Indium-promoted reformatsky reaction: A straightforward access to β-amino and β-hydroxy α,α-difluoro carbonyl compounds

Article abstract of DOI:10.1021/jo301873y

A versatile and practical methodology to access β-amino and β-hydroxy α,α-difluoro carbonyl compounds using indium metal is described. This methodology has been successfully applied to a broad range of substrates including aldehydes, ketones, and imines,

Full text of DOI:10.1021/jo301873y

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Article
Indium Promoted Reformatsky Reaction: A Straightforward Access to
beta-amino and beta-hydroxy alpha,alpha-difluoro Carbonyl Compounds.
Thomas Poisson, Marie-Charlotte Belhomme, and Xavier Pannecoucke
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Sep 2012
Downloaded from http://pubs.acs.org on September 25, 2012
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Indium Promoted Reformatsky Reaction: A Straightforward Access to βꢀ
amino and βꢀhydroxy α,αꢀdifluoro Carbonyl Compounds.
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Thomas Poisson,†, ‡, §* MarieꢀCharlotte Belhomme†, ‡, § and Xavier Pannecoucke†, ‡, §
*
†INSA de Rouen, Avenue de l’Université, 76800 St Etienne du Rouvray, France.
‡Université de Rouen, Laboratory COBRA UMR 6014 & FR 3038, IRCOF, 1 Rue
Tesnière, 76821 Mont St Aignan Cedex, France.
§CNRS Délégation Normandie, 14 Rue Alfred Kastler, 14052 Caen Cedex, France.
thomas.poisson@insaꢀrouen.fr, xavier.pannecoucke@insaꢀrouen.fr
Abstract: A versatile and practical methodology to access to βꢀaminoꢀ and βꢀhydroxy
α,αꢀdifluoro carbonyl compounds using indium metal is described. This methodology
has been successfully applied to a broad range of substrates including aldehydes,
ketones and imines affording the corresponding and highly valuable gemꢀdifluoro
esters. The high substrate scope highlight the chemoselectivity of the process.
Introduction
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Fluorinated molecules are of utmost interest in medicinal 1 and agrochemical
chemistry.2 The unique properties of the fluorine atom, such as its electronegativity
and its small ionic radius, strongly affect several molecular properties.3 For instance
the lipophilicity, the bioavailability and the metabolic stability of a drug might be
enhanced with the introduction of fluorine atoms onto its backbone. This remarkable
ability to modify those properties is demonstrated by the presence of at least one
fluorine atom in almost 20% of the entire pharmaceuticals and 30% of the entire
agrochemicals.1 Therefore it is not surprising that the introduction of fluorine atoms
into molecules is becoming a remarkable challenge and several efforts were recently
devoted to develop straightforward access to fluorinated molecules.4 Among all of
these fluorinated molecules, βꢀamino and βꢀhydroxy gemꢀdifluorocarbonyl
compounds are important compounds and relevant building blocks for the synthesis
of more complex fluorinated molecules and biomolecules. For example α,αꢀ
difluorinated βꢀamino acid are often used for the conformational analysis of peptides
or as enzymes inhibitors or to perform ,5 while βꢀhydroxy α,αꢀdifluorinated ester are
important building blocks for the synthesis of fluorinated peptides 6 and other
bioactive compounds.7
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The introduction of highly relevant gemꢀdifluoromethylene units is usually achieved
by fluorination of the corresponding ketones using DAST or Deoxofluor,8 by addition
of fluorinated building blocks to an aldehyde or an imine through a Mukaiyama
9
addition reaction of an unstable fluorinated silicon enolates, or fluorinated
Reformatskyꢀtype reagents (scheme 1).
Scheme 1. Classical methods for the synthesis of βꢀaminoꢀ and βꢀhydroxy α,αꢀ
difluoro carbonyl compounds
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The latter strategy mainly uses zinc metal to perform the Reformatsky process and it
is still hampered by several major drawbacks.10,11
Scheme 2. Reformatsky and HondaꢀReformatsky reaction with BrCF2CO2Et
Firstly, the preparation of unstable organozinc reagents usually requires specific and
sometimes difficultꢀtoꢀcontrol protocols in order to enahance the reactivity of the zinc
metal .12 Secondly, the use of large excesses of the organometallic reagent in
c
b
11
combination with several additives such as AgOAc or Et2AlCl,10 Cp2TiCl2
and
e
CuCl,11 poses a significant problem in terms of atom economy. To ensure good
conversions of desired fluorinated Reformatsky adducts is the use of exotic activation
protocols or unusual reaction conditions. Sonication has been found helpful to
enhance the reactivity of the electrophile and to extend the halfꢀlife of the unstable
Reformatsky reagent.13 An electrochemical process involving a sacrificial Zn anode
and a nickel catalyst has been reported by Périchon and coworkers.14
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The other preferred pathway to have access to the Reformatsky adduct is the Hondaꢀ
Reformatsky reaction. 15 This methodology uses an excess of expensive and
pyrophoric Et2Zn along with a catalytic amount of RhCl(PPh3)3 (Wilkinson’s catalyst).
Although this catalytic process does not require the use of activated zinc metal, it can
be severely affected by a lack of selectivity due to radical side reactions. In fact,
depending on the reaction solvent, α,βꢀunsaturated ketones might afford either 1,2 or
1,3 adducts.
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In order to tackle these major drawbacks, we speculated that indium metal might be
a convenient and practical alternative to zinc. Indium metal gives numerous
advantages compared to others metals. First, indium (0) is stable and easy to handle
and in contrast to zinc it does not require any priorꢀtoꢀuse activation. Moreover,
indiumꢀmediated addition reactions can be performed under Barbier conditions, thus
providing a practical procedure that does not require an initial generation of an
organometallic species. 16 Additionally, the low toxicity of indium metal and its
associated reagents,17 combined with the broad functional group tolerance and the
impressive level of chemoselectivity, make it very appealing from a synthetic point of
view.
Extensive use of indium in allylation, crotylation, propargylation and allenylation
reactions of aldehydes, ketones and imines have been reported.18 For example, Yus
and coworkers recently described an elegant In(0)ꢀpromoted diastereoselective
allylation reaction of imines.19 It should be noted that In(0) has been previously used
in Reformatsky reactions with aldehydes and ketones. 20 Interestingly, when the
reaction was carried out with an imine as the electrophile, lower yields were obtained
i
with In(0) comparatively to Zn.20 Pioneer results on the Inꢀpromoted Reformatsky
a
reactions were reported by Rieke using In(0) generated from potassium and InCl3.20
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Later, Araki20bꢀd showed that commercially available indium metal was suitable and
extended the scope of those reactions. During the last decade, Baba20eꢀg reported the
use of mixtures of In (0) and In(I) and enhanced remarkably the diastereoselectivity
of the reaction. This elegant work showed that both In(I) and In(III) enolates were
formed in the reaction media and the authors proposed the In(I) enolate to be the
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f,21
most reactive organometallic species. 20
To the best of our knowledge the In(0)ꢀmediated Reformatsky reaction with haloꢀ
gemꢀdifluoroacetate has not been investigated to date. Thus, taking into account the
appealing properties of In(0), we decided to explore this new pathway to access to βꢀ
aminoꢀ and βꢀhydroxy α,αꢀdifluoro carbonyl compounds. Herein we report a
straightforward and practical access to the Reformatsky adduct using indium metal.
Results and Discussion
At the very beginning, the aldolꢀtype Reformatsky reaction was carried out with
benzaldehyde using 1.05 equivalent of indium metal and 1.05 equivalent of ethyl
bromodifluoroacetate in THF at room temperature and after 18 hours the desired
product 2a was formed in a modest 24% conversion . To our delight, increasing the
reaction temperature to 60 °C led to a complete conversion and 2a was isolated in
76% yield (scheme 3).
Scheme 3. Initial experiments.
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Remarkably, a further screening revealed that the reaction could be performed in
several organic solvents without erosion of the reaction yield.22
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With this optimized reaction conditions, we extended the reaction scope using
several aldehydes and ketones (Table 1).
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Table 1. Indium mediated Reformatsky reaction with aldehyde and ketones.a
Entry
1
R1
C6H5
R2
H
Product Yield (%)b
2a
2b
2c
2d
2e
2f
76
60
61
72
69
91
66
52
63
61
68
66
99
84
69
91
2
2ꢀMeꢀC6H5
1ꢀnaphthyl
4ꢀBrꢀC6H4
H
3
H
4
H
5
3,4ꢀCl2ꢀC6H4
4ꢀCF3ꢀC6H4
4ꢀCNꢀC6H4
4ꢀCO2MeꢀC6H4
3ꢀOHꢀC6H4
3,4ꢀ(OCH2O)ꢀC6H4
(E)ꢀ C6H5ꢀCH2=CH2
C6H5
H
6
H
7
H
2g
2h
2i
8
H
9
H
10
11c
12c
13c
14c
15c
16c
H
2j
C6H5
Me
Et
2k
2l
C6H5
2m
2n
2o
2p
αꢀtetralone
3ꢀthienyl
C6H5
Me
CH2CH2Cl
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a Conditions: 1 (0.5 mmol), BrCF2CO2Et (1.05 equiv), In0 (1.05 equiv), THF (1 mL), 60
°C, 6h. b Isolated yield. c 1.5 equiv of In0 and BrCF2CO2Et were used and the reaction
time was extended to 12h.
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We were pleased to find that our practical process could be applied to a broad range
of aromatic aldehydes.23 Halogens substituents (2d, 2e, entries 4 and 5) as well the
CF3 group (entry 6) were tolerated. Nitrile and ester groups are also compatible with
the reaction conditions (entries 7 and 8). These last results further highlight the high
level of chemoselectivity of this reaction. Impressively, a phenolic hydrogen did not
affect the reaction and the corresponding adduct 2i was obtained in good yield (entry
9). Ketones reacted smoothly but a slight excess of indium metal (1.5 equiv) and
ethyl bromodifluoroacetate (1.5 equiv) was used in order to ensure complete
conversions after 18 hours. Under these modified reaction conditions the
corresponding tertiary alcohols 2l-p were isolated in good to excellent yields. In
contrast with the HondaꢀReformatsky, α,βꢀunsaturated ketones such as chalcone
gave exclusively the 1,2ꢀ adduct 2k in good yield (entry 11), while the Rh catalyzed
HondaꢀReformatsky reaction affords a mixture of 1,2ꢀ and 1,3ꢀ adduct.15 Remarkably,
an aliphatic chlorinated substituent was compatible and the corresponding 1,2ꢀ
addition product 2p was obtained in excellent yield (entry 16). Having evaluated the
scope of the Inꢀpromoted Refomatsky process, we speculated that 2’ꢀhydroxy
ketones could undergo a subsequent cyclization, allowing the formation of the
corresponding fluorinated lactones. Thus, using 2’ꢀhydroxy ketones 3a and 3b we
were pleased to observe the oneꢀpot formation of the gemꢀdifluorinated lactones 4a
and 4-b in 41% and 48% yields respectively (scheme 4).
Scheme 4. Synthesis of fluorinated lactones.
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A further extension of our methodology would be represented by the Mannichꢀtype
Reformatsky reaction. The success of this strategy would give easy access to highly
valuable gemꢀdifluorinated βꢀamino ester.
Table 2. Optimization of the Mannich type Reformatsky reaction.a
Entry
1
Pg
Ph
x
y
Convb (%)c
1.05
1.05
1.05
2.0
1
13
16
2d 4ꢀOMePh
1
3
4
5
6
7
8
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
1
58
2.0
2.0
2.0
1.5
1.5
100 (70)
92
1.5
1.05
1.05
1.5
58
59
93
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9e
SO2Ph
1.5
1.5
100 (71)
5
6
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8
aConditions: imine (0.5 mmol), In0 (x equiv), BrCF2CO2Et (y equiv), THF (1 mL), 60
°C, 18h. bDetermined by 1H and 19F NMR using an internal standard. c Isolated yield.
d Imine was formed in situ. e Reaction time: 24 h.
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First, using the reaction conditions previously established, a survey of Nꢀprotecting
groups revealed the sulfonamide protecting group to be ideal and the corresponding
adduct was obtained in 58% conversion after 18h (table 2, entry 3). Interestingly, no
traces of the corresponding gemꢀdifluoroꢀβꢀlactam were detected. This is in contrast
to the Znꢀ mediated Reformatsky addition 24 and the previous indium based
reactions.20i A further increase of the of indium and ethyl bromodifluoroacetate, from
1 to 2 equivalents, led to a full conversion and the desired adduct was isolated as the
sole product in 70% yield (entry 4). It should be noted that the amount of indium and
bromodifluoro ester could be reduced to 1.5 equivalents by extension of the reaction
time from 18h to 24h (entry 9).
With these optimized conditions in hand, the reaction scope was successfully
extended to several NꢀTs aldimine. Substrates bearing an halogen substituent were
suitable and the corresponding products were isolated in excellent yield (entries 6ꢀ8).
Nitrile and ester functionalities were also compatible and the corresponding products
were obtained in good yield (entries 9 and 10). Heteroaromatic aldimines proved to
be suitable substrates yielding the corresponding βꢀamino gemꢀdifluoro esters
(entries 11 to 13). α,βꢀUnsaturated imine derived from cinnamaldehyde was also a
suitable substrate affording exclusively the 1,2ꢀ adduct in 73% yield (entry 14).
Unfortunately our methodology could not be extended to NꢀTos ketimines.25
Table 3. Indium mediated Reformatsky reaction with N-Tos imine.a
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Entry
1c
2
R1
Ph
Product Yield (%)b
6a
6b
6c
6d
6e
6f
70
68
80
71
75
81
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73
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73
4ꢀOMeꢀC6H4
1ꢀnaphthyl
3,4ꢀOCH2OꢀC6H4
4ꢀCF3ꢀC6H4
4ꢀBrꢀC6H4
4ꢀClꢀC6H4
3,4ꢀCl C6H3
4ꢀCNꢀC6H4
4ꢀCO2MeꢀC6H4
3ꢀfuryl
3
4
5
6
7
6g
6h
6i
8
9
10
11
12
13
14
6j
6k
6l
2ꢀthienyl
3ꢀpyridyl
6m
6n
Cinnamyl
a Conditions: imine (0.5 mmol), In0 (2 equiv), BrCF2CO2Et (2 equiv), THF (1 mL), 60
°C, 18h. b Isolated yield. c Nꢀbenzensulfonylimine was used instead of NꢀTs imine.
Then, in order to highlight the high chemoselectivity of our methodology we
performed competition reactions between, aldehyde, ketone and imine (scheme 5).
Scheme 5. Competition reactionsa
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a Ratios were determined by 19F NMR using C6H5CF3 as an internal standard.
In order to evaluate the reactivity of the different starting materials used in our study
several competition experiments were performed. As shown in Scheme 5, the
reaction in the presence of benzaldehyde and Nꢀbenzenesulfonylimine revealed that
the aldehyde reacts faster than the imine. When benzaldehyde was reacted in the
presence of acetophenone, a similar trend was observed with ketones reacting faster
than imines. These initial experiments clearly highlight the high chemoselectivity of
the organoindium reagents.
We next sought to extend our methodology employing the highly valuable ethyl
bromofluoroacetate. The resulting αꢀfluoro βꢀamino esters are of great interest for the
development of fluorinated analogue of βꢀamino αꢀhydroxy esters and for
conformational studies of βꢀamino acids. 26 Using our optimized conditions, the
reaction proceeded smoothly and the Mannich adduct 7 was isolated in 78% yield as
an inseparable 1.6: 1 mixture of diastereoisomers (scheme 6). Further attempts to
improve the diastereoselectivity were unsuccessful. 27
Scheme 6: Addition of ethyl bromofluoroacetate to Nꢀsulfonylimine.
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Presumably, the observed low diastereoselectivity arises from the presence of a
mixture of E and Z Inꢀenolate.28 Unfortunately, all our attempts to characterize the
1
indium reagents or to quantify the E/Z ratio by use of H or 19F NMR spectroscopy
were unsuccessful. Nevertheless, in order to get information about the reaction
pathway and to demonstrate the practicability of our methodology, reactions were
carried out with commercially available InCl and unactivated Zn in place of In(0)
(scheme 7).
Scheme 7. Test experiments.
Interestingly, when unactivated Zn was used instead of In(0) a significant drop of
reactivity was observed. After 14h only 43% of the corresponding product was
detected by 19F NMR. This result clearly point out the advantage to use indium metal
instead of Zn. When InCl was used, the reaction proceeded smoothly affording the
Reformatsky adduct in 79% NMR yield (vs 76% isolated yield with In(0)). According
f
to Baba’s observations,20 this result might be explained invoking the formation of an
In(I) enolate, which might then react with the electrophile. Therefore, by analogy with
Baba’s proposal, the following tentative mechanism was envisaged (figure 1).
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Figure 1. Proposed mechanism.
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As depicted in figure 1, the reaction of indium metal with ethyl bromodifluoroacetate
in THF affords a mixture of In(III) and In(I) enolate. The latter reacts faster with the
electrophile affording the Reformatsky adduct. Although radical process cannot be
ruled out, we assume the radical derived from ethyl bromodifluoroacetate would not
be nucleophilic enough to react with aldehydes, ketones or imines.29
Conclusion
In summary a straightforward and practical access to αꢀhydroxy and αꢀamino gemꢀ
difluoroesters has been reported using indium (0) as metal. The remarkable
functional groups tolerance associated with the unique properties of indium allowed
the extension of this methodology to a broad selection of substrates in good to
excellent yields. This method allows a straightforward access to highly valuable βꢀ
amino and βꢀhydroxy gemꢀdifluorinated carbonyl compounds.
Experimental section
Residual CHCl3 served as internal standards (δ = 7.26) for 1H NMR, CFCl3 served as
internal standard (δ = 0.0) for 19F NMR and CDCl3 served as internal standard (δ =
77.16) for 13C NMR. Flash chromatographies were performed with silica gel (0.063 –
0.200 mm). Analytical thin layer chromatographies (TLC) were performed on silica
gel aluminum plates with Fꢀ254 indicator and visualized by UV fluorescence and/or
staining with KMnO4 or PMA. THF was distilled over Na/benzophenone prior to use.
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HRMS analyses were performed under (ESI) conditions with a micro TOF detector.
All experiments were conducted under nitrogen atmosphere in ovenꢀdried glassware
with magnetic stirring using standard Schlenk techniques. All aldehydes were
recrystallized, distilled or filtered through basic alumina prior to use. All ketones were
used as received. NꢀTosꢀaldimines were prepared according to literature methods30
and recrystallized from a boiling mixture of petroleum ether and ethyl acetate prior to
use.
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Reformatsky reaction with aldehyde: To a solution of In0 (powder, 0.55 mmol, 60 mg)
and the corresponding aldehyde (0.5 mmol) in THF (1 mL) was added BrCF2CO2Et
(0.55 mmol, 64 ꢁL). The resulting mixture was stirred at 60°C for 6h and then cooled
to room temperature. The solution was quenched with aqueous HCl (0.5 M, 5 mL)
and extracted with DCM (3 times). The combined organic layers were washed with
brine, dried over MgSO4 and concentrated. The residue was purified by flash
chromatography (SiO2, Petroleum ether/EtOAc) to afford the corresponding βꢀ
hydroxy gemꢀdifluoroester 2a-j.
Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀphenylꢀpropionate 2a:
Compound 2a was obtained as a colorless oil in 76% yield (87 mg), after flash
chromatography (SiO2, cyclohexane/EtOAc, 4: 1, Rf = 0.30 cyclohexane/EtOAc 4:1).
1H NMR (300 MHz, CDCl3): 7.47ꢀ7.39 (m, 5H), 5.24ꢀ5.14 (m, 1H), 4.32 (q, 2H, J =
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7.1 Hz), 2.62 (dd, 1H, J = 5.3 Hz, J = 0.4 Hz), 1.30 (t, 3H, J = 7.1 Hz) C NMR (75
MHz, CDCl3): 163.7 (dd, J = 32.4 Hz, J = 30.8 Hz), 134.6 (d, J = 2.0 Hz), 129.3,
128.5, 127.8, 113.9 (dd, J = 259.2 Hz, J = 254.1 Hz), 73.8 (dd, J = 27.8 Hz, J = 24.4
Hz), 63.3, 13.9. 19F NMR (282 MHz, CDCl3): ꢀ113.9 (dd, 1F, J = 262.4 Hz J = 8.0 Hz),
ꢀ120.4 (dd, 1F, J = 262.4 Hz J = 15.3 Hz). IR (cmꢀ1): 2989, 1755, 1456, 1376, 1192,
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1092, 856, 718, 698. HRMS (ESIꢀ): calcd for [MꢀH] C11H11F2O3: 229.0676, found:
229.0671 (ꢀ2.1 ppm).
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Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀ(2ꢀmethylꢀphenyl)propionate 2b:
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Compound 2b was obtained as a colorless oil in 60% yield (73 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc, 19: 1 to 9:1, Rf = 0.54 Petroleum
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ether/EtOAc 4:1). H NMR (300 MHz, CDCl3): 7.54ꢀ7.51 (m, 1H), 7.26ꢀ7.24 (m, 2H),
7.19ꢀ7.16 (m, 1H), 5.46 (dt, 1H, J = 16.8 Hz, J = 5.1 Hz), 4.31 (q, 2H, J = 7.1 Hz),
2.53 (d, 1H, J = 5.4 Hz), 2.38 (s, 3H), 1.29 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz,
CDCl3): 163.9 (t, J = 31.8 Hz), 137.0, 133.1,130.7, 129.2, 127.6 (d, J = 1.5 Hz),
126.3, 114.3 (t, J = 256.9 Hz), 69.8 (dd, J = 28.9 Hz, J = 24.0 Hz), 63.3, 19.6, 14.0.
19F NMR (282 MHz, CDCl3): ꢀ112.8 (d, 1F, J = 263.6 Hz), ꢀ121.4 (d, 1F, J = 263.6
Hz). IR (cmꢀ1): 3216, 1759, 1294, 1121, 1058, 1002, 831, 731. HRMS (ESIꢀ): calcd
for [MꢀH] C12H13F2O3: 243.0833, found: 243.0829 (+1.6 ppm).
Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀ(1ꢀnaphtyl)propionate 2c:
Compound 2c was obtained as a yellow oil in 61% yield (86 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 9: 1, Rf = 0.50 Petroleum
ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): 8.12ꢀ8.09 (m, 1H), 7.89 (d, 2H, J = 8.0
Hz), 7.79 (d, 1H, J = 7.2 Hz), 7.59ꢀ7.49 (m, 3H), 6.11ꢀ6.02 (m, 1H), 4.27 (q, 2H, J =
7.1 Hz), 2.87 (d, 1H, J = 5.1 Hz), 1.23 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3):
163.8 (t, J = 31.8 Hz), 133.7, 131.5, 130.8 (d, J = 1.6 Hz), 130.0, 129.0, 126.7, 126.3,
125.9, 125.3, 123.3 (t, J = 1.3 Hz), 114.4 (t, J = 257.3 Hz), 69.9 (dd, J = 28.3 Hz, J =
24.4 Hz), 63.3, 13.9. 19F NMR (282 MHz, CDCl3): ꢀ112.9 (d, J = 261.03 Hz), ꢀ120.1
(d, J = 260.85 Hz). IR (cmꢀ1): 3493, 1755, 1305, 1081, 1065, 788. HRMS (ESIꢀ): calcd
for [MꢀH] C15H13F2O3: 279.0833, found: 279.0835 (+ 0.7 ppm).
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Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀ(4ꢀbromoꢀphenyl)propionate 2d:
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Compound 2d was obtained as a pale yellow oil in 72% yield (111 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 9: 1, Rf = 0.50 Petroleum
ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): 7.51 (d, 2H, J = 8.4 Hz), 7.31 (d, 2H, J
= 8.3 Hz), 5.13 (ddd, 1H, J = 15.3 Hz, J = 7.4 Hz, J = 5.3 Hz), 4.30 (q, 2H, J = 7.1
Hz), 2.94 (d, 1H, J = 5.2 Hz), 1.30 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3):
163.5 (t, J = 31.6 Hz), 133.6 (d, J = 1.7 Hz), 131.7, 129.5, 123.6, 113.5 (t, J = 257.2
Hz), 73.3 (dd, J = 28.0 Hz, J = 24.4 Hz), 63.4, 14.0. 19F NMR (282 MHz, CDCl3): ꢀ
113.7 (d, J = 264.0 Hz), ꢀ121.1 (J = 264.3 Hz). IR (cmꢀ1): 3218, 1768, 1289, 1118,
1066, 1009, 833, 734. HRMS (ESIꢀ) : calcd for [MꢀH] C11H10F2O3Br: 306.9781, found :
306.9778 (ꢀ1.0 ppm).
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Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀ(3,4ꢀdichloroꢀphenyl)propionate 2e:
Compound 2e was obtained as a white solid in 69% yield (103 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 9: 1, Rf = 0.61 Petroleum
ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): 7.55 (d, 1H, J = 1.5 Hz), 7.45 (d, 1H, J
= 8.3 Hz), 7.29ꢀ7.26 (m, 1H), 5.14 (ddd, 1H, J = 15.2 Hz, J = 7.0 Hz, J = 5.3 Hz), 4.32
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(q, 2H, J = 7.1 Hz), 3.05 (d, 1H, J = 5.2 Hz), 1.31 (t, 3H, J = 7.15 Hz). C NMR (75
MHz, CDCl3): 163.4 (t, J = 31.5 Hz), 134.7 (d, J = 1.4 Hz), 133.6, 132.8, 130.5, 129.8
(d, J = 1.3 Hz), 127.1, 113.4 (t, J = 257.6 Hz), 72.7 (dd, J = 28.4 Hz J = 24.6 Hz),
63.6, 14.0. 19F NMR (282 MHz, CDCl3): ꢀ113.1 (dd, J = 265.9 Hz, J = 7.21 Hz), ꢀ
121.1 (dd, J = 265.8 Hz J = 15.26 Hz). IR (cmꢀ1): 3431, 1764, 1466, 1302, 1181,
1120, 1000, 850, 757, 679. HRMS (ESIꢀ): calcd for [MꢀH] C11H9Cl2F2O3: 296.9897,
found: 296.9904 (+ 2.3 ppm). Mp: 74ꢀ75 °C.
Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀ(4ꢀtrifluoromethylꢀphenyl)propionate 2f:
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Compound 2f was obtained as a white solid in 91% yield (135 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 9: 1 to 4:1 to 7:3). 1H NMR (300 MHz,
CDCl3): 7.65 (d, 2H, J = 8.4 Hz), 7.58 (d, 2H, J = 8.3 Hz), 5.29ꢀ5.20 (m, 1H), 4.31 (q,
2H, J = 7.1 Hz), 3.03 (d, 1H, J = 5.2 Hz), 1.29 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz,
CDCl3): 163.4 (dd, J = 32.2 Hz, J = 30.8 Hz), 138.5, 131.5 (q, J = 32.63 Hz), 128.3
(d, J = 1.0 Hz), 125.5 (q, J = 3.8 Hz), 124.1 (d, J = 272.3 Hz), 113.5 (dd, J = 260.7
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Hz, J = 254.7 Hz), 73.31 (dd, , J = 28.1 Hz, J = 24.5 Hz), 63.5, 13.9. F NMR (282
MHz, CDCl3): ꢀ63.3, ꢀ113.2 (dd, J = 266.3 Hz, J =7.2 Hz), ꢀ121.1 (dd, J = 266.3 Hz, J
= 15.4 Hz). IR (cmꢀ1): 3217, 1767, 1320, 1161, 1065, 1016, 836, 709, 543. HRMS
(ESIꢀ): calcd for [MꢀH] C12H10F5O3: 297.0550, found: 297.0545 (ꢀ1.7 ppm). Mp: 99ꢀ
100 °C.
Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀ(4ꢀcyanoꢀphenyl)propionate 2g:
Compound 2g was obtained as a colorless oil in 66% yield (84 mg), after flash
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chromatography (SiO2, Petroleum ether/EtOAc 9: 1 to 4: 1). H NMR (300 MHz,
CDCl3): 7.65 (d, 2H, J = 8.3 Hz), 7.57 (d, 1H, J = 8.1 Hz), 5.23 (dt, J = 15.7 Hz, J =
6.1 Hz), 4.31 (q, 2H, J = 7.1 Hz), 3.52 (d, 1H, J = 5.4 Hz), 1.29 (t, 3H, J = 7.1 Hz). 13C
NMR (75 MHz, CDCl3): 163.3 (t, J = 31.5 Hz), 140.1 (J = 1.0 Hz), 132.1, 128.6,
118.5, 113.4 (t, J = 254.5 Hz), 112.8, 72.9 (dd, J = 28.4 Hz, J = 24.5 Hz), 63.5, 13.9.
19F NMR (282 MHz, CDCl3): ꢀ112.2 (dd, J = 265.5 Hz, J = 6.9 Hz), ꢀ121.2 (dd, J =
265.5 Hz, J = 15.9 Hz). IR (cmꢀ1): 3434, 2232, 1756, 1315, 1190, 1102, 1071, 565.
HRMS (ESIꢀ): calcd for [MꢀH] C12H10F2NO3: 254.0629, found: 254.0624 (ꢀ2.0 ppm).
Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀ(4ꢀmethylꢀbenzoate)propionate 2h:
Compound 2h was obtained as a pale yellow oil in 52% yield (75 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 9: 1 to 4: 1, Rf = 0.34 Petroleum
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ether/EtOAc 4:1). H NMR (300 MHz, CDCl3): 8.01 (d, J = 8.2 Hz), 7.51 (d, J = 8.2
Hz), 5.27ꢀ5.18 (m, 1H), 4.30 (q, 2H, J = 7.1 Hz), 3.90 (s, 3H), 3.26 (d, 1H, J = 5.2
Hz), 1.28 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3): 166.9, 163.4 (t, J = 31.5 Hz),
139.6 (d, J = 1.6 Hz), 130.9, 129.7, 127.9, 113.7 (t, J = 257.4 Hz), 73.4 (dd, J = 28.0
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Hz, J = 24.4 Hz), 63.4, 52.4, 14.0. F NMR (282 MHz, CDCl3): ꢀ113.4 (d, J = 264.2
Hz), ꢀ120.9 (d, J = 265.5 Hz). IR (cmꢀ1): 3461, 1758, 1721, 1438, 1278, 1104, 1071,
1019, 731. HRMS (ESI+): calcd for [M+NH4] C13H18F2NO5: 306.1153 found:
306.1154 (+0.3 ppm).
Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀ(3ꢀhydroxyꢀphenyl)propionate 2i:
Compound 2i was obtained as a colorless oil in 63% yield (78 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 17: 1 to 4: 1, Rf = 0.23 Petroleum
ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): 7.27ꢀ7.20 (m, 1H), 6.95 (d, 2H, J = 7.4
Hz), 6.85 (dd, 1H, J = 7.4 Hz, J = 1.7 Hz), 6.00 (brs, 1H), 5.14ꢀ5.07 (m, 1H), 4.30 (q,
2H, J = 7.1 Hz), 3.38 (brs, 1H), 1.29 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3):
163.9 (t, J = 31.6 Hz), 155.9, 136.2 (d, J = 2.0 Hz), 129.6, 120.3, 116.6, 114.7, 113.9
(t, J = 259.3 Hz), 73.7 (dd, J = 27.7 Hz, J = 24.5 Hz), 63.5, 13.9. 19F NMR (282 MHz,
CDCl3): ꢀ114.4 (d, J = 260.6 Hz), ꢀ120.6 (d, J = 260.6 Hz). IR (cmꢀ1): 3401, 1750,
1593, 1458, 1095, 1071, 771. HRMS (ESIꢀ): calcd for [MꢀH] C11H11F2O4: 245.0625,
found: 245.0632 (+2.9 ppm).
Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀ(3,4ꢀmethylenedioxyphenyl)propionate 2j:
Compound 2j was obtained as a yellow oil in 61% yield (83 mg), after flash
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chromatography (SiO2, Petroleum ether/EtOAc 9: 1 to 4: 1). H NMR (300 MHz,
CDCl3): 6.94 (s, 1H), 6.87 (d, 1H, J = 8.1 Hz), 6.79 (d, 1H, J = 8.0 Hz), 5.96 (d, 2H),
5.11ꢀ5.02 (m, 1H), 4.31 (q, 2H, J = 7.1 Hz), 2.81 (d, 1H, J = 4.9 Hz), 1.31 (t, 3H, J =
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7.1 Hz). 13C NMR (75 MHz, CDCl3): 163.7 (t, J = 31.7 Hz), 148.5, 148.0, 128.3 (d, J =
2.1 Hz), 121.8 (d, J = 0.9 Hz), 113.8 (t, J = 258.7 Hz), 108.2, 108.2 (t, J = 1.5 Hz),
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101.4, 73.7 (dd, J = 27.9 Hz, J = 24.2 Hz), 63.2, 14.0. F NMR (282 MHz, CDCl3): ꢀ
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114.6 (dd, J = 261.3 Hz, J = 8.1 Hz), ꢀ121.0 (dd, J = 261.3 Hz, J = 15.1 Hz). IR (cmꢀ
1): 3503, 1755, 1505, 1489, 1489, 1306, 1244, 1096, 1067, 1036, 926, 853, 791, 712,
547. HRMS (ESIꢀ): calcd for [MꢀH] C12H11F2O5: 273.0575, found: 273.0569 (ꢀ2.2
ppm).
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Reformatsky reaction with ketone: To a solution of In0 (powder, 0.75 mmol, 90 mg)
and the corresponding ketones (0.5 mmol) in THF (1 mL) was added BrCF2CO2Et
(0.75 mmol, 96 ꢁL). The resulting mixture was stirred at 60°C for 12h and then
cooled to room temperature. The solution was quenched with aqueous HCl (0.5 M, 5
mL) and extracted with DCM (3 times). The combined organic layers were washed
with brine, dried over MgSO4 and concentrated. The residue was purified by flash
chromatography (SiO2, Petroleum ether/EtOAc) to afford the corresponding βꢀ
hydroxy gemꢀdifluoroester 2k-p and 4a-b.
Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3,5ꢀdiphenylpentꢀ4ꢀenoate 2k:
Compound 2k was obtained as a viscous pale yellow oil in 68% yield (113 mg), after
flash chromatography (SiO2, Petroleum ether/EtOAc, 9: 1 to 4:1). 1H NMR (300 MHz,
CDCl3): 7.59 (d, 2H, J = 7.3 Hz), 7.39ꢀ7.21 (m, 8H), 6.80 (m, 2H), 4.15 (q, 2H, J = 7.1
Hz), 3.47 (brs, 1H), 1.10 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3): 136.6 (t, J =
32.0 Hz), 138.1, 136.1, 132.7 (d, J = 1.2 Hz), 128.7, 128.6, 128.4, 128.3, 127.0,
126.9 (t, J = 1.9 Hz), 126.8 (d, J = 2.5 Hz), 114.4 (t, J = 262.8 Hz), 77.9 (t, J = 24.0
Hz), 63.3, 13.8. 19F NMR (282 MHz, CDCl3): ꢀ114.8 (d, J = 16.9 Hz). IR (cmꢀ1): 3496,
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1756, 1603, 1454, 1373, 1095, 1004, 975, 745, 687. HRMS (ESIꢀ): calcd for [Mꢀ
H] C19H17F2O3: 331.1146, found: 331.1148 (+0.6 ppm).
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Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀphenylꢀbutanoate 2l:
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Compound 2l was obtained as a yellow oil in 66% yield (80 mg), after flash
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chromatography (SiO2, Petroleum ether/EtOAc 9: 1). H NMR (300 MHz, CDCl3):
7.52 (d, 2H, J = 7.2 Hz), 7.40ꢀ7.32 (m, 3H), 4.15 (q, 2H, J = 7.1 Hz), 3.11 (s, 1H),
1.75 (s, 3H), 1.12 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3): 163.7 (t, J = 32.2
Hz), 139.7 (d, J = 1.3 Hz), 128.4, 128.3, 126.1 (t, J = 1.7 Hz), 114.9 (t, J = 261.4),
76.1 (t, J = 24.5 Hz), 63.1, 23.4 (d, J = 2.6Hz), 13.8. 19F NMR (282 MHz, CDCl3): ꢀ
116.0 (d, J = 15.1 Hz). IR (cmꢀ1): 1753, 1307, 1126, 1106, 1036, 761, 699. HRMS
(ESIꢀ): calcd for [MꢀH] C12H13F2O3: 243.0833, found: 243.0841 (+3.3 ppm).
Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀphenylꢀpentanoate 2m:
Compound 2m was obtained as a white solid in 99% yield (128 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 9: 1, Rf = 0.35 Petroleum
ether/EtOAc 9:1). 1H NMR (300 MHz, CDCl3): 7.49 (d, 2H, J = 7.5 Hz), 7.38ꢀ7.29 (m,
3H), 4.11 (q, 2H, J = 7.1 Hz), 3.09 (s, 1H), 2.28ꢀ2.04 (m, 2H), 1.07 (t, 3H, J = 7.1 Hz),
0.76 (t, 3H, J = 7.4 Hz). 13C NMR (75 MHz, CDCl3): 163.7 (t, J = 31.8 Hz), 137.4,
128.2, 128.1, 126.6 (t, J = 1.8 Hz), 115.3 (t, J = 260.1 Hz), 78.6 (t, J = 23.4 Hz), 62.9,
27.2 (t, J = 2.2 Hz), 13.6, 6.7. 19F NMR (282 MHz, CDCl3): ꢀ116.3. IR (cmꢀ1): 3501,
2979, 1756, 1454, 1310, 1157, 1128, 1109, 989, 831, 759. HRMS (ESIꢀ): calcd for
[MꢀH] C13H15F2O3: 257.0989, found: 257.0998 (+3.5 ppm). Mp: 44ꢀ45 °C.
Ethyl 1ꢀ(Hydroxyꢀ1,2,3,4ꢀtetrahydronaphtalenꢀ1ꢀyl)ꢀ1,1ꢀdifluoroacetate 2n:
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Compound 2n was obtained as a colourless oil in 84% yield (114 mg), after flash
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chromatography (SiO2, Petroleum ether/EtOAc 9: 1). H NMR (300 MHz, CDCl3):
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7.66 (d, 1H, J = 7.2 Hz), 7.29ꢀ7.20 (m, 2H), 7.15ꢀ7.12 (m, 1H), 4.27 (qd, 2H, J = 7.1
Hz, J = 1.9 Hz), 2.85ꢀ2.69 (m, 3H), 2.35ꢀ2.23 (m, 1H), 2.04ꢀ1.95 (m, 2H), 1.89ꢀ1.77
(m, 1H), 1.23 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3): 163.8 (t, J = 32.4 Hz),
138.9, 133.7 (d, J = 1.4 Hz), 129.1, 128.7, 127.8 (t, J = 3.4 Hz), 126.2, 116.0 (t, J =
261.0 Hz), 73.6 (t, J = 22.6 Hz), 33.2 (t, J = 1.6 Hz), 29.5, 18.7 (t, J = 1.8 Hz), 13.8.
19F NMR (282 MHz, CDCl3): ꢀ112.3 (d, J = 257.3 Hz), ꢀ113.9 (d, J = 257.3 Hz).
IR (cmꢀ1): 3500, 1754, 1451, 1372, 1305, 1123, 1017, 760, 729. HRMS (ESI+): calcd
for [M+NH4] C14H20F2NO3: 288.1411, found: 288.1407 (ꢀ1.4 ppm).
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Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀ(3ꢀthienyl)ꢀbutyrate 2o:
Compound 2o was obtained as a yellow oil in 69% yield (86 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 4: 1, Rf = 0.34 Petroleum
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ether/EtOAc 4:1). H NMR (300 MHz, CDCl3): 7.33ꢀ7.28 (m, 2H), 7.12 (dd, 1H, J =
5.0 Hz, J = 0.8 Hz), 4.19 (q, 2H, J = 7.1 Hz), 3.25 (s, 1H), 1.17 (t, 3H, J = 7.1 Hz). 13C
NMR (75 MHz, CDCl3): 163.7 (t, J = 32.1 Hz), 141.6 (d, J = 2.1 Hz), 126.2 (t, J = 2.1
Hz), 126.à, 122.7 (t, J = 1.6 Hz), 114.6 (t, J = 261.3 Hz), 75.3 (t, J = 25.3 Hz), 63.1,
23.3, 13.8. 19F NMR (282 MHz, CDCl3): ꢀ115.8 (d, J = 257.9 Hz), ꢀ116.5 (d, J = 257.9
Hz). IR (cmꢀ1): 3510, 1753, 1308, 1106, 1035, 792, 657. HRMS (ESIꢀ): calcd for [Mꢀ
H] C10H11F2SO3: 249.0397, found: 249.0390 (ꢀ2.8 ppm).
Ethyl 2,2ꢀdifluoroꢀ3ꢀhydroxyꢀ3ꢀphenylꢀ5ꢀchloroꢀpentanoate 2p:
Compound 2p was obtained as a white solid in 91% yield (133 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc, 9: 1, Rf = 0.45 Petroleum
ether/EtOAc 9:1). 1H NMR (300 MHz, CDCl3): 7.48 (d, 2H, J = 7.4 Hz), 7.42ꢀ7.32 (m,
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3H), 4.11 (q, 2H, J = 7.1 Hz), 3.56 (td, 1H, J = 10.2 Hz, J = 6.8 Hz), 3.49 (s, 1H), 3.21
(td, 1H, J = 10.2 Hz, J = 6.2 Hz), 2.70ꢀ2.55 (m, 2H), 1.06 (t, 3H, J = 7.1 Hz). 13C NMR
(75 MHz, CDCl3): 163.3 (t, J = 31.6 Hz), 136.5 (d, J = 2.5 Hz), 128.7, 128.6, 126.3 (t,
J = 2.1 Hz), 114.4 (t, J = 262.9 Hz), 77.8 (t, J = 23.5 Hz), 63.2, 39.0, 37.8, 13.6. 19F
NMR (282 MHz, CDCl3): ꢀ115.6 (d, J = 258.6 Hz), ꢀ116.8 (d, J = 258.6 Hz). IR (cmꢀ1):
3440, 1746, 1449, 1321, 1180, 947, 767, 701, 610. HRMS (ESIꢀ): calcd for [Mꢀ
H] C13H14F2O3Cl: 291.0600, found: 291.0608 (+2.7 ppm). Mp: 73ꢀ74 °C.
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4ꢀhydroxyꢀ4ꢀethylꢀ3,3ꢀdifluoroꢀ3,4ꢀdihydrocoumarin 4a:
Compound 4a was obtained as a white solid in 41% yield (47 mg), after flash
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chromatography (SiO2, Petroleum ether/EtOAc 9: 1). H NMR (300 MHz, CDCl3):
7.62 (d, 1H, J = 8.1 Hz), 7.55ꢀ7.49 (m, 1H), 7.38ꢀ7.33 (m, 2H), 2.89 (qd, 2H, J = 7.6
Hz, J = 2.3 Hz), 1.31 (t, 3H, J = 7.6 Hz). 13C NMR (75 MHz, CDCl3): 155.4 (d, J =
30.3 Hz), 150.9 (d, J = 2.7 Hz), 145.2, 141.9, 136.4 (d, J = 12.7 Hz), 130.7, 125.1,
124.6, 117.4, 17.8 (d, J = 2.8 Hz), 13.1 (d, J = 1.6 Hz). 19F NMR (282 MHz, CDCl3): ꢀ
136.80. IR (cmꢀ1): 2983, 1727, 1649, 1448, 1150, 1093, 775, 754, 459. HRMS (ESIꢀ):
calcd for [M+OH]ꢀ C11H11F2O4: 245.0625, found: 245.0631 (+2.4 ppm). Mp: 69ꢀ70 °C.
4ꢀhydroxyꢀ4ꢀphenethylꢀ3,3ꢀdifluoroꢀ3,4ꢀdihydrocoumarin 4b:
Compound 4b was obtained as a white solid in 48% yield (73 mg), after flash
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chromatography (SiO2, Petroleum ether/EtOAc 9: 1). H NMR (300 MHz, CDCl3):
7.56 (d, 1H, J = 8.1 Hz), 7.51ꢀ7.46 (m, 1H), 7.34ꢀ7.25 (m, 4H), 7.21ꢀ7.17 (m, 3H),
3.14ꢀ3.08 (m, 2H), 2.95ꢀ2.90 (m, 2H). 13C NMR (75 MHz, CDCl3): 155.2 (d, J = 30.2
Hz), 150.8 (d, J = 2.72 Hz), 142.9 (d, J = 253.0 Hz), 139.9, 134.0 (d, J = 12.7 Hz),
130.7 (d, J = 2.7 Hz), 128.8, 128.4, 126.9, 125.1, 124.6 (d, J = 6.1 Hz), 118.8 (d, J =
3.1 Hz), 117.4 (d, J = 1.4 Hz), 34.6 (d, J = 1.8 Hz), 18.4 (d, J = 1.6 Hz). 19F NMR
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(282 MHz, CDCl3): ꢀ135.19. IR (cmꢀ1): 1731, 1601, 1448, 1146, 1098, 902, 748, 716,
698, 454. HRMS (ESIꢀ): calcd for [M+OH]ꢀ C17H15F2O4: 321.0938, found: 321.0944
(+1.9 ppm). Mp: 101ꢀ102 °C.
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Reformatsky reaction with aldimine: To a solution of In0 (powder, 1.0 mmol, 120 mg),
aldimine (0.5 mmol) in THF (1 mL) was added BrCF2CO2Et (1.0 mmol, 0.128 mL).
The resulting mixture was stirred at 60°C for 18h and then cooled to room
temperature. The solution was quenched with HCl (0.5 M, 5 mL) and extracted with
DCM. The combined organic layers were washed with brine, dried (MgSO4) and
concentrated. The residue was purified by flash chromatography (SiO2, Petroleum
ether/ EtOAc) to afford the Mannich adduct 6a-n.
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Ethyl 2,2ꢀDifluoroꢀ3ꢀ(benzenesulfonylamino)ꢀ3ꢀphenylpropionate 6a:
Compound 6a was obtained as a white solid in 70% yield (129 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 85: 15, Rf = 0.36 Petroleum
ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): 7.67 (d, 2H, J = 7.7 Hz), 7.41 (t, 1H, J
= 7.4 Hz), 7.28 (t, 2H, J = 7.6 Hz), 7.22ꢀ7.11 (m, 5H), 5.91 (d, 1H, J = 10.2 Hz), 5.05
(dt, 1H, J = 16.5 Hz, J = 9.8 Hz), 4.22 (q, 2H, J = 7.1 Hz), 1.25 (t, 3H, J = 7.1 Hz). 13C
NMR (75 MHz, CDCl3): 162.7 (t, J = 31.5 Hz), 140.1, 132.7, 131.7 (d, J = 2.0 Hz),
129.1, 128.8, 128.6, 128.3, 127.0, 113.7 (t, J = 257.8 Hz), 63.5, 59.8 (dd, J = 27.4
Hz, J = 23.6 Hz), 13.8. 19F NMR (282 MHz, CDCl3): ꢀ111.6 (dd, J = 258.4 Hz, J = 9.5
Hz), ꢀ115.6 (dd, J = 258.4 Hz, J = 16.5 Hz). IR (cmꢀ1): 3242, 1758, 1337, 1165, 1063,
717, 685, 543. HRMS (ESI+): calcd for [M+H] C17H18F2SNO4: 370.0925, found:
370.0916 (ꢀ2.4 ppm). Mp: 109ꢀ110 °C.
Ethyl 2,2ꢀDifluoroꢀ3ꢀ(paraꢀtolylsulfonylamino)ꢀ3ꢀ(4ꢀmethoxyꢀphenyl)ꢀpropionate 6b:
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Compound 6b was obtained as a viscous colourless oil in 68% yield (140 mg), after
flash chromatography (SiO2, Petroleum ether/EtOAc 4: 1 to 7:3). 1H NMR (300 MHz,
CDCl3): 7.54 (d, 2H, J = 8.3 Hz), 7.10 (d, 2H, J = 8.1 Hz), 7.04 (d, 2H, J = 8.7 Hz),
6.70 (d, 2H, J = 8.7 Hz), 5.63 (d, 1H, J = 9.9 Hz), 4.96 (dt, 1H, J = 16.1 Hz, J = 10.0
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Hz), 4.21 (q, 2H, J = 7.1 Hz), 3.74 (s, 3H), 2.33 (s, 3H), 1.25 (t, 3H, J = 7.1 Hz). C
NMR (75 MHz, CDCl3): 162.8 (t, J = 31.6 Hz), 160.1, 143.6, 137.3, 129.6, 129.5,
127.2, 124.0 (d, J = 2.2 Hz), 114.0, 113.8 (t, J = 254.9 Hz), 63.5, 59.3 (dd, J = 26.9
Hz, J = 23.8 Hz), 55.4, 21.5, 13.9. 19F NMR (282 MHz, CDCl3): ꢀ112.1 (dd, J = 257.6
Hz, J = 10.1 Hz), 115.3 (dd, J = 257.6 Hz, J = 16.1 Hz). IR (cmꢀ1): 3255, 1774, 1613,
1518, 1441, 1330, 1258, 1160, 912, 808, 666, 544. HRMS (ESI+): calcd for
[M+H] C19H22F2NSO5: 414.1187, found: 414.1182 (ꢀ1.2 ppm).
Ethyl 2,2ꢀDifluoroꢀ3ꢀ(paraꢀtolylsulfonylamino)ꢀ3ꢀ(1ꢀnaphtyl)ꢀpropionate 6c:
Compound 6c was obtained as a viscous yellow oil in 80% yield (173 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 4: 1, Rf = 0.24 Petroleum
ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): 7.93 (d, 2H, J = 8.5 Hz), 7.68 (d, 1H, J
= 7.6 Hz), 7.62 (d, 1H, J = 8.1 Hz), 7.50ꢀ7.37 (m, 2H), 7.29ꢀ7.26 (m, 3H), 7.17 (dd,
1H, J = 8.5 Hz, J = 6.9 Hz), 6.66 (d, 2H, J = 8.1 Hz), 5.98ꢀ5.85 (m, 2H), 4.18ꢀ4.07 (m,
2H), 2.05 (s, 3H), 1.10 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3): 162.7 (t, J =
31.7 Hz), 143.3, 136.6, 133.5, 131.6, 129.6, 129.0, 128.7, 128.4 (d, J = 1.7 Hz),
127.0, 126.9, 126.1, 125.1, 122.7, 114.1 (t, J = 257.7 Hz), 63.6, 54.2 (dd, J = 28.0
Hz, J = 23.5 Hz), 21.3, 13.8. 19F NMR (282 MHz, CDCl3): ꢀ110.7 (d br, J = 262.0 Hz),
ꢀ114.4 (d br, J = 257.0 Hz). IR (cmꢀ1): 1774, 1331, 1199, 1051, 773, 555, 407. HRMS
(ESI+): calcd for [M+H] C22H22F2NSO4: 434.1238, found: 434.1227 (ꢀ2.5 ppm).
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Ethyl
2,2ꢀDifluoroꢀ3ꢀ(paraꢀtolylsulfonylamino)ꢀ3ꢀ(3,4ꢀmethylenedioxyphenyl)ꢀ
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propionate 6d:
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Compound 6d was obtained as a yellow solid in 71% yield (152 mg), after flash
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chromatography (SiO2, Petroleum ether/EtOAc 4: 1 to 7:3). H NMR (300 MHz,
CDCl3): 7.52 (d, 2H, J = 8.3 Hz), 7.11 (d, 2H, J = 8.0 Hz), 6.59 (m, 3H), 5.98 (d, 1H, J
= 10.1 Hz), 5.87 (dd, 1H, J = 3.8 Hz, J = 1.3 Hz), 4.96ꢀ4.87 (m, 1H), 4.23 (q, 2H, J =
7.1 Hz), 2.33 (s, 3H), 1.27 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3): 162.7 (t, J
= 31.6 Hz), 148.2, 147.8, 143.6, 137.2, 129.4, 127.2, 125.5 (d, J = 2.1 Hz), 122.7,
113.6 (t, J = 257.5 Hz), 108.4, 108.2, 101.4, 63.6, 59.5 (dd, J = 27.4 Hz, J = 23.5 Hz),
21.5, 13.9. 19F NMR (282 MHz, CDCl3): ꢀ111.8 (dd, J = 257.3 Hz, J = 9.6 Hz), ꢀ115.7
(dd, J = 257.3 Hz, J = 16.6 Hz). IR (cmꢀ1): 1774, 1443, 1324, 1246, 1161, 1040, 917,
808, 670, 542. HRMS (ESI+): calcd for [M+H] C19H20F2NSO6: 428.0979, found:
428.0988 (+2.1 ppm). Mp: 107ꢀ108 °C.
Ethyl 2,2ꢀDifluoroꢀ3ꢀ(paraꢀtolylsulfonylamino)ꢀ3ꢀ(4ꢀtrifluoromethylꢀphenyl)ꢀpropionate
6e:
Compound 6e was obtained as a white solid in 75% yield (170 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 9: 1, Rf = 0.36 Petroleum
ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): 7.49 (d, 2H, J = 8.3 Hz), 7.41 (d, 2H, J
= 8.2 Hz), 7.25 (d, 2H, J = 7.8 Hz), 7.05 (d, 2H, J = 8.1 Hz), 5.95 (d, 1H, J = 10.2 Hz),
5.16ꢀ5.04 (m, 1H), 4.27 (q, 2H, J = 7.1 Hz), 2.30 (s, 3H), 1.29 (t, 3H, J = 7.1 Hz). 13C
NMR (75 MHz, CDCl3): 162.4 (t, J = 31.5 Hz), 144.1, 136.8, 135.8, 131.1 (q, J = 32.7
Hz), 129.5, 129.1, 127.1, 125.4 (q, J = 3.7 Hz), 123.9 (d, J = 272.3 Hz), 113.4 (t, J =
258.2 Hz), 63.9, 59.4 (dd, J = 28.7 Hz, J = 23.4 Hz), 21.3, 13.9. 19F NMR (282 MHz,
CDCl3): ꢀ63.4, (dd, J = 260.8 Hz, J = 7.9 Hz), (dd, J = 260.8 Hz, J = 17.9 Hz). IR (cmꢀ
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1): 3228, 1761, 1449, 1325, 1162, 1061, 807, 668, 553. HRMS (ESI+): calcd for
[M+H] C19H19F5NSO4: 452.0955, found: 452.0954 (ꢀ0.2 ppm). Mp: 134ꢀ135 °C.
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Ethyl 2,2ꢀDifluoroꢀ3ꢀ(paraꢀtolylsulfonylamino)ꢀ3ꢀ(4ꢀbromoꢀphenyl)ꢀpropionate 6f:
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Compound 6f was obtained as a white solid in 81% yield (187 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 85: 15, Rf = 0.36 Petroleum
ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): 7.52 (d, 2H, J = 8.3 Hz), 7.30 (d, 2H, J
= 8.4 Hz), 7.10 (d, 2H, J = 8.2 Hz), 7.00 (d, 2H, J = 8.4 Hz), 5.92 (d, 1H, J = 10.1 Hz),
5.05ꢀ4.93 (m, 1H), 4.24 (q, 2H, J = 7.1 Hz), 2.35 (s, 3H), 1.28 (t, 3H, J = 7.1 Hz). 13C
NMR (75 MHz, CDCl3): 162.5 (t, J = 31.6 Hz), 144.0, 136.9, 131.8, 130.9 (d, J = 1.7
Hz), 130.1, 129.6, 127.1, 123.4, 113.4 (t, J = 257.9 Hz), 63.8, 59.3 (dd, J = 28.0 Hz, J
= 23.6 Hz), 21.6, 13.9. 19F NMR (282 MHz, CDCl3): ꢀ111.0 (dd, J = 259.8 Hz, J = 8.9
Hz), ꢀ116.2 (dd, J = 259.8 Hz, J = 17.1 Hz). IR (cmꢀ1): 3228, 1764, 1447, 1338, 1163,
1067, 794, 668, 552. HRMS (ESI+): calcd for [M+H] C18H19BrF2NSO4: 462.0186,
found: 462.0183 (ꢀ0.6 ppm). Mp: 131ꢀ132 °C.
Ethyl 2,2ꢀDifluoroꢀ3ꢀ(paraꢀtolylsulfonylamino)ꢀ3ꢀ(4ꢀchloroꢀphenyl)ꢀpropionate 6g:
Compound 6g was obtained as a white solid in 85% yield (177 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 85: 15, Rf = 0.33 Petroleum
ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): 7.53 (d, 2H, J = 8.3 Hz), 7.17ꢀ7.05 (m,
6H), 5.90 (d, 1H, J = 10.0 Hz), 5.00 (dt, 1H, J = 17.0 Hz, J = 9.4 Hz), 4.24 (q, 2H, J =
7.1 Hz), 2.35 (s, 3H), 1.27 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3): 162.5 (t, J
= 31.6 Hz), 144.0, 137.0, 135.2, 130.4 (d, J = 1.7 Hz), 129.8, 129.6, 128.8, 127.1,
113.4 (t, J = 256.0 Hz), 63.7, 59.2 (dd, J = 27.9 Hz, J = 23.7 Hz), 21.6, 13.9. 19F NMR
(282 MHz, CDCl3): ꢀ110.5 (dd, J = 259.7 Hz, J = 8.8 Hz), ꢀ115.7 (dd, J = 259.7 Hz, J
= 16.9 Hz). IR (cmꢀ1): 3228, 1767, 1446, 1318, 1162, 1118, 1066, 911, 806, 551.
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HRMS (ESI+): calcd for [M+H] C18H19F2ClNSO4: 418.0691, found: 418.0676 (ꢀ3.6
ppm). Mp: 121ꢀ122 °C.
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Compound 6h was obtained as a white solid in 81% yield (183 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 85: 15, Rf = 0.29 Petroleum
ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3): 7.51 (d, 2H, J = 8.3 Hz), 7.25 (d, 1H, J
= 8.3 Hz), 7.12ꢀ7.10 (m, 3H), 7.05ꢀ7.02 (m, 1H), 7.11 (d, 1H, J = 10.2 Hz), 4.97 (ddd,
1H, J = 17.9 Hz, J = 10.0 Hz, J = 7.9 Hz), 4.29 (q, 2H, J = 7.1 Hz), 2.35 (s, 3H), 1.31
(t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3): 162.4 (t, J = 31.5 Hz), 144.3, 136.7,
133.5, 132.8, 131.9 (d, J = 1.2 Hz), 130.6, 130.6, 129.6, 127.8, 113.2 (t, J = 258.1
Hz), 63.9, 58.9 (dd, J = 28.8 Hz, J = 23.6 Hz), 21.5, 13.9. 19F NMR (282 MHz,
CDCl3): ꢀ110.2 (dd, J = 260.8 Hz, J = 7.9 Hz), ꢀ116.9 (dd, J = 260.8 Hz, J = 17.8 Hz).
IR (cmꢀ1): 3237, 1756, 1469, 1459, 1344, 1215, 1167, 1071, 807, 682, 534. HRMS
(ESI+): calcd for [M+H] C18H18Cl2F2NSO4: 452.0302, found: 452.0304 (+0.4 ppm).
Mp: 117ꢀ118 °C.
Ethyl 2,2ꢀDifluoroꢀ3ꢀ(paraꢀtolylsulfonylamino)ꢀ3ꢀ(4ꢀcyanoꢀphenyl)ꢀpropionate 6i:
Compound 6i was obtained as a white solid in 73% yield (149 mg), after flash
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chromatography (SiO2, Petroleum ether/EtOAc 7: 3). H NMR (300 MHz, CDCl3):
7.51 (m, 2H), 7.31ꢀ7.26 (m, 2H), 7.12 (d, 2H, J = 8.1 Hz), 6.11 (dd, 1H, J = 10.2 Hz, J
= 0.1 Hz), 5.15ꢀ5.03 (m, 1H), 4.25 (q, 2H, J = 7.1 Hz), 2.35 (s, 3H), 1.29 (t, 3H, J =
7.1 Hz). 13C NMR (75 MHz, CDCl3): 162.2 (t, J = 31.2 Hz), 144.3, 137.2 (d, J = 1.1
Hz), 136.8, 132.3, 129.7, 129.3, 127.1, 118.1, 113.2 (t, J = 258.3 Hz), 113.0, 64.0,
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59.3 (dd, J = 28.5 Hz, J = 23.7 Hz), 21.6, 13.9. F NMR (282 MHz, CDCl3): ꢀ109.8
(dd, J = 261.6 Hz, J = 7.6 Hz), ꢀ116.7 (dd, J = 261.6 Hz, J = 17.6 Hz). IR (cmꢀ1):
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3256, 2245, 1174, 1448, 1332, 1283, 1163, 1088, 917, 836 , 666, 549. HRMS
(ESI+): calcd for [M+H] C19H19F2N2SO4: 409.1034, found: 409.1020 (ꢀ3.4 ppm). Mp:
171ꢀ172 °C.
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Ethyl
2,2ꢀDifluoroꢀ3ꢀ(paraꢀtolylsulfonylamino)ꢀ3ꢀ(4ꢀmethylꢀcarboxylateꢀphenyl)ꢀ
propionate 6j:
Compound 6j was obtained as a white solid in 65% yield (143 mg), after flash
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chromatography (SiO2, Petroleum ether/EtOAc 85: 15 to 7:3). H NMR (300 MHz,
CDCl3): 7.83 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 8.3 Hz), 7.23 (d, 2H, J = 8.2 Hz),
7.05 (d, 2H, J = 8.0 Hz), 6.23 (d, 1H, J = 10.3 Hz), 5.09 (dt, 1H, J = 17.7 Hz, J = 9.0
Hz), 4.24 (q, 2H, J = 7.1 Hz), 3.89 (s, 3H), 2.28 (s, 3H), 1.27 (t, 3H, J = 7.1 Hz).. 13C
NMR (75 MHz, CDCl3): 166.5, 162.4 (t, J = 31.5 Hz), 143.9, 137.0, 136.8, 130.7,
129.7, 129.5, 128.8, 127.1, 113.5 (t, J = 258.2 Hz), 63.7, 59.5 (dd, J = 28.0 Hz, J =
23.6 Hz), 52.4, 21.4, 13.9. 19F NMR (282 MHz, CDCl3): ꢀ110.1 (dd, J = 259.5 Hz, J =
8.5 Hz), ꢀ115.7 (ddd, J = 259.5 Hz, J = 17.3 Hz, J = 2.6 Hz). IR (cmꢀ1): 1768, 1703,
1446, 1346, 1285, 1190, 1115, 1071, 1013, 906, 817, 701, 671. HRMS (ESI+): calcd
for [M+H] C20H22F2NSO6: 442.1136, found: 442.1143 (+1.6 ppm). Mp: 156ꢀ157 °C.
Ethyl 2,2ꢀDifluoroꢀ3ꢀ(paraꢀtolylsulfonylamino)ꢀ3ꢀ(3ꢀfuryl)ꢀpropionate 6k:
Compound 6k was obtained as a white solid in 72% yield (134 mg), after flash
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chromatography (SiO2, Petroleum ether/EtOAc 85: 15). H NMR (300 MHz, CDCl3):
7.65 (d, 2H, J = 8.3 Hz), 7.25ꢀ7.20 (m, 4H), 6.22 (s, 1H), 5.54 (d, 1H, J = 10.0 Hz),
5.02 (dt, 2H, J = 15.5 Hz, J = 9.8 Hz), 4.24 (qd, 2H, J = 7.1 Hz, J = 1.9 Hz), 2.38 (s,
3H), 1.28 (t, 3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3): 162.6 (t, J = 31.6 Hz),
143.9, 143.8, 141.7, 137.3, 129.7, 127.2, 117.6 (d, J = 2.6 Hz), 113.5 (t, J = 257.5
Hz), 109.2, 63.6, 52.5 (dd, J = 28.0 Hz, J = 25.2 Hz), 21.6, 13.9. 19F NMR (282 MHz,
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CDCl3): ꢀ111.9 (dd, J = 259.7 Hz, J = 9.7 Hz), ꢀ115.5 (dd, J = 259.7 Hz, J = 15.6 Hz).
IR (cmꢀ1): 1773, 1448, 1321, 1247, 1161, 1040, 918, 808, 669, 551. HRMS (ESI+):
calcd for [M+H] C16H18F2NSO5: 374.0874, found: 374.0881 (+1.9 ppm). Mp: 79ꢀ80
°C.
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Ethyl 2,2ꢀDifluoroꢀ3ꢀ(paraꢀtolylsulfonylamino)ꢀ3ꢀ(2ꢀthienyl)ꢀpropionate 6l:
Compound 6l was obtained as a white solid in 69% yield (134 mg), after flash
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chromatography (SiO2, Petroleum ether/EtOAc 85: 15). H NMR (300 MHz, CDCl3):
7.60 (d, 2H, J = 8.3 Hz), 7.20 (dd, 1H, J = 5.0 Hz, J = 1.2 Hz), 7.18ꢀ7.15 (m, 2H),
6.89ꢀ6.88 (m, 1H), 6.83 (dd, 1H, J = 5.0 Hz, J = 3.6 Hz), 5.48 (d, 1H, J = 10.0 Hz),
5.33 (dt, 1H, J = 15.1 Hz, J = 9.6 Hz), 4.25 (q, 2H, J = 7.1 Hz), 2.36 (s, 3H), 1.27 (t,
3H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3): 162.4 (t, J = 31.7 Hz), 143.8, 137.2,
134.1 (d, J = 2.1 Hz), 129.6, 128.4, 127.2 (2C), 127.0, 113.1 (t, J = 258.3 Hz), 63.7,
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55.7 (dd, J = 27.9 Hz, J = 25.3 Hz), 21.6, 13.9. F NMR (282 MHz, CDCl3): ꢀ111.6
(dd, J = 258.8 Hz, J = 9.2 Hz), ꢀ115.2 (dd, J = 258.8 Hz, J = 15.1 Hz). IR (cmꢀ1):
3240, 1775, 1444, 1328, 1289, 1160, 1066, 912, 809, 725, 685, 539. HRMS (ESI+):
calcd for [M+H] C16H18F2NS2O4: 390.0645, found: 390.0650 (+1.3 ppm). Mp: 123ꢀ124
°C.
Ethyl 2,2ꢀDifluoroꢀ3ꢀ(paraꢀtolylsulfonylamino)ꢀ3ꢀ(3ꢀpyridyl)ꢀpropionate 6m:
Compound 6m was obtained as a yellow solid in 76% yield (146 mg), after flash
chromatography (SiO2, Petroleum ether/EtOAc 1: 1 to 2: 3, Rf = 0.22 Petroleum
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ether/EtOAc 1:1). H NMR (300 MHz, CDCl3): 8.50 (dd, 1H, J = 4.7 Hz, J = 1.3 Hz),
8.41 (d, 1H, J = 1.8 Hz), 7.56ꢀ7.50 (m, 3H), 7.17ꢀ7.11 (m, 3H), 6.08 (d, 1H, J = 9.9
Hz), 5.14ꢀ5.02 (m, 1H), 4.26 (q, 2H, J = 7.1 Hz), 2.33 (s, 3H), 1.29 (t, 3H, J = 7.1 Hz).
13C NMR (75 MHz, CDCl3): 162.3 (t, J = 31.4 Hz), 150.2, 149.7, 144.1, 136.9, 135.8,
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