Selective mono-alkylation of N-methoxybenzamides

Article abstract of DOI:10.1039/c7cc01201b

We report our latest discovery of norbornene derivative modulated highly mono-selective ortho-C-H activation alkylation reactions on arenes bearing simple mono-dentate coordinating groups. The reaction features the use of readily available benzamides and alkyl halides. During the study, we prepared 30 mono-alkylated aryl amides in good yields with good mono-selectivity. We have also demonstrated that structurally rigid alkenes such as norbornene and its derivatives are a good class of ligand and could be used for future direct C-H functionalizations. The utilization of norbornene type ligands for assistance in C-H activation processes has opened a new window for future molecular design using direct C-H functionalization strategies.

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ARTICLE TYPE
Selective mono-alkylation of N-methoxybenzamides
Zenghua Chen,‡
Le’an Hu,‡
Fanyun Zeng,a,b,c Ranran Zhu,a,b,c Shasha Zheng,a,b,c Qingzhen Yua,b,c and
a,b,c
a,b,c
Jianhui Huang*a,b,c
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
5
DOI: 10.1039/b000000x
We report our latest discovery of norbornene derivative
Figure 1. Anti-cancer agents containing arene skeletons with
a coordinative group and an adjacent alkyl group
modulated highly mono-selective ortho-C–H activation
alkylation reactions on arenes bearing simple mono-
dentate coordinating group. Reaction features the
O
O
N
O
N
O
10 employment of readily available benzamides and alkyl
halides. During the studies, we have prepared 30 mono-
alkylated aryl amides in good yields with good mono-
selectivity. We have also demonstrated that structurally
rigid alkenes such as norbornene and derivatives are a
15 good class of additives could be used for the future C-H
direct functionalizations. The utilization of norbornene
type of additives for the assistance of C–H activation
processes has opened a new window for the future
molecular design using C–H direct functionalization
20 strategies.
NH Cl
N
N
H
S
N
HN
N
N
N
NH
N
N
O
O
CF3
CN
HO
Alectinib 1
Dasatinib 3
Sonidegib 2
O
O
H
N
N
N
N
H
N
N
N
HN
N
N
NH
O
N
NH
O
N
N
N
N
N
CF3
N
N
H
Nilotinib 4
Palbociclib 6
Imatinib 5
N
50
Introduction
Using easily available benzamide 7a, a common monoꢀdentate
directing group developed by Yu,37 we started screening sets of
conditions for the reaction. The reaction of benzamide 7a in the
presence of 10% of Pd(OAc)2 as the catalyst, with no additives
In organometallic chemistry, the utilization of directing group for
the activation and regulation of C–H direct functionalization on
the specific position has become one of the most studied areas in
25 the last 10 years. The directed orthoꢀC–H activation of arenes
possess coordinative groups for the direct introduction of arenes,
alkenes as well as heteroatoms is very well studied.1ꢀ8 More
recently, metaꢀC–H activation attracted considerable attention for
the access functionalities at the distal position.9ꢀ19 The directed
30 paraꢀC–H activation was also beautifully demonstrated by Maiti
using nitrile directing groups via the Dꢀshaped template.20
Arenes bearing potentially coordinative groups with orthoꢀ
aliphatic groups are often found in drug molecules. A number of
selected nibꢀtype of antiꢀcancer agents 1ꢀ6 are shown in Figure 1.
35 These molecules are all having a simple monoꢀdentate directing
group with an adjacent alkyl group. Transitionꢀmetal mediated
orthoꢀC–H activation alkylations have already been very well
studied under Pd,21ꢀ25 Ru,26 Rh,27,28 Ni,29,30 Cu,31 and Fe32ꢀ34
catalysed conditions. Approaches developed so far have been
40 focused on the use of bidentate directing groups35 as well as the
monodentate directing groups36. In addition, the selective monoꢀ
alkylation over diꢀalklyation is also a synthetic challenge. Herein,
we report our latest discovery on the norbornene derivative
modulated highly monoꢀselective orthoꢀC–H activation
45 alkylation reactions on arenes bearing monoꢀdentate coordinative
group.
55 did not give any of our desired monoꢀalkylated product 8aa nor
diꢀalkylated benzamide 8aa’. A range of inorganic bases such as
KOAc, K2HPO4 and K2CO3 as the additives were examined, the
reactions were not very successful, no desired products were
observed (supporting information Table 1). When CsOAc was
60 utilized, the desired monoꢀalkylated product 8aa was isolated in
25% yield together with 5% of diꢀalkylated product 8aa’.
Interestingly, inspired by Dong’s ‘acetate cocktail’ idea,18 the
addition of acetic acid together with CsOAc gave the desired
monoꢀalkylated product 8aa in 34% together with 15% of diꢀ
65 alkylated product 8aa’. A total 96% conversion was observed
while 2.0 equivalents of PivOH was employed and the monoꢀ
alkylated product 8aa was isolated in 53% yield together with
43% of dialkylated benzamide 8aa’. Under Chen’s conditions25
on the corresponding bidentate quinolyl amides, only a trace
70 amount of desired product was formed; the reaction conversion
was very low.
With the good conditions for high starting material conversion
in hand, we have examined the relatively weak ligand for the
increase of steric of Pd catalyst. A number of ligands L-01ꢀL-09
75 were tested. These ligands include pyridine type of ligands,
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amine ligands, crown ether, diaza crown ether and norbornene.
The corresponding results are listed in Table 2. The reaction
using 1.0 equivalent of bispyridine L-01 did not provide any of
our desired products, the use of 10% of ligand L-01 gave our
desired product 8aa in 29% yield together with 4% of diꢀ
alkylated arene 8aa’. The selectivity was very good, however, the
reaction conversion was rather low. Similar results were also
obtained on other cases when ligands having heteratom lone pairs
available. The use of less eletrondonating additive such as
5
10 norborene37 did not affect the reactivity much. More interestingly,
when increasing the amount of norbornene used to 1.0 equivalent,
the reaction resulted in good conversion with potential monoꢀ
selectivity.
Table 1. Ligand screening
aThe conversions of 7a to 8aa and 8aa’ within a period of 18 h.
35 With the optimal conditions in hand, we have evaluated the
scope and limitations of this reaction. Using iodobutane as the
alkylating reagent, a broad range of substrates with both electron
rich and electron deficient substituents on paraꢀ, metaꢀ and orthoꢀ
positions were examined. For the examples with no substituent or
40 substituents on paraꢀpositions, the reaction are all working
smoothly with good monoꢀselectivity. (Table 2)
15
The further detailed process monitoring was proceeded on a
series of norbornene derivatives. The conversion of monoꢀ
alkylated product 8aa and diꢀalkylated benzamide 8aa’ as well as
the consumption of starting benzamide were showing in graphs aꢀ
20 f Figure 2.
Table 2. Synthesis of monoalkylated aryl amides
From the six figures, we could clearly see that in the absence of
external additive the formation diꢀalkylated benzamide 8aa’
started after 6 hours, and the ratio of monoꢀ and dialkylated
product was nearly 1:1 after 18 hours. The reaction with L-10
25 seems very promising as we could see the selective formation of
monoalkylated 8aa during the processes. The utilization of L-11
was less effient as the reaction went slow with poor selectivity.
Encouragingly, the reaction with L-12 provide our desired
product in a much better selectivity over diꢀalkylated product
30 8aa’ comparing to the reactions with other norbornene additives.
Figure 2. Additive screening on norbornene derivativesa
45 All the paraꢀsubstituted benzamides were successfully alkylated
in
a monoꢀselective fashion and the corresponding butyl
substituted arenes 8aaꢀ8ga were obtained in good yields with
good selectivity. Benzamides with orthoꢀsubstituents could also
be converted to the corresponding alkylated products under our
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conditions. The reactions with metaꢀsubstituted aryl amides did
shown in Figure 3. From the graph we could see that the
not give the alkyl group in a position between the two
relatively slow C–H activation processes led to better nomoꢀ
substituents due to the steric reasons and products 8la, 8ma and 45 alkylation selectivity, however, if the C–H activation is too slow,
8na were isolated in good to excellent yields. In addition,
reactions on benzamides with other protecting groups such as
methyl and phenyl were also examined and the desired products
8ra and 8sa were also isolated in 17% and 12% yields due to the
low reaction conversion.
then the reaction would then result in low conversion (blue line
with 500% of L-13).
5
Figure 3. Conversion for the preparation of the palladacycle 9
Under our standard conditions, reactions with a number of alkyl
10 halides were also evaluated. The corresponding alkylated
products with alkyl iodides were all successfully obtained in good
yields. (Table 3) The utilization of alkyl bromides and chloride
were also studied. It seemed that the reactions with alkyl
bromides gave similar results as the ones using alkyl iodides,
15 however, reaction with alkyl chloride was less efficient due to the
low conversion.
No ligand
L12 (20%)
L12 (500%)
L13 (100%)
L12 (100%)
L13 (20%)
L13 (500%)
100%
75%
50%
25%
0%
Table 3. Reactions with various alkyl halides
2
5
8
Time (h)
50
Conditions: Benzamide 7a (0.01 mmol), Pd(OAc)2 (0.01 mmol), PivOH
(0.02 mmol), toluene (1 mL), 100oC by using L-12 or L-13.
Based on these results, we have proposed a reaction mechanism.
Under standard CMD processes, starting from benzamide 7a, a
55 low energy palladacycle 9 could be formed followed by a
possible ligand/additive assisted monomer formation to give a
more active species 10.
20
Figure 4. Plausible reaction mechanism
The sequential alkylation reactions with different alkyl halides
were also demonstrated. (Scheme 1) Benzamides 8ja and 8jh
were successfully prepared after two separate alkylation steps.
25 The oneꢀpot reaction only provided the desired products in low
yields.
Scheme 1. Sequential alkylation reaction
To help us understand this reaction better, the KIE studies were
30 carried out. A mixture of 7a and 7a-5D was treated with
Pd(OAc)2 under the standard conditions, the reaction was stopped
at 20% conversion. A KIE value of 2.7 was then obtained. These
results suggested that the initial CMD processes could be the rate
limiting step during the catalytic system.38,39
35 Scheme 2. KIE studies of mono-alkylation of benzamide
60
We have further studied the effects of norbornene additives on
the the formation of palladacycle 9. Similar to Catellani
reaction,40 the palladacycle 9 we isolated has no norbornene
40 associated in the complex. Under our standard reaction conditions,
when stoichiometric amount of Pd(OAc)2 was used, the results of
reactions in the presence of various amount of additives are
The use of additive may slow down the CMD processes while
the addition of norbornene additive would at the same time speed
up the ligand association processes. The use of additive would
65 also slow down the second C–H activation processes due to the
steric reasons. Therefore, the choose of appropriate amount of
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additive is crucial for both reactivity and monoꢀselectivity. An
oxidative addition of Pd(II) onto the alkyl halide to give a Pd(IV)
intermediate 11 which could then undergo a reductive elimination
gives rise to the alkylated Pd(II) complex 12 and further metal
deassociation to provide our desired product 8a together with
Pd(II). The Pd(II) catalyst could be then used for the next
catalytic cycle.
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