Difluoromethylation of Alkyl Bromides and Iodides with TMSCF2H

Article abstract of DOI:10.1021/acs.joc.0c02783

We describe, for the first time, two protocols for direct difluoromethylation of unactivated alkyl bromides and iodides. Reactions of alkyl iodides with TMSCF2H were mediated by a copper catalyst using CsF as the activator, while reactions of less reactive alkyl bromides required a combination of palladium and a stoichiometric amount of CuI as the catalysts. Preliminary mechanistic studies of the synergistic Pd/Cu-catalyzed difluoromethylation of alkyl bromides suggest that it proceeds likely via a Pd(I)/Pd(III) catalytic cycle.

Full text of DOI:10.1021/acs.joc.0c02783

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Difluoromethylation of Alkyl Bromides and Iodides with TMSCF2H
Haiwei Zhao, Changhui Lu, Simon Herbert, Wei Zhang, and Qilong Shen*
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ABSTRACT: We describe, for the first time, two protocols for direct
difluoromethylation of unactivated alkyl bromides and iodides. Reactions of
alkyl iodides with TMSCF2H were mediated by a copper catalyst using CsF as the
activator, while reactions of less reactive alkyl bromides required a combination of
palladium and a stoichiometric amount of CuI as the catalysts. Preliminary
mechanistic studies of the synergistic Pd/Cu-catalyzed difluoromethylation of
alkyl bromides suggest that it proceeds likely via a Pd(I)/Pd(III) catalytic cycle.
nucleophilic phenylsulfonyldifluoromethylation and subse-
quent desulfonylation processes. An alternative route for the
generation of the C(sp3)−CF2H bond is the reaction of an
enolate with a difluorocarbene precursor under basic
conditions. In this aspect, several difluoromethyl precursors
such as difluoromethyl-(4-nitrophenyl)-bis(carbomethoxy)-
methylide sulfonium ylide,11 S-difluoromethyl-S-phenyl-S-
(2,3,4,5-tetramethylphenyl) sulfonium salt,12 S-
(bromodifluoromethyl)diarylsulfonium salts,13 or
TMSCF2Br14 have been reported. However, the substrates
for such a reaction were mainly limited to activated soft carbon
nucleophiles such as malonates, β-ketoesters, 2,2-diaryl
acetates, or acetamides. A third route toward the C(sp3)−
CF2H bond formation relied on photoredox catalysis-
promoted difluoromethyl radical addition to an unsaturated
double bond, followed by proton abstraction.15 Several stable
reagents such as HCF2 SO2 Cl,16 HCF2 CO2 H,17
INTRODUCTION
■
Organofluorine compounds are continuously gaining momen-
tum, particularly in the field of pharmaceutical and agro-
chemical industries, as an emerging tool to leverage the
compounds’ chemical and biological properties including the
metabolic stability and cell permeability that are important for
the pharmacokinetics and pharmacodynamics of the drug
candidates.1 Consequently, development of efficient methods
for the installation of a fluorine or a fluoroalkyl group such as
trifluoromethyl, difluoromethyl, and trifluoromethoxy has
become an active research topic in synthetic community.2
Among many fluoroalkyl groups, the difluoromethyl group
(−CF2H) has attracted great attention, mainly owing to its
different property from other fluoroalkyl groups. Largely
because of the strong electronegativity of fluorine, it has
been estimated that the kinetic acidity of the proton in
PhCF2H in dimethyl sulfoxide (DMSO) is roughly 104 times
higher than that in PhMe.3 The weakly acidic proton in the
difluoromethyl group is therefore able to act as a hydrogen
bonding donor to interact with the heteroatom in the host
protein, and the difluoromethyl group is now generally
considered by the medicinal chemists as an isosteric and
isopolar functional group to hydroxyl (−OH) and thiol (−SH)
units in drug design.4
To date, most efforts for the incorporation of the
difluoromethyl group have been focused on the construction
of the C(sp2)−CF2H bond,5 while synthetic routes to install a
difluoromethyl group onto a sp3-hybridized carbon are far less
developed. One of the well-known methods for the formation
of the C(sp3)−CF2H bond is the reaction of a nucleophilic
difluoromethylation reagent TMSCF2H with activated electro-
philes such as aldehydes, ketones, or imines using CsF6 or
KOtBu7 as the promoter. Notably, Xiao and co-workers
reported a Ph3P/ICH2CH2I system which could effectively
activate the hydroxyl group for nucleophilic difluoromethyla-
tion.8 Likewise, PhSO2CF2H9 and PhSO2CF2TMS10 can also
be used as the nucleophilic “difluoromethyl” surrogates under
basic conditions to react with the activated electrophiles via
18
19
20
−
Ph3P+CF2CO2 , [Ph3PCF2Br]+Br−, [Ph3PCF2H]+Br−,
N-tosyl-S-difluoromethyl-S-phenylsulfoximine,21 and 2-
((difluoromethyl)sulfonyl) benzo[d]thiazole22 have been
identified as the suitable difluoromethyl radical precursors for
this transformation. More recently, Liu and co-workers
reported two copper-catalyzed difluoromethylation approaches
for the reactions of aliphatic acids or alkyl-substituted
pyridinium salts with [(DMPU)2Zn(CF2H)2] under mild
conditions.23 Despite these achievements, methods that are
able to construct the C(sp3)−CF2H bond under mild
conditions are still highly demanded (Figure 1).
An attractive approach for the formation of C(sp3)−CF2H
bond would be a transition-metal-mediated or -catalyzed
difluoromethylation of alkyl halides using TMSCF2H as the
Received: November 20, 2020
Published: January 19, 2021
https://dx.doi.org/10.1021/acs.joc.0c02783
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the development of reaction conditions. Extensive screening of
the copper salts, the activators, and the solvents disclosed that
a reaction using CuI as the promoter and CsF as the activator
occurred in polar solvent dimethylformamide (DMF) and gave
the desired product 1a in 87% yield after 6 h at 40 °C
(standard condition A in Scheme 1). Control experiments
showed that the reaction in the absence of CuI occurred in less
than 5% yield (Scheme 1, entry 2). Likewise, the direct
reaction of 3-phenyl propyl iodide and TMSCF2H in the
presence of a combination of CsF and 18-crown-6 as the
promoter also gave the desired product in less than 5% yield
(Scheme 1, entry 3). Replacing CuI with CuBr, CuCl, or
reducing the amount of CuI to 0.5 equiv led to dramatically
decreasing the product yield (Scheme 1, entries 4−6). The use
of CsF as the activator is important since reactions using other
activators such as KOtBu or NaOtBu of TBAF gave much
lower yields (Scheme 1, entries 7−9). Likewise, the use of
DMF as a solvent is crucial because reactions in NMP or
DMAc offered low yields of 35−49%, while reactions in other
solvents such as DMSO or tetrahydrofuran did not take place
at all (Scheme 1, entries 10−13). Notably, under the standard
reaction conditions, reactions of analogous alkyl electrophiles,
tosylate and mesylate, gave difluoromethylated alkanes in 53
and 49% yields, respectively, while reactions of alkyl triflate and
nosylate did not afford the desired products (Scheme 1, entries
14−17). Most striking, reaction of alkyl bromide with
TMSCF2H did not occur to give the corresponding
difluoromethylated alkanes under the standard conditions
(Scheme 1, entry 19).
To address the challenge in the reaction of alkyl bromide
with TMSCF2H, we decided to reexamine the reaction
conditions by addition of different additives. A broadband
screening of the additives led us to find that the reaction in the
presence of Pd(dba)2 (10 mol %) and DPPF (10 mol %) as
the catalyst occurred in full conversion after 6 h at 50 °C to
give the coupled product in 92% yield (standard condition B in
Scheme 1). Control experiments showed that the reaction in
the absence of either palladium catalyst or CuI did not occur,
thus illustrating that the synergistic bimetallic catalytic system
might operate under these conditions. Previously, we found
that direct transmetalation of the difluoromethyl group from
TMSCF2H to [LPd(Ar)(X)] in the presence of various
activators was a rather difficult process. Often, the formation
of CF2H2, CF2HCF2H, or difluoroethylene was observed.25
Likewise, the same phenomena was observed for the
stoichiometric reaction of the alkyl-substituted Pd(II) complex
[LPd(Me)(X)] with TMSCF2H. Instead, we found that it is
much easier for the difluoromethyl group to transfer from
TMSCF2H to CuI to form a stable [CuCF2H] species which
then can readily transmetalate the difluoromethyl group to the
putative palladium complex. Thus, in this reaction, the
[CuCF2H] complex could act as a transmetalation shuttle for
the cooperative bimetallic catalytic system. Efforts to further
optimize the reaction conditions in terms of the different
palladium precursors, ligands, solvents, and copper(I) salts led
to inferior results (Scheme 1, entries 20−32). Finally, we also
tried to reduce the amount of the palladium catalyst and CuI.
However, reaction using 5 mol % palladium catalyst or 0.5
equiv of CuI gave the coupled product in significantly reduced
58 and 45% yields, respectively (Scheme 1, entries 33−34).
Scope for Difluoromethylation of Primary Alkyl
Electrophiles with TMSCF2H. Under the standard con-
ditions A and B, we studied the generality and scope of the
Figure 1. Approaches for the formation of C(sp3)−CF2H bond.
difluoromethyl source since both starting materials are easily
available, and the transition-metal catalytic reactions are
conducted under mild conditions which could tolerate various
functional groups and are amenable to late-stage functionaliza-
tion of the multi-functionalized drug molecules. Previously, we
have established a copper-catalyzed direct difluoromethylation
of activated alkyl halides such as allylic and propargylic
bromides and iodides.24 However, efforts to extend this
methodology to unactivated alkyl halides failed to give the
desired difluoromethylated products. Herein, we have now
discovered two different approaches for the direct difluor-
omethylation of primary alkyl iodides and bromides with
TMSCF2H. We found that reactions of primary alkyl iodides
with TMSCF2H occurred smoothly at 40 °C in the presence of
1 equiv of CuI using CsF as the activator. However, under the
same reaction conditions, reaction of primary alkyl bromides
with TMSCF2H did not occur. The addition of 10 mol % of
the palladium catalyst derived from Pd(dba)2 and 1,1′-
ferrocenediyl-bis(diphenylphosphine) (DPPF) promoted the
reaction to full conversion and gave the desired difluoromethy-
lated alkanes in high yields. Initial mechanistic studies suggest
that the Pd-catalyzed difluoromethylation of alkyl bromides
might proceed via a Pd(I)−Pd(III) catalytic cycle.
RESULTS AND DISCUSSION
■
Optimization of Conditions for Difluoromethylation
of Primary Alkyl Electrophiles with TMSCF2H. 3-Phenyl
propyl iodide and TMSCF2H were chosen as the substrates for
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Scheme 1. Optimization of Reaction for Copper-Mediated Difluoromethylation of Primary Alkyl Electrophiles with
a
,b
TMSCF2H
a
Reaction condition A: alkyl electrophiles (0.10 mmol), TMSCF2H (0.45 mol), CuI (0.15 mmol), and CsF (0.45 mmol) in DMF (1.0 mL) at 40
°C for 6 h; condition B: alkyl bromide (0.10 mmol), TMSCF2H (0.40 mmol), Pd(dba)2 (0.010 mmol), DPPF (0.010 mmol), CuI (0.10 mmol),
and CsF (0.40 mmol) in DMF (1.0 mL) at 50 °C for 6 h. bYields were determined by 19F NMR spectroscopy using trifluorotoluene as an internal
standard.
substrates of alkyl electrophiles for the difluoromethylation
reaction. As summarize in Scheme 2, a wide range of
unhindered alkyl iodides and bromides reacted with
TMSCF2H under conditions A or B to give the difluor-
omethylated alkanes in good yields. In general, reactions of
alkyl bromides under condition B gave the desired
difluoroalkanes in higher yields than that of alkyl iodides
under condition A. For example, the reaction of (3-
bromopropoxy)benzene with TMSCF2H under condition B
occurred to give compound 2e in 92% yield, while the reaction
of (3-iodopropoxy)benzene under condition A generated
compound 2e in 80% yield. Under both conditions, a variety
of common functional groups including aryl fluoride (2c),
ester (2d, 2h−q), nitro (2f), protected aldehyde (2g), cyano
(2k), amide (2t), and alkene (2u, 2w) were compatible. It is
noteworthy that a substrate with aryl chloride, which is the
common coupling partner in the traditional cross-coupling
reaction, reacted under both conditions in high yields (2l).
The reaction of alkyl bromide with an aryl bromide group,
however, reacted under condition B in low 28% yield because
of the competition aryl difluoromethylation (Scheme 2, 2j).
Nevertheless, the aryl bromide group is compatible with the
condition A. For example, the reaction of 3-iodopropyl 4-
bromobenzoate with TMSCF2H under condition A generated
product 2j in 58% yield. Additionally, alkyl halides with
heteroarene such as thiophene (2o), pyrazole (2p), indole
(2r), and carbazole (2s) can be difluoromethylated in good to
excellent yields.
are easy to undergo elimination to give stable alkenes. For
examples, reactions of β-benzoxyl-ethyl bromide and iodides
under both conditions gave the difluoromethylated product 2y
in low 27 and 20% yields, respectively. The main side products
in these reactions were vinyl benzyl ether. In addition, our
system is rather sensitive to the steric hindrance of the alkyl
bromides and iodides. Accordingly, the reaction of alkyl iodide
with a quaternary carbon center at γ-position gave the product
in a low yield of 33%, while secondary alkyl halides and
substrates with β-substituents are unreactive. Specifically,
reactions of secondary benzylic bromides did not give the
coupled product.
Mechanistic Studies of Palladium-Mediated Difluor-
omethylation of Primary Alkyl Bromides. Since palla-
dium-catalyzed cross-coupling reactions usually undergo a
Pd(0)/Pd(II) catalytic cycle, we did a study to check whether
the synergistic Pd/Cu-catalyzed difluoromethylation of alkyl
bromide with TMFCF2H proceeds via a typical Pd(0)/Pd(II).
We synthesized [(DPPF)Pd(CH3)(I)] and then used it in
stoichiometric amounts in the reaction with TMSCF2H under
the mock catalytic conditions. We assume that transmetalating
the difluoromethyl group from TMSCF2H to [(DPPF)Pd-
(CH3)(I)] would generate [(DPPF)Pd(CH3)(CF2H)], which
would then undergo reductive elimination to give CH3CF2H.
However, under these conditions, the formation of CH3CF2H
was not observed, as determined by 19F NMR spectroscopy
(Figure 2, eq 1), which indicates that the Pd(0)/Pd(II)
catalytic cycle is not in operation. An often proposed
alternative catalytic cycle for Pd-catalyzed cross coupling of
alkyl halides is that the reaction goes through a Pd(I)/Pd(III)
catalytic cycle. To gain evidence of the possible Pd(I)/Pd(III)
catalytic cycle, we synthesized Pd(I) complex
Furthermore, reactions of alkyl tosylates with TMFCF2H
under condition A occurred smoothly to give the correspond-
ing difluoromethylated products in good yields (2a, 2w−x).
However, our system gave low yields for those substrates that
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a
,b
Scheme 2. Scope for Difluoromethylation of Primary Alkyl Electrophiles with TMSCF2H
a
Reaction condition A: alkyl iodide or tosylate (0.3 mmol), TMSCF2H (1.35 mmol), CuI (0.45 mmol), and CsF (1.35 mmol) in DMF (3.0 mL) at
40 °C for 6 h; condition B: alkyl bromide (0.3 mmol), TMSCF2H (1.35 mmol), Pd(dba)2 (0.030 mmol), DPPF (0.031 mmol), CuI (0.30 mmol),
and CsF (1.19 mmol) in DMF (3.0 mL) at 50 °C for 6 h. bYields were determined by 19F NMR spectroscopy using trifluorotoluene as an internal
standard.
[Pd2(CH3CN)6]2BF4 and then used it as a catalyst for the
coupling of 11-bromoundec-1-ene with TMFCF2H under
otherwise identical conditions with condition B. Under these
conditions, the reaction went smoothly to generate 12,12-
difluorododec-1-ene in the quantitative yield (Figure 2, eq 2),
thus providing evidence that a Pd(I)/Pd(III) catalytic cycle
might be operating for the current difluoromethylation
protocol. Furthermore, if the reaction does proceed via a
Pd(I)/Pd(III) cycle, the oxidative addition of an alkyl halide to
a Pd(I) intermediate to generate a key Pd(III) intermediate for
product-forming reductive elimination might involve a single-
electron-transfer (SET) process and an alkyl radical. To probe
whether this is the case, we studied two different set of
experiments. In the first experiment, we add 4.0 equiv of
TEMPO to the Pd-catalyzed difluoromethylation of 3-phenyl
propyl bromide with TMFCF2H (Figure 2, eq 3). It was found
that the reaction was completely shut down. In the second
experiment, we conducted a standard radical clock experiment
by choosing bromomethylcyclopropane as the substrate. Under
condition B, we found that the reaction occurred smoothly to
give (2,2-difluoroethyl)cyclopropane in 60% yield and 4,4-
difluorobut-1-ene in 16% yield (Figure 2, eq 4). Both the
radical inhibition and the radical clock experiments are
consistent with a pathway that involves an alkyl free radical
in the coupling reaction, thus supporting the Pd(I)/Pd(III)
cycle, even though we could not rule out other possible
pathways such as a Pd(0)/Pd(II) catalytic cycle via a SET
oxidative addition of alkyl bromide to an ionic Pd(0) complex.
On the other hand, the mechanism for the copper-mediated
difluoromethylation of alkyl iodides is complicated, just like
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Figure 2. Mechanistic studies of palladium-mediated difluoromethylation of primary alkyl bromides.
Figure 3. Application of the difluoromethylating protocols in the preparation of difluoromethylated derivatives of drug molecules.
other copper-catalyzed cross-coupling reactions, that will be
investigated in our future studies.
CONCLUSIONS
■
For the first time, we demonstrated that unactivated alkyl
bromides and iodides were able to couple with TMSCF2H to
give the corresponding difluoromethylated derivatives. It was
found that reactions of alkyl iodides with TMSCF2H could be
mediated by a copper catalyst using CsF as the activator, while
less reactive alkyl bromides required the combination of
palladium and a stoichiometric amount of CuI to promote the
reaction. A variety of common functional groups were
compatible with both conditions. However, these conditions
were highly sensitive to the steric hindrance of the substrates.
Secondary alkyl halides and β-branched primary alkyl bromides
did not react at all, and alkyl halides with a quaternary carbon
center at γ-position were not suitable as well. Mechanistic
studies of the synergistic Pd/Cu-catalyzed difluoromethylation
of alkyl bromides suggest that the reaction proceeds via a
Pd(I)/Pd(III) catalytic cycle. Applications of the methods in
the preparation of three difluoromethylated drug molecule
derivatives were conducted to demonstrate the protocols’
potential application in the late-stage modification of lead
compounds. Currently, expanding the protocols to sterically
Application. To demonstrate the applicability of the
protocols, we tried to utilize both reactions for the preparation
of difluoromethylated drug molecules. As summarized in
Figure 3, 3-iodo- or 3-bromo-propyl esters of probenecid, a
uric acid reducer, were successfully difluoromethylated under
conditions A or B to give difluoromethylated product 4 in 58
and 72%, respectively (Figure 3, eq 5). Similarly, alkyl halides
5a and 5b derived from naproxen, a nonsteroidal anti-
inflammatory drug, reacted with TMSCF2H under conditions
A or B to generate difluoromethylated derivative 6 in 70 and
87% yield, respectively (Figure 3, eq 6). Remarkably, both
reactions of 3-bromo- or 3-iodo-propyl ester of naproxen 5b
could be conducted in the gram scale without erosion of the
yield under conditions A or B, thus demonstrating the
robustness and scalability of the protocol for its potential
applications. Likewise, alkyl halides 7a−b derived from another
nonsteroidal anti-inflammatory drug pranoprofen reacted with
TMSCF2H under conditions A or B to generate difluor-
omethylated derivative 8 in 65 and 40% yield, respectively.
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NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.4
Hz, 2H), 4.44 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 6.5 Hz, 2H), 2.29 (p, J =
6.2 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 165.6, 131.7,
131.1, 128.8, 128.2, 62.9, 31.7, 29.3 ppm. MS (DART): 320.9 [M +
H]+; HRMS (DART-Positive) m/z: [M + H]+ calcd for C10H11Br2O2,
320.9120; found, 320.9119. IR (KBr): νmax 2930, 1721, 1590, 1398,
1271, 1116, 1012, 756 cm−1.
3-Iodopropyl 4-Bromobenzoate. Yellow oil (574 mg, 78%).
Eluent: ethyl acetate/petroleum ether (1/40), Rf = 0.4. 1H NMR (400
MHz, CDCl3): δ 7.87 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H),
4.38 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.8 Hz, 2H), 2.26 (p, J = 6.4 Hz,
2H); 13C{1H} NMR (101 MHz, CDCl3): δ 165.6, 131.7, 131.1,
128.8, 128.2, 62.8, 32.4, 1.2 ppm. HRMS (FI-TOF) m/z: [M]+ calcd
for C10H10BrIO2, 367.8910; found, 367.8903. IR (KBr): νmax 2957,
1721, 1590, 1398, 1270, 1115, 1102, 849, 755 cm−1.
3-Bromopropyl 4-Cyanobenzoate. Colorless oil (347 mg,
65%). Eluent: ethyl acetate/petroleum ether (1/8), Rf = 0.4. 1H
NMR (400 MHz, CDCl3): δ 8.13−8.06 (m, 2H), 8.13−8.06 (m, 2H),
4.47 (t, J = 6.1 Hz, 2H), 3.51 (t, J = 6.5 Hz, 2H), 2.30 (p, J = 6.3 Hz,
2H); 13C{1H} NMR (151 MHz, CDCl3): δ 164.8, 133.8, 132.3,
130.1, 117.9, 116.5, 63.5, 31.6, 29.2 ppm. MS (EI): 130 (100), 167
(3.59). HRMS (FI-TOF) m/z: [M]+ calcd for C11H10NBrO2,
266.9889; found, 266.9888. IR (KBr): νmax 2965, 2231, 1727, 1404,
1277, 1108, 1019, 861, 767 cm−1.
3-Iodopropyl 4-Cyanobenzoate. Yellow oil (460 mg, 73%).
Eluent: ethyl acetate/petroleum ether (1/8), Rf = 0.4. 1H NMR (400
MHz, CDCl3): δ 8.14−8.08 (m, 2H), 7.74−7.70 (m, 2H), 4.42 (t, J =
6.1 Hz, 2H), 3.27 (t, J = 6.8 Hz, 2H), 2.28 (p, J = 6.4 Hz, 2H);
13C{1H} NMR (126 MHz, CDCl3): δ 164.8, 133.8, 132.3, 130.1,
118.0, 116.6, 65.4, 32.2, 1.0 ppm. MS (EI): 130 (100), 315 (5.22).
HRMS (FI-TOF) m/z: [M]+ calcd for C11H10NIO2, 314.9755; found,
314.9751. IR (KBr): νmax 2956, 1709, 1461, 1282, 1259, 1095, 913,
748 cm−1.
hindered β-branched primary alkyl halides and secondary
halides is undergoing in our laboratory and will be reported in
due course.
EXPERIMENTAL SECTION
■
General Information. All solvents were purified by the standard
1
method. H, 19F, and 13C NMR spectra were acquired on 400; 376;
101, 126, and 151 MHz spectrometer (400 MHz for 1H; 376 MHz for
19F; and 101, 126, and 151 MHz for 13C). H NMR and 13C NMR
1
chemical shifts were determined relative to an internal standard TMS
at δ 0.0 ppm, and 19F NMR chemical shifts were determined relative
to CFCl3 as an internal standard. Chemical shifts (δ) are reported in
parts per million, and coupling constants (J) are reported in hertz
(Hz). The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, p =
pentet, and m = multiplet. All reactions were monitored by thin-layer
chromatography or 19F NMR. Flash column chromatography was
carried out using 300−400 mesh silica gel at medium pressure.
Materials. All reagents were received from commercial sources.
Solvents were freshly dried and degassed according to the purification
handbook Purification of Laboratory Chemicals26 before using.
Preparation of Alkyl Electrophiles. Alkyl electrophiles were
prepared by the known methods according to the reported
procedure.27
2-(4-(3-Bromopropoxy)phenyl)-1,3-dioxolane. 4-(3-
Bromopropoxy)benzaldehyde28 (1.0 g, 4.1 mmol), ethylene glycol
(1.0 g, 16 mmol), p-toluenesulfonic acid (17 mg, 0.10 mmol), and
toluene (30.0 mL) were added to a round-bottomed flask equipped
with a Dean−Stark trap with a condenser. The solution was heated to
150 °C in an oil bath for 10 h. The solution was washed with NaOH
(0.1 M) and extracted with EtOAc (50.0 mL). The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel.
Colorless oil (915 mg, 80%). Eluent: ethyl acetate/petroleum ether
3-Bromopropyl 4-Iodobenzoate. Yellow oil (574 mg, 78%).
Eluent: ethyl acetate/petroleum ether (1/30), Rf = 0.4. 1H NMR (400
MHz, CDCl3): δ 7.77 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H),
4.43 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 6.5 Hz, 2H), 2.29 (p, J = 6.1 Hz,
2H); 13C{1H} NMR (101 MHz, CDCl3): δ 165.8, 137.7, 131.0,
129.4, 100.9, 62.9, 31.7, 29.3 ppm. MS (DART): 368.9 [M + H]+;
HRMS (DART-Positive) m/z: [M + H]+ calcd for C10H11IBrO2,
368.8982; found, 368.8979. IR (KBr): νmax 2962, 1722, 1586, 1420,
1268, 1116, 1008, 752 cm−1.
1
(1/8), Rf = 0.4. H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 8.6 Hz,
2H), 6.91 (d, J = 8.5 Hz, 2H), 5.75 (s, 1H), 4.17−3.95 (m, 6H), 3.59
(t, J = 6.4 Hz, 2H), 2.31 (p, J = 6.1 Hz, 2H); 13C{1H} NMR (101
MHz, CDCl3): δ 159.4, 130.3, 127.9, 114.3, 103.6, 65.4, 65.2, 32.3,
30.0 ppm. MS (EI): 286 (100). HRMS (FI-TOF) m/z: [M]+ calcd
for C12H15BrO3, 286.0199; found, 286.0206. IR (KBr): νmax 2940,
1693, 1600, 1509, 1251, 1161, 1025, 833, 616 cm−1.
2-(4-(3-Iodopropoxy)phenyl)-1,3-dioxolane. To a solution of
2-(4-(3-bromopropoxy)phenyl)-1,3-dioxolane (572 mg, 2.00 mmol)
in acetone (10.0 mL), KI (1.0 g, 6.0 mmol) was added gradually.
Then, the reaction mixture was stirred at 50 °C in an oil bath
overnight. Solvent was removed and then diluted with water. The
mixture was extracted with ethyl acetate for three times. The organic
layer was dried over anhydrous Na2SO4 and concentrated in vacuo to
3-Iodopropyl 4-Iodobenzoate. White solid (384 mg, 61%). mp
1
49.8 °C. Eluent: ethyl acetate/petroleum ether (1/30), Rf = 0.4. H
NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0
Hz, 2H), 4.37 (t, J = 6.0 Hz, 2H), 3.27 (t, J = 6.8 Hz, 2H), 2.26 (p, J =
6.4 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 165.8, 137.8,
131.0, 129.4, 100.9, 64.8, 32.4, 1.2 ppm. MS (EI): 231 (100), 416
(3.24). HRMS (FI-TOF) m/z: [M]+ calcd for C10H10I2O2, 415.8765;
found, 415.8771. IR (KBr): νmax 2956, 1720, 1586, 1393, 1268, 1115,
1007, 752 cm−1.
1
give the product. Colorless oil (648 mg, 97%). H NMR (400 MHz,
CDCl3): δ 7.39 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.74 (s,
1H), 4.15−3.95 (m, 6H), 3.34 (t, J = 6.7 Hz, 2H), 2.25 (p, J = 6.2 Hz,
2H); 13C{1H} NMR (101 MHz, CDCl3): δ 159.4, 130.3, 127.9,
114.4, 103.6, 67.3, 65.2, 32.9, 2.5 ppm. MS (EI): 333 (100). HRMS
(FI-TOF) m/z: [M]+ calcd for C12H15IO3, 334.0060; found,
334.0067. IR (KBr): νmax 2952, 1693, 1601, 1493, 1281, 1177,
1026, 823, 706 cm−1.
General Procedure for Preparation of Alkyl Bromides and
Iodides. To a solution of alkyl acid (1.2 equiv), 4-dimethylaminepyr-
idine (0.2 equiv), and dicyclohexylcarbodiimide (1.2 equiv) in dry
CH2Cl2 (10.0 mL) at room temperature was added 3-bromopropan-
1-ol or 3-iodopropan-1-ol (1.0 equiv) in dry CH2Cl2 (3.0 mL). The
reaction was stirred at room temperature for overnight before being
diluted with CH2Cl2 (10.0 mL) and quenched with H2O (200 mL).
The aqueous layer was separated and extracted two times with
CH2Cl2 (10.0 mL). The combined organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel.
3-Bromopropyl 5-Methylthiophene-2-carboxylate. Colorless
oil (408 mg, 78%). Eluent: ethyl acetate/petroleum ether (1/30), Rf =
0.4. 1H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 3.6 Hz, 1H), 6.74 (d,
J = 3.5 Hz, 1H), 4.38 (t, J = 6.0 Hz, 2H), 3.50 (t, J = 6.5 Hz, 2H),
2.49 (s, 3H), 2.25 (p, J = 6.2 Hz, 2H); 13C{1H} NMR (101 MHz,
CDCl3): δ 161.9, 148.2, 140.0, 130.7, 126.4, 62.5, 31.8, 29.4, 15.7
ppm. MS (EI): 125 (100), 262 (13.46). HRMS (EI-TOF) m/z: [M]+
calcd for C9H11BrSO2, 261.9663; found, 261.9653. IR (KBr): νmax
3400, 2926, 2854, 2117, 1711, 1541, 1462, 1383, 1284, 1165 cm−1.
3-Iodopropyl 5-Methylthiophene-2-carboxylate. Colorless
oil (483 mg, 78%). Eluent: ethyl acetate/petroleum ether (1/30),
1
Rf = 0.4. H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 3.6 Hz, 1H),
6.74 (d, J = 3.5 Hz, 1H), 4.31 (t, J = 6.0 Hz, 2H), 3.25 (t, J = 6.7 Hz,
2H), 2.49 (s, 3H), 2.22 (p, J = 6.4 Hz, 2H); 13C{1H} NMR (101
MHz, CDCl3): δ 161.9, 148.2, 134.0, 130.7, 126.4, 64.4, 32.5, 1.4
ppm. MS (EI): 125 (100), 310 (7.55). HRMS (EI-TOF) m/z: [M]+
calcd for C9H11ISO2, 309.9525; found, 309.9518. IR (KBr): νmax
3095, 2932, 2877, 1618, 1580, 1427, 1351, 1180, 1027, 737 cm−1.
3-Bromopropyl 4-Bromobenzoate. Colorless oil (457 mg,
1
71%). Eluent: ethyl acetate/petroleum ether (1/40), Rf = 0.4. H
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3-Bromopropyl 4-Chloro-5-ethyl-2-methyl-pyrazole-3-car-
ppm. MS (EI): 185 (100), 350 (12.22). HRMS (EI-TOF) m/z: [M]+
calcd for C17H19BrO3, 350.0518; found, 350.0515. IR (KBr): νmax
3429, 3000, 2971, 1720, 1604, 1502, 1483, 1247, 1160, 858 cm−1.
3-Iodopropyl (2S)-2-(6-Methoxy-2-naphthyl)propanoate.
White solid (485 mg, 61%). mp 56 °C. Eluent: ethyl acetate/
boxylate. Colorless oil (419 mg, 68%). Eluent: ethyl acetate/
1
petroleum ether (1/30), Rf = 0.4. H NMR (400 MHz, CDCl3): δ
4.41 (t, J = 5.8 Hz, 2H), 4.03 (s, 3H), 3.54 (t, J = 6.4 Hz, 2H), 2.57
(q, J = 7.5 Hz, 2H), 2.24 (p, J = 6.1 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3): δ 158.9, 150.3, 128.5, 113.0, 62.7,
1
petroleum ether (1/20), Rf = 0.4. H NMR (400 MHz, CDCl3): δ
40.5, 31.4, 29.4, 19.2, 12.7 ppm. MS (EI): 173 (100), 307 (81.42).
HRMS (EI-TOF) m/z: [M]+ calcd for C10H14O2N2ClBr, 307.9922;
found, 307.9926. IR (KBr): νmax 2972, 1721, 1474, 1273, 1123, 1031,
985, 770 cm−1.
3-Iodopropyl 4-Chloro-5-ethyl-2-methyl-pyrazole-3-car-
boxylate. White solid (528 mg, 77%). mp 29 °C. Eluent: ethyl
acetate/petroleum ether (1/30), Rf = 0.4. 1H NMR (400 MHz,
CDCl3): δ 4.38 (t, J = 5.8 Hz, 2H), 4.06 (s, 3H), 3.33 (t, J = 6.7 Hz,
2H), 2.61 (q, J = 6.3 Hz, 2H), 2.23 (p, J = 6.3 Hz, 2H), 1.20 (t, J = 7.6
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 158.9, 150.4, 128.6,
113.1, 64.6, 40.5, 32.0, 19.2, 12.7, 1.6 ppm. MS (EI): 171 (100), 356
(27.85). HRMS (EI-TOF) m/z: [M]+ calcd for C10H14N2IClO2,
355.9789; found, 355.9798. IR (KBr): νmax 2971, 1718, 1449, 1273,
1121, 1031, 983, 772 cm−1.
7.69 (d, J = 8.6 Hz, 2H), 7.64 (s, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.15−
7.08 (m, 2H), 4.13 (dq, J = 11.0, 5.4 Hz, 2H), 3.90 (s, 3H), 3.84 (q, J
= 7.1 Hz, 1H), 3.03 (td, J = 6.8, 2.1 Hz, 2H), 2.04 (p, J = 6.5 Hz, 2H),
1.57 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ 174.5,
157.7, 135.6, 133.7, 129.3, 128.9, 127.2, 126.1, 125.9, 119.0, 105.6,
64.3, 55.3, 45. 4, 32. 2, 18.4, 1.4 ppm. MS (EI): 185 (100), 398
(36.67). HRMS (EI-TOF) m/z: [M]+ calcd for C17H19IO3, 398.0379;
found, 398.0380. IR (KBr): νmax 3436, 2978, 1731, 1631, 1459, 1417,
1324, 1271, 1121, 1029 cm−1.
3-Bromopropyl 2-(5H-Chromeno[2,3-b]pyridin-7-yl)-
propanoate. Yellow oil (360 mg, 48%). Eluent: ethyl acetate/
petroleum ether (1/3), Rf = 0.4. 1H NMR (400 MHz, CDCl3): δ 8.10
(d, J = 3.7 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.13−7.02 (m, 3H),
6.97 (dd, J = 7.3, 4.8 Hz, 1H), 4.21−4.10 (m, 2H), 4.04 (s, 2H), 3.64
(q, J = 7.2 Hz, 1H), 3.27 (tq, J = 6.4, 3.6 Hz, 2H), 2.06 (p, J = 6.2 Hz,
2H), 1.44 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3): δ
174.3, 158.4, 150.8, 146.6, 138.4, 135.8, 127.4, 127.2, 119.8, 119.7,
117.3, 115.3, 62.4, 44.8, 31.5, 29.3, 28.1, 18.5 ppm. MS (DART):
376.1 [M + H]+; HRMS (DART-Positive) m/z: [M + H]+ calcd for
C18H19NBrO3, 376.0543; found, 376.0538. IR (KBr): νmax 2968,
1733, 1666, 1512, 1340, 1106, 979, 727 cm−1.
General Procedure for Copper-Mediated Difluoromethyla-
tion of Alkyl Iodides or Tosylates. In an argon-filled glovebox, an
oven-dried 25 mL Schlenk tube with the Teflon-coated stirrer bar was
charged with copper iodide (86 mg, 0.45 mmol), cesium fluoride (205
mg, 1.35 mmol), and difluoromethyltrimethylsilane (169 mg, 1.35
mmol) in DMF (3.0 mL). The suspension was stirred at room
temperature for 6 h before the alkyl iodide (0.3 mmol) or alkyl
tosylate (0.3 mmol) was added. The mixture was then stirred at 40 °C
in an oil bath for 6 h. The solution was diluted with Et2O (20.0 mL),
filtered through a short plug of silica gel, and washed with Et2O (20.0
mL). The resulting organic solution was washed with saturated
aqueous NH4Cl solution (20.0 mL), water (20.0 mL), and brine (20.0
mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The
crude product was purified by column chromatography on silica gel.
General Procedure for a Pd/Cu Co-catalyzed Difluorome-
thylation of Alkyl Bromides. In an argon-filled glovebox, an oven-
dried 25 mL Schlenk tube with the Teflon-coated stirrer bar was
charged with alkyl bromide (0.3 mmol), Pd(dba)2 (17 mg, 0.030
mmol), DPPF (17 mg, 0.031 mmol), copper iodide (57 mg, 0.30
mmol), cesium fluoride (182 mg, 1.19 mmol), and difluoromethyl-
trimethylsilane (150 mg, 1.20 mmol) in DMF (3.0 mL). The mixture
was stirred at 50 °C in an oil bath for 6 h. The solution was diluted
with Et2O (20.0 mL), filtered through a short plug of silica gel, and
washed with Et2O (20.0 mL). The resulting organic solution was
washed with saturated aqueous NH4Cl solution (20.0 mL), water
(20.0 mL), and brine (20.0 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel.
3 - B r o m o p r o p y l 1 - ( 4 - M e t h o x y p h e n y l ) -
cyclopropanecarboxylate. Colorless oil (555 mg, 89%). Eluent:
1
ethyl acetate/petroleum ether (1/30), Rf = 0.4. H NMR (400 MHz,
CDCl3): δ 7.24 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.14 (t, J
= 6.0 Hz, 2H), 3.79 (s, 3H), 3.27 (t, J = 6.5 Hz, 2H), 2.05 (p, J = 6.2
Hz, 2H), 1.56 (q, J = 3.8 Hz, 2H), 1.16 (q, J = 3.8 Hz, 2H); 13C{1H}
NMR (101 MHz, CDCl3): δ 174.6, 158.6, 131.4, 131.4, 113.5, 62.5,
55.2, 31.6, 29.4, 28.3, 16.8 ppm. MS (EI): 191 (100), 312 (20.87).
HRMS (EI-TOF) m/z: [M]+ calcd for C14H17BrO3, 312.0361; found,
312.0365. IR (KBr): νmax 3006, 2957, 2836, 2117, 1679, 1581, 1464,
1384, 1293, 1166 cm−1.
3 - I o d o p r o p y l 1 - ( 4 - M e t h o x y p h e n y l ) -
cyclopropanecarboxylate. Yellow oil (560 mg, 78%). Eluent:
1
ethyl acetate/petroleum ether (1/30), Rf = 0.4. H NMR (400 MHz,
CDCl3): δ 7.23 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.06 (t, J
= 5.9 Hz, 2H), 3.78 (s, 3H), 3.02 (t, J = 6.8 Hz, 2H), 2.00 (p, J = 6.5
Hz, 2H), 1.56 (q, J = 3.6 Hz, 2H), 1.15 (q, J = 3.6 Hz, 2H); 13C{1H}
NMR (101 MHz, CDCl3): δ 174.6, 158.6, 131.5, 131.5, 113.5, 64.4,
55.3, 32.1, 28.3, 16.8, 1.6 ppm. MS (EI): 191 (100), 360 (81.39).
HRMS (EI-TOF) m/z: [M]+ calcd for C14H17IO3, 360.0222; found,
360.0216. IR (KBr): νmax 3419, 3005, 2956, 2834, 1720, 1612, 1516,
1464, 1336, 1246 cm−1.
3-Bromopropyl 4-(Dipropylsulfamoyl)benzoate. Colorless oil
(567 mg, 70%). Eluent: ethyl acetate/petroleum ether (1/4), Rf = 0.4.
1H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 8.5 Hz, 2H), 7.84 (d, J =
8.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 6.5 Hz, 2H), 3.06 (t,
J = 7.6 Hz, 4H), 2.30 (p, J = 6.2 Hz, 2H), 1.50 (h, J = 7.4 Hz, 4H),
0.82 (t, J = 7.4 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3): δ 160.2,
139.6, 128.5, 125.4, 122.2, 58.5, 45.1, 26.8, 24.5, 17.1, 6.2 ppm. MS
(EI): 405.8 (100). HRMS (EI-TOF) m/z: [M]+ calcd for
C16H25BrNSO4, 406.0682; found, 406.0679. IR (KBr): νmax 2966,
2935, 2875, 1467, 1217, 1088, 994, 869, 778, 603 cm−1.
3-Iodopropyl 4-(Dipropylsulfamoyl)benzoate. Colorless oil
(661 mg, 73%). Eluent: ethyl acetate/petroleum ether (1/4), Rf = 0.4.
1H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.3 Hz, 2H), 7.85 (d, J =
8.3 Hz, 2H), 4.42 (t, J = 6.1 Hz, 2H), 3.28 (t, J = 6.8 Hz, 2H), 3.07
(dd, J = 8.5, 6.8 Hz, 4H), 2.28 (p, J = 6.2 Hz, 2H), 1.52 (h, J = 7.4 Hz,
4H), 0.84 (t, J = 7.4 Hz, 6H); 13C{1H}NMR (101 MHz, CDCl3): δ
165.0, 144.4, 133.2, 130.2, 127.0, 65.2, 49.9, 32.3, 21.9, 11.2, 1.0 ppm.
MS (EI): 424 (100), 454 (1.57). HRMS (EI-TOF) m/z: [M]+ calcd
for C16H24INSO4, 453.0471; found, 453.0481. IR (KBr): νmax 3426,
2965, 2874, 1723, 1599, 1574, 1466, 1399, 1272, 1105 cm−1.
3-Bromopropyl (2S)-2-(6-Methoxy-2-naphthyl)propanoate.
Colorless oil (504 mg, 72%). Eluent: ethyl acetate/petroleum ether
(1/20), Rf = 0.4. 1H NMR (400 MHz, CDCl3): δ 7.74−7.63 (m, 3H),
7.39 (dd, J = 8.5, 1.8 Hz, 1H), 7.17−7.09 (m, 2H), 4.27−4.15 (m,
2H), 3.90 (s, 3H), 3.86 (q, J = 7.2 Hz, 1H), 3.28 (td, J = 6.6, 1.9 Hz,
2H), 2.08 (p, J = 6.3 Hz, 2H), 1.58 (d, J = 7.2 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3): δ 174.5, 157.7, 135.6, 133.7, 129.3, 128.9,
127.2, 126.1, 125.9, 119.1, 105.6, 62.4, 55.3, 45.4, 31.6, 29.4, 18.5
(5,5-Difluoropentyl)benzene (2a). Colorless oil (X = I, 42 mg,
76%; X = Br, 55 mg, quant.; X = OTs, 25 mg, 45%). Eluent:
petroleum ether, Rf = 0.5. 1H NMR (400 MHz, CDCl3): δ 7.33−7.13
(m, 5H), 5.78 (tt, J = 56.9, 4.5 Hz, 1H), 2.63 (t, J = 7.6 Hz, 2H), 1.85
(ttd, J = 17.6, 8.0, 4.6 Hz, 2H), 1.68 (dt, J = 15.5, 7.6 Hz, 2H), 1.50
(dd, J = 16.7, 9.2 Hz, 2H); 19F NMR (376 MHz, CDCl3): δ −115.76
(dt, J = 56.9, 17.6 Hz); 13C{1H} NMR (126 MHz, CDCl3): δ 142.0,
128.4, 125.9, 117.4 (t, 1J(C, F) = 239.3 Hz), 35.7, 34.0 (t, 2J(C, F) =
3
20.4 Hz), 30.9, 21.8 (t, J(C, F) = 5.3 Hz) ppm. The physical and
spectral data were consistent with those previously reported.29
1-(4,4-Difluorobutyl)-4-methoxybenzene (2b). Colorless oil
(X = I, 46 mg, 76%; X = Br, 55 mg, 92%). Eluent: ethyl acetate/
1
petroleum ether (1/50), Rf = 0.4. H NMR (400 MHz, CDCl3): δ
7.10 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 5.80 (tt, J = 56.8,
4.2 Hz, 1H), 3.80 (s, 2H), 2.63 (t, J = 7.2 Hz, 2H), 1.92−1.67 (m,
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4H); 19F NMR (376 MHz, CDCl3): δ −115.75 (dt, J = 56.8, 17.1
Hz); 13C{1H} NMR (126 MHz, CDCl3): δ 158.1, 133.4, 129.4, 117.4
δ 166.6, 135.6, 132.5, 131.1, 129.4, 128.3, 127.8, 127.3, 126.7, 125.1,
116.8 (t, 1J(C, F) = 239.3 Hz), 64.0, 31.0(t, 2J(C, F) = 21.9 Hz), 21.7
(t, 3J(C, F) = 5.3 Hz) ppm. MS (DART): 282.1 [M + NH4]+; HRMS
(DART-Positive) m/z: [M + H]+ calcd for C15H15O2F2, 265.1035;
found, 265.1033. IR (KBr): νmax 2970, 1716, 1468, 1286, 1228, 1197,
1058, 983, 779 cm−1.
1
2
(t, J(C, F) = 239.4 Hz), 114.0, 55.4, 34.3, 33.6 (t, J(C, F) = 20.8
3
Hz), 24.1 (t, J(C, F) = 5.0 Hz) ppm. The physical and spectral data
were consistent with those previously reported.30
1-(4,4-Difluorobutyl)-4-fluorobenzene (2c). Colorless oil (X =
I, 31 mg, 56%; X = Br, 52 mg, 93%). Eluent: petroleum ether, Rf = 0.6.
1H NMR (400 MHz, CDCl3): δ 7.13 (dd, J = 8.7, 5.4 Hz, 2H), 6.98
(t, J = 8.8 Hz, 2H), 5.81 (tt, J = 56.8, 4.1 Hz, 1H), 2.65 (t, J = 7.3 Hz,
2H), 1.91−1.70 (m, 4H); 19F NMR (376 MHz, CDCl3): δ −115.9
(dt, J = 56.8, 17.1 Hz, 2 F), −117.4 (ddd, J = 14.1, 8.8, 5.4 Hz, 1 F);
13C{1H} NMR (151 MHz, CDCl3): δ 161.4 (d, 1J(C, F) = 244.1 Hz),
4,4-Difluorobutyl 4-Chlorobenzoate (2i). Yellow oil (X = I, 57
mg, 62%; X = Br, 74 mg, quant.). Eluent: ethyl acetate/petroleum
1
ether (1/30), Rf = 0.4. H NMR (400 MHz, CDCl3): δ 7.95 (d, J =
8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 5.91 (tt, J = 56.7, 4.1 Hz, 1H),
4.35 (t, J = 6.0 Hz, 2H), 2.06−1.88 (m, 4H); 19F NMR (376 MHz,
CDCl3): δ −116.35 (dt, J = 56.7, 17.2 Hz); 13C{1H} NMR (151
1
4
3
MHz, CDCl3): δ 165.6, 139.6, 131.0, 128.8, 128.5, 116.7 (t, J(C, F)
137.0 (d, J(C, F) = 2.7 Hz), 129.7 (d, J(C, F) = 8.0 Hz), 117.2 (t,
2
3
1J(C, F) = 239.3 Hz), 115.2 (d, J(C, F) = 21.1 Hz), 34.3, 33.4 (t,
2
= 239.3 Hz), 64.13, 30.9 (t, J(C, F) = 21.9 Hz), 21.5 (t, J(C, F) =
6.0 Hz) ppm. MS (DART): 266.1 [M + NH4]+; HRMS (DART-
Positive) m/z: [M + NH4]+ calcd for C11H15F2NClO2, 266.0754;
found, 266.0753. IR (KBr): νmax 2971, 1723, 1595, 1403, 1274, 1120,
1016, 851, 760 cm−1.
2J(C, F) = 21.1 Hz), 23.8 (t, J(C, F) = 4.5 Hz) ppm. MS (EI): 109
3
(100), 188 (30.79). HRMS (EI-TOF) m/z: [M]+ calcd for C10H11F3,
188.0807; found, 188.0811. IR (KBr): νmax 2957, 2865, 2837, 1613,
1584, 1442, 1301, 1178, 1004, 832 cm−1.
4,4-Difluorobutyl 4-Bromobenzoate (2j). Yellow oil (X = I, 51
mg, 58%; X = Br, 24 mg, 28%). Eluent: ethyl acetate/petroleum ether
(1/30), Rf = 0.4. 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8.6 Hz,
2H), 7.57 (d, J = 8.6 Hz, 2H), 5.91 (tt, J = 56.7, 4.1 Hz, 1H), 4.35 (t, J
= 6.0 Hz, 2H), 2.07−1.88 (m, 4H); 19F NMR (376 MHz, CDCl3): δ
−116.35 (dt, J = 56.7, 17.2 Hz); 13C{1H} NMR (151 MHz, CDCl3):
Methyl 4-(4,4-Difluorobutyl)benzoate (2d). Yellow oil (X = I,
44 mg, 65%; X = Br, 54 mg, 79%). Eluent: ethyl acetate/petroleum
1
ether (1/30), Rf = 0.4. H NMR (400 MHz, CDCl3): δ 7.96 (d, J =
8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 5.80 (tt, J = 56.6, 3.8 Hz, 1H),
3.89 (s, 3H), 2.72 (t, J = 7.2 Hz, 2H), 1.91−1.73 (m, 4H); 19F NMR
(376 MHz, CDCl3): δ −115.96 (dt, J = 56.6, 17.0 Hz); 13C{1H}
NMR (126 MHz, CDCl3): δ 167.1, 146.8, 129.9, 128.5, 128.3, 117.2
(t, 1J(C, F) = 239.0 Hz), 52.1, 35.2, 33.5 (t, 2J(C, F) = 21.0 Hz), 23.4
(t, 3J(C, F) = 5.4 Hz) ppm. MS (EI): 91 (100), 228 (16.64). HRMS
(EI-TOF) m/z: [M]+ calcd for C12H14O2F2, 228.0962; found,
228.0966. IR (KBr): νmax 2954, 1720, 1610, 1436, 1282, 1180,
1112, 1004, 975, 764 cm−1.
1
δ 165.7, 131.8, 131.0, 128.9, 128.2, 116.7 (t, J(C, F) = 240.1 Hz),
2
3
64.16, 30.0 (t, J(C, F) = 21.1 Hz), 21.5 (t, J(C, F) = 6.0 Hz) ppm.
MS (DART): 312.0 [M + NH4]+; HRMS (DART-Positive) m/z: [M
+ H]+ calcd for C11H12F2BrO2, 292.9983; found, 292.9982. IR (KBr):
νmax 2970, 1722, 1591, 1398, 1273, 1119, 849, 757 cm−1.
4,4-Difluorobutyl 4-Cyanobenzoate (2k). Yellow oil (X = I, 28
mg, 39%; X = Br, 54 mg, 75%). Eluent: ethyl acetate/petroleum ether
(1/7), Rf = 0.4. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.6 Hz,
2H), 7.74 (d, J = 8.6 Hz, 2H), 5.89 (tt, J = 56.0, 3.6 Hz, 1H), 4.39 (t, J
= 6.0 Hz, 2H), 2.08−1.91 (m, 4H); 19F NMR (376 MHz, CDCl3): δ
−116.41 (dt, J = 56.5, 17.2 Hz); 13C{1H} NMR (151 MHz, CDCl3):
(4,4-Difluorobutoxy)benzene (2e). Colorless oil (X = I, 45 mg,
80%; X = Br, 51 mg, 92%). Eluent: ethyl acetate/petroleum ether (1/
1
50), Rf = 0.4. H NMR (400 MHz, CDCl3): δ 7.29 (dd, J = 7.4, 2.0
Hz, 2H), 6.99−6.83 (m, 3H), 5.92 (tt, J = 56.8, 4.3 Hz, 1H), 4.00 (t, J
= 5.9 Hz, 2H), 2.13−1.90 (m, 4H). 19F NMR (376 MHz, CDCl3): δ
−116.16 (dt, J = 56.8, 17.4 Hz); 13C{1H} NMR (151 MHz, CDCl3):
δ 158.7, 129.5, 120.9, 117.1 (t, 1J(C, F) = 238.8 Hz), 114.5, 66.7, 31.1
(t, 2J(C, F) = 21.3 Hz), 22.1 (t, 3J(C, F) = 5.5 Hz) ppm. The physical
and spectral data were consistent with those previously reported.17
1-(4,4-Difluorobutoxy)-4-nitrobenzene (2f). Brown oil (X = I,
33 mg, 48%; X = Br, 53 mg, 77%). Eluent: ethyl acetate/petroleum
ether (1/6), Rf = 0.3. 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 9.2
Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 5.98 (tt, J = 56.9, 4.0 Hz 1H), 4.12
(t, J = 5.7 Hz, 2H), 2.16−1.96 (m, 4H); 19F NMR (376 MHz,
CDCl3): δ −115.66 (dt, J = 56.9, 17.7 Hz); 13C{1H} NMR (151
MHz, CDCl3): δ 163.7, 141.6, 126.0, 114.4 (t, 1J(C, F) = 239.3 Hz),
1
δ 164.8, 133.8, 132.3, 130.1, 118.2, 117.9, 116.6 (t, J(C, F) = 239.3
2
3
Hz), 64.7, 30.8 (t, J(C, F) = 21.9 Hz), 21.4 (t, J(C, F) = 5.3 Hz)
ppm. MS (DART): 257.1 [M + NH4]+; HRMS (DART-Positive) m/
z: [M + H]+ calcd for C12H12F2NO2, 240.0831; found, 240.0830. IR
(KBr): νmax 2971, 2232, 1725, 1277, 1178, 1057, 768, 692 cm−1.
4,4-Difluorobutyl 4-(Trifluoromethyl)benzoate (2l). Yellow
oil (X = I, 47 mg, 56%; X = Br, 73 mg, 87%). Eluent: ethyl acetate/
1
petroleum ether (1/30), Rf = 0.4. H NMR (400 MHz, CDCl3): δ
8.13 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 5.89 (tt, J = 56.4,
3.8 Hz, 1H), 4.39 (t, J = 6.0 Hz, 2H), 2.09−1.85 (m, 4H); 19F NMR
(376 MHz, CDCl3): δ −63.20 (s, 3 F), −116.41 (dt, J = 56.4, 17.1
Hz, 2 F); 13C{1H} NMR (151 MHz, CDCl3): δ 165.2, 134.5 (q, 2J(C,
2
3
1
114.4, 67.7, 30.8 (t, J(C, F) = 21.9 Hz), 21.8 (t, J(C, F) = 5.3 Hz)
ppm. MS (DART): 249.1 [M + NH4]+; HRMS (DART-Positive) m/
z: [M + H]+ calcd for C10H12O3NF2, 232.0780; found, 232.0779. IR
(KBr): νmax 2970, 1608, 1343, 1263, 1111, 989, 845, 753 cm−1.
2-(4-(4,4-Difluorobutoxy)phenyl)-1,3-dioxolane (2g). Yellow
oil (X = I, 40 mg, 52%; X = Br, 71 mg, 92%). Eluent: ethyl acetate/
petroleum ether (1/8), Rf = 0.3. 1H NMR (400 MHz, CDCl3): δ 7.39
(dd, J = 6.8, 1.8 Hz, 2H), 6.87 (dd, J = 6.8, 1.8 Hz, 2H), 5.94 (tt, J =
56.7, 4.0 Hz, 1H), 5.74 (s, 1H), 4.16−3.95 (m, 6H), 2.10−1.88 (m,
4H); 19F NMR (376 MHz, CDCl3): δ −116.19 (dt, J = 56.7, 17.4
Hz); 13C{1H} NMR (126 MHz, CDCl3): δ 159.5, 130.2, 128.0, 117.1
F) = 49.1 Hz), 133.3, 130.0, 125.5, 123.6 (q, J(C, F) = 272.8 Hz),
116.6 (t, 1J(C, F) = 239.3 Hz), 64.4, 30.9 (t, 2J(C, F) = 21.9 Hz), 21.5
(t, 3J(C, F) = 6.0 Hz) ppm. MS (DART): 300.1 [M + NH4]+; HRMS
(DART-Positive) m/z: [M + NH4]+ calcd for C12H15F5NO2,
300.1017; found, 300.1016. IR (KBr): νmax 2970, 1727, 1413, 1327,
1277, 1128, 1018, 863, 776 cm−1.
4,4-Difluorobutyl 4-(Difluoromethyl)benzoate (2m). Color-
less oil (X = I, 46 mg, 58%; X = Br, 17 mg, 22%). Eluent: ethyl
acetate/petroleum ether (1/30), Rf = 0.4. 1H NMR (400 MHz,
CDCl3): δ 8.10 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 6.68 (t, J
= 56.1 Hz, 1H), 5.92 (tt, J = 56.6, 4.0 Hz, 1H), 4.38 (t, J = 6.0 Hz,
2H), 2.10−1.90 (m, 4H); 19F NMR (376 MHz, CDCl3): δ −112.33
(d, J = 56.1 Hz, 2 F), −116.37 (dt, J = 56.6, 17.2 Hz, 2 F); 13C{1H}
1
2
(t, J(C, F) = 239.4 Hz), 114.3, 103.7, 66.8, 65.3, 31.0 (t, J(C, F) =
21.4 Hz), 22.0 (t, 3J(C, F) = 5.7 Hz) ppm. MS (DART): 259.1 [M +
H]+; HRMS (DART-Positive) m/z: [M + H]+ calcd for C13H17O3F2,
259.1140; found, 259.1139. IR (KBr): νmax 2362, 1685, 1603, 1509,
1257, 1162, 1028, 820 cm−1.
2
NMR (151 MHz, CDCl3): δ 165.6, 138.6 (t, J(C, F) = 22.5 Hz),
3
1
132.2, 130.0, 125.7 (t, J(C, F) = 6.0 Hz), 116.7 (t, J(C, F) = 239.3
1
2
Hz), 114.0 (t, J(C, F) = 239.3 Hz), 64.3, 30.9 (t, J(C, F) = 21.9
3
4,4-Difluorobutyl 2-Naphthoate (2h). Yellow oil (X = I, 55 mg,
70%; X = Br, 71 mg, 90%). Eluent: ethyl acetate/petroleum ether (1/
20), Rf = 0.4. 1H NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 8.04 (dd,
J = 8.6, 1.5 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.8 Hz,
2H), 7.61−7.51 (m, 2H), 5.95 (tt, J = 56.7, 4.0 Hz, 1H), 4.43 (t, J =
6.0 Hz, 2H), 2.13−1.91 (m, 4H); 19F NMR (376 MHz, CDCl3): δ
−116.26 (dt, J = 56.8, 17.2 Hz); 13C{1H} NMR (151 MHz, CDCl3):
Hz), 21.5 (t, J(C, F) = 5.3 Hz) ppm. MS (DART): 282.1 [M +
NH4]+; HRMS (DART-Positive) m/z: [M + H]+ calcd for
C12H13F4O2, 265.0846; found, 265.0845. IR (KBr): νmax 2960,
1724, 1375, 1277, 1218, 1122, 766, 709 cm−1.
4,4-Difluorobutyl Benzofuran-2-carboxylate (2n). Yellow oil
(X = I, 58 mg, 76%; X = Br, 67 mg, 89%). Eluent: ethyl acetate/
1
petroleum ether (1/30), Rf = 0.4. H NMR (400 MHz, CDCl3): δ
2861
https://dx.doi.org/10.1021/acs.joc.0c02783
J. Org. Chem. 2021, 86, 2854−2865

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
2
3
7.72 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.53−
7.49 (m, 1H), 7.34 (t, J = 7.5 Hz, 1H), 5.97 (tt, J = 56.6, 4.1 Hz, 1H),
4.46 (t, J = 6.1 Hz, 2H), 2.09−1.90 (m, 4H); 19F NMR (376 MHz,
CDCl3): δ −116.36 (dt, J = 56.6, 17.2 Hz); 13C{1H} NMR (151
MHz, CDCl3): δ 159.4, 155.8, 145.3, 127.8, 126.9, 123.9, 122.9, 116.7
33.8 (t, J(C, F) = 21.1 Hz), 28.5, 20.0 (t, J(C, F) = 5.3 Hz) ppm.
MS (EI): 180 (100), 273 (39.14). HRMS (EI-TOF) m/z: [M]+ calcd
for C17H17F2N, 273.1329; found, 273.1333. IR (KBr): νmax 3051,
2962, 2865, 1594, 1350, 1215, 1185, 1071, 993, 888 cm−1.
2-(4,4-Difluorobutyl)isoindoline-1,3-dione (2t). Yellow oil (X
= I, 40 mg, 56%; X = Br, 61 mg, 85%). Eluent: ethyl acetate/
petroleum ether (1/6), Rf = 0.3. 1H NMR (400 MHz, CDCl3): δ 7.83
(dd, J = 5.4, 3.0 Hz, 2H), 7.71 (dd, J = 5.4, 3.0 Hz, 2H), 5.84 (tt, J =
56.4, 3.7 Hz, 1H), 3.73 (t, J = 6.6 Hz, 2H), 1.96−1.78 (m, 4H); 19F
NMR (376 MHz, CDCl3): δ −116.24 (dt, J = 56.4, 16.9 Hz);
13C{1H} NMR (151 MHz, CDCl3): δ 168.3, 134.1, 132.0, 123.3,
116.6 (t, 1J(C, F) = 239.3 Hz), 37.1, 31.6 (t, 2J(C, F) = 21.1 Hz), 21.4
1
2
(t, J(C, F) = 239.3 Hz), 114.1, 112.4, 64.3, 30.9 (t, J(C, F) = 21.9
3
Hz), 21.6 (t, J(C, F) = 5.3 Hz) ppm. MS (EI): 162 (100), 254
(74.52). HRMS (EI-TOF) m/z: [M]+ calcd for C13H12F2O3,
254.0755; found, 254.0759. IR (KBr): νmax 2973, 1758, 1599, 1456,
1408, 1369, 1090, 978, 893, 762 cm−1.
4,4-Difluorobutyl 5-Methylthiophene-2-carboxylate (2o).
Yellow oil (X = I, 49 mg, 70%; X = Br, 59 mg, 85%). Eluent: ethyl
acetate/petroleum ether (1/40), Rf = 0.4. 1H NMR (400 MHz,
CDCl3): δ 7.59 (d, J = 3.7 Hz, 1H), 6.75 (dd, J = 3.7, 1.0 Hz, 1H),
5.87 (tt, J = 56.6, 4.1 Hz, 1H), 4.29 (t, J = 6.0 Hz, 2H), 2.50 (s, 3H),
2.05−1.82 (m, 4H); 19F NMR (376 MHz, CDCl3): δ −116.29 (dt, J
= 56.6, 17.2 Hz); 13C{1H} NMR (151 MHz, CDCl3): δ 162.1, 148.2,
134.0, 130.8, 126.4, 116.8 (t, 1J(C, F) = 238.6 Hz), 63.8, 31.0 (t, 2J(C,
3
(t, J(C, F) = 5.3 Hz) ppm. The physical and spectral data were
consistent with those previously reported.31
N-Allyl-N-(4,4-difluorobutyl)-4-methylbenzenesulfonamide
(2u). Yellow oil (X = I, 43 mg, 48%; X = Br, 68 mg, 75%). Eluent:
ethyl acetate/petroleum ether (1/4), Rf = 0.3. H NMR (400 MHz,
1
CDCl3): δ 7.66 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 5.81 (tt,
J = 56.7, 4.2 Hz, 1H), 5.59 (ddt, J = 16.7, 10.0, 6.5 Hz, 1H), 5.19−
5.09 (m, 2H), 3.75 (d, J = 6.5 Hz, 2H), 3.13 (t, J = 7.1 Hz, 2H), 2.40
(s, 3H), 1.91−1.75 (m, 2H), 1.73−1.62 (m, 2H); 19F NMR (376
MHz, CDCl3): δ −116.22 (dt, J = 56.7, 17.7 Hz); 13C{1H} NMR
(126 MHz, CDCl3): δ 143.5, 136.6, 133.0, 129.8, 127.1, 119.2, 115.9
(t, 1J(C, F) = 239.4 Hz), 50.9, 46.6, 31.1 (t, 2J(C, F) = 21.4 Hz), 21.5,
3
F) = 21.1 Hz), 21.6 (t, J(C, F) = 5.3 Hz), 15.7 ppm. MS (EI): 125
(100), 234 (24.6). HRMS (EI-TOF) m/z: [M]+ calcd for
C10H12F2O2S, 234.0526; found, 234.0529. IR (KBr): νmax 2970,
1708, 1461, 1407, 1340, 1217, 1018, 980, 815, 749 cm−1.
4,4-Difluorobutyl 4-Chloro-3-ethyl-1-methyl-1H-pyrazole-
5-carboxylate (2p). Yellow oil (X = I, 30 mg, 36%; X = Br, 61
mg, 72%). Eluent: ethyl acetate/petroleum ether (1/10), Rf = 0.4. 1H
NMR (400 MHz, CDCl3): δ 5.88 (tt, J = 56.4, 3.7 Hz, 1H), 4.36 (t, J
= 6.0 Hz, 2H), 4.07 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 2.29−1.77 (m,
4H), 1.21 (t, J = 7.6 Hz, 3H). 19F NMR (376 MHz, CDCl3): δ
−116.52 (dt, J = 56.4, 17.3 Hz); 13C{1H} NMR (101 MHz, CDCl3):
3
20.9 (t, J(C, F) = 5.7 Hz) ppm. MS (DART): 304.1 [M + H]+;
HRMS (DART-Positive) m/z: [M + H]+ calcd for C14H20O2SNF2,
304.1177; found, 304.1175. IR (KBr): νmax 2930, 2878, 1598, 1494,
1305, 1287, 1033, 935, 816, 706 cm−1.
1,1-Difluorotridecane (2v). Colorless oil (X = I, 41 mg, 56%; X
= Br, 61 mg, 91%). Eluent: petroleum ether, Rf = 0.9. 1H NMR (400
MHz, CDCl3): δ 5.79 (tt, J = 57.0, 4.5 Hz, 1H), 1.92−1.72 (m, 2H),
1.44 (dt, J = 14.9, 6.8 Hz, 2H), 1.26 (s, 13H), 0.88 (t, J = 6.6 Hz,
3H); 19F NMR (376 MHz, CDCl3): δ −120.98 (dt, J = 57.0, 17.6
Hz); 13C{1H} NMR (101 MHz, CDCl3): δ 116.1 (t, 1J(C, F) = 239.9
1
δ 159.09, 150.45, 128.67, 116.64 (t, J(C, F) = 239.1 Hz), 113.11,
2
3
64.13, 40.52, 30.87 (t, J(C, F) = 21.5 Hz), 21.31 (t, J(C, F) = 5.6
Hz), 19.20, 12.71 ppm. MS (EI): 173 (100), 280 (85.58). HRMS (EI-
TOF) m/z: [M]+ calcd for C11H15F2O2N2Cl, 280.0790; found,
280.0785. IR (KBr): νmax 3417, 2974, 1720, 1475, 1450, 1276, 1123,
1092, 980, 955 cm−1.
2
Hz), 32.7 (t, J(C, F) = 20.7 Hz), 30.6, 28.28, 28.22, 28.07, 27.99,
4,4-Difluorobutyl 1-(4-Methoxyphenyl)cyclopropane-1-car-
boxylate (2q). Yellow oil (X = I, 53 mg, 62%; X = Br, 70 mg, 82%).
Eluent: ethyl acetate/petroleum ether (1/20), Rf = 0.4. 1H NMR (400
MHz, CDCl3): δ 7.23 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H),
5.69 (tt, J = 56.7, 4.1 Hz, 1H), 4.06 (d, J = 5.6 Hz, 2H), 3.79 (s, 3H),
1.82−1.64 (m, 4H), 1.56 (d, J = 2.9 Hz, 2H), 1.16 (d, J = 2.9 Hz,
2H). 19F NMR (376 MHz, CDCl3): δ −116.27 (dt, J = 56.7, 16.8 Hz,
2 F); 13C{1H} NMR (151 MHz, CDCl3): δ 174.8, 158.7, 131.6,
131.5, 116.8 (t, 1J(C, F) = 238.9 Hz), 113.6, 63.9, 55.3, 30.9 (t, 2J(C,
F) = 21.5 Hz), 28.3, 21.4 (t, 3J(C, F) = 5.7 Hz), 16.8 ppm. MS (EI):
147 (100), 284 (66.12). HRMS (EI-TOF) m/z: [M]+ calcd for
C15H18F2O3, 284.1224; found, 284.1218. IR (KBr): νmax 2962, 2838,
1720, 1613, 1517, 1293, 1247, 1169, 1092, 987 cm−1.
27.69, 21.32, 20.75 (t, 3J(C, F) = 5.6 Hz), 12.7 ppm. The physical and
spectral data were consistent with those previously reported.32
12,12-Difluorododec-1-ene (2w). Colorless oil (X = I, 34 mg,
56%; X = Br, 56 mg, 92%; X = OTs, 24 mg, 40%). Eluent: petroleum
1
ether, Rf = 0.9. H NMR (400 MHz, CDCl3): δ 5.93−5.61 (m, 2H),
5.02−4.87 (m, 2H), 2.06−1.97 (q, J = 6.9 Hz, 1H), 1.88−1.71 (m,
1H), 1.46−1.23 (m, 14H); 19F NMR (376 MHz, CDCl3): δ −115.78
(d, J = 57.1, 17.5 Hz); 13C{1H} NMR (151 MHz, CDCl3): δ 139.2,
1
2
117.5 (t, J(C, F) = 238.7 Hz), 114.1, 34.1 (t, J(C, F) = 20.6 Hz),
33.8, 29.41, 29.37, 29.35, 29.1, 29.0, 28.9, 22.1 (t, 3J(C, F) = 5.5 Hz)
ppm. The physical and spectral data were consistent with those
previously reported.8
((4,4-Difluorobutoxy)methyl)benzene (2x). Colorless oil (X =
I, 43 mg, 72%; X = Br, 52 mg, 87%; X = OTs, 29 mg, 48%). Eluent:
ethyl acetate/petroleum ether (1/100), Rf = 0.5. 1H NMR (400 MHz,
CDCl3): δ 1H NMR (400 MHz, CDCl3): δ 7.38−7.26 (m, 5H), 5.85
(tt, J = 56.9, 4.5 Hz, 1H), 4.50 (s, 2H), 3.51 (t, J = 6.1 Hz, 2H), 2.02−
1.86 (m, 2H), 1.81−1.71 (m, 2H); 19F NMR (376 MHz, CDCl3): δ
−116.01 (dt, J = 56.9, 17.7 Hz); 13C{1H} NMR (126 MHz, CDCl3):
1-(4,4-Difluorobutyl)-1H-indole (2r). Yellow oil (X = I, 33 mg,
52%; X = Br, 56 mg, 90%). Eluent: ethyl acetate/petroleum ether (1/
1
15), Rf = 0.4. H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 7.8 Hz,
1H), 7.39 (d, J = 8.2 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.2
Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H), 6.55 (t, J = 2.6 Hz, 1H), 5.79 (tt, J
= 56.5, 4.1 Hz, 1H), 4.21 (t, J = 6.9 Hz, 2H), 2.04 (dt, J = 14.9, 7.1
Hz, 2H), 1.91−1.74 (m, 2H); 19F NMR (376 MHz, CDCl3): δ
−116.12 (dt, J = 56.5, 17.7 Hz); 13C{1H} NMR (126 MHz, CDCl3):
1
δ 138. 3, 128.5, 127.7, 127.6, 117.3 (t, J(C, F) = 239.4 Hz), 73.0,
2
3
1
69.2, 31.2 (t, J(C, F) = 21.4 Hz), 22.5 (t, J(C, F) = 5.6 Hz) ppm.
MS (DART): 218.1 [M + NH4]+; HRMS (DART-Positive) m/z: [M
+ H]+ calcd for C11H15OF2, 201.1085; found, 201.1085. IR (KBr):
νmax 3064, 2969, 2879, 1716, 1600, 1587, 1473, 1207, 1034, 989 cm−1.
((4,4-Difluoropropoxy)methyl)benzene (2y). Colorless oil (X
= I, 11 mg, 20%; X = Br, 15 mg, 27%). Eluent: ethyl acetate/
δ 135.9, 128.8, 127.7, 121.8, 121.2, 119.6, 116.8 (t, J(C, F) = 239.4
Hz), 109.3, 101.6, 45.6, 31.4 (t, 2J(C, F) = 21.4 Hz), 22.9 (t, 3J(C, F)
= 5.0 Hz) ppm. MS (EI): 130 (100), 209 (74.19). HRMS (EI-TOF)
m/z: [M]+ calcd for C12H13F2N, 209.1011; found, 209.1014. IR
(KBr): νmax 2968, 1512, 1484, 1464, 1403, 1317, 1122, 743 cm−1.
9-(5,5-Difluoropentyl)-9H-carbazole (2s). White solid (X = I,
57 mg, 70%; X = Br, 78 mg, 95%). mp 71.6 °C. Eluent: ethyl acetate/
1
petroleum ether (1/100), Rf = 0.5. H NMR (400 MHz, CDCl3): δ
1H NMR (400 MHz, CDCl3): δ 7.41−7.27 (m, 5H), 6.01 (tt, J =
56.9, 4.8 Hz, 1H), 4.52 (s, 2H), 3.63 (t, J = 6.1 Hz, 2H), 2.14 (tq, J =
16.7, 6.0 Hz, 2H); 19F NMR (376 MHz, CDCl3): δ −117.87 (dt, J =
56.8, 16.5 Hz); 13C{1H} NMR (126 MHz, CDCl3): δ 137.8, 128.4,
127.8, 127.6, 115.9 (t, 1J(C, F) = 239.4 Hz), 73.2, 64.0 (t, 3J(C, F) =
7.1 Hz), 34.8 (t, 2J(C, F) = 21.7 Hz) ppm. The physical and spectral
data were consistent with those previously reported.33
1
petroleum ether (1/10), Rf = 0.4. H NMR (400 MHz, CDCl3): δ
8.12 (d, J = 7.8 Hz, 2H), 7.56−7.42 (m, 2H), 7.41−7.36 (m, 2H),
7.28−7.21 (m, 2H), 5.74 (tt, J = 56.7, 4.4 Hz, 1H), 4.32 (t, J = 7.1 Hz,
2H), 1.98−1.75 (m, 2H), 1.82 (tdt, J = 17.5, 8.2, 3.8 Hz, 2H), 1.59−
1.49 (p, J = 7.8 Hz, 2H); 19F NMR (376 MHz, CDCl3): δ −116.04
(dt, J = 56.7, 17.5 Hz); 13C{1H} NMR (151 MHz, CDCl3): δ 140.3,
125.7, 122.9, 120.4, 118.9, 116.9 (t, 1J(C, F) = 239.3 Hz), 108.5, 42.6,
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4,4-Difluorobutyl 4-(N,N-Dipropylsulfamoyl)benzoate (4).
Yellow oil (X = I, 65 mg, 58%; X = Br, 81 mg, 72%). Eluent: ethyl
acetate/petroleum ether (1/3), Rf = 0.4. 1H NMR (400 MHz,
CDCl3): δ 8.12 (d, J = 8.3 Hz, 2H), 7.89−7.80 (d, J = 8.3 Hz, 2H),
5.91 (tt, J = 57.0, 4.0 Hz, 1H), 4.38 (t, J = 5.8 Hz, 2H), 3.07 (t, J = 7.6
Hz, 4H), 2.07−1.90 (m, 4H), 1.52 (h, J = 7.4 Hz, 4H), 0.84 (t, J = 7.4
Hz, 6H); 19F NMR (376 MHz, CDCl3): δ −116.46 (dt, J = 56.5, 17.1
Hz); 13C{1H} NMR (126 MHz, CDCl3): δ 164.7, 143.9, 132.8, 129.8,
Changhui Lu − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, P. R. China; orcid.org/0000-0002-7932-9954
Simon Herbert − Bayer AG, Research & Development,
Pharmaceuticals, Berlin 13342, Germany
Wei Zhang − Centre for Green Chemistry and Department of
Chemistry, University of Massachusetts Boston, Boston,
Massachusetts 02125, United States; orcid.org/0000-
0002-6097-2763
1
2
126.6, 116.2 (t, J(C, F) = 239.4 Hz), 64.1, 49.5, 30.4 (t, J(C, F) =
3
21.4 Hz), 21.5, 21.0 (t, J(C, F) = 5.0 Hz), 10.7 ppm. MS (DART):
378 [M + H]+; HRMS (Dart-Positive) m/z: [M + H]+ calcd for
C17H26F2O4NS, 378.1545; found, 378.1543. IR (KBr): νmax 2968,
2936, 2877, 1724, 1468, 1400, 1343, 1159, 1054, 765 cm−1.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02783
4,4-Difluorobutyl (S)-2-(6-Methoxynaphthalen-2-yl)-
propanoate (6). Yellow oil (X = I, 667 mg, 69%; X = Br, 840 mg,
1
87%). Eluent: ethyl acetate/petroleum ether (1/15), Rf = 0.4. H
NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.8 Hz, 2H), 7.65 (s, 1H),
7.38 (dd, J = 8.5, 1.6 Hz, 1H), 7.16−7.08 (m, 2H), 5.71 (tt, J = 56.8,
3.9 Hz, 1H), 4.10 (t, J = 5.8 Hz, 2H), 3.90 (s, 3H), 3.84 (q, J = 7.1
Hz, 1H), 1.85−1.68 (m, 4H), 1.57 (d, J = 7.2 Hz, 3H); 19F NMR
(376 MHz, CDCl3): δ −116.39 (dt, J = 56.8, 17.2 Hz, 2F); 13C{1H}
NMR (151 MHz, CDCl3): δ 174.6, 157.7, 135.6, 133.8, 129.3, 128.9,
127.2, 126.1, 125.9, 119.1, 116.7 (t, 1J(C, F) = 239.3 Hz), 105.6, 63.6,
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
2
3
55.3, 45.5, 30.7 (t, J(C, F) = 21.9 Hz), 21.4 (t, J(C, F) = 5.3 Hz),
18.4 ppm. MS (EI): 185 (100), 322 (34.12). HRMS (EI-TOF) m/z:
[M]+ calcd for C18H20F2O3, 322.1381; found, 322.1385. IR (KBr):
νmax 2973, 2938, 1633, 1606, 1485, 1392, 1231, 1178, 1061, 981 cm−1.
4,4-Difluorobutyl 2-(5H-Chromeno[2,3-b]pyridin-7-yl)-
propanoate (8). Yellow oil (X = I, 41 mg, 40%; X = Br, 67 mg,
65%). Eluent: ethyl acetate/petroleum ether (1/2), Rf = 0.4. 1H NMR
(400 MHz, CDCl3): δ 8.14 (d, J = 3.7 Hz, 1H), 7.51 (d, J = 7.1 Hz,
1H), 7.17−7.04 (m, 3H), 7.01 (t, J = 7.1 Hz, 1H), 5.78 (tt, J = 56.4,
4.0 Hz, 1H), 4.15−4.02 (m, 4H), 3.66 (q, J = 7.1 Hz, 1H), 1.88−1.67
(m, 4H), 1.47 (d, J = 7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3): δ
−118.93 (dt, J = 56.4, 16.9 Hz); 13C{1H} NMR (151 MHz, CDCl3):
δ 174.4, 158.4, 150.8, 146.7, 138.4, 135.8, 127.4, 127.2, 119.8, 119.7,
117.4, 116.6 (t, 1J(C, F) = 239.3 Hz), 115.3, 63.7, 44.8, 30.8 (t, 2J(C,
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge financial support from the
National Natural Science Foundation of China (21625206,
21632009, 21572258, and 21421002) and the Strategic
Priority Research Program of the Chinese Academy of
Sciences (XDB20000000).
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02783.
1H, 19F, and 13C NMR spectra of compounds, 2a−y and
3−8, and high-resolution mass spectrometry data of
alkyl halides and compounds 2c−d, 2f−s, 2u, 2x, 4, 6,
and 8 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Qilong Shen − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, P. R. China; orcid.org/0000-0001-5622-153X;
Email: shenql@sioc.ac.cn
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Authors
Haiwei Zhao − Key Laboratory of Organofluorine Chemistry,
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Institute of Organic Chemistry, University of Chinese
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