Chelation-promoted Efficient C?H/N?H Cross Dehydrogenative Coupling between Picolinamides and Simple Ethers under Copper Catalysis

Article abstract of DOI:10.1002/adsc.201701508

A highly efficient copper-catalyzed C?H/N?H cross dehydrogenative coupling between picolinamides and simple ethers was developed. The reaction was promoted by the chelation assistance of removable picolinyl group and exhibited excellent TON and TOF number. This method was applicable to both N-aryl and alkyl picolinamides as well as various cyclic and acyclic ethers with good functional group compatibility. It also possessed the merit of air and moisture tolerance and easy operation. (Figure presented.).

Full text of DOI:10.1002/adsc.201701508

Title: Chelation-promoted efficient C−H/N−H cross dehydrogenative
coupling between picolinamides and simple ethers under copper
catalysis
Authors: Qiang Yue, Zhen Xiao, Zhengkun Kuang, Zhengding Su, Qian
Zhang, and Dong Li
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701508
Link to VoR: http://dx.doi.org/10.1002/adsc.201701508

10.1002/adsc.201701508
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Chelation-promoted efficient C−H/N−H cross dehydrogenative
coupling between picolinamides and simple ethers under copper
catalysis
Qiang Yue,a Zhen Xiao,a Zhengkun Kuang,b Zhengding Su,b Qian Zhang,a, * and Dong
Lia, *
a
School of Materials and Chemical Engineering, Hubei University of Technology, Wuhan 430068, China
Phone: +86-27-59750481; E-mails: zhangqian620@hotmail.com; dongli@mail.hbut.edu.cn
School of Food and Biological Engineering, Hubei University of Technology, Wuhan 430068, China
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A highly efficient copper-catalyzed C−H/N−H various cyclic and acyclic ethers with good functional
cross dehydrogenative coupling between picolinamides and group compatibility. It also possessed the merit of air and
simple ethers was developed. The reaction was promoted by moisture tolerance and easy operation.
the chelation assistance of removable picolinyl group and
exhibited excellent TON and TOF number. This method was
applicable to both N−aryl and alkyl picolinamides as well as
Keywords: copper; cross dehydrogenative coupling;
amides; ethers; C−N bond formation
between simple ethers and general amides was less
developed.[9, 10]
Introduction
The picolinamide moiety was first employed as a
directing group for Pd-catalyzed γ-C(sp3)−H arylation
by Daugulis and co-workers in 2005.[11] Subsequently
it has been widely used as a removable and reusable
bidentate directing group for various transition-metal-
The construction of C−N bond is of great importance
as nitrogen-containing compounds are found in
numerous biological active compounds, functional
materials and organic synthetic intermediates.[1]
Significant progress has been made towards the
C(sp2)−N bond formation through transition-metal-
catalyzed C−H amination over the past decade.[2]
However, facile and efficient methods for formation
of C(sp3)−N bonds are still highly demanded.[3]
Cross dehydrogenative coupling (CDC) reaction
has emerged as an useful tool for the atom-
economical construction of new C–C and C–
heteroatom bonds between C−H and another C−H or
X−H (X=O, S, N etc.) bond.[4] In recent years, the use
of simple ethers in CDC reaction has attracted much
attention, which can generate various α-C(sp3)−H
functionalized ether derivatives.[5] Despite the
importance of ether functionality which is ubiquitous
in organic compounds, the functionalization of simple
ethers is challenging because of their chemical
inertness.[6] A number of methodologies has been
developed for direct functionalization of the α-
C(sp3)−H bonds of simple ethers through CDC
reaction.[7] The formation of C(sp3)–N bond through
C(sp3)−H/N−H CDC between simple ethers and a
N−H reagent was also reported.[8] However, in these
methods the N−H source was limited to azoles,
sulfonamide, imides and saccharins. The CDC
catalyzed
remote
C(sp2)−H
or
C(sp3)−H
functionalization (Scheme 1a).[12] In recent years, Pd-
catalyzed picolinamide-directed intramolecular C−N
bond formation was also reported in which both the
remote C−H bond and the amide N−H bond were
activated (Scheme 1b).[13] Inspired by these studies,
we envisioned the employment of picolinamide as the
N−H source for C(sp3)−H/N−H CDC reaction with
simple ethers (Scheme 1c).[14] With the chelation
assistance of the picolinoyl group, the N−H bond
could be activated to couple with the α-carbon-
centered radical generated form ethers. Herein, we
reported an efficient copper-catalyzed C−H/N−H
CDC reaction between picolinamides and simple
ethers, which provided the C(sp3)−N bond coupling
product without influence of the γ-C−H bonds.
Results and Discussion
We carried out initial study with the reaction
between N-phenylpicolinamide (1a) and THF (2a)
under copper catalysis (Table 1). It was found that the
1
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10.1002/adsc.201701508
Advanced Synthesis & Catalysis
Scheme 1. Divergent reactivity of (diacyloxyiodo)arenes.
Table 1. Optimization of the reaction conditions.[a]
exhibited by PhI(OPiv)2, unreactive results were
obtained by others. A higher product yield
(77%) was achieved after increase the the
amount of TBHP to 3 equiv, which could be
further improved to 84% with 3.5 equiv. of
TBHP (entries 10 and 11). Then, we attempted
to promote the catalyst efficiency with some
common nitrogen ligand. At first, the addition of
10 mol% pyridine lead to a decreased yield
(entry 12). However great improvement was
exhibited with 10 mol% 2,2’-bypyridine (2,2’-
bpy) (entry 13). To our delight, complete
Cu(II)
(10 mol%)
Cu(OAc)2
CuCl2
oxidant
(equiv)
ligand
yield
Entry
(10 mol%) (%)[b]
1
2
3
4
5
6
7
8
9
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
DTBP (2)
Oxone (2)
K2S2O8 (2)
53
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
11
CuBr2
conversion
was
achieved
with
1,10-
Cu(OTf)2
Cu(OTFA)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
phenanthroline (1,10-phen) and more than 99%
product could be isolated (entry 14).
To further optimize the reaction conditions and
examine the unprecedented efficiency of this reaction,
we investigated the effect of catalyst loading and
reaction temperature (Table 2). With 10 mol%
catalyst, the reaction was completed at 25 °C after 8
hours (entry 1). Soon we found that the reaction time
could be dramatically reduced under higher
temperature. Full conversion was finished within 5
minutes at 65 °C, which demonstrated the TON of 10
and TOF of 100 (h–1) (entry 2). Subsequently we
performed the reaction with lower catalyst loading
such as 5, 2.5, 1, 0.5, 0.2 and 0.1 mol%. As shown in
Table 2, in most cases elevating reaction temperature
could effectively reduce reaction time and promote
the reaction to full conversion. Notably, the reaction
finished within 30 minutes with 0.5 mol% catalyst
under 85 °C, which showed the TON of 200 and
highest TOF of 400 (h–1) (entry 12). Highest TON
(345) was displayed by the reaction with 0.2 mol%
catalyst under 85 °C, which generated 69% product
after 8 hours (entry 14). Even with 0.1 mol% catalyst
the reaction could produce 30% of 3aa under 85 °C
for 8 hours (entry 16).
Cu(OAc)2 PhI(OPiv)2 (2)
10
11
12
13
14
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
TBHP (3)
TBHP (3.5)
TBHP (3.5)
TBHP (3.5)
TBHP (3.5)
77
84
58
91
>99
pyridine
2,2’-bpy
1,10-phen
[a]Reaction conditions: N-phenylpicolinamide (1a) (0.2
mmol), Cu(II) catalyst (10 mol%), ligand (10 mol%),
oxidant in THF (2a) (2.0 mL) stirring at 65 °C for 8 h.
[b]Isolated yields.
reaction proceeded in the presence of 10 mol%
Cu(OAc)2 and 2 equiv of tert-butylhydroperoxide
(TBHP) at room temperature (25 °C), affording the
cross dehydrogenative coupling product 3aa in 53%
yield after 8 hours (entry 1). The structure of 3aa was
unambiguously confirmed by X-ray crystallography.
[15]
It was worth noting that the reaction was handled
under air and anhydrous solvent was not necessary.
Other copper catalysts such as CuCl2, CuBr2,
Cu(OTf)2 and Cu(OTFA)2 were subsequently
examined but all resulted in no reaction (entries 2−5).
Next we investigated other oxidants such as di-tert-
butylperoxide (DTBP), oxone, K2S2O8 and
PhI(OPiv)2 (entries 6−9). Except for a poor efficiency
A preliminary kinetic study was carried out to
illustrate the reaction process. The plots of reaction
process with 2.5 and 0.5 mol% catalysts under
different temperatures were determined separately.
As shown in Fig. 1, the initial reaction rate was
2
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10.1002/adsc.201701508
Advanced Synthesis & Catalysis
Table 2. Examination of the effect of catalyst loading and
Table 3. Substrate scope of picolinamides (1).[a, b]
temperature.[a]
x
(mol%)
10
T
(°C)
25
65
25
65
25
45
65
25
65
45
65
85
65
85
65
85
time
(h)
8
0.1
8
0.25
8
6
1
8
2
8
4
0.5
8
8
8
yield TON [TOF
entry
(%)b
>99
>99
>99
>99
15
(h–1)]
10
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
10 (100)
20
20 (80)
6
5
2.5
>99
>99
0
40
40 (40)
0
1
>99
19
100 (50)
38
0.5
>99
>99
51
200
200 (400)
255
0.2
0.1
69
22
345 (43)
220
8
30
300 (38)
[a]Reaction conditions: N-phenylpicolinamide (1a) (0.2
mmol), Cu(OAc)2 (x mol%), 1,10-phenanthroline (x
mol%), TBHP (0.7 mmol) in THF (2a) (2.0 mL) under air.
[b] GC yields.
(a)
[a]Reaction conditions: picolinamide (1) (0.2 mmol),
Cu(OAc)2 (5 mol%), 1,10-phenanthroline (5 mol%), TBHP
(0.7 mmol) in THF (2a) (2.0 mL) stirring at 25 °C for 8 h.
[b]Isolated yields.
[c]With 10 mol% catalyst.
[d]Reaction for 24 h.
greatly facilitated under higher temperature. The
reaction with 2.5 mol% catalyst finished after 1 hour
at 65 °C and 6 hours at 45 °C. With lower catalyst
loading, equal outcome can be got with higher
temperature and longer reaction time. However the
reaction almost ceased after 8 hours even if it did not
complete, which probably due to the deactivation of
catalyst.
(b)
Figure 1. Plots of reaction process with different catalyst
loading. Reaction conditions: (a) catalyst loading (2.5
mol%), (b) catalyst loading (0.5 mol%). Yields determined
by GC.
3
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10.1002/adsc.201701508
Advanced Synthesis & Catalysis
In the point of view of easy operation, we chose
conducted for high efficiency, which was indicated
under each product. Cyclic ethers such as 2-methyl-
tetrahydrofuran (3ab), tetrahydropyrane (3ac), 1,6-
dioxane (3ad) and 1,3-dioxolane (3ae) all coupled
with the picolinamide in moderate to excellent yields.
the conditions of Table 2 entry 3 as the optimal one
for substrate scope examination as it can produce full
conversion under room temperature. A series of N-
substituted picolinamide (1) were applied for this
copper-catalyzed CDC with THF as shown in Table 3. Acyclic ethers such as diethyl ether (3af), dibutyl
Various N-aryl picolinamide can undergo this
transformation to provide the desired product in
excellent yields (3ba−3oa). Functional groups such
as OMe, F, Br, Cl are tolerated on the benzene ring.
All electron-donating, electron-withdrawing and
multi-group substituted substrate reacted smoothly
without significant electronic effect. Only if there is
substituent on the ortho-position (3da and 3fa), the
product yield decreased which perhaps due to the
steric hindrance. N-Alkyl picolinamides are also
applicable in this method, the product yields of which
are slightly lower than N-aryl picolinamides but still
considerable (3pa−3ua). Various sterically hindered
ether (3ag), dimethoxyethane (3ah) and tert-butyl
methyl ether (3ai) are also applicable in this reaction,
affording the products in relatively lower yields. Two
regioisomeric products were generated in the reaction
of DME as there are two kinds of α-C(sp3)−H bonds,
which were isolated and characterized respectively
(3ah and 3ah’). The terminal coupling product 3ah
was obtained in 75% yield and the internal one 3ah’
in 22% yield. Notably, thioether such as
tetrahydrothiophene also proceeded under this
condition to provide the corresponding product in
moderate yield (3aj).
To clarify the reaction mechanism, several control
experiments were carried out. The addition of a
radical scavenger such as 2,2,6,6-tetramethyl-1-
substituents
such
as
isobutyl
(3ra),
cyclopropylmethyl (3sa), cyclohexylmethyl (3ta) and
benzyl (3ua) groups were tolerated without
significant effect on product yield. Notably, γ-C−H
bonds existed in most of these substrates which might
be activated and become reaction sites in previous
reports[12, 13] did not influence this transformation at
all.
piperidinyloxy
(TEMPO)
or
butylated
hydroxytoluene (BHT) completely suppressed the
reaction. Two radical-trapping products 4 and 5 have
been isolated, which suggested that radical
intermediates might be involved in the reaction
pathway (Scheme 2a and 2b). Next we conducted the
reaction with 1:1 of THF and d8-THF to examine the
kinetic isotope effect. The kH/kD value was
determined to be 6.7, which implied the involvement
of C(sp3)−H bond cleavage of THF in the rate-
determining step (Scheme 2c). Finally, an analogous
substrate N-phenylbenzamide (6) was prepared and
examined under the standard reaction conditions but
no reaction occurred (Scheme 2d). It indicated the
essential role of the pyridyl group in this process,
which might enable the reaction by chelation
assistance.
Subsequently various simple ethers were
investigated
for
this
reaction
with
N-
phenylpicolinamide (1a) and the results were showed
in Table 4. The CDC reaction was handled in a series
of ethers. Modulations of reaction temperature are
Table 4. Substrate scope of ethers (2).[a, b]
[a]Reaction conditions: picolinamide (1) (0.2 mmol),
Cu(OAc)2 (5 mol%), 1,10-phenanthroline (5 mol%), TBHP
(0.7 mmol) in THF (2a) (2.0 mL) stirring at 25 °C for 8 h.
[b]Isolated yields.
Scheme 2. Control experiments.
4
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10.1002/adsc.201701508
Advanced Synthesis & Catalysis
coupling between picolinamides and simple ethers
under copper catalysis. The reaction was promoted by
the chelation assistance of picolinyl group and
exhibited excellent TON and TOF number. Both
N−aryl and alkyl picolinamides can be applied in this
method with various cyclic and acyclic ethers. It also
possessed the merit of good functional group
compatibility, mild reaction conditions and easy
operation. The product is also useful for further
transformation through easily removal of the pyridyl
group. Further studies on the reaction mechanism and
application of this synthetic methodology are
currently underway and will be reported in due
course.
Experimental Section
General procedure for the copper-catalyzed C−H/N−H
CDC between picolinamides and ethers.
Scheme 3. Plausible mechanism.
A mixture of N-phenylpicolinamide (0.2 mmol), Cu(OAc)2
(5 mol%), 1,10-phenanthroline (5 mol%) and TBHP (3.5
equiv, 70% aqueous solution) were added into a vial
containing a stirring bar and sealed with a Teflon-lined cap.
Then THF (2 mL) was introduced. The resulting mixture
was stirred at 25 °C for 8 h. After reaction the mixture was
added into H2O (25 mL) and extracted with ethyl acetate
(10 mL) for three times. The combined organic layer was
dried over anhydrous MgSO4 and filtered. After removal of
the solvent in vacuo, the residue was purified by column
chromatography (EtOAc/hexane) to afford the pure
product.
Scheme 4. Reduction of the N-(tetrahydrofuran-2-yl)-
picolinamide.
Based on the above results and previous reports,
we proposed a possible mechanism for this copper-
catalyzed C−H/N−H CDC reaction as shown in
Scheme 3. Initially, the picolinamide (1) coordinated
with Cu(OAc)2 to form a Cu(II) intermediate A with
Acknowledgements
16]
the chelation-assistance of pyridyl group.[12−14,
We are grateful to the National Natural Science Foundation of
China (No. 21702054, Q.Z.), the Hubei Provincial Innovative
Project (2016ACA128, Z.S.) and the Hubei Province Hundred-
Talent Program Fund of Hubei University of Technology (D.L.)
for financial support.
Meanwhile the ether 2a converted to an α-carbon-
centered radical species B mediated by tert-butoxy
radical, which was generated from TBHP under the
copper catalysis. Then intermediate A reacted with B
to produce a Cu(III) complex C.[17] Reductive
elimination of C generated the C(sp3)−N coupling
product 3 along with a Cu(I) species which would be
re-oxidized to Cu(II) under the reaction conditions.[18]
To further extend the synthetic application of this
method, we finally examined the transformation of
the N-(tetrahydrofuran-2-yl)picolinamide product
through reduction of amide. With 5 equiv of NaBH4,
the picolinoyl group was easily removed and the
cyclic ether ring broke to produce 4-phenylamino-1-
butanol (7) in high yield (Scheme 4). It will provide a
novel and efficient route for the preparation of N-
substituted amino alcohols, which can be easily
transformed to other useful compounds.[19]
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6
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Advanced Synthesis & Catalysis
FULL PAPER
Chelation-promoted efficient C−H/N−H cross
dehydrogenative coupling between picolinamides
and simple ethers under copper catalysis
Adv. Synth. Catal. Year, Volume, Page – Page
Author(s), Corresponding Author(s)*
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