Aza-michael access to fluoroalkylidene analogues of biomolecules

Article abstract of DOI:10.1021/jo401356j

The synthesis of fluoroaminosulfones derived from piperidine and nucleic bases followed by the study of their chemical behavior in the modified Julia reaction are described. The resulting aminosulfones open a straightforward access to a series of new fluorinated biomolecules including a potent DPP-II inhibitor and acyclonucleoside analogues as potential enzyme inhibitors.

Full text of DOI:10.1021/jo401356j

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Article
Aza-Michael Access to Fluoroalkylidenes Analogues of Biomolecules
Anais Prunier, Charlene Calata, Julien Legros, Jacques Maddaluno, Emmanuel Pfund, and Thierry Lequeux
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401356j • Publication Date (Web): 19 Jul 2013
Downloaded from http://pubs.acs.org on July 22, 2013
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Aza-Michael Access to Fluoroalkylidenes Analogues of
Biomolecules
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Anaïs Prunier,† Charlène Calata,† Julien Legros,‡ Jacques Maddaluno,‡ Emmanuel Pfund,†
Thierry Lequeux†*
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†Laboratoire de Chimie Moléculaire et Thioorganique, CNRS UMR 6507 & FR3038,
Normandie Université, UNICAEN, ENSICAEN 6 Boulevard du Maréchal Juin, 14050 Caen
Cedex, France
‡COBRA UMR 6014 CNRS & FR3038, INSA et Université de Rouen, 1 rue Tesnière, 76821
Mont Saint Aignan, France
*E-mail: Thierry.Lequeux@ensicaen.fr
Graphical abstract
ABSTRACT: The synthesis of fluoroaminosulfones derived from piperidine and nucleic
bases, followed by the study of their chemical behaviour in the modified Julia reaction are
described. The resulting aminosulfones open a straightforward access to a series of new
fluorinated biomolecules including a potent DPP-II inhibitor, and acyclonucleoside analogues
as potential enzyme inhibitors.
INTRODUCTION
It is well established that the fluorovinylic moiety plays an increasingly important role in
medicinal chemistry. When introduced onto nucleotides, carbohydrates, vitamins,
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prostaglandins, steroids, and peptides it has been shown to improve their physiological
stabilities or their biological activities.1-3 Furthermore, Allmendinger’s pioneer work on the
structural analogy between an amide bond and a fluorinated carbon-carbon double bond,4 has
triggered interest on the effect of fluoroallylamines to prevent either rapid enzymatic
degradation or natural isomerization occurring in vivo with peptides and their derivatives.5-10
This last feature was already emphasized with the fluorinated PNA analogue I, as well as
Dipeptidyl Peptidase (DPP) inhibitors II and III, in which increased activity was assigned to
the fluoroalkene motif (Figure 1).11-14 In the nucleoside field, a significant positive effect of
the fluorovinylic moiety was also reported as exemplified by the potent antitumor fluorinated
neplanocin A analogue IV,15 and series of new fluorovinylic acyclic nucleosides (ACN) with
anticancer properties.16
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Figure 1. Biologically Active Fluoroalkenes
However, the access to functionalized fluoroallylamines, such as peptidomimetics or acyclo-
nucleosides, is not straightforward. Most synthetic routes rely on the chemical modifications
of α-fluoro-α,β-unsaturated esters. In general, these latters were prepared from the
corresponding carbonyl compounds through Horner-Wadworth-Emmons, modified Julia, or
Peterson reactions.17-24 Up to date, the direct synthesis of fluoroallylamines can be achieved
from aldehydes and piperidino-phosphonium ylide generated in situ,25 by reduction of amino-
fluoroketosulfones through a Smile rearrangement,26 and recently via the modified Julia
reaction between carbonyl compounds and fluoroaminosulfones (Scheme 1).27,28 In this paper,
we report the synthesis of aminosulfones by direct aza-Michael addition of functionalized
amines and nucleic bases onto a fluorovinylsulfone, and a rapid access to important analogues
of biomolecules including a DPP-II inhibitor and acyclonucleoside precursors.
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Scheme 1. Direct Routes for the Preparation of Fluoroallylamines
RESULTS AND DISCUSSION
In connection with our previous results regarding the synthesis of fluoroallylamines,28 the
preparation of the DPP-II inhibitor II was first explored from the readily available
benzothiazolylfluorovinylsulfone 1 (Scheme 2). While this inhibitor presents a good activity
towards DPP-II,13 its synthesis requires 6 steps from cyclohexanone. With a new tool for the
synthesis of allylamines in hand, we explored a flexible and convergent preparation of this
compound from piperidine derivatives. We recently reported an efficient conjugate addition
of nucleophilic amines such as propylamine and cyclohexylamine onto fluorovinylsulfone 1.
This reaction proceeded smoothly in dichloromethane at 20 °C in a few minutes and afforded
the corresponding aminosulfones in excellent yields.27 The addition was found to be much
slower when conducted with 4-amino-benzylpiperidine, and reached completion after 6 h of
stirring at 20 °C in dichloromethane. Fluoroaminosulfone 2, isolated in 88% yield, was next
employed in the modified Julia reaction. A mixture of sulfone 2 and cyclohexanone (1.1
equiv) in THF was treated with NaHMDS (1.5 equiv) from -78 °C to 20 °C, and the
fluoroallylamine II was obtained in 80% yield.
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NBn
4
H2N
5
6
7
F
F
HN
NBn
CH2Cl2, 6h, 20 °C
88%
N
S
N
S
SO2
SO2
8
1
2
9
cyclohexanone
NaHMDS, THF
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80%
-78 °C to 20 °C, 2h
F
HN
NBn
DPP-II inhibitor (II)
Scheme 2. Two-step Synthesis of the DPP-II Inhibitor (II)
This expeditious synthesis of DPP-II inhibitor II illustrates the efficiency of this approach,
increasing the overall yield and the flexibility of compound II synthesis.13 These results
prompted us to apply a similar method to the preparation of fluorovinylic acyclonucleosides
from sulfones bearing nucleic bases. However, the aza-Michael addition of nitrogen
heterocycles is a challenging reaction that requires specific activation (e.g. high-pressure
conditions).29 Recently, Pathak reported the addition of heterocyclic amines, including nucleic
bases, onto vinylic sulfones to afford the corresponding adducts in good yields when the
reaction was performed in the presence of an excess of 1,1,3,3-tetramethylguanidine (TMG, 5
equiv) and amines (7 equiv).30 Accordingly, the conjugate addition of nucleic bases was
explored following Pathak’s original procedure, and fluorovinylsulfone 1 was treated with
thymine (7 equiv) in the presence of TMG (5 equiv). After 3 h of stirring at 20 °C in DMF,
the reaction reached completion and the corresponding N1/N3 regioisomeric mixture of
thymidyl fluorobenzothiazolylsulfone 3 was isolated in 50% yield in a 4:1 ratio. This medium
yield is mainly due to difficulties to remove the excess of reagents from the reaction mixture
(Scheme 3).
O
HN
Thymine (7 equiv),
TMG (5 equiv)
DMF, 3 h, 20 °C
O
NH
O
O
F
N
F
N
F
N
S
N
S
N
S
+
SO2
SO2
SO2
50%
3, N1/N3: 4/1
1
Scheme 3. Conjugate Addition of Thymine onto Fluorovinylsulfone (1)
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Table 1. Conjugate Addition of Nucleic Bases onto Fluorovinylsulfone (1)
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Compound
(Yield %)a
Entry
Nucleic base
Product
7
8
9
O
O
HN
3 (67%)b
N1/N3: 4/1
O
HN
F
N
1
N
S
O
N
H
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SO2
O
O
HN
N
4 (55%)b
N1/N3: 9/1
O
F
HN
2
3
4
5
N
O
N
H
SO2
S
O
O
HN
5 (84%)b
N1/N3: 100/0
O
F
F
HN
F
N
N
O
N
H
SO2
S
O
O
BzN
O
F
6 (95%)b
7 (84%)b
BzN
O
N
N
N
H
SO2
S
O
O
BzN
N
O
F
BzN
N
O
N
H
SO2
S
Cl
N
Cl
8 (74%)c
N7/N9: 0/100
N
F
N
N
N
6
N
N
N
H
N
SO2
S
H
N
H
N
O
O
9 (73%)c
N7/N9: 2/3
O
NH
O
N
N
N
7
N
H
F
N
N
N
H
N
S
SO2
a Isolated yield; b Nucleic base (1.3 equiv), TBAF (0.2 equiv), THF, 20 °C, 16 h;
c Nucleic base (1.1 equiv), TBAF (0.2 equiv), DMF, 20 °C, 24 h.
Other catalysts were explored, such as tetrabutylammonium fluoride (TBAF). This reagent
has been used for a variety of base-catalyzed reactions,31 including Michael addition,32,33 and
we already reported that TBAF enhances the reactivity of nitrogen nucleophiles such as
phtalimide.27 Addition of thymine onto vinylsulfone 1 was performed in the presence of
TBAF in THF. Best results were obtained when the aza-Michael reaction was conducted over
16 h at 20 °C in the presence of 20 mol% of catalyst. The fluorinated thymine derivative 3
was obtained in 67% yield as a 4:1 mixture of N1 and N3 isomers. This reaction was extended
to other protected and unprotected nucleic bases (Table 1).
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The conjugate addition of unprotected uracil gave roughly the same results than those
obtained from thymine, and sulfonyl-uracil derivative 4 was isolated in 55% yield as a
mixture of both N1 and N3 regioisomers (Table 1, entry 2). In contrast, from 5-fluorouracil,
the N1 isomer was exclusively detected and benzothiazolylfluorosulfone 5 was isolated in
84% yield (Table 1, entry 3). In this case, the presence of the fluorine atom onto the nucleic
base decreased the N3 atom nucleophilicity leading to the exclusive alkylation of the N1
position. To prevent the formation of the undesired N3 alkylated thymine and uracil
derivatives, the aza-Michael reaction was conducted from their corresponding N3-benzoylated
derivatives. The protected fluorosulfonyl-thymine and -uracil 6, 7 were prepared in good
yields, and the protecting group survived the reaction conditions (Table 1, entries 4 and 5).
These mild conditions were then applied to the purine series. To overcome the poor solubility
of purines, DMF was preferred to THF as solvent. From 6-chloropurine, the conjugate
addition reaction was slower and the reaction reached completion after 24 h of stirring at 20
°C. Fluorosulfonyl 6-chloropurine 8 was isolated in 74% yield as a single isomer (Table 1,
entry 6). In contrast, a non separable mixture of both N7 and N9 regioisomers 9 was obtained
when the aza-Michael reaction was conducted with N2-(isobutanoyl)-guanine (Table 1, entry
7).
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The chemical behaviours of these fluorosulfones in the modified Julia reaction was next
investigated in an attempt to access fluorovinylic acyclonucleosides. The reactivity of
pyrimidinyl sulfones 6, 7 was first evaluated with benzaldehyde in the presence of NaHMDS
(1.5 equiv) in THF (Scheme 4). After stirring for 30 min at –78 °C, the mixture was
maintained 1.5 h at –20 °C to avoid the debenzoylation of the heterocycle. Fluoroalkylidene
derivatives 11, 12 were obtained in good yields (69–87%), and a high Z selectivity (Z/E > 9:1,
Scheme 4). In the presence of tBuOK, similar selectivities were observed, but the yield
tumbled down to 45%. We noticed this selectivity was depended strongly on the presence of
the N3-benzoyl group onto the nucleic base. Indeed, a 1:1 mixture of both Z/E isomers 13 was
obtained from 5.
O
PhCHO, NaHMDS
O
RN
RN
THF, 2h, –78 °C
to –20 °C
O
R'
O
R'
F
N
F
N
N
S
SO2
6, R = Bz, R' = CH3
7, R = Bz, R' = H
5, R = H, R' = F
11, R = Bz, R' = CH3, E/Z = 5:95, 87%
12, R = Bz, R' = H, E/Z = 6:94, 69%
13, R = H, R' = F, E/Z = 47:53, 69%
14, R = Bz, R' = F, E/Z = 5:95, 39%
10, R = Bz, R' = F
Scheme 4. Fluoroolefination Reaction of Benzaldehyde with Pyrimidinyl Fluorosulfones
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In contrast, when the reaction was achieved with the corresponding protected sulfone 10,34
once again the Z isomer 14 was obtained as the major product (Z/E > 9:1). Surprisingly, when
applied to the more sensitive purine series (sulfones 8 and 9), the reaction afforded a mixture
of unidentified products. A clean reaction was observed when tBuOK was used as base
instead of NaHMDS. In these cases, corresponding fluoroalkenes 15 and 16 were isolated in
61% and 55% yield, respectively, but without any selectivity (Scheme 5). These results
suggest that the steric hindrance of the nucleic bases is not the only parameter controlling the
selective formation of the carbon-carbon double bond.
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R'
R'
N
N
R
R
PhCHO, tBuOK
N
N
N
N
THF, 2h, –17 °C
to 20 °C
F
N
F
N
N
S
SO2
8, R = H, R' = Cl
9, R = NHC(O)CH(CH3)2, R' = OH
15, R = H, R' = Cl, E/Z = 55:45, 61%
16, R = NHC(O)CH(CH3)2, R' = OH, E/Z = 2:3, 55%
Scheme 5. Fluoroolefination Reaction of Benzaldehyde with Purinyl Fluorosulfones
To approach acyclic structures related to precursors of acyclonucleosides such as thymidine
nucleoside phosphorylase (TPase) inhibitors,35 the olefination of a series of carbonyl
compounds was explored with the fluorosulfone 6. It has been shown that alkylated nucleic
bases would be good candidates, and the presence of a heterocycle or an aromatic ring
influenced strongly the inhibition activity towards nucleoside phosphorylases.36,37 In a first
instance, the synthesis of aromatic derivatives, as potential non-ionic TPase inhibitor
analogues, was performed from sulfone 6 and aldehydes (Scheme 6, Table 2).
Scheme 6. Synthesis of Fluoroallylthymine Derivatives.
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Table 2. Fluoroolefination Reaction of Aldehydes with Fluorosulfone (6)
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7
8
9
R = Bz
(Yield, E/Z)a
R = H
(Yield, E/Z)b
Entry
1
Aldehyde
Product
O
RN
10
11
12
13
14
15
16
17
18
19
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21
22
23
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27
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17a
17b
O
4-MeO-PhCHO
F
N
(79%, 4:96)
(76%, 7:93)
MeO
O
RN
18a
18b
O
2
3
4-Br-PhCHO
F
N
(86%, 8:92)
(55%, 17:83)
Br
O
RN
N
19a
O
4-NO2-PhCHO
-
F
(63%, 32:68)
O2N
O
RN
N
O
20a
20b
F
4
5
Ph3CHO
(82%, 17:83)
(65%, 15:85)
O
RN
N
O
21a
21b
F
C5H4N-CHO
(61%, 16:84)
(66%, 12:88)
N
O
RN
N
22a
22b
O
6
7
8
C6H11CHO
MeCHO
F
(83%, 28:72)
(57%, 21:79)
O
RN
N
23a
23b
O
F
(88%, 41:59)
(82%, 39:61)
24a
24b
CH3(CH2)5CHO
(61%, 29:71)
(67%, 30:70)
O
RN
25a
25b
O
9
CH3(CH2)7CHO
F
N
(52%, 30:70)
(78%, 28:72)
7
a E/Z ratio in the crude mixture determined by 19F NMR. Yield after 2 steps including modified Julia reaction
b
followed by thymine deprotection using 1% NaOH in MeOH.
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From aromatic aldehydes bearing a para electron-donating substituent such as a methoxy
group or a bromine atom, corresponding fluoroalkenes derived from thymine 17–18a were
formed with a high Z-selectivity after 2 h of stirring, and the expected products were isolated
in 71–76% yields (Table 2, entries 1, 2). The presence of an electron-withdrawing substituent
on the aromatic ring did not alter the reaction efficiency and compound 19a was obtained also
in good yield (Table 2, entry 3). The reaction carried out with anthraldehyde and 3-
pyridinecarboxaldehyde furnished fluoroolefins 20–21a in 61–82% yields, and the Z-
selectivities were preserved (Table 2, entries 4, 5). From aliphatic aldehydes such as
cyclohexylcarboxaldehyde, the olefination reaction was faster and reached completion after
30 min of stirring. The corresponding 3-benzoylthyminyl derivative 22a was isolated in 83%
yield, but the Z-selectivity was slightly altered (Table 2, entry 6). Applied to a series of linear
aliphatic aldehydes the reaction afforded compounds 23–25a in moderate to good yields, and
Z alkenes were formed as major products (Table 2, entries 7, 8, 9). While excellent yield was
obtained from acetaldehyde, isolated yields gradually decreased from heptanal to nonanal. For
these latters, partial deprotection of the thymine occurred during the olefination process. A
two-step process was carried out by treatment of the crude mixture of alkenes with NaOH
(1%) in CH3OH (Scheme 6), as exemplified by the preparation of compound 25b isolated in
78% overall yield (Table 2, entry 9), and the other compounds of the series (compounds 17-
18b, 20–24b). This additional step increased the overall yields without alterating the
selectivity of the modified Julia reaction.
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This approach was applied to polyhydroxylated carbonyl compounds in an attempt to open a
new access to analogues of acyclonucleosides. It has been reported that the trans-butenyl
moiety could mimic the conformation of the C1'-O4'-C4'-C5' atoms of the natural 2-deoxyribose
(dUMP).38-40 Due to the highest electronegative character of the fluorine atom, fluoroalkene
moiety could enhance this feature better than an alkene. This prompted us to carry out the
olefination of polyhydroxylated carbonyl compounds (Scheme 7). To start with the synthesis
of the closest analogue of the trans-butenyl moiety, 1,3-isopropylidene acetone was
considered as a fine partner. The modified Julia reaction was run with sulfone 6 and 1,3-
isopropylidene acetone. By treatment of 6 and the ketone with NaHDMS in THF, we were
pleased to observe the formation of the expected alkene 26. After work-up and purification by
flash chromatography, compound 26 was isolated in 60% yield. Finally, acetal hydrolysis
followed by thymine deprotection according to a standard protocol furnished the fluorinated
trans-butenyl 27 in good overall yield.
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Scheme 7. Preparation of a Fluorinated Analogue of Acyclonucleosides.
To extend this synthesis to other series containing larger spacers between the hydroxyl
function and the nucleic base, 41 the reaction was carried out from alkoxyaldehydes. While α
and βbenzyloxyaldehydes, such as benzyloxyacetaldehyde and 3-benzyloxypropanal, failed to
react with 6, γ, δ, and ωalkoxyaldehydes afforded the corresponding alkenes in moderate
yields (Scheme 8). From 4-benzyloxybutanal, 5-benzyloxypentanal and 6-benzyloxyhexanal
the reaction reached completion in the presence of NaHMDS, after stirring for 30 min at -78
°C and 1.5 h at -20 °C. In these cases, thymine deprotection did not occurred, and the
corresponding acyclonucleosides 28-30a were isolated in 52-66% yields. Although the Z
isomer was the major product of the reaction, an inseparable mixture of both E/Z isomers was
obtained. Finally, corresponding fluoroallylthymines derivatives 28-30c were obtained after
treatment with NaOH (1%) in MeOH followed by a selective debenzylation with TiCl4 (5
equiv) in methylene chloride.42,43
Scheme 8. Fluoroolefination Reaction of Functionalized Aldehydes with Sulfone (6)
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In summary, the chemical behavior of a large variety of benzothiazolylfluoroaminosulfones in
the modified Julia reaction was reported. Fluorinated aminosulfone 2, easily obtained by
conjugate addition of 4-benzylamino-piperidine onto benzothiazolyl-fluorovinylsulfone 1,
appeared as an efficient fluoroolefination reagent to carry out a straightforward and flexible
synthesis of a potent DPP-II inhibitor. The synthesis of modified acyclonucleoside precursors
was explored from a series of new fluoroaminosulfones containing pyrimidine and purine
heterocycles. The modified Julia reaction was highly Z-selective from benzoylated
thymidinylsulfones and aromatic as well as aliphatic aldehydes, and corresponding
acyclonucleoside precursors were isolated in moderate to good yields. Biological evaluation
of these compounds as Thymidine Phosphorylase inhibitors and antiviral agents are in
progress and results will be reported in due course. To conclude, these examples illustrated
the efficiency of the modified Julia reaction, appearing as a convenient tool for the convergent
synthesis of highly functionalized fluoroalkylidenes.
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EXPERIMENTAL SECTION
General. All commercially available reagents were bought and used as received. For
anhydrous conditions, the glassware was flamed under a continuous nitrogen flow and cooled
to 20 °C before running the experiment. Anhydrous solvents (THF, CH2Cl2, CH3CN and
Toluene) were dried in a solvent generator, which uses an activated alumina column to
remove water. DMF, Et3N and pyridine were distilled under CaH2 or 4 Å molecular sieves.
Flash column chromatography was realized on silica gel 60 (40-63 ꢀm) with air pressure and
products were detected by thin layer chromatography, on which the spots were visualized by
UV-irradiation and/or KMnO4 solution. NMR spectra were recorded on a 400 MHz or 500
MHz apparatus in deutered solvent at 25 °C. All chemical shifts are reported in δ parts per
million (ppm) and coupling constants (J) are in hertz (Hz). The following abbreviations mean:
s: singlet; d: doublet; t triplet; q: quadruplet; quint: quintuplet; sext: sextet; sep: septet; m:
multiplet. High-resolution mass data were recorded on a Micromass Q-TOF (Quadrupole
Time-of-Flight) instrument with an electrospray source in the EI or ESI mode.
N-[2-(1,3-Benzothiazole-2-sulfonyl)-2-fluoroethyl]-1-benzylpiperidin-4-amine (2). To a
solution of 2-(1-fluoroethenesulfonyl)-1,3-benzothiazole 127 (200 mg, 0.82 mmol, 1 equiv) in
CH2Cl2 (4 mL) was added 4-amino-1-benzylpiperidine (0.22 mL, 1.07 mmol, 1.3 equiv). The
mixture was stirred for 6 h at 20 °C then quenched with a saturated aqueous solution of
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NH4Cl (2 mL). The aqueous layer was extracted with CH2Cl2 (3 x 8 mL). The combined
organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. The
crude product was purified by flash column chromatography (CH2Cl2/MeOH, 95:5) to give
1
aminosulfone 2 (314 mg, 88%) as a yellow oil. H NMR (CDCl3, 400 MHz) δ 8.22–8.20 (m,
9
1H), 7.98–7.95 (m, 1H), 7.62–7.54 (m, 2H), 7.27–7.25 (m, 4H), 7.23–7.19 (m, 1H), 5.72
(ddd, 2JHF = 46.5 Hz, 3JHH = 7.5 Hz, 3JHH = 3.6 Hz, 1H), 3.56–3.32 (m, 2H), 3.44 (s, 2H), 2.79–
2.76 (m, 2H), 2.54–2.47 (m, 1H), 1.98 (t, 3JHH = 10.3 Hz, 2H), 1.79–1.76 (m, 2H), 1.69 (sbr,
1H), 1.40–1.29 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 162.4, 152.6, 138.1, 137.2, 128.9
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(2C), 128.3, 128.0 (2C), 127.7, 126.8, 125.6, 122.2, 101.4 (d, JCF = 223.3 Hz), 62.7, 54.2,
2
51.8 (2C), 43.4 (d, JCF = 20.0 Hz), 32.3, 32.1; 19F NMR (CDCl3, 376 MHz) δ –181.1 (ddd,
3
3
2JFH = 46.5 Hz, JFH = 27.9 Hz, JFH = 18.3 Hz, 1F); MS (ESI) m/z 434 [M + H]+ (12), 174
(100), 91 (11); HRMS (ESI) m/z [M + H]+ calcd for C21H25FN3O2S2 434.1372, found
434.1375.
1-Benzyl-N-(2-cyclohexylidene-2-fluoroethyl)piperidin-4-amine (II). To a solution of
aminosulfone 2 (80 mg, 0.18 mmol, 1 equiv), and cyclohexanone (21 ꢀL, 0.20 mmol, 1.1
equiv) at –78 °C in THF (2 mL) was added NaHMDS (1 M in THF, 0.28 mL, 0.28 mmol, 1.5
equiv). After 30 min at –78 °C, the mixture was stirred for 1 h 30 at 20 °C, quenched with a
saturated aqueous solution of NH4Cl (1 mL) and extracted with CH2Cl2 (3 x 5 mL). Combined
organic layers were washed with brine, dried over MgSO4, filtered and evaporated under
reduced pressure. The crude product was purified by flash column chromatography
(CH2Cl2/MeOH, 9:1) to give amino-alkene II (47 mg, 80%) as a yellow oil. 1H NMR (CDCl3,
400 MHz) δ 7.28–7.22 (m, 4H), 7.20–7.16 (m, 1H), 3.47 (s, 2H), 3.36 (d, 3JHF = 22.1 Hz, 2H),
2.83–2.78 (m, 2H), 2.50–2.44 (m, 1H), 2.15 (m, 2H), 2.04–1.99 (m, 4H), 1.79–1.76 (m, 2H),
1.46–1.45 (m, 6H), 1.41–1.35 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 149.2 (d, 1JCF = 241.8
2
Hz), 137.9, 129.1 (2C), 128.1 (2C), 127.0, 118.3 (d, JCF = 15.2 Hz), 62.8, 52.9, 51.9 (2C),
42.7 (d, 2JCF = 30.3 Hz), 32.1 (2C), 28.2 (d, 3JCF = 5.1 Hz), 27.6 (d, 4JCF = 2.5 Hz), 26.8, 26.3,
3
3
25.5 (d, JCF = 8.4 Hz); 19F NMR (CDCl3, 376 MHz) δ –121.3 (t, JFH = 22.1 Hz, 1F); MS
(ESI) m/z 317 [M + H]+ (32), 174 (100); HRMS (ESI) m/z [M + H]+ calcd for
C20H30FN2 317.2393, found 317.2393.
General procedure A: conjugate addition of nucleic bases (pyrimidine series) onto
fluorovinylsulfone. To a solution of nucleic base (1.3 equiv) in THF (0.2 M) were added
TBAF (1 M in THF, 0.2 equiv) and 2-(1-fluoroethenesulfonyl)-1,3-benzothiazole 1 (1 equiv).
The mixture was stirred for 16 h at 20 °C, quenched with a saturated aqueous solution of
NH4Cl and extracted with CH2Cl2. Combined organic layers were dried over MgSO4, filtered
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and evaporated under reduced pressure. The crude product was purified by flash column
chromatography or by filtration to give fluorinated aminosulfones 3-7.
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1-[2-(1,3-Benzothiazole-2-sulfonyl)-2-fluoroethyl]-5-methyl-1,2,3,4-
tetrahydropyrimidine-2,4-dione (3). General procedure A was followed with sulfone 1 (100
mg, 0.41 mmol, 1 equiv), thymine (63 mg, 0.53 mmol, 1.3 equiv) and TBAF (1 M in THF, 82
ꢀL, 0.08 mmol, 0.2 equiv) in THF (2 mL). The purification by flash chromatography
(CH2Cl2/AcOEt, 9:1 then 8:2) afforded compound 3 as a mixture of regioisomers (N1/N3, 4:1)
as a white solid (102 mg, 67%). Mp 205 °C; 1H NMR (DMSO, 400 MHz) δ 11.44 (s, 1H, N1-
isomer), 11.12 (s, 1H, N3-isomer), 8.40–8.38 (m, 2H, N1 and N3-isomers), 8.35–8.33 (m, 2H,
N1 and N3-isomers), 7.77–7.75 (m, 4H, N1 and N3-isomers), 7.53 (s, 1H, N1-isomer), 7.34 (s,
1H, N3-isomer), 6.46 (ddd, 2JHF = 46.7 Hz, 3JHH = 6.0 Hz, 3JHH = 1.8 Hz, 1H, N1-isomer), 6.45
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(ddd, 2JHF = 46.7 Hz, JHH = 6.0 Hz, 3JHH = 1.8 Hz, 1H, N3-isomer), 4.70–4.59 (m, 2H, N1 and
N3-isomers), 4.41–4.32 (m, 2H, N1 and N3-isomers), 1.76 (s, 3H, N3-isomer), 1.72 (s, 3H, N1-
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isomer); C NMR (DMSO, 125 MHz) N3-isomer δ 164.1, 161.7, 152.3, 150.8, 141.0, 137.2,
128.9, 128.4, 125.4, 123.7, 109.2, 99.2 (d, 1JCF = 222.4 Hz), 44.7 (d, 2JCF = 20.7 Hz), 11.9; 19F
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3
3
NMR (DMSO, 376 MHz) δ –183.6 (ddd, JFH = 46.7 Hz, JFH = 33.8 Hz, JFH = 12.8 Hz, 1F,
2
3
3
N3-isomer), –183.8 (ddd, JFH = 46.7 Hz, JFH = 30.8 Hz, JFH = 15.8 Hz, 1F, N1-isomer); MS
(ESI) m/z 370 [M + H]+ (95), 171 (100); HRMS (ESI) m/z [M + H]+ calcd for
C14H13FN3O4S2 370.0335, found 370.0332.
1-[2-(1,3-Benzothiazole-2-sulfonyl)-2-fluoroethyl]-1,2,3,4-tetrahydropyrimidine-2,4-
dione (4). General procedure A was followed with sulfone 1 (100 mg, 0.41 mmol, 1 equiv),
uracil (60 mg, 0.53 mmol, 1.3 equiv) and TBAF (1 M in THF, 82 ꢀL, 0.08 mmol, 0.2 equiv)
in THF (2 mL). The purification by flash chromatography (CH2Cl2/AcOEt 1:1) afforded
compound 4 as a mixture of regioisomers (N1/N3, 9:1) as a white solid (53 mg, 55%). Mp 190
1
°C; H NMR (DMSO, 400 MHz) δ 11.45 (s, 1H, N1-isomer), 11.34 (s, 1H, N3-isomer), 8.42–
3
8.32 (m, 4H, N1 and N3-isomers), 7.79–7.73 (m, 4H, N1 and N3-isomers), 7.65 (d, JHH = 7.9
3
2
Hz, 1H, N1-isomer), 7.48 (d, JHH = 7.6 Hz, 1H, N3-isomer), 6.47 (ddd, 3JHF = 46.6 Hz, JHH
=
8.1 Hz, 3JHH = 2.7 Hz, 1H, N1-isomer), 6.30 (ddd, 3JHF = 46.9 Hz, 2JHH = 8.4 Hz, 3JHH = 2.7 Hz,
3
3
1H, N3-isomer), 5.63 (d, JHH = 7.6 Hz, 1H, N3-isomer), 5.61 (d, JHH = 7.9 Hz, 1H, N1-
isomer), 4.74–4.36 (m, 4H, N1 and N3-isomer); 13C NMR (DMSO, 100 MHz) δ 163.6 (N1-
isomer), 162.8 (N3-isomer), 161.9 (N3-isomer), 161.7 (N1-isomer), 152.3 (2C, N1 and N3-
isomers), 151.2 (N3-isomer), 150.8 (N1-isomer), 145.4 (N1-isomer), 141.5 (N3-isomer), 137.2
(N1-isomer), 137.1 (N3-isomer), 128.9 (2C, N1 and N3-isomers), 128.4 (2C, N1 and N3-isomer),
125.4 (2C, N1 and N3-isomer), 123.7 (2C, N1 and N3-isomer), 101.7 (N1-isomer), 99.6 (N3-
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isomer), 99.1 (d, JCF = 222.2 Hz, N1-isomer), 98.7 (d, JCF = 223.9 Hz, N3-isomer), 44.9 (d,
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7
2
2JCF = 20.5 Hz, N1-isomer) 37.2 (d, JCF = 20.5 Hz, N3-isomer); 19F NMR (DMSO, 376 MHz)
δ –183.3 (ddd, JFH = 46.9 Hz, JFH = 33.1 Hz, JFH = 14.5 Hz, 1F, N3-isomer), –183.6 (ddd,
2JFH = 46.6 Hz, JFH = 30.5 Hz, JFH = 16.1 Hz, 1F, N1-isomer); HRMS (ESI) m/z [M + Na]+
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3
3
3
3
8
9
calcd for C13H10FN3NaO4S2 377.9994, found 377.9995.
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1-[2-(1,3-Benzothiazole-2-sulfonyl)-2-fluoroethyl]-5-fluoro-1,2,3,4-
tetrahydropyrimidine-2,4-dione (5). General procedure A was followed with sulfone 1 (100
mg, 0.41 mmol, 1 equiv), 5-fluorouracil (70 mg, 0.53 mmol, 1.3 equiv) and TBAF (1 M in
THF, 82 ꢀL, 0.08 mmol, 0.2 equiv) in THF (2 mL). The CH2Cl2 was added to the crude
product and the pure solid compound 5 was recovered by filtration (129 mg, 84%) as a white
solid. Mp 225 °C; 1H NMR (DMSO, 400 MHz) δ 11.99 (s, 1H), 8.44–8.40 (m, 1H), 8.38–8.34
(m, 1H), 8.11 (d, 3JHF = 6.7 Hz, 1H), 7.82–7.75 (m, 2H), 6.46 (ddd, 2JHF = 46.6 Hz, JHH = 8.4
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2
3
Hz, JHH = 2.7 Hz, 1H), 4.64 (ddd, 3JHF = 31.1 Hz, JHH = 15.2 Hz, JHH = 2.7 Hz, 1H), 4.35
2
3
(ddd, 3JHF = 15.7 Hz, JHH = 15.2 Hz, JHH = 8.4 Hz, 1H); 13C NMR (DMSO, 100 MHz)
2
1
δ 161.6, 157.3 (d, JCF = 25.9 Hz), 152.3, 149.5, 139.6 (d, JCF = 229.9 Hz), 137.2, 129.8 (d,
2JCF = 34.6 Hz), 128.9, 128.4, 125.4, 123.7, 99.0 (d, 1JCF = 222.9 Hz), 45.0 (d, 2JCF = 20.6 Hz);
3
2
19F NMR (DMSO, 376 MHz) δ –169.0 (d, JFH = 6.7 Hz, 1F), –183.7 (ddd, JFH = 46.6 Hz,
3
3JFH = 31.1 Hz, JFH = 15.7 Hz, 1F); MS (ESI) m/z 374 [M + H]+ (72), 175 (100), 136 (36);
HRMS (ESI) m/z [M + H]+ calcd for C13H10F2N3O4S2 374.0081, found 374.0082.
3-Benzoyl-1-[2-(1,3-benzothiazole-2-sulfonyl)-2-fluoroethyl]-5-methyl-1,2,3,4-
tetrahydropyrimidine-2,4-dione (6). General procedure A was followed with sulfone 1 (2.0
g, 8.22 mmol, 1 equiv), N3-benzoylthymine (2.46 g, 10.69 mmol, 1.3 equiv) and TBAF (1 M
in THF, 1.6 mL, 1.64 mmol, 0.2 equiv) in THF (40 mL). The purification by flash
chromatography (CH2Cl2/AcOEt, 95:5) afforded compound 6 (3.73 g, 95%) as a white solid.
1
Mp 88 °C; H NMR (CDCl3, 400 MHz) δ 8.27–8.25 (m, 1H), 8.05–8.03 (m, 1H), 7.94–7.91
(m, 2H), 7.70–7.62 (m, 3H), 7.51–7.47 (m, 2H), 7.20 (s, 1H), 6.04 (ddd, 2JHF = 47.7 Hz, 3JHH
7.6 Hz, 3JHH = 4.5 Hz, 1H), 4.77 (ddd, 3JHF = 23.3 Hz, 2JHH = 15.0 Hz, 3JHH = 4.5 Hz, 1H), 4.35
=
2
3
3
(ddd, 3JHF = 11.9 Hz, JHH = 15.0 Hz, JHH = 7.6 Hz, 1H), 1.96 (d, JHH = 1.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 168.3, 162.8, 161.1, 152.7, 149.7, 140.1, 137.4, 135.2, 131.2,
1
130.4 (2C), 129.2 (2C), 128.8, 128.1, 126.0, 122.4, 111.7, 97.4 (d, JCF = 225.4 Hz), 46.6 (d,
2
2JCF = 22.6 Hz), 12.3; 19F NMR (CDCl3, 376 MHz) δ –182.4 (ddd, JFH = 47.7 Hz, 3JFH = 23.3
Hz, 3JFH = 11.9 Hz, 1F); MS (ESI) m/z 474 [M + H]+ (80), 105 (100); HRMS (ESI) m/z [M +
H]+ calcd for C21H17FN3O5S2 474.0594, found 474.0601.
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3-Benzoyl-1-[2-(1,3-benzothiazole-2-sulfonyl)-2-fluoroethyl]-1,2,3,4-
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tetrahydropyrimidine-2,4-dione (7). General procedure A was followed with sulfone 1 (100
mg, 0.41 mmol, 1 equiv), N3-benzoyluracil (116 mg, 0.53 mmol, 1.3 equiv) and TBAF (1 M
in THF, 82 ꢀL, 0.08 mmol, 0.2 equiv) in THF (2 mL). The purification by flash
chromatography (CH2Cl2/AcOEt, 95:5) afforded compound 7 (159 mg, 84%) as a white solid.
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Mp 65 °C; H NMR (CDCl3, 400 MHz) δ 8.25–8.23 (m, 1H), 8.03–8.01 (m, 1H), 7.93–7.91
(m, 2H), 7.68–7.60 (m, 3H), 7.50–7.46 (m, 2H), 7.38 (d, 3JHH = 8.1 Hz, 1H), 6.03 (ddd, 2JHF =
47.4 Hz, 3JHH = 7.4 Hz, 3JHH = 4.5 Hz, 1H), 5.82 (d, 3JHH = 8.1 Hz, 1H), 4.75 (ddd, 3JHF = 22.8
Hz, JHH = 15.0 Hz, JHH = 4.5 Hz, 1H), 4.40 (ddd, JHF = 12.7 Hz, 2JHH = 15.0 Hz, JHH = 7.4
2
3
3
3
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 168.1, 161.9, 161.0, 152.6, 149.6, 144.4, 137.3,
1
135.3, 131.0, 130.4 (2C), 129.2 (2C), 128.8, 128.1, 125.8, 122.3, 102.9, 97.3 (d, JCF = 225.4
Hz), 46.5 (d, 2JCF = 22.7 Hz); 19F NMR (CDCl3, 376 MHz) δ –182.3 (ddd, 2JFH = 47.4 Hz, 3JFH
= 22.8 Hz, JFH = 12.7 Hz, 1F); HRMS (ESI) m/z [M + Na]+ calcd for
3
C20H14FN3NaO5S2 482.0257, found 482.0245.
General procedure B: conjugate addition of nucleic bases (purine series) onto
fluorovinylsulfone. To a solution of nucleic base (1.1 equiv) in DMF (0.2 M) were added
TBAF (1 M in THF, 0.2 equiv) and 2-(1-fluoroethenesulfonyl)-1,3-benzothiazole 1 (1 equiv).
The mixture was stirred for 24 h at 20 °C, quenched with a saturated aqueous solution of
NH4Cl and extracted with CH2Cl2. Combined organic layers were dried over MgSO4, filtered
and evaporated under reduced pressure. The crude product was purified by filtration to give
fluorinated aminosulfones 8-9.
9-[2-(1,3-Benzothiazole-2-sulfonyl)-2-fluoroethyl]-6-chloro-9H-purine
(8).
General
procedure B was followed with sulfone 1 (1.0 g, 4.11 mmol, 1 equiv), 6-chloropurine (703
mg, 4.52 mmol, 1.1 equiv) and TBAF (1 M in THF, 0.82 mL, 0.82 mmol, 0.2 equiv) in DMF
(20 mL). The CH2Cl2 was added to the crude product and the pure solid compound 8 was
1
recovered by filtration (1.21 g, 74%) as a yellow solid. Mp 207 °C; H NMR (DMSO, 400
MHz) δ 8.81 (s, 1H), 8.73 (s, 1H), 8.41–8.39 (m, 1H), 8.32–8.29 (m, 1H), 7.80–7.74 (m, 2H),
6.77 (ddd, 2JHF = 46.0 Hz, JHH = 7.5 Hz, JHH = 3.0 Hz, 1H), 5.34-5.10 (m, 2H); 13C NMR
(DMSO, 100 MHz) δ 161.5, 152.2, 152.1, 151.9, 149.1, 147.5, 137.1, 130.5, 128.9, 128.4,
125.3, 123.7, 99.0 (d, 1JCF = 223.5 Hz), 41.2 (d, 2JCF = 20.2 Hz); 19F NMR (DMSO, 376 MHz)
3
3
2
3
3
δ –181.9 (ddd, JFH = 46.0 Hz, JFH = 27.9 Hz, JFH = 19.2 Hz, 1F); MS (ESI) m/z 398 [M +
H]+ (100), 244 (79); HRMS (ESI) m/z [M + H]+ calcd for C14H10ClFN5O2S2 397.9948 and
399.9919, found 397.9953 and 399.9921.
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N-{9-[2-(1,3-Benzothiazole-2-sulfonyl)-2-fluoroethyl]-6-oxo-6,9-dihydro-1H-purine-2-
yl}-2-methylpropanamide (9). General procedure B was followed with sulfone 1 (200 mg,
0.82 mmol, 1 equiv), N2-(isobutanoyl)-guanine (200 mg, 0.90 mmol, 1.1 equiv) and TBAF (1
M in THF, 0.16 mL, 0.16 mmol, 0.2 equiv) in DMF (4 mL). The CH2Cl2 was added to the
crude product and the pure solid compound 9 was recovered by filtration (279 mg, 73%) as a
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beige solid as a mixture of regioisomers (N9/N7, 3:2). Mp 153 °C; H NMR (DMSO, 400
MHz) δ 12.18 (s, 1H, N9-isomer), 12.10 (s, 1H, N7-isomer), 11.75 (s, 1H, N7-isomer), 11.58
(s, 1H, N9-isomer), 8.41–8.39 (m, 2H, N9 and N7-isomer), 8.35–8.32 (m, 2H, N9 and N7-
isomer), 8.25 (s, 1H, N9-isomer), 8.05 (s, 1H, N7-isomer), 7.79–7.76 (m, 4H, N9 and N7-
3
3
isomer), 6.69 (ddd, 2JHF = 46.6 Hz, JHH = 8.4 Hz, JHH = 3.0 Hz, 1H, N7-isomer), 6.65 (ddd,
3
3
2JHF = 46.6 Hz, JHH = 8.4 Hz, JHH = 3.0 Hz, 1H, N9-isomer), 5.32–4.84 (m, 4H, N9 and N7-
isomers), 2.81-2.69 (m, 2H, N9 and N7-isomers), 1.13–1.10 (m, 12H, N9 and N7-isomer); 13C
NMR (DMSO, 100 MHz) δ 180.3 (N7-isomer), 180.0 (N9-isomer), 161.5 (2C, N9 and N7-
isomers), 157.2 (N9-isomer), 154.7 (N7-isomer), 152.7 (N9-isomer), 152.3 (2C, (N9 and N7-
isomer)), 149.0 (N7-isomer), 148.2 (N7-isomer), 147.4 (N9-isomer), 145.2 (N9-isomer), 140.0
(N9-isomer), 137.2 (2C, N9 and N7-isomer), 128.9 (2C, N9 and N7-isomer), 128.4 (2C, N9 and
N7-isomer), 125.4 (2C, N9 and N7-isomer), 123.7 (2C, N9 and N7-isomer), 119.8 (N7-isomer),
111.4 (N9-isomer), 99.4 (d, 1JCF = 222.9 Hz, N9-isomer), 99.0 (d, 1JCF = 223.5 Hz, N7-isomer),
43.7 (d, 2JCF = 20.9 Hz, N9-isomer), 40.5 (d, 2JCF = 20.7 Hz, N7-isomer), 18.9 (4C, N9 and N7-
isomer), 13.5 (2C, N9 and N7-isomer); 19F NMR (DMSO, 376 MHz) δ –182.4 (ddd, 2JFH = 46.6
3
3
2
3
Hz, JFH = 30.7 Hz, JFH = 16.0 Hz, 1F, N7-isomer), –184.0 (ddd, JFH = 46.6 Hz, JFH = 29.5
3
Hz, JFH = 15.1 Hz, 1F, N9-isomer); MS (ESI) m/z 465 [M + H]+ (42), 395 (35), 244 (100),
222 (18); HRMS (ESI) m/z [M + H]+ calcd for C18H18FN6O4S2 465.0815, found 465.0824.
3-Benzoyl-1-[2-(1,3-benzothiazole-2-sulfonyl)-2-fluoroethyl]-5-fluoro-1,2,3,4-
tetrahydropyrimidine-2,4-dione (10). To a solution of sulfone 5 (400 mg, 1.071 mmol, 1
equiv) and pyridine (0.26 mL, 3.21 mmol, 3 equiv) in MeCN (1 mL) were added dropwise
benzoyl chloride (0.14 mL, 1.18 mmol, 1.1 equiv) at 0 °C. The mixture was stirred for 48 h at
20 °C then toluene was added. The solvents were removed by evaporation under reduced
pressure. The crude product was purified by flash chromatography (CH2Cl2/AcOEt, 96:4) to
1
give the sulfone 10 (473 mg, 93%) as a white solid. Mp 135 °C; H NMR (CDCl3, 400 MHz)
δ 8.30–8.27 (m, 1H), 8.08–8.06 (m, 1H), 7.95–7.93 (m, 2H), 7.73–7.65 (m, 3H), 7.55–7.50
3
3
(m, 3H), 6.03 (ddd, 2JHF = 47.3 Hz, JHH = 7.0 Hz, JHH = 5.0 Hz, 1H), 4.75 (ddd, 3JHF = 20.5
2
3
2
3
Hz, JHH = 15.2 Hz, JHH = 5.0 Hz, 1H), 4.42 (ddd, 3JHF = 12.6 Hz, JHH = 15.2 Hz, JHH = 7.0
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 166.8, 168.8, 156.0 (d, 2JCF = 25.8 Hz), 152.5, 148.2,
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140.2 (d, JCF = 239.5 Hz), 137.3, 135.6, 130.5 (2C), 130.4, 129.3 (2C), 128.9 (d, 2JCF = 32.8
4
5
6
7
8
9
1
2
Hz), 128.8, 128.1, 125.7, 122.3, 97.4 (d, JCF = 225.3 Hz), 46.3 (d, JCF = 22.8 Hz); 19F NMR
3
2
3
(CDCl3, 376 MHz) δ –162.8 (d, JFH = 5.3 Hz, 1F), –182.3 (ddd, JFH = 47.3 Hz, JFH = 20.5
Hz, 3JFH = 12.6 Hz, 1F); MS (ESI) m/z 478 [M + H]+ (100), 105 (55); HRMS (ESI) m/z [M +
H]+ calcd for C20H14F2N3O5S2 478.0343, found 478.0349.
10
11
12
13
14
15
16
17
18
19
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23
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25
26
27
28
29
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General procedure C: preparation of fluorinated allylamines in the presence of
NaHMDS. To a solution of fluoroaminosulfone 5-10 (1 equiv), and aldehyde (1.05 equiv) at
–78 °C in THF (0.1 M) was added NaHMDS (1 M in THF, 1.5 equiv). After 30 min at –78
°C, the mixture was stirred for 1 h 30 at –20 °C, quenched with a saturated aqueous solution
of NH4Cl and extracted with CH2Cl2. Combined organic layers were washed with brine, dried
over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified
by flash column chromatography to give amino-alkenes 11-30a.
(Z/E)-3-Benzoyl-1-(2-fluoro-3-phenylprop-2-en-1-yl)-5-methyl-1,2,3,4-
tetrahydropyrimidine-2,4-dione (11). General procedure C was followed with aminosulfone
6 (100 mg, 0.21 mmol, 1 equiv), benzaldehyde (23 ꢀL, 0.22 mmol, 1.05 equiv) and NaHMDS
(1 M in THF, 0.32 mL, 0.32 mmol, 1.5 equiv) in THF (2 mL). The purification by flash
chromatography (pentane/AcOEt, 6:4) afforded compound 11 (67 mg, 87%) as a white oil
1
(E/Z = 5:95). (Z)-11: H NMR (CDCl3, 400 MHz) δ 7.94–7.92 (m, 2H), 7.66–7.62 (m, 1H),
4
7.51–7.46 (m, 4H), 7.38–7.34 (m, 2H), 7.31–7.27 (m, 1H), 7.23 (t, JHH = 1.0 Hz, 1H), 5.88
3
4
(d, JHFtrans = 38.1 Hz, 1H), 4.55 (d, 3JHF = 18.0 Hz, 2H), 1.96 (d, JHH = 1.0 Hz, 3H); 13C
1
NMR (CDCl3, 100 MHz) δ 168.8, 162.9, 152.5 (d, JCF = 266.6 Hz), 149.6, 139.1, 135.0,
4
131.7 (d, 3JCF = 3.5 Hz), 131.4, 130.3 (2C), 129.1 (2C), 128.9 (d, JCF = 7.3 Hz, 2C), 128.6
6
2
2
(2C), 128.2 (d, JCF = 2.5 Hz), 111.5 (d, JCF = 6.4 Hz), 111.2, 48.9 (d, JCF = 29.1 Hz), 12.3;
3
3
19F NMR (CDCl3, 376 MHz) δ –111.2 (dt, JFHtrans = 38.1 Hz, JFH = 18.0 Hz, 1F); MS
(EI) m/z 364 [M]+• (44), 105 (100), 77 (34); HRMS (ESI) m/z [M + Na]+ calcd for
1
C21H17FN2NaO3 387.1121, found 387.1139. (E)-11: H NMR (CDCl3, 400 MHz) δ 7.93–7.91
(m, 2H), 7.66–7.63 (m, 1H), 7.51–7.47 (m, 2H), 7.39–7.35 (m, 2H), 7.32–7.28 (m, 3H), 7.06
3
4
(m, 1H), 6.61 (d, JHFcis = 20.5 Hz, 1H), 4.74 (d, 3JHF = 17.2 Hz, 2H), 1.95 (d, JHH = 1.0 Hz,
1
3H); 13C NMR (CDCl3, 100 MHz) δ 168.7, 162.9, 153.5 (d, JCF = 254.2 Hz), 149.7, 139.0,
4
135.0, 131.5 (d, 3JCF = 11.4 Hz), 131.4, 130.5 (2C), 129.1 (2C), 128.9 (2C), 128.6 (d, JCF
=
2
2.7 Hz, 2C), 128.1, 113.9 (d, JCF = 24.6 Hz), 111.3, 44.7 (d, 2JCF = 26.9 Hz), 12.5; 19F NMR
3
3
(CDCl3, 376 MHz) δ −109.2 (dt, JFHcis = 20.4 Hz, JFH = 17.9 Hz, 1F); MS (EI) m/z 364
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[M]+• (44), 105 (100), 77 (34); HRMS (ESI) m/z [M
+
H]+ calcd for
C21H17FN2NaO3 387.1121, found 387.1139.
6
7
8
9
(Z/E)-3-Benzoyl-1-(2-fluoro-3-phenylprop-2-en-1-yl)-1,2,3,4-tetrahydropyrimidine-2,4-
dione (12). General procedure C was followed with aminosulfone 7 (100 mg, 0.22 mmol, 1
equiv), benzaldehyde (23 ꢀL, 0.23 mmol, 1.05 equiv) and NaHMDS (1 M in THF, 0.33 mL,
0.33 mmol, 1.5 equiv) in THF (2.2 mL). The purification by flash chromatography
(pentane/AcOEt, 1:1) afforded compound 12 (53 mg, 69%) as a yellow oil (E/Z = 6:94). (Z)-
12: 1H NMR (CDCl3, 400 MHz) δ 7.96–7.94 (m, 2H), 7.67–7.63 (m, 1H), 7.51–7.47 (m, 4H),
7.40 (d, 3JHH = 7.9 Hz, 1H), 7.38–7.28 (m, 3H), 5.89 (d, 3JHFtrans = 38.3 Hz, 1H), 5.84 (d, 3JHH
= 7.9 Hz, 1H), 4.57 (d, 3JHF = 17.9 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 168.5, 162.1,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
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37
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40
41
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44
45
46
47
48
49
50
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52
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54
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60
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152.1 (d, JCF = 266.5 Hz), 149.6, 143.3, 135.2, 131.6 (d, 3JCF = 3.2 Hz), 131.2, 130.4 (2C),
129.2 (2C), 129.0 (d, 4JCF = 7.1 Hz, 2C), 128.6 (2C), 128.3 (d, 6JCF = 2.1 Hz), 111.9 (d, 2JCF =
2
3
5.8 Hz), 102.6, 49.3 (d, JCF = 29.0 Hz); 19F NMR (CDCl3, 376 MHz) δ –111.6 (dt, JFHtrans
=
3
38.3 Hz, JFH = 17.9 Hz, 1F); MS (ESI) m/z 351 [M + H]+ (52), 135 (26), 105 (100); HRMS
(ESI) m/z [M + H]+ calcd for C20H16FN2O3 351.1145, found 351.1148. (E)-12: 19F NMR
3
3
(CDCl3, 376 MHz) δ –109.2 (dt, JFHcis = 20.4 Hz, JFH = 17.9 Hz, 1F); MS (ESI) m/z 351 [M
+ H]+ (52), 135 (26), 105 (100); HRMS (ESI) m/z [M + H]+ calcd for C20H16FN2O3 351.1145,
found 351.1148.
(Z/E)-5-Fluoro-1-(2-fluoro-3-phenylprop-2-en-1-yl)-1,2,3,4-tetrahydropyrimidine-2,4-
dione (13). General procedure C was followed with aminosulfone 5 (100 mg, 0.27 mmol, 1
equiv), benzaldehyde (29 ꢀL, 0.28 mmol, 1.05 equiv) and NaHMDS (1 M in THF, 0.80 mL,
0.80 mmol, 3 equiv) in THF (3 mL). The purification by flash chromatography
(CH2Cl2/AcOEt, 85:15) afforded compound 13 (49 mg, 69%) as a colorless oil (E/Z = 47:53).
1H NMR (CDCl3, 400 MHz) δ 9.10 (s, 2H, E and Z), 7.51–7.21 (m, 12H, E and Z), 6.62 (d,
3
3JHFcis = 20.3 Hz, 1H, E), 5.92 (d, 3JHFtrans = 38.1 Hz, 1H, Z), 4.70 (d, JHF = 17.8 Hz, 2H, E),
2
4.55 (d, 3JHF = 17.6 Hz, 2H, Z); 13C NMR (CDCl3, 100 MHz) δ 156.7 (d, JCF = 27.3 Hz, E),
156.7 (d, 2JCF = 26.5 Hz, Z), 153.2 (d, 1JCF = 253.5 Hz, Z), 151.9 (d, 1JCF = 266.3 Hz, E), 149.2
(Z), 149.1 (E), 140.8 (d, 1JCF = 239.8 Hz, E), 140.6 (d, 1JCF = 238.9 Hz, Z), 131.4 (d, 3JCF = 3.5
Hz, E), 131.3 (d, 3JCF = 11.5 Hz, Z), 129.1 (Z or E), 129.0 (2C, Z or E), 128.8 (Z or E), 128.7
(Z or E), 128.6 (d, 4JCF = 2.5 Hz, 2C, Z), 128.4 (d, 4JCF = 2.0 Hz, 2C, E), 128.3 (Z or E), 127.6
(d, 2JCF = 33.2 Hz, E), 127.5 (d, 2JCF = 32.2 Hz, Z), 114.4 (d, 2JCF = 23.8 Hz, Z), 112.1 (d, 2JCF
2
2
= 6.4 Hz, E), 49.3 (d, JCF = 29.7 Hz, E), 44.9 (d, JCF = 27.7 Hz, Z); 19F NMR (CDCl3, 376
3
3
3
MHz) δ –109.1 (dt, JFHcis = 20.3 Hz, JFH = 17.8 Hz, 1F, E), −111.4 (dt, JFHtrans = 38.1 Hz,
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3JFH = 17.6 Hz, Z), –164.4 (m, 1F, E and Z); MS (ESI) m/z 365 [M + H]+ (34), 135 (100);
HRMS (ESI) m/z [M + H]+ calcd for C13H11F2N2O2 265.0789, found 265.0796.
6
7
(Z/E)-3-Benzoyl-5-fluoro-1-(2-fluoro-3-phenylprop-2-en-1-yl)-1,2,3,4-
tetrahydropyrimidine-2,4-dione (14). General procedure C was followed with aminosulfone
10 (130 mg, 0.27 mmol, 1 equiv), benzaldehyde (29 ꢀL, 0.29 mmol, 1.05 equiv) and
NaHMDS (1 M in THF, 0.41 mL, 0.41 mmol, 1.5 equiv) in THF (3 mL). The purification by
flash chromatography (pentane/AcOEt, 6:4) afforded compound 14 (39 mg, 39%) as a yellow
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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31
32
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34
35
36
37
38
39
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44
45
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48
49
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51
52
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60
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oil (E/Z = 5:95). (Z)-14: H NMR (CDCl3, 400 MHz) δ 7.94–7.92 (m, 2H), 7.69–7.65 (m,
3
1H), 7.52–7.48 (m, 5H), 7.38–7.29 (m, 3H), 5.90 (d, JHFtrans = 38.2 Hz, 1H), 4.55 (d, 3JHF
=
17.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 167.0, 156.1 (d, 2JCF = 26.0 Hz), 151.7 (d, 1JCF
1
= 265.7 Hz), 148.2, 140.1 (d, JCF = 239.7 Hz), 135.5, 131.4 (d, 3JCF = 2.9 Hz), 130.8, 130.5
4
6
(2C), 129.3 (2C), 129.0 (d, JCF = 7.3 Hz, 2C), 128.6 (2C), 128.4 (d, JCF = 2.2 Hz), 127.5 (d,
2
2
2JCF = 32.5 Hz), 112.4 (d, JCF = 6.5 Hz), 49.5 (d, JCF = 28.9 Hz); 19F NMR (CDCl3, 376
MHz) δ –111.8 (dt, 3JFHtrans = 38.2 Hz, 3JFH = 17.8 Hz, 1F), –163.7 (d, 3JFH = 5.2 Hz, 1F); MS
(ESI) m/z 369 [M + H]+ (100), 135 (69), 105 (78); HRMS (ESI) m/z [M + H]+ calcd for
C20H15F2N2O3 369.1051, found 369.1063. (E)-14: 19F NMR (CDCl3, 376 MHz) δ –109.2 (dt,
3
3JFHcis = 20.1 Hz, JFH = 17.4 Hz, 1F), –163.5 (d, 3JFH = 5.2 Hz, 1F); MS (ESI) m/z 369 [M +
H]+ (100), 135 (69), 105 (78); HRMS (ESI) m/z [M + H]+ calcd for C20H15F2N2O3 369.1051,
found 369.1063.
General procedure D: preparation of fluorinated allylamines in the presence of tBuOK.
To a solution of fluoroaminosulfone 8-9 (1 equiv), and aldehyde (1.05 equiv) at –17 °C in
THF (0.1 M) was added tBuOK (2 equiv). After 10 min at –17 °C, the mixture was stirred at
20 °C, (4 h to 8 h) quenched with a saturated aqueous solution of NH4Cl and extracted with
CH2Cl2. Combined organic layers were washed with brine, dried over MgSO4, filtered and
evaporated under reduced pressure. The crude product was purified by flash column
chromatography to give amino-alkenes 15-16.
(Z/E)-6-Chloro-9-(2-fluoro-3-phenylprop-2-en-1-yl)-9H-purine (15). General procedure D
was followed with aminosulfone 8 (100 mg, 0.25 mmol, 1 equiv), benzaldehyde (27 ꢀL, 0.26
mmol, 1.05 equiv) and tBuOK (37 mg, 0.33 mmol, 2 equiv) in THF (2.5 mL). The mixture
was stirred during 4 h. The purification by flash chromatography (CH2Cl2/AcOEt, 9:1)
1
afforded compound 15 (47 mg, 61%) as a colorless oil (E/Z = 55:45). (Z)-15: H NMR
(CDCl3, 400 MHz) δ 8.78 (s, 1H), 8.26 (s, 1H), 7.50–7.47 (m, 2H), 7.36–7.28 (m, 3H), 5.99
(d, 3JHFtrans = 37.7 Hz, 1H), 5.12 (d, 3JHF = 17.1 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 152.3,
3
151.7, 151.6 (d, 1JCF = 265.8 Hz), 151.3, 144.7, 131.5, 131.3 (d, JCF = 3.4 Hz), 128.8 (d, 4JCF
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= 7.3 Hz, 2C), 128.7 (2C), 128.4 (d, JCF = 2.4 Hz), 111.4 (d, JCF = 6.3 Hz), 45.5 (d, JCF
=
4
5
6
7
3
3
30.7 Hz); 19F NMR (CDCl3, 376 MHz) δ –110.6 (dt, JFHtrans = 37.7 Hz, JFH = 17.1 Hz, 1F);
MS (ESI) m/z 289 [M + H]+ (100), 135 (21); HRMS (ESI) m/z [M + H]+ calcd for
1
C14H11ClFN4 289.0656 and 291.0627, found 289.0669 and 291.0636. (E)-15: H NMR
8
9
5
(CDCl3, 400 MHz) δ 8.77 (s, 1H), 8.17 (d, JHF = 1.1 Hz, 1H), 7.44–7.33 (m, 5H), 6.64 (d,
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
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38
39
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44
45
46
47
48
49
50
51
52
53
54
55
56
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59
60
3JHFcis = 19.6 Hz, 1H), 5.22 (d, 3JHF = 19.1 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 152.9 (d,
5
3
1JCF = 254.1 Hz), 152.2, 151.7, 151.2, 144.8 (d, JCF = 1.6 Hz), 131.5 (d, JCF = 11.5 Hz),
4
2
131.3, 129.0 (2C), 128.6 (d, JCF = 2.4 Hz, 2C), 128.3, 114.0 (d, JCF = 24.1 Hz), 41.5 (d, 2JCF
3
3
= 28.3 Hz); 19F NMR (CDCl3, 376 MHz) δ –107.2 (dt, JFHcis = 19.6 Hz, JFH = 19.1 Hz, 1F);
MS (ESI) m/z 289 [M + H]+ (100), 135 (21); HRMS (ESI) m/z [M + H]+ calcd for
C14H11ClFN4 289.0656 and 291.0627, found 289.0669 and 291.0636.
(Z/E)-N-[9-(2-Fluoro-3-phenylprop-2-en-1-yl)-6-oxo-6,9-dihydro-1H-purin-2-yl]-2-
methylpropanamide (16). General procedure D was followed with aminosulfone 9 (100 mg,
0.22 mmol, 1 equiv), benzaldehyde (23 ꢀL, 0.23 mmol, 1.05 equiv) and tBuOK (48 mg, 0.43
mmol, 2 equiv) in THF (2.1 mL). The mixture was stirred during 8 h. The purification by
flash chromatography (CH2Cl2/MeOH, 94:6) afforded compound 16 (42 mg, 55%) as a white
oil (E/Z = 2:3). N7-(Z)-16: 1H NMR (CDCl3, 400 MHz) δ 12.02 (s, 1H), 8.26 (s, 1H), 7.77 (s,
1H), 7.47–7.44 (m, 2H), 7.35–7.27 (m, 3H), 5.74 (d, 3JHFtrans = 37.9 Hz, 1H), 4.84 (d, 3JHF
=
15.2 Hz, 2H), 2.68-2.62 (m, 1H), 1.30 (s, 3H), 1.28 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 178.0, 155.5, 152.7 (d, 1JCF = 288.9 Hz), 151.3, 147.5, 138.6, 131.6 (d, 3JCF = 3.4 Hz), 128.8
4
2
(d, JCF = 7.4 Hz, 2C), 128.7 (2C), 128.3 (d, 6JCF = 2.9 Hz), 121.2, 110.1 (d, JCF = 6.9 Hz),
44.7 (d, 2JCF = 32.4 Hz), 36.6, 19.0 (2C); 19F NMR (CDCl3, 376 MHz) δ –110.0 (dt, 3JFHtrans
=
3
37.9 Hz, JFH = 15.2 Hz, 1F); MS (ESI) m/z 356 [M + H]+ (52), 222 (13), 135 (100); HRMS
(ESI) m/z [M + H]+ calcd for C18H19FN5O2 356.1523, found 356.1526. N9-(Z)-16, N9-(E)-16
1
& N7-(E)-16: H NMR (CDCl3, 400 MHz) δ 12.59, 12.38, 12.35 (s, 3H, ZN9, EN9 and EN7),
10.73, 10.71, 9.84 (s, 3H, ZN9, EN9 and EN7), 7.91 (s, 1H, EN9), 7.83 (d, J = 1.0 Hz, 1H, EN7),
5
7.72 (d, JHF = 0.8 Hz, 1H, ZN9), 7.48-7.22 (m, 15H, ZN9, EN9, EN7), 6.62 (d, 3JHFcis = 19.8 Hz,
1H, EN7), 6.52 (d, 3JHFcis = 19.8 Hz, 1H, EN9), 6.06 (d, 3JHFtrans = 37.9 Hz, 1H, ZN9), 5.40 (d,
3JHF = 18.5 Hz, 2H, EN7), 5.22 (d, 3JHF = 18.5 Hz, 2H, EN9), 4.96 (d, 3JHF = 19.4 Hz, 2H, ZN9),
2.96–2.83 (m, 3H, ZN9, EN9 and EN7), 1.26–1.22 (m, 18H, ZN9, EN9 and EN7); 13C NMR
(CDCl3, 100 MHz) δ 180.1 (EN9), 180.0 (EN7), 178.1 (ZN9), 156.8 (ZN9 or EN9 or EN7), 156.6
(ZN9 or EN9 or EN7), 156.3 (ZN9 or EN9 or EN7), 153.6 (d, 1JCF = 253.0 Hz, EN9), 153.4 (d, 1JCF =
253.0 Hz, EN7), 152.4 (d, 1JCF = 265.7 Hz, ZN9), 153.1 (ZN9 or EN9 or EN7), 149.0 (ZN9 or EN9 or
EN7), 148.3 (ZN9 or EN9 or EN7), 148.2 (ZN9 or EN9 or EN7), 147.3 (ZN9 or EN9 or EN7), 143.0
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(EN9), 142.5 (EN7), 138.7 (ZN9), 131.8 (ZN9 or EN9 or EN7), 131.6 (ZN9 or EN9 or EN7), 128.9 (ZN9
or EN9 or EN7), 128.9 (2C, ZN9 or EN9 or EN7), 128.8 (2C, ZN9 or EN9 or EN7), 128.8 (2C, ZN9 or
6
7
8
E
N9 or EN7), 128.5 (2C, ZN9 or EN9 or EN7), 128.5 (2C, ZN9 or EN9 or EN7), 128.5 (2C, ZN9 or EN9
or EN7), 128.4 (ZN9 or EN9 or EN7), 128.4 (ZN9 or EN9 or EN7), 128.1 (ZN9 or EN9 or EN7), 127.9
9
2
2
(ZN9 or EN9 or EN7), 120.4 (ZN9 or EN9 or EN7), 113.9 (d, JCF = 24.2 Hz, EN9), 113.3 (d, JCF =
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24.2 Hz, EN7), 112.0 (ZN9 or EN9 or EN7), 111.7 (ZN9 or EN9 or EN7), 111.1 (d, JCF = 5.5 Hz,
ZN9), 48.2 (d, 2JCF = 29.1 Hz, EN9), 44.0 (d, 2JCF = 27.7 Hz, EN7), 40.9 (d, 2JCF = 29.1 Hz, ZN9),
38.7 (EN7), 35.9 (EN9), 35.9 (ZN9), 19.0 (6C, ZN9, EN9 and EN7); 19F NMR (CDCl3, 376 MHz)
δ –106.6 (dt, JFHcis = 19.8 Hz, JFH = 18.5 Hz, 1F, EN9), –107.4 (dt, JFHcis = 19.8 Hz, JFH
18.5 Hz, 1F, EN7), –111.1 (dt, JFHtrans = 37.9 Hz, JFH = 19.4 Hz, 1F, ZN9); MS (ESI) m/z 356
[M + H]+ (52), 222 (13), 135 (100); HRMS (ESI) m/z [M + H]+ calcd for
C18H19FN5O2 356.1523, found 356.1526.
3
3
3
3
=
3
3
(Z/E)-3-Benzoyl-1-[2-fluoro-3-(4-methoxyphenyl)prop-2-en-1-yl]-5-methyl-1,2,3,4-
tetrahydropyrimidine-2,4-dione (17a). General procedure
C
was followed with
aminosulfone 6 (100 mg, 0.21 mmol, 1 equiv), p-methoxybenzaldehyde (27 ꢀL, 0.22 mmol,
1.05 equiv) and NaHMDS (1 M in THF, 0.32 mL, 0.32 mmol, 1.5 equiv) in THF (2 mL). The
purification by flash chromatography (pentane/AcOEt, 6:4) afforded compound 17a (66 mg,
1
79%) as a colorless oil (E/Z = 4:96). (Z)-17a: H NMR (CDCl3, 400 MHz) δ 7.93–7.91 (m,
2H), 7.65–7.61 (m, 1H), 7.50–7.43 (m, 4H), 7.23 (s, 1H), 6.89–6.87 (m, 2H), 5.82 (d, 3JHFtrans
= 38.6 Hz, 1H), 4.53 (d, 3JHF = 18.4 Hz, 2H), 3.81 (s, 3H), 1.96 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 168.8, 162.9, 159.3 (d, 6JCF = 2.8 Hz), 151.1 (d, 1JCF = 163.4 Hz), 149.6, 139.1, 135.0,
131.4, 130.3 (2C), 130.2 (d, JCF = 7.9 Hz, 2C), 129.1 (2C), 124.3 (d, 3JCF = 3.0 Hz), 113.9
(2C), 111.2 (d, JCF = 8.5 Hz), 111.1, 55.2, 48.9 (d, JCF = 29.3 Hz), 12.3; 19F NMR (CDCl3,
4
2
2
3
3
376 MHz) δ −114.2 (dt, JFHtrans = 38.6 Hz, JFH = 18.4 Hz, 1F); MS (EI) m/z 395 [M +
H]+ (81), 165 (100); HRMS (ESI) m/z [M + H]+ calcd for C22H20FN2O4 395.1407, found
1
395.1408. (E)-17a: H NMR (CDCl3, 400 MHz) δ 7.93–7.91 (m, 2H), 7.66–7.63 (m, 1H),
7.51–7.47 (m, 2H), 7.23–7.21 (m, 2H), 7.08 (m, 1H), 6.90–6.88 (m, 2H), 6.54 (d, 3JHFcis = 20.7
Hz, 1H), 4.73 (d, 3JHF = 17.6 Hz, 2H), 3.80 (s, 3H), 1.95 (d, 4JHH = 0.9 Hz, 3H); 13C NMR
1
(CDCl3, 100 MHz) δ 168.7, 162.9, 159.4, 152.7 (d, JCF = 250.0 Hz), 149.8, 139.0, 135.0,
131.5, 130.5 (2C), 129.8 (d, JCF = 2.5 Hz, 2C), 129.1 (2C), 123.7 (d, 3JCF = 11.8 Hz), 114.4
(2C), 113.6 (d, JCF = 25.3 Hz), 111.2, 55.3, 44.8 (d, JCF = 27.7 Hz), 12.5; 19F NMR (CDCl3,
376 MHz) δ –110.2 (dt, 3JFHcis = 20.7 Hz, 3JFH = 17.6 Hz, 1F); MS (EI) m/z 395 [M + H]+ (81),
165 (100); HRMS (ESI) m/z [M + H]+ calcd for C22H20FN2O4 395.1407, found 395.1408.
4
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(Z/E)-3-Benzoyl-1-[3-(4-bromophenyl)-2-fluoroprop-2-en-1-yl]-5-methyl-1,2,3,4-
3
4
5
tetrahydropyrimidine-2,4-dione (18a). General procedure
C
was followed with
6
7
8
9
aminosulfone 6 (100 mg, 0.21 mmol, 1 equiv), p-bromobenzaldehyde (41 mg, 0.22 mmol,
1.05 equiv) and NaHMDS (1 M in THF, 0.32 mL, 0.32 mmol, 1.5 equiv) in THF (2 mL). The
purification by flash chromatography (pentane/AcOEt, 6:4) afforded compound 18a (81 mg,
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13
14
15
16
17
18
19
20
21
22
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60
1
86%) as a yellow solid (E/Z = 8:92). Mp 219 °C; (Z)-18a: H NMR (CDCl3, 400 MHz) δ
7.93–7.91 (m, 2H), 7.66–7.62 (m, 1H), 7.51–7.46 (m, 4H), 7.38–7.34 (m, 2H), 7.20 (t, 4JHH
1.0 Hz, 1H), 5.83 (d, 3JHFtrans = 37.6 Hz, 1H), 4.55 (d, 3JHF = 17.9 Hz, 2H), 1.99 (d, 4JHH = 1.0
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.7, 162.9, 153.0 (d, JCF = 267.6 Hz), 149.6,
139.1, 135.1, 131.7 (2C), 131.4, 130.6 (d, 6JCF = 2.8 Hz), 130.5, 130.4 (3C), 129.1 (2C), 122.1
=
1
2
2
2
(d, JCF = 3.6 Hz), 111.4, 110.5 (d, JCF = 6.1 Hz), 49.0 (d, JCF = 29.4 Hz), 12.4; 19F NMR
3
3
(CDCl3, 376 MHz) δ –110.0 (dt, JFHtrans = 37.6 Hz, JFH = 17.9 Hz, 1F); MS (EI) m/z 444
[M]+• (22), 442 (21), 105 (100), 77 (32); HRMS (ESI) m/z [M + Na]+ calcd for
1
C21H16BrFN2NaO3 465.0226, found 465.0210. (E)-18a: H NMR (CDCl3, 400 MHz) δ 7.92–
4
7.90 (m, 2H), 7.66–7.62 (m, 1H), 7.51–7.46 (m, 4H), 7.20–7.18 (m, 2H), 7.07 (t, JHH = 1.1
Hz, 1H), 6.49 (d, 3JHFcis = 20.3 Hz, 1H), 4.68 (d, 3JHF = 17.4 Hz, 2H), 1.95 (d, 4JHH = 1.1 Hz,
1
3H); 13C NMR (CDCl3, 100 MHz) δ 168.6, 162.9, 153.9 (d, JCF = 254.3 Hz), 149.7, 139.2,
4
135.1, 132.0 (2C), 131.4, 130.5 (2C), 130.4, 130.2 (d, JCF = 2.7 Hz, 2C), 129.1 (2C), 122.2,
112.7 (d, 2JCF = 25.7 Hz), 111.4, 45.0 (d, 2JCF = 26.4 Hz), 12.5; 19F NMR (CDCl3, 376 MHz) δ
–107.6 (dt, JFHcis = 20.3 Hz, JFH = 17.4 Hz, 1F); MS (EI) m/z 444 [M]+• (22), 442 (21), 105
(100), 77 (32); HRMS (ESI) m/z [M + Na]+ calcd for C21H16BrFN2NaO3 465.0226, found
465.0210.
3
3
(Z/E)-3-Benzoyl-1-[2-fluoro-3-(4-nitrophenyl)prop-2-en-1-yl]-5-methyl-1,2,3,4-
tetrahydropyrimidine-2,4-dione (19a). General procedure
C
was followed with
aminosulfone 6 (100 mg, 0.21 mmol, 1 equiv), p-nitrobenzaldehyde (34 mg, 0.22 mmol, 1.05
equiv) and NaHMDS (1 M in THF, 0.32 mL, 0.32 mmol, 1.5 equiv) in THF (2 mL). The
purification by flash chromatography (pentane/AcOEt, 1:1) afforded compound 19a (54 mg,
63%) as a yellow oil (E/Z = 32:68). (Z)-19a: 1H NMR (CDCl3, 400 MHz) δ 8.18 (d, 3JHH = 9.0
Hz, 2H), 7.93–7.91 (m, 2H), 7.67–762 (m, 3H), 7.50–7.46 (m, 2H), 7.22 (m, 1H), 5.97 (d,
3JHFtrans = 36.7 Hz, 1H), 4.60 (d, 3JHF = 17.4 Hz, 2H), 1.98 (d, 4JHH = 0.7 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 168.6, 162.8, 155.3 (d, 1JCF = 273.3 Hz), 149.6, 146.9 (d, 6JCF = 3.6 Hz),
3
4
139.1, 138.2 (d, JCF = 3.7 Hz), 135.2, 131.3, 130.4 (2C), 129.6 (d, JCF = 7.9 Hz, 2C), 129.2
(2C), 123.8 (2C), 111.7, 109.6 (d, JCF = 6.1 Hz), 49.0 (d, JCF = 28.0 Hz), 12.4; 19F NMR
2
2
3
3
(CDCl3, 376 MHz) δ –105.6 (dt, JFHtrans = 36.7 Hz, JFH = 17.4 Hz); MS (ESI) m/z 410 [M +
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H]+ (73), 105 (100); HRMS (ESI) m/z [M + H]+ calcd for C21H17FN3O5 410.1152, found
4
5
6
7
1
410.1149. (E)-19a: H NMR (CDCl3, 400 MHz) δ 8.20–8.18 (m, 2H), 7.92–7.90 (m, 2H),
3
7.68–7.63 (m, 1H), 7.55 (d, JHH = 8.5 Hz, 2H), 7.51–7.48 (m, 2H), 7.13 (m, 1H), 6.56 (d,
3JHFcis = 20.5 Hz, 1H), 4.70 (d, 3JHF = 17.4 Hz, 2H), 1.97 (d, 4JHH = 1.2 Hz, 3H); 13C NMR
8
9
1
(CDCl3, 100 MHz) δ 168.6, 162.8, 155.3 (d, JCF = 258.1 Hz), 149.6, 147.2, 139.6, 138.4 (d,
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4
3JCF = 13.1 Hz), 135.2, 131.3, 130.5 (2C), 129.5 (d, JCF = 2.6 Hz, 2C), 129.2 (2C), 124.0
(2C), 111.8 (d, JCF = 27.2 Hz), 111.5, 45.4 (d, JCF = 26.2 Hz), 12.4; 19F NMR (CDCl3, 376
2
2
MHz) δ –103.8 (dt, JFHcis = 20.5 Hz, JFH = 17.4 Hz, 1F); MS (ESI) m/z 410 [M + H]+ (73),
105 (100); HRMS (ESI) m/z [M + H]+ calcd for C21H17FN3O5 410.1152, found 410.1149.
(Z/E)-1-[3-(Anthracen-9-yl)-2-fluoroprop-2-en-1-yl]-3-benzoyl-5-methyl-1,2,3,4-
3
3
tetrahydropyrimidine-2,4-dione (20a). General procedure
C
was followed with
aminosulfone 6 (100 mg, 0.21 mmol, 1 equiv), 9-anthraldehyde (46 mg, 0.22 mmol, 1.05
equiv) and NaHMDS (1 M in THF, 0.32 mL, 0.32 mmol, 1.5 equiv) in THF (2 mL). The
purification by flash chromatography (CH2Cl2, 100%) afforded compound 20a (80 mg, 82%)
as a yellow oil (E/Z = 17:83). (Z)-20a: 1H NMR (CDCl3, 400 MHz) δ 8.45 (s, 1H), 8.02–7.98
(m, 6H), 7.68–7.63 (m, 1H), 7.50–7.41 (m, 6H), 7.26 (m, 1H), 6.72 (d, 3JHFtrans = 36.6 Hz,
1H), 4.76 (d, 3JHF = 16.9 Hz, 2H), 1.95 (d, 4JHH = 1.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ 168.8, 162.9, 153.4 (d, 1JCF = 263.0 Hz), 149.7, 139.6, 135.0, 131.4 (2C), 131.1, 130.4 (2C),
129.4, 129.2 (2C), 128.7 (2C), 127.6, 126.0 (2C), 125.4 (2C), 125.2 (2C), 124.6 (2C), 111.4,
107.9 (d, JCF = 12.4 Hz), 49.1 (d, JCF = 29.9 Hz), 12.3; 19F NMR (CDCl3, 376 MHz) δ –
107.4 (dt, 3JFHtrans = 36.6 Hz, 3JFH = 16.9 Hz, 1F); MS (ESI) m/z 465 [M + H]+ (100), 235 (72),
105 (21); HRMS (ESI) m/z [M + H]+ calcd for C29H22FN2O3 465.1614, found 465.1623. (E)-
20a: 1H NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.10–8.05 (m, 4H), 7.81–7.79 (m, 2H), 7.62–
2
2
7.52 (m, 5H), 7.50–7.41 (m, 2H), 7.07 (d, 3JHFcis = 15.6 Hz, 1H), 6.22 (m, 1H), 4.18 (d, 3JHF
16.5 Hz, 2H), 1.57 (d, 4JHH = 1.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.6, 162.6, 156.2
=
1
(d, JCF = 261.2 Hz), 149.5, 138.6, 134.9, 131.4 (2C), 131.3, 130.3 (2C), 129.5, 129.1 (4C),
2
128.1, 126.8 (2C), 125.6 (2C), 124.9 (2C), 124.4 (2C), 110.8, 108.8 (d, JCF = 22.6 Hz), 44.8
(d, JCF = 30.6 Hz), 12.1; 19F NMR (CDCl3, 376 MHz) δ –103.7 (dt, JFHcis = 15.6 Hz, JFH
16.5 Hz, 1F); MS (ESI) m/z 465 [M + H]+ (100), 235 (72), 105 (21); HRMS (ESI) m/z [M +
H]+ calcd for C29H22FN2O3 465.1614, found 465.1623.
2
3
3
=
(Z/E)-3-Benzoyl-1-[2-fluoro-3-(pyridin-3-yl)prop-2-en-1-yl]-5-methyl-1,2,3,4-
tetrahydropyrimidine-2,4-dione (21a). General procedure
C
was followed with
aminosulfone 6 (100 mg, 0.21 mmol, 1 equiv), 3-pyridinecarboxaldehyde (21 ꢀL, 0.22 mmol,
1.05 equiv) and NaHMDS (1 M in THF, 0.32 mL, 0.32 mmol, 1.5 equiv) in THF (2 mL). The
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purification by flash chromatography (CH2Cl2/AcOEt, 1:1) afforded compound 21a (47 mg,
4
5
1
61%) as a colorless oil (E/Z = 16:84). H NMR (CDCl3, 400 MHz) δ 8.64 (s, 2H, Z and E),
8.49–8.48 (m, 2H, Z and E), 7.92–7.88 (m, 4H, Z and E), 7.85 (d, 3JHH = 8.0 Hz, 1H, Z), 7.75
(d, 3JHH = 8.0 Hz, 1H, E), 7.65–7.61 (m, 2H, Z and E), 7.49–7.45 (m, 4H, Z and E), 7.29–7.26
(m, 2H, Z and E), 7.22 (m, 1H, Z), 7.11 (m, 1H, E), 6.48 (d, 3JHFcis = 19.7 Hz, 1H, E), 5.87 (d,
3JHFtrans = 38.1 Hz, 1H, Z), 4.66 (d, 3JHF = 17.2 Hz, 2H, E), 4.57 (d, 3JHF = 17.6 Hz, 2H, Z), 1.95
(m, 3H, Z), 1.93 (m, 3H, E); 13C NMR (CDCl3, 100 MHz) δ 168.7 (Z), 168.6 (E), 162.8 (2C, Z
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
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1
4
and E), 154.8 (d, JCF = 256.9 Hz, E), 154.3 (d, JCF = 269.2 Hz, Z), 149.7 (d, JCF = 6.7 Hz,
2C, Z and E), 149.6 Z, 149.5 (E), 149.4 (d, 6JCF = 2.8 Hz, E), 148.8 (d, 6JCF = 2.5 Hz, Z), 139.5
4
(E), 139.1 (Z), 135.7 (d, JCF = 8.9 Hz, 2C, Z and E), 135.1 (2C, Z and E), 131.3 (E), 131.2
(Z), 130.4 (2C, Z and E), 130.3 (2C, Z and E), 129.1 (4C, Z and E), 127.9 (d, 3JCF = 3.2 Hz, Z),
3
2
127.8 (d, JCF = 5.1 Hz, Z), 123.6 (E), 123.5 (Z), 111.5 (Z), 111.3 (E), 109.9 (d, JCF = 26.3
2
2
2
Hz, E), 108.1 (d, JCF = 6.4 Hz, Z), 48.8 (d, JCF = 28.4 Hz, Z), 45.1 (d, JCF = 25.6 Hz, E),
3
3
12.4 (2C, Z and E); 19F NMR (CDCl3, 376 MHz) δ –105.5 (dt, JFH = 17.2 Hz, JFHcis = 19.7
3
3
Hz, 1F, E), –108.2 (dt, JFHtrans = 38.1 Hz, JFH = 17.6 Hz, 1F, Z); MS (ESI) m/z 366 [M +
H]+ (32), 105 (100); HRMS (ESI) m/z [M + H]+ calcd for C20H17FN3O3 366.1254, found
366.1262.
(Z/E)-3-Benzoyl-1-(3-cyclohexyl-2-fluoroprop-2-en-1-yl)-5-methyl-1,2,3,4-
tetrahydropyrimidine-2,4-dione (22a). General procedure
C
was followed with
aminosulfone 6 (100 mg, 0.21 mmol, 1 equiv), cyclohexanecarboxaldehyde (27 ꢀL, 0.22
mmol, 1.05 equiv) and NaHMDS (1 M in THF, 0.32 mL, 0.32 mmol, 1.5 equiv) in THF (2
mL). The purification by flash chromatography (pentane/AcOEt, 8:2) afforded compound 22a
1
(65 mg, 83%) as a colorless oil (E/Z = 28:72). H NMR (CDCl3, 400 MHz) δ 7.91–7.89 (m,
4H, E and Z), 7.65–7.62 (m, 2H, E and Z), 7.50–7.46 (m, 4H, E and Z), 7.14 (m, 2H, E and Z),
5.25 (dd, 3JHFcis = 21.2 Hz, 3JHH = 10.8 Hz, 1H, E), 4.85 (dd, 3JHFtrans = 37.1 Hz, 3JHH = 9.3 Hz,
1H, Z), 4.51 (d, 3JHF = 20.1 Hz, 2H, E), 4.36 (d, 3JHF = 17.4 Hz, 2H, Z), 2.50–2.41 (m, 1H, Z),
2.35–2.29 (m, 1H, E), 1.96 (d, 4JHH = 1.1 Hz, 3H, Z), 1.91 (d, 4JHH = 2.6 Hz, 3H, E), 1.79–1.63
(m, 6H, Z and E), 1.49–1.40 (m, 2H, Z and E), 1.40–1.00 (m, 10H, Z and E), 0.90–0.83 (m,
2H, Z and E); 13C NMR (CDCl3, 100 MHz) δ 168.8 (E), 168.7 (Z), 163.0 (E), 162.9 (Z), 151.3
1
1
(d, JCF = 247.4 Hz, E), 150.7 (d, JCF = 254.1 Hz, Z), 149.5 (E), 149.4 (Z), 139.4 (E), 138.9
(Z), 135.0 (2C, E and Z), 131.4 (2C, Z and E), 130.4 (2C, E), 130.3 (2C, Z), 129.1 (4C, E and
2
2
Z), 118.3 (d, JCF = 15.1 Hz, E), 118.1 (d, JCF = 12.8 Hz, Z), 111.0 (Z), 110.9 (E), 48.1 (d,
2
4
3
2JCF = 30.2 Hz, Z), 44.3 (d, JCF = 28.6 Hz, E), 34.8 (d, JCF = 6.4 Hz, E), 33.5 (d, JCF = 2.2
3
Hz, E), 33.4 (d, JCF = 2.4 Hz, Z), 32.6 (d, 4JCF = 1.2 Hz, Z), 29.6 (E), 28.7 (Z), 25.7 (Z), 25.5
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(2C, Z), 25.4 (E), 25.3 (2C, E), 12.4 (2C, E and Z); 19F NMR (CDCl3, 376 MHz) δ –113.5 (dt,
3JFHcis = 21.2 Hz, 3JFH = 20.1 Hz, 1F, E), –118.4 (dt, 3JFHtrans = 37.1 Hz, 3JFH = 17.4 Hz, 1F, Z);
MS (EI) m/z 371 [M + H]+ (84), 105 (100); HRMS (ESI) m/z [M + H]+ calcd for
C21H24FN2O3 371.1771, found 371.1786.
9
(Z/E)-3-Benzoyl-1-(2-fluorobut-2-en-1-yl)-5-methyl-1,2,3,4-tetrahydropyrimidine-2,4-
dione (23a). General procedure C was followed with aminosulfone 6 (150 mg, 0.32 mmol, 1
equiv), acetaldehyde (19 ꢀL, 0.33 mmol, 1.05 equiv) and NaHMDS (1 M in THF, 0.48 mL,
0.48 mmol, 1.5 equiv) in THF (3 mL). The purification by flash chromatography
(pentane/AcOEt, 6:4) afforded compound 23a (84 mg, 88%) as a colorless oil (E/Z = 41:59).
1H NMR (CDCl3, 400 MHz) δ 7.91–7.89 (m, 4H, E and Z), 7.64–7.61 (m, 2H, E and Z), 7.49–
7.45 (m, 4H, E and Z), 7.16 (s, 2H, E and Z), 5.39 (dq, 3JHFcis = 20.6 Hz, 3JHH = 7.1 Hz, 1H, E),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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27
28
29
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35
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3
4.99 (dq, 3JHFtrans = 36.3 Hz, JHH = 7.1 Hz, 1H, Z), 4.47 (d, 3JHF = 20.2 Hz, 2H, E), 4.35 (d,
3
4
3JHF = 17.4 Hz, 2H, Z), 1.92 (s, 6H, E and Z), 1.67 (dd, JHH = 7.1 Hz, JHF = 2.0 Hz, 3H, E),
1.63 (m, 3H, Z); 13C NMR (CDCl3, 100 MHz) δ 168.9 (2C, E and Z), 163.0 (E), 162.9 (Z),
1
1
152.8 (d, JCF = 253.9 Hz, Z), 152.7 (d, JCF = 244.2 Hz, E), 149.5 (2C, E and Z), 139.7 (E),
139.3 (Z), 135.0 (E), 134.9 (Z), 131.4 (Z), 131.3 (E), 130.3 (2C, E), 130.2 (2C, Z), 129.1 (4C,
E and Z), 110.9 (Z), 110.8 (E), 107.1 (d, 2JCF = 20.8 Hz, E), 106.7 (d, 2JCF = 13.4 Hz, Z), 48.0
2
2
3
(d, JCF = 29.9 Hz, Z), 43.9 (d, JCF = 28.7 Hz, E), 12.3 (2C, E and Z), 10.2 (d, JCF = 7.9 Hz,
3
E), 8.9 (d, JCF = 5.5 Hz, Z); 19F NMR (CDCl3, 376 MHz) δ –112.2 (dt, 3JFHcis = 20.6 Hz, 3JFH
= 20.2 Hz, 1F, E), –119.2 (dt, 3JFHtrans = 36.3 Hz, 3JFH = 17.4 Hz, 1F, Z); MS (ESI) m/z 303 [M
+ H]+ (80), 105 (100); HRMS (ESI) m/z [M + H]+ calcd for C16H16FN2O3 303.1145, found
303.1134.
(Z/E)-3-Benzoyl-1-(2-fluoronon-2-en-1-yl)-5-methyl-1,2,3,4-tetrahydropyrimidine-2,4-
dione (24a). General procedure C was followed with aminosulfone 6 (100 mg, 0.21 mmol, 1
equiv), heptanal (31 ꢀL, 0.22 mmol, 1.05 equiv) and NaHMDS (1 M in THF, 0.32 mL, 0.32
mmol, 1.5 equiv) in THF (2 mL). The purification by flash chromatography (pentane/AcOEt,
7:3) afforded compound 24a (48 mg, 61%) as a colorless oil (E/Z = 29:71). (Z)-24a: 1H NMR
(CDCl3, 400 MHz) δ 7.93–7.90 (m, 2H), 7.66–7.62 (m, 1H), 7.50–7.46 (m, 2H), 7.14 (t, 4JHF =
1.1 Hz, 1H), 4.97 (dt, 3JHFtrans = 36.8 Hz, 3JHH = 7.7 Hz, 1H), 4.38 (d, 3JHF = 17.4 Hz, 2H), 2.12
(q, 3JHH = 7.7 Hz, 2H), 1.97 (d, 4JHH = 1.1 Hz, 3H), 1.38–1.25 (m, 8H), 0.88 (t, 3JHH = 7.7 Hz,
1
3H); 13C NMR (CDCl3, 100 MHz) δ 168.8, 163.0, 152.0 (d, JCF = 253.5 Hz), 149.6, 139.0,
2
2
135.0, 131.5, 130.4 (2C), 129.1 (2C), 112.6 (d, JCF = 12.9 Hz), 111.1, 48.2 (d, JCF = 30.0
3
Hz), 31.5, 28.8 (d, 4JCF = 1.7 Hz), 28.7, 23.6 (d, JCF = 3.7 Hz), 22.5, 14.0, 12.5; 19F NMR
(CDCl3, 376 MHz) δ –118.4 (dt, 3JFHtrans = 36.8 Hz, 3JFH = 17.4 Hz, 1F); MS (ESI) m/z 373 [M
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+ H]+ (100), 105 (97); HRMS (ESI) m/z [M + H]+ calcd for C21H26FN2O3 373.1927, found
4
5
6
7
1
373.1928. (E)-24a: H NMR (CDCl3, 400 MHz) δ 7.93–7.90 (m, 2H), 7.66–7.62 (m, 1H),
7.51–7.47 (m, 2H), 7.15 (t, JHF = 1.2 Hz, 1H), 5.39 (dt, 3JHFcis = 21.1 Hz, JHH = 7.7 Hz, 1H),
4.50 (d, 3JHF = 20.6 Hz, 2H), 2.09 (q, JHH = 7.7 Hz, 2H), 1.96 (d, 4JHH = 1.2 Hz, 3H), 1.36–
4
3
3
8
9
1.23 (m, 8H), 0.85 (t, 3JHH = 7.7 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.8, 163.0, 152.3
(d, 1JCF = 246.1 Hz), 149.6, 139.3, 135.0, 131.5, 130.5 (2C), 129.1 (2C), 112.8 (d, 2JCF = 18.2
Hz), 111.0, 44.1 (d, 2JCF = 27.3 Hz), 31.5, 29.6 (d, 4JCF = 2.3 Hz), 28.6, 25.2 (d, 3JCF = 7.5 Hz),
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25
26
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
3
22.5, 14.0, 12.4; 19F NMR (CDCl3, 376 MHz) δ –111.9 (dt, JFHcis = 21.1 Hz, JFH = 20.6 Hz,
1F); MS (ESI) m/z 373 [M + H]+ (100), 105 (97); HRMS (ESI) m/z [M + H]+ calcd for
C21H26FN2O3 373.1927, found 373.1928.
(Z/E)-3-Benzoyl-1-(2-fluoroundec-2-en-1-yl)-5-methyl-1,2,3,4-tetrahydropyrimidine-2,4-
dione (25a). General procedure C was followed with aminosulfone 6 (100 mg, 0.21 mmol, 1
equiv), nonanal (38 ꢀL, 0.22 mmol, 1.05 equiv) and NaHMDS (1 M in THF, 0.32 mL, 0.32
mmol, 1.5 equiv) in THF (2 mL). The purification by flash chromatography (CH2Cl2, 100%)
1
afforded compound 25a (44 mg, 52%) as a colorless oil (E/Z = 30:70). (Z)-25a: H NMR
(CDCl3, 400 MHz) δ 7.93–7.90 (m, 2H), 7.66–7.62 (m, 1H), 7.51–7.47 (m, 2H), 7.15 (t, 4JHH
3
= 1.0 Hz, 1H), 4.98 (dt, 3JHFtrans = 36.8 Hz, JHH = 7.5 Hz, 1H), 4.38 (d, 3JHF = 17.8 Hz, 2H),
3
3
2.12 (q, JHH = 7.5 Hz, 2H), 1.97 (d, 4JHH = 1.0 Hz, 3H), 1.39–1.26 (m, 12H), 0.88 (t, JHH
=
13
1
7.5 Hz, 3H); C NMR (CDCl3, 100 MHz) δ 168.8, 163.0, 152.0 (d, JCF = 253.0 Hz), 149.6,
2
2
139.0, 135.0, 131.5, 130.4 (2C), 129.1 (2C), 112.6 (d, JCF = 13.5 Hz), 111.1, 48.2 (d, JCF
=
3
30.2 Hz), 31.8, 29.3, 29.2, 29.1, 28.8, 23.6 (d, JCF = 3.1 Hz), 22.6, 14.1, 12.4; 19F NMR
(CDCl3, 376 MHz) δ –118.4 (dt, 3JFHtrans = 36.8 Hz, 3JFH = 17.8 Hz, 1F); MS (ESI) m/z 401 [M
+ H]+ (45), 105 (100); HRMS (ESI) m/z [M + H]+ calcd for C23H30FN2O3 401.2240, found
1
401.2243. (E)-25a: H NMR (CDCl3, 400 MHz) δ 7.92–7.90 (m, 2H), 7.66–761 (m, 1H),
7.50–7.46 (m, 2H), 7.14 (t, 4JHH = 1.2 Hz, 1H), 5.39 (dt, 3JHFcis = 20.9 Hz, 3JHH = 7.5 Hz, 1H),
3
4.49 (d, 3JHF = 20.6 Hz, 2H), 2.09 (q, JHH = 7.5 Hz, 2H), 1.96 (d, 4JHH = 1.2 Hz, 3H), 1.36–
1.22 (m, 12H), 0.86 (t, 3JHH = 7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.8, 163.0, 152.3
(d, 1JCF = 246.2 Hz), 149.6, 139.3, 135.0, 131.5, 130.5 (2C), 129.1 (2C), 112.9 (d, 2JCF = 18.5
Hz), 111.1, 44.1 (d, 2JCF = 28.3 Hz), 31.8, 29.6, 29.3, 29.2, 29.0, 25.2 (d, 3JCF = 7.4 Hz), 22.6,
3
3
14.1, 12.4; 19F NMR (CDCl3, 376 MHz) δ –111.9 (dt, JFHcis = 20.9 Hz, JFH = 20.6 Hz, 1F);
MS (ESI) m/z 401 [M + H]+ (45), 105 (100); HRMS (ESI) m/z [M + H]+ calcd for
C23H30FN2O3 401.2240, found 401.2243.
General procedure E: preparation of fluorinated allylamines derived from thymine. To a
solution of aminosulfone 6 (1 equiv), and aldehyde (1.05 equiv) at –78 °C in THF (0.1 M)
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was added NaHMDS (1 M in THF, 1.5 equiv). After 30 min at –78 °C, the mixture was
stirred for 1 h 30 at 20 °C, quenched with a saturated aqueous solution of NH4Cl and
extracted with CH2Cl2. Combined organic layers were washed with brine, dried over MgSO4,
filtered and evaporated under reduced pressure. To the crude mixture of fluoroallylamine
derived from N3-benzoyl-thymine 17a-30a was added a methanolic solution of NaOH (1% in
MeOH) and stirred 16 h at 20 °C. The solution was neutralized by the addition of 1N HCl and
then concentrated. The crude product was purified by flash chromatography to give amino-
alkenes 17b-30b.
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(Z/E)-1-[2-Fluoro-3-(4-methoxyphenyl)prop-2-en-1-yl]-5-methyl-1,2,3,4-
tetrahydropyrimidine-2,4-dione (17b). General procedure
E was followed with
aminosulfone 6 (200 mg, 0.42 mmol, 1 equiv), p-methoxybenzaldehyde (54 ꢀL, 0.44 mmol,
1.05 equiv) and NaHMDS (1 M in THF, 0.63 mL, 0.63 mmol, 1.5 equiv) in THF (4 mL). The
crude mixture was treated with a solution of NaOH in MeOH (5 mL). The purification by
flash chromatography (pentane/AcOEt, 4:6) afforded compound 17b (94 mg, 76%) as a
1
yellow solid (E/Z = 7:93). Mp > 250 °C; (Z)-17b: H NMR (CDCl3, 400 MHz) δ 8.72 (sbr,
1H), 7.45–7.43 (m, 2H), 7.11 (m, 1H), 6.88–6.86 (m, 2H), 5.81 (d, 3JHFtrans = 38.7 Hz, 1H),
4.52 (d, 3JHF = 17.3 Hz, 2H), 3.81 (s, 3H), 1.94 (d, 4JHH = 1.0 Hz, 3H); 13C NMR (CDCl3, 100
6
1
MHz) δ 163.8, 159.4 (d, JCF = 3.1 Hz), 151.4 (d, JCF = 263.5 Hz), 150.6, 139.2, 130.3 (d,
3
2
4JCF = 7.6 Hz, 2C), 124.5 (d, JCF = 3.0 Hz), 114.0 (2C), 111.3, 110.8 (d, JCF = 6.9 Hz), 55.3,
2
3
48.7 (d, JCF = 29.6 Hz), 12.3; 19F NMR (CDCl3, 376 MHz) δ –113.8 (dt, JFHtrans = 38.7 Hz,
3JFH = 17.3 Hz, 1F); MS (ESI) m/z 291 [M + H]+ (86), 165 (100); HRMS (ESI) m/z [M + H]+
1
calcd for C15H16FN2O3 291.1145, found 291.1154. (E)-17b: H NMR (CDCl3, 400 MHz) δ
8.80 (sbr, 1H), 7.25–7.23 (m, 2H), 6.97 (s, 1H), 6.93–6.91 (m, 2H), 6.52 (d, 3JHFcis = 20.3 Hz,
1H), 4.69 (d, 3JHF = 18.2 Hz, 2H), 3.82 (s, 3H), 1.90 (s, 3H); 13C NMR (CDCl3, 100 MHz)
1
4
δ 163.8, 159.4, 153.1 (d, JCF = 252.1 Hz), 150.7, 139.2, 129.8 (d, JCF = 2.5 Hz, 2C), 123.9
3
2
2
(d, JCF = 12.0 Hz), 114.3 (2C), 113.4 (d, JCF = 25.4 Hz), 111.2, 55.3, 44.5 (d, JCF = 27.4
3
3
Hz), 12.4; 19F NMR (CDCl3, 376 MHz) δ –110.0 (dt, JFHcis = 20.3 Hz, JFH = 18.2 Hz, 1F);
MS (ESI) m/z 291 [M + H]+ (86), 165 (100); HRMS (ESI) m/z [M + H]+ calcd for
C15H16FN2O3 291.1145, found 291.1154.
(Z/E)-1-[3-(4-Bromophenyl)-2-fluoroprop-2-en-1-yl)-5-methyl-1,2,3,4-
tetrahydropyrimidine-2,4-dione (18b). General procedure
E was followed with
aminosulfone 6 (200 mg, 0.42 mmol, 1 equiv), p-bromobenzaldehyde (82 mg, 0.44 mmol,
1.05 equiv) and NaHMDS (1 M in THF, 0.63 mL, 0.63 mmol, 1.5 equiv) in THF (4 mL). The
crude mixture was treated with a solution of NaOH in MeOH (5 mL). The purification by
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flash chromatography (CH2Cl2/AcOEt, 7:3) afforded compound 18b (79 mg, 55%) as a white
solid (E/Z = 17:83). Mp 200 °C; (Z)-18b: 1H NMR (CDCl3, 400 MHz) δ 8.71 (sbr, 1H), 7.48–
4
7.45 (m, 2H), 7.37–7.34 (m, 2H), 7.08 (t, JHF = 1.2 Hz, 1H), 5.81 (d, 3JHFtrans = 37.8 Hz, 3JHH
= 7.5 Hz, 1H), 4.52 (d, 3JHF = 17.1 Hz, 2H), 1.94 (d, 4JHH = 1.2 Hz, 3H); 13C NMR (CDCl3,
9
1
6
100 MHz) δ 163.7, 153.4 (d, JCF = 268.4 Hz), 150.5, 139.2, 131.8 (2C), 130.7 (d, JCF = 3.2
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4
3
2
Hz), 130.4 (d, JCF = 7.4 Hz, 2C), 122.1 (d, JCF = 3.5 Hz), 111.5, 110.1 (d, JCF = 6.4 Hz),
48.7 (d, JCF = 29.7 Hz), 12.4; 19F NMR (CDCl3, 376 MHz) δ –109.8 (dt, JFHtrans = 37.8 Hz,
3JFH = 17.1 Hz, 1F); MS (EI) m/z 340 [M]+• (45), 338 (47), 215 (55), 213 (58), 134 (100);
HRMS (ESI) m/z [M + H]+ calcd for C14H13BrFN2O2 339.0144, found 339.0154. (E)-18b: 1H
NMR (CDCl3, 400 MHz) δ 8.79 (sbr, 1H), 7.53–7.51 (m, 2H), 7.24–7.22 (m, 2H), 6.96 (t, 4JHF
= 1.2 Hz, 1H), 6.47 (d, 3JHFcis = 20.2 Hz, 1H), 4.64 (d, 3JHF = 17.9 Hz, 2H), 1.92 (d, JHF = 1.2
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 163.8, 154.2 (d, JCF = 254.3 Hz), 150.6, 139.4,
132.0 (2C), 130.6 (d, 6JCF = 12.0 Hz), 130.3 (d, 4JCF = 2.8 Hz, 2C), 122.2, 112.5 (d, 2JCF = 26.1
Hz), 111.4, 44.7 (d, JCF = 26.8 Hz), 12.4; 19F NMR (CDCl3, 376 MHz) δ –107.4 (dt, JFHcis
20.2 Hz, JFH = 17.9 Hz, 1F); MS (EI) m/z 340 [M]+• (45), 338 (47), 215 (55), 213 (58), 134
(100); HRMS (ESI) m/z [M + H]+ calcd for C14H13BrFN2O2 339.0144, found 339.0154.
(Z/E)-1-[3-(Anthracen-9-yl)-2-fluoroprop-2-en-1-yl]-5-methyl-1,2,3,4-
2
3
4
1
2
3
=
3
tetrahydropyrimidine-2,4-dione (20b). General procedure
E was followed with
aminosulfone 6 (150 mg, 0.32 mmol, 1 equiv), 9-anthraldehyde (69 mg, 0.33 mmol, 1.05
equiv) and NaHMDS (1 M in THF, 0.47 mL, 0.47 mmol, 1.5 equiv) in THF (3 mL). The
crude mixture was treated with a solution of NaOH in MeOH (5 mL). The purification by
flash chromatography (CH2Cl2/AcOEt, 7:3) afforded compound 20b (74 mg, 65%) as a
1
yellow solid (E/Z = 15:85). Mp 198 °C; (Z)-20b: H NMR (CDCl3, 400 MHz) δ 8.70 (sbr,
1H), 8.44 (s, 1H), 8.02–7.99 (m, 4H), 7.51–7.44 (m, 4H), 7.20 (s, 1H), 6.72 (d, 3JHFtrans = 37.9
Hz, 1H), 4.78 (d, 3JHF = 15.8 Hz, 2H), 1.95 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 163.9,
1
153.7 (d, JCF = 263.0 Hz), 150.6, 139.8, 131.2 (2C), 129.5, 128.8 (2C), 127.7, 126.1 (2C),
125.4 (2C), 125.2 (2C), 124.7 (2C), 111.5, 107.4 (d, 2JCF = 12.6 Hz), 48.7 (d, 2JCF = 30.3 Hz),
12.4; 19F NMR (CDCl3, 376 MHz) δ –106.7 (dt, JFHtrans = 37.9 Hz, JFH = 15.8 Hz, 1F); MS
(ESI) m/z 361 [M + H]+ (44), 235 (100); HRMS (ESI) m/z [M + H]+ calcd for
C22H18FN2O2 361.1352, found 361.1347. (E)-20b: 1H NMR (CDCl3, 400 MHz) δ 8.47 (s, 1H),
8.11–8.03 (m, 4H), 7.58–7.50 (m, 4H), 7.05 (d, 3JHFcis = 17.4 Hz, 1H), 6.08 (s, 1H), 4.22 (d,
3JHF = 14.7 Hz, 2H), 1.45 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 163.1, 156.3 (d, 1JCF = 259.2
3
3
3
Hz), 150.1, 138.9, 131.3 (2C), 130.3 (d, JCF = 1.7 Hz), 129.0 (2C), 127.8, 126.6 (2C), 125.6
(2C), 125.1 (2C), 124.5, 124.4, 110.4, 107.9 (d, 2JCF = 22.6 Hz), 45.0 (d, 2JCF = 33.0 Hz), 11.9;
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19F NMR (CDCl3, 376 MHz) δ –102.8 (dt, JFHcis = 17.4 Hz, JFH = 14.7 Hz, 1F); MS
(ESI) m/z 361 [M + H]+ (44), 235 (100); HRMS (ESI) m/z [M + H]+ calcd for
C22H18FN2O2 361.1352, found 361.1347.
(Z/E)-1-[2-Fluoro-3-(pyridin-3-yl)prop-2-en-1-yl]-5-methyl-1,2,3,4-
8
9
tetrahydropyrimidine-2,4-dione (21b). General procedure
E was followed with
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
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aminosulfone 6 (200 mg, 0.42 mmol, 1 equiv), 3-pyridinecarboxaldehyde (42 ꢀL, 0.44 mmol,
1.05 equiv) and NaHMDS (1 M in THF, 0.63 mL, 0.63 mmol, 1.5 equiv) in THF (4 mL). The
crude mixture was treated with a solution of NaOH in MeOH (5 mL). The solution was
neutralized by the addition of 1 N HCl and 1 M NaOH was added until pH 7. The aqueous
layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4,
filtered and evaporated under reduced pressure. The purification by flash chromatography
(CH2Cl2/MeOH, 95:5) afforded compound 21b (73 mg, 66%) as a yellow solid (E/Z = 12:88).
1
Mp 184 °C; H NMR (CDCl3, 400 MHz) δ 9.58 (sbr, 2H, Z and E), 8.67–8.49 (m, 4H, Z and
E), 7.90–7.84 (m, 2H, Z and E), 7.38–7.36 (m, 1H, E), 7.31–7.27 (m, 1H, Z), 7.10 (s, 1H, Z),
7.0 (s, 1H, E), 6.47 (d, 3JHFcis = 19.6 Hz, 1H, E), 5.89 (d, 3JHFtrans = 38.0 Hz, 1H, Z), 4.64 (d,
3JHF = 17.6 Hz, 2H, E), 4.56 (d, 3JHF = 16.4 Hz, 2H, Z), 1.94 (s, 3H, Z), 1.91 (m, 3H, E); 13C
NMR (CDCl3, 100 MHz) (Z)-isomer δ 164.0, 154.9 (d, 1JCF = 269.1 Hz), 150.7, 149.4 (d, 4JCF
6
4
3
= 7.0 Hz), 148.5 (d, JCF = 2.8 Hz), 139.2, 135.9 (d, JCF = 9.1 Hz), 128.2 (d, JCF = 2.8 Hz),
2
2
123.6, 111.6, 107.5 (d, JCF = 6.8 Hz), 48.5 (d, JCF = 29.7 Hz), 12.3; 19F NMR (CDCl3, 376
3
3
3
MHz) δ –104.8 (dt, JFH = 19.6 Hz, JFHcis = 17.6 Hz, 1F, E), −107.6 (dt, JFHtrans = 38.0 Hz,
3JFH = 16.4 Hz, 1F, Z); MS (ESI) m/z 262 [M + H]+ (100), 242 (33), 199 (63), 171 (23), 136
(85); HRMS (ESI) m/z [M + H]+ calcd for C13H13FN3O2 262.0992, found 262.0989.
(Z/E)-1-(3-(Cyclohexyl-2-fluoroprop-2-en-1-yl)-5-methyl-1,2,3,4-tetrahydropyrimidine-
2,4-dione (22b). General procedure E was followed with aminosulfone 6 (200 mg, 0.42
mmol, 1 equiv), cyclohexanecarboxaldehyde (54 ꢀL, 0.44 mmol, 1.05 equiv) and NaHMDS
(1 M in THF, 0.63 mL, 0.63 mmol, 1.5 equiv) in THF (4 mL). The crude mixture was treated
with a solution of NaOH in MeOH (5 mL). The purification by flash chromatography
(CH2Cl2/AcOEt, 8:2) afforded compound 22b (64 mg, 57%) as a white solid (E/Z = 21:79).
1
Mp 184 °C; (Z)-22b: H NMR (CDCl3, 400 MHz) δ 8.74 (sbr, 1H), 7.02 (s, 1H), 4.82 (dd,
3
3JHFtrans = 37.1 Hz, JHH = 9.4 Hz, 1H), 4.33 (d, 3JHF = 17.0 Hz, 2H), 2.48–2.39 (m, 1H), 1.92
(s, 3H), 1.69–1.66 (m, 4H), 1.34–1.03 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 163.9, 151.0
1
2
2
(d, JCF = 254.2 Hz), 150.5, 139.2, 117.6 (d, JCF = 12.7 Hz), 111.1, 47.8 (d, JCF = 31.8 Hz),
3
33.4 (d, JCF = 2.9 Hz), 32.7 (2C), 25.8, 25.6 (2C), 12.4; 19F NMR (CDCl3, 376 MHz) δ –
3
3
118.3 (dt, JFHtrans = 37.1 Hz, JFH = 17.0 Hz, 1F); MS (ESI) m/z 267 [M + H]+ (100), 127
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