Electrophilic α-cyanation of 1,3-dicarbonyl compounds

Article abstract of DOI:10.1039/c3ra41376d

Electrophilic α-cyanation of activated methylene compounds was achieved under mild basic conditions using commercially available TsCN as a CN⁺ equivalent. A series of 1,3-dicarbonyl compounds, both cyclic and acyclic, were found to be suitable substrates for this transformation. Subjecting 1,1,1-trifluoro-1,3-dicarbonyl compounds to a modified procedure resulted in the formation of α-cyano ketones after trifluoroacetyl group fragmentation. An efficient one-pot cyanation/pyrazole formation sequence to 4-cyano pyrazoles from 1,3-diketones has also been developed. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra41376d

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Electrophilic a-cyanation of 1,3-dicarbonyl compounds3
Ramulu Akula, Yan Xiong and Hasim Ibrahim*
Cite this: DOI: 10.1039/c3ra41376d
Electrophilic a-cyanation of activated methylene compounds was achieved under mild basic conditions
using commercially available TsCN as a CN+ equivalent. A series of 1,3-dicarbonyl compounds, both cyclic
and acyclic, were found to be suitable substrates for this transformation. Subjecting 1,1,1-trifluoro-1,3-
dicarbonyl compounds to a modified procedure resulted in the formation of a-cyano ketones after
trifluoroacetyl group fragmentation. An efficient one-pot cyanation/pyrazole formation sequence to
4-cyano pyrazoles from 1,3-diketones has also been developed.
Received 20th March 2013,
Accepted 18th April 2013
DOI: 10.1039/c3ra41376d
www.rsc.org/advances
strong bases under anhydrous conditions. Moreover, issues
with reactivity, stability and the use of excess reagent further
hamper the general utility of these methods.
Introduction
a-Cyano 1,3-dicarbonyls are a class of compounds with wide
ranging applications and diverse biological activity.1 They are
versatile intermediates en route to a variety of biologically
active and medicinally relevant molecules.2 Consequently,
many routes have been developed to access this class of
compounds of which the most important is the aldol reaction
between a-cyano carbonyl derivatives and acyl equivalents.3
4-Acyl isoxazoles have also been utilised as precursors.2c For
instance, a large number of patented a-cyano 1,3-dicarbonyls
with herbicidal activity were synthesised from 4-acyl isoxazoles
by base induced isoxazol isomerisation.4 Other methods
include the reaction of acyl equivalents with isocyanates,5
and the dehydration of nitrile precursors such as oximes.6
A direct access to these compounds from the reaction of
easily synthesisable 1,3-dicarbonyl compounds and electro-
philic cyanating agents is an attractive and economic but
widely overlooked alternative to the above multistep strategies.
Such ‘‘CN+’’ reagents include cyanogen chloride,7 dicyan,8 aryl
cyanates,9 as well as the N-cyano reagents 3-cyano-thiazolidine
1,10 2-cyanopyridazin-3(2H)-ones 2,11 and 1-cyanobenzotriazole
3 (Scheme 1a).12
A formal electrophilic cyanation by an electrochemical
process has been reported; however, the need for specialised
equipment and the use of an excess of highly toxic NaCN
limits the general utility of this method (Scheme 1b).13
We report herein on a straightforward, high-yielding and
general method that addresses the limitations of the above
electrophilic strategies by employing commercially available
p-toluenesulfonyl cyanide (TsCN) as an electrophilic
C-cyanating agent in conjunction with potassium carbonate
as a mild base (Scheme 1c).
Cyanogen chloride and dicyan are highly toxic and difficult
to handle, with the latter mostly generated in situ.8 Aryl
cyanates and reagents 1–3 have to be synthesised by the
reaction of the parent hydroxy arene or the N-heterocycle with
toxic cyanogen bromide. From these reagents only 1 has been
systematically studied in the a-cyanation of 1,3-dicarbonyl
compounds and gives moderate to good yields of the cyano
products, but has to be used in excess. Without exception,
reactions with these reagents have to be carried out with
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical
Biology, University College Dublin, Belfield, Dublin 4, Ireland.
E-mail: hasim.ibrahim@ucd.ie; Fax: 353 1 7161178; Tel: 353 1 7162978
Electronic supplementary information (ESI) available: Copies of 1H NMR and
3
13C NMR spectra of all a-cyano carbonyl compounds, as well as 1H NMR spectra
Scheme 1 Overview on electrophilic a-cyanation of 1,3-dicarbonyl compounds.
of 4-cyano pyrazoles. See DOI: 10.1039/c3ra41376d
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Table 1 Reaction parameter optimisation in the a-cyanation of benzoylacetonea
improvement was observed when a 9 : 1 mixture of THF–H2O
was used as the solvent which gave a homogenous reaction
mixture. We were delighted to find that complete conversion
occurred within 1 h with the product isolated in an excellent
yield of 93% (Table 1, entry 7). Decreasing the amounts of
TsCN or K2CO3 resulted in lower conversions (Table 1, entries
8 and 9).
TsCN
K2CO3
(equiv.)
Time
(h)
Convb
(%)
Yieldc
(%)
Entry
(equiv.)
Solvent
With reaction conditions from entry 7 in hand, we
embarked on a screen of various 1,3-dicarbonyls and a b-keto
phosphonate (Table 2). b-Keto esters were amenable to the
reaction conditions and were a-cyanated in excellent yields
(Table 2, entries 1–4), as did two additional 1,3-diketones
(entries 5 and 7). We report here, to best of our knowledge, the
first direct a-cyanation of cyclic 1,3-diketones. Thus, dimedone
and 1,3-indanedione readily underwent electrophilic cyanation
in good yields, with the a-cyano 1,3-indanedione isolated by
simple precipitation owing to its solubility in water (Table 2,
entries 8 and 9). This is especially noteworthy as previous
preparations involved, among others, condensation methods
from acyclic precursors.1a,15
1
2
3
4
5
6
7
1.2
1.2
1.2
1.5
1.5
1.5
1.5
1.2
1.2
1.2
1.2
1.5
1.5
1.5
THF
THF
MeCN
THF
THF
MeCN
THF–H2O
(9 : 1)
THF–H2O
(9 : 1)
THF–H2O
(9 : 1)
2
6
6
6
5
2
1
60
78
75
80
90
86
¢98
50
70
66
73
83
79
93
8
9
1.2
1.5
1.5
1.2
2
2
88
94
80
86
a
Reactions were performed with 1.0 mmol of benzoylacetone at rt.
Determined by 1H NMR spectroscopy of the crude material.
Isolated yield after flash column chromatography.
b
c
Subjecting 2-furyl and 2-thienyl derived 1,3-diketones with
a trifluoroacetyl group to the reaction conditions in Table 2
resulted in decomposition of the starting material. However,
by adding K2CO3 to a mixture of the substrate and TsCN, we
were able to obtain a-cyano ketones instead of the expected
a-cyano 1,3-diketones after apparent trifluoroacetyl group
fragmentation. This fragmentation could provide an alter-
native route to acyclic a-cyano ketones, as the direct electro-
philic a-cyanation of acyclic ketones using TsCN proceeds with
very low conversions.14
Results and discussion
The electrophilic cyanation of kinetic lithium enolates derived
from cyclic ketones has previously been reported using
TsCN.14 Thus, we decided to examine the utility of TsCN in
the a-cyanation of 1,3-dicarbonyl compounds. Employing
benzoylacetone as our test substrate in THF at room
temperature, we added 1.2 equivalents of K2CO3 as the base
followed by the addition of 1.2 equivalents of TsCN, which
gave a thick heterogeneous reaction mixture. TLC monitoring
of the reaction indicated that after 2 h a new product had
Next, we examined the a-cyanation of 1,3-dimethylbarbi-
turic acid which pleasingly gave the expected novel a-cyano
product in an excellent yield of 91%, albeit after a longer
reaction time of 12 h (Table 2, entry 12).
1
formed. We were pleased to find that after work-up, H NMR
analysis of the crude material indicated that the a-cyano
product had been formed in 60% conversion. However,
purification of the crude material by column chromatography
proved difficult as the purified product contained TsCN-
derived by-product impurities with similar polarity. After
substantial optimisation involving various work-up procedures
and eluents for chromatography, we found that by adding
triethylamine (TEA) to the eluent we were able to isolate the
a-cyanated triethylammonium adduct after chromatogra-
phy,1b,c which upon washing with aqueous 1 M HCl gave the
pure a-cyanated benzoylacetone product in 50% isolated yield
(Table 1, entry 1). Increasing the reaction time to 6 h gave a
78% conversion to the product with an improved yield of 70%
(Table 1, entry 2). Switching to MeCN as the solvent had no
effect on the conversion; however, increasing the amount of
the reagents to 1.5 equivalents gave higher conversions and
the product was isolated in 83% yield (Table 1, entry 5). Under
otherwise identical reaction conditions, conducting the reac-
tion in MeCN instead of THF gave comparable results in a
shorter reaction time of 2 h (Table 1, entry 5 vs. 6). We
assumed that due to the poor solubility of the K2CO3 in THF or
MeCN, the reaction did not proceed to completion. A marked
We also subjected a b-keto phosphonate to the reaction
conditions and were delighted to find that it underwent
a-cyanation in good yield. However, 2 equivalents of TsCN and
K2CO3, as well as longer reaction time were needed for a good
conversion (Table 2, entry 13). To the best of our knowledge,
this represents the first successful direct electrophilic a-cyana-
tion of a b-keto phosphonate.
a-Cyano 1,3-dicarbonyl compounds are useful intermedi-
ates for the synthesis of a variety of biologically active
compounds, especially heterocyclic compounds such as
4-cyano pyrazoles.2a,2b,16 We were successful in devising a
one-pot electrophilic cyanation/pyrazole formation sequence
from 1,3-diketones. Thus, adjusting the pH of the cyanation
reaction mixture to y2 using 1.25 M ethanolic HCl and
subsequent addition of 2 equivalents of hydrazine hydrate
gave the depicted 4-cyano pyrazoles in good yields (Scheme 2).
We propose that the mechanism operating in the presented
a-cyanation of 1,3-dicarbonyl compounds is ionic in nature.
Literature precedent suggests two possible pathways. The first
involves addition of the generated potassium enolate onto the
cyano carbon of TsCN, which leads to ionic intermediate 4.
Potassium p-toluenesulfinate elimination from 4, followed by
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Table 2 a-Cyanation of activated methylene compounds using TsCN and
Table 2 (Continued)
a
K2CO3
Entry Substrate
13
Product
Time
12 h
Yieldb (%)
74e
Entry Substrate
1
Product
Time
1 h
Yieldb (%)
92
a
2
3
4
5
6
7
8
1 h
1 h
2 h
1 h
1 h
1 h
89
90
94
83
93
95
Reaction conditions: substrate (1.0 mmol), TsCN (1.5 mmol),
b
K2CO3 (1.5 mmol), THF–H2O (9 : 1, 5.0 mL). Isolated yield after
flash column chromatography. Reaction performed with 1.2 mmol
of TsCN and K2CO3. Isolated yield after precipitation. Reaction
performed with 2.0 mmol of TsCN and K2CO3.
c
d
e
Scheme 2 One-pot preparation of 4-cyano pyrazoles from 1,3-diketones.
tautomerisation to the more stable enol isomer gives the
C-cyanated product (Scheme 3, pathway A).17 The second
pathway involves attack of the enolate onto the cyanate carbon
of sulfinyl cyanate 5, forming intermediate 6. We propose that
under the basic reaction conditions, sulfinyl cyanate 5 is
generated in situ from TsCN by base catalysed rearrange-
ment.18 Subsequent p-toluenesulfinate liberating fragmenta-
10 min 79c
9
15 min 74cd
10
11
12
30 min 90
30 min 85
12 h
91
Scheme 3 Proposed mechanism for C-cyanation with TsCN.
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tion of 6, via an aromatic transition state, furnishes the
C-cyanated product (Scheme 3, pathway B).
Benzyl-2-cyano-3-hydroxybut-2-enoate
Isolated as a cream coloured solid (193 mg, 89%); Mp: 104–108
uC; IR (KBr, cm21): u 3450, 3070, 2223, 1637, 1610, 1458, 1406,
1
1220; H NMR (400 MHz, CDCl3): d 2.35 (3 H, s, CH3), 5.31 (2
H, s, OCH2), 7.35–7.41 (5 H, m, Ar-H), 13.50 (1 H, s, OH); 13C
NMR (100 MHz, CDCl3): d 21.3, 67.7, 81.4, 114.7, 128.2, 128.7,
128.7, 134.4, 169.8, 188.3; HRMS (ESI): C12H10NO3 [M 2 H]2
calculated 216.0661, found 216.0658.
Conclusion
We have described a simple, efficient and high-yielding
procedure for the electrophilic a-cyanation of 1,3-dicarbonyl
compounds employing commercially available TsCN as the
CN+ equivalent. This transformation proceeds under mild
reaction conditions and is amenable to a variety of activated
1,3-Dimethyl-5-cyanobarbituric acid
Isolated as a white solid (165 mg, 91%); Mp: >300 uC; IR (KBr,
cm21): u 3446, 3071, 2250, 1687, 1621, 1437, 1220; 1H NMR
(400 MHz, DMSO-d6) d 3.04 (6 H, s, CH3); 13C NMR (100 MHz,
DMSO-d6) d 27.5, 66.6, 120.7, 152.6, 163.3; HRMS (ESI):
C7H6N3O3 [M 2 H]2 calculated 180.0409, found 180.0406.
methylene compounds including
a b-keto phosphonate.
Trifluoromethyl derived 1,3-diketones undergo trifluoroacetyl
group fragmentation to give a-cyano ketones by a modified
procedure. We have also developed an efficient one-pot
cyantion/pyrazole formation sequence to 4-cyano pyrazoles.
Further studies on the reactivity of TsCN as a functional group
transfer agent are currently underway in our laboratory and
will be reported in due course.
2-Cyanoindane-1,3-dione
TsCN (1.2 mmol) was added in one portion to a stirred
suspension of 1,3-indanedione (1.0 mmol) and K2CO3 (1.2
mmol) in THF–H2O (9 : 1, 5 mL). The reaction mixture was
stirred at rt for 2 h, diluted with water (10 mL), cooled to 0 uC
and the pH was adjusted to y5 with aq. 1 M HCl. The
resulting solution was washed with EtOAc (2 6 5 mL) and its
pH was adjusted to y2 with conc. HCl. This solution was
stirred at 0 uC for 2 h and the precipitated solid was filtered,
washed with chilled water (5 mL) and dried under high
vacuum to give the title compound as a yellow solid (127 mg,
74%). The spectral data were in accordance with those
reported in the literature.1a
Experimental
All reagents were obtained from commercial suppliers and
used without further purification. Thin layer chromatography
was performed on aluminum-backed silica gel sheets (silica
gel 60 F254). Detection was by UV and/or by coloration with
ceric ammonium molybdate (CAM) or vanillin. Flash column
chromatography was performed using silica gel (230–400
mesh). NMR spectra were recorded on 400 MHz FT spectro-
meter at room temperature. All NMR spectra are referenced
relative to the solvent residual peak. High-resolution mass
spectra were obtained by electrospray ionization (ESI) in the
negative ion mode. Melting points were recorded in open
capillaries and are uncorrected. Infrared spectra were recorded
on a FT-IR spectrometer at room temperature using KBr
pellets.
General procedure for the a-cyanation of 1,1,1-trifluoro-1,3-
diketones
K2CO3 (1.2 mmol) was added in one portion to a stirred
solution of the substrate (1.0 mmol) and TsCN (1.2 mmol) in
THF–H2O (9 : 1, 5 mL). The reaction mixture was stirred at rt
for 30 min, cooled to 0 uC and the pH was adjusted to y2 with
aq. 1 M HCl. The reaction mixture was extracted with EtOAc (3
6 10 mL), the combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The residue
was purified by flash column chromatography (SiO2; pentane–
EtOAc, 90 : 10) to give the a-cyano ketone as a white solid. The
spectral data for 3-(2-furyl)-3-oxopropanenitrile and 3-oxo-3-(2-
thienyl)propanenitrile were in accordance with those reported
in the literature.19
General procedure for the a-cyanation of 1,3-dicarbonyl
compounds
TsCN (1.5 mmol) was added in one portion to a stirred
suspension of the substrate (1.0 mmol) and K2CO3 (1.5 mmol)
in THF–H2O (9 : 1, 5 mL). The reaction mixture was stirred at
rt and the reaction progress was monitored by TLC analysis.
After the consumption of the starting material, the reaction
mixture was cooled to 0 uC and the pH was adjusted to y2
with aq. 1 M HCl. The reaction mixture was extracted with
EtOAc (3 6 10 mL), the combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography (SiO2;
EtOAc–TEA, 97 : 3, followed by CHCl3–MeOH–TEA, 95 : 3 : 2)
to give the a-cyanated compound as the triethylammonium
salt. The obtained salt was dissolved in CHCl3 or EtOAc and
washed with aq. 1 M HCl (5 mL). The aqueous layer was
extracted with CHCl3 or EtOAc (2 6 5 mL), the combined
organic layers were dried over Na2SO4 and the solvent was
evaporated under reduced pressure to yield the a-cyanated
product.
General procedure for the one-pot preparation of 4-cyano
pyrazoles from 1,3-diketones
TsCN (1.5 mmol) was added in one portion to a stirred
suspension of the substrate (1.0 mmol) and K2CO3 (1.5 mmol)
in THF–H2O (9 : 1, 5 mL). The reaction mixture was stirred at
rt and the reaction progress was monitored by TLC analysis.
After the consumption of the starting material, the reaction
mixture was cooled to 0 uC and the pH was adjusted to y2
with 1.25 M ethanolic HCl. Hydrazine hydrate (2.0 mmol) was
added and the reaction mixture was heated at reflux for 3 h.
The solvent was evaporated under reduced pressure and water
(5 mL) was added to the obtained residue. This mixture was
extracted with EtOAc (2 6 5 mL), the combined organic layers
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were dried over Na2SO4 and the solvent was removed under
reduced pressure. Purification of the residue by flash column
chromatography (SiO2; pentane–EtOAc, 90 : 10) gave the
4-cyano pyrazole products. The spectral data for 4-cyano
pyrazoles in Scheme 2 with R = Me20 and R = Ph21 were in
accordance with those reported in the literature.
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Acknowledgements
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This work was supported by Science Foundation Ireland (07/
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