Aldehyde-Promoted One-Pot Regiospecific Synthesis of Acrylamides Using an in Situ Generated Molybdenum Tetracarbonyl Amine [Mo(CO)4(amine)2] Complex

Article abstract of DOI:10.1021/acs.orglett.5b02231

A novel complex system generated in situ from Mo(CO)₆ and an amine is described for the regiospecific aminocarbonylation of various terminal alkynes. The Mo(CO)₆-amine system played a dual role as complexing agent and as CO donor, thus making this process palladium-free.

Full text of DOI:10.1021/acs.orglett.5b02231

Letter
pubs.acs.org/OrgLett
Aldehyde-Promoted One-Pot Regiospecific Synthesis of Acrylamides
Using an in Situ Generated Molybdenum Tetracarbonyl Amine
[Mo(CO)4(amine)2] Complex
Atulya Nagarsenkar, Santosh Kumar Prajapti, Sravanthi Devi Guggilapu, and Bathini Nagendra Babu*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana
India 500037
S
* Supporting Information
ABSTRACT: A novel complex system generated in situ from Mo(CO)6 and an
amine is described for the regiospecific aminocarbonylation of various terminal
alkynes. The Mo(CO)6−amine system played a dual role as complexing agent and
as CO donor, thus making this process palladium-free.
crylamide and its derivatives play a significant role in a
itself as a complexing agent, in the presence of suitable ligands
it is known to become active making the desired reactions
possible.16 To achieve this, substitution of one or more of the
CO units in the structure with other ligands is carried out. It is
well-known that Mo(CO)6 can easily undergo ligand exchange
with amines, and in this process carbon monoxide is released
into the reaction mixture usually at elevated temperatures.17
In this context, we envisioned the development of an in situ
generated complex system using Mo(CO)6 and an amine for
the regiospecific aminocarbonylation of terminal alkynes in
which the generated complex could play the dual role of the
complexing agent as well as the CO donor (Scheme 1).
A
wide range of organic reactions such as nucleophilic
additions, cycloaddition reactions, radical reactions, etc.1 They
are also extensively used as starting materials in the synthesis of
various bioactive and polymeric materials.2
Although the most widely used process for the synthesis of
acrylamides has been by the hydration of acrylonitriles, the N-
substituted acrylamides are usually synthesized stepwise from
acrylic acid or its esters.3 In an alternative approach, N-
substituted acrylamides could be prepared in 35−52% yields by
reacting alkylidenecarbenes with isonitriles.4 Recently, nickel-
catalyzed synthesis of acrylamides using α-olefins and
isocyanates was reported.5 However, a commonly applied
direct and clean synthesis of substituted acrylamides is by the
carbonylation of alkynes in the presence of amines, that is,
aminocarbonylation.6 Indeed, also reported was the synthesis of
2-substituted acrylamides via a palladium-catalyzed amino-
carbonylation of terminal alkynes either in a strongly acidic
medium7 or in the presence of organic iodide,8 and p-TsOH.9
Thus, literature reports on the carbonylative regioselective
coupling of alkylamines with terminal alkynes have certainly
been relatively few in number.7 Also, the acid constituents of
the aminocarbonylation catalyst, in the cases where they are
applied, makes the process corrosive. Hence, developing
aminocarbonylation reactions that do not involve the use of
corrosive agents would be highly desirable.10
Moreover, there are major concerns in the chemical industry
regarding the use of reactive gases and their efficient utilization.
Specifically, the difficulty in the handling of toxic carbon
monoxide in synthesis has created interest in finding alternative
sources of CO11 and has led to the development of modified
gas-free aminocarbonylation protocols,12 especially in the
preparation of N,N-dimethylbenzamides and acrylamides.13
The commercially available Mo(CO)6 functions as a con-
venient and solid carbon monoxide source in palladium-
catalyzed aminocarbonylations of terminal alkynes.14
Scheme 1. Proposed Synthesis of 2-Phenyl-1-(piperidin-1-
yl)prop-2-en-1-one
Thus, experiments were carried out using phenylacetylene
and piperidine as the substrates in toluene, and the results are
summarized in Table 1. Phenylacetylene 1 (1 mmol),
piperidine 2 (1.5 mmol), and Mo(CO)6 [1 mmol] were
dissolved in toluene, and the solution was stirred at room
temperature for 6 h under a nitrogen atmosphere. On the basis
of TLC analysis, it was observed that the reaction failed to
proceed even at elevated temperatures (Table 1, entry 1).
Hence, we assumed that Mo(CO)4(pip)2 requires an additional
activator to promote the reaction.
Phenols (2-fluorophenol/4-chlorophenol) are well-known to
assist Mo(CO)6 in catalyzing metathesis reactions.18 To the
best of our knowledge, there are no earlier reports on a
Molybdenum coordination chemistry is an intriguing
research area owing to its numerous potential applications in
organic synthesis.15 Though, Mo(CO)6 is not generally active
Received: August 11, 2015
© XXXX American Chemical Society
A
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Letter
an, dichloromethane, acetonitrile, and ethanol. Interestingly,
the reaction was found to be solvent-specific for toluene.
A variety of substrates bearing a terminal alkyne unit were
screened under the optimized reaction conditions, and very
good results were obtained (Table 3).
Table 1. Optimization of the Reaction Conditions for the
Synthesis of Acrylamides
a
Reactions involving different halogen-substituted phenyl-
acetylenes, such as 4-fluoro- and 3-chloro- derivatives gave
good to excellent yields (Table 3, entries 2 and 3). Reaction
b
Mo(CO)6/piperidine
[mmol]
isobutyraldehyde
(mmol)
time
(h)
yield
entry
1
(%)
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/2.0
1/2.5
1.5/2.0
48
12
6
c
Table 3. Mo(CO)6/Amine-Mediated Synthesis of
2
20
55
77
72
83
79
81
a
Acrylamides
3
4
5
6
7
8
0.5
1
4
2
4
1
2
1
2
1
2
a
Reaction conditions: Phenylacetylene (1 mmol), piperidine, iso-
b
c
butyraldehyde, Mo(CO)6, toluene, reflux. Isolated yields. Acetalde-
hyde (0.5 mmol) was added as promoter.
carbonyl compound (aldehyde/ketone) assisting in organo-
metallic reactions. Hence, to explore this area we repeated the
same reaction by adding a simple aldehyde such as
acetaldehyde (0.5 mmol) (Table 1, entry 2). We observed
that the color of the reaction turned from clear light brown to
dark brown. Though the anticipated product 3 was formed, the
yield was below par; however, when the reaction was performed
again using isobutyraldehyde, the yield slightly improved
(Table 1, entry 3). When the concentration of isobutyraldehyde
was increased to 1 mmol, the product was formed in good yield
(Table 1, entry 4). No improvement in the yield was observed
with a further increment in the isobutyraldehyde concentration
(Table 1, entry 5). Next, we conducted a number of
experiments to optimize Mo(CO)6/piperidine concentration.
It was observed that Mo(CO)6 [1 mmol] and piperidine (2
mmol) is the optimum concentration for the smooth reaction
(Table 1, entries 6−8).
Out of all the aliphatic aldehydes screened, isobutyraldehyde
gave the best result as an activator (Table 2).
Surprisingly, reactions with aromatic aldehydes were not
productive (Table 2, entries 5−7). Studies were also performed
using ketones as a reaction promoter, but no success was
achieved (Table 2, entries 8 and 9). Further, solvent studies
were performed using different solvents such as tetrahydrofur-
Table 2. Screening of Carbonyl Compounds as Promoter for
a
the Synthesis of Acrylamides
b
entry
carbonyl compound
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
isobutyraldehyde
acetaldehyde
2
6
83
45
78
75
butyraldehyde
hexanal
2
2
benzaldehyde
12
12
12
12
12
2-phenylacetaldehyde
2-napthaldehyde
acetone
2,4-dimethylpentan-3-one
a
Reaction conditions: Alkyne (1 mmol), amine (2 mmol),
a
Reaction conditions: Phenylacetylene (1 mmol), piperidine (2
isobutyraldehyde (1 mmol), Mo(CO)6 (1 mmol), toluene, reflux.
b
c
d
mmol), aldehyde/ketone (1 mmol), Mo(CO)6 (1 mmol), toluene,
reflux. Isolated yields.
Isolated yields. Ratio calculated with the help of UPLC. For
b
structures, please refer to Figure 1.
B
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using phenylacetylenes substituted with alkyl moieties, such as
4-tert-butyl- resulted in an increased product yield (Table 2,
entry 4). To explore further the range of substituted terminal
alkynes, we tried reactions using O-propargylated compounds,
such as 1-nitro-3-[(prop-2-yn-1-yloxy)methyl]benzene and 1-
methoxy-4-[(prop-2-yn-1-yloxy)methyl]benzene. Compound
3e was formed without being accompanied by any rearrange-
ment product (Table 3, entry 5), but compounds 3f and 4f
were formed as an inseparable mixture in a ratio of 62:38
(expected product/rearrangement product) [Table 3, entry 6].
Amused by this observation, we further tried a reaction using an
alkyne bearing an acid sensitive protecting group, namely
TBDPS. We were surprised to see that the rearrangement
product 4g was formed with absence of the regular anticipated
product (Table 3, entry 7). The rearranged product 4g was
the reaction, which prompted us to assume that it remains
coordinated with the molybdenum forming the complex E.
Even though we have proposed a plausible reaction
mechanism, the stepwise details for this aminocarbonylation
process are still open to debate and remain an area for further
experimental and computational investigations.
In conclusion, the regioselective control in the synthesis of 2-
acrylamides 3(a−r) and 4g was achieved by the amino-
carbonylation of terminal alkynes using an in situ generated
complex system Mo(CO)4(amine)2, along with the assistance
of an aliphatic aldehyde as promoter. A wide range of terminal
alkynes along with cyclic and acyclic secondary aliphatic amines
were well suited. Most importantly, the products were easily
separated and purified using conventional column chromatog-
raphy. Novel, unprecedented, rearrangement products were
seen in the case of propargyl ethers. Striking advantages of the
present protocol are that it is regiospecific, is compatible with
acid sensitive protecting groups such as TBDPS, is palladium-
free, utilizes a dual-acting complex system, is of short reaction
time, is easy to work up, and provides good yields. A
computational study of the suggested mechanistic pathway is
currently underway.
1
formed selectively as the Z isomer (confirmed by H NMR
through ppm shift value of the alkene unit at δ 6.45) with
negligible amounts of the E isomer. The cause for this unusual
rearrangement could not be explained, although this phenom-
enon was observed only in the case of propargyl ethers (Figure
1).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02231.
Figure 1. Rearrangement products 4f and 4g.
Experimental procedures and characterization data for
acrylamides 3(a−r) and 4g(PDF)
Next, to check the versatility of the protocol, a wide range of
amines were screened. We were surprised to see that the
reaction proceeded only with secondary aliphatic amines. The
reaction involving primary amines, benzylamines, anilines and
N,N-dibenzylamine did not proceed. Reactions with morpho-
line furnished moderate yields (Table 3, entries 8 and 9),
whereas reactions involving 4-methylpiperidine (Table 3,
entries 10−13), pyrrolidine (Table 3, entries 14 and 15) and
diethylamine (Table 3, entries 16 and 17) provided good yields.
Higher yields were observed when the reaction was carried out
using 1-methyl piperazine (Table 3, entry 18).
Although the mechanism for this reaction is unclear, our
hypothesized mechanism includes the formation of the active
neutral species B via the coordination of the alkyne to the
neutral species A (Figure 2).
Insertion of CO forms the intermediate C. This step may be
promoted by the coordination of the molybdenum nucleus with
aldehyde in enol form which facilitates the CO moiety release,
followed by the addition of piperidine to the carbonyl carbon
forming the product D. The added aldehyde was consumed in
AUTHOR INFORMATION
Corresponding Author
■
*Tel: +9140 23073740. E-mail: bathini@niperhyd.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Authors are thankful to the Department of Pharmaceuticals
(Ministry of Chemicals and Fertilizers, Govt. of India) for
providing funds and Prof. K.P.R. Kartha, Department of
Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER), Sector 67, S. A. S. Nagar,
Punjab 160062, India, for his valuable suggestions in the
manuscript.
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