Ligand-promoted ortho-C-H amination with Pd catalysts

Article abstract of DOI:10.1002/anie.201408651

2,4,6-Trimethoxypyridine is identified as an efficient ligand for promoting a Pd-catalyzed ortho-C-H amination of both benzamides and triflyl-protected benzylamines. This finding provides guidance for the development of ligands that can improve or enable Pd^II-catalyzed C_sp2-H activation reactions directed by weakly coordinating functional groups.

Full text of DOI:10.1002/anie.201408651

Angewandte
Chemie
DOI: 10.1002/anie.201408651
À
C H Amination
À
Ligand-Promoted ortho-C H Amination with Pd Catalysts**
Dajian Zhu, Guoqiang Yang, Jian He, Ling Chu, Gang Chen, Wei Gong, Ke Chen,
Martin D. Eastgate, and Jin-Quan Yu*
Abstract: 2,4,6-Trimethoxypyridine is identified as an efficient
than 10% yield. We further optimized reaction parameters
À
ligand for promoting a Pd-catalyzed ortho-C H amination of
both benzamides and triflyl-protected benzylamines. This
finding provides guidance for the development of ligands
for this particular substrate by carrying out extensive screen-
ing of Pd sources, solvents, and bases to obtain the optimum
yield (see the Supporting Information (SI), Tables S1–S3).
Thus, stirring 1a with O-benzoyl hydroxylmorpholine
(2 equiv) in the presence of Pd(OAc)2 (10 mol%), AgOAc
(2 equiv), K3PO4 (1 equiv), and 4 ꢀ molecular sieves (40 mg)
in C6F6 at 1308C for 24 h afforded the product 2a in 24%
yield.
that can improve or enable PdII-catalyzed Csp2 H activation
reactions directed by weakly coordinating functional groups.
À
À
C
atalytic C H amination has the potential to become
À
a complementary tool for C N bond forming reaction when
the aryl halides are not readily available in a synthetic
sequence.[1] Several catalytic systems have been reported.[2–16]
However, the limited substrate scope and poor efficiency of
these reactions have prevented their synthetic applications.[1]
Based on the impact of ligand development on the Buchwald–
Hartwig amination reaction,[17] it is reasonable to assume that
With this initial result in hand, we set out to search for
ligands that can significantly improve this reaction. Mono-
protected amino acid ligands (MPAA) have been shown to
[18]
À
accelerate Csp2 H activation, whereas pyridine and quino-
[19]
À
line ligands have been shown to promote Csp3 H activation.
These observations prompted us to test whether these types of
À
À
identification of a ligand scaffold for promoting catalytic C H
amination could partially overcome the current limitations.
ligands can be modified to improve this Csp2 H amination
reaction. Whereas MPAA ligands are found to have negli-
gible effects, pyridine and quinoline-based ligands signifi-
cantly improve this reaction (Table 1). The use of 2,4,6-
trimethoxypyridine L12 increased the yield to 58%.
Herein we report the development of a ligand that signifi-
cantly promotes Pd -catalyzed C H amination reactions of
two distinct classes of substrates: triflyl-protected benzyl-
II
À
amines and benzamides, thus demonstrating the feasibility of
With the optimal ligand L12 identified, we performed the
second round of optimizations of the reaction parameters (see
SI, Tables S4–S6) and found that the use of binary bases
(2 equiv Na2CO3, 1 equiv K3PO4) improved the yield to 85%.
Although the use of binary bases afforded significant
improvement, the removal of L12 from these reaction
conditions reduced the yield to 31%, confirming the pre-
dominant effect of the ligand. Notably, this ligand-promoted
amination reaction also proceeds without AgOAc to give 2a
in 69% yield (see Table S6 in SI).
À
using a ligand to promote or enable directed Csp2
amination [Eq. (1)].
H
A wide range of benzylamine substrates is compatible
with this amination protocol (Table 2). Electron-donating
groups at the ortho, meta and para positions are all well
tolerated (2a–2 f). Excellent monoselectivity is achieved with
all substrates including the nonsubstituted arene 2g. Elec-
tron-withdrawing fluoro, chloro, bromo and trifluoromethyl
groups are all compatible with this reaction. We also
examined the scope of the amine donors using substrate 1a
(Table 3). Both piperidine and piperazine donors coupled
well to give the desired amination product in good yields (2p–
2r). A dialkylamine unit can also be installed through this
amination reaction (2s, 2t). Based on the reaction conditions,
a tentative catalytic cycle for this reaction can be proposed
(Figure 1). Although the triflyl-protected amine could be
potentially deprotonated and coordinate with the PdII center
as a neutral sulfonimidate,[20] a precursor I coordinated to the
anionic triflamide and the pyridine ligand is proposed.
To establish a platform for ligand development, we
selected triflyl-protected benzylamine 1a as the substrate.
À
Pd-catalyzed C H amination of 1a under our previously
reported conditions[6a] gave the amination product 2a in less
[*] Dr. D. Zhu, Dr. G. Yang, J. He, L. Chu, Dr. G. Chen, Dr. W. Gong,
Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
Dr. K. Chen, Dr. M. D. Eastgate
Chemical Development
1 Squibb Drive, New Brunswick, NJ 08903 (USA)
[**] We gratefully acknowledge The Scripps Research Institute, and the
U.S. NSF (CHE-1011898) for financial support. D.Z. is a visiting
scholar from Huazhong University of Science and Technology,
sponsored by the China Scholarship Council (201206165031). G.Y.
thanks the Shanghai Jiao Tong University for HaiWai ShiZi ChuBei
postdoctoral fellowship support.
À
Subsequent C H activation occurs to give intermediate II
which is then oxidized to the PdIV species III by the aminating
1
2
À
reagent R R NOBz. C N reductive elimination from III
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408651.
affords the amination product as well as regenerates the PdII
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Table 1: Ligand optimization.[a,b]
Table 2: Scope of triflyl-protected benzylamines.[a,b]
[a] Reaction conditions: 1a (0.1 mmol), O-benzoyl hydroxylmorpholine
(2 equiv), Pd(OAc)2 (10 mol%), ligand (20 mol%), AgOAc (2 equiv),
K3PO4 (1 equiv), 4 ꢀ MS (40 mg), C6F6 (1 mL), 1308C, 24 h. [b] The yield
was determined by 1H NMR analysis of the crude product using
dibromomethane as the internal standard.
[a] Reaction conditions: 1a-1o (0.1 mmol), O-benzoyl hydroxylmorpho-
line (2 equiv), Pd(OAc)2 (10 mol%), L12 (20 mol%), AgOAc (2 equiv),
Na2CO3 (2 equiv), K3PO4 (1 equiv), 4 ꢀ MS (40 mg), C6F6 (1 mL), 1308C,
24 h. [b] Yields of isolated products.
Table 3: Scope of amine donors for substrate 1a.[a,b]
À
Figure 1. Catalytic cycle for ligand-promoted C H amination.
catalyst. It is conceivable that the coordinated trimethoxy-
pyridine ligand promotes both the oxidation step (from II to
III) and the reductive elimination step. Based on this catalytic
cycle, the observed enhancing effect of AgOAc (typically
increases the yield of the amination by about 15%) can be
attributed to the reoxidation of Pd0 generated by off-cycle
pathways.
[a] Reaction conditions: 1a (0.1 mmol), O-benzoyl hydroxylmorpholine
(2 equiv), Pd(OAc)2 (10 mol%), L12 (20 mol%), AgOAc (2 equiv),
Na2CO3 (2 equiv), K3PO4 (1 equiv), 4 ꢀ MS (40 mg), C6F6 (1 mL), 1308C,
24 h. [b] Yields of isolated products.
2
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Table 4: Ligand-promoted amination of benzamides.[a,b,c]
Scheme 1. Amination of triflyl-protected benzylamine on a gram scale.
Reaction conditions: 1d (4 mmol), O-benzoyl hydroxylmorpholine
(2 equiv), Pd(OAc)2 (10 mol%), L12 (20 mol%), AgOAc (2 equiv),
Na2CO3 (2 equiv), K3PO4 (1 equiv), 4 ꢀ MS (1.60 g), C6F6 (40 mL),
1308C, 24 h.
Scheme 2. Amination of benzamide on a gram scale. Reaction con-
ditions: 3j (3 mmol), O-benzoyl hydroxylmorpholine (2 equiv), Pd-
(OAc)2 (10 mol%), L12 (20 mol%), AgOAc (1 equiv), CsF (2 equiv),
DCE (30 mL), 1308C, 18 h. DCE=dichloroethane, ArF =(4-CF3)C6F4.
[a] Reaction conditions: 3a–3j (0.1 mmol), O-benzoyl hydroxylamine
(2 equiv), Pd(OAc)2 (10 mol%), L12 (20 mol%), AgOAc (1 equiv), CsF
(2 equiv), DCE (1 mL), 1308C, 18 h. [b] Yields of isolated products.
[c] Yield without ligand in parentheses.
Scheme 3. Removal of the auxiliaries. [a] 1) 2d (0.5 mmol), BrCH2CN
(2.4 equiv), K2CO3 (2.4 equiv), acetone (5 mL), 408C, 24 h; 2) Cs2CO3
(2.4 equiv), THF (5 mL), 408C, 24 h; 3) 1m HCl (aq) (5 mL), reflux,
2 h. [b] 1) 2d (0.2 mmol), MeI (3 equiv), K2CO3 (1.5 equiv), acetone
(5 mL), reflux, 12 h; 2) LiAlH4 (2 equiv), THF (5 mL), reflux, 20 h. [c] 4j
(0.2 mmol), BF3·Et2O (10 equiv), MeOH (5 mL), 1108C, 48 h.
The ligand effect is further demonstrated in the ortho-
amination of benzamides (Table 4). Since benzamides con-
taining electron-donating substituents worked well under
previously reported ligandless conditions,[6a] we focused on
the less effective electron-deficient arenes and compared the
reactions with and without ligand in each case. The use of
ligand L12 significantly improved the reaction to give the
ortho-aminated products in excellent yields (4a–4i). In light
of the abundance of the 1,3-diacid and the potential utility of
the ortho-aminated products for preparing polyfunctionalized
arenes, we coupled 3j (derived from 1,3-diacid) with various
alkylamine donors. Ligand L12 is shown to be crucial in all
cases for obtaining good yields (4j–4o). Considering the
distinct structures of triflyl-protected benzylamines and
benzamides, these results demonstrate the versatility of
ligand L12.
be removed under various conditions to give different
synthetically useful products (Scheme 3).
In conclusion, we have identified the first ligand to
À
promote the Csp2 H amination reaction of two distinct classes
of substrates derived from benzylamines and benzoic acids.
Mechanistic investigations of the precise role of this ligand
and further optimizations of the ligand structure to improve
À
the scope and efficiency of C H amination reactions are
under way in our laboratory.
The amination of both the triflyl-protected benzylamine
and benzamide substrates can be easily run on gram scales to
give the desired products and the recovered ligands in
excellent yields (Schemes 1 and 2). The auxiliaries can also
Received: September 2, 2014
Revised: October 18, 2014
Published online: && &&, &&&&
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Keywords: amination · benzamide · benzylamine ·
.
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C H activation · pyridine ligands
À
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Communications
À
C H Amination
D. Zhu, G. Yang, J. He, L. Chu, G. Chen,
W. Gong, K. Chen, M. D. Eastgate,
J.-Q. Yu*
&&& — &&&
À
Ligand-Promoted ortho-C H Amination
with Pd Catalysts
Trimethoxylpyridine is an efficient ligand
ligands that can improve or enable PdII-
À
À
for promoting Pd-catalyzed ortho-C H
catalyzed Csp2 H activation reactions
amination of both benzamides and triflyl-
protected benzylamines. This finding
provides guidance for the development of
directed by weakly coordinating func-
tional groups.
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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