Design of New Ligands for the Palladium-Catalyzed Arylation of α-Branched Secondary Amines

Article abstract of DOI:10.1002/anie.201502626

In Pd-catalyzed C-N cross-coupling reactions, α-branched secondary amines are difficult coupling partners and the desired products are often produced in low yields. In order to provide a robust method for accessing N-aryl α-branched tertiary amines, new catalysts have been designed to suppress undesired side reactions often encountered when these amine nucleophiles are used. These advances enabled the arylation of a wide array of sterically encumbered amines, highlighting the importance of rational ligand design in facilitating challenging Pd-catalyzed cross-coupling reactions.

Full text of DOI:10.1002/anie.201502626

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502626
German Edition: DOI: 10.1002/ange.201502626
Cross-Coupling
Design of New Ligands for the Palladium-Catalyzed Arylation of
a-Branched Secondary Amines**
Nathaniel H. Park, Ekaterina V. Vinogradova, David S. Surry, and Stephen L. Buchwald*
À
Abstract: In Pd-catalyzed C N cross-coupling reactions,
a-branched secondary amines are difficult coupling partners
and the desired products are often produced in low yields. In
order to provide a robust method for accessing N-aryl a-
branched tertiary amines, new catalysts have been designed to
suppress undesired side reactions often encountered when these
amine nucleophiles are used. These advances enabled the
arylation of a wide array of sterically encumbered amines,
highlighting the importance of rational ligand design in
facilitating challenging Pd-catalyzed cross-coupling reactions.
T
ertiary, N-aryl a-branched amines are frequently found as
structural components of pharmaceutically relevant com-
pounds and biologically active natural products (Figure 1).[1]
À
Although Pd-catalyzed carbon–nitrogen (C N) cross-cou-
pling would provide an efficient means of accessing this
valuable class of compounds, the use of a-branched secondary
amine nucleophiles has seen only limited success, and in many
instances low yields of the desired product are obtained.[2]
Other methods for preparing tertiary N-aryl a-branched
amines rely on the addition of an amine to an aryne[3] or
nucleophilic aromatic substitution.[4] While effective, these
methods typically have a narrow substrate scope or result in
a mixture of regioisomeric products.[3] Copper-catalyzed
electrophilic amination has also been utilized,[5] with
a recent report by Lalic demonstrating its effectiveness for
the arylation of sterically hindered secondary O-benzoyl
hydroxylamine electrophiles.[5b] Despite these advances, there
remains no general method for the direct arylation of
a-branched secondary amines. Therefore, we sought to
develop a catalyst system capable of cross-coupling sterically
encumbered secondary amines.
Figure 1. Selected examples of biologically active compounds contain-
ing tertiary N-aryl a-branched amines.[1]
The development of a highly effective catalyst system for
the arylation of a-branched secondary amines must address
the specific challenges presented by these coupling partners.
Their poor nucleophilicity as a consequence of steric hin-
drance can lead to slower rates of amine transmetalation,
resulting in the competitive reaction of the alkoxide base and
the formation of the corresponding aryl tert-butyl ether
(ArOtBu, V, Figure 2). Additionally, b-hydride elimination
may occur from the intermediate PdII-amido complex[6,7] (IV,
Figure 2), leading to the formation of the reduced arene (VI,
[*] N. H. Park, E. V. Vinogradova, Dr. D. S. Surry,
Prof. Dr. S. L. Buchwald
Department of Chemistry
Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[**] We acknowledge the National Institutes of Health for support of this
work (grant GM58160). The content is solely the responsibility of
the authors and does not represent the official views of the National
Institutes of Health. N.H.P. acknowledges funding from a National
Science Foundation Graduate Research Fellowship. We thank Dr.
Xiaohua Huang (MIT) for previous work on the arylation of
diisopropylamine. We thank Dr. Michael T. Pirnot (MIT), Dr. Aaron
C. Sather (MIT), and Dr. Christine Nguyen (MIT) for aid in the
preparation of this manuscript. MIT holds or has filed patents on
the ligands and precatalysts used in this work for which S.L.B and
current and/or former co-workers receive royalty payments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502626.
Figure 2. Proposed catalytic cycle and potential challenges presented
by sterically hindered a-branched secondary amine nucleophiles.
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Figure 2). In this regard, the supporting ligand for the
palladium catalyst must be carefully designed in order to
facilitate the preferential formation of the desired aryl amine
while suppressing side reactions.
We began our investigation by examining the effect of the
supporting ligands on the efficiency of the catalyst system for
the reaction shown in Table 1.[8] Catalyst systems based on
improved yield, although the reduced arene remained the
major product (Table 1, entry 4).
In the proposed catalytic cycle, the b-hydride elimination
pathway competes with reductive elimination from the PdII–
amido intermediate (IV, Figure 2). We thus envisioned that
using a less electron-rich biaryl phosphine ligand would
[12]
À
increase the rate of C N reductive elimination.
A less
electron-rich biaryl phosphine ligand could also increase the
rate of transmetalation (amine binding and deprotonation,
Figure 2) by rendering the PdII intermediates II and III more
electrophilic (Figure 2).[13] Based on this hypothesis, we
examined a catalyst system based on the ligand L5 (P5,
Table 1).[14,15] The use of precatalyst P5 dramatically increased
the yield of 1c, while the amount of reduced arene decreased
(Table 1, entry 5). Following these results, we changed the
phosphorus substituents from phenyl to 3,5-bis(trifluorome-
thyl)phenyl groups to provide ligand L6 (P6, Table 1). The use
of precatalyst P6 led to an additional improvement in the
yield and further diminished the formation of the reduced
arene (Table 1, entry 6). To achieve additional improvements
in catalyst performance, we incorporated methoxy groups at
positions 3 and 6 of the biaryl framework (Table 1), as these
groups are known to increase the rate of reductive elimination
from PdII complexes.[16] This modification led to L7 (P7),
Table 1: Evaluation of supporting ligands.[a]
Entry
Precatalyst
Conversion
Reduction
Yield
1
2
3
4
5
6
7
P1
P2
P3
P4
P5
P6
P7
100%
100%
37%
100%
100%
94%
68%
85%
15%
53%
18%
trace
trace
10%
15%
2%
27%
77%
85%
93%[b,c]
100%
[a] Reaction conditions: 1a (0.25 mmol), 1b (0.30 mmol), NaOtBu
(0.35 mmol), 2 mol% precatalyst, CPME (0.5 mL), 808C, 1 h. Conver-
À
sion, C N cross-coupling, and reduction product yields were measured
by GC analysis of the crude reaction mixture using dodecane as the
internal standard. [b] The reaction also produced 6% of the corre-
sponding ArOtBu. [c] Yield of isolated product: 89% (1 mmol scale,
average of two runs). CPME=cyclopentyl methyl ether.
RuPhos (L1) have been demonstrated to be highly effective
for the cross-coupling of secondary amines,[9] including some
cases of reactions between sterically demanding coupling
partners.[2a,c] However, when RuPhos precatalyst P1 was used
in the reaction of 2-bromo-p-xylene (1a) and 2-ethylpiper-
idine (1b), the desired product was obtained in only 10%
yield (Table 1, entry 1). Other biaryl phosphine ligands such
as XPhos (L2) and BrettPhos (L3) have also been used for
[9]
À
promoting Pd-catalyzed C N bond formation. Neverthe-
À
Scheme 1. Scope of C N cross-coupling reactions using P7. Reaction
less, these catalyst systems (P2 and P3, respectively) proved to
be inefficient in facilitating the desired transformation
(Table 1, entries 2 and 3). In all cases, the major by-product
was the reduced arene, which presumably arises as a result of
b-hydride elimination.[10]
conditions: aryl halide (1.0 mmol), amine (1.2 mmol), NaOtBu
(1.4 mmol), 2 mol% P7, 0–2 mol% L7, CPME (2 mL), 60–808C, 6–
16 h. Yields are of isolated products, average of two runs. [a] 1:49
cis:trans isomers of the arylated amine. Determined by GC analysis of
the crude reaction mixture. 2% reduction, 4% ArOtBu. [b] 9% ArOtBu.
[c] 27% reduction, 6% ArOtBu [d] 22:1 cis:trans isomers of the arylated
amine. Determined by GC analysis of the crude reaction mixture.
[e] 28% reduction. [f] K3PO4 (6.0 mmol) used as base. [g] 34% reduc-
tion. [h] Amine (9.6 mmol), NaOtBu (10.8 mmol), 7% reduction, 9%
ArOtBu. [i] 37% reduction.
Given these results, we turned to CPhos (L4, Table 1),
which has been demonstrated to suppress b-hydride elimi-
nation in Pd-catalyzed Negishi cross-coupling reactions.[11]
Indeed, CPhos precatalyst P4 produced aryl amine 1c in an
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which provided the most efficient catalyst system for the
desired transformation (Table 1, entry 7).[17]
presence in many pharmaceutically relevant compounds.[2]
However, our initial attempts to utilize activated heteroaryl
electrophiles (3a, 3b, and 3c, Scheme 2) resulted in low yields
and the formation of significant amounts of the corresponding
ArOtBu.[23,24] Through systematic ligand modification,[25] we
found that ligand L8 (P8, Scheme 2) provided higher yields in
these cases. With all other substrates, P7 was again very
effective in producing high yields of the desired product. In
certain instances, the use of additional equivalents of the
amine was necessary to further deter the formation of
ArOtBu (3a, 3g, and 3i, Scheme 2). Additionally, a trace of
the epimerized product was observed when cis-2,6-dimethyl-
piperidine (3g, Scheme 2) or an enantiomerically enriched
amine was used (3h and 3i, Scheme 2). Despite these
considerations, the combined substrate scope using precata-
lysts P7 and P8 allows efficient cross-coupling of a wide
variety of challenging a-branched secondary amines with
different heteroaryl halides (Scheme 2).
À
Precatalyst P7 enabled a wide variety of C N cross-
coupling reactions with a-branched secondary amines
(Scheme 1). Hindered cyclic secondary amines were well-
tolerated, including in reactions with aryl halides containing
ortho substituents (2a, 2c, 2e, 2g, and 2i, Scheme 1). Lower
yields were obtained in the more sterically encumbered
cases,[18,19] where the formation of the reduced arene by-
product was observed. Acyclic a-branched amines could also
be efficiently arylated (2b and 2h, Scheme 1). Previously, the
À
arylation of diisopropylamine through Pd-catalyzed C N
cross-coupling has resulted in very low yields,[2f, 20] presumably
as a result of its steric hindrance. By using P7, however,
diisopropylamine was successfully arylated in 65% yield (2h,
Scheme 1), although additional equivalents of amine and base
were necessary to favor the formation of the desired
product.[21,22]
We were interested in applying the developed conditions
to the amination of heteroaryl halides because of their
In summary, we have developed two new catalyst systems
for the arylation of sterically demanding a-branched secon-
dary amines. Notably, the unprecedented levels of reactivity
À
in C N cross-coupling reactions with these amines were
achieved because of the ability of the new precatalysts to
suppress both the b-hydride elimination pathway and aryla-
tion of the alkoxide base. Overall, this work highlights the
potential of rational ligand design to modulate catalyst
behavior and ultimately facilitate the cross-coupling of steri-
cally demanding amine coupling partners.
Keywords: amination · cross-coupling · ligand design ·
palladium · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2015, 54, 8259–8262
Angew. Chem. 2015, 127, 8377–8380
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16 h. Yields are of isolated products, average of two runs. [a] Amine
(2.4 mmol), NaOtBu (2.8 mmol). [b] 9% reduction, 8% ArOtBu.
[c] 2% reduction, 3% ArOtBu. [d] 13% reduction. [e] Amine
(3.6 mmol), NaOtBu (4.2 mmol); 20:1 cis:trans isomers of the arylated
amine product. Determined by GC analysis of the crude reaction
mixture. [f] Starting amine: 99% ee; product: 98% ee. [g] Amine
(2.4 mmol), NaOtBu (2.8 mmol), dioxane (2 mL); 24% ArOtBu, 6%
reduction; starting amine: ꢀ97% ee; product: 83% ee.
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À
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[12] Phosphine ligands containing aryl rings with electron-withdraw-
À
ing substituents facilitate
a faster rate of C N reductive
elimination from a PdII amido complex. See: J. F. Hartwig,
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[15] Changing the substituents on the phosphorus from cyclohexyl to
aryl groups can also reduce the size of the ligand, which could
potentially make the catalyst more accommodating to larger
amine nucleophiles.
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À
[18] The length of the C F bond is more similar to the length of the
À
À
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[19] The amounts of the corresponding reduced arene and ArOtBu
by-products that were observed have been indicated in the table
footnotes. In most cases, these by-products could be readily
separated from the desired aryl amine product. Only in the case
of 2c was the separation difficult and the isolated material
contained less than 5% of the corresponding ArOtBu.
[20] The cross-coupling of diisopropylamine with 4-bromoanisole
was reported by Herrmann to provide the aryl amine product in
78% yield. In our hands, the products under these conditions
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[7] Reduction of the aryl halide can occur during catalyst activation
from PdII salts (see Ref. [6c]). However, this is unlikely with the
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[21] A control experiment produced none of the arylated diisopro-
pylamine or the corresponding ArOtBu, see the Supporting
Information.
[22] An excess of amine relative to NaOtBu led to the incomplete
conversion of the aryl electrophile. As such, the same amine-to-
base ratio was maintained for all reactions, see the Supporting
Information.
[23] Control experiments for substrates 3a, 3b, and 3c showed no
formation of the product or the corresponding ArOtBu, see the
Supporting Information.
[8] The presence of carbazole from the activation of the 2-amino
biphenyl palladium methanesulfonate precatalysts inhibited the
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methanesulfonate precatalysts were used instead. a) N. C.
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[24] When P7 was used, the yields of 3a, 3b and 3c were 5%, 60%,
and 70% respectively, see the Supporting Information.
[25] See the Supporting Information.
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Received: March 21, 2015
Revised: April 7, 2015
Published online: June 1, 2015
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