Asymmetric Organocatalytic Approach to 2,4-Disubstituted 1,2,3

Article Cite This: J. Org. Chem. 2018, 83, 793−804

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Asymmetric Organocatalytic Approach to 2,4-Disubstituted 1,2,3Triazoles by N2-Selective Aza-Michael Addition Ujjawal Kumar Bhagat and Rama Krishna Peddinti* Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee-247 667, Uttarakhand, India S Supporting Information *

ABSTRACT: Despite the fact that N1-functionalization of NH-1,2,3-triazoles has been known for several decades, enantioselective variants of this reaction have only recently been developed. Nevertheless, functionalization at the N2-position of NH-1,2,3-triazoles leading to optically active N2-substituted triazoles is not yet developed. In this article, we report, for the first time, the asymmetric aza-Michael reaction of 4-aryl-NH-1,2,3-triazoles to cyclic enones under the catalytic influence of chiral bifunctional thiourea organocatalysts for the enantioselective generation of 2,4-disubstituted 1,2,3-triazoles. The cinchoninederived thiourea catalyst III worked efficiently in the current transformation to produce N2-functionalized 1,2,3-triazoles as major products in optical yields up to >99.9% along with minor 1,4-disubstitued 1,2,3-triazoles.

T

catalyzed click chemistry reactions.9 In 2008, Ramachary et al. investigated the functionalized NH-1,2,3-triazoles from γactivated enones and organic azides under proline catalysis.9a,d Bressy9c and Wang9b,e independently reported the enaminecatalyzed organocatalytic 1,3-dipolar cycloaddition of ketones to azides to generate multisubstituted 1,2,3-triazoles. N2 alkylation of 1,2,3-triazoles involving nucleophilic substitution of alkylating reactants with NH-1,2,3-triazoles encounters the regioselectivity issues. However, examples for the synthesis of N2-substituted 1,2,3-triazoles as sole products or major products are documented in the literature.10,11 N2functionalization by post-triazole formation10 and construction of a 1,2,3-triazole moiety with N2-substituted precursors11 have been accomplished. Despite the enormous work presented in the literature on the synthesis of 1,4-disubstituted (N1) 1,2,3-triazoles, the production of their chiral analogues is still in its infancy.12 The general routes to chiral 1,2,3-triazoles are (i) click reaction of alkyne and azide, where one of them is a chiral building block, (ii) kinetic resolution approach during the dipolar cycloaddition of click reaction partners from either of the racemic starting materials, where enantioselective generation of triazole takes place in the presence of a chiral catalyst,13 and (iii)

he substituted 1,2,3-triazoles are among the most important N-heterocyclic compounds which display a broad spectrum of applications in the areas of medicinal chemistry, agrochemicals, and material science.1 1,2,3-Triazole containing heterocyclic compounds serve as intermediates for the synthesis of biologically active compounds.2 The 1,3-dipolar [3 + 2] cycloaddition of azides and alkynes is the most conventional and efficient method for the synthesis of a mixture of 1,4- and 1,5-disubstituted 1,2,3-triazoles and was comprehensively studied by Huisgen.3 Sharpless4 and Meldal5 independently developed a powerful and highly regioselective construction of 1,4-disubstituted 1,2,3-triazoles through a Cu(I)-catalyzed azide−alkyne cycloaddition (CuAAC) process, known as “click chemistry”. Later, Ru-catalyzed azide−alkyne cycloaddition (RuAAC) reactions were developed to access 1,5disubstituted 1,2,3-triazoles.6 Recently, strain-promoted [3 + 2] cycloaddition reaction between cyclooctynes and aryl azides leading to 1,4,5-trisubstituted 1,2,3-triazoles has been reported, and these heterocycles have become superior bioorthogonal probes.7 However, there are some apprehensions on metal mediated reactions due to the residual metal species present in the products for their biological studies.8 In succinct, the arrival of novel organocatalytic methodologies which are devoid of these deficiencies would be of great value and principally essential to the synthetic community. Recently, organocatalytic synthesis of 1,2,3-triazoles has been used as a powerful methodology, albeit a less populated alternative to metal© 2017 American Chemical Society

Received: November 4, 2017 Published: December 19, 2017 793

DOI: 10.1021/acs.joc.7b02793 J. Org. Chem. 2018, 83, 793−804

Article

The Journal of Organic Chemistry Scheme 1. Enantioselective Approaches to Functionalized 1,2,3-Triazoles

Figure 1. Bifunctional thiourea organocatalysts for initial screening of aza-Michael addition.

desymmetrization of bis-alkynes through asymmetric CuAAC14 (Scheme 1a). To the best of our knowledge, there are no routes to N2-selective asymmetric 1,2,3-triazole formation.15 Recently, Wang reported organocatalytic N1 functionalization of benzotriazole, where N2 substituted products were obtained in minor amount.15a We envisioned that the conjugate addition of aryl triazoles to α,β-unsaturated systems under the influence of basic organocatalysts would provide N2 selective disubstituted 1,2,3-triazoles. Herein, we present the first enantioselective organocatalytic aza-Michael addition of 4-aryl-NH-1,2,3triazoles to α,β-unsaturated cyclic enones using a cinchona alkaloid-based chiral bifunctional thiourea organocatalyst (Scheme 1b). Activity of Catalysts. For the screening process, we have selected 2-cyclohexen-1-one (1a) and 4-chlorophenyl-NH1,2,3-triazole16 (2g) as model substrates. To evaluate the asymmetric induction on aza-Michael reaction between 1a and 2g, cinchona alkaloid-based thioureas I−IV17 and Takemoto catalyst V18 were chosen as bifunctional organocatalysts (Figure 1). The organocatalytic conjugate addition of 2-cyclohexenone 1a with triazole 2g in acetonitrile proceeded in the presence of chiral thiourea V at room temperature for 72 h to furnish two isomeric products. The major 2,4-disubstituted triazole 3g was obtained through N2 addition in 73% yield. The enantioselectivity of 3g was found to be 65% from the HPLC analysis on

a chiralpak AS-H column using 80:20 of Hexane/IPA solvent system (Table 1, entry 1). The N1 addition gave the minor 1,4disubstituted triazole 4g in 23% yield with 30% optical purity. At this juncture, to evaluate the effect of organic bases as additives on the reaction outcome, some bases were tested. Thus, when we carried out the reaction in the presence of V (10 mol %) and DABCO (20 mol %), the product 3g was obtained in a similar chemical yield, albeit in lower enantioselectivity (entry 2). Replacement of DABCO with DMAP and DIPEA provided almost similar results (entries 3 and 4). The use of DBU as an additive for Michael reaction resulted in a minor improvement in both chemical and optical yield of 3g (entry 5). The cinchonine-derived thiourea III promoted the aza-Michael reaction in the presence of DABCO to afford the disubstituted triazole 3g in 65% ee (entry 6). It appeared that the presence of basic additives in conjunction with chiral thiourea drives the catalytic Michael addition in a less-enantioselective route to provide the product 3g in diminished optical purity (entries 2−6) which may be attributed to the partial background reaction mediated by exogenous base. Consequently, we obviate the use of additives in the subsequent screening. When the reaction was performed with thiourea catalyst III without achiral base, the disubstituted triazole 3g was obtained in 71% chemical yield with an excellent enantioselectivity of 97% ee (entry 7). With the quasi794


Article

The Journal of Organic Chemistry Table 1. Organocatalytic Conjugate Addition of 4Chlorophenyl-NH-1,2,3-triazole (2g) to 2-Cyclohexen-1-one (1a)a

3g entry

catalyst

1 2 3 4 5 6 7 8 9 10 11

V V V V V III III IV II I VI

additive DABCO DMAP DIPEA DBU DABCO

b

yield (ee) 73% 71% 73% 64% 77% 78% 71% 64% 61% 71% 52%

Table 2. Aza-Michael Addition of 1,2,3-Triazole 2g to 2Cyclohexen-1-one (1a) in the Presence of Catalyst IIIa

(65%) (25%) (31%) (32%) (41%) (65%) (97%) (−71%) (75%) (−78%) (-)

b

yield (ee)

solvent

1 2 3 4 5

DCM 1,4-Dioxane DCE CHCl3 CH3OH

3g

4g

yieldb (ee)c

yieldb (ee)b

70% 68% 66% 68% 51%

17% 30% 25% 22% 36%

(73%) (62%) (82%) (81%) (26%)

(18%) (9%) (20%) (15%) (2%)

a

The reactions were carried out in solvent (1 mL) using 1a (1.2 mmol) and 2g (0.2 mmol) in the presence of chiral catalyst III (10 mol %) at room temperature for 72 h. bYields are of pure and isolated products. cEnantiomeric excess was determined by HPLC analysis using a chiral column Chiralpak AS-H and mobile phase IPA/Hexane.

4g c

entry

c

23% (30%) 13% (11%) 14% (38%) 21% (24%) 10% (25%) 18% (26%) 22% (19%) 25% (21%) 17% (18%) 17% (32%) 9% (-)

Scope of the Substrates. After optimizing the asymmetric Michael addition with catalyst III in acetonitrile, we extended our studies to evaluate the scope of 4-aryl-NH-1,2,3-triazoles 2. A range of ortho-, meta-, and para-substituted aryl triazoles were employed as Michael donors in the reaction with cyclohexenone 1a using 10 mol % catalyst III at room temperature. The results are collected in Table 3. The reaction of 4phenyltriazole with 1a furnished the adduct 3a in 66% chemical yield with 89% enantioselectivity (entry 1). The parasubstituted aryl triazoles participated equally good in the reaction and gave the products 3c−e, 3g, and 3k in 68−74% yield and 82−>99% ee without significant variation irrespective of the electronic nature of the substituents on the aromatic ring (entries 3−5, 7, and 11). The absolute configuration of the adduct 3g was deduced by its single-crystal X-ray analysis (vide infra). The triazoles bearing meta-substitution on the aryl moiety reacted with 1a under the optimized reaction conditions to furnish the Michael adducts 3b and 3i in good optical yield (entries 2 and 9). The ortho-substituted aryl triazoles with groups such as chloro-, nitro-, and bromo- also tolerated in the current asymmetric transformation and the corresponding adducts 3f, 3h, and 3j were isolated in 72−89% ee (entries 6, 8, and 10). 2,5-Dimethoxyphenyl 1,2,3-triazole afforded Michael adduct 3l in 75% yield and 77% ee (entry 12), while 3,4-dimethoxyphenyl triazole gave 3m in 72% yield and 86% ee (entry 13). 2,3-Dichlorophenyl substituted 1,2,3-triazole also participated in aza-Michael addition with 1a to provide 2,4disubstituted 1,2,3-triazole 3n in significant yield with 88% ee. The 2,4,5-trimethoxyphenyl 1,2,3-triazole underwent conjugate addition with 1a and released the Michael adduct 3o in 65% yield and 63% ee, comparatively less productivity and enantioselectivity has been observed (entry 15). When 2methoxynaphthalen-1-yl substituted triazole was treated with 1a, the 2,4-disubstituted adduct 3p was procured in 70% yield and 81% ee (entry 16). The minor 1,4-disubstituted triazoles 4 were obtained 17−25% chemical yield with optical yield up to 40%. Encouraged by the results obtained from the reactions of aryl 1,2,3-triazoles with Michael acceptor 1a, we then broadened the substrate scope by performing the aza-Michael addition of 4aryl 1,2,3-triazoles to 4,4-dimethylcyclohexenone 1b. Differently substituted aryl triazoles 2 were used for this purpose. In most of the cases, the enone 1b reacted with aryl triazoles slowly in comparison to the parent 2-cyclohexenone 1a and slight erosion in chemical and optical yield was witnessed. The enantioselectivity of the adducts 5a−i was found to be in the range of 49−99% (Table 4, entries 1−9). Gratifyingly, the

a

The reactions were carried out in acetonitrile (1 mL) using 2cyclohexen-1-one (1a, 1.2 mmol) and 4-(4-chlorophenyl)-NH-1,2,3triazole (2g, 0.2 mmol) in the presence of additive (20 mol %) and chiral catalyst (10 mol %) at room temperature. bYields are of pure and isolated products. cEnantiomeric excess was determined by HPLC analysis using a chiral column Chiralpak AS-H and mobile phase IPA/ Hexane.

enantiomer IV of the catalyst III, the opposite enantiomer of 3g was obtained in 64% yield with some drop in optical yield (entry 8). Furthermore, another quasi-enantiomeric pair of thiourea catalysts II and I furnished the adduct 3g in good yield, under the same set of conditions, in almost the same enantioselectivity (75% and 78% ee) but with opposite setereochemistry (entries 9 and 10). In all these reactions, the minor product 4g was obtained in varying amount in the range of 10−25% chemical yields with 11−38% ee (entries 1− 10). The symmetric achiral catalyst VI also catalyzed the reaction of 1a and 2g to give the racemic product 3g in acceptable yield (entry 11). Optimization of Solvents. Having identified the thiourea catalyst III as the champion of the set of catalysts studied, the screening of the solvents in the conjugate addition of aryl 1,2,3triazole 2g with 2-cyclohexenone 1a was carried out using chiral catalyst III (10 mol %). Thus, solvents such as DCM, 1,4dioxane, DCE, CHCl3, and methanol were used to evaluate the catalytic activity of catalyst III under the optimized reaction conditions. The reaction in chlorinated solvents afforded the Michael adduct 3g in good yield, and the enantioselectivity ranged from 73% to 82% ee (Table 2, entries 1, 3, and 4). The asymmetric transformation in 1,4-dioxane furnished the product 3g in a similar chemical yield, albeit a marginally reduced enantioselectivity (entry 2). When the Michael addition was carried out in polar, protic solvent methanol, diminished activity of chiral catalyst III was observed (entry 5). The reduced optical induction in this reaction may be attributed to the competitive activation of acceptor 1a with methanol and catalyst III. Thus, in acetonitrile, the aza-Michael addition with catalyst III gives best result with the highest optical purity for product 3g (Table 1, entry 7). 795


Article

The Journal of Organic Chemistry Table 3. Organocatalytic Aza-Michael Addition of 4-Aryl-NH-1,2,3-triazoles 2 with 2-Cyclohexen-1-one (1a)a

3

4

entry

Ar

time (h)

yieldb (ee)c

yieldb (ee)c

1 2 3 4 5 6 7e 8 9 10 11 12 13 14 15 16

C6H5 3-OMeC6H4 4-OMeC6H4 4-MeC6H4 4-iPrC6H4 2-ClC6H4 4-ClC6H4 2-NO2C6H4 3-NO2C6H4 2-BrC6H4 4-BrC6H4 2,5-(OMe)2C6H3 3,4-(OMe)2C6H3 2,3-(Cl)2C6H3 2,4,5-(OMe)3C6H2 2-OMe-Nap-1-yl

96 84 72 84 72 72 72 108 108 84 84 72 72 108 96 96

3a, 66% (89%) 3b, 67% (84%) 3c, 72% (>99%) 3d, 68% (82%) 3e, 72% (83%) 3f, 71% (89%) 3g, 74% (>99%) 3h, 63% (80%) 3i, 65% (71%) 3j, 68% (72%) 3k, 70% (82%) 3l, 75% (77%) 3m, 72% (86%) 3n, 69% (88%) 3o, 65% (63%) 3p, 70% (81%)

4a, 24% (-) 4b, 21% (31%) 4c, - (-)d 4d, 25% (37%) 4e, 22% (19%) 4f, 23% (40%) 4g, 22% (20%) 4h, - (-)d 4i, 17% (35%) 4j, - (-)d 4k, - (-)d 4l, 19% (24%) 4m, - (-)d 4n, 23% (-)f 4o, 23% (-)f 4p, 24% (-)f

a The reactions were carried out in acetonitrile (1 mL) using 2-cyclohexen-1-one (1a, 1.2 mmol) and 4-aryl-1H-1,2,3-triazole (2, 0.2 mmol) in the presence of chiral catalyst III (10 mol %) at room temperature. bYields are of pure and isolated products. cEnantiomeric excess was determined by HPLC analysis using chiral columns Chiralpak AD-H, Chiralpak AS-H, and Chiralcel OD-H and mobile phase IPA/Hexane. dMinor isomer could not be isolated in pure form. eAbsolute configuration of 3g with >99% ee was determined by single-crystal X-ray. fee could not be measured as the enantiomers were not separated.

Table 4. Asymmetric Aza-Michael Addition of 4-Aryl-NH-1,2,3-triazoles 2 with 4,4-Dimethyl-2-cyclohexen-1-one (1b)a

5 b

6 c

entry

Ar

time (h)

yield (ee)

1 2 3 4 5 6 7 8 9

4-OMeC6H4 3-OMeC6H4 2-BrC6H4 2-ClC6H4 4-ClC6H4 4-iPrC6H4 3-NO2C6H4 2,5-(OMe)2 C6H3 3,4-(OMe)2 C6H3

108 108 120 108 108 108 120 108 108

5a, 64% (84%) 5b, 58% (56%) 5c, 65% (49%) 5d, 65% (60%) 5e, 62% (64%) 5f, 66% (67%) 5g, 58% (51%) 5h, 63% (>99%) 5i, 63% (78%)

b

yield (ee)c 6a, 21% (-)d 6b, 19% (11%) 6c, 21% (24%) 6d, 19% (11%) 6e, 18% (-)d 6f, 27% (-)d 6g, 19% (-)d 6h, 19% (13%) 6i, 20% (-)d

a

Reactions conditions: 4,4-dimethyl-2-cyclohexen-1-one (1b, 1.2 mmol) and 4-aryl-NH-1,2,3-triazole (2, 0.2 mmol) in acetonitrile (1 mL), using chiral catalyst III (10 mol %) at room temperature. bIsolated yields. cEnantiomeric excess was determined by HPLC analysis using chiral columns Chiralpak AD-H and Chiralcel OD-H and mobile phase IPA/Hexane. dee could not be measured as the enantiomers were not separated.

dimethoxy substituted aryl triazoles participated in the azaMichael addition with 1b smoothly to furnish the adducts 5h and 5i in good yield and >99% and 78% ee, respectively (entries 8 and 9). Having succeeded in the aza-Michael reaction of 4-aryl 1,2,3triazoles with cyclic enones1a and 1b, we next carried out the conjugate addition of 4-aryl-NH-1,2,3-triazoles 2 to 2-cyclopentenone 1c. Thus, we investigated the reactions of 1c with variously substituted aryl 1,2,3-triazoles in the presence of catalyst III (10 mol %), and the results are presented in Table

5. We observed that, though the yields of the adducts 7a−i are comparable to those of 5, the enantioselectivity was diminished significantly. The N2 adducts 7b−i with alkyl, alkoxy, and halo substituents on the aryl moiety were obtained in 44−62% optical purity (entries 2−9). Determination of Absolute Configuration of 3g by Single-Crystal X-ray Analysis. We were delighted to obtain single crystals19 for major aza-Michael adduct 3g, a 2,4disubstituted 1,2,3-triazole having a chlorine atom attached with a phenyl ring, with >99.9% ee from the DCM−ethyl 796


Article

The Journal of Organic Chemistry Table 5. Enantioselective Aza-Michael Addition of 4-Aryl-NH-1,2,3-triazoles 2 with 2-Cyclopenten-1-one (1c)a

7

8

entry

Ar

time (h)

yieldb (ee)c

yieldb (ee)c

1 2 3 4 5 6 7 8 9

C6H5 3-OMeC6H4 4-OMeC6H4 4-iPrC6H4 2-ClC6H4 4-ClC6H4 2,5-(OMe)2 C6H3 3,4-(OMe)2 C6H3 2-BrC6H4

108 120 108 108 120 108 108 108 108

7a, 67% (46%) 7b, 66% (44%) 7c, 71% (62%) 7d, 68% (57%) 7e, 69% (58%) 7f, 70% (50%) 7g, 75% (62%) 7h, 75% (57%) 7i, 64% (50%)

8a, 21% (25%) 8b, - (-)d 8c, 20% (13%) 8d, 22% (-)e 8e, 18% (-)e 8f, 20% (-)e 8g, 18% (-)e 8h, 20% (59%) 8i, 22% (-)e

a Reactions conditions: 2-cyclopenten-1-one (1c, 1.2 mmol) and 4-aryl-1H-1,2,3-triazole (2, 0.2 mmol) in acetonitrile (1 mL) with chiral catalyst III (10 mol %) at room temperature. bIsolated yields. cEnantiomeric excess was determined by HPLC analysis of 7 and 8 using a chiral column Chiralpak AD-H and mobile phase IPA/Hexane. dMinor isomer could not be isolated in pure form. eee could not be measured as the enantiomers were not separated.

acetate−hexane solvent system. This single crystal paved a way for us to determine its absolute configuration by analyzing the X-ray crystallographic method. The absolute configuration of the compound 3g was determined by refinement of the Flack parameter x, which should be 0 for correct and +1 for incorrect absolute configuration. The Sheldrick least-squares refinement of the crystal structure gave a Flack parameter of x = 0.130(3). Thus, the analysis of the Flack parameter confirmed the configuration of the Michael adduct 3g to be (3R). A view of the molecular structure of (3R)-3g is shown in Figure 2. The absolute configuration of all other N2-functionalized triazoles was assigned by analogy.

Scheme 2. Plausible Reaction Mechanism for Aza-Michael Addition

Figure 2. ORTEP diagram of ellipsoids at 50% probability level for the crystal structure of (3R)-3-(4-chlorophenyl triazol-2-yl)cyclohexanone 3g (numbering is arbitrary).

facilitates to enhance the nucleophilicity of internal nitrogen, and reacts with electron-deficient α,β-unsaturated cyclic enone to generate the enolate and protonated catalyst. With the transfer of proton to enolate, the catalyst is regenerated for further catalytic cycles. The enolic adduct finally tautomerizes to liberate the Michael adduct.

Proposed Mechanism. The organocatalytic aza-Michael reaction is an important methodology for the formation of carbon−nitrogen bonds in biologically important optically active compounds. Here, the conjugate addition of 4-aryl-NH1,2,3-triazole to the electron-deficient α,β-unsaturated cyclic enone under the catalytic behavior of bifunctional thiourea organocatalyst affords the Michael adduct. The proposed mechanism for asymmetric aza-Michael reaction is illustrated in Scheme 2. Initially, the chiral bifunctional thiourea organocatalyst III activates both 2-cyclohexen-1-one and 4aryl-NH-1,2,3-triazole simultaneously. The activation of both the substrates takes place by hydrogen-bond formation between both N-H of the thiourea moiety and ketonic oxygen of enone, and N-H of triazole by tertiary nitrogen of the catalyst. This activated triazole, under basic nature of the catalyst,10p

■

CONCLUSION In conclusion, we observed catalytic activity of the bifunctional thiourea organocatalysts on direct aza-Michael addition of 4aryl-NH-1,2,3-triazoles to various cyclic enones. We demonstrated that cinchonine-derived thiourea organocatalyst III played a key role in the model enantioselective aza-Michael addition. The catalytic process proceeded, for the first time, through N2 selective addition of triazoles to furnish 2,4disubstituted 1,2,3-triazoles as major Michael adducts in good to high chemical yield with remarkable enantioselectivity along with minor 1,4-disubstituted 1,2,3-triazoles. The asymmetric 797


Article

The Journal of Organic Chemistry

160.0, 147.5, 131.5, 131.0, 129.9, 118.3, 114.3, 111.2, 62.6, 55.3, 46.5, 40.5, 31.0, 21.3 ppm; HRMS (ESI+): m/z calcd for C15H17N3NaO2 (M + Na)+ 294.1213, found: 294.1213. 3-(4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)cyclohexanone (4b). Reaction time: 84 h; Yield: 11.4 mg (21%), as white solid; MP: 164.2−165.9 °C; 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.43 (s, 1H), 7.35−7.26 (m, 2H), 6.89−6.87 (m, 1H), 4.86 (sept, J = 4.8 Hz, 1H), 3.85 (s, OCH3, 3H), 3.03 (dd, J = 10.0, 14.4 Hz, 1H), 2.96 (dd, J = 5.2, 14.8 Hz, 1H), 4.51−2.32 (m, 4H), 2.15−2.06 (m, 1H), 1.86−1.75 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.5, 159.9, 147.4, 131.6, 129.9, 118.3, 118.0, 114.2, 110.7, 58.8, 55.3, 47.2, 40.4, 31.6, 21.6 ppm; HRMS (ESI+): m/z calcd for C15H17N3NaO2 (M + Na)+ 294.1213, found: 294.1206. (3R)-3-(4-(4-Methoxyphenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3c). Reaction time: 72 h; Yield: 39.1 mg (72%), as white solid; MP: 117−118 °C; [α]25 D −20.94 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 2961, 2369, 1704, 1638, 1555, 1483, 1416, 1309, 1252, 1174, 1101, 977, 824, 603, 528; 1H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 4.97 (sept, J = 4.8 Hz, 1H), 3.83 (s, OCH3, 3H,), 3.11 (dd, J = 9.2, 14.8 Hz, 1H), 2.90 (dd, J = 5.2, 14.8 Hz, 1H), 2.48−2.44 (m, 2H), 2.37−2.56 (m, 2H), 2.07−1.98 (m, 1H), 1.83−1.73 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.4, 159.8, 147.4, 130.2, 127.1, 122.9, 114.2, 62.4, 55.3, 46.5, 40.5, 31.0, 21.3 ppm; HRMS (ESI+): m/z calcd for C15H17N3NaO2 (M + Na)+ 294.1213, found: 294.1213. (3R)-3-(4-p-Tolyl-2H-1,2,3-triazol-2-yl)cyclohexanone (3d). Reaction time: 84 h; Yield: 34.7 mg (68%), as light brown viscous liquid; −1 [α]25 D −5.9 (c 0.025, CH3CN); IR (KBr thin film, cm ): νmax 2949, 2858, 2090, 1636, 1548, 1409, 1306, 1180, 1094, 980, 617, 503; 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 4.98 (sept, J = 4.8 Hz, 1H), 3.12 (dd, J = 9.6, 14.8 Hz, 1H), 2.91 (dd, J = 4.8, 14.8 Hz, 1H), 2.47 (dd, J = 6.0, 7.6 Hz, 2H), 2.38 (s, CH3, 3H), 2.41−2.28 (m, 2H), 2.09−2.00 (m, 1H), 1.84−1.75 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.3, 147.7, 138.4, 130.7, 129.5, 127.4, 125.8, 62.5, 46.5, 40.6, 31.1, 29.7, 21.3 ppm. HRMS (ESI+): m/z calcd for C15H17N3NaO (M + Na)+ 278.1264, found: 278.1263. 3-(4-p-Tolyl-1H-1,2,3-triazol-1-yl)cyclohexanone (4d). Reaction time: 84 h, Yield: 12.8 mg (25%), as brown solid; MP: 111.8−113.5 °C; 1H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 4.96 (sept, J = 4.8 Hz, 1H), 3.07−2.95 (m, 2H), 2.55−2.32 (m, 4H), 2.37 (s, CH3, 3H), 2.16−2.07 (m, 1H), 1.87−1.56 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.5, 147.7, 138.2, 129.5, 127.5, 125.6, 117.7, 58.8, 47.3, 40.5, 31.7, 21.7, 21.3 ppm; HRMS (ESI+): m/z calcd for C15H17N3NaO (M + Na)+ 278.1264, found: 278.1262. (3R)-3-(4-(4-Isopropylphenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3e). Reaction time: 72 h; Yield: 40.8 mg (72%), as white solid; MP: 104.1−105.8 °C; [α]25 D −21.4 (c 0.10, CH3CN); IR (KBr thin film, cm−1): νmax 2954, 2870, 2065, 1712, 1639, 1554, 1417, 1319, 1226, 1109, 981, 835, 603, 555; 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 4.98 (sept, J = 4.8 Hz, 1H), 3.12 (dd, J = 9.2, 14.8 Hz, 1H), 2.97−2.89 (m, 2H), 2.47 (dd, J = 6.0, 7.6 Hz, 2H), 2.38−2.26 (m, 2H), 2.08−2.00 (m, 1H), 1.84−1.74 (m, 1H), 1.27 (d, J = 6.8 Hz, 6H, 2CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 207.2, 149.4, 147.7, 130.6, 127.8, 126.9, 125.9, 62.5, 46.5, 40.5, 33.9, 31.0, 23.9, 21.3 ppm; HRMS (ESI+): m/z calcd for C17H21N3NaO (M + Na)+ 306.1576, found: 306.1576. 3-(4-(4-Isopropylphenyl)-1H-1,2,3-triazol-1-yl)cyclohexanone (4e). Reaction time: 72 h; Yield: 12.5 mg (22%), as brown solid; MP: 97.5−99.0 °C; 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.29 (d, J = 8.0 Hz, 2H), 4.87 (sept, J = 4.8 Hz, 1H), 3.07−2.90 (m, 3H), 2.56−2.30 (m, 4H), 2.16−2.07 (m, 1H), 1.87−1.76 (m, 1H), 1.27 (d, J = 6.8 Hz, 6H, 2CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 206.6, 149.1, 147.7, 127.8, 126.9, 125.7, 117.7, 58.8, 47.3, 40.5, 33.9, 31.7, 23.9, 21.6 ppm; HRMS (ESI+): m/z calcd for C17H21N3NaO (M + Na)+ 306.1576, found: 306.1576. (3R)-3-(4-(2-Chlorophenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3f). Reaction time: 72 h; Yield: 39.1 mg (71%), as brown solid; MP: 68.5−69.2 °C; [α]25 D −17.8 (c 0.10, CH3CN); IR (KBr thin film,

nucleophilic addition of 4-aryl-NH-1,2,3-triazoles to other Michael acceptors is in progress in our laboratory.

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EXPERIMENTAL SECTION

General Method. All solvents were distilled by using standard methods. The chemicals were purchased from commercial suppliers at the highest purity grade available unless otherwise noted and were used without further purification. Reactions were monitored by thinlayer chromatography (TLC) performed on Merck precoated 0.25 mm silica gel plates (60F254) using UV light as visualizing agent and iodine as developing agent. All the target compounds were purified by forced-flow column chromatography using silica gel (particle size 100−200 mesh) with mixtures of hexanes/ethyl acetate as eluent. Instrumentation. Melting points were recorded on an Automated Melting Point System and are uncorrected. IR spectra of the compounds were recorded on an FT-IR spectrometer and are expressed as wavenumbers (cm−1). HRMS (ESI+) were recorded on a micrOTOF-QII. 1H (400 MHz) NMR and 13C (100 MHz) NMR spectra were recorded on an NMR spectrometer. Chemical shifts (δ) were reported as parts per million (ppm) in δ scale downfield relative to TMS (δ 0.00). Spectra were referenced internally to the residual proton resonance in CDCl3 (δ 7.26 ppm) as the internal standard. 13C NMR spectra were referenced to CDCl3 (δ 77.0 ppm, the middle peak). Coupling constants were expressed in Hz. The following abbreviations were used to indicate the multiplicities: s − singlet, d − doublet, t − triplet, q − quartet, quint − quintet, sext − sextet, sept − septet, dd − doublet of doublet, dt − doublet of triplet, td − triplet of doublet, ddd − doublet of doublet of doublet, m − multiplet. General Procedure for Organocatalytic Aza-Michael Addition of 4-Aryl-NH-1,2,3-triazoles to Cyclic Enones. To a stirred solution of α,β-unsaturated cyclic enone (1.2 mmol, 6.0 equiv) and 4aryl-NH-1,2,3-triazole (0.2 mmol 1.0 equiv) in acetonitrile (1 mL) was added the chiral bifunctional thiourea organocatalyst III (10 mol %, 11.3 mg) at room temperature. Upon complete consumption of the starting materials (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The residue was purified with gradient elution in 10−50% ethyl acetate−hexanes (in all cases) by force flow column chromatography to afford the two chiral azaMichael adducts (major and minor). (3R)-3-(4-Phenyl-2H-1,2,3-triazol-2-yl)cyclohexanone (3a). Reaction time: 96 h; Yield: 31.8 mg (66%), as pale yellow viscous liquid; −1 [α]25 D −28.2 (c 0.10, CH3CN); IR (KBr thin film, cm ): νmax 2952, 2101, 1639, 1555, 1465, 1415, 1312, 1105, 971, 765, 691, 611, 515; 1H NMR (400 MHz, CDCl3): δ 7.84 (s, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.42 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 4.99 (sept, J = 4.8 Hz, 1H), 3.12 (dd, J = 9.6, 14.8 Hz, 1H), 2.91 (dd, J = 4.8, 14.8 Hz, 1H), 2.47 (t, J = 7.6 Hz, 2H), 2.37−2.29 (m, 2H), 2.09−2.00 (m, 1H), 1.85−1.74 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.2, 147.6, 130.8, 130.2, 128.8, 128.4, 125.8, 62.5, 46.5, 40.5, 31.0, 21.3 ppm; HRMS (ESI+): m/z calcd for C14H15N3NaO (M + Na)+ 264.1107, found: 264.1103. 3-(4-Phenyl-1H-1,2,3-triazol-1-yl)cyclohexanone (4a). Reaction time: 96 h; Yield: 11.6 mg (24%), as brown solid; MP: 111.2−112.7 °C; 1H NMR (100 MHz, CDCl3): δ 7.82 (d, J = 7.6 Hz, 2H), 7.77 (s, 1H), 7.43 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 4.88 (sept, J = 4.8 Hz, 1H), 3.05 (dd, J = 10.0, 14.8 Hz, 1H), 2.99 (dd, J = 5.6, 14.8 Hz, 1H), 2.55−2.31 (m, 4H), 2.17−2.08 (m, 1H), 1.88−1.77 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.4, 147.7, 130.4, 128.9, 128.3, 125.7, 118.0, 58.9, 47.3, 40.5, 31.7, 21.7 ppm; HRMS (ESI+): m/z calcd for C14H15N3NaO (M + Na)+ 264.1107, found: 264.1102. (3R)-3-(4-(3-Methoxyphenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3b). Reaction time: 84 h; Yield: 36.4 mg (67%), as pale yellow viscous −1 liquid; [α]25 D −39.9 (c 0.05, CH3CN); IR (KBr thin film, cm ): νmax 2964, 1716, 1635, 1557, 1478, 1312, 1171, 1097, 1042, 1000, 848, 785, 690, 617, 556; 1H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 7.35− 7.30 (m, 3H), 6.92−6.86 (m, 1H), 4.98 (sept, J = 4.8 Hz, 1H), 3.85 (s, OCH3, 3H), 3.12 (dd, J = 9.6, 14.8 Hz, 1H), 2.91 (dd, J = 4.8, 14.8 Hz, 1H), 2.46 (t, J = 6.8 Hz, 2H), 2.38−2.27 (m, 2H), 2.08−1.99 (m, 1H), 1.84−1.73 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.1, 798


Article

The Journal of Organic Chemistry cm−1): νmax 2961, 2923, 2834, 1704, 1639, 1554, 1460, 1409, 1365, 1312, 1177, 1104, 1059, 770, 723, 609, 547; 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 7.84 (dd, J = 1.6, 7.6 Hz, 1H), 7.55 (dd, J = 1.2, 7.6 Hz, 1H), 7.35−7.28 (m, 2H), 5.02 (sept, J = 4.8 Hz, 1H), 3.13 (dd, J = 9.2, 14.8 Hz, 1H), 2.93 (dd, J = 5.2, 14.8 Hz, 1H), 2.48 (dd, J = 6.4, 7.6 Hz, 2H), 2.39−2.30 (m, 2H), 2.08−2.00 (m, 1H), 1.86−1.75 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.2, 144.8, 134.0, 132.0, 130.4, 130.2, 129.4, 129.1, 127.0, 62.6, 46.4, 40.5, 31.0, 21.3 ppm; HRMS (ESI+): m/z calcd for C14H14ClN3NaO (M + Na)+ 298.0717, found: 298.0720. 3-(4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanone(4f). Reaction time: 72 h; Yield: 12.7 mg (23%), as brown solid; MP: 95.9− 97.2 °C; 1H NMR (400 MHz, CDCl3): δ 8.24 (dd, J = 1.6, 8.0 Hz, 1H), 8.21 (s, 1H), 7.45 (dd, J = 1.6, 8.0 Hz, 1H), 7.37 (td, J = 1.2, 7.6 Hz, 1H), 7.28 (dd, J = 2.0, 7.6 Hz, 1H), 4.89 (sept, J = 4.8 Hz, 1H), 3.07 (dd, J = 10.4, 14.4 Hz, 1H), 3.00 (dd, J = 5.2, 14.4 Hz, 1H), 5.23− 2.37 (m, 4H), 2.19−2.11 (m, 1H), 1.88−1.78 (m, 1H) ppm; HRMS (ESI+): m/z calcd for C14H14ClN3NaO (M + Na)+ 298.0717, found: 298.0722. (3R)-3-(4-(4-Chlorophenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3g). Reaction time: 72 h; Yield: 40.8 mg (74%), as white solid; MP: −1 109.8−110.7 °C [α]25 D −24.1 (c 0.05, CH3CN); IR (KBr film, cm ): νmax 2964, 2867, 2080, 1704, 1640, 1552, 1470, 1421, 1374, 1309, 1225, 1174, 1096, 976, 829, 624, 553, 510; 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 4.99 (sept, J = 4.8 Hz, 1H), 3.11 (dd, J = 9.2, 14.8 Hz, 1H), 2.90 (dd, J = 5.2, 14.8 Hz, 1H), 2.47 (t, J = 7.2 Hz, 2H), 2.38−2.25 (m, 2H), 2.08−1.99 (m, 1H), 1.84−1.75 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.1, 146.5, 134.2, 130.8, 129.0, 128.7, 127.1, 62.6, 46.4, 40.5, 31.0, 21.2 ppm; HRMS (ESI+): m/z calcd for C14H14ClN3NaO (M + Na)+ 298.0717, found: 298.0717. 3-(4-(4-Chlorophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanone (4g). Reaction time: 72 h; Yield: 12.1 mg (22%), as white solid; MP: 166−167.8 °C; 1H NMR (400 MHz, CDCl3): δ 7.77 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.88 (sept, J = 4.8 Hz, 1H), 3.04 (dd, J = 9.6, 14.4, 1H), 2.97 (dd, J = 5.6, 14.4 Hz, 1H), 2.56−2.30 (m, 4H), 1.88−1.77 (m, 1H), 2.16−2.07 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.4, 146.6, 134.0, 129.1, 128.8, 126.9, 118.2, 59.0, 47.2, 40.5, 31.6, 21.6 ppm. HRMS (ESI+): m/z calcd for C14H14ClN3NaO (M + Na)+ 298.0717, found: 298.0718. (3R)-3-(4-(2-Nitrophenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3h). Reaction time: 108 h; Yield: 36.1 mg (63%), as yellow viscous −1 liquid; [α]25 D −38.3 (c 0.05, CH3CN); IR (KBr thin film, cm ): νmax 3187, 2984, 2369, 2082, 1707, 1642, 1533, 1415, 1362, 1233, 1171, 1109, 985, 847, 753, 706, 609, 566; 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.69 (dd, J = 1.2, 7.6 Hz, 1H), 7.62 (t, J = 7.6, 1H), 7.50 (dt, J = 7.6, 1.2 Hz, 1H), 4.99 (sept, J = 4.8 Hz, 1H), 3.07 (dd, J = 9.2, 14.8 Hz, 1H), 2.90 (dd, J = 5.2, 14.8 Hz, 1H), 2.47−2.43 (m, 2H), 2.37−2.23 (m, 2H), 2.06−1.97 (m, 1H), 1.84−1.74 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.0, 148.6, 142.8, 132.7, 132.3, 130.8, 129.3, 129.3, 124.1, 62.7, 46.2, 40.4, 30.9, 21.1 ppm. HRMS (ESI+): m/z calcd for C14H14N4NaO3 (M + Na)+ 309.0958, found: 309.0957. (3R)-3-(4-(3-Nitrophenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3i). Reaction time: 108 h; Yield: 37.2 mg (65%), as light brown solid. MP: 110.8−112.03 °C; [α]25 D −15.5 (c 0.10, CH3CN); IR (KBr thin film, cm−1): νmax 3105, 2953, 2843, 2079, 1715, 1639, 1530, 1406, 1344, 1229, 1168, 1092, 997, 877, 809, 740, 668, 612, 536, 465; 1H NMR (400 MHz, CDCl3): δ 8.60 (t, J = 2.0 Hz, 1H), 8.18 (dd, J = 1.6, 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 5.02 (sept, J = 4.8 Hz, 1H), 3.13 (dd, J = 9.2, 14.8 Hz, 1H), 2.93 (dd, J = 4.8, 14.8 Hz, 1H), 2.49 (dd, J = 6.0, 7.2 Hz, 2H), 2.41−2.28 (m, 2H), 2.10−2.01 (m, 1H), 1.87−1.79 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.0, 148.6, 145.4, 132.0, 131.6, 131.2, 129.9, 123.0, 120.6, 62.9, 46.4, 40.5, 31.0, 21.3 ppm; HRMS (ESI+): m/z calcd for C14H14N4NaO3 (M + Na)+ 309.0958, found: 309.0958. 3-(4-(3-Nitrophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanone (4i). Reaction time: 108 h; Yield: 9.7 mg (17%), as yellow viscous liquid; 1H NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.18 (dd, J = 0.8, 8.0 Hz, 1H), 7.96 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H),

4.94 (sept, J = 4.8 Hz, 1H), 3.10−2.98 (m, 2H), 2.58−2.33 (m, 4H), 2.18−2.09 (m, 1H), 1.91−1.80 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.2, 148.6, 145.5, 132.1, 131.5, 130.0, 122.9, 120.4, 119.1, 59.1, 47.2, 40.5, 31.6, 21.6 ppm; HRMS (ESI+): m/z calcd for C14H14N4NaO3 (M + Na)+ 309.0958, found: 309.0951. (3R)-3-(4-(2-Bromophenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3j). Reaction time: 84 h; Yield: 43.5 mg (68%); [α]25 D −14.7 (c = 0.10, CH3CN); IR (KBr thin film, cm−1): νmax 2978, 2381, 1716, 1640, 1554, 1454, 1412, 1304, 1109, 1039, 977, 765, 715, 626, 547;1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.72 (dd, J = 1.6, 7.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.21 (td, J = 1.6, 7.6 Hz, 1H), 5.01 (sept, J = 4.8 Hz, 1H), 3.13 (dd, J = 9.2, 14.8 Hz, 1H), 2.93 (dd, J = 4.8, 14.8 Hz, 1H), 2.47 (t, J = 6.8 Hz, 2H), 2.40−2.30 (m, 2H), 2.10−2.01 (m, 1H), 1.86−1.75 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.1, 146.1, 133.9, 133.7, 131.2, 130.9, 129.7, 127.5, 121.7, 62.6, 46.4, 40.5, 31.0, 21.3 ppm; HRMS (ESI+): m/z calcd for C14H14BrN3NaO (M + Na)+ 342.0212, found: 342.0212. (3R)-3-(4-(4-Bromophenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3k). Reaction time: 84 h; Yield: 44.8 mg (70%); [α]25 D −18.8 (c 0.10, CH3CN); IR (KBr thin film, cm−1): νmax 2960, 2869, 2099, 1915, 1702, 1642, 1555, 1418, 1309, 1226, 1173, 1082, 979, 8025, 714, 617, 508; 1H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 4.99 (sept, J = 4.8 Hz, 1H), 3.11 (dd, J = 9.2, 14.8 Hz, 1H), 2.91 (dd, J = 4.8, 14.8 Hz, 1H), 2.47 (t, J = 6.8 Hz, 2H), 2.38−2.27 (m, 2H), 2.08−1.99 (m, 1H), 1.85−1.75 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.2, 146.6, 132.0, 137.8, 129.2, 127.4, 122.4, 62.6, 46.4, 40.5, 31.0, 21.3 ppm; HRMS (ESI+): m/z calcd for C14H14BrN3NaO (M + Na)+ 342.0212, found: 342.0212. (3R)-3-(4-(2,5-Dimethoxyphenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3l). Reaction time: 72 h; Yield: 45.2 mg (75%), as brown viscous liquid; [α]25 D −16.3 (c 0.10, CH3CN); IR (KBr thin film, cm−1): νmax 2952, 2840, 2071, 1716, 1638, 1545, 1486, 1421, 1365, 1315, 1265, 1221, 1171, 1091, 1044, 856, 806, 738, 609, 526; 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.54 (d, J = 2.8 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 2.8, 8.8 Hz, 1H), 4.99 (sept, J = 4.8 Hz, 1H), 3.88 (s, OCH3, 3H), 3.83 (s, OCH3, 3H), 3.13 (dd, J = 9.6, 14.8 Hz, 1H), 2.92 (dd, J = 5.2, 14.8 Hz, 1H), 2.47 (dd, J = 5.6, 7.6 Hz, 2H), 2.39−2.27 (m, 2H), 2.10−2.01 (m, 1H), 1.84−1.73 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.3, 153.8, 151.0, 144.0, 134.4, 119.8, 115.0, 113.0, 112.6, 62.4, 56.0, 55.8, 46.6, 40.6, 31.1, 21.4 ppm; HRMS (ESI+): m/z calcd for C16H19N3NaO3 (M + Na)+ 324.1318, found: 324.1318. 3-(4-(2,5-Dimethoxyphenyl)-1H-1,2,3-triazol-1-yl)cyclohexanone (4l). Reaction time: 2 h; Yield: 11.5 mg (19%), as brown solid; MP: 144−145.5 °C; 1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 7.91 (d, J = 2.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.85 (dd, J = 2.8, 8.8 Hz, 1H), 4.84 (sept, J = 4.8 Hz, 1H), 3.88 (s, OCH3, 3H), 3.83 (s, OCH3, 3H), 3.05 (dd, J = 10.4, 14.4 Hz, 1H), 2.96 (dd, J = 5.2, 14.8 Hz, 1H), 2.50 (m, 4H), 2.16−2.07 (m, 2H), 1.84−1.75 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.6, 153.8, 149.9, 142.9, 121.7, 119.6, 115.1, 112.1, 111.7, 58.7, 55.8, 47.3, 40.4, 31.6, 21.6 ppm; HRMS (ESI +): m/z calcd for C16H19N3NaO3 (M + Na)+ 324.1318, found: 324.1316. (3R)-3-(4-(3,4-Dimethoxyphenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3m). Reaction time: 72 h; Yield: 43.4 mg (72%), as white solid; MP: 94.8−96.2 °C; [α]25 D −28.2 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 3431, 2959, 2838, 2355, 2046, 1709, 1636, 1549, 1500, 1455, 1368, 1317, 1246, 1152, 1094, 1020, 818, 760, 613, 534; 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.32 (s, 1H), 7.29 (dd, J = 2.0, 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.97 (sept, J = 4.8 Hz, 1H), 3.96 (s, OCH3, 3H), 3.92 (s, OCH3, 3H), 3.13 (dd, J = 9.2, 14.8 Hz, 1H), 2.91 (dd, J = 5.2, 14.8 Hz, 1H), 2.47 (t, J = 6.4 Hz, 2H), 2.39− 2.28 (m, 2H), 2.10−2.01 (m, 1H), 1.84−1.74 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.3, 149.4, 149.3, 147.5, 130.4, 123.2, 118.5, 111.3, 108.9, 62.5, 56.0, 55.9, 46.6, 40.6, 31.1, 21.3 ppm; HRMS (ESI+): m/z calcd for C16H19N3NaO3 (M + Na)+ 324.1318, found: 324.1318. (3R)-3-(4-(2,3-Dichlorophenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3n). Reaction time: 108 h; Yield: 42.8 mg (69%), as yellow viscous liquid; [α]25 D −23.8 (c 0.10, CH3CN); IR (KBr thin film, 799


Article

The Journal of Organic Chemistry cm−1): νmax 2952, 2875, 2363, 2100, 1714, 1639, 1551, 1420, 1371, 1303, 1227, 1168, 1095, 1038, 992, 780, 709, 524; 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 5.02 (sept, J = 8.0 Hz, 1H), 3.11 (dd, J = 9.2, 14.8 Hz, 1H), 2.92 (dd, J = 5.2, 14.8 Hz, 1H), 2.46 (t, J = 6.8 Hz, 2H), 2.39−2.26 (m, 2H), 2.08−1.99 (m, 1H), 1.85−1.75 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.9, 144.5, 134.2, 133.9, 131.4, 130.5, 130.2, 128.6, 127.4, 62.7, 46.3, 40.5, 31.0, 21.2 ppm; HRMS (ESI+): m/z calcd for C14H13Cl2N3NaO (M + Na)+ 332.0327, found: 332.0327. 3-(4-(2,3-Dichlorophenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (4n). Reaction time: 108 h; Yield: 14.3 mg (23%), as white solid; MP: 133−134 °C; 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 8.15 (dd, J = 1.2, 8.0 Hz, 1H), 7.47 (dd, J = 1.2, 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 4.90 (sept, J = 8.0 Hz, 1H), 3.08 (dd, J = 10.4, 14.4 Hz, 1H), 3.01 (dd, J = 5.2, 14.4 Hz, 1H), 2.56−2.32 (m, 4H), 2.21−2.12 (m, 1H), 1.89−1.77 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.1, 143.7, 133.8, 131.3, 129.9, 129.5, 128.2, 127.6, 122.1, 59.0, 47.4, 40.5, 31.7, 21.7 ppm; HRMS (ESI+): m/z calcd for C14H13Cl2N3NaO (M + Na)+ 332.0327, found: 332.0325. (3R)-3-(4-(2,4,5-Trimethoxyphenyl)-2H-1,2,3-triazol-1-yl)cyclohexanone (3o). Reaction time: 96 h; Yield: 43.1 mg (65%), as pale yellow solid; MP: 106.0 °C; [α]25 D −12.8 (c 0.025, CH3CN); IR (KBr thin film, cm−1): νmax 2943, 2849, 2378, 2062, 1711, 1638, 1545, 1458, 1353, 1276, 1213, 1153, 1085, 1032, 856, 805, 621, 520; 1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H), 7.50 (s, 1H), 6.58 (s, 1H), 4.97 (sept, J = 4.8 Hz, 1H), 3.92 (s, 2OCH3, 6H), 3.90 (s, OCH3, 3H), 3.12 (dd, J = 9.6, 14.8 Hz, 1H), 2.90 (dd, J = 4.8, 14.8 Hz, 1H), 2.45 (t, J = 6.4 Hz, 2H), 2.37−2.26 (m, 2H), 2.08−1.99 (m, 1H), 1.83−1.72 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.4, 151.2, 149.8, 144.0, 143.4, 133.7, 111.0, 110.8, 97.4, 62.3, 56.4, 56.3, 56.0, 46.6, 40.5, 31.0, 21.3 ppm. HRMS (ESI+): m/z calcd for C17H21N3KO4 (M + K)+ 370.1163, found: 370.1159. 3-(4-(2,4,5-Trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)cyclohexanone (4o). Reaction time: 96 h; Yield: 15.2 mg (23%), as brown viscous liquid; 1H NMR (400 MHz, CDCl3): δ 7.99 (s, 1H), 7.87 (s, 1H), 6.57 (s, 1H), 4.84 (sept, J = 4.8 Hz, 1H), 3.93 (s, OCH3, 3H), 3.91 (s, OCH3, 3H), 3.90 (s, OCH3, 3H), 3.05 (dd, J = 10.4, 14.8 Hz, 1H), 2.95 (dd, J = 5.2, 14.4 Hz, 1H), 2.50−2.30 (m, 4H), 2.15−2.07 (m, 1H), 1.84−1.73 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.6, 150.1, 149.4, 143.4, 143.0, 120.6, 110.8, 110.2, 97.0, 58.6, 56.3, 56.0, 47.4, 40.4, 31.7, 21.6 ppm; HRMS (ESI+): m/z calcd for C17H21N3NaO4 (M + Na)+ 354.1424, found: 354.1435. (3R)-3-(4-(2-Methoxynaphthalen-1-yl)-2H-1,2,3-triazol-2-yl)cyclohexanone (3p). Reaction time: 96 h; Yield: 45.0 mg (70%), as pale yellow viscous liquid; [α]25 D −9.2 (c 0.10, CH3CN); IR (KBr thin film, cm−1): νmax 2954, 2386, 2097, 1636, 1562, 1464, 1416, 1344, 1259, 1083, 1029, 956, 758, 605, 519; 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.86 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.38−7.33 (m, 2H), 5.08 (sept, J = 4.8 Hz, 1H), 3.90 (s, OCH3, 3H), 3.21 (dd, J = 9.6, 14.8 Hz, 1H), 3.01 (dd, J = 4.8, 14.4 Hz, 1H), 2.48 (dd, J = 5.6, 8.0 Hz, 2H), 2.44− 2.34 (m, 2H), 2.15−2.06 (m, 1H), 1.88−1.77 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.4, 155.1, 142.3, 136.0, 133.1, 130.7, 129.0, 128.0, 127.0, 124.6, 123.7, 113.1, 113.0, 62.4, 56.5, 46.6, 40.5, 31.1, 21.4 ppm; HRMS (ESI+): m/z calcd for C19H19N3NaO2 (M + Na)+ 344.1369, found: 344.1342. 3-(4-(2-Methoxynaphthalen-1-yl)-1H-1,2,3-triazol-1-yl)cyclohexanone (4p). Reaction time: 96 h; Yield: 15.4 mg (24%), as brown viscous liquid; 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.84 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.38−7.32 (m, 2H), 4.94 (sept, J = 4.8 Hz, 1H), 3.89 (s, OCH3, 3H), 3.16−3.04 (m, 2H), 2.58−2.41 (m, 4H), 2.22−2.13 (m, 1H), 1.90−1.79 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.7, 154.6, 141.8, 133.2, 130.5, 129.1, 127.9, 127.0, 125.3, 123.8, 123.4, 113.1, 112.9, 58.8, 56.5, 47.5, 40.5, 31.8, 21.8 ppm; HRMS (ESI+): m/z calcd for C19H19N3NaO2 (M + Na)+ 344.1369, found: 344.1360. (3S)-3-(4-(4-Methoxyphenyl)-2H-1,2,3-triazol-2-yl)-4,4-dimethylcyclohexanone (5a). Reaction time: 108 h; Yield: 38.3 mg (64%), as

pale yellow solid; MP: 107.0−109.0 °C; [α]25 D +6.9 (c 0.10, CH3CN); IR (KBr thin film, cm−1): νmax 2970, 2923, 2858, 2360, 2057, 1637, 1551, 1473, 1417, 1362, 1299, 1250, 1177, 1087, 1026, 980, 828, 615, 529; 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 6.9 (d, J = 8.8 Hz, 2H), 4.75 (dd, J = 6.0, 7.2 Hz, 1H), 3.84 (s, 3H, OCH3), 3.05 (dd, J = 7.6, 16.0 Hz, 1H), 2.84 (dd, J = 5.6, 16.0 Hz, 1H), 2.63−2.44 (m, 2H), 2.07 (sept, J = 6.8 Hz, 1H), 1.69−1.62 (m, 1H), 1.21 (s, 3H, CH3), 0.98 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 207.7, 159.8, 147.0, 129.9, 127.2, 123.0, 114.2, 70.3, 55.3, 42.8, 37.3, 35.0, 34.9, 26.8, 23.4 ppm; HRMS (ESI+): m/z calcd for C17H21N3NaO2 (M + Na)+ 322.1525, found: 322.1525. 3-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-4,4-dimethylcyclohexanone (6a). Reaction time: 108 h; Yield: 12.6 mg (21%); 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 6.96 (d, J = 8.4 Hz, 2H), 4.59 (dd, J = 5.2, 10.0 Hz, 1H), 3.84 (s, 3H, OCH3), 3.18 (dd, J = 10.4, 15.6 Hz, 1H), 2.84 (dd, J = 5.2, 15.6 Hz, 1H), 2.66−2.56 (m, 1H), 2.49 (dt, J = 5.6, 16.0 Hz, 1H), 1.97 (dt, J = 6.0, 14.0 Hz, 1H), 1.76−1.69 (m, 1H), 1.14 (s, 3H, CH3), 1.09 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 206.8, 159.7, 146.9, 127.0, 123.0, 118.8, 114.2, 66.7, 55.3, 43.1, 37.3, 35.8, 34.9, 27.5, 21.5 ppm; HRMS (ESI+): m/z calcd for C17H21N3NaO2 (M + Na)+ 322.1525, found: 322.1524. (3S)-3-(4-(3-Methoxyphenyl)-2H-1,2,3-triazol-2-yl)-4,4-dimethylcyclohexanone (5b). Reaction time: 108 h; Yield: 34.7 mg (58%); −1 [α]25 D +9.9 (c 0.05, CH3CN); IR (KBr thin film, cm ): νmax 2962, 2360, 2084, 1717, 1632, 1551, 1475, 1415, 1365, 1318, 1243, 1163, 1045, 1003, 849, 784, 688, 615, 568, 467; 1H NMR (400 MHz, CDCl3): δ 8.81 (s, 1H), 7.35−7.32 (m, 3H), 6.92−6.88 (m, 1H), 4.77 (dd, J = 5.6, 7.2 Hz, 1H), 3.86 (s, 3H, OCH3), 3.07 (dd, J = 7.6, 16.0 Hz, 1H), 2.85 (dd, J = 5.6, 16.0 Hz, 1H), 2.64−2.56 (m, 1H), 2.52− 2.44 (m, 1H), 2.09−2.02 (m, 1H), 1.70−1.63 (m, 1H), 1.21 (s, 3H, CH3), 0.98 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 207.6, 160.0, 147.0, 131.6, 131.6, 129.9 118.4, 114.1, 111.4, 70.4, 55.3, 42.8, 37.3, 35.1, 35.0, 26.9, 23.3 ppm; HRMS (ESI+): m/z calcd for C17H21N3NaO2 (M + Na)+ 322.1525, found: 322.1525. 3-(4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-4,4-dimethylcyclohexanone (6b). Reaction time: 108 h; Yield: 11.4 mg (19%); 1H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.44 (s, 1H), 7.35−7.30 (m, 2H), 6.88 (d, J = 6.0 Hz, 1H), 4.59 (dd, J = 4.0, 8.0 Hz, 1H), 3.85 (s, 3H, OCH3), 3.17 (dd, J = 8.0, 12.4 Hz, 1H), 2.83 (dd, J = 3.6, 12.4 Hz, 1H), 2.62−2.56 (m, 1H), 2.50−2.45 (m, 1H), 1.97−1.40 (m, 1H), 1.74−1.68 (m, 1H), 1.13 (s, 3H, CH3), 1.07 (s, 3H, CH3) ppm; HRMS (ESI+): m/z calcd for C17H21N3NaO2 (M + Na)+ 322.1525, found: 322.1527. (3S)-3-(4-(2-Bromophenyl)-2H-1,2,3-triazol-2-yl)-4,4-dimethylcyclohexanone (5c). Reaction time: 120 h; Yield: 45.3 mg (65%), as light yellow viscous liquid; [α]25 D +12.5 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 2953, 2857, 2161, 1717, 1639, 1455, 1315, 1106, 1035, 849, 762, 623, 487. 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.69 (dd, J = 1.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.23−7.19 (m, 1H), 4.80 (t, J = 6.4 Hz, 1H), 3.07 (dd, J = 16.0, 7.6 Hz, 1H), 2.87 (dd, J = 5.6, 16.0 Hz, 1H), 2.63−2.44 (m, 2H), 2.08 (sept, J = 6.8 Hz, 1H), 1.67 (quint, J = 6.8 Hz, 1H), 1.23 (s, CH3, 3H), 0.99 (s, CH3, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.6, 145.7, 133.6, 133.4, 131.2, 130.9, 129.6, 127.5, 121.7, 70.5, 42.7, 37.3, 35.0, 34.8, 26.8, 23.5 ppm; HRMS (ESI+): m/z calcd for C16H18BrN3NaO (M + Na)+ 370.0525, found: 370.0523. 3-(4-(2-Bromophenyl)-1H-1,2,3-triazol-1-yl)-4,4-dimethylcyclohexanone (6c). Reaction time: 120 h; Yield: 14.6 mg (21%), as light brown solid; MP: 162.0−163.5 °C; 1H NMR (400 MHz, CDCl3): δ 8.17 (s, 1H), 8.11 (dd, J = 1.2, 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.20 (dt, J = 1.6, 7.6 Hz, 1H), 4.63 (dt, J = 5.2, 10.4 Hz, 1H), 3.22 (dd, J = 10.4, 15.6 Hz, 1H), 2.87 (dd, J = 5.2, 15.6 Hz, 1H), 2.66−2.56 (m, 1H), 2.49 (dt, J = 4.8, 16.8 Hz, 1H), 1.97 (dt, J = 5.6, 14.0 Hz, 1H), 1.77−1.69 (m, 1H), 1.15 (s, CH3, 3H), 1.10 (s, CH3, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.7, 144.6, 133.6, 131.2, 130.7, 129.5, 127.9, 123.4, 121.3, 66.8, 43.2, 37.5, 35.9, 35.2, 27.6, 21.5 ppm; HRMS (ESI+): m/z calcd for C16H18BrN3NaO (M + Na)+ 370.0525, found: 370.0512. 800


Article


1.12 (s, CH3, 3H), 1.07 (s, CH3, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.8, 149.0, 146.9, 127.8, 126.9, 126.8, 125.6, 119.4, 66.6, 43.0, 37.3, 35.6, 34.8, 33.8, 27.4, 23.8, 21.4 ppm; HRMS (ESI+): m/z calcd for C19H25N3NaO (M + Na)+ 334.1889, found: 334.1887. (3S)-4,4-Dimethyl-3-(4-(3-nitrophenyl)-2H-1,2,3-triazol-2-yl)cyclohexanone (5g). Reaction time: 120 h; Yield: 36.5 mg (58%), as yellow viscous liquid; [α]25 D +7.8 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 2964, 2346, 1633, 1548, 1415, 1351, 1086, 1012, 616, 547; 1 H NMR (400 MHz, CDCl3): δ 8.58 (t, J = 1.6 Hz, 1H), 8.18 (dd, J = 1.2, 8.0 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 4.80 (dd, J = 5.6, 7.2 Hz, 1H), 3.06 (dd, J = 7.6, 15.6 Hz, 1H), 2.87 (dd, J = 5.2, 15.6 Hz, 1H), 2.65−2.46 (m, 2H), 2.06 (sept, J = 6.8 Hz, 1H), 1.72−1.65 (m, 1H), 1.22 (s, CH3, 3H), 0.98 (s, CH3, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.4, 148.6, 145.0, 132.0, 131.6, 130.9, 129.9, 122.9, 120.6, 70.8, 42.7, 37.3, 35.0, 34.8, 26.8, 23.3 ppm; HRMS (ESI+): m/z calcd for C16H18N4NaO3 (M + Na)+ 337.1271, found: 337.1271. 4,4-Dimethyl-3-(4-(3-nitrophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanone (6g). Reaction time: 120 h; Yield: 11.9 mg (19%), as brown solid; MP: 121.5−123.0 °C; 1H NMR (400 MHz, CDCl3): δ 8.59 (t, J = 2.0 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.18 (dd, J = 1.6, 8.0 Hz, 1H), 7.89 (s, 1H), 7.62 (t, J = 8.0 Hz, 1H), 4.66 (dd, J = 5.2, 10.0 Hz, 1H), 3.20 (dd, J = 10.0, 15.6 Hz, 1H), 2.87 (dd, J = 4.8, 15.2 Hz, 1H), 2.67− 2.58 (m, 1H), 2.51 (dt, J = 5.6, 16.0 Hz, 1H), 1.99 (dt, J = 6.0, 14.0 Hz, 1H), 1.79−1.71 (m, 1H), 1.17 (s, CH3, 3H), 1.10 (s, CH3, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.6, 148.5, 144.8, 132.1, 131.5, 130.0, 122.8, 120.7, 120.4, 67.1, 43.0, 37.3, 35.6, 34.9, 27.4, 21.6 ppm; HRMS (ESI+): m/z calcd for C16H18N4NaO3 (M + Na)+ 337.1271, found: 337.1270. (3S)-3-(4-(2,5-Dimethoxyphenyl)-2H-1,2,3-triazol-2-yl)-4,4-dimethylcyclohexanone (5h). Reaction time: 108 h; Yield: 41.5 mg (63%), as pale yellow viscous liquid; [α]25 D +5.8 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 2924, 2856, 2358, 1716, 1638, 1542, 1480, 1362, 1315, 1262, 1222, 1153, 1039, 864, 797, 730, 609, 467; 1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 7.54 (d, J = 3.2 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.86 (dd, J = 2.8, 8.8 Hz, 1H), 4.77 (t, J = 6.8 Hz, 1H), 3.88 (s, OCH3, 3H), 3.83 (s, OCH3, 3H), 3.07 (dd, J = 7.6, 15.6 Hz, 1H), 2.84 (dd, J = 5.2, 16.0 Hz, 1H), 2.63−2.44 (m, 2H), 2.09−2.02 (m, 1H), 1.69−1.62 (m, 1H), 1.20 (s, CH3, 3H), 0.98 (s, CH3, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.7, 153.7, 151.0, 143.6, 134.0, 119.9, 114.7, 113.3, 112.5, 70.2, 56.0, 55.8, 42.9, 37.4, 35.1, 35.0, 26.9, 23.3 ppm; HRMS (ESI+): m/z calcd for C18H23N3NaO3 (M + Na)+ 352.1631, found: 352.1631. 3-(4-(2,5-Dimethoxyphenyl)-1H-1,2,3-triazol-1-yl)-4,4-dimethylcyclohexanone (6h). Reaction time: 108 h; Yield: 12.5 mg (19%), as white solid; MP: 135.2−136.8 °C; 1H NMR (400 MHz, CDCl3): δ 7.99 (s, 1H), 7.92 (d, J = 3.2 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.85 (dd, J = 2.8, 8.8 Hz, 1H), 4.58 (dd, J = 4.8, 10.0 Hz, 1H), 3.87 (s, OCH3, 3H), 3.84 (s, OCH3, 3H), 3.19 (dd, J = 10.0, 15.6 Hz, 1H), 2.83 (dd, J = 4.8, 15.6 Hz, 1H), 2.64−2.55 (m, 1H), 2.46 (dt, J = 5.6, 16.0 Hz, 1H), 1.97 (dt, J = 6.0, 14.0 Hz, 1H), 1.74−1.67 (m, 1H), 1.13 (s, CH3, 3H), 1.08 (s, CH3, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.8, 153.9, 150.0, 142.2, 123.4, 119.7, 115.2, 112.2, 111.6, 66.4, 55.9, 55.8, 43.1, 37.3, 35.8, 34.9, 27.4, 21.5 ppm; HRMS (ESI+): m/z calcd for C18H23N3NaO3 (M + Na)+ 352.1631, found: 352.1632. (3S)-3-(4-(3,4-Dimethoxyphenyl)-2H-1,2,3-triazol-2-yl)-4,4-dimethylcyclohexanone (5i). Reaction time: 108 h; Yield: 41.5 mg (63%), as pale yellow solid; MP: 135.136.5 °C; [α]25 D +12.3 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 3129, 2956, 2856, 2028, 1711, 1635, 1546, 1494, 1448, 1395, 1316, 1256, 1183, 1133, 1026, 869, 809, 761, 706, 627, 559; 1H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.30−7.28 (m, 2H), 6.91 (d, J = 8.8 Hz, 1H), 4.75 (q, J = 6.0 Hz, 1H), 3.96 (s, OCH3, 3H), 3.91 (s, OCH3, 3H), 3.06 (dd, J = 7.6, 16.0 Hz, 1H), 2.85 (dd, J = 5.2, 16.0 Hz, 1H), 2.63−2.44 (m, 2H), 2.10− 2.03 (m, 1H), 1.70−1.63 (m, 1H), 1.21 (s, CH3, 3H), 0.99 (s, CH3, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.8, 149.2, 149.2, 147.0, 130.1, 123.2, 118.4, 111.2, 108.8, 70.3, 55.9, 42.8, 37.3, 35.0, 34.9, 26.9, 23.4 ppm; HRMS (ESI+): m/z calcd for C18H23N3NaO3 (M + Na)+ 352.1631, found: 352.1631.

(3S)-3-(4-(2-Chlorophenyl)-2H-1,2,3-triazol-2-yl)-4,4-dimethylcyclohexanone (5d). Reaction time: 108 h; Yield: 39.5 mg (65%), as white solid; MP: 86.5−88.5 °C; [α]25 D +6.1 (c 0.10, CH3CN); IR (KBr thin film, cm−1): νmax 2961, 2872, 2363, 2091, 1712, 1639, 1557, 1639, 1557, 1458, 1416, 1367, 1306, 1203, 1139, 1049, 992, 855, 761, 662, 609, 500, 473; 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 7.81 (dd, J = 1.6, 7.6 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.33−7.26 (m, 2H), 4.80 (t, J = 6.4 Hz, 1H), 3.05 (dd, J = 7.2, 16.0 Hz, 1H), 2.87 (dd, J = 5.6, 16.0 Hz, 1H), 2.63−2.44 (m, 2H), 2.07 (sept, J = 6.8 Hz, 1H), 1.66 (quint, J = 6.4 Hz, 1H), 1.22 (s, CH3, 3H), 0.97 (s, CH3, 3H) ppm; 13 C NMR (100 MHz, CDCl3): δ 207.6, 144.4, 133.6, 132.0, 130.3, 130.3, 129.3, 129.1, 127.0, 70.5, 42.7, 37.3, 35.0, 34.8, 26.8, 23.5 ppm; HRMS (ESI+): m/z calcd for C16H18ClN3NaO (M + Na)+ 326.1030, found: 326.1030. 3-(4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)-4,4-dimethylcyclohexanone (6d). Reaction time: 108 h; Yield: 11.6 mg (19%), as white solid; MP: 165.5−167.0 °C; 1H NMR (400 MHz, CDCl3): δ 8.24 (dd, J = 1.6, 7.6 Hz, 1H), 8.13 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.28 (dd, J = 1.2, 7.6 Hz, 1H), 4.62 (dd, J = 4.2, 10.0 Hz, 1H), 3.23 (dd, J = 10.4, 15.6 Hz, 1H), 2.86 (dd, J = 4.8, 15.6 Hz, 1H), 2.66−2.56 (m, 1H), 2.48 (dt, J = 6.4, 16.4 Hz, 1H), 1.97 (dt, J = 6.0, 14.0 Hz, 1H), 1.77−1.69 (m, 1H), 1.15 (s, CH3, 3H), 1.10 (s, CH3, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.6, 143.1, 131.1, 130.1, 129.8, 129.1, 129.0, 127.2, 123.5, 66.7, 43.1, 37.3, 35.8, 35.0, 27.5, 21.4 ppm; HRMS (ESI+): m/z calcd for C16H18ClN3NaO (M + Na)+ 326.1030, found: 326.1031. (3S)-3-(4-(4-Chlorophenyl)-2H-1,2,3-triazol-2-yl)-4,4-dimethylcyclohexanone (5e). Reaction time: 108 h; Yield: 37.7 mg (62%), as yellow viscous liquid; [α]25 D +6.7 (c 0.10, CH3CN); IR (KBr thin film, cm−1): νmax 2925, 2859, 2087, 1718, 1638, 1544, 1462, 1375, 1318, 1159, 1095, 1020, 979, 820, 717, 620, 516; 1H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.77 (t, J = 6.4 Hz, 1H), 3.03 (dd, J = 7.6, 16.0 Hz, 1H), 2.85 (dd, J = 5.6, 16.0 Hz, 1H), 2.64−2.44 (m, 2H), 2.09−2.02 (m, 1H), 1.67 (quint, J = 6.8 Hz, 1H), 1.21 (s, CH3, 3H), 0.97 (s, CH3, 3H) ppm; 13 C NMR (100 MHz, CDCl3): δ 207.6, 146.2, 134.2, 130.4, 129.0, 128.8, 127.1, 70.6, 42.8, 37.3, 35.0, 34.8, 26.8, 23.5 ppm; HRMS (ESI +): m/z calcd for C16H18ClN3NaO (M + Na)+ 326.1030, found: 326.1030. 3-(4-(4-Chlorophenyl)-1H-1,2,3-triazol-1-yl)-4,4-dimethylcyclohexanone (6e). Reaction time: 108 h; Yield: 10.9 mg (18%), as white solid; MP: 161.0−162.5 °C. 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.4 Hz, 2H), 7.68 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 4.60 (dd, J = 5.2, 10.0 Hz, 1H), 3.17 (dd, J = 10.0, 15.6 Hz, 1H), 2.84 (dd, J = 5.2, 15.6 Hz, 1H), 2.65−2.56 (m, 1H), 2.49 (dt, J = 5.2, 16.0 Hz, 1H), 1.97 (dt, J = 6.0, 14.0 Hz, 1H), 1.76−1.69 (m, 1H), 1.15 (s, CH3, 3H), 1.08 (s, CH3, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.7, 145.9, 133.9, 129.0, 128.8, 126.9, 119.8, 66.8, 43.1, 37.3, 35.7, 34.9, 27.4, 21.5 ppm; HRMS (ESI+): m/z calcd for C16H18ClN3NaO (M + Na)+ 326.1030, found: 326.1028. (3S)-3-(4-(4-Isopropylphenyl)-2H-1,2,3-triazol-2-yl)-4,4-dimethylcyclohexanone (5f). Reaction time: 108 h; Yield: 41.1 mg (66%), as white solid; MP: 102.6−103.5 °C; [α]25 D +16.1 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 2955, 2858, 2104, 1636, 1554, 1474, 1412, 1306, 1239, 1095, 1027, 603, 550; 1H NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.76 (t, J = 6.8 Hz, 1H), 3.06 (dd, J = 7.2, 16.0 Hz, 1H), 2.93 (quint, J = 6.8 Hz, 1H), 2.85 (dd, J = 5.6, 16.0 Hz, 1H), 2.63−2.44 (m, 2H), 2.10− 2.03 (m, 1H), 1.66 (quint, J = 6.8 Hz, 1H), 1.27 (d, J = 6.8 Hz, 6H, 2CH3), 1.21 (s, CH3, 3H), 0.97 (s, CH3, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 207.7, 149.4, 147.2, 130.3, 127.9, 126.9, 125.9, 70.3, 42.8, 37.3, 35.0, 34.9, 33.9, 26.9, 23.9, 23.4 ppm; HRMS (ESI+): m/z calcd for C19H25N3NaO (M + Na)+ 334.1889, found: 334.1888. 3-(4-(4-Isopropylphenyl)-1H-1,2,3-triazol-1-yl)-4,4-dimethylcyclohexanone (6f). Reaction time: 108 h; Yield: 16.8 mg (27%); 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 4.60 (dd, J = 5.2, 10.0 Hz, 1H), 3.17 (dd, J = 10.0, 15.6 Hz, 1H), 2.92 (quint, J = 6.8 Hz, 1H), 2.83 (dd, J = 4.8, 15.6 Hz, 1H), 2.63−2.54 (m, 1H), 2.47 (dt, J = 5.2, 16.0 Hz, 1H), 1.95 (dt, J = 5.6, 14.4 Hz, 1H), 1.74−1.67 (m, 1H), 1.27 (d, J = 7.2 Hz, 6H, 2CH3), 801


Article

The Journal of Organic Chemistry 3-(4-(3,4-Dimethoxyphenyl)-1H-1,2,3-triazol-1-yl)-4,4-dimethylcyclohexanone (6i). Reaction time: 108 h; Yield: 13.2 mg (20%); 1H NMR (400 MHz, CDCl3): δ 7.62 (s, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.29−7.26 (m, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.60 (dd, J = 5.2, 10.0 Hz, 1H), 3.96 (s, OCH3, 3H), 3.92 (s, OCH3, 3H), 3.18 (dd, J = 10.0, 15.2 Hz, 1H), 2.85 (dd, J = 5.2, 15.6 Hz, 1H), 2.65−2.57 (m, 1H), 2.50 (dt, J = 5.6, 16.0 Hz, 1H), 2.03−1.96 (m, 1H), 1.77−1.70 (m, 1H), 1.15 (s, CH3, 3H), 1.10 (s, CH3, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 206.9, 157.9, 149.3, 123.2, 119.0, 118.6, 118.1, 111.2, 108.8, 66.7, 55.9, 43.1, 37.3, 35.8, 34.9, 27.5, 21.5 ppm; HRMS (ESI+): m/z calcd for C18H23N3NaO3 (M + Na)+ 352.1631, found: 352.1629. (3R)-3-(4-Phenyl-2H-1,2,3-triazol-2-yl)cyclopentanone (7a). Reaction time: 108 h; Yield: 30.5 mg (67%), as white solid; MP: 62.0−63.5 −1 °C; [α]25 D −25.7 (c 0.05, CH3CN); IR (KBr thin film, cm ): νmax 3123, 2978, 2928, 2340, 2094, 1745, 1638, 1555, 1467, 1412, 1365, 1307, 1242, 1154, 1092, 983, 768, 688, 606, 515; 1H NMR (400 MHz, CDCl3): δ 7.85 (s, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.2 Hz, 2H), 7.37−7.33 (m, 1H), 5.41−5.35 (m, 1H), 3.00 (dd, J = 4.8, 18.8 Hz, 1H), 2.81 (dd, J = 7.6, 18.8 Hz, 1H), 2.66−2.56 (m, 3H), 2.42− 2.32 (m, 1H), ppm; 13C NMR (100 MHz, CDCl3): δ 214.9, 147.9, 131.0, 130.1, 128.9, 128.5, 125.8, 61.8, 44.3, 36.2, 29.8 ppm; HRMS (ESI+): m/z calcd for C13H13N3NaO (M + Na)+ 250.0950, found: 250.0950. 3-(4-Phenyl-1H-1,2,3-triazol-1-yl)cyclopentanone (8a). Reaction time: 108 h; Yield: 7.3 mg (16%), as pale yellow viscous liquid; 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.81 (d, J = 7.6 Hz, 2H), 7.43 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 5.25 (quint, J = 6.4 Hz, 1H), 2.91 (d, J = 7.2 Hz, 2H), 2.72−2.62 (m, 2H), 2.60−2.52 (m, 1H), 2.46−2.37 (m, 1H) ppm; HRMS (ESI+): m/z calcd for C13H13N3NaO (M + Na)+ 250.0950, found: 250.0952. (3R)-3-(4-(3-Methoxyphenyl)-2H-1,2,3-triazol-2-yl)cyclopentanone (7b). Reaction time: 120 h; Yield: 34.0 mg (66%), as brown viscous liquid; [α]25 D −26.2 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 2946, 2838, 2401, 2089, 1746, 1625, 1478, 1413, 1245, 1159, 1095, 1044, 1000, 847, 785, 688, 570; 1H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.34−7.31 (m, 3H), 6.91−6.88 (m, 1H), 5.39−5.33 (m, 1H), 3.85 (s, OCH3, 3H), 2.99 (dd, J = 4.8, 18.4 Hz, 1H), 2.79 (dd, J = 7.6, 18.4 Hz, 1H), 2.64−2.54 (m, 3H), 2.40−2.31 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 215.0, 159.9, 147.7, 131.3, 131.1, 129.9, 118.2, 114.2, 111.1, 61.7, 55.3, 44.2, 36.2, 29.8 ppm; HRMS (ESI+): m/z calcd for C14H15N3NaO2 (M + Na)+ 280.1056, found: 280.1056. (3R)-3-(4-(4-Methoxyphenyl)-2H-1,2,3-triazol-2-yl)cyclopentanone (7c). Reaction time: 108 h; Yield: 36.5 mg (71%), as white solid; MP: 93.0−94.0 °C; [α]25 D −39.3 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 2964, 2867, 2369, 2100, 1705, 1639, 1554, 1470, 1418, 1368, 1310, 1221, 1174, 1096, 977, 880, 828, 615, 556, 509; 1H NMR (400 MHz, CDCl3): δ 7.77 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.38−5.32 (m, 1H), 3.84 (s, 3H, OCH3), 2.99 (dd, J = 4.8, 18.8 Hz, 1H), 2.79 (dd, J = 7.6, 18.8 Hz, 1H), 2.67− 2.54 (m, 3H), 2.39−2.33 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 215.0, 159.9, 147.8, 130.5, 127.2, 122.8, 114.3, 61.7, 55.3, 44.3, 36.2, 29.8 ppm; HRMS (ESI+): m/z calcd for C14H15N3NaO2 (M + Na)+ 280.1056, found: 280.1050. 3-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)cyclopentanone (8c). Reaction time: 108 h; Yield: 10.3 mg (20%); 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H), 6.96 (d, J = 8.4 Hz, 2H), 5.23 (quint, J = 6.4 Hz, 1H), 3.84 (s, 3H, OCH3), 2.91 (d, J = 6.4 Hz, 2H), 2.71−2.63 (m, 2H), 2.60−2.52 (m, 1H), 2.47−2.37 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 213.5, 159.7, 147.9, 127.0, 122.9, 117.6, 122.8, 114.3, 57.7, 55.3, 44.6, 36.6, 30.3 ppm; HRMS (ESI+): m/z calcd for C14H15N3NaO2 (M + Na)+ 280.1056, found: 280.1055. (3R)-3-(4-(4-Isopropylphenyl)-2H-1,2,3-triazol-2-yl)cyclopentanone (7d). Reaction time: 108 h; Yield: 36.6 mg (68%), as white solid; MP: 111.2−112.5 °C; [α]25 D −23.8 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 2964, 2098, 1741, 1640, 1551, 1477, 1413, 1304, 1236, 1159, 1094, 986, 891, 835, 712, 662, 606, 562; 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 5.39−5.33 (m, 1H), 2.99 (dd, J = 4.8, 18.8 Hz, 1H), 2.95−

2.88 (m, 1H), 2.79 (dd, J = 7.6, 18.8 Hz, 1H), 2.64−2.53 (m, 3H), 2.40−2.31 (m, 1H), 1.26 (d, J = 7.2 Hz, 6H, 2CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 215.0, 149.4, 147.9, 130.8, 127.6, 126.9, 125.8, 61.7, 44.2, 36.2, 33.9, 29.8, 23.8 ppm; HRMS (ESI+): m/z calcd for C16H19N3NaO (M + Na)+ 292.1420, found: 292.1416. 3-(4-(4-Isopropylphenyl)-1H-1,2,3-triazol-1-yl)cyclopentanone (8d). Reaction time: 108 h; Yield: 11.8 mg (22%), as white solid; 1H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.24 (quint, J = 8.0 Hz, 1H), 2.99−2.88 (m, 3H), 2.71−2.62 (m, 2H), 2.59−2.51 (m, 1H), 2.46−2.36 (m, 1H), 1.27 (d, J = 6.8 Hz, 6H, 2CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 213.4, 149.2, 148.1, 127.8, 126.9, 125.7, 118.1, 57.7, 44.6, 36.6, 33.9, 30.3, 23.9 ppm; HRMS (ESI+): m/z calcd for C16H19N3NaO (M + Na)+ 292.1420, found: 292.1428. (3R)-3-(4-(2-Chlorophenyl)-2H-1,2,3-triazol-2-yl)cyclopentanone (7e). Reaction time: 120 h; Yield: 36.1 mg (69%), as brown viscous −1 liquid; [α]25 D −23.0 (c 0.01, CH3CN); IR (KBr thin film, cm ): νmax 2966, 2928, 2857, 2362, 2094, 1747, 1637, 1553, 1456, 1399, 1311, 1255, 1150, 1053, 987, 901, 763, 658, 606, 458; 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 7.83 (dd, J = 2.0, 7.2 Hz, 1H), 7.46 (dd, J = 1.6, 7.6 Hz, 1H), 7.32−7.27 (m, 2H), 5.43−5.37 (m, 1H), 3.00 (dd, J = 4.8, 18.4 Hz, 1H), 2.81 (dd, J = 7.6, 18.8 Hz, 1H), 2.68−2.56 (m, 3H), 2.41−2.34 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 214.8, 145.0, 134.2, 131.9, 130.3, 130.2, 129.4, 128.9, 127.0, 61.8, 44.2, 36.1, 29.8 ppm; HRMS (ESI+): m/z calcd for C13H12ClN3NaO (M + Na)+ 284.0561, found: 284.0563. 3-(4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)cyclopentanone (8e). Reaction time: 120 h; Yield: 9.4 mg (18%), as brown viscous liquid; 1 H NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 8.23 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 5.27 (quint, J = 6.4 Hz, 1H), 2.95−2.92 (m, 2H), 2.73−2.65 (m, 2H), 2.62−2.54 (m, 1H), 2.47−2.37 (m, 1H) ppm; HRMS (ESI+): m/z calcd for C13H12ClN3NaO (M + Na)+ 284.0561, found: 284.0567. (3R)-3-(4-(4-Chlorophenyl)-2H-1,2,3-triazol-2-yl)cyclopentanone (7f). Reaction time: 108 h; Yield: 36.6 mg (70%), as white solid; MP: 99.0−100.5 °C; [α]25 D −23.3 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 2966, 2928, 2857, 2362, 2094, 1747, 1637, 1553, 1456, 1399, 1311, 1256, 1151, 1053, 987, 901, 763, 658, 606, 458; 1H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 5.40−5.34 (m, 1H), 2.98 (dd, J = 4.8, 18.8 Hz, 1H), 2.80 (dd, J = 7.6, 18.8 Hz, 1H), 2.64−2.55 (m, 3H), 2.40−2.34 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 214.8, 146.8, 134.3, 130.9, 129.1, 128.6, 127.1, 61.8, 44.2, 36.1, 29.8 ppm; HRMS (ESI+): m/z calcd for C13H12ClN3NaO (M + Na)+ 284.0561, found: 284.0561. 3-(4-(4-Chlorophenyl)-1H-1,2,3-triazol-1-yl)cyclopentanone (8f). Reaction time: 108 h; Yield: 10.5 mg (20%), as white solid; MP: 135.0−137.0 °C; 1H NMR (400 MHz, CDCl3): δ 7.80 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.24 (quint, J = 6.8 Hz, 1H), 2.91 (d, J = 7.2 Hz, 2H), 2.71−2.62 (m, 2H), 2.60−2.50 (m, 1H), 2.48−2.37 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 213.2, 147.0, 134.1, 129.0, 128.7, 126.9, 118.6, 57.9, 44.5, 36.5, 30.3 ppm; HRMS (ESI+): m/z calcd for C13H12ClN3NaO (M + Na)+ 284.0561, found: 284.0589. (3R)-3-(4-(2,5-Dimethoxyphenyl)-2H-1,2,3-triazol-2-yl)cyclopentanone (7g). Reaction time: 108 h; Yield: 43.1 mg (75%), as creamy white solid; MP: 85.5−86.9 °C; [α]25 D −25.1 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 2939, 2837, 2352, 2072, 1742, 1637, 1548, 1496, 1436, 1360, 1313, 1223, 1160, 1044, 992, 900, 853, 735, 594; 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.52 (d, J = 3.2 Hz, 1H), 6.92−6.84 (m, 2H), 5.40−5.34 (m, 1H), 3.87 (s, OCH3, 3H), 3.82 (s, OCH3, 3H), 3.00 (dd, J = 4.8, 18.8 Hz, 1H), 2.79 (dd, J = 7.6, 18.8 Hz, 1H), 2.66−2.53 (m, 3H), 2.38−2.31 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 215.1, 153.7, 150.9, 144.2, 134.5, 119.6, 114.9, 112.9, 112.5, 61.6, 56.0, 55.8, 44.2, 36.2, 29.8 ppm; HRMS (ESI+): m/z calcd for C15H17N3NaO3 (M + Na)+ 310.1162, found: 310.1162. 3-(4-(2,5-Dimethoxyphenyl)-1H-1,2,3-triazol-1-yl)cyclopentanone (8g). Reaction time: 108 h; Yield: 10.4 mg (18%), as brown solid; MP: 127.0−128.0 °C; 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.91 (d, J = 2.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 2.8, 9.2 Hz, 1H), 5.24 (quint, J = 6.4 Hz, 1H), 3.90 (s, OCH3, 3H), 802



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3.85 (s, OCH3, 3H), 2.92 (t, J = 5.6 Hz, 2H), 2.72−2.62 (m, 2H), 2.60−2.52 (m, 1H), 2.45−2.36 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 213.6, 153.9, 150.0, 143.2, 122.1, 119.6, 112.2, 111.8, 57.6, 55.9, 55.8, 44.6, 36.6, 30.3 ppm; HRMS (ESI+): m/z calcd for C15H17N3NaO3 (M + Na)+ 310.1162, found: 310.1163. (3R)-3-(4-(3,4-Dimethoxyphenyl)-2H-1,2,3-triazol-2-yl)cyclopentanone (7h). Reaction time: 108 h; Yield: 43.1 mg (75%), as white solid; MP: 102.0−103.0 °C; [α]25 D −29.3 (c 0.10, CH3CN); IR (KBr thin film, cm−1): νmax 2923, 2837, 2356, 1736, 1639, 1554, 1498, 1417, 1365, 1312, 1248, 1151, 1016, 762, 659, 609, 508; 1H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.29−7.26 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 5.36−5.31 (m, 1H), 3.93 (s, OCH3, 3H), 3.87 (s, OCH3, 3H), 2.97 (dd, J = 4.8, 18.8 Hz, 1H), 2.77 (dd, J = 7.6, 18.4 Hz, 1H), 2.64− 2.52 (m, 3H), 2.37−2.31 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 215.0, 149.2, 149.1, 147.7, 130.5, 122.9, 118.4, 111.1, 108.7, 61.6, 55.8, 55.8, 44.1, 36.1, 29.7 ppm; HRMS (ESI+): m/z calcd for C15H17N3NaO3 (M + Na)+ 310.1162, found: 310.1152. 3-(4-(3,4-Dimethoxyphenyl)-1H-1,2,3-triazol-1-yl)cyclopentanone (8h). Reaction time: 108 h; Yield: 11.5 mg (20%). 1H NMR (400 MHz, CDCl3): δ 7.74 (s, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.27 (dd, J = 1.2, 7.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.24 (quint, J = 6.4 Hz, 1H), 3.95 (s, OCH3, 3H), 3.91 (s, OCH3, 3H), 2.91 (d, J = 6.8 Hz, 2H), 2.71−2.62 (m, 2H), 2.59−2.51 (m, 1H), 2.46−2.35 (m, 1H) ppm; HRMS (ESI+): m/z calcd for C15H17N3NaO3 (M + Na)+ 310.1162, found: 310.1153. (3R)-3-(4-(2-Bromophenyl)-2H-1,2,3-triazol-2-yl)cyclopentanone (7i). Reaction time: 108 h; Yield: 39.2 mg (64%); [α]25 D −19.1 (c 0.05, CH3CN); IR (KBr thin film, cm−1): νmax 2981, 2051, 1746, 1637, 1548, 1452, 1396, 1311, 1250, 1152, 1034, 977, 902, 847, 765, 712, 644; 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.71 (dd, J = 1.6, 8.0 Hz, 1H), 7.65 (dd, J = 1.2, 8.0 Hz, 1H), 7.36 (td, J = 1.2, 7.6 Hz, 1H), 7.21 (td, J = 1.6, 7.6 Hz, 1H), 5.42 (m, 1H), 3.00 (dd, J = 4.8, 18.8 Hz, 1H), 2.81 (dd, J = 7.6, 18.4 Hz, 1H), 2.68−2.56 (m, 3H), 2.40−2.34 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 214.9, 146.3, 134.0, 133.6, 131.0, 130.7, 129.7, 127.5, 121.6, 61.8, 44.2, 36.1, 29.8 ppm; HRMS (ESI+): m/z calcd for C13H12BrN3NaO (M + Na)+ 328.0056, found: 328.0055. 3-(4-(2-Bromophenyl)-1H-1,2,3-triazol-1-yl)cyclopentanone (8i). Reaction time: 108 h; Yield: 13.5 mg (22%). 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 8.11 (dd, J = 1.6, 7.6 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.21 (td, J = 1.6, 7.6 Hz, 1H), 5.27 (quint, J = 6.4 Hz, 1H), 2.95−2.93 (m, 2H), 2.74−2.65 (m, 2H), 2.63−2.55 (m, 1H), 2.49−2.38 (m, 1H) ppm; HRMS (ESI+): m/z calcd for C13H12BrN3NaO (M + Na)+ 328.0056, found: 328.0056.

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ACKNOWLEDGMENTS This work was supported by SERB for financial support and DST-FIST program (HRMS facility), and U.K.B. gratefully thanks MHRD, New Delhi, India. for providing a research fellowship.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02793. Tables of HPLC analysis, copies of 1H and 13C NMR spectra for new products, and ORTEP diagram for product 3g (PDF) HPLC chromatograms (PDF) Crystallographic data for 3g (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], [email protected]. ORCID

Ujjawal Kumar Bhagat: 0000-0002-4879-7691 Rama Krishna Peddinti: 0000-0001-7340-1516 Notes

The authors declare no competing financial interest. 803


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Asymmetric Organocatalytic Approach to 2,4-Disubstituted 1,2,3

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