Direct Csp3-H methylenation of 2-arylacetamides using DMF/Me2NH-BH3 as the methylene source

Article abstract of DOI:10.1039/c9ob00875f

A direct Csp³-H methylenation of 2-arylacetamides using DMF/Me₂NH-BH₃ as the methylene source was developed. The formyl group of DMF delivered the carbon and one hydrogen atoms, and the Me₂NH-BH₃ dona

Full text of DOI:10.1039/c9ob00875f

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DOI: 10.1039/C9OB00875F
ARTICLE
Direct Csp3-H methylenation of 2-arylacetamides using
DMF/Me2NH-BH3 as the methylene source
Received 00th January 20xx,
Accepted 00th January 20xx
Yuting Liu,‡a Chang-Ling Wang,‡b Hui-Min Xia,b Zhijuan Wang,* a and Yi-Feng Wang* b
DOI: 10.1039/x0xx00000x
A direct Csp3-H methylenation of 2-arylacetamides using DMF/Me2NH-BH3 as the methylene source was developed. The
formyl group of DMF delivered the carbon and one hydrogen atoms, and the Me2NH-BH3 donated the remaining one
hydrogen atom. This protocol offers a new alternative to make useful 2-arylacrylamides from simple starting materials.
formation, and carboxylation.13 Thus, this method suffers from
limited functional group tolerance and less step- and atom-
economy. Recently, palladium-catalyzed aminocarbonylation
Introduction
Alkenes have been substantially applied in chemical synthesis,
medicinal chemistry, and materials science. Over the past
decades, a large number of methods for their synthesis have
been developed.1 Arguably, direct Csp3-H methylenation
reactions represent a promising strategy to access terminal
alkenes in terms of atom- and step-economy, simple
operations, and sustainability.2 In this context, the use of
cheap and abundant N,N-dimethylformamide (DMF) as the C1
source has shown appealing applications.3 The groups of Xu,4
Wang,5 Miura,6 Lei,7 and others8 have reported elegant
examples on the oxidative methylenation reactions of C-H
bonds (Scheme 1a). Mechanistic studies revealed that the
methylene group (CH2) is derived from the N-methyl of DMF.
While notable, the requirement of strong oxidants limits the
functionality and applicability. For example, the C-H
methylenation of electron-rich acetamides has not been
documented yet. Therefore, developing new mild C-H
methylenation methods is highly desirable.
reactions of alkynes14 have been described, while the use of
CO raised safety concern. Herein, we describe an efficient and
conceptually different C-H methylenation reaction of 2-
arylacetamides for the direct synthesis 2-arylacrylamides
(Scheme 1b). Notably, a DMF/Me2NH-BH3 system is used as
the CH2 source. Different from oxidative C-H methylenation
with DMF as shown in Scheme 1a, in this reaction, the DMF
formyl group delivers the carbon atom and one of the
hydrogen atoms of the methylene motif, meanwhile Me2NH-
BH3 contributes the other hydrogen atom. Significantly, the
starting 2-arylacetamides can be easily prepared from broadly
available 2-arylacetic acids and N-H amines, thus rendering
this method applicable for diverse and economical synthesis of
valuable 2-arylacrylamides.
Acrylamides having a terminal alkene moiety are significant
building blocks in organic synthesis,9 drug development,10 and
materials chemistry.11 Despite the fact that many methods
have been reported for their synthesis,12 the preparation of 2-
arylacrylamides still remains a synthetic problem. The classical
method to make these molecules relies on the condensation of
2-arylacrylic acids with amines. However, the preparation of 2-
arylacrylic acids requires a multiple-step synthesis that consists
of hydrobromination of arylacetylenes, Grignard reagent
Scheme 1 Direct C-H methylenation with DMF
Results and discussion
a. Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering,
Nanjing Tech University, Nanjing, 211816, China. E-mail:
ias_zjwang@njtech.edu.cn
b. Hefei National Laboratory for Physical Sciences at the Microscale, Center for
Excellence in Molecular Synthesis of CAS, Department of Chemistry, University of
Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026. China. E-
mail: yfwangzj@ustc.edu.cn
Recently, we have disclosed an intriguing α-methylation
protocol of arylacetonitriles and arylacetamides using a
DMF/R3N-BH3 system as the methyl source.15 In the reaction
process, a terminal alkene intermediate through Csp3-H
methylenation was observed only in the reaction of N,N-
dimethyl-2-phenylacetamide. However, both the yield and
‡Yu-Ting Liu and Chang-Ling Wang contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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selectivity were inferior. If we could improve the efficiency of
Journal Name
Using the optimal conditions, we next investigated the
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DOI: 10.1039/C9OB00875F
this transformation, a new C-H methylenation protocol to substrate scope of this methylenation protocol. A variety of 2-
afford acrylamides would be established. For this purpose, we arylacetamides were converted to 2-arylacrylamides in
began our study by investigating the reaction of phenyl moderate to good yields (Table 2). Notably, the over reduction
acetamides 1a. The methylenation proceeded smoothly with to methylated products were not observed in all cases. Both
the use of Me3N-BH3 in DMF, affording 2a in 45% yield (Table 1, the N-aryl and 2-aryl rings bearing a wide range of functional
entry 1). It is noteworthy that no further reduction to form the groups could be converted to methylenated products 2b-2m in
methylated product was detected. Moreover, the NH amide good to excellent yields regardless of the their electronic
moiety kept intact and no additional protection was required. nature and substitution patter. The substrate with an alkyne
Delightfully, switching the amine-borane complex to Me2NH- tether (for 1n) was methylenated in a moderate yield, while no
BH3 dramatically increased the yield to 83%, and a gram scale other reduction product was observed. Remarkably, the
reaction also gave a comparable yield (entry 2). However, nucleophilic hydroxyl group (for 2o) was tolerated, without the
reducing the amount of Me2NH-BH3 led to decreased yields need for a protecting group. Furthermore, a wide range of
(entries 3 and 4). Moreover, the reaction became sluggish heteroaromatic motifs, including quinoline (for 2p), pyridine
when the temperature was lowered to 100 °C (entry 5). The (for 2q-2s), and indole (for 2t) could be installed in the
utilization of NH3-BH3 and pyridine-BH3 resulted in no products. The present method also allowed for the
formation of 2a, and a very complex mixture was observed preparation of N-monoalkyl (for 2u) and dialkyl (for 2v)
instead (entries 6 and 7). This is probably due to the less substituted acrylamides, albeit the yield of 2v is moderate. As
stability of these complexes under the present reaction for
a limitation, the reaction of 2-alkylacetamide was
conditions. A comparable yield was obtained when t-BuONa unsuccessful, probably due to the lower acidity of the α-
was used instead of t-BuOK (entry 8), while no product methylene group.
formation was observed in the presence of K2CO3 (entry 9) or
Table 2 Scope of α-methylenation of 2-arylacetamides (1)a
KOH (entry 10).
Table 1 Optimization of reaction conditionsa
Entry
LB-BH3
Base
Time
2a Yieldb 1a Yieldc
(x equiv)
Me3N-BH3
(2.5)
(%)
45
(%)
18
1
2
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
25 min
Me2NH-BH3
(2.5)
25 min 83d (82)e
ND
4
3
Me2NH-BH3
(2.0)
85 min
7 h
61
27
4
Me2NH-BH3
(1.0)
57
11
ND
ND
ND
78
14
5f
6
Me2NH-BH3
(2.5)
2.5 h
6 h
65
NH3-BH3
(2.5)
NDg
NDg
74
7
pyridine-BH3 t-BuOK
6 h
(2.5)
8
Me2NH-BH3
(2.5)
t-BuONa 30 min
a
Reaction conditions: 1 (0.3-0.5 mmol), Me2NH-BH3 (2.5 equiv), t-
9
Me2NH-BH3
(2.5)
K2CO3
KOH
11 h
11 h
ND
ND
BuOK (3 equiv), DMF (0.1 M), 120 °C, N2, isolated yield.
10
Me2NH-BH3
(2.5)
Our previous isotope-labeling experiments revealed that the
methylene group of the present protocol should originate
from the combination of DMF and R3N-BH3.15 Namely, the
formyl group of DMF donates the carbon and one of the
hydrogen atoms, and the R3N-BH3 contributes the other
hydrogen atom. To further confirm it, an experiment using
DMF-d7/Me2NH-BH3 was attempted. As expected, mono-
a
Reaction conditions: 1a (0.3-0.5 mmol), Lewis base-BH3 (x equiv),
base (3 equiv), DMF (0.1 M). b 1H NMR yield using tetrachloroethane as
c
an internal standard. Recovery yield of 1a is determined using
d
e
tetrachloroethane as an internal standard. Isolated yield. Isolated
yield of a gram scale reaction of 1a. f The reaction was carried out at
100 °C. g A complex mixture was obtained.
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deuterium labeled 2-arylacrylamide 2a-D1 was afforded in 69%
yield with excellent level of D-incorporation (Scheme 2).
indolyl-3-methyl oxindole products in good yields (Table 3).
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Under the acidic condition, intermDedOiIa: 1t0e.s1039/C9OB00875F
V are first
protonated to form indolium ions VI, which are attacked by
the intramolecular N-aryl ring to construct the oxindole
framework. Finally, the aromatization takes place to deliver
products 3. In this procedure, no isolation of each
intermediate was required.
Scheme 2 Synthesis of mono-deuterium labeled 2a-D1.
Table 3 One-pot synthesis of 3-indolyl-3-methyl oxindolesa
Based on this result and our previous findings,15 a plausible
reaction mechanism is depicted in Scheme 3. N,2-
Diphenylacetamide (1a) is first deprotonated by t-BuOK to
generated carbon anion I. The following nucleophilic attack to
the formyl group of DMF gives hemiaminal intermediate II.
After that, elimination of a hydroxyl group takes place to
generate an iminium intermediate III, which is reduced by
Me2NH-BH3 to afford α-dimethylaminomethyl substituted
arylacetamide IV. Finally, product 2a was formed by an E1cB
elimination reaction. For the reaction using DMF-d7, the final
elimination from IV (in this case the hydrogen atom labeled as
red is a deuterium atom) proceeds without stereoselectivity,
because of no significant steric difference between the
hydrogen and deuterium atoms. As such, a mixture of D-
labeled E/Z isomers is obtained. It is worth mentioning that in
our previous methylation protocol, a further reduction of
analogous alkene products took place immediately to give
methylated products. However, in the present methylenation
reaction, such reduction is not proceeding, and the reaction
stops at this alkene formation selectively. This is most likely
because 2-arylacrylamides 2 are not electron-deficient enough
to be reduced by an amine-borane complex.
a
Reaction conditions: 1 (0.3-0.5 mmol), Me2NH-BH3 (2.5 equiv), t-
BuOK (3 equiv), DMF (0.1 M), 120 °C, N2, then, R4I (2.5 equiv), NaH (1.5
equiv), THF (0.1 M), 0 °C to rt, then, HCl (aq. 1M, 4 equiv), CH3CN (0.1
M), 100 °C, isolated yield based on 1.
Conclusions
In conclusion, we have developed
a
direct Csp3-H
methylenation of 2-arylacetamides using DMF/R3N-BH3 as the
methylene source. The method offers a direct way to make
useful 2-arylacrylamides, which show potential applications in
synthetic and medicinal chemistry. In addition, a one-pot
procedure is also developed to make 3-indolyl-3-methyl
oxindoles that are difficult to access by other methods. Further
applications of this methylenation method to make other
terminal alkenes are currently underway in our lab。
Scheme 3 A proposed reaction mechanism.
3-Indolyl-3-alkyl oxindole framework has been found in
many bioactive molecules and natural products.16 These
compounds are usually prepared by nucleophilic addition of
indoles to isatines, followed by Brønsted acid-catalyzed
alkylation of the resulting 3-indolyl-3-hydroxy oxindole
intermediates.17 However, the direct assembly of 3-indolyl-3-
methyl oxindoles still remains a synthetic challenge,17d due to
the lack of suitable methylating nucleophiles. To develop a
new strategy to make these targets as well as to demonstrate
the synthetic utility of our methylenation method, a one-pot
procedure to synthesize 3-indolyl-3-methyl oxindoles was
attempted. First, the C-H methylenation reaction of 2-indolyl-
N-arylacetamides 1 proceeded smoothly to give desired 2-
indolyl-N-arylacrylamides. After alkylation of the amide N-H
group, the following treatment with HCl directly led to 3-
Experimental section
General procedure for the synthesis of compounds 2
To an N2 flushed, oven-dried glass tube with a magnetic stir
bar, 2-arylacetamides 1 (0.5 mmol), Me2NH-BH3 (2.5 equiv.)
and t-BuOK (3.0 equiv.), and DMF (5 mL) was added. The
reaction mixture was stirred at 120 °C. After the disappearance
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of the substrate as indicated by TLC, the reaction was then
quenched with H2O and extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated. The crude residue was purified by
flash column chromatography on silica gel to afford products 2.
Notes and references
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General procedure for the synthesis of compounds 3
To an N2 flushed, oven-dried glass tube with a magnetic stir
bar, 1 (0.5 mmol), Me2NH-BH3 (2.5 equiv.) and t-BuOK (3.0
equiv.), and DMF (5 mL) was added. The reaction mixture was
stirred at 120 °C until the consumption of the substrates as
indicated by TLC. The reaction was then quenched with H2O
and extracted with ethyl acetate. The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated.
The crude residue was dissolved in THF (5 mL), and then was
treated with NaH (1.5 equiv.) at 0 °C for 30 minutes. After that,
alkyl iodide (2.5 equiv.) was added. The reaction mixture was
stirred for additional 3 h, and then was quenched with NH4Cl.
The aqueous layer was extracted with ethyl acetate, and the
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated. The resulting residue was treated
with HCl (1M, 4 equiv.) in CH3CN (5 mL) at 100 °C overnight.
After evaporation of solvent, the residue was diluted with
saturated NaHCO3 and ethyl acetate. The aqueous layer was
extracted with ethyl acetate, and the combined organic layers
were washed with brine, dried over Na2SO4, and concentrated.
Purification by flash column chromatography on silica gel
afforded products 3.
1
N,2-Diphenylacrylamide (2a) (92.1 mg, 83%). H NMR (CDCl3,
400 MHz) δ 5.62 (s, 1H), 6.14 (s, 1H), 7.02 (t, J = 7.2 Hz, 1H),
7.21 (dd, J = 7.6, 7.6 Hz, 2H), 7.31-7.35 (m, 5H), 7.42-7.44 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 119.9, 122.9, 124.5, 128.1,
128.7, 128.8, 128.9, 136.5, 137.6, 145.1, 165.3.
1,3-Dimethyl-3-(1-methyl-1H-indol-3-yl)indolin-2-one
(3a)
(116.4 mg, 76%).
1H NMR (CDCl3, 400 MHz) δ 1.85 (s, 3H), 3.29 (s, 3H), 3.73 (s,
3H), 6.86-6.93 (m, 2H), 7.01-7.06 (m, 2H), 7.12-7.14 (m, 2H),
7.16 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 7.6,
8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 23.4, 26.4, 32.7, 47.9,
108.0, 109.3, 114.3, 119.1, 119.9, 121.6, 122.7, 123.8, 125.7,
127.3, 127.9, 135.0, 137.5, 143.0, 179.6.
Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (21672195, 21705078), Natural Science
Foundation for Youth of Jiangsu Province (BK20170972), and
Nanjing Tech University (39837119) for financial support.
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