Monodentate phosphines provide highly active catalysts for Pd-catalyzed C-N bond-forming reactions of heteroaromatic halides/amines and (H)N-heterocycles

Article abstract of DOI:10.1002/anie.200601612

(Chemical Equation Presented) A good alternative: Highly reactive catalysts based on palladium and dialkylbiarylphosphino ligands provide unprecedented reactivity and selectivity in C-N bond-forming processes. The bulky monophosphine catalyst system Pd/1 was effective for the reaction of aryl/heteroaryl halides bearing primary amides and 2-aminoheterocycles (see scheme; dba = dibenzylideneacetone, R = CONH₂, NH₂), thus showing that monodentate phosphines are viable alternatives to, and sometimes superior to, chelating ligands.

Full text of DOI:10.1002/anie.200601612

Angewandte
Chemie
[
4]
[1b,3]
catalyzed carbon–carbon, carbon–nitrogen,
oxygen
and carbon–
[
1b,5]
bond-forming reactions. Our previous studies
indicated that a catalyst system based on Pd/2-dicyclohex-
ylphosphino-2’,4’,6’-triisopropylbiphenyl (XPhos; 1; Cy = cy-
clohexyl)demonstrated both a greater degree of activity and
stability than those derived from our previous generations of
[
6]
Amination
ligands. The substitution of the 2’,2’-positions on the lower
[
7]
aromatic ring prevents palladacycle formation, and the
added bulk causes the equilibrium to shift from that favoring
L Pd ] to one in which [L Pd ] predominates, thus facilitating
2 1
DOI: 10.1002/anie.200601612
0
0
[
Monodentate Phosphines Provide Highly Active
[7–10]
all steps in the catalytic cycle.
Catalysts for Pd-Catalyzed CÀN Bond-Forming
Recently, a long-lived catalyst based on the combination
of a Pd precatalyst and bidentate Josiphos-type ligand 2 was
shown to provide good results for the coupling of highly
functionalized aryl/heteroaryl chlorides and primary
Reactions of Heteroaromatic Halides/Amines and
(
H)N-Heterocycles**
[
11]
amines. It was postulated that the high reactivity of the
system was, to a significant extent, as a result of the tight
chelation of 2 to the Pd center, thus decreasing the chance for
the binding of a heterocycle or basic amine, which may
facilitate the loss of the ligand or otherwise deactivate the
catalyst. Although this is an extremely reasonable supposi-
tion, we wondered whether, in fact, the use of chelating
ligands was necessary for successful reactions with substrates
of this type. Herein, we report our results which indicate that
monodentate phosphines are viable alternatives to and are
sometimes superior to chelating ligands in Pd-catalyzed CÀN
Kevin W. Anderson, Rachel E. Tundel, Takashi Ikawa,
Ryan A. Altman, and Stephen L. Buchwald*
Despite advances in the scope of palladium-catalyzed CÀN
bond-forming reactions through the development of more
[
1,2]
active catalysts, limitations to the method still remain: 1)In
many cases the coupling of substituted heteroaryl halides with
amines is still problematic; 2)the N-arylation reactions of
nitrogen heterocycles is limited in scope with respect to both
coupling partners; 3)chemoselectivity in C ÀN bond-forming
processes has not been explored in great detail.
bond-forming processes.
Palladium catalysts based on dialkylphosphinobiaryl
We first explored the coupling of 4-chlorophenol and n-
hexylamine (Table 1). Ligand 1 proved to be ineffective for
this reaction, with its use resulting in incomplete conversion
and lower yields as a result of diarylation (Table 1, entries 1
and 2). Interestingly, we found that the combination of 3 as
[
1b,3]
ligands
have not only been shown to display high stability,
but also have manifested increased reactivity in palladium-
[
*] K. W. Anderson, R. E. Tundel, T. Ikawa, R. A. Altman,
Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18–490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
[
12]
the ligand and lithium hexamethyldisilazide (LiHMDS) as
the base was the most effective for this transformation at
5
08C, thus providing the product in 94% yield in 2 h (Table 1,
entry 6). This system is also proficient at room temperature,
as the aryl amine is provided in 94% yield, although the
reaction required 46 h to go to completion (Table 1, entry 4).
While Josiphos-type ligand 2 was reported to perform well at
1008C for a similar transformation, its efficiency was far less
than 3 at 408C (Table 1, compare entry 3 vs entry 5).
Fax: (+1)617-253-3297
E-mail: sbuchwal@mit.edu
[
**] We thank the National Institutes of Health (GM 58160) and the
National Cancer Institute (Cancer Training Grant GM 5-T32-
CAO9112-30) for support of this work. R.E.T. would like to thank
Pfizer for a SURF fellowship and MIT (UROP) for financial support.
T.I. thanks the Uehara Memorial Foundation for a fellowship. We are
We previously disclosed that a catalyst system comprised
of a Pd precatalyst and 1 displayed excellent chemoselectivity
grateful to Merck, Amgen, and Engelhard (Pd(OAc) ) for additional
2
support. The Bruker Advance 400 MHz instrument used in this
study was purchased with funding from the National Institutes of
Health (GM 1S10RR13886-01), and the Varian 300 and 500 MHz
instruments were purchased with funding from the National
Science Foundation (CHE 9808061 and DBI 9729592).
for reaction at an aniline NH group over that of a primary
2
[
6a]
amide.
We have found that use of [Pd (dba) ]/1 (dba =
2 3
dibenzylideneacetone)and LiHMDS allows the reaction of
aliphatic primary and cyclic secondary amines with a sub-
strate containing a primary amide (3-chlorobenzamide),
which has been problematic with previous catalyst systems
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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II
Table 1: Ligands used for the coupling of 4-chlorophenol and n-hexyl- a bidentate ligand would prevent any coordination to a Pd
amine.
species of the “guanidine-like” moiety of these substrates.
Thus, the discovery that a catalyst comprised of [Pd (dba) ]
2
3
and 3 was effective in the N-arylation of 2-aminopyridine was
somewhat surprising. We explored the use of Pd/3 for a
[
15]
[
a]
diverse array of reaction combinations. Substrates bearing
Entry Ligand Base
Solvent T [8C] t [h] Conv. [%] Yield [%]
a free hydroxy and indole ÀNH group react well with 2-
[
b]
1
2
3
4
5
6
7
1
1
2
3
3
3
3
LiN(TMS)2 THF
NaOtBu toluene 100
40
24
24
24
84
44
17
31
15
2
aminopyridine and 2-aminopyrimidine, respectively, provid-
ing 92 and 57% of the resultant diaryl amines (Table 3). In
accord with the previous results, reaction at the heteroar-
[
b]
[
c]
[b]
LiN(TMS)2 THF
LiN(TMS)2 THF
LiN(TMS)2 THF
LiN(TMS)2 toluene 50
NaOtBu toluene 100
40
RT 46
>99
>99
>99
>99
94
94
94
89
omatic ÀNH group prevails over that at a primary amide and
40
24
2
2
provides 94% yield in the coupling of 5-bromonicotinamide
[
15]
24
and 2-aminopyridine.
[a] Yield of the isolated product. [b] Yield determined by GC analysis.
[
1
c] Reagents and condition: ligand 2, octylamine, LiN(TMS) , 1,4-dioxane,
008C; yield=72%. TMS=trimethylsilyl.
2
[
11]
Table 3: Palladium-catalyzed N-arylation of aminoheterocycles.
[
12]
(
Table 2). 2-Aminohaloheterocycles have previously been
inefficient electrophilic components for CÀN bond-forming
processes with monophosphine ligands. Thus, we examined
the coupling of 2-amino-5-chloropyridine with aniline and
morpholine (with 1)and benzylamine (with 3)and were
pleased to find that these reactions proceeded in good yield.
The use of 2-aminoheterocycles as a nucleophilic compo-
nent had only successfully been accomplished with aryl
Product
X
Yield [%]
92
Cl
Br
Br
94
[
13]
bromides utilizing
a
Pd/XantPhos
or binaphthol
[
14]
(
BINAP) catalyst system. A common belief is that using
[
a]
a]
57
Table 2: Chemoselectivity in Pd-catalyzed amination.
[
Cl
Br
Cl
60
75
74
Product
Yield [%]
[
[
a,b]
a,c]
7
8
9
2
[
b]
[
a] Cs CO and N,N-dimethylformamide used as base and solvent,
2 3
[
d]
8
8
8
1
3
9
respectively. [b] 1,4-Dioxane used as solvent.
Prior work on the N-arylation of indoles and pyrroles
revealed that catalytic systems based on monophosphino-
[
[
d]
d]
[
16]
biaryl ligands were somewhat effective. In contrast, more
acidic heterocycles, such as indazole or pyrazole, have not
been reported to be coupling partners in palladium-based
methods. Given our success with the Pd/3 combination for the
coupling of less basic 2-aminoheterocycles (Table 3), we felt
that it might also be quite effective for the coupling of these
nitrogen heterocycles. Indazole/pyrazole are expected to be
less basic than their indole/pyrrole counterparts,
more bulky phosphine moiety might speed up reductive
elimination from a Pd aryl/amido intermediate.
[
d]
7
7
9
7
[
17]
thus a
[
d,e]
[18]
We first explored the N-arylation of indazole with 3-
bromoanisole using Pd/3 with K PO in 1,4-dioxane at 1008C.
[
a] Previously reported, see Ref. [6a]. [b] K CO in tBuOH, 1008C, 20 h.
3
4
2
3
This system provided 52% conversion and 48% yield (GC)of
the N1-arylated product exclusively; a result which is also
[
2
c] NaOtBu in toluene, 1008C, 18 h. [d] LiN(TMS) in THF, 658C, 16–
4 h. [e] Ligand 3 was used.
2
6
524
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Chemie
observed for the coupling of aryl iodides using Cu-catalysis
3-chloroanisole, 3-chloropyridine, 5-bromonicotinonitrile,
[
19]
methodology.
Optimization of the reaction conditions
and 6-chloroquinoline in respectable yields. Also, 5-nitro-
indazole is effectively treated with 3-bromoanisole and 3-
bromoquinoline, thus providing the N-arylated heterocycles
in 93 and 89% yields, respectively. Further, for the first time,
pyrazole is efficiently combined with an aryl bromide and aryl
chloride using a palladium catalyst.
revealed that use of the bases NaOtBu (toluene, 808C)and
Cs CO (1,4-dioxane, 1058C)provided the N1-arylated inda-
2
3
zole in excellent yields using [Pd (dba) ]/3. Interestingly,
2
3
when NaOtBu is used as the base at 1008C, mixtures of the
N1- and N2-arylated products were observed. One explan-
ation for this result is that I (Scheme 1)is the kinetically
To our knowledge, palladium-catalyzed amination reac-
tions of benzimidazole and/or imidazole
with unactivated aryl halides have not
[
20]
been accomplished.
As is seen in
Table 5, the use of the especially hindered
ligand 4 facilitates CÀN bond-formation of
these weakly basic nitrogen nucleophiles.
Benzimidazole is coupled with 3-bromoqui-
noline and 4-chlorotoluene and provides the
Scheme 1. Hypothesis for chemoselectivity in the N-arylation of indazole.
formed species (binding at the lone pair of electrons on N1
would disrupt the aromaticity, I’) . At 808C (with NaOtBu)or
Table 5: Palladium-catalyzed N-arylation of imidazole and benzimida-
zole.
1
058C with Cs CO , conversion into II occurs faster than
2 3
deprotonation. As is seen in Table 4, indazole is arylated with
Table 4: Palladium-catalyzed N-arylation of indazole and pyrazole.
Product
X
Yield [%]
94
Product
R
X
T [8C]
Yield [%]
Br
H
NO2
Cl
Br
80
80
97
91
Cl
Br
97
H
CN
Cl
Br
80
60
97
62
[
a]
70
[a] With N,N-dimethylaniline used as solvent.
–
Cl
80
99
N-arylated products in 94 and 97% yields, respectively
Table 5). Imidazole is combined with 4-bromotoluene in a
0% yield, thus representing the first known palladium-
catalyzed example of this coupling with an unactivated aryl
bromide. Here the use of 4 may be necessary to facilitate the
(
7
–
–
–
–
Br
Br
Br
Cl
90
60
92
79
88
76
rate of reductive elimination from a [L Pd(Ar)(N-Het)]
1
[
21]
intermediate.
We have also explored the coupling of some amino-
heterocycles and/or pyrazole substrates (Table 6). The results
that we have obtained, in some cases, complement those
previously seen with Cu-catalyzed protocols. The chemo-
80
selectivity of the aniline NH group causes it to react in
2
preference to the indazole ÀNH group, thus providing a 67%
yield in the reaction of 5-aminoindazole with 5-bromo-m-
xylene. We were particularly surprised to find that 5-amino-3-
phenylpyrazole could be selectively arylated at the primary
amino group, which is the first time, to our knowledge, that an
unprotected aminopyrazole has ever reacted with this mode
105
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www.angewandte.org
6525

Communications
Table 6: Interesting chemoselectivity in palladium-catalyzed CÀN bond
Keywords: amination · chemoselectivity · palladium ·
phosphines
.
formation.
[
1] a)J. F. Hartwig in Handbook on Organopalladium Chemistry for
Organic Synthesis (Ed.: E. Negishi), Wiley-Interscience, New
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Product
Yield
%]
Product
Yield
[%]
[
[
7
6
2
7
94
88
3
861; c)S. Harkal, F. Rataboul, A. Zapf, C. Fuhrmann, T.
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1
1
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2
[
[
3] J. P. Wolfe, H. Tomori, J. Yin, J. Sadighi, S. L. Buchwald, J. Org.
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1
871.
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[
[
process. For example, we have previously shown with Cu
catalysts that aminopyrazoles react preferentially at the
pyrazole ÀNH group, thus representing complementarity
2
6] a)X. Huang, K. W. Anderson, D. Zim, L. Jiang, A. Klapars, S. L.
Buchwald, J. Am. Chem. Soc. 2003, 125, 6653; b)E. R. Strieter,
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[
19]
between the Pd- and Cu-based methods. Finally, for the
first time a free (H)N-bromopyrazole can be successfully
aminated, in this case with aniline as shown.
[
[
[
In conclusion, we have developed highly reactive catalysts
based on palladium and dialkylbiarylphosphino ligands,
particularly 1, 3, or 4. These provide unprecedented reactivity
and selectivity in CÀN bond-forming processes. The bulky
5
969; b)J. F. Hartwig, F. Paul, J. Am. Chem. Soc. 1995, 117, 5373.
9] For other studies with aryl chlorides, see: a)M. Portnoy, D.
Milstein, Organometallics 1993, 12, 1665; b)A. F. Littke, G. C.
Fu, Angew. Chem. 2002, 114, 4350; Angew. Chem. Int. Ed. 2002,
41, 4176.
monophosphine catalyst system Pd/1 was effective for the
reaction of aryl/heteroaryl halides bearing primary amides
and 2-aminoheterocycles. Also, the more sterically encum-
bered catalyst systems based on Pd and ligands 3 or 4 were
found to be more proficient for the arylation of 2-amino-
heterocycles and weakly basic HN heterocycles: pyrazoles,
indazole, benzimidazole, and imidazole. The chemoselectivity
of these catalysts was explored and the rough order of
reactivity for amines follows the general trend: aryl amines @
primary and secondary aliphatic amines > 2-aminoheteroar-
omatics > primary amides ꢀ HN heterocycles. We hypothe-
size that the efficacy of palladium catalysts based on ligands 1,
[
10] E. Galardon, S. Ramdeehul, J. M. Brown, A. Cowley, K. K. Hii,
A. Jutand, Angew. Chem. 2002, 114, 1838; Angew. Chem. Int. Ed.
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[
[
2
12] For the use of LiN(TMS) to enhance the substrate scope, see:
2
M. C. Harris, X. Huang, S. L. Buchwald, Org. Lett. 2002, 4, 2885.
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2
[
14] T. H. M. Jonckers, B. U. W. Maes, G. L. F. Lemiere, R. Dom-
misse, Tetrahedron 2001, 57, 7027.
[
15] To date, 2-aminobenzothiazole and 2-aminothiazole could not
be N-arylated by using Pd/3 or other monophosphine catalyst
systems; these amino heterocycles inhibit the normally success-
ful coupling of simple aryl halides and aniline, thus indicating
their roles as catalyst poisons.
16] a)G. Mann, J. F. Hartwig, M. S. Driver, C. Fernandez-Rivas, J.
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3, or 4 is attributed to a combination of factors: 1)A
maximization of the amount of L Pd intermediates, thus
1
speeding the desired catalytic process relative to different
modes of catalyst decomposition; 2)providing quasi-stable
[
[
L Pd], [L Pd(Ar)X], and [L Pd(Ar)amido] intermediates
1 1 1
because the size of these complexes slows bimolecular
decomposition processes and because of stabilizing Pd/arene
interactions; 3)providing [L 1Pd(Ar)amido] intermediates
with especially sterically demanding ligand L facilitates the
[17] Pyrrole: K = 23.0 (DMSO); indole: K = 20.95 (DMSO); pyra-
1
a
a
rate of reductive elimination in forming the product. Further,
this study demonstrates that monodentate ligands are viable
alternatives to and sometimes superior to chelating ligands in
Pd-catalyzed CÀN bond-forming processes.
zole: K
= 19.8 (DMSO); see: F. G. Bordwell, Acc. Chem. Res.
a
1988, 21, 456.
[
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Received: April 24, 2006
Published online: September 6, 2006
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6
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 6523 –6527

Angewandte
Chemie
[
20] For two examples of N-arylation of imidazole using palladium
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[
Angew. Chem. Int. Ed. 2006, 45, 6523 –6527
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6527