Supporting Information 1 PDF n-bromoalkanoic acid (25 mmol)

15-Aug-2011 acid chloride using oxalyl chloride and a catalytic amount ... lyl chloride. The procedure was quite successful with ??- unsaturated acids ...

Supporting Information 1

n-bromoalkanoic acid (25 mmol) in DCM (50 mL) with oxalyl chloride (50 mmol) and General procedure for the synthesis of the diazides.

A more convenient method of preparation of amide derivatives of

formation of the acid chloride by heating the carboxylic acid The procedure has often ... the excess thionyl chloride with the amine.

THE USE OF OXALYL CHLORIDE AND BROMIDE FOR

Either acid anhydrides or acid chlorides may be obtained depending upon the condi- tions and proportions of materials used. Aliphatic and aromatic acid.

SYNTHETIC METHODS General methods

Product 17 - 118 Compounds were synthesized using standard procedures. ... 5-methyl-4-nitroisoxazole-3-carboxylic acid oxalyl chloride

1 The Acid Chloride Procedure

The acid chloride (about 3 g) is a colorless oil [5]. It The same acid chloride can be prepared by treating the tosylamino acid with thionyl chloride.

A Convenient Preparation of Volatile Acid Chlorides

The usual procedure for the preparation of or- ganic acid action of oxalyl chloride on organic acids. ... very simple: the acid is mixed with an excess.

www.rsc.org/advances

reaction by treating carboxylic acids with thionyl chloride and stoichiometric amounts of amines General procedure for one pot synthesis of amides 1-19.

Mild deprotection of the N-tert?butyloxycarbonyl (N-Boc) group using

23-Jun-2020 many applications: from the routine synthesis of acid chlorides ... a N-Boc protected peptidomimetic using oxalyl chloride we.

Nucleophilic Acyl Substitution via Aromatic Cation Activation of

18-Mar-2010 using oxalyl chloride thionyl chloride

S1- 1

Supporting Information 1

"High-Throughput Synthesis of Azide Libraries Suitable for Direct "Click"

Chemistry and in situ Screening

Rajavel Srinivasan, Lay Pheng Tan, Hao Wu, Peng-Yu Yang, Karunakaran A. Kalesh, and Shao Q. Yao* Departments of Chemistry and Biological Sciences, NUS MedChem Program of the Office of Life Sciences, National University of Singapore, 3 Science Drive 3, Singapore

117543

1. Chemical Synthesis:

1.1. Synthesis of the alkyne warhead (1)

O O O OH

OTsDibenzo-18-Crown-6

2CO3,CH3CN,

Reflux, 6 h(1) NaOMe

Dimethyloxalate

Reflux, 12 h

(2) NH

2OH.HCl

MeOH, Reflux, 3 d

O ON

MeOOCNaOH

MeOH:Water

(3:1) O ON HOOC 43
2F F FF1

Scheme S1. Synthesis of alkyne warhead 1

1-(4-Fluoro-2-(prop-2-ynyloxy)phenyl)ethanone acid (3):

Potassium carbonate (99 mmol) and benzo-18-crown-6 (3.3 mmol) were added to a solution of propargyl p-toluenesulfonate (66 mmol) and hydroxyl acetophenone 4 (66 mmol) in acetonitrile (100 mL) followed by refluxing for 6 h, after which the organic phase was removed under reduced pressure and taken into dichloromethane layer (80 mL) and extracted with NaHCO3 (2 x 40 mL), water (2 x 40 mL) and brine (1 x 40 mL). The organic phase was then dried with anhydrous Na 2 SO 4 , and the solvent was removed in vacuo to afford the crude product, which, upon further purification by flash column chromatography, afforded the pure propargyl phenyl ether 3 as a yellow solid (88% yield). 1

H-NMR (300 MHz, CDCl

3 ) į 7.85 - 7.79 (m, 1H), 6.82 - 6.72 (m, 2H), 4.80 (d, J = 2.46 Hz, 2H), 2.61 - 2.59 (m, 4H); 13

C-NMR (75 MHz, CDCl

3 ) į 197.6, 167.6, 164.2,

158.5, 132.7 (J

CF = 10.9 Hz), 125.0 (J CF = 3.3 Hz), 108.6 (J CF = 21.3 Hz), 101.0 (J CF

26.2 Hz), 76.7, 56.5, 31.8; ESI-MS: m/z [M-H]

= 191.2. Methyl 5-(4-fluoro-2-(prop-2-ynyloxy)phenyl)isoxazole-3-carboxylate (2): To a mixture of alkyne-derivatized acetophenone (53 mmol) and dimethyl oxalate (53 mmol) was added freshly prepared NaOMe (0.5 M in MeOH, 53 mmol). The reaction mixture was refluxed for 12 h before cooled to room temperature. To the same reaction

MeOH (80 mL), NH2

OH.HCl (53 mmol) and a catalytic amount of p-TsOH.H 2

O were

added and the resulting mixture was refluxed continuously for 3 days. Upon cooling to S1- 2room temperature, the precipitated compound was collected, washed with water and ice- cold methanol to afford the pure isoxazole-3-carboxylic acid methyl ester 2 as an off white solid (38% yield). 1

H-NMR (300 MHz, DMSO- d

6 ) į 8.02 - 7.99 (m, 1H), 7.27 (dd, J 1 = 2.39 Hz,, J 2 = 11.3 Hz, 1H), 7.15 (s, 1H), 7.09 - 7.03 (m, 1H), 5.12 (d, J = 2.31

Hz, 2H), 3.94 (s, 3H), 3.76 (t, J = 2.22 Hz, 1H);

ESI-MS: m/z [M+H]

= 274.7.

5-(4-Fluoro-2-(prop-2-ynyloxy)phenyl)isoxazole-3-carboxylic acid (1):

The methyl ester (4 mmol) was suspended in methanol (10 mL) and a NaOH solution (10 mL; 10 M solution) was added slowly and the reaction was stirred for 3 h before the pH was adjusted to ~2 using HCl (2 N solution) in ice-bath. The resulting precipitate was collected, washed with cold water, dried in vacuo to furnish the desired product 1 as a pale brown solid (92% yield). 1

H-NMR (300 MHz, DMSO-d

6 ) į 7.95 (t, J = 7.65 Hz,

1H), 7.21 (d, J = 11.19 Hz, 1H), 7.08 (s, 1H), 7.00 (t, J = 8.48 Hz, 1H), 5.08 (s, 2H), 3.71

(s, 1H); 13

C-NMR (75 MHz, DMSO- d

6 ) į 165.8 (d, J CF = 2.18 Hz), 166.2, 162.5, 160.9,

157.7, 155.5 (d, J

CF = 10.9 Hz), 129.0 (d, J CF = 10.4 Hz), 112.0 (d, J CF = 3.3 Hz), 108.7 (d, J CF = 21.8 Hz), 103.2, 102.0 (d, J CF = 26.2 Hz), 79.3, 78.1, 56.9; ESI-MS: m/z [M+H] = 262.1.

1.2. Synthesis of the azide libraries

1.2.1. Synthesis of linkers

ClO N 3 ClO N 3 ClO N 3 ClO N 3 ClO N 3 H 2 NN 3H 2 NN 3 H 2 NN 3H 2 NN 3 N 3 H 2

N5a 5b 5c 5d 5e

6a 6b 6c 6d 6e

Scheme S2. Synthesis of linkers.

Linkers 5a, 5b, were prepared from their corresponding acids as reported 2,3 . Linkers 5c,

5d and 5e were prepared as previously reported.

Linkers 6a-b was prepared as reported

5 . 6c-e were prepared from the diazides as reported. 6

Scheme for the synthesis of the linker 5a

HOBrO1. NaN

3 , H 2 O 0 o

C to RT

2. (COCl)

2 , DCM

Cat.DMFCl

N 3 O 5a Sodium azide (6.95 g, 50 mmol) was dissolved in 30 mL of distilled water and cooled to 0C. Bromoacetic acid (7.15 g, 100 mmol) was then added over 10 mins and the reaction was allowed to slowly warm to room temperature overnight. The reaction was acidified to pH = 1 and extracted with 5 10 mL diethyl ether. The organic layers were

S1- 3combined, dried over MgSO

4 , and concentrated to afford 2-azidoacetic acid as a colorless oil (70% yield). The 2-azidoacetic acid was then dissolved in 50 mL of DCM with two drops of DMF and cooled to 0C. Oxalyl chloride (3 mL, 35 mmol) was added slowly using a syringe over 15 min. The reaction was allowed to stir for 5 hours and the crude azido chloride 5a (in DCM) as used directly for solid-phase synthesis without further purification. HON 3 O 1

H-NMR (300 MHz, CDCl

3 ) į 10.97 (s, 1H), 3.97 (s, 2H). 13

C-NMR (75 MHz, CDCl

174.4, 49.9.

Scheme for the synthesis of the linker 5b

HOO1. NaN

3 , CH 3 CN

Reflux, 4 h

2. (COCl)

2 , DCMClO N 3 5b Br

3-Bromopropionic acid (25 mmol) was dissolved in acetonitrile (40 mL) and Sodium

azide was (50 mmol) added to the solution, the mixture was refluxed for 4 hours after which acetonitrile was removed in vacuo and the resulting residue was suspended in ethyl acetate (50 mL) and extracted with 0.1 N HCl (3 x 40mL), water (3 x 40 mL) and brine (1 x 30 mL). The organic layer was dried using anhydrous Na 2 SO 4 to afford the 3- azidopropionic acid in 87% yield. 3-Azidopropionic acid (20 mmol) was dissolved in DCM (40 mL) and treated with oxalyl chloride (20 mmol). The reaction was allowed to stir for 6 hours at room temperature to afford 3-azidoprionyl chloride 5b, which was used directly without any further purification. HOO N 3 1

H-NMR (300 MHz, CDCl

3quotesdbs_dbs14.pdfusesText_20

[PDF] Supporting Information 1 n-bromoalkanoic acid (25 mmol)

Supporting Information 1

Chemistry and in situ Screening

117543

1. Chemical Synthesis:

1.1. Synthesis of the alkyne warhead (1)

OTsDibenzo-18-Crown-6

2CO3,CH3CN,

Reflux, 6 h(1) NaOMe

Dimethyloxalate

Reflux, 12 h

2OH.HCl

MeOH, Reflux, 3 d

MeOOCNaOH

MeOH:Water

Scheme S1. Synthesis of alkyne warhead 1

1-(4-Fluoro-2-(prop-2-ynyloxy)phenyl)ethanone acid (3):

H-NMR (300 MHz, CDCl

C-NMR (75 MHz, CDCl

158.5, 132.7 (J

26.2 Hz), 76.7, 56.5, 31.8; ESI-MS: m/z [M-H]

MeOH (80 mL), NH2

O were

H-NMR (300 MHz, DMSO- d

Hz, 2H), 3.94 (s, 3H), 3.76 (t, J = 2.22 Hz, 1H);

ESI-MS: m/z [M+H]

5-(4-Fluoro-2-(prop-2-ynyloxy)phenyl)isoxazole-3-carboxylic acid (1):

H-NMR (300 MHz, DMSO-d

1H), 7.21 (d, J = 11.19 Hz, 1H), 7.08 (s, 1H), 7.00 (t, J = 8.48 Hz, 1H), 5.08 (s, 2H), 3.71

C-NMR (75 MHz, DMSO- d

157.7, 155.5 (d, J

1.2. Synthesis of the azide libraries

1.2.1. Synthesis of linkers

N5a 5b 5c 5d 5e

6a 6b 6c 6d 6e

Scheme S2. Synthesis of linkers.

5d and 5e were prepared as previously reported.

Linkers 6a-b was prepared as reported

Scheme for the synthesis of the linker 5a

HOBrO1. NaN

C to RT

2. (COCl)

Cat.DMFCl

S1- 3combined, dried over MgSO

H-NMR (300 MHz, CDCl

C-NMR (75 MHz, CDCl

174.4, 49.9.

Scheme for the synthesis of the linker 5b

HOO1. NaN

Reflux, 4 h

2. (COCl)

3-Bromopropionic acid (25 mmol) was dissolved in acetonitrile (40 mL) and Sodium

H-NMR (300 MHz, CDCl