kynes in Water Under Mild Conditions - ACS Publications

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Micelles-Enabled Photo-Assisted Selective Oxyhalogenation of Alkynes in Water Under Mild Conditions Lucie Finck, Jeremy Brals, Bhavana Pavuluri, Fabrice Gallou, and Sachin Handa J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03143 • Publication Date (Web): 09 Feb 2018 Downloaded from http://pubs.acs.org on February 9, 2018

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The Journal of Organic Chemistry

Micelles-Enabled Photo-Assisted Selective Oxyhalogenation of Alkynes in Water Under Mild Conditions Lucie Finck,§ Jeremy Brals,§ Bhavana Pavuluri,§ Fabrice Gallou,‡ Sachin Handa*§ § ‡

Department of Chemistry, University of Louisville, 2320 S. Brook Street, Louisville, Kentucky 40292, United States Novartis Pharma AG, Basel CH-4002 Switzerland

We dedicate this work to Prof. Michael Nantz on the occasion of his upcoming 60th birthday.

Supporting Information Placeholder ABSTRACT: Using micelles of FI-750-M, visible-light, photocatalyst, and inexpensive halogenating reagents, i.e., NBS and NCS, selective oxyhalogenations of alkynes were achieved in water under very mild conditions. No halogenation at the aromatic rings was detected, and control experiments revealed the radical pathway. The easily conducted protocol exhibited high reproducibility, was readily adjusted to gram-scale, and allowed for recycling of reaction medium and catalyst.

Introduction. In the pursuit of novel technologies to rigorously support the essential chemical events that meet current challenges of sustainable chemical catalysis, micellar catalysis is one of the idiosyncratic one that addresses many current important issues by following the Nature’s lead.1 A selection of salient features of micellar catalysis includes obviation of toxic organic solvent as reaction media,2 in-flask catalyst recycling,3 support for nanocatalysis,3 and the as yet underexplored leveraging of the hydrophobic effect for better reactivity and selectivity.1c Lipshutz2a,4 and Kobayashi5 have pioneered this field, especially with their highly practical work pertaining to chemical catalysis with a very low catalyst loading.6 Further advancing the field, very recently, our group developed an inexpensive, environmentally benign, and potentially biodegradable amphiphile, FI-750-M, to mimic toxic polar organic solvents such as DMF, 1,4-dioxane, NMP, DMAc, etc.2c When dissolved in water, FI-750-M forms spherical nanomicelles with low-hydrophobicity interiors that solubilize polar reactants and catalysts which would otherwise require such toxic and polar aprotic organic solvents. Accordingly, arylation of nitroalkanes is now possible in water under mild conditions with a low catalyst loading. Similarly, selective sulfonylation of perfluoroarenes can also be achieved in water at room temperature without use of a polar-aprotic solvent as gross reaction medium.2d Beyond control of solubility, amphiphiles may also more directly impact reactivity. We hypothesized that the

proline linker in FI-750-M, i.e., the micellar interface, could be further synergistically utilized as a binding site for a reactant/reagent to facilitate a desired transformation. Along these lines, N-bromosuccinimide (NBS) or N-chlorosuccinimde (NCS) may effectively bind with a proline linker of FI-750-M which could enhance the solubility of NBS or NCS at the micellar interface at room temperature.2c,7 A catalyst in close proximity could then assist the homolytic N–X (X = Br, Cl) bond cleavage, thus facilitate useful chemical transformations, such as the oxyhalogenation of alkynes to achieve α,αdihaloketones in much sustainable fashion (Figure 1).8 Br

O

Br

Br

O

Br Br O

Br

O Br

O

Br

Br Br

Br O

sustainable, mild conditions no use of toxic organic solvents functional group tolerance recyclable catalyst and medium single step oxyhalogenation

Br

O N Br Br O

Me

catalyst

O catal

yst

O N O O

Figure 1. Micellar oxyhalogenation of alkynes promoted by the FI-750-M proline linker. If the reaction pathway is not very selective, alkyne oxyhalogenation could lead to many side products, including α-haloketones, α,α-dihaloketones, and vinyl halides.9 α,α-Dihaloketones are highly valuable structural motifs, especially due to their applications in the synthesis of medicinally important heterocycles,10 fine chemicals,11 agrochemicals,12 pharmaceuticals,13 and intermediates for natural products.14 For their synthesis at least

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one harsh or non-sustainable reaction parameter is indeed always required (e.g., use of a transition-meta l catalyst,9b,15 expensive/toxic halogenating reagent,9a,16

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conditions: 1 (0.5 mmol), 2 (1.0 mmol), catalyst (5 mol%), 1.0 mL 3 wt% surfactant in H2O, rt, 3 h, visible-light (9 W), argon atmosphere. BPO = benzoyl peroxide; all yields are isolated.

mild conditions. Our investigation began with reaction of phenylacetylene with NBS in various aqueous surfactants in the presence of visible-light and organocatalyst eosin Y (Figure 2), which can assist the cleavage of the halo radical from NBS or NCS and subsequently promote oxidation of a vinyl halide intermediate to obtain the desired product 3 (Table 1).

Figure 2. Structures of different amphiphiles and eosin Y. corrosive oxidant,17 or toxic organic solvents9,15), and the results suffer from moderate to poor selectivity and poor functional group tolerance, especially for boc, cbz, and nitro groups. Results and Discussion. In light of the aforementioned drawbacks of oxyhalogenation and the special structural features of FI-750-M, we herein report a mild, general, sustainable, photo assisted oxyhalogenation protocol that can be applied to synthesize α,α-dibromooketones as well as α,α-dichloro ketones with the use of inexpensive and stable reagents NBS and NCS in water under very

Although the reaction slowly proceeded in TPGS-750M and Triton X-100, FI-750-M was found to be superior in terms of reaction kinetics and yield (Table 1, entries 1-3). SDS surfactant showed inferior results and only 42% isolated yield was obtained (entry 4). The reaction also proceeded in the absence of any catalyst (entry 4), however, in many other cases from Table 2, conversions were not very clean and fast. Use of benzoylperoxide as a catalyst did not improve reaction yield (entry 6), which may be due to possibility of other side reactions. The low yield obtained when conducting the reaction on water (entry 7) revealed the importance of surfactant. Full optimization study revealed the importance of visiblelight, eosin Y, 3 wt% aqueous FI-750-M, and 2.0 equivalents of halogen source (NBS) for optimal reactivity. Notably, in the absence of light and catalyst, only 9% of product 3 was obtained (entry 7). Table 2. Substrate scope of micellar oxybromination

Table 1. Optimization of micellar oxyhalogenation

entry

catalyst

solvent

% yield 3

1

eosin Y

aq. TPGS-750-M

69

2

eosin Y

aq. Triton X-100

68

3

eosin Y

aq. FI-750-M

80

4

eosin Y

aq. SDS

42

5

-

aq. FI-750-M

60

6

BPO

aq. FI-750-M

58

7

eosin Y

neat water

35

8

dark-no cat.

aq. FI-750-M

9

conditions: alkyne (0.5 mmol), 2 (1.0 mmol), eosin Y (5 mol%), 1.0 mL 3 wt% FI-750-M in H2O, argon atmosphere, visible-light (9 W), rt; †reaction temperature 45 °C.


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After arriving at final optimized conditions, substrate scope was explored for both oxybromination and oxychlorination while paying attention to sterics, electronics, functional group tolerance. Both oxybromination and oxychlorination were smoothly achieved using optimal conditions. However, this protocol was not successful for oxyfluorination of alkynes, regardless of what fluorinating agent was used (i.e., Selectfluor, Olah reagent,18 etc.). Notwithstanding a few substrates needing mild heating at 45 °C to enhance the reaction rate, most of products were obtained at room temperature without investing additional energy. Where used, heating may merely serve to enhance the solubility of poorly soluble alkynes; indeed, use of THF as a co-solvent in lieu of heat also facilitated such cases. Notably, aromatic halogens did not display any hydrodehalogentaion (Table 2, 4 and 5). In all examples, the potential side reaction of bromination on the aromatic ring was not observed. Substrates containing an active methylene substituent (7) or an amine nucleophile (8) were very well tolerated. No bromination at the acetyl carbon was observed (7). Although intermolecular a nucleophilic substitution reaction was expected during formation of 8, no such side reaction was observed due to the extremely mild conditions. Both electron-rich (6, 8, 9) and -deficient (5, 7, 10-13) substrates displayed good reactivity. Good functional group tolerance was also observed, and boc (10), cbz (12), and nitro (13) groups were very well tolerated. Very clean and full conversion was observed in all cases, and the few cases Table 3. Substrate scope of micellar oxychlorination

conditions: alkyne (0.5 mmol), NCS (1.0 mmol), eosin Y (5 mol%), 1.0 mL 3 wt% FI-750-M in H2O, argon atmosphere, visible-light (9 W), 45 °C.

of moderate yield were attributable to the small scale, volatile nature, and instability of the compounds over silica gel. Likewise, alkyne oxychlorination was achieved with excellent functional group compatibility and reactivity. Although oxychlorinations were generally slower, they followed the same reactivity trends as described for oxybrominations in Table 2. Notably, the substrate containing a nitro residue displayed better reactivity in oxychlorination (Table 3, 24) than for oxybromination; 82% isolated yield was obtained at such a low scale. Control experiments were also conducted to confirm the roles of light, catalyst, and oxygen (Scheme 1). With ambient air exposure, only ca. 18% of desired product 3 was obtained. In darkness and the absence of catalyst, less than 10% of product 3 was obtained, indicating the significant role of light in generating the bromo radical. However, as shown in Table 1, without use of catalyst but in the presence of light, moderate yield was obtained. However, this was not general with all examples; use of eosin Y in such cases was still preferred in order to generalize the protocol. The reaction was also conducted in the presence of 1.0 equivalent of TEMPO, which significantly dropped the yield from 80% to 35%, suggesting the significance of the radical pathway.



conditions: 1 (0.5 mmol), 2 (1.0 mmol), eosin Y (5 mol%), 1.0 mL 3 wt% FI-750-M in H2O, eosin Y (5.0 mol%), visible-light (9 W), rt (for details, see SI).

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point, carbons of starting alkyne are now saturated and no further halogenation was observed. This technology did not work well for aliphatic alkynes since radical from aliphatic alkynes are not as stable as those from aromatic alkynes, e.g., a and d in Scheme 3.

Scheme 1. Control experiments suggesting an involvement of a radical in mechanism. Validity of our protocol was also tested on a gramscale reaction (Scheme 2). A clean conversion to desired product 3 was observed with 87% isolated yield. The yield on a gram-scale reaction was in fact higher than the small-scale reaction.

conditions: 1 (9.79 mmol), NBS (19.6 mmol), eosin Y (5 mol%), 10 mL 3 wt% FI-750-M in H2O, argon atmosphere, rt, 3 h.

Scheme 2. Gram-scale reaction in FI-750-M. Based on control experiment and photo-physical properties of eosin Y (EY)19 a plausible mechanism is described in Scheme 3. Upon reaction of alkyne, NBS (or

Scheme 3. Plausible mechanism of selective oxyhalogenation. NCS), and single-electron from EY*, halo vinyl radical a is formed (step I). Radical cation of EY generated in the first step accepts electron and forms strained intermediate b (step II), which reacts very fast with hydroxide ion that is generated in step I to form α-hydroxy halostyrene intermediate c (step III). Another halogenation occurs with the aid of single-electron transfer from EY* to form α-hydroxy dihaloradical d (step IV). Hydroxide ion generated in step IV and radical cation of EY mediate the formation of e as final product. At this

Scheme 4. Measure of greenness by E factor and recycle study. Mostly, these micelle-enabled transformations did not display side reactions. Eosin Y was found to be more soluble in aqueous FI-750-M compared to diethyl ether or MTBE; consequently, MTBE (methyl tert-butyl ether) was used in minimal amounts as a solvent for product extraction to better facilitate catalyst recycling. To assess protocol greenness the E-factor20 was determined for the model reaction after 4 recycles. Recycle reactions were performed with full recovery of catalyst and FI-750-M (Scheme 4). Reuse of micellar reaction media did not affect outcome of reactions in terms of yield and reaction time. After obtaining 3 in the zeroth cycle, recovered aqueous solution of nanomicelles containing catalyst was reused for first recycle to obtain 3. A similar process was repeated up to four recycles to obtain desired product. E-factor = 6.7 was found which advocates the greenness21 of this protocol. Aqueous micellar media can be potentially recycled even beyond the fourth recycle. Conclusion. In summary, this work demonstrates the development of a green and sustainable reaction protocol that involves use of environmentally benign amphiphiles, mild conditions, and, above all, no toxic organic solvents, transition metal catalyst, or harsh oxidants. The protocol is scalable, involves commercially available and inexpensive reagents, and no special precautions are required in reaction setup. In addition to mimicking toxic polar organic solvents such as acetonitrile, the inherent structure of amphiphile FI-750-M ap-


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pears to assist with catalysis through anticipated hydrogen bonding. General Experimental Details All manipulations were carried out under argon unless otherwise noted. TLC plates (UV 254 indicator, glass backed, thickness 200 mm) and silica gel (standard grade, 230 – 400 mesh) were purchased from EMD. Diethyl ether, THF, ethyl acetate, methylene chloride, and hexanes were purchased from Fisher Scientific. Nbromosuccinimide (NBS) and N-bromosuccinimide (NCS) were purchased from Acros Organic and used as such without any further purification. Eosin YH+ was purchased from Chem-impex International. Alkynes were either purchased from Oakwood chemicals, Combi-blocks, Alfa Aesar, Chem-impex or synthesized by Sonogashira couplings. Pure NMR solvents were purchased from Cambridge Isotopes Laboratories. Bulk aqueous solution of surfactant FI-750-M2c was prepared by dissolving neat surfactant wax in HPLC grade water and thoroughly purged with argon before use. Purifications of crude compounds were performed on silica gel (purchased from Sorbtech) using Combi-Flash Rf-150 equipment. Catalytic reactions were performed in 4 mL microwave reaction vials purchased from Biotage. Melting points were determined using a MEL-TEMP II melting point apparatus with samples in Kimble-Kimex 51 capillaries (1.5-1.8 x 90 mm). Unless otherwise mentioned, all NMR spectra were recorded at 23°C on Varian Unity INOVA (400 and 500 MHz) spectrometers. Reported chemical shifts are referenced to residual solvent peaks.22 All HRMS data were recorded either using electrospray ionization (ESI) or chemical ionization (CI). Electrospray ionization (ESI) data were recorded on a Thermo LTQ Orbitrap XL mass spectrometer at 30,000 resolving power and using reserpine (M+H+ = 609.2806) for internal calibration. Electron ionization (EI) and chemical ionization (CI, 1.5*10-4 mbar of methane as reagent gas) data were recorded at 5,000 resolving power on a MAT-95 XP magnetic sector mass spectrometer using perflourokerosene for internal calibration. IR spectra were obtained on a Perkin Elmer (Spectrum 100 FT-IR Spectrometer) apparatus. Optimal General Procedure of Catalytic Oxyhalogenation of Alkynes In a 4.0 mL reaction vial containing a PTFE-coated magnetic stir bar, NBS (2.0 equiv., 1.0 mmol, 178 mg) or NCS (2.0 equiv., 1.0 mmol, 133.5 mg), eosin YH+ (5.0 mol%, 0.025 mmol, 16.2 mg) and alkyne (1.0 equiv., 0.5 mmol) were sequentially added. The reaction vial was closed with a rubber septum and subsequently evacuated and back-filled with argon. 1.0 mL volume of 3 wt% aqueous FI-750-M was added to the reaction mixture. The septum was wrapped with PTFE tape and black electrical tape. The reaction mixture was irradiated

under 9 W compact fluorescent bulb and allowed to stir at room temperature or 45 °C. After complete consumption of starting material, as monitored by TLC or GCMS, 1.0 mL ethyl acetate and 1.0 mL water was added to the reaction mixture, which was then gently stirred for 2 min. The organic layer was separated via centrifuge. This extraction was repeated using additional 1.0 mL EtOAc. The combined extracts were dried over anhydrous sodium sulfate and volatiles were evaporated under reduced pressure at room temperature to obtain crude product, which was further purified by flash chromatography (wet load in DCM) over silica gel using hexanes/ethyl acetate as eluent. Note: For compound 14, the reaction was set up in a 1.8 mL vial. Gram Scale Synthesis of 3 In a 50 mL round-bottom flask (RBF) containing a PTFE-coated magnetic stir bar, NBS (2 equiv., 19.6 mmol, 3.49 g), eosin-YH+ (5 mol%, 0.49 mmol, 318 mg) and phenylacetylene (1 equiv., 9.8 mmol, 1 g) were sequentially added. The RBF was closed with a rubber septum and subsequently evacuated and back-filled with argon. 10 mL volume of 3 wt% aqueous FI-750-M (freshly sparged with argon) was added to the reaction mixture. The septum was wrapped with PTFE tape and black electrical tape. The reaction mixture was irradiated with a 9 W compact fluorescent bulb and it was allowed to stir at room temperature for 3-4 h. After complete consumption of starting material, as monitored by GCMS and/or TLC, 25 mL ethyl acetate and 15 mL water was added to the reaction mixture. The organic layer was separated using separatory funnel. This extraction was repeated three times using additional 3 x 10 mL EtOAc. The combined extracts were dried over anhydrous sodium sulfate and volatiles were evaporated under reduced pressure at room temperature to obtain crude product as an orange oil, which was further purified by flash chromatography (wet load in methylene chloride) over silica gel using 1% ethyl acetate/hexanes as eluent. Pure product was obtained as a yellow oil, Rf = 0.42 (9:1, hexanes/ethyl acetate), yield 2.4 g (87%). Analytical Data 2,2-dibromo-1-phenylethanone (3)23

Yellow oil, yield 111.2 mg (80%), Rf 0.42 (9:1, hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 9,5 Hz, 2H), 7.64 (t, J = 7.5 – 14.5Hz, 1H), 7.51 (t, J = 10 – 15.5 Hz, 2H), 6.71 (s, 1H).



24

2,2-dibromo-1-(4-bromophenyl)-ethanone (4)

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(w), 2812 (w), 1662 (m), 1581 (s), 1443 (m), 1322 (m), 1286 (s), 1179 (s); HRMS (CI), m/z [M + H]+ calcd for C8H8Br2NO 293.8952, found 293.8949. 2,2-dibromo-1-(3-thienyl)-ethanone (9)24,25

White solid, yield 132.9 mg (75%), Rf 0.48 (9:1, hexanes/ethyl acetate), mp = 83-88°C; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 6.60 (s, 1H).

Yellow oil, yield 112.9 mg (80%), Rf 0.16 (hexanes). H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.67 (d, J = 5.2 Hz, 1H), 7.37 (d, J = 4.8 Hz, 1H), 6.43 (s, 1H). 1

2,2-dibromo-1-(4-chlorophenyl)-ethanone (5)24,25

tert-butyl (10) Off white solid, yield 114.5 mg (74%), Rf 0.36 (9:1, hexanes/ethyl acetate), mp = 92-94°C; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J =8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 6.60 (s, 1H).

2,2-dibromo-1-(4-methoxyphenyl)-ethanone (6)24,25

White solid, yield 124.4 mg (81%), Rf 0.31 (9:1, hexanes/ethyl acetate), mp = 90-92°C; 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J =9 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.68 (s, 1H), 3.88 (s, 3H).

(4-(2,2-dibromoacetyl)phenyl)carbamate

Orange oil, yield 108.9 mg (56%), Rf 0.30 (8:2, hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 7.5 Hz, 2H), 7.50 (d, J = 8 Hz, 2H), 6.81 (s, 1H), 6.67 (s, 1H), 1.53 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 184.8, 152.0, 144.3, 131.5, 125.0, 117.7, 81.8, 39.9, 28.3; IR ν (cm–1) = 3344 (w), 2979 (w), 1712 (m), 1682 (m), 1586 (m), 1525 (m), 1233 (m), 1152 (s); HRMS (ESI), m/z [M + Na]+ calcd for C13H15Br2NO3Na 415.9296, found 415.9291. 2,2-dibromo-1-(4-fluorophenyl)-ethanone (11)24,25

1-(4-acetylphenyl)-2,2-dibromo-ethanone (7) 25,26 Colorless oil, yield 80.6 mg (55%), Rf 0.23 (9:1, hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3) δ 8.16 (m, 2H), 7.19 (t, J = 9 – 17.5 Hz, 2H), 6.61 (s, 1H). White solid, yield 122.9 mg (77%), Rf 0.21 (8:2, hexanes/ethyl acetate), mp = 75-77°C; 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J =8.5 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 6.67 (s, 1H), 2.65 (s, 3H).

benzyl(4-(2,2-dibromoacetyl)phenyl)carbamate (12)

1-(4-aminophenyl)-2,2-dibromo-ethanone (8)

Orange solid, yield 88.3 mg (61%), Rf 0.27 (7:3, hexanes/ethyl acetate), mp = 86-89°C; 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 8.5 Hz, 2H), 6.66 (d, J = 8 Hz, 2H), 6.66 (s, 1H), 4,33 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 184.3, 152.4, 132.5, 120.4, 114.0, 40.3; IR ν (cm–1) = 3426 (w), 3339 (m), 3229 (w), 3000 (w), 2890

Off-white solid, yield 177.2 mg (83%), Rf 0.39 (8:2, hexanes/ethyl acetate), mp = 133-135°C; 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.35-7.38 (m, 5H), 7.28 (s, 1H), 6.68 (s, 1H), 5.21 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 185.0, 152.9, 144.8, 135.6, 131.6, 128.8, 128.7, 128.8, 125.4, 118.0, 67.7, 40.0; IR ν (cm–1) = 3352 (m), 3066 (w), 3014 (w), 2921 (w), 2851 (w), 1684 (s), 1589 (m), 1527


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(s), 1269 (m), 1178 (m); HRMS (CI), m/z [M + H]+ calcd for C16H14Br2NO3 427.9320, found 427.9326. 2,2-dibromo-1-(4-nitrophenyl)-ethanone (13) 25,26

Colorless oil, yield 67.2 mg (42%), Rf 0.40 (8:2, hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3) 8.36 (d, J = 9 Hz, 1H), 8.31 (d, J = 9 Hz, 2H), 6.58 (s, 1H).

White solid, yield 87.6 mg (76%), Rf 0.16 (8:2, hexanes/ethyl acetate), mp = 81-84°C; 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J =8.5 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H), 6.64 (s, 1H), 2.66 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 197.1, 185.5, 141.2, 134.6, 130.2, 128.6, 67.9, 27.0; IR ν (cm–1) = 3032 (w), 2925 (w), 1698 (m), 1681 (s); HRMS (ESI), m/z [M + H]+ calcd for C10H9Cl2O2 230.9980, found 230.9984.

2,2-dichloro-1-phenylethanone (14)23,24 1-(4-aminophenyl)-2,2-dichloro-ethanone (19)

Yellow oil, yield 70.3 mg (74%), Rf 0.41 (9:1, hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J =7,5 Hz, 2H), 7.65 (t, J =7.5 – 15Hz, 1H), 7.52 (t, J = 8 – 16 Hz, 2H), 6.69 (s, 1H). 2,2-dichloro-1-(4-bromophenyl)-ethanone (15)23,24

Yellow oil, yield 81.3 mg (61%), Rf 0.42 (hexanes). H NMR (400 MHz, CDCl3) δ 7.97 (t, J =8.8 Hz, 2H), 7.67 (d, J = 9.2 Hz, 2H), 6.58 (s, 1H).

Orange solid, yield 52.3 mg (52%), Rf 0.25 (7:3, hexanes/ethyl acetate), mp = 79-81°C; 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 9.0 Hz, 2H), 6.67 (d, J = 9.0 Hz, 2H), 6.64 (s, 1H), 4.35 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 184.2, 152.5, 132.6, 121.1, 113.9, 68.0; IR ν (cm–1) = 3408 (m), 3335 (m), 3227 (m), 2924 (w), 2853 (w), 2692 (w), 1678 (m), 1633 (m), 1582 (s), 1560 (s), 1633 (m), 1443 (s), 1321 (s), 1288 (s), 1172 (s), 1138 (s); HRMS (CI), m/z [M + H]+ calcd for C8H8Cl2NO 203.9983, found m/z 203.9984.

1

2,2-dichloro-1-(3-thienyl)-ethanone (20)23,24

2,2-dichloro-1-(4-chlorophenyl)-ethanone (16)23,24 Yellow oil, yield 79.7 mg (82%), Rf 0.16 (hexanes). H NMR (500 MHz, CDCl3) δ 8.4 (s, 1H), 7.67 (s, 1H), 7.39 (s, 1H), 6.43 (s, 1H).

1

Yellow oil, yield 75.5 mg (68%), Rf 0.24 (9:1, hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 6.59 (s, 1H).

tert-butyl-(4-(2,2-dichloroacetyl)phenyl)carbamate (21)

2,2-dichloro-1-(4-methoxyphenyl)-ethanone (17)23,24

Yellow oil, yield 81.1 mg (74%), Rf 0.16 (9:1, hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J =8.5 Hz, 2H), 6.98 (d, J = 9 Hz, 2H), 6.64 (s, 1H), 3.90 (s, 3H). 1-(4-acetylphenyl)-2,2-dichloro-ethanone (18)

Yellowish-orange oil, yield 96.2 mg (63%), Rf 0,29 (8:2, hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 6.81 (s, 1H), 6.64 (s, 1H), 1.53 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 184.7, 152.0, 144.4, 131.6, 125.5, 117.7, 81.8, 67.7, 67.5; IR ν (cm–1) = 3339 (m), 2987 (w), 1740 (m), 1686 (m), 1583 (m), 1525 (s), 1416 (m), 1318 (m), 1203 (m), 1174 (m); HRMS (ESI), m/z [M + Na]+ calcd for C13H15Cl2NO3Na 326.0327, found 326.0323.



Page 8 of 10

ACKNOWLEDGMENT 23,24

2,2-dichloro-1-(4-fluorophenyl)-ethanone (22)

Yellow oil, yield 75.6 mg (73%), Rf 0.14 (hexanes). H NMR (500 MHz, CDCl3) δ 8.15 (m, 2H), 7.20 (m, 2H), 6.60 (s, 1H). 1

benzyl(4-(2,2-dichloroacetyl)phenyl)carbamate (23)

This research work was supported in part by an award from Kentucky Science and Engineering Foundation as per grant agreement #KSEF-148-502-17-396 with the Kentucky Science and Technology Corporation. We warmly acknowledge Novartis Pharmaceuticals for partial financial support. High resolution, accurate mass spectra were recorded by Ms. Angela Hansen at the Indiana University Mass Spectrometry Facility using a MAT-95XP mass spectrometer purchased with NIH grant 1S10RR016657-01. We also thank Dr. Yadagiri Dongari for a trial reaction.

REFERENCES

White solid, yield 133.2 mg (79%), Rf 0.26 (8:2, hexanes/ethyl acetate), mp = 119-122°C; 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.37-7.40 (m, 5H), 7.07 (s, 1H), 6.64 (s, 1H), 5.23 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 184.8, 152.8, 143.7, 135.5, 131.6, 128.8, 128.7, 128.5, 126.0, 117.9, 67.9, 40.0; IR ν (cm–1) = 3352 (m), 3066 (w), 3014 (w), 2921 (w), 2851 (w), 1684 (s), 1589 (m), 1527 (s), 1269 (m), 1178 (m); HRMS (CI), m/z [M + H]+ calcd for C16H14Cl2NO3 338.0351, found m/z 338.0344. 2,2-dichloro-1-(4-nitrophenyl)-ethanone (24)23,24

White solid, yield 95.5 mg (82%), Rf 0.45 (8:2, hexanes/ethyl acetate). 1H NMR (500 MHz, CDCl3) δ 8.4 (s, 1H), 7.67 (d, J = 5.2 Hz, 1H), 7.37 (d, J = 4.8 Hz, 1H), 6.43 (s, 1H).

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: xxx Reaction optimization, details of control-experiments, analytical data of compounds, and NMR data (PDF).

AUTHOR INFORMATION Corresponding Author

[email protected] Notes

The authors declare competing financial interest for the surfactant FI-750-M and their derivatives.

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kynes in Water Under Mild Conditions - ACS Publications

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