Copper-Catalyzed C(sp2)-H Difluoroalkylation of Aldehyde Derived Hydrazones with Diboron as Reductant

Article abstract of DOI:10.1021/acs.joc.6b00324

An efficient and general method for C(sp²)-H difluoroalkylation of aldehyde derived hydrazones via a Cu^II/B₂pin₂-catalyzed reaction between difluoroalkyl bromides and hydrazones was developed. In this reaction,

Full text of DOI:10.1021/acs.joc.6b00324

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Article
Copper-Catalyzed C(sp2)-H Difluoroalkylation of
Aldehyde-Derived Hydrazones with Diboron as Reductant
Miaolin Ke, and Qiuling Song
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 29 Mar 2016
Downloaded from http://pubs.acs.org on March 29, 2016
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The Journal of Organic Chemistry
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Copper-Catalyzed
C(sp2)-H
Difluoroalkylation
of
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Aldehyde-Derived Hydrazones with Diboron as Reductant
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Miaolin Ke and Qiuling Song*
Institute of Next Generation Matter Transformation, College of Chemical Engineering,
College of Materials Science & Engineering at Huaqiao University
Fax: 86ꢀ592ꢀ6162990; email: qsong@hqu.edu.cn
Abstract
An efficient and general method for C(sp2)ꢀH difluoroalkylation of aldehydeꢀderived
hydrazones via Cu(II)/B2pin2 catalyzed reaction between difluoroalkyl bromides and
hydrazones was developed. In this reaction, both aromatic and aliphatic aldehydeꢀderived
hydrazones could be achieved in good to excellent yields. For some heteroaromatic
aldehydeꢀderived hydrazones, two fluoroacetates could be introduced onto the final products.
Preliminary mechanism study manifested that a difluoroalkyl radical via SET pathway was
involved in the reaction. And catalytic diboron reagent plays an indispensible role in this
transformation.
INTRODUCTION
The incorporation of fluorinated functional groups into organic molecules has generated
extraordinary research activity because of the enhanced metabolic stability, lipophilicity,
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reactivity of the molecules compared to their nonfluorinated counterparts.
Although
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significant advances have been made on functionalized fluoroalkylation of aromatic
compounds, 4 ꢀ6 efficient and general methods for the synthesis of hydrazones containing
difluorinated functional groups with high stereoselectivity through copperꢀcatalyzed
transformations are relatively rare.9e Aldehydeꢀderived hydrazones are an important
intermediate in organic synthesis.7 Conceptually, introduction of the CF2 group into such a
structual motif would open a good possibility to discover some novel bioactive molecules.
Recently, the fluoroalkyl radical addition of aldehydeꢀderived hydrazones has become an
efficient tactic to synthesize ɑ,ɑꢀdifluoroꢀβꢀketoesters. There are several known methods to
achieve fluoroalkylated aldehydeꢀderived hydrazone compounds: a) visibleꢀlight
photoredoxꢀcatalyzed cross coupling between aldehyde hydrazones and fluoroalkyl reagent
(for example, with iridium or gold catalysts); 8 b) transitionꢀmetalꢀcatalyzed cross coupling of
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aldehydeꢀderived hydrazones and fluoroalkyl halides. In the latter case, Monteiro and
coꢀworkers reported an elegant Pdꢀcatalyzed CꢀH alkylation of aldehydeꢀderived hydrazones
with functional difluoromethyl bromides. 9d Very recently, they also reported a Cuꢀcatalyzed
difluoroalkylation of aldehyde hydrazones.9e However, in both cases aliphatic
aldehydeꢀderived hydrazones failed to provide difluoroacetated hydrazones, and expensive
metals or ligands were essential to the success of the reactions. Inspired by our recent work on
the Cu(II)/B2pin2ꢀcatalyzed hydrodifluoroacetylation of alkynes or phenylpropiolic acids with
bromodifluoroacetate, in which difluoroalkyl radicals were generated via a singleꢀelectron
transfer (SET) pathway (scheme 1a), 10 we envisioned that C(sp2)ꢀH difluoroalkylation of
aldehydeꢀderived hydrazones might be synthesized via the same novel radical generation
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system: Cu/B2pin2, undoubtedly and ideally, if catalytic amount of B2pin2 was enough for the
success of the transformation instead of stoichiometric amount, this reaction will become
more attractive. Most interestingly, we successfully obtained C(sp2)ꢀH difluoroalkylation of
aldehydeꢀderived hydrazones with our Cu(II)ꢀB2pin2 catalytic system in which only 30 mol%
of B2pin2 was enough for this transformation and aliphatic aldehydeꢀderived hydrazones can
also smoothly difluoroalkylated.
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Scheme 1. Synthetic methods involving •CF2COOEt radical with Cu(II)/B2pin2 catalyst
system.
RESULTS AND DISCUSSIONS
In order to examine our hypothesis, our investigation commenced with aldehyde hydrazones 1
and ethyl bromodifluoroacetate 2 as the model substrates with 1 equivalent of B2pin2
according to our previous work.10 To our delight, the desired difluoroalkylated aldehyde
o
hydrazones compounds 3 was obtained in 52% isolated yield at 80 C using 10% CuBr2 as
catalyst, 10% DTBDPy as ligand, 1 equivalent of B2pin2 as additive and 2 equivalent of KOAc
as base in 1,4ꢀdioxane. Subsequently, other reaction parameters, such as base, loading of
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B2pin2, Cu salt, ligand, reaction atmosphere were surveyed (table 1, entry 1ꢀ24). Among the
tested bases (table 1, entry 1ꢀ7), NaHCO3 showed the superior activity over others (KOAc,
K2CO3, Na2CO3, NaOAc, KF, Cs2CO3), providing the desired product 3 in 93% isolated yield
(table 1, entry 1ꢀ7). Surprisingly, we found that the loading of B2pin2 could be dropped to 30
mol% without deteriorating the yield (table 1, entry 9ꢀ10). However, lowering the loading of
B2pin2 significantly reduced the yield (table 1, 83%, entry 8). As we can see, CuCl, CuBr,
CuCl2 and Cu(OAc)2 were all good catalysts when combined with ligand L1, yet CuBr2 was
the best among them (table 1, entry 11ꢀ14). In terms of other ligands, the yields of the desired
product dropped dramatically, and no desired one was observed when P ligand L5 was used in
the transformation (table 1, entry 15ꢀ18). Control experiments suggested that the additive
B2pin2 is indispensable to the reaction since no reaction occurred in its absence (table 1, entry
22). No desired product 3 was observed as well in the absence of copper catalyst, ligand or
base (table 1, entry 19ꢀ21), demonstrating that both copper salt, ligand and base play essential
roles for the promotion of the reaction. This reaction is anaerobic and could not proceed under
air or molecular oxygen (table 1, entries 23 and 24).
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Table 1.
Optimization of the reaction conditions.
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N
Cu salt (10 mol %)
ligand (10 mol %)
N
N N
O
BrCF2COOEt
+
base (2 equiv), dioxane
B2pin2 (X mol %)
CF2COOEt
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N2 ,16 h
N
N
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N
N
N
L1
L2
L3
O
P
P
N
N
L4
L5
yield (%)
entey
ligand (10 mol%)
base (2 equiv)
catalyst (10 mol%)
CuBr2
CuBr2
CuBr2
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2
3
L1
L1
L1
KOAc
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72
78
K2CO3
Na2CO3
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
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7
8a
9b
L1
L1
L1
L1
L1
L1
L1
NaOAc
NaHCO3
KF
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96 (93 )
Cs2CO3
NaHCO3
NaHCO3
NaHCO3
30
83
>99 (96)
>99
10c
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12
NaHCO3
NaHCO3
CuCl
CuBr
L1
L1
95
89
CuCl2
NaHCO3
NaHCO3
NaHCO3
13
14
15
L1
L1
L2
93
91
75
Cu(OAc)2
CuBr2
CuBr2
NaHCO3
16
L3
18
CuBr2
CuBr2
NaHCO3
NaHCO3
NaHCO3
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18
L4
L5
8
NR
19
20
-
L1
-
NR
NR
CuBr2
NaHCO3
-
CuBr2
CuBr2
CuBr2
L1
L1
L1
NR
NR
NR
21
22d
23e
NaHCO3
NaHCO3
24f
CuBr2
NaHCO3
L1
NR
Reaction Condition:1 (0.2 mmol), 2 (0.4 mmol), Cu salt(10 mol %), ligand (10 mol %), base (2 equiv.),
B2pin2 (entry 1- 7, 1 equiv), B2pin2 (entry 11- 23, 30 mol%), dioxane (1 mL), at N2, 16 h. a B2pin2 (20 mol
%). B2pin2 (30 mol %). B2pin2 (40 mol %).d under air. under O2, absence of B2pin2.GC yield by
b
c
e
f
using n-dodecane as an internal standard. The isolated yield was listed in parathesis.
In order to test the scope of the method, a variety of aldehydeꢀderived hydrazones was
surveyed (scheme 2). A series of difluoroacetylated aldehyde hydrazones was obtained in
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good to excellent yields with versatile substituents on the aromatic rings regardless of the
electronꢀdonating or electronꢀwithdrawing nature (3-12). Notably, 4ꢀN, Nꢀdimethyl product
13 was obtained in good yield under our standard conditions. Moreover, the position of
substituents on the aromatic ring has less impact on the reactions albeit ortho ones with
relatively lower yields (16-20). With multiple substituents on the aromatic rings, the
Scheme 2. Substrate scope of aldehydeꢀderived hydrazones for difluoroacetylation.
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corresponding products were also obtained with good yields (14-15). However, the reaction of
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naphthylaldehyde hydrazone gave
a surprisingly low yield (21). Heteroaromatic
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aldehydeꢀderived hydrazones were also compatible under the standard conditions (22-28),
interestingly, some bisꢀfluoroacetates were selectively synthesized from thiophene or furanyl
or benzothiophene aldehydeꢀderived hydrazones (23ꢀ27). Importantly, aliphatic aldehyde
hydrazones were good substrates in this transformation and the corresponding desired
products were obtained in decent yields, albeit with relatively low stereoselectivities (29-33),
which makes our method an alternative one for the reported Pdꢀ or Cuꢀcatalyzed
difluoroalkylation of aldehydeꢀderived hydrazones, in which aliphatic aldehydeꢀderived
hydrazones only rendered trace amount of desired products. 9d, 9e It needs to be pointed out
that our conditions were also applicable for the N,Nꢀdimethyl aliphatic aldehydeꢀderived
hydrazone and 30% of corresponding product 30 was obtained. However, when
(E)ꢀNꢀhexylidenemorpholinꢀ4ꢀamine was subjected under Monteiro’s conditions9e in the presence
of B2Pin2，the corresponding desired product was only obtained in 14% yield, much lower than the
one under our current standard conditions (49% yield).
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Next, we investigated the scope of Nꢀsubstituent aldehyde hydrazones and the scope of
difluoro regents (scheme 3). Delightedly, the reactions were not just restricted to
morpholineꢀderived hydrazones, phenylamine, piperidinyl and 4ꢀmethylpiperazinylꢀderived
hydrazones were also suitable candidates for this transformations, with corresponding desired
products obtained in reasonable yields (34ꢀ36). Whereas the NꢀBs (Bs = benzenesulfonyl)
hydrazones (37) and oxime hydrazones (38) failed to furnish the desired product, probably
due to their low HOMO level. Gratifyingly, the corresponding difluorinated hydrazone (39)
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was obtained with excellent yield using bromodifluoroacetamide, which was prepared from
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bromodifluoroacetate 2 with phenylamine. 11
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Scheme 3. Investigation of the effect of the Nꢀsubstituents and bromodifluoroacetamide
Satisfyingly, this reaction could be easily scaled up to 5 mmol and desired product 3 was
achieved in a high isolated yield of 86% in 1.4 gram (Scheme 4, eq 1), which illustrated the
practicality and robustness of our transformation. Aldehydeꢀderived hydrazones is a facile
important intermediate in organic chemistry which could be easily subjected for further
structural manipulation. For instance, compound
3
could be hydrolyzed into
ɑ,ɑꢀdifluoroꢀβꢀketoester 40 in 88% yield (scheme 4, eq 2). And difluorinated hydrazine 41
was readily generated when compound 3 was subjected with lithium aluminum hydride in
anhydrous THF (scheme 4, eq 3), in which ester group was also reduced simultaneously along
with C=N bond to render an alcohol. Noteworthily, the ester group in compound 3 was
transformed into hydroxyl group while the C=N double bond was untouched in compound 42
when compound 3 was treated with sodium borohydride (scheme 4, eq 4).
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O
O
CuBr2 (10 mol %)
DTBDPy(10 mol %)
B2pin2 (30 mol %)
N
N
N
N
COOEt
(eq 1)
+
BrCF2COOEt
NaHCO3 (2 equiv.)
dioxane, N2, 16h
F
F
1, 5 mmol
2, 10 mmol
3, 1.40 g, 86%
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O
N
O
N
HCl
COOEt
COOEt
(eq 2)
(eq 3)
(eq 4)
THF
F
F
F
F
40
, 88 %
3
O
O
N
N
NH
F
N
LiAlH4
CH2OH
COOEt
anhydrous THF
F
F
F
41 74%
3
O
O
N
N
N
N
NaBH4
CH2OH
COOEt
anhydrous THF
F
F
F
F
42
, 62%
3
Scheme 4. The application of difluoroalkylation of aldehydeꢀderived hydrazones
Radical trapping experiments were subsequently performed in order to understand the
mechanism of this Cu(II)/B2pin2ꢀcatalyzed C(sp2)ꢀH difluoroalkylation of aldehydeꢀderived
hydrazones. The desired product
3 was not obtained when radical scavenger
2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO) was added, instead, TEMPOꢀCF2COOEt was
generated in ca. 20% yield, implying that a radical pathway was involved in this reaction (eq
5). Furthermore, when 1ꢀphenylstyrene (43) was added to the mixture of compound 1 and 2
under the standard conditions, desired product 3 was only formed in trace with 40% of
compound 43 remained along with formation of compounds 44 and 45. This result further
confirmed the involvement of a free radical pathway in this transformation (eq 6).
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On the base of the above control experiments, our previous work, 10 as well as precedent
reports, 9e a plausible mechanism is postulated (Figure 1). Initially, interaction between a
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Cu(II) salt A and B2pin2 generates a Cu(I)ꢀBpin species B.10,
Subsequently, an
electrophilic fluoroalkyl radical from bromodifluoro reagent is formed via bromide
abstraction by the copper(I) complex B with concomitant generation of copper(II) C.10, 12b The
radical can be trapped by aldehydeꢀderived hydrazone to form the aminyl radical D which
13
further converts into intermediate E via SET process.8, Then the removal of proton
eventually produces the desired product 3.
Figure 1. Plausible mechanistic pathway.
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In summary, we described
a
novel, efficient C(sp2)ꢀH difluoroalkylation of
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aldehydeꢀderived hydrazones via Cu(II)/B2pin2 catalyzed reaction between difluoroalkyl
bromides and hydrazones. A broad range of functional groups was tolerated well under
standard conditions with good to excellent yields. And aliphatic aldehydeꢀderived hydrazones
are also good candidates in this method to render the corresponding products, which make our
method as a complement protocol for the existing methods. Further applications about this
transformation are under investigation in our laboratory.
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EXPERIMENTAL SECTION
General information: All reactions were accomplished in Schlenk tubes or round flasks
under an atmosphere of N2. Column chromatography was performed over silica gel (200ꢀ300
mesh). 1H NMR spectra were recorded on a 500 M spectrometer and chemical shifts (in ppm)
were referred to CDCl3 (δ = 7.26 ppm) as an internal standard. 13C NMR spectra were
obtained by using the same NMR spectrometer and were calibrated with CDCl3 (δ = 77.0
ppm). 19F NMR spectrometers were operated on the same NMR spectrometer
(CFCl3 as an
external standard and low field is positive). The following abbreviations were used to
illuminate the diversities: δ = chemical shifts, J = coupling constant, s = singlet, d= doublet, t
= triplet, q = quartet, m = multiplet. HRMS (EI) were measured with a quadrupole and TOF
mass spectrometers. CH2Cl2 was distilled from CaH2. All reagents and solvents were obtained
from commercial suppliers, and used without further purification. Reactions were monitored
by thinꢀlayer chromatography (TLC), GC or GCꢀMS analysis. The products were purified by
column chromatography on silica gel using petroleum ether and ethyl acetate as the eluent.
The synthesis of aldehyde-derived hydrazones (1a -1ah) 15
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Morpholinꢀ4ꢀamine (2.2 mmol), aldehyde (2.0 mmol) and anhydrous MgSO4 (0.5 g) in
CH2Cl2 (10 mL) was stirred overnight at room temperature until consumption of the raw
material aldehyde (TLC tracking). After filtration of MgSO4, the solvent was removed under
reduced pressure and the residue was subjected to column chromatography to give the
aldehydeꢀderivative hydrazone (1a-1ah) with good yields.
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General procedure for the synthesis of Difluoroalkylation of Aldehyde-Derived
Hydrazones. aldehyde hydrazone (0.3 mmol)，bis(pinacolato)diboron (30 mol%, 22.9 mg),
CuBr2 (10 mol%, 6.7 mg), 4, 4’ꢀDibutylꢀ2, 2’ꢀbiꢀpyridyl (10 mol%, 8.1 mg), NaHCO3 (2
equiv, 50.5 mg) were added to a 25 mL of Schlenk tube under air. Then the mixture was
evacuated and backfilled with N2 (3 times). Ethyl bromodifluoroacetate (2 equiv, 77 ꢁL) and
dioxane (1 mL) were added subsequently. The Schlenk tube was screwꢀcapped and put into a
o
preꢀheated oil bath (80 C). The reaction mixture was cooled to room temperature after
stirring for 16 h. After the reaction was finished, the mixture was concentrated under vacuum
to remove dioxane, and the residue was purified by chromatography on silica gel (petroleum
ether: ethyl acetate = 10:1ꢀ1:2) to afford the product.
(E)ꢀNꢀ(4ꢀmethylbenzylidene)morpholinꢀ4ꢀamine (1a).16 Afforded 1a (390 mg, 96%) as a
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white solid, m.p. 92ꢀ93 C. H NMR (500 MHz, CDCl3) δ 7.59 (s, 1H), 7.50 (d, J = 8.1 Hz,
2H), 7.16 (d, J = 7.9 Hz, 2H), 3.89 (t, J = 5.0 Hz, 4H), 3.16 (t, J = 5.0 Hz, 4H), 2.35 (s, 3H).
13C{1H}NMR (125 MHz, CDCl3): δ 138.3, 136.7, 133.2, 129.2, 126.2, 66.5, 52.0, 21.3.
(E)ꢀNꢀbenzylidenemorpholinꢀ4ꢀamine (1b).17 Afforded 1b (360 mg, 95%) as a white solid,
m.p. 68ꢀ69 oC. 1H NMR (500 MHz, CDCl3): δ 7.65 – 7.58 (m, 3H), 7.35 (t, J = 7.5 Hz, 2H),
7.29 (ddd, J = 7.3, 3.8, 1.2 Hz, 1H), 3.89 (t, J = 5.0 Hz, 4H), 3.18 (t, J = 5.0 Hz, 4H).
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13C{1H}NMR (125 MHz, CDCl3): δ 136.2, 135.9, 128.5, 128.3, 126.2, 66.4, 51.8.
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(E)ꢀNꢀ(4ꢀmethoxybenzylidene)morpholinꢀ4ꢀamine (1c).18 Afforded 1c (396 mg, 90%) as a
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white solid, m.p. 74ꢀ75 C. H NMR (500 MHz, CDCl3) δ 7.58 (s, 1H), 7.54 (d, J = 8.8 Hz,
2H), 6.88 (d, J = 8.8 Hz, 2H), 3.88 (t, J = 5.0 Hz, 4H), 3.81 (s, 3H), 3.13 (t, J = 5.0 Hz, 4H).
13C{1H}NMR (125 MHz, CDCl3): δ 159.9, 136.7, 128.7, 127.5, 114.0, 66.4, 55.2, 52.1.
(E)ꢀNꢀ(4ꢀfluorobenzylidene)morpholinꢀ4ꢀamine (1d).8a Afforded 1d (408 mg, 98%) as a
white solid, m.p. 77ꢀ78 oC. 1H NMR (500 MHz, CDCl3) δ 7.61 – 7.53 (m, 3H), 7.03 (t, J = 8.7
Hz, 2H), 3.88 (t, J = 5.0 Hz, 4H), 3.15 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz, CDCl3): δ
162.8 (d, J = 246.3 Hz), 135.0, 132.1 (d, J = 2.5 Hz), 127.7 (d, J = 5.0 Hz), 115.4 (d, J = 8.8
Hz), 66.4, 51.8.
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(E)ꢀNꢀ(4ꢀchlorobenzylidene)morpholinꢀ4ꢀamine (1e).8a Afforded 1e (426 mg, 95%) as a
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white solid, m.p. 94ꢀ95 C. H NMR (500 MHz, CDCl3) δ 7.56 – 7.46 (m, 3H), 7.30 (d, J =
8.5 Hz, 2H), 3.86 (t, J = 5.0 Hz, 4H), 3.15 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz,
CDCl3): δ 134.5, 134.4, 133.8, 128.6, 127.2, 66.3, 51.6.
(E)ꢀNꢀ(4ꢀbromobenzylidene)morpholinꢀ4ꢀamine (1f).8b Afforded 1f (472 mg, 88%) as a
white solid, m.p. 128ꢀ129 oC. 1H NMR (500 MHz, CDCl3): δ 7.50 (s, 1H), 7.47 ꢀ7.44 (m, 4H),
3.88 (t, J = 5.0 Hz, 4H), 3.17 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz, CDCl3): δ 134.9,
134.5, 131.6, 127.6, 122.4, 66.4, 51.7.
(E)ꢀ1ꢀ(4ꢀ((morpholinoimino)methyl)phenyl)ethanone (1g). Afforded 1g (418 mg, 90%) as
a yellow solid, m.p. 97ꢀ98 oC. 1H NMR (500 MHz, CDCl3): δ 7.92 (d, J = 8.4 Hz, 2H), 7.65
(d, J = 8.4 Hz, 2H), 7.55 (s, 1H), 3.88 (t, J = 5.0 Hz, 4H), 3.22 (t, J = 5.0 Hz, 4H), 2.58 (s,
3H). 13C{1H}NMR (125 MHz, CDCl3): δ 197.5, 140.5, 136.3, 133.6, 128.7, 125.9, 66.3, 51.4,
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26.6. HRMS: m/z (EIꢀTOF) calculated [M]: 232.1212, found: 232.1208.
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(E)ꢀ4ꢀ((morpholinoimino)methyl)benzonitrile (1h).19 Afforded 1h (357 mg, 83%) as a
white solid, m.p. 124ꢀ125 oC. 1H NMR (500 MHz, CDCl3): δ 7.66 (d, J = 8.4 Hz, 2H), 7.60 (d,
J = 8.4 Hz, 2H), 7.49 (s, 1H), 3.88 (t, J = 5.0 Hz, 4H), 3.22 (t, J = 5.0 Hz, 4H). 13C{1H}NMR
(125 MHz, CDCl3): δ 140.4, 132.4, 132.3, 126.2, 119.0, 110.8, 66.2, 51.3.
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(E)ꢀNꢀ(4ꢀnitrobenzylidene)morpholinꢀ4ꢀamine (1i).9a Afforded 1i (423 mg, 90%) as a
yellow solid, m.p. 145ꢀ146 oC. 1H NMR (500 MHz, CDCl3): δ 8.15 (d, J = 8.8 Hz, 2H), 7.68
(d, J = 8.8 Hz, 2H), 7.50 (s, 1H), 3.87 (t, J = 5.0 Hz, 4H), 3.24 (t, J = 5.0 Hz, 4H).
13C{1H}NMR (125 MHz, CDCl3): δ 146.8, 142.4, 131.4, 126.1, 123.8, 66.1, 51.1.
(E)ꢀNꢀ(4ꢀ(trifluoromethyl)benzylidene)morpholinꢀ4ꢀamine (1j).8a Afforded 1j (475 mg,
92%) as a white solid, m.p. 75ꢀ76 oC. 1H NMR (500 MHz, CDCl3): δ 7.68 (d, J = 8.2 Hz, 2H),
7.58 (d, J = 8.3 Hz, 2H), 7.55 (s, 1H), 3.89 (t, J = 5.0 Hz, 4H), 3.21 (t, J = 5.0 Hz, 4H).
13C{1H}NMR (125 MHz, CDCl3): δ 139.4, 133.5, 129.7 (t, J = 31.3 Hz), 125.1, 125.4 (t, J =
3.8 Hz), 124.2 (t, J = 270 Hz), 66.3, 51.5.
(E)ꢀNꢀ(4ꢀ(dimethylamino)benzylidene)morpholinꢀ4ꢀamine (1k).20 Afforded 1k (419 mg,
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90%) as a pale yellow solid, m.p. 154ꢀ155 C. 1H NMR (500 MHz, CDCl3) δ 7.61 (s, 1H),
7.50 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.9 Hz, 2H), 3.88 (t, J = 5.0 Hz, 4H), 3.11(t, J = 5.0 Hz,
4H), 2.98 (s, 6H). 13C{1H}NMR (125 MHz, CDCl3): δ 150.7, 138.7, 127.5, 124.1, 112.0, 66.5,
52.5, 40.3.
(E)ꢀNꢀ(3,4ꢀdimethoxybenzylidene)morpholinꢀ4ꢀamine (1l).21 Afforded 1l (490 mg, 95%)
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as a white solid, m.p. 68ꢀ69 C. H NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 7.31 (d, J = 1.8
Hz, 1H), 6.99 (dd, J = 8.2, 1.8 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H),
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3.87 (t, J = 5.0 Hz, 4H), 3.14 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz, CDCl3): δ 149.5,
149.1, 136.7, 128.9, 120.4, 110.5, 107.2, 66.4, 55.8, 55.7, 52.0.
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(E)ꢀ2ꢀmethoxyꢀ4ꢀ((morpholinoimino)methyl)phenol (1m).20 Afforded 1m (420 mg, 89%)
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as a brown solid, m.p. 152ꢀ153 C. H NMR (500 MHz, CDCl3): δ 7.56 (s, 1H), 7.30 (d, J =
1.5 Hz, 1H), 6.96 (dd, J = 8.1, 1.4 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 3.91 (s, 3H), 3.88 (t, J =
5.0 Hz, 4H), 3.14 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz, CDCl3): δ 146.9, 146.4, 137.2,
128.5, 121.2, 114.1, 107.0, 66.5, 55.8, 52.1.
(E)ꢀNꢀ(3ꢀchlorobenzylidene)morpholinꢀ4ꢀamine (1n).8a Afforded 1n (430 mg, 96%) as a
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white solid, m.p. 43ꢀ44 C. H NMR (500 MHz, CDCl3) δ 7.62 (t, J = 1.6 Hz, 1H), 7.48 (s,
1H), 7.42 (dt, J = 7.4, 1.4 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.25 – 7.21 (m, 1H), 3.88 (t, J =
5.0 Hz, 4H), 3.18 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz, CDCl3): δ 137.9, 134.6, 133.9,
129.7, 128.0, 125.7, 124.4, 66.3, 51.6.
(E)ꢀNꢀ(3ꢀnitrobenzylidene)morpholinꢀ4ꢀamine (1o).22 Afforded 1o (428 mg, 91%) as a
yellow solid, m.p. 145ꢀ146 oC. 1H NMR (500 MHz, CDCl3) δ 8.41 (s, 1H), 8.07 (dd, J = 8.1,
2.3 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.54 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 3.88 (t, J = 5.0 Hz,
4H), 3.22 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz, CDCl3): δ 148.6, 138.0, 132.0, 131.4,
129.3, 122.3, 120.6, 66.3, 51.4.
(E)ꢀNꢀ(2ꢀmethylbenzylidene)morpholinꢀ4ꢀamine (1p).8b Afforded 1p (384 mg, 94%) as a
brown solid, m.p. 64ꢀ65 oC. 1H NMR (500 MHz, CDCl3) δ 7.82 (s, 1H), 7.81 – 7.77 (m, 1H),
7.21 – 7.18 (m, 2H), 7.17 – 7.12 (m, 1H), 3.91 (t, J = 5.0 Hz, 4H), 3.19 (t, J = 5.0 Hz, 4H),
2.43 (s, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 135.4, 134.9, 133.7, 130.5, 128.1, 126.1,
125.5, 66.4, 51.9, 19.5.
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(E)ꢀNꢀ(2ꢀmethoxybenzylidene)morpholinꢀ4ꢀamine (1q).8a Afforded 1q (722 mg, 96%) as
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a pale yellow solid, m.p. 76ꢀ77 C. 1H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.87 (dd, J =
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7.7, 1.7 Hz, 1H), 7.26 (dt, J = 7.5, 5.0 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.3 Hz,
1H), 3.89 (t, J = 5.0 Hz, 4H), 3.85 (s, 3H), 3.18 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz,
CDCl3): δ 157.0, 132.3, 129.4, 125.4, 124.4, 120.8, 110.7, 66.4, 55.4, 52.0.
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(E)ꢀNꢀ(2ꢀbromobenzylidene)morpholinꢀ4ꢀamine (1r). Afforded 1r (509 mg, 95%) as a
white solid, m.p. 77ꢀ78 oC. 1H NMR (500 MHz, CDCl3) δ 7.92 (dd, J = 7.9, 1.7 Hz, 1H), 7.87
(s, 1H), 7.52 (dd, J = 8.0, 1.1 Hz, 1H), 7.28 (t, J = 5.0 Hz, 1H), 7.12 (td, J = 7.9, 1.7 Hz, 1H),
3.89 (t, J = 5.0 Hz, 4H), 3.22 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz, CDCl3): δ 134.6,
34.6, 132.8, 129.3, 127.4, 126.7, 123.2, 66.3, 51.7. HRMS: m/z (EIꢀTOF) calculated [M]:
268.0211, found: 268.0203.
(E)ꢀNꢀ(naphthalenꢀ2ꢀylmethylene)morpholinꢀ4ꢀamine (1s).18 Afforded 1s (432 mg, 92%)
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as a white solid, m.p. 125ꢀ127 C. 1H NMR (500 MHz, CDCl3): δ 7.95 (dd, J = 8.6, 1.4 Hz,
1H), 7.86 (s, 1H), 7.85 – 7.80 (m, 3H), 7.75 (s, 1H), 7.46ꢀ 7.45 (m, 2H), 3.92 (t, J = 5.0 Hz,
4H), 3.24 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz, CDCl3): δ 136.2, 133.7, 133.5, 133.4,
128.3, 128.0, 127.8, 126.6, 126.2, 126.0, 123.0, 66.4, 51.8
(E)ꢀNꢀ(pyridinꢀ3ꢀylmethylene)morpholinꢀ4ꢀamine (1t). Afforded 1t (330 mg, 86%) as a
brown solid, m.p. 31ꢀ32 oC. 1H NMR (500 MHz, CDCl3): δ 8.70 (d, J = 1.8 Hz, 1H), 8.47 (dd,
J = 4.8, 1.6 Hz, 1H), 7.96 (dt, J = 8.0, 1.8 Hz, 1H), 7.52 (s, 1H), 7.25 (dd, J = 7.9, 4.8 Hz, 1H),
3.87 (t, J = 5.0 Hz, 4H), 3.19 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz, CDCl3): δ 149.0,
148.2, 132.3, 131.9, 131.8, 123.5, 66.3, 51.5. HRMS: m/z (EIꢀTOF) calculated [M]: 191.1059,
found: 191.1057.
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(E)ꢀNꢀ(thiophenꢀ2ꢀylmethylene)morpholinꢀ4ꢀamine (1u).23 Afforded 1u (345 mg, 88%) as
a brown solid, m.p. 92ꢀ93 oC. 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H), 7.2 (d, J = 5.0 Hz,
1H), 7.07 (dd, J = 3.6, 0.8 Hz, 1H), 6.99 (dd, J = 5.1, 3.6 Hz, 1H), 3.86 (t, J = 5.0 Hz, 4H),
3.13 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz, CDCl3): δ 141.5, 131.2, 127.1, 126.3, 125.5,
66.3, 51.8.
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(E)ꢀNꢀ(furanꢀ2ꢀylmethylene)morpholinꢀ4ꢀamine (1v). Afforded 1v (299 mg, 83%) as a
pale yellow solid, m.p. 53ꢀ54 oC. 1H NMR (500 MHz, CDCl3) δ 7.45 (s, 1H), 7.41 (d, J = 0.8
Hz, 1H), 6.46 (d, J = 3.4 Hz, 1H), 6.43 – 6.38 (m, 1H), 3.85 (t, J = 5.0 Hz, 4H), 3.13 (t, J =
5.0 Hz, 4H). 13C{1H}NMR (125 MHz, CDCl3): δ 151.1, 142.7, 126.6, 111.3, 109.2, 66.2, 51.6.
HRMS: m/z (EIꢀTOF) calculated [M]: 180.0899, found: 180.0894.
(E)ꢀNꢀ(benzo[b]thiophenꢀ3ꢀylmethylene)morpholinꢀ4ꢀamine (1w). Afforded 1w (423 mg,
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86%) as a brown solid, m.p. 73ꢀ74 oC. H NMR (500 MHz, CDCl3): δ 8.67 (dd, J = 7.4, 0.7
Hz, 1H), 7.93 (s, 1H), 7.87 – 7.83 (m, 1H), 7.51 (s, 1H), 7.41 (dtd, J = 14.9, 7.2, 1.2 Hz, 2H),
3.92 (t, J = 5.0 Hz, 4H), 3.22 (t, J = 5.0 Hz, 4H). 13C{1H}NMR (125 MHz, CDCl3): δ 140.7,
136.3, 132.7, 132.4, 126.6, 124.9, 124.9, 124.6, 122.5, 66.4, 51.8. HRMS: m/z (EIꢀTOF)
calculated [M]: 342.0827, found:246.0826.
(E)ꢀNꢀ((1Hꢀindolꢀ3ꢀyl)methylene)morpholinꢀ4ꢀamine (1x).24 Afforded 1x (357 mg, 78%)
as a pale white solid, m.p. 128ꢀ129 oC. 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 8.32 (d, J
= 7.4 Hz, 1H), 7.99 (s, 1H), 7.34 (dd, J = 7.1, 1.1 Hz, 1H), 7.30 (d, J = 2.6 Hz, 1H), 7.25 –
7.23 (m, 1H), 7.22 – 7.17 (m, 1H), 3.93 (t, J = 5.0 Hz, 4H), 3.18 (t, J = 5.0 Hz, 4H).
13C{1H}NMR (125 MHz, CDCl3): δ 136.7, 135.2, 125.5, 124.8, 123.0, 122.0, 120.7, 114.0,
111.1, 66.5, 52.6.
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(E)ꢀNꢀ(3ꢀphenylpropylidene)morpholinꢀ4ꢀamine (1y).8a Afforded 1y (392 mg, 90%) as a
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clear colorless liquid. H NMR (500 MHz, CDCl3) δ 7.29 (dd, J = 10.1, 4.9 Hz, 2H), 7.24 –
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J = 7.5 Hz, 2H), 2.62 – 2.54 (m, 2H). 13C{1H}NMR (125 MHz, CDCl3): δ 141.1, 140.6, 128.4,
128.3, 126.0, 66.4, 52.3, 34.6, 33.6.
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(E)ꢀethyl 3ꢀ(2,2ꢀdimethylhydrazono)ꢀ2,2ꢀdifluoroꢀ5ꢀphenylpentanoate (1z).9a Afforded 1z
(290mg, 48%) as a pale yellow liquid. 1H NMR (500 MHz, CDCl3) δ 7.31 – 7.27 (m, 2H),
7.24 – 7.20 (m, 3H), 6.67 (t, J = 5.4 Hz, 1H), 2.84 – 2.79 (m, 2H), 2.73 (s, 6H), 2.60 – 2.52
(m, 2H). 13C{1H}NMR (125 MHz, CDCl3): δ 141.4, 138.0, 128.4, 128.3, 125.9, 43.3, 34.7,
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(E)ꢀNꢀoctylidenemorpholinꢀ4ꢀamine (1aa).25 Afforded 1aa (352mg, 83%) as a clear
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colorless liquid. H NMR (500 MHz, CDCl3) δ 6.95 (t, J = 5.6 Hz, 1H), 3.80 (t, J = 5.0 Hz,
4H), 2.92 (t, J = 5.0 Hz, 4H), 2.25 – 2.19 (m, 2H), 1.46 (dt, J = 15.1, 7.4 Hz, 2H), 1.31 – 1.23
(m, 8H), 0.85 (t, J = 6.9 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 142.4, 67.0, 66.4, 52.5,
33.0, 31.7, 29.1, 29.0, 27.4, 22.6, 14.0.
(E)ꢀNꢀhexylidenemorpholinꢀ4ꢀamine (1ab). Afforded 1ab (302 mg, 82%) as a clear
colorless liquid. 1H NMR (500 MHz, CDCl3) δ 6.96 (t, J = 5.6 Hz, 1H), 3.80 (t, J = 5.0 Hz,
4H), 2.92 (t, J = 5.0 Hz, 4H), 2.26 – 2.18 (m, 2H), 1.52 – 1.40 (m, 2H), 1.33 – 1.26 (m, 4H),
0.87 (t, J = 7.5 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 142.4, 66.4, 52.5, 33.0, 31.3,
27.0, 22.4, 13.9. HRMS: m/z (EIꢀTOF) calculated [M]: 184.1576, found:184.1570.
(E)ꢀNꢀpentylidenemorpholinꢀ4ꢀamine (1ac). Afforded 1ac (296 mg, 87%) as a clear
colorless liquid. 1H NMR (500 MHz, CDCl3) δ 6.95 (t, J = 5.6 Hz, 1H), 3.80 (t, J = 5.0 Hz,
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4H), 2.92 (t, J = 5.0 Hz, 4H), 2.27 – 2.18 (m, 2H), 1.48 – 1.40 (m, 2H), 1.38 – 1.29 (m, 2H),
0.89 (t, J = 7.3 Hz, 3H). 113C{1H}NMR (125 MHz, CDCl3): δ 142.4, 66.4, 52.4, 32.7, 29.5,
22.2, 13.9. HRMS: m/z (EIꢀTOF) calculated [M]: 170.1419, found:170.1415.
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(E)ꢀ1ꢀ(4ꢀmethylbenzylidene)ꢀ2ꢀphenylhydrazine (1ad).26 Afforded 1ad (412 mg, 98%) as
a brown solid, m.p. 108ꢀ109 oC. 1H NMR (500 MHz, CDCl3): δ 7.63 (s, 1H), 7.57 (d, J = 8.1
Hz, 2H), 7.53 (s, 1H), 7.33 – 7.27 (m, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.12 (dd, J = 8.5, 0.9 Hz,
2H), 6.92 – 6.85 (m, 1H), 2.39 (s, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 144.8, 138.4,
137.5, 132.5, 129.3, 129.2, 126.1, 119.9, 112.7, 21.4.
(E)ꢀNꢀ(4ꢀbromobenzylidene)piperidinꢀ1ꢀamine (1ae). Afforded 1ae (495 mg, 93%) as a
white solid, m.p. 51ꢀ52 oC. 1H NMR (500 MHz, CDCl3) δ 7.54 – 7.37 (m, 5H), 3.16 (t, J = 5.0
Hz, 4H), 1.74 (dt, J = 11.6, 5.8 Hz, 4H), 1.57 – 1.52 (m, 2H). 13C{1H}NMR (125 MHz,
CDCl3): δ 135.7, 132.7, 131.5, 127.3, 121.3, 51.9, 25.1, 24.1. HRMS: m/z (EIꢀTOF)
calculated [M]: 266.0419, found:266.0417.
(E)ꢀNꢀ(4ꢀbromobenzylidene)ꢀ4ꢀmethylpiperazinꢀ1ꢀamine (1af). Afforded 1af (489 mg,
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87%) as a white solid, m.p.140ꢀ141 C. 1H NMR (500 MHz, CDCl3) δ 7.49 ꢀ7.45 (m, 5H),
3.20 (t, J = 5.0 Hz, 4H), 2.60 (t, J = 5.0 Hz, 4H), 2.35 (s, 3H). 13C{1H}NMR (125 MHz,
CDCl3): δ 135.2, 134.0, 131.5, 127.4, 121.7, 54.4, 50.8, 45.9. HRMS: m/z (EIꢀTOF)
calculated [M]: 281.0528, found: 281.0525.
(E)ꢀ4ꢀmethylbenzaldehyde oxime (1ag).27 Afforded 1ag (182 mg, 75%) as a white solid,
m.p. 70ꢀ71 oC. 1H NMR (500 MHz, CDCl3) δ 9.24 (s, 1H), 8.17 (s, 1H), 7.49 (d, J = 8.1 Hz,
2H), 7.21 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 150.3, 140.3,
129.5, 129.0, 127.0, 21.4.
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(E)ꢀN'ꢀ(4ꢀmethylbenzylidene)benzenesulfonohydrazide (1ah).8a Afforded 1ah (507 mg,
88%) as a white solid, m.p. 116ꢀ117 oC. 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 8.02 (s,
1H), 8.00 (d, J = 1.4 Hz, 1H), 7.77 (s, 1H), 7.61 – 7.55 (m, 1H), 7.50 (dd, J = 10.5, 4.7 Hz,
2H), 7.46 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H). 13C{1H}NMR (125 MHz,
CDCl3): δ 148.4, 140.8, 138.1, 133.2, 130.3, 129.3, 129.0, 127.8, 127.3, 21.4.
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2ꢀBromoꢀ2,2ꢀdifluoroꢀNꢀphenylacetamide (2b).9d Afforded 2b (488 mg, 98%) as a white
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solid, m.p. 83ꢀ84 C. 1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.57 (d, J = 8.2 Hz, 2H),
7.39 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H). 13C{1H}NMR (125 MHz, CDCl3): δ 157.5 (t,
J = 27.5 Hz), 135.3, 129.4, 126.24, 114.00, 111.5 (t, J = 315.0 Hz). 19F NMR (471 MHz,
CDCl3): δ ꢀ60.6.
(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(pꢀtolyl)propanoate (3).8a The procedure
was operated in general method. The reaction gave 63 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(pꢀtolyl)propanoate in 96 % isolated yield as a pale
yellow solid (PE/EA=10:1), m.p. 68ꢀ69oC. 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 8.0 Hz,
2H), 7.21 (d, J = 8.0 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.60 (t, J = 5.0 Hz, 4H), 2.93 (t, J =
5.0 Hz, 4H), 2.37 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 163.7
(t, J = 31.3 Hz), 141.1 (t, J = 31.3 Hz), 139.7, 129.4, 128.5, 128.2, 114.32 (t, J = 248.6 Hz),
65.98, 62.5, 54.1, 21.4, 14.0. 19F NMR (471 MHz, CDCl3): δ ꢀ101.54.
(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀphenylpropanoate (4).8a The procedure was
operated in general method. The reaction gave 79 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀphenylpropanoate in 87 % isolated yield as a clear
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yellow liquid (PE/EA=10:1). H NMR (500 MHz, CDCl3) δ 7.47 (dd, J = 6.1, 2.6 Hz, 2H),
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7.43 – 7.38 (m, 3H), 4.37 (q, J = 7.1 Hz, 2H), 3.58 (t, J = 5.0 Hz, 4H), 2.92 (t, J = 5.0 Hz, 4H),
1.37 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 163.64(t, J = 31.3 Hz), 140.63 (t,
J = 30.0 Hz), 131.2, 129.7, 128.6, 128.6, 114.3 (t, J = 247.5 Hz), 65.9, 62.5, 54.1, 14.0. 19F
NMR (471 MHz, CDCl3): δ ꢀ101.49.
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(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ(morpholinoimino)propanoate (5). The
procedure was operated in general method. The reaction gave 99 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ(morpholinoimino) propanoate in 97 % isolated yield as
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a pale yellow liquid (PE/EA=5:1). H NMR (500 MHz, CDCl3): δ 7.44 (d, J = 8.8 Hz, 2H),
6.92 (d, J = 8.9 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.60 (t, J = 5.0 Hz, 4H), 2.92
(t, J = 5.0 Hz, 4H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3) δ 163.7 (t, J =
31.3Hz), 160.46, 141.5 (t, J = 31.3Hz), 129.9, 123.0, 116.33, 114.35 (t, J = 247.5Hz), 114.1,
66.0, 62.5, 55.2, 54.0, 14.0.19F NMR (471 MHz, CDCl3) δ ꢀ101.52. HRMS: m/z (EIꢀTOF)
calculated [M]: 342.1391, found: 342.1388.
(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(4ꢀfluorophenyl)ꢀ3ꢀ(morpholinoimino)propanoate (6).8a The
procedure was operated in general method. The reaction gave 84 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(4ꢀfluorophenyl)ꢀ3ꢀ(morpholinoimino) propanoate in 85 % isolated yield as a
clear colorless liquid (PE/EA=10:1). 1H NMR (500 MHz, CDCl3) δ 7.48 (dd, J = 8.6, 5.4 Hz,
2H), 7.11 (t, J = 8.7 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.60 (t, J = 5.0 Hz, 4H), 2.91 (t, J = 5.0
Hz, 4H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 163.45 (t, J = 31.3 Hz),
163.2 (d, J = 248.8 Hz), 140.0 (t, J = 31.3 Hz), 130.7 (t, J = 7.5 Hz), 127.1 (t, J = 2.5 Hz)
115.9 (t, J = 21.3 Hz), 114.2 (t, J = 247.5 Hz), 65.9, 62.6, 54.1, 14.0. 19F NMR (471 MHz,
CDCl3): δ ꢀ101.5, ꢀ109.8
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(E)ꢀethyl 3ꢀ(4ꢀchlorophenyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)propanoate (7).8a The
procedure was operated in general method. The reaction gave 86 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(4ꢀchlorophenyl)ꢀ3ꢀ(morpholinoimino) propanoate in 83 % isolated yield as a
pale yellow liquid (PE/EA=10:1). 1H NMR (500 MHz, CDCl3) δ 7.46 – 7.36 (m, 4H), 4.37 (q,
J = 7.1 Hz, 2H), 3.60 (t, J = 5.0 Hz, 4H), 2.93 (t, J = 5.0 Hz, 4H), 1.37 (t, J = 7.1 Hz, 3H).
13C{1H}NMR (125 MHz, CDCl3): δ 163.64, 163.38 (t, J = 32.5 Hz), 139.46 (t, J = 31.3 Hz),
135.9, 130.09, 129.59, 129.09, 114.1 (t, J = 247.5 Hz), 65.9, 62.6, 54.1, 14.0. 19F NMR (471
MHz, CDCl3): δ ꢀ101.3.
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(E)ꢀethyl 3ꢀ(4ꢀbromophenyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)propanoate (8). The
procedure was operated in general method. The reaction gave 95 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(4ꢀbromophenyl)ꢀ3ꢀ(morpholinoimino) propanoate in 81 % isolated yield as a
pale yellow liquid (PE/EA=10:1).1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.5 Hz, 2H), 7.36
(d, J = 8.5 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.60 (t, J = 5.0 Hz, 4H), 2.93 (t, J = 5.0 Hz, 4H),
1.37 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 163.36 (t, J = 31.3 Hz), 139.35 (t,
J = 32.5 Hz), 132.0, 130.2, 130.0, 124.2, 114.1 (t, J = 251.3 Hz), 65.9, 62.6, 54.1, 14.0. 19F
NMR (471 MHz, CDCl3): δ ꢀ101.3. HRMS: m/z (EIꢀTOF) calculated [M]: 390.0391, found:
390.0386.
(E)ꢀethyl 3ꢀ(4ꢀacetylphenyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)propanoate (9). The
procedure was operated in general method. The reaction gave 86 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(4ꢀacetylhenyl)ꢀ3ꢀ(morpholinoimino) propanoate in 83 % isolated yield as a
yellow liquid (PE/EA=5:1). 1H NMR (500 MHz, CDCl3): δ 7.98 (d, J = 8.3 Hz, 2H), 7.58 (d,
J = 8.2 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.58 (t, J = 5.0 Hz, 4H), 2.92 (t, J = 5.0 Hz, 4H),
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2.61 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 197.2, 163.30 (t, J
= 31.3 Hz), 138.8 (t, J = 31.3 Hz), 137.7, 136.0, 129.0, 128.4, 114.08 (t, J = 248.8 Hz), 65.8,
62.7, 54.2, 26.6, 14.0. 19F NMR (471 MHz, CDCl3): δ ꢀ101.1. HRMS: m/z (EIꢀTOF)
calculated [M]: 354.1391, found: 354.1385.
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(E)ꢀethyl 3ꢀ(4ꢀcyanophenyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)propanoate (10). The
procedure was operated in general method. The reaction gave 75 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(4ꢀacetylhenyl)ꢀ3ꢀ(morpholinoimino) propanoate in 74 % isolated yield as a
yellow solid (PE/EA=10:1). 1H NMR (500 MHz, CDCl3): δ 7.72 (d, J = 8.5 Hz, 2H), 7.60 (d,
J = 8.4 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.60 (t, J = 5.0 Hz, 4H), 3.92 (t, J = 5.0 Hz, 4H),
1.37 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 163.0 (t, J = 31.3 Hz), 137.7 (t, J
= 31.3 Hz), 136.0, 132.3, 129.5, 117.9, 114.0 (t, J = 31.3 Hz), 113.6, 65.8, 62.8, 54.3, 14.0. 19F
NMR (471 MHz, CDCl3): δ ꢀ100.8. HRMS: m/z (EIꢀTOF) calculated [M]: 377.1238, found:
337.1240.
(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(4ꢀnitrophenyl)propanoate (11).9d The
procedure was operated in general method. The reaction gave 91 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(4ꢀnitrophenyl) propanoate in 85 % isolated yield as a
yellow solid (PE/EA=10:1), m.p. 119ꢀ120 oC. 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.8
Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.60 (t, J = 5.0 Hz, 4H), 2.94 (t, J
= 5.0 Hz, 4H), 1.38 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 163.0 (t, J =
30.0Hz), 148.3, 137.9, 137.2 (t, J = 32.5 Hz), 129.9, 123.8, 113.93 (t, J = 248.8Hz), 65.8, 62.8,
54.3, 14.0. 19F NMR (471 MHz, CDCl3): δ ꢀ100.7.
(E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(4ꢀ(trifluoromethyl)phenyl)propanoate
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(12).8a The procedure was operated in general method. The reaction gave 92 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(4ꢀtrifluoromethylphenyl) propanoate in 80% isolated
yield as a yellow solid (PE/EA=10:1), m.p. 78ꢀ79 oC. 1H NMR (500 MHz, CDCl3) δ 7.68 (d,
J = 8.2 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.60 (t, J = 5.0 Hz, 4H),
2.93 (t, J = 5.0 Hz, 4H), 1.38 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 163.3 (t,
J = 31.3 Hz), 138.5 (t, J = 31.3 Hz), 135.0, 131.7 (q, J = 32.5 Hz), 129.2, 125.6 (q, J = 3.8
Hz), 123.6 (q, J = 271.3 Hz), 114.1 (t, J = 248.8 Hz), 65.9, 62.7, 54.2, 14.0. 19F NMR (471
MHz, CDCl3): δ ꢀ63.0, ꢀ101.1.
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(E)ꢀethyl 3ꢀ(4ꢀ(dimethylamino)phenyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)propanoate (13).
The procedure was operated in general method. The reaction gave 65 mg of (E)ꢀethyl
3ꢀ(4ꢀ(dimethylamino)phenyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)propanoate in 61 % isolated
yield as a clear colorless liquid (PE/EA=1:1). 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 8.8
Hz, 2H), 6.68 (d, J = 9.0 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.63 (t, J = 5.0 Hz, 4H), 3.00 (s,
6H), 2.94 (t, J = 5.0 Hz, 4H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ
163.95 (t, J = 31.9 Hz), 150.9, 143.38 (t, J = 30.0 Hz), 129.4, 117.4, 114.67 (t, J = 248.8 Hz),
111.40, 66.1, 62.4, 54.0, 40.0, 14.0. 19F NMR (471 MHz, CDCl3): δ ꢀ101.3. HRMS: m/z
(EIꢀTOF) calculated [M]: 355.1707, found: 355.1706.
(E)ꢀethyl 3ꢀ(3,4ꢀdimethoxyphenyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)propanoate (14).
The procedure was operated in general method. The reaction gave 107 mg of (E)ꢀethyl
3ꢀ(3,4ꢀdimethoxyphenyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)propanoate in 96 % isolated yield
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as a clear colorless liquid (PE/EA=5:1). H NMR (500 MHz, CDCl3): δ 7.07 (d, J = 8.1 Hz,
1H), 7.03 (s, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 3.87 (s, 3H),
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3.60 (t, J = 5.0 Hz, 4H), 2.93 (t, J = 5.0 Hz, 4H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125
MHz, CDCl3): δ 163.7 (t, J = 31.3 Hz), 150.1, 148.9, 141.0 (t, J = 31.9 Hz), 123.0, 121.6,
114.4 (t, J = 248.1 Hz), 111.3, 111.0, 66.1, 62.5, 56.0, 55.8, 54.0, 14.0. 19F NMR (471 MHz,
CDCl3): δ ꢀ101.4. HRMS: m/z (EIꢀTOF) calculated [M]: 372.1497, found: 372.1500.
(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(4ꢀhydroxyꢀ3ꢀmethoxyphenyl)ꢀ3ꢀ(morpholinoimino)propanoate
(15). The procedure was operated in general method. The reaction gave 100 mg of (E)ꢀethyl
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3ꢀ(4ꢀhydroxyꢀ3ꢀmethoxyphenyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)propanoate in 97
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isolated yield as a clear colorless liquid (PE/EA=3:1).1H NMR (500 MHz, CDCl3): δ 7.05 –
7.00 (m, 2H), 6.93 (d, J = 8.2 Hz, 1H), 5.95 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H),
3.61 (t, J = 5.0 Hz, 4H), 2.93 (t, J = 5.0 Hz, 4H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125
MHz, CDCl3): δ 163.7 (t, J = 31.3Hz), 146.9, 146.5, 141.1 (t, J = 31.3Hz), 122.4, 114.7, 114.4
(t, J = 253.4Hz), 110.7, 66.1, 62.5, 56.1, 54.0, 24.8, 14.1. 19F NMR (471 MHz, CDCl3): δ
ꢀ101.4. HRMS: m/z (EIꢀTOF) calculated [M]: 358.1340, found: 358.1342.
(E)ꢀethyl 3ꢀ(3ꢀchlorophenyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)propanoate (16).8a The
procedure was operated in general method. The reaction gave 103 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(3ꢀchlorophenyl)ꢀ3ꢀ(morpholinoimino) propanoate in 99% isolated yield as a
pale yellow liquid (PE/EA=10:1).1H NMR (500 MHz, CDCl3) δ 7.48 (s, 1H), 7.41 – 7.33 (m,
3H), 4.37 (q, J = 7.1 Hz, 2H), 3.60 (t, J = 5.0 Hz, 4H), 2.94 (t, J = 5.0 Hz, 4H), 1.37 (t, J = 7.1
Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 163.3 (t, J = 31.9Hz), 138.5 (t, J = 31.9Hz),
134.7, 132.9, 129.9, 129.9, 128.7, 126.9, 114.1 (t, J = 248.8 Hz), 65.9, 62.6, 54.2, 14.0. 19F
NMR (471 MHz, CDCl3): δ ꢀ101.2.
(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(3ꢀnitrophenyl)propanoate (17). The
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yellow solid (PE/EA=10:1). H NMR (500 MHz, CDCl3): δ 8.38 (s, 1H), 8.28 (ddd, J = 8.3,
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2.2, 1.0 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H),
3.61 (t, J = 5.0 Hz, 4H), 2.95 (t, J = 5.0 Hz, 4H), 1.39 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125
MHz, CDCl3) δ 163.0 (t, J = 31.9 Hz), 148.2, 137.0 (t, J = 31.2Hz), 134.6, 132.8, 129.8, 124.5,
123.8, 113.9 (t, J =250.0 Hz), 65.8, 62.8, 54.3, 14.0. 19F NMR (471 MHz, CDCl3) δ ꢀ100.84(d,
J = 9.4 Hz). HRMS: m/z (EIꢀTOF) calculated [M]: 357.1136, found: 357.1131.
(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(oꢀtolyl)propanoate (18). The procedure
was operated in general method. The reaction gave 63 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(oꢀtolyl)propanoate in 64 % isolated yield as a clear
colorless liquid (PE/EA=10:1). 1H NMR (500 MHz, CDCl3): δ 7.34 – 7.28 (m, 2H), 7.21 (t, J
= 8.1 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.62 – 3.52 (m, 4H), 2.97 – 2.84 (m, 4H), 2.28 (s, 3H),
1.38 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 163.90 (t, J = 32.5 Hz), 138.8 (t,
J = 31.3 Hz), 138.1, 131.2, 130.0, 129.7, 128.8, 125.7, 114.4 (t, J = 247.5 Hz), 66.3, 62.5,
53.8, 19.7, 14.1. 19F NMR (471 MHz, CDCl3) δ ꢀ101.0 (d, J = 273.2 Hz), ꢀ103.3 (d, J = 273.2
Hz). HRMS: m/z (EIꢀTOF) calculated [M]: 326.1442, found: 326.1441.
(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(2ꢀmethoxyphenyl)ꢀ3ꢀ(morpholinoimino)propanoate (19).8a The
procedure was operated in general method. The reaction gave 77 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(2ꢀmethoxyphenyl)ꢀ3ꢀ(morpholinoimino) propanoate in 75 % isolated yield as
a clear colorless liquid (PE/EA=5:1).1H NMR (500 MHz, CDCl3) δ 7.37 (t, J = 7.9 Hz, 1H),
7.24 (s, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.83
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(s, 3H), 3.57 (t, J = 5.0 Hz, 4H), 2.97 (t, J = 5.0 Hz, 4H), 1.36 (t, J = 7.1 Hz, 3H).
13C{1H}NMR (125 MHz, CDCl3): δ 164.1 (t, J = 33.1 Hz), 157.6, 135.0 (t, J = 31.1 Hz),
131.2, 130.5, 120.5, 114.2 (t, J =248.1 Hz), 111.12, 66.2, 62.4, 55.8, 53.4, 14.1.19F NMR (471
MHz, CDCl3): δ ꢀ101.6, ꢀ103.2.
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(E)ꢀethyl 3ꢀ(2ꢀbromophenyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)propanoate (20). The
procedure was operated in general method. The reaction gave 53 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(2ꢀbromophenyl)ꢀ3ꢀ(morpholinoimino) propanoate in 45 % isolated yield as a
pale yellow liquid (PE/EA=10:1).1H NMR (500 MHz, CDCl3): δ 7.61 (d, J = 8.0 Hz, 1H),
7.36 (dt, J = 14.8, 7.5 Hz, 2H), 7.31 – 7.26 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.61 (t, J = 4.9
Hz, 4H), 3.01 (dtd, J = 17.0, 11.9, 4.7 Hz, 4H), 1.38 (t, J = 7.1 Hz, 3H).13C{1H}NMR (125
MHz, CDCl3): δ 163.7 (t, J = 33.9 Hz), 133.5, 132.7, 131.3, 131.0, 127.2, 127.0, 124.3, 114.2
(t, J = 248.8 Hz), 66.3, 62.5, 53.4, 14.1. 19F NMR (471 MHz, CDCl3): δ ꢀ99.6 (d, J =268.5
Hz), ꢀ102.8 (d, J =268.5 Hz). HRMS: m/z (EIꢀTOF) calculated [M]: 390.0391, found:
390.0392.
(E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(naphthalenꢀ2ꢀyl)propanoate
(21,
E/Z=67:33). The procedure was operated in general method. The reaction gave 56 mg of
(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(naphthalenꢀ2ꢀyl)propanoate in 51 % isolated
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yield as a pale yellow liquid (PE/EA=10:1). H NMR (500 MHz, CDCl3) δ 8.37 – 8.26 (m,
1H), 7.99 (s, 1H), 7.92 – 7.86 (m, 2H), 7.63 – 7.45 (m, 3H), 4.41 (q, J = 7.1 Hz, 3H), 3.60 (t,
J = 5.0 Hz, 4H), 2.96 (t, J = 5.0 Hz, 4H), 1.40 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz,
CDCl3): δ 163.7 (t, J = 35.0 Hz), 140.7 (t, J = 32.5 Hz), 133.5, 132.8, 131.3, 128.5, 128.4,
128.4, 127.8, 127.3, 126.8, 125.4, 114.4 (t, J = 211.3 Hz), 66.0, 62.6, 54.3, 14.1. 19F NMR
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(471 MHz, CDCl3): δ ꢀ101.1. HRMS: m/z (EIꢀTOF) calculated [M]: 362.1442, found:
362.1439.
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(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(pyridinꢀ3ꢀyl)propanoate (22). The
procedure was operated in general method. The reaction gave 38 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(pyridinꢀ3ꢀyl)propanoate in 41 % isolated yield as a pale
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yellow liquid (PE/EA=5:1). H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.65 (d, J = 4.2 Hz,
1H), 7.79 (d, J = 7.8 Hz, 1H), 7.38 (dd, J = 7.8, 4.9 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.60 (t,
J = 5.0 Hz, 4H), 2.94 (t, J = 5.0 Hz, 4H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz,
CDCl3): δ 163.2 (t, J = 31.3Hz), 150.6, 149.4, 136.2, 127.7, 123.5, 114.00 (t, J = 248.1Hz),
65.8, 62.7, 54.2, 14.0. 19F NMR (471 MHz, CDCl3): δ ꢀ101.3. HRMS: m/z (EIꢀTOF)
calculated [M]: 313.1238, found: 326.1237.
(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(thiophenꢀ2ꢀyl)propanoate (23). The
procedure was operated in general method. The reaction gave 21 mg of (E)ꢀethyl
2,2ꢀdifluoroꢀ3ꢀ(morpholinoimino)ꢀ3ꢀ(pyridinꢀ3ꢀyl)propanoate in 21 % isolated yield as a pale
yellow liquid (PE/EA=7:1). 1H NMR (500 MHz, CDCl3) δ 7.64 (s, 1H), 7.26 – 7.23 (m, 1H),
6.96 (d, J = 3.8 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.86 (t, J = 5.0 Hz, 4H), 3.16 (t, J = 5.0 Hz,
4H), 1.35 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 163.2 (t, J = 35.0 Hz),
145.63, 132.6 (t, J = 30.0 Hz), 129.0, 128.4 (t, J = 5.6 Hz), 125.1, 111.6 (t, J = 248.7 Hz),
66.2, 63.4, 51.4, 13.9. 19F NMR (471 MHz, CDCl3): δ ꢀ93.9. HRMS: m/z (EIꢀTOF) calculated
[M]: 318.0850, found: 318.0848.
(E)ꢀethyl 2,2ꢀdifluoroꢀ3ꢀ(furanꢀ2ꢀyl)ꢀ3ꢀ(morpholinoimino)propanoate (24). The procedure
was operated in general method. The reaction gave 46 mg of (E)ꢀethyl
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2,2ꢀdifluoroꢀ3ꢀ(furanꢀ2ꢀyl)ꢀ3ꢀ(morpholinoimino) propanoate in 51 % isolated yield as a pale
yellow liquid (PE/EA=7:1). 1H NMR (500 MHz, CDCl3) δ 7.40 (s, 1H), 6.77 (dd, J = 3.4,
1.6 Hz, 1H), 6.57 (d, J = 3.5 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 3.86 (t, J = 5.0 Hz, 4H), 3.16
(t, J = 5.0 Hz, 4H), 1.36 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, CDCl3): δ 162.3 (t, J =
33.8 Hz), 154.3, 143.5 (t, J = 33.1Hz), 124.8, 113.5, 108.59 (t, J = 246.9 Hz), 107.18, 66.2,
63.5, 51.2, 13.9. 19F NMR (471 MHz, CDCl3): δ ꢀ102.2. HRMS: m/z (EIꢀTOF) calculated [M]:
302.1078, found: 302.1076.
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(E)ꢀethylꢀ3ꢀ(5ꢀ(2ꢀethoxyꢀ1,1ꢀdifluoroꢀ2ꢀoxoethyl)thiophenꢀ2ꢀyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholi
noimino)propanoate (25). The procedure was operated in general method. The reaction gave
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(E)ꢀethylꢀ3ꢀ(5ꢀ(2ꢀethoxyꢀ1,1ꢀdifluoroꢀ2ꢀoxoethyl)thiophenꢀ2ꢀyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholin
oimino)propanoate propanoate in 39 % isolated yield as a pale yellow liquid (PE/EA=7:1).
1H NMR (500 MHz, CDCl3) δ 7.63 – 7.57 (m, 1H), 7.38 – 7.33 (m, 1H), 4.38 (q, J = 7.1 Hz,
4H), 3.84 (t, J = 5.0 Hz, 4H), 2.91 (t, J = 5.0 Hz, 4H), 1.37 (t, J = 7.1, 3H), 1.36 (t, J = 7.1,
3H). 13C{1H}NMR (125 MHz, CDCl3): δ 162.76 (t, J = 34.4 Hz), 162.3 (t, J = 30.0 Hz),
147.72 (t, J = 31.3 Hz), 138.9 (t, J = 33.8 Hz), 132.0 (t, J = 3.1 Hz), 130.2 (t, J = 1.9 Hz),
127.5 (t, J = 5.6 Hz), 113.8 (t, J = 252.5 Hz), 111.4 (t, J = 250.0 Hz), 65.8, 63.7, 63.0, 54.5,
13.9, 13.9. 19F NMR (471 MHz, CDCl3): δ ꢀ94.2, ꢀ102.5. HRMS: m/z (EIꢀTOF) calculated
[M]: 440.1029, found: 440.1033.
(E)ꢀethyl3ꢀ(5ꢀ(2ꢀethoxyꢀ1,1ꢀdifluoroꢀ2ꢀoxoethyl)furanꢀ2ꢀyl)ꢀ2,2ꢀdifluoroꢀ3ꢀ(morpholinoi
mino)propanoate (26). The procedure was operated in general method. The reaction gave 68
mg
of
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