Synthesis 2019; 51(23): 4434-4442
DOI: 10.1055/s-0039-1690677
paper
© Georg Thieme Verlag Stuttgart · New York

Base-Mediated 1,6-Aza-Michael Addition of Heterocyclic Amines and Amides to para-Quinone Methides Leading to Meclizine-, Hydroxyzine- and Cetirizine-like Architectures

Deblina Roy
,
Gautam Panda
Lab No. CSS 106, Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Jankipuram Extension, Lucknow 226031, UP, India   Email: [email protected]   Email: [email protected]
› Author Affiliations
This work was supported by the Ministry of Earth Sciences (MoES, 09-DS/3/201P5C-IV), New Delhi, India.
Further Information

Publication History

Received: 23 July 2019

Accepted after revision: 22 August 2019

Publication Date:
13 September 2019 (online)

 


Abstract

An expeditious, cost-effective synthetic methodology for a wide range of nitrogen-containing unsymmetrical trisubstituted methanes (TRSMs) is reported. The synthesis involves base-mediated 1,6-conjugate addition of heterocyclic amines and amides to substituted para-quinone methides, giving the unsymmetrical TRSMs in moderate to very good yields (up to 83%) in one pot. The low cost, mild temperature, high atom economy and yields, easy scale-up and broad substrate scope are some of the salient features of this protocol. Further, the methodology could be extended for the synthesis of meclizine-, ­hydroxyzine- and cetirizine-like molecules. The structure of one such compound, 2,6-di-tert-butyl-4-((4-chlorophenyl)(4-methylpiperazin-1-yl)methyl)phenol, was determined by single crystal X-ray analysis.


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Trisubstituted methanes (TRSMs) are a select framework in organic chemistry possessing ubiquitous features of both biological and therapeutic pertinence.[1] Some examples have also revealed significant materials properties.[2] TRSM units are broadly found in various biologically active compounds.[3] [4] For example, letrozole, vorozole and compound A are potent nonsteroidal aromatase inhibitors whereas compound B is a potent antifungal agent (Figure [1]). Another subgroup of the antihistamine class are the piperazine-containing tertiary amines like meclizine and cetirizine (Figure [1]). All carry the same 1,1-diaryl motif with their structures differing at the other N-substituent of the piperazine ring. Our group has also reported the synthesis and bioactivity of diverse unsymmetrical triarylmethanes (TRAMs).[5] In this paper, especially nitrogen-containing TRSMs are our concern.

Zoom Image
Figure 1 Some biologically active TRSMs
Zoom Image
Scheme 1 Strategies for 1,6-conjugate addition to p-QMs
Zoom Image
Scheme 2 Substrate scope with different p-QMs. Reagents and conditions: 1 (0.1 mmol), 2 (0.1 mmol), NaH (0.2 mmol), DMF (2 mL), RT, 20–40 min. Isolated yields after silica gel column chromatography.

Quinone methides (QMs) are very common and highly reactive intermediates in organic chemistry. Two types of QMs are known, namely o-QMs and p-QMs. Aromatisation is the operating force for their distinctive reactivity towards various nucleophiles and therefore they have drawn a lot of attention from organic chemists.[6] Recently, p-QMs have emanated as an interesting intermediate for 1,6-conjugate addition reactions to produce highly substituted diaryl- and triarylmethane derivatives. In the past few years, R. Vijaya Anand’s group and others have reported that a diversity of nucleophiles, including cyanide, malonates, thiols, glycine Schiff bases, dicyanoolefins, the Seyferth–Gilbert reagent, allenic esters, styrenes and β-naphthols, can be used for 1,6-conjugate additions to p-QMs (Scheme [1]).[7] [8] Eventually, enantioselective 1,6-conjugate additions to p-QMs have emerged as an attractive approach for the asymmetric synthesis of diarylmethane-containing molecules.[6c,9] We have also reported the successful synthesis of triarylmethanes, tetraarylmethanes and related molecules through the ­Friedel–Crafts alkylation of QMs.[10] Motivated by these well-advanced approaches, we aimed to explore whether heterocyclic amines (HCAs) and amides could be used for the 1,6-conjugate addition reaction to produce nitrogen-containing unsymmetrical TRSMs. Herein, we report an efficient and atom economical, base-mediated strategy for the synthesis of nitrogen-containing unsymmetrical TRSMs through 1,6-addition of HCAs and amides to p-QMs (Scheme [1]).

Table 1 Optimisation of the Reaction Conditionsa

Entry

Solvent

Base (equiv)

Time

Temp

Yieldb (%)

 1

THF

t-BuOK (1.5)

 1 h

RT

 60

 2

THF

K2CO3 (2)

24 h

RT

 nrc

 3

THF

K2CO3 (6)

24 h

RT

  5

 4

toluene

K2CO3 (6)

24 h

RT

<10

 5

EtOAc

KOH (2)

24 h

RT

 25

 6

EtOH

KOH (2)

24 h

RT

 10

 7

EtOH

NaOEt (2)

 1.30 h

RT

 40

 8

MeCN

DBU (2)

24 h

RT

 <5

9

DMF

NaH (2)

20 min

RT

82

10

THF

NaH (1.5)

 1.15 h

RT

 65

11

MeCN

NaH (2)

24 h

RT

 30

12

acetone

NaH (2)

20 h

RT

 42

13

DMF/MeCN/DCM

t-BuOK (1.5)

 3–4 h

RT

<30

14

DMSO

NaH (2)

 1.5 h

RT

 40

a Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), base (0.2 mmol), solvent (2 mL).

b Isolated yield after column chromatography.

c nr = no reaction.

To test the viability of the proposed protocol, we began our inspection by treating 2,6-di-tert-butyl-p-QM 1a and N-methylpiperazine (2a) as model substrates. The various reaction conditions such as base, solvent, time and temperature were screened, and the results obtained are summarised in Table [1]. Initially, a 60% yield of product 3a was observed when the reaction was performed using 1.5 equivalents of t-BuOK in THF at RT (entry 1). Notably, there was no product formation using 2 equivalents of K2CO3 in THF at RT (entry 2). When the reaction was performed using 6 equivalents of K2CO3 in THF at RT for 24 hours, no improvement in the yield (only 5%) was observed (entry 3). When the solvent was changed from THF to toluene, there was no significant change in the yield (<10%) (entry 4). Similarly, KOH (2 equiv) in EtOAc at RT resulted in the formation of 3a in 25% yield (entry 5). But, when the solvent was changed from EtOAc to EtOH, the yield of 3a decreased (10%) (entry 6). Delightfully, the reaction using NaOEt (2 equiv) in EtOH proceeded smoothly to furnish 3a in 40% yield (entry 7). Unfortunately, our study with DBU (2 equiv) in MeCN was not successful (entry 8). Interestingly, in the presence of NaH (2 equiv) in DMF, the reaction furnished product 3a in 82% yield (entry 9); furthermore, the reaction was very fast, only taking 20 minutes for completion at RT. Using the same substrates and NaH, further optimisation reactions were conducted using a series of solvents (entries 10–14). The best yield was obtained in DMF (entry 9) which indicated a polar aprotic solvent was needed for the proposed conversion. Heating the reaction mixture to a higher temperature did not improve the reaction yield, while application of lower or higher loadings of NaH resulted in decreased yields.

Further, to demonstrate the scope of this methodology, p-QMs 1 were reacted with a series of secondary HCAs and amides 2 under the optimised reaction conditions so as to obtain the corresponding products 3 (Scheme [2]). Unfortunately, the reactions with acyclic amines and benzamides were not lucrative. A vast range of functional groups on the phenyl ring of the p-QMs and a huge set of nitrogen-containing nucleophiles were investigated. As is evident from Scheme [2], both electron-rich as well as electron-poor p-QMs were well suited for the conversion, giving a wide set of nitrogen-containing TRSMs in moderate to very good yields (65–83%).

The p-QM containing halo substitution at the ortho position of the phenyl ring was effectively converted into the corresponding TRSM products 3bi in very good yields. ­Reactions of p-QMs with halo substitution at the para ­position of the phenyl ring proceeded smoothly to give the corresponding products 3jr, 3z, 3z′ in moderate to very good yields. Electron-rich p-QMs also worked well to produce the TRSM products 3su. Notably, heteroaryl-derived p-QMs reacted nicely, furnishing the conjugate adducts 3w, 3x in fairly good yields. The p-QM generated from biphenyl-4-carboxaldehyde could also be successfully utilised in the reaction, providing 3v. Similarly, p-QMs without any substitution in the phenyl ring also worked very well to give the corresponding products 3a, 3y in very good yields within a short period of time. Particularly, cyclic amides reacted with the p-QMs faster than HCAs. The structure of 3k was confirmed by X-ray analysis (Figure [2]).[11]

Zoom Image
Figure 2 X-ray crystal structure of 3k; ellipsoids are drawn at the 30% probability level

Based on our observations and the literature, a plausible mechanism for the 1,6-conjugate addition of heterocyclic amines and amides to p-QMs has been depicted in Scheme [3].[7j] [8c] [12] The beginning step involves abstraction of a proton from HCAs and amides by the base to form a nitrogenous anion C. Afterwards, anion C readily reacts with the electrophilic p-QM in a 1,6-conjugate addition manner to furnish intermediate D. Ultimately, intermediate D through protonation gives the required product, for example 3a (Scheme [3]).

Zoom Image
Scheme 3 Proposed mechanistic pathway

To further illustrate the applicability of the protocol towards development of new bioactive molecules, we made a new class of histamine H1 antagonist, hydroxyzine-like molecule 8, through this methodology (Scheme [4]). Thus, piperazine (4) was reacted with (Boc)2O in MeOH to give 5 in excellent yield (90%). The Boc-protected compound 5 was then reacted with 2-(2-chloroethoxy)ethanol using K2CO3 as a base in DMF to give compound 6 in 65% yield. After Boc deprotection, compound 7 was reacted with NaH and 2,6-di-tert-butyl-4-(4-chlorobenzylidene)cyclohexa-2,5-dien-1-one in DMF to give hydroxyzine-like molecule 8.

To demonstrate the potential utility of our method, we performed a gram-scale reaction of 2,6-di-tert-butyl-4-(4-chlorobenzylidene)cyclohexa-2,5-dien-1-one with 1-(3-methylbenzyl)piperazine (Scheme [5]). The desired meclizine-like antihistamine product 2,6-di-tert-butyl-4-((4-chlorophenyl)(4-(3-methylbenzyl)piperazin-1-yl)methyl)phenol (3r) was obtained in 82% yield (1.30 g), demonstrating that the reaction is scalable. Moreover, one tert-butyl group in product 3n could be efficiently removed to generate product 3n′ (Scheme [5]).

The current work describes an efficient protocol for the one-pot synthesis of nitrogen-containing unsymmetrical trisubstituted methanes in high yields and atom economy. The methodology could further be extended for the synthesis of biologically important first-generation antihistamines, namely meclizine-, hydroxyzine- and cetirizine-like molecules, highlighting the utility of the work. Importantly, the presence of a halo substituent in most of the molecules allows for further late-stage functionalisation which paves the way for the generation of chemical libraries for drug discovery.

Zoom Image
Scheme 4 Synthesis of hydroxyzine-like molecule 8
Zoom Image
Scheme 5 Synthetic utility of the reaction

Unless otherwise noted, all commercial reagents were used without further purification. All reactions were performed in a round-bottom flask, stirred with a magnetic bar under nitrogen atmosphere and monitored by TLC (0.2 mm silica gel coated GF254 plates) with visualisation under UV light or by staining with Dragendorff solution. The starting para-quinone methides were prepared through literature procedures.[7a] Flash column chromatography was carried out on silica gel 60–120 and 100–200 mesh basified by triethylamine. NMR spectra were recorded using a Bruker Avance 400 spectrometer. 1H and 13C chemical shifts are reported in ppm downfield of tetramethylsilane and referenced to the residual solvent peak (CHCl3, δH = 7.26 and δC = 77.00). Standard abbreviations are used for peak multiplicities. High-resolution mass spectra were taken using a Waters Agilent 6520 Q-TOF MS/MS system or a JEOL AccuTOF JMS-T100LC system. Melting points are uncorrected and were determined in capillary tubes on an SMP10 melting point apparatus.


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Unsymmetrical Trisubstituted Methanes 3; General Procedure

To a solution of 1 (0.1 mmol) in DMF (2 mL) in a 10-mL round-bottom flask, 2 (0.1 mmol) was added. Then, the reaction mixture was cooled to 0 °C, NaH (2 equiv) was added, and the mixture was stirred for 20–40 min at RT. The solvent was evaporated and the crude mixture was extracted several times with chilled Et2O. The combined organic extracts were washed with water and brine, dried (anhydrous Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography to give pure product 3.


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2,6-Di-tert-butyl-4-((4-methylpiperazin-1-yl)(phenyl)methyl)phenol (3a)

Off-white solid; mp 133 °C; yield: 33 mg (83%).

1H NMR (400 MHz, CDCl3): δ = 7.42–7.40 (m, 2 H), 7.26–7.22 (m, 2 H), 7.17–7.12 (m, 3 H), 5.05 (s, 1 H), 4.14 (s, 1 H), 2.43 (br s, 8 H), 2.26 (s, 3 H), 1.40 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.55, 143.62, 135.61, 132.93, 128.33, 127.95, 126.58, 124.52, 76.13, 55.55, 51.71, 45.99, 34.34, 30.45.

HRMS (ESI): m/z [M + H] calcd for C26H39N2O: 395.3057; found: 395.3032.


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4-((2-Bromophenyl)(thiomorpholino)methyl)-2,6-di-tert-butylphenol (3b)

Off-white solid; mp 191 °C; yield: 35 mg (72%).

1H NMR (400 MHz, CDCl3): δ = 7.72–7.70 (m, 1 H), 7.48–7.45 (m, 1 H), 7.29–7.27 (m, 1 H), 7.24 (s, 2 H), 7.03–6.99 (m, 1 H), 5.07 (s, 1 H), 4.83 (s, 1 H), 2.71–2.62 (m, 8 H), 1.40 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.73, 142.28, 135.67, 133.00, 131.29, 129.04, 127.90, 127.64, 124.90, 124.67, 72.59, 53.44, 34.35, 30.39, 28.04.

HRMS (ESI): m/z [M + H] calcd for C25H35BrNOS: 476.1617; found: 476.1633.


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4-((2-Bromophenyl)(4-methylpiperazin-1-yl)methyl)-2,6-di-tert-butylphenol (3c)

White solid; mp 190 °C; yield: 38 mg (80%).

1H NMR (400 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.78–7.76 (m, 1 H), 7.47–7.44 (m, 1 H), 7.28–7.26 (m, 2 H), 7.02–6.97 (m, 1 H), 5.07 (s, 1 H), 4.68 (s, 1 H), 2.94 (s, 4 H), 2.88 (s, 4 H), 2.27 (s, 3 H), 1.39 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 162.54, 152.64, 142.53, 135.55, 132.89, 131.67, 129.12, 127.77, 127.57, 124.85, 124.43, 72.84, 55.42, 51.60, 45.90, 34.32, 30.38.

HRMS (ESI): m/z [M + H] calcd for C26H38BrN2O: 473.2162; found: 473.2158.


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1-((2-Bromophenyl)(3,5-di-tert-butyl-4-hydroxyphenyl)methyl)pyrrolidin-2-one (3d)

White solid; mp 173 °C; yield: 34 mg (75%).

1H NMR (400 MHz, CDCl3): δ = 7.53–7.51 (m, 1 H), 7.17–7.13 (m, 1 H), 7.09–7.04 (m, 1 H), 6.91–6.88 (m, 1 H), 6.80 (s, 2 H), 6.49 (s, 1 H), 5.10 (s, 1 H), 3.18–3.12 (m, 1 H), 2.89–2.83 (m, 1 H), 2.44–2.40 (m, 2 H), 1.98–1.94 (m, 2 H), 1.31 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 174.66, 152.98, 139.50, 135.94, 133.23, 130.62, 129.11, 128.49, 127.12, 125.23, 124.07, 58.90, 45.92, 34.34, 31.14, 30.28, 18.75.

HRMS (ESI): m/z [M + H] calcd for C25H33BrNO2: 458.1689; found: 458.1694.


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4-((2-Bromophenyl)(1H-1,2,4-triazol-1-yl)methyl)-2,6-di-tert-­butylphenol (3e)

White solid; mp 164 °C; yield: 34 mg (76%).

1H NMR (400 MHz, CDCl3): δ = 7.76–7.74 (m, 1 H), 7.40–7.37 (m, 1 H), 7.23–7.16 (m, 5 H), 6.95–6.91 (m, 1 H), 4.98 (s, 1 H), 4.43 (s, 1 H), 1.33 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.67, 143.12, 135.49, 132.86, 132.47, 128.98, 127.77, 127.66, 126.30, 124.79, 124.13, 75.05, 34.34, 30.40.

HRMS (ESI): m/z [M + H] calcd for C23H29BrN3O: 442.1489; found: 442.1480.


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4-((4-Benzylpiperazin-1-yl)(2-bromophenyl)methyl)-2,6-di-tert-butylphenol (3f)

Colourless oil; yield: 40 mg (72%).

1H NMR (400 MHz, CDCl3): δ = 7.71–7.68 (m, 1 H), 7.37–7.35 (m, 1 H), 7.21–7.15 (m, 8 H), 6.92–6.88 (m, 1 H), 4.95 (s, 1 H), 4.61 (s, 1 H), 3.43–3.42 (m, 2 H), 2.36 (br s, 8 H), 1.31 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.64, 142.60, 138.26, 135.49, 132.89, 131.74, 129.23, 129.21, 128.15, 127.76, 127.53, 126.95, 124.96, 73.05, 63.09, 53.44, 51.77, 34.33, 30.41.

HRMS (ESI): m/z [M + H] calcd for C32H42BrN2O: 549.2475; found: 549.2479.


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4-((2-Bromophenyl)(morpholino)methyl)-2,6-di-tert-butylphenol (3g)

Off-white solid; mp 195 °C; yield: 34 mg (73%).

1H NMR (400 MHz, CDCl3): δ = 7.74–7.71 (m, 1 H), 7.39–7.37 (m, 1 H), 7.21–7.16 (m, 3 H), 6.94–6.90 (m, 1 H), 4.99 (s, 1 H), 4.59 (s, 1 H), 3.63–3.60 (m, 4 H), 2.30–2.29 (m, 4 H), 1.32 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.79, 142.06, 135.65, 133.00, 131.04, 129.11, 127.93, 127.65, 124.99, 124.60, 73.40, 67.26, 52.52, 34.35, 30.40.

HRMS (ESI): m/z [M + H] calcd for C25H35BrNO2: 460.1846; found: 460.1855.


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4-((2-Bromophenyl)(1H-imidazol-1-yl)methyl)-2,6-di-tert-butylphenol (3h)

Off-white solid; mp 160 °C; yield: 33 mg (75%).

1H NMR (400 MHz, CDCl3): δ = 7.61–7.59 (m, 1 H), 7.36 (br s, 1 H), 7.31–7.27 (m, 1 H), 7.21–7.17 (m, 1 H), 7.10 (br s, 1 H), 6.88–6.82 (m, 4 H), 6.75 (s, 1 H), 1.36 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 153.86, 139.35, 136.50, 133.32, 129.69, 129.21, 127.73, 125.06, 124.09, 64.63, 34.38, 30.20.

HRMS (ESI): m/z [M + H] calcd for C24H30BrN2O: 441.1536; found: 441.1533.


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4-((2-Bromophenyl)(piperidin-1-yl)methyl)-2,6-di-tert-butylphenol (3i)

Colourless solid; mp 182 °C; yield: 34 mg (74%).

1H NMR (400 MHz, CDCl3): δ = 7.80–7.77 (m, 1 H), 7.45–7.43 (m, 1 H), 7.27 (s, 2 H), 7.25–7.23 (m, 1 H), 6.99–6.95 (m, 1 H), 5.02 (s, 1 H), 4.65 (s, 1 H), 2.31–2.30 (m, 5 H), 1.55–1.51 (m, 5 H), 1.40 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.48, 143.25, 135.40, 132.77, 132.38, 129.33, 127.56, 127.49, 124.91, 124.50, 73.52, 53.01, 34.34, 30.44, 26.27, 24.06.

HRMS (ESI): m/z [M + H] calcd for C26H37BrNO: 458.2053; found: 458.2051.


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2,6-Di-tert-butyl-4-((4-chlorophenyl)(morpholino)methyl)phenol (3j)

Colourless oil; yield: 30 mg (72%).

1H NMR (400 MHz, CDCl3): δ = 7.30–7.28 (m, 2 H), 7.18–7.15 (m, 2 H), 7.05 (m, 2 H), 5.00 (s, 1 H), 4.00 (s, 1 H), 3.63–3.60 (m, 4 H), 2.28–2.24 (m, 4 H), 1.32 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.80, 141.77, 135.88, 132.31, 131.96, 129.20, 128.59, 124.40, 75.96, 67.24, 52.52, 34.34, 30.37.

HRMS (ESI): m/z [M + H] calcd for C25H35ClNO2: 416.2351; found: 416.2341.


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2,6-Di-tert-butyl-4-((4-chlorophenyl)(4-methylpiperazin-1-yl)methyl)phenol (3k)

White solid; mp 142 °C; yield: 35 mg (81%).

1H NMR (400 MHz, CDCl3): δ = 7.36–7.34 (m, 2 H), 7.23–7.21 (m, 2 H), 7.11 (m, 2 H), 5.06 (s, 1 H), 4.12 (s, 1 H), 2.43–2.42 (br s, 8 H), 2.27 (s, 3 H), 1.40 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.68, 142.19, 135.75, 132.28, 129.21, 128.47, 124.44, 75.29, 55.50, 51.61, 45.98, 34.33, 30.40.

HRMS (ESI): m/z [M + H] calcd for C26H38ClN2O: 429.2667; found: 429.2660.


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2,6-Di-tert-butyl-4-((4-chlorophenyl)(4-(2-fluorophenyl)piperazin-1-yl)methyl)phenol (3l)

Off-white solid; mp 139 °C; yield: 39 mg (79%).

1H NMR (400 MHz, CDCl3): δ = 7.40–7.37 (m, 2 H), 7.26–7.23 (m, 1H), 7.16 (s, 2 H), 7.05–6.86 (m, 5 H), 5.07 (s, 1 H), 4.19 (s, 1 H), 3.14–3.08 (m, 4 H), 2.57–2.51 (m, 4 H), 1.40 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 156.99, 152.80, 142.02, 135.85, 132.29, 132.24, 129.28, 128.59, 124.48, 122.32, 122.24, 118.87, 116.21, 116.00, 75.42, 51.82, 50.85, 34.38, 30.43.

HRMS (ESI): m/z [M + H] calcd for C31H39ClFN2O: 509.2729; found: 509.2712.


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2,6-Di-tert-butyl-4-((4-chlorophenyl)(thiomorpholino)methyl)phenol (3m)

Light yellow solid; mp 135 °C; yield: 34 mg (75%).

1H NMR (400 MHz, CDCl3): δ = 7.24–7.22 (m, 2 H), 7.17–7.15 (m, 2 H), 7.00 (s, 2 H), 5.01 (s, 1 H), 4.23 (s, 1 H), 2.59–2.55 (m, 8 H), 1.32 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.77, 141.46, 135.81, 132.30, 131.62, 129.35, 128.52, 124.56, 75.12, 53.37, 34.36, 30.39, 28.21.

HRMS (ESI): m/z [M + H] calcd for C25H35ClNOS: 432.2122; found: 432.2068.


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1-((4-Chlorophenyl)(3,5-di-tert-butyl-4-hydroxyphenyl)methyl)pyrrolidin-2-one (3n)

Yellow solid; mp 220 °C; yield: 33 mg (78%).

1H NMR (400 MHz, CDCl3): δ = 7.31–7.29 (m, 2 H), 7.13–7.10 (m, 2 H), 6.92 (s, 2 H), 6.48 (s, 1 H), 5.25 (s, 1 H), 3.20–3.16 (m, 2 H), 2.50–2.46 (m, 2 H), 2.06–1.99 (m, 2 H), 1.39 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 174.91, 153.24, 138.06, 136.01, 133.06, 129.65, 128.50, 128.35, 125.29, 58.10, 44.20, 34.36, 31.24, 30.29, 18.31.

HRMS (ESI): m/z [M + H] calcd for C25H33ClNO2: 414.2194; found: 414.2196.


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4-((4-Benzylpiperazin-1-yl)(4-chlorophenyl)methyl)-2,6-di-tert-butylphenol (3o)

Off-white solid; mp 154 °C; yield: 39 mg (76%).

1H NMR (400 MHz, CDCl3): δ = 7.35–7.33 (m, 2 H), 7.29–7.28 (m, 4 H), 7.24–7.21 (m, 3 H), 7.09 (s, 2 H), 5.04 (s, 1 H), 4.13 (s, 1 H), 3.50–3.49 (m, 2 H), 2.45–2.36 (m, 8 H), 1.38 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.67, 142.16, 138.19, 135.71, 132.29, 132.11, 129.26, 128.43, 128.16, 126.98, 124.54, 75.33, 63.15, 53.48, 51.63, 34.33, 30.40.

HRMS (ESI): m/z [M + H] calcd for C32H42ClN2O: 505.2980; found: 505.2981.


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2,6-Di-tert-butyl-4-((4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl)phenol (3p)

Yellow solid; mp 140 °C; yield: 29 mg (72%).

1H NMR (400 MHz, CDCl3): δ = 7.44–7.41 (m, 1 H), 7.39–7.36 (m, 3 H), 7.25–7.23 (m, 2 H), 7.12–7.11 (m, 2 H), 5.06 (s, 1 H), 3.92 (s, 1 H), 1.40 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.68, 142.90, 140.61, 135.72, 133.20, 131.47, 129.08, 128.95, 128.49, 124.26, 77.48, 34.33, 30.39.

HRMS (ESI): m/z [M + H] calcd for C23H29ClN3O: 398.1994; found: 398.1930.


#

3-((4-Chlorophenyl)(3,5-di-tert-butyl-4-hydroxyphenyl)methyl)oxazolidin-2-one (3q)

Off-white solid; mp 205 °C; yield: 31 mg (75%).

1H NMR (400 MHz, CDCl3): δ = 7.34–7.32 (m, 2 H), 7.18–7.16 (m, 2 H), 6.96 (m, 2 H), 6.23 (s, 1 H), 4.39–4.30 (m, 2 H), 3.41–3.30 (m, 2 H), 1.40 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 171.12, 158.25, 153.56, 137.40, 136.19, 133.40, 129.40, 128.65, 127.75, 125.34, 67.95, 62.08, 60.37, 41.56, 34.37, 30.25, 25.61, 21.03, 14.19.

HRMS (ESI): m/z [M + H] calcd for C24H31ClNO3: 416.1987; found: 416.1968.


#

2,6-Di-tert-butyl-4-((4-chlorophenyl)(4-(3-methylbenzyl)piperazin-1-yl)methyl)phenol (3r)

Yellow solid; mp 108 °C; yield: 43 mg (82%).

1H NMR (400 MHz, CDCl3): δ = 7.26–7.24 (m, 2 H), 7.13–7.11 (m, 2 H), 7.08–7.05 (m, 2 H), 7.01–6.98 (m, 4 H), 4.95 (s, 1 H), 4.05 (s, 1 H), 3.37–3.36 (m, 2 H), 2.38–2.27 (m, 8 H), 2.22 (s, 3 H), 1.30 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.72, 142.17, 138.08, 137.71, 135.70, 132.30, 132.18, 129.99, 129.27, 128.46, 128.06, 127.76, 126.40, 124.59, 75.38, 63.25, 53.59, 51.63, 34.34, 30.43, 22.77.

HRMS (ESI): m/z [M + H] calcd for C33H44ClN2O: 519.3137; found: 519.3136.


#

1-((3,5-Di-tert-butyl-4-hydroxyphenyl)(3,4,5-trimethoxyphenyl)methyl)pyrrolidin-2-one (3s)

White solid; mp 168 °C; yield: 38 mg (80%).

1H NMR (400 MHz, CDCl3): δ = 6.90 (s, 2 H), 6.37 (s, 1 H), 6.34 (s, 2 H), 5.15 (s, 1 H), 3.78 (s, 3 H), 3.71 (s, 6 H), 3.18–3.11 (m, 2 H), 2.44–2.40 (m, 2 H), 1.98–1.91 (m, 2 H), 1.33 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 174.91, 153.09, 137.27, 135.81, 134.93, 128.27, 125.11, 105.92, 60.85, 58.59, 56.19, 44.27, 34.37, 31.36, 30.33, 18.45.

HRMS (ESI): m/z [M + H] calcd for C28H40NO5: 470.2901; found: 470.2893.


#

2,6-Di-tert-butyl-4-((1H-imidazol-1-yl)(4-methoxyphenyl)methyl)phenol (3t)

White solid; mp 142 °C; yield: 28 mg (72%).

1H NMR (400 MHz, CDCl3): δ = 7.93 (s, 1 H), 6.98 (m, 3 H), 6.81–6.75 (m, 5 H), 6.29 (s, 1 H), 3.73 (s, 3 H), 1.29 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 162.51, 159.28, 153.67, 137.37, 136.43, 132.10, 129.79, 129.05, 128.96, 124.77, 119.33, 114.00, 64.86, 55.28, 34.36, 30.19.

HRMS (ESI): m/z [M + H] calcd for C25H33N2O2: 393.2537; found: 393.2523.


#

2,6-Di-tert-butyl-4-(morpholino(3,4,5-trimethoxyphenyl)methyl)phenol (3u)

White solid; mp 158 °C; yield: 34 mg (71%).

1H NMR (400 MHz, CDCl3): δ = 7.20 (s, 2 H), 6.70 (s, 2 H), 5.10 (s, 1 H), 3.85 (s, 6 H), 3.80 (s, 3 H), 3.71–3.69 (m, 4 H), 2.35–2.34 (m, 4 H), 1.42 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 153.13, 152.77, 138.93, 136.66, 135.73, 132.36, 124.48, 104.64, 76.96, 67.23, 60.77, 56.05, 52.61, 34.35, 30.41.

HRMS (ESI): m/z [M + H] calcd for C28H42NO5: 472.3057; found: 472.3054.


#

4-([1,1′-Biphenyl]-4-yl(morpholino)methyl)-2,6-di-tert-butyl­phenol (3v)

Yellow solid; mp 165 °C; yield: 30 mg (66%).

1H NMR (400 MHz, CDCl3): δ = 7.56–7.54 (m, 2 H), 7.50 (s, 4 H), 7.42–7.38 (m, 2 H), 7.25 (s, 1 H), 7.22 (s, 2 H), 5.06 (s, 1 H), 4.14 (s, 1 H), 3.73–3.70 (m, 4 H), 2.39–2.37 (m, 4 H), 1.41 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.72, 142.31, 140.95, 139.61, 135.77, 132.49, 128.70, 128.30, 127.19, 127.07, 126.98, 124.51, 67.32, 52.66, 34.35, 30.41, 29.72.

HRMS (ESI): m/z [M + H] calcd for C31H40NO2: 458.3034; found: 458.3023.


#

4-((6-Bromo-2-methoxyquinolin-3-yl)(piperidin-1-yl)methyl)-2,6-di-tert-butylphenol (3w)

Yellow solid; mp 232 °C; yield: 36 mg (65%).

1H NMR (400 MHz, CDCl3): δ = 8.11 (s, 1 H), 7.82–7.81 (s, 1 H), 7.58–7.55 (m, 1 H), 7.52–7.50 (m, 1 H), 7.12 (s, 2 H), 4.95 (s, 1 H), 4.52 (s, 1 H), 3.96 (s, 3 H), 2.26 (s, 4 H), 1.54–1.47 (m, 6 H), 1.31 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 160.94, 152.47, 143.83, 135.41, 133.88, 131.71, 130.06, 129.48, 128.42, 127.16, 124.95, 116.87, 68.06, 53.42, 53.14, 34.30, 30.43, 26.30, 24.86.

HRMS (ESI): m/z [M + H] calcd for C30H40BrN2O2: 539.2268; found: 539.2271.


#

4-((4-Benzylpiperazin-1-yl)(6-bromo-2-chloroquinolin-3-yl)methyl)-2,6-di-tert-butylphenol (3x)

Yellow solid; mp 149 °C; yield: 45 mg (70%).

1H NMR (400 MHz, CDCl3): δ = 8.27 (s, 1 H), 7.87–7.86 (m, 1 H), 7.69–7.67 (m, 1 H), 7.60–7.57 (m, 1 H), 7.29–7.28 (m, 5 H), 7.24 (s, 2 H), 5.04 (s, 1 H), 4.74 (s, 1 H), 3.51–3.50 (m, 2 H), 2.45 (br s, 8 H), 1.37 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 163.08, 152.70, 144.77, 135.47, 134.91, 133.41, 131.76, 131.71, 129.31, 129.25, 128.18, 127.53, 127.02, 124.86, 117.58, 68.92, 63.17, 53.56, 52.33, 34.32, 30.38.

HRMS (ESI): m/z [M + H] calcd for C35H42BrClN3O: 634.2194; found: 634.2156.


#

2,6-Diisopropyl-4-((4-methylpiperazin-1-yl)(phenyl)methyl)­phenol (3y)

Colourless oil; yield: 27 mg (73%).

1H NMR (400 MHz, CDCl3): δ = 7.75–7.73 (m, 1 H), 7.29–7.26 (m, 2 H), 7.16 (s, 2 H), 7.06–7.04 (m, 2 H), 5.02 (s, 1 H), 4.30 (s, 1 H), 2.41–2.36 (m, 10 H), 2.28 (s, 3 H), 1.38 (s, 12 H).

13C NMR (100 MHz, CDCl3): δ = 152.45, 141.86, 135.67, 135.45, 134.86, 132.23, 130.84, 130.42, 127.04, 126.11, 126.00, 124.98, 71.18, 55.51, 51.92, 45.92, 34.28, 30.39.

HRMS (ESI): m/z [M + H] calcd for C24H35N2O: 367.2744; found: 367.2723.


#

2,6-Di-tert-butyl-4-((4-methylpiperazin-1-yl)(4-(trifluoromethoxy)phenyl)methyl)phenol (3z)

Colourless oil; yield: 34 mg (70%).

1H NMR (400 MHz, CDCl3): δ = 7.44–7.42 (m, 2 H), 7.12–7.09 (m, 4 H), 5.08 (s, 1 H), 4.17 (s, 1 H), 2.43 (br s, 8 H), 2.27 (s, 3 H), 1.40 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.74, 147.87, 142.26, 135.78, 132.19, 129.11, 124.53, 120.75, 75.21, 55.49, 51.60, 45.95, 34.34, 30.88.

HRMS (ESI): m/z [M + H] calcd for C27H38F3N2O2: 479.2880; found: 479.2875.


#

2,6-Di-tert-butyl-4-((4-methylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)phenol (3z′)

Colourless oil; yield: 35 mg (75%).

1H NMR (400 MHz, CDCl3): δ = 7.56–7.50 (m, 4 H), 7.13 (s, 2 H), 5.08 (s, 1 H), 4.20 (s, 1 H), 2.43 (br s, 8 H), 2.28 (s, 3 H), 1.40 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.84, 147.83, 135.89, 131.85, 130.34, 128.07, 125.34, 124.50, 75.68, 55.44, 51.66, 45.96, 34.34, 30.37.

HRMS (ESI): m/z [M + H] calcd for C27H38F3N2O: 463.2931; found: 463.2929.


#

2-(2-(Piperazin-1-yl)ethoxy)ethan-1-ol (7)

Colourless oil; yield: 140 mg (80%).

1H NMR (400 MHz, CDCl3): δ = 3.69–3.66 (m, 2 H), 3.64–3.62 (m, 2 H), 3.58–3.55 (m, 2 H), 2.90–2.88 (m, 4 H), 2.58–2.55 (m, 2 H), 2.49 (s, 4 H).

13C NMR (100 MHz, CDCl3): δ = 72.53, 67.63, 61.27, 58.32, 54.35, 45.51.


#

2,6-Di-tert-butyl-4-((4-chlorophenyl)(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)methyl)phenol (8)

Yellow crystalline solid; mp 106 °C; yield: 38 mg (75%).

1H NMR (400 MHz, CDCl3): δ = 7.35–7.33 (m, 2 H), 7.23–7.21 (m, 2 H), 7.10 (s, 2 H), 5.06 (s, 1 H), 4.09 (s, 1 H), 3.68–3.64 (m, 4 H), 3.60–3.58 (s, 2 H), 2.61–2.59 (s, 2 H), 2.40 (s, 8 H), 1.39 (s, 18 H).

13C NMR (100 MHz, CDCl3): δ = 152.72, 140.60, 135.80, 134.85, 134.37, 131.46, 129.08, 128.54, 124.33, 75.52, 67.48, 62.09, 57.98, 53.61, 51.42, 34.32, 30.37.

HRMS (ESI): m/z [M + H] calcd for C29H44ClN2O3: 503.3035; found: 503.3032.


#
#

Acknowledgment

We thank Dr. Ruchir Kant, Crystallographic Unit, CSIR-CDRI and IIT Kanpur for supervising the X-ray data collection and structure determination. The instrument facilities of SAIF, CDRI are highly acknowledged (CDRI Communication No. 9878).

Supporting Information

  • References

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    • 1b Al-Qawasmeh RA, Lee Y, Cao M.-Y, Gu X, Vassilakos A, Wright JA, Young A. Bioorg. Med. Chem. Lett. 2004; 14: 347
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    • 1d Palchaudhuri R, Nesterenko V, Hergenrother PJ. J. Am. Chem. Soc. 2008; 130: 10274
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    • 2b Shchepinov MS, Korshun VA. Chem. Soc. Rev. 2003; 32: 170
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  • 4 Mondal S, Panda G. RSC Adv. 2014; 4: 28317
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    • 5b Kumar S, Das SK, Dey S, Maity P, Guha M, Choubey V, Panda G, Bandyopadhyay U. Antimicrob. Agents Chemother. 2008; 52: 705
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    • 5d Panda G, Parai MK, Srivastava AK, Chaturvedi V, Manju YK, Sinha S. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2009; 48: 1121

      For selected relevant examples, see:
    • 6a Ma C, Huang Y, Zhao Y. ACS Catal. 2016; 6: 6408
    • 6b Yuan Z, Wei W, Lin A, Yao H. Org. Lett. 2016; 18: 3370
    • 6c Chen M, Sun J. Angew. Chem. Int. Ed. 2017; 56: 4583
    • 6d Saha S, Alamsetti SK, Schneider C. Chem. Commun. 2015; 51: 1461
    • 6e Mondal S, Roy D, Jaiswal MK, Panda G. Tetrahedron Lett. 2018; 59: 89
    • 7a Goswami P, Sharma S, Singh G, Anand RV. J. Org. Chem. 2018; 83: 4213
    • 7b Goswami P, Singh G, Anand RV. Org. Lett. 2017; 19: 1982
    • 7c Jadhav AS, Anand RV. Eur. J. Org. Chem. 2017; 3716
    • 7d Jadhav AS, Anand RV. Org. Biomol. Chem. 2017; 15: 56
    • 7e Arde P, Anand RV. Org. Biomol. Chem. 2016; 14: 5550
    • 7f Arde P, Anand RV. RSC Adv. 2016; 6: 77111
    • 7g Goswami P, Anand RV. ChemistrySelect 2016; 1: 2556
    • 7h Reddy V, Anand RV. Org. Lett. 2015; 17: 3390
    • 7i Zhang XZ, Deng YH, Yan X, Yu KY, Wang FX, Ma XY, Fan CA. J. Org. Chem. 2016; 81: 5655
    • 7j Gupta AK, Ahamad S, Vaishanv NK, Kant R, Mohanan K. Org. Biomol. Chem. 2018; 16: 4623
    • 7k Vaishanv NK, Gupta AK, Kant R, Mohanan K. J. Org. Chem. 2018; 83: 8759
    • 7l Jadhav AS, Pankhade YA, Hazra R, Anand RV. J. Org. Chem. 2018; 83: 10107
    • 7m Zhou T, Li S, Huang S, Li C, Zhao Y, Chen J, Chen A, Xiao Y, Liu L, Zhang J. Org. Biomol. Chem. 2017; 15: 4941
    • 8a Santra S, Porey A, Guin J. Asian J. Org. Chem. 2018; 7: 477
    • 8b Molleti N, Kang JY. Org. Lett. 2017; 19: 958
    • 8c Yang C, Gao S, Yao H, Lin A. J. Org. Chem. 2016; 81: 11956
    • 8d Pan R, Hu L, Han C, Lin A, Yao H. Org. Lett. 2018; 20: 1974
    • 8e Yuan Z, Liu L, Pan R, Yao H, Lin A. J. Org. Chem. 2017; 82: 8743
    • 9a Zhang ZP, Chen L, Li X, Cheng JP. J. Org. Chem. 2018; 83: 2714
    • 9b Zhang ZP, Xie KX, Yang C, Li M, Li X. J. Org. Chem. 2018; 83: 364
    • 9c Wang H, Wang K, Man Y, Gao X, Yang L, Ren Y, Li N, Tang B, Zhao G. Adv. Synth. Catal. 2017; 359: 3934
    • 9d Chu WD, Zhang LF, Bao X, Zhao XH, Zeng C, Du JY, Zhang GB, Wang FX, Ma XY, Fan CA. Angew. Chem. Int. Ed. 2013; 52: 9229
    • 9e Zhang XZ, Gan KJ, Liu XX, Deng YH, Wang FX, Yu KY, Zhang J, Fan CA. Org. Lett. 2017; 19: 3207
    • 9f Caruana L, Kniep F, Johansen TK, Poulsen PH, Jørgensen KA. J. Am. Chem. Soc. 2014; 136: 15929
    • 9g Zhao K, Zhi Y, Wang A, Enders D. ACS Catal. 2016; 6: 657
    • 9h Zhao K, Zhi Y, Shu T, Valkonen A, Rissanen K, Enders D. Angew. Chem. Int. Ed. 2016; 55: 12104
    • 9i Liu Q, Li S, Chen XY, Rissanen K, Enders D. Org. Lett. 2018; 20: 3622
    • 9j Wang Z, Wong YF, Sun J. Angew. Chem. Int. Ed. 2015; 54: 13711
    • 9k Li S, Liu S, Huang B, Zhou T, Tao H, Xiao Y, Liu L, Zhang J. ACS Catal. 2017; 7: 2805
    • 9l Deng YH, Zhang XZ, Yu KY, Yan X, Du JY, Huanga H, Fan CA. Chem. Commun. 2016; 52: 4183
  • 10 Roy D, Panda G. Tetrahedron 2018; 74: 6270
  • 11 CCDC 1901622 (3k) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
    • 12a Mahesh S, Anand RV. Org. Biomol. Chem. 2017; 15: 8393
    • 12b Ge L, Lu X, Cheng C, Chen J, Cao W, Wu X, Zhao G. J. Org. Chem. 2016; 81: 9315

  • References

    • 1a Parai MK, Panda G, Chaturvedi V, Manju YK, Sinha S. Bioorg. Med. Chem. Lett. 2008; 18: 289
    • 1b Al-Qawasmeh RA, Lee Y, Cao M.-Y, Gu X, Vassilakos A, Wright JA, Young A. Bioorg. Med. Chem. Lett. 2004; 14: 347
    • 1c Shagufta G, Srivastava AK, Sharma R, Mishra R, Balapure AK, Murthy PS. R, Panda G. Bioorg. Med. Chem. 2006; 14: 1497
    • 1d Palchaudhuri R, Nesterenko V, Hergenrother PJ. J. Am. Chem. Soc. 2008; 130: 10274
    • 2a Gindre CA, Screttas CG, Fiorini C, Schmidt C, Nunzi JM. Tetrahedron Lett. 1999; 40: 7413
    • 2b Shchepinov MS, Korshun VA. Chem. Soc. Rev. 2003; 32: 170
    • 2c Beija M, Afonso CA. M, Martinho JM. G. Chem. Soc. Rev. 2009; 38: 2410
  • 3 Conn MM, Rebek JJr. Chem. Rev. 1997; 97: 1647
  • 4 Mondal S, Panda G. RSC Adv. 2014; 4: 28317
    • 5a Panda G, Shagufta Shagufta, Mishra JK, Chaturvedi V, Srivastava AK, Srivastava R, Srivastava BS. Bioorg. Med. Chem. 2004; 12: 5269
    • 5b Kumar S, Das SK, Dey S, Maity P, Guha M, Choubey V, Panda G, Bandyopadhyay U. Antimicrob. Agents Chemother. 2008; 52: 705
    • 5c Goyal M, Singh P, Alam A, Das SK, Iqbal MS, Dey S, Bindu S, Pal C, Das SK, Panda G, Bandyopadhyay U. Free Radical Biol. Med. 2012; 53: 129
    • 5d Panda G, Parai MK, Srivastava AK, Chaturvedi V, Manju YK, Sinha S. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2009; 48: 1121

      For selected relevant examples, see:
    • 6a Ma C, Huang Y, Zhao Y. ACS Catal. 2016; 6: 6408
    • 6b Yuan Z, Wei W, Lin A, Yao H. Org. Lett. 2016; 18: 3370
    • 6c Chen M, Sun J. Angew. Chem. Int. Ed. 2017; 56: 4583
    • 6d Saha S, Alamsetti SK, Schneider C. Chem. Commun. 2015; 51: 1461
    • 6e Mondal S, Roy D, Jaiswal MK, Panda G. Tetrahedron Lett. 2018; 59: 89
    • 7a Goswami P, Sharma S, Singh G, Anand RV. J. Org. Chem. 2018; 83: 4213
    • 7b Goswami P, Singh G, Anand RV. Org. Lett. 2017; 19: 1982
    • 7c Jadhav AS, Anand RV. Eur. J. Org. Chem. 2017; 3716
    • 7d Jadhav AS, Anand RV. Org. Biomol. Chem. 2017; 15: 56
    • 7e Arde P, Anand RV. Org. Biomol. Chem. 2016; 14: 5550
    • 7f Arde P, Anand RV. RSC Adv. 2016; 6: 77111
    • 7g Goswami P, Anand RV. ChemistrySelect 2016; 1: 2556
    • 7h Reddy V, Anand RV. Org. Lett. 2015; 17: 3390
    • 7i Zhang XZ, Deng YH, Yan X, Yu KY, Wang FX, Ma XY, Fan CA. J. Org. Chem. 2016; 81: 5655
    • 7j Gupta AK, Ahamad S, Vaishanv NK, Kant R, Mohanan K. Org. Biomol. Chem. 2018; 16: 4623
    • 7k Vaishanv NK, Gupta AK, Kant R, Mohanan K. J. Org. Chem. 2018; 83: 8759
    • 7l Jadhav AS, Pankhade YA, Hazra R, Anand RV. J. Org. Chem. 2018; 83: 10107
    • 7m Zhou T, Li S, Huang S, Li C, Zhao Y, Chen J, Chen A, Xiao Y, Liu L, Zhang J. Org. Biomol. Chem. 2017; 15: 4941
    • 8a Santra S, Porey A, Guin J. Asian J. Org. Chem. 2018; 7: 477
    • 8b Molleti N, Kang JY. Org. Lett. 2017; 19: 958
    • 8c Yang C, Gao S, Yao H, Lin A. J. Org. Chem. 2016; 81: 11956
    • 8d Pan R, Hu L, Han C, Lin A, Yao H. Org. Lett. 2018; 20: 1974
    • 8e Yuan Z, Liu L, Pan R, Yao H, Lin A. J. Org. Chem. 2017; 82: 8743
    • 9a Zhang ZP, Chen L, Li X, Cheng JP. J. Org. Chem. 2018; 83: 2714
    • 9b Zhang ZP, Xie KX, Yang C, Li M, Li X. J. Org. Chem. 2018; 83: 364
    • 9c Wang H, Wang K, Man Y, Gao X, Yang L, Ren Y, Li N, Tang B, Zhao G. Adv. Synth. Catal. 2017; 359: 3934
    • 9d Chu WD, Zhang LF, Bao X, Zhao XH, Zeng C, Du JY, Zhang GB, Wang FX, Ma XY, Fan CA. Angew. Chem. Int. Ed. 2013; 52: 9229
    • 9e Zhang XZ, Gan KJ, Liu XX, Deng YH, Wang FX, Yu KY, Zhang J, Fan CA. Org. Lett. 2017; 19: 3207
    • 9f Caruana L, Kniep F, Johansen TK, Poulsen PH, Jørgensen KA. J. Am. Chem. Soc. 2014; 136: 15929
    • 9g Zhao K, Zhi Y, Wang A, Enders D. ACS Catal. 2016; 6: 657
    • 9h Zhao K, Zhi Y, Shu T, Valkonen A, Rissanen K, Enders D. Angew. Chem. Int. Ed. 2016; 55: 12104
    • 9i Liu Q, Li S, Chen XY, Rissanen K, Enders D. Org. Lett. 2018; 20: 3622
    • 9j Wang Z, Wong YF, Sun J. Angew. Chem. Int. Ed. 2015; 54: 13711
    • 9k Li S, Liu S, Huang B, Zhou T, Tao H, Xiao Y, Liu L, Zhang J. ACS Catal. 2017; 7: 2805
    • 9l Deng YH, Zhang XZ, Yu KY, Yan X, Du JY, Huanga H, Fan CA. Chem. Commun. 2016; 52: 4183
  • 10 Roy D, Panda G. Tetrahedron 2018; 74: 6270
  • 11 CCDC 1901622 (3k) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
    • 12a Mahesh S, Anand RV. Org. Biomol. Chem. 2017; 15: 8393
    • 12b Ge L, Lu X, Cheng C, Chen J, Cao W, Wu X, Zhao G. J. Org. Chem. 2016; 81: 9315

Zoom Image
Figure 1 Some biologically active TRSMs
Zoom Image
Scheme 1 Strategies for 1,6-conjugate addition to p-QMs
Zoom Image
Scheme 2 Substrate scope with different p-QMs. Reagents and conditions: 1 (0.1 mmol), 2 (0.1 mmol), NaH (0.2 mmol), DMF (2 mL), RT, 20–40 min. Isolated yields after silica gel column chromatography.
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Figure 2 X-ray crystal structure of 3k; ellipsoids are drawn at the 30% probability level
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Scheme 3 Proposed mechanistic pathway
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Scheme 4 Synthesis of hydroxyzine-like molecule 8
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Scheme 5 Synthetic utility of the reaction