Photoinduced Decarboxylative Amino-Fluoroalkylation of Maleic Anhydride

Article abstract of DOI:10.1002/chem.201904751

A photoinduced decarboxylative three-component coupling reaction involving amine, maleic anhydride, and fluorinated alkyl iodides has been developed, leading to synthetically valuable fluoroalkyl-containing acrylamides with a high E selectivity. A broad array of substrates including monoprotected amino acid are capable coupling partners. Preliminary mechanistic studies suggest a stepwise process. This reaction represents the first example of photoinduced decarboxylative difunctionalization of maleic anhydride.

Full text of DOI:10.1002/chem.201904751

A Journal of
Accepted Article
Title: Photo-Induced Decarboxylative Amino-Fluoroalkylation of Maleic
Anhydride
Authors: Youwen Sun and Guozhu Zhang
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To be cited as: Chem. Eur. J. 10.1002/chem.201904751
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Photo-Induced Decarboxylative Amino-Fluoroalkylation of Maleic
Anhydride
Youwen Sun, Guozhu Zhang*[a]
Dedication ((optional))
Abstract:
A
photo-induced decarboxylative three-component
this transformation is highly stereoselective, as only E-product
was isolated from the reaction. More importantly, bio-relevant
amino acid derivatives are suitable substrate as well, rendering
this methodology added synthetic value.
coupling reaction involving amine, maleic anhydride and fluorinated
alkyl iodides has been developed, leading to synthetically valuable
fluoroalkyl-containing acrylamides in a high E selectivity. A broad
array of substrates including monoprotected amino acid are capable
Maleic anhydride easily undergoes ring opening in the
presence of amine.[9] The resulting cis-amide alkenylcarboxylic
acid is potentially suitable substrate for decarboxylative
functionalization. As far as we know, examples engaging two
transformations of maleic anhydride in a single reaction have not
been reported. We hypothesized that a suitable combination of
base, amine, fluoroalkyl halide, photocatalyst and maleic
anhydride could generate fluoroalkylated acrylamide through
tandem ring opening and photo-induced decarboxylative
fluoroalkylation.
coupling partners. Preliminary mechanistic studies suggest
a
stepwise process. This reaction represents the first example of
photo-induced decarboxylative difunctionalization of maleic
anhydride.
Amides are ubiquitous in both simple and complex molecules
such as drugs, polymers, enzymes, proteins, antibodies, and
collagen – all molecules of high relevance to human lives.[1]
There are many ways to prepare amides, but environmentally
benign and green methodologies with significant reduction in
waste and cost are still highly desired.[2] In this regard, transition-
metal-catalyzed multicomponent reactions prove to be an ideal
technology. Avoiding the synthesis of starting material, in a
single operation, several new bonds are formed and new
functionalities are introduced.[3] In the meantime, incorporation of
fluorine atoms into organic motifs has a significant influence on
the lipophilicity, metabolic stability, and bioavailability of organic
molecules.[4] Fluoroalkylation using relatively mild fluoroalkyl
halides as a fluorine source has been the focus of current
research.[5] Therefore, more mild and practical catalytic systems
need to be developed to provide a convenient strategy for the
construction of fluorinated amides bearing functional groups for
easy derivatization.
Our investigations began with Ru(bpy)3Cl2.6H2O as the
photocatalyst. The targeted product could be obtained in 14%
yield using 3 equiv of ethyl difluoroiodoacetate, 2 equiv of maleic
anhydride,
1
equiv of aniline and
2
equiv of
sodium hydrogen carbonate as a base (Table 1, entry 1). Then,
the adjustment of base to triethylamine (2 equiv) gave a
moderate yield (Table 1, entries 1-5). Various solvents and
photocatalysts were subsequently screened (Table 1, entries 5-
12), the best results were obtained using tetrahydrofuran as
solvent and triethylamine as the base. Further optimization of
reaction conditions revealed that 8 equivalent of triethylamine
was optimal (Table 1, entry 13-16). The results from reactions by
varying the ratios of three reactants suggest excess of reactive
maleic anhydride and ethyl difluoroiodoacetate benefit the
product yield (Table 1, entry 17-20). Lastly, control experiments
confirmed that light, photosensitizer and base are essential for
the success of this chemistry, because when any one
component is absent, no desired product was observed (Table 1,
entries 21-23). The reaction scale could be increased to 1mmol
under current set-up, a similar 78% yield was obtained (Table 1,
entries 24).
Recently, photoredox catalysis has emerged as a valuable
alternative to the traditional initiator-promoted radical reactions,
allowing the generation of active species under mild reaction
conditions.[6] Photo-induced decarboxylative functionalization of
readily available organocarboxylic acid is one of the well-
established methodologies.[7] We were interested in developing
one-step protocol for the difunctionalization of feed stock
chemicals.[8] Herein, we disclose a novel, photoinduced three-
component decarboxylative aminofluoroalkylation of maleic
anhydride with fluorinated alkyl iodide and a series of amines,
leading to synthetically useful fluorinated acrylamides. Notably,
With the optimized conditions in hand (Table 1, entry 15), we
next examined the scope of amine (Scheme 1). Our protocol
was found to readily accommodate a variety of anilines with
different substitutions, including electron-neutral (Scheme 1, 1a),
electron-donating (Scheme 1, 1b), and electron-withdrawing
groups (Scheme 1, 1c-1f). Halogens were well tolerated,
offering opportunities for further decoration of the molecule
(Scheme 1, 1d-1e). In addition, heterocyclic substrates, such as
2-aminothiazole (Scheme 1, 1g) was found to be competent
substrate. Meanwhile, benzyl amine and simple aliphatic amine
can also provide the target products (Scheme 1, 1h-1k).
Remarkably, bio relevant amino acids were converted into the
desired products with moderate yields (Scheme 1, 1l-1r), in
those reactions the chiral centers remain intact. Notably,
[a]
Y.-W, Sun, Prof. G.-Z, Zhang.
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Center for Excellence in Molecular
Synthesis, University of Chinese Academy of Sciences, Chinese
Academy of Sciences, 345 Lingling Road, Shanghai 200032,
(China)
E-mail: guozhuzhang@sioc.ac.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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However, our attempts to explore other hetero nucleophiles
including hydroxy, thiol and phenylhydrazine were not
successful under current reaction conditions.
secondary amines are suitable substrates as well thus resulting
in fully substituted amides (Scheme 1, 1t-1u).
Table 1. Optimization of the reaction conditions.
Entry[a]
Photocatalyst
Base(equiv.)
NaHCO3(2.0)
Cs2CO3(2.0)
DBU(2.0)
Solvent
THF
Yield/%[b]
1
2
3
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
14
36
24
THF
THF
4
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ir(ppy)3
iPr2NEt(2.0)
Et3N(2.0)
Et3N(2.0)
Et3N(2.0)
Et3N(2.0)
Et3N(2.0)
Et3N(2.0)
Et3N(2.0)
Et3N(2.0)
Et3N(4.0)
Et3N(6.0)
Et3N(8.0)
Et3N(10.0)
Et3N(8.0)
Et3N(8.0)
Et3N(8.0)
Et3N(8.0)
Et3N(8.0)
-
THF
THF
30
57
5
6
CH3CN
DCM
DMF
DMA
Dioxane
THF
40
7
20
8
30
9
40
10
11
12
13
14
15
16
17[c]
18[d]
19[e]
20[f]
21
22
23[g]
24[h]
20
53
Ir(dtbpy)2(ppy)
THF
50
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
-
THF
66
THF
70
THF
82
THF
71
THF
23
THF
41.
22.
15.
N.D.
N.D.
N.D.
78
THF
THF
THF
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
THF
Et3N(8.0)
Et3N(8.0)
THF
THF
[a] Reactions were carried out in 0.2 mmol scale and the procedure was same as
the general procedure. [b] Measured by 1H NMR analysis using diethyl phthalate
as internal standard. [c] The ratios of Aniline, maleoside, ethyl
difluoroiodoacetate is 0.2mmol:0.2mmol:0.2mmol. [d] The ratios of Aniline,
maleoside, ethyl difluoroiodoacetate is 0.2mmol:0.2mmol:0.4mmol. [e] The
ratios
of
Aniline,
maleoside,
ethyl
difluoroiodoacetate
is
0.2mmol:0.4mmol:0.2mmol. [f] The ratios of Aniline, maleoside, ethyl
difluoroiodoacetate is 0.4mmol:0.2mmol:0.2mmol. [g] No light. N.D. not
determined. [h] Reactions were carried out in 1.0 mmol scale.
To further demonstrate the utility and generality of this novel
reaction, we tried to replace the maleic acid glycosides,
delightfully, citraconic anhydride also reacted well (scheme 1,
1v).We then turned our attention to different fluoroalkyl iodides.
Reactions of pentafluoroiodoethane and perfluoroiodobutane
with aromatic amines (scheme 1, 1w, 1ab) and common amino
acid esters (scheme 1, 1x-1aa, 1ac-1af) proceeded smoothly.
For the example (1t, 1u, 1w, 1x,1y) of low yield, it may be due to
the instability of raw materials and reaction intermediates, which
are easy to decompose. It is known methionine is not stable and
easily oxidized, but the target product derived from methionine
can be obtained successfully under standard conditions.
Scheme 1. Scope studies with coupling partners.[a][b] [a] The reactions were
carried out under these optimized conditions (Table 1, entry 15). [b] Isolated
yield.
In order to elucidate the mechanism, a series of control
experiments were performed as outlined in Scheme 2. The
product could be obtained by a two-step procedure in equal
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efficiency, suggesting a stepwise mechanism is viable (Scheme
2, eq a). The high E selectivity is possibly attributed to the
following downstream decarboxylation. Without amine, a product
through atom transfer radical addition-elimination (ATRE)
reaction was obtained in good yield and no ring-opening or
decarboxylative products were observed (eq b). Using maleic
acid as substrate, no desired product was found (eq c).
inhibitors 4, could be constructed in one step through our
method. In contrast, literature procedure required a four step
synthesis from not easily available starting material.[13]
Scheme 3. Representative dual ACE/NEP inhibitors analogues 4 and typical
synthetic route. Reagents and conditions: (a) phthaloyl dichloride, 180 oC, (70-
77%); (b) H-AA-OMe, TEA, DCM, 0 oC (73-96%); (c) AcSH, EtOH, rt (rd = 1:1,
30-89%); (d) for R1 = 4-tert-BuO-Ph-CH2-, 20% TFA, DCM, rt, 1 h (98%); (e)
degassed 2 N NaOH in MeOH, 0 oC, 1 h (quantitative).
Scheme 2. Control experiments for mechanistic study.[a][b] [a] The reactions
were carried out under these optimized conditions (Table 1, entry 15). [b] The
results were analyzed by GC/MS.
Then, the fluorescence quenching experiments were
conducted (See Supporting Information for details). we found
that both halogenated alkane and triethylamine had the same
quenching effect on photosensitizer, but the quenching
coefficient of halogenated alkane (KSV (ICF2CO2Et), 0.6 uM-1)
was much larger than that of triethylamine (KSV (Et3N), 0.05 uM-
1), so halogenated hydrocarbon might be the major quenching
agent. A reaction quantum yield was measured to be φ= 3.2%,
indicating the radical chain mechanism is less likely. Based on
above results, a plausible mechanism is outlined in Figure 1.
Photoexcitation of Ru(bpy)3Cl2.6H2O upon blue irradiation
results in a metal-to-ligand charge transfer (MLCT) excited
state.[11] Then difluoroalkyl radical is generated through oxidative
quenching. Next, Aniline attacks maleate to produce cis-oleic
acid, which captures fluoroalkyl radical to afford intermediate B.
Finally, the product is obtained by oxidative decarboxylation. It is
worth mentioning that the last step is highly stereospecific as
only E-products were observed[12], We think that it's mainly
thermodynamic that leads to a more stable E structure.
In summary, we have reported a highly effective and
synthetically convenient method of decarboxylative three-
component aminofluoroalkylation reaction of maleic anhydride
induced by visible light. The reaction couples are readily
available Maleic anhydride, a variety of fluorinated alkyl halides,
and a broad range of amines. The resulting fluoroalkylated
acrylamide are valuable building block which could find
applications in synthetic and medicinal chemistry.
Experimental Section
General procedure of the reaction: In a dried sealed tube, under N2
atmosphere, Ru(bpy)3Cl2.6H2O (3.0 mg, 0.004 mmol, 2 mol %) and
maleic acid glycosides (0.4 mmol, 2.0 equiv.) were dissolved in THF (2.0
mL), then anilin (0.2 mmol, 1.0 equiv.), ethyl difluoroiodoacetate (0.6
mmol, 3.0 equiv.) and triethylamine (1.6 mmol, 8.0 equiv.) were added in
sequence.The mixture was placed 5 cm away from the 35-watt blue lamp
and stirred at 25 ºC for 24 hours. After that, the mixture was filtered short
silica gel column and concentrated under vacuum. The residue was
purified by column chromatography on silica gel with a gradient eluent of
petroleum ether (PE) and ethyl acetate (EA) to afford the product.
Acknowledgements
We thank NSFC (21772218, 21821002), XDB20000000, the
“Thousand Plan” Youth program, State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
and the Chinese Academy of Sciences for financial support.
Conflict of interest
The authors declare no conflict of interest.
Figure 1. Proposed reaction mechanism.
The highly functionalized products could serve as useful
platform for further derivatizations. The synthetic potential was
briefly shown in Scheme 3. Amino acid bonded compound 3, an
analogue of advanced intermediate leading to dual ACE/NEP
Keywords: photo-induced • three-component • decarboxylative •
fluoroalkyl-containing acrylamides • high E selectivity
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Youwen Sun, Corresponding Author(s)*
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Title
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Youwen Sun, Guozhu Zhang*[a]
Page No. – Page No.
Photo-Induced Decarboxylative
Amino-Fluoroalkylation of Maleic
Anhydride
A photo-induced decarboxylative three-component coupling reaction involving amine, maleic anhydride and fluorinated alkyl iodides
has been developed, leading to synthetically valuable fluoroalkyl-containing acrylamides in a high E selectivity. A broad array of
substrates including monoprotected amino acid are capable coupling partners. Preliminary mechanistic studies suggest a stepwise
process. This reaction represents the first example of photo-induced decarboxylative difunctionalization of maleic anhydride.
This article is protected by copyright. All rights reserved.