A Versatile Palladium-Triphosphane System for Direct

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All reagents were purchased from commercial suppliers and used without .... NFSI (2). PhCF3. 110. 62. 42. 0. 20. Table SI-5. Screening of dibromination of ...
SUPPORTING INFORMATION

N-(2-pyridyl)sulfonyl groups for ortho-directing palladium carbon–halogen C–X bond formation at functionalized arenes (X = I, Br, Cl, F)

Johan Guilbaud, Marine Labonde, Hélène Cattey, Sylvie Contal, Christian Montalbetti, Nadine Pirio, Julien Roger, and Jean-Cyrille Hierso

Table of contents

General conditions

2

Screening of the conditions

2

Crystal data and experimental

5

1

H, 13C and 19F NMR copy of new products.

1

10

General conditions All reagents were purchased from commercial suppliers and used without further purifications. All reactions were performed under an inert argon atmosphere using conventional vacuum-line and Schlenk techniques. 2(Arylsulfone)pyridine substrates were synthesized according literature reports. 1H (500 MHz),

13

C (125 MHz),

19

F

(302 MHz) spectra were recorded on Bruker AVANCE III instrument in CDCl3 solutions. Chemical shifts are reported in ppm relative to CDCl3 (1H: 7.26 and

13

C: 77.16) and coupling constants J are given in Hz. GC

experiments were performed with a Shimadzu GC 2010 instrument. GC-MS experiments were performed with a Trace GC Ultra equipped with a mass-selective detector. High resolution mass spectra (HR-MS) were obtained on a Thermo LTQ-Orbitrap XL with ESI source. Flash chromatography was performed on silica gel (230-400 mesh) or with PuriFlash 450 from Interchim. Elemental analysis experiments were performed on a Thermo Electron Flash EA 1112 Series.

Screening of the conditions Table SI-1. Screening of monobromination of 2-(phenylsuphonyl)pyridine (1)

Entry

Pd (mol%)

NBS (eq.)

Solvent

T °C

Conv. (%)

1a (%)

1b (%)

1

-

NBS (1)

CH3NO2

110

0

0

0

2

Pd(OAc)2 (10)

NBS (2)

PhCF3

110

60

57

0

3

Pd(OAc)2 (10)

NBS (2)

HOAc

110

100

79

21

4

Pd(OAc)2 (10)

NBS (2)

CH3CN

80

3

3

0

5

Pd(OAc)2 (10)

NBS (2)

DCM

TA

0

0

0

6

Pd(OAc)2 (10)

NBS (2)

EtOAc

80

50

48

0

7

Pd(OAc)2 (10)

NBS (2)

DCE

80

100

76

24

8

Pd(OAc)2(10)

NBS (2)

CH3NO2

110

98

80

11

9

PdCl2 (10)

NBS (1)

CH3NO2

110

89

82

07

10

Pd(OAc)2 (10)

NBS (1)

CH3NO2

110

83

78

4

11

Pd(OAc)2 (10)

NBS (1)

CH3NO2

90

87

78

8

12

Pd(OAc)2 (5)

NBS (1.2)

CH3NO2

90

100

85

15

2

Table SI-2. Screening of monoiodination of 2-(phenylsulphonyl)pyridine (1)

Entry

Pd (mol%)

NBS (eq.)

Solvent

T °C

Conv. (%)

17a (%)

17b (%)

1

Pd(OAc)2 (5)

NIS (1.2)

CH3NO2

90

3

3

0

2

Pd(OAc)2 (10)

NIS (3)

HOAc

110

100

50

50

3

Pd(OAc)2 (5)

NIS (1.2)

HOAc

110

86

80

6

4

Pd(OAc)2 (5)

NIS (1.5)

HOAc

90

63

53

9

5

Pd(OAc)2 (5)

NIS (2)

HOAc

90

100

75

25

Table SI-3. Screening of monochlorination of 2-(phenylsulphonyl)pyridine (1)

Entry

Pd (mol%)

NBS (eq.)

Solvent

T °C

Conv. (%)

23a (%)

23b (%)

1

Pd(OAc)2 (5)

NCS (1.2)

CH3NO2

90

2

2

0

2

Pd(OAc)2 (10)

NCS (3)

HOAc

110

86

76

10

3

Pd(OAc)2 (5)

NCS (1.2)

HOAc

110

70

60

9

4

Pd(Cl)2 (5)

NCS (1.2)

HOAc

110

10

10

0

5

Pd(OAc)2 (5)

NCS (1.5)

HOAc

90

26

18

7

6

Pd(OAc)2 (5)

NCS (2)

HOAc

90

24

23

0

3

Table SI-4. Screening of monofluorination of 2-(phenylsulphonyl)pyridine (1)

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

Pd (mol%) Pd(OAc)2 (10) Pd(dba)2 (10) Pd2(dba)3 (5) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (5) Pd(OAc)2 (20)

Fluorinated reagent (eq.) NFSI (2)

Solvent

T °C

Conv. (%)

28a (%)

28b (%)

28c (%)

PhCF3

110

0

0

0

0

NFSI (2)

PhCF3

110

67

52

0

15

NFSI (2)

PhCF3

110

37

37

0

0

NFSI (2)

PhCF3

110

38

38

0

0

NFSI (2)

CH3NO2

110

17

17

0

0

NFSI (2)

HOAc

110

100

0

0

19

NFSI (2)

EtOAc

80

63

44

0

19

NFSI (2)

DCE

80

24

6

0

18

Selectfluor (2)

PhCF3

110

0

0

0

0

PyF.BF4 (2)

PhCF3

110

8

3

0

5

PhCF3

110

0

0

0

0

PhCF3

110

17

7

0

10

NFSI (3)

PhCF3

110

61

57

0

4

NFSI (4)

PhCF3

110

81

78

0

2

NFSI (2)

PhCF3

110

53

53

0

0

NFSI (2)

PhCF3

110

62

42

0

20

Me3PyF.BF4 (2) Me3PyF.OTf (2)

Unidentified product (%)

62+20

Table SI-5. Screening of dibromination of 2-(phenylsulphonyl)pyridine (1)

Entry 1 2 3 4

5

Pd (mol%) Pd(OAc)2 (5) Pd(OAc)2 (5) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10)

NBS (equiv) NBS (4) NBS (4) NBS (4) NBS (4) NBS (3)

Solvent

T °C

HOAc HOAc HOAc HOAc CH3NO2

120 90 110 90 110

4

Conv. (%) 100 81 100 100 100

1a (%) 53 72 39 70 0

1b (%) 47 9 61 29 100

Crystal data and experimental

Figure: The two fluoro phenyl and pyridyl groups were found disordered over two positions with occupation factors converged to 0.70:0.30, hence these two groups could share the same positions. Experimental. A single colourless prism-shaped crystal of 28a (0.30×0.18×0.07) mm3 was mounted on a mylar loop with grease on a Bruker APEX-II CCD diffractometer. The crystal was kept at T = 115 K during data collection. Using Olex2 (Dolomanov et al., 2009), the structure was solved with the ShelXT (Sheldrick, 2015) structure solution program, using the Direct Methods solution method. The model was refined with version 2014/7 of ShelXL (Sheldrick, 2015) using Least Squares minimisation. Crystal Data. C11H8FNO2S, Mr = 237.24, monoclinic, P21/c (No. 14), a = 7.5306(17) Å, b = 20.683(5) Å, c = 7.5212(16) Å,  = 118.981(6)°,  =  = 90°, V = 1024.8(4) Å3, T = 115 K, Z = 4, Z' = 1, (MoK) = 0.312, 13557 reflections measured, 2350 unique (Rint = 0.0902) which were used in all calculations. The final wR2 was 0.0971 (all data) and R1 was 0.0539 (I > 2(I)).

CCDC

1558706

Formula Dcalc./ g cm-3 /mm-1 Formula Weight Colour Shape Size/mm3 T/K Crystal System Space Group a/Å b/Å c/Å /° /° /° V/Å3 Z Z' Wavelength/Å Radiation type min/° max/° Measured Refl. Independent Refl. Reflections Used Rint Parameters Restraints Largest Peak Deepest Hole GooF wR2 (all data) wR2 R1 (all data) R1

C11H8FNO2S 1.538 0.312 237.24 colourless prism 0.30×0.18×0.07 115 monoclinic P21/c 7.5306(17) 20.683(5) 7.5212(16) 90 118.981(6) 90 1024.8(4) 4 1 0.71073 MoK 1.969 27.503 13557 2350 1447 0.0902 203 150 0.285 -0.397 1.031 0.0971 0.0825 0.1110 0.0539

A colourless prism-shaped crystal with dimensions 0.30×0.18×0.07 mm3 was mounted on a mylar loop with grease. X-ray diffraction data were collected using a Bruker APEX-II CCD diffractometer equipped with a Oxford Cryosystems low-temperature device, operating at T = 115 K. Data were measured using  and  scans using MoK radiation (X-ray tube, 50 kV, 32 mA). The total number of runs and images was based on the strategy calculation from the program APEX2 (Bruker).The maximum resolution achieved was  = 27.50°. Cell parameters were retrieved using the SAINT (Bruker, V8.34A, 2013) software and refined using SAINT 5

(Bruker, V8.34A, 2013) on 1625 reflections, 12 % of the observed reflections. Data reduction was performed using the SAINT (Bruker, V8.34A, 2013) software which corrects for Lorentz polarisation. The final completeness is 99.90 out to 27.503 in . The absorption coefficient  of this material is 0.312 at this wavelength ( = 0.71073) and the minimum and maximum transmissions are 0.6492 and 0.7456. The structure was solved in the space group P21/c (# 14) by Direct Methods using the ShelXT (Sheldrick, 2015) structure solution program and refined by Least Squares using version 2014/7 of XL (Sheldrick, 2015). All non-hydrogen atoms were refined anisotropically. Hydrogen atom positions were calculated geometrically and refined using the riding model. Table 1: Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 28a. Ueq is defined as 1/3 of the trace of the orthogonalised Uij. Atom S F C6 C7 C8 C9 C10 C11 FA C6A C7A C8A C9A C10A C11A O1 O2 N C1 C2 C3 C4 C5 NA C1A C2A C3A C4A C5A

x 7481.3(11) 3362(3) 5880(20) 6620(20) 5361(16) 3406(15) 2683(15) 3903(18) 9352(8) 7660(60) 7000(50) 7280(40) 8110(30) 8840(30) 8700(50) 6401(3) 9399(3) 8776(18) 7870(30) 7150(20) 7428(16) 8388(14) 9046(14) 4160(30) 5930(60) 6440(50) 5030(40) 3170(40) 2770(40)

y 6191.8(4) 6117.8(12) 6829(7) 7459(6) 7981(5) 7870(5) 7249(4) 6737(6) 6596(3) 5744(14) 5100(11) 4729(10) 5009(9) 5627(9) 5988(10) 5786.3(10) 6461.8(9) 6074(4) 5741(6) 5120(6) 4813(4) 5139(4) 5767(4) 6674(11) 6883(16) 7526(14) 7973(11) 7773(11) 7117(9)

z 1654.6(11) 1165(4) 1520(40) 1680(30) 1481(19) 1188(18) 1061(17) 1220(20) 5938(8) 3760(40) 3370(30) 5030(30) 6950(30) 7330(30) 5760(30) -101(3) 2052(3) 5557(13) 3839(19) 3679(16) 5413(13) 7236(13) 7245(12) 1290(50) 1550(110) 1640(80) 1520(50) 1180(50) 1120(40)

Ueq 23.06(19) 35.9(8) 19(3) 23(3) 25(2) 25(2) 28(2) 26(2) 31.9(18) 19(6) 9(4) 17(4) 18(4) 16(4) 14(5) 29.8(5) 29.3(5) 29(2) 20(2) 28(2) 25.8(18) 28.6(19) 30.2(19) 21(5) 21(8) 23(7) 20(6) 27(6) 17(5)

Table 2: Anisotropic Displacement Parameters (×104) 28a. The anisotropic displacement factor exponent takes the form: -22[h2a*2 × U11+ ... +2hka* × b* × U12] Atom S F C6 C7 C8 C9 C10 C11 FA O1 O2 N C1

U11 23.9(4) 22.9(13) 21(4) 20(4) 26(4) 29(4) 23(3) 18(4) 37(3) 38.6(12) 23.9(10) 32(3) 13(4)

U22 29.8(4) 35.1(16) 26(4) 32(4) 33(4) 32(4) 33(4) 35(4) 31(4) 33.4(12) 35.9(12) 33(4) 30(4)

U33 21.4(3) 50.7(17) 13(4) 21(4) 25(3) 18(3) 32(4) 29(4) 29(3) 20.5(10) 37.6(12) 25(3) 23(3) 6

U23 -1.1(3) 8.4(13) -2(3) -5(3) -1.8(19) 8(3) 14(3) 8(3) -12(3) -7.1(9) 3.3(10) -1(2) 1.0(17)

U13 15.6(3) 18.6(12) 10(2) 13(3) 18(3) 15(3) 17(2) 15(3) 17(3) 16.6(9) 22.6(10) 16(2) 14(2)

U12 -1.7(3) -4.4(11) -3(2) -3(3) -2(3) 6(3) 9(3) -2(3) -10(3) -3.2(10) -1.2(9) 3(3) 3(2)

Atom C2 C3 C4 C5

U11 23(4) 25(3) 28(4) 38(4)

U22 40(4) 28(4) 37(5) 30(4)

U33 21(4) 31(4) 20(3) 24(3)

U23 -5(3) -1(3) 1(3) 0(3)

U13 11(4) 18(3) 11(3) 15(2)

U12 -3(2) 0(3) 6(3) 4(3)

Table 3: Bond Lengths in Å for 28a. Atom S S S S S S F C6 C6 C7 C8 C9 C10 FA C6A C6A

Atom C6 C6A O1 O2 C1 C1A C11 C7 C11 C8 C9 C10 C11 C11A C7A C11A

Length/Å 1.755(15) 1.78(3) 1.4378(19) 1.4384(19) 1.785(13) 1.82(3) 1.338(13) 1.397(13) 1.408(13) 1.396(12) 1.398(11) 1.381(11) 1.369(13) 1.333(18) 1.40(2) 1.41(2)

Atom C7A C8A C9A C10A N N C1 C2 C3 C4 NA NA C1A C2A C3A C4A

Atom C8A C9A C10A C11A C1 C5 C2 C3 C4 C5 C1A C5A C2A C3A C4A C5A

Length/Å 1.39(2) 1.387(17) 1.365(17) 1.363(19) 1.326(11) 1.345(9) 1.375(13) 1.373(11) 1.377(10) 1.389(10) 1.32(2) 1.351(18) 1.38(2) 1.37(2) 1.363(19) 1.385(19)

Table 4: Bond Angles in ° for 28a. Atom C6 C6A O1 O1 O1 O1 O1 O2 O2 O2 O2 C7 C7 C11 C8 C7 C10 C11 F F C10 C7A C7A C11A

Atom S S S S S S S S S S S C6 C6 C6 C7 C8 C9 C10 C11 C11 C11 C6A C6A C6A

Atom C1 C1A C6 C6A O2 C1 C1A C6 C6A C1 C1A S C11 S C6 C9 C8 C9 C6 C10 C6 S C11A S

Angle/° 104.4(10) 102(2) 108.6(8) 106.1(8) 118.77(12) 107.9(4) 110.7(19) 108.2(4) 112.5(12) 108.1(5) 105.2(9) 117.6(9) 119.0(12) 123.4(10) 119.6(10) 119.7(9) 121.0(8) 119.2(8) 114.7(10) 123.7(9) 121.5(11) 116.3(18) 121(2) 121.6(18)

Atom C8A C9A C10A C11A FA FA C10A C1 N N C2 C3 C2 C3 N C1A NA NA C2A C3A C4A C3A NA

7

Atom C7A C8A C9A C10A C11A C11A C11A N C1 C1 C1 C2 C3 C4 C5 NA C1A C1A C1A C2A C3A C4A C5A

Atom C6A C7A C8A C9A C6A C10A C6A C5 S C2 S C1 C4 C5 C4 C5A S C2A S C1A C2A C5A C4A

Angle/° 117.0(19) 119.7(17) 123.0(18) 118.3(17) 115.8(18) 123.9(17) 120.0(18) 116.5(9) 113.7(9) 124.4(11) 121.7(9) 118.5(9) 119.0(8) 118.4(7) 123.2(7) 118(2) 109(2) 124(3) 127(2) 118(2) 120(2) 119(2) 121(2)

Table 5: Torsion Angles in ° for 28a. Atom S S S S S S S S C6 C6 C6 C7 C7 C7 C8 C9 C9 C11 C6A C6A C6A C7A C7A C7A C8A C9A C9A C11A O1 O1 O1 O1 O1 O1 O1 O1 O2 O2 O2 O2 O2 O2 O2 O2 N C1 C1 C1 C1 C2 C3 C5 C5 NA C1A C1A C1A C1A C2A C3A C5A

Atom C6 C6 C6 C6A C6A C6A C1 C1A S S C7 C6 C6 C8 C9 C10 C10 C6 S S C7A C6A C6A C8A C9A C10A C10A C6A S S S S S S S S S S S S S S S S C1 S S N C2 C3 C4 N N C1A S S NA C2A C3A C4A NA

Atom C7 C11 C11 C7A C11A C11A C2 C2A C1 C1 C8 C11 C11 C9 C10 C11 C11 C7 C1A C1A C8A C11A C11A C9A C10A C11A C11A C7A C6 C6 C6A C6A C1 C1 C1A C1A C6 C6 C6A C6A C1 C1 C1A C1A C2 C6 C6 C5 C3 C4 C5 C1 C1 C2A C6A C6A C5A C3A C4A C5A C1A

Atom C8 F C10 C8A FA C10A C3 C3A N C2 C9 F C10 C10 C11 F C6 C8 NA C2A C9A FA C10A C10A C11A FA C6A C8A C7 C11 C7A C11A N C2 NA C2A C7 C11 C7A C11A N C2 NA C2A C3 C7 C11 C4 C4 C5 N S C2 C3A C7A C11A C4A C4A C5A NA S

Angle/° 176.9(15) 4(3) -178.0(15) 175(3) 7(5) -179(3) -176.9(11) 179(4) -61.6(14) 114.0(16) 2(2) -177.5(18) 0(3) -0.9(19) -0.3(17) 178.2(12) 1(2) -2(3) -59(5) 123(6) 2(5) 176(3) -10(6) -6(4) 2(4) 180(2) 6(4) 5(6) -126.4(18) 52(2) 8(4) 178(3) -177.0(11) -1.4(17) 54(5) -124(5) 4(2) -177.8(18) -124(3) 46(4) 53.4(14) -131.0(14) -177(4) 6(6) -2(3) 118.7(19) -63(2) -1.5(17) 1(2) -0.1(15) 0.6(14) 177.6(9) 2(2) 2(9) 124(3) -66(4) 2(5) -4(6) 5(5) -4(4) -178(3) 8

Atom C5A

Atom NA

Atom C1A

Atom C2A

Angle/° -1(8)

Table 6: Hydrogen Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 28a. Ueq is defined as 1/3 of the trace of the orthogonalised Uij. Atom H7 H8 H9 H10 H7A H8A H9A H10A H2 H3 H4 H5 H2A H3A H4A H5A

x 7960 5833 2563 1354 6404 6892 8167 9431 6485 6963 8595 9719 7710 5356 2150 1504

y 7531 8411 8227 7177 4924 4286 4760 5800 4909 4383 4939 5990 7657 8420 8081 6977

z 1918 1546 1074 867 2041 4856 8035 8669 2399 5356 8459 8505 1791 1663 984 966

Ueq 28 30 30 33 11 20 21 20 34 31 34 36 28 24 33 20

Table 7: Atomic Occupancies for all atoms that are not fully occupied in 28a. Atom F C6 C7 H7 C8 H8 C9 H9 C10 H10 C11 FA C6A C7A H7A C8A H8A C9A H9A C10A H10A C11A N C1 C2 H2 C3 H3 C4 H4 C5 H5 NA C1A C2A

Occupancy 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.301(4) 0.301(4) 0.301(4) 0.301(4) 0.301(4) 0.301(4) 0.301(4) 0.301(4) 0.301(4) 0.301(4) 0.301(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.699(4) 0.301(4) 0.301(4) 0.301(4)

Atom H2A C3A H3A C4A H4A C5A H5A

Occupancy 0.301(4) 0.301(4) 0.301(4) 0.301(4) 0.301(4) 0.301(4) 0.301(4)

9

Citations APEX2 suite for crystallographic software: Bruker V8.34A : SADABS, SAINT, APEX2. Bruker AXS Inc Bruker axs, Madison, WI (2014).

Sheldrick, G. M. Acta Cryst. (2008) A64, 112-12.

O.V. Dolomanov and L.J. Bourhis and R.J. Gildea and J.A.K. Howard and H. Puschmann, Olex2: A complete structure solution, refinement and analysis program, J. Appl. Cryst., (2009), 42, 339-341. Sheldrick, G.M., Crystal structure refinement with ShelXL, Acta Cryst., (2015), C71, 3-8. Sheldrick, G.M., ShelXT-Integrated space-group and crystal-structure determination, Acta Cryst., (2015), A71, 3-8.

1

H, 13C and 19F NMR copy of new products.

2-(2-bromoparatoluensulfonyl)pyridine (2a):

2-(2,6-dibromoparatoluensulfonyl)pyridine (2b):

11

2-(2-bromo-4-tert-butylphenylsulfonyl)pyridine (3a):

12

2-(2-bromo-4-chlorophenylsulfonyl)pyridine (4a):

13

2-(2-bromo-4-fluorophenylsulfonyl)pyridine (5a):

14

15

2-(2-bromo-4-trifluorophenylsulfonyl)pyridine (6a):

16

2-(2-bromo-5-methylphenylsulfonyl)pyridine (7a):

17

2-(2-bromo-5-chlorophenylsulfonyl)pyridine (8a):

18

2-(2-bromo-6-methylphenylsulfonyl)pyridine (9a):

19

2-(2-bromo-6-chlorophenylsulfonyl)pyridine (10a):

20

2-(2-bromo-6-trifluorophenylsulfonyl)pyridine (11a):

21

22

2-(2-bromophenylsulfonyl)-5-methylpyridine (12a):

23

2-(2-bromophenylsulfonyl)-4-methylpyridine (13a):

24

2-(2,6-dibromophenylsulfonyl)-4-methylpyridine (13b):

25

2-(2-bromophenylsulfonyl)-pyrimidine (14a):

26

2-(2-iodophenylsulfonyl)pyridine (17a):

27

2-(2-iodo-4-tert-butylphenylsulfonyl)pyridine (18a):

28

2-(2-iodo-4-fluorophenylsulfonyl)pyridine (19a):

29

2-(2-iodo-5-methylphenylsulfonyl)pyridine (20a):

30

2-(2-iodo-6-methylphenylsulfonyl)pyridine (21a):

31

2-(2-iodophenylsulfonyl)-4-methylpyridine (22a):

32

2-(2,6-diiodophenylsulfonyl)-4-methylpyridine (22b):

33

2-(2-chlorophenylsulfonyl)pyridine (23a):

34

2-(2-chloro-4-tert-butylphenylsulfonyl)pyridine (24a):

35

2-(2-chloro-4-fluorophenylsulfonyl)pyridine (25a):

36

2-(2-chloro-6-methylphenylsulfonyl)pyridine (26a): 37

2-(2-chlorophenylsulfonyl)-4-methylpyridine (28a): 38

2-(2-fluorophenylsulfonyl)pyridine (28a):

39

40

2-(2-fluoro-4-tert-butylphenylsulfonyl)pyridine (29a): contaminated by the difluorinated product (29b)

41

42