Chemoselective N-Difluoromethylation of Functionalized Tertiary Amines

Article abstract of DOI:10.1021/acs.joc.6b01728

A practical, convenient, and general method for the difluoromethylation of tertiary amines, using diethyl bromodifluoromethylphosphonate and fluoride, is described. This commercially available phosphonate smoothly reacts with a fluoride ion to liberate a difluorocarbene intermediate that in the presence of a proton source and a tertiary amine generates the corresponding α-difluoromethylammonium compound in good to excellent yields. Despite the involvement of a difluorocarbene intermediate, this difluoromethylation occurs almost exclusively on the nitrogen atom with diverse molecular structures, including drugs, surfactants, chiral phase transfer catalysts, polymers, ionic liquids, and other fine chemicals. A preliminary assessment of the effects that an α-difluoromethyl groupT has on hydrogen bonding and logP of quaternary ammonium salts is also described.

Full text of DOI:10.1021/acs.joc.6b01728

Subscriber access provided by Northern Illinois University
Article
Chemoselective N-Difluoromethylation of Functionalized Tertiary Amines
Yossi Zafrani, Dafna Amir, Lea Yehezkel, Moran Madmon,
Sigal Saphier, Naama Karton-Lifshin, and Eytan Gershonov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01728 • Publication Date (Web): 08 Sep 2016
Downloaded from http://pubs.acs.org on September 9, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
Chemoselective N-Difluoromethylation of Functionalized
Tertiary Amines
7
8
9
Yossi Zafrani,* Dafna Amir, Lea Yehezkel, Moran Madmon, Sigal Saphier,
Naama KartonꢀLifshin and Eytan Gershonov*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The Department of Organic Chemistry, Israel Institute for Biological Research, NessꢀZiona, 74100, Israel
ABSTRACT. A practical, convenient and general method for the difluoromethylation of tertiary
amines, using diethyl bromodifluoromethylphosphonate and fluoride, is described. This commercially
available phosphonate smoothly reacts with a fluoride ion to liberate a difluorocarbene intermediate
that in the presence of a proton source and a tertiary amine generates the corresponding αꢀ
difluoromethyl ammonium compound in good to excellent yields. Despite the involvement of a
difluorocarbene intermediate, this difluoromethylation occurs almost exclusively on the nitrogen
atom with diverse molecular structures including drugs, surfactants, chiral phase transfer catalysts,
polymers, ionic liquids and other fine chemicals. A preliminary assessment of effects like hydrogen
bonding and logP, αꢀdifluoromethyl versus methyl group has on quaternary ammonium salt, is also
described.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 25
1
2
3
4
INTRODUCTION
5
6
7
8
Synthesis of organic compounds containing fluorine atoms has become one of the more
important issues in the field of organic synthesis because of the central role fluorinated
functions play as bioisosteres in medicinal chemistry, leading to changes in affinity,
metabolic stability, hydrophobicity and bioavailability of various bioactive compounds.1,2
Apart from the pharmaceutical domain, in the world of organic synthesis, the incorporation of
a fluorine atom is also frequently employed for various other applications to modify both
chemical and physical properties of molecules.3 Among various fluorinated moieties,
difluoromethyl (ꢀCF2H) is one of the most promising.4 Therefore, it is not surprising that
considerable efforts are being made in order to develop new strategies for incorporating this
important group into a wide scope of substrates.5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Quaternary ammonium salts are a wellꢀknown and abundant family of compounds used in
medical applications, cosmetics, agriculture, chemical catalysis, and so on.6 Since the charged
moiety is responsible for the unique properties of these compounds, the influence of a
difluoromethyl group adjacent to the cationic center may be of interest. In recent years three
practical methods for the synthesis of simple difluoromethyltrialkylammonium salts were
reported (Figure 1AꢀC).7ꢀ9 In methods A and B reactive electrophilic difluoromethylation
reagents that are not commercially available are used, and in method C the ozone depleting
chlorofluorocarbon CHF2Cl (Freon Rꢀ22) is used as a difluorocarbene precursor under strong
basic conditions. Important ammonium compounds such as drugs, chiral phase transfer
catalysts, monomers, polymers and so on, usually contain other reactive/sensitive functional
groups that may be unstable under the reaction conditions of these methods. Therefore, the
development of a practical and chemoselective difluoromethylation method for tertiary
amines is still a significant challenge. Herein we wish to disclose our results on a facile and
highly chemoselective difluoromethylation of tertiary amines to αꢀdifluoromethyl ammonium
2
ACS Paragon Plus Environment

Page 3 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
compounds using the commercially available diethyl bromodifluoromethylphosphonate (1)
(Figure 1D). We will show that despite the fact that the mechanism of this
difluoromethylation involves the difluorocarbene intermediate, it occurs almost exclusively
on the nitrogen atom, even in molecules containing hydroxyl, alkynyl or alkenyl groups.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Methods for the synthesis of difluoromethyltrialkylammonium salts.
RESULTS AND DISCUSSION
In previous work, we have shown that phosphonate 1 is an efficient difluorocarbene
precursor for difluoromethylation of phenols and thiophenols under strong basic conditions.
Unfortunately, these conditions were found to be inapplicable for other interesting functions,
inter alia, amines.5c We hypothesized that cleaving the PꢀC bond using the appropriate
fluoride ion10ꢀ12 instead of a hydroxide would give a difluorocarbene under mild nonꢀ
hydrolytic conditions, and that this intermediate would react selectively with a tertiary amine
free base to give the difluoromethylammonium product upon protonation. Indeed, we have
found that phosphonate 1 reacts completely and rapidly with various fluorides, which in the
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 25
1
2
3
4
presence of triethylamine and
a
proton source yield the desired product
5
6
difluoromethyltriethylammonium bromide (3a). Selected optimization conditions for the
7
8
difluoromethylation of triethylamine are tabulated in table 1. Initially,
using
9
tetramethylammonium fluoride (TMAF) and methanol yielded 3a (87 %) and the undesired
side products triethylamine hydrobromide (4a, 13 %) together with the main phosphorus byꢀ
products 5a (55 %) and 5b (44 %) (entry 1). Replacing TMAF with TBAF.H2O somewhat
increased the relative amounts of both side products 4a and 5a (entry 2), yet a significant
decrease in the relative amount of fluorophosphate 5a was observed, when a catalytic amount
of TBAF.H2O was used (entry 3). Charged side products such as 4a directly decrease the
reaction yield and pose difficulties in the isolation of 3a at neutral pH. In addition, phosphate
triester 5b is considered as environmentally benign and safe while fluoridate 5a has moderate
toxicity.13 Therefore, our goal in the optimization study was to completely eliminate 4a and
5a as side products and to facilitate the isolation of the desired difluoromethyl ammonium
bromide salt from other charged starting materials or side products. In an attempt to use solid
support to facilitate effective separation of the ammonium product from the fluoride source,
we proceeded to investigate the reaction using polystyreneꢀsupported ammonium fluoride14
(ResinꢀF). With one fluoride equivalent of nonꢀswelled ResinꢀF, the reaction was found to be
sluggish and, even worse, gave only 24 % of 3a together with 76 % of 4a and 22 % of the
phosphorus by product 5a (entry 4). On the other hand, using a catalytic amount of ResinꢀF,
3a was obtained in 85 % yield and the amount of undesired side products 4a and 5a was
reduced to 15 % and 16 %, respectively (entry 5). Among the proton sources, methanol, isoꢀ
propanol, tertiary butanol and water, the former was found to be superior (entries 5ꢀ8). It
should be noted that all reactions mentioned above were performed using neat reagents and
were therefore found to be somewhat violent. Thus, the addition of dichloromethane (DCM)
as a solvent led to milder conditions in which much less fluorophosphate 5a was observed
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
ACS Paragon Plus Environment

Page 5 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(entries 9, 10). Complete eradication of side products 4a and 5a along with the best yields of
3a, were obtained after turning to CsF (1 equiv.) as an inorganic fluoride source (entries 11,
12). This may have resulted from the relatively higher basicity of CsF in the reaction
medium, compared to TMAF and TBAF (for Et3N, MeOH, F; pH 13 vs 12, respectively),
precluding the formation of side products 4a and 5a.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1: Selected optimization conditions for the difluoromethylation of trimethylamine
.
entry Fꢀ source
(equivalents)
TMAF (1)
H+ source
(1.1 equiv.)
MeOH
solvent Ta
(h)
Products (%)b
3a
87
77
78
24
85
63
57
50
70
85
100
93
90
90
4a
13
23
22
76
15
37
43
50
ꢀe
5a
55
63
5
5bc
44
1
ꢀ
1
2
TBAF (1)
MeOH
ꢀ
1
21
3
TBAF (0.05)
ResinꢀF (1)
MeOH
ꢀ
1
71
4
MeOH
ꢀ
24
3.5
1
22
16
11d
17d
25d
ꢀ
76
5
ResinꢀF (0.05) MeOH
ResinꢀF (0.05) 2ꢀPrOH
ResinꢀF (0.05) tꢀBuOH
ResinꢀF (0.05) H2O
ꢀ
73
6
ꢀ
58d
47d
48d
92
7
ꢀ
1
8
ꢀ
1
9
ResinꢀF (1)
MeOH
DCM
DCM
ꢀ
24
3.5
5
10
11
12
13
14
ResinꢀF (0.05) MeOH
15
2
95
CsF (1)
CsF (1)
CsF (0.05)
none
MeOH
MeOH
MeOH
MeOH
MeOH
ꢀ
ꢀ
81
DCM
DCM
ꢀ
3.5
3.5
1.5
4.5
ꢀe
ꢀ
89
10
10
9
ꢀ
83
22
ꢀ
75
15
none
DCM
91
100
a
b
1
Time for full conversion. Products 3a and 4a were determined by H NMR; products 5a and 5b were
c
d
determined by 31P NMR . In some cases these percent contain diethylphosphate as minor product. The
appropriate phosphate was observed. e 2a was observed.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 25
1
2
3
4
5
6
7
8
9
Interestingly and unexpectedly, control reactions without a fluoride source led to
mixtures of 3a, 4a, 5b and 3a-5a and 5b, with and without DCM, respectively (entries 14,
15). The fact that fluorophosphate 5a was observed in the reaction without a fluoride source
(in DCM) implies that phosphonate 1 may also act as a fluoride "source" by the possible
degradation of the difluorocarbene. This could occur, for example, by its hydrolysis to
fluoride and formate ions.5c Hence, this may be the reason why in the presence of only 0.05
equivalents of fluoride, the reaction without DCM led to relatively large amounts of
fluorophosphate 5a, much more than the maximum expected 5 % (entries 5ꢀ8 and 14). The
absence of 5a when DCM was added suggests that the undesired side reaction of the
difluorocarbene intermediate leading to the formation of the fluoride ion is much less
dominant when this solvent is used as a reaction medium. Therefore, we propose the
mechanism depicted in scheme 1 for the reaction in DCM. The catalytic cycle, starting with
PꢀC bond cleavage, can be initiated by either fluoride from a source such as CsF or
R3N/MeOH which directly attacks the phosphonate to obtain difluorocarbene intermediate.
The efficiency of the latter initiator obviously strongly depends on the amine structure (steric
effect) and on its basicity (electronic effect). For example, contrary to trimethylamine, the
reaction with the more sterically hindered trioctylamine, in the absence of cesium fluoride,
was sluggish and led to a mixture of the corresponding difluoromethyl ammonium product 3d
and the undesired trioctylamine hydrobromide 4d in a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
ACS Paragon Plus Environment

Page 7 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
O
O
(EtO)2P OR
5
(EtO)2P CBrF2
1
F
O
5a
+ Br
(EtO)2P F
5a
5
RR'R''N
2
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ROH
RO
via CF2Br
CF2
RR'R''NH
4
RR'R''N
2
RR'R''NCF2H
3
RR'R''NCF2
ROH
Scheme 1. Proposed reaction mechanism for the reaction of tertiary amine with phosphonate 1 with
and without fluoride ion in the presence of alcohol.
3.5:1 ratio (scheme 2). However, the same reaction with cesium fluoride led rapidly and
exclusively to the desired product 3d. The basicity of the amine compound dramatically
determines the reaction course, for example, as we will show later the reactions of pyridine
derivatives (weak bases) without CsF do not occur at all, emphasizing the importance of this
catalyst.
Scheme 2. The reaction of trioctylamine with phosphonate 1 with and without cesium fluoride.
Evidence for the next step in the cyclic mechanism, involving a nucleophilic attack of the
amine free base on difluorocarbene followed by protonation at the CF2 carbanion, was
obtained by performing the reaction of triethylamine with 1 in the presence of 1 equivalent of
deuterated methanol (scheme 3). The deuterated product 3a(d1) observed as a singlet by 19F
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 25
1
2
3
4
NMR at ꢀ33.3 ppm, was the major product of this reaction (the minor product 3a was
5
6
obtained due to residual water).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. The reaction of triethylamine with phosphonate 1 in the presence of deuterated methanol
(CD3OD).
The substrate scope of this fluorideꢀpromoted difluoromethylation was explored under the
optimized conditions described in table 1 entry 12, using DCM as a solvent. Over the course
of our study we realized that for successful workꢀup of product isolation one should leave the
reaction for 24h (rt), a period of time in which the side product 5a, if nevertheless formed, is
converted to the favored product 5b. However, in a few cases in which an extended reaction
time was required to gain full conversion of the amine itself or secꢀBuOH was used as a
proton source (3o, 3r), side product 5a was obtained in relatively large amounts (see
experimental section). Inspection of the structures and data presented in table 2 reveals that
the reaction tolerates functionalities such as hydroxyl, alkene, alkyne, ester, carbonyl, oxirane
and thiophene. Therefore, this reaction may be considered as a mild and highly
chemoselective difluoromethylation approach. Simple difluoromethylated quaternary
ammonium bromide compounds were easily synthesized in excellent isolated yields (3a-f).
Bicyclic ammonium compounds bearing azabicyclo skeleton such as 3g and 3h were
obtained in fair isolated yields. With starting materials containing an alkene group or both
alkyne and hydroxyl groups the difluoromethylation occurred only on the amine moiety
yielding 3i and 3j, respectively. Contrary to the stability of the propargylic ammonium
product 3j, the unsubstituted allylic ammonium product 3i was found to be unstable under the
isolation procedure, and therefore, its isolated yield was not determined. Aromatic amines
8
ACS Paragon Plus Environment

Page 9 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
such as DMAP or imidazoles react exclusively via the nitrogen located at the C(sp2)ꢀN(sp2)
bond to give the corresponding products 3k-3m in good to excellent yields. A notable
expression for both the chemoselectivity and the mildness of our difluoromethylation
procedure was shown with the reactions of the multifunctional compound cinchonidine. With
this compound the difluoromethylation occured solely on the nitrogen at the N(sp3) moiety
(3n, 98 % conversion), but not on the hydroxyl, N(sp2) or ethenyl groups. With challenging
sensitive esters, products 3o and 3p were obtained in excellent isolated yields. As mentioned
above, without CsF, the pyridinium product 3p was not obtained at all even after prolonged
reaction time (2 weeks). The poorly reactive pyridine precursor emphasizes the necessity of
the fluoride ion source for this reaction. Exploring the unique system pyridoxime in which
the oxime group is known as a reactive functionality
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2: Substrate scope
.
N
Br
CF2H
3g, 41%a
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 25
1
2
3
4
5
6
7
O
CF2H
N
Br
N
Br
O
CF2H
OH
3o, 86%a (100%)b, d
8
N
9
3n, 47%a (98%)b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CF2H
Br
N
O
S
O
O
OH
S
f
3r, 18% (100%) b,
a
Isolated yield. b Amine conversion. c The product was not isolated after full conversion due to its degradation
a
d
e
during the work up procedure. 2ꢀmethylꢀ2ꢀbutanol was used instead of methanol. The product was not
isolated from the sodium bromide salt used during the purification process, therefore, the yield was calculated
according to an internal standard. f This product is unstable at room temperature, and therefore, the isolated yield
is considerably low.
10
ACS Paragon Plus Environment

Page 11 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
m
O
n
O
o
m
O
n
O
o
1, CsF (0.5 equiv)
MeOH (1.1 equiv.)
O
O
O
O
O
O
O
O
DCM, rt, 1 h
8
9
N
Br
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CF2H
Eudragit Eꢀ100
3s
Scheme 4. The difluoromethylation of Eudragit E-100 using phosphonate 1.
towards active phosphorus compounds15 revealed that its difluoromethylation (3q) was
slower and led to the formation of undesired and unknown side products. Therefore the
product 3q was isolated after partial conversion (ca 10 %). The product 3r revealed again that
the difluoromethylation took place exclusively on the nitrogen atom even with a
multifunctional amine containing thiophene, hydroxyl, ester and epoxide groups (100%
conversion). However, the product was found to be unstable at room temperature, and
unfortunately, it decomposed during and after workꢀup. Finally, also polymers bearing
tertiary amines such as Eudragit Eꢀ100 could be difluoromethylated on the nitrogen moiety to
produce the appropriate quaternized polymer 3s, as observed by its solution 19F and 1H NMR
(scheme 4). This reaction was analyzed only by H and 19F NMR (see SI Figure S32) of an
1
incompletely separated product 3s, which still awaits further optimization and analysis.
The substrate scope described above represents high chemoselectivity and tolerability of
the reaction conditions to diverse functional groups and was designed to include
representative compounds from a wide range of practical disciplines. For example,
compounds 3e and 3f (CTABꢀF2 and DODABꢀF2) are representatives of the surfactant
family and antibacterial compounds,16 3l and 3m represent the ionic liquids family, 3n acts as
a phase transfer catalyst (PTC),17 3o may serve as a methacrylate monomer,18 3p-3r can act
as difluromethylated analogs of Pyridostigmine, 2ꢀPAM and Tiotropium (scopine di(2ꢀ
thienyl)glycolate) drugs,19 respectively. Eudragit analog Polymer 3s is an example for
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 25
1
2
3
4
5
6
possible post polymerization approach for difluoromethylation of polymers containing
tertiary amines.
7
8
9
A preliminary assessment of the effect of a αꢀdifluoromethyl group on quaternary
ammonium compounds has been performed using two of the aboveꢀmentioned compounds.
Located at the carbon positioned α to the nitrogen in quaternary ammonium salt, the fluorine
atoms may cause some interesting effects on their physical, chemical and where relevant,
biological properties. It has been shown that the positive charge of ammonium salts is
delocalized on the hydrogen atoms of the αꢀcarbons, which interact with the counter anion
through hydrogen bonding.20 An interesting hydrogenꢀbonding catalysis with a scholarly
designed quaternary ammonium salts that contains electron withdrawing groups at the α
positions was reported, most recently, by Shirakawa et al.21 The dual property of the fluorine
group as a hydrophobic moiety together with its high electronegativity (enforcing hydrogenꢀ
bonding strength of the adjacent hydrogen) and relatively small size may result in different
types of interactions (Figure 2). We examined the effect solvents have on the chemical shifts
of the representatives pairs (NCH3 vs NCF2H) using Abraham's method where calculating
ꢀδ(DMSOꢀCDCl3) may lead to interesting insights into the soluteꢀsolvent interaction, inter
alia, hydrogen bonds.22 In this case, the counter ion itself significantly affects the chemical
shift of the αꢀhydrogens. 23 Using bromide as a counter ion, we compared only the adjacent
CF2H vs CH3 group and found a significant shielding effect from DMSO, which strongly
implies that the proton at the CF2H group is more prone to participate in Hꢀbonding (Figure
2). For each pair there are further interesting data, i.e. shifting the other hydrogens at the αꢀ
carbons, shifting and changes in the fluorine atoms, counter ion effects and so forth. This
important interaction may significantly affect various chemical, physical and drugꢀlike
properties. For example, attenuation of the hydrophilicity of the quaternary ammonium
compounds may be achieved through the addition of fluorine atoms. This may facilitate
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12
ACS Paragon Plus Environment

Page 13 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
absorption of such compounds, which are generally highly water soluble and poorly absorbed
through biological membranes. The measurement of log P (hydrophobicity) for both couples
of compounds, i.e. ꢀLog P(CF2HꢀCH3) showed an increase of 0.25 and 0.41 log P unit, for 3n
and 3k, respectively. These results show that, as in many other cases, the addition of fluorine
atoms lead to an increase in lipophilicity. These issues are currently under investigation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. A preliminary assessment of the effect of a α-difluoromethyl group on quaternary
ammonium compounds.
CONCLUSIONS
To conclude, the described method for difluoromethylation of tertiary amines, using
phosphonate 1, CsF and methanol was found to be very practical for the synthesis of various
αꢀdifluoromethylated quaternary ammonium compounds. Although the reaction mechanism
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 25
1
2
3
4
5
6
7
8
9
involves a difluorocarbene intermediate, the use of fluoride as a trigger under mild
conditions, enables a remarkable tolerance of functional groups such as hydroxyl, alkenyl,
alkynyl, esters and so forth. Combining the two highly important issues of fluorinated organic
compounds and quaternary ammonium salts may lead to interesting changes in chemical and
physical properties and seems to be promising for applications in the research fields of
surfactants, ionic liquids, phase transfer catalysts, drugs and polymers.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General. Commercially available high grade reagents and solvents were used without further
purification. NMR spectra were recorded on 300 MHz spectrometer (1H NMR: 300.1 MHz,
13C NMR: 75.5 MHz, 31P NMR: 121.5 MHz and 19F NMR: 282.4 MHz) or 500 MHz
spectrometer (1H NMR: 500.2 MHz, 13C NMR: 125.8 MHz, 31P NMR: 202.5 MHz and 19F
1
NMR: 470.7 MHz). Chemical shifts are reported in parts per million (δ ppm). H and 13C
NMR chemical shifts were referenced to the residual CDCl3 solvent peaks (δ=7.26 ppm for
1H and δ=77.0 ppm for 13C). 31P and 19F chemical shifts are reported downfield from external
trimethyl phosphate (TMP) and trifluoroacetic acid in D2O, respectively. High resolution
mass spectra were obtained with LCꢀHRMS mass spectrometer operated in the positive ESI
mode. Ion exchange chromatography was performed with commercial SCX columns (2g).
UV Absorbance for log P calculations were recorded on a UVꢀVis Spectrophotometer.
General Procedure for difluoromethylation of tertiary amines
All reactions were conducted under inert atmosphere in a sealed tube or vial, equipped
with a magnetic stirrer. To a mixture of tertiary amine (1 mmol), CsF (1.05 mmol) and
14
ACS Paragon Plus Environment

Page 15 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
anhydrous methanol (1.5 mmol) in anhydrous dichloromethane (1 ml), diethyl
bromodifluoromethylphosphonate (1.1 mmol) was added in one portion. The reaction mixture
7
8
ο
was stirred at 25 C until completion (specific times are reported in the following
9
procedures). The crude product was extracted from the reaction mixture with dry CHCl3 (3 x
2 ml) and then dry CH3CN (3 x 2 ml), filtered and evaporated under reduced pressure. The
residue was purified by ion exchange chromatography (SCX column, 2 g): The SCX column
was prewashed with water and methanol, then charged with the residue, impurities were
washed out with methanol and the desired product was eluted with 10% NaBr in methanol.
Spot detection of the product was obtained by Dragendorff's reagent spray. Removal of NaBr
from the purified product/NaBr mixture was accomplished by evaporation of the methanol
and extraction of the product from the solid residue with dry CHCl3 (3 x 2 ml) or with dry
CHCl3/CH3CN, 1:1 (3 x 2 ml). The solvent was evaporated under reduced pressure to give
the difluoromethyl ammonium bromide product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Specific experimental data for the difluoromethyl ammonium compounds are reported
below. Experimental data for products 3a,7,8,24 3b,24 3c,9 3d,9 3e,9 3h,24 3k,24 3l7 and 3m7
were reported previously. NMR characterization data for known compounds prepared by our
new method were consistent with literature precedent. Full NMR and HRMS analyses for all
new compounds are reported below.
Difluoromethyl-triethyl ammonium bromide (3a). Known product. According to the
general procedure. The mixture was stirred for 3h. The product was isolated as a white solid
1
(229 mg, 99% yield); H NMR (500 MHz, CDCl3); δ 8.28 (t, JHF = 57.5 Hz, 1H), 3.89 (q,
6H), 1.51 (t, J = 10 Hz, 9H); 19F NMR (470.7 MHz, CDCl3); δ ꢀ35.17 (d, JHF = 57.4 Hz); 13C
NMR (125.8 MHz, CDCl3); δ 115.1 (t, JCF = 277.9 Hz), 52.8, 8.9.
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 25
1
2
3
4
5
6
7
8
Difluoromethyl-trimethyl ammonium bromide (3b). Known product. According to the
general procedure. For this reaction trimethyl amine in ethanol (4.2 M) was used, therefore
no methanol was added to the reaction mixture. The mixture was stirred overnight. The
9
1
product was isolated as a white solid (163 mg, 86% yield); H NMR (500 MHz, CD3OD);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19
δ 7.25 (t, JHF = 60 Hz, 1H), 3.38 (s, 9H); F NMR (470.7 MHz, CD3OD); δ ꢀ40.63 (d, JHF
=
58.8 Hz); 13C NMR (125.8 MHz, CD3OD); δ 115.9 (t, JCF = 276.3 Hz), 48.65.
Difluoromethyl-tributyl ammonium bromide (3c). Known product. According to the
general procedure. The mixture was stirred overnight. The product was isolated as a white
1
solid (285 mg, 90% yield); H NMR (300 MHz, CDCl3); δ 8.45 (t, JHF = 57.8 Hz, 1H), 3.75
19
(t, J = 8.6 Hz, 6H), 1.84 (m, 6H), 1.45 (m, 6H), 1.02 (t, J = 7.4, 9H); F NMR (282.4 MHz,
CDCl3); δ ꢀ32.99 (d, JHF = 57.5 Hz,).
Difluoromethyl-trioctyl ammonium bromide (3d). Known product. According to the
general procedure. The mixture was stirred overnight. The product was isolated as a white
1
solid (446 mg, 92% yield); H NMR (300 MHz, CDCl3); δ 8.46 (t, JHF = 57.9 Hz, 1H), 3.68ꢀ
3.73 (m, 6H), 1.75ꢀ1.85 (m, 6H), 1.21ꢀ1.38 (m, 30H), 0.85 (t, J = 6.6 Hz, 9H) ; 19F NMR
(282.4 MHz, CDCl3); δ ꢀ33.50 (d, JHF = 58.4 Hz).
Difluoromethyl-hexadecyl-dimethyl ammonium bromide (3e). Known product. According
to the general procedure. The mixture was stirred overnight. The residue was purified by
1
SCX column (5g) and the product was isolated as a white solid (380 mg, 95% yield); H
NMR (300 MHz, CDCl3); δ 8.26 (t, JHF = 59.0 Hz, 1H), 3.82 (m, 2H), 3.58 (s, 6H), 1.38ꢀ1.25
(m, 28H) 0.87 (t, J = 6.6 Hz, 3H); 19F NMR (282.4 MHz, CDCl3); δ ꢀ38.62 (d, JHF = 59.2
Hz).
Difluoromethyl-methyl-dioctadecyl ammonium bromide (3f). According to the general
procedure. The mixture was stirred overnight. The residue was purified by SCX column (5g)
16
ACS Paragon Plus Environment

Page 17 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
and impurities were washed out with CHCl3:MeOH (1:4). The product was isolated as a
1
white solid (600 mg, 90% yield). Mp 94ꢀ98 oC. H NMR (300 MHz, CDCl3); δ 8.28 (t, JHF
=
7
8
9
58.5 Hz, 1H), 3.73 (m, 4H), 3.51 (s, 3H), 1.81ꢀ1.79 (m, 4H), 1.34ꢀ1.22 (m, 60H), 0.84 (t, J =
6.4 Hz, 6H); 19F NMR (282.4 MHz, CDCl3); δ ꢀ35.63 (d, JHF = 57.8 Hz); 13C NMR (75.5
MHz, CDCl3); δ, 114.6 (t, JCF = 248.8 Hz), 59.1, 44.6, 31.9, 29.8, 29.8, 29.8, 29.7, 29.7, 29.7,
29.6, 29.6, 29.5, 29.4, 29.4, 29.0, 26.5, 22.9, 22.7, 14.1; HRMS (ESI+ꢀQTOF) m/z: calcd for
C38H78F2N [M+H]+ 586.6097, found: 586.6093.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(difluoromethyl)quinuclidin-1-ium bromide (3g). According to the general procedure.
The mixture was stirred overnight. The product was isolated as a white solid (99 mg, 41%
o
1
yield). Mp 73ꢀ78 C. H NMR (500 MHz, CD3OD); δ 6.98 (t, JHF = 60 Hz, 1H), 3.69 (m,
6H), 2.29 (m, 1H), 2.10 (m, 6H); 19F NMR (470.7 MHz, CD3OD); δ ꢀ41.5 (d, JHF = 58.8 Hz);
13C NMR (125.8 MHz, CD3OD); δ 115.5 (t, JCF = 273.0 Hz), 79.4, 51.4, 23.8; HRMS (ESI+ꢀ
QTOF) m/z: calcd for C8H14F2N [M+H]+ 162.1089, found: 162.1089.
1-Difluoromethyl-4-aza-1-azonia-bicyclo[2.2.2]-octane bromide (3h). Known product.
According to the general procedure. The mixture was stirred overnight. The product was
1
isolated as a white solid (182 mg, 75% yield); H NMR (500 MHz, MeOD); δ 7.17 (t, JHF
=
58.5 Hz, 1H), 3.71 (t, J = 7.2 Hz, 6H), 3.38 (t, J = 8.5 Hz, 6H); 19F NMR (470.7 MHz,
MeOD); δ ꢀ40.59 (d, JHF = 58.2 Hz).
Allyl-difluoromethyl-dimethyl-ammonium bromide (3i). According to the general
procedure. The mixture was stirred overnight. Full conversion was determined by 19FꢀNMR
and 1HꢀNMR spectroscopy. The product was not isolated due to its poor stability on the SCX
column; 1H NMR (500 MHz, CDCl3); δ 7.90 (t, JHF = 57.5 Hz, 1H), 5.98ꢀ5.88, (m, 1H), 5.82
(d, J = 17.0 Hz, 1H), 5.67 (d, J = 10.5 Hz, 1H), 4.45 (d, J = 7.5 Hz, 2H), 3.36 (s, 6H); 19F
NMR (470.7 MHz, CDCl3); δ ꢀ38.30 (d, JHF = 58 Hz).
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 25
1
2
3
4
Difluoromethyl-diethyl-(4-hydroxy-but-2-ynyl) ammonium bromide (3j). According to
5
6
the general procedure. The mixture was stirred overnight. The product was isolated as a
7
8
1
brown oil (212 mg, 78% yield); H NMR (500 MHz, CD3OD); δ 7.41 (t, JHF = 60 Hz, 1H),
9
19
4.70 (s, 2H), 4.32 (s, 2H), 3.84 (q, J = 10 Hz, 4H), 1.50 (t, J = 10 Hz, 6H); F NMR (470.7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, CD3OD); δ ꢀ37.82 (d, JHF = 57.4 Hz); 13C NMR (125.8 MHz, CD3OD); δ 116.7 (t, JCF
= 276.0 Hz), 93.4, 71.3, 54.3, 49.5, 47.8, 8.6; HRMS (ESI+ꢀQTOF) m/z: calcd for C9H16F2NO
[M+H]+ 192.1194, found: 192.1200.
Difluoromethyl-4-dimethylamino-pyridinium bromide (3k). Known product. According
to the general procedure. The mixture was stirred overnight. The product was isolated as a
1
brown solid (240 mg, 95% yield); H NMR (500 MHz, CDCl3); δ 8.85 (d, J = 10 Hz, 2H),
8.55 (t, JHF = 58.5 Hz, 1H), 7.16 (d, J = 10 Hz, 2H), 3.41 (s, 6H); 19F NMR (470.7 MHz,
CDCl3); δ ꢀ19.85 (d, JHF = 58.3 Hz); 13C NMR (125.8 MHz, CDCl3); δ 158.3, 138.1, 111.7 (t,
JCF = 261.5 Hz), 109.5, 41.4.
1-Difluoromethyl-3-methyl-3H-imidazol-1-ium bromide (3l). Known product. According
to the general procedure. The mixture was stirred overnight. The product was isolated as an
orange solid (145 mg, 68% yield); 1H NMR (300 MHz, CD3CN); δ 9.97 (t, 1H), 8.18 (t, JHF
=
58.8 Hz, 1H), 7.63 (t, J = 1.95 Hz, 1H), 7.54 (t, J = 1.65 Hz, 1H), 3.98 (s, 3H); 19F NMR
(282.4 MHz, CD3CN); δ ꢀ21.39 (d, JHF = 59 Hz); 13C NMR (75.5 MHz, CD3CN); δ 137.6,
126.0, 119.4, 109.4 (t, JCF = 248.8 Hz), 37.7.
3-(difluoromethyl)-1-ethyl-1H-imidazol-3-ium bromide (3m). Known product. According
to the general procedure. The mixture was stirred overnight. The product was isolated as a
1
brown oil (152 mg, 67% yield); H NMR (300 MHz, D2O); δ 10.3 (s, 1H), 8.30 (t, J = 58.5
Hz, 1H),7.85 (br d, 2H), 4.34 (q, J = 7.5 Hz, 2H), 1.52 (t, J = 7.2 Hz, 3H); 19F NMR (282.4
MHz, CDCl3); δ ꢀ21.20 (d, JHF = 57.6 Hz).
18
ACS Paragon Plus Environment

Page 19 of 25
The Journal of Organic Chemistry
1
2
3
4
1-Difluoromethyl-2-(hydroxy-quinolin-4-yl-methyl)-5-vinyl-1-azonia-
5
6
7
8
bicyclo[2.2.2]octane bromide (3n). According to the general procedure. To a mixture of
cinchonidine (1 mmol), CsF (1.1 mmol) and anhydrous methanol (2.4 mmol) in anhydrous
dichloromethane (4 ml), diethyl bromofluoromethyl phosphonate (1.1 mmol) was added in
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ο
one portion. The mixture was stirred at 40 C in a pressure tube for 1h and then cooled to
room temperature and stirred for an additional 1h. The crude product was extracted from the
reaction mixture with CHCl3:MeOH, 9:1, (3 x 2 ml) and the product was isolated on SCX as
described in the general procedure. Removal of NaBr from the purified product/NaBr mixture
was accomplished by evaporation of the methanol and extraction of the product with dry
DCM:MeOH, 9:1, (3 x 2 ml). The product was then subjected to further purification by silica
gel chromatography with DCM:MeOH, 92:8, as eluent, to give the isolated product as a
1
yellow liquid (199 mg, 47% yield); H NMR (500 MHz, MeOD); δ 8.9 (d, J = 4.6 Hz, 1H),
8.09 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 4.7 Hz, 1H), 7.83 (t, J = 8.2
Hz, 1H), 7.81 (t, JHF = 57.6 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 6.41 (bs, 1H), 5.70ꢀ5.67 (m,
1H), 5.17 (d, J = 17.2 Hz, 1H), 5.00 (d, J = 10.5 Hz, 1H), 4.65ꢀ4.61 (m, 1H), 4.17 (t, J = 8.6
Hz, 1H), 4.11 (t, J = 10.8 Hz, 1H), 3.78ꢀ3.75 (m, 2H), 3.02 (bs, 1H), 2.37ꢀ2.16 (m, 4H), 1.42
(t, J = 12.6 Hz, 1H); 19F NMR (470.7 MHz, MeOD); δ ꢀ36.32 (dd, JHF = 57 Hz, 217 Hz, 1F),
δ ꢀ41.35 (dd, JHF = 57 Hz, 217 Hz, 1F); 13C NMR (125.8 MHz, MeOD); δ 149.7, 147.21,
145.1, 136.5, 129.8, 129.0, 127.8, 124.5, 121,7, 119.8, 116.5, 114.3 (t, JCF = 271.9 Hz), 65.9,
64.7, 56.1, 50.4, 36.7, 26.4, 23.6, 19.9. HRMS (ESI+ꢀQTOF) m/z: calcd for C20H23F2N2O
[M+H]+ 345.1773, found: 345.1772.
Difluoromethyl-dimethyl-[2-(2-methyl-acryloyloxy)-ethyl]-ammonium bromide (3o).
The reaction was conducted according to the general procedure with slight modification: 2ꢀ
methylꢀ2ꢀbutanol was used as a proton source instead of MeOH. The mixture was stirred
1
overnight. The product was isolated as a brown liquid (247 mg, 86% yield); H NMR (500
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 25
1
2
3
4
MHz, CDCl3); δ 8.16 (t, JHF = 59 Hz, 1H), 6.10 (s, 1H), 5.62 (s, 1H), 4.70 (t, J = 4.5 Hz, 2H),
5
6
7
8
4.34 (t, J = 4.5 Hz, 2H), 3.60(s, 6H), 1.89 (s, 3H); 19F NMR (470.7 MHz, CDCl3); δ ꢀ38.48
(d, JHF = 59 Hz); 13C NMR (75.5 MHz, CDCl3); δ 166.2, 135.1, 127.5, 113.9 (t, JCF = 278.0
Hz), 60.2, 57.6, 46.6, 18.2; HRMS (ESI+ꢀQTOF) m/z: calcd for C9H16F2NO2 [M+H]+
208.1144, found: 208.1140.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-Difluoromethyl-3-dimethylcarbamoyloxy-pyridinium bromide (3p). According to the
general procedure. The mixture was stirred for 5 days. The product was isolated as a brown
liquid (258 mg, 87% yield); 1H NMR (300 MHz, CDCl3); δ 9.84 (d, J = 5.9 Hz, 1H), 9.61 (s,
1H), 9.25 (t, JHF = 58.5 Hz, 1H), 8.71 (d, J = 8.6 Hz, 1H), 8.51 (dd, J = 8.4 Hz, 6.4 Hz, 1H),
3.17 (s, 3H), 3.04 (s, 3H); 19F NMR (282.4 MHz, CDCl3); δ ꢀ20.86 (d, JHF = 58.3 Hz); 13C
NMR (75.5 MHz, CDCl3); δ 150.9, 143.5, 138.2, 134.0, 129.5, 111.8 (t, J = 273.2 Hz), 37.2,
36.9; HRMS (ESI+ꢀQTOF) m/z: calcd for C9H11F2N2O2 [M+H]+ 217.0783, found: 217.0785.
1-Difluoromethyl-2-(hydroxyimino-methyl)-pyridinium bromide (3q). According to the
general procedure. The mixture was stirred overnight. At the last step of the work up, the
product (purple solid) could not be separated from the NaBr. Therefore, the yield of the
19
reaction was determined by 19F NMR spectroscopy by comparing the F NMR resonance of
1
the product to that of an internal standard (trifluorotoluene), 19F NMR yield: 10%; H NMR
(500 MHz, CD3OD); δ 9.43 (d, J = 6.0 Hz, 1H), 8.90 (t, J = 8.0 Hz, 1H), 8.76 (s, 1H), 8.69 (d,
J = 8.0 Hz, 1H), 8.54 (t, JHF = 57.0 Hz, 1H), 8.32 (t, J = 7.0 Hz, 1H); 19F NMR (470.7 MHz,
13
CD3OD); δ ꢀ21.2 (d, JHF = 57.0 Hz); C NMR (125.8 MHz, CD3OD); δ 149.8, 146.8, 140.4,
140.1, 127.4, 127.3, 112.2 (t, JCF = 287.0 Hz); HRMS (ESI+ꢀQTOF) m/z: calcd for
C7H7F2N2O [M+H]+ 173.0521, found: 173.0527.
9-Difluoromethyl-7-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-9-methyl-3-oxa-9-azonia-
tricyclo[3.3.1.02,4]nonane bromide (9-difluoromethyl-tiotropium bromide) (3r). The
20
ACS Paragon Plus Environment

Page 21 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
reaction was conducted according to the general procedure with slight modification: 2ꢀ
methylꢀ2ꢀbutanol was used as a proton source instead of MeOH. The mixture was stirred
overnight and the crude product was extracted from the reaction mixture with CHCl3:MeOH,
9:1, (3 x 2 ml). The product was isolated on SCX as described in the general procedure.
Removal of NaBr from the purified product/NaBr mixture was accomplished by evaporation
of the methanol and extraction of the product with dry CHCl3:MeOH, 9:1, (3 x 2 ml). The
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
product was isolated as unstable purple solid (91 mg, 18% yield); H NMR (300 MHz,
CD3OD +CDCl3); δ 7.76 (t, JHF = 57.0 Hz, 1H), 7.42 (d, J = 3.9 Hz, 2H), 7.18 (d, J = 3.3 Hz,
2H), 7.04ꢀ7.02 (m, 2H), 5.31 (t, J = 5.7 Hz, 1H), 4.49 (s, 2H), 3.51 (s, 2H), 3.40 (s, 3H), 2.92ꢀ
2.79 (m, 2H), 2.24 (d, J = 18.0 Hz, 2H); 19F NMR (282 MHz, CD3OD); δ ꢀ41.15 (d, JHF
=
57.0 Hz); 13C NMR (125.8 MHz, CD3OD+CDCl3); δ 170.8, 146.5, 127.6, 127.16, 126.9,
113.7 (t, JCF = 272 Hz), 67.7, 64.2, 53.8, 28.8; HRMS (ESI+ꢀQTOF) m/z: calcd for
C19H20F2NO4S2 [M+H]+ 428.0796, found: 428.0790.
Eudragit-E-100-CF2H (3s). The reaction was conducted according to the general procedure
with slight modifications: the amount of DCM was doubled and that of cesium fluoride was
halved. Immediate precipitation of the polymeric mass was observed during the addition of
phosphonate 1. After 1 h at room temperature the reaction solution was removed and the
polymeric chunk was dissolved in methanol (2 mL). Impurities were precipitated by the
addition of 6 mL of chloroform and the solution was filtered. The solvent was removed under
reduced pressure to give a semiꢀsolid colorless product. 1H NMR (500 MHz, CD3OD); δ 7.41
(m, CHF2, 1H), 4.56 (m, 2H), 4.11ꢀ4.00 (m, 4H), 3.63 (bs, 3H), 3.50 (bs, 6H), 1.93 (m, 6H),
1.66 (m, 2H), 1.46 (m, 2H), 1.12ꢀ0.89 (m, 12H); 19F NMR (282 MHz, CD3OD); δ ꢀ39.5 (m,
2F).
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 25
1
2
3
4
Determination of Octanol-Water Partition Coefficients (Log P)
5
6
7
8
The partition coefficients were calculated as the logarithm of the ratio of the salt
concentration in the octanol phase to its concentration in the aqueous phase. The "shakeꢀ
flask" method was used for the determination of log P values.25 Both octanol and water were
preꢀsaturated with each other for at least 24 hours before the experiment. The representative
salts were dissolved in octanol saturated water to obtain a concentration of 10 mM. The
maximum wavelength (λmax) for each compound was determined and the absorbance
recorded using UV Spectroscopy. Measurements were performed on dilute solutions giving
absorbance in the range of 0.2ꢀ1. To 45 mL of water saturated octanol, 0.3 mL of the water
solution was added and the mixture was shaken for 5 minutes. The solutions were then
centrifuged at 3000 rpm for 5 min. An aliquot of the aqueous phase was diluted and
absorbance was measured. The experiment was repeated three times for each sample. The
extraction ratio was obtained by difference and log P was calculated taking account of the
volume ratio between the water and octanol.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publication website at
DOI:. NMR spectra for all new compounds.
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: yossiz@iibr.gov.il
*Eꢀmail: eytang@iibr.gov.il
22
ACS Paragon Plus Environment

Page 23 of 25
The Journal of Organic Chemistry
1
2
3
Notes
4
5
The authors declare no competing financial interest.
6
7
8
9
ACKNOWLEDGMENTS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This work was internally funded by the Israeli prime minister’s office.
REFERENCES
(1) (a) Wang, J.; SánchesꢀRoselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.;
Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432. (b) Kirsh, P.;
Modern Fluoroorganic Chemistry: Synthesis Reativity, Applicatins, 2nd ed., Wileyꢀ
VCH, Weinheim, 2013. (c) Fluorine in Medicinal Chemistry and Chemical Biology
(Ed.: I Ojima), Wiley, Chichester, 2009. (d) Bégué, J.ꢀP.; BonnetꢀDelpon, D.
Bioorganic and Medicinal Chemistry of Fluorine, Wiley, Hoboken, NJ, 2008.
(2) (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (b) Hagmann, W. K.
J. Med. Chem. 2008, 51, 4359. (c) Swallow, S. Prog. Med. Chem. 2015, 54, 65. (d)
Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med.
Chem. 2015, 58, 8315.
(3) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214.
(4) (a) Li, L.; Wang, F.; Ni, C.; Hu, J. Angew. Chem. In. Ed. 2013, 52, 12390. (b) Ritter,
S. K. Chem. Eng. News 2013, 91 (8), 32. (c) O'Hagan, D.; Wang, Y.; Skibinski, M.;
Slawin, A. M. Z. Pure Apll. Chem. 2012, 84, 1587. (d) Hu, J.; Zhang, W.; Wang, F.
Chem. Commun. 2009, 7465.
(5) Selected examples on difluoromethylation of the heteroatoms N, O and S: (a) Zhu,
D.; Gu, Y.; Lu, L.; Shen, Q. J. Am. Chem. Soc. 2015, 137, 10547. (b) Prakash, G. K.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 25
1
2
3
4
5
6
7
8
9
S.; Krishnamoorthy, S.; Kar, S.; Olah, G. A. J. Fluorine Chem. 2015, 180, 186. (c)
Zafrani, Y.; SodꢀMoriah, G.; Segall, Y. Tetrahedron 2009, 65, 5278.
(6) Searching in Scopus for the term "quaternary ammonium" in the Field Type "Article
Title" resulted in 4,580 document results from 1977 in various disciplines. Few
selected examples are: (a) Prakash, S.; Muralirajan, K.; Cheng, CꢀH. Angew. Chem.
Int. ed. 2016, 55, 1844. (b) Y. Ge, S. Wang, X. Zhou, H. Wang, H. H. K. Xu, L.
Cheng, Material 2015, 8, 3532. (c) Weiber, E. A.; Meis, D.; Jannasch, P. Polym.
Chem. 2015, 6, 1986. (d) Novacek, J.; Waser, M. Eur. J. Org. Chem. 2013, 637. (e)
Tischer, M.; Pradel, G.; Ohlsen, K.; Holzgrabe, U. ChemMedChem 2012, 7, 22.
(7) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. Org. Lett. 2007, 9, 1863.
(8) Prakash, G. K. S.; Zhang, Z.; Wang, F.; Ni, C.; Olah, G. A. J. Fluorine Chem. 2011,
132, 792.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) Nawrot, E.; Jonczyk, A. J. Org. Chem. 2007, 72, 10258.
(10) (a) Kirby, A. J.; Lima, M. F.; da Silva, D.; Roussev, C. D.; Christo, D.; Nome, F. J.
Am. Chem. Soc. 2006, 106, 3252. (b) Kirby, A. J.; M. Lima, F.; da Silva, D.; Nome,
F. J. Am. Chem. Soc. 2004, 126, 1350. (c) Admiraal, S. J.; Herschlag, D. J. Am.
Chem. Soc. 1999, 121, 5837.
(11) (a) Kirby, A. J.; Younas, M. J. Chem. Soc. (B) 1970, 1165. (b) Khan, S. A.; Kirby,
A. J. J. Chem. Soc. (B) 1970, 1172.
(12) Marciano, D.; Columbus, I.; Elias, S.; Goldvaser, M.; Shoshanim, O.; Ashkenazi,
N.; Zafrani, Y. J. Org. Chem. 2012, 77, 10042.
(13) (a) Kiddle, J. J.; Mezyk, S. P. J. Phys. Chem. B 2004, 108, 9568. (b) TOXNET:
Toxicology Data Network fact Sheet, U.S. National Library of Medicine,
http://chem.sis.nlm.nih.gov/chemidplus/rn/358ꢀ74ꢀ7 (accessed May 4, 2016).
24
ACS Paragon Plus Environment

Page 25 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
(14) (a) Marciano, D.; Goldvaser, M.; Columbus, I.; Zafrani, Y. J. Org. Chem. 2011, 76,
8549. (b) Fringuelli, F.; Lanari, D.; Pizzo, F. ; Vaccaro, L. Curr. Org. Syn. 2009, 6,
203.
9
(15) (a) Tarkka, R. M.; Buncel, E. J. Am. Chem. Soc. 1995, 117, 1503. (b) Delfino, R. T.;
FigueroaꢀVillar, J. D. J. Phys. Chem. B 2009, 113, 8402.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(16) Lincopan, N.; E. Mamizuka, M.; CarmonaꢀRibeiro, A. M. J. Antimicrob.
Chemother. 2005, 55, 727.
(17) (a) Macdonald, G.; Alcaraz, L.; Lewis, N. J.; Taylor, R. J. K. Tetrahedron Lett.
1998, 39, 5433. (b) Zhang, FꢀY.; Corey, E. J. Org. Lett. 2004, 6(19), 3397.
(18) (a) Zhou, Z.; Yu, P.; Geller, H. M.; Ober, C. K. Biomacromolecules 2013, 14, 529.
(b) Politakos, N.; Azinas, S.; Moya, S. E. Macromol. Rapid Commun. 2016, 37, 662.
(19) These drugs contain a quaternary ammonium moiety with a methyl group adjacent to
the nitrogen. Our CHF2 analogues were synthesized for the first time and their
biological activity may be improved related to their defluorinated original
counterpart.
(20) Reetz, M. T. Angew. Chem. Int. Ed. Engl. 1988, 27, 994.
(21) Shirakawa, S.; Liu, S.; Kaneko, S.; Kumatabara, Y.; Fukuda, A.; Omagari, Y.;
Maruoka, K. Angew. Chem. Int. Ed. 2015, 54, 15767.
(22) Abraham, M. H.; Abraham, R. J.; Byrne, J.; Griffiths, L. J. Org. Chem. 2006, 71,
3389.
(23) FederꢀKubis, J. Polimery 2011, 56, 676.
(24) Pasenok, S. V. S.; Kirij, N. V.; Yagupolskii, Yu. L.; Naumann, D.; Tyrra, W.;
Fitzner, A. Z. Anorg. Allg. Chem. 1999, 625, 834.
(25) Leo, A.; Hansch, C.; Elkins, D. Chem. Rev. 1971, 71, 525ꢀ616.
25
ACS Paragon Plus Environment