Synthesis of β-fluoro(dicarbonyl)ethylamines from 2-fluoro-ethylacetoacetate and dimethyl-2-fluoromalonate ester by batch and semi-continuous flow three-component Mannich reactions

Article abstract of DOI:10.1016/j.jfluchem.2017.12.012

Multi-component Mannich reactions between 2-fluoro-ethylacetoacetate or dimethyl-2-fluoromalonate ester, aldehyde and amine components allowing convenient synthesis of β-fluoro(dicarbonyl)ethylamine systems using both batch and continuous flow techniques are reported.

Full text of DOI:10.1016/j.jfluchem.2017.12.012

Accepted Manuscript
Title: Synthesis of ␤-fluoro(dicarbonyl)ethylamines from
2-fluoro-ethylacetoacetate and dimethyl-2-fluoromalonate
ester by batch and semi-continuous flow three-component
Mannich reactions
Authors: Etienne Lisse, Graham Sandford
PII:
S0022-1139(17)30534-1
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2017.12.012
FLUOR 9092
To appear in:
FLUOR
Received date:
Accepted date:
6-12-2017
19-12-2017
Please cite this article as: Etienne Lisse, Graham Sandford, Synthesis
of
and
flow
␤-fluoro(dicarbonyl)ethylamines
dimethyl-2-fluoromalonate ester
three-component Mannich
from
by batch
reactions,
2-fluoro-ethylacetoacetate
and
semi-continuous
of Fluorine
Journal
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Synthesis of β-fluoro(dicarbonyl)ethylamines from 2-fluoro-ethylacetoacetate
and dimethyl-2-fluoromalonate ester by batch and semi-continuous flow three-
component Mannich reactions
Etienne Lisse and Graham Sandford*
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK
graham.sandford@durham.ac.uk
Graphical abstracts
Highlights
 Mannich reactions of fluoroketoester and fluoromalonates successful
 Polyfunctional β-fluoro(dicarbonyl)ethylamines synthesised
 Semi continuous flow gas/liquid liquid/liquid flow process
Abstract
Multi-component Mannich reactions between 2-fluoro-ethylacetoacetate or dimethyl-
2-fluoromalonate ester, aldehyde and amine components allowing convenient
synthesis of β-fluoro(dicarbonyl)ethylamine systems using both batch and continuous
flow techniques are reported.
1

1.
Introduction
The incorporation of fluorine atoms into pharmaceutical candidates is a well-
established approach to, for example, affect lipophilicity, pKa and metabolic stability
of new chemical entities as part of drug discovery programs [1]. While many
pharmaceuticals bearing fluorine atoms attached to aromatic rings are currently
commercially available, lead compounds with fluorine atom attached to sp3 carbon
are increasingly appearing in pharmaceutical company pipelines [2] and,
consequently, effective and inexpensive methodology for the synthesis of selectively
fluorinated multifunctional building blocks for incorporation into drug synthesis
campaigns are very desirable. However, the building block approach relies on the
ready availability of a wide range of inexpensive fluorinated substrates of differing
functionality and the establishment of appropriate reactivity profiles [3].
Recently, we reported the optimized synthesis of 2-fluoromalonate esters by a direct
fluorination strategy [4] which is very efficient, inexpensive, does not generate
significant waste and is readily scalable. Analogous selective direct fluorination
routes using fluorine gas to corresponding 2-fluoro-ketoesters [5] have also been
developed and scaled up by industry [6]. Surprisingly, however, reactions of 2-fluoro
malonate ester and 2-fluoro-ketoester derivatives are not particularly well developed
despite the anticipated synthetic potential of these polyfuctional substrates and we
recently reviewed the chemistry of fluoromalonate substrates to indicate some of the
synthetic utility of these systems [7]. For example, in the context of developing the
use of dimethyl 2-fluoro-malonate ester for the synthesis of more structurally complex
fluorinated intermediates, we established routes to various fluoroheterocyclic systems
[8].
In this paper, we describe the use of 2-fluoro-ethylacetoacetate 1 and dimethyl 2-
fluoromalonate ester 2 in multi-component (MCR) Mannich reactions. The first
[4]
reported MCR was the Strecker synthesis of the α-amino nitrile in 1850 [9]
and
since then, MCR chemistry has been extensively developed. Well-known examples
of MCRs are associated mainly with reactions of carbonyl compounds, used as
substrates in the Biginelli reaction, the Hantzsch dihydropyridine synthesis and,
particularly, Mannich-type reactions [10] giving rapid access to large libraries of
molecules possessing a high degree of functionality and structural diversity.
2

However, while carbonyl compounds have played a crucial role in the development of
multi-component reactions, use of corresponding fluorinated carbonyl compounds
have been much less investigated as MCR substrates. Applications of Mannich-type
reactions utilizing fluorinated carbonyl substrates have been reported previously [11]
such as, for example, the synthesis of β-fluoronitro(phenylsulfonyl)ethylamines from
fluoro-ketosulfone substrates described by Prakash and Olah [12]. Of particular
relevance to the research reported here, Zhang and coworkers developed a Mannich
reaction involving various fluoro-ketoesters catalyzed by zinc nitrate and irradiated by
microwave at high temperature [13].
Here we use 2-fluoroethylacetoacetate 1 and dimethyl 2-fluoromalonate ester 2 as
MCR components in Mannich reactions involving formaldehyde or benzaldehyde
and different types of amines as educts to give polyfunctional fluorinated products
bearing amine and carbonyl functionalities by both batch and continuous flow
protocols in simple, scalable reaction processes.
2.
Results and discussion
In initial studies we investigated reactions of 2-fluoro-ethylacetoacetate 1 with an
amine 3 and formaldehyde in multi component Mannich-type processes (Table 1).
Reactions were carried out by first mixing both amine 3 and formalin together before
addition of the fluorinated dicarbonyl substrate 1 in order to limit the formation of any
alcohol by-product by Aldol condensation. Our optimized conditions were found to be
1.7 equivalents of amine 3 and 1.5 equivalents of formaldehyde, stirred together for
two hours at room temperature, preceding the addition of the 2-fluoro-
ethylacetoacetate 1 and further reaction at room temperature. Reactions involving
less reactive amines such as benzylamine were carried out at 90°C, providing the
corresponding Mannich products 4 in full conversion. Analogous reactions between
2-ethyl 2-fluoro-acetoacetate 1 with an amine 3 and benzaldehyde were also
performed in high yields (Table 2).
3

During the course of this work, related Mannich reactions of fluorinated 1,3-
o
dicarbonyl compounds catalyzed by Zn(NO3)2 using microwave irradiation at 120 C
were reported [13]. However, the method we have described above does not require
such vigorous heating and allows access to various products from, for example 5b
and 5c, which reportedly cannot be obtained by the zinc nitrate catalyzed method
[13]. Furthermore, Mannich reactions of fluoromalonate ester 2 were not described
using the zinc catalyzed method.
Many organic reactions have been adapted to laboratory scale continuous flow
processes and the advantages of flow techniques such as mass transfer, reaction
control and continuous operation are now well established [14]. Mannich reactions
have been performed in continuous flow micro-fluidic devices [15] and asymmetric
anti-Mannich reactions in continuous flow packed bed reactor [16] using various
polystyrene-supported chiral amine-based catalyst have also been reported. We
have previously reported continuous flow fluorination reactions using fluorine gas in
gas-liquid processes including fluorination of ketoester and diester substrates [17].
Following optimization of continuous flow reactions of ethyl fluoro-ethylacetoacetate 1
with amine/formaldehyde mixtures in a one-step liquid-liquid flow process, we
adapted our synthetic procedure described above to a two-step gas-liquid, liquid-
liquid semi-continuous flow process using stainless steel coiled tube reactors (Fig. 1)
that we have described previously [18]. A schematic diagram of the process is shown
in Figure 1. Fluorine gas in nitrogen (10% v/v) was introduced into input 1 of the first
coiled steel tube reactor and passed along the tube concurrently with ethyl
acetoacetate in acetonitrile which was simultaneously added to the reactor system
via inlet 2. The flow of the gaseous reactant stream was controlled by gas mass
flowmeter and the liquid dicarbonyl reagent solution was introduced by hplc pump so
that the fluorine gas : dicarbonyl addition ratio was ca.1.3 : 1. The flow rate of each
reagent was adjusted to ensure a retention time of 2 to 5 min of the dicarbonyl
substrate within the tubular reactor. The crude product mixture for the fluorination
reaction was collected in a gas liquid separator flask where liquid was collected and
gaseous waste passed through a scrubbing tower filled with soda-lime. The crude
4

fluoro-dicarbonyl product mixture was then pumped without any work-up procedure
directly into input 3 of the second continuous flow coiled steel tube reactor while,
simultaneously, a solution containing the amine and aldehyde solution was added at
a controlled flow rate via Input 4. The crude product mixture for the two-step one
continuous flow process was collected and, following work-up, the Mannich products
were isolated in good yield and purity confirming the efficiency of this semi
continuous flow process strategy (Table 4).
Combined gas-liquid liquid-liquid sequential flow reaction using fluorine gas have not
been well developed and only examples demonstrating the synthesis of
fluoropyrazole derivatives have been recorded [19]. The reasonable yields of
Mannich products 4 obtained from fluorine, ketoester and aminal inputs in the two-
step one semi-continuous flow process demonstrates the possible opportunities for
process intensification of multi-step synthetic strategies using fluorine gas.
In summary, a direct Mannich-type three component MCR reaction has been
developed for the ready synthesis of β-fluoro(dicarbonyl)ethylamine derivatives
starting from fluorinated dicarbonyl substrates further demonstrating that such
systems are particularly useful as starting substrates for further transformations or
functionalization, opening up opportunities for the synthesis of more complex
fluorinated systems for life science projects from simple, readily accessible
fluorinated systems.
3.
Experimental
General
3.1
All the chemicals and solvents used were commercially purchased from Alfa Aesar,
Apollo Scientific, Fluorochem or Sigma Aldrich and, unless otherwise stated, were
5

used without any further purification. 1,3-Dimethyl-2-fluoromalonate was synthesized
as described previously [4c].
19
13
Proton, fluorine and carbon nuclear magnetic resonance spectra (1H, F, C NMR)
were obtained using a Bruker 400 Ultrashield spectrometer (1H NMR at 400 MHz, 19F
NMR at 376 MHz and 13C NMR at 101 MHz) using residual solvent peaks as the
internal standard (1H NMR; CDCl3 at 7.26 ppm, 19F NMR; CFCl3 at 0.00 ppm and 13C
NMR; CDCl3 at 77.16 ppm). NMR spectroscopic data are reported as follows:
chemical shift (ppm), integration, multiplicity (s = singlet, d = doublet, t = triplet, q =
quarter, m = multiplet), coupling constant (Hz) and assignment. GC-MS data were
obtained using a Trace GC-MS device (Thermo-Finnigan Corporation) operating in
electron impact ionization (EI) mode. Accurate mass analysis was performed on a
Xevo QtoF mass spectrometer (Waters Ltd, UK) with an accurate solids analysis
probe (ASAP) or a TQD UPLC (Waters) instrument operating in electrospray
ionization mode.
Mannich-type reaction by conventional batch process.
General procedure: In a 50 mL two-necked flask containing dichloromethane (10
mL) were added the amine (17 mmol) followed by the aldehyde (15 mmol) and the
resulting reaction mixture was allowed to stir at rt for 2 h., before the fluorinated
dicarbonyl system (10 mmol) was added. The reaction mixture was stirred at rt for 16
h, evaporated and the residue dissolved in dichloromethane (20 mL), washed with
distilled water (2 x 20 mL), dried over magnesium sulfate and evaporated, to give the
desired product. Further purification by distillation or column chromatography eluting
from hexane/ethyl acetate was carried out when appropriate.
Analytical and spectroscopic data for each individual compound are listed below. For
NMR data only resonances of one diastereoisomer or conformer is given for clarity.
Mannich reactions of 2-Fluoro ethylacetoacetate and formaldehyde
Ethyl-2-((benzylamino)methyl)-2-fluoro-3-oxobutanoate 4a
6

1H NMR (400 MHz, CDCl3) δH 1.31 (t, J = 7.1 Hz, 3H, -OCH2CH3), 2.39
(d, J = 4.8 Hz, 3H, -C(O)CH3), 3.80 – 4.08 (m, 2H, -CF-CH2), 4.28 (q, J
= 7.1 Hz, 2H, -OCH2CH3), 6.63 – 6.95 (m, 3H, ArH), 7.12 – 7.24 (m,
19
3
2H, ArH). F NMR (376 MHz, CDCl3) δF -169.37 (tq, JHF = 22.4 Hz,
4JHF = 4.8 Hz). 13C NMR (101 MHz, CDCl3) δC 13.97 (-OCH2CH3), 26.27 (-C(O)CH3),
47.53 (d, 2JCF = 20.5 Hz, -CF-CH2), 62.96 (-OCH2CH3), 100.23 (d, 1JCF = 198.8 Hz, -
2
CF), 113.62 (Ar), 118.80 (Ar), 129.27 (Ar), 147.17 (Ar), 165.01 (d, JCF = 25.4 Hz, -
2
C(O)O), 201.35 (d, JCF = 28.6 Hz, -C(O)CH3). MS (ESI) m/z 115.02 (100%), 123.98
(68.4%), 224.12 (62.7%), 254.15 ([M+H]+, 72.2%). HRMS (ESI) m/z calcd for [M+H]+
C13H17FNO3 254.1200, found 254.1192.
Ethyl-2-((diethylamino)methyl)-2-fluoro-3-oxobutanoate 4b
1H NMR (400 MHz, CDCl3) δH 0.87 (t, J = 7.1 Hz, 6H, –NCH2CH3),
4
1.22 (t, J = 7.1 Hz, 3H, -OCH2CH3), 2.23 (d, JHF = 5.0 Hz, 3H, -
C(O)CH3), 2.51 (q, J = 7.1, 4H, –NCH2CH3), 3.05 (t, 3JHF = 26.1, 2H, -
CF-CH2), 4.18 (q, J = 7.1 Hz, 2H, -OCH2CH3). 19F NMR (376 MHz,
3
4
13
CDCl3) δF -166.64 (tq, JHF = 26.1 Hz, JHF 5.0 Hz). C NMR (101 MHz, CDCl3) δC
11.45 (NCH2CH3), 13.86 (-OCH2CH3), 26.41 (-C(O)CH3), 47.89 (m, –NCH2CH3),
56.42 (d, 2JCF = 18.4 Hz, -CF-CH2), 62.18 (-OCH2CH3), 102.21 (d, 1JCF = 199.1 Hz, -
2
2
CF), 165.39 (d, JCF = 26.0 Hz, -C(O)O), 201.94 (d, JCF = 29.6 Hz, -C(O)CH3). MS
(ESI) m/z 234.07 ([M+H]+, 100%), 86.04 ([M-C6H8FO3]+, 95.3%), 266.10 (81.7%).
HRMS (ESI) m/z calcd for [M+H]+ C11H21FNO3 234.1505; found 234.1504.
Ethyl-2-((diisopropylamino)methyl)-2-fluoro-3-oxobutanoate 4c
1H NMR (400 MHz, CDCl3) δH 0.97 (d, J = 6.7 Hz, 12H, -CH(CH3)2),
4
1.32 (t, J = 7.1 Hz, 3H, -OCH2CH3), 2.32 (d, JHF = 5.1 Hz, 3H, -
C(O)CH3), 3.08 (m, 2H, -CF-CH2), 3.24 (m, 2H, -CH(CH3)2), 4.13 – 4.39
(m, 2H, -OCH2CH3).19F NMR (376 MHz, CDCl3) δF -163.81 (ddq, 3JHF
=
3
4
22.3 Hz, JHF = 20.8 Hz, JHF - 4.7 Hz). 13C NMR (101 MHz, CDCl3) δC 13.98 (-
OCH2CH3), 20.66 (s, -CH(CH3)2), 26.87 (-C(O)CH3), 48.66 (s, -NCH), 49.45 (d, 2JCF
=
2
18.7 Hz, -CF-CH2), 62.29 (-OCH2CH3), 102.78 (d, JCF = 198.7 Hz, -CF), 165.72 (d,
2JCF = 26.0 Hz, -C(O)O), 202.63 (d, 2JCF = 30.3 Hz, -C(O)CH3). MS (ESI) m/z 102.10
• +
• +
([M-C7H10FO3 ] , 100%), 114.10 ([M-C6H8FO3 ] , 77.9%), 262.13 ([M+H]+, 74.3%),
7

294.2 (55.8%). HRMS (ESI) m/z calcd for [M+H]+ C13H25FNO3 262.1818; found
262.1803.
Ethyl-2-(pyrrolidin-1-methyl)-2-fluoro-3-oxobutanoate 4d
1H NMR (400 MHz, CDCl3) δH 1.25 (t, J = 7.1 Hz, 3H, -OCH2CH3), 1.66
– 1.86 (m, 4H, -CH2), 2.27 (s, 3H, -C(O)CH3), 2.49-2.65 (m, 4H, -
19
NCH2), 3.06-3.31 (m, 2H, -CFCH2), 4.10-4.36 (m, 2H, -OCH2CH3). F
3
3
4
NMR (376 MHz, CDCl3) δF -166.84 (ddq, JHF = 29.7 Hz, JHF = 25.1 Hz, JHF = 4.8
Hz). 13C NMR (101 MHz, CDCl3) δC 13.93 (-OCH2CH3), 23.83 (CH2), 26.23 (-
2
C(O)CH3), 55.28 (-NCH2), 58.41 (d, JCF = 19.4 Hz, -CF-CH2), 62.34 (-OCH2CH3),
101.62 (d, 1JCF = 199.2 Hz, CF), 165.35 (d, 2JCF = 25.8 Hz, -C(O)O), 201.39 (d, 2JCF
=
28.6 Hz, -C(O)CH3). MS (ESI) m/z 232.10 ([M+H]+, 100%), 264.18 (56.4%), 84.01
• +
([M-C5H6FO4 ] , 49.3%). HRMS (ESI) m/z calcd for [M+H]+ C11H19FNO3 232.1349;
found 231.1350.
Ethyl-2-(piperidin-1-methyl)-2-fluoro-3-oxobutanoate 4e
1H NMR (400 MHz, CDCl3) δH 1.29 (t, J = 7.1 Hz, 3H, -OCH2CH3), 1.35
– 1.46 (m, 2H, -CH2), 1.48 – 1.60 (m, 4H, CH2), 2.30 (d, 4JHF = 4.9 Hz,
3
3H, -C(O)CH3), 2.49 – 2.57 (m, 4H, -NCH2), 3.02 (d, JHF = 26.8 Hz, -
CF-CH2), 4.09 – 4.43 (m, 2H, -OCH2CH3). 19F NMR (376 MHz, CDCl3)
3
4
13
δF -165.59 (tq, JHF = 26.6, JHF = 4.9 Hz). C NMR (101 MHz, CDCl3) δC 14.01 (-
OCH2CH3), 23.84 (CH2), 26.18 (CH2), 26.40 (-C(O)CH3), 55.82 (s, NCH2), 61.10 (d,
1
2JCF = 18.5 Hz, -CF-CH2), 62.30 (-OCH2CH3), 102.16 (d, JCF = 199.9 Hz, -CF),
2
2
165.40 (d, JCF = 25.8 Hz, -C(O)O), 201.75 (d, JCF = 29.3 Hz, -C(O)CH3). MS (ESI)
m/z 246.31 ([M+H]+, 100%). HRMS (ESI) m/z calcd for [M+H]+ C12H21FNO3 246.1505;
found 246.1508.
Ethyl-2-((benzylmethylamino)methyl)-2-fluoro-3-oxobutanoate 4f
1H NMR (400 MHz, CDCl3) δH 1.30 (t, J = 7.1 Hz, 3H, -OCH2CH3), 2.26
4
3
(m, 3H, -NCH3), 2.34 (d, JHF = 4.7 Hz, 3H, -C(O)CH3), 3.24 (t, JHF
=
26.0, 2H, -CFCH2), 3.63 (s, 2H, -NCH2), 4.28 (q, J = 7.2 Hz, 2H, -
19
OCH2CH3), 7.09 – 7.41 (m, 5H, ArH). F NMR (376 MHz, CDCl3) δF -
3
4
13
166.35 (tq, JHF = 25.8, JHF = 4.8 Hz). C NMR (101 MHz, CDCl3) δC
14.02 (-OCH2CH3), 26.27 (-C(O)CH3), 43.40 (d, 4JCF = 3.2 Hz, -NCH3), 59.84 (d, 2JCF
8

= 18.4 Hz, -CF-CH2), 62.50 (-OCH2CH3), 63.51 (d, 4JCF = 2.5 Hz, -NCH2), 102.16 (d,
1JCF = 199.5 Hz, CF), 127.12 (Ar), 128.22 (Ar), 128.90 (Ar), 138.59 (Ar), 165.36 (d,
2JCF = 26.0 Hz, -C(O)O), 201.13 (d, 2JCF = 28.8 Hz, -C(O)CH3). MS (ESI) m/z 122.23
([C8H10N•]+, 100%), 282.23 ([M+H]+, 90.5%), 300.36 (72.4%). HRMS (ESI) m/z calcd
for [M+H]+ C15H20FNO3 282.1505 ; found 282.1516.
Ethyl-2-((dicyclohexylamino)methyl)-2-fluoro-3-oxobutanoate 4g
1H NMR (400 MHz, CDCl3) δH 0.85 – 1.86 (m) (23H, CH2 and CH3),
4
2.19 (d, JHF = 5.2 Hz, 3H, -C(O)CH3), 2.36 – 2.56 (m, 2H, NCH),
19
3.14 - 3.35 (m, 2H, -CF-CH2), 3.90 – 4.26 (m, 2H, -OCH2CH3). F
NMR (376 MHz, CDCl3) δF -171.87 (ddq, 3JHF = 26.6 Hz, 3JHF = 21.8
Hz, 4JHF 4.8 Hz). 13C NMR (101 MHz, CDCl3) δC 13.83 (-OCH2CH3),
2
25.16, 25.92, 26.00 (CH2), 26.75 (-C(O)CH3), 50.28 (d, JCF = 18.5 Hz, -CFCH2),
52.92 (N-CH), 62.07 (-OCH2CH3), 102.82 (d, 1JCF = 198.9 Hz, -CF), 165.55 (d, 2JCF
=
2
26.0 Hz, -C(O)O), 202.48 (d, JCF = 30.3 Hz, -C(O)CH3). MS (ESI) m/z 182.2
• +
([C12H22N•+H]+, 100%), 191.3 ([M-C6H8FO3 ] , 28.9%), 312.4 (38.5%), 342.4 ([M+H]+,
31.5%), HRMS (ESI) m/z calcd for [M+H]+ C19H33FNO3 342.2444, found 342.2445.
Mannich reactions of fluorinated dicarbonyl systems and benzaldehyde
Ethyl-2-(phenyl(benzylmethylamino)methyl)-2-fluoro-3-oxobutanoate 5a
1H NMR (400 MHz, CDCl3) δH 0.96 (t, J = 7.1 Hz, 3H, -OCH2CH3),
4
2.13 (d, JHF = 5.6 Hz, 3H, -C(O)CH3), 2.16 (s, 3H, -NCH3), 3.46 -
3.67 (m, 2H, -N-CH2), 3.96 – 4.13 (m, 2H, -OCH2CH3), 4.88 (d,
3JHF = 35.0 Hz, 1H, -CF-CH), 7.08 – 7.97 (m, 10H, ArH).19F NMR
3
4
13
(376 MHz, CDCl3) δF -176.64 (dq, JHF = 34.6, JHF = 5.5 Hz). C NMR (101 MHz,
CDCl3) δC 13.59 (OCH2CH3), 26.99 (-C(O)CH3), 38.92 (-NCH3), 61.00 (-N-CH2),
2
1
62.39 (-OCH2CH3), 70.79 (d, JCF = 15.8 Hz, -CF-CH), 105.73 (d, JCF = 209.4 Hz, -
CF), 126.98, 128.15, 128.25, 128.74, 129.00, 130.25, 134.44, 138.99 (Ar), 164.57 (d,
2
2JCF = 25.5 Hz, -C(O)O), 201.85 (d, JCF = 30.6 Hz, -C(O)CH3). MS (ESI) m/z 122.2
•
([C8H10N•], 100%), 282.3 ([M-C6H5 +H]+, 26.6%), 358.2 ([M+H]+, 6.0%) HRMS (ESI)
m/z calcd for [M+H]+ C21H24FNO3 358.1818; found 358.1825.
9

Ethyl-2-(phenyl(phenylamino)methyl)-2-fluoro-3-oxobutanoate 5b
1H NMR (400MHz, CDCl3) δH 1.12 (t, J = 7.1 Hz, 3H, -OCH2CH3), 1.96
(d, 4JHF = 5.8 Hz, 3H, -OCH3), 4.13 (q, J = 7.1 Hz, 2H, -OCH2CH3), 5.47
(d, 4JHF = 27.9, 1H, -CF-CH), 6.63 – 6.87 (m, 2H, ArH), 7.23 – 7.48 (m,
19
3H, ArH), 7.23 – 7.48 (m, 5H, ArH), 8.50 (s, 1H, NH). F NMR (376
MHz, CDCl3) δF -179.28 (dq, 3JHF = 28.1, 4JHF = 5.9 Hz). 13C NMR (101
MHz, CDCl3) δC 13.99 (-OCH2CH3), 26.65 (-C(O)CH3), 60.51 (d, 2JCF = 18.3 Hz, -CF-
1
CH), 63.10 (-OCH2CH3), 103.03 (d, JCF = 204.7 Hz, -CF), 114.47, 118.52, 119.29,
125.95, 128.48 – 128.66 (m), 131.39, 135.47, 145.46 (Ar), 164.61 (d, 2JCF = 24.3 Hz,-
• +
C(O)O), 201.05 (d, 2JCF = 28.3 Hz, -C(O)CH3). MS (ESI) m/z 182.08 ([M- C6H8FO3 ] ,
100%), 330.17 ([M+H]+, 34.0%). HRMS (ESI) m/z calcd for [M+H]+ C19H21FNO3
330.1505; found 330.1510.
Ethyl-2-(phenyl(4-methoxyphenylamino)methyl)-2-fluoro-3-oxobutanoate 5c
1H NMR (400 MHz, CDCl3) δH 1.27 (t, J = 7.2 Hz, 3H, -OCH2CH3), 1.94
4
(d, JHF = 5.7 Hz, 3H, -C(O)CH3), 3.70 (s, 3H, -OCH3), 4.24-4.39 (m,
3
2H, -OCH2CH3), 5.34 (d, JHF = 28.2 Hz, 1H, -CF-CH), 6.60-6.73 (m,
2H, ArH), 6.68-6.73 (m, 2H, ArH), 7.13-7.46 (m, 5H, ArH). 19F NMR
3
4
13
(376 MHz, CDCl3) δF -179.57 (dq, JHF = 28.2 Hz, JHF = 5.8 Hz). C
NMR (101 MHz, CDCl3) δC 14.01 (-OCH2CH3), 26.63 (-C(O)CH3), 55.55 (-OCH3),
2
1
61.74 (d, JCF = 18.2 Hz, -CF-CH), 63.01 (-OCH2CH3), 103.21 (d, JCF = 204.6 Hz, -
CF), 114.67 (Ar), 128.43 – 128.59 (m, Ar), 135.56 (Ar), 139.37 (Ar), 153.04 (C-OMe),
2
2
164.57 (d, JCF = 26.7 Hz, -C(O)O), 200.99 (d, JCF = 29.5 Hz, -C(O)CH3). MS
• +
(ASAP) m/z 212.11 ([M-C6H8FO3 ] , 100%), 360.17 ([M+H]+, 1.9%). HRMS (ASAP)
m/z calcd for [M]+ C20H22FNO4 359.1533; found 359.1538.
Mannich reactions of 2-Fluoro-1,3-dimethymalonate and formaldehyde
Dimethyl-2-((diethylamino)methyl)-2-fluoromalonate 6a
1H NMR (400 MHz, CDCl3) δH 0.91 (t, J = 7.1 Hz, 6H,–CH2CH3), 2.57
3
(q, J = 7.1 Hz, 4H, CH2CH3), 3.17 (t, JHF = 26.2 Hz, 2H, -CF-CH2),
19
3
3.78 (s, 6H, -OCH3). F NMR (376 MHz, CDCl3) δF -166.73 (t, JHF
=
10

26.1 Hz). 13C NMR (101 MHz, CDCl3) δC 11.62 (-NCH2CH3), 47.97 (-NCH2CH3),
2
1
52.99 (-OCH3), 56.38 (d, JCF = 18.7 Hz, -CF-CH2), 97.27 (d, JCF = 200.0 Hz, -CF),
165.82 (d, 2JCF = 26.3 Hz, -C(O)OCH3). MS (ESI) m/z 236.14 ([M+H]+, 100%), 178.08
•
• +
([M-C2H3O2 +2H]+, 64.1%), 122.04 (43.1%), 86.02 ([M-C5H6FO4 ] , 36.9%). HRMS
(ESI) m/z calcd for [M+H]+ C10H19FNO4 236.1298; found 236.1299.
Dimethyl-2-((diisopropylamino)methyl)-2-fluoromalonate 6b
1H NMR (400 MHz, CDCl3) δH 0.95 (d, J = 6.7 Hz, 6H, -CH(CH3)2),
2.97 – 3.13 (m, 1H, -CF-CH2), 3.29 (m, 1H, -N-CH), 3.80 (s, 3H, -
OCH3).19F NMR (376 MHz, CDCl3) δF -163.14 (t, J = 26.7 Hz). 13C
NMR (101 MHz, CDCl3) δC 20.62 (-CH(CH3)2), 48.42 (-N-CH), 49.51
2
1
(d, JCF = 19.1 Hz, -CF-CH2), 52.96 (-C(O)OCH3), 97.98 (d, JCF = 199.3 Hz, -CF),
• +
166.05 (d, 2JCF = 26.4 Hz, -C(O)OCH3). MS (ESI) m/z 102.26 ([M-C6H8FO4 ] , 100%),
• +
114.10 ([M-C5H6FO4 ] , 49.6%), 264.29 ([M+H]+, 68.5%). HRMS (ESI) m/z calcd for
[M+H]+ C12H23FNO4 264.1620; found 264.1611.
Dimethyl-2-(pyrrolidin-1-methyl)-2-fluoromalonate 6c
1H NMR (400 MHz, CDCl3) δH 1.63 – 1.74 (m, 4H, CH2), 2.54 – 2.66
3
(m, 4H, -NCH2), 3.24 (d, JHF = 26.6 Hz, 2H, -CF-CH2), 3.81 (s, 6H,–
19
C(O)OCH3). F NMR (376 MHz, CDCl3) δF -166.92 (t, J = 26.7 Hz).
13C NMR (101 MHz, CDCl3) δC 23.89 (-NCH2CH2), 53.
18 (-C(O)OCH3), 55.26 (-NCH2), 58.67 (d, 2JCF = 19.5 Hz, -CF-CH2), 96.43 (d, 1JCF
=
2
200.4 Hz, -CF), 165.81 (d, JCF = 25.9 Hz, -C(O)OCH3). MS (ESI) m/z 152.23 ([M-
• +
C5H6FO4 ] , 50.4%), 234.21 ([M+H]+, 100%). HRMS (ESI) m/z calcd for [M+H]+
C10H17FNO4 234.1142; found 234.1145.
Dimethyl-2-(piperidin-1-methyl)-2-fluoromalonate 6d
1H NMR (400 MHz, CDCl3) δH 1.24-1.38 (m, 2H, CH2), 1.44 (m, 4H,
3
CH2), 2.35 - 2.44 (m, 4H, NCH2), 3.00 (d, JHF = 26.6 Hz, 2H, -CF-
CH2), 3.74 (s, 6H, -OCH3).19F NMR (376 MHz, CDCl3) δF -165.65 (t,
3JHF = 26.6 Hz). 13C NMR (101 MHz, CDCl3) δ 23.79 (CH2), 26.17
(CH2), 52.88 (-C(O)OCH3), 55.62 (-NCH2), 61.11 (d, 2JCF = 18.8 Hz, -CF-CH2), 97.11
1
2
(d, JCF = 200.9 Hz, -CF), 165.71 (d, JCF = 26.1 Hz, -C(O)OCH3). MS (ESI) m/z
11

•
•
85.85 ([M-C6H8FO4 +H]+, 100%), 190.10 ([M-C2H3O2 +H]+, 95.7%), 248.15 ([M+H]+,
73.6%). HRMS (ESI) m/z calcd for [M+H]+ C11H19FNO4 248.1298; found 248.1296.
Dimethyl-2-((benzylmethylamino)methyl)-2-fluoromalonate 6e
3
1H NMR (400 MHz, CDCl3) δH 2.31 (s, 3H, -NCH3), 3.31 (d, JHF
=
25.9 Hz, 2H, -CF-CH2), 3.68 (m, 2H, -N-CH2), 3.85 (s, 6H, -OCH3),
19
7.11 – 7.55 (m, 5H, ArH). F NMR (376 MHz, CDCl3) δF -166.08 (t,
13
3JHF = 25.9 Hz). C NMR (101 MHz, CDCl3) δC 43.53 (-NCH3), 53.22
2
(-C(O)OCH3), 59.89 (d, JCF = 18.7 Hz, -CF-CH2), 63.46 (-N-CH2),
1
97.03 (d, JCF = 200.2 Hz, -CF), 126.76, 128.18, 128.90 (Ar), 138.73 (Ar), 165.73 (d,
•
2JCF = 26.1 Hz, -C(O)OCH3). MS (ESI) m/z 122.09 ([M-C6H8FO4 +2H]+, 100%), 90.98
• +
([M-C7H11FNO4 ] , 65.3%), 284.12 ([M+H]+, 44.8%). HRMS (ESI) m/z calcd for
[M+H]+ C14H19FNO4 284.1298; found 284.1301.
Dimethyl-2-((dicyclohexylamino)methyl)-2-fluoromalonate 6f
1H NMR (400 MHz, CDCl3) δH 0.96 –1.98 (m) (20H, CH2), 2.42 –
3
2.70 (m, 2H, –N-CH), 3.39 (d, JHF = 26.4 Hz, 2H, -CF-CH2), 3.79
3
(s, 6H, -OCH3).19F NMR (376 MHz, CDCl3) δF -166.39 (t, JHF
=
21.9 Hz). 13C NMR (101 MHz, CDCl3) δC 25.23 (CH2), 28.4 (CH2),
2
33.57 (NCH2), 52.96 (N-CH), 53.46 (-C(O)OCH3), 63.47 (d, JCF
=
1
2
21.5 Hz, -CF-CH2), 95.59 (d, JCF = 199.9 Hz, -CF), 165.28 (d, JCF = 25.5 Hz, -
• +
C(O)OCH3). MS (ESI) m/z 182.31 ([C12H22N•+H]+, 100%), 194.34 ([M-C5H6FO4 ] ,
79.3%), 344.20 ([M+H]+,15.8%). HRMS (ESI) m/z calcd for [M+H]+
C18H31FNO4 344.2237, found 344.2247.
Mannich-type reaction by semi-continuous flow two-step process general
procedure
After purging the continuous flow reactor apparatus described previously [18] with
nitrogen, a 10% mixture of fluorine in nitrogen (v.v-1) (11 mmol, 1.1 eq.) was passed
through the first flow reactor via Input 1 at a prescribed flow rate that was controlled
by a gas mass flow controller (Brooks Instruments). The flow reactor was cooled by
an external cryostat to 0-5°C. The ethyl-acetoacetate solution in acetonitrile (10 mL,
12

1 mmol/mL) was injected by a HPLC pump into the flow reactor channel at a
prescribed flow rate through Input 2 (5 mL/h). The gas-liquid flow stream was passed
through the first reactor and the product mixture was collected in a three-neck round-
bottomed flask.
This collected mixture was directly injected by a HPLC pump into the second flow
reactor at a prescribed flow rate (5 mL/h). Formaldehyde (15 mmol) and the amine 3
(17 mmol) were mixed together in acetonitrile for 2 h at rt and then injected by HPLC
pump into the second flow reactor channel at a prescribed flow rate through the
corresponding substrate Input via a T-piece. The molar ratio of fluorinated
ethylacetoacetate:formaldehyde:amine was ca. 1:1.5:1.7. The liquid flow stream was
passed through the second reactor and the product mixture was collected in a
second two-neck round-bottomed flask. All flow streams were passed through the
reactor and the product mixture was collected in a two-neck round-bottom flask. The
collected mixture was then poured into water, extracted with dichloromethane (3 × 50
mL) and washed with brine (20 mL) and water (20 mL). The combined extracts were
then dried (MgSO4), filtered and the solvent evaporated to give a yellow oil, which
was purified by micro-distillation or column chromatography on silica gel using
hexane/ethyl acetate as eluent system when appropriate.
Acknowledgements
Financial support from the European Union’s Seventh Framework Programme for
research, technological development and demonstration under the Marie Curie ITN
Scheme [Fluor21: grant number FP7-PEOPLE-2013-ITN-607787] is gratefully
acknowledged.
References
[1].
a) K. Muller, C. Faeh, F. Diederich, Science 317 (2007)1881-1886; b) I. Ojima,
(Ed), Fluorine in Medicinal Chemistry and Chemical Biology. Wiley-Blackwell,
Oxford, 2009; c) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem.
Soc. Rev. 37 (2008) 320-330; d) C. Isanbor, D. O'Hagan, J. Fluorine Chem.
127 (2006) 303-319; e) K.L. Kirk, J. Fluorine Chem. 127 (2006) 1013-1029.
13

[2].
a)
FY
2011
Innovative
Drug
Approvals.
http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm276385.htm
; b) E.A. Ilardi, E. Vitaku, J.T. Njardarson, J. Med. Chem. 57 (2014) 2832-
2842; c) F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 52 (2009) 6752 –
6757; d) N.J. Willis, C.A. Fisher, C.M. Alder, A. Harsanyi, L. Shukla, J.P.
Adams, G. Sandford, Green Chem. 18 (2016) 1313-1318.
[3].
[4].
J.M. Percy, Top. Curr. Chem. 199 (1997) 131-195.
a) R. D. Chambers, J. Hutchinson, J. Fluorine Chem. 92 (1998) 45-51; b)
R.D. Chambers, M.A. Fox, D. Holling, T. Nakano, T. Okazoe, G. Sandford,
Chem. Eng. Tech, 28 (2005) 344-352; c) A. Harsanyi, G. Sandford, Green
Chem. 17 (2015) 3000-3009.
[5].
[6].
R.D. Chambers, M.P. Greenhall, J. Hutchinson, Tetrahedron 52 (1996)1-8.
M. Butters, J. Ebbs, S.P. Green, J. MacRae, M.C. Morland, C.W. Murtiashaw,
A.J. Pettman, Org. Proc. Res. Dev. 5 (2001) 28-35.
[7].
[8].
A. Harsanyi, G. Sandford, Org. Proc. Res. Dev. 18 (2014) 981-992.
a) A. Harsanyi, G. Sandford, D.S. Yufit, J.A.K. Howard, Bielstein J. Org. Chem.
10 (2014) 1213–1219; b) C.A. Fisher, A. Harsanyi, G. Sandford, D.S. Yufit,
J.A.K. Howard, CHIMIA 68 (2014) 425-429.
[9].
A. Strecker, Liebigs Ann. Chem. 75 (1850) 27-45.
[10]. a) O. Kappe, Acc. Chem. Res. 33 (2000) 879-888; b) S. K. Burr, S. F. Martin,
Tetrahedron 57 (2001) 3221-3242; c) S. F. Martin, Acc. Chem. Res. 35 (2002)
895-904.
[11] a) Y. K. Kang, D. Y. Kim, Tetrahedron Lett. 52 (2011) 2356-2358; b) S. J.
Yoon, Y. K. Kang, D. Y. Kim, Synlett 3 (2011) 420-424; c) Y. Zhao, Y. Pan, H.
Liu, Y. Yang, Z. Jiang, C. H. Tan, Chem. Eur. J. 17 (2011) 3571-3574; d) S. T.
Kadam, S. S. Kim, Tetrahedron 66 (2010) 5647-5652; e) J. H. Lee, D. Y. Kim,
Synthesis 11 (2010) 1860-1864; f) S. Fustero, F. Mojarrad, M. D. P. Carrion, J.
F. Sanz-Cervera, J. L. Acena, Eur. J. Org. Chem. 2009, 5208-5214; g) X. Han,
J. Kwiatkowski, F. Xue, K. W. Huang, Y. Lu, Angew. Chem. Int. Ed. 48 (2009)
7604-7607; h) S. Mizuta, N. Shibata, Y. Goto, T. Furukawa, S. Nakamura, T.
14

Toru, J. Am. Chem. Soc. 129 (2007) 6394-6395; i) M. Lu, Y. Lu, P. K. M. Tan,
Q. Y. Lau, G. Zhong, Synlett 4 (2011) 477-480.
[12] G. K. Prakash, L. Gurung, P. V. Jog, S. Tanaka, T. E. Thomas, N. Gansh, R.
Haiges, T. Mathew, G. Olah, Chem. Eur. J. 19 (2013) 3579.
[13] K. Pham, X. Huang, W. Zhang, Tetrahedron Lett. 56 (2015)1998-2000.
[14] a) K.G. Gadamasetti, Process Chemistry in the Pharmaceutical Industry
Marcel Dekker, New York, 1999; b) W. Ehrfeld, V. Hessel, H. Lowe,
Microreactors. New Technology for Modern Chemistry; Wiley-VCH: New York,
2000; c) C. Wiles, P. Watts, Microreaction Technology in Organic Synthesis;
CRC Press: Boca Raton, 2011.
[15] A. Odedra, P. H. Seeberger, Angew. Chem. Int. Ed. 48 (2009) 2699-2702.
[16] a) C. Ayats, A. H. Henseler, E. Dibello, M. A. Pericàs, ACS Catal. 4 (2014)
3027-3033; b) E. Alza, C. Rodriguez-Escrich, S. Sayalero, A. Bastero, M. A.
Pericàs, Chem. Eur. J. 15 (2009) 10167-10172; c) R. Martìn-Rapùn, S.
Sayalero, M. A. Pericàs, Green Chem. 15 (2013) 3295-3301.
[17] C.B. McPake, G. Sandford, Org. Proc. Res. Dev. 16 (2012) 844-851.
[18] A. Harsanyi, A. Conte, L. Pichon, A. Rabion, S. Grenier, G. Sandford, Org.
Proc. Res. Dev. 21 (2017) 273-276.
[19] J.R. Breen, G. Sandford, D.S. Yufit, J.A. K. Howard, J. Fray, B. Patel,
Beilstein. J. Org. Chem. 7 (2011) 1048–1054.
15

Figures
Figure 1. Schematic diagram of semi-continuous flow process (top); coiled stainless
steel flow reactors (bottom)
16

Tables
Table 1 Three-component Mannich-type reaction of 2-fluoro-ethylacetoacetate 1,
formaldehyde and amine 3
17

Table 2 Three-component Mannich-type reaction of 2-fluoro-ethylacetoacetate 1,
benzaldehyde and amine 3
The synthetic conditions developed above were then applied to reactions between
dimethyl 2-fluoro-malonate ester 2 and a range of amines 3 (Table 3), resulting in
analogous products 6 but in lower yield reflecting the lower nucleophilicity of the
diester substrate.
18

Table 3 Three-component Mannich-type reaction of diethyl 2-fluoro-malonate ester 2,
formaldehyde and amine 3
19

Table 4 Synthesis of β-fluoro(dicarbonyl)alkylamines 4 from ethylacetoacetate,
amines 3 and formaldehyde by semi-continuous flow process
R1
CH2CH3
iPr
R2
Product
Yield [%][a]
CH2CH3
4b
4c
4d
4e
4f
71
43
55
59
67
iPr
-(CH2)4-
-(CH2)5-
Bn
-
-
CH3
[a] isolated yield
20