Багатограмовий синтез β-флуорованих насичених гетероциклічних метанамінів
An efficient multigram synthesis of β-fluorinated saturated heterocyclic methanamines - promising building blocks for drug discovery, starting from the corresponding saturated heterocyclic ketones is described. The method includes Wittig olefination, bromofluorination, nucleophilic substitution with...
Gespeichert in:
| Datum: | 2023 |
|---|---|
| Hauptverfasser: | , |
| Format: | Artikel |
| Sprache: | Englisch |
| Veröffentlicht: |
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2023
|
| Schlagworte: | |
| Online Zugang: | https://bioorganica.com.ua/index.php/journal/article/view/73 |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Назва журналу: | Ukrainica Bioorganica Acta |
| Завантажити файл: |  |
Institution
Ukrainica Bioorganica Acta| _version_ | 1871193598753505280 |
|---|---|
| author | Semeno, Volodymyr V. Melnykov, Kostiantyn P. |
| author_facet | Semeno, Volodymyr V. Melnykov, Kostiantyn P. |
| author_institution_txt_mv | [
{
"author": "Volodymyr V. Semeno",
"institution": "Enamine Ltd., Kyiv, Ukraine; Taras Shevchenko National University of Kyiv, Kyiv, Ukraine"
},
{
"author": "Kostiantyn P. Melnykov",
"institution": "Enamine Ltd., Kyiv, Ukraine; Taras Shevchenko National University of Kyiv, Kyiv, Ukraine"
}
] |
| author_sort | Semeno, Volodymyr V. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:54Z |
| description | An efficient multigram synthesis of β-fluorinated saturated heterocyclic methanamines - promising building blocks for drug discovery, starting from the corresponding saturated heterocyclic ketones is described. The method includes Wittig olefination, bromofluorination, nucleophilic substitution with azide, and Staudinger reaction and works well for four- to seven-membered nitrogen- and oxygen-containing heterocyclic derivatives |
| doi_str_mv | 10.15407/bioorganica2023.02.016 |
| first_indexed | 2025-07-17T12:19:56Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
UDC 547.51:547.7+546.16
DOI: https://doi.org/10.15407/bioorganica2023.02.016
16
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
RESEARCH ARTICLE
Multigram synthesis of -fluorinated saturated heterocyclic
methanamines
Volodymyr V. Semeno1,2, Kostiantyn P. Melnykov1,2*
1 Enamine Ltd.(www.enamine.net), Kyiv, Ukraine
2 Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
Abstract: An efficient multigram synthesis of β-fluorinated saturated heterocyclic methanamines - promising building blocks for drug
discovery, starting from the corresponding saturated heterocyclic ketones is described. The method includes Wittig olefination,
bromofluorination, nucleophilic substitution with azide, and Staudinger reaction and works well for four- to seven-membered nitrogen-
and oxygen-containing heterocyclic derivatives.
Keywords: organofluorine compounds; heterocycles; amines; building blocks; drug discovery.
Introduction
Over the recent years, saturated heterocyclic scaffolds
have gained much attention in drug discovery due to three-
dimensionality, improved aqueous solubility, and increased
hydrophilicity of their derivatives [1-3]. On the other hand,
fluorination can improve binding to the biological target, as
well as pharmacokinetic and physicochemical properties of
the compound, and it is, therefore, an important design
approach in medicinal chemistry [4-8]. Fluorinated
saturated heterocyclic building blocks are becoming
increasingly popular in drug discovery projects [9, 10]. In
particular, derivatives of β-fluorinated saturated
heterocyclic methanamines (general structure 1) include
potent and selective 5-hydroxytriptamine 1A (5-HT1A)
receptor agonists Befiradol and F-15,599 [11], covalent
Bruton tyrosine kinase (BTK) inhibitors [12], estrogen
receptor (ER) antagonists [13], and retinoic acid receptor-
related orphan receptor (RORγ) inverse agonists [14]
(Figure 1).
Received:
Revised:
Accepted:
Published online:
19.09.2023
30.10.2023
28.11.2023
30.12.2023
Corresponding author. Tel.: +380-44-239-3315;
e-mail: konstantyn.melnykov@gmail.com (K.P. Melnykov)
ORCID: 0009-0003-6522-681X
F
NH2
Het
X
1, X = O, NBoc N X
F
Cl
Befiradol, X = CH
F-15,599, X = N
5-HT1A agonists
NH
N
O
F
O
N
FF
F
RORg inverse agonist
IC50 = 10 nM
N
N
H
S
O
O
N
O
O
F
ER antagonist
IC50 = 0.6 nM
O
N
F
N
H
N
N
O
NH2
BTK inhibitor
O
N
F
H
N
Figure 1. Biologically active derivatives of β-fluorinated saturated
heterocyclic methanamines 1
Some β-fluorinated saturated heterocyclic methanamine
building blocks (e.g., compounds 1a and 1f) have been.
© Semeno V.V. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
https://orcid.org/0009-0003-6522-681X
V.V. Semeno, K.P. Melnykov
17
N
Boc
F NH2
1a (270/4)
No. of patents/papers in Reaxys®
N
Boc
F
NH2
1b (7/2)
N
Boc
F NH2
1c (59/0)
NBoc
F NH2
1d (9/0)
O
F NH2
O
1j (21/0)
O
F NH2
1g (1/0)
O
F NH2
1f (291/1)
O
F
NH2
1h (0/0)
O
F NH2
1i (36/0)
F NH2
N
Boc
1e (0/0)
Figure 2. β-Fluorinated saturated heterocyclic methanamine
building blocks 1a-k in Reaxys® database.
N
Boc
F
Br
N
Boc
n
Et3N.HF, NBS
CH2Cl2, rt
68-92%
n
2a,b 3a,b
NaN3, NaI
DMSO,
80-91%
N
Boc
F
N3
n
4a,b
H2, Pd-C
MeOH, rt
67-90%
N
Boc
F
H2N
n
1a,b
a: n = 2; b: n = 1
Scheme 1. Synthesis of amines 1a and 1b according to De Kimpe
and co-authors.
widely used in medicinal chemistry, which is confirmed by
the number of patents referenced in Reaxys® database
(Figure 2) [15]. Meanwhile, approaches to their synthesis
are covered scarcely in the literature. Thus, De Kimpe and
co-authors described preparation of compound 1a and 1b
starting from exomethylene derivatives 2a and 2b via
bromofluorination, SN2 reaction with azide, and reduction
reaction sequence (Scheme 1) [16]. Other methods relied on
phthalimide alkylation [17] and [3+2] cycloaddition of
α-fluoroacrylate [18].
In this work, we describe application of a modified De
Kimpe’s approach for the synthesis of a series of fluorine-
containing saturated heterocyclic building blocks 1b-j. The
title compounds have been prepared at multigram scale (up
to 77 g in a single run).
Results and Discussion
Synthesis of the title compounds started with Wittig
olefination of saturated heterocyclic ketones 5b-i. For non-
volatile N-Boc derivatives 5b-e, the reaction was performed
upon action of Ph3PCH3
+I–- t-BuOK in THF according to
the literature method [19, 20] (Scheme 2). For volatile oxa-
heterocyclic ketones 5f-i, NaH was used as the base (to
avoid formation of tert-butanol), and DMSO - as the high-
boiling solvent; olefination products 2f-i were distilled from
the reaction mixture. Alkene 2j is more commercially
accessible than the corresponding ketone and was used
directly.
Et3N.3HF, NBS
CH2Cl2, rt
NaN3, NaI
DMF, 100 C
Het
5b-i
O
+ Ph3PMe+I
t-BuOK, THF, 10 C to rt
(X = NBoc) or
NaH, DMSO, rt (X = O)
38-62%
2b-j
3b-j4b-j
PPh3, H2O
THF, 10 C to rt
16-54% (from 2)
X
F
NH2
Het
X
F
N3
Het
X
F
Br
Het
X
1b-j
Het
X
Scheme 2. Synthesis of amines 1b-j.
Bromofluorination of alkenes 2b-j was performed with
Et3N3HF-NBS in CH2Cl2 using the protocol reported
previously by our group [19]. Notably, the reaction had
limited regioselectivity with azeditine derivative 2c (a detail
that was not documented in the previous work). With
tetrahydropyran derivative 2g, the reaction was complicated
by partial HF elimination. We used resulting crude products
3b and 3g, respectively (as well as all other products 3b-j)
in the next step without purification.
The nucleophilic substitution step was carried out in
DMF at 100 C in the presence of NaI to transform
substrate 3b-j into the corresponding iodide and hence
facilitate the subsequent SN2 reaction with NaN3. Due to the
potentially explosive nature of products 4b-j, they were also
used in the next step without purification.
For the final step of the synthesis-azide reduction, we
initially tried the catalytic hydrogenation conditions
reported by the previous authors for the synthesis of 1a,b
[16]. It was found that upon attempted scale-up, the
conversion at 1 atm was very slow due to N2 evolution (and
hence H2 partial pressure decrease). Even with periodic
refilling the reaction system with H2, the reaction was not
complete after a week. Therefore, we turned our attention to
the Staudinger reaction (PPh3-H2O) as the alternative
method for the azide reduction. Although this approach had
poorer atom economy, it worked well at multigram scale
and allowed preparation of all target products 1b-j in a
reasonable time (overnight). Importantly, compounds 1b-j
could be purified by distillation and hence isolated as free
bases or hydrochlorides in 21-54% overall yield without the
use of chromatographic purification (Table 2).
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
18
Table 1. Yields of alkenes 2b-j and amines 1b-j prepared
according to Scheme 2.
# Starting
ketone
Alkene Yield Amine Yielda
g % g %
1 5b 2b 99 50 1b 63 54
2 5c 2c 72 49 1c 33 38
3 5d 2d 74 50 1d 34 25
4 5e 2e 55 58 1e 27 42
5 5f 2f 48 49 1f 31 48
6 5g 2g 61 62 1g 18 21
7 5h 2h 145 60 1h 77 38
8 5i 2i 37 38 1i 25 45
9 – 2j – – 1j 32 16
a Yield over three steps
Conclusions
An efficient multigram synthesis of β-fluorinated
saturated heterocyclic methanamines is described. The
proposed procotol is based on the literature method
described for the simplest N-heterocyclic derivatives (i.e.,
Wittig olefination of the corresponding heterocyclic ketone,
bromofluorination with Et3N3HF-NBS, SN2 reaction with
NaN3, and azide reduction) but included several important
modifications required for the successful scale up. In
particular, Wittig olefination of volatile oxygen-containing
heterocyclic ketones was performed with NaH in DMSO to
enable isolation of the corresponding alkenes by distillation.
Furthermore, azide reduction was very efficient under the
Staudinger reaction conditions (Ph3P-H2O) instead of
catalytic reduction. The optimized protocol was
successfully applied for the synthesis of nine title saturated
N- or O-containing 4- to 7-membered heterocyclic amines
on up to 77 g scale. The obtained products are promising
fluorinated sp3-enriched building blocks for medicinal
chemistry, and in our opinion, they have a great potential
for drug discovery programs.
Experimental section
Alkene 2c was prepared according to the literature
method [19]. Alkenes 2b [20], 2d [21], and 2e were
synthesized in a similar manner; their spectral and physi-
cal data were in accordance with the literature. All
other reagents were obtained from Enamine Ltd. or
UkrOrgSyntez. Melting points were measured on MPA100
OptiMelt automated melting point system. 1H, 13C and 19F
NMR spectra were recorded on an Agilent ProPulse 600
spectrometer (at 600 MHz for 1H NMR, 151 MHz for
13C NMR), Bruker 170 Avance 500 spectrometer (at 500
MHz for 1H NMR, 126 MHz for 13C NMR and 470 MHz
for 19F NMR) or Varian Unity Plus 400 spectrometer (at
400 MHz for 1H NMR, 101 MHz for 13C NMR and 376
MHz for 19F NMR). NMR chemical shifts are reported in
ppm (δ scale) downfield from TMS as an internal standard
and are referenced using residual NMR solvent peaks at
7.26 and 77.16 ppm for 1H and 13C in CDCl3, 2.50 and
39.52 ppm for 1H and 13C in DMSO-d6. Coupling constants
(J) are given in Hz. Spectra are reported as follows:
chemical shift (δ, ppm), multiplicity, integration, coupling
constants (Hz). Mass spectra were recorded on an Agilent
1100 LCMSD SL instrument (chemical ionization (CI)) and
Agilent 5890 Series II 5972 MS instrument (electron impact
ionization (EI)). High-resolution mass spectra (HRMS)
were obtained on an Agilent 1260 Infinity UHPLC
instrument coupled with an Agilent 6224 Accurate Mass
TOF mass spectrometer.
General procedure for the preparation of alkenes 2f-i
Sodium hydride (52 g, 1.30 mol, 60% in mineral oil) was
added in portions to DMSO (500 mL) at rt, and the mixture
was stirred at 70 °C for 2 h, then cooled to rt, and methyl-
triphenylphosphonium iodide (525 g, 1.30 mol) was added
in portions. The mixture was stirred for 20 min, and a
solution of ketone 2 (1 mol) in THF (100 mL) was added
dropwise at rt upon stirring. The resulting mixture was
stirred at rt for 14 h, then connected to a liquid nitrogen trap
(-198 C), in turn connected to vacuo. The crude product
was distilled directly into the trap at 1 mmHg and then
purified by fractional distillation.
4-Methylenetetrahydro-2H-pyran (2f)
Yield 31.0 g (48%); bp 39-41 C (40 mmHg) (lit. [22]
104-107 C). All spectral and physical data were in
accordance to the literature [19].
3-Methylenetetrahydro-2H-pyran (2g)
Yield 18.1 g (21%); bp 40-41 C (40 mmHg). All
spectral and physical data were in accordance to the
literature [23].
3-Methylenetetrahydrofuran (2h)
Yield 145.2 g (60%); bp = 91-93 C. 1H NMR (400
MHz, CDCl3) δ 4.99 (q, J = 2.2 Hz, 1H), 4.92 (q, J = 2.2
Hz, 1H), 4.23 (q, J = 2.0 Hz, 2H), 3.87 (td, J = 6.9, 1.5 Hz,
2H), 2.53 (ddd, J = 7.1, 5.0, 2.5 Hz, 2H). All other spectral
data were in accordance to the literature [24].
3-Methyleneoxetane (2i)
Yield 37.1 g (38%); bp 67-69 C (lit. [25] 70 C). All
spectral and physical data were in accordance to the
literature [20].
General procedure for the preparation of amines 1b-j
Alkene 2 (1 mol) was dissolved in CH2Cl2 (1.5 L), and
Et3N·3HF (483 g, 3 mol) was added at rt. The mixture was
cooled to 5 °C, and NBS (196 g, 1.1 mol) was added in one
portion at the same temperature. The resulting mixture was
warmed to rt and stirred overnight. Then, the reaction
V.V. Semeno, K.P. Melnykov
19
mixture was washed with H2O (1 L), 10% aq K2CO3 (1 L),
and brine (1 L), dried over Na2SO4, and evaporated in
vacuo below 45 °C. Crude bromide 3 (ca. 0.7 mol) thus
obtained was dissolved in DMF (1 L), and sodium iodide
(115 g, 0.77 mol) was added. The mixture was stirred at rt
for 10 min, and sodium azide (136 g, 2.1 mol) was added in
portions. The resulting mixture was stirred at 100 °C for 16-
50 h (monitored by 1H NMR spectroscopy), then cooled to
40 °C, poured into water (1 L), and extracted with ethyl
acetate (31.5 L). The combined organic layers were
washed with brine (50.5L), dried over Na2SO4, filtered,
and concentrated in vacuo below 45 °C. Crude azide 4 (ca.
0.4 mol) was dissolved in THF (1 L), cooled to 10 °C, and
PPh3 (115 g, 0.44 mol) was added in portions at 10 °C. The
mixture was stirred at rt for 2 h, and H2O (216 mL, 12 mol)
was added to the mixture in one portion. The resulting
mixture was stirred at rt overnight, most of THF was
evaporated in vacuo at 40 °C, and the residue was triturated
with 20% aq. NaHSO4 (480 mL, ca. 0.8 mol). The aqueous
solution was separated, washed with t-BuOMe (30.5 L),
then K2CO3 (124 g, 0.9 mol) was added in portions. The
resulting mixture extracted with CH2Cl2 (21.5 L). The
combined organic layers were washed with brine (0.5 L),
dried over Na2SO4, and evaporated in vacuo below 45 °C.
Crude product 1 was purified by distillation in vacuo.
tert-Butyl 3-(aminomethyl)-3-fluoropyrrolidine-1-carboxy-
late (1b)
Yield 63.0 g (54%); bp 85-87 C (1 mmHg). All spectral
and physical data were in accordance to the literature [16].
tert-Butyl 3-(aminomethyl)-3-fluoroazetidine-1-carboxylate
(1c)
Yield 33.4 g, 0.164 mol, 38%. Colourless oil, bp = 71-
73 °C (1 mmHg). 1H NMR (500 MHz, DMSO-d6) δ 4.04-
3.90 (m, 2H), 3.86-3.74 (m, 2H), 2.81 (d, J = 21.1 Hz, 2H),
1.70 (s, 2H), 1.36 (s, 9H). 13C{1H} NMR (151 MHz,
CDCl3) δ 156.3, 91.8 (d, J = 207.0 Hz), 80.0, 57.9, 46.6 (d,
J = 24.6 Hz), 28.3. 19F{1H} NMR (376 MHz, DMSO-d6)
δ -155.6. MS (APCI) m/z = 205 ([M+H]+). HRMS
(ESI/QTOF) m/z: [M + H]+ Calcd for C9H18FN2O2
+:
205.1347; Found: 205.1347.
tert-Butyl 4-(aminomethyl)-4-fluoroazepane-1-carboxylate
(1d)
Yield 34.2 g, 0.139 mol, 25%. Colourless oil, bp = 124-
126 °C (1 mmHg). 1H NMR (500 MHz, CDCl3) δ 3.80-3.45
(m, 2H), 3.34-3.10 (m, 2H), 2.96-2.60 (m, 2H), 2.16-1.86
(m, 3H), 1.79-1.53 (m, 2H), 1.44 (s, 12H). 13C{1H} NMR
(126 MHz, DMSO-d6) δ 155.1 and 155.0, 97.0 (d, J = 173.5
Hz), 78.9, 50.6 (d, J = 23.4 Hz) and 50.5 (d, J = 22.9 Hz),
46.1, 45.1, 39.5, 39.1, 36.4 (d, J = 23.1 Hz) and 36.0 (d,
J = 23.1 Hz), 32.7 (d, J = 23.0 Hz) and 32.4 (d, J = 22.4
Hz), 28.0, 20.2 (d, J = 5.5 Hz) and 19.8 (d, J = 6.1 Hz).
19F{1H} NMR (376 MHz, CDCl3) δ -162.4, -163.1.
MS (APCI) m/z = 247 ([M+H]+). HRMS (ESI/QTOF) m/z:
[M + H]+ Calcd for C12H24FN2O2
+: 247.1816; Found:
247.1815.
tert-Butyl 6-(aminomethyl)-6-fluoro-2-azaspiro[3.3]hepta-
ne-2-carboxylate (1e)
Yield 27.3 g, 0.112 mol, 42%, bp = 110-112 C (1
mmHg). Analytical sample was obtained by precipitation
via trituration of the ethereal base solution with 1M HCl in
Et2O. Colourless powder, mp = 46-49 °C. 1H NMR (500
MHz, CDCl3) δ 3.90 (d, J = 41.5 Hz, 4H), 2.77 (d, J = 23.2
Hz, 2H), 2.52-2.29 (m, 4H), 1.45 (s, 2H), 1.41 (s, 9H).
13C{1H} NMR (126 MHz, CDCl3) δ 155.5, 92.3 (d,
J = 210.9 Hz), 79.00, 60.4 (br), 47.7 (d, J = 24.0 Hz), 41.9
(d, J = 22.4 Hz), 28.2 (d, J = 13.0 Hz), 27.8. 19F{1H} NMR
(376 MHz, CDCl3) δ -145.7. MS (APCI) m/z = 245.2
([M+H]+). Anal. calcd. for C12H21FN2O2: C 59.00; H 8.66;
N 11.47. Found: C 58.86; H 8.75; N 11.65.
(4-Fluorotetrahydro-2H-pyran-4-yl)methanamine (1f).
Yield 31.1 g, 0.183 mol, 48%, bp 38-40 C (40 mmHg).
Analytical sample was obtained by precipitation via
trituration of the ethereal base solution with 1M HCl in
Et2O. Beige solid, mp = 138-140 °C. 1H NMR (400 MHz,
DMSO-d6) δ 8.38 (s, 3H), 3.75 (dt, J = 11.6, 3.9 Hz, 2H),
3.53 (ddd, J = 11.7, 8.7, 4.1 Hz, 2H), 3.17-2.96 (m, 2H),
1.92-1.51 (m, 4H). 19F NMR (376 MHz, DMSO-d6) δ
-162.4. MS (APCI) m/z = 134 ([M+H]+). Anal. calcd. for
C6H13ClFNO: C 42.49; H 7.73; N 8.26; Cl 20.90. Found:
C 42.75; H 7.50; N 7.87; Cl 20.85.
(3-Fluorotetrahydro-2H-pyran-3-yl)methanamine (1g).
Yield 31.0 g, 0.183 mol, 48%, bp = 70-72 C (20
mmHg). Analytical sample was obtained by precipitation
via trituration of the ethereal base solution with 1M HCl in
Et2O. Beige solid, mp = 141-143 °C. 1H NMR (500 MHz,
DMSO-d6) δ 8.35 (s, 3H), 3.84-3.66 (m, 2H), 3.47 (dd,
J = 29.0, 12.8 Hz, 1H), 3.37 (t, J = 10.5 Hz, 1H), 3.02 (d,
J = 20.3 Hz, 2H), 1.98-1.87 (m, 1H), 1.83-1.65 (m, 2H),
1.59-1.48 (m, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ
90.4 (d, J = 177.9 Hz), 69.6 (d, J = 22.4 Hz), 66.4, 42.7 (d,
J = 21.4 Hz), 29.2 (d, J = 21.5 Hz), 21.2. 19F{1H} NMR
(376 MHz, DMSO-d6) δ -165.5. MS (APCI) m/z = 134
([M+H]+). Anal. calcd. for C6H13ClFNO: C 42.49; H 7.73;
N 8.26; Cl 20.90. Found: C 42.78; H 7.78; N 8.64; Cl 21.16.
(3-Fluorotetrahydrofuran-3-yl)methanamine (1h)
Yield 77.2 g, 0.496 mol, 38%, bp = 54-56 C (20
mmHg). Analytical sample was obtained by precipitation
via trituration of the ethereal base solution with 1M HCl in
Et2O. Beige powder, mp = 110-112 °C. 1H NMR (500
MHz, DMSO-d6) δ 8.58 (s, 3H), 4.00-3.79 (m, 3H), 3.73
(dd, J = 34.3, 11.2 Hz, 1H), 3.26 (d, J = 20.4 Hz, 2H), 2.24-
2.06 (m, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ
103.3, 74.7 (d, J = 24.6 Hz), 67.2, 42.5 (d, J = 24.1 Hz),
36.2 (d, J = 21.9 Hz). 19F{1H} NMR (376 MHz, DMSO-d6)
δ -156.7. MS (APCI) m/z = 120 ([M+H]+). Anal. calcd. for
C5H11ClFNO: C 38.60; H 7.13; N 9.00; Cl 22.78. Found:
C 38.88; H 7.30; N 8.80; Cl 22.95.
(3-Fluorooxetan-3-yl)methanamine (1i)
ISSN 1814-9758. Ukr. Bioorg. Acta, 2023, Vol. 18, N 2
20
Yield 25.3 g, 0.179 mol, 45%, bp = 41-43 C (20
mmHg). Analytical sample was obtained by precipitation
via trituration of the ethereal base solution with 1M HCl in
Et2O. Yellowish crystals, mp = 164-165 °C. 1H NMR (500
MHz, DMSO-d6) δ 8.47 (s, 3H), 4.70 (dd, J = 20.7, 8.9 Hz,
2H), 4.62 (dd, J = 21.3, 8.9 Hz, 2H), 3.42 (d, J = 20.0 Hz,
2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 93.1 (d,
J = 209.4 Hz), 77.9 (d, J = 23.0 Hz), 41.3 (d, J = 23.8 Hz).
19F{1H} NMR (376 MHz, DMSO-d6) δ -154.2. HRMS
(ESI/QTOF) m/z: [M + H]+ Calcd for C4H9FNO+:
106.0663; Found: 106.0665.
(6-Fluoro-1,4-dioxepan-6-yl)methanamine (1j)
Yield 32.3 g, 0.174 mol, 16%, bp = 46-48 C (20
mmHg). Analytical sample was obtained by precipitation
via trituration of the ethereal base solution with 1M HCl in
Et2O. Colourless powder, mp = 127-130 °C. 1H NMR (500
MHz, DMSO-d6) δ 8.51 (s, 3H), 3.99-3.79 (m, 4H), 3.79-
3.71 (m, 2H), 3.66 (dd, J = 13.2, 5.5 Hz, 2H), 3.22-2.96 (m,
12H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 97.8 (d,
J = 179.6 Hz), 73.9, 73.6 (d, J = 28.7 Hz), 41.4 (d, J = 22.9
Hz). 19F{1H} NMR (376 MHz, DMSO-d6) δ -160.3. HRMS
(ESI/QTOF) m/z: [M + Na]+ Calcd for C6H12FNO2Na+:
172.0744; Found: 172.0749.
Notes
Acknowledgments and finances. The work was
supported by Enamine Ltd. and Ministry of Education and
Science of Ukraine (Grants No. 0121U100387 (21BF037-
01M) and 0122U001962 (22BF037-02)). The authors thank
Prof. Dr. Oleksandr Grygorenko and Oleksandr Liashuk for
their help with manuscript preparation, Prof. Andrey A.
Tolmachev for his encouragement and support, and all the
brave people of Ukraine for making this publication
possible.
Conflict of interests. The authors are employees of
Enamine Ltd. that offers the building blocks described in
this paper in the company’s catalog.
Supporting information
The Supporting Information contains copies of NMR
spectra for the synthesized products.
References
1. Grygorenko, O.O.; Volochnyuk, D.M.; Ryabukhin, S.V.; Judd, D.B.
The symbiotic relationship between drug discovery and organic
chemistry. Chem. Eur. J. 2020, 26, 1196-1237.
2. Aldeghi, M.; Malhotra, S.; Selwood, D.L.; Chan, A.W.E. Two‐and
three‐dimensional rings in drugs. Chem. Biol. Drug Des. 2014, 83,
450-461.
3. Taylor, R.D.; MacCoss, M.; Lawson, A.D.G. Rings in drugs:
Miniperspective. J. Med. Chem. 2014, 57, 5845-5859.
4. Shah, P.; Westwell, A.D. The role of fluorine in medicinal chemistry.
J. Enzyme Inhib. Med. Chem. 2007, 22, 527-540.
5. Yerien, D.E.; Bonesi, S.; Postigo, A. Fluorination methods in drug
discovery. Org. Biomol. Chem. 2016, 14, 8398-8427.
6. Han, J.; Remete, A.M.; Dobson, L.S.; Kiss, L.; Izawa, K.; Moriwaki,
H.; Soloshonok, V.A.; O’Hagan, D. Next generation organofluorine
containing blockbuster drugs. J. Fluor. Chem. 2020, 239, 109639.
7. Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J.L.;
Soloshonok, V.A.; Izawa, K.; Liu, H. Next generation of fluorine-
containing pharmaceuticals, compounds currently in phase II-III
clinical trials of major pharmaceutical companies: new structural
trends and therapeutic areas. Chem. Rev. 2016, 116, 422-518.
8. Wang, J.; Sánchez-Roselló, M.; Aceña, J.L.; del Pozo, C.;
Sorochinsky, A.E.; Fustero, S.; Soloshonok, V.A.; Liu, H. Fluorine in
pharmaceutical industry: fluorine-containing drugs introduced to the
market in the last decade (2001-2011). Chem. Rev. 2014, 114, 2432-
2506.
9. Grygorenko, O.O.; Volochnyuk, D.M.; Vashchenko, B.V. Emerging
building blocks for medicinal chemistry: recent synthetic advances.
Eur. J. Org. Chem. 2021, 6478-6510.
10. Grygorenko, O.O.; Melnykov, K.P.; Holovach, S.; Demchuk, O.
Fluorinated cycloalkyl building blocks for drug discovery.
ChemMedChem 2022, 17, e202200365.
11. Vacher, B.; Bonnaud, B.; Funes, P.; Jubault, N.; Koek, W.; Assié, M.
B.; Cosi, C.; Kleven, M. Novel derivatives of 2-pyridinemethylamine
as selective, potent, and orally active agonists at 5-HT1A receptors.
J. Med. Chem. 1999, 42, 1648-1660.
12. WO Patent No 2021/142257 A1. C5AR Antagonists / Rothbaum,
W.P. Patent appl. No PCT/US2021/012696 08.01.2021. Publ.
15.07.2021.
13. Liang, J.; Zbieg, J.R.; Blake, R.A.; Chang, J.H.; Daly, S.;
Dipasquale, A.G.; Friedman, L.S.; Gelzleichter, T.; Gill, M.;
Giltnane, J.M.; Goodacre, S.; Guan, J.; Hartman, S.J.; Ingalla, E.R.;
Kategaya, L.; Kiefer, J.R.; Kleinheinz, T.; Labadie, S.S.; Lai, T.; et
al. GDC-9545 (giredestrant): a potent and orally bioavailable
selective estrogen receptor antagonist and degrader with an
exceptional preclinical profile for ER+ breast cancer. J. Med. Chem.
2021, 64, 11841-11856.
14. Ouvry, G.; Atrux-Tallau, N.; Bihl, F.; Bondu, A.; Bouix-Peter, C.;
Carlavan, I.; Christin, O.; Cuadrado, M.J.; Defoin-Platel, C.; Deret,
S.; Duvert, D.; Feret, C.; Forissier, M.; Fournier, J.F.; Froude, D.;
Hacini-Rachinel, F.; Harris, C.S.; Hervouet, C.; Huguet, H.; et al.
Discovery and characterization of CD12681, a potent RORγ inverse
agonist, preclinical candidate for the topical treatment of psoriasis.
ChemMedChem 2018, 13, 321-337.
15. Reaxys Database [Internet] Available from: www.reaxys.com
(accessed on September 19, 2023).
16. Verniest, G.; Piron, K.; Van Hende, E.; Thuring, J.W.; MacDonald,
G.; Deroose, F.; De Kimpe, N. Org. Synthesis of aminomethylated 4-
fluoropiperidines and 3-fluoropyrrolidines. Biomol. Chem. 2010, 8,
2509-2512.
17. Shipe, W.D.; Barrow, J.C.; Yang, Z.Q.; Lindsley, C.W.; Yang, F.V.;
Schlegel, K.A.S.; Shu, Y.; Rittle, K.E.; Bock, M.G.; Hartman, G.D.;
Tang, C.; Ballard, J.E.; Kuo, Y.; Adarayan, E.D.; Prueksaritanont, T.;
Zrada, M.M.; Uebele, V.N.; Nuss, C.E.; Connolly, T.M.; et al.
Design, synthesis, and evaluation of a novel 4-aminomethyl-4-
fluoropiperidine as a T-type Ca2+ channel antagonist. J. Med. Chem.
2008, 51, 3692-3695.
18. Yarmolchuk, V.S.; Mykhalchuk, V.L.; Mykhailiuk, P.K. Convenient
synthesis of enantiopure (R-) and (S-)-3-fluoro-3-aminomethyl-
pyrrolidines. Tetrahedron 2014, 70, 3011-3017.
19. Gurbanov, R.; Sokolov, A.; Golovach, S.; Melnykov, K.; Dobrydnev,
A.V.; Grygorenko, O.O. Synthesis of sp3-Enriched β-Fluoro
Sulfonyl Chlorides. Synthesis 2020, 53, 1771-1784.
20. Green, S.A.; Vásquez-Céspedes, S.; Shenvi, R.A. Iron–nickel dual-
catalysis: a new engine for olefin functionalization and the formation
of quaternary centers. J. Am. Chem. Soc. 2018, 140, 11317-11324.
21. Law, J.A.; Bartfield, N.M.; Frederich, J.H. Site‐Specific Alkene
Hydromethylation via Protonolysis of Titanacyclobutanes. Angew.
Chem. Int. Ed. 2021, 60, 14360-14364.
22. Margot, C.; Rizzolio, M.; Schlosser, M. 1,2-Elimination of alcohol
from homoallyl ethers under the influence of mixed metal bases.
Tetrahedron 1990, 46, 2411-2424.
23. Kirmse, W.; Rode, K. Desaminierungsreaktionen, 47 Zerfall von 1‐
(3‐Hydroxypropyl) cyclopropandiazonium‐Ionen. Chem. Ber. 1987,
120, 847-848 (in German).
24. Senda, Y.; Ohno, A.; Ishiyama, J.; Imaizumi, S.; Kamiyama, S.
Carbon-13 NMR and IR spectroscopic studies on some 7-oxabicyclo
[2.2.1] heptanes and-heptenes. n-.PI. Interaction and hydrogen
bonding. Bull. Chem. Soc. Jpn. 1987, 60, 613-616.
25. Applequist, D.E.; Roberts, J.D. Small-Ring Compounds. XV.
Methylenecyclobutene and Related Substances1. J. Am. Chem. Soc.
1956, 78, 4012-4022.
http://www.reaxys.com/
V.V. Semeno, K.P. Melnykov
21
Багатограмовий синтез -флуорованих насичених гетероциклічних метанамінів
В.В. Семено1,2, К.П. Мельников1,2*
1 ТОВ НВП «Єнамін», Київ, Україна
2 Київський національний університет імені Тараса Шевченка, Київ, Україна
Резюме: У роботі описано ефективний багатограмовий синтез -флуорованих насичених гетероциклічних метанамінів - перспективних
будівельних блоків для створення лікарських засобів, виходячи з відповідних насичених гетероциклічних кетонів. Метод передбачає
використання олефінування за Віттігом, нуклеофільного заміщення азид-іоном та реакції Штаудінгера і добре працює для нітрогено- та
оксигеновмісних гетероциклічних сполук із розміром циклу від чотирьох до семи.
Ключові слова: флуороорганічні сполуки; гетероцикли; аміни; будівельні блоки; розробка ліків.
|
| id | oai:ojs2.bioorganica.com.ua:article-73 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:16Z |
| publishDate | 2023 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/bc/32de93a6ca290993ac2bdaf941e581bc.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-732026-07-19T14:56:54Z Multigram synthesis of β-fluorinated saturated heterocyclic methanamines Багатограмовий синтез β-флуорованих насичених гетероциклічних метанамінів Semeno, Volodymyr V. Melnykov, Kostiantyn P. organofluorine compounds heterocycles amines building blocks drug discovery флуороорганічні сполуки гетероцикли аміни будівельні блоки розробка ліків An efficient multigram synthesis of β-fluorinated saturated heterocyclic methanamines - promising building blocks for drug discovery, starting from the corresponding saturated heterocyclic ketones is described. The method includes Wittig olefination, bromofluorination, nucleophilic substitution with azide, and Staudinger reaction and works well for four- to seven-membered nitrogen- and oxygen-containing heterocyclic derivatives У роботі описано ефективний багатограмовий синтез b-флуорованих насичених гетероциклічних метанамінів - перспективних будівельних блоків для створення лікарських засобів, виходячи з відповідних насичених гетероциклічних кетонів. Метод передбачає використання олефінування за Віттігом, нуклеофільного заміщення азид-іоном та реакції Штаудінгера і добре працює для нітрогено- та оксигеновмісних гетероциклічних сполук із розміром циклу від чотирьох до семи. V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2023-12-30 Article Article application/pdf application/pdf https://bioorganica.com.ua/index.php/journal/article/view/73 10.15407/bioorganica2023.02.016 Ukrainica Bioorganica Acta; Vol. 18 No. 2 (2023): Ukrainica Bioorganica Acta; 16-21 Ukrainica Bioorganica Acta; Том 18 № 2 (2023): Ukrainica Bioorganica Acta; 16-21 1814-9766 1814-9758 10.15407/bioorganica2023.02 en https://bioorganica.com.ua/index.php/journal/article/view/73/72 https://bioorganica.com.ua/index.php/journal/article/view/73/73 Copyright (c) 2023 Volodymyr V. Semeno, Kostiantyn P. Melnykov https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | флуороорганічні сполуки гетероцикли аміни будівельні блоки розробка ліків Semeno, Volodymyr V. Melnykov, Kostiantyn P. Багатограмовий синтез β-флуорованих насичених гетероциклічних метанамінів |
| title | Багатограмовий синтез β-флуорованих насичених гетероциклічних метанамінів |
| title_alt | Multigram synthesis of β-fluorinated saturated heterocyclic methanamines |
| title_full | Багатограмовий синтез β-флуорованих насичених гетероциклічних метанамінів |
| title_fullStr | Багатограмовий синтез β-флуорованих насичених гетероциклічних метанамінів |
| title_full_unstemmed | Багатограмовий синтез β-флуорованих насичених гетероциклічних метанамінів |
| title_short | Багатограмовий синтез β-флуорованих насичених гетероциклічних метанамінів |
| title_sort | багатограмовий синтез β-флуорованих насичених гетероциклічних метанамінів |
| topic | флуороорганічні сполуки гетероцикли аміни будівельні блоки розробка ліків |
| topic_facet | organofluorine compounds heterocycles amines building blocks drug discovery флуороорганічні сполуки гетероцикли аміни будівельні блоки розробка ліків |
| url | https://bioorganica.com.ua/index.php/journal/article/view/73 |
| work_keys_str_mv | AT semenovolodymyrv multigramsynthesisofbfluorinatedsaturatedheterocyclicmethanamines AT melnykovkostiantynp multigramsynthesisofbfluorinatedsaturatedheterocyclicmethanamines AT semenovolodymyrv bagatogramovijsintezbfluorovanihnasičenihgeterociklíčnihmetanamínív AT melnykovkostiantynp bagatogramovijsintezbfluorovanihnasičenihgeterociklíčnihmetanamínív |