N-Heterocyclic carbene-chromium-catalyzed alkylative cross-coupling of benzamide derivatives with aliphatic bromides

Article abstract of DOI:10.1039/c8cc05026k

Described here is a chromium-catalyzed alkylative cross-coupling of benzamide derivatives with aliphatic electrophiles under mild conditions. This reaction was promoted by a low-cost and air-stable chromium(iii) chloride salt combined with an N-heterocycl

Full text of DOI:10.1039/c8cc05026k

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DOI: 10.1039/C8CC05026K
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N-Heterocyclic Carbene-Chromium-Catalyzed Alkylative Cross-
Coupling of Benzamide Derivatives with Aliphatic Bromides
Jinghua Tang, ab Pei Liu ab and Xiaoming Zeng *ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Described here is a chromium-catalyzed alkylative cross-coupling of
benzamide derivatives with aliphatic electrophiles under mild
conditions. This reaction was promoted by low-cost, air-stable
chromium(III) chloride salt combined with N-heterocyclic carbene
ligand and phenylmagnesium bromide as reductant, probably
occurring with low-valent chromium to catalytic cleavage of ortho-
C–H bonds of benzamides, followed by coupling with alkyl
bromides through radical-involving mechanism.
Transition-metal-catalyzed alkylative reactions are of powerful
and useful tools in modern chemistry.1 Since Murai and co-
workers disclosed the first alkylation of aromatic ketones by
ruthenium catalysis at the early stage of 1990s,2 the
incorporation of an aliphatic scaffold into aromatic
hydrocarbons by the direct functionalization of unactivated and
ubiquitous C–H bonds has attracted immense interest of
chemists, which has largely revolutionized the means of modern
synthesis to construct fundamental feedstock chemicals.3,4
Recent progress in the field mainly focused on using earth-
abundant, non-rare base metals to replace precious transition
metal catalysts in developing cost-effective strategies.5–8
Among those reaction, chelation system using N,N-bidentate
directing group especially 8-aminoquinoline which was
pioneering reported by Daugulis9 proved to be successful. For
example, Chatani and co-workers disclosed that nickel
complexes show high reactivity in the catalytic alkylation and
methylation of aromatics at elevated temperature (Scheme
1a).10,11 Cobalt-enabled alkylation of C–H bonds was also
described by Nakamura12 and Yoshikai13 by the use of alkyl
chlorides and bromides as partners. The groups of Nakamura,14
Cook15 and Ackermann16 described the examples of alkylation
of aryl carboxamides with iron catalysis. Interestingly,
Kakiuchi17 reported that zero-valent iron complex ligated by
trimethylphosphine was able to catalyse the ortho-alkylation of
aryl ketones by anti-Markovnikov addition of C–H bonds to
olefins. In addition, the group of Wang reported the example of
Mn-catalyzed alkylation of C–H bonds by conjugated addition to
α,β-unsaturated carbonyls.18 In contrast to the great
achievements with nickel, cobalt and iron catalysis, the use of
other first-row base metal catalysts for alkylation of C–H bonds
has rarely been studied.19
Group 6 metal chromium catalysis, traditionally used for
ethylene oligomerization and oxidations,20 recently shows the
ability to cleavage and cross-coupling of unactivated chemical
bonds such as C–O and C–N bonds,21 as well achieving the
annulation for phenanthrene synthesis.22,23 Despite the
progress, reactive Grignard reagents are still used as coupling
partners in these Cr-catalyzed cross-coupling reactions. Herein,
we report a chromium-catalyzed method for the ortho-
alkylation of benzamide derivatives with alkyl halides. This
reaction was promoted by low-cost and air-stable chromium(III)
chloride salt combined with N-heterocyclic carbene ligand and
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DOI: 10.1039/C8CC05026K
Table 1 Optimization of Reaction Conditionsa
entry
1
Cr salt
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl3
CrCl2
Cr(acac)3
Cr(CO)6
ligand
–
dppe
dppe
dppe
RMgX
PhMgBr
PhMgBr
MeMgCl
EtMgBr
TMSCH2MgCl
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
3a (%)b
22
37
13
20
< 5
25
29
40
47
43
83
73
2
3c
4c
5c
dppe
6c
dppbz
2,2’-bpy
PCy3
IPr–HCl
IMes–HCl
IPr–HCl
IPr–HCl
IPr–HCl
IPr–HCl
IPr–HCl
7c
8
9
10
11d
12e
13
14
15
70
59
ndf
aConditions: 1a (0.2 mmol), 2a (0.8 mmol), Cr salt (0.02 mmol), ligand (0.04
mmol), RMgX (0.7 mmol), 2-MeTHF (1.0 mL), 65 oC, 24 h. bIsolated yields
were given. c10 mol % ligand was used. d40 oC. eThe reaction was performed
at room temperature. fNot detected.
phenylmagnesium bromide as reductant and base, providing
access to ortho-alkylated compounds by catalytic cleavage of
unactivated C–H bond at ambient temperature (Scheme 1b).
It was shown that chromium species in the low-valent state
possesses high catalytic activities in cross-coupling reactions.
We envisioned that the in-situ generated low-valent Cr species
by reduction of the Cr (III) salt with aryl Grignard reagent might
have the ability to cleave unactivated C–H bonds in the
assistance of auxiliary, the resulting cyclochromate
intermediate could couple with electrophiles such as alkyl
halides to form C–C bonds. To test our hypothesis, we
commenced our study to probe the reaction between 8-
quinolinyl-substituted benzamide 1a and n-butyl bromide with
chromium catalysis (Table 1). In the presence of 10 mol % of
CrCl3 and 3.5 equivalents of phenylmagnesium bromide, we
were pleased to find that the ortho-alkylation occurred
smoothly to give the related product 3a in low yield (entry 1).
Putting phosphine ligand of 1,2-bis(diphenylphosphino)ethane
(dppe) into the reaction slightly improved the conversion (entry
2). In contrast, the use of organomagnesium reagents such as
MeMgCl, EtMgBr and TMSCH2MgCl led to inferior results
(entries 3–5). The effect of ligands on the Cr-catalyzed alkylation
was studied. 1,2-Bis(diphenylphosphino)benzene (dppbz) and
2,2'-bipyridine (bpy) cannot improve the transformation
(entries 6 and 7). Interestingly, electron-rich N-heterocyclic
aReaction conditions: 1a (0.2 mmol), 2 (0.8 mmol), CrCl3 (0.02 mmol),
IPr–HCl (0.04 mmol), PhMgBr (0.7 mmol in 2-MeTHF), 2-MeTHF (1.0 mL),
40 oC, 24 h. bIsolated yields.
Grignard reagent with n-butyl bromide did not take place under
present conditions. Other chromium salts such as CrCl2 and
Cr(acac)3 gave inferior performance in the alkylation (entries 13
and 14). However, the reaction was completely inhibited when
Cr(CO)6 was used (entry 15).
carbene of IPr–HCl slightly increased the reaction rates, giving
3a in 83% yield when decreasing the reaction temperature to
40 oC (entries 9 and 11). Interestingly, the formation of biphenyl
as side product in small amount of yield (< 8%) was observed in
the reaction. Whereas the cross-coupling between phenyl
Having the optimal reaction conditions in hand, the substrate
scope was next examined. As shown in Scheme 2, this N-
heterocyclic carbene-chromium catalytic system can be applied
to the ortho-alkylation of benzamide with a variety of primary
2 | J. Name., 2012, 00, 1-3
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aliphatic halides. The reaction using n-hexyl bromide occurred benzamide motif did not largely hamper the reaction (3v
View Article Oanlninde
DOI: 10.1039/C8CC05026K
effectively, giving ortho-hexylated derivative 3b in 85% yield 3w).
(entry 2). In addition to alkyl bromide, the related iodide
According to previous reports, low-valent Cr species can be
counterpart can be utilized as suitable electrophile to couple formed by reduction of Cr salts with Grignard reagents.24 To
with 1a (entry 3). It was noted that functionalities of alkoxy, probe the possibility of low-valent Cr catalysis responsibility for
chloride, bromide and alkenyl on the scaffolds of alkyl bromides the alkylation, chromium(III) chloride was initially treated with
o
can be well compatible in the chromium-catalyzed protocol PhMgBr and IPr ligand at 40 C for 2 h. After the addition of
(entries 6–9). 1-Bromo-2-methylpropane coupled with benzamide 1a and n-butyl bromide, it was found that the
benzamide derivative 1a smoothly, giving the desired product related alkylation product 3a could be formed, albeit in low
3j in preparatively useful yield (entry 10). Interestingly, the Cr- yield (Scheme 4, eq 1). Furthermore, quenching the reaction
catalyzed alkylation tolerated the chloride and bromide between 1a and CrCl3/IPr/PhMgBr with D2O allowed the
moieties in the phenolyl scaffold of alkyl bromides, providing incorporation of 29% of deuterium into the ortho position of
access
to
2-chloro-
and
bromophenoxy-substituted benzamide (eq 2). These indicate that in-situ generated reactive
propylbenzamide derivatives 3k and 3l in good yields. This Cr- Cr species could be considered, which was able to cleave the
catalyzed protocol can be applied to the selective introduction ortho-C–H bond of 1a. If 1-hexene was used, alkylated product
of heterocycle of benzo[d][1,3]dioxole into the ortho position of was not formed, showing that a hydroarylation process of olefin
benzamide motif (3m). However, the treatment of secondary was not involved in the transformation (eq 3). Interestingly, the
aliphatic bromide with 1a did not form the desired coupling formation of cyclized compound
8 combined with the related
product in the Cr-catalyzed alkylation. product was observed when using 6-bromo-1-hexene (eq 4).
7
We next probed the scope of 8-aminoquinoline-containing This Cr-catalyzed alkylation may take place by alkyl radical-
benzamides by the reaction with n-butyl bromide (Scheme 3). involving pathway, resulting in the formation of cyclic coupling
The incorporation of methoxy group into the ortho position of product.12,14 The addition of radical scavenger of 2,2,6,6-
benzamide has no influence on the alkylation, forming the
desired product 3n in 80% yield. The alkylation with ortho-
phenyl-substituted benzamide occurred smoothly with Cr
catalysis. In addition, 1-naphthyl amide was also amenable to
couple with aliphatic bromide to give the alkylated compound
3p. 1,2- or 1,3-disubstituted benzamides containing methyl,
methoxy, chloride and fluoride groups were suitable coupling
partners in the alkylative reaction, forming the related products
3q–3u in 50–74% yields. Interestingly, the steric hindrance
aroused from 3-methyl or fluoride substituent on the
aReaction conditions: 1 (0.2 mmol), 2a (0.8 mmol), CrCl3 (0.02 mmol),
IPr–HCl (0.04 mmol), PhMgBr (0.7 mmol in 2-MeTHF), 2-MeTHF (1.0 mL),
40 oC, 24 h. bIsolated yields.
Scheme 3 The Scope of Benzamide Derivativesa,b
Scheme 4 Mechanistic Studies
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Chem., Int. Ed., 2018, 57, 5858. (r) L. D. Tran and O. Daugulis,
tetramethylpiperidine-1-oxyl (TEMPO) completely inhibited the
alkylation (eq 5).25 A low KIE value of 1.42 was obtained,
implying that the cleavage of ortho-C−H bond of benzamide
may not be rate-limiting step in the alkylation (eq 6).
View Article Online
Org. Lett., 2010, 12, 4277.
5
6
Selected reviews of nickel catalysis:D(Oa)I: 1M0..10T3o9/bCis8uCCa0n5d026NK.
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Standley and T. F. Jamison, Nature, 2014, 509, 299.
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Acc. Chem. Res., 2014, 47, 1208. (b) Y. Kommagalla and N.
Chatani, Coord. Chem. Rev., 2017, 350, 117. (c) M. Moselage,
In summary, we have developed an ortho-selective
chromium-catalyzed alkylative cross-coupling of C–H bonds
using benzamide derivatives to couple with alkyl bromides. This
reaction was enabled by a simple, low-cost chromium salt as
precatalyst combined with N-heterocyclic carbene as ligand and
phenylmagnesium bromide as the base and reductant, allowing
for the formation of ortho-alkylated coupling products at
ambient temperature. It was noted that the alkylation
proceeded in high selectivity while giving trace amount of the
cross-coupling byproduct by reaction of phenyl Grignard with
alkyl bromide. Further studies by expanding the application of
Cr-catalyzed cross couplings in synthesis are under way.
Support for this work by SCU from a start-up fund and the
National Natural Science Foundation of China [Nos. 21202128
and 21572175 (X.Z.)] is gratefully acknowledged.
J. Li and L. Ackermann, ACS Catal., 2016, 6, 498.
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Conflicts of interest
There are no conflicts to declare.
Notes and references
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