Reaction of Epichlorohydrin with 2-aryl-4,5-dimethyl-1-hydroxy imidazole: A Combined DFT and Experimental Study

doi:10.21203/rs.3.rs-2991168/v1

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Reaction of Epichlorohydrin with 2-aryl-4,5-dimethyl-1-hydroxy imidazole: A Combined DFT and Experimental Study

https://doi.org/10.21203/rs.3.rs-2991168/v1

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This pandemic situation has made us to understand that we need to have look for more potential anti-viral agents in order to combat the SARS virus. During this period many existing anti-viral agents are directly being used to find their efficacy or being modified to increase their efficacy. In an ongoing effort to discover a noble series of imidazole-based epoxides, which can act as synthon for the synthesis of β-Amino alcohols, were designed and synthesized using a mild, efficient, and metal free approach starting from N₁-hydroxy-2,4,5-trisubstituted-imidazoles and epichlorohydrin as precursor compound which may have higher potential to show biological activity. To support the experimental finding, we have performed Density Functional Theory (DFT) calculation. On the basis of the experimental findings and theoretical calculation we have drawn the reaction pathway that led to the product formation.

N1-hydroxy-imidazole

Oxiranes

Epichlorohydrin

DFT

β-Amino alcohols

Concern has been raised over the increasing trend for drug resistant diseases which had reached 7 lakhs by 2020. If it continues like that it will reach to 10 million per year by 2050, which is more than the number of people is struggling to survive cancer worldwide every year. With respect to the demand there is a drastic reduction of new drugs coming to the market because of several reasons.[1] In this regard development of new anti-microbial drugs play a paramount role.

Multifunctional β-Amino alcohols which are well-known versatile synthons and important reagents in the field of organic synthesis has attracted attention in recent years. Because of its common structural features widely present in a vast group of naturally occurring and synthetic molecules and amino acids^[2], is a great advantage in the synthesis of several natural products. The presence of amino alcohol moiety and the relative stereo-chemistry are generally important for the biological activity of molecules used as drug or pharmacological agents including antimalarial drugs^[3], HIV protease inhibitors^[4], adjuvant in cancer treatment^[5], inhibitor in multidrug resistance (MDR) in drug resistance cancer cells^[6], antiasthmatic agents^[7], anti HBV agents^[8], antihypertensives^[9] and antianginal agents^[10]. In addition, they are widely used as β-blockers^[8,10]as well as insecticidal agents^[11] and chiral auxiliaries^[12] which act as key synthetic intermediate for the complex compound and synthetic intermediate for complex compounds and synthetic drug candidates acting as a hydrogen bonding site in a single molecule along with substituents at α and β positions which might be so effective in enantioselective reactions. More reports of synthesis of new amino alcohols have been well documented^[13–15]. This pandemic situation led to experiment out some molecules against SARS Covid-19 starting from quinoline to many molecules which are reported to be anti-cancer or anti-HIV agents. Molecules which have 2-amino alcohols are enlisted below.

Structure of Various Amino alcohols as HIV inhibitors and active against SARS Covid-2 virus.

Similarly, oxime ethers have drawn lot of interest because of their versatile biological activity. Application of oxime ethers in organic synthesis is well documented. As a synthon, they are utilized for the synthesis of substituted heteroaromatic compounds, amino alcohols [16] and amines [17].

Recently, catalytic asymmetric cyclopropanation of diazo oxime ethers with olefins was reported [18]. Thus, there is a broad interest in several reactions of oxime ethers with epichlorohydrin in search of new scaffolds of medicinal interest. Angelone et al. [17]have reported the synthesis and cardiac activity of new β-blockers. Similarly, Martin and coworkers [19] have synthesized enantiopure isooxazolidin-4-ol by the reaction of (S)-epichlorohydrin with N-hydroxy phthalimide in the presence of base through the formation of an oxime ether analogue.

In general, synthesis of amino alcohol is done simply by opening of epoxide by excess of amines^[20]. Though, the acute reaction conditions such as excess necessity of amines, high boiling temperature, prolonged reaction time and use of heavy metal catalysts would hamper the concept of green chemistry, the finding of a simple and compatible method for the synthesis of amino alcohol would be more beneficial.

Thus, there is a broad interest on several reactions of oxime ethers with epichlorohydrin in the search of new scaffolds of medicinal interest.

Chen and coworkers [21] have reported structure 4 to be a non-purine xanthine oxidase inhibitor which was modified by Zhang et al. [22] at the later stage by changing R₂ from a carboxylic acid moeity to pyridyl.

As we have in hand the imidazole derivative 5 [23], which is analougous to 4; however, there is no report on studies of oxime ether widely. Thus, here we report the first synthesis of imidazole-based oxime ether derivatives with a view to explore their medicinal application and as a synthon for new molecular scaffolds.

Materials and Methods

All the chemicals are procured from Sigma Aldrich India Pvt. Ltd. and all the solvents are purchased from Merck and used without further purification unless otherwise stated. All reactions were monitored by thin-layer chromatography (TLC) on Silica gel 60 F₂₅₄ Plate. Column chromatography purifications were performed with silica gel (100 − 200 mesh) as well as Trituration were performed. Melting points were determined in open capillary tubes on an electrically heated block uncorrected. The ¹H and ¹³C NMR spectra were recorded with Bruker NMR spectrometer operating at 300 MHz and 400 MHz Deuterated chloroform (CDCl3) was used as solvent for the measurements and the calibration performed using the residual peak of the deuterated solvents with TMS as an internal reference (chemical shifts d in ppm, J in Hz). (δ 7.26 for ¹H; 77.0 for ¹³C) in deuterated solvents. High-resolution mass spectra (HRMS) were recorded on a 6520 Agilent Q-TOF instrument using Chloroform Solution.

General Procedure

Synthesis of N₁-Hydroxy-2,4,5-trisubstituted-imidazole (5)

A mixture of diacetyl monoxime (2.525g 0.025 mole), aromatic aldehyde (0.025mole), NH₄OAc (2 g) in acetic acid (20 ml) were stirred at room temperature for 24 hrs. The resulting solution on neutralization with liq. ammonia gave the product which was filtered, washed with distilled water, and dried [23].

Synthesis of 4,5-dimethyl-1-(oxiran-2-ylmethoxy)-2-phenyl-1H-imidazole (6), 1-((4,5-dimethyl-2-phenyl-1H-imidazol-1-yl)-oxy)-3-methoxypropan-2-ol (7), 1,3-bis((4,5-dimethyl-2-phenyl-1H-imidazol-1-yl)-oxy)-propan-2-ol (8): To a solution of imidazole derivative (0.01mol) in methanol (15mL) a pinch of potassium carbonate was added and the mixture was stirred at 50⁰C for 30 minutes. Epichlorohydrin (0.01mol) was added over a period of 15 minutes with stirring. Stirring was continued at 50⁰C over a period of 22 hrs. Then the solvent was evaporated under vacuo and the crude mixture was subjected to column chromatography with Hexane: Ethyl acetate (73:27 v/v) as eluent. The first phase was collected and on evaporation of the solvent gave compound 6 (1 gm, 0.003 mol). The second phase was collected with the increase in polarity of the solvent mixture with a ratio of Hexane: Ethyl acetate (55:45 v/v) as eluent. Evaporation of the solvent gave the compound 7 (1.6 gm, 0.005 mol). The third phase was obtained by running the column with Hexane: ethyl acetate (25:75 v/v). On evaporation of the solvent gave the desired product 8 (0.5 gm, 0.001 mol).

¹HNMR (CDCl₃): 6a: δ2.19 (s, 3H, CH₃); 2.27 (s, 3H, CH₃); 2.40 (s, 3H, Ar-CH₃), 2.56(dd, 1H, -CH-CH₂-), 2.84 (dd, 1H, -CH-CH₂-); 3.25 (m, 1H,-CH-); 3.8(dd, 1H, -O-CH₂-CH-), 4.24((dd, 1H, -O-CH₂-CH-); 7.23 (d,2H, ArH(m)); 7.42(d, 2H, ArH(o)); 6b: δ2.19 (s, 3H, CH₃); 2.27 (s, 3H, CH₃); 2.56(dd, 1H, -CH-CH₂-), 2.84 (dd, 1H, -CH-CH₂-); 3.25 (m, 1H,-CH-); 3.8(dd, 1H, -O-CH₂-CH-), 4.24((dd, 1H, -O-CH₂-CH-); 7.36 (d,2H, ArH(m)); 7.5(d, 2H, ArH(o)); 6c:δ2.19 (s, 3H, CH₃); 2.27 (s, 3H, CH₃); 2.56(dd, 1H, -CH-CH₂-), 2.84 (dd, 1H, -CH-CH₂-); 3.25 (m, 1H,-CH-); 3.8(dd, 1H, -O-CH₂-CH-), 4.24((dd, 1H, -O-CH₂-CH-); 7.4 (d,2H, ArH(o)); 7.54(d, 2H, ArH(m)); 6d: δ2.19 (s, 3H, CH₃); 2.27 (s, 3H, CH₃); 2.56(dd, 1H, -CH-CH₂-), 2.84 (dd, 1H, -CH-CH₂-); 3.25 (m, 1H,-CH-); 3.73(s, 3H, Ar-OCH₃) 3.8(dd, 1H, -O-CH₂-CH-), 4.24((dd, 1H, -O-CH₂-CH-); 6.88(d, 1H, ArH), 6.91(m,1H, ArH), 7.19 (d,1H, ArH); 7.42(d, 1H, ArH); 6e: δ2.20 (s, 3H, CH₃); 2.27 (s, 3H, CH₃); 2.56(dd, 1H, -CH-CH₂-), 2.84 (dd, 1H, -CH-CH₂-); 3.25 (m, 1H,-CH-); 3.8(dd, 1H, -O-CH₂-CH-), 4.24((dd, 1H, -O-CH₂-CH-); 7.8 (d,2H, ArH); 8.32(d, 2H, ArH); 6f: δ2.21 (s, 3H, CH₃); 2.29 (s, 3H, CH₃); 2.56(dd, 1H, -CH-CH₂-), 2.85 (dd, 1H, -CH-CH₂-); 3.25 (m, 1H,-CH-); 3.85(dd, 1H, -O-CH₂-CH-), 4.26((dd, 1H, -O-CH₂-CH-); 7.61 (t,1H, ArH); 8.15(m, 1H, ArH); 8.36(m, 1H, ArH), 8.89 (s, 1H, ArH); 6g: δ2.19 (s, 3H, CH₃); 2.27 (s, 3H, CH₃); 2.56(dd, 1H, -CH-CH₂-), 2.84 (dd, 1H, -CH-CH₂-); 3.25 (m, 1H,-CH-), 3.82(dd, 1H, -O-CH₂-CH-), 4.24(dd, 1H, -O-CH₂-CH-), 8.15(d, 2H, ArH), 8.69 (d, 2H, ArH).

¹HNMR (CDCl₃):7a: δ 2.19(s, 3H, -CH₃), 2.27 (s, 3H, -CH₃), 3.37 (s, 3H, -OCH₃), 3.52 (dd, 2H, -CH₂-), 3.73(s, 3H, Ar-CH₃) 4.04(m, 2H, -CH₂-), 4.15(m, 1H, -CH-), 7.21(m, 2H, ArH),7.58(m, 2H, ArH); 7b: δ 2.19(s, 3H, -CH₃), 2.27 (s, 3H, -CH₃), 3.37 (s, 3H, -OCH₃), 3.52 (dd, 2H, -CH₂-), 4.04(m, 2H, -CH₂-), 4.15(m, 1H, -CH-), 7.19(m, 2H, ArH),7.7(m, 2H, ArH); 7c: δ 2.19(s, 3H, -CH₃), 2.27 (s, 3H, -CH₃), 3.37 (s, 3H, -OCH₃), 3.52 (dd, 2H, -CH₂-), 4.04(m, 2H, -CH₂-), 4.15(m, 1H, -CH-), 7.19(m, 2H, ArH),7.62(m, 2H, ArH); 7d: δ 2.19(s, 3H, -CH₃), 2.27 (s, 3H, -CH₃), 3.37 (s, 3H, -OCH₃), 3.52 (dd, 2H, -CH₂-), 3.8 (s, 3H, Ar-OCH₃), 4.04(m, 2H, -CH₂-), 4.15(m, 1H, -CH-), 7.19(m, 2H, ArH),7.62(m, 2H, ArH); 7e: δ 2.19(s, 3H, -CH₃), 2.27 (s, 3H, -CH₃), 3.37 (s, 3H, -OCH₃), 3.52 (dd, 2H, -CH₂-), 3.8 (s, 6H, Ar-OCH₃), 4.04(m, 2H, -CH₂-), 4.15(m, 1H, -CH-), 7.19(d, 1H, ArH), 7.51(s, 1H, ArH), 7.62(d, 1H, ArH); 7f: δ 2.19(s, 3H, -CH₃), 2.27 (s, 3H, -CH₃), 3.37 (s, 3H, -OCH₃), 3.52 (dd, 2H, -CH₂-), 4.04(m, 2H, -CH₂-), 4.15(m, 1H, -CH-), 7.61 (t,1H, ArH); 8.15(m, 1H, ArH); 8.36(m, 1H, ArH), 8.89 (s, 1H, ArH); 7g: δ 2.19(s, 3H, -CH₃), 2.27 (s, 3H, -CH₃), 3.37 (s, 3H, -OCH₃), 3.52 (dd, 2H, -CH₂-), 4.04(m, 2H, -CH₂-), 4.15(m, 1H, -CH-),8.15(d, 2H, ArH), 8.69 (d, 2H, ArH).

Theoretical Calculations

Theoretical calculations were carried on a representative system in the framework of density functional theory, introducing the popular B3LYP functional with triple − ζ def2-TZVP basis set, as implemented in the ORCA 5.0.1 and Avogadro software package. CPCM model has been used for the solvent correction and D3 for dispersion correction. The def2/J keyword is used to select general auxiliary basis set and RIJCOSX approximation has been taken in to account for Coulomb and numerical integrals.

Recent studies found that 2-amino alcohols found to be active in the two human cancer cell line [24] one being gastric adenocarcinoma cells and the other lung adenocarcinoma cells (A549).

This paper deals with the studies on reaction of various 2-aryl-4, 5-dimethyl- N1- hydroxyimidazole derivatives with epichlorohydrin in alkaline medium. In view of our objectives, initially reaction of 4,5-dimethyl-2-(3-nitrophenyl) imidazo-1-ol [23] 5f was treated with epichlorohydrin in presence of potassium carbonate in methanol at room temperature. Interestingly it was observed that in addition to the desired product oxime-ether derivative 6f, two other different products were formed, which were easily separated by column chromatography using hexane: ethylacetate as eluent.

The formation of the desired oxime ether is confirmed by the analysis of the NMR (1H and 13C) and the mass spectra. 1H NMR spectra of the oxime ether shows peaks at δ2.21 and 2.29 corresponding to the two methyl protons at 4- and 5- position of the imidazole ring respectively. Peaks at δ 2.56 and 3.85 correspond to the methylene group of the epoxide ring and the –O-CH₂-CH- respectively. Peak at δ 3.25, corresponds to the methyne proton of the epoxide ring. Peaks ranging from δ7.6 to 8.9 correspond to the three aromatic protons of the benzene ring.

In order to ascertain the structure of the other two products in hand we have analyzed the spectroscopic data of these two compounds. Compound obtained in the second phase collection during column chromatography shows peaks at δ 2.20, 2.27, 3.37, 3.51, 4.04 and 4.15 in the aliphatic region. The total proton count indicates that there is one additional peak corresponding to three protons is being observed in comparison to the oxime ether aliphatic protons. The position and the proton count clearly indicate the presence of a –OCH₃ group. The possibility of existence of the –OCH3 group can only be explained by the participation of the solvent in the opening of the epoxide ring giving rise to afford the new product 7e. The mass spectra (HRMS) show the molecular ion peak at m/e 322.14 emphasizes our demand of solvent assisted ring opening of the epoxide ring of the oxime ether. The incorporation of the –OCH3 group to the terminal carbon atom also helps in the downfield shift of the methylene protons from δ2.56 in oxime ether to δ3.51.

The product obtained from the last phase of the column chromatography is also analyzed for its structure using spectroscopic techniques using NMR (¹H and ¹³C) spectra and the mass spectra. ¹H NMR spectra indicate presence of peaks at δ2.16, 2.22, 4.08 and 4.36 corresponding to the two methyl groups, methyne proton(-CH-) and methylene (-CH₂-) protons respectively. Absence of any other peak in the aliphatic region led us to analyze the mass (HRMS) spectra which indicate the existence of a peak corresponding to m/e 522 and a molecular ion peak at m/e 266 clearly suggest that the epoxide ring is being opened by another molecule of N-hydroxyimidazole giving rise to the dimer 8.

To the best of our knowledge, in almost all cases of nucleophilic substitution reactions of epichlorohydrin with either phenol [25] or oxime [17] reported till date, it results in the ether keeping the epoxide ring intact, which thereby reacts with amines and other nucleophiles to yield molecules of medicinal interest.

Contrary to this for the first time we have observed formation of three different products in one pot. One being the normal oxime ether 6f (35%) as predicted earlier, the second one is the solvent assisted ring opening of the epoxide product 7f (50%) and the third one is the nucleophilic substitution of the epoxide ring to give rise to the dimer product 8f (13%) (Scheme 2).

The attack of epichlorohydrin with the imidazole derivative to give rise products 6f and 7f respectively can be explained either through S_N1 mechanism as suggested by Parker and coworkers [26] or by S_N2 mechanism on the basis of Krasuskii rule.

It has been observed that if the reaction was continued for longer times (> 24hrs), the dimer could not be isolated and only compounds 6 and 7were formed. This is probably the dimer decompose to give rise the oxime ether 6 and imidazole derivative 5 (Scheme 2). The crude reaction mixture also got decomposed if it was kept overnight after work up

We have extended this methodology with various other substitutions over the phenyl ring at 2-position (Table-1)31. It worked successfully for all substituents and obtained all three products, except for 4,5-dimethyl-2-(4-Br-Phenyl)-imidazol derivative (13c) and 4,5-dimethyl-2-(3,4-dimethoxy-phenyl) derivative (13g). We could not able to isolate the dimer 16, for 13c and 13g, may be due to possible decomposition of the product over the silica gel column, as a result the starting imidazole 13c and 13g were obtained.

Since the involvement of solvent giving rise to the product 13, which is resulted by the solvent assisted ring opening of the epoxide ring, prompted us to explore the possibility of using other alcohol as solvent. Thus, the reaction of 13e &13f was attempted in ethanol instead of methanol. However, we got a 1.2-dihydroxy derivative instead of the solvent assisted ring opening product 15f. The solvent assisted product formation can be explained on the basis of nucleophilicity of the solvent used [27].The formation of diol 15h-i as the product can be speculate that the water of crystallization may be participating as a nucleophile by SN2 mechanism.

Table 1

Yield of various products in Methanol
Comp No	Ar=	Solvent	%Yield of 12	%Yield of 13	%Yield of 14	State of 1	State of 2	State of 3
a.	4-CH₃C₆H₄	MeOH	34	51	11	Liquid	Solid	Solid
b.	4-Cl C₆H₄	MeOH	35	48	12	Solid	Solid	Solid
c.	4-Br C₆H₄	MeOH	38	54.5	Not Observed	Solid	Solid	- - - -
d.	2-OCH₃ C₆H₄	MeOH	30	45	12	Liquid	Solid	Solid
e.	3,4-(OCH₃)₂ C₆H₃	MeOH	22	57	Could not be recovered	Liquid	Solid	- - - -
f.	3-NO₂ C₆H₄	MeOH	34	55	10	Solid	Solid	Liquid
g.	4-NO₂ C₆H₄	MeOH	34	51	13	Solid	Solid	Liquid

Table 2

Yield of various products in Ethanol
Comp no	Ar=	Solvent	%Yield of 1	%Yield of 2	%Yield of 3	State of 1	State of 2	State of 3
h.	3-NO₂ C₆H₄	EtOH	24	64	6	Solid	Solid	Solid
i.	4-NO₂ C₆H₄	EtOH	22	65	4	Solid	Solid	Solid

Computational Section

DFT study was carried out using the ORCA 5.0 [28, 29]. The B3LYP [30, 31] functional and def2-TZVP [32] basis set was used for all atoms for the optimization of the geometry of the structures. Solvent effects for methanol and ethanol were taking into consideration using the CPCM model as implemented in ORCA. From the optimized structures single point energy has been calculated for all the molecules involved in the reaction in vacuum and CPCM [33, 34] model. Further, frequency calculations were performed using the same level of theory to calculate the Gibbs free energy profile for each step. The presence of only one negative frequency was confirmed for the transition states.

Energy profile-

The 1-hydroxy-imidazole undergoes reaction with epichlorohydrin and give three different products which pass through the formation of three Transition States such as TS1, TS2 and TS3. With progress of reaction the imidazole act as nucleophile and undergo SN₂ mechanism where it passes through a transition state TS1 where attack of nucleophile and removal of chlorine takes place simultaneously which was confirmed by vibrational frequency calculation for the predicted transition state where one and only one negative frequency was observed which suggests the imaginary mode which form 6 which is act as an intermediate but also found at the end of reaction as second major product. As the intermediate possess comparatively higher energy being not that much stable it undergoes two transition states as TS2 and TS3 where the imidazole and solvent methanol act as nucleophile for SN₂ reaction. In TS2 opening of epoxide and attack of the nucleophile takes place simultaneously which was confirmed theoretically as there found one and only one negative vibrational frequency which was visualized in Avogadro where the concerted reaction has been seen. These two transition states give two products as 7 and 8 respectively. 7 possess the lowest energy that is 4.5 kcal/mol which matches the experimental result as a major product. As complete conversion of intermediate does not take place it was observed to be second major product. The third product which was a dimeric form was found to be the minor product. From the energy label diagram, it was observed that from the intermediate, it passes through transition state TS3 which have lower energy as compare to TS2. Although, kinetically it should form the 8 more significantly as compared to 7 but experimentally it was found that 7 is more suggestively formed. As we know bulkier a nucleophile is, the more difficult it is to attack the substrate, and weaker the nucleophile becomes. In this reaction nucleophiles plays the major role as the hydroxy-imidazole is bulkier as compared to Methanol, for the opening of epoxide the imidazole faces steric hinderance and proper orientation is needed hence 7 formed more significantly. It suggests that the reaction is thermodynamically controlled rather than kinetically.

Proposed Mechanism

N1-Hydroxy imidazole in presence of base K₂CO₃ act as nucleophile and opening of epoxide as well as closer of epoxide take place with removal of chlorine [26] Scheme: II shows the proposed mechanism for ring opening of epoxide in presence of excess methanol by methoxide ion and form the 7 [27]. During this process it also forms the dimeric product which again converted to 7 by attack of methoxide ion.

In conclusion, the present method is a novel, mild, and efficient for the synthesis of new series of Imidazole based Epoxides and ring opened hydroxy imidazole derivatives accomplished by N₁-hydroxy Imidazole as nucleophile. The greatest advantage to our methods, though, lies in their convenience like experimental simplicity, cost effective, mild reaction conditions, reduced reaction times, avoiding use of expensive metal catalysts, and good yields of the products where solvent itself act as Nucleophile which may also called green synthetic approach.

The authors declare that there is no funding source for this work and there is no conflict of interest.

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Schemes 2 and 3 are available in the Supplementary Files section

No competing interests reported.

GA.png
Scheme2.png
Scheme 2. Reaction of imidazole derivative with epichlorohydrin
Scheme3.png
Scheme 3. Decomposition of the dimer
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Reaction of Epichlorohydrin with 2-aryl-4,5-dimethyl-1-hydroxy imidazole: A Combined DFT and Experimental Study

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Energy profile-

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