Copper(II)-mediated intermolecular amination of inert C(sp3)[sbnd]H bonds with simple alkylamines to construct α,α-disubstituted β-amino acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2017.01.079

Disclosed herein is a copper(II)-mediated chelation-assisted intermolecular amination of inert C(sp³)[sbnd]H bonds using simple alkylamines as the amino source. A straightforward and step-economic alternative to α,α-disubstituted β-amino acid derivatives is provided consequently. This reaction features good functional group tolerance and relatively broad substrate scope. Furthermore, a coupling product between morpholine and radical inhibitor 2,6-di-tert-butyl-p-cresol (BHT) was isolated, indicating that a single electron transfer (SET) process might be involved in this transformation.

Full text of DOI:10.1016/j.tetlet.2017.01.079

Accepted Manuscript
Copper(II)-Mediated Intermolecular Amination of Inert C(sp3)−H Bonds with
Simple Alkylamines to Construct α,α-Disubstituted β-Amino Acid Derivatives
Chunxia Wang, Yudong Yang
PII:
S0040-4039(17)30110-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.079
TETL 48582
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
3 December 2016
17 January 2017
23 January 2017
Please cite this article as: Wang, C., Yang, Y., Copper(II)-Mediated Intermolecular Amination of Inert C(sp3)−H
Bonds with Simple Alkylamines to Construct α,α-Disubstituted β-Amino Acid Derivatives, Tetrahedron Letters
(2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.079
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Copper(II)-Mediated Intermolecular
Amination of Inert C(sp3)−H Bonds with
Simple Alkylamines to Construct α,α-
Disubstituted β-Amino Acid Derivatives
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Chunxia Wang, Yudong Yang*

1
Tetrahedron Letters
Copper(II)-Mediated Intermolecular Amination of Inert C(sp3)−H Bonds with Simple
Alkylamines to Construct α,α-Disubstituted β-Amino Acid Derivatives
Chunxia Wang, Yudong Yang
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, and State Key Laboratory of Biotherapy, West China
Medical School, Sichuan University, 29 Wangjiang Road, Chengdu 610064, PR China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Disclosed herein is a copper(II)-mediated chelation-assisted intermolecular amination of inert
C(sp3)−H bonds using simple alkylamines as the amino source. A straightforward and step-
economic alternative to α,α-disubstituted β-amino acid derivatives is provided consequently.
This reaction features good functional group tolerance and relatively broad substrate scope.
Furthermore, a coupling product between morpholine and radical inhibitor 2,6-di-tert-butyl-p-
cresol (BHT) was isolated, indicating that a single electron transfer (SET) process might be
involved in this transformation.
Available online
Keywords:
C(sp3)−H activation
Amination
2009 Elsevier Ltd. All rights reserved.
Amino acids
C−H/N−H coupling
α,α-Disubstituted β-amino acid derivatives are a kind of
important structural motifs often encountered in pharmaceuticals
and biologically active molecules, such as LSD1 inhibitors, H1/5-
HT2A antagonist and cephalosporin antibiotics (Scheme 1).1
Therefore, the synthesis of such compounds has been extensively
studied. Although a variety of methods for the synthesis of α,α-
disubstituted β-amino acids have been developed, these reactions
typically suffer from tedious synthetic steps, harsh reaction
conditions and/or limited substrate scope.2 Thus, it is still
desirable to develop a concise and efficient strategy to construct
these privileged skeletons. Recently, transition-metal-catalyzed
C−H bond activation has emerged as a straightforward and
highly efficient strategy for the construction of carbon−carbon
and carbon−heteroatom bonds and synthesis of diverse
synthetically useful molecules. Furthermore, this tactic allows the
late-stage functionalization of a variety of pivotal frameworks
which exist in natural products, pharmaceutical candidates and
organic functional materials.3,4 Thus, it would be an ideal method
to construct the α,α-disubstituted β-amino acid scaffolds by
selective C(sp3)−H activation/amination of the corresponding
carboxylic acid derivatives.
Scheme 1 Selected Pharmaceutical and Biologically Active
Molecules Containing α,α-Disubstituted β-Amino Acid
Derivatives.
Over the past decades, a significant progress has been
achieved in direct C(sp2)−H amination, established a rapid access
to a variety of aromatic amines.5,6 Meanwhile, a few examples on
the directed C(sp3)−H activation/amination using preactivated
amino source (Scheme 2), such as 3-substituted 1,4,2-dioxazol-5-
ones,7a O-benzoyl hydroxylamines,7b,c organic azides,7d or N-
fluorobis(phenylsulfonyl)imide (NFSI),7e have been reported.
From the viewpoint of substrate availability and step- and atom-
economy, the employment of unactivated amines as the amino
source represents a more ideal approach to construct C−N bonds
because it eliminates the extra steps for the preparation of
preactivated amine partners. However, to the best of our
knowledge, the examples describing C(sp3)−H/N−H oxidative
cross-coupling reactions are only limited in amidations.8 The
direct C(sp3)−H activation/amination using unactivated amino
———
 Corresponding author. Tel.: +86-28-85412285; e-mail: yangyudong@scu.edu.cn (Y. Yang).

2
Tetrahedron
precursors is still underrepresented. Following our continued
interest in C(sp3)−H activation9 and synthesis of biologically
important molecules by direct C(sp3)−H functionalization,10
herein we disclose an aerobic copper-mediated intermolecular
C(sp3)−H amination using simple alkylamines as the amino
source, which provides a straightforward and efficient alternative
toward the synthesis of α,α-disubstituted β-amino acid
derivatives. It is noted that both cyclic and acyclic amines were
effective amine coupling partners in this protocol.11
Entry
Metal salts
Base
Solvent
Yield of 3aab
1
2
Cu(OAc)2
CuCl
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
PhCl
PhCl
23%
n.d.
3
CuCl2
PhCl
n.d.
4
Cu(OTf)2
Ni(OAc)2
Co(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
PhCl
n.d.
5c
6c
7
PhCl
n.d.
PhCl
n.d.
PhCl
12%
26%
21%
trace
n.d.
8
Na2HPO4
NaH2PO4
DIPEA
Et3N
PhCl
9
PhCl
10
11
12
13
14
15
PhCl
PhCl
Na2CO3
Na2CO3
Na2CO3
Na2CO3
DMSO
trace
32%
trace
51%
EDMAB
NMP
PhCN
EDMAB/DMSO
(2/1)
16
17
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Na2CO3
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
48%
56%
67%
72%
36%
Scheme
2 Transition-Metal-Catalyzed Activation of Inert
C(sp3)−H Bonds and Subsequent Amination.
EDMAB/DMSO
(2/1)
EDMAB/DMSO
(2/1)
Recently, our group reported the 8-aminoquinoline-assisted
intramolecular C(sp3)−H amidation by employment of a Cu(I)/O2
catalytic system.8d It was expected that the intermolecular
C−H/N−H coupling could proceed under similar reaction
conditions. However, no desired product was detected in the
catalysis of CuI when morpholine was used as the amino
precusor. Gratifyingly, 23% yield of the corresponding β-amino
acid derivative 3aa was obtained when the reaction was
performed in the presence of 2.0 equiv of Cu(OAc)2 and 4.0
equiv of Na2CO3 under an air atmosphere (Table 1, entry 1).
Other inexpensive metal salts such as CuCl, CuCl2, Cu(OTf)2,
Ni(OAc)2 and Co(OAc)2 gave only trace or no desired product
(Table 1, entries 2-6). Most of the common inorganic bases could
promote this reaction (see Table S1 in the Supporting
Information). Na2HPO4 and NaH2PO4 showed comparative
efficiencies to Na2CO3 in this transformation (Table 1, entries 8
and 9). However, organic bases such as N,N-
diisopropylethylamine (DIPEA) and Et3N were ineffective to
promote this reaction (Table 1, entries 10 and 11). The
investigation of solvents revealed that aromatic solvents were
typically more effective than other solvents (see Table S2 in the
Supporting Information). Although 51% yield of the desired
product was delivered in benzonitrile, a complex mixture of by-
products was generated in a significant amount (Table 1, entry
15). Thus, although less efficient the mixture of ethyl benzoate
(EDMAB) and DMSO (2/1, v/v) was chosen to be the most
suitable solvent (Table 1, entry 16). Finally, 72% yield of 3aa
could be afforded when the reaction was carried out in the
presence of copper acetate (2.5 eq.), benzonitrile (2 eq.) and
Na2HPO4 (6.0 equiv) under an air atmosphere (Table 1, entry 19).
Although trace amounts of the corresponding ß-lactone product
were also detected,8d the rest of the substrate remained intact. In
addition, a significantly diminished yield was obtained under a
N2 atmosphere (Table 1, entry 20).
18d
EDMAB/DMSO
(2/1)
19d,e
20d,e,f
EDMAB/DMSO
(2/1)
a 1a (0.15 mmol), 2a (4.0 equiv ), metal salts (2.0 equiv) and base (4.0 equiv)
were stirred in solvent (1.0 mL) at 150 °C for 24 h under an air atmosphere.
b Isolated yields. n. d. = not detected. EDMAB = ethyl benzoate.
c Metal salts (20 mol%) and Ag2CO3 (2.0 equiv) were used.
d Cu(OAc)2 (2.5 equiv) and PhCN (2.0 equiv).
e 6.0 equiv of Na2HPO4.
f Under a N2 atmosphere.
With the optimized reaction conditions in hand, we next
investigated the substrate scope of acid derivatives. As
summarized in Table 2, a diverse set of aliphatic carboxylic acid
derivatives were aminated to give the corresponding β-amino
acid derivatives in moderate to excellent yields. Only
monofunctionalized products were observed even in presence of
two or three potential reactive sites (β-methyl groups) (3aa-3ha),
indicating this reaction might be sensitive to the steric hindrance
effect. In addition, a site-selectivity on the β-methyl groups over
the γ- and δ-methyl was showed (3ba and 3ca). Notably, in the
case of amide 3da which has a phenyl group at the α-carbon site,
significant amounts of the corresponding ß-lactone product were
generated. This reaction showed a preference on the β-methyl
groups over the methylene groups even in the existence of a more
reactive β-benzylic site (3ja-3la). Besides chain alkyl carboxylic
acid derivatives, cyclic substrates could also undergo this
transformation albeit in lower yields (3ia). It should be noted that
the successful amination of heteroaryl-containing substrate
further identified the good substrate compatibility of this reaction
(3na).
Table 2. Substrate Scope of Aliphatic Acid Derivativesa,b
Table 1. Optimization of the Reaction Conditionsa

3
the C(sp3)−H bond cleavage might be involved in the rate-
determining step.
a
Reaction conditions: 1 (0.15 mmol), 2a (4.0 equiv), Cu(OAc)2 (2.5 equiv),
PhCN (2 equiv) and Na2HPO4 (6.0 equiv) were stirred in a mixture of ethyl
benzoate and DMSO (v/v, 2/1) (1.5 mL) at 150 oC for 24 h under an air
atmosphere.
b Isolated yields.
c Isobutyl benzoate was used as solvent, 30 h, 150 oC.
d Without the addition of benzonitrile as additive.
Scheme 3 Hydrogen-Deuterium Exchange Experiments and
Deuterium-Labeling Experiments.
With the substrate scope of acid derivatives was established,
we then probed the scope with respect to amine partners (Table
3). Diverse cyclic amines such as morpholine, piperazine and
piperidines were effective coupling partners under the standard
conditions (3ab-3ad). Functional groups including ester, ketal
and methoxy, were compatible (3ae-3ag). Besides cyclic amines,
acyclic amines could also couple with the acid derivatives in
moderate to high yields (3ag-3ai). Interestingly, 26% yield of the
desired product could be obtained when primary amine
cyclopentylamine was attempted (3aj).
Table 3. Substrate Scope of Amine Reagents for C(sp3)−H
Scheme 4 Radical Trapping Experiments.
Aminationa,b
To understand the mechanism further, a radical trapping
experiment was performed. It was found that the reaction was
completely inhibited when 2.0 equivalents of 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO) or BHT was added.
Furthermore, a coupling product between morpholine and BHT
was isolated (Scheme 4). These results implied that a single
electron transfer (SET) process might be involved in this
transformation.6a,b
a Reaction conditions: 1a (0.15 mmol), 2 (4.0 equiv), Cu(OAc)2 (2.5 equiv),
PhCN (2 equiv), and Na2HPO4 (6.0 equiv) were stirred in a mixture of ethyl
benzoate and DMSO (v/v, 2/1) at 150 oC for 24 h under an air atmosphere.
b Isolated yields.
c Isobutyl benzoate was used as solvent without benzonitrile as additive, 36 h,
150 oC.
d o-Xylene was used as solvent without benzonitrile as additive, 36 h, 150 oC.
To gain insight into the reaction mechanism, deuterium-
labeling experiments were conducted. The hydrogen-deuterium
exchange experiments with CD3OD/D2O as deuterium source
indicated that the cleavage step of primary C(sp3)−H bond was an
irreversible process (Scheme 3a). A primary kinetic isotope
effect (KIE) values of 2.43 was determined for two parallel
reactions between 1b and its [D3]methyl derivative (Scheme 3b).
And similar KIE value of 2.45 was observed when a competetion
reaction was carried out (Scheme 3c). These results indicated that
Scheme 5 Proposed mechanism.
Based on these observations and the previous reports,12
plausible mechanism for this reaction is proposed (Scheme 5).
a

4
Tetrahedron
4.
For selected examples on C(sp3)−H activation: (a) Yang, X.; Sun,
Y.; Sun, T.-Y.; Rao, Y. Chem. Commun. 2016, 52, 6423; (b)
Zhang, Q.; Yin, X.-S.; Chen, K.; Zhang, S.-Q.; Shi, B.-F. J. Am.
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Initially, coordination of the NH in amide substrate 1 to Cu(II)
generates IM1 (pathway I). Subsequently, a base-assisted
C(sp3)−H bond cupration takes place to provide the cyclic Cu(II)
intermediate IM2.8e,f Meanwhile, a nitrogen radical species
would be generated through the Cu(II)-mediated oxidation of an
amine substrate.13,14 Then an oxidative radical coupling between
the nitrogen radical species and IM2 gives a Cu(III) complex
IM3. Following C−N reductive elimination affords the desired β-
amino acid derivative 3 and releases a Cu(I) species which might
be oxidized by O2 to regenerate the reactive Cu(II). Alternatively,
coordination of amide and amine to Cu(II) delivers
cyclometallic complex IM4, which then undergoes
a
a
disproportionation process to generate Cu(III) complex IM5
(pathway II). Following C(sp3)−H activation and reductive
elimination affords the corresponding product. That 36% yield of
the desired product 3aa could be afforded under a N2 atmosphere
indicated the possibility of pathway II (Table 1, entry 20).
However, the radical trapping experiments and the positive effect
of O2 to this transformation implied that pathway I might be a
possible route as well.
To conclude, we have developed an aerobic copper-mediated
intermolecular direct amination of unactivated C(sp3)−H bonds
using simple alkylamines as the amino source. This work
represents a rare example on intermolecular direct amination of
inert C(sp3)−H bonds. This reaction features good functional
group tolerance and relatively broad substrate scope. Both cyclic
and acyclic amines are effective substrates under the standard
conditions. This method offers an alternative to rapid assemble a
diverse set of α,α-disubstituted β-amino acid derivatives. Further
investigation on the mechanism and expansion of the substrate
scope are currently undergoing in our laboratory.
5.
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Acknowledgments
7.
8.
This work was supported by grants from the National NSF of
China (No. 21502123), and Comprehensive Training Platform of
Specialized Laboratory, College of Chemistry, Sichuan
University.
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5
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