19F-NMR Diastereotopic Signals in Two N-CHF2 Derivatives of (4S,7R)-7,8,8-Trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole

In this paper, we report the anisochrony of the fluorine atoms of a CHF2 group when linked to a pyrazole ring. The pyrazole is part of (4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole also known as (4S,7R)-campho[2,3-c]pyrazole, which has two stereogenic centers. Gauge-Independent Atomic Orbital (GIAO)/Becke, 3-parameter, Lee-Yang-Parr (B3LYP)/6-311++G(d,f) calculated 19F chemical shifts of the minimum energy conformations satisfactorily agree with the experimental data. The energy differences between minima need to consider solvent effects (continuum model) to be satisfactorily reproduced.


Introduction
Anisochrony in NMR is observed when a prochiral group is linked to a molecule possessing a stereogenic center. In these conditions, the studied nuclei became diastereotopic [1][2][3][4]. In the majority of cases, the literature reports concern 1 H-NMR and often the protons of CH 2 X groups (e.g., benzyl groups) [5,6]. The phenomenon can be observed on the methyl groups of Me 2 X substituents (e.g., isopropyl groups), with both 1 H-and 13 C-NMR [7]. Much less common is the observation of the anisochrony of phenyl substituents in CPh 2 X groups, also with 1 H-and 13 C-NMR [8,9].
In the present paper, we present our results concerning the observation of 19 F diastereotopic signals. In 1957, anisochronous signals were already observed for F 2 BrC-C*HBrPh, before the phenomenon was clearly understood [24]. Since then, the phenomenon has been repeatedly described, mainly for CHF 2 groups [25][26][27], but also for CRF 2 groups [28,29] as well as CRAr 2 (Ar = meta and para substituted with F atoms) and CR(CH 2 F) 2 [30].

Chemistry
As indicated in Scheme 1, compounds 13 and 14 were prepared for the first time by direct difluoromethylation of camphopyrazole 15 with sodium chlorodifluoroacetate (SCDA) [45], according to the Mehta and Greaney conditions [46] or by adding a phase transfer catalyst [47], in both cases using N,N -dimethylformamide as solvent and K 2 CO 3 as base. Both isomers were obtained in an 85:15 ratio (see Experimental Section). The only other paper where the N-substitution of 15 was reported (with 1,2-dichloroethane) yielded a 50:50 mixture of both isomers [48]. The structure elucidation of compounds 13 and 14 was based on the close correlation of the 13 C chemical shifts of the pyrazole ring with those of a reference compound [48].

NMR Spectroscopy
In both configurational isomers, the fluorine atoms are diastereotopic, and two distinct signals were observed for each one. From the spectra (Figures 2 and 3 and data given in Supplementary Materials), 2 J( 1 H-19 F) and 2 J( 19 F-19 F) coupling constants can be measured.  The 2 J FF SSCC (spin-spin coupling constant) in F-C-F compounds is very sensitive to structural aspects, especially the C atom hybridization; for sp 3 carbons range between 3.5 and 340 Hz [49].
There are no 2 J FF values published for N-azolyl derivatives, and thus the values we have measured (about 225 Hz) are the only representatives of this kind of compound.
In 1 H-NMR (see experimental part and Supplementary Material), the most interesting information concerning the CHF 2 group where when the anisochrony is larger (compound 13) the two 2 J HF couplings are different and when the anisochrony is smaller (compound 14) they are identical. Moreover, the signal of the 9-CH 3 group in compound 13 shows a long-distance 6 J HF coupling of 1.4 Hz (also measured in the 19 F-NMR spectrum, see Figure 2); in compound 14, this coupling is not observed due to the additional bond (it would be a 7 J HF ).
This conformational preference can most probably be explained by the dominance of vicinal hyperconjugation, with electron donation from the electron-rich sigma N-N bonding orbital into both of the very electron deficient vicinal C-F anti-bonding orbitals [52][53][54][55].
A natural bond orbital (NBO) analysis shows that the energetic difference between the conformations minima at 0 • and 180 • can be explained based on the stabilization due to the sum of the charge transfer between the lone pair of the pyridine-like nitrogen and the σ* C-H bond and between the σ N-N and the σ* C-F bonds. This stabilization amount is 6.6 kJ·mol -1 in the minima at 0 • of 13 and 14, while in the minima at 180 • it is between 1.1 and 1.0 kJ·mol -1 , respectively. Gauge-Independent Atomic Orbital (GIAO) calculated parameters (absolute shieldings) accounted for the experimental results obtained by multinuclear NMR ( 1 H, 13 C, 15 N and 19 F) (see Supplementary Materials). We will focus on the 19 F chemical shifts (Table 1).   Table 2.
We have calculated the chemical shifts in CHCl 3 , obtaining the values reported in Table 2. With these values, we have calculated that the difference of energies for 13 and 14 are −4.9 and −4.3 kJ·mol −1 , respectively, comparable to those obtained for the gas phase (−6.0 and −3.7 kJ·mol −1 ) to be compared with −7.6 and −5.1 kJ·mol −1 . We have also calculated the 13 C chemical shifts of the three carbon atoms of the pyrazole ring (C3, C3a, C7a named C4, C9, and C11 in Figure 3). The results are reported in Table 3 and correlates well with the experimental carbon signal shifts, and aided the assignment of the pyrazole ring carbons.

Chemistry
General All chemicals cited in the synthetic procedure are commercial compounds. Melting points were determined by differential scanning calorimetry (DSC) with a SEIKO DSC 220 C connected to a model SSC5200H disk station. Thermograms (sample size 0.003-0.005 g) were recorded with a scan rate of 5.0 • C. Column chromatography was performed on silica gel 60 (Merck KGaA, Darmstadt, Germany), 70-230 mesh), and elemental analyses using a Perkin-Elmer 240 apparatus (Madrid, Spain).
Procedure A from Ref. [46]. Into a 100-mL round-bottom three-necked flask equipped with reflux condenser and magnetic stirring, 2 equivalents of sodium chlorodifluoroacetate (SCDA) and 1.5 equivalents of the base (K 2 CO 3 ) were introduced. The vacuum was established for 15 min and then purged with argon for another 15 min (this process was repeated three times). Six milliliters of N,N-dimethylformamide (DMF) was added slowly with stirring and under an argon stream, and then 1 equivalent of (4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole (15) dissolved in 2 mL of DMF was added from an addition funnel over 15 min. The flask was immersed in a silicone bath previously heated to 100 • C and left stirring for 8 h. To control the temperature, a thermometer was used which was connected to the heating plate and immersed in the silicone oil bath. After the reaction time was completed, it was cooled to room temperature and EtOAc (15 mL) and water (15 mL) were added to the mixture. The organic fraction was washed with brine, and the aqueous fraction was extracted with EtOAc. The organic fractions were combined, dried over anhydrous MgSO 4 , and the solvent evaporated off. The yield of the reaction crude-in which both isomers are present in a ratio (85% of 13: 15% of 14)-is quantitative. The purification was carried out by column chromatography using dichloromethane/hexane (1:1) as eluent. Compound 14 was eluted first.

NMR
NMR spectra were recorded on a Bruker (Bruker Biospin GmbH, Rheinstetten, Germany) DRX 400 (9.4 Tesla, 400.13 MHz for 1 H, 100.61 MHz for 13 C and 40.54 MHz for 15 N using a 5-mm inverse-detection H-X probe equipped with a z-gradient coil, at 300 K. Chemical shifts (δ in ppm) are given from internal solvent, CDCl 3 7.26 for 1 H and 77.0 for 13 C and for 15 N, nitromethane (0.00) was used as external reference. Signals were characterized as s (singlet), d (doublet), and cm (complex multiplet) and the J coupling constants are given in Hz.
Typical parameters for 1 H-NMR spectra were spectral width 4800 Hz and pulse width 9.5 µs at an attenuation level of 0 dB. Typical parameters for 13 C-NMR spectra were spectral width 21 kHz, pulse width 12.5 µs, at an attenuation level of −6 dB and relaxation delay 2 s, WALTZ-16 was used for broadband proton decoupling; the Free Induction Decays (FIDs) were multiplied by an exponential weighting (lb = 1 Hz) before Fourier transformation.
Inverse proton detected heteronuclear shift correlation spectra, ( 1 H-13 C) gs-HMQC, and ( 1 H-13 C) gs-HMBC were acquired and processed using standard Bruker NMR software and in non-phase-sensitive mode. Gradient selection was achieved through a 5% sine truncated shaped pulse gradient of 1 ms.
Selected parameters for ( 1 H-13 C) gs-HMQC and ( 1 H-13 C) gs-HMBC spectra were spectral width 4800 Hz for 1 H and 20.5 kHz for 13 C, 1024 × 256 data set, number of scans two (gs-HMQC) or four (gs-HMBC) and relaxation delay 1 s. The FIDs were processed using zero filling in the F 1 domain and a sine-bell window function in both dimensions was applied prior to Fourier transformation. In the gs-HMQC experiments, Globally Optimized Alternating Phase Rectangular Pulse (GARP) modulation of 13 C was used for decoupling. Selected parameters for ( 1 H-15 N) gs-HMQC, and ( 1 H-15 N) gs-HMBC spectra were spectral width 3500 Hz for 1 H and 12.5 kHz for 15 N, 1024 × 256 data set, number of scans four, relaxation delay 1 s, 37-60 ms delay for evolution of the 15 N-1 H long-range coupling. The FIDs were processed using zero filling in the F 1 domain and a sine-bell window function in both dimensions was applied prior to Fourier transformation. 19 F-NMR spectra were recorded on the same spectrometer (376.50 for 19 F) using a 5 mm Quattro Nucleus Probe (QNP) direct-detection probehead equipped with a z-gradient coil, at 300 K. Chemical shifts (δ in ppm) are given from CFCl 3 as external reference (one drop of CFCl 3 in CDCl 3 (0.00)). Typical parameters for 19 F NMR spectra were spectral width of 55 kHz, pulse width of 13.75 µs at attenuation level of −6 dB and relaxation delay of 1 s. WALTZ-16 was used for broadband proton decoupling 19 F{ 1 H}, the FIDS were multiplied by an exponential weighting (lb = 1 Hz) before Fourier transformation.

Computational Details
Calculations were carried out at the B3LYP/6-311++G(d,p) level [56,57]. Subsequent frequency calculations verify that the structures obtained correspond to energetic minima (imaginary frequencies = 0) or to transition states (imaginary frequencies = 1). In the optimization process, the 0 • and 180 • angles get slightly modified (Tables 1 and 2). These resulting geometries have been used for the calculation of the absolute chemical shieldings with the GIAO method [58,59]. Solvent effects were calculated within the PCM approximation (continuum model) [60][61][62]. All the calculations have been performed with the Gaussian-09 package [63].

Conclusions
In summary, we have found a new and original example of diastereotopic fluorine atoms, measured two values of 2 J FF in an original environment and successfully carried out GIAO/B3LYP/6-311++G(d,p) calculations of 19 F chemical shifts that agree with the calculated energies of the two minima of the potential energy curve when solvent was taken into account.
Computer, storage, and other resources from the CTI (CSIC) are gratefully acknowledged.

Conflicts of Interest:
The authors declare no conflict of interest.