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410083, PR China. J. Org. Chem. , 2017, 82 (18), pp 9837–9843. DOI: 10.1021/acs.joc.7b01339. Publication Date (Web): August 17, 2017. Copyright ...
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Selectfluor-Triggered Tandem Cyclization of o‑Hydroxyarylenaminones To Access Difluorinated 2‑AminoSubstituted Chromanones Qinglan Zhao, Haoyue Xiang,* Jun-An Xiao, Peng-Ju Xia, Jun-Jie Wang, Xiaoqing Chen,* and Hua Yang* College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China S Supporting Information *

ABSTRACT: A practical and straightforward synthetic route through a Selectfluor-triggered tandem cyclization of ohydroxyarylenaminone was developed to construct a variety of difluorinated 2-amino-substituted chromanones. This novel protocol features mild reaction conditions, operational simplicity, and broad substrate scope. The enamine moiety in o-hydroxyarylenaminone played dual roles to enable high efficiency in the difluorination and intramolecular cyclization, leading to the accomplishment of a new class of difluorinated 2amino-substituted chromanones for pharmaceutical studies.

C

structure of chromanone,5 which would be certainly conducive to bioactive studies on this type of important biological scaffold. As well-known, fluorine or fluorinated group is widely present in many pharmaceuticals, biologically active natural products and agrochemicals.6 Among all the fluorinated moieties, CF2 group is usually regarded as a bioisostere for oxygen or carbonyl group, causing evident changes in dipole moments, acidity of the neighboring group, and conformation.7 Consequently, a variety of synthetic methods have been developed for introducing CF2 groups.8 Unfortunately, few success was achieved for difluoro-engineered chromanones, which might possess interesting biological profiles and essentially remains elusive at this stage. To date, rare examples have been reported by employing the difluorination of chromone or chromanone to give difluoro-engineered chromanones in disappointingly low yields,9 in which multiple synthetic steps were usually requisite (Figure 1, bottom). In 2005, Shreeze developed an effective method to prepare difluorinated carbonyl compounds in high yields10 by virtue of the corresponding enamines via difluorination with Selectfluor. Hinted by this interesting finding and driven by our continued and keen interest in the bioactive fluorinated heterocycles,11 we came up with an innovative strategy by intentionally merging the difluorination and cyclization of enamine, which was expected to circumvent the hurdle of low efficacy in the difluoroination of chromone. The fundamental rationale of this strategy is illustrated in Scheme 1. Prominently, the presence of enamine moiety in o-hydroxyarylenaminone 1 is pivotal for the success in the tandem reaction sequence as it is able to enhance the nucleophilicity of CC and thus promote the α-

hromanones are privileged structural motifs in numerous natural products and pharmaceuticals that possess a broad array of physiological and biological activities, such as antitumor, antioxidant, antibacterial, and anti-inflammatory properties (Figure 1).1 The preparation of functionalized

Figure 1. Representative compounds containing chromanone core as well as synthetic route for difluorinated analogue.

chromanones has received considerable synthetic attention over the last few decades.2 Primarily, 2-substituted chromanones were synthesized by starting from o-hydroxyacetophenone via a chalocone precursor followed by cyclization to form the pyranone ring.3 Alternatively, a conjugate addition to the preformed chromones offered another pathway.4 At this stage, novel synthetic routes are still persistently desired to enable the facile manipulation of substitution patterns on the core © 2017 American Chemical Society

Received: May 31, 2017 Published: August 17, 2017 9837

DOI: 10.1021/acs.joc.7b01339 J. Org. Chem. 2017, 82, 9837−9843

Note

The Journal of Organic Chemistry Table 1. Investigation of Reaction Conditionsa

Scheme 1. Accessing Difluorinated 2-Amino-Substitued Chromanones from o-Hydroxyarylenaminones

fluorination of ketone by Selectfluor.10 It is predictable that the first round of fluorination delivers the corresponding iminium ion IT-I, which immediately tautomerize to yield an enamine IT-II in the presence of the base. In a similar manner, the following fluorination of the enamine can furnish the difluorinated iminium intermediate IT-III. Conceivably, the resulting reactive iminium ion would significantly drive the intramolecular cyclization to rapidly accomplish the difluorinated chromanones. Noticeably, the amino group as effective activator would ultimately remain intact to result in forming 2amino-substituted chromanones, which were scarcely documented in the literature.12 In fact, chemical and physical properties of heterocycles could be readily altered upon introduction of amino group, which is beneficial for the discovery of drugs and further structural modifications.13 This designed tandem reaction system might offer an facile entry to 2-amino-substituted chromanones. Herein, we disclose our investigation results on the synthetic pathway to difluorinated 2-amino-substituted chromanones with Selectfluor under mild reaction conditions. We commenced our tests with the reaction of (E)-3(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one (1a) with Selectfluor (2) (3 equiv) (Table 1). A series of inorganic and organic bases (2 equiv) were first examined using acetone as the solvent. Pleasingly, the desired difluorinated 2-aminosubstituted chromanone 3a was successfully obtained at room temperature and NaOAc was found to give the highest yield (Table 1, entries 1−7). N-Fluorobenzenesulfonimide (NSFI) was also employed in the reaction, but gave a relatively lower yield (Table 1, entry 8). Modifying the equivalence of NaOAc consistently sabotaged the yield of 3a (Table 1, entries 9−10). Afterward, the amount of Selectfluor was taken into consideration (Table 1, entries 11−12). The yield of the desired product was unable to be improved with 4 equiv of Selectfluor, and was obviously reduced with the decreased amount of Selectfluor. Subsequently, various solvents were screened and acetone was found to be the optimal choice (Table 1, entries 13−18). Finally, the structure of compound 3a was confirmed by X-ray analysis of single crystal.14 To evaluate the substrate scope of this approach, various (E)3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-ones were subjected to the optimized reaction conditions. As summarized in Scheme 2, the substitution patterns on the phenyl moiety were first modulated and evaluated, which were generally tolerated well in the reaction. Specifically, for the substituent at para-position of phenol groups in substrate, the presence of methoxy group evidently undermined the yield (Scheme 2, 3b and 3h) while other substituents consistently provided

entry

solvent

base

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone acetone CH2Cl2 toluene CH3OH DMF CH3CN H2O

none Na2CO3 DMAP KH2PO4 Me3N DBU NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc

trace 32 41 trace 30 27 61 43c 46d 38e 33f 62g 29 trace 8 23 nrh nr

a

Reaction conditions: 1a (0.4 mmol), Selectfluor (2) (1.2 mmol, 3 equiv), and base (0.8 mmol, 2 equiv) in solvent (2.0 mL) at room temperature for 1 h. bIsolated yields. cNSFI was used instead of Selectfluor. d1 equiv of NaOAc used. e4 equiv of NaOAc used. f2 equiv of Selectfluor used. g4 equiv of Selectfluor used. hNo reaction.

Scheme 2. Substrate Scope for o-Hydroxyarylenaminonea,b

a Reaction conditions: 1 (0.4 mmol, 1 equiv), Selectfluor (2) (1.2 mmol, 3 equiv), NaOAc (0.8 mmol, 2 equiv) in acetone (2.0 mL) at room temperature for 1 h. bIsolated yields.

moderate to good yields (Scheme 2, 3c−3i). It is noteworthy that small amount of unidentified byproduct was also observed, especially for those substrates with electron-donating group attached at the para position. However, the electronic feature of 9838

DOI: 10.1021/acs.joc.7b01339 J. Org. Chem. 2017, 82, 9837−9843

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The Journal of Organic Chemistry substituents at meta-position of phenol moiety slightly affected the chemical yields and satisfactory yields were thoroughly secured (Scheme 2, 3i−3l). Pleasingly, the disubstituted substrates were also successfully prepared in moderate yields (Scheme 2, 3m and 3n). Moreover, naphthalene analogue also delivered the corresponding chromanone 3o in modest yield. Encouraged by the above results, we next turned our attention to the effect of N-substituents (as illustrated in Scheme 3). Both acyclic (diethyl) and cyclic (pyrrolidinyl and

(Scheme 4). Meanwhile, the benzyl group of 5f could be effectively removed via hydrogenation of N-benzyl chromanone Scheme 4. Scale-up and Synthetic Utility of This Reaction

Scheme 3. Substrate Scope for the Synthesis of Difluorinated 2-Amino-Substituted Chromanonesa,b,c

5f in the presence of Pd/C in a moderate yield (Scheme 4). The operational ease and diversity for the derivatization of free amino group in chromanone 7 could greatly broaden the versatility for this protocol in drug discovery. In conclusion, we successfully developed a facile and general protocol by employing o-hydroxyarylenaminone to access a range of difluorinated 2-amino-substituted chromanones via a Selectfluor-triggered tandem reaction sequence. The enamine moiety in o-hydroxyarylenaminone is crucial to the success in difluorination and cyclization, endowing this process with stepeconomy and practicality owing to mild conditions and reasonably short reaction time. More importantly, the asprepared difluorinated 2-amino-substituted chromanones by virtue of the innovative strategy would surely enrich the library of fluorinated heterocycles and provide valuable synthetic options for medicinal studies.

a

Reaction conditions: 4 (0.4 mmol, 1 equiv), Selectfluor (2) (1.2 mmol, 3 equiv), NaOAc (0.8 mmol, 2 equiv) in acetone (2.0 mL) at room temperature for 1 h. bIsolated yields. c3.3:1 dr.

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EXPERIMENTAL SECTION

General Experimental Methods. Unless otherwise noted, all solvents and other reagents are commercially available and used without further purification. All reagents were weighed and handled in air at room temperature. Column chromatography was performed on silica gel (200−300 mesh). NMR spectra were recorded on Bruker AVANCE III 400 NMR spectrometer. Chemical shifts were reported in parts per million (ppm, δ) relative to tetramethylsilane. Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multipet (m) and broad (br). Infrared spectra (IR) were measured by FT-IR spectroscopy. HRMS were recorded on a Q-TOF mass. Melting points (mp) were measured by Büchi 510 melting point apparatus and uncorrected. o-Hydroxyarylenaminones 1 and 4 were prepared according to the reported protocol.15 General Procedure for Synthesis of Difluorinated 2-Aminosubstitued chromanones. o-Hydroxyarylenaminone 1 or 4 (0.4 mmol), Selectfluor (1.2 mmol, 3.0 equiv), and NaOAc (0.8 mmol, 2.0 equiv) were added to acetone (2.0 mL) in a 5 mL reaction tube equipped with a stirring bar. The reaction mixture was then stirred at room temperature for 1 h. After completion of the reaction (confirmed by TLC analysis, petroleum ether/ethyl acetate = 5/1), the solvent was removed in vacuo, and the resulting residue was purified via silica gel chromatography (petroleum ether/ethyl acetate = 10/1) to yield the corresponding chromanones. Characterization Data for 3a−3o and 5a−5n. 2-(Dimethylamino)-3,3-difluorochroman-4-one (3a). Following general procedure, 3a was obtained as a white solid in 61% yield (55 mg). mp 82− 84 °C; IR (KBr) ν 3402, 3083, 1706, 1606, 1463, 940, 831 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.60 (ddd, J = 8.4, 7.3, 1.7 Hz, 1H), 7.08−7.13 (m, 2H), 4.98 (dd, J = 20.0, 3.2 Hz, 1H), 2.96 (s, 6H); 13C NMR (100 MHz, Chloroform-d) δ 181.7 (t, J = 25.2 Hz, PhCOCF2), 160.8, 137.7, 128.2, 122.4, 118.4, 109.4 (dd, J = 259.1, 256.2 Hz, CF2), 93.9 (dd, J = 26.6, 21.3 Hz,

piperidinyl) secondary amines were well tolerated in the reaction though the yields (Scheme 3, 5a−5c) were relatively lower than N,N-dimethylamino functionalized enaminones (3a). Presumably, the steric effect imparted a negative impact on this reaction sequence. Notably, besides secondary amines, primary amines were also proven viable to this transformation to enable the synthesis of 2-amino-substituted chromanones (Scheme 3, 5d−5n). Generally, the yields for N-monosubstituted substrates were obviously superior to those of N,Ndisubstituted analogues due to the steric issue. Gratifyingly, the enaminones with propenyl and propynyl group were also compatible with the reaction (Scheme 3, 5i and 5j), which can provide the side arm for further modifications. Not surprisingly, the existence of a stereogenic center in the branched substituent led to 3.3:1 dr for the corresponding product 5k. Interestingly, in contrast to N-substituted substrate, the Csubstituted counterpart chalocone was unable to proceed the cyclization to give chromanone 6 under the standard conditions, which also confirmed the key role of the enamine in the tandem process. Noticing the mildness of reaction conditions, we were devoted to exploiting the practicality and scalability of this protocol. Thus, the reactions for enaminones 1a and 4f were performed at gram-scale under standard reaction conditions. A slightly reduced yield (46%) for 3a was obtained, which was attributed to the unexpected decomposition of 3a at the larger scale. Pleasingly, a comparable yield (82%) for 5f was achieved 9839

DOI: 10.1021/acs.joc.7b01339 J. Org. Chem. 2017, 82, 9837−9843

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The Journal of Organic Chemistry CCF2), 41.1; 19F NMR (376 MHz, Chloroform-d) δ −124.77 (d, J = 276.0 Hz), −126.44 (d, J = 275.9 Hz); HRMS (ESI) m/z [M + H]+ calcd for C11H12F2NO2+: 228.0831, found 228.0833. 2-(Dimethylamino)-3,3-difluoro-6-methoxychroman-4-one (3b). Following general procedure, 3b was obtained as a white solid in 34% yield (35 mg). mp 75−77 °C; IR (KBr) ν 3454, 2957, 1706, 1621, 1488, 1360, 1223, 841 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.26−7.28 (m, 1H), 7.21 (dd, J = 8.8, 3.2 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 4.93 (dd, J = 21.6, 2.4 Hz, 1H), 3.82 (s, 3H), 2.69 (s, 6H); 13C NMR (100 MHz, Chloroform-d) δ 181.7 (t, J = 25.3 Hz, PhCOCF2), 155.7, 154.8, 127.6, 119.9, 118.2, 109.5 (dd, J = 257.0, 254.0 Hz, CF2), 107.37, 93.7 (dd, J = 26.4, 20.7 Hz, CCF2), 55.8, 41.2; 19F NMR (376 MHz, Chloroform-d) δ −124.42 (d, J = 276.1 Hz), −126.89 (d, J = 276.2 Hz); HRMS (ESI) m/z [M + H]+ calcd for C12H14F2NO3+: 258.0936, found 258.0940. 2-(Dimethylamino)-3,3-difluoro-6-methylchroman-4-one (3c). Following general procedure, 3c was obtained as a white solid in 59% yield (57 mg). mp 83−85 °C; IR (KBr) ν 3453, 2922, 1623, 1484, 1262, 1134, 966 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 1.2 Hz, 1H), 7.41 (dd, J = 8.4, 2.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.93 (dd, J = 20.2, 3.2 Hz, 1H), 2.68 (s, 6H), 2.33 (s, 3H); 13 C NMR (100 MHz, Chloroform-d) δ 181.8 (t, J = 25.2 Hz, PhCOCF2), 158.9, 139.0, 132.1, 127.5, 118.2, 118.1, 109.5 (dd, J = 259.2, 256.0 Hz, CF2), 93.7 (dd, J = 26.5, 21.3 Hz, CCF2), 41.1, 20.3; 19 F NMR (376 MHz, Chloroform-d) δ −124.72 (d, J = 275.9 Hz), −126.48 (d, J = 276.0 Hz); HRMS (ESI) m/z [M + H]+ calcd for C12H14F2NO2+: 242.0987, found 242.0994. 2-(Dimethylamino)-3,3,6-trifluorochroman-4-one (3d). Following general procedure, 3d was obtained as a white solid in 54% yield (53 mg). mp 128−130 °C; IR (KBr) ν 3453, 3080, 2965, 2862, 1715, 1486, 1261, 1242, 923, 853 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.55 (dd, J = 7.9, 3.2 Hz, 1H), 7.30−7.36 (m, 1H), 7.08 (dd, J = 9.1, 4.1 Hz, 1H), 4.96 (dd, J = 20.7, 3.2 Hz, 1H), 2.69 (s, 6H); 13C NMR (100 MHz, Chloroform-d) δ 181.1 (t, J = 25.7 Hz, PhCOCF2), 157.6 (d, J = 244.0 Hz, CF2), 157.2 (d, J = 1.9 Hz, CCCCF), 125.6 (d, J = 24.8 Hz, CCF), 120.3 (d, J = 7.5 Hz, CCCF), 118.8 (d, J = 7.1 Hz, CCCF), 112.7 (d, J = 24.0 Hz, CCF), 109.2 (dd, J = 257.0, 255.3 Hz, CF2), 94.1 (dd, J = 26.5, 21.1 Hz, CCF2), 41.1; 19F NMR (376 MHz, Chloroform-d) δ −119.80, −124.59 (d, J = 276.8 Hz), −127.07 (d, J = 276.8 Hz); HRMS (ESI) m/z [M + H]+ calcd for C11H11F3NO2+: 246.0736, found 246.0736. 6-Chloro-2-(dimethylamino)-3,3-difluorochroman-4-one (3e). Following general procedure, 3e was obtained as a white solid in 73% yield (76 mg). mp 76−78 °C; IR (KBr) ν 3393, 3077, 2917, 2860, 1703, 1605, 1466, 1323, 1251, 968, 834 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J = 2.5 Hz, 1H), 7.53 (dd, J = 8.9, 2.6 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 4.99 (dd, J = 19.6, 3.1 Hz, 1H), 2.68 (s, 6H); 13CNMR (100 MHz, Chloroform-d) δ 180.8 (t, J = 26.0 Hz, PhCOCF2), 159.3, 137.7, 128.0, 127.2, 120.2, 119.1, 109.1 (dd, J = 259.3, 256.7 Hz, CF2), 94.2 (dd, J = 26.7, 21.1 Hz, CCF2), 41.1; 19F NMR (376 MHz, Chloroform-d) δ −124.62 (d, J = 276.7 Hz), −126.46 (d, J = 276.9 Hz); HRMS (ESI) m/z [M + H]+ calcd for C11H11ClF2NO2+: 262.0441, found 262.0440. 6-Bromo-2-(dimethylamino)-3,3-difluorochroman-4-one (3f). Following general procedure, 3f was obtained as a white solid in 70% yield (86 mg). mp 72−74 °C; IR (KBr) ν 2957, 2923, 2853, 1726, 1467, 1121, 1079, 966, 825 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 2.5 Hz, 1H), 7.67 (dd, J = 8.9, 2.5 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 4.99 (dd, J = 19.7, 3.4 Hz, 1H), 2.68 (s, 6H); 13C NMR (100 MHz, Chloroform-d) δ 180.6 (t, J = 25.7 Hz, PhCOCF2), 159.7, 140.4, 130.3, 120.5, 119.7, 115.0, 109.0 (dd, J = 259.3, 256.7 Hz, CF2), 94.3 (dd, J = 26.3, 21.7 Hz, CCF2), 40.9; 19F NMR (376 MHz, Chloroform-d) δ −124.62 (d, J = 277.0 Hz), −126.31 (d, J = 277.1 Hz); HRMS (EI) m/z [M + H]+ calcd for C11H11BrF2NO2+: 305.9936, found 305.9930. Methyl 4-(2-(dimethylamino)-3,3-difluoro-4-oxochroman-6-yl)benzoate (3g). Following general procedure, 3g was obtained as a white solid in 56% yield (81 mg). mp 83−85 °C; IR (KBr) ν 3449, 2957, 2923, 2852, 1725, 1653, 1464, 1190, 1121, 768 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J = 2.3 Hz, 1H), 8.11 (d, J = 8.4

Hz, 2H), 7.87 (dd, J = 8.7, 2.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.7 Hz, 1H), 5.05 (dd, J = 19.5, 3.6 Hz, 1H), 3.94 (s, 3H), 2.71 (s, 6H); 13C NMR (100 MHz, Chloroform-d) δ 181.59 (t, J = 25.4 Hz, PhCOCF2), 166.7, 160.7, 143.2, 136.4, 134.4, 130.3, 129.3, 126.6, 126.3, 119.2, 118.6, 109.3 (dd, J = 258.0, 255.0 Hz, CF2), 94.2 (dd, J = 26.0, 21.0 Hz, CCF2), 52.2, 41.1; 19F NMR (376 MHz, Chloroform-d) δ −124.59 (d, J = 276.5 Hz), −126.14 (d, J = 276.4 Hz); HRMS (ESI) m/z [M + H]+ calcd for C19H18F2NO4+: 362.1198, found 362.1215. 2-(Dimethylamino)-3,3-difluoro-6-(4-methoxyphenyl)chroman4-one (3h). Following general procedure, 3h was obtained as a white solid in 44% yield (59 mg). mp 82−84 °C; IR (KBr) ν 3456, 1717, 1633, 1475, 1153, 1082, 961 cm−1; 1H NMR (400 MHz, Chloroformd) δ 8.06 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 8.7, 2.4 Hz, 1H), 7.47−7.51 (m, 2H), 7.13 (d, J = 8.7 Hz, 1H), 6.96−6.99 (m, 2H), 5.00 (dd, J = 19.9, 3.4 Hz, 1H), 3.85 (s, 3H), 2.70 (s, 6H); 13CNMR (100 MHz, Chloroform-d) δ 181.8 (t, J = 25.3 Hz, PhCOCF2), 159.7, 159.5, 136.2, 135.4, 131.4, 127.8, 125.3, 118.9, 118.5, 114.4, 109.4 (dd, J = 259.2, 256.2 Hz, CF2), 94.0 (dd, J = 26.7, 21.3 Hz, CCF2), 55.4, 41.1; 19 F NMR (376 MHz, Chloroform-d) δ −124.59 (d, J = 276.3 Hz), −126.31 (d, J = 276.2 Hz); HRMS (ESI) m/z [M + H]+ calcd for C18H18F2NO3+: 334.1249, found 334.1229. 2-(Dimethylamino)-3,3-difluoro-7-methoxychroman-4-one (3i). Following general procedure, 3i was obtained as colorless liquid in 70% yield (72 mg). IR (KBr) ν 2953, 1701, 1609, 1442, 1243, 1103, 852 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J = 8.9 Hz, 1H), 6.67 (dd, J = 8.9, 2.2 Hz, 1H), 6.50 (d, J = 2.2 Hz, 1H), 4.98 (dd, J = 19.4, 3.7 Hz, 1H), 3.88 (s, 3H), 2.69 (s, 6H); 13C NMR (100 MHz, Chloroform-d) δ 180.1 (t, J = 25.0 Hz, PhCOCF2), 167.5, 163.1, 129.9, 112.1, 111.8, 109.4 (dd, J = 257.3, 253.5, CF2), 100.9, 94.1 (dd, J = 27.0, 21.5 Hz, CCF2), 55.9, 41.1; 19F NMR (376 MHz, Chloroform-d) δ −124.36 (d, J = 276.4 Hz), −125.83 (d, J = 276.5 Hz); HRMS (ESI) m/z [M + H]+calcd for C12H14F2NO3+: 258.0936, found 258.0943. 2-(Dimethylamino)-3,3-difluoro-7-methylchroman-4-one (3j). Following general procedure, 3j was obtained as colorless liquid in 60% yield (57 mg). IR (KBr) ν 3456, 2955, 2358, 1709, 1616, 1454, 1241, 1118, 856 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 8.4 Hz, 1H), 6.90−6.94 (m, 2H), 4.96 (dd, J = 20.0, 3.6 Hz, 1H), 2.68 (s, 6H), 2.40 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 181.3 (t, J = 25.2 Hz, PhCOCF2), 160.8, 149.8, 128.0, 123.9, 118.4, 116.2, 109.4 (dd, J = 254.2, 253.9 Hz, CF2), 93.8 (dd, J = 26.7, 21.1 Hz, CCF2), 41.1, 22.1; 19F NMR (376 MHz, Chloroform-d) δ −124.69 (d, J = 275.9 Hz), −126.24 (d, J = 276.0 Hz); HRMS (ESI) m/z [M + H]+ calcd for C12H14F2NO2+: 242.0987, found 242.0993. 2-(Dimethylamino)-3,3,7-trifluorochroman-4-one (3k). Following general procedure, 3k was obtained as colorless liquid in 79% yield (79 mg). IR (KBr) ν 3561, 2958, 2359, 1715, 1616, 1443, 1260, 1098, 855 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.95 (dd, J = 8.8, 6.5 Hz, 1H), 6.84 (td, J = 8.5, 2.3 Hz, 1H), 6.77 (dd, J = 9.6, 2.3 Hz, 1H), 5.02 (dd, J = 19.2, 3.6 Hz, 1H), 2.69 (s, 6H); 13C NMR (100 MHz, Chloroform-d) δ 180.4 (t, J = 25.0 Hz, PhCOCF2), 168.6 (d, J = 259.9 Hz, CF), 162.7 (d, J = 13.9 Hz, CCCF), 130.9 (d, J = 11.8 Hz, CCCF), 115.3, 111.3 (d, J = 23.3 Hz, CCF), 109.1 (dd, J = 257.0, 254.0 Hz, CF2), 105.3 (d, J = 25.9 Hz, CCF), 94.5 (dd, J = 26.8, 21.2 Hz, CCF2), 41.1; 19F NMR (376 MHz, Chloroform-d) δ −97.00, −124.61 (d, J = 276.9 Hz), −126.13 (d, J = 276.8 Hz); HRMS (ESI) m/z [M + H]+ calcd for C11H11F3NO2+: 246.0736, found 246.0736. 7-Bromo-2-(dimethylamino)-3,3-difluorochroman-4-one (3l). Following general procedure, 3l was obtained as colorless liquid in 57% yield (68 mg). IR (KBr) ν 3456, 2945, 2874, 1716, 1634, 940 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 1.7 Hz, 1H), 7.24−7.28 (m, 1H), 5.01 (dd, J = 19.5, 3.4 Hz, 1H), 2.68 (s, 6H); 13C NMR (100 MHz, Chloroform-d) δ 181.0 (t, J = 25.5 Hz, PhCOCF2), 160.9, 132.7, 129.2, 126.2, 121.7, 117.3, 109.1 (dd, J = 259.1, 256.4 Hz, CF2), 94.5 (dd, J = 26.7, 22.2 Hz, CCF2), 41.1; 19F NMR (376 MHz, Chloroform-d) δ −124.62 (d, J = 277.1 Hz), −126.09 (d, J = 276.8 Hz); HRMS (ESI) m/z [M + H]+ calcd for C11H11BrF2NO2+: 305.9936, found 305.9936. 2-(Dimethylamino)-3,3-difluoro-6,7-dimethylchroman-4-one (3m). Following general procedure, 3m was obtained as a white solid 9840

DOI: 10.1021/acs.joc.7b01339 J. Org. Chem. 2017, 82, 9837−9843

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The Journal of Organic Chemistry

δ −123.95; HRMS (ESI) m/z [M + H]+ calcd for C14H16F2NO2+: 268.1144, found 268.1146. 2-(Butylamino)-3,3-difluorochroman-4-one (5d). Following general procedure, 5d was obtained as colorless liquid in 88% yield (90 mg). IR (KBr) ν 2960, 1712, 1607, 1466, 1206, 1147, 945 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.92 (dd, J = 7.9, 1.5 Hz, 1H), 7.59−7.63 (m, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 5.08 (d, J = 14.0 Hz, 1H), 3.09−3.16 (m, 1H), 2.83−2.90 (m, 1H), 2.36 (br s, 1H), 1.51−1.60 (m, 2H), 1.36−1.42 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ 181.5 (t, J = 24.9 Hz, PhCOCF2), 159.6, 137.9, 128.1, 122.7, 118.8, 108.3 (t, J = 255.6 Hz, CF2), 90.1 (dd, J = 26.5, 22.6 Hz, CCF2), 45.7, 32.4, 20.1, 13.8; 19 F NMR (376 MHz, Chloroform-d) δ −124.67 (d, J = 280.7 Hz), −130.44 (d, J = 280.7 Hz); HRMS (ESI) m/z [M + H]+ calcd for C13H16F2NO2+: 256.1144, found 256.1143. 3,3-Difluoro-2-((4-phenylbutyl)amino)chroman-4-one (5e). Following general procedure, 5e was obtained as colorless liquid in 74% yield (98 mg). IR (KBr) ν 3363, 2934, 2860, 1711, 1608, 1466, 1208, 1147, 945, 754, 699 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.57−7.61 (m, 1H), 7.24−7.29 (m, 2H), 7.16−7.19 (m, 3H), 7.11 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.04 (dd, J = 17.2, 11.8, 1H), 3.08−3.16 (m, 1H), 2.83−2.92 (m, 1H), 2.64 (t, J = 7.2 Hz, 2H), 2.31−2.37 (m, 1H), 1.57−1.73 (m, 4H); 13C NMR (100 MHz, Chloroform-d) δ 181.5 (t, J = 24.8 Hz, PhCOCF2), 159.5, 142.2, 139.0, 128.4, 128.3, 128.1, 125.8, 122.7, 118.8, 108.2 (t, J = 256.1 Hz, CF2), 90.0 (dd, J = 27.6, 23.5 Hz, CCF2), 45.9, 35.6, 29.9, 28.7; 19F NMR (376 MHz, Chloroform-d) δ −124.61 (d, J = 280.7 Hz), −130.35 (d, J = 280.7 Hz); HRMS (ESI) m/z [M + H]+ calcd for C19H20F2NO2+: 332.1457, found 332.1457. 2-(Benzylamino)-3,3-difluorochroman-4-one (5f). Following general procedure, 5f was obtained as a white solid in 81% yield (94 mg). mp 113−115 °C; IR (KBr) ν 3405, 3352, 3062, 2905, 2872, 1711, 1608, 1461, 1328, 1147, 941 cm−1; 1H NMR (400 MHz, Chloroformd) δ 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.59−7.64 (m, 1H), 7.41 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.3 Hz, 2H) 7.29 (d, J = 7.2 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 5.06 (ddd, J = 17.5, 11.9, 1.8 Hz, 1H), 4.26 (dd, J = 13.6, 4.4 Hz, 1H), 4.13 (dd, J = 13.2, 5.6 Hz, 1H), 2.78−2.84 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 181.3 (t, J = 24.8 Hz, PhCOCF2), 159.4, 138.2, 138.0, 128.6, 128.2, 128.1, 127.6, 122.8, 118.9, 118.7, 108.3 (t, J = 255.9 Hz, CF2), 88.7 (dd, J = 26.6, 22.7 Hz, CCF2), 49.1; 19F NMR (376 MHz, Chloroform-d) δ −124.81 (d, J = 281.3 Hz), −130.21 (d, J = 281.3 Hz); HRMS (ESI) m/z [M + H]+ calcd for C16H14F2NO2+: 290.0987, found 290.0991. 2-((4-Chlorobenzyl)amino)-3,3-difluorochroman-4-one (5g). Following general procedure, 5g was obtained as a white solid in 89% yield (116 mg). mp 64−66 °C; IR (KBr) ν 3449, 2912, 1707, 1609, 1463, 1207, 1146, 943, 757 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.91 (dd, J = 8.0, 1.6 Hz, 1H), 7.58−7.63 (m, 1H), 7.28−7.35 (m, 4H), 7.12 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 5.02 (ddd, J = 17.7, 12.0, 1.6 Hz, 1H), 4.22 (dd, J = 13.9, 4.4 Hz, 1H), 4.10 (dd, J = 13.9, 5.6 Hz, 2H), 2.79−2.85 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 181.2 (t, J = 24.7 Hz, PhCOCF2), 159.3, 138.1, 136.7, 133.3, 129.5, 128.7, 128.1, 122.9, 118.8, 118.7, 108.2 (t, J = 256.0 Hz, CF2), 88.5 (dd, J = 25.2, 22.5 Hz, CCF2), 48.4; 19F NMR (376 MHz, Chloroform-d) δ −124.94 (d, J = 281.5 Hz), −130.11 (d, J = 281.1 Hz); HRMS (ESI) m/z [M − H] − calcd for C16H11ClF2NO2−: 322.0452, found 322.0451. 2-((2-Chlorobenzyl)amino)-3,3-difluorochroman-4-one (5h). Following general procedure, 5h was obtained as colorless liquid in 91% yield (118 mg). IR (KBr) ν 3400, 3363, 3075, 2930, 1915, 1707, 1609, 1464, 1327, 1248, 1145, 947 cm−1; 1H NMR (400 MHz, Chloroformd) δ 7.90 (dd, J = 7.6, 1.2 Hz, 1H), 7.56−7.61 (m, 1H), 7.50 (dd, J = 7.6, 1.6 Hz, 1H), 7.36 (dd, J = 7.5, 1.6 Hz, 1H), 7.20−7.28 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.09 (ddd, J = 16.6, 11.4, 2.0 Hz, 1H), 4.30 (dd, J = 14.8, 5.6 Hz, 1H), 4.21 (dd, J = 14.8, 6.2 Hz, 1H), 2.88−2.94 (m, 1H); 13C NMR (100 MHz, Chloroformd) δ 181.3 (t, J = 24.0 Hz, PhCOCF2), 159.3, 138.1, 136.2, 133.7, 129.8, 128.8, 128.0, 127.1, 122.9, 118.8, 108.2 (t, J = 256.0 Hz, CF2), 89.2 (dd, J = 26.3, 23.2 Hz, CCF2), 47.0; 19F NMR (376 MHz, Chloroform-d) δ −124.24 (d, J = 281.8 Hz), −130.43 (d, J = 281.4

in 65% yield (63 mg). mp 99−101 °C; IR (KBr) ν 3401, 2986, 2867, 1710, 1620, 1458, 1248, 1056, 849 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.64 (s, 1H), 6.87 (s, 1H), 4.92 (dd, J = 19.8, 3.7 Hz, 1H), 2.67 (s, 6H), 2.30 (s, 3H), 2.24 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 181.39 (t, J = 25.0 Hz, PhCOCF2), 159.13, 148.96, 113.46, 127.76, 118.81, 116.12, 109.52 (dd, J = 259.2, 255.6 Hz, CF2), 93.65 (dd, J = 26.7, 20.9 Hz, CCF2), 41.13, 20.74, 18.81; 19F NMR (376 MHz, Chloroform-d) δ −124.63 (d, J = 275.9 Hz), −126.16 (d, J = 275.9 Hz); HRMS (ESI) m/z [M + H]+ calcd for C13H16F2NO2+: 256.1144, found 256.1153. 6-Chloro-2-(dimethylamino)-3,3-difluoro-7-methylchroman-4one (3n). Following general procedure, 3n was obtained as a white solid in 58% yield (61 mg). mp 104−106 °C; IR (KBr) ν 3455, 2946, 2907, 2845, 1701, 1634, 1601, 1446, 1166, 960 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.85 (s, 1H), 6.99 (s, 1H), 4.96 (dd, J = 19.6, 3.6 Hz, 1H), 2.67 (s, 6H), 2.42 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ 180.48 (t, J = 25.5 Hz, PhCOCF2), 159.1, 147.4, 128.8, 127.5, 120.5, 117.3, 109.1 (dd, J = 259.3, 256.2 Hz, CF2), 94.1 (dd, J = 26.5, 21.4 Hz, CCF2), 41.1, 21.1; 19F NMR (376 MHz, Chloroform-d) δ −124.59 (d, J = 276.9 Hz), −126.17 (d, J = 277.0 Hz); HRMS (ESI) m/z [M + H]+calcd for C12H13ClF2NO2+: 276.0597, found 276.0597. 2-(Dimethylamino)-3,3-difluoro-2H-benzo[h]chromen-4(3H)-one (3o). Following general procedure, 3o was obtained as a white solid in 66% yield (73 mg). mp 87−89 °C; IR (KBr) ν 3443, 2921, 2852, 1699, 1622, 1459, 1230, 1081, 1057, 841 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 8.37 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.67−7.72 (m, 1H), 7.57−7.62 (m, 1H), 7.47 (d, J = 8.7 Hz, 1H), 5.22 (dd, J = 20.0, 3.4 Hz, 1H), 2.80 (s, 6H); 13 C NMR (100 MHz, Chloroform-d) δ 181.3 (t, J = 25.1 Hz, PhCOCF2), 159.8, 138.1, 130.7, 128.1, 126.9, 124.7, 123.6, 122.5, 121.8, 113.0, 109.2 (dd, J = 259.0, 255.3 Hz, CF2), 95.1 (dd, J = 27.1, 21.2 Hz, CCF2), 41.3; 19F NMR (376 MHz, Chloroform-d) δ −124.02 (d, J = 276.0 Hz), −125.96 (d, J = 276.0 Hz); HRMS (ESI) m/z [M + H]+ calcd for C15H14F2NO2+: 278.0987, found 278.0986. 2-(Diethylamino)-3,3-difluorochroman-4-one (5a). Following general procedure, 5a was obtained as colorless liquid in 42% yield (43 mg). IR (KBr) ν 2971, 1714, 1605, 1528, 1214, 1076, 937, 870 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.55−7.60 (m, 1H), 7.09 (t, J = 7.6 Hz,1H), 7.05 (d, J = 8.4 Hz, 1H), 5.05 (dd, J = 22.0, 3.2 Hz, 1H), 2.95−3.15 (m, 4H), 1.16 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, Chloroform-d) δ 182.3 (t, J = 26.0 Hz, PhCOCF2), 160.2, 137.5, 128.2, 122.2, 118.7, 118.4, 109.4 (dd, J = 254.9, 254.8 Hz, CF2), 92.8 (dd, J = 25.0, 20.0 Hz, CCF2), 44.7, 14.2; 19 F NMR (376 MHz, Chloroform-d) δ −125.02 (d, J = 274.0 Hz), −126.39 (d, J = 274.3 Hz); HRMS (ESI) m/z [M + H]+ calcd for C13H16F2NO2+: 256.1144, found 256.1144. 3,3-Difluoro-2-(pyrrolidin-1-yl)chroman-4-one (5b). Following general procedure, 5b was obtained as a white solid in 49% yield (50 mg). mp 83−85 °C; IR (KBr) ν 3455, 2986, 2866, 1701, 1634, 1602, 1470, 1200, 1106, 872 cm−1; 1H NMR (400 MHz, Chloroformd) δ 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.56−7.61 (m, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 5.24 (dd, J = 20.8, 2.4 Hz, 1H), 3.14−3.18 (m, 4H) 1.84−1.91 (m, 4H); 13C NMR (100 MHz, Chloroform-d) δ 182.0 (t, J = 25.2 Hz, PhCOCF2), 160.9, 137.7, 128.1, 122.3, 118.6, 109.1 (dd, J = 258.0, 255.8 Hz, CF2), 91.0 (dd, J = 25.3, 21.7 Hz, CCF2), 48.6, 24.9; 19F NMR (376 MHz, Chloroform-d) δ −124.30 (d, J = 277.0 Hz), −126.10 (d, J = 276.6 Hz); HRMS (ESI) m/z [M + H]+ calcd for C13H14F2NO2+: 254.0987, found 254.0983. 3,3-Difluoro-2-(piperidin-1-yl)chroman-4-one (5c). Following general procedure, 5c was obtained as colorless liquid in 42% yield (45 mg). IR (KBr) ν 2936, 1714, 1608, 1466, 1212, 1107, 943 cm−1; 1 H NMR (400 MHz, Chloroform-d) δ 7.90 (d, J = 7.7 Hz, 1H), 7.56− 7.61 (m, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 4.8 Hz, 1H), 4.98 (t, J = 11.6 Hz, 1H), 3.10 (dt, J = 11.1, 5.4 Hz, 2H), 2.83 (dt, J = 11.2, 5.4 Hz, 2H), 1.59−1.65 (m, 4H), 1.46−1.52 (m, 2H); 13C NMR (100 MHz, Chloroform-d) δ 181.7 (t, J = 25.4 Hz, PhCOCF2), 160.9, 137.8, 128.0, 122.2, 118.4, 109.5 (t, J = 257.8 Hz, CF2), 94.7 (t, J = 24.7 Hz, CCF2), 50.1, 26.0, 23.9; 19F NMR (376 MHz, Chloroform-d) 9841

DOI: 10.1021/acs.joc.7b01339 J. Org. Chem. 2017, 82, 9837−9843

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The Journal of Organic Chemistry

F NMR (376 MHz, Chloroform-d) δ −124.63 (d, J = 280.8 Hz), −130.39 (d, J = 281.2 Hz); HRMS (ESI) m/z [M + H]+ calcd for C14H16F2NO2+: 268.1144, found 268.1129. 2-(Cyclohexylamino)-3,3-difluorochroman-4-one (5n). Following general procedure, 5n was obtained as colorless liquid in 86% yield (97 mg). IR (KBr) ν 3449, 2927, 2854, 1707, 1609, 1465, 1208, 1147, 949, 751 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.91 (dd, J = 7.9, 1.2 Hz, 1H), 7.57−7.62 (m, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 5.19 (dd, J = 17.2, 10.8 Hz, 1H), 2.93−3.02 (m, 1H), 2.38 (d, J = 9.0 Hz, 1H), 1.92−1.95 (m, 2H), 1.75−1.79 (m, 2H), 1.61−1.64 (m, 1H), 1.16−1.36 (m, 5H); 13C NMR (100 MHz, Chloroform-d) δ 176.8 (t, J = 24.9 Hz, PhCOCF2), 155.0, 133.2, 123.3, 117.8, 114.1, 114.0, 103.6 (t, J = 255.3, CF2), 83.2 (dd, J = 26.3, 22.5 Hz, CCF2), 48.5, 29.9, 28.1, 21.0, 20.1, 19.8; 19F NMR (376 MHz, Chloroform-d) δ −124.58 (d, J = 279.4 Hz), −130.80 (d, J = 279.3 Hz); HRMS (ESI) m/z [M + H]+calcd for C15H18F2NO2+: 282.1300, found 282.1301. General Procedure for Synthesis of 2-Amino-3,3-difluorochroman-4-one 7. A suspension of chromanone 5f (0.4 mmol) and Pd/C (10% palladium on carbon, 12.0 mg) in formic acid-methanol (4.4%, v/v, 4.0 mL) was stirred at room temperature for 10 h. Afterward, the reaction was filtered and washed with methanol. The filtrate was concentrated to dryness and the resulting residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to yield the corresponding chromanone 7 as colorless liquid (52 mg, 65% yield). IR (KBr) ν 3387, 2927, 1716, 1611, 1468, 1286, 1235, 1180, 1107, 1007, 936, 771 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.94 (dd, J = 7.9, 1.6 Hz, 1H), 7.61−7.66 (m, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 5.76 (t, J = 4.0 Hz, 1H), 3.56 (br s, 2H); 13C NMR (100 MHz, Chloroform-d) δ 180.8 (t, J = 24.5 Hz, PhCOCF2), 157.0, 138.1, 127.8, 123.3, 119.0, 118.8, 107.6 (dd, J = 261.1, 249.1 Hz, CF2), 94.3 (dd, J = 34.8, 28.0 Hz, CCF2); 19F NMR (376 MHz, Chloroform-d) δ −119.95 (d, J = 281.4 Hz), −134.57 (d, J = 281.4 Hz); HRMS (ESI) m/z [M + H]+calcd for C9H8F2NO2+: 200.0518, found 200.0518.

Hz); HRMS (ESI) m/z [M + H]+ calcd for C16H13ClF2NO2+: 324.0597, found 324.0616. 2-(Allylamino)-3,3-difluorochroman-4-one (5i). Following general procedure, 5i was obtained as a white solid in 66% yield (63 mg). mp 65−67 °C; IR (KBr) ν 3451, 2956, 2921, 2851, 1698, 1648, 1462, 1376, 1258, 803 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.94 (dd, J = 8.0, 1.6 Hz, 1H), 7.59−7.65 (m, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 5.88−5.99 (m, 1H), 5.31 (dd, J = 17.2, 1.6 Hz, 1H), 5.19 (dd, J = 10.2, 1.3 Hz, 1H), 5.09 (ddd, J = 17.7, 11.9, 1.8 Hz, 1H), 3.54−3.74 (m, 2H), 2.52−2.57 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 181.3 (t, J = 24.8 Hz, PhCOCF2), 159.5, 138.0, 135.1, 128.1, 122.8, 118.8, 117.5, 108.3 (t, J = 255.8 Hz, CF2), 88.9 (dd, J = 26.6, 22.6 Hz, CCF2), 48.0; 19F NMR (376 MHz, Chloroform-d) δ −124.85 (d, J = 281.0 Hz), −130.22 (d, J = 280.6 Hz); HRMS (ESI) m/z [M + H]+ calcd for C12H12F2NO2+: 240.0831, found 240.0831. 3,3-Difluoro-2-(prop-2-yn-1-ylamino)chroman-4-one (5j). Following general procedure, 5j was obtained as a white solid in 61% yield (58 mg). mp 85−87 °C; IR (KBr) ν 3450, 2958, 2922, 2852, 1704, 1636, 1465, 946 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.94 (d, J = 8.0 Hz, 1H), 7.60−7.66 (m, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.31 (ddd, J = 15.2, 10.0, 2.4 Hz, 1H), 3.77− 3.79 (m, 2H), 2.58−2.61 (m, 1H), 2.33 (t, J = 2.4 Hz, 1H); 13C NMR (100 MHz, Chloroform-d) δ 180.9 (t, J = 24.0 Hz, PhCOCF2), 158.9, 138.1, 128.1, 123.0, 118.7, 108.1 (t, J = 255.0 Hz, CF2), 87.8 (dd, J = 28.0, 24.0 Hz, CCF2), 79.7, 73.0, 34.5; 19F NMR (376 MHz, Chloroform-d) δ −123.90 (d, J = 282.3 Hz), −130.59 (d, J = 282.2 Hz); HRMS (ESI) m/z [M + H]+ calcd for C12H10F2NO2+: 238.0674, found 238.0677. 3,3-Difluoro-2-((1-phenylethyl)amino)chroman-4-one (5k). Following general procedure, 5k was obtained as colorless liquid in 67% yield (81 mg, 3.3:1 dr). IR (KBr) ν 3356, 2971, 2924, 1712, 1608, 1466, 1207, 1147, 950, 760, 701 cm−1; 1H NMR (400 MHz, Chloroform-d, mixture of two diastereomers, 3.3:1 dr) δ 7.86−7.91 (m, 1.3H), 7.52−7.60 (m, 1.3H), 7.37−7.42 (m, 2.6H), 7.31−7.37 (m, 2.6H), 7.23−7.29 (m, 1.3H), 7.04−7.11 (m, 2.3H), 6.86 (d, J = 8.4 Hz, 0.3H), 5.19 (ddd, J = 16.7, 11.7, 2.2 Hz, 0.3H), 4.77 (dd, J = 19.2, 12.6 Hz, 1H), 4.46 (q, J = 6.6 Hz, 1H), 4.39−4.30 (m, 0.3H), 2.74−2.81 (m, 1.3H), 1.46 (d, J = 6.8 Hz, 3.8H); 13C NMR (100 MHz, Chloroform-d, major diastereomer) δ 181.4 (t, J = 24.8 Hz, PhCOCF2), 159.7, 143.0, 138.0, 128.8, 128.1, 127.1, 122.7, 118.8, 118.6, 108.3 (dd, J = 253.3, 253.4 Hz, CF2), 87.3 (dd, J = 25.9, 22.2 Hz, CCF2), 53.3, 25.1; 19F NMR (376 MHz, Chloroform-d, mixture of two diastereomers) δ −124.39 (d, J = 280.1 Hz), −125.79 (d, J = 281.1 Hz), −130.18 (d, J = 280.9 Hz) −130.46 (d, J = 280.1 Hz) ; HRMS (ESI) m/z [M − H]− calcd for C17H14F2NO2−: 302.0998, found 302.0991. 2-(Cyclopropylamino)-3,3-difluorochroman-4-one (5l). Following general procedure, 5l was obtained as a white solid in 70% yield (67 mg). mp 80−82 °C; IR (KBr) ν 3452, 1683, 1467, 1144, 950, 756 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.59−7.64 (m, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 5.11 (ddd, J = 18.2, 11.9, 1.9 Hz, 1H), 3.06 (d, J = 12.4 Hz, 1H), 2.65−2.70 (m, 1H), 0.60−0.66 (m, 2H), 0.50−0.58 (m, 1H), 0.41− 0.48 (m, 1H); 13C NMR (100 MHz, Chloroform-d) δ 181.4 (t, J = 24.8 Hz, PhCOCF2), 159.7, 138.0, 128.1, 122.7, 118.8, 108.1 (t, J = 255.6 Hz, CF2), 90.0 (dd, J = 26.1, 22.0 Hz, CCF2), 26.7, 7.5, 6.4; 19F NMR (376 MHz, Chloroform-d) δ −125.43 (d, J = 281.4 Hz), −130.01 (d, J = 281.1 Hz); HRMS (ESI) m/z [M − H]− calcd for C12H10F2NO2−: 238.0685, found 238.0679. 2-(Cyclopentylamino)-3,3-difluorochroman-4-one (5m). Following general procedure, 5m was obtained as colorless liquid in 82% yield (88 mg). IR (KBr) ν 3332, 3062, 3026, 2936, 2957, 1711, 1607, 1495, 1464, 1204, 1147, 941, 695 cm−1; 1H NMR (400 MHz, Chloroform-d) δ 7.93 (dd, J = 7.9, 1.6 Hz, 1H), 7.58−7.64 (m, 1H), 7.10−7.14 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 5.11 (ddd, J = 17.2, 12.0, 1.6 Hz, 1H), 3.53−3.61 (m, 1H), 2.42 (d, J = 8.8 Hz, 1H), 1.85−1.98 (m, 2H), 1.72−1.78 (m, 2H), 1.55−1.62 (m, 2H), 1.42−1.49 (m, 2H); 13 C NMR (100 MHz, Chloroform-d) δ 181.6 (t, J = 24.9 Hz, PhCOCF2), 159.7, 137.9, 128.1, 122.6, 118.9, 108.3 (t, J = 255.5 Hz, CF2), 89.3 (dd, J = 26.5, 22.6 Hz, CCF2), 56.5, 34.5, 32.7, 23.7, 23.4;

19

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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.7b01339. 1 H NMR, 13C NMR and 19F NMR spectra for compounds 3a−3o, 5a−5n and 7; X-ray structure of 3a (PDF) Crystal data (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*Tel.: +86-731-88830833. E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Haoyue Xiang: 0000-0002-7404-4247 Hua Yang: 0000-0002-5518-5255 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the financial support from the National Natural Science Foundation of China (21576296 and 21676302), China Postdoctoral Science Foundation (2017M610504), Natural Science Foundation of Hunan Province (2017JJ3401) and Central South University.

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