Supporting Information Palladium-catalyzed, ortho-selective C-H halogenation of benzyl nitriles, aryl Weinreb amides and anilides. Riki Das and Manmohan Kapur* Department of Chemistry, Indian Institute of Science Education and Research Bhopal Bhopal Bypass Road, Bhauri, Bhopal 462066, Madhya Pradesh, INDIA E-mail: mk@iiserb.ac.in Optimization table Page S2 Mechanistic and Kinetic Studies Pages S3-S9 1 H- and 13 C-NMR spectra of new compounds Pages S10-S66 X-ray crystallographic data Pages S67-S68 GC-MS data to check purity Page S69-S85 S1
1. Optimization table (Table S1): S2
2. Mechanistic Study: (i) Reversibility Experiment: i) Reversibility experiment in presence of NBS: In a pressure tube equipped with a stir bar, substrate (0.303 mmol) was dissolved in dry dichloroethane (1.5 ml). The reaction mixture was degassed with nitrogen for about 10 min, followed by the addition of Pd(OAc) 2 (0.03 mmol), Cu(OTf) 2 (0.151 mmol), D 2 O (1.515 mmole), and the N-halosuccinimide (0.606 mmol). The tube was fitted with a Teflon screw cap under nitrogen flow. The reaction mixture was heated to 80 o C and stirred at that temperature for 2h (in case of anilide: 5 min). After 2h (in case of anilide: 5min) and subsequent cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through a short pad of Celite, extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure and the crude product was purified by silica gel column chromatography. The extent of deuteration of starting material and product were checked by 1 HNMR. In case of the Weinreb amide and benzyl nitrile there was no significant deuteration in recovered starting material as well as product. But in case of 4-methyl anilide, the recovered starting material showed 26%-D incorporation and the product had around 6% -D incorporation. ii) Reversibility Experiment in absence of NBS: In a pressure tube equipped with a stir bar, substrate (0.303 mmol) was dissolved in dry dichloroethane (1.5 ml). The reaction mixture was degassed with nitrogen for about 10 min, followed by the addition of Pd(OAc) 2 (0.03 mmol), Cu(OTf) 2 (0.151 mmol) and D 2 O (1.515 mmole). The tube was fitted with a Teflon screw cap under nitrogen flow. The reaction mixture was heated to 80 o C and stirred at that temperature for 2h. After subsequent cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through a short pad of Celite and the organic filtrate was washed with brine. The organic layer was S3
conversion (%) dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure and the crude product was purified by silica gel flash column chromatography. The extent of deuteration of starting material was checked by 1 HNMR. In case of Weinreb amide and benzyl nitrile there was no significant deuterationbut in case of 4-methyl anilide, the starting material showed 78%-D incorporation. 3. Kinetic Studies: i) For Weinreb amide: Two parallel reactions for Weinreb amide and D 5 -Weinreb amide were performed according to the general procedure-(viii). Aliquots were drawn atone minute intervals and the conversion was checked by GC-MS, using dodecane as the internal standard. The conversion of starting material was plotted with time and k H /k D was found to be 1.35. Fig-S1 (Weinreb amide): 102 100 Equation y = a + b*x 0.95478 Adj. R-Square Value Standard Error conversion Intercept 100.8 0.92736 conversion Slope -3.5 0.37859 conversion Linear Fit of conversion 98 96 94 92 90 88 86 0 1 2 3 4 time (min) S4
Conversion (%) conversion (%) Fig-S2 (D 5 -Weinreb amide): Equation y = a + b*x 0.97674 Adj. R-Square Value Standard Error conversion Intercept 100.4 0.4899 conversion Slope -2.6 0.2 conversion Linear Fit of conversion 100 98 96 94 92 90 0 1 2 3 4 time (min) ii) For benzyl nitrile: Two parallel reactions for benzyl nitrile and D 7 -benzyl nitrile were performed according to the general procedure-(viii). Aliquots were drawn at one minute intervals and conversion was checked by HPLC using pentafluorobenzene as the internal standard. The conversion of starting material was plotted with time and k H /k D were found 1.40 Fig-S3 (Benzyl nitrile): 101 100 Equation y = a + b*x 0.98966 Adj. R-Square Value Standard Error Conversion Intercept 100.1 0.26458 Conversion Slope -2.4 0.14142 Conversion Linear Fit of Conversion 99 98 97 96 95 94 93 92 0.0 0.5 1.0 1.5 2.0 2.5 3.0 time (min) S5
consumption (%) Fig-S4 (D 7 -Benzyl nitrile): 100 Equation y = a + b*x 0.96949 Adj. R-Square Value Standard Error consumption Intercept 100.3 0.32404 consumption Slope -1.7 0.17321 consumption Linear Fit of consumption 99 98 97 96 95 0.0 0.5 1.0 1.5 2.0 2.5 3.0 time (min) iii) For anilide: Two parallel reactions for 4-methyl acetanilide and D 2-4-methyl acetanilide were performed according to the general procedure-(viii). Aliquots were drawn at one minute intervals and conversion was checked by HPLC using pentafluorobenzene as the internal standard. The conversion of starting material was plotted with time and k H /k D were found 1.60 Fig-S5 (4-methyl acetanilide): S6
Conversion (%) conversion (%) 100 Equation y = a + b*x 0.99342 Adj. R-Square Value Standard Error conversion Intercept 100.33333 0.26427 conversion Slope -2.4 0.08729 conversion Linear Fit of conversion 98 96 94 92 90 88 0 1 2 3 4 5 time (min) Fig-S6 (D 2-4-methyl acetanilide): 101 Equation y = a + b*x 0.9776 Adj. R-Square Value Standard Error Conversion Intercept 100.04762 0.30379 Conversion Slope -1.48571 0.10034 Conversion Linear Fit of Conversion 100 99 98 97 96 95 94 93 92 0 1 2 3 4 5 time (min) iv) Kinetic study by NMR: For Weinreb amide: S7
A mixture of Weinreb amide and D 5 -Weinreb amide (1:1) was taken and competition reaction was performed according to general procedure (viii). After 2h and subsequent cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through a short pad of Celite and the filtrate was washed with brine. The organic layer was dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure and the crude mixture was purified by silica gel column chromatography. Relative integration of the peaks of the recovered starting materials yielded a value of k H /k D = 1.28. For 4-methyl anilide: A mixture of 4-methyl acetanilide and D 2-4-methyl acetanilide (1:1) was taken and the competition reaction was performed according to general procedure (viii). After 5 min, and subsequent cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered through a short pad of Celite and the filtrate washed with brine. The organic layer was dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure and the crude mixture was purified by silica gel column chromatography. Relative integration of the peaks of the recovered starting material yielded a value of k H /k D = 1.35. 4. Relative rate determination: Three parallel reactions were performed for Weinreb amide, benzyl nitrile and 4-methyl acetanilide. The reaction was performed according to general procedure of palladium catalyzed C-H halogenation. Aliquots were drawn at one minute intervals and conversion of starting material was estimated by HPLC in presence of pentafluorobenzene as internal standard. The conversion of starting material was plotted with time. It was found that relative rate of acetanilide is much faster than other two substrates. S8
percentage of remained starting material (%) Fig S7:Relative rate plot: 100 80 Nitrile Weinreb amide Anilide 60 Weinreb amide 40 Nitrile 20 0 Anilide(p-methylacetanilide) 0 5 10 15 20 25 30 time (min) S9
5. 1 H and 13 C spectra S10
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6. X-ray crystallographic study of compound 4g: Figure S8: ORTEP of the compound 4g drawn with 50% ellipsoidal probability. Table S2: Single Crystal Data Collection and Refinement. Data 4g Formula C 8 H 5 Br I N Formula weight 321.94 Temperature/K 150(2) Wavelength (Å) 0.71073 CCDC number 1479412 Crystal system orthorhombic Space group Pnma a (Å) 10.8401(12) b (Å) 7.0137(8) c (Å) 11.9424(15) α ( ) 90 β ( ) 90 S67
( ) 90 V(Å 3 ) 907.97(18) Z 4 Density(g cm -3 ) 2.355 μ (mm -1 ) 7.861 F (000) 592 θ (min, max) 2.538, 30.562 h min, max, k min, max, l min, max -15 15, -10 10, -17 17 No. of ref. 25860 No. of unique ref./ obs. 1488/ 1295 Ref. No. parameters 67 R all, R obs 0.0393, 0.0315 wr2 all, wr2 obs 0.1196, 0.1127 ρ min, max (eå -3 ) -0.905, 1.859 G. O. F. 0.976 Data collection and refinement details: Single crystal data of the compound 4g was collected on the X-ray diffractometer using monochromated Mo Kα radiation (λ = 0.71073 Å). The crystal structure was solved by direct methods using SHELXT 2014 [1] and refined by the full matrix least squares method using SHELXL 2014 [2]. Absorption correction was applied using SADABS [3]. All non-hydrogen atoms were refined anisotropically and all hydrogen atoms were positioned geometrically and refined using a riding model. ORTEP was generated using Mercury 3.5.1 (CCDC) program [4]. References: 1. Sheldrick, G. M. Acta Crystallogr. 2015, A71, 3. 2. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112.. 3. Sheldrick, G. M. SADABS; Bruker AXS, Inc.: Madison, WI, 2007. 4. Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock E.; Rodriguez-Monge, L.; Taylor, R.; Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466. S68
7. Experiment for anilide substrate(6f) In case of anilide (6f) we carried out reaction in uncatalyzed as well as copper catalyzed condition and conversion was checked by HPLC by standardizing the product, and electrophilic halogenation product at para position. According to HPLC signal ortho halogenated product elutes at 6.8 min and para-halogenated product elutes at 15.8 min. HPLC data for uncatalyzed reaction(15 min): S69
In uncatalyzed condition only para-product formed no ortho halogenation occurred. HPLC data for Cu(II)-catalyzed reaction(15 min): In Cu(II)-catalyzed condition only 22% ortho-halogenated product formed along with 78% para-halogenated product. S70
HPLC data for our standard reaction condition (15 min): In our standard reaction condition, for this particular substrate, 70% ortho-halogenated product and 30% para-halogenated product was formed. The para-product was easily separated by column chromatography. S71
GCMS data to check the purity of select products: S72
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In this case starting material and product have same polarity, so after extensive purification still 4% starting material was there with product. S83
Variable temperature NMR for 4e: 60 o C 45 o C 25 o C S84
HRMS data for 5h: S85