Copper-catalyzed synthesis of arylcarboxamides from aldehydes and isocyanides: The isocyano group as an N1 synthon

Article abstract of DOI:10.1039/c7ob01449j

An interesting radical coupling reaction of aromatic aldehydes with isocyanides was disclosed for the synthesis of amides catalyzed by copper. According to the experimental results and mechanistic study, the isocyano group acted as an N1 synthon rather than exhibiting the carbene-like reactivity, exploiting a new reactivity profile of isocyanides.

Full text of DOI:10.1039/c7ob01449j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Copper-Catalyzed Synthesis of Arylcarboxamides from Aldehyde
and Isocyanides: Isocyano Group as an N1 Synthon
Jian-Quan Liu+,a* Xuanyu Shen+,a Zhenhua Liu,b Xiang-Shan Wanga*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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An interesting radical coupling reaction of aromatic aldehydes skilfully avoided the over insertion of isocyanides and used it
with isocyanides was disclosed for the synthesis of amides as radical coupling/isomerization strategy for the
catalyzed by copper. According to the experimental results and construction of
-aminoenones and tricarbonylmethanes.9
a
β
mechanistic study, the isocyano group acted as an N1 synthon Nanni and Curran discovered a method for the synthesis of
rather than the carbene-like reactivity, exploiting a new reactivity quinoxalines via a radical cascade progress.10 Surprisingly,
profile of isocyanide.
these strategies were rapidly developed for the construction of
important nitrogen heterocycles, such as phenanthridines and
other N-containing heterocycles.6d,6e Lately, Studer came true
the synthesis of iodinated alkyl quinoxalines by using ortho-
diisocyanoarenes as radical acceptors via atom transfer and
radical addition progress.11 However, all these transformations
were relied on the radicals addition to the isonitrile carbon
atom leading to the imidoyl radical intermediate, which
indicated that isonitriles was acted as radical acceptors (Figure
1b). Herein, we reported a novel radical C-N cross-coupling
strategy for aromatic aldehyde with isocyanides affording
amides. In our current work, C-N bond coupling event
immediately occurs via a radical coupling process with the
generation of amidogen radical intermediate (Figure 1c).
Remarkably, isocyano group as the source of N1 synthon was
less reported formerly.12
C-N bond formation is of utmost importance in organic
chemistry, biological molecules, pharmaceutical industries and
materials science.1 In the recent past, substantial advances on
C-N bond formation have been dramatically achieved. To the
best of our knowledge, three kinds of prominent C-N bond
formation reactions have been well-established including
Goldberg reaction,2 Chan-Lam coupling3 and Buchwald-Hartwig
aminations.4 However, compared to these electrophilic and
nucleophilic animation reactions, the development of C–N
bonds related to nitrogen-centred radicals is relatively dilatory
which is held back by the limited source of nitrogen radicals.
Thus, exploring suitable and novel type of nitrogen radicals is
still an important and highly attractive research.
Isocyanides are very versatile reagents in organic synthesis,
especially in the field of multi-component reactions (IMCRs)5
and heterocyclic chemistry.6 However, most of these reported
accomplishments are mainly focused on developing them as
the carbene-like reactivity; or emerging them as a valuable C1
building block (Figure 1a).6c Additionally, isocyanide insertion
reactions, polymerization processes and C-H functionalization
reactions have been well-established by using transition
metals as the catalysts which are also based on carbene-like
reactivity of isocyano groups.7,8 In contrast, radical isonitrile
reaction was less intensively investigated. Very recently, we
Figure 1. Reactivity patterns of isonitriles.
a). Carbene-like reactivity
EI
EI
Nu
R
N
R
NC
R
N
EI
Nu
b). Our previous work
EWG1
EWG2
EWG1
EWG2
EWG1
EWG2
R = Ar
R
NC
Ag(I) cat.
ArHN
RN
Imidoyl radical intermediate
c). This work
O
ArCHO
R
R
N
C
R
NH
Amidogen radical intermediate
Isocyano group as N1 synthon
Ar
N
H
Broad substrate scope
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We initiated the exploratory reaction between benzaldehyde smoothly, leading to the corresponding product
benzaldehyde (1a) and p-bromophenyl isonitrile (2a) as a 3j in 73% yield. Furthermore, a series of alkyl isonitriles was
model reaction by varying the metal salts, solvents and oxidant also tested, and found in delight that they were all suitable for
to optimize the protocol (Table 1). Delightfully, the reaction this transform (3k-3n) in appropriate yields, even if the
catalysed by CuI in the presence of 2 equiv of KBr and tert- substrates with strong steric effect, such as 2-isocyano-2-
butyl hydroperoxide (TBHP) afforded 3a in 81% yield (entry 1) methylpropane and (isocyanomethanetriyl)tribenzene, also
under nitrogen atmosphere. Compared to CuI, other metal could efficiently react with 1a, affording the corresponding
catalysts (FeCl2, CuBr2, AgNO3, CuBr, CuCl, and Ag2CO3) products 3m and 3n.
presented lower catalytic activity or even failed in this
transformation (entries 2-7). Subsequently, a series of solvents
Scheme 1. The scope of isonitrilesa,b
including 1,4-dioxane, DCE, CH3CN, benzene (entries 8-11)
were tested to further improve the result, and toluene was
CuI (10 mmol%)
KBr (2.0 equiv. )
TBHP (3.0 equiv.)
O
O
more adequate for the reaction than other solvents.
Encouraged by these finding, we also explored the influence of
the oxidants, including K2S2O8 and DTBP, regrettably, no
desired product 3a was formed (entries 12−14). It is worth
mentioning that no reaction was observed in the absence of
catalyst (entry 15). Additionally, no desired product was
obtained under the O2 atmosphere (entry 16). There was no
doubt that entry 1 was as the optimal reaction conditions.
R
+
R NC
N
H
Ph
Ph
1a
H
Toulene, 100 oC, N2
12 h
2
3
R
3a, 81%, R = 4-Br
3b, 84%, R = H
3f, 63%, R = 2-Me
3g, 42%, R = 2,4-Cl2
O
N
H
Ph
Ph
3c, 87%, R = 3-MeO
3d, 46%, R = 4-CF3
3e, 72%, R = 4-Me
3h, 59%, R = 2-Br-4-Me
3i, 76%, R = 3,4-dimethoxy
Table 1. Optimization of the Reaction Conditionsa
O
O
O
Ph
N
H
Ph
N
H
Ph
N
H
3j, 73%
3k, 61%
3l, 76%
entry
1
catalyst
CuI
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
DCE
oxidant
TBHP
3a (%)b
O
Ph
O
Ph
Ph
81
0
N
N
H
Ph
Ph
H
2
FeCl2
CuBr2
AgNO3
CuBr
CuCl
Ag2CO3
CuI
TBHP
3m, 78%
3n, 32%
3
TBHP
23
0
a All reactions were carried out with 1a (1.0 mmol), 2 (0.5 mmol), TBHP (1.5
mmol), KBr (1.0 mmol) and CuI (10 mmol%) in toluene (2.0 mL) at 100 °C under
N2 atmosphere for 12 h. b Isolated yields.
4
TBHP
5
TBHP
43
32
0
6
TBHP
7
TBHP
Subsequently, to further expand the scope of substrates, we
focused our concentration on investigating the influence on
aldehydes under the standard conditions (Scheme 2).
Delightfully, a range of aromatic aldehydes reacted with 2a
stably, furnishing the expected products (4a-4g) in 37~89%
yields. Among these, the aromatic rings with electron-donating
(R = OMe or Me) or withdrawing groups (R = Br, NO2 and CN)
presented high reactivity along with little electronic effect.
Unfortunately, when 4-pyridinecarboxaldehyde was used as a
substrate, there was no expected product in a mixture system.
Besides, as an example of alkyl aldehydes, n-pentanal was also
tested for this reaction. Regretfully, the experimental results
showed that it was ineffective substrate, and no reaction took
place as we expected.
8
TBHP
48
57
0
9
CuI
TBHP
10
11
12
13
14
15
16c
CuI
CH3CN
TBHP
CuI
benzene
toluene
toluene
toluene
toluene
toluene
TBHP
65
0
CuI
K2S2O8
DTBP
CuI
0
CuI
Selectfluor
TBHP
0
--
0
CuI
TBHP
0
a All reactions were carried out with 1a (1.0 mmol), 2a (0.5 mmol), oxidant (1.5 mmol),
KBr (1.0 mmol) and catalyst (10 mol%) in solvent (2.0 mL) at 100 °C under N2
atmosphere for 12 h. b Isolated yields. c under O2 atmosphere for 12 h.
Scheme 2. The scope of aldehydes a,b
With the optimized reaction in hand, we next investigated
the scopes and limitations of this transformation (Scheme 1). A
variety of alkyl and aryl isonitriles underwent the coupling with
benzaldehyde (1a) smoothly. There was little electronic effect
on this conversion, which could tolerate compatibly with
various groups at the position of aromatic ring (such as Br,
MeO, Me, CF3 and H, etc.) affording the desired products (3a-
3f) in moderate to good yields. To our delight, the bis-
substituted substrates were also well tolerated to give
products (3g-3i) in 42~76% yields. Additionally, it is worth to
be noted that the 2-isocyanonaphthalene could react with
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On the basis of the above experimental results and related
literature precedents,9,12,15
plausible mechanism was
a
tentatively outlined by using 1a and 2a as model substrates in
Scheme 4. In the radical initiation stage, the low-valent copper
catalyst transfers an electron to TBHP affording copper species
B17 and tert-butoxyl radical. Then, the complex CuI(RNC)n may
be formed and reacts with
Afterwards, the fate of
, is to donate an electron to X- (X = Br
or I), generating , radical and simple substance X2, thereby
leading to the regeneration of catalyst and completing the
catalytic cycle. Subsequently, the intermediate then
eliminates carbon monoxide to form radical . Meanwhile,
tert-butoxyl radical abstracts a hydrogen atom from aldehyde
1a leading to acyl radical and tertiary butanol. Finally, two
radicals and couple directly to release the product 3a
B to give the intermediate C.
C
A
D
A
D
E
F
E
F
.
a All reactions were carried out with
1 (1.0 mmol), 2a (0.5 mmol), TBHP (1.5
Scheme 4. Plausible Mechanism
mmol), KBr (1.0 mmol) and CuI (10 mmol%) in toluene (2.0 mL) at 100 °C
under N2 atmosphere for 12 h. b Isolated yields.
To probe a plausible mechanistic route for this reaction,
several experimental investigations were conducted and
performed under the standard conditions (Scheme 3). Once
the radical inhibitor 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) or 2,6-di-tert-butylhydroxytoluene (BHT) was added
to the solution of 1a and 2a, the reaction was completely
suppressed. Despite the adducts were failed to be captured,
the result predicted that the reaction should go through a free
radical intermediate [Eq. (1)].13 Meanwhile, N-(4-
bromophenyl)formamide was tested the plausible mechanistic
progress, and there was no desired products [Eq. (2)].14
Further, the possibility of the solvent as the acyl source via
oxidation process was excluded as no 3a could be isolated
from the reaction [Eq. (3)]. However, we detected the product
3a’ in 21% yield, suggesting the mechanism route is different
from that of ref.12. Finally, using [13C]-1a as a reactant,
isotope-labelling study unambiguously confirmed the aromatic
aldehyde compounds as the source of acyl affording [13C]-3a in
56% yield [Eq. (4)].
In conclusions, we have developed an intriguing and novel
copper-catalyzed radical coupling reaction of aromatic
aldehyde with isocyanides, providing a very convenient and
modular approach to the synthesis of amides. This report
presented a new fundamental C-N bond forming reaction
between two basic chemicals with broad range of substrates.
Importantly, this approach is mechanistically different from
the classical transition-metal-catalyzed isocyanides chemistry,
which isocyano group as an N1 synthon rather than the
carbene-like reactivity was disclosed.
Scheme 3. Control reactions for Mechanistic
Investigationsa
Acknowledgments
We are grateful to the Major Natural Science Foundation of
Jiangsu Province (14KJA150004), a project funded by the
Priority Academic Program Development of Jiangsu Higher
Education Institutions of Jiangsu Province for financial support
and the talent plan of Jiangsu Normal University (16XLR013).
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