Ag2CO3-mediated direct functionalization of alkyl nitriles: Facile synthesis of γ-ketonitriles through nitrile alkylation of enol acetates

Article abstract of DOI:10.1016/j.tetlet.2019.04.042

Direct C(sp3)-H functionalization of alkyl nitriles is a low toxic and facile route to nitrile-containing compounds. In this research, the Ag₂CO₃-mediated nitrile methylenation of enol acetates is developed to prepare γ-ketonitriles through the direct C(sp³)-H oxidative functionalization of acetonitrile. A radical pathway is proposed, and acetonitrile serves both as solvent and CN-containing radical source.

Full text of DOI:10.1016/j.tetlet.2019.04.042

Accepted Manuscript
Ag2CO3-mediated direct functionalization of alkyl nitriles: facile synthesis of
γ-ketonitriles through nitrile alkylation of enol acetates
Pi Cheng, Wei Wang, Lin Wang, Jianguo Zeng, Oliver Reiser, Yun Liang
PII:
S0040-4039(19)30379-X
https://doi.org/10.1016/j.tetlet.2019.04.042
TETL 50757
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 February 2019
18 April 2019
22 April 2019
Please cite this article as: Cheng, P., Wang, W., Wang, L., Zeng, J., Reiser, O., Liang, Y., Ag2CO3-mediated direct
functionalization of alkyl nitriles: facile synthesis of γ-ketonitriles through nitrile alkylation of enol acetates,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.04.042
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Ag2CO3-mediated direct functionalization of alkyl
nitriles: facile synthesis of γ-ketonitriles through nitrile
alkylation of enol acetates:
Pi Cheng1*, Wei Wang1, Lin Wang1, Jianguo Zeng1, Oliver Reiser2 Yun Liang3
1 Key Laboratory of Traditional Chinese Veterinary Medicine of Hunan Province, Hunan
Agricultural University, Changsha, Hunan 410128, China
2 Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, 93053
Regensburg, Germany.
3 Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan
Province, Hunan Normal University, Changsha, Hunan 410081, China.
* corresponding authors: picheng55@126.com
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Abstract: Direct C(sp3)-H functionalization of alkyl nitriles is a low toxic and
facile route to nitrile-containing compounds. In this research, the Ag2CO3-mediated
nitrile methylenation of enol acetates is developed to prepare γ-ketonitriles through
the direct C(sp3)-H oxidative functionalization of acetonitrile. A radical pathway is
proposed, and acetonitrile serves both as solvent and CN-containing radical source.
Keywords: alkyl nitriles, silver carbonate, radical, enol acetates, γ-ketonitriles
Nitriles are among the most useful synthons and can serve as precursors for
aldehydes, amides, nitrogen-containing heterocycles and carboxylic acids, etc.1 In
particular, ketonitriles are important building blocks which are used in the synthesis
of pharmaceutically active compounds including pyridinones,2-hydroxy ketones,3
and thiophenes.4 A typical and efficient way to γ-ketonitriles makes use of the direct
installation of a CN functional group into -unsaturated ketones via Michael
additions5 Although less toxic CN sources such as TMSCN and acetone cyanohydrin
have been used for the introduction of the CN group as an alternative to the highly
toxic cyanides,6 the preparation of the required agents remains tedious.
The direct C(sp3)-H functionalization of alkyl nitriles represents an economic and
low toxic strategy for the synthesis of substituted nitrile compounds.7 These are of
particular importance and interest because the nitrile group is robust yet readily
converted to other functional groups. Based on transition metal or peroxide mediated
direct C(sp3)-H oxidative functionalization strategies, the addition of nitriles,
especially of simple alkyl nitriles, to alkenes for the 1,2-difunctionalization of alkenes
via a radical process has been investigated.8
Enol acetates 1 (Scheme 1) are easily accessible and widely used in the synthesis
of multi-substituted alkenes,9 heterocylcles10 and -functionalized ketones.11 Recent
advances in the cross-coupling reactions of enol acetates with various radical species
to forge new carbon-carbon bonds have broadened the methods for ketone
construction. A variety of radical species including phenyl (A, Scheme 1),11a-c azide
(B, Scheme 1),11d trifluoromethyl (C, Scheme 1),11d-e sulfonyl (D, Scheme 1),11e-f
benzyl (E, Scheme 1)11g and oxygen-substituted alkyl radicals (F, scheme 1)11h are
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able to attack the enol double bond, which ultimately results in the formation of
-substituted ketones. Meanwhile, the use of -halogen substituted alkyl nitriles as
radical precursors has also shown its application in cyanoalkylations of enol acetates
to γ-ketonitriles,12 however, with the drawback that an additional halogenation step is
needed for the synthesis of the starting material.
Scheme 1. Synthesis of -functionalized ketones with enol acetates as substrates
We report here the synthesis of γ-ketonitriles with enol acetates and alkyl nitriles
as coupling partners based on a direct alkyl nitrile C(sp3)-H functionalization strategy.
Different catalytic systems have been reported to generate nitrile alkyl radicals from
alkyl nitriles including the utilization of CuI or II/peroxide 8a-b and AgI salts.8c-d In this
study, 1-phenylvinyl acetate (1a) was initially used as starting material, and a
combination of Ag2CO3 (3.0 equiv) and FeCl3 (10 mol%), 120 °C and 24h was found
to be optimal providing the desired compound 2a in 73% yield (entry 1, Table 1). A
significant decrease of yield was observed when the amount of Ag2CO3 was reduced
to 2.0 and 1.0 equivalent (entries 2–3, Table 1), respectively. Moreover, when the
reaction was attempted with AgNO3 instead of Ag2CO3, only traces of 2a could be
observed after 24 h (entry 4, Table 1). Additionally, the coupling reaction was also
conducted in the absence of Ag2CO3 (entry 5, Table 1) or with K2CO3 instead of
Ag2CO3 (entry 6, Table 1), but none of the desired compound could be observed
under these conditions. It was worth noting that compound 2a was obtained in 57%
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yield when the reaction was conducted in the absence of FeCl3 (entry 7, Table 1).
These preliminary results strongly suggested that Ag2CO3 served as the real catalyst
and oxidant, while FeCl3 only promoted the reaction by acting as a Lewis acid.
Furthermore, the coupling reaction was found to be sensitive to temperature: As
shown in entry 8, running the reaction at 100 °C for 24 h provided compound 2a only
in 34% yield. Nevertheless, a higher reaction temperature (130 °C) did not increase
the yield (entry 9, Table 1).
Table 1. Variation of reaction parameters a
entry
Variation from the optimal conditions
Yield of compound 2a (%)b
1
2
3
4
5
6
7
8
9
None
73%
51%
32%
trace
0%
Ag2CO3 (2.0 equiv)
Ag2CO3 (1.0 equiv)
AgNO3 instead of Ag2CO3
without Ag2CO3
K2CO3 instead of Ag2CO3
without FeCl3
0%
57%
34%
71%
at 100 °C
at 130 °C
a Experiments were performed with 1a (0.2 mmol), MeCN (2 ml), FeCl3 (10 mol%), Ag2CO3
(3 equiv), 120 °C and 24 h; b isolated yields.
With this optimized set of conditions, we evaluated the scope of enol acetates with
acetonitrile as coupling partner (Scheme 2). Firstly, various para-substituted phenyl
enol acetates were subjected to this Ag2CO3-mediated coupling reaction. Good yields
of the coupling products were generally obtained using electron rich enol acetates as
substrates (2b-e, 2h), reflecting the electrophilic nature of the nitrile methyl radical
intermediate. A significant decrease of yield was observed with 4-acetoxyl phenyl
enol acetate (1f) as substrate. In this case, the hydrolysis of enol acetate to the
corresponding acetophenone was found to be the main side reaction. The reaction also
proceeded well (2g, 2l-2o) with moderately electron deficient substrates. Nevertheless,
strongly electron withdrawing substituents (p-NO2, p-CF3, p-CHO) were not found to
be tolearted in the coupling. The coupling reaction was also found to be sensitive to
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sterically more demanding enol acetates (2h-2k), for which only moderate yields of
coupling products were obtained. Furthermore, 2-thiophenyl enol acetate was well
tolerated as substrate.
Scheme 2. Scope of enol acetatsa,b
substrates
products
2a 68%
2c 65%
2e 79%
2g 61%
2i 54%
substrates
products
2b 64%
2d 69%
2f 43%
2h 53%
2j 45%
2l 70%
2n 63%
2p 51%
1a
1c
1e
1g
1i
1b
1d
1f
1h
1j
1k
1m
1o
2k 33%
2m 69%
2o 55%
1l
1n
1p
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1q
1s
2q 0%
2s 0%
1r
1t
2r 0%
2t 0%
a Experiments were performed with 1a (0.2 mmol), MeCN (2 ml), FeCl3 (10 mol%), Ag2CO3
(3 equiv), 120 °C and 24 h; b isolated yields.
Scheme 3. Scope of alkyl nitriles
To screen the scope of nitriles, several-substituted alkyl nitriles were evaluated as
coupling partner (Scheme 3). Under the optimized conditions, butyronitrile (R2 = Et),
isobutyronitrile (R2 = di-Me) and 2-phenylacetonitrile (R2 = Ph) were found not to be
compatible with the current reaction. In contrast, when ethyl 2-cyanoacetate (R2 =
COOEt) was used, compound 4e could be isolated in 58% yield after 4 hours reaction.
In this case, coumpound 4e undergoes further coupling with enol acetate 1a to give 4d
after another 20 hours reaction. Apparently, electron deficient radicals, i.e. the one
generated from 3d, are highly effective in the coupling process with enol acetates,
while alkyl substituted -cyanoradicals, i. e. those generated from 3a-c are already
too nucleophilic to undergo the coupling reaction.
Scheme 4. Control experiments
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To understand the mechanism, a radical trapping experiment was conducted. When
10.0 equiv of the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO)
were added, the coupling reaction was completely inhibited while giving the adduct 6
of TEMPO and -cyano radical which could be detected by HRMS (A, Scheme 4).
These results suggest that the reaction proceed by a free-radical process. Finally, a
kinetic isotope effect (KIE) was found to be KH/KD = 2.4 for the formation of
2a/2a-d2, indicating that the C(sp3)−H bond cleavage of acetonitrile is the rate
determining step (B, Scheme 4).
Scheme 5. Possible reaction mechanism
On the basis of our experimental results and previous research,8 a plausible
mechanism is proposed for the reaction (scheme 5). The coordination of Ag2CO3 with
the nitrogen atom in MeCN gives the intermediate 8 which is subsequently
deprotonated by Ag2CO3 and reacts with AgI species to provide the AgCH2CN
intermediate 9 and AgHCO3. The AgCH2CN intermediate decomposes under heating
to form the alkyl radical 10 through ligand to metal charge transfer (LMCT).
Subsequently, the addition of the -cyano radical 10 to the C-C double bond in enol
acetate 1a produces the acetoxyl substituted benzyl radical 11. Intermediate 11 is
oxidized by AgI and converted to the carbon-centered cation 12, which hydrolyzes to
target compound 2a and gives acetyl cation intermediate 13. Intermediate 13 is highly
7 / 11

-
sensitive to nucleophilic species11e and might be captured by HCO3 or CO32- in the
reaction system.
In summary, a Ag2CO3-mediated coupling reaction between aryl enol acetates and
alkyl nitriles was developed to prepare γ-ketonitriles based on the direct C(sp3)-H
oxidative functionalization of alkyl nitriles. A radical pathway for the present reaction
is suggested by radical trapping and kinetic isotope effect experiments. The process
developed here offers an alternative approach to γ-ketonitriles in moderate to good
yields with good functional group tolerance.
Acknowledgement
This research was financially supported by Natural Science Foundation of Hunan
Province (No. 2017JJ2115), Science and Technology Planning Project of Hunan
Province (No. 2018TP1017), and the DFG (Graduiertenkolleg Photocatalysis 1626).
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Graphical abstract
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Highlights
 Starting material enol acetates are easily accessible.
 Cheap and low toxic acetonitrile is used as solvent and reactant.
 Direct C(sp3)-H functionalization of alkyl nitriles through a radical pathway.
 Highly toxic CN sources or -halogen alkyl nitriles are avoided for preparing
γ-ketonitriles compared with previous methods.
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