Deep eutectic solvent (DES) as dual solvent/catalyst for synthesis of α-diazocarbonyl compounds using aldol-type coupling

Article abstract of DOI:10.1016/j.molliq.2017.03.065

Deep eutectic solvent (DES) was employed as dual solvent/catalyst in the green synthesis of α-diazocarbonyl compounds using aldol-type coupling. α-Diazocarbonyl compounds are important synthetic intermediates with useful application for synthesis of amino alcohols and acids and many natural products. Moreover, the method is environmentally friendly because of avoidance of toxic solvents or hazardous catalysts.

Full text of DOI:10.1016/j.molliq.2017.03.065

Accepted Manuscript
Deep eutectic solvent (DES) as dual solvent/catalyst for synthesis
of α-diazocarbonyl compounds using aldol-type coupling
Maryam Kazemi Miraki, Jamshid Azarnia Mehraban, Elahe
Yazdani, Akbar Heydari
PII:
DOI:
Reference:
S0167-7322(17)30847-4
doi: 10.1016/j.molliq.2017.03.065
MOLLIQ 7100
To appear in:
Journal of Molecular Liquids
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Accepted date:
24 February 2017
17 March 2017
Please cite this article as: Maryam Kazemi Miraki, Jamshid Azarnia Mehraban, Elahe
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ACCEPTED MANUSCRIPT
Deep eutectic solvent (DES) as dual solvent/catalyst for synthesis of α-diazocarbonyl
compounds using aldol-type coupling
Maryam Kazemi Miraki, Jamshid Azarnia Mehraban, Elahe Yazdani, Akbar Heydari*
* Chemistry Department, Tarbiat Modares University, P.O. Box 14155-4838 Tehran, Iran.
(+98)-21- 82883455; phone: (+98)-21-82883444;
E-mail: heydar_a@modares.ac.ir
Abstract
Deep eutectic solvent (DES) was employed as dual solvent/catalyst in the green synthesis of α-
diazocarbonyl compounds using aldol-type coupling. α-Diazocarbonyl compounds are important
synthetic intermediates with useful application for synthesis of amino alcohols and acids and
many natural products. Moreover, the method is environmentally friendly because of avoidance
of toxic solvents or hazardous catalysts.
Introduction
Solvents play a very important role in a number of areas, particularly in the synthesis.
Solvents generally as the largest single component by weight in most reactions are a clear
target for concern and interest due to the growing importance placed upon ‘greenness’[1].
However, the use of green solvents still remains a lasting challenge, even when
conventional hazardous volatile organic solvents (VOCs, commonly used as reaction
media in organic procedures) can cause well-established environmental and safety-related
problems [2]. Many alternative solvents such as water, supercritical fluids, room
temperature ionic liquids (RTILs) have been proposed [1]. ILs are relatively a new class
of promising solvents which are gaining increasing interest by both scientific and
industrial communities due to solving the economic challenges as well as environmental
ones.
However, the low vapor pressures [3, 4], the low volatility and less toxicity allow greener
synthesis with reduced environmental impacts, in contrast to volatile organic solvents[5-
7].
Each of these alternatives has some great benefits, but each also has significant
limitations, including reactivity problems, solubility issues, high price, the need for exotic

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reactors and toxicity [8]. A recent alternative solvent is the category of deep eutectic
solvents (DES) which is regarded as ionic liquids analogues (ILA). Although they share
many characteristics and properties with ILs, they represent a different type of solvent [9].
Deep Eutectic Solvents (DES) are emerging as new class of superior green solvents with
the intrinsic favourable properties of low cost, low toxicity, non-flammability, minimum
volatility, biodegradability and suitability for many industrial applications [10]. In metal
deposition, DESs were applied as media and electrolytes for plating of metals [11, 12].
Additionally, they have been utilized in the electropolishing of stainless steel, for the
removal of residual palm oil-based biodiesel catalyst and as template-delivery agents [13,
14]. DES have been extensively explored in certain contexts, [15] however, they have not
received as much attention for their potential in synthesis [16-21].
This family covers a considerable range of different mixtures. Conventionally, deep
eutectic solvents are synthesized by complexion of the different ratios of ammonium or
phosphonium based salts with varieties of hydrogen bond donors such as: alcohols,
carboxylic acids, esters, ethers, amides, halides, amines, amino acids and many more and
hydrated metal salts of chlorides, nitrates and acetates for the decrease in the freezing
point of the mixture relative to the melting points of the individual components [22]. In
addition, metal halides based DESs were also reported later [23]. The most commonly
employed DES, is the 1:2 molar mixture of choline chloride and urea which affords a
viscous liquid at room temperature [9]. In 2013, a new class of DES has been reported
that potassium carbonate has been used as a salt with glycerol as a hydrogen bond donor
(HDB) [24].
α-Diazocarbonyl compounds have attracted attention because they undergo diverse
synthetically useful transformations. The α-diazocarbonyl compounds are widely used as
potential source of amino alcohols and acids and useful synthetic intermediates for many
natural products [25]. Although the synthesis of diazocarbonyl compounds can be
achieved by a number of routes [26]. one potentially attractive method is to carry out a
substitution reaction on a readily available diazo compound. The most straightforward
synthesis of versatile α-diazo carbonyl compounds involves the condensation of
aldehydes and acyldiazomethanes. This is usually carried out by reaction with a strong
base, such as butyllithium, [27] lithium diisopropylamide (LDA), [28, 29] sodium hydride

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or potassium hydroxide, [30-33] 1,8-diazabicyclo- [5.4.0]undec-7-ene (DBU), [34]
potassium tert-butoxide (KOtBu), [35] Pyrrolidine, [36] quaternary ammonium hydroxide
[37] and Piperidine [38] under controlled conditions in organic solvents to promote this
addition. However, some of the methods require low temperatures, absolute anhydrous
conditions or expensive reagents. Moreover, the use of strong bases may not be
compatible with certain functional groups in the substrates and make these reactions less
attractive for synthetic organic chemists.
Therefore, developing of milder base conditions for the synthesis of α-diazo carbonyl
compounds is highly desirable. For this purpose, heterogeneous catalysts have been
playing an increasingly important role in a variety of organic transformations. Likhar and
co- workers have reported efficient synthesis of α-diazocarbonyl catalyzed by supported
ionic liquid, [39] heterogeneous nanocrystalline magnesium oxide (nano-MgO) [40] and
magnesium/lanthanum mixed oxide (Mg/LnO) [41]. In brief, the above reactions afforded
α- diazo compounds through a heterogeneous-catalyzed c-c bond forming process. The
separation of the desired product and the catalyst from the reaction mixture can be
challenging in heterogeneous catalytic reaction. Filtration and centrifugation are available
routes to recover heterogeneous catalysts but these methods can result in catalyst lose.
Also typical separations are difficult to apply for nanoparticles with less than 100 nm
diameter [42]. Therefore expensive ultra-centrifugation is often the only way to separate
product and catalyst.
These problems encourage researchers to design new green and catalyst- free strategies,
such as solvent-free methods or the use of media with dual solvent/catalyst roles, for
example, trifluoroethanol (TFE) [43, 44] and deep eutectic solvents (DES) [16, 45] for
chemical synthesis.
As part of our ongoing studies to search for new carbon-carbon bond formation processes
using diazo compounds, [46] we decided to investigate the use of DES as dual
solvent/catalyst in the reaction between ethyl diazoacetate (EDA) and carbonyl
compounds (Scheme 1).
Scheme 1. The aldol-type coupling by the reaction of various aldehydes with ethyl diazoacetate (EDA)

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Results and Discussion
For the direct condensation of aldehydes with diazoacetate to occur, first we used ethyl
diazoacetate (1.2 mmol) and benzaldehyde (1.0 mmol) as the substrates in DES as dual
solvent/catalyst at room temperature (Scheme 2).
Scheme 2. The aldol-type coupling by the reaction of benzaldehyde with ethyl diazoacetate (EDA)
After the appropriate time, the desired product was prepared in excellent yields. Since the
initial experiments suggested that DES could give favorable yields, this catalytic system
was chosen, and we proceeded to optimize other conditions. The first experiment is to test
the effect of the base in our reaction. We observed that in the absence of the base in
glycerol, corresponding product was not obtained after long time. In the next step, using
K2CO3 as base in the glycerol led to formation of the product in negligible yield after 24h.
Subsequently, we considered effect of different molar ratios of potassium carbonate to
glycerol (1:5, 1:7, 1:10,) in the reaction and tested the model reaction in the different DES
ratios as shown in table 1.the best result was obtained in 1:5 molar raito. Hence we
subsequently investigated its substrate scope. A variety of different aromatic aldehydes,
containing electron-withdrawing or donating groups, heterocyclic aldehydes and aliphatic
aldehydes react with EDA in DES to afford the corresponding products.
As expected, all aromatic and heterocyclic aldehydes were extremely reactive and the
process was complete after 2 h. aliphatic aldehydes afforded high yields of the desired
products albeit in longer reaction times (4h) and the results are summarized in Tables 1.
Furthermore, Glutaraldehyde bearing two carbonyl groups could be successfully
converted into the corresponding product after over longer reaction times (5 h) in DES led
to the selective formation of the monocondensation derivative (89%). It was observed that
on the other hand, α,β-Unsaturated aldehydes such as cinnamaldehyde, curton aldehyde
gave moderate yields of the corresponding compounds in reasonable time.

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Table 1: Aldol-type reactions of various aldehydes with ethyl diazoacetate
Experimental
All compounds have been prepared from Aldrich and Merck companies and used without further
purifications. IR spectra (KBr) were recorded by Nicolet IR100 instrument. 1H-NMR spectra
were recorded by Brucker 250 and 500 MHz. NMR chemical shifts were expressed in ppm
versus the chemical shift of tetramethylsilane (TMS) as an internal reference. Mass spectra
were obtained on a 5975C VL MSD apparatus at ionization potential of 70 eV.
General Procedure:
Preparation of the DESs
DESs were prepared according to the procedure reported in the literature [17]. The preparation
method involved mixing of different molar ratios potassium carbonate to glycerol at 80 °C for a
period of 2 hours until a clear solution was obtained. The mixture (prepared DES) was used
without any purification.

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General Procedure for Aldol-Type Coupling of Aldehydes with EDA
A mixture of carbonyl compound (1.0 mmol) and EDA (1.2 mmol) was stirred in DES at room
temperature for the appropriate time. Completion of the reaction was confirmed by TLC. After
the completion of reaction, water (50 mL) was added to the reaction mixture and extracted with
EtOAc (3 × 20 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to
give the crude product and was purified using column chromatography (ethyl acetate/hexane).
Conclusion
In conclusion, the developments of general methods for the C-C bond formation with dual
solvent/catalysts are highly desired from synthetic, industrial, and environmental
viewpoints. Thus, DES affords a readily accessible, inexpensive, and efficient dual
solvent/catalyst for the C-C bond formation. Moreover, the method is environmentally
friendly because of avoiding the use of toxic solvents or hazardous catalysts.
Acknowledgments
We acknowledge Tarbiat Modares University for partial support of this work.
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Supporting information
Deep eutectic solvent (DES) as dual solvent/catalyst for synthesis of α-
diazocarbonyl compounds using aldol-type coupling
Maryam Kazemi Miraki, Jamshid Azarnia Mehraban, Elahe Yazdani, Akbar Heydari*
* Chemistry Department, Tarbiat Modares University, P.O. Box 14155-4838 Tehran, Iran.
(+98)-21- 82883455; phone: (+98)-21-82883444;
E-mail: heydar_a@modares.ac.ir
Table of Contents
Experimental Procedures
Characterization Data
Copy of 1H NMR, and mass spectra

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Experimental Procedures
All compounds have been prepared from Aldrich and Merck companies and used without
further purifications. IR spectra (KBr) were recorded by Nicolet IR100 instrument. 1H-
NMR spectra were recorded by Brucker 250 and 500 MHz. NMR chemical shifts were
expressed in ppm versus the chemical shift of tetramethylsilane (TMS) as an internal
reference. Mass spectra were obtained on a 5975C VL MSD apparatus at ionization
potential of 70 eV.
General Procedure:
Preparation of the DESs
DESs were prepared according to the procedure reported in the literature [17]. The
preparation method involved mixing of different molar ratios potassium carbonate to
glycerol at 80 °C for a period of 2 hours until a clear solution was obtained. The mixture
(prepared DES) was used without any purification.
General Procedure for Aldol-Type Coupling of Aldehydes with EDA
A mixture of carbonyl compound (1.0 mmol) and EDA (1.2 mmol) was stirred in DES at
room temperature for the appropriate time. Completion of the reaction was confirmed by
TLC. After the completion of reaction, water (50 mL) was added to the reaction mixture
and extracted with EtOAc (3 × 20 mL) and dried over Na2SO4. The solvent was removed
under reduced pressure to give the crude product and was purified using column
chromatography (ethyl acetate/hexane).

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Ethyl 2-diazo-3-hydroxy-3-phenylpropanoate
IR (KBr): ν =3430, 2983, 2101, 1680, 1531, 1350, 1293, 1113, 1036, 730 cm-1.
1H NMR (500 MHz, CDCl3): 1.23 (t, J = 7.1 Hz, 3H), 3.64 (br s, 1H), 4.23(q, J = 7.1 Hz, 2H),
5.89 (s, 1H), 7.26–7.42 (m, 5H).
Ethyl 3-(4-chlorophenyl)-2-diazo-3-hydroxypropanoate
IR (KBr): ν = 3386, 2988, 2844, 2099, 1699, 1590, 1487, 1358, 1290, 1095, 829 cm1.
1H NMR (500 MHz, DMSO):1.19 (t, J = 7.1 Hz, 3H), 4.16 (q, J = 6.05 Hz, 2H), 5.62 (s, 1H),
6.47 (br s, 1H), 7.39 (d, J = 8.60 Hz, 2H), 7.42 (d, J = 8.55 Hz, 2H).
Ethyl 2-diazo-3-hydroxyhexanoate
IR (KBr): ν = 3438, 2961, 2875, 2095, 1658, 1460, 1378, 1293, 1101, 1020, 752 cm-1.
1H NMR (500 MHz, CDCl3): δ 4.68 (t, J = 7.7 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 2.80 (br s, 1H),
1.74-1.68 (m, 1H), 1.60-1.54 (m, 1H), 1.53-1.48 (m, 1H), 1.46-1.40 (m, 1H), 1.29 (t, J = 7.2 Hz,
3H), 0.95 (t, J = 6.8 Hz, 3H);
Ethyl 2-diazo-3-hydroxydecanoate
1H NMR (500 MHz, CDCl3): 1.11 (t, J = 7.2 Hz, 3H), 1.13-1.78 (m, 15H), 2.89 (d, J = 8.7 Hz,
1H), 4.24 (q, J = 7.1 Hz, 2H), 4.67 (t, J = 6.9 Hz, 1H). EI – MS: m/z (%) = 41 (100), 56 (69),69
(60), 87 (30), 115 (25), 143 (28), 241 (M+, 3).
Ethyl 2-diazo-3-hydroxy-3-(2-methoxyphenyl)propanoate

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IR (KBr): ν = 3433, 2122, 1659, 1252, 1026, 823, 762, 619 cm-1.
1H NMR (250 MHz, DMSO): 1.30 (t, J = 7.1 Hz, 3H), 3.38 (s, 3H), 3.92 (s, 1H), 4.33 (q, J = 7.1,
2H), 5.76 (s, 1H), 6-96-7.79 (m, 4H).
Ethyl 2-diazo-3-hydroxy-3-(p-tolyl)propanoate
IR (KBr): ν = 3444, 3270, 2111, 1684, 1045, 822, 761, 619 cm-1.
1H NMR (250 MHz, DMSO):1.24 (t, J = 7.25 Hz, 3H), 2.56 (s, 3H), 4.24 (q, J = 6.50 Hz, 2H),
5.66 (d, J = 3.25 Hz, 1H), 6.30 (d, J = 3.75 Hz, 1H), 7.23 (d, J = 7.75, 2H), 7.32 (d, J = 7 Hz,
2H). EI – MS: m/z (%) = 43 (14), 77 (60), 91 (80), 104 (90), 119 (100), 160 (95), 234 (M+, 14).
Ethyl 3-(3-bromophenyl)-2-diazo-3-hydroxypropanoate
IR (KBr): ν = 3422, 3255, 2983, 2096, 1689, 1343, 1285, 1036, 760 cm-1.
1H NMR (250 MHz, DMSO):1.20 (t, J = 7 Hz, 3H), 4.18 (q, J = 7.83 Hz, 2H), 5.65 (d, J = 4 Hz,
1H), 6.47 (d, J = 4.75 Hz, 1H), 7.34 – 7.57 (m, 4H). EI – MS: m/z (%) = 51 (25), 69 (50), 77
(72), 89 (100), 117 (61), 158 (48), 185 (91), 198 (60), 224 (58), 298 (M+, 15).
Ethyl 2-diazo-3-hydroxy-3-(pyridin-2-yl)propanoate
IR (KBr): ν = 3377, 2982, 2927, 2097, 1687, 1375, 1339, 1287, 1111, 1038, 752 cm-1. 1H NMR
(250 MHz, DMSO):1.21 (t, J = 6.5 Hz, 3H), 4.18 (q, J = 7 Hz, 2H), 5.71 (s, 1H), 5.77 (s, 1H),
7.39- 8.53 (m, 4H).
Ethyl 2-diazo-3-hydroxy-3-(naphthalen-2-yl)propanoate
IR (KBr): ν = 3257, 2983, 2095, 1686, 1374, 1282, 1046, 794 cm-1.
1H NMR (250 MHz, DMSO):1.23 (t, J = 7Hz, 3H), 4.26 (q, J = 7.9 Hz, 2H), 6.32 (d, J = 4 Hz,
1H), 6.48 (d, J = 4.25 Hz, 1H), 7.52 – 7.97 (m, 7H).

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Ethyl 3-cyclohexyl-2-diazo-3-hydroxypropanoate
IR (KBr): ν = 3350, 2930, 2093, 1677, 1449, 1381, 1287, 1102, 740 cm-1.
1H NMR (500 MHz, CDCl3): d 0.92–1.31 (m, 8H), 1.45–1.80 (m, 5H), 2.00 (d, J = 12.35 Hz,
1H), 2.90 (br s, 1H), 4.20 (q, J = 7.25 Hz, 2H), 4.27 (d, J = 8.25 Hz, 1H);
Ethyl 2-diazo-3-hydroxy-4-phenylbutanoate
IR (KBr): ν = 3350, 2930, 2093, 1677, 1493, 1449, 1381, 1287, 1102, 740 cm-1.
1H NMR (500 MHz, CDCl3):1.23 (t, J = 7.9 Hz, 3H), 4.20 (q, J = 7.1 Hz, 2H), 4.87 (t, J = 6.9
Hz, 1H), 6.66 (s, 1H), 7.17-7.31 (m, 5H).
Ethyl 2-diazo-3-hydroxy-7-oxoheptanoate
IR (KBr): ν = 3444, 2922, 2855, 2093, 1734, 1536, 1450, 1246, 1016, 750 cm-1.
1H NMR (500 MHz, CDCl3): 1.55 (br,3H), 1.95 (dm, 2H), 3.61 (AB-q, 3J = 5.3, 2J = 11.1 Hz,
2H), 3.61(AB-q, 3J = 3.8, 2J = 23.0, 2H), 3.93 (t, J = 5.3 Hz, 1H),4.27 (q, J = 5.2 Hz, 2H), 4.83
(br s, 1H), 8.01 (s, 1H).

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Graphical Abstract
Graphical Abstract
Deep eutectic solvent (DES) as dual solvent/catalyst for synthesis of α-diazocarbonyl
compounds using aldol-type coupling
Maryam Kazemi Miraki, Jamshid Azarnia Mehraban, Elahe Yazdani, Akbar Heydari*
* Chemistry Department, Tarbiat Modares University, P.O. Box 14155-4838 Tehran, Iran.
(+98)-21- 82883455; phone: (+98)-21-82883444;
E-mail: heydar_a@modares.ac.ir

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Highlight
Complication reaction is short time
Mild reaction condition, high selectivity, efficiency, simple workup
Excellent yields
Green solvent (DESs)