Copper-catalysed oxidative C-H/N-H cross-coupling between formamides and amides through chelation-assisted N-H activation

Article abstract of DOI:10.1039/c3ob40094h

A copper-catalysed oxidative C-H/N-H cross-coupling between formamides and amides through chelation-assisted N-H activation has been developed for the preparation of various multi-substituted ureas.

Full text of DOI:10.1039/c3ob40094h

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Copper-catalysed oxidative C–H/N–H cross-coupling
between formamides and amides through
chelation-assisted N–H activation†
Cite this: Org. Biomol. Chem., 2013, 11,
1925
Received 17th January 2013,
Accepted 1st February 2013
Xiaoyu Li, Bijin Li, Jingsong You and Jingbo Lan*
DOI: 10.1039/c3ob40094h
www.rsc.org/obc
A copper-catalysed oxidative C–H/N–H cross-coupling between available sources, is still necessary for synthetic and medicinal
formamides and amides through chelation-assisted N–H activation chemists. No doubt, the direct oxidative cross-coupling
has been developed for the preparation of various multi-substi- between formamides and amides would be an ideal strategy to
tuted ureas.
form the C–N bond and prepare substituted ureas. The use of
copper salts as catalysts for oxidative cross-coupling reactions
has always attracted much interest due to their low toxicity and
economical attractiveness.12 Recently, copper-catalysed direct
amidation of sp2 or sp3 C–H bonds was achieved in the pres-
ence of alkyl peroxides,13 which demonstrated that the N–H
bond of amides can be activated by copper and alkyl peroxides.
In addition, according to the results of Zhu, Wang and
Reddy,4,5 the alkyl peroxide can also activate the C–H bond of
formamides. Therefore, we envisioned that the copper-cata-
lysed oxidative cross-coupling between the C–H bond of form-
amides and the N–H bond of amides might be achieved in the
presence of an alkyl peroxide to build various multi-substi-
tuted ureas (Scheme 1).
To verify our hypothesis, the cross-coupling of N-phenyl
benzamide with DMF was investigated by using CuBr2 (5 mol%)
as a catalyst and tert-butyl hydroperoxide (TBHP, 65 wt% in
water, 1.5 equiv.) as an oxidant, but none of the desired coup-
ling product was detected (Scheme 1, entry 1). Inspired by the
chelation-assisted strategy for oxidative coupling reactions and
as a continuation of our recent work,14 we thus resorted to the
directed role of pyridine.15 N-Phenyl-2-picolinamide and
N-(pyridin-2-yl)benzamide were designed and synthesized as
test substrates. It was gratifying that both substrates reacted
N,N-Dimethylformamide (DMF) is not only an excellent solvent
for a great many of chemical reactions, but can also be utilized
as a multipurpose reagent, an effective ligand, or even as a cata-
lyst, and thus has been given increasing attention.1
Especially, in recent years, significant achievements have been
made in transition metal catalysed aminocarbonylation reac-
tions through the C–H bond activation of DMF. Highlights of
these research efforts include the aminocarbonylation of aryl
halides,2 the addition of DMF to alkenes and alkynes,3 and the
aminocarbonylation of β-ketoesters, ortho-carbonyl substituted
phenols and N-alkoxy amides via a cross-dehydrogenative
coupling reaction.4 In addition, a metal-free oxidative C–H/
C–H cross-coupling between azoles and DMF has also been
achieved by employing tert-butyl perbenzoate as an oxidant.5
The C–H bond activation of DMF can usually be extended to
other formamide derivatives. However, the oxidative C–H/N–H
cross-coupling between formamides and amides to construct
the C–N bond remains rarely developed.4a
Highly functionalized ureas have been paid much attention
due to their applications in pharmaceuticals6 and agrochem-
icals.7 Although numerous methods such as the substitution
reaction based on ureas with alkyl halides and acyl chlorides,8
the substitution or addition reaction based on phosgene, iso-
cyanates and their equivalents,6a,9 the oxidative acylation start-
ing from the thioureas,10 and transition-metal catalysed
coupling reactions4a,11 have been reported for the preparation
of multi-substituted ureas, development of the preferred and
alternative method, especially starting from other readily
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College
of Chemistry, and State Key Laboratory of Biotherapy, West China Medical School,
Scheme 1 Investigation of chelation-assisted N–H activation. Reactions were
carried out using amide (0.5 mmol), DMF (1 mL), CuBr2 (5 mol%), TBHP (65 wt%
in water, 1.5 equiv.), 80 °C, 12 h, N2. aYield of isolated product. n.d. = not
detected.
Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China.
E-mail: jingbolan@scu.edu.cn; Fax: (+86) 28-85412203
†Electronic supplementary information (ESI) available: Detailed experimental
procedures, analytical data. See DOI: 10.1039/c3ob40094h
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smoothly with DMF affording the corresponding coupling
products in 75% and 70% yields in the presence of CuBr2
and TBHP (Scheme 1, entries 2 and 3). Next, to get further
support for the chelation-assisted role of the 2-pyridyl
group, N-phenyl-3-picolinamide and N-(pyridin-3-yl)benz-
amide were synthesized and subjected to the cross-coupling
reaction with DMF. It was no surprise that the coupling reac-
tion did not occur under the same conditions (Scheme 1,
entries 4 and 5).
Table 1 Oxidative cross-coupling of formamides with N-substituted-
2-picolinamidesa,b
Subsequently, N-phenyl-2-picolinamide (1a) was chosen as
the standard substrate for screening out the optimal reaction
condition (ESI, Table S1†). Catalytic effects of various tran-
sition metal salts on the cross-coupling of 1a with DMF were
firstly evaluated in the presence of TBHP. Almost all of the
common copper salts were available, but CuBr was the most
effective one (Table S1,† entries 1–8). CoCl2·6H2O was also able
to work in this transformation, affording the coupling product
in 59% yield (Table S1,† entry 9). Other transition metal cata-
lysts such as Pd(OAc)2, FeCl3 and NiCl2·6H2O did not show sig-
nificant catalytic activities (Table S1,† entries 10–12). After
screening a series of peroxides and other oxidants, TBHP
turned out to be still the best choice (Table S1,† entries 2 and
14–19). Higher temperature was not beneficial for this reaction
(Table S1,† entry 23), meanwhile, yields were slowly decreasing
with lowering of the reaction temperature (Table S1,† entries 2
and 20–22). It was worth noting that the cross-coupling reac-
tion could also occur even at room temperature giving the
coupling product in a moderate yield (Table S1,† entry 22).
Although a high coupling yield could be obtained in just one
hour (75%, Table S1,† entry 24), 12 h was finalized as the
optimal reaction time for higher yields and generality
(Table S1,† entries 2 and 24–27). Attempts to reduce the
amount of formamide by loading 3 equivalents of DMF in no
or another solvent led to a low reactivity (Table S1,† entries
28–32). Not surprisingly, TEMPO, a common radical scavenger,
could strongly inhibit the reaction (Table S1,† entry 33), which
indicated that the reaction was likely to proceed by a radical
mechanism.
With the optimized conditions in hand, the scope of oxi-
dative cross-coupling between formamides and N-substituted-
2-picolinamides was investigated. A variety of N-aryl-2-picolin-
amides were found to be competent substrates and could
efficiently couple with DMF, affording the corresponding
multi-substituted ureas in good to excellent yields (Table 1,
3a–3g). Especially, this catalytic system could be tolerant to not
only fluoride, chloride and bromide but also the more challen-
ging iodide to give various halogenated N-aryl ureas, which
provided an opportunity for further synthetic transformations
(Table 1, 3d–3g). N-Alkyl-2-picolinamides showed lower activi-
ties under the same reaction conditions, providing the coup-
ling products in moderate yields. On increasing the loading of
TBHP to 2.5 equivalents, good yields could be obtained
(Table 1, 3h–3i). Other N,N-dialkyl formamides were also
available for coupling with N-aryl or alkyl substituted
2-picolinamides to produce a diversity of substituted ureas
(Table 1, 3j–3n).
a Conditions: N-substituted-2-picolinamide (0.5 mmol, 1.0 equiv.),
formamide (1 mL), CuBr (5 mol%), TBHP (65 wt% in water, 1.5 equiv.),
80 °C, 12 h, N2. b Isolated yield. c2.5 equiv. TBHP.
The optimized condition was also applicable to the cross-
coupling of formamides with N-(pyridin-2-yl)amides. A series
of N-(pyridin-2-yl)arylamides could successfully couple with
DMF to produce the corresponding substituted ureas in mode-
rate to good yields (Table 2, 5a–5g). 2-Fluorobenzamides may
be prone to decompose in the course of the reaction, especially
during heating, and thus the coupling of 4b with DMF only
gave the desired product in 40% yield at room temperature. It
is worth noting that N-(3-methylpyridin-2-yl)benzamide with
steric hindrance could undergo the coupling process to afford
the benzoyl urea 5g in 63% yield. However, it was unexpected
that when N-(pyridin-2-yl)propanamide was employed as the
coupling substrate, the corresponding product was not
detected (Table 2, 5h), which might be attributed to the
unstable imine intermediate.
Many a tri-substituted urea exhibits extensive pharma-
ceutical activities with potential applications such as anti-mela-
noma therapeutics,6a antiobesity therapeutics,6d and anti-HIV
drugs.6e So, it is necessary to remove the 2-pyridoyl group from
the coupling product to get a tri-substituted urea. After several
attempts, we were pleased to find that when 3a was treated
with NaOH in methanol at 50 °C, the tri-substituted urea 6a
was obtained with a high yield of 96% (Scheme 2). The
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Table 2 Oxidative cross-coupling of formamides with N-(pyridin-2-yl)-amidesa,b
Scheme 3 (a) Structure of [CuL2(H2O)2]·(NO3)2 (L = 1a) confirmed by X-ray
diffraction from the literature.17 (b) Possible coordination of Cu with 4a.
Scheme 4 Proposed mechanism.
a Conditions: N-(pyridin-2-yl)amide (0.5 mmol, 1.0 equiv.), formamide
(1 mL), CuBr (5 mol%), TBHP (65 wt% in water, 1.5 equiv.), 80 °C,
12 h, N2. b Isolated yield. c rt. d Not detected.
diffraction (Scheme 3, a).17 In the single crystal structure, the
nitrogen atom of the pyridine and the oxygen atom of the
amide coordinate to Cu(II) in a bidentate fashion. Similarly, if
4a is considered as a bidentate ligand, it is much more likely
to chelate copper forming a stable six-membered ring through
O-bonding rather than
a four-membered ring through
N-bonding (Scheme 3, b). So we speculated that the plausible
mechanism for the coupling reaction between 1a (or 4a) and
DMF might be shown in Scheme 4. Firstly, Cu(I) is oxidized by
TBHP to Cu(II), which is chelated by 1a (or 4a) to form 1aa (or
4aa). In the meantime, TBHP dissociates into a butoxy radical
and a hydroxyl radical through a homolytic cleavage. A Cu(III)-
complex of imine 1ab (or 4ab) was formed via depriving the
hydrogen of 1aa (or 4aa) by the hydroxyl radical and a single
electron transfer (SET) process of Cu(II). It is inferred that the
Scheme 2 Removal of the aroyl group.
benzoyl group of 5a could also be removed under the same complex of Cu(III) is a key intermediate, in which the imine
conditions to obtain 1,1-dimethyl-3-(pyridin-2-yl) urea (7a) structure is stabilized through a conjugate effect. On the other
with a yield of 68% (Scheme 2). It is worth mentioning that hand, an aminoacyl radical is generated from DMF by the
2-pyridylurea derivatives are the potent inhibitors of gastric butoxy radical.5 The addition of the aminoacyl radical to 1ab
acid secretion.16 Our method provides an alternative approach (or 4ab) results in the formation of the target product 3a
for their preparation.
(or 5a).
In summary, we have developed a copper-catalysed oxidative
To get insight into the mechanism of the oxidative C–H/N–H
cross-coupling between formamides and amides, we investi- C–H/N–H cross-coupling between formamides and amides
gated the coordination modes of copper with an amide. A Cu(II) through chelation-assisted N–H activation for the preparation
complex with N-phenyl-2-picolinamide (1a) has been reported of multi-substituted ureas. Amides containing a 2-pyridyl
and its crystal structure has been confirmed by X-ray group turn out to be crucial in this reaction. Our methodology
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is not only suitable for various formamides, but also for a rela-
tively wide range of N-substituted-2-picolinamides and N-
(pyridin-2-yl)amides. Particularly noteworthy is that the 2-pyri-
doyl group employed as the auxiliary coordination group can
be removed to get a tri-substituted urea. Further studies are
currently underway to find the applications of this strategy.
This work was supported by grants from the 973 Program
(2011CB808600), the Sichuan Provincial Foundation
(2012JQ0002), and the National NSF of China (Nos 21172155,
21025205 and 21021001).
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