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. 2021 Nov 12;6(46):31236–31243. doi: 10.1021/acsomega.1c04961

Identification of a Novel Series of Potent Organosilicon Mosquito Repellents

Akshay S Kulkarni †,‡, Remya Ramesh †,‡, Safal Walia ∥, Shahebaz I Sayyad §, Ganesh B Gathalkar ‡,§, Seetharamsing Balamkundu †,‡, Manali Joshi ∥, Avalokiteswar Sen ‡,§,*, D Srinivasa Reddy †,‡,⊥,*
PMCID: PMC8613865  PMID: 34841167

Abstract

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Mosquito control by personal protection is one of the most efficient ways of curtailing deadly diseases such as malaria and dengue with the potential to save millions of lives per year. DEET (N,N-diethyl-3-methyl benzamide) is currently considered as the gold standard for mosquito repellents, being used for the past several decades. Control by DEET, however, is being threatened by emerging resistance among mosquitoes. To address this concern and also to improve protection times, we synthesized a novel series of 25 silicon-containing acyl piperidines using acid–amine coupling protocol and tested their activity against Aedes aegypti in mosquito-repellent assays. Several compounds from this series appear to possess good mosquito-repellent properties. Most notably, at 0.5 mg/cm2 concentrations, the mean protection time for NDS100100 was 756 min, which was higher than that of DEET (616 min). The details of design, synthesis, and biological evaluation are discussed herein.

Introduction

Hematophagous arthropod vectors such as mosquitoes, ticks, and flies transmit several vector-borne debilitating diseases like malaria, dengue, Chikungunya, yellow fever, Zika, encephalitis, filariasis, Lyme disease, Rocky Mountain spotted fever, etc. Mosquito-borne diseases affect more than 700 million people worldwide, resulting in over a million deaths each year.1 Efforts to control these vectors under field conditions have largely relied on the use of synthetic insecticides. However, indiscriminate spraying has led to the development of resistance in several species of mosquitoes.2−4 Another approach focuses on personal protection involving the use of repellents. In the absence of vaccines for malaria, dengue, or encephalitis, the use of repellents offers a suitable alternative in reducing or preventing these deadly infectious diseases.

DEET (N,N-diethyl-3-methyl benzamide), developed by the US Army in 1945, has been in use as a repellent for over 75 years now and is considered as a gold standard given its long lasting repellency toward mosquitoes, ticks, fleas, and flies5,6 as well as skin-penetrating parasites.7,8 Subsequent to DEET, a plethora of structurally diverse chemotypes have been reported to possess mosquito-repellent properties.3,9,10 Compounds containing specific functional groups like oximes,11 amides, and imides12,13 are more effective as repellents. Some insect repellents with amide moiety are shown in Figure 1. Among these, picaridin is a popular mosquito repellent after DEET.3

Figure 1.

Figure 1

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Structures of insect repellents with amide functional groups.

Despite its widespread use, DEET nevertheless has certain limitations. It is a viscous, oily substance with an unpleasant odor. It is a skin irritant and can rarely cause severe epidermal reactions.14 It has a plasticizing action on polymeric materials.15 It has relatively less activity on Anopheles mosquitoes, particularly Anopheles albimanus in Central America and the Caribbean,16,17 and resistance in other species of mosquitoes18,19 and flies20 have been reported. Neurotoxic side effects21−23 and encephalopathy in children24 have also been suggested. In view of these limitations, there is an urgent need to develop repellents that are safer and longer-lasting.

Bioisosteric replacement is a key strategy used by medicinal chemists while optimizing the lead compound to improve the desired biological and physical properties of a potential compound without modifying its core structure. Our group has continued interest in synthesizing novel leads using the silicon switch approach.25,26 Silicon can be used as bioisostere of carbon due to its similar properties. The effect of change in biological activities due to sila-substitution has been previously investigated in agrochemicals and odorants.27,28 In addition, our continued efforts on silicon-containing compounds and their biological activities prompted us to design, synthesize, and profile DEET analogs and select amide-containing insect repellents with silicon incorporation.

In this study, we report the repellent activity of 25 sila-analogs of DEET against adult females of Aedes aegypti and compared it with DEET and its carbon counterparts (NDS101623 and NDS101259). Compound NDS101259 has been previously reported to possess a protection time superior to DEET.29 Most notably, we find in our studies that the compound NDS100100 has better repellency than DEET and its carbon analogs (NDS101623 and NDS101259). Overall, our studies indicate that NDS100100, a sila-DEET analog, appears to possess the potential to be developed as an effective mosquito repellent.

Results and Discussion

A series of silicon-containing acyl piperidines were synthesized in an effort to understand the effects of incorporating silicon in insect repellents. The repellent activity of this series against adult females of A. aegypti was measured in terms of total protection time (min), and the results are presented in Table 1. The two-way ANOVA indicates significant differences between the different analogs (F = 2650.35; df 27, P < 0.001) and their concentrations (F = 6585.81; df 1, P < 0.001) with a strong interaction between compound/concentration (F = 102.604, df 27, P < 0.001) (Supporting Information Table S1). The analysis of contrasts by Tukey’s method indicated differential activity of the individual analogs, DEET, and their concentrations (Table 1). At a concentration of 0.25 mg/cm2, the mean protection time for DEET was 526 min, which was comparable to NDS100100 (548 min) but significantly higher than that of the non-silicon compounds, including NDS101259 (405 min) and NDS101623 (290 min). Interestingly, at higher concentrations of 0.5 mg/cm2, NDS100100, with a mean protection time of 756 min, was significantly higher than DEET (616 min), NDS101259 (562 min), and NDS101623 (520 min).

Table 1. Mean ± SEa to First Bite by Adult Females of A. aegypti after Exposure to Different Sila-Analogs (N = 5).

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a

Means in each column followed by the same letter are not significantly different (P < 0.001) by Tukey’s test.

The main goal of this research was to understand the effect of silicon introduction on insect repellency. Since our previous research indicated that replacement of C with Si improves potency and other pharmacokinetic parameters,25,32 the 4,4-dimethyl-1,4-azasilinane part was kept constant while the other groups were varied. Compound NDS100107 has the same acyl portion as DEET with a silapiperidinyl group. However, this compound showed almost a 5-fold reduction in activity as compared to DEET. Next, cyclobutyl (NDS100110), cyclopentyl (NDS100102), and cyclohexyl (NDS10098) were used to replace the tolyl group of DEET. However, upon this replacement, activity decreased even further approximately in direct proportion to the size of the group. Changing the position of the methyl to the ortho (NDS100115) or para position (NDS100116) did not improve activity. However, removal of the methyl group (NDS10099) slightly improved the activity as compared to other substitutions, but it was still 2–3-fold lower than the activity of DEET. Further, tolyl was replaced by cyclohexenyl (NDS100100 and NDS10097), cyclopentenyl (NDS100101), and cycloheptenyl (NDS101629). The analog with cycloheptene had 2-fold lower activity than DEET, while cyclopentene had 1.5-fold lower activity. Interestingly, of the two cyclohexene analogs, NDS10097 with an isolated double bond showed an activity that was 2-fold lower than DEET, but NDS100100, an α,β-unsaturated amide, showed higher activity than DEET. At an application of 0.5 mg/cm2, NDS100100 has 1.2-fold activity compared to that of DEET. Thus, it was concluded that an unsaturation next to the amide group was important for activity.

To explore whether the carbonyl group was dispensable, NDS101638 and NDS101640 were synthesized. These compounds showed a 50% decline in activity as compared with DEET and NDS100100. This indicates that a carbonyl group from the amide is essential for activity. A series of compounds with electron-withdrawing groups such as pyridine (NDS100103), pyrazine (NDS100104), and chlorobenzene (NDS100105 and NDS100106) in place of toluene were also tested. The addition of electron-withdrawing groups caused the activity to drop substantially as compared with DEET. Compound NDS101625 was synthesized, which contained only an ethene group in place of the aromatic ring. Interestingly, although the activity was half as compared to that of DEET, this compound had better activity than several others. An additional methyl group (NDS101630) did not cause a decline in activity; however, a dimethyl group (NDS100112, NDS101624) caused a drop in the activity. Replacement with longer alkyl chains (NDS100108, NDS100109 and NDS100114) also caused a significant decline in activity except for NDS100113, which has an n-pentyl group. The increased protection time of NDS100100 as compared to the carbon analog NDS101623 shows that silicon incorporation was beneficial for repellent activity. The carbon compound NDS101259 showed better activity than the gem-dimethyl analog NDS101623; however, the silicon compound NDS100100 turned out to be the best of all in terms of protection times. We have also made a few attempts to understand this further using computational methods.30

Materials and Methods

Synthesis

A library of DEET analogs was prepared by reacting 4,4-dimethyl-1,4-azasilinane hydrochloride 1 with a broad range of acids using EDC·HCl and HOBt as coupling reagents and DIPEA as a base in DMF at room temperature.31 Synthesis of the sila-amine partner was achieved by using a protocol reported in the literature.32 From this library of analogs, compounds 5, 7, 23, and 24 were prepared by hydrogenation of corresponding olefinic compounds 4, 6, 17, and 18, respectively, using Pd/C in hydrogen atmosphere at room temperature, while compounds 25 and 26 were prepared by reduction of amide moiety from 4 and 9 using lithium aluminum hydride at room temperature (Scheme 1).

Scheme 1. Synthesis of Silicon-Incorporated DEET Analogs.

Scheme 1

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Compounds 5, 7, 23, and 24 are prepared using hydrogenation of corresponding olefinic compounds from 4, 6, 17, and 18.

Compounds 25, and 26 are prepared using LiAlH4 reduction of corresponding amides 4 and 9.

As a choice of acyl partner, we used aromatic functionalities like phenyl, substituted phenyl pyridyl, and pyrazine. We also considered a wide range of aliphatic functionalities ranging from saturated and unsaturated alkyl chains of varying chain lengths to cyclic ring systems of varying size.

To compare the activity of silicon compounds with the corresponding carbon counterparts, compound 29 (NDS101623) was prepared. 29 was accessed through coupling of commercial 1-cyclohexene-1-carboxylic acid3327 and 4,4-dimethyl-piperidine3428 using EDC, HOBt, and DIPEA in DMF solvent (Scheme 2).

Scheme 2. Synthesis of Compound 29 for Comparative Studies.

Scheme 2

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Mosquito Repellency Bioassays

The various analogs of DEET were assessed for repellency toward adult females of A. aegypti on the basis of protection time (min) using established methods.9 The protection time was measured on the basis of the concept of “time until the first bite”.35 Adult nulliparous females of A. aegypti (3–5 days old, disease-free, and blood-starved) fed on sucrose (0.5 M solution) were obtained from a colony maintained in the laboratory for several generations at 27 ± 1οC, 70 ± 5% RH, and a 12:12 h light:dark cycle. Five volunteers (three males and two females) with no history of allergic reactions to arthropod bites, stings, or repellents were selected for the study. The forearm of each volunteer was washed with unscented soap, rinsed in water, and subsequently air-dried. A 1% stock solution of each analog of DEET was prepared using isopropyl alcohol (IPA). One hundred and two hundred microliters of the stock solutions of the different analogs were spread evenly on a muslin screen (to avoid direct contact with skin) stuck over a small window (2 × 2 cm, thereby yielding doses of 0.25 and 0.50 mg/cm2, respectively) cut out of a polyethylene glove worn by a volunteer so as to allow mosquitoes to bite through. This was done so as to avoid the potential risk involved in the evaluation of experimental compounds of unknown mammalian toxicity (long-term toxicity test not done). A similar polyethylene glove, with a muslin cloth screen and treated with solvent alone, served as the control. Before the start of the experiment, an untreated arm of a volunteer (control) was placed in the mosquito cage (30 × 30 × 30 cm) containing about 200 blood-starved mosquitoes for 15 s to estimate the readiness of the mosquitoes to take a bite. Subsequently, the mosquitoes were blown from the hand before any blood was taken. Following evaporation of the solvent, the hand of a volunteer covered with the polyethylene glove with the treated muslin screen was introduced into the mosquito cage, and the number of mosquito bites received in the subsequent 5 min were counted. In the event of no bites during the initial 5 min exposure, the test hand was exposed repeatedly after every consecutive 1/2 h for 5 min until the time a confirmed bite was received. The time period (in min) between the application of the compound and the first two consecutive bites or two bites in successive observation was recorded as the protection time. In control, the frequency of mosquito bite was 10–12 bites/min with the first bite occurring within 10 s. The above test was repeated with all (three male and two female) human volunteers using a new batch of mosquitoes for each volunteer/test. Repellency tests were carried out between the hours of 09:00–17:00, and light intensity was regulated at 300–500 lux. The mean protection time over multiple readings and the standard error is reported.

Conclusions

Twenty-five silicon-containing piperidines were synthesized, and the influence of silicon incorporation on insect repellency was investigated. One of the compounds (NDS100100) showed better protection time than the gold-standard DEET and corresponding carbon analogs. The novel organosilicon mosquito repellents possess the potential to be developed as effective mosquito repellents.

Experimental Section

General

All reactions were carried out in oven-dried glassware with magnetic stirring under a positive pressure of argon or nitrogen unless otherwise mentioned. Air-sensitive reagents and solutions were transferred via syringe or cannula and were introduced to the apparatus via rubber septa. All reagents, starting materials, and solvents were obtained from commercial suppliers and used as such without further purification. Reactions were monitored by thin-layer chromatography (TLC) with 0.25 mm precoated silica gel plates (60 F254). Visualization was accomplished with either UV light or immersion in ethanolic solution of phosphomolybdic acid (PMA), para-anisaldehyde, 2,4-DNP stain, KMnO4, ninhydrin solution, and iodine adsorbed on silica gel followed by heating on a heat gun for ∼15 s. Column chromatography was performed on silica gel (100–200 or 230–400 mesh size). Deuterated solvents for NMR spectroscopic analyses were used as received. All 1H NMR and 13C NMR spectra were obtained using a 200, 400, or 500 MHz spectrometer. Coupling constants were measured in hertz. All chemical shifts were quoted in ppm relative to CDCl3 using the residual solvent peak as a reference standard. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. HRMS (ESI) were recorded on an ORBITRAP mass analyzer (Thermo Scientific, Q Exactive). Infrared (IR) spectra were recorded on a FT-IR spectrometer as a thin film. Chemical nomenclature was generated using ChemBioDraw.

General Procedure for Acid Amine Coupling (Synthesis of 2, 3, 4, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and 29)

EDC·HCl (1.2 equiv), HOBt (1.2 equiv) and DIPEA (3 equiv) were added in a stirred solution of amine (1 equiv) and acid (1.2 equiv) in dry DMF (4 mL), stirred reaction mixture for 12 h at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (15 mL), washed with 1 N HCl (15 mL), saturated aq. NaHCO3 solution (15 mL), and dried over anhydrous Na2SO4. The crude material obtained after the removal of solvent was purified by silica gel column chromatography (EtOAc, petroleum ether).

General Procedure for Hydrogenation (Synthesis of 5, 7, 23, and 24)

A pinch of 10% Pd/C was added to a solution of olefinic compound in ethanol, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere. After completion of the reaction, the mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was further purified by silica gel column chromatography (EtOAc, petroleum ether) to isolate the pure product.

General Procedure for LiAlH4 Reduction (Synthesis of 25 and 26)

Lithium aluminum hydride (1.2 equiv) was added to a stirred solution of amide (1 equiv) in THF at 0 °C, and the reaction mixture was stirred at room temperature for 4 h and quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic extract was washed with brine (20 mL), dried with Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was further purified by silica gel column chromatography (EtOA, petroleum ether) to isolate the pure product.

Cyclohept-1-en-1-yl(4,4-dimethyl-1,4-azasilinan-1-yl)methanone (2; NDS101629)

Yield = 69%; IRυmax(film): 2921, 1621, 1430, 1289 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.93 (t, J = 6.3 Hz, 1H), 3.69–3.66 (m, 4H), 2.35–2.33 (m, 2H), 2.21–2.20 (m, 2H), 1.76–1.75 (m, 2H), 1.64–1.63 (m, 2H), 1.62–1.56 (m, 2H), 0.78–0.75 (m, 4H), 0.10 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 173.5, 140.5, 131.1, 46.4, 41.3, 31.9, 31.1, 28.6, 27.0, 26.5, 15.2, 13.6, −3.1; HRMS (ESI): m/z calculated for C14H26NOSi [M + H]+ = 252.1778, observed = 252.1788.

Cyclohex-3-en-1-yl(4,4-dimethyl-1,4-azasilinan-1-yl)methanone (3; NDS10097)

Yield = 57%; IRυmax(film): 3024, 1727, 1637, 1250 cm–1; 1H NMR (200 MHz, CDCl3) δ 5.71 (s, 2H), 3.77–3.60 (m, 4H), 2.79–2.72 (m, 1H), 2.12–2.05 (m, 3H), 1.84–1.77 (m, 3H), 0.84–0.75 (m, 4H), 0.11 (s, 6H); 13C NMR (50 MHz, CDCl3) δ 174.7, 126.3, 125.8, 44.9, 42.2, 36.3, 28.4, 25.9, 24.8, 15.6, 13.6, −3.1, −3.2.; HRMS (ESI): m/z calculated for C13H24NOSi [M + H]+ = 238.1622, observed = 238.1622.

Cyclohex-1-en-1-yl(4,4-dimethyl-1,4-azasilinan-1-yl)methanone (4; NDS100100)

Yield = 67%; IRυmax(film): 3068, 2938, 1688, 1283 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.68–5.67 (m, 1H), 3.56 (br. s., 4H), 2.10 (br. s., 2H), 1.99–1.98 (m, 2H), 1.60–1.52 (m, 4H), 0.67 (br. s., 4H), 0.01 (d, J = 1.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 172.0, 134.7, 125.4, 46.0, 41.0, 25.9, 24.2, 21.8, 21.3, 15.1, 13.4, −3.3.; HRMS (ESI): m/z calculated for C13H24NOSi [M + H]+ = 238.1622, observed = 238.1624.

Cyclohexyl(4,4-dimethyl-1,4-azasilinan-1-yl)methanone (5; NDS10098)

Yield = 60%; IRυmax(film): 3020, 2932, 1617, 1253 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.68–3.65 (m, 2H), 3.61–3.57 (m, 2H), 2.48–2.45 (m, 1H), 1.79–1.76 (m, 5H), 1.68 (m, 2H), 1.25–1.23 (m, 3H), 0.78–0.74 (m, 4H), 0.08 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 175.0, 44.9, 42.1, 40.5, 29.7, 25.8, 25.8, 15.6, 13.7, −3.0.; HRMS (ESI): m/z calculated for C13H26NOSi [M + H]+ = 240.1778, observed = 240.1779.

Cyclopent-1-en-1-yl(4,4-dimethyl-1,4-azasilinan-1-yl)methanone (6; NDS100101)

Yield = 73%; IRυmax(film): 3050, 1714, 1615, 1251 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.86 (br. s., 1H), 3.74 (br. s., 2H), 3.61 (br. s., 2H), 2.63–2.59 (m, 2H), 2.46–2.43 (m, 2H), 1.95–1.91 (m, 2H), 0.82 (br. s., 2H), 0.74 (br. s., 2H), 0.11 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 168.9, 139.0, 130.5, 46.1, 41.4, 34.7, 33.2, 22.9, 15.6, 13.6, −3.1.; HRMS (ESI): m/z calculated for C12H22NOSi [M + H]+ = 224.1465, observed = 224.1466.

Cyclopentyl(4,4-dimethyl-1,4-azasilinan-1-yl)methanone (7; NDS100102)

Yield = 90%; IRυmax(film): 2953, 1654, 1252 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.68–3.59 (m, 4H), 2.85 (quin, J = 8.0 Hz, 1H), 1.81–1.70 (m, 6H), 1.52 (m, 2H), 0.76–0.71 (m, 4H), 0.06 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 174.7, 44.8, 42.1, 40.9, 30.5, 25.9, 15.3, 13.6, −3.1; HRMS (ESI): m/z calculated for C12H24NOSi [M + H]+ = 226.1622, observed = 226.1622.

Cyclobutyl(4,4-dimethyl-1,4-azasilinan-1-yl)methanone (8; NDS100110)

Yield = 32%; IRυmax(film): 2950, 1640, 1251 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.69–3.66 (m, 2H), 3.49–3.45 (m, 2H), 3.26 (quin, J = 8.6 Hz, 1H), 2.38–2.33 (m, 2H), 2.14–2.13 (m, 2H), 2.11–1.93 (m, 2H), 0.79–0.72 (m, 2H), 0.71–0.69 (m, 2H), 0.08 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 173.2, 44.4, 42.0, 37.3, 25.4, 17.9, 15.2, 13.6, −3.1.; HRMS (ESI): m/z calculated for C11H22NOSi [M + H]+ = 212.1465, observed = 212.1468.

(4,4-Dimethyl-1,4-azasilinan-1-yl)(phenyl)methanone (9; NDS10099)

Yield = 59%; IRυmax(film): 3030, 1626, 1555, 1263 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.37 (m 5H), 3.86 (br. s., 2H), 3.49 (br. s., 2H), 0.92 (br. s., 2H), 0.66 (br. s., 2H), 0.12 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 170.7, 136.9, 129.0, 128.2, 126.2, 46.8, 41.8, 15.0, 13.6, −3.1.; HRMS (ESI): m/z calculated for C13H20NOSi [M + H]+ = 234.1309, observed = 234.1310.

(4,4-Dimethyl-1,4-azasilinan-1-yl)(m-tolyl)methanone (10; NDS100107)

Yield = 56%; IRυmax(film): 3018, 1618, 1585, 1252 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.35–7.31 (m, 1H), 7.27–7.23 (m, 3H), 3.93 (br. s., 2H), 3.57 (br. s., 2H), 2.43 (s, 3H), 0.99 (br. s., 2H), 0.74 (br. s., 2H), 0.20 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 171.0, 138.2, 136.9, 129.8, 128.2, 126.9, 123.2, 47.0, 41.9, 21.4, 15.1, 13.7, −3.1; HRMS (ESI): m/z calculated for C14H22NOSi [M + H]+ = 248.1465, observed = 248.1466.

(4,4-Dimethyl-1,4-azasilinan-1-yl)(o-tolyl)methanone (11; NDS100115)

Yield = 64%; IRυmax(film): 3063, 2924, 1631, 1251 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.37–7.27 (m, 4H), 4.25 (br. s., 1H), 3.73 (br. s., 1H), 3.48 (d, J = 4.8 Hz, 2H), 2.39 (s, 3H), 1.04–1.02 (m, 2H), 0.73–0.68 (m, 2H), 0.22 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 170.3, 136.9, 133.8, 130.2, 128.5, 125.7, 125.4, 46.3, 41.3, 18.9, 14.9, 13.8, −2.8, −3.4.; HRMS (ESI): m/z calculated for C14H22NOSi [M + H]+ = 248.1465, observed = 248.1464.

(4,4-Dimethyl-1,4-azasilinan-1-yl)(p-tolyl)methanone (12; NDS100116)

Yield = 62%; IRυmax(film): 2957, 1630, 1252 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.38–7.35 (m, 2H), 7.25 (s, 2H), 3.93 (br. s., 2H), 3.60 (br. s., 2H), 2.44 (s, 3H), 1.00 (br. s., 2H), 0.76 (br. s., 2H), 0.20 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 171.0, 139.1, 134.0, 128.9, 126.4, 47.0, 42.0, 21.3, 15.1, 13.6, −3.1.; HRMS (ESI): m/z calculated for C14H22NOSi [M + H]+ = 248.1465, observed = 248.1464.

(2-Chlorophenyl)(4,4-dimethyl-1,4-azasilinan-1-yl)methanone (13; NDS100106)

Yield = 72%; IRυmax(film): 3060, 2891, 1651, 1594 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.36–7.29 (m, 1H), 7.29–7.25 (m, 3H), 4.04–4.01 (m, 1H), 3.75 (ddd, J = 5.5, 7.8, 13.2 Hz, 1H), 3.40–3.36 (m, 2H), 0.94–0.90 (m, 2H), 0.71–0.61 (m, 1H), 0.58 (ddd, J = 5.8, 8.2, 14.4 Hz, 1H), 0.10 (d, J = 4.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 167.1, 136.5, 130.1, 129.8, 129.6, 127.2, 126.9, 46.4, 41.5, 14.7, 13.6, −3.0, −3.4.; HRMS (ESI): m/z calculated for C13H19ClNOSi [M + H]+ = 268.0919, observed = 268.0919.

(2,5-Dichlorophenyl)(4,4-dimethyl-1,4-azasilinan-1-yl)methanone (14; NDS100105)

Yield = 93%; IRυmax(film): 3062, 2952, 1651, 1588 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.35–7.32 (m, 1H), 7.32–7.29 (m, 2H), 4.02 (td, J = 6.2, 12.9 Hz, 1H), 3.80–3.77 (m, 1H), 3.43–3.39 (m, 2H), 0.96–0.92 (m, 2H), 0.87–0.76 (m, 1H), 0.63 (ddd, J = 5.7, 8.3, 14.2 Hz, 1H), 0.14 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 165.6, 137.9, 133.0, 130.9, 129.9, 128.6, 127.3, 46.5, 41.6, 14.8, 13.6, −3.0, −3.3.; HRMS (ESI): m/z calculated for C13H18Cl2NOSi [M + H]+ = 302.0529, observed = 302.0528.

(4,4-Dimethyl-1,4-azasilinan-1-yl)(pyridin-2-yl)methanone (15; NDS100103)

Yield = 56%; IRυmax(film): 3020, 1623, 1568, 1251 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.58–8.56 (m, 1H), 7.76 (dt, J = 1.8, 7.7 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.32–7.30 (m, 1H), 3.89–3.86 (m, 2H), 3.57–3.54 (m, 2H), 0.96–0.93 (m, 2H), 0.80–0.77 (m, 2H), 0.12 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 168.1, 155.1, 148.4, 136.8, 124.0, 122.7, 46.7, 42.3, 15.0, 13.6, −3.1.; HRMS (ESI): m/z calculated for C12H19N2OSi [M + H]+ = 235.1261, observed = 235.1261.

(4,4-Dimethyl-1,4-azasilinan-1-yl)(pyrazin-2-yl)methanone (16; NDS100104)

Yield = 63%; IRυmax(film): 2988, 1638, 1572, 1483, 1267 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.60 (d, J = 2.5 Hz, 1H), 8.54–8.53 (m, 1H), 3.91–3.88 (m, 2H), 3.59–3.56 (m, 2H), 0.97–0.93 (m, 2H), 0.85–0.82 (m, 2H), 0.13 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 165.6, 150.4, 144.9, 144.6, 142.7, 46.8, 42.6, 15.1, 13.7, −3.1.; HRMS (ESI): m/z calculated for C11H18N3OSi [M + H]+ = 236.1214, observed = 236.1213.

1-(4,4-Dimethyl-1,4-azasilinan-1-yl)-3-methylbut-2-en-1-one (17; NDS100112)

Yield = 90%; IRυmax(film): 3017, 1656, 1606, 1252 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.79 (s, 1H), 3.71–3.68 (m, 2H), 3.59–3.56 (m, 2H), 1.86 (s, 3H), 1.80 (s, 3H), 0.81–0.77 (m, 2H), 0.72–0.69 (m, 2H), 0.07 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 167.3, 144.9, 118.4, 45.7, 41.4, 26.0, 20.0, 15.0, 13.7, −3.1.; HRMS (ESI): m/z calculated for C11H22NOSi [M + H]+ = 212.1465, observed = 212.1467.

1-(4,4-Dimethyl-1,4-azasilinan-1-yl)undec-10-en-1-one (18; NDS100108)

Yield = 63%; IRυmax(film): 3077, 2929, 1651, 1456, 1251 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.77 (tdd, J = 6.7, 10.1, 16.9 Hz, 1H), 4.97–4.88 (m, 2H), 3.66 (t, J = 6.4 Hz, 2H), 3.57–3.53 (m, 2 H), 2.29 (t, J = 7.7 Hz, 2H), 2.00 (q, J = 6.7 Hz, 2H), 1.62–1.57 (m, 2H), 1.34–1.27 (m, 10H), 0.77–0.71 (m, 4H), 0.07 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 171.7, 139.0, 114.0, 45.1, 41.9, 33.7, 33.1, 29.4, 29.3, 29.2, 29.0, 28.8, 25.4, 15.0, 13.5, −3.1.; HRMS (ESI): m/z calculated for C17H34NOSi [M + H]+ = 296.2404, observed = 296.2406.

(E)-1-(4,4-Dimethyl-1,4-azasilinan-1-yl)-2-methylbut-2-en-1-one (19; NDS101624)

Yield = 72%; IRυmax(film): 2919, 1619, 1427, 1290 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.59 (dddd, J = 1.6, 5.3, 6.8, 8.4 Hz, 1H), 3.63 (br. s., 4H), 1.83 (m, 3H), 1.69–1.67 (m, 3H), 0.76 (br. s., 4H), 0.10 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 173.0, 132.7, 123.8, 46.2, 41.3, 15.2, 14.3, 13.7, 13.1, −3.1.; HRMS (ESI): m/z calculated for C11H22NOSi [M + H]+ = 212.1465, observed = 212.1472.

1-(4,4-Dimethyl-1,4-azasilinan-1-yl)prop-2-en-1-one (20; NDS101625)

Yield = 75%; IRυmax(film): 2923, 1644, 1442, 1260 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.49 (dd, J = 10.5, 16.8 Hz, 1H), 6.18 (dd, J = 1.9, 16.8 Hz, 1H), 5.55 (dd, J = 1.9, 10.6 Hz, 1H), 3.66–3.63 (m, 2H), 3.57–3.53 (m, 2H), 0.75–0.65 (m, 4H), −0.01 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 165.5, 127.9, 127.4, 45.5, 42.5, 15.4, 13.7, −3.1.; HRMS (ESI): m/z calculated for C9H18NOSi [M + H]+ = 184.1152, observed = 184.1158.

(E)-1-(4,4-dimethyl-1,4-azasilinan-1-yl)but-2-en-1-one (21; NDS101630)

Yield = 78%; IRυmax(film): 2918, 1612, 1437, 1248 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.91–6.83 (m, 1H), 6.29 (qd, J = 1.7, 14.9 Hz, 1H), 3.76–3.72 (m, 2H), 3.67–3.64 (m, 2H), 1.88–1.86 (m, 3H), 0.80 (td, J = 6.4, 19.8 Hz, 4H), 0.10 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 165.6, 141.1, 121.8, 45.3, 42.5, 18.2, 15.4, 13.7, −3.0.; HRMS (ESI): m/z calculated for C10H20NOSi [M + H]+ = 198.1309, observed = 198.1316.

1-(4,4-Dimethyl-1,4-azasilinan-1-yl)hexan-1-one (22; NDS100113)

Yield = 85%; IRυmax(film): 2956, 1652, 1251 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.70–3.67 (m, 2H), 3.59–3.56 (m, 2H), 2.33–2.29 (m, 2H), 1.65–1.61 (m, 2H), 1.32–1.31 (m, 4 H), 0.89 (t, J = 6.7 Hz, 4H), 0.79–0.75 (m, 3H), 0.09 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 171.8, 45.1, 42.0, 33.2, 31.7, 25.2, 22.5, 15.1, 13.9, 13.6, −3.1.; HRMS (ESI): m/z calculated for C12H26NOSi [M + H]+ = 228.1778, observed = 228.1777.

1-(4,4-Dimethyl-1,4-azasilinan-1-yl)-3-methylbutan-1-one (23; NDS100114)

Yield = 100%; IRυmax(film): 2957, 1638, 1252 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.64 (t, J = 6.3 Hz, 2H), 3.56–3.52 (m, 2H), 2.16–2.09 (m, 3H), 0.91 (d, J = 6.3 Hz, 6H), 0.72 (td, J = 6.4, 12.1 Hz, 4H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 171.0, 45.2, 41.9, 41.8, 25.6, 22.6, 15.0, 13.6, −3.2.; HRMS (ESI): m/z calculated for C11H24NOSi [M + H]+ = 214.1622, observed = 214.1622.

1-(4,4-Dimethyl-1,4-azasilinan-1-yl)undecan-1-one (24; NDS100109)

Yield = 100%; IRυmax(film): 2925, 1639, 1251 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.68 (t, J = 6.3 Hz, 2H), 3.59–3.55 (m, 2H), 2.31 (t, J = 7.7 Hz, 2H), 1.62–1.60 (m, 2H), 1.29–1.24 (m, 14H), 0.86 (t, J = 6.5 Hz, 3H), 0.79–0.75 (m, 4H), 0.09 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 171.9, 45.1, 42.0, 33.2, 31.8, 29.5, 29.5, 29.4, 29.3, 25.5, 22.6, 15.1, 14.1, 13.6, −3.1.; HRMS (ESI): m/z calculated for C17H36NOSi [M + H]+ = 298.2561, observed = 298.2563.

1-(Cyclohex-1-en-1-ylmethyl)-4,4-dimethyl-1,4-azasilinane (25; NDS101638)

Yield = 71%; IRυmax(film): 2920, 1450, 1244, 1174 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.54 (m, 1H), 2.84 (m, 2H), 2.61–2.58 (m, 4H), 2.01–1.98 (m, 4H), 1.60–1.56 (m, 4H), 0.74–0.71 (m, 4H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 136.0, 123.6, 65.5, 52.3, 27.3, 25.2, 22.9, 22.7, 13.6, −3.0.; HRMS (ESI): m/z calculated for C13H26NSi [M + H]+ = 224.1829, observed = 224.1838.

1-Benzyl-4,4-dimethyl-1,4-azasilinane (26; NDS101640)

Yield = 78%; IRυmax(film): 2904, 1454, 1392, 1242 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.29–7.23 (m, 5H), 3.51 (s, 2H), 2.65–2.62 (m, 4H), 0.72–0.69 (m, 4H), −0.01 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 139.3, 128.9, 128.1, 126.7, 62.9, 52.4, 13.8, −3.0.

Cyclohex-1-en-1-yl(4,4-dimethylpiperidin-1-yl)methanone (29; NDS101623)

Yield = 70%; IRυmax(film): 3060, 2930, 1682, 1281 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.75 (td, J = 2.0, 3.8 Hz, 1H), 3.48 (br. s., 4H), 2.17–2.16 (m, 2H), 2.07 (dt, J = 3.7, 6.2 Hz, 2H), 1.67–1.61 (m, 4H), 1.34–1.31 (m, 4H), 0.96 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 171.8, 134.7, 126.6, 29.2, 27.7, 26.0, 24.5, 22.0, 21.6.; HRMS (ESI): m/z calculated for C14H24NO [M + H]+ = 222.1853, observed = 222.1856.

Acknowledgments

A.S.K., R.R., and S.B. thank CSIR, New Delhi for the award of research fellowships. S.W. thanks DBT for MSc studentship. D.S.R. and A.S. thank CSIR–National Chemical Laboratory, Pune for providing all necessary infrastructures.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c04961.

  • Details about ANOVA activity; copies of 1H and 13C NMR spectra (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao1c04961_si_001.pdf (1.7MB, pdf)

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