Intermolecular Amination of Unactivated C(sp3)?H Bonds with Cyclic Alkylamines: Formation of C(sp3)?N Bonds through Copper/Oxygen-Mediated C(sp3)?H/N?H Activation

Article abstract of DOI:10.1002/chem.201603370

The first example of intermolecular amination of unactivated C(sp³)?H bonds by cyclic alkylamines mediated by Cu(OAc)₂/O₂is reported. This method avoids the use of benzoyloxyamines as the aminating reagent, which are normally prepared from alkylamines in extra steps. A variety of unnatural β^{2, 2}-amino acid analogues are synthesized by this simple and efficient procedure. This approach offers a solution to the previous unmet challenge of C(sp³)?H/N?H activation for the formation of C(sp³)?N bonds.

Full text of DOI:10.1002/chem.201603370

DOI: 10.1002/chem.201603370
Communication
&
CÀH Activation
Intermolecular Amination of Unactivated C(sp3)ÀH Bonds with
Cyclic Alkylamines: Formation of C(sp3)ÀN Bonds through
Copper/Oxygen-Mediated C(sp3)ÀH/NÀH Activation
Quan Gou, Yu-Wen Yang, Zi-Ning Liu, and Jun Qin*[a]
Abstract: The first example of intermolecular amination of
unactivated C(sp3)ÀH bonds by cyclic alkylamines mediat-
ed by Cu(OAc)2/O2 is reported. This method avoids the
use of benzoyloxyamines as the aminating reagent, which
are normally prepared from alkylamines in extra steps. A
variety of unnatural b2,2-amino acid analogues are synthe-
sized by this simple and efficient procedure. This ap-
proach offers a solution to the previous unmet challenge
of C(sp3)ÀH/NÀH activation for the formation of C(sp3)ÀN
bonds.
CÀN bonds are important structural units that are widely pres-
ent in natural products, pharmaceuticals, and agrochemicals.[1]
Recent years have witnessed a rapid development of CÀH acti-
vation/CÀN bond-forming reactions. Nevertheless, those reac-
tions are mainly focusing on C(sp2)ÀH amination/amidation by
using various preactivated aminating reagents such as benzoy-
loxyamines, N-chloroamines, N-nosyloxycarbamate, or sulfonyl/
Scheme 1. Intermolecular amination of C(sp3)ÀH bonds by alkylamines.
acyl azides catalyzed by different metals.[2–10] Amination of
NMO=N-methylmorpholine-N-oxide; NMP=N-methyl-2-pyrrolidone.
C(sp2)ÀH bonds by alkylamines was recently reported by Dau-
gulis (Scheme 1a).[7d] Due to lack of p-bond coordinating char-
acter, C(sp3)ÀH activation for C(sp3)ÀN bond formation is chal-
amides with cyclic alkylamines, producing diverse unnatural
2,2-amino acid derivatives, a set of important compounds with
lenging, and limited examples have been developed until
b
now,[11–12] exemplified by C(sp3)ÀH amidation by Che[11a] and
C(sp3)ÀH aminations by Yu[12b] and Qin[12c] by using benzoyloxy-
amines as aminating reagents (Scheme 1b,c). Direct amination
of unactivated C(sp3)ÀH bonds by alkylamines to construct
C(sp3)ÀN bonds represents an unmet challenge and has never
been reported, but offers a great advantage in that it saves
extra steps for the preparation of benzoyloxyamines and sim-
plifies the overall synthetic procedure. To achieve such chal-
lenging transformations, proper oxidative conditions are to be
identified. Herein, we report the first example of intermolecular
amination of unactivated C(sp3)ÀH bonds with cyclic alkyl-
amines mediated by CuII/O2 (Scheme 1d). This protocol directly
couples b-C(sp3)ÀH bonds of a,a-disubstituted propionic
wide biological and medicinal properties.[13] It is worth noting
that this method is mediated by CuII/oxygen. Copper is an
abundant and cheap metal, and oxygen is environmentally
friendly and rich terminal oxidant on the earth.
In our continuing efforts to develop new C(sp3)ÀN bond-for-
mation reactions,[12c] we became interested in 8-aminoquino-
line (AQ)-directed[14] amination of b-C(sp3)ÀH bonds of a,a-dis-
ubstituted propionic amides by alkylamines as aminating
agents. This transformation could produce a variety of unnatu-
ral b2,2-amino acid analogues in a straightforward fashion if it
was successful. Amination of 1a by 2a was chosen as the
model reaction for optimization (Table 1). Screening of various
copper metals in DMSO revealed that 20 mol% Cu(OAc)2 af-
forded the amination product 3aa in 18% yield (Table 1,
entry 5). Investigation of solvent showed that DMSO remained
optimal (entries 6–9). Additives such as Ag2CO3/NMO[7d] or IBD
did not improve the yield (entries 10–11). Gratifyingly, when
the quantity of Cu(OAc)2 used was one equivalent, the yield of
3aa was improved to 47% (entry 12). Base Na2CO3 was detri-
mental to the reaction[7f] (entry 13). The yield was increased to
[a] Q. Gou, Y.-W. Yang, Z.-N. Liu, Prof. J. Qin
Key Laboratory of Medicinal Chemistry for Natural Resource
Ministry of Education, School of Chemical Science and Technology
Yunnan University, Kunming, Yunnan 650091 (P.R. China)
E-mail: qinjun@ynu.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201603370.
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a lipid-lowering drug,[16] was successfully aminated in 68%
yield (3pa). Further exploration revealed that a bulkier sub-
strate was also tolerated (3qa). Finally, cyclic substrates also
delivered the products, though in lower yields (3ra–3sa). Intri-
guingly, we found that substrates containing a-hydrogen or
amination of the secondary C(sp3)ÀH bond were not working.
Afterwards, we explored the scope of amine partners. Diverse
alkyl- or aryl-substituted piperidines proceeded the aminations
in good yield (3ab–3ag). Moreover, various functional piperi-
dines with ester, ketal, or ether groups (3ah–3aj) were also
well tolerated. In addition, thiomorpholine and piperazine
were successful as amine partners (3ak, 3al). The scope of
amine can be further expanded to azepane, pyrrolidine, and
azetidine (3am, 3an, 3ao). It is worth noting that diallylamine
also proceeded the amination though in low yield (3ap). The
allyl protection of the product could be removed to release
the amine group, which is a useful handle for further derivati-
zation. However, in general, acyclic dialkylamines or primary al-
kylamines (e.g. Bu2NH, BuNH2) did not currently work as amine
partners. It should be noted that the major mass balance of
those reactions with low yields was the unreacted 1. Overall,
the reaction showed useful substrate scope of quaternary car-
boxylic amides and cyclic alkylamines. The resulting products
are important structural motifs that widely exist in medicinally
and biologically active compounds. The utility of this method
was further highlighted in a synthesis of CNS disorder modula-
tor HY-2901 (Scheme 2).[17] Under the reaction conditions, ami-
nation of 1.0 mmol 1a by 2q successfully afforded 3aq in
62% yield. Removal of the AQ was achieved by NaOEt to
afford HY-2901 in 90% yield.
Table 1. Optimization of the reaction conditions.[a]
Entry
Cu metal (equiv)
Additive
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
CuI (0.2)
CuBr2 (0.2)
CuF2 (0.2)
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
trace
0
5
0
18
11
Cu(TFA)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
toluene
DCE
0
0
9
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
trace
9
trace
47
15
72
71
trace
trace
10[c]
11[d]
12
13[e]
14[f]
15
16[g]
17[h]
Ag2CO3, NMO
IBD
Na2CO3
[a] General procedure: 1a (0.20 mmol), 2a (0.60 mmol), Cu metal
(x equiv), and additive (x equiv) in solvent (2.0 mL) under O2 at 1308C for
2 h. [b] Determined by 1H NMR analysis of the crude product using
CH2Br2 as the internal standard. [c] Ag2CO3 (0.2 equiv), NMO (2 equiv). 1a
recovered in 90%. [d] IBD (PhI(OAc)2) (2 equiv). [e] Na2CO3 (2 equiv). 1a
recovered in 60%. [f] 1a recovered in 13%. [g] Reaction under Ar. [h] Re-
action at 1108C.
72% when two equivalents of Cu(OAc)2 were used (entry 14).
A further increase in the amount of Cu(OAc)2 to three equiva-
lents had no positive effect on the yield (entry 15). Dioxygen
was essential to the reaction (entry 16). Lowering the reaction
temperature to 1108C led to no reaction (entry 17). Overall, the
optimal reaction conditions were using two equivalents
Cu(OAc)2 in DMSO under O2 at 1308C.
Next, we evaluated the potential of other known directing
groups in assisting this transformation, including the perfluor-
oaniline,[15a] 2-(pyridine-2-yl)-isopropylamine,[15b] 2-methylthioa-
niline,[15c] picolinamide,[15d] 2-aminopyridine N-oxide,[15e] and 2-
(4,4-dimethyl-4,5-dihydrooxazol-2-yl)aniline.[15f] We found that
none of those groups were effective in directing the amination
under the reaction conditions (see the Supporting Informa-
tion).
Scheme 2. Synthesis of CNS disorder modulator HY-2901.
With the optimal conditions in hand, we explored the reac-
tion scope (Table 2). Substrates with simple aliphatic chains
were well tolerated to deliver the products in good yields
(3ba–3 fa). Sterically hindered aryl analogues afforded the
product in moderate yield (3ga). Benzyl analogues regardless
of their electronic properties were well tolerated to give the
products (3ha–3ma). The aryl substitution of the substrate
can be further extended to the d-position to proceed the ami-
nation (3na). An olefinic substrate was also tolerated (3oa).
Late-stage functionalization of pharmaceutical agents could di-
versify the chemical structure with the potential to modify the
PK/PD profiles of the agent. An analogue of gemfibrozil,
The preliminary data of kinetic isotope experiments (parallel
intermolecular KIE=2.7, see the Supporting Information) im-
plied that the cleavage of the b-C(sp3)ÀH bond occurred as the
rate-limiting step. It was found that radical quencher 2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO) inhibited the reaction
between 1a and 2a completely, suggesting a radical pathway
was involved. Additionally, we found that in the absence of
2a, 1a produced acetoxylation and hydroxylation product 5
and 6 in 8 and 21% yield, respectively, under the conditions.
Based on these observations, we putatively proposed a reaction
pathway (Scheme 3). First, complexation of 1a with Cu(OAc)2
generated intermediate I. Then a base-assisted C(sp3)ÀH activa-
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Table 2. Substrate scope of the reaction.[a]
[a] Reaction conditions: 1 (0.20 mmol), 2 (0.60 mmol), and Cu(OAc)2 (2.0 equiv) in DMSO (2.0 mL) under O2 at 1308C for 2 h. Yield is the isolated yield.
tion took place to produce CuII intermediate II. Meanwhile, 2a
was oxidized by another equivalent Cu(OAc)2 together with O2
to afford a nitrogen radical species,[19] which then underwent
an oxidative radical coupling with II to afford a CuIII intermedi-
ate III. Subsequent reductive elimination led to 3aa together
with the formation of CuI, which was oxidized by O2 to regen-
erate CuII (path a). In the absence of 2a, path b was dominant.
In this case, CuII intermediate II was further oxidized by
Cu(OAc)2 to form CuIII intermediate IV, which underwent a re-
ductive acetoxylation to give 5, followed by hydrolysis afford-
ing 6.[7a,20] Nevertheless, additional solid evidence is needed to
fully elaborate the reaction pathway.
In summary, the first example of intermolecular amination of
unactivated C(sp3)ÀH bonds with cyclic alkylamines has been
successfully developed. This protocol is mediated by Cu(OAc)2/
O2. The method demonstrates useful substrate scope of qua-
ternary carboxylic amides and cyclic alkylamines. Various un-
natural b2,2-amino acid analogues are prepared by the method.
Scheme 3. Proposed reaction mechanism.
The utility of the method is further illustrated in a synthesis of
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scope.
Experimental Section
General method
A
10 mL Schlenk tube was charged with 1 (0.20 mmol), 2
(0.60 mmol), Cu(OAc)2 (0.40 mmol), and DMSO (2.0 mL). Then the
mixture was purged with high-purity oxygen and tightly capped. It
was stirred at rt for 1 min for proper mixing of the reactants, and
then heated at 1308C with vigorous stirring for 2 h. Afterwards, the
tube was cooled to rt, diluted with ethyl acetate, and washed with
30% ammonium hydroxide and brine. The organic layer was dried
over anhydrous Na2SO4, concentrated in vacuo to give the residue.
The crude residue was purified by flash chromatography on silica
gel to afford the title product 3.
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We gratefully acknowledge financial support from National
Natural Science Foundation of China (No. 21272201), Program
for Changjiang Scholars and Innovation Research Team in Uni-
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Keywords: amination · CÀH activation · CÀN bonds · copper ·
cyclic alkylamine
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Received: August 5, 2016
Published online on && &&, 0000
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COMMUNICATION
&
CÀH Activation
Q. Gou, Y.-W. Yang, Z.-N. Liu, J. Qin*
&& – &&
Intermolecular Amination of
Unactivated C(sp3)ÀH Bonds with
Cyclic Alkylamines: Formation of
C(sp3)ÀN Bonds through Copper/
Oxygen-Mediated C(sp3)ÀH/NÀH
Activation
Intermolecular amination of unactivat-
ed C(sp3)ÀH bonds by cyclic alkylamines
mediated by Cu(OAc)2/O2 has been re-
ported. This method avoids the use of
benzoyloxyamines as the aminating re-
agent. A variety of unnatural b2,2-amino
acid analogues are synthesized by this
simple and efficient procedure (see
scheme).
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Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!