Direct nucleophilic difluoromethylation of enolizable ketones with CHF2TMS/HMPA

Article abstract of DOI:10.1016/j.tet.2016.01.032

Easily available difluoromethylating reagent Me₃SiCF₂H enables multigram synthesis of difluoromethyl alcohols in good yields under mild conditions from a number of aldehydes and ketones in the presence of HMPA. This additive makes possible the previously challenging nucleophilic difluoromethylation of enolizable ketones. DMPU can be used as a non-toxic alternative to the HMPA in the difluoromethylation reaction, albeit the yields were slightly lower in this case. The method works well with cyclic, acyclic, aryl ketones and tolerates various functional groups.

Full text of DOI:10.1016/j.tet.2016.01.032

Accepted Manuscript
Direct Nucleophilic Difluoromethylation of Enolizable Ketones with CHF TMS/HMPA
2
Oleg M. Michurin, Dmytro S. Radchenko, Igor V. Komarov
PII:
S0040-4020(16)30032-1
10.1016/j.tet.2016.01.032
TET 27439
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 October 2015
Revised Date: 6 January 2016
Accepted Date: 18 January 2016
Please cite this article as: Michurin OM, Radchenko DS, Komarov IV, Direct Nucleophilic
Difluoromethylation of Enolizable Ketones with CHF TMS/HMPA, Tetrahedron (2016), doi: 10.1016/
2
j.tet.2016.01.032.
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ACCEPTED MANUSCRIPT
Direct Nucleophilic Difluoromethylation of Enolizable Ketones
with CHF2TMS/HMPA
Oleg M. Michurina,b, Dmytro S. Radchenkoa,b,*, Igor V. Komarova,b
a Institute of High Technologies, Taras Shevchenko National University of Kyiv, Volodymyrska 60, 01601 Kyiv,
Ukraine, Tel: +38 097 9931939; Fax: +38 044 5373253
bEnamine Ltd., Matrosova 23, 01103 Kyiv, Ukraine
E-mail: dmitry.radchenko@mail.google.com
,
dmitry.radchenko@mail.enamine.net
Abstract
Easily available difluoromethylating reagent Me3SiCF2H enables multigram synthesis of
difluoromethyl alcohols in good yields under mild conditions from a number of aldehydes and ketones
in the presence of HMPA. This additive makes possible the previously challenging nucleophilic
difluoromethylation of enolizable ketones. DMPU can be used as a non-toxic alternative to the HMPA
in the difluoromethylation reaction, albeit the yields were slightly lower in this case. The method
works well with cyclic, acyclic, aryl ketones and tolerates various functional groups.
Key words: addition, catalysis, fluorine, ketones, nucleophilic difluoromethylation.
Introduction
Incorporation of fluorine in organic molecules modulates their pharmacological properties and
has become almost a standard practice in medicinal chemistry. The unique properties of fluorine such
as high electronegativity, excellent NMR parameters, low abundance in biosphere, ability to mimic
hydrogen and block metabolic processes, increased lipophilicity and bioavailability of fluoroorganic
molecules has made fluorine the “second-favourite heteroatom” after the nitrogen in drug design.1 It is
estimated that 30–40% of agrochemicals and 20% of pharmaceuticals contain fluorine.2 The
difluoromethyl group (CF2H) has a great potential in the design of pharmaceuticals, agrochemicals,
and materials. In the area of medicinal chemistry, the CF2H groups prove to be a useful bioisostere of
a hydroxy group, mainly because it is a lypophilic hydrogen bond donor, offering a potential for
1

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improved membrane permeability.3 Recently, the CF2H group has been used as a non-reactive –SH
bioisostere in the design of cysteine-containing hexapeptide analogues, leading to potent inhibitors of
NS3/4A protease.4 It is therefore not surprising that the number of studies on synthetic methods of the
CF2H-containing compounds has been dramatically increased in the last decade.5
In the course of the work on the synthesis of new fluorinated building blocks6 we became
interested in α-difluoromethyl alcohols. Several methods have been described in the literature for their
synthesis, most of them applicable to either aldehydes or ketones as the starting compounds.7 The most
frequently used methods involved the use of the nucleophilic reagents possessing the CF2 fragment
connected to auxiliary groups which stabilize the carbanion, e.g. (phenylsulfonyl)difluoromethyl anion
–
–
(PhSO2CF2 ),8 diethyl difluoromethylphosphonate anion ((EtO)2OPCF2 ),9 difluoro(phenylthio)methyl
(PhSCF2 ),10
N-tert-butyldimethylsilyl-S-difluoromethyl-S-phenylsulfoximine
anion
–
anion
(PhSO(NTBS)CF2 ),11 etc. Application of these reagents to the difluoromethylation of carbonyl
compounds requires strong alkali reagents (e.g. LDA, MeONa, t-BuOK, Na/Hg) and an additional step
to remove the auxiliary group.
–
In the search for a cheaper and milder difluoromethylating method, we decided to use the
trimethylsilyldifluoromethane (Me3SiCF2H) as a CF2H group source. Me3SiCF2H is commercially
available, and can also be prepared in a laboratory by the NaBH4 reduction of Me3SiCF3.12 Recently it
was reported as a convenient source of the CF2H group by several authors.13 Notably, use of this
reagent could allow direct, one-pot conversion of ketones to α-difluoromethyl alcohols, like in the
case of the more common Ruppert-Prakash reagent (Me3SiCF3).14 Me3SiCF2H adds to the aldehydes
and non-enolizable ketones in high yields, but nucleophilic addition to enolizable ketones is often
accompanied by side reactions, leading to low yields and contaminated products. Fuchikami et al.
reported that although Me3SiCF2H and PhMe2SiCF2H converted aldehydes to difluoromethyl alcohols
in good yields (in the presence of KF in DMF at 100 ºC), their reaction with ketones proceeded with
low yields (20–25%).15 More recently, similar results were obtained by other authors who used various
bases in DMF or THF at ambient or low temperatures.16, 17 Clearly, there was a need for a practical,
general approach for Me3SiCF2H addition to ketones.i Here, we disclose a convenient protocol for
direct difluoromethylation of enolizable ketones.
Results and discussion
Our initial attempts to induce nucleophilic difluoromethylation with enolizable ketones were
focused on Me3SiCF2H as a source of the difluoromethyl anion and CsF as the fluoride ion source.
Under conditions similar to those reported previously for the nucleophilic addition to aldehydes (CsF,
THF),16 no reaction occurred either with cyclohexanone or 4-phenylcyclohexanone as model
i
Igoumnov et al. (Fluorine Notes 2011, 5, 78) reported that aldehydes and ketones behave similar in direct
difluoromethylation reaction. However, we were not able to reproduce these results.
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substrates. Obviously, CsF generated only a low concentration of fluoride ions due to its low solubility
in THF; the reaction rate was very slow under these conditions. Increasing the fluoride ion
concentration by performing reaction in DMF,16 DMSO or using a soluble fluoride ion source, e.g.
tetramethylammonium fluoride (TMAF) in THF allowed us to increase the reaction rate, but the yields
of the desired alcohols were still low (~ 20% by 19F NMR). It should be noted that the main problem,
in this case, was the formation of a number of unidentified and non-separable by-products (shown by
1H NMR and GSMS of crude reaction mixture, see the Supporting Information), presumably due to
substantial enolization and subsequent condensation reaction of the ketone. We hypothesized that
maintaining a low concentration of the fluoride ions is the key to achieve clean transformation. This
led us to an idea of performing the synthesis in THF in the presence of a polar additive, e.g. HMPA or
DMPU in order to accelerate the reaction and at the same time generate a low concentration of the
"naked" fluoride ions. The first experiment we performed with in the presence of HMPA in THF
showed that the nucleophilic addition took place smoothly, but the conversion was ~50%. The only
detectable products in the reaction mixture (in the case of cyclohexanone) were difluoromethyl alcohol
(d, δF –134.8 ppm), its silyl ether (d, δF –132.8 ppm) and CH2F2 (t, δF –143.8 ppm). Formation of
CH2F2 can be explained taking into account the enolization of ketones through the difluoromethyl
anion species. Indeed, use of 2,2,6,6-tetradeuterocyclohexanone as a carbonyl component led to the
formation of a small amount of CHDF2 (shown by 19F NMR). As expected, when TMAF was used as
the fluoride ion source, no detectable effect of the HMPA addition on the reaction yield was observed.
Further optimization experiments were performed using 4-phenylcyclohexanone, which proved to be
more convenient model substrate because its low volatility (Table 1).
Table 1 Optimization of reaction conditions
Equiv.
Equiv. Equiv. Conversion
Entry
TMSCF2H HMPA CsF
(%)
46
93
96
96
96
52
66
81
93
30
37
45
49
1
2
3
4
5
6
7
8
9
10
11
12
13
2
2
2
2
2
2
2
2
2
5
5
5
5
5
1
3
4
5
5
5
5
5
0.1
0.2
0.3
0.4
1
0.2
0.2
0.2
0.2
0.1
0.1
0.1
0.1
1
1.5
2
3
3

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Varying the reaction conditions showed that increase in the amount of CsF had beneficial
effect on the yield of the reaction. Although CsF is almost insoluble in THF/HMPA, the increased
quantity of CsF led to higher conversion of the ketone. The optimal amount of CsF was determined to
be about 30 mol% (Table 1, entry 1–4). The same is true for HMPA: 5 equivalents of the additive
provided the best conversion of the starting material (Table 1, entry 5–10). It is worth mentioning that
performing the reaction in neat HMPA or at higher concentration of HMPA led to low yields and
unidentified byproducts. Addition of DMPU instead of HMPA to the reaction medium gave similar
results but the conversion was somewhat less (DMPU – 57%, HMPA – 76% yield by 19F NMR).
Nevertheless, it was demonstrated that at least in case of cyclohexanone, DMPU can be used instead
of HMPA. This possibility might be useful for large-scale preparation of α-difluoromethyl alcohols.
Finally, the use of excess Me3SiCF2H was important to achieve good conversion; it was obvious from
the experiments with 10 mol% of CsF (Table 1, entries 10–13). The optimal amount of Me3SiCF2H
was determined to be 2 equivalents; it gave the highest conversion of the ketone and was at the same
time economical. It should be noted, however, that in some cases the use of more than 2 equivalents of
Me3SiCF2H could lead to better yields of the difluoromethyl alcohols. In case of 4-
phenylcyclohexanone elevated temperatures did not lead to increase in the conversion of the starting
material. In summary, the optimal general conditions we propose for the difluoromethylation reaction
are the following: 2 equivalents of Me3SiCF2H, 5 equivalents of HMPA and 30 mol% of CsF in THF
at room temperature. The reaction was not particularly fast and took about a day to achieve 95%
conversion.
From a mechanistic point of view, the overall process seems to be similar to the addition of the
well-known Me3SiCF3 reagent.14 A plausible reaction mechanism explaining the experimental facts is
illustrated in Scheme 1. In the first step, the base (the fluoride or alcoxy anion, X) coordinates with the
silicon atom of Me3SiCF2H to form 1. The rate of its addition to ketone seems to be relatively slow as
compared to the rate of side reactions, e.g., enolization and condensation of the ketone. Coordination
of 1 with HMPA might lead to another hypervalent silicon species, compound 2, which is more
reactive towards ketones.17,18 The addition product could react with Me3SiCF2H to complete the
catalytic cycle. The role of additional amount of insoluble CsF is unclear, but could be rationalized
assuming that it allows generation of low concentration of fluoride ion on the surface of the CsF
during the course of the reaction. We speculate that it is the low concentration of the fluoride ions that
allows for Me3SiCF2H activation without significant enolization of the ketone, and therefore, avoiding
the side reactions.
Scheme 1 Possible mechanism for HMPA promoted difluoromethylation.
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In order to test if the reaction is autocatalytic, we performed model studies using sodium
difluoroethylate (CF2НCH2ONa) as an initiator. CF2НCH2ONa has similar nucleophilicity to the
intermediate anion 3, produced in the difluoromethylation reaction. Indeed, in this case the
difluoromethylation reaction of cyclohexanone in THF proceeded with moderate yield (as determined
by 19F NMR) of the corresponding difluoromethyl alcohol without (36%) or in the presence (54%) of
HMPA. Hence, CF2НCH2ONa was found to be rather good initiator, despite some unidentified by-
products were formed. In contrast to previous studies,16 these experiments clearly demonstrated the
autocatalytic nature of the ketone difluoromethylation reaction.
Applying the general procedure to a representative set of ketones led to a number of
difluoromethyl alcohols (Figure 1). In general, the yields of the corresponding difluoromethyl alcohols
were good, their purification were simple and straightforward. We found that acyclic ketones, seven-,
six-, and five-membered cyclic ketones reacted well, whereas cyclobutanone formed unidentified
mixture of compounds, presumably due to fast enolization and subsequent aldol reaction (compounds
4–10). Other highly enolizable ketones (ethyl pyruvate and 3-pyranone) also failed to give the desired
products 12 and 15, an exothermic reaction leading to a mixture of unidentified compounds occurred
upon addition of CsF instead. In the case of ketones containing a basic nitrogen atom, the yields were
usually better (compounds 16–21). Thus, even the four-membered azetidinone derivative formed the
product 19, albeit in low yield. Aryl ketones gave good yields of the difluoromethyl alcohols 21–25.
Notably, aryl ketones demonstrated better conversion at elevated temperatures.
Finally, as can be seen from the Fig. 1, the ester, nitro, cyano and protected amino groups in
the substrates tolerated the difluoromethylation reaction conditions. In general, the method worked
well in preparations of difluoromethyl alcohols on a relatively large scale (up to 70 g, see the
experimental procedures for the compounds 16 and 17).
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In conclusion, we have developed a new protocol for the direct difluoromethylation reaction of
enolizable ketones with Me3SiCF2H. Using a base with low solubility in THF (CsF) and addition of
HMPA as a promoter is crucial for the reaction efficiency. Various alicyclic and acyclic
difluoromethyl alcohols can be prepared in one step in moderate to good yields. Moreover, DMPU can
be used instead of HMPA as a non-toxic substitute. Reaction conditions are mild and tolerate various
functionalities. We believe that the overall simplicity of the procedure, scalability and accessibility of
starting materials will make this method a preferred alternative to indirect difluoromethylation
reaction.
Figure 1 Difluoromethyl alcohols and their isolated yields.
aNo product was obtained. bCombined yield for two isomers. Diastereomers were separated by column chromatography.
cObtained as ca. 1:1 mixture of diastereomers.
Supporting Information for this article is available online. It includes the copies of 1H, 13C,19F NMR
spectra and additional details of the experiments.
6

ACCEPTED MANUSCRIPT
Experimental section
Solvents were purified according to the standard procedures. Starting materials were supplied
from Enamine LTD. Melting points were measured on an automated melting point system. Analytical
TLC was performed using Polychrom SI F254 plates. Column chromatography was performed using
1
silica gel (230–400 mesh) as the stationary phase. H, 13C, 19F NMR, and 2D NMR spectra were
recorded on either Bruker Avance 500 spectrometer at 499.9 (1H), 124.9 (13C) and 470 (19F) MHz, or
on Varian Unity Plus 400 spectrometer at 400 (1H), 101 (13C) and 377 (19F) MHz. Chemical shifts are
reported in ppm downfield from TMS (1H, 13C) or CFCl3 (19F) as an internal standard. HRMS analyses
were performed on a Surveyor HPLC system interfaced to an LTQ Orbitrap (Bremen, Germany),
equipped with electrospray (ESI) ion source. Infrared spectra were measured on a Perkin Elmer
Spectrum 100 FTIR and are reported in reciprocal centimeters (cm-1). All compound names were
generated using ChemBioDraw.
General procedure A for difluoromethylation of ketones:
CsF (1.39 g, 9.17 mmol) was added to a solution of ketone (31 mmol) and HMPA (26.7 mL, 155
mmol) in 65 mL of THF under an Ar atmosphere. Me3SiCF2H (7.6 g, 61 mmol) was then added, and
the mixture was stirred at room temperature for 24 h. A solution of TBAF (31 mL, 1 M in THF) was
added at the end of this period, and the mixture was stirred for another 1 h. Then the mixture was
poured into water (200 mL). The product was extracted with a mixture of hexanes-ethyl acetate (1:1,
3×70 mL), and the combined organic phase was washed with water (2×70 mL), dried over Na2SO4,
and evaporated. The products contaminated with unreacted ketone were purified as described below.
A solution of crude difluoromethyl alcohol in methanol (30 mL) was added to a solution of
semicarbazide hydrochloride (2 g, 18 mmol) and sodium acetate (2.2 g, 27 mmol) in water (10 mL) at
room temperature and stirred for 10 h. Methanol was evaporated, water (50 mL) was added, and the
obtained solution was extracted with hexanes (3×50 mL), dried over Na2SO4 and evaporated to afford
sufficiently pure difluoromethyl alcohol. It could be further purified either by distillation or by column
chromatography.
General procedure B for difluoromethylation of ketones (for water-soluble difluoromethyl
alcohols):
CsF (1.39 g, 9.17 mmol) was added to a solution of ketone (31 mmol) and HMPA (26.7 mL, 155
mmol) in 65 mL of THF under an Ar atmosphere. Me3SiCF2H (7.6 g, 61 mmol) was then added, and
the mixture was stirred at room temperature for 24 h. The reaction mixture was poured into water (200
mL). The product was extracted with a mixture of hexanes-ethyl acetate (1:1, 3×70 mL), and the
combined organic phase was washed with water (2×70 mL) and dried over Na2SO4. The drying agent
was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in methanol (50
7

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mL), conc. HCl was added to pH 2. The mixture was then stirred for 1 h at r.t. and methanol was
removed by rotatory evaporation. The crude product was purified either by distillation or by column
chromatography.
General procedure C for difluoromethylation of ketones at elevated temperature:
CsF (1.39 g, 9.17 mmol) was added to a solution of ketone (31 mmol) and HMPA (26.7 mL, 155
mmol) in 65 mL of THF under an Ar atmosphere. Me3SiCF2H (7.6 g, 61 mmol) was then added, and
the mixture was stirred at reflux for 24 h. A solution of TBAF (31 mL, 1 M in THF) was then added,
and the mixture was stirred for another 1 h, and was then poured into water (200 mL). The product
was extracted with a mixture of hexanes-ethyl acetate (1:1, 3×70 mL), and the combined organic
phase was washed with water (2×70 mL), dried over NaSO4. The drying agent was filtered off and the
filtrate was evaporated to dryness. The crude products were purified either by distillation or by column
chromatography.
1-(Difluoromethyl)cycloheptanol 4 was prepared according to general procedure A. The product
was purified by distillation (25 mbar, 89–92 ºC). Colorless crystals; 2.28 g (yield 45%); m.p. 35–
1
36 ºC; νmax(KBr) 3500-3200 (br), 2933, 2863, 1464, 1448, 1130, 1106, 1062, 1047, 1032 cm-1; H
NMR (500 MHz, CDCl3), δ: 5.47 (t, J = 56.7 Hz, 1H), 1.88-1.73 (m, 3H), 1.73-1.57 (m, 6H), 1.58-
1.45 (m, 4H); 13C NMR (126 MHz, CDCl3), δ: 118.5 (t, J = 248.2 Hz), 75.4 (t, J = 20.0 Hz), 34.4 (s),
29.8 (s), 21.8 (s); 19F NMR (376 MHz, CDCl3), δ: -132.8 (d, J = 56.8 Hz); Anal. calcd. for C8H14F2O:
C, 58.52; H, 8.59. Found: C, 58.35; H, 8.83.
1-(Difluoromethyl)cyclohexanol 5 was prepared according to general procedure A. The product
was purified by distillation (25 mbar, 82–85 ºC). Colorless crystals; 2.80 g (yield 60%); m.p. 38–39
1
ºС; νmax(KBr) 3500-3250 (br), 2939, 2866, 1450, 1286, 1191, 1143, 1093, 1083, 1052 cm-1; H NMR
(500 MHz, CDCl3), δ: 5.46 (t, J = 56.6 Hz, 1H), 1.77-1.56 (m, 8H), 1.55-1.41 (m, 2H), 1.30-1.15 (m,
13
1H); C NMR (126 MHz, CDCl3), δ: 118.0 (t, J = 247,3 Hz), 71.8 (t, J = 19,8 Hz), 30.1, 25.6, 20.5.
19F NMR (376 MHz, CDCl3), δ: -134.8 (d, J = 56.6 Hz); Anal. calcd. for C7H12F2O: C, 55.99; H, 8.05.
Found: C, 56.18; H, 7.96.
1-(Difluoromethyl)cyclopentanol 6 was prepared according to general procedure A. The product
was purified by distillation (25 mbar, 75–78 ºC). Colorless liquid; 2.36 g (yield 56%); νmax(KBr) 3595,
1
3560-3200 (br), 2960, 2877, 1633, 1442, 1386, 1193, 1110, 1056, 1018 cm-1; H NMR (500 MHz,
CDCl3), δ: 5.66 (t, J = 56.4 Hz, 1H), 2.11 (s, 1H), 1.91-1.77 (m, 4H), 1.74-1.55 (m, 4H); 13C NMR
19
(126 MHz, CDCl3), δ: 117.1 (t, J = 244.9 Hz), 82.0 (t, J = 21.7 Hz), 34.6 (s), 24.3 (s); F NMR (376
MHz, CDCl3), δ: -130.3 (d, J = 56.6 Hz); Anal. calcd. for C6H10F2O: C, 52.93; H, 7.40. Found: C,
53.17; H, 7.68.
4-(Difluoromethyl)heptan-4-ol 8 was prepared according to general procedure A. The product was
purified by distillation (25 mbar, 72–74 ºC). Colorless liquid; 3.19 g (yield 62%); νmax(KBr) 3604,
8

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3550-3300 (br), 2964, 2877, 1467, 1108, 1062, 1024 cm-1; 1H NMR (400 MHz, CDCl3), δ: 5.60 (t, J =
56.3 Hz, 1H), 1.70 (s, 1H), 1.62 – 1.46 (m, 4H), 1.46 – 1.28 (m, 4H), 0.94 (t, J = 7.2 Hz, 6H); 13C
NMR (126 MHz, CDCl3), δ: 117.8 (t, J = 247.3 Hz), 74.4 (t, J = 20.3 Hz), 36.0(s), 16.1 (s), 14.7 (s);
19F NMR (376 MHz, CDCl3), δ: -133.3 (d, J = 56.3 Hz). Anal. calcd. for C8H16F2O: C, 57.81; H, 9.70.
Found: C, 57.97; H, 9.51.
E-1-Difluoromethyl-4-phenyl-cyclohexanol E-9 was prepared according to general procedure A.
The product was purified by column chromatography (Hexanes : EtOAc = 3:1, Rf=0.45). White
crystals; 2.03 g (yield 29%); m.p. 50-51 ºС; νmax(KBr) 3500-3200 (br), 2950, 2865, 1492, 1452, 1357,
1
1114, 1101, 1057 cm-1; H NMR (500 MHz, CDCl3), δ: 7.36 (t, J = 7.5 Hz, 2H), 7.31-7.22 (m, 3H),
5.89 (t, J = 55.9 Hz, 1H), 2.78 (tt, J = 10.6, 3.8 Hz, 1H), 2.25 (s, 1H), 2.14 (d, J = 13.2 Hz, 2H), 2.03 –
1.94 (m, 2H), 1.84-1.63 (m, 4H). 13C NMR (126 MHz, CDCl3), δ: 145.4 (s), 128.6 (s), 126.9 (s), 126.3
(s), 116.9 (t, J = 246.2 Hz), 71.1 (t, J = 19.7 Hz), 41.9 (s), 32.4 (s), 29.2 (s).19F NMR (376 MHz,
CDCl3), δ: -134.0 (d, J = 55.9 Hz). Anal. calcd. for C13H16F2O: C, 69.01; H, 7.13. Found: C, 68.88; H,
7.28.
Z-1-Difluoromethyl-4-phenyl-cyclohexanol Z-9 was prepared according to general procedure A.
The product was purified by column chromatography (Hexanes : EtOAc = 3:1, Rf=0.55). White
crystals; 2.59 g (yield 37%); m.p. 64–65 ºС; νmax(KBr) 3542, 3500-3350 (br), 2944, 2862, 1494, 1442,
1386, 1168, 1118, 1060, 1051 cm-1; 1H NMR (500 MHz, CDCl3), δ: 7.36 (t, J = 7.5 Hz, 2H), 7.29 (d, J
= 7.3 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), δ 5.56 (t, J = 56.6 Hz, 1H), 2.56 (tt, J = 12.05, 3.0 Hz, 1H),
2.02 – 1.78 (m, 7H), 1.70 (td, J = 13.7, 3.9 Hz, 2H). 13C NMR (126 MHz, CDCl3), δ: 146.6 (s), 128.5
19
(s), 126.9 (s), 126.3 (s), 118.0, (t, J = 246.9 Hz), 71.2 (t, J = 20.9 Hz), 43.7 (s), 30.2 (s), 27.8 (s). F
NMR (376 MHz, CDCl3), δ: -134.1 (d, J = 56.6 Hz). Anal. calcd. for C13H16F2O: C, 69.01; H, 7.13.
Found: C, 68.91; H, 7.25.
Ethyl 6,6-difluoro-5-hydroxy-5-methylhexanoate 11 was prepared according to general procedure
A. The product was purified by column chromatography (Hexanes : EtOAc = 5:1, Rf=0.23). Colorless
liquid; 2.73 g (yield 42%); νmax(KBr) 3600-3200 (br), 2983, 2944, 1731, 1718, 1465, 1377, 1192,
1
1093, 1062 cm-1; H NMR (500 MHz, CDCl3), δ: 5.52 (t, J = 56.6 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H),
2.34 (t, J = 7.2 Hz, 2H), 2.19 (s, 1H), 1.84 – 1.68 (m, 2H), 1.63 – 1.51 (m, 2H), 1.30 – 1.19 (m, 6H);
13C NMR (126 MHz, CDCl3), δ: 173.6 (s), 117.7 (t, J = 247.6 Hz), 72.6 (t, J = 21.5 Hz), 60.6 (s), 34.6
19
(s), 34.4 (s), 19.8 (s), 18.1 (s), 14.3 (s); F NMR (376 MHz, CDCl3), δ: -132.0 (dd, J = 279.4, 56.6
+
Hz, 1F), -133.6 (dd, J = 279.4, 56.6 Hz, 1F). HRMS (EI+) calcd. for [M]+ C9H16F2O3 210.1062, found
210.1061.
(1,1-Difluoro-3-methoxy-2-methylpropan-2-yl)cyclopropane 13 was prepared according to
general procedure B. The product was purified by distillation (7 mbar, 89–91 ºC). Colorless liquid;
2.73 g (yield 53%); νmax(KBr) 3600-3200 (br), 3093, 3012, 2935, 2900, 2832, 1673, 1456, 1419, 1382,
1189, 1114, 1059 cm-1; 1H NMR (500 MHz, CDCl3), δ: 5.73 (t, J = 56.2 Hz, 1H), 3.63 (d, J = 9.6 Hz,
9

ACCEPTED MANUSCRIPT
1H), 3.40 (s, 3H), 3.35 (d, J = 9.6 Hz, 1H), 2.51 (s, 1H), 0.966-0.847 (m, 1H), 0.656-0.547 (m, 1H),
0.503-0.320 (m, 3H); 13C NMR (126 MHz, CDCl3), δ: 116.8 (t, J = 247.9 Hz), 74.7 (s), 71.6 (t, J =
21.0 Hz), 59.6 (s), 11.0 (s), -0.4 (s), -1.4 (s); 19F NMR (376 MHz, CDCl3), δ: -132.0 (dd, J = 282.4,
56.1 Hz, 1F), -136.3 (dd, J = 282.5, 56.3 Hz, 1F). Anal. calcd. for C7H12F2O2: C, 50.60; H, 7.28.
Found: C, 50.89; H, 7.50.
4-(Difluoromethyl)tetrahydro-2H-pyran-4-ol 14 was prepared according to general procedure B.
The product was purified by column chromatography (Hexanes : EtOAc = 2:1, Rf=0.3). m.p. 80–
81 ºС; White solid; 2.45 g (yield 52%); νmax(KBr) 3550-3200 (br), 2972, 2875, 1388, 1288, 1247,
1
1203, 1132, 1051 cm-1; H NMR (500 MHz, CDCl3), δ: 5.47 (t, J = 56.3 Hz, 1H), 3.84 (dd, J = 11.4,
5.0 Hz, 2H), 3.75 (dd, J = 11.9 Hz, J = 11.8 Hz 2H), 2.26 (s, 1H), 1.83 (td, J = 13.1, 5.1 Hz, 2H), 1.48
13
(d, J = 13.8 Hz, 2H); C NMR (126 MHz, CDCl3), δ: 117.2 (t, J = 246.7 Hz), 69.6 (t, J = 21.5 Hz),
62.5 (s), 30.5 (t, J = 3.0 Hz); 19F NMR (376 MHz, CDCl3), δ: -135.4 (d, J = 56.3 Hz). Anal. calcd. for
C6H10F2O2: C, 47.37; H, 6.63. Found: C, 47.52; H, 6.39.
1-Benzyl-3-(difluoromethyl)pyrrolidin-3-ol 16 was prepared according to general procedure A.
The product was purified by column chromatography (Hexanes : EtOAc = 1:1+3% triethylamine,
Rf=0.5). Colorless liquid; 4.08 g (yield 58%). For the scale-up synthesis, 50 g of 1-benzylpyrrolidin-3-
one was used as the starting material and 35 g (54%) of 1-benzyl-4-(difluoromethyl)piperidin-4-ol was
obtained according to general procedure A, but using proportional amounts of reactants. In this case
the product was purified by distillation (2.7 mbar, 111–113 ºC). νmax(KBr) 3600-3200 (br), 2950, 2811,
1650, 1604, 1454, 1382, 1211, 1135, 1058 cm-1; 1H NMR (500 MHz, CDCl3), δ: 7.43 – 7.18 (m, 5H),
5.74 (t, J = 56.1 Hz, 1H), 4.14 (s, 1H), 3.63 (dd, J = 42.0, 12.7 Hz, 2H), 3.00 – 2.86 (m, 1H), 2.67 (dd,
J = 25.3, 10.6 Hz, 2H), 2.46 (dd, J = 16.4, 8.0 Hz, 1H), 2.28 – 2.15 (m, 1H), 1.92 – 1.78 (m, 1H); 13C
NMR (126 MHz, CDCl3), δ: 137.8 (s), 129.1 (s), 128.4 (s), 127.4 (s), 116.2 (t, J = 245.0 Hz), 79.8 (t, J
= 21.7 Hz), 61.2 (s), 60.1 (s), 53.1 (s), 34.5 (s); 19F NMR (376 MHz, CDCl3), δ: -130.7 (dd, J = 280.2,
56.1 Hz, 1F), -131.8 (dd, J = 280.1, 56.2 Hz, 1F). HRMS (EI+ + 3NBA) calcd. for [M+H]+
C12H16F2NO+ 228.1194, found 228.1196.
1-Benzyl-4-(difluoromethyl)piperidin-4-ol 17 was prepared according to general procedure A. The
product was purified by column chromatography (Hexanes : EtOAc = 1:1+3% triethylamine, Rf=0.5).
Colorless liquid; 6.57 g (yield 88%). For the scale-up synthesis, 60 g of N-benzyl-4-piperidone was
used as starting material and 68 g (89%) of 1-benzyl-4-(difluoromethyl)piperidin-4-ol was obtained
according to general procedure A, but using proportional amounts of reactants. νmax(KBr) 3550-3150
(br), 2954, 2819, 1652, 1602, 1454, 1365, 1305, 1197, 1122, 1058 cm-1; 1H NMR (500 MHz, CDCl3),
δ: 7.41 – 7.23 (m, 5H), 5.51 (t, J = 56.4 Hz, 1H), 3.57 (s, 2H), 2.77 (d, J = 11.3 Hz, 2H), 2.37 (td, J =
13
11.7, 2.0 Hz, 2H), 1.89 (s, 1H), 1.83 (td, J = 13.3, 4.4 Hz, 2H), 1.60 (d, J = 12.4 Hz, 2H); C NMR
(126 MHz, CDCl3), δ: 138.4 (s), 129.2 (s), 128.4 (s), 127.2 (s), 117.6 (t, J = 246.5 Hz), 70.1 (t, J =
21.1 Hz), 63.1 (s), 47.9 (s), 30.2 (s); 19F NMR (376 MHz, CDCl3), δ: -134.46 (d, J = 56.4 Hz). HRMS
(EI+ + 3NBA) calcd. for [M+H]+ C13H18F2NO+ 242.1351, found 242.1349.
10

ACCEPTED MANUSCRIPT
1-Benzyl-3-(difluoromethyl)piperidin-3-ol 18 was prepared according to general procedure A. The
product was purified by column chromatography (Hexanes : EtOAc = 1:1+3% triethylamine, Rf=0.5).
Colorless liquid; 4.03 g (yield 54%). Alternatively, the product can be purified by distillation (2.7
mbar, 119–120 ºC); νmax(KBr) 3600-3200 (br), 2948, 2806, 1662, 1585, 1454, 1371, 1297, 1147, 1105,
1058 cm-1; 1H NMR (500 MHz, CDCl3), δ: 7.35-7.19 (m, 5H), 5.61 (t, J = 55.9 Hz, 1H), 3.55 (s, 2H),
3.31 (s, 1H), 2.76 (d, J = 10.7 Hz, 1H), 2.67 (d, J = 11.2 Hz, 1H), 2.22 (d, J = 11.0 Hz, 1H), 2.07 (td, J
= 11.3, 3.2 Hz, 1H), 1.89-1.74 (m, 1H), 1.73 – 1.55 (m, 2H), 1.50 (dt, J = 13.1, 6.6 Hz, 1H); 13C NMR
(101 MHz, CDCl3), δ: 137.52 (s), 129.0 (s), 128.4 (s), 127.4 (s), 116.7 (t, J = 245.6 Hz), 70.5 (t, J =
19
21.6 Hz), 62.7 (s), 57.4 (t, J = 3.9 Hz), 53.2 (s), 28.2 (s), 20.5 (s); F NMR (376 MHz, CDCl3), δ: -
134.90 (d, J = 56.0 Hz). Anal. calcd. for C13H17F2NO: C, 64.71; H, 7.10; N, 5.81. Found: C, 64.96; H,
7.29; N, 6.01.
1-Benzhydryl-3-(difluoromethyl)azetidin-3-ol 19 was prepared according to general procedure С.
The product was purified by column chromatography (Hexanes : EtOAc = 2:1, Rf=0.55). Yellow oil;
1.61 g (yield 18%); νmax(KBr) 3600-3200 (br), 3062, 3027, 2958, 2848, 1806, 1599, 1492, 1452, 1226,
1
1095, 1068, 1027 cm-1; H NMR (500 MHz, CDCl3), δ: 7.50 – 7.15 (m, 10H), 6.01 (t, J = 55.6 Hz,
1H), 4.45 (s, 1H), 3.47 (d, J = 9.4 Hz, 2H), 3.17 (s), 3.11 (d, J = 9.3 Hz, 2H). 13C NMR (126 MHz,
CDCl3), δ: 141.6 (s), 128.7 (s), 127.49 (s), 115.5 (t, J = 243.6 Hz), 77.5 (s), 69.5 (t, J = 23.1 Hz), 60.3
(t, J = 3.8 Hz). 19F NMR (376 MHz, CDCl3), δ: -134.17 (d, J = 55.7 Hz). HRMS (EI+ + 3NBA) calcd.
for [M+H]+ C17H18F2NO+ 290.1351, found 290.1350.
1-Benzylpyrrolidin-3-yl-1,1-difluoropropan-2-ol 20 was prepared according to general procedure
A. The product was purified by column chromatography (Hexanes : EtOAc = 1:1+3% triethylamine,
Rf=0.5). Colorless liquid; 3.71 g (yield 47%); νmax(KBr) 3600-3200 (br), 2973, 2807, 1658, 1454,
1380, 1352, 1211, 1128, 1089, 1061 cm-1; 1H NMR (500 MHz, CDCl3), δ: 7.43 – 7.20 (m, 1H), 5.65 (t,
J = 57 Hz, 0.6H), 5.59 (t, J = 56,35 Hz, 0.4H), 3.91 (s, 1H), 3.63 (s, 2H), 2.95 (d, J = 7.9 Hz, 0,44H),
2.90 – 2.73 (m, 1.7H), 2.50 (t, J = 8.1 Hz, 0.7H), 2.44 – 2.23 (m, 2.6H), 2.06 – 1.86 (m, 2.24H), 1.24
(s, 1.77H), 1.20 (s, 1.35H);13C NMR (126 MHz, CDCl3), δ: 138.5 (s), 138.3 (s), 128.7 (s), 128.7 (s),
128.6 (s), 128.5 (s), 128.4 (s), 127.4 (s), 127.3 (s), 117.9 (t, J = 249.28 Hz), 117.2 (t, J = 247.38 Hz),
74.0 (t, J = 20.39 Hz), 73.7 (s), 73.7 (s), 73.7 (t, J = 20.11 Hz), 60.0 (s), 59,8 (s), 55.4 (s), 55.0 (s),
19
53.3 (s), 52.7 (s), 41.9 (s), 41.1 (s), 24.6 (s), 24.1 (s), 19.1 (s), 18.4 (s); F NMR (376 MHz, CDCl3),
δ: -127.9 (dd, J = 280.2 Hz, 56.3 Hz, 1F), -134.1 (dd, J = 280.1, J = 56.6 Hz, 1F), -129.0 (dd, J =
283.8 Hz, 56.1 Hz, 1F), -136.6 (dd, J = 283.8, J = 57.2 Hz, 1F). HRMS (EI+ + 3NBA) calcd. for
[M+H]+ C14H20F2NO+ 256.1507, found 256.1507.
1,1-Difluoro-2-(pyridin-4-yl)propan-2-ol 21 was prepared according to general procedure C. The
product was purified by column chromatography (Hexanes : EtOAc = 1:2, Rf=0.3). White solid; 3.91 g
(yield 73%); m.p. 84–85 ºС; νmax(KBr) 3300-3000 (br), 2985, 2809, 2636, 1608, 1417, 1384, 1228,
1159, 1106, 1061, 1007 cm-1; 1H NMR (500 MHz, CDCl3), δ: 8.53 (d, J = 5.9 Hz, 2H), 7.49 (d, J = 5.6
11

ACCEPTED MANUSCRIPT
Hz, 2H), 5.70 (t, J = 56.2 Hz, 1H), 4.98 (s, 1H), 1.64 (s, 3H).13C NMR (126 MHz, CDCl3), δ: 150.1
(s), 149.6 (s), 121.3 (s), 116.6 (t, J = 250.0 Hz), 73.7 (t, J = 22.2 Hz), 22.4 (s). 19F NMR (376 MHz,
CDCl3), δ: -129.6 (dd, J = 278.9, 56.1 Hz, 1F), -130.5 (dd, J = 279, 56.4 Hz, 1F). HRMS (EI+) calcd.
for [M]+ C8H9F2NO+ 173.0647, found 173.0645.
1,1-Difluoro-2-phenylpropan-2-ol 22 was prepared according to general procedure C. The product
was purified by distillation (7 mbar, 72–74 ºC). Colorless liquid; 3.04 g (yield 57%); νmax(KBr) 3600-
1
3200 (br), 2939, 2877, 1604, 1448, 1386, 1348, 1203, 1099, 1072, 1057, 1029 cm-1; H NMR (500
MHz, CDCl3), δ: 7.54 (d, J = 7.4 Hz, 2H), 7.48-7.39 (m, 2H), 7.39 – 7.33 (m, 1H), (m, 2H), 5.74 (t, J
= 56.4 Hz, 1H), 2.55 (s, 1H), 1.67 (s, 3H). 13C NMR (126 MHz, CDCl3), δ: 140.5 (s), 128.5 (s), 128.2
(s), 125.9 (s), 117.0 (t, J = 249.2 Hz), 74.3 (t, J = 22.0 Hz), 22.4 (s). 19F NMR (376 MHz, CDCl3), δ: -
129.46 (dd, J = 276.1, 56.1 Hz, 1F), -130.9 (dd, J = 276.1, 56.8 Hz, 1F). Anal. calcd. for C9H10F2O: C,
62.78; H, 5.85. Found: C, 62.53; H, 5.64.
2-(4-(Dimethylamino)phenyl)-1,1-difluoropropan-2-ol 23 was prepared according to general
procedure C. The product was purified by column chromatography (Hexanes : EtOAc = 2:1, Rf=0.5).
Yellow crystals; 2.33 g (yield 35%); m.p. 42–43 ºС; νmax(KBr) 3550-3100 (br), 2993, 2892, 2856,
1
1616, 1519, 1484, 1465, 1317, 1199, 1149, 1095, 1062, 1051 cm-1; H NMR (500 MHz, CDCl3), δ:
7.40 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 5.71 (t, J = 56.7 Hz, 1H), 2.98 (s, 6H), 2.58 (s, 1H),
1.65 (s, 3H).13C NMR (126 MHz, CDCl3), δ: 150.3 (s), 128.1 (s), 126.7 (s), 117.2 (t, J = 249.1 Hz),
112.3 (s), 73.9 (t, J = 22.0 Hz), 40.5 (s), 22.0 (s).19F NMR (376 MHz, CDCl3), δ: -129.6 (dd, J =
274.2, 56.3 Hz, 1F), -130.6 (dd, J = 274.1, 57.1 Hz, 1F). HRMS (EI+) calcd. for [M]+ C11H15F2NO+
215.1116, found 215.1118.
2-(4-Bromophenyl)-1,1-difluoropropan-2-ol 24 was prepared according to general procedure C.
The product was purified by distillation (1 mbar, 68–69 ºC). Yellow liquid; 5.37 g (yield 69%);
ν
max(KBr) 3581, 3550-3200 (br), 2987, 2942, 2879, 1592, 1488, 1402, 1346, 1141, 1074, 1051, 1010
1
cm-1; H NMR (500 MHz, CDCl3), δ: 7.52 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 5.67 (t, J =
56.4 Hz, 1H), 2.39 (s, 1H), 1.63 (s, 3H).13C NMR (126 MHz, CDCl3), δ: 139.4 (s), 131.6 (s), 127.8 (s),
122.6 (s), 116.7 (t, J = 249.5 Hz), 74.2 (t, J = 22.2 Hz), 22.5 (s).19F NMR (376 MHz, CDCl3), δ: -129.8
(dd, J = 277.2, 56.1 Hz, 1F), -130.8 (dd, J = 277.2, 56.7 Hz, 1F). Anal. calcd. for C9H9BrF2O: C,
43.06; H, 3.61; Br, 31.83. Found: C, 43.32; H, 3.34; Br, 31.55.
4-(1,1-difluoro-2-hydroxypropan-2-yl)benzonitrile 25 was prepared according to general
procedure C. The product was purified by column chromatography (Hexanes : EtOAc = 4:1, Rf=0.27).
m.p. 68–69 ºС; Yellow crystals; 5.37 g (yield 63%); νmax(KBr) 3500-3300 (br), 2993, 2973, 2240,
1
1610, 1506, 1411, 1353, 1209, 1159, 1097, 1072, 1057 cm-1; H NMR (500 MHz, CDCl3), δ: 7.75 –
7.56 (m, 4H), 5.69 (t, J = 56.2 Hz, 1H), 2.62 (s, 1H), 1.67 (s, 3H). 13C NMR (126 MHz, CDCl3), δ:
145.6 (s), 132.3 (s), 127.0 (s), 118.6 (s), 116.4 (t, J = 250.0 Hz), 112.2 (s), 74.3 (t, J = 22.4 Hz), 22.6
12

ACCEPTED MANUSCRIPT
(s). 19F NMR (376 MHz, CDCl3), δ: -129.64 (dd, J = 278.9, 56.0 Hz, 1F), -130.64 (dd, J = 279.0, 56.5
Hz, 1F). HRMS (EI+) calcd. for [M]+ C10H9F2NO+ 197.0647, found 197.0648.
Acknowledgment
This work was supported by Enamine Ltd., Kyiv, Ukraine. We acknowledge Sergii Afonin and
Denis V. Bylina for carrying out HRMS analysis.
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