Copper-Catalyzed Cross-Dehydrogenative Coupling of N-Iminoquinolinium Ylides with Secondary Amines

Article abstract of DOI:10.1002/ejoc.201600905

The copper-catalyzed cross-dehydrogenative coupling of N-iminoquinolinium ylides with secondary amines led to ortho-amino-substituted quinoline derivatives with high levels of regioselectivity in good yields. This direct C–H bond amination transformation employs CuI as the catalyst without the use of a ligand, external oxidant, or base. The reaction is operationally simple and can be conducted under mild conditions. The N-benzoyl directing group can be removed without any additional steps.

Full text of DOI:10.1002/ejoc.201600905

A Journal of
Accepted Article
Title: Copper-Catalyzed Cross-Dehydrogenative Coupling of N-Iminoquinolinium Yli-
des with Secondary Amines
Authors: Zerui Hua; Lei Fang; Shengying Wu; Limin Wang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600905
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European Journal of Organic Chemistry
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COMMUNICATION
Copper-Catalyzed Cross-Dehydrogenative Coupling of N-
Iminoquinolinium Ylides with Secondary Amines
Zerui Hua,[a] Lei Fang,[a] Shengying Wu,*[a] Limin Wang,*[a]
Abstract: Copper-catalyzed cross-dehydrogenative coupling of N-
Iminoquinolinium ylides with secondary amines leads to the ortho-
oxides forming 2-aminoquinolines (Scheme 2, eq. 1).[11]
Therefore, a new approach to obtain the 2-aminoquinoline in a
more efficient way is needed. To continue our work toward the
construction pyridine and quinoline derivatives using N-
iminopyridinium ylides,[4,12] we herein report, the copper-
catalyzed C(sp2)-H bond functionalization of quinoline with
secondary amines in the absence of additives using N-benzoyl
as a traceless directing group (Scheme 2, eq. 2).
amino-substituted quinoline derivatives in
a
high level of
regioselectivity in good yields. This direct C-H bond amination
transformation employed CuI as the catalyst without the use of
ligand, external oxidant and base. The reaction is operationally
simple and can be conducted under mild conditions. The
N-
benzoyl directing group can be removed without additional step.
Introduction
Quinolines, present in many synthetic drugs, are a class of
nitrogen-containing heterocycles.[1] For example, the ortho-
amino quinoline and isoquinoline derivatives are widely
prescribed as antihypertensive agents, antidepression drugs,
inhibitors of beta-site amyloid precursor protein cleaving enzyme
1 (BACE1), and CB2 receptor agonists (Scheme 1).[2] Thus, the
functionalizations of quinoline have great importance in organic
chemistry.
Compared with traditional cross-coupling reactions, which
usually involves additional prefunctionalization steps, direct
functionalization processes have emerged as extremely effective
alternatives.[3] Against this background, Charette, Wang, Jiao
and other groups have paid special attention to transition-metal-
catalyzed ortho-arylation,[4] alkenylation,[5] alkylation,[6] and
cascade cyclization[7] through C-H functionalization of N-
iminopyridinium ylides. N-iminopyridinium ylides have emerged
as versatile structures whereby complicated pyridine derivatives
can be prepared.[8]
Scheme 1. Various biologically active ortho-amino quinoline derivatives
Cross-dehydrogenative coupling (CDC) reactions have
become known as a powerful tool for the selective construction
of C-C, C-N, C-O, and C-P bonds,[9] among which atom
economy can be maximized by avoiding the prefunctionalization
steps of the substrates. Hence, compared with traditional
methods, CDC reactions are more efficient and environmentally
friendly.[10]
In 2014, Cui’s group has reported the copper-catalyzed direct
amination of quinoline N-oxide via C-H bond activation. However,
the toxic PCl3 was used to reduce the 2-aminoquinoline N-
[a]
Key Laboratory of Advanced Materials and Institute of
FineChemicals
Scheme 2. Different approaches to the synthesis of 2-aminoquinoline.
East China University of Science and Technology
130 Meilong Road, Shanghai 200237, P. R. China
E-mail: wanglimin@ecust.edu.cn
http://webmanage.ecust.edu.cn/s/230/t/243/a/54080/info.jspy
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
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COMMUNICATION
Results and Discussion
With an optimized set of conditions in hand, the scope of
secondary amines were then investigated (Table 2). Cyclic
secondary amines and more sterically hindered acyclic amines
could be converted to their corresponding 2-amino-substituted
quinoline derivatives in moderate to good yields (3a-3j).
Piperidine and pyrrolidine could provide the products 3a and 3c
in 80% and 78% yields, respectively. However, the 2-methyl
piperidine afforded the corresponding product 3b in 52% yield
due to steric hindrance. Morpholine and tetrahydroisoquinoline
were smoothly coupled with N-iminoquinolinium ylide, affording
the desired products 3d and 3e in 81% and 50% yields,
respectively. It was worth noting that caprolactam could afford
the desired product 3f in 51% yield under unmodified conditions.
Moreover, N-methylbenzylamine and dibenzylamine gave the
product 3g and 3h in 70% and 64% yields, respectively.
Reactants with long alkyl chains displayed poorer reactivity (3i,
3j). Unfortunately, diphenyl amine was inoperative (3k). In
addition, this methodology showed a limitation to the primary
amines.
Initially, we began our investigation by employing N-
iminoquinolinium ylide 1a and piperidine 2a as the model
substrates. 1a is readily available on a large scale according to
the previous report.[8] The screening of reaction conditions was
showed in Table 1. To our delight, we observed that CuI-
catalyzed coupling of 1a and 2a could afford the 2-amino-
substituted quinoline 3a with the removing of N-benzoyl directing
group in 80% isolated yield (Table 1, entry 1). Encouraged by
the results, we proceeded to optimize the reaction conditions by
screening copper catalysts including Cu(I) and Cu(II) (Table 1,
entries 2-5). CuI offered the highest yield. When Pd(OAc)2 was
employed instead of CuI, no desired product was observed
(Table 1, entry 6). The adding of Ag2CO3 as an oxidant was
unfavorable to the reaction (Table 1, entry 7). Adding the ligand
(TMEDA) led to a lower yield (Table 1, entry 8). The yield
promoted slightly when the reaction was performed under
oxygen (Table 1, entry 9). When the reaction was carried out
under argon, trace product was detected (Table 1, entry 10),
indicating the importance of O2 in this transformation. The
screening of solvents revealed that the conversion to the desired
product 3a was more efficient in toluene than in 1,4-dioxane,
xylene, DMF or DMSO (Table 1, entries 11-14). Decreasing the
temperature was unfavorable to the reaction (Table 1, entries 15
and 16). Increasing the temperature to 150 oC afforded the
product in 79% yield with no further promotion (Table 1, entry
17).
Table 2. Scope of Secondary Amines.[a]
Table 1. Screening of Reaction Conditions.[a]
Entry
1
Catalyst
CuI
Additive
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1,4-dioxane
xylene
T.(oC)
130
130
130
130
130
130
130
130
130
130
130
130
130
130
100
110
150
Yield [b] (%)
80
2
CuCl
CuBr
Cu(OTf)2
Cu(OAc)2
Pd(OAc)2
CuI
66
3
42
4
67
5
75
6
N.R.
55
7
Ag2CO3
TMEDA
8
CuI
52
9[c]
10[d]
11
12
13
14
15
16
17
CuI
81
CuI
trace
59
CuI
[a] Reaction conditions: 1a (0.2 mmol), 2 (2.0 mmol), CuI (20 mmol %) in the
toluene (1.0 mL) was stirred at 130 oC for 12 h. [b] Isolated yield.
CuI
70
CuI
DMF
trace
trace
23
The scope of the N-iminoquinolinium ylides was considered
next (Table 3). We were pleased to note that 6-substituted N-
iminoquinolinium species bearing methyl and methoxyl
substituents reacted in good yields (4a-4d). It is noted that 6-
bromo-substituted substrate can react smoothly to form the
desired product 4e, which may provide attractive scaffold for
further elaboration of product. Unfortunately, when the ylide
derived from 4-methylquinoline was employed, the yield of 4f
was decreased to 44%. In case of pyrrolidine, only trace of
product was obtained (4g). Notably, the N-iminoisoquinolinium
CuI
DMSO
CuI
toluene
toluene
toluene
CuI
55
CuI
79
[a] Reaction conditions: 1a (0.2 mmol), 2a (2.0 mmol), catalyst (20 mmol %) in
the solvent (1.0 mL) was stirred at 130 oC for 12 h; N.R.= no reaction. [b]
Isolated yield. [c] Under O2. [d] Under Ar.
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European Journal of Organic Chemistry
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COMMUNICATION
ylide was also viable partners (4h and 4i) in comparison to N-
iminoquinolinium ylide, with the latter giving the 2-amino-
substituted quinoline derivatives in excellent yield. N-
iminopyridinium was limited to this catalytic system (4j).
Table 3. Scope of N-iminoquinolinium Ylides.[a]
Scheme 3. Control experiments
On the basis of the above results and previous reports[5,11], a
plausible catalytic cycle was proposed (Scheme 4). CuI and N-
iminoquinolinium ylide can undergo deprotonation/metallization
to generate an organocupracycle 1 stabilized by the Lewis basic
iminobenzoyl moiety (A). Oxidative addition (B) into the
piperidine could make Cu (Ⅰ) oxidized into Cu (Ⅲ) complex 2
by O2 from air. And a subsequent reductive elimination (C)
afforded the intermediate 3 (detected by LC-MS, see ESI for Fig.
S2). CuI was regenerated to continue the catalytic cycle. Then
the intermediate 3 underwent hydrolysis to form the desired
product and benzoyl amide (detected by LC-MS, see ESI for Fig.
S3).
[a] Reaction conditions: 1 (0.2 mmol), 2a or 2c (2.0 mmol), CuI (20 mmol %) in
the toluene (1.0 mL) was stirred at 130 oC for 12 h. [b] Isolated yield.
To gain some insights on the reaction mechanism, control
experiments were carried out. Firstly, the addition of TEMPO, a
radical inhibitor, showed no significant effect on the reaction
yield, implying that radicals might not be involved in the catalytic
process (Scheme 3, eq. 1). Secondly, using quinoline instead of
N-iminoquinolinium ylide gave no desired product under the
standard conditions, indicating that the N-benzoyl group as a
Lewis basic activated the C-H bond at 2-position resulting in
high regioselectivity (Scheme 3, eq. 2). Finally, the yield suffered
a noticeable decrease when the reaction was conducted under
Ar, indicating that the oxygen in the air played an oxidant role in
this transformation. (Scheme 3, eq. 3).
Scheme 4. Plausible reaction mechanism
Conclusions
In summary, we have developed a new methodology for the
selective construction of C-N bond using N-iminoquinolinium
ylides with secondary amines on copper-catalyzed C-H bond
activation. This reaction features simple operation, no need for
ligand, base, and external oxidant. A series of 2-amino-
sustituted quinoline derivatives were afforded in moderate to
good yields. And a plausible mechanism was proposed.
Experimental Section
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European Journal of Organic Chemistry
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COMMUNICATION
General procedure for preparation of N-iminoquinolinium ylide:
Quinoline (0.26 mL, 2.0 mmol) and O-(2,4-Dinitrophenyl)hydroxylamine
(478 mg, 2.4 mmol) were added to 1.0 mL of a (1:1) mixture of H2O and
THF. The reaction flask was sealed, and the resulting suspension was
stirred at 40 oC for 12 h. During this period, the reaction mixture turned
dark red. Benzoyl chloride (0.35 mL, 3 mmol) was slowly added first and
let it react for 30 min before adding the aqueous NaOH (2.5 N, 12 mL) at
room temperature. After 4 h, the reaction was diluted with 10 mL of H2O
and extracted three times with 20 mL of CH2Cl2. The organic phase was
dried over Na2SO4. The mixture was evaporated under vacuum. The
corresponding N-iminoquinolinium ylide was isolated by silica gel column
chromatography with a dichlormethane/ methanol mixture as eluent,
affording the product as a beige solid.
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Typical procedure for CuI-catalyzed reaction of N-iminoquinolinium
ylides with secondary amines: The mixture of N-iminoquinolinium
ylides 1 (0.20 mmol), secondary amines 2 (2.0 mmol), CuI (0.04 mmol)
and toluene (1 mL) were added into a sealed tube. After being stirred
vigorously at 130 oC for 12 h, the mixture was evaporated under vacuum.
The corresponding product was isolated by silica gel column
chromatography with a petroleum ether/ethyl acetate (20:1) mixture as
eluent.
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Acknowledgements
This research was financially supported by the National Nature
Science Foundation of China (21272069, 20672035) and the
Fundamental Research Funds for the Central Universities and
Key Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences.
Keywords: N-Iminoquinolinium ylides • CDC reaction • CuI-
catalyzed
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European Journal of Organic Chemistry
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COMMUNICATION
COMMUNICATION
Coupling reaction*
Z. -R. Hua, L. Fang, S. -Y. Wu,* L. -M.
Wang*
Page 1. – Page 4.
Copper-catalyzed cross-
dehydrogenative coupling of N-
Iminoquinolinium ylides with
secondary amines
Copper-catalyzed cross-dehydrogenative coupling of N-Iminoquinolinium ylides with
secondary amines leads to the ortho-amino-substituted quinoline derivatives with
high regioselectivity in moderate to good yields without an additional reduction step
to remove the activated group.
*cross-dehydrogenative coupling, N-iminoquinolinium ylides
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