supporting information - rsc · 2021. 2. 16. · 2.3 synthesis of bcp amides. to a solution of...

SI 1

Supporting Information

A Continuous Flow Synthesis of [1.1.1]Propellane Enabling Rapid Access to Bicyclo[1.1.1]pentane Derivatives

Kian Donnellya and Marcus Baumanna*

School of Chemistry, University College Dublin, Science Centre South, Belfield, D04 N2E2, Ireland

Table of Contents:

1. Materials and Methods SI 22. General Experimental Procedures SI 33. Reaction Optimisation SI 54. Spectroscopic Data SI 75. References SI 116. Copies of NMR Spectra SI 12

Electronic Supplementary Material (ESI) for ChemComm.This journal is © The Royal Society of Chemistry 2021

SI 2

1. Materials and Methods

Unless otherwise stated, all solvents were purchased from Fisher Scientific and used without further purification. Substrates and reagents were purchased from Fluorochem or Sigma Aldrich and used as received.

1H-NMR spectra were recorded on 400 MHz, 500 MHz and 600 MHz instruments and are reported relative to residual solvent: CDCl3 (δ 7.26 ppm). 13C-NMR spectra were recorded on the same instruments (100, 125 and 150 MHz) and are reported relative to CHCl3 (δ 77.16 ppm). 19F-NMR were recorded on a 400 and 500 MHz (376 and 470 MHz) spectrometer.

Data for 1H-NMR are reported as follows: chemical shift (δ/ ppm) (integration, multiplicity, coupling constant (Hz)). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, sext = sextet, sept = septet, m = multiplet. Data for 13C-NMR are reported in terms of chemical shift (δ/ ppm) and multiplicity (C, CH, CH2 or CH3). COSY, HSQC and HMBC experiments were used in the structural assignment.

IR spectra were obtained by use of a Bruker Platinum spectrometer (neat, ATR sampling) with the intensities of the characteristic signals being reported as weak (w, <20% of tallest signal), medium (m, 21-70% of tallest signal) or strong (s, >71% of tallest signal) .

High-resolution mass spectrometry was performed using the indicated techniques on a micromass LCT orthogonal time-of-flight mass spectrometer with leucine-enkephalin (Tyr-Gly-Phe-Leu) as an internal lock mass.

Photochemical experiments were performed on a Vapourtec E-series system with the UV150 photoreactor that is equipped with a medium-pressure Hg lamp (75-150 W) and used in combination with a low pass filter (emission spectra shown below).

Continuous flow experiments were performed using Chemyx Inc Fusion 100 syringe pumps in combination with a PolarBear Plus system. Flow reactor consisted of 1/8” PFA tubing combined with a stainless-steel T-piece mixer, followed by a Teflon helical static mixer.

SI 3

2. General Experimental Procedures.

2.1 Synthesis of [1.1.1]propellane

Tricyclo[1.1.1.0]pentane ([1.1.1]propellane) (2)

General procedure A (batch):1

Under N2 atmosphere, 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (3.00 g, 10.1 mmol) was dissolved in pentane (10 mL) and cooled to -78℃. A solution of MeLi in Et2O (1.6 M, 14 mL, 2.2 equiv.) was added dropwise over 15 minutes with vigorous stirring. The mixture was maintained at this temperature for a further 15 minutes before warming to 0 ℃ and stirring for a further 2 hours. The volatile materials were then transferred to a collection flask cooled to -78 ℃ under reduced pressure. The resulting solution containing [1.1.1]propellane was quantified by 1H-NMR using 1,3,5-trimethoxybenzene as internal standard.

General procedure B (flow):

1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (A) (594 mg, 2 mmol) was dissolved in pentane (10 mL). MeLi (B) (2.65 mL, 4.24 mmol, 2.1 equiv.) was transferred to a flame-dried flask under N2 atmosphere and diluted with freshly distilled Et2O (7.35 mL, final conc. 0.42 M). The flow system was flushed with a dilute solution of MeLi (0.16 M, 5 mL) prior to introducing reagents. A and B were injected at a flow rate of 0.566 mL min-1 (combined flow: 1.132 mL min-1, 6 min residence time) and combined in a T-piece mixer at -15 ℃. Cooling was achieved using Polar Bear Plus system, alternatively a salt-ice bath maintained at -15 ℃ was sufficient. The resulting solution was collected in a cooled flask (0 ℃) and washed with water. The resulting organic phase was separated and used for subsequent reaction without further purification. The concentration of the resulting [1.1.1]propellane solution was determined by 1H-NMR using 1,3,5-trimethoxybenzene as an internal standard.

2.2 Synthesis of chloro-oxoacetates.Oxalyl chloride (0.51 mL, 6 mmol) was diluted with CH2Cl2 (1 mL) and cooled to 0 ℃. A solution of alcohol (3 mmol) in CH2Cl2 (1 mL) was added dropwise while stirring. The mixture was stirred for 20 minutes before allowing to warm to room temperature for a further 2 hours. Solvent and excess oxalyl chloride were evaporated in vacuo yielding a colourless liquid. The material obtained was used for subsequent reactions without further purification.

2.3 Synthesis of BCP amides.To a solution of [1.1.1]propellane (2 mL, 0.17 M, 0.34 mmol) was added 2-chloro-2-oxoacetate (0.34 mmol) and acetone (1 drop). The mixture was pumped through a Vapourtec E-Series UV-150 photochemical reactor (medium pressure Hg-lamp (90 W), 10 mL reactor volume) at a flow rate of 2 mL min-1 (5 min residence time). 4-Fluoroaniline (32 µL, 0.34 mmol) and triethylamine (47 µL, 0.34 mmol) were added to the resulting output solution. The mixture was stirred for 2 hours at room temperature. The mixture was acidified using HCl (1 M) and extracted with EtOAc. Solvent was evaporated in vacuo and the resulting residue was purified by flash chromatography.

Chemical Formula: C5H6Exact Mass: 66.0470

SI 4

Flow reaction set-up:

UV-Vis spectra of medium-pressure Hg-lamp and effect of low-pass filter used:

SI 5

3. Reaction Optimisation.

3.1 Flow synthesis of [1.1.1]propellane.

Table 1. Solvent optimisation.

Entry MeLi Equiv. Residence Time (min) Solvent NMR Yield (%)1 2.1 3.8 Et2O 272 2.1 3.8 THF 113 2.1 3.8 Pentane 274 2.4 3.8 MeTHF 29

Reaction conditions: A (0.4 M) was combined with MeLi (B) (1.38 M in Et2O) at -10℃. The reaction material was collected in a test tube containing water (0℃) and the resulting organic phase was separated. [1.1.1]Propellane was quantified by 1H-NMR using 1,3,5-trimethoxybenzene as internal standard. Stoichiometry was controlled by adjusting the flow rates of A and B.

Table 2. Steady state study.

Entry A conc. (M) B conc. (M)MeLi (B)

Equiv.

Residence time (min)

Reactor volumes to reach steady state

5 0.4 1.6 2.1a 3 26 0.5 1.05 2.1 4 17 0.18 0.4 2.2 6 28 0.18 0.4 2.2 3 29 0.18 0.4 2.2 9 2.5

aStoichiometry controlled using flow rate.

3.2 Synthesis of BCP acyl chlorides.

O

OCl

OO

O

Cl

O

2 5b 6b

Table 3. Stoichiometry optimisation.

Entry 5b: 2 Concentration (M) NMR Yield (%)10 1.2: 1 0.26 1511 1.2:1 0.13 1412 3:1 0.27 113 1:1 0.16 3414 1:2 0.16 1915 1:3 0.16 3

Reaction conditions: 5b was added to a solution of [1.1.1]propellane. The mixture was passed through the photochemical reactor (5 min residence time, 90 W, gold light filter). Solvent was evaporated in vacuo and the residue was quantified by 1H-NMR using 1,3,5-trimethoxybenzene as internal standard.

SI 6

Table 4. Co-solvent study.

Entry Co-solvent NMR Yield (%)16 Acetonitrile 117 DMF 1418 DMSO 119 Acetone 020 DCM 021 THF 1022 EtOAc 22

Reaction conditions: 5b (0.23 mmol) was added to a solution of [1.1.1]propellane (1 mL, 0.23 M, 0.23 mmol). The mixture was diluted with co-solvent (1 mL) and passed through the photochemical reactor (10 min residence time, 90 W, gold light filter). Solvent was evaporated in vacuo and the residue was quantified by 1H-NMr using 1,3,5-trimethoxybenzene as internal standard.

Table 5. Photosensitiser study.

Entry Additive Equivalents NMR Yield (%)23 Acetone 0.2 2824 Acetone 0.5 3425 Acetone 1 2926 Acetone 5 2127 Acetone 10 1528 Benzophenone 0.2 1129 Benzophenone 0.5 1930 Benzophenone 1 2631 Benzophenone 2 1132 Benzophenone 3 1333 Acetophenone 0.2 1534 Acetophenone 0.5 735 Acetophenone 1 736 Pinacolone 0.2 1237 Pinacolone 0.5 1938 Pinacolone 1 10

Reaction conditions: Additive and 5b (0.2 mmol) was added to a solution of [1.1.1]propellane (1 mL, 0.2 M, 0.2 mmol). The mixture was passed through the photochemical reactor (5 min residence time, 90 W, gold light filter). Solvent was evaporated in vacuo and the residue was quantified by 1H-NMR using 1,3,5-trimethoxybenzene as internal standard.

SI 7

4. Spectroscopic Data.

Bicyclo[1.1.1]pentan-1-yl(2-methoxyphenyl)sulfane (3):2

Yield: 88% (50 mg, 0.24 mmol).Appearance: colourless liquid.

1H-NMR (400 MHz, CDCl3) δ/ppm 7.47 (dd, J = 7.6 Hz, 1.7 Hz, 1H), 7.26 (m, 1H), 6.89 (m, 2H) 3.86 (s, 3H), 2.69 (s, 1H), 1.96 (s, 6H). 13C-NMR (100 MHz, CDCl3) δ/ppm 158.9 (C), 135.1 (CH), 129.0 (CH), 122.1 (CS), 120.7 (CH), 110.8 (CH), 55.6 (CH3), 54.1 (3CH2), 45.2 (CS), 28.6 (CH).

[1.1.1]Propellane (synthesised either by general procedure A or B) (0.275 mmol) was transferred to a flame dried flask under N2 atmosphere. 4-Methoxybenzenethiol (67 µL, 0.55 mmol) was added while stirring. The mixture was stirred at room temperature for 1 hour. The mixture was washed with NaOH (1 M). The resulting organic phase was washed with water followed by brine. The organic phase was dried over Na2SO4 and solvent was evaporated in vacuo. The yellow residue was purified by flash chromatography (25% EtOAc in hexanes, Rf: 0.3) to yield a colourless liquid (50 mg, 88%).

Bicyclo[1.1.1]pentan-1-yl(4-(tert-butyl)phenyl)sulfane (4):2


HR-MS (QTOF) m/z: [M]+ Calcd for C15H20S+ 232.1286; found 232.1285.

1H-NMR (400 MHz, CDCl3) δ/ppm 7.38 - 7.35 (m, 2H), 7.33 - 7.29 (m, 2H), 2.71 (s, 1H), 1.94 (s, 6H), 1.31 (s, 9H). 13C-NMR (100 MHz, CDCl3) δ/ppm 150.5 (C), 133.2 (2 CH), 130.4 (C), 125.7 (CH), 53.9 (3 CH2), 45.7

(C), 34.5 (C), 31.3 (3 CH3), 28.6 (CH).

[1.1.1]Propellane (synthesised either by general procedure A or B) (0.275 mmol) was transferred to a flame dried flask under N2 atmosphere. 4-(Tert-butyl)benzenethiol (51 µL, 0.296 mmol) was added while stirring. The mixture was stirred at room temperature for 1 hour. The mixture was washed with NaOH (1 M). The resulting organic phase was washed with water followed by brine. The organic phase was dried over Na2SO4 and solvent was evaporated in vacuo. The yellow residue was purified by flash chromatography (5% EtOAc in hexanes) to yield a colourless liquid (53 mg, 83%).

1,3-Bis(phenylthiol)bicyclo[1.1.1]pentane (5):3

Yield: 95% (249 mg, 0.88 mmol) Appearance: white solid

1H-NMR (400 MHz, CDCl3) δ/ppm 7.43 – 7.40 (m, 4H), 7.31 - 7.27 (m, 6H), 2.03 (s, 6H). 13C-NMR (100 MHz, CDCl3) δ/ppm 134.0 (4CH), 133.3 (2C), 129.0 (4CH), 128.1 (2CH), 57.5 (3CH2), 42.7 (2C).

To a solution of [1.1.1]propellane synthesised by general procedure B (4 mL, 0.23 M, 0.92 mmol) was added diphenyl disulfide (606 mg, 2.78 mmol). The mixture was pumped through a Vapourtec E-Series UV-150 photochemical reactor (medium-pressure Hg lamp at 90 W, 10 mL reactor volume) at a flow rate of 1 mL min-1 (10 min residence time). The solvent was evaporated in vacuo and the resulting residue was purified by flash chromatography.

1,3-Diiodobicyclo[1.1.1]pentane (6):4

SH

Chemical Formula: C15H20SExact Mass: 232.1286

SHOMe

Chemical Formula: C12H14OSExact Mass: 206.0765

SS

Chemical Formula: C17H16S2Exact Mass: 284.0693

SI 8

Yield: 59% (982 mg, 3.07 mmol).Appearance: off-white solid.1H-NMR (400 MHz, CDCl3) δ/ppm 2.67 (s, 6H). 13C-NMR (100 MHz, CDCl3) δ/ppm: 68.3 (3CH2), -1.6 (C).

Iodine (1.3 g, 5.1 mmol) was added slowly to a stirring solution of [1.1.1]propellane (synthesised by general procedure B) until a dark red colour persisted. The mixture was stirred for a further 1 hour before washing with sat. sodium thiosulfate solution. The organic phase was dried over Na2SO4 and solvent was evaporated in vacuo. The residue was triturated from cold EtOAc yielding an off-white solid (982 mg, 59%).

Isopropyl 2-chloro-2-oxoacetate (7a):


1H-NMR (600 MHz, CDCl3) δ/ppm 5.19 (sept, J = 6.2 Hz, 1H), 1.39 (d, J = 6.3 Hz, 6H). 13C-NMR (150 MHz, CDCl3) δ/ppm: 161.6 (C), 155.4 (C), 74.2 (CH), 21.6 (2CH3).

Methyl 2-chloro-2-oxoacetate (7b):


1H-NMR (500 MHz, CDCl3) δ/ppm 3.99 (s, 3H). 13C-NMR (125 MHz, CDCl3) δ/ppm: 161.0 (C), 156.3 (C), 55.1 (CH3).

Ethyl 2-chloro-2-oxoacetate (7c):

Yield: 81% (331 mg, 2.42 mmol).Appearance: pale yellow liquid.

1H-NMR (600 MHz, CDCl3) δ/ppm 4.42 (q, J = 7.1 Hz, 2H), 1.41 (d, J = 7.1 Hz, 3H). 13C-NMR (150 MHz, CDCl3) δ/ppm: 161.3 (C), 155.8 (C), 65.2 (CH2), 14.0 (CH3).

Sec-butyl 2-chloro-2-oxoacetate (7d):


1H-NMR (400 MHz, CDCl3) δ/ppm 5.03 (sext, J = 6.3 Hz, 1H), 1.81-1.66 (m, 2H), 1.36 (d, J = 6.3 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ/ppm: 161.5 (C), 155.6 (C), 78.8 (CH), 28.6 (CH2), 19.2 (CH3), 9.6 (CH3).

Dodecyl 2-chloro-2-oxoacetate (7e):

Cl

OO

OChemical Formula: C6H9ClO3

Exact Mass: 164.0240

I I

Chemical Formula: C5H6I2Exact Mass: 319.8559

Cl

OO



Cl

OO



Cl

OO



SI 9

Yield: quantitative (829 mg, 2.99 mmol).Appearance: colourless liquid.

1H-NMR (600 MHz, CDCl3) δ/ppm 4.36 (t, J = 6.8 Hz, 2H), 1.76 (p, J = 6.8 Hz, 2H), 1.42-1.37 (m, 2H), 1.33-1.23 (m, 16H), 0.88 (t, J = 6.9 Hz, 3H). 13C-NMR (150 MHz, CDCl3) δ/ppm: 161.3 (C), 156.0 (C), 69.25 (CH2), 32.0 (CH2), 29.8 (2CH2), 29.7 (CH2), 29.54 (CH2), 29.47

(CH2), 29.2 (CH2), 28.3 (CH2), 25.7 (CH2), 22.8 (CH2), 14.3 (CH3).

Isopropyl 3-((4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate (9a):

Yield: 48% (47 mg, 0.16 mmol).Appearance: pale yellow solid.

HR-MS (QTOF) m/z: [M+Na]+ Calcd for C16H18O3FNa+ 314.1168; Found 314.1183.

1H-NMR (400 MHz, CDCl3) δ/ppm 7.50-7.47 (m, 2H), 7.16 (br s, NH), 7.04-6.99 (m, 2H), 5.01 (sept, J = 6.2 Hz, 1H), 2.35 (s, 6H), 1.25 (d, J = 6.2 Hz, 6H). 13C-NMR (100 MHz, CDCl3) δ/ppm 169.0 (C), 167.4

(C), 159.7 (d, J = 243 Hz, CF), 133.4 (d, J = 3 Hz, C), 121.7 (d, J = 8 Hz, 2CH), 115.9 (d, J = 22 Hz, 2CH), 68.6 (CH), 52.4 (3CH2), 39.9 (C), 37.2 (C), 21.9 (2CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -117.5 (m). IR (neat): v/cm-1: 3291 (br w), 2979 (w), 1721 (m), 1651 (m), 1613 (m), 1508 (s), 1408 (m),1309 (m), 1208 (s), 1149 (s), 1068 (m), 822 (s), 519 (m).

Methyl 3-((4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate (9b):

Yield: 18% (15 mg, 57 µmol).Appearance: pale yellow solid.

HR-MS (QTOF) m/z: [M+H]+ Calcd for C14H14FNO3+ 264.1030; Found

264.1034.

1H-NMR (500 MHz, CDCl3) δ/ppm 7.50 – 7.47 (m, 2H), 7.13 (br s, NH), 7.05 – 6.99 (m, 2H), 3.72 (s, 3H), 2.38 (s, 6H). 13C-NMR (125 MHz, CDCl3) δ/ppm 169.7 (C), 167.2 (C), 159.5 (d, J = 243 Hz, CF)

133.4 (d, J = 3 Hz, C), 121.8 (d, J = 8 Hz, 2CH), 115.9 (d, J = 22, 2CH), 52.6 (3CH2), 52.1 (CH3), 40.1 (C), 36.9 (C). 19F-NMR (376 MHz, CDCl3) δ/ppm -117.5 (m). IR (neat): v/cm-1: 3288 (br w), 2958 (w), 1722 (m), 1651 (s), 1614 (m), 1539 (m), 1506 (s), 1408 (m), 1314 (s), 1213 (s), 1156 (m), 1044 (m), 821 (s), 519 (m).

Ethyl 3-((4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate (9c):

Cl

OOC12H25



O

iPrO

NH

O

F

Chemical Formula: C16H18FNO3Exact Mass: 291.1271

O

MeO

NH

O

F


SI 10

Yield: 33% (31 mg, 0.11 mmol)Appearance: pale yellow solid


278.1192.

1H-NMR (500 MHz, CDCl3) δ/ppm 7.50-7.47 (m, 2H), 7.15 (br s, NH), 7.03-7.00 (m, 2H), 4.16 (q, J = 7.2 Hz, 2H), 2.37 (s, 6H), 1.28 (t, J = 7.1 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ/ppm 169.4 (C), 167.1

(C), 159.5 (d, J = 243 Hz, CF), 133.4 (d, J = 3 Hz, C), 121.8 (d, J = 22 Hz, 2CH), 115.9 (d, J = 22 Hz, 2CH), 61.1 (CH2), 52.5 (3 CH2), 40.0 (C), 37.0 (C), 14.3 (CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -117.5 (m). IR (neat): v/cm-1: 3329 (br w), 3052 (w), 1722 (s), 1650 (s), 1613 (m), 1505 (s), 1374 (m), 1210 (s), 1010 (m), 809 (s).

Sec-butyl 3-((4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate (9d):

Yield: 38% (39 mg, 0.13 mmol).Appearance: pale yellow solid.


306.1502.

1H-NMR (500 MHz, CDCl3) δ/ppm 7.49 (dd, J = 8.9, 4.8 Hz, 2H), 7.17 (br s, NH), 7.02 (t, J = 8.7 Hz, 2H), 4.85 (sext, J = 6.3 Hz, 1H), 2.36 (s, 6H), 1.60 (m, 2H), 1.22 (d, J = 6.3 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ/ppm 169.1 (C), 167.4 (C), 159.7 (d, J =

243 Hz, CF), 133.4 (d, J = 3 Hz, C), 121.7 (d, J = 8 Hz, 2CH), 115.9 (d, J = 22 Hz, 2CH), 73.0 (CH), 52.5 (3CH2), 40.0 (C), 37.17 (C), 28.9 (CH2), 19.6 (CH3), 9.7 (CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -117.5 (m). IR (neat): v/cm-1: 3280 (br w), 2978 (w), 1719 (m), 1650 (m), 1532 (m), 1507 (s), 1407 (m), 1311 (m), 1278 (m), 1173 (s), 1036 (m), 825 (s), 518 (m).

Dodecyl 3-((4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate (9e):

Yield: 30% (43 mg, 0.10 mmol).Appearance: off-white solid


418.2755.

1H-NMR (500 MHz, CDCl3) δ/ppm 7.51 - 7.46 (m, 2H), 7.16 (br s), NH), 7.04-6.99 (m, 2H), 4.09 (t, J = 6.8 Hz, 2H), 2.37 (s, 6H), 1.64 (pent, J = 5.7 Hz, 2H), 1.29 (m, 18H), 0.88 (t, J = 5.7 Hz, 3H). 13C-NMR

(125 MHz, CDCl3) δ/ppm 169.5 (C), 167.3 (C), 159.7 (d, J = 243 Hz, CF), 133.4 (d, J = 3 Hz, C), 121.7 (d, J = 8 Hz, 2CH), 115.9 (d, J = 22 Hz, 2CH), 65.3 (CH2), 52.5 (3 CH2), 40.0 (C), 37.0 (C), 32.1 (CH2), 29.79 (CH2), 29.77 (CH2), 29.71 (CH2), 29.65 (2 CH2), 29.5 (CH2), 29.4 (CH2), 28.6 (CH2), 26.0 (CH2), 22.8 (CH2), 14.3 (CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -117.5 (m). IR (neat): v/cm-1: 3312 (w, br), 2916 (m), 2847 (m), 1720 (s), 1651 (s), 1537 (s), 1507 (s), 1408 (m), 1277 (m), 1210 (s), 832 (m).

O

sBuO

NH

O

F


O

C12H25O

NH

O

F


O

EtO

NH

O

F


SI 11

5. References:

1. K. R. Mandanaro, W. P. Dailey, Org. Synth., 1998, 75, 98. 2. R. M. Bär, S. Kirschner, M. Nieger, S. Bräse, Chem. Eur. J., 2018, 24, 1373. 3. R. M. Bär, G. Heinrich, M. Nieger, O. Fuhr, S. Bräse, Beilstein J. Org. Chem. 2019, 15, 1172.4. K. B. Wiberg, S. T. Waddell, J. Am. Chem. Soc., 1990, 112, 2194.

SI 12

6. Copies of NMR SpectraBicyclo[1.1.1]pentan-1-yl(2-methoxyphenyl)sulfane (3):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

6.00

0.94

3.47

2.39

1.11

1.04

1.96

2.69

3.86

6.87

6.87

6.89

6.89

6.91

6.91

6.92

6.92

6.93

6.94

7.24

7.24

7.26

7.26

7.26

7.26

7.46

7.46

7.47

7.48

0102030405060708090100110120130140150160170180190200f1 (ppm)

28.5

8

45.1

5

54.1

455

.62

110.

79

120.

7112

2.21

129.

00

135.

06

158.

86

SI 13

Bicyclo[1.1.1]pentan-1-yl(4-(tert-butyl)phenyl)sulfane (4):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

9.69

6.00

0.94

4.00

1.31

1.94

2.717.

297.

307.

307.

317.

317.

327.

327.

337.

337.

347.

357.

357.

367.

377.

377.

377.

38

0102030405060708090100110120130140150160170180190200f1 (ppm)

28.5

931

.26

34.5

2

45.6

7

53.9

4

125.

7313

0.44

133.

23

150.

54

SI 14

1,3-Bis(phenylthiol)bicyclo[1.1.1]pentane (5):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

6.00

5.87

3.89

2.03

7.27

7.28

7.28

7.29

7.29

7.30

7.30

7.30

7.31

7.40

7.40

7.41

7.41

7.41

7.42

7.42

7.42

7.43

0102030405060708090100110120130140150160f1 (ppm)

42.6

8

57.5

0128.

0612

9.04

133.

3313

3.98

SI 15

1,3-Diiodobicyclo[1.1.1]pentane (6):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

0.99

2.67

-505101520253035404550556065707580859095100105110115120125130135140f1 (ppm)

-1.5

9

68.2

9

SI 16

Isopropyl 2-chloro-2-oxoacetate (7a):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

6.69

1.00

1.39

1.40

5.16

5.17

5.18

5.19

5.20

5.21

5.22

0102030405060708090100110120130140150160170180190200f1 (ppm)

21.5

6

74.2

2

155.

41

161.

57

SI 17

Methyl 2-chloro-2-oxoacetate (7b):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

3.00

3.99

0102030405060708090100110120130140150160170180190200f1 (ppm)

55.1

3

156.

31

161.

01

SI 18

Ethyl 2-chloro-2-oxoacetate (7c):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

3.18

2.00

1.39

1.41

1.42

4.40

4.41

4.43

4.44

0102030405060708090100110120130140150160170180190200f1 (ppm)

13.9

5

65.2

2

155.

83

161.

30

SI 19

Sec-butyl 2-chloro-2-oxoacetate (7d):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

3.27

3.29

1.98

1.00

0.94

0.96

0.97

1.35

1.36

1.65

1.66

1.66

1.66

1.67

1.68

1.68

1.69

1.70

1.70

1.71

1.72

1.72

1.73

1.73

1.74

1.75

1.76

1.77

1.77

1.79

1.81

4.99

5.00

5.02

5.04

5.05

5.07

0102030405060708090100110120130140150160170180190200f1 (ppm)

9.56

19.1

8

28.6

3

78.7

5

155.

61

161.

50

SI 20

Dodecyl 2-chloro-2-oxoacetate (7e):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

2.65

16.0

02.

22

2.08

2.05

0.87

0.88

0.89

1.23

1.24

1.26

1.27

1.28

1.29

1.29

1.30

1.31

1.32

1.32

1.33

1.33

1.33

1.34

1.35

1.35

1.37

1.37

1.38

1.38

1.38

1.39

1.39

1.40

1.40

1.41

1.42

1.42

1.43

1.74

1.75

1.76

1.77

1.78

4.34

4.36

4.37

0102030405060708090100110120130140150160170180190200f1 (ppm)

14.2

522

.83

25.7

328

.33

29.2

129

.47

29.5

429

.65

29.7

532

.05

69.2

5

155.

96

161.

27

27.528.028.529.029.530.0f1 (ppm)

28.3

3

29.2

129

.47

29.5

429

.65

SI 21

Isopropyl 3-((4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate (9a):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

6.38

6.00

0.95

1.98

1.05

2.05

1.24

1.26

2.35

4.97

4.98

5.00

5.01

5.03

5.04

5.06

6.99

7.00

7.01

7.01

7.01

7.02

7.02

7.03

7.03

7.04

7.16

7.47

7.48

7.49

7.50

7.07.17.27.37.47.5f1 (ppm)

6.98

536.

9943

7.00

007.

0061

7.01

127.

0149

7.01

697.

0208

7.02

597.

0321

7.03

76

7.16

24

7.46

877.

4742

7.48

057.

4860

7.49

137.

4980

7.50

31

0102030405060708090100110120130140150160170f1 (ppm)

21.9

1

37.1

639

.89

52.4

4

68.5

6115.

7611

5.98

121.

6912

1.77

133.

4013

3.43

158.

4416

0.87167.

3716

9.00

SI 22

-165-160-155-150-145-140-135-130-125-120-115-110-105-100-95-90-85f1 (ppm)

1.00

-117

.556

9-1

17.5

447

-117

.534

7

-117

.510

5-1

17.5

007

-117

.488

1

Methyl 3-((4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate (9b):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

6.00

2.99

1.88

0.94

1.78

2.38

3.72

6.99

7.00

7.00

7.01

7.02

7.02

7.02

7.03

7.03

7.04

7.04

7.05

7.13

7.47

7.48

7.49

7.50

7.07.17.27.37.47.5f1 (ppm)

6.99

7.00

7.00

7.01

7.02

7.02

7.02

7.03

7.03

7.04

7.04

7.05

7.13

7.47

7.47

7.48

7.49

7.49

7.50

7.50

SI 23

0102030405060708090100110120130140150160170f1 (ppm)

36.8

5

40.0

9

52.1

052

.59

115.

7811

6.01

121.

7212

1.80

133.

3413

3.37

158.

4716

0.90

167.

1616

9.74

-150-145-140-135-130-125-120-115-110-105-100-95-90-85f1 (ppm)

1.00

-117

.49

-117

.47

-117

.46

-117

.44

-117

.43

-117

.42

SI 24

Ethyl 3-((4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate (9c):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

2.96

6.00

2.09

2.06

1.09

2.00

1.27

1.28

1.30

2.37

4.14

4.16

4.17

4.18

7.00

7.00

7.01

7.01

7.02

7.02

7.02

7.03

7.03

7.03

7.16

7.47

7.48

7.49

7.50

7.07.17.27.37.47.5f1 (ppm)

7.01

7.02

7.02

7.03

7.03

7.03

7.03

7.04

7.04

7.05

7.17

7.48

7.49

7.49

7.50

7.50

7.51

7.51

0102030405060708090100110120130140150160170f1 (ppm)

14.3

0

36.9

8

39.9

9

52.5

2

61.0

8115.

7911

5.97

121.

7212

1.78

133.

3813

3.40

158.

6916

0.63

167.

2816

9.41

SI 25

-165-160-155-150-145-140-135-130-125-120-115-110-105-100-95-90-85f1 (ppm)

1.00

-117

.527

6-1

17.5

151

-117

.505

3

-117

.480

9-1

17.4

710

-117

.458

4

Sec-butyl 3-((4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate (9d):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

3.16

3.09

2.66

6.00

0.96

2.07

0.99

2.15

0.88

0.89

0.911.22

1.23

1.51

1.53

1.54

1.55

1.56

1.57

1.58

1.58

1.60

1.61

1.63

1.64

1.66

2.36

4.82

4.83

4.85

4.86

4.87

4.88

7.00

7.02

7.03

7.17

7.47

7.48

7.49

7.07.17.27.37.47.5f1 (ppm)

7.00

7.03

7.17

7.47

7.48

7.49

7.50

SI 26

0102030405060708090100110120130140150160170f1 (ppm)

9.74

19.5

7

28.8

8

37.1

739

.92

52.4

5

73.0

1

115.

7811

5.96

121.

6912

1.75

133.

4113

3.43

158.

6816

0.62

167.

3516

9.13

-145-140-135-130-125-120-115-110-105-100-95-90-85-80f1 (ppm)

1.00

-117

.558

8-1

17.5

462

-117

.536

1

-117

.512

4-1

17.5

023

-117

.489

8

SI 27

Dodecyl 3-((4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate (9e):

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)

2.67

18.7

7

2.11

5.86

2.11

1.97

1.00

1.97

0.86

0.88

0.89

1.26

1.27

1.28

1.29

1.29

1.30

1.30

1.31

1.32

1.33

1.33

1.34

1.34

1.35

1.61

1.63

1.64

1.65

1.67

2.37

4.08

4.09

4.11

6.99

7.00

7.00

7.01

7.01

7.02

7.02

7.02

7.02

7.03

7.03

7.04

7.16

7.47

7.48

7.49

0102030405060708090100110120130140150160170f1 (ppm)

14.2

6

22.8

325

.98

29.3

729

.49

29.6

529

.71

29.7

729

.79

32.0

636

.99

40.0

1

52.5

2

65.2

7

115.

7911

5.97

121.

7112

1.77

133.

3913

3.41

158.

6916

0.6316

7.27

169.

45

SI 28

-150-145-140-135-130-125-120-115-110-105-100-95-90-85-80f1 (ppm)

0.88

-117

.506

2-1

17.4

960

-117

.488

6

-117

.468

4-1

17.4

609

-117

.450

8

supporting information - rsc · 2021. 2. 16. · 2.3 synthesis of bcp amides. to a solution of...

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