Beckmann fragmentation and successive carbon-carbon bond formation using Grignard reagents via phosphonium salt intermediates

Article abstract of DOI:10.1248/cpb.c16-00006

The intermediates formed during the Beckmann fragmentation of α-alkoxy and α-alkoxy-α-alkyl oxime acetates have been successfully trapped as phosphonium salts, which were subsequently reacted with a variety of Grignard reagents to give the corresponding s

Full text of DOI:10.1248/cpb.c16-00006

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Chem. Pharm. Bull. 64, 718–722 (2016)
Vol. 64, No. 7
Special Collection of Papers
This article is dedicated to Professor Satoshi Ōmura in celebration of his 2015 Nobel Prize.
Regular Article
Beckmann Fragmentation and Successive Carbon–Carbon Bond Formation
Using Grignard Reagents via Phosphonium Salt Intermediates
Hiromichi Fujioka,* Nao Matsumoto, Yuichi Kuboki, Hidenobu Mitsukane, Reiya Ohta,
Takashi Kimura, and Kenichi Murai
Graduate School of Pharmaceutical Sciences, Osaka University; 1–6 Yamada-oka, Suita, Osaka
565–0871, Japan.
Received January 4, 2016; accepted January 18, 2016
The intermediates formed during the Beckmann fragmentation of α-alkoxy and α-alkoxy-α-alkyl oxime
acetates have been successfully trapped as phosphonium salts, which were subsequently reacted with a vari-
ety of Grignard reagents to give the corresponding substituted products in good yields. Notably, this reaction
proceeded smoothly even from α-alkoxy-α-alkyl oxime acetates.
Key words Beckmann fragmentation; phosphonium salt intermediate; Grignard reagent; carbon–carbon
bond formation
We recently found that the treatment of acetals with tion/carbon–carbon (C–C) bond forming reactions, which has
a
combination of trifluoromethanesulfonic acid trialkyl- been previously reported by our group using organoaluminum
silyl ester (R3SiOTf) and base (e.g., pyridinium-type bases reagents.12–15) The treatment of α-alkoxy oxime acetates with
or triarylphosphines) gave the corresponding electrophilic trifluoromethanesulfonic acid trimethylsilyl ester (TMSOTf)
pyridinium or phosphonium salts as stable intermediates. We and 2,4,6-collidine produced the corresponding collidinium
subsequently showed that these salts can be used as stable salt intermediates, which were successfully subjected to a
synthetic equivalents of oxonium ions from acetals, and went C–C bond forming reaction with a variety of different Gil-
on to develop a series of acetal substitution reactions using a man reagents (Eq. 2).16) Gilman reagents were found to be
variety of different nucleophiles (Eq. 1).1–10) One of the main the best type of organometallic carbon nucleophile for this
advantages of our new methods is that the nucleophiles can be reaction, with several other more popular organometallic re-
added to the reaction mixture long after the formation of the agents, including organolithium and Grignard reagents, failing
intermediate salts. Furthermore, these methods are compatible to provide good results. However, we previously found that
with a wide variety of nucleophiles, including acid and base the phosphonium salts derived from O,O-acetals and (o-tol)3P
labile nucleophiles. It is noteworthy that acid labile nucleo- reacted smoothly with Grignard reagents.8–10) We therefore
philes cannot normally be used in the reactions of oxonium envisioned that the formation of a phosphonium salt instead
ions, because oxonium ions are usually formed under Lewis of a collidinium salt would make it possible to use Grignard
acidic conditions in the presence of a nucleophile, which reagents in this reaction, which would represent a significant
would preclude the use of an acid labile nucleophile.11) We improvement over our previous method in terms of its scope
subsequently investigated the application of this salt chemistry and convenience.
to another reaction involving sequential Beckmann fragmenta-
*To whom correspondence should be addressed. e-mail: fujioka@phs.osaka-u.ac.jp
© 2016 The Pharmaceutical Society of Japan

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Chem. Pharm. Bull.
719
Fig. 1. 1H-NMR Spectra of 1a and a Reaction Mixture of 1a, TMSOTf and (o-tol)3P in CDCl3
a) Tetramethylsilane as an internal standard. b) No tetramethylsilane and CHCl3 was used as an internal standard.
Table 1. Examination of Different Solvents and Organometalic Nucleo- Table 2. Use of Various α-Alkoxy Oxime Acetates and Grignard Re-
philes agents
Entry
Substrate
R′
Product
Yield
Entry
Solvent
PhM
Yield
1
2
3
4
5
6
7
8
1a
Ph
Allyl
Me
Me
Me
Me
Me
Me
3a
3b
3c
3d
3e
3f
71%
80%
82%
90%
85%
74%
95%
93%
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Ph2CuLi
PhMgBr
59%
71%
66%
N.D.
N.D.
58%
64%
55%
1a
1a
PhMgBr+CuI (1eq.)
PhLi
1b (n=1, R=Bn)
1c (n=1, R=PMB)
1d (n=1, R=TBS)
1e (n=3, R=Bn)
1f (n=7, R=Bn)
Ph2Zn
Ph2CuLi
3g
3h
THF
PhMgBr
THF
PhMgBr+CuI (1eq.)
N.D.=Not determined.
then added to the reaction mixture. The addition of Ph2CuLi,
Results and Discussion
We initially investigated the generation of the phosphonium PhMgBr or (PhMgBr)-CuI to the reaction mixture led to the
salt intermediate 2a from the model α-methoxy oxime acetate formation of the desired product 3a (Table 1, Entries 1–3),
1
substrate 1a by H-NMR spectroscopy. Compound 1a is an whilst the addition of PhLi or Ph2Zn provided a complex mix-
E,Z-mixture and its stereochemistry was not determined. The ture (Table 1, Entries 4, 5). When THF was used as the reac-
spectra of 1a and the reaction mixture obtained by the treat- tion solvent instead of CH2Cl2, we observed a slight decrease
ment of 1a with TMSOTf (2eq.) and (o-tol)3P (3eq.) in CDCl3 in the yield of 3a following the addition of Ph2CuLi, PhMgBr
are shown in Fig. 1. The appearance of a characteristic signal or (PhMgBr)–CuI (Table 1, Entries 6–8). Pleasingly, the Gri-
around 5.8ppm suggested the formation of the O,P-acetal salt gnard reagent PhMgBr gave the best results in both solvents
intermediate 2a (Spectrum B).
(Table 1, Entries 2, 7). Based on these results, CH2Cl2 was
Consequently, we investigated the optimum conditions selected as the optimum solvent for the transformation, and
for the transformation (Table 1). The treatment of 1a with the Grignard reagent was selected as the best carbon-based
TMSOTf (2eq.) and (o-tol)3P (3eq.) in CH2Cl2 at 0°C afforded nucleophile.
the phosphonium salt 2a, which was detected by TLC as a
With the optimized conditions in hand, we proceeded to
polar spot. Several different organometallic reagents were investigate the scope of the reaction using a variety of differ-

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Chart 1. The Reactivity of PR3 and 2,4,6-Collidine toward α-Methyl-α-methoxy Oxime Acetate 4a
Table 3. Optimization of Reaction with α-Alkyl-α-methoxy Oxime Table 4. Examination of Phosphines
Acetate
Entry
Phosphine
Yield
Entry
Temp.
Yield
1
2
3
PPh3
PnBu3
84%
32%
40%
1
0°C
−40°C
−78°C
−40°C
34%
84%
19%
Trace
2
(o-tol)3P
3
4a)
Table 5. Evaluation of Various α-Substituted α-Alkoxy Oxime Acetates
and Grignard Reagents
a) Without PPh3.
ent oxime acetates and Grignard reagents (Table 2). Several
Grignard reagents, including PhMgBr (Table 2, Entry 1), al-
lylMgBr (Table 2, Entry 2) and MeMgBr (Table 2, Entries
3–8) reacted smoothly under these conditions. Various alkyl
and silyl ethers, including methyl (Table 2, Entries 1–3),
benzyl (Table 2, Entry 4), p-methoxybenzyl (PMB) (Table 2,
Entry 5) and tert-butyldimethylsilyl (TBS) ethers (Table 2,
Entry 6) were also well tolerated. The eight- and twelve-mem-
bered ring oxime acetates 1e and f afforded the corresponding
products 3g and h in high yields (Table 2, Entries 7, 8).
Entry
Substrate
R3
Product
Yield
1
2
3
4
5
4a (R1=Me, R2=Me)
4a (R1=Me, R2=Me)
4b (R1=Bn, R2=Me)
4c (R1=Me, R2=Allyl)
4d (R1=Me, R2=Ph)
Ph
Allyl
Me
6b
6c
6d
6c
6b
64%
68%
70%
77%
73%
Me
Me
The advantage of using a phosphine in this reaction
was demonstrated by the following experiments involving (Table 3, Entries 1–3). The oxime substrate 4a disappeared
α-methyl-α-methoxy oxime acetate (4a), which has a ter- completely and gave the desired product 6a in 84% yield
tiary alkoxide group (Chart 1). None of the desired pyridinium when the reaction was conducted at −40°C (Table 3, Entry
salt was formed by the treatment of 4a with TMSOTf and 2). These results indicated that the phosphonium salt interme-
2,4,6-collidine, with the reaction resulting instead in the for- diate generated from α-alkyl-α-methoxy oxime acetate was
mation of a complex mixture. The use of the smaller and less less stable than the intermediate generated from α-methoxy
sterically encumbered pyridinium base, pyridine, resulted in oxime acetate. Furthermore, although the phosphonium salt
the same outcome. In contrast, the use of phosphine as a base intermediate generated from the acetal (not the ketal) and
resulted in the formation of ketone 5 in moderate yield. Thus, PPh3 required a longer reaction time to undergo the substi-
the treatment of 4a with TMSOTf and (o-tol)3P (3eq.) afforded tution reaction (0°C, 96h, 47%) in our previous work,8) the
5 in 35% yield. Pleasingly, the use of PPh3 instead of (o-tol)3P substitution reaction of the phosphonium salt from 4a reached
led to an increase in the yield of 5 to 50% yield. It was sug- completion in 2h. However, the oxime substrate 4a was not
gested that this reaction proceeds through a phosphonium salt completely consumed at −78°C (Table 3, Entry 3). It is note-
intermediate or oxonium ion to give ketone 5. Unfortunately, worthy that only trace quantities of the desired product 6a
1H-NMR analysis could not be used to monitor the progress of were detected when the reaction was conducted in the absence
this reaction because of the poor stability of the intermediate.
of PPh3 (Table 3, Entry 4), which proved that the addition of
It is noteworthy that tert-methoxycyanide 6a having quater- a phosphine base was necessary for this reaction and that the
nary carbon was obtained in 34% yield by following the addi- reaction proceeded via a phosphonium salt intermediate.
tion of the Grignard reagent MeMgBr to the intermediate in-
The reactivities of two different phosphines (i.e., PnBu3 and
stead of H2O (Table 3, Entry 1). We then conducted a detailed (o-tol)3P) were also examined in this reaction (Table 4). These
screening process to allow for the optimization of the reaction two phosphines afforded the poor results. In the case of PnBu3
conditions. We initially examined the reaction temperature substitution step maybe didn’t work well,17–19) whereas in the

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
721
case of (o-tol)3P the formation of salt intermediate might be 4.51 (d, 1H, J=11.5Hz), 7.26–7.35 (m, 5H). 13C-NMR (CDCl3,
insufficient most likely because of its larger steric bulk (Table 125MHz) δ: 19.8, 20.5, 20.9, 24.0, 26.0, 41.2, 64.7, 77.0,
4, Entries 2, 3 vs. Entry 1).
127.1, 127.3, 128.3, 138.6, 169.2, 169.5. IR (KBr) cm−1: 1771.
We subsequently examined a variety of oxime acetates and MALDI-TOF-MS m/z: 222.1099 (Calcd for C16H21NO3Na
Grignard reagents (Table 5). α-Methyl (Table 5, Entries 1–3), [M+Na] +: 222.1101).
α-allyl (Table 5, Entry 4) and α-phenyl (Table 5, Entry 5)
oxime acetates reacted smoothly under the optimized condi-
2-Allyl-2-methoxycyclohexanone Oxime Acetate (4c)
1H-NMR (CDCl3, 400MHz) δ: 1.30–1.45 (m, 2H), 1.51–1.61
tions. Several Grignard reagents, including PhMgBr (Table 5, (m, 1H), 1.76–1.92 (m, 2H), 2.01 (td, 1H, J=13.5, 5.3Hz), 2.12
Entry 1), allylMgBr (Table 5, Entry 2) and MeMgBr (Table 5, (dd, 1H, J=6.0, 2.7Hz), 2.16 (dd, 1H, 6.0, 2.7Hz), 2.21 (s,
Entries 3–5) also worked well under these conditions.
3H), 2.41 (m, 1H), 2.88 (m, 1H), 3.12–3.17 (m, 1H), 3.15 (s,
3H), 5.14 (m, 2H), 5.84 (m, 1H). 13C-NMR (CDCl3, 125MHz)
δ: 19.8, 20.2, 24.0, 25.9, 36.2, 37.6, 50.2, 78.0, 118.2, 133.0,
Conclusion
We have successfully trapped the intermediate formed 168.7, 169.2. IR (KBr) cm−1: 1641, 1763. MALDI-TOF-MS m/z:
during the Beckmann fragmentation reaction as a phospho- 248.1258 (Calcd for C12H19NO3Na [M+Na] +: 248.1257).
nium salt and evaluated its reactivity towards a variety of dif-
ferent Grignard reagents in a C–C bond forming reaction. It
2-Methoxy-2-phenylcyclohexanone Oxime Acetate (4d)
1H-NMR (CDCl3, 400MHz) δ: 1.56–1.67 (m, 2H), 1.80–1.90
is noteworthy that α-alkoxy-α-alkyl oxime acetates performed (m, 2H), 2.11–2.17 (m, 1H), 2.12 (s, 3H), 2.21–2.28 (m, 1H),
well as substrates for these reactions via the corresponding 2.55–2.62 (m, 1H), 2.74–2.80 (m, 1H), 3.14 (s, 3H), 7.27–7.31
phosphonium salts, whereas the reactions via the correspond- (m, 1H), 7.35–7.39 (m, 2H), 7.43–7.46 (m, 2H). 13C-NMR
ing collidinium salt intermediates were unsuccessful.
(CDCl3, 125MHz) δ: 19.8, 21.3, 24.8, 25.5, 38.5, 51.1, 81.7,
The application of this method to other reactions involving 127.5, 127.7, 128.0, 138.9, 168.5, 169.9. IR (KBr) cm−1: 1768.
oxonium ions is currently underway in our laboratory.
MALDI-TOF-MS m/z: 284.1258 (Calcd for C15H19NO3Na
[M+Na] +: 284.1257).
Typical Procedure for Beckmann Fragmentation and the
Experimental
General Information 1H-NMR and 13C-NMR spectra Following C–C Bond Formation (Tables 1, 2) Synthesis of 3a
were measured by JEOL JNM-GX 500, JEOL JNM-ECS
TMSOTf (130µL, 0.704mmol) was added slowly to a
400 or JEOL JNM-AL 300 spectrometers with tetramethyl- solution of 1a (65.2mg, 0.352mmol) and (o-tol)3P (320mg,
silane as an internal standard. IR spectra were recorded by 1.05mmol) in dry CH2Cl2 (3.5mL, 0.1 M) at −5°C under N2
Shimadzu FTIR 8400 using a diffuse reflectance measurement atmosphere. After the disappearance of 1a (judged by TLC
of samples dispersed in KBr powder. Column chromatogra- analysis), PhMgBr (1.05mmol) was added to the reaction
phy was performed with SiO2 (Silicagel 60 (230–400 mesh or mixture and the resulting mixture was warmed to room tem-
spherical, 63–210µm).
perature. After 2h, sat. aq. NH4Cl was added to the reaction
Compounds 1a–f, 3a, b and d–h Are Known Compounds15) mixture. The resulting solution was extracted by CH2Cl2.
General Procedure for the Synthesis of Oxime Acetate The organic layer was dried over Na2SO4, and concentrated
Substrates 1 or 4
in vacuo. The residue was purified by SiO2 column chroma-
Ketone (1eq.) and NH2OH·HCl (1.5eq.), sodium acetate tography (hexane–AcOEt=4:1) to give 3a (50.8mg, 71%) as
(1.65eq.) were combined in MeOH (0.3M ketone) at room yellow oil.
temperature under N2 atmosphere. After the disappearance of
starting material (judged by TLC analysis), H2O was added
6-Methoxyheptanenitrile (3c)
1H-NMR (CDCl3, 500MHz) δ: 1.14 (d, 3H, J=6.3Hz),
to the reaction mixture. The resulting mixture was extracted 1.41–1.58 (m, 4H), 1.65–1.71 (m, 2H), 2.36 (t, 2H, J=7.2Hz),
by CH2Cl2. The organic layer was dried over Na2SO4, and 3.28–3.33 (m, 1H), 3.32 (s, 3H). 13C-NMR (CDCl3, 125MHz)
concentrated in vacuo. The residue, Ac2O (1.5eq.), pyridine δ: 17.1, 18.8, 24.6, 25.4, 35.5, 56.0, 76.3, 119.7. IR (KBr) cm−1:
(1.5eq.) and N,N-dimethyl-4-aminopyridine (DMAP) (0.1eq.) 2247. MALDI-TOF-MS m/z: 164.1046 (Calcd for C8H15NONa
were dissolved in CH2Cl2 (0.3 M) at room temperature under [M+Na] +: 164.1046).
N2 atmosphere. After the disappearance of substrate (judged
by TLC analysis), H2O was added to the reaction mixture.
1-Cyano-5-oxohexane (5)
1H-NMR (CDCl3, 300MHz) δ: 1.59–1.77 (m, 4H), 2.16 (s,
The resulting mixture was extracted by CH2Cl2. The organic 3H), 2.36 (t, 2H, J=6.7Hz), 2.51 (t, 2H, J=6.7Hz). 13C-NMR
layer was dried over Na2SO4, and concentrated in vacuo. The (CDCl3, 125MHz) δ: 16.9, 22.5, 24.7, 29.8, 42.2, 119.4, 207.6.
residue was purified by SiO2 column chromatography to give IR (KBr) cm−1: 1713, 2246. MALDI-TOF-MS m/z: 148.0732
1 (E,Z-mixture) or 4 (single isomer) as colorless oil.
(Calcd for C7H11NONa [M+Na] +: 148.0733).
Typical Procedure for Beckmann Fragmentation and the
2-Methoxy-2-methylcyclohexan-1-one Oxime Acetate (4a)
1H-NMR (CDCl3, 400MHz) δ: 1.18–1.32 (m, 1H), 1.32 (s, Following C–C Bond Formation (Tables 4, 5) Synthesis of
3H), 1.41–1.49 (m, 2H), 1.73–1.84 (m, 2H), 1.90–1.99 (m, 2H), 6a
2.12 (s, 3H), 3.04 (m, 1H), 3.07 (s, 3H). 13C-NMR (CDCl3,
TMSOTf (83µL, 0.460mmol) was added slowly to a
100 MHz) δ: 19.8, 19.9, 20.3, 23.7, 26.0, 41.0, 50.2, 76.7, 169.2, solution of 4a (45.8mg, 0.230mmol) and PPh3 (180mg,
169.4. IR (KBr) cm−1: 1751. Matrix assisted laser desorption/ 0.690mmol) in dry CH2Cl2 (2.3mL, 0.1M) at −40°C under N2
ionization-time of flight (MALDI-TOF)-MS m/z: 200.1287 atmosphere. After the disappearance of 4a (judged by TLC
(Calcd for C10H17NO3 [M+H]+ : 200.1281).
analysis), MeMgBr (0.690mmol) was added to the reaction
mixture and the resulting solution was warmed to room tem-
2-Benzyloxy-2-methylcyclohexanone Oxime Acetate (4b)
1H-NMR (CDCl3, 300MHz) δ: 1.37–1.62 (m, 4H), 1.52 (s, perature. After 2h, sat. aq. NH4Cl was added to the reaction
3H), 1.90–2.20 (m, 4H), 2.21 (s, 3H), 4.20 (d, 1H, J=11.5Hz), mixture. The mixture was extracted by CH2Cl2. The organic

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layer was dried over Na2SO4, and concentrated in vacuo. The charts of the reaction mixture of 2a, obtained by treatment of
1
residue was purified by SiO2 column chromatography (hex- 1a with TMSOTf and P(o-tol)3; H- and 13C-NMR charts of
ane–AcOEt=5:1) to give 6a (30.0mg, 84%) as yellow oil.
6-Methoxy-6-methylheptanenitrile (6a)
TMSOAc).
1H-NMR (CDCl3, 300MHz) δ: 1.15 (s, 6H), 1.47–1.58 (m,
4H), 1.65–1.69 (m, 2H), 2.36 (t, 2H, J=7.2Hz), 3.18 (s, 3H).
13C-NMR (CDCl3, 125MHz) δ: 17.1, 23.0, 24.7, 25.8, 39.2,
49.0, 74.2, 119.7. IR (KBr) cm−1: 2247. MALDI-TOF-MS m/z:
178.1198 (Calcd for C9H17NONa [M+Na] +: 178.1202).
6-Methoxy-6-phenylheptanenitrile (6b)
References and Notes
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12) We reported Beckmann fragmentation of α-alkoxy oxime esters and
the following introduction of nucleophile using Lewis acid–organo-
silicon reagent or organoalminium reagent. See refs. 13–15.
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Chem. Soc., Chem. Commun., 1991, 533–534 (1991).
1H-NMR (CDCl3, 400MHz) δ: 1.32–1.40 (m, 2H), 1.55
(s, 3H), 1.56–1.62 (m, 2H), 1.73–1.77 (m, 2H), 2.27 (t, 2H,
J=6.8Hz), 3.09 (s, 3H), 7.34–7.39 (m, 5H). 13C-NMR (CDCl3,
125MHz) δ: 17.0, 22.6, 23.2, 25.7, 42.4, 50.3, 78.7, 119.6,
126.0, 126.9, 128.2, 144.7. IR (KBr) cm−1: 2252. High reso-
lution (HR)-FAB-MS m/z: 217.1451 (Calcd for C14H19NONa
[M+Na] +: 217.1466).
6-Methoxy-6-methyl-8-nonenenitrile (6c)
1H-NMR (CDCl3, 500MHz) δ: 1.12 (s, 3H), 1.44–1.74 (m,
6H), 2.24 (d, 2H, J=7.0Hz), 2.36 (t, 2H, J=7.5Hz), 3.18 (s,
3H), 5.06–5.09 (m, 2H), 5.78 (m, 1H). 13C-NMR (CDCl3,
125MHz) δ: 17.1, 22.4, 22.5, 25.8, 36.6, 42.0, 48.9, 75.9, 117.6,
119.7, 134.0. IR (KBr) cm−1: 2253. MALDI-TOF-MS m/z:
182.1538 (Calcd for C11H19NO [M+H+]: 182.1539).
6-Benzyloxy-6-methylheptanenitrile (6d)
1H-NMR (CDCl3, 400MHz) δ: 1.17–1.19 (m, 1H), 1.19 (s,
6H), 1.48–1.62 (m, 5H), 2.28 (t, 2H, J=7.1Hz), 4.34 (s, 2H),
7.17–7.27 (m, 5H). 13C-NMR (CDCl3, 125MHz) δ: 17.2, 23.2,
25.4, 25.9, 40.0, 63.7, 74.8, 119.8, 127.15, 127.24, 128.3, 139.6.
IR (KBr) cm−1: 2253. HR-FAB-MS m/z: 231.1615 (Calcd for
C15H21NO [M] +: 231.1623).
Acknowledgments This work was financially supported
by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology of Japan
((B) 15H04632) and Platform for Drug Discovery, Informatics
and Structural Life Science.
16) Fujioka H., Matsumoto N., Ohta R., Yamakawa M., Shimizu N.,
Kimura T., Murai K., Tetrahedron Lett., 56, 2656–2658 (2015).
17) Steric bulk of trialkylphosphine is much smaller than that of tri-
phenylphosphine. We also reported that the nucleophilic ability of
trialkylphosphine is much stronger than that of triarylphosphine.
See refs. 18 and 19.
18) Fujioka H., Yahata K., Kubo O., Sawama Y., Hamada T., Maegawa
T., Angew. Chem. Int. Ed., 50, 12232–12235 (2011).
19) Yahata K., Minami M., Yoshikawa Y., Watanabe K., Fujioka H.,
Chem. Pharm. Bull., 61, 1298–1307 (2013).
Conflict of Interest The authors declare no conflict of
interest.
Supplementary Materials The online version of this ar-
ticle contains supplementary materials (1H-, 13C- and 19F-NMR