF, filtered through
a 0.45 lm frit
and purified by direct RP-HPLC using a C18 YMC
column.
18. In general when using automated reverse-phase purifica-
tion an average 10% loss of mass is observed due to
incomplete transfer during injection and inter-tube diver-
sion to waste during collection.
19. Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1998, 120, 9722.
20. BuchwaldÕs group has shown such substrates can be
competent in the amination reaction, however either t-
BuOH or THF was employed as solvent. See Refs. 10 and
12, respectively.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.02.095.
References and notes
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Combs, A. P. Tetrahedron Lett. 2003, 44, 1691.
22. Microwave-assisted conditions have recently been found
to give 2 in <10 min in comparable yield.
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