Room-temperature palladium-catalyzed coupling of heteroaryl amines with aryl or heteroaryl bromides

Article abstract of DOI:10.1055/s-0031-1290069

Heteroaryl amines readily undergo Buchwald-Hartwig amination reactions with a range of aryl and heteroaryl bromides at room temperature using t-BuXPhos Pd-precatalyst and NaOt-Bu. The pharmaceutically attractive biaryl amines are generally formed in short reaction times (0.5-16 h) and in good to excellent yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0031-1290069

LETTER
285
Room-Temperature Palladium-Catalyzed Coupling of Heteroaryl Amines
with Aryl or Heteroaryl Bromides
B
uchwald–Hart
h
w
ig Aminati
o
on Reactions
m
of
H
eteroaryl
A
mi
a
s
s A. Moss,* Matthew S. Addie, Thorsten Nowak, Michael J. Waring
AstraZeneca, Mereside, Alderley Park, Cheshire, SK10 4TG, UK
E-mail: thomas.moss@astrazeneca.com
Received 6 October 2011
tion of active catalyst due to the coordinating dba ligands,
and Pd(OAc)2 requires in situ reduction to Pd(0).7 As ox-
idative addition has been shown to occur at temperatures
as low as –40 °C, employing a readily activated precata-
lyst potentially allows cross-coupling reactions to take
place at low temperature.3f,8
Abstract: Heteroaryl amines readily undergo Buchwald–Hartwig
amination reactions with a range of aryl and heteroaryl bromides at
room temperature using t-BuXPhos Pd-precatalyst and NaOt-Bu.
The pharmaceutically attractive biaryl amines are generally formed
in short reaction times (0.5–16 h) and in good to excellent yields.
Key words: amination, biaryl amine, coupling, heteroaryl amine,
palladium
The incorporation of heterocyclic ring systems into organ-
ic molecules is of particular interest in medicinal chemis-
try. Five-membered amino heterocycles, such as pyrazole,
imidazole, oxazole and isoxazole, are particularly desir-
able substructures in molecular design due to their low
lipophilicity, metabolic susceptibility and their defined ar-
rangement of hydrogen bonding elements. Examples of
this include ATP competitive kinase inhibitors where
these functionalities present an essential molecular recog-
nition element.9 Hence we were interested in developing a
methodology that would allow facile incorporation of
such substituents via an amination strategy.
The palladium-catalyzed amination of aryl and heteroaryl
halides has quickly emerged as a valuable tool in the syn-
thesis of natural products and pharmaceuticals.1 Since the
pioneering studies by Buchwald and Hartwig,2 this pro-
cess has attracted widespread interest from both academic
and industrial groups, with significant improvements in
substrate scope being realised in recent years.3 Despite
these advancements, the coupling of heteroaryl amines
with aryl and heteroaryl halides remains problematic, of-
ten requiring long reaction times and considerable tailor-
ing of reaction conditions.4 One notable exception was
reported by Schulte, where several electron-deficient het-
eroaryl amines were coupled with aryl and heteroaryl ha-
lides using a Pd2(dba)3/xantphos catalyst system with
sodium phenolate as base under thermal or microwave
irradiation.5 In this case, the authors suggested the high
solubility of sodium phenolate in 1,4-dioxane was respon-
sible for the rate acceleration and functional group toler-
ance observed.
Table 1 Optimisation of Conditions for the C–N Coupling of 3-
Methyl-5-aminopyrazole with Bromobenzenea
H
NH2
N
+
N
NH
N NH
Br
2
Entry
Base
Solvent
dioxane
dioxane
dioxane
dioxane
dioxane
DMA
Conditions
Yield (%)b
69
1
2
3
4
5
6
7
NaOt-Bu
NaOt-Bu
NaOt-Bu
Cs2CO3
r.t., 24 hc
r.t., 2 h
(10) n.d.
(50) 28
(80) 59
(<10) n.d.
(50) n.d.
96
90 °C, 3 h
90 °C, 3 h
r.t., 2 h
LPd(0)
NaOt-Bu
+
r.t., 2–3 min
LPd
Cl
LPd
N
LiHMDS
NaOt-Bu
NaOt-Bu
NH2
H
1
N
H
r.t., 3 h
L = t-Bu-XPhos
t-BuOH
r.t., 4 h
Scheme 1 Readily activated palladium precatalysts
a Reaction conditions: 1.5-mmol scale, amine (1 equiv), bromoben-
zene (1.25 equiv), base (2.1 equiv), t-BuXPhos precatalyst 1 (0.5
mol%), solvent (5 mL).
One important advancement in Pd-catalyzed amination is
the development of readily activated phosphine precata-
lysts, which allow the monoligated Pd(0) species to be
formed at or below room temperature (Scheme 1).6 This
has advantages over traditional catalyst systems;
b Isolated yields. Values in parentheses refer to1H NMR conversion.
c A higher amount of the catalyst (5 mol%) was used.
Pd2(dba)3, a stable source of Pd(0), can retard the forma- To establish the ideal reaction conditions, an initial study
was conducted with 3-methyl-5-aminopyrazole (2) and
bromobenzene. We chose t-BuXPhos precatalyst 1 as the
Pd source, as it is known to be a particularly effective cat-
alyst in weakly nucleophilic heteroaryl systems.4 Further-
SYNLETT 2012, 23, 285–289
Advanced online publication: 04.01.2012
DOI: 10.1055/s-0031-1290069; Art ID: D52511ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

286
T. A. Moss et al.
LETTER
more, by judicious choice of base, the precatalysts can Table 2 Room-Temperature Coupling of 3-Methyl-5-aminopyra-
zole (2) with Aryl and Heteroaryl Halides with t-BuXPhos Precatalyst
readily form the active Pd(0) species at or below room
temperature, allowing C–N coupling reactions to be per-
1a
H
formed under milder conditions and at lower catalyst
NH2
N
Ar
loadings than under typical coupling conditions (Table 1).
Using NaOt-Bu as base in 1,4-dioxane, the reaction pro-
ceeded smoothly at 5 mol% catalyst loading, affording the
Ar-Br
+
N
NH
N
NH
2
biaryl amine in a 69% isolated yield (entry 1). The aryla- Entry Aryl halide
Time Product
(h)
Yield
(%)b
tion was completely selective for the exocyclic amine; no
1
arylation of the N(H) heterocycle was observed by H
H
N
NMR, which is consistent with literature findings for the
Pd-catalyzed amination of amino pyrazoles.4 Unfortu-
nately, on lowering the catalyst loading to a more practical
0.5 mol%, the product was only observed in trace amounts
after two hours at room temperature (entry 2). During the
course of the reaction significant amounts of solids pre-
cipitated from the initially homogenous mixture, which
we hypothesized may have been the sodium salt of the
pyrazole starting material. In an attempt to improve solu-
bility, the reaction was conducted at 90 °C (entry 3), giv-
ing the product in a slightly improved 28% yield after
three hours. Switching the base to the milder Cs2CO3 (en-
try 4), gave a marked improvement in yield following stir-
ring at 90 °C for three hours, but the conversion was still
at an unacceptable level. LiHMDS has been used as base
in cases where an acidic proton is present in the starting
materials,4a,10 however in our hands this gave a complex
mixture of products (entry 5). Pleasingly, employing more
polar solvent mixtures led to improved reactivity; t-BuOH
giving the product in near quantitative yield following
stirring at room temperature for four hours (entry 7). For
direct comparison, the reaction was conducted under the
same conditions using Pd2(dba)3 as the catalyst with t-
BuXPhos as the ligand, giving only trace amounts of
product (<5%) after four hours at room temperature.
1c
2
3
4
5
6
7
8
9
4
96
HN
N
Br
Br
Cl
Br
Br
H
N
4
88
89
HN
HN
HN
N
N
N
N
N
N
H
N
6
N
H
N
4
88
N
N
N
H
N
6
57
HN
N
N
H
N
Cl
N
2
93
HN
N
Br
Cl
H
N
6
0
HN
HN
N
N
N
N
N
N
Br
H
N
N
4
(92) 70
61
N
We next evaluated a range of aryl bromides in order to as-
sess the generality of the reaction (Table 2). Heteroaryl
halides which can coordinate with the Pd species are
known to be difficult coupling partners, and thus have at-
tracted particular attention in the literature,11 particularly
in light of their prevalence in natural products and phar-
maceutical agents. Pleasingly, using our optimal condi- 10
tions as an initial start point, 3-methyl-5-aminopyrazole
(2) was successfully coupled with a range of heteroaryl
bromides including pyridines, pyrimidines, pyrazine and
pyridazines at room temperature in moderate to high
yields. In these cases, the catalyst loading was increased
to 1 mol% and an additional 1 mol% of the t-BuXPhos
ligand was added to ensure stability of the catalyst in so-
lution. 2-, 3- and 4-Bromopyridine (entries 2, 4 and 5)
were all readily coupled in moderate to good yields and in
relatively short reaction times. Aryl and heteroaryl chlo-
rides are generally more accessible than their bromo ana-
logues, thus we were pleased to find that 2-chloropyridine
reacted in a comparable time and in similar yield to 2-bro-
mopyridine (entry 3), demonstrating that these conditions
are not limited only to aryl bromides. 4-Chlorobromoben-
zene (entry 6) reacted smoothly and chemoselectively at
Br
Br
Br
N
H
N
N
N
N
N
6
HN
HN
N
N
N
N
H
N
N
6
74
N
N
N
N
H
N
N
N
11
16
6
(75) 48
0
N
HN
HN
N
N
Br
Br
H
N
12d
N
N
a Reaction conditions: 1.5-mmol scale, amine (1 equiv), aryl halide
(1.25 equiv), NaOt-Bu (2.1 equiv), t-BuXPhos precatalyst 1 (1
mol%), t-BuXPhos ligand (1 mol%), t-BuOH (5 mL), r.t.
b Isolated yields. Values in parentheses refer to the 1H NMR conver-
sion.
c A lower amount of the precatalyst (0.5 mol%) was used, without
additional ligand. Refer to Table 1 (entry 7) for details.
d 4-Bromopyridazine hydrobromide was used, with base (3.1 equiv).
Synlett 2012, 23, 285–289
© Thieme Stuttgart · New York

LETTER
Buchwald–Hartwig Amination Reactions of Heteroaryl Amines
287
the bromo position to give a single product in a 93% yield, We then turned our attention to the amine component
with no discernible amounts of dimer being observed. Un- (Table 3). Using our optimal conditions, a range of both
der the reaction conditions, bromopyrimidines (entries 7– unprotected and (N-)protected heteroaryl amines includ-
9) were slightly less reactive than their pyridine ana- ing pyrazoles, imidazoles, triazoles and isoxazoles were
logues, with 2-bromopyrimidine (entry 9) in particular evaluated with both aryl and heteroaryl bromides. In gen-
only giving a moderate 61% yield of the desired product. eral the reaction performed well on both unprotected (en-
4-Bromopyrimidine failed to give any observable product tries 1–6 and 10) and N-protected (entries 7–9 and 11–13)
(entry 7). Further evaluation of the literature revealed that heterocycles, indicating that additional protection of N(H)
very few successful Buchwald–Hartwig aminations have endocyclic amines is not necessary for reactivity, or to
been performed on 4-halopyrimidines compared to their avoid undesired heterocycle arylation. In almost all cases
2- and 5-analogues.12 Pyrazine could also be coupled effi- the biaryl amines were formed in good yield and in short
ciently (entry 10), however 3- and 4-bromopyridazines reaction times (0.5–6 h) at room temperature, the excep-
(entries 11 and 12) were somewhat problematic coupling tion being the 3-amino-1,2,4-triazole (entry 10), which re-
partners due to the instability of halopyridazines;13 only 3- quired heating to 90 °C for seven hours to achieve a 40%
bromopyridazine (entry 11) gave any observable product. conversion to the product.
Table 3 Coupling of Various Protected and Unprotected Heteroaryl Amines with Aryl and Heteroaryl Bromidesa
Entry
Amine
Aryl bromide
Time (h)
Product
Yield (%)b
92
H
N
H2N
1
4
HN
HN
HN
N
N
N
HN
N
N
N
Br
H
N
H2N
H2N
2
3
4
5
6
4
6
4
4
6
82
70
74
79
74
HN
HN
N
N
Br
H
N
N
Br
Br
Br
Br
N
H
N
H2N
H2N
NH
NH
N
N
H
N
NH
NH
N
N
N
N
H
N
H2N
H2N
NH
NH
N
N
N
N
N
N
H
N
N
N
7
8
4
83
80
N
N
N
N
Br
Br
Me
H2N
Me
H
N
16
N
N
Me
H2N
Me
H
N
N
N
N
N
9
16
7c
97
N
N
N
Br
Br
N
Me
H2N
Me
H
N
N
N
10
(40) 34
HN
HN
© Thieme Stuttgart · New York
Synlett 2012, 23, 285–289

288
T. A. Moss et al.
LETTER
Table 3 Coupling of Various Protected and Unprotected Heteroaryl Amines with Aryl and Heteroaryl Bromidesa (continued)
Entry
11
Amine
Aryl bromide
Time (h)
0.5
Product
Yield (%)b
93
H
N
Me
Me
N
H2N
Me
Me
N
Br
N
N
N
N
N
H
N
12
13
1
93
77
N
H2N
N
N
N
Br
Br
N
N
N
H
2
N
Me
N
H2N
H2N
Me
N
N
N
N
N
N
N
N
H
N
14
15
2
4
97
O
O
N
N
O
O
Br
Br
H
N
H2N
(75) 65
N
N
N
a Reaction conditions: 1.5-mmol scale, amine (1 equiv), aryl bromide (1.25 equiv), NaOt-Bu (2.1 equiv), t-BuXPhos precatalyst 1 (1 mol%),
t-BuXPhos ligand (1 mol%), t-BuOH (5 mL), r.t.
b Isolated yields. Values in parentheses refer to 1H NMR conversion.
c Reaction was performed at 90 °C.
(4) (a) Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R.
A.; Buchwald, S. L. Angew. Chem. Int. Ed. 2006, 45, 6523.
(b) Tundel, R. E.; Anderson, K. W.; Buchwald, S. L. J. Org.
Chem. 2006, 71, 430. (c) Usui, S.; Suzuki, T.; Hattori, Y.;
Etoh, K.; Fujieda, H.; Nishizuka, M.; Imagawa, M.;
Nakagawa, H.; Kohda, K.; Miyata, N. Bioorg. Med. Chem.
Lett. 2005, 15, 1547. (d) Byth, K. F.; Culshaw, J. D.; Green,
S.; Oakes, S. E.; Thomas, A. P. Bioorg. Med. Chem. Lett.
2004, 14, 2245.
(5) Schulte, J. P.; Tweedie, S. R. Synlett 2007, 2331.
(6) (a) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 6686. (b) Kinzel, T.; Zhang, Y.; Buchwald,
S. L. J. Am. Chem. Soc. 2010, 132, 14073.
In conclusion, we have developed a general set of condi-
tions which allows five-membered heteroaryl amines to
be coupled at room temperature to aryl and heteroaryl bro-
mides and chlorides.14 The transformation generally pro-
ceeds in relatively short reaction times and in good yields,
giving a diverse range of pharmaceutically attractive biar-
yl amines. The use of t-BuXPhos precatalyst 1 allows this
challenging coupling reaction to proceed at much lower
temperatures than normally possible for heteroaryl
amines and without the requirement for protection of the
heterocyclic NH, making this method attractive in future
medicinal chemistry campaigns.
(7) Buchwald has described a system for preactivating
Pd(OAc)2/X-Phos systems in water, see: Fors, B. P.;
Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008,
10, 3505.
References and Notes
(8) (a) Aryl iodides have been shown to undergo Kumada–
Corriu cross-coupling reactions with Grignard reagents at
–20 °C: Martin, R.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3844. (b) Benzophenone imine has been used as an
ammonia surrogate in Buchwald–Hartwig aminations:
Bhagwanth, S.; Adjabeng, G. M.; Hornberger, K. R.
Tetrahedron Lett. 2009, 50, 1582.
(9) (a) Bikker, J. A.; Brooijmans, N.; Wissner, A.; Mansour, T.
S. J. Med. Chem. 2009, 52, 1493. (b) Quintas-Cardama, A.;
Kantarjian, H.; Cortes, J. Nat. Rev. Drug Discovery 2007, 6,
834.
(1) (a) Torborg, C.; Beller, M. Adv. Synth. Catal. 2009, 351,
3027. (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L.
Chem. Rev. 2003, 103, 893.
(2) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1348. (b) Louie, J.; Hartwig,
J. F. Tetrahedron Lett. 1995, 36, 3609.
(3) (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27.
(b) Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.;
Buchwald, S. L. Chem. Sci. 2011, 2, 57. (c) Hartwig, J. F.
Acc. Chem. Res. 2008, 41, 1534. (d) Marion, N.; Nolan, S.
P. Acc. Chem. Res. 2008, 41, 1440. (e) Shen, Q.; Ogata, T.;
Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586.
(f) Marion, N.; Navarro, O.; Mei, J. G.; Stevens, E. D.; Scott,
N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101.
(10) Henderson, J. L.; Buchwald, S. L. Org. Lett. 2010, 12, 4442.
(11) (a) Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc.
2008, 130, 6586. (b) Shen, Q. L.; Shekhar, S.; Stambuli,
Synlett 2012, 23, 285–289
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LETTER
Buchwald–Hartwig Amination Reactions of Heteroaryl Amines
289
J. P.; Hartwig, J. F. Angew. Chem. Int. Ed. 2005, 44, 1371.
(c) Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995,
14, 3030.
2-bromopyridine (1.88 mmol, 296 mg) were added via
syringe and the reaction was stirred at r.t. for 4 h. The solvent
was removed then H2O, sat. aq NH4Cl and EtOAc were
added. The layers were separated and the aqueous layer was
extracted with EtOAc (3 ×). The combined organics were
dried over Na2SO4 and concentrated. The residue was
purified by silica gel chromatography (EtOAc–MeOH, 9:1)
to give the biaryl amine as a white solid (229.5 mg, 88%);
mp 177–179 °C. IR: 3521 (br), 2995 (m), 1525 (s), 1503 (m),
1495 (m), 1420 (s), 1281 (m) cm–1. 1H NMR (400 MHz,
DMSO-d6): d = 2.19 (s, 3 H, Me), 6.04 (s, 1 H, CHpyrazole),
6.68 (m, 1 H, CHAr), 7.22 (m, 1 H, CHAr), 7.52 (dd, 1 H, J =
7.2, 7.0 Hz, CHAr), 8.09 (d, 1 H, J = 4.1 Hz, CHAr), 9.00 (s,
1 H, NH), 11.73 (s, 1 H, NH). 13C NMR (100 MHz, DMSO-
d6): d = 10.95, 94.12, 109.22, 113.60, 137.12, 138.87,
147.40, 149.06, 155.39. MS (ES): m/z (%) = 175 [M +
H]+(100), 158 (100), 134 (80), 107 (25). HRMS: m/z [M +
H]+ calcd for C9H11N4: 175.09782; found: 175.09778.
(12) (a) Lippa, B.; Morris, J.; Corbett, M.; Kwan, T. A.; Noe,
M. C.; Snow, S. L.; Gant, T. G.; Mangiaracina, M.; Coffey,
H. A.; Foster, B.; Knauth, E. A.; Wessel, M. D. Bioorg. Med.
Chem. Lett. 2006, 16, 3444. (b) Park, S.-E.; Kang, S. B.;
Jung, K.-J.; Won, J.-E.; Lee, S.-G.; Yoon, Y.-J. Synthesis
2009, 815.
(13) Evans, R. C.; Wiselogle, F. Y. J. Am. Chem. Soc. 1944, 67,
60.
(14) Representative General Procedure; Coupling of
Pyrazole 2 and 2-Bromopyridine: 3-Methylpyrazol-
5-amine (2; 1.50 mmol, 146 mg), t-BuXPhos Pd(II)
phenethylamine chloride 1 (0.015 mmol, 10.3 mg), t-
BuXPhos (0.015 mmol, 6.4 mg) and NaOt-Bu (3.15 mmol,
303 mg) were charged into a round-bottom flask which was
evacuated and back-filled with nitrogen (3 ×), then purged
with a stream of nitrogen for 10 min. t-BuOH (5 mL) and
© Thieme Stuttgart · New York
Synlett 2012, 23, 285–289

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