Deadly KCN and pricey metal free track for accessing β-ketonitriles employing mild reaction conditions

Article abstract of DOI:10.1080/00397911.2021.1910846

A one pot synthesis of β-ketonitriles from readily accessible 3-chloropropenals using economically benign iodine, aqueous ammonia and sodium hydroxide solution, employing mild reaction conditions have been described. This report presents a convenient, inexpensive, highly toxic-matter-free and eco-friendly approach for β-ketonitriles.

Full text of DOI:10.1080/00397911.2021.1910846

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Deadly KCN and pricey metal free track for
accessing β-ketonitriles employing mild reaction
conditions
Pawan K. Sharma, Rajiv Kumar, Sita Ram & Navneet Chandak
To cite this article: Pawan K. Sharma, Rajiv Kumar, Sita Ram & Navneet Chandak (2021): Deadly
KCN and pricey metal free track for accessing β-ketonitriles employing mild reaction conditions,
Synthetic Communications, DOI: 10.1080/00397911.2021.1910846
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https://doi.org/10.1080/00397911.2021.1910846
Deadly KCN and pricey metal free track for accessing
b-ketonitriles employing mild reaction conditions
Pawan K. Sharmaa, Rajiv Kumara,b, Sita Rama,c, and Navneet Chandaka
b
aDepartment of Chemistry, Kurukshetra University, Kurukshetra, India; Ch. Mani Ram Godara
c
Government College for Women, Fatehabad, India; Department of Chemistry, J. C. Bose University of
Science & Technology, YMCA, Faridabad, India
ABSTRACT
ARTICLE HISTORY
Received 25 January 2021
A one pot synthesis of b-ketonitriles from readily accessible 3-chloro-
propenals using economically benign iodine, aqueous ammonia and
sodium hydroxide solution, employing mild reaction conditions have
been described. This report presents a convenient, inexpensive,
highly toxic-matter-free and eco-friendly approach for b-ketonitriles.
KEYWORDS
Aqueous ammonia; iodine;
b-ketonitriles; 3-
methoxypropenenitrile; one-
pot; transition metal free
GRAPHICAL ABSTRACT
DMSO,
Aq. NaOH
DCM
O
DCM
Ammonia
I2
CN
Ar
Solution
Mild reaction conditions
One pot synthesis
Transition metal free
Economic synthesis
Non-toxic
Cl
CHO
Ar
Introduction
b-Ketonitriles are extremely versatile and valuable synthetic intermediates for the syn-
thesis of a wide variety of biologically and pharmacologically active heterocycles includ-
ing pyrazoles,[1] isoxazoles,[2] thiazoles,[3] imidazoles,[4] furans,[5,6] pyrroles,[6]
thiophenes,[7] 2-pyridones,[8] pyrazolopyrimidines,[9] 1,2,3-triazoles,[10] benzothia-
zoles,[11] imidazo[1,2-a]pyridines,[12] dihydropyridazines,[6] etc. (Figure 1.) as well as
many drugs targeting different therapeutic areas such as anti-HIV,[13] anti-inflamma-
tory,[14] antidepressants[15] etc. Further, b-ketonitriles can be converted to benzochro-
menes,[16] dioxaprollenes,[17] 1-naphthols,[18] and b-hydroxy nitriles.[19] b-Hydroxy
nitriles, obtained by enantioselective reduction of the carbonyl group of b-ketonitriles,
CONTACT Pawan K. Sharma
pksharma@kuk.ac.in
Department of Chemistry, Kurukshetra University,
Kurukshetra, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

2
P. K. SHARMA ET AL.
Figure 1. General synthetic utility of b-ketonitriles in synthesis of heterocyclic compounds.
can be further converted to optically pure b-hydroxy carboxylic acids and their deriva-
tives which are other very important precursors in organic chemistry.
Consequently, continuous efforts have understandably been devoted for developing
efficient approaches for the synthesis of b-ketonitriles. Conventional methods of their
synthesis involve the condensation of acetonitrile with excess of various esters or amides
in presence of strong base,[20] reaction of a-haloketones with highly toxic metal cya-
nides,[21] such as KCN and reaction of cyclic enamines with toxic cyanogen chloride
(Cl–CN).[22] Beside these, some other methods of their synthesis include C-acylation of
resin bound cynoacetate,[23] indium-mediated coupling of bromoacetonitriles with aro-
matic aryl cyanides,[24] conversion of enaminones via isoxazoles,[25] Pd-catalyzed car-
bonylation of aryl halides (–I, –Br)[26] and copper-catalyzed oxidative coupling of
aromatic alcohols with acetonitrile.[27] Recently some more methods involving cyanation
of silyl enolates using hypervalent-iodine along with trimethylsilyl cyanide (TMSCN) as
cyanating reagent[28] and boron enolates using either N-cyano-N-phenyl-p-toluenesulfo-
namide (NCTS) or TsCN as a cyanating reagent have been reported[29] (Scheme 1A).
All the aforestated methods suffer from certain serious drawbacks/bottlenecks: (1)
Some methods use toxic metal cyanides (KCN or NaCN) or Cl-CN either in the direct
synthesis or at any stage during synthesis of reagents e.g. TMSCN, TsCN; (2) Some pro-
tocols use costly metals e.g. Pd, In, Mo etc. while others use costly reagents like trime-
thylsilyl acetonitriles which give rise to cost issues besides making these methods
unfavorable for commercial applications; (3) Some methods use comparatively less sta-
ble substrates, or their reagent synthesis increases the number of steps in overall synthe-
sis. Mainly tedious experimental procedures and use of highly toxic chemicals limit the

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SYNTHETIC COMMUNICATIONSV
3
(A)
(B)
Scheme 1. Methods of synthesis of b-ketonitriles.
applicability of these methods to well established laboratories and well-trained man-
power rendering these methods unsuitable for undergraduate students’ labs. Thus,
development of a convenient synthetic method for b-ketonitriles that uses inexpensive
and nontoxic reagents under aqueous condition is still highly desired.
In previous work, our research group reported, economic and eco-friendly, transition
metal-free synthesis of propynenitriles and 3-chloropropenenitriles starting from 3-
chloropropenals.[30] Considering the fact that propynenitriles are good substrates for
nucleophilic addition reactions, it was conceived that conversion of propynenitriles to
b-ketonitriles can be achieved via nucleophilic addition of water followed by tautomeri-
zation. After numerous failed attempts, we developed a simple, inexpensive, toxic
matter free, novel, one pot protocol for the synthesis of b-ketonitriles 3 starting from 3-
chloropropenals 1. The reaction initiates with transformation of formyl group to nitrile
by treatment of iodine and aqueous ammonia in dichloromethane solvent followed by
treatment with aqueous base in DMSO solvent in one pot (Scheme 1B). Use of common
lab chemicals such as iodine, aqueous ammonia and sodium hydroxide as a base in
overall conversion increases its significance making it suitable for any undergradu-
ate lab.
Results and discussion
Conversion of 3-chloropropenals 1 to isolable intermediate, 3-chloropropenenitriles 2
was reported earlier by our group.[30] Optimization studies were initiated taking one of
the intermediates; (Z)-3-(4-bromophenyl)-3-chloropropenenitrile (2a) as reactant

4
P. K. SHARMA ET AL.
Table 1. Optimization of Solvent and Base Equivalentsa.
Entry
Solvent
Aq. NaOH (%)
Time
Yield (%)b
Upc (91)
62
4a (88)
Mixture
Mixture
Mixture
Mixture
Mixture
42
1
2
3
4
5
6
7
8
MeOH
t-Butanol
THF
10
10
10
10
10
10
10
10
10
10
15
20
25
20 min–24 h
4 h
15 min
30 h
THF
p-Dioxane
CH3CN
DMF
12 h
6 h
8 h
4 h
DME
9
Acetone
DMSO
DMSO
DMSO
DMSO
12 h
10
11
12
13
15 min
10 min
4 min
4 min
66
71
77
74
c
aReaction conditions: 2a (1.00 mmol), Aq. NaOH (1 mL). bIsolated yield. Undesired product.
Bold indicates the reaction conditions for obtaining best results.
Scheme 2. Synthesis of undesired product 5. Reaction conditions: 2a (1.00 mmol), Aq. NaOH (1 mL,
10%), MeOH (10 mL)
because it could be obtained conveniently from 4-bromoacetophenone as solid in high
yield. For obtaining b-ketonitrile 3a, reactant 2a was treated with sodium hydroxide as
base in various solvents as described in Table 1.
Initially, polar protic solvent, methanol was screened and we were pleased to observe
a single spot that was different from reactant as seen in thin layer chromatography
1
(TLC) within 20 min (Table 1, entry 1). However, rigorous analysis of H and 13C NMR
along with 2D-NMR spectra suggested the formation of undesired Z-alkene 5, the struc-
ture of which was confirmed as (Z)-3-(4-bromophenyl)-3-methoxypropenenitrile 5
(Scheme 2; see Supporting Information (SI) for complete details). Next, we stirred the
reaction mixture for 24 h under aforestated reaction conditions but no further reaction
was observed. This led to the conclusion that polar protic solvent undergoes nucleo-
philic addition reaction with propynenitrile intermediate 4a formed by elimination of
HCl from reactant 2a in presence of NaOH base (Scheme 2).
After that t-butanol was selected as solvent for the reaction since it is bulkier and
weaker nucleophile than methanol. Surprisingly desired product 3a was obtained in
acceptable amount in t-butanol, even though poor solubility of reactant 2a in solvent at

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5
Scheme 3. One pot synthesis of target product (3a). Reaction conditions: 3-Chloropropenal 1a
(3.0 mmol), I2 (3.0 mmol), ammonia solution (4 mL), DCM (20mL), Aq. NaOH (3 mL, 20%), DMSO
(15 mL) at r.t.
Scheme 4. Synthesis of various b-ketonitriles 3 from 3-chloropropenals 1. Reaction conditions: 3-
Chloropropenals 1 (3.0 mmol), I2 (3.0 mmol), ammonia solution (4 mL), DCM (20 mL), Aq. NaOH (3 mL,
a
20%), DMSO (15mL) at r.t. 2 equiv. of reagents were used.
room temperature remained an issue (Table 1, entry 2). In order to overcome the issues
arising in protic solvents, we turned our attention toward polar aprotic solvents and
reaction in THF led to formation of propynenitrile 4a within 15 min (Table 1, entry
3),[30] however prolonged stirring even for 30 h at room temperature resulted into mix-
ture of products instead of desired product 3a (Table 1, entry 4).Similarly, reactions in
p-dioxane, CH3CN, DMF and DME solvents afforded mixture of products (Table 1,
entries 5, 6, 7 and 8). Use of acetone resulted into desired product 3a, nevertheless the
procedure suffered from poor conversion (42%, Table 1, entry 9). After many futile
attempts, desired product 3a was obtained in substantial amount at room temperature
in DMSO solvent (Table 1, entry 10). Yield was further improved by normalizing of
equivalents of base along with reaction time optimization (Table 1, entries 11, 12, and
13). Best results were obtained by using DMSO solvent and 20% of aqueous NaOH
base (Table 1, entry 12). Finally, our target was to convert two step procedure of syn-
thesis of b-ketonitriles 3 starting from 3-chloropropenals 1 in one pot manner which
was achieved by treating 3-chloropropenal with I2 and ammonia in DCM followed by

6
P. K. SHARMA ET AL.
Scheme 5. Formation of propynenitrile 4t in case of ortho substituted derivative 1t. Reaction condi-
tions: 3-Chloropropenal 1t (3.0 mmol), I2 (3.0 mmol), ammonia solution (4 mL), DCM (20mL), Aq. NaOH
(3 mL, 20%), DMSO (15 mL) at r.t.
Scheme 6. Proposed mechanism.
evaporation of DCM solvent on a rotary evaporator and reacting the residual mass with
aqueous NaOH in DMSO solvent (Scheme 3). Poor solubility of residual solid in t-buta-
nol made it less attractive option for the one pot reaction. It is pertinent to mention
here that various 3-chloropropenals 1 were easily synthesized from commercially avail-
able substituted acetophenones under Vilsmeier Haack reaction conditions[31]
.
With the optimized reaction conditions in hand, the substrate scope for synthesis of
variety of b-ketonitriles using differently substituted 3-chloropropenals 1 was examined.
Interestingly substrates bearing electron donating as well as electron withdrawing groups
at para and meta positions at phenyl ring afforded corresponding b-ketonitriles in high
yields with equal ease (Scheme 4).
On the other hand, substrate incorporating ortho methoxy substituents at phenyl ring
(1t) resulted into corresponding propynenitrile product 4t probably due to slow reac-
tion caused by steric effect of ortho substituent to incoming nucleophile (Scheme 5).
However, the isosteric ortho substituted derivatives e.g. 1-naphthyl (1q) and 1,2,3-tri-
azole ring containing derivative (1 s) resulted into desired products 3q and 3 s in rela-
tively low yields upon recrystallization.
On the basis of results of above substrate studies, literature review and earlier report
from our group,[30] a plausible reaction pathway was proposed as shown in Scheme 6.
Conversion of 3-chloropropenals 1 to corresponding 3-chloropropenenitriles 2 is paral-
lel to general mechanism for the conversion of aldehydes into nitriles. Iodine acts as an
oxidizing agent and reaction proceeds via formation of N-iodoaldemine 7 which
upon removal of HI under basic conditions of aqueous ammonia results in

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SYNTHETIC COMMUNICATIONSV
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3-chloropropenenitriles 2. Thereafter, NaOH in DMSO solvent eliminates HCl from 3-
chloropropenenitrile 2 to form propynenitrile 4 which is subsequently attacked by
hydroxyl group nucleophilically to afford enolnitrile intermediate 8. This intermediate 8
is further attacked by NaOH base to generate enolate intermediate 9 which upon acidic
work up and tautomerization results into b-ketonitrile 3.
Conclusion
In conclusion, a convenient, inexpensive, eco-friendly and toxic-matter-free one pot
synthesis of b-ketonitriles 3 from 3-chloropropenals 1 have been developed, employing
mild reaction conditions with the use of I2, aqueous ammonia and NaOH reagents.
This method is so handy that it can be easily used by undergraduate students in a frugal
lab. In addition, development of new and simple method for b-ketonitriles may open
new avenues to explore expeditious synthesis of novel pharmacologically potent com-
pounds, natural products and drugs.
Experimental section
Materials and general methods
All the commercially available chemicals were used without further purification. All the
solvents were dried and/or purified according to standard procedures prior to use. All
the reactions were monitored by TLC on TLC silica gel on F254 aluminum plates using
a mixture of chloroform and methanol as eluent while visualization was achieved by
UV lamp. Melting points were determined in open capillaries in an electrical melting
point apparatus and are uncorrected. IR spectra were recorded on ABB MB 3000 DTGS
1
IR instrument. H NMR spectra were recorded on 400 MHz, while 13C NMR spectra
were registered at 100 MHz, using deuterated chloroform (CDCl3) or dimethyl sulfoxide
(DMSO-d6) as solvent, and tetramethylsilane (TMS) as internal standard at room tem-
perature. Chemical shifts are reported as d values in parts per million (ppm) downfield
from TMS. High resolution mass spectra were obtained from a MicroMass ESI-TOF MS
spectrometer. Multiplicities are described as singlet (s), doublet (d), doublet of doublet
(dd), triplet (t), triplet of triplet (tt), multiplet (m), exchangeable proton (ex) for NMR
assignments and strong (s), medium (m), broad (br) for IR assignments. The coupling
constants are expressed in hertz (Hz).
General procedure for the synthesis of b-ketonitriles 3
To a solution of 3-chloropropenal (1, 3.0 mmol) in 20 mL of dichloromethane, added
molecular iodine (3.0 mmol) in one lot and allowed to stir for 3–5 minutes. Then 4 mL
of 30% aqueous ammonia solution was added to reaction mixture and stirred further
for 45 minutes. Slight excess of iodine was neutralized with few drops of aqueous
sodium thiosulfate solution and organic layer was evaporated under reduced pressure.
DMSO (15 mL) was added to solid mass left followed by addition of 3 mL of aqueous
NaOH (20%) maintaining the equilibrium temperature, 25 ꢀC by using water bath.
Reaction was monitored by TLC. After completion of reaction (3–10 minutes), reaction

8
P. K. SHARMA ET AL.
mixture was poured into ice cold water and neutralized with dilute HCl. Solid product
was filtered, dried and recrystallized with minimum amount of ethanol.
3-(4-Bromophenyl)-3-oxopropanenitrile (3a)
Yield 74 %; yellow solid; Lit. m. p. 158-162 ꢀC,[26a] Obs. m. p. 152–154 ꢀC; IR(KBr) (ꢀ,
1
cmꢁ1): 2947, 2924 (C–H stretch), 2214 (CꢂN stretch), 1690 (C¼O stretch); H NMR
(400 MHz, CDCl3) d (ppm): 7.81–7.78 (m, 2H, Ar), 7.70–7.67 (m, 2H, Ar), 4.06 (s, 2H,
–CH2–); 13C NMR (100 MHz, CDCl3) d (ppm): 186.2, 133.0, 132.6, 130.3, 129.9,
113.4, 29.4.
Supplemental data (full experimental detail, copies of H-H COSY, HSQC, ROESY
1
and DEPT-135 spectra of compound 5 as well as H and 13C NMR spectra for com-
pounds 5, 3a-3s, 4t ) can be accessed on the publisher’s website.
Acknowledgments
One of the authors (Rajiv Kumar) is thankful to University Grants Commission, New Delhi,
India for the providing JRF/SRF. HRMS facility of Materials Research Centre, MNIT Jaipur,
India is gratefully acknowledged.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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