All reagents were purchased from commercial suppliers and used without .... As a typical experiment, the pyrazole derivative (0.5 mmol), NFSI (X mmol), and ...
Supporting Information
Palladium-Catalysed C–H Bond Electrophilic Fluorination of Highly Substituted Arylpyrazoles: Experimental and DFT Mechanistic Insights
Christelle Testa, Julien Roger, Stephanie Scheib, Paul Fleurat-Lessard, and Jean-Cyrille Hierso
Table of contents
General conditions
2
Screening of the fluorination conditions
2
Purification procedures
3
Typical experimental procedure for the reactions of Table S1 and Table S2
4
Computational detailed studies
5
Experimental mechanistic studies
11
References
13
1
14
13
19
H, C and F NMR copy of new products.
General conditions All reagents were purchased from commercial suppliers and used without purifications. All reactions were performed in Schlenk tubes under argon. Unless otherwise stated, starting materials pyrazole derivatives were synthesized according to the literature.
[1] 1
13
H (300 MHz), C (75 or
19
125 MHz), F (282 or 470 MHz) spectra were recorded on Brucker AVANCE III instrument in CDCl3 solutions. Chemical shifts are reported in 1
ppm relative to CDCl3 ( H: 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 (HRMS) were obtained on a Thermo LTQ-Orbitrap XL with ESI source. Flash chromatography was performed on silica gel (230-400 mesh). Elemental analysis experiments were performed Thermo Electron Flash EA 1112 Series. All reactions were performed under an inert argon atmosphere using conventional vacuum-line and Schlenk techniques. Arylpyrazoles substrates were synthesized in one-step from Ullmann coupling or aromatic nucleophilic substitution with commercial halides and pyrazoles. All the fluorinated products were isolated and purified (+99%) via standard procedures.
Screening of the fluorination conditions Table S1. Screening of fluorination with 2-(1H-pyrazol-1-yl)benzonitrile using literature reported conditions.
+
[F ]
[Pd]
N-fluoro-2,4,6-trimethylpyridium
[a]
Yields
Solvent
Additive
PhCF3
CH3CN
0 0
(%)
Ref.[2]
Pd(OAc)2
Ref. [3]
Pd(OTf)2
N-fluoro-2,4,6-trimethylpyridium triflate
DCE
NMP
Ref. [4]
Pd(OAc)2
NFSI
CH3NO2
TFA
15
Ref. [5]
Pd2(dba)3
NFSI
CH3NO2
KNO3
0
[a]
tetrafluoroborate
[b]
[c]
+
Reaction conditions: 1 (0.5 mmol), [Pd] (10 mol%), [F ] (0.75 mmol), solvent (5 mL), co-solvent (CH3CN or NMP,
0.25 mL), at 110 °C, under argon, 17 h. NFSI = N-fluorobenzenesulfonimide. TFA = Trifluoroacetic acid (2.0 equiv). KNO3 (30 mol%).
2
[b]
NMR and GC yield.
[c]
Reaction performed at 70 °C.
Table S2. Screening of fluorination with 2-(1H-pyrazol-1-yl)benzonitrile.
+
[a]
Entry
[Pd]
[F ]
Solvent
Additive
Yields (%)
1
Pd(OAc)2
A
PhCF3
CH3CN
Trace
2
Pd(OAc)2
B
PhCF3
CH3CN
0
3
Pd(OAc)2
C
PhCF3
CH3CN
0
4
Pd(OAc)2
D
PhCF3
CH3CN
0
5
Pd(OAc)2
E
PhCF3
CH3CN
31
6
Pd(OAc)2
E
PhCF3
-
90 (51)
7
Pd(OAc)2
E
CH3CN
-
26
[d]
8
Pd(OAc)2
E
DCE
-
21
[d]
9
Pd(OAc)2
E
DMF
-
Trace
10
Pd(OAc)2
E
EtOAc
-
15
11
Pd(OAc)2
E
Ph(CF3)2
-
82
11
Pd(OAc)2
E
PhCF3
DCE
58
12
Pd(OAc)2
E
PhCF3
EtOAc
63
13
PdCl2
E
PhCF3
-
46
14
Pd(OOCCF3)2
E
PhCF3
-
25
15
Pd(OAc)2
E
PhCF3
PivOH
13
16
Pd(OAc)2
E
PhCF3
TFA
35
17
Pd(OAc)2
E
PhCF3
HOAc
10
[a]
[b]
[c]
[d] [e]
[f] [f] [f]
+
Reaction conditions: 1 (0.5 mmol), [Pd] (10 mol%), [F ] (0.75 mmol), solvent (5 mL), additive
(0.25 mL) 110 °C, under argon, 17 h. Reaction performed at 90 °C.
[e]
[b]
NMR and GC yield.
[c]
Reaction performed at 125 °C.
[f]
Isolated yield under bracket.
[d]
Acid (2 equiv).
Purification procedures Table S3. Work-up and purification procedures with 2-(1H-pyrazol-1-yl)benzonitrile.
Entry 1 2
Ref. [3] Ref. [4,5]
Work-up before chromatography
Yields (%)
[a]
Comments
Crude product
97
NFSI or NHSI as the major product
Solvents evaporation only
94
NFSI or NHSI as the major product
75
NFSI or NHSI as the major product
94
No effect on NFSI, no more NHSI
Filtration on Celite®
3
-
4
Ref. [2]
5
-
Extraction CH2Cl2/NaOH+H2O
82
No effect on NFSI, no more NHSI
6
-
Extraction CH2Cl2/ H2O + 3% NEt3
95
No more NFSI and NHSI
[a]
3
Ref
NMR and GC yield to 1a.
washing with ethyl acetate Dissolution with CH2Cl2/MeCN Extraction CH2Cl2/Na2CO3+H2O
After extraction, several conditions on silica gel column chromatography were attempted, for examples: a) heptane/CH2Cl2 or (ethyl acetate + 3% TEA) to remove NFSI from starting materials and products; b) heptane/Et2O or ethyl acetate to separate final product from others sideproducts.
Typical experimental procedure for the reactions of Table S1 and Table S2 As a typical experiment, the pyrazole derivative (0.5 mmol), NFSI (X mmol), and Pd(OAc)2 (0.05 mmol) were introduced in a Schlenk tube, equipped with a magnetic stirring bar. Dry trifluoromethylbenzene (5 mL) was added, and the Schlenk tube purged several times with argon. The Schlenk tube was placed in a pre-heated oil bath at 110 °C and reactants were allowed to stir for 17 h. After cooling to room temperature, the reaction mixture was filtered through a plug of silica and washed with ethyl acetate. The solvent was removed in vacuo and the residue was analyzed by NMR and gas chromatography to determine the conversion of the fluorinated product. Then, the residue was diluted with dichloromethane, and was washed three times with water + 3% of TEA. The combined organic layer was washed with water and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography using an appropriate ratio of the eluent.
4
Computational detailed studies We first considered different isomers for the resting state of the Pd(II) catalyst, as shown in Scheme S1. Starting from the solvated Pd(OAc)2 complex A, one solvent molecule is replaced by the arylpyrazole substrate 1 to form the complex B. Transition states for solvent replacement have not been searched. B can evolve in D via a hydrogen abstraction by the acetate group (TS-B). Starting from the AcOH molecule gave E without barrier. Substitution of the solvent by the 2-cyano-benzylpyrazole leads to the most stable Pd(II) complex of this process: I. B can evolve also evolve to C via replacement of the second solvent molecule by the arylpyrazole substrate 1. C then gives I via a hydrogen abstraction by the acetate group (TS-C). From I, a last hydrogen abstraction required an activation barrier of 38.8 kcal/mol (TS-I), which leads to F that evolves in G without any energetic barrier. As the two N2 atoms are in cis position in complex G, we also computed the trans-isomer H that lie much higher in energy. Both G and H complexes are much higher in energy than I that have thus been used as the most probable resting state for the mechanistic study of the fluorination process.
Scheme S1. Formation of different isomers for the resting state of the palladium complex. Pathways without investigated connections are represented by dashed grey lines. It is worth noting that Pd(OAc)2 naturally exists as a dimer or a trimer in solution. We thus checked their stability under our experimental conditions. Their reaction with arylpyrazole 1 give [Pd(1)2(OAc)2] monomeric complexes (C) in very exothermic processes (ΔE ≤ –60 kcal.mol 1
, Scheme S2). This is in agreement with previously reported experiments
[6]
that showed that dimer existence is not favoured when ratio
Pd:Ligand is larger than 1:2; under our conditions, this ratio is 1:20.
Scheme S2. Stability of Pd(OAc)2 dimer or trimer with arylpyrazole 1. 5
-
In order to check the accuracy of the computed geometries and energies, we also optimized the reaction intermediates encountered in the formation of the catalyst resting state (see Scheme S1) with the cc-pVDZ-PP basis set and associated pseudo potentials for Pd,
[7]
and the 6-
31++G(d,p) basis sets for all other atoms. In the following, this basis set will be denoted by BS2. Energies were then refined with single point [8]
calculations with the LANL08(f) basis set and associated pseudopotentials for Pd and the 6-311++G(2d,p) basis set for other atoms, and will be denoted by BS1//BS2. Single point energies at the triple-ζ level on both sets of geometries are gathered in Table S4. Table S4. Electronic energies (in kcal/mol) using the triple- ζ basis set BS1 on geometries optimized with the LANLD2Z basis set and the BS2 basis set. Energies (kcal/mol)
A
B
TS-B
C
D
E
I
TS-I
F
G
H
BS1//LANL2DZ
0
-19.4
+17.0
-37.0
-19.6
-11.2
-30.5
+8.3
-20.5
-12.2
-5.2
BS1//BS2
0
-18.8
+17.1
-35.9
-19.4
-11.0
-29.8
+8.7
-20.2
-12.0
-4.9
The average deviation between the two calculation levels is less than 0.5 kcal/mol with a maximum of 1.1 kcal/mol. This proves that the BS1//LANL2DZ level is accurate enough to describe the fluorination mechanism. The full mechanism we propose in Scheme S1 starts from the most stable resting state Pd(II) complex I-1 we found previously. Geometries of the main structures involved in the fluorination mechanism are shown in Scheme S3. We detail also several hypotheses, suggested in the current literature, that we confronted to the mechanism.
Scheme S3. Mechanism for the palladium catalysed fluorination of the o-cyano-benzylpyrazole 1.
6
I-1
II’-1
III’-1
III-1
TS-2
TS-1
II-1
TS-4
Scheme S4. Geometries of the main intermediates shown in Scheme S3 and Scheme 3 (main text).
a)
Pd(II)/Pd(IV) hypothesis and Pd(III) single electron-transfer
Following previous mechanistic studies,
[9,10]
we considered the oxidative addition of NFSI to the Pd(II) complex I-1 leading to a Pd(IV) complex -1
II'-1 through a rather high barrier of 46.3 kcal.mol (TS-2). Previous studies have suggested that a single electron transfer could take place to give a Pd(III) neutral complex.
[11]
Therefore, the ion-pair nature of this Pd(IV) complex was confirmed by comparing the natural charges of the -
°
atoms to those the isolated moieties N(SO2Ph)2 , N(SO2Ph)2 and the Pd complex in its radical or cationic form. Such an ionic system was already postulated,
[10]
The II'-1 pair rearranges via TS-3 into the neutral Pd(IV) complex II-1 stabilized by an intramolecular π-staking
interaction between the two phenyl pyrazole moieties. A reductive elimination from II-1 leads to the product III-1 and fluorination of the phenyl ring. The fluorination transition state TS-4 is similar to those found in studies by Saeys et al. -1
kcal.mol is lower than previous theoretical and experimental values.
7
[10,12]
[12]
even though the activation energy of 17.8
b)
Pd(II) outer-sphere attack hypothesis
In the course of our modeling an alternative pathway emerged thus that involves an outer-sphere direct fluorination. Following this -1
mechanistic proposal the metal centre remains Pd(II): a Pd(II) stabilized ion-pair III'-1 (–36.9 kcal.mol ) is formed through TS-1 (+29.2 -1
kcal.mol barrier). Intermediate III'-1 then evolves to the Pd(II) complex III-1.
[13]
Unexpectedly this path appears to be the most favourable one -1
since a classical path consisting of the oxidative addition of NFSI to Pd(II) complex is located almost 20 kcal.mol higher in energy, and is thus comparatively much disfavoured. The fluorinated arylpyrazole of III-1 is then replaced by the starting material 1 to give IV-1. Hydrogen abstraction by the acetate ligand gives V-1. The acetic acid just formed protonates the sulfonimide ligand via the low lying transition state TS8 to give VI-1 that releases HN(SO2Ph)2 barrierless to form I-1 back.
c)
Bimetallic [Pd–Pd] dimers formation
In addition, it has been postulated that the catalysts in fluorination reactions may form dimers.
14
In our case, however, as shown on Scheme
S4, such a dimer should react with the arylpyrazole 1 (in excess in the solution) to give two monometallic Pd complexes I-1, rendering this hypothesis less plausible.
Scheme S5. Reaction of a bimetallic Pd dimer with arylpyrazole 1
8
Table S5 and Table S6 gather the electronic energies (in Hartree) for all structures with the ωB97X-D functional and different basis sets or combination of basis sets. Table S5. Electronic energies for structures show in Scheme S1 at the ωB97X-D /LANL2DZ, ωB97X-D/BS1//ωB97X-D/LANL2DZ, ωB97XD/BS2 and ωB97X-D/BS1//ωB97X-D/BS2 levels. Electronic energy (Hartree) with the wB97X-D functional
9
Structure
LANL2DZ
BS1//LANL2DZ
BS2
BS1//BS2
1
-549.205888
-549.446508
-549.333817
-549.451402
1a
-648.413744
-648.681143
-648.539865
-648.687910
F-N(SO2Ph)2
-938.109909
-1714.863355
-1714.500960
-1714.989668
H-N(SO2Ph)2
-838.979508
-1615.722778
-1615.371537
-1615.840124
Ph-CF3
-569.096038
-569.288155
-569.153900
-569.296156
AcOH
-228.981924
-229.092028
-229.034825
-229.095497
A
-1721.730254
-1722.322905
-1722.711482
-1722.345206
B
-1701.879670
-1702.512141
-1702.915674
-1702.530404
TS-B
-1701.818392
-1702.454114
-1702.858413
-1702.473005
C
-1682.025429
-1682.698501
-1683,122268
-1682.712929
D
-1701.871476
-1702.512498
-1702.914511
-1702.531429
E
-1472.871881
-1473.407158
-1473.868615
-1473.422442
I-1
-1453.020457
-1453.596162
-1454.078088
-1453.607646
TS-I
-1452.956374
-1453.534392
-1454.015889
-1453.546282
F
-1452.993979
-1453.580197
-1454.061370
-1453.592356
G
-1223.995752
-1224.475015
-1225.015403
-1224.483783
H
-1223.984525
-1224.463897
-1225.004888
-1224.472583
Table S6. Electronic energies for structures shown in Scheme S3 at the ωB97X-D /LANL2DZ and ωB97X-D/BS1//ωB97X-D/LANL2DZ levels. Electronic energy (Hartree) with the wB97X-D functional 6-311++G(2d,p)|LANL08
Structure
LANL2DZ
I-1
-1453.020457
-1453.596162
II’-1
-2391.142005
-3168.478527
II-1
-2391.180766
-3168.497263
III’-1
-2391.186734
-3168.518366
III-1
-2391.257662
-3168.586922
IV-1
-2292.059629
-3069.360362
V-1
-2292.060362
-3069.368025
VI-1
-2292.042524
-3069.352325
TS-2
-2391.067016
-3168.385759
TS-1
-2391.098404
-3168.412948
TS-3
-2391.138546
-3168.475151
TS-4
-2391.149720
-3168.468946
TS-5
-2940.439077
-3718.006193
TS-6
-2291.998209
-3069.302380
TS-7
-2292.033620
-3069.344143
//LANL2DZ
Cartesian coordinates of all intermediates for the fluorination process are given in a separate file called Cartesian_Coordinates.xyz.
10
Experimental mechanistic studies Stoichiometric conditions with the 2-(1H-pyrazol-1-yl)-methoxybenzene (6) The 2-(1H-pyrazol-1-yl)-methoxybenzene (34.8 mg, 0.2 mmol), NFSI (63.1 mg, 0.2 mmol), and Pd(OAc)2 (44.9 mg, 0.2 mmol) were introduced in a Schlenk tube, equipped with a magnetic stirring bar. Acetonitrile (2 mL) was added, and the Schlenk tube purged several times with argon. The Schlenk tube was placed in a pre-heated oil bath at 80 °C. Samples of the reaction mixture were taken at the time of 1 1
h, 7 h, and 24 h. The residue was analyzed by H (300 MHz, CDCl3) and subjected directly to Orbitrap ionisation-MS analysis.
1
Figure S1. H NMR of the crude after 24 h.
11
19
F (282 MHz, CDCl3) NMR and also diluted by methanol and then
19
Figure S2. F NMR of the crude after 24 h.
Figure S3. MS spectrum of the crude after 24 h (full range).
12
References
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Deeming, I. P. Rothwell J. Organomet. Chem. 1981, 205, 117; d) A. D. Ryabov, I. K. Sakodinskaya, A. K. Yatsimirsky J. Chem. Soc., Dalton Trans. 1985, 2629. [7]
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a) P. Hay, W. Wadt, J. Chem. Phys. 1985, 82, 299; b) A. Ehlers, M. Böhme, S. Dapprich, A. Gobbi, A. Höllwarth, V. Jonas, K. Köhler, R.
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a) T. Furuya, D. Benitez, E. Tkatchouk, A. E. Strom, P. Tang, W. A. Goddard, T. Ritter, J. Am. Chem. Soc. 2010, 132, 3793; b) D.-V.
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[13]
An outer-sphere fluorination has been recently proposed for a nucleophilic allylic fluorination, see: M. H. Katcher, P.-O. Norrby, A. G.
Doyle, Organometallics 2014, 33, 2121. 14
a) D. C. Powers, T. Ritter Nat Chem 2009, 1, 302. b) D. C. Powers, M. A. L. Geibel, J.E.M.N. Klein, T. Ritter J. Am. Chem. Soc. 2009, 131,
17050. c) D. C. Powers, E. Lee, A. Ariafard, M.S. Sanford, B.F. Yates, A.J. Canty, T. Ritter J Am Chem Soc. 2012, 134, 12002. d) D. C. Powers, T. Ritter Acc Chem Res. 2011, 45, 840 and ref. therein.
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1
H, 13C and 19F NMR copy of new products.
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