Monofluorinated Nitrogen Containing Heterocycles: Synthesis, Characterization and Fluorine Effect

Article abstract of DOI:10.1002/zaac.202000239

A straight forward synthesis and efficient introduction of fluoromethyl group in nitrogen heterocycles is reported. Starting from the respective NH heterocycles fluoromethylation is performed with fluoroiodomethane and proceeds under mild reaction conditions. Structural information of monofluoromethylated nitrogen-containing cyclic compounds containing the biologically active NCH₂F moiety are reported. The particularly impressively change of physical and spectroscopic properties by the substitution of a methyl group by a monofluoromethyl group is discussed based on these examples.

Full text of DOI:10.1002/zaac.202000239

Journal of Inorganic and General Chemistry
DOI: 10.1002/zaac.202000239 SHORT COMMUNICATION
Zeitschrift für anorganische und allgemeine Chemie
Monofluorinated Nitrogen Containing Heterocycles: Synthesis,
Characterization and Fluorine Effect
Marco Reichel[a] and Konstantin Karaghiosoff*[a]
Abstract. A straight forward synthesis and efficient introduction of
fluoromethyl group in nitrogen heterocycles is reported. Starting from
the respective NH heterocycles fluoromethylation is performed with
fluoroiodomethane and proceeds under mild reaction conditions. Struc-
tural information of monofluoromethylated nitrogen-containing cyclic
compounds containing the biologically active NCH2F moiety are
reported. The particularly impressively change of physical and spectro-
scopic properties by the substitution of a methyl group by a mono-
fluoromethyl group is discussed based on these examples.
Due to the strong and polar C–F bond the introduction of
fluorine in organic compounds changes (in part dramatically)
their physical properties and compounds with unique physical
and properties can be obtained.[6] Monofluoromethyl diaalkyl-
amines are a good example; unlike the corresponding chloro-,
bromo- and iodomethyl analogues they no longer have a salt-
like character.[7] This affects the boiling / melting points as
well as the solubility and reaction behavior. The synthesis of
amines with a fluoromethyl group attached to nitrogen is still a
challenge, however. It is well known, that fluoromethyl halides
CH2FCl, CH2FBr and CH2FI can be used for electrophilic
fluoromethylation of various oxygen-, sulfur-, carbon- and ni-
trogen- nucleophiles.[8] While secondary fluoromethylamines
are likely to eliminate hydrogen fluoride and are of limited
stability, tertiary fluoromethylamines and N–CH2F ammonium
salts are stable and are prepared starting from the correspond-
ing secondary or tertiary amines by reaction mostly with
CH2FCl.[8,9] However, the use of cheap CH2FCl and CH2FBr
as fluoromethylating agents becomes increasingly problematic
due to the ozone depleting properties of these compounds. In
addition, handling of volatile CH2FCl and CH2FBr is challeng-
ing, particularly taking into account the harsh reaction condi-
tions necessary.[6,8]
Introduction
Nitrogen containing heterocycles with a fluoromethyl group
directly bonded to nitrogen are of great interest due to their
application in different areas. While heterocycles with the
NCH2F structural motive have been used as reagents in nickel
catalyzed cross coupling reactions,[1] most of their applications
are related to biologically active compounds. Five membered
nitrogen heterocycles with an N-bonded CH2F group are used
for agro chemicals, especially for microbiocides and herbi-
cides.[2] In addition, based on the bioisosteric relationship be-
tween CH2F and a variety of functional groups, they are essen-
tial for the pharmaceutical industry. Thus, NCH2F containing
heterocycles act as biologically active building blocks in endo-
thelial lipase inhibitors (1),[3] in agents for the treatment of
CRF-1 related disorders (2)[4] or acting as choline transporter
inhibitors (3) (Figure 1).[5]
Structural information is of crucial importance in develop-
ment and design of new pharmaceutically active agents. Al-
though a large number of nitrogen compounds with a N-
bonded CH2F group have been prepared and many of them
are used as pharmaceutical drugs, surprisingly practically no
structural information is available for the NCH2F motive. Only
one crystal structure – that of Me3NCH2F+ PbI3–[10] – has been
described in the literature so far.
Herein, we report a simple and practical method to synthe-
size new monofluoromethylated nitrogen heterocycles under
mild reaction conditions with high yields using fluoroiodome-
thane. The change in physical properties and the influence of
fluorine were investigated by comparing the CH2F containing
new nitrogen heterocycles with the corresponding methyl or
hydroxymethyl derivatives. The molecular and crystal struc-
tures of selected nitrogen heterocycles containing the NCH2F
Figure 1. Biological active NCH2F containing heterocycles.
* Prof. Dr. K. Karaghiosoff
E-Mail: klk@cup.uni-muenchen.de
[a] Department of Chemistry
Ludwig-Maximilian-University
Butenandtstr. 5–13 (D)
81377 Munich, Germany
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/zaac.202000239 or from the au-
thor.
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Co. KGaA. · This is an open access article under the terms of the
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Journal of Inorganic and General Chemistry
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group were determined by single-crystal X-ray diffraction and temperature, most probably due to slow hydrolysis of the
offer an insight on the structural properties of this fascinating NCH2F group. A similar behavior has been observed in the
building block.
case of primary fluoromethylamines.[8] The molecular struc-
tures of 4 and 5 in the crystal are shown in Figure 2.
Results and Discussion
N-Fluormethyl phthalimide (4) is an important intermediate
in the production of agrochemicals acting as herbicides or
microbiocides.[11] Its synthesis starting from phthalimide and
introducing the CH2F group by reaction with CH2FCl is un-
attractive due to the low yield (23%), while alternative routes
are more complicated and more expensive.[12] Parallel to our
investigation Pace et al. reported, that compound 4a can be
obtained in a high (82%) starting from the Cs salt of phthal-
imide using fluoroiodomethane.[12c]
For the synthesis of 4 we have used potassium phthalimide
as the starting material, which was readily prepared from
phthalimide according to a modified literature known pro-
cedure.[14] Reaction of potassium phthalimide with CH2FI re-
sults in the formation of 4, which can be readily isolated by
Figure 2. Molecular structure of 4 (a) and 5 (b) in the crystal. DIA-
MOND representation, thermal ellipsoids are shown with 50% prob-
ability. Selected bond length and angles of 4: N1–C9, 1.427(4); C9–
F1, 1.388(3); F1–C9–N1, 109.3(2); F1–C9–N1–C1, 95.6(3).
The crystal structures of 4 and 5 offer the unique possibility
crystallization. The reaction conditions were optimized to give to compare the structural behavior of two molecules differing
the best yield of 71% (Table 1).
only in F / OH at the same position. In both cases the mol-
ecules are completely planar and only the functional groups (F
and OH) are positioned out of the molecular plane. The most
interesting feature of the molecular structure of 4 is the NCH2F
group. The nitrogen atom in 4 and 5 displays a trigonal planar
environment. The N1–C9 distance of 1.427(4) Å in 4 is
somewhat shorter as compared to the N1–C9 distance of
1.456(3) Å in 5 and significantly shorter as compared to the
distance of 1.51(2) Å reported for the Me3NCH2F cation.[10]
In this last case, however, the CH2F group is disordered and
structural parameters are less accurate. The C9-F1 bond length
[1.388(3) Å] compares well to the value of a 1.399 Å for a
Csp3–F single bond, found in the literature[14] and also to the
C,F distance reported for the PCH2F group [1.379(5) Å] (Fig-
ure 2).[6] However, the CH2–F bond length is shorter than the
C,O distance in the bioisosteric CH2–OH moiety in 5 of
1.402(3) Å and the Me3NCH2F cation with 1.43(2) Å.[10]
There are considerable differences in the physical properties
Table 1. Optimization of the reaction conditions for the synthesis
of 4.
Entry
T /°C
p /bar
Solvent
t /h
Yield /%
1
2
3
4
5
6
7
35.6
40
82
100
100
100
120
1
1
1
7
6.1
1,9
3,3
Et2O
DCM
CH3CN
Et2O
DCM
3
3
3
3
3
3
3
5
12
34
9
39
52
71
CH3CN
CH3CN
Potassium phthalimide was refluxed at ambient pressure in between 4 and 5. For example, with a melting point of 82 °C,
different solvents. The resulting yields were nearly as poor as 4 is melting much lower than 5 (168 °C)[15] or the analogous
for CH2FCl (23%), the reaction in acetonitrile giving the best methyl derivative (CH3 in place of CH2F, 134 °C).[16] In order
results (Table 1). In a previous study it was shown that fluoro- to understand the difference in physical properties of the fluo-
methylation under increased pressure can lead to better romethyl compound 4 and the hydroxymethyl compound 5 it is
yields.[6,13] Following this experience we performed the syn- necessary to look into the interactions in the crystal (Figure 3).
thesis in a pressure tube and in fact for all solvents the yields
In the case of 5 the OH group acts as H-donor and un-
of 4 were higher at 100 °C as compared to ambient conditions dergoes hydrogen bonding with the oxygen atom of one of
(Table 1). This further confirms the great impact of the pres- the carbonyl groups. This results in the formation of chains of
sure for fluoromethylation reactions with CH2FI. Acetonitrile hydrogen bonded molecules of 5 in the crystal. In the case of
as solvent led to the highest yield (52%). The yield could be 4 the electronegative fluorine atom can act only as a H-ac-
further improved to 71% by performing the reaction in aceto- ceptor in hydrogen bonding and interactions are less strong as
nitrile at 120 °C. Higher temperatures resulted in a brownish compared to 5. The strongest interactions are between a proton
color of the reaction solution most probably indicating decom- of CH2 and the oxygen atom of C=O of another molecule,
position. Single crystals of compound 4 were obtained by slow followed by the interaction between fluorine of the same CH2F
evaporation of the acetonitrile solution. Unexpectedly single group and an aromatic proton of the same second molecule.
crystals of the corresponding hydroxymethyl derivative 5 This also results in the formation of chains in the crystal of 4
formed in the crystallization batch after one month at ambient with the only difference of weaker interactions. This behavior
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This is in accord with and explains the dramatic difference of
the melting points of both compounds.
Another pair of heterocycles, which can be compared and
display the effect of fluorine are 1H-2-methylimidazole[19] and
the new 1H-1-fluoromethyl-2-methylimidazole 6. Similar to
the synthesis of 4, the fluoromethyl derivative 6 was obtained
by reaction of potassium 2-methylimidazolate with CH2FI
(Scheme 1). However, parallel to this publication, Pace et al.
reported that imidazole and other nitrogen containing heterocy-
cles can also be N-fluoromethylated in high yields starting
from the corresponding Cs with fluoroiodomethane.[12c] Potas-
sium 2-methylimidazolate is readily prepared starting from
1H-2-methylimidazole by reaction with potassium carb-
onate.[20] Fluoromethyl imidazole 6 is isolated as a slightly
yellowish oil (63% yield), which tends to form a super cooled
melt.
Figure 3. Two-dimensional fingerprint plot as well as the correspond-
ing Hirshfeld surface (bottom right in 2D plot) of 4 (a) and 5 (b).
Color coding: white, distance d equals VDW distance; blue, d exceeds
VDW distance; red, d is smaller than VDW distance). Population of
close contacts of 4 (top) and 5 (bottom) in crystal stacking. View of
hydrogen bonding in 4 (d) and 5 (e), showing the strongest interac-
tions. DIAMOND representation. Thermal ellipsoids are drawn at 50%
probability level. Symmetry code: i) 1 –x, 0.5+y, –z; ii) 1+x, y, z.
Scheme 1. Synthesis of fluoromethyl imidazole 6.
Single crystals of 6a and its monohydrate 6b (Figure 4) were
formed by slow evaporation of a solution of 6 in chloroform.
is confirmed also by the Hirshfeld analysis of the structures of The nitrogen atom in 6a and 6b displays a trigonal planar envi-
4 and 5. For strong O–H bonding the 2D fingerprint plot exhib- ronment, as observed for 4 (Figure 2). The N2–C5 distance to
its two distinct spikes.[17] Comparing Figure 2a and b it be- the fluoromethyl group in both, 6a [1.420(3) Å] and the hy-
comes obvious, that O–H hydrogen bonding in 5 is much drate 6b [1.423(2) Å] is almost the same and in good agree-
stronger than in 4. Evaluation of the population of the close ment with that found in 4 [1.427(4) Å]. The crystal water
contacts (Figure 3c) shows, that 5 with 35.5% O···H close con- seems to not affect the C5–F1 bond length. With values of
tacts displays more H-bridges than 4. With respect to di + de 1.400(3) Å (5) and 1.388(2) Å (6b) these distances fit well to
(di: distance from the Hirshfeld surface to the nearest atom that observed in the case of 4 [1.388(3) Å]. However, some-
interior; de: distance from the Hirshfeld surface to the nearest what shorter C,F distances are reported for PCH2F
atom exterior) we can follow that 8.7% F···H contacts for 4 [1.379(5) Å],[6] CH2FI [1.380(17) Å],[21] and CH2FBr
are weak due to their long distance and so these interactions [1.377(4) Å].[21] Compounds 6a and 6b mainly differ in the
cannot compensate the lower number of O···H contacts in 4. intermolecular interactions in the crystal (Figure 3).
The hydrogen bonding in Figure 3d and 3e shows the shortest
Looking at the Hirshfeld analysis of the structures of 6a and
contacts in the crystal. Considering these short contacts as well 6b, from the distinct spikes of 6b in the 2D Plot it becomes
as the angles at the respective hydrogen atoms of 175(3)° in evident, that the H···F interactions in the sum are less but
5 and of 150(1)°, 163(2)° in 4 (Table 2), the intermolecular stronger,[17] as compared to 6a (Figure 6a–c). The larger angle
interactions in 5 are considered to be stronger than in 4.[18] at hydrogen of 166(2)° in 6b as compared to 142(2)° in 6a
Table 2. Bond length /Å and bond angles /° of selected hydrogen bonds.
Compound
Bond
d(D–H)
d(H···A)
d(D···A)
D–H···A
4
C9i–H9Ai···O2
C6–H6···F1i
0.96(2)
0.99(4)
0.86(3)
0.98
0.96(2)
0.83(2)
0.95
0.91(2)
0.92(2)
0.92(2)
0.90(3)
0.92(2)
2.416(2)
2.68(3)
1.98(4)
2.593(2)
2.39(2)
1.97(2)
2.686(2)
2.49(2)
2.37(2)
3.59(2)
3.16(3)
3.49(2)
3.284(4)
3.651(5)
2.835(3)
3.420(3)
3.329(2)
2.795(2)
3.563(2)
3.221(3)
3.055(3)
4.005(3)
3.954(3)
4.159(3)
150(1)
163(2)
175(3)
142(2)
166(2)
174(2)
153.81(8)
137(2)
131.0(8)
110.4(8)
148(2)
5
6a
6b
O1ii–H1ii···O2
C4–H4B···F1i
C2–H2···O1
O1–H3···N1ii
C1ii–H1ii···F1
C4–H4A···F1i
C6–H6B···F2iii
C6–H6A···I1
C1iii–H1iii···I1
C6iii–H6Biii···I1
7
131.8(7)
Symmetry code: 4) i) 1 –x, 0.5+y, –z; 5) ii) 1+x, y, z; 6a) i) 0.5+x, 0.5–y, 1 –z; 6b) i) 0.5+x, 0.5–y, 1 –z; ii) 1 –x, –0.5+y, 0.5–z 7) i) 1 –x,
–y, –z; iii) 1.5–x, 0.5+y, z.
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Both nitrogen atoms in compound 7 display a trigonal planar
environment. As compared to 6a [N2–C5: 1.420(3) Å,
1.423(2) Å], the N–C bond length in 7 [N2–C5: 1.439(3) Å,
N1–C6 (1.444(3) Å]) are slightly longer. However, the C5–F1
and C6–F2 distances of 1.370(3) Å and 1.376(3) Å, respec-
tively, are significantly shorter than in 6a [1.400(3) Å,
1.388(2) Å] and are similar to those reported for PCH2F
[1.379(5) Å],[6] CH2FI [1.380(17) Å],[21] or CH2FBr
[1.377(4) Å].[21] The intermolecular interactions also change
dramatically, due to the introduction of ionic charges and of
the iodide anion. The H···N close contacts, which are charac-
teristic for 6a, are replaced by H···I and H···F contacts (Fig-
ure 6c, e). As a result, about 62% attractive contacts are pres-
ent in 7, in contrast to 42.5% in 6b. This is in accord with the
fact, that 7 can be heated up to 252 °C without observable
decomposition. The non-distinct spikes for the H···F and H···I
contacts (Figure 6d) and the sum di + de (di = distance from
the Hirshfeld surface to the nearest atom interior; de = distance
from the Hirshfeld surface to the nearest atom exterior) indi-
cate, that these interactions are weak (Table 2).[17,18] As an
example, the strongest H···I contact (Figure 6h), with a dis-
tance of 3.15(2) Å is by far longer than the only weak interac-
Figure 4. Molecular structure of 6a (a) and of the monohydrate 6b (b)
in the crystal. In the case of 6b one proton of the H2O molecule is
disordered over two positions (50% disorder). DIAMOND representa-
tion, thermal ellipsoids are drawn with 50% probability. Selected bond
length and angles of 6a: C5–F1, 1.400(3); C5–N2, 1.420(3); N2–C5–
F1, 109.3(2); F1–C5–N2–C3, –84.3(3). 6b: C5–F1, 1.388(2); C5–N2,
1.423(2); F1–C5–N2, 109.8(2); F1–C5–N2-C3, –84.8(2).
(Table 2) confirms that intermolecular H···F interactions in 6b
are stronger than in 6a (Figure 6f, g).[18] The sum di + de (di
= distance from the Hirshfeld surface to the nearest atom inte-
rior; de = distance from the Hirshfeld surface to the nearest
atom exterior) indicates, that for 6a in general all interactions
in the crystal are very weak (Table 2), due to the long distances
of the H···N and H···F contacts (Figure 6a) and the angles at
hydrogen with values of 142(2)–175(2)°.[17–18] The low melt-
ing point of 27 °C observed for 6a is in accord with these weak
interactions. Compared to its methyl analogue (m.p. 51 °C;
b.p. 206 °C),[22] 6a shows lower melting and boiling points.
This is in good agreement with the observation made for 4,
where the melting point of which is about 50 °C lower than
that of the corresponding methyl derivative.
tion with a distance of 2.83(2) Å found in [PPh3CH2F]I.[6]
A
similar weak contact was observed in [PPh3CH2OH]I, where
Fluoromethyl imidazole 6a was allowed to react with CH2FI
yielding 76% of the corresponding 1H-1,3-bis(fluoromethyl)-
2-methyl imidazolium iodide (7) (Scheme 2). Single crystals
of 7 were obtained by slow evaporation of a solution of 7 in
acetonitrile. The molecular structure of 7 in the crystal is
shown in Figure 5.
Scheme 2. Synthesis of bisfluoromethyl imidazole 7.
Figure 6. Two-dimensional fingerprint plot as well as the correspond-
ing Hirshfeld surface (bottom right in 2D plot) of 6a (a), 6b (b) and 7
(d). Color coding: white, distance d equals VDW distance; blue, d
exceeds VDW distance; red, d is smaller than VDW distance. Popula-
tion of close contacts of 6a (c) top, 6b (c) bottom and 7 (e) in crystal
stacking. Strongest hydrogen bonds in 6a (f), 6b (g) and 7 (h). DIA-
Figure 5. Molecular structure of 7 in the crystal. DIAMOND represen-
tation, thermal ellipsoids are drawn with 50% probability. Selected
bond length and angles of 7: F1–C5, 1.370(3); C5–N2, 1.439(3); F2– MOND representation. Thermal ellipsoids are drawn at 50% prob-
C6, 1.376(3); C6–N1, 1.444(3); F1–C5–N2, 108.8(2); F2–C6–N1, ability level. Symmetry codes: i) 0.5+x, 0.5–y, 1 –z; ii) 1 –x, 0.5+y,
108.6(2); F1–C5–N2-C3, –92.2(3); F2–C6–N1–C3, –84.5(3).
0.5–z; iii) 1.5–x, 0.5+y, z.
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In summary, we have synthesized new fluoromethylated ni-
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and versatile ligands for transition metals. Single crystal X-ray
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Acknowledgements
Financial support by the Ludwig–Maximilian University is grateful
acknowledged. We are thankful to F-Select GmbH for a generous do-
nation of fluoroiodomethane. Open access funding enabled and orga-
nized by Projekt DEAL.
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Keywords: Monofluoromethylation; Fluorine effect; Hetero-
cycles; Fluoroiodomethane; X-ray diffraction
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Published Online: ᭿
Z. Anorg. Allg. Chem. 2020, 1–6
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© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Journal of Inorganic and General Chemistry
SHORT COMMUNICATION
Zeitschrift für anorganische und allgemeine Chemie
M. Reichel, K. Karaghiosoff* ........................................... 1–6
Monofluorinated Nitrogen Containing Heterocycles: Synthesis,
Characterization and Fluorine Effect
Z. Anorg. Allg. Chem. 2020, 1–6
www.zaac.wiley-vch.de
6
© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim