An expedient synthesis of cyanoformates via DAST-mediated C–C bond cleavage of α-oximino-β-ketoesters

Article abstract of DOI:10.1016/j.tetlet.2021.153116

A new protocol to synthesize cyanoformates was developed using simple β-ketoesters as substrates. (Diethylamino)sulfur trifluoride (DAST) was used as a dual-role reagent to activate the oxime moiety and to donate a fluoride. The key intermediates, α-oximino-β-ketoesters, were prepared by highly efficient acid-assisted oximation of β-ketoesters. Then, the deconstruction of α-oximino-β-ketoesters by the fluorinative C–C bond cleavage was demonstrated to provide cyanoformates. In this event, the fluoride addition followed by the C–C bond cleavage selectively occurred in the ketones over esters. Due to simple and mild reaction conditions, variously functionalized cyanoformates were exemplified.

Full text of DOI:10.1016/j.tetlet.2021.153116

Tetrahedron Letters 73 (2021) 153116
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Tetrahedron Letters
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An expedient synthesis of cyanoformates via DAST-mediated CAC bond
cleavage of a-oximino-b-ketoesters
Danhee Kim b,c, Hee Nam Lim a,b,
⇑
a Department of Chemistry and Biochemistry, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk 38541, Republic of Korea
b Eco-Friendly New Materials Research Center, Therapeutics&Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), 141 Gajeong-ro, Yuseong-gu,
Daejeon 34114, Republic of Korea
c Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A new protocol to synthesize cyanoformates was developed using simple b-ketoesters as substrates.
Received 13 March 2021
Revised 8 April 2021
Accepted 18 April 2021
Available online 23 April 2021
(Diethylamino)sulfur trifluoride (DAST) was used as a dual-role reagent to activate the oxime moiety
and to donate a fluoride. The key intermediates,
cient acid-assisted oximation of b-ketoesters. Then, the deconstruction of
a
-oximino-b-ketoesters, were prepared by highly effi-
-oximino-b-ketoesters by
a
the fluorinative CAC bond cleavage was demonstrated to provide cyanoformates. In this event, the fluo-
ride addition followed by the CAC bond cleavage selectively occurred in the ketones over esters. Due to
simple and mild reaction conditions, variously functionalized cyanoformates were exemplified.
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Beckmann fragmentation
DAST-mediated
Cyanoformate
CAC bond cleavage
Oxime activation
Mander’s reagent, ethyl cyanoformate, has been used as a
handy reagent to prepare b-keto esters from ketones. In general,
regioselective C-acylation of ketones with acylating reagents such
as acyl halides or anhydrides is nontrivial because of competing
O-acylation. In this regard, the discovery of ethyl cyanoformate
has offered an exceptionally reliable method for selective C-acyla-
tion [1,2]. Since its introduction, the reagent has been often applied
in synthesis of complex molecules to install ester functionality at
a-ketoesters by a distinct way [14]. C–CN bond of cyanoformates
could be activated and added across unsaturated bonds via ‘‘cut-
and-sew” process [15] by Ni-based catalytic systems; Nakao and
coworkers reported Ni-catalyzed cyanoesterification of 1,2-dienes
[16] and later expanded the reaction scope using alkynes as unsat-
urated bonds under modified catalytic conditions [17]. More
recently, a Pd-catalyzed C–CN bond activation was discovered by
Douglas and coworkers, and it afforded the butenolides from
cyanoformates containing alkynes via intramolecular cyano group
transfer [18].
a-carbon of ketones [3].
In principle, the cyanoformates have two reactive carbons; both
sp carbon of cyano group and sp2 carbon of ester can react with
external nucleophiles. The reported examples of the simple substi-
tution reaction with cyano group as a leaving group used nucle-
ophiles such as organomagnesium [4], organolithium [5],
lithiated amides [6], alcohols [7], and amines [8]. On the other
hand, under acidic conditions active methylenes [9], electron-rich
arenes [10], alcohols [11], azides [12], and organocadmiums [13]
were selectively added to the sp carbon of cyano group. Beyond
simple substitution or addition reactions, the transition-metal-cat-
alyzed transformations with cyanoformates have been reported. In
2007, Shimizu and Murakami disclosed Rh-catalyzed selective
addition of aryl groups to the cyano group, which provided
Despite interesting reactivity modes of the reagents, only few
methods were reported for preparation of the cyanoformates.
The representative synthetic approaches to cyanoformates are
nucleophilic substitution of alkyl- or aryl chloroformates by metal
cyanides [19], transforming a-amidoketones to cyanofomates [20]
or monosubstitution of carbonyl dicyanide with alcohols [21].
However, a use of toxic metal cyanides and water-sensitive car-
bonyl dicyanide is the limitation of these methods. Beyond the
conventional approaches, Bazhin and coworkers reported an inter-
esting method to afford ethyl cyanoformate during their studies for
synthesis of acyl cyanides via CAC bond cleavage strategy [22].
Importantly, the hydrated ketoester II was a major product in oxi-
mation step of ethyl 4,4,4-trifluoro-3-oxobutanoate I. The interme-
diate II was smoothly transformed to ethyl cyanoformate III in the
presence of acetic anhydride or acetic acid under refluxing chloro-
form. The CAC bond cleavage was likely substrate-driven; the
⇑
Corresponding author.
E-mail address: heenam@yu.ac.kr (H.N. Lim).
https://doi.org/10.1016/j.tetlet.2021.153116
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

D. Kim and Hee Nam Lim
Tetrahedron Letters 73 (2021) 153116
hydrate form of ketone (geminal-diol) was a key structural factor,
and this appeared to be induced by highly electron-withdrawing
properties of CF3 group [23]. However, the general scope of the
reaction was not demonstrated for cyanoformates and only one
case III with the moderate yield was exemplified (Scheme 1a).
Herein, we report a simple and highly efficient route to
cyanoformates by two-step transformation using readily available
b-ketoesters as starting materials. Previously, we developed a syn-
thetic method of acyl fluorides V by SF3-NEt2 (DAST)-mediated flu-
orinative Beckmann fragmentation of
a-oximino ketones IV
(Scheme 1b). Notably, DAST was a distinctive reagent that plays
a dual role of oxime activator and of releasing nucleophilic fluo-
rides [24]. Inspired by the previous work, we envisaged that the
selective C A C bond cleavage reaction of a-oximino-b-ketoesters
2 can take place to give cyanoformates 3, and further, the two-step
reaction is operative in one-pot (Scheme 1c). Compared to Bazhin’s
discovery, our protocol uses more common 1,3-dicarbonyl com-
pounds as starting materials and does not require geminal-diol
substrates such as II as intermediates, thus being mechanistically
different.
We first explored the feasibility of the designed reaction
through two separate reactions (Scheme 2a). Oximation of b-
ketoesters is known to be facile because they are readily enoliz-
able. Indeed, the oximation with either alkyl nitrite or sodium
nitrite under acidic medium showed perfectly clean conversion.
Gratifyingly, the reaction of 2a with DAST gave the desired com-
pound 3a in excellent yield. Note that the possible Beckmann rear-
rangement product was not observed in the given reaction
conditions.
Next, the other types of oxime activators were examined to
evaluate the efficiency of CAC bond cleavage reaction
(Scheme 2b). When Bazhin’s procedure was applied to 2a, O-acety-
lation of 2a was the only product instead of getting 3a (entry 1).
Use of tosyl chloride did not furnish the desired product, albeit full
consumption of 2a (entry 2). Neither phosphorous-based activator
such as phosphorus(V) oxychloride [25] nor bis(2-oxo-3-oxazo-
lidinyl)phosphinic chloride (BOPCl) [26] was effective in this trans-
formation while their applications in oxime activation for the
Beckman rearrangement were quite successful (entry 3 and 4).
Although chloride nucleophiles generated after oxime activation
(entry 2–4) were not efficient to selectively lead to CAC bond
cleavage, use of 2,2-dichloroimidazolidine-4,5-dione [27] afforded
3a in good yield and it was comparable to that of DAST (entry 5).
Contrary to our expectation, the deoxyfluorination method using
Scheme 2. Reaction optimization.
NBS/PPh3 and HF-NEt3 [28] that was profitably applied to fluorina-
tive CAC bond cleavage of -oximinoketones was not suitable in
a
this transformation (entry 6). A sulfur-free deoxyfluorination
reagent (Ishikawa’s reagent) proved to work (entry 7). Investiga-
tion of the oxime-activating reagents demonstrated excellence of
the DAST in the nucleophile-intercepted C A C bond cleavage reac-
tions [29].
We attempted to optimize the two-step reaction in one-pot
(Scheme 2c). In the first step, anhydrous conditions using 4 M
HCl in dioxane and n-butyl nitrite were adopted for compatibility
with the DAST in the second step. Interestingly, when DAST was
directly subjected to the THF solution of 2a, the reaction was rela-
tively complex compared with clean conversion observed in
Scheme 2a. Fortunately, the yield of 3a was greatly improved by
removal of n-butanol which is a by-product of the first step; upon
treatment with the DAST, n-butanol is a probable competitor with
oxime-hydroxyl group and it is a latent nucleophile that can attack
activated ketones. Notably, the product yield obtained from the
sequential reactions in a single flask without separation of the
intermediate 2a was comparable to the overall yield of the two-
separate reactions from 1a. However, owing to poor stability of
cyanoformates compared with the cyanoformamides [30], the iso-
lated yield was reduced during silica gel column chromatography.
Later, we confirmed that partial decomposition of 3a generated the
benzyl alcohol 4a in 14% yield and dibenzyl carbonate in 2% yield.
Despite the efforts, use of the neutral-, basic alumina or Florisil
Scheme 1. Prior arts and proposed one-pot strategy.
2

D. Kim and Hee Nam Lim
Tetrahedron Letters 73 (2021) 153116
instead of silica gel could not completely solve the decomposition
problems.
After setting an optimized procedure, we surveyed the reaction
scope with respect to O-substituents. The substrates 1a-o are
known compounds and readily obtained by DMAP-catalyzed trans-
esterification of ethyl acetoacetate [31]. The two-step reactions (1
to 3) could be completed in less than 2 h for all cases. The transfor-
mation proved to be general (Table 1). The functional groups were
tolerated, such as benzyl (1a), phenylethyl (1b), halogens (1c-e),
methoxy (1f), and nitro (1g), to provide corresponding cyanofor-
mates in excellent yields. It is notable that a,b-unsaturated ketone
1h was intact in the given conditions, furnishing 3h in 94% yield.
Other common functional groups such as bromoalkyl (1i), naph-
thyl (1j), adamantyl (1k), cyanoethyl (1l), octyl (1m), and methox-
yethyl (1n) were also compatible. Finally, the substrate 1o
containing optically pure (R)-menthol was transformed to the cor-
responding cyanoformate 3o. Most of the products in Table 1 were
not stable enough during the silica gel chromatography, and thus
were obtained in the reduced isolated yields compared to NMR
yields. Nonetheless, the normal work-up procedure still gave rela-
tively pure crude products in excellent NMR yields [32].
The developed protocol was scalable; benzyl acetoacetate 1a
was converted to benzyl cyanoformate 3a in a five gram-scale
and 3a could be purified by short path distillation with reasonable
mass recovery (Scheme 3). Because the distillation is not facile in
small-scale preparation, we foresee that direct use of the crude
product obtained right after normal work-up process is likely a
great advantage in a practical point of view. To compare efficiency
in use of the purified and crude products, C-acylation of 1-tetralone
4 was conducted. Gratifyingly, use of both reagents showed suc-
cessful conversions to the desired acylation product 5 although
the purified 3a was slightly better than the crude 3a.
Scheme 3. Gram-scale reaction and control experiments.
cleavage reaction (2 to 3). While two activated carbonyl groups,
ketone and ester, are present in 2, the ketone was the better accep-
tor of fluoride nucleophile. The high conversion of 2 to 3 supports
the selective fluoride addition to ketones. Whereas acetyl fluoride
D was unidentified during the reaction, a control experiment
firmly supports the proposed reaction pathway (Scheme 4b). For
example, when DAST was subjected to the a-oximino-b-ketoester
6, 2-naphthoyl fluoride 7 and benzyl cyanoformate 3a were
obtained in 60 and 78%, respectively. The identification of 7 sup-
ports the fluorinative CAC bond cleavage step (C to D). An addi-
tional experiment adds interesting reactivity of an activated
malonate 8; the ester functionality in 8 was discovered to react
with DAST to provide a mixture of cyanoformate 3a and the highly
reactive fluoroformate 9. This unreported reactivity of the ester
We tentatively proposed a mechanism (Scheme 4a). The two-
step process involves an oximation of readily enolizable b-ketoe-
sters (1 to 2) and oxime activation by DAST followed by CAC bond
group toward DAST is likely due to the presence of a-oxime that
Table 1
Reaction scope.a
aIsolated yields, bNMR yields with the internal standard of 1,3,5-trimethoxybenzene.
cFully decomposed during silica gel column chromatography
3

D. Kim and Hee Nam Lim
Tetrahedron Letters 73 (2021) 153116
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Scheme 4. A plausible mechanism and control experiments.
significantly increases electrophilicity of the ester functionality
[33].
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to facile enolization of b-ketoesters and the latter step required
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
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to influence the work reported in this paper.
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This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (NRF-
2019R1C1C1004970). We also thank Prof. Inji Shin (Seoul National
University of Science and Technology) for proofreading the
manuscript.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153116.
4