Organocatalytic mediated green approach: A versatile new L-valine promoted synthesis of diverse and densely functionalized 2-amino-3-cyano-4H-pyrans

Article abstract of DOI:10.1080/00397911.2017.1393087

The discovery of a new L-valine promoted facile and versatile green synthesis of diversified 2-amino-3-cyano-4H-pyrans using a one pot multicomponent-tandem reaction of aromatic aldehydes, malononitrile, and diverse electron-rich enolizable carbonyl compo

Full text of DOI:10.1080/00397911.2017.1393087

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Organocatalytic mediated green approach: A
versatile new L-valine promoted synthesis of
diverse and densely functionalized 2-amino-3-
cyano-4H-pyrans
Jyoti Tiwari, Swastika Singh, Mohammad Saquib, Fatima Tufail, Amit Kumar
Sharma, Shailesh Singh, Jaya Singh & Jagdamba Singh
To cite this article: Jyoti Tiwari, Swastika Singh, Mohammad Saquib, Fatima Tufail, Amit Kumar
Sharma, Shailesh Singh, Jaya Singh & Jagdamba Singh (2017): Organocatalytic mediated green
approach: A versatile new L-valine promoted synthesis of diverse and densely functionalized 2-
amino-3-cyano-4H-pyrans, Synthetic Communications, DOI: 10.1080/00397911.2017.1393087
To link to this article: https://doi.org/10.1080/00397911.2017.1393087
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Date: 27 December 2017, At: 01:41

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1393087
Organocatalytic mediated green approach: A versatile new
L-valine promoted synthesis of diverse and densely
functionalized 2-amino-3-cyano-4H-pyrans
Jyoti Tiwaria, Swastika Singha, Mohammad Saquiba,b, Fatima Tufaila, Amit Kumar Sharmaa,
Shailesh Singha, Jaya Singhc, and Jagdamba Singha
aEnvironmentally Benign Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad, India;
c
bDepartment of Chemistry, S. S. Khanna Girls Degree College, Alaahabad, India; Department of Chemistry,
LRPG College, Sahibabad, Ghaziabad, India
ABSTRACT
ARTICLE HISTORY
Received 10 August 2017
The discovery of a new L-valine promoted facile and versatile green
synthesis of diversified 2-amino-3-cyano-4H-pyrans using a one pot
multicomponent-tandem reaction of aromatic aldehydes, malononi-
trile, and diverse electron-rich enolizable carbonyl compounds is
described. To the best of our knowledge this is the first report on the
use of native L-valine as a catalyst in organic synthesis. Environmental
friendly, mild reaction conditions, use of easily available inexpensive
starting materials, short reaction time, excellent yields, high atom
economy, and recyclability of organocatalyst are the major advan-
tages of the disclosed protocol.
KEYWORDS
2-Amino-3-cyano-4H-pyrans;
L-valine; green synthesis;
multicomponent; water
GRAPHICAL ABSTRACT
Introduction
In modern organic synthesis, the main goal is the development of an efficient, practical,
and environmentally benign methodology for the synthesis of biologically and synthetically
CONTACT Jagdamba Singh
dr.jdsau@gmail.com
Environmentally Benign Synthesis Lab, Department of Chemistry,
University of Allahabad, Allahabad 211002, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Jyothi Tiwari and Swastika Singh were contributed equally.
Supplemental data (full experimental detail, 1H and 13C NMR spectra, IR and MS) can be accessed on the
publisher’s website.
© 2017 Taylor & Francis

2
J. TIWARI ET AL.
relevant molecules. In recent approaches, the most appropriate syntheses are based on
multicomponent reactions which have gained increasing recognition as a most useful
new tool in organic synthesis and drug discovery.[1,2]
Recently, green chemistry or sustainable chemistry is increasing awareness in the design
of products using less hazardous substances in organic synthesis. In this regard, use of
green solvents and avoidance of conventional solvent is the essential goal.[3] The use of
water, which is eco-friendly, abundant and safe solvent for organic transformations has
gained too much interest and serves also as an excellent supporting medium with numer-
ous factors, such as hydrogen-bonding, polarity, hydrophobicity, and acidity aid to the
rate-enhancing outcome of water.[4] Organocatalysis has emerged as one of the fastest
growing areas in synthetic organic chemistry due to its manifold benefits like easy avail-
ability, cost-effectiveness, non-toxicity, and insensitivity to moisture and air.[5] Nowadays,
amino acids are prominently used in the synthesis of organic compounds.[6] There are
many amino acids like-glycine, L-proline, etc. which are extensively used in the organic
transformation[7] but there are no reports on using L-valine alone as organocatalyst in
any organic synthesis but several L-valine derived compounds are used as a catalyst in
organic synthesis.[8] Wang et al. used L-valine derived chiral N-sulfinamides as effective
organocatalysts for the asymmetric hydrosilylation of N-alkyl and N-aryl protected
ketimines.[8d]
4H-pyrans and their derivatives are a major constituent of many natural products[9]
and very important molecules as key components of various biological activities,[10] these
compound showed wide pharmacological activities and some of them emerged as
anticancer,[11] antimicrobial,[12] molluscicidal,[12b] cytotoxic,[13] anti-HIV,[14] antimalarial,[15]
anti-inflammatory,[16] antihyperglycemic, and antidyslipidemic[17] agents. In addition, they
possess a potential activity against many neurodegenerative diseases, e.g., Parkinson’s disease
and Alzheimer’s disease (Figure 1).[18]
Taking into consideration the broad spectrum of biological activities of 4H-pyrans,
chemists have developed several protocols for their synthesis.[19] Recently, some new
Figure 1. Some biologically important 4H pyrans and its activities.

SYNTHETIC COMMUNICATIONS®
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Scheme 1. Comparision of our work with the work reported in literature.
methods like as BN@Fe3O4, Ce-V/SiO2, PPh3, sodium alginate, triethanolamine, and mont-
morillonite as a solid support are reported in literature for the synthesis of 4H-pyran
(Scheme 1).[20] However, these methods often suffer from numerous drawbacks like low
yields, long reaction time and tedious workup procedure. In continuation of our ongoing
research program on the development of efficient green routes for the synthesis of biolo-
gically active heterocyclic compounds,[21] we wish to develop an efficient, multicomponent,
one-pot facile synthesis of biologically relevant, densely functionalized 2-amino-3-cyano-
4H-pyrans and pyran-annulated heterocyclic scaffolds from the reaction of aldehydes,
malononitrile and a variety of C−H-activated acids in water at 40 °C using L-valine as
an inexpensive and environmentally benign organo-catalyst.
Results and discussion
We began our initial investigation using 4-nitro-benzaldehyde (1a, 1 mmol), malononitrile
(2, 1 mmol), and acetylacetone (3a, 1 mmol) in absence of any solvent or catalyst. The yield
of product was very poor in the absence of catalyst, (Table 1, entry 1) clearly point outs that
the catalyst plays a key role in this reaction. Within this perspective, we performed our
reaction with several catalysts such as K2CO3, sulfamic acid, beta CD, chitosan, megulmine,
thiamine hydrochloride (VB1), citric acid, and different amino acids. The screening results
revealed that the performance of L-valine was superior and gave maximum yield (96%) of
the product 4a (Table 1, entry 11). Thus we concluded that L-valine played a surprising
catalytic role in the reported strategy. After finalization of L-valine as a suitable promoter
for the test reaction, we further investigated the optimum amount of catalyst. From
observation 10 mol.% of L-valine has proved to be sufficient for the present pathway
(Table 1, entry 11). A further increase in the amount of catalyst did not affect the yield

4
J. TIWARI ET AL.
Table 1. Comparison of catalytic nature of L-valine with other catalyst.a
Entry
Catalyst
Time (min)
Yield of 4a (%)b
1
None
90
85
75
65
70
70
65
70
60
50
30
30
45
30
40
40
45
50
66
55
45
50
85
96
96
86
2
K2CO3
3
Sulfamic acid
Beta CD
4
5
Chitosan
6
Meglumine
7
VB1
8
Citric acid
9
Sarcosine (10 mol.%)
Glycine (10 mol.%)
L-valine (10 mol.%)
L-valine (20 mol.%)
L-valine (5 mol.%)
10
11
12
13
aAll Reactions were performed using 4-nitro-benzaldehyde (1a, 1 mmol), and malononitrile (2, 1 mmol) and acetylacetone
(3a, 1 mmol) in water (5 mL) with different catalysts.
bIsolated yield.
of the product and the reaction time while reduction in the amount of L-valine led to a
decrease in yield and increases reaction time (Table 1, entries 12 and 13).
Next, we examined the effect of solvents on the course of the reaction with a choice
of solvents such as toluene, CH2Cl2, ethanol, water, PEG, glycerol, etc. (Table 2). It was
Table 2. Optimization of solvent.a
Entry
Solvent
Temperature
Time (min)
Yield of 4a (%)b
1
2
3
4
5
6
7
8
9
9
10
None
RT
90
85
90
90
80
75
60
30
30
40
35
30
45
30
30
50
70
76
96
96
80
90
None
40 °C
40 °C
40 °C
RT
Toluene
CH2Cl2
Ethanol
Ethanol
Water
Water
Water
PEG
40 °C
RT
40 °C
50 °C
40 °C
40 °C
Glycerol
aAll reactions were performed with 1a (1 mmol) and 2 (1 mmol), 3a (1 mmol), solvent (5 mL) under in presence of L-valine
(12 mg, 0.1 mmol).
bIsolated yields.

SYNTHETIC COMMUNICATIONS®
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observed that water gave best results with 96% quantitative conversion (Table 2). We now
turned our attention toward the role of temperature on the present strategy. Temperature
played a significant role because the reaction proceeded poorly at room temperature and
low yield of product being obtained in long time. As the temperature was increased up
to 40 °C, the yield of the product increased while the reaction time decreased. However,
when the temperature was increased beyond 40 °C, it did not affect the rate and time of
the reaction (Table 2). Consequently, the best result was obtained using 10 mol.% of
L-valine as the catalyst and water as the solvent.
To evaluate the generality of the developed synthetic protocol, we prepared a range
of 2-amino-3-cyano-4H-pyran derivatives with the variety of differently substituted
aromatic aldehydes under the optimized reaction conditions (Table 3). In all the cases
the desired product was obtained in high yield and short reaction times (Table 3). It
was observed that when an electron withdrawing group was present on the aldehyde,
the reaction proceeded faster while the presence of an electron donating group slowed
down the reaction (Table 3).
An uncertain mechanistic pathway for the L-valine catalyzed synthesis of 4H-pyran has
been illustrated in Scheme 2. The reaction seems to be initiated by Knovenagel
Table 3. Substrate scope.a,b,c
Entry
R1/R2
Product
Time (min)
Yield (%)b
1
4-Cl/CH3
4-F/CH3
4-CH3/CH3
H/CH3
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
45
40
80
70
75
45
70
55
60
70
45
50
55
80
65
80
50
55
70
92
92
84
88
83
94
86
92
86
86
92
90
86
78
88
84
86
85
80
2
3
4
5
4-OCH3/CH3
3-NO2/CH3
2-Furyl/CH3
4-NO2/OCH3
4-Cl/OCH3
4-CH3/OCH3
4-NO2/OC2H5
4-Cl/OC2H5
4-Br/OC2H5
4-CH3/OC2H5
H/OC2H5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
4-OH/OC2H5
3-NO2/OC2H5
2-Furyl/OC2H5
4-OCH3/OC2H5
4s
4t
aAll reactions were performed with 1b–j (1 mmol) and 2 (1 mmol), 3a–c (1 mmol), water (5 mL) in presence of L-valine
(12 mg, 0.1 mmol) under air.
bYields reported are isolated.
cAll synthesized compounds are known in literature.[19,20] See Table S1 in supplementary information for literature reference
to characterization data of individual compounds.

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J. TIWARI ET AL.
Scheme 2. Plausible mechanism.
condensation of aromatic aldehydes and malononitrile to give cyano-olefin I. Subse-
quently, the intermediate (I) on Michael type addition with enolates of active methylene
compounds yield corresponding 4H-pyran.
After that, we study the possibility of recovery and recyclability of L-valine using the
model reaction, under the optimized reaction conditions. Upon completion of the reaction,
the reaction mixture was quenched with cold water and the compound was dissolved
in EtOAc while catalyst was dissolved in water. The EtOAc layer was separated and the
aqueous fraction was extracted with EtOAc (10 mL). The combined organic layers were
dried over Na2SO4 and concentrated in vacuo to give the crude product and water fraction
was then dried in vacuo and washed with a minimum amount of MeTHF to remove any
trace of residual reagents/product and the pure recycled L-valine so obtained was used for
the next cycle. The recycled promoter could be reused multiple times with comparable
efficiency without any further treatment. The recyclability of the promoter offsets the
perceived disadvantage of the high catalyst loading needed for this reaction.
Experimental section
All chemicals were reagent grade and purchased from Aldrich, Alfa Aesar, Merck,
Spectrochem, and Qualigens and were used without further purification. The reactions
were monitored using pre-coated TLC plates of silica gel G/UV-254 of 0.25 mm thickness
(Merck 60 F-254). NMR spectra were recorded on a Bruker Avance-II 400 FT spectrometer
at 400 MHz (1 H) and 100 MHz (13 C) in DMSO using TMS as an internal reference. Mass
spectra (ESIMS) were obtained on Micromass Quadro II spectrometer. Elemental analysis
was performed in a Perkin Elmer 2400 CHN elemental analyzer. Melting points were
determined by open glass capillary method and are uncorrected. Chemical shifts (δ) and
coupling constants (J) are expressed in ppm and Hz, respectively. Multiplicity: s ¼ singlet,

SYNTHETIC COMMUNICATIONS®
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d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet. The infrared spectra were recorded on
an Alpha ATR spectrometer from Bruker Optic.
General method for synthesis of 2-amino-3-cyano-4h-pyrans
To a round bottom flask containing 5 ml water were added aromatic aldehydes (1a–j,
1 mmol), malononitrile (2, 1 mmol), and L–valine (12 mg, 0.1 mmol) under stirring and
the temperature of the reaction was set at 40 °C. After formation of intermediate, 1,3
dicarbonyl (3a–c, 1 mmol) was added to the reaction mixture and it was allowed to stir till
the completion of the reaction (TLC). The reaction was quenched with cold water and the
compound was dissolved in EtOAc. The EtOAc layer was separated and the aqueous
fraction was extracted with EtOAc (10 mL). The combined organic layers were dried over
Na2SO4 and concentrated in vacuo to give the crude product. The crude product was
purified by column chromatography over silica gel to obtain the pure 4H-pyrans.
5-Acetyl-2-amino-3-cyano-6-methyl-4-(4-nitrophenyl)-4H-pyran (4a)
Yellow crystal; mp: 182–185 °C; IR (KBr): 3292, 2352, 1686, 1262 cm−1; 1H NMR (DMSO-
d6) (δ, ppm): 2.10 (3H, s), 2.32 (3H, s), 4.60 (1H, s), 6.78 (2H, s), 7.44 (2H, dd, J ¼ 8.2 Hz),
8.17 (2H, dd, J ¼ 8.0 Hz) ppm; 13C NMR (DMSO-d6) (δ, ppm): 19.0, 31.9, 39.2, 60.4, 114.6,
118.2, 124.4, 128.3, 147.2, 150.1, 156.1, 157.6, 197.4; MS (ESI): m/z 299; found 300
[MþH]þ; Anal. calcd for C15H13N3O4: C 60.20, H 4.38, N 14.04; found C 60.16 H 4.45,
N 14.08%.[19g]
Conclusion
In conclusion, we have established a new and efficient, L-valine promoted, one pot,
green synthetic approach to obtain 4H-pyran which is a ubiquitous skeleton of various
pharmaceuticals and bioactive natural products. To the best of our knowledge, this is
the first report on the use of L-valine—an easily available and cheap, promising amino acid
as a catalyst in organic synthesis. The use of eco-friendly solvent, noncorrosive catalyst,
mild reaction conditions, wide substrate tolerance, good to excellent yields, short reaction
time, and reusability of the promoter are the other important features of the reported
method.
Funding
The authors are thankful to SAIF, PU, Chandigarh for spectral data. The authors also acknowledge
the financial support from UGC, New Delhi in form of fellowships for Fatima Tufail and Amit
Kumar Sharma. Jyoti Tiwari and Shailesh Singh thank CSIR, New Delhi for SRF and JRF,
respectively.
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