Trifluoroacetylation of Alcohols During NMR Study of Compounds with Bicyclo[2.2.1]heptane, Oxabicyclo[3.3.0]octane and Bicyclo[3.3.0]octane Skeleton

TFA was added to a solution of a bicyclo[2.2.1]heptane azide-alcohol in CDCl3 to correctly characterize the compound, but during 24 h gave the trifluoro acetylated compound in quantitative yield. NMR spectra of the esterified compound helped us also to correctly attribute the NMR signals to the protons, and also confirmed the identification of the carbon atoms. The study was extended to other 14 compounds containing a primary alcohol group alone or with an ethylene ketal, a δor -lactone group, a primary and a secondary group, two primary and an alkene group and two primary and a secondary alcohol groups on scaffolds containing bicyclo[2.2.1]heptane, oxabicyclo[3.3.0]octane, bicyclo [2.2.1]heptane constrained with a cyclopropane ring and bicyclo[3.3.0]octane fragments. The esterification of all compounds was also quantitative in 24 to 72 h; this helped us to correct attribute the NMR signals to the protons and carbon atoms of the un-esterified compounds by comparison with those of the trifluoro acetylated compounds. A graphical presentation of Hand C-NMR spectra of a few un-esterified and esterified compounds are presented in the paper.


1.Introduction
A routine NMR characterization of a compound with a primary alcohol group needed to distinguish between two protons and after adding trifluoroacetic acid (TFA) in the tube we observed the appearance of signals which proved to be those of the trifluoro acetylated compound formed quantitatively after a day. Browsing the literature, we found that alcohols are even quantitative esterified with TFA [1,2]. For example, synthesis of ethyl trifluoroacetate from ethyl alcohol and TFA is also mentioned in patents [3][4][5][6] and journals [7]. Methyl and isopropyl trifluoroacetate was also synthesized from TFA and methanol or isopropanol [8,9]. The esterification of alcohols in TFA as solvent was performed and followed in NMR tube [10][11][12] to observe the transformation of alcohols into the corresponding trifluoroacetates, because the deshielding effect of the trifluoro acetyl group produces a considerable shift of the signal for the proton(s) linked to the hydroxyl group, by comparison with that of the corresponding protons in trifluoroacetate compound, which are moved to lower field. Though an esterification of hydroxyl groups were observed in CDCl3 + TFA during NMR spectra registration, a paper on the trifluoroacetyl esterification during NMR studies was not found in the literature. And the paper is presented as a scholar theme exemplified for primary and secondary alcohol groups linked to different bicyclic and tricyclic scaffolds and in different configurations.

Materials and methods
The compounds were dissolved in CDCl3, and 1 H, 13 C, 2D-NMR spectra have been done. Then near 0.03 mL TFA were added and the NMR spectra were followed until the esterification approach the end in specified time of reaction. The same spectra have been done in DMSO-d6 for a few of the compounds. C), chemical shifts (δ) are given in ppm relative to TMS as internal standard. Complementary 2D-NMR spectra were done for correct assignment of NMR signals. The numbering of the atoms in the compounds is presented in Figure 1.

Cl
13.NMR spectra of the optically active diol compound 15a and of the bis-trifluoroacetylated compound 15c. 14.NMR spectra of the compound 12a and of the bis-trifluoroacetylated compound 12c. The un-symmetric triol 12 was esterified with trifluoroacetic anhydride in TFA (in NMR tube) and the complete esterification proceeded in 4 h. The signals of the bis-triflouroacetylated compound 12c are described below: 1  15.NMR spectra of the ent-Corey compound 11a and of the bis-trifluoroacetylated compound 11c. CH [20]).
The compound 11a was not completely esterified, even after 10 days and with a significant excess of TFA. No proton and carbon NMR spectra couldn't be decipherable, as in the case of 10a + TFA.
The symmetric triol 11 was esterified with trifluoacetic anhydride in TFA (in NMR tube) and the complete esterification proceeded in 4 h. The signals of the tri-esterified compound 11c are described The influence of the solvent showed the uselessness of this esterification effort, because the NMR signals were of no help to find these signals in the NMR spectra in DMSO-d6.

Results and discussions
TFA is usual used in NMR of alcohols, amines or thiols, whose signals overlap over those of the protons linked to vicinal carbon atoms and made difficult to calculate the coupling constants and to assign the signals to the corrected protons. Due to its acidity, it moved the labile protons (OH, NH, SH) to lower field, and also suppress their coupling with the protons linked to the carbon atoms vicinal to oxygen, nitrogen or sulfur. In this paper, NMR spectra of the compounds 1-10 and 13-15 have been done in CDCl3 as solvent and for the compounds 11 and 12 (insoluble in CDCl3) in DMSO, followed by addition of TFA in NMR tube. This paper started from this idea that for the correct assignment of the signals for the protons H2 and H5 of the endo-azide 1a (Figure 1), TFA was added; but in spectrum began to appear signals at lower field suggesting that here started the esterification reaction of the compound with TFA. The endo-azide 1a was completely esterified in 24 h to the trifluoroacetate 1b, and this can be observed in both 1 H and 13 C-NMR. In 1 H-NMR, the methylene protons of primary alcohol are deshielded from 3.95 to 4.78ppm, respectively 3.92 to 4.68 ppm. In 13 C-NMR, the chemical shift of carbon atom C8 is deshielded from 60.35 ppm to 66.37 ppm, and the vicinal carbon atom C7 is shielded from 51,74 to 47.88 ppm. And the signals for trifluoroacetate group are present in the spectrum at: 158.21 (COCF3) and 114.55 (COCF3) ppm. A comparison of 1 H and 13 C-NMR spectra of the starting compound 1a and the esterified compound 1b is presented in Figure 2.  Starting from this observation, the exo-azide compound 2a was similarly studied by addition of TFA in NMR tube, and the esterification to 2b was also finished in 24 h (Figure 3 and Experimental, 2): Then the study was extended to other compounds with primary alcohol groups (3a-7a), with primary and secondary alcohol groups (8a-12a), a secondary alcohol group alone (13) and a secondary alcohol group in the presence of a secondary allylic alcohol (14)(15), in racemic: 5a, 10a-12a, or optically active form: 1a-4a, 6a-9a, 13-15, usually used in our laboratory, presented in Figure 1, which contain: -a 5-keto group in the bicyclo[2.2.1]heptane skeleton (compounds 3a and 4a) or protected with an ethylene ketal group as in the compound 5a, or in a more constrained structure containing a cyclopropane ring (compound 6a).
-a double bond in a bicyclo [3.3.0]octane diol with two primary alcohol groups (compound 10a).
-a bicyclo[3.3.0]octane triol containing two primary alcohol groups and a secondary alcohol group linked to C5 carbon atom (compounds 11a) or to C6 carbon atom (12a, with a primary alcohol protected as acetate).
-an enone (13) and two diols (14,15) in prostaglandin intermediate, containing a double bond. The 5-keto compounds 3a and 4a were cleanly esterified with TFA in 24 h to the compounds 3b and 4b, and the deshielding of the H8 protons from δ = 4.05 to 4.79 and δ = 3.95 ppm to 4.70 ppm and of the carbon atom C8 from δ = 59.62 ppm to 64.95 ppm by trifluoro acetyl esterification is observed in NMR spectra, as previously. After 3 days (over weekend), the compound 3b was obtained pure ( Figure  4 and Experimental, 3). In the case of the ethylene-ketal protected compound (±)-5a, trifluoroacetic acid esterified the primary alcohol, but in the same time it deprotected the ethylene ketal group giving the compound 3b, as can been observed in 13 C-NMR spectrum where the ketal C5 carbon atom (δ = 113.84 ppm) no more appear in the spectrum, but appear the C5-ketone carbon atom at 216.01 ppm ( Figure 5). The ethylene ketal seems to be transformed into ethylene glycol and ethylene glycol mono-trifluoroacetate in a ratio of 1:1, as can be observed in 1 H-NMR and 13 C-NMR (Experimental 5, were the signals of ethylene glycol and of the mono-trifluoroacetate are evidenced in red color). For the compound 7a, the δ-lactone resists during its quantitative TFA-esterification to the trifluoroacetylated compound 7b in 24h (Experimental, 7).
The diol 8a was esterified with TFA to both the primary alcohol and the secondary alcohol ( Figure  6a) and this was observed even after two hours (Figure 6b), but it was not observed that the esterification of the primary alcohol to 8b proceeded selectively before begins the esterification of the secondary one; in 24 h the reaction proceeded quantitatively and gave the compound 8c (Experimental 8), which is clearly observed in 1 H-and 13 C-NMR (Experimental,8). In 1 H-NMR, H5 was deshielded from δ = 4.23 ppm to δ = 5.20 ppm, and the H8-protons were deshielded from δ = 3.96 to 5.20 ppm, respectively 3.91 to 4.81 ppm. Both trifluoro acetyl groups appear in 13   .0]octane fragment, was esterified to both primary and secondary alcohols group, without the observation of the selective trifluoro acetylation of the primary alcohol before begins the trifluoroacetylation of the secondary alcohols (Experimental,9). In 13 C-NMR, both trifluoro acetyl groups appear in NMR spectra, at 157.41 and 114.26 ppm for COCF3 and COCF3 of the primary alcohol ester, respectively 157.10 and 114.61 ppm for COCF3 and COCF3 for the secondary alcohol ester. The deshieldings of the H5 and H7-protons from 5.27, 4.19 and 3.78 ppm to 5.27, 4.45 and 4.39 ppm and the deshieldings of the corresponding carbon atoms C5 and C7 from 75.65 to 80.60 ppm and 63.73 to 66.57 ppm are clearly observed as previously for 8a to 8c. The same shieldings of the vicinal carbon atoms to C7 and C5, C4 and C-6 from 55.02 and 40.81 ppm to 50.61 and 37.59 ppm are also observed, as can been seen in Figure 7. The double bond of the diol-alkene 10a was not affected during trifluoroacetylation of the primary double bonds to 10b. In 4 h, near half esterification of the hydroxyl groups had been done and both hydroxyl groups were esterified after 24 h (Figure 8, Experimental, 10). (where it appears together with H9 proton) and of the corresponding carbon atom C11 from 76.55 ppm to 81.73 ppm is also observed (Figure 9). Deshielding of the vicinal carbon atoms C10 and C12 from 40.39, respectively 56.35 ppm to 37.10 respectively 54.01 is also observed (experimental, 11). https://doi.org /10.37358/Rev.Chim.1949 Rev. Chim., 72 (2)  The prostaglandin diol intermediate 14a, containing a secondary (11-OH) and an allylic secondary (15-OH) alcohol groups was esterified with TFA over weekend (4 days; in 24 h the bis-trifluoroacetylation did not ended), without concluding that the 15-OH allylic alcohol is selectively esterified than the 9-secondary alcohol ( Figure 10 and Experimental 12). The deshielding of the protons H11 and H15 from 4.00 and 4.54 ppm to the multiplets centered at 5.25 and 5.85 ppm and of the corresponding carbon atoms C11 and C15 from 76.52 and 70.50 ppm to 81.74 and 76.39 ppm is clearly observed ( Figure  10). The shielding of the vicinal carbon atoms, C10, C12 and C16 from 39.85, 56.35, respectively 71.81 ppm to 36.66, 53.79, respectively 68.47 is also observed on this diol.  The triols 11 and 12 have low solubility in CDCl3 and NMR spectra were performed in DMSO. In both cases, the esterification with TFA is very slow and the 1 H-and 13 C-NMR spectra were not complicated by the formation of the trifluoroacetyl esters. At longer reaction time, the formation of the esters complicated indeed both proton and carbon NMR spectra and the signals couldn't be attributed https://doi.org/10.37358/RC.21.2.8428 (Experimental, 14, for compound 12a with TFA). The esterification with trifluoroacetic anhydride in TFA proceeded cleanly to the esterified compounds 12c and 11c, and both compounds were fully characterized; unfortunately, because of the different solvents in NMR experiments, the signals of the trifluoroacetylated compounds couldn't be useful to identify them between the compounds formed in DMSO-d6 + TFA (Experimantal 14 and 15). In conclusion, the use of TFA to clarify the NMR spectra of the alcohol compounds in DMSO-d6 at shorter times (even until hours) is beneficial, because the secondary trifluoroacetylated compounds are not formed in amounts to complicate the NMR spectrum.
So, the transformation of the alcohol compounds 1a-10a and 13a-15a into the corresponding trifluoroacetates in CDCl3 + TFA in NMR tubes helped us to correctly attribute or to confirm the NMR signals of some protons and carbon atoms in the molecules, otherwise difficult. Some observations should be mentioned. The primary alcohol groups of the compounds 1a-7a and 10a were quantitatively transformed with TFA into the trifluoroacetylated compounds 1b-4b, 6b-7b, 10b in short time (mainly 24 h). Only the ethylene ketal group of the compound 5a was deprotected during the esterification of primary alcohol, giving the trifluoro acetylated compound 3b. The secondary alcohol groups of the compounds 8a and 9a were concomitant esterified with TFA with the primary alcohol groups (to the compounds 8c and 9c), without the observation that the esterification of the secondary alcohols begins after the primary hydroxyl groups were esterified. For compounds 14a and 15a, the esterification of the secondary 15-allylic alcohols proceeded not selectively against the 11-secondary alcohols; at longer time (3-4 days) both alcohols groups were esterified. It is worth mentioned that the trifluoroacetylation proceeded faster than that in DMSO-d6, where also an additional amount of TFA did not lead to completion of the esterification reaction. The results are to be taken into consideration when TFA is added in NMR tube, because not only the shifting of the couplings of the deuterable protons could help us to simplify the NMR spectrum, but also trifluoro acetylation could help us to more precisely attribute the signals in 1 H-and 13 C-NMR spectra to the protons and carbon atoms in the molecule.

Conclusions
TFA added to the solutions of the compounds 1a-10a and 13a-15a in CDCl3 esterified the primary and the secondary alcohols to the corresponding trifluoro acetylated compounds 1b-7b, 8c-10c and 13b-15c in 24 to 72 h in quantitative yield. Ethylene ketal group of the compound 5a was deprotected to the ketone group of the compound 3b, concomitant with the esterification of the primary alcohol. The δlactone group of the compound 7a and -lactone group of the ent-Corey lactone 9a were not opened during esterification of the alcohol groups. The esterification of the secondary 15-allylic alcohols of the compounds 14a and 15a proceeded not selectively against the 11-secondary alcohols, so at longer time (3-4 days) both alcohols groups were esterified.
In DMSO-d6, the esterification of the secondary and primary alcohol groups of the triols 11a and 12a is much slower and didn't went to complete even after 7 days, though the amount of TFA was greater.
In conclusion, TFA added in NMR tube, not only shifts the deuterable protons and simplify the NMR spectrum, but by trifluoroacetylation of the alcohol groups cloud make easier and more precisely attribution of the signals in 1 H-and 13 C-NMR spectra to the protons and carbon atoms in the molecule.