Trifluoromethylation of Electron-Rich Alkenyl Iodides with Fluoroform-Derived ligandless CuCF3

Article abstract of DOI:10.1021/acs.joc.8b00927

We herein present a flexible approach for the incorporation of CF₃ units into a predefined site of electron-rich alkenes that exploits the regiocontrolled introduction of an iodine handle and subsequent trifluoromethylation of the C(sp²)-I bond using fluoroform-derived ligandless CuCF₃. The broad substrate scope and functional group tolerance together with the scalability and purity of the resulting products enabled the controlled, late-stage synthesis of single regioisomers of complex CF₃-scaffolds, such as sugars, nucleosides (antivirals), and heterocycles (indoles and chromones), with potential for academic and industrial applications.

Full text of DOI:10.1021/acs.joc.8b00927

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Article
Trifluoromethylation of Electron-Rich Alkenyl
3
Iodides with Fluoroform-Derived “Ligandless” CuCF
Jordi Mestre, Anton Lishchynskyi, Sergio Castillón, and Omar Boutureira
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00927 • Publication Date (Web): 19 Jun 2018
Downloaded from http://pubs.acs.org on June 19, 2018
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Trifluoromethylation of ElectronꢀRich Alkenyl Iodides with
FluoroformꢀDerived “Ligandless” CuCF3
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Jordi Mestre,†,‡ Anton Lishchynskyi,‡ Sergio Castillón,† and Omar Boutureira*,†
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†Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili
C/Marcelꢀlí Domingo 1, 43007 Tarragona, Spain
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‡Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science
and Technology (BIST), Av. Països Catalans 16, 43007 Tarragona, Spain
*Eꢁmail: omar.boutureira@urv.cat
ABSTRACT: We herein present a flexible approach for the introduction of CF3
units into a predefined site of electronꢀrich alkenes that exploits the regiocontrolled
introduction of an iodine handle and subsequent trifluoromethylation of the C(sp2)–I
bond using fluoroformꢀderived “ligandless” CuCF3. The broad substrate scope and
functional group tolerance together with the scalability and purity of the resulting
products enabled the controlled, lateꢀstage synthesis of single regioisomers of
complex CF3ꢀscaffolds such as sugars, nucleosides (antivirals), and heterocycles
(indoles, chromones) with potential for academic and industrial applications.
INTRODUCTION
The incorporation of CF3 units into unsaturatedꢀC(sp2)1 systems (RꢀCH=CHꢀR’)
using wellꢀestablished electrophilic,2,3 radical,3,4 and metalꢀmediated3,5,6
reagents/protocols is now routine. However, the application to the regioselective
modification of ubiquitous electronꢀrich alkenes (XꢀCH=CHꢀR, X = heteroatom) and
excluding the trifluoromethylation of carbonyl compounds via silyl enol ethers or
enamines as transient, reactive intermediates,7 has received less attention (Scheme
1a). While mixtures of regioisomers are typically achieved with benzoꢀfused
heterocycles,8 modification at the more electronꢀrich position is exclusive in glycals
and nucleobases.9,10 Alternatively, the rational positioning of a reacting group (Y =
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I, B(OH)2, etc.)11 in combination with a metalꢀmediated reaction ensures specificity
via crossꢀcoupling between the C(sp2)–Y and the organometallic partner CuCF3
(Scheme 1b). However, this protocol is so far limited to few examples and certain
regioisomers, using simple, electronꢀrich benzoꢀfused heterocycles12 and “nonꢀ
electronꢀrich” (X ≠ heteroatom) vinyl13 and styryl14,15 halides. Among them, only
one report deals with the use of fluoroformꢀderived CuCF3, which confirms the
origin of CuCF3 has not been systematically investigated in such electronꢀrich
systems. Among methods6 for the preparation of CuCF3, the activation of fluoroform
(CHF3),16 a sideꢀproduct in Teflon manufacturing, by direct cupration leading to
“ligandless”17 CuCF3 has represented a key milestone in the field.14,18–20 This reagent
provides highly selective transformations overcoming current substrate,
functional/protecting group limitations (e.g. addition to carbonyls)21 and reduces
potential side reactions (e.g. hydrodehalogenation induced by either the formation of
metal(0) species and/or the release of Pꢀ or Nꢀligands from organometallic
reagents).22,23
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State of the art
(a) Substrate control
CF3
benzo-fused
heterocycles
(mixtures)
X
X
electron-deficient
position
X=O,N-PG
CF3
O
+CF3
F3C
electron-rich
position
BnO
BnO
NH
O
BnO
N
O
Expensive CF3 sources
H
Regioselectivity is substrate-controlled
Not suitable with unprotected substrates
CF3
nucleobases
glycals
(b) Early examples with a directing/reacting group
via specific
cross-coupling
CF3
CF3
1R
R
X
control by
R2
CuICF3
steering group
(Y=I, B(OH)2, etc.)
X
R1=Aryl, Alkyl
Y
access to
R
single isomers at
X=NH, S
R2=H, CO2Me, etc.
C(sp2)
Y
Limited scope
Regioselectivity is Y-controlled
benzo-fused
heterocycles
styryl & vinyl
(R1 heteroatom)
Only one work with CHF3-derived CuCF3
This Work
(c) Halogen-guided with fluoroform-derived "ligandless" CuCF3
X
CF3
X
I
via specific
cross-coupling
benzo-fused
heterocycles
diversity-oriented nucleobases
X
chemical
CuICF3
from CHF3
same core
established
methods
editing (I)
& glycals
X
X
X=O,NH, N-PG
CF3
I
Regioselectivity modulable - all regioisomers
Expanded scope with ligandless CuCF3
Low cost CF3 source
Broad substrate scope & operational simplicity
Gram scale & high functional group tolerance
Late-stage & amenable to 18F-radiolabeling
Scheme 1. Stateꢀofꢀtheꢀart trifluoromethylation of electronꢀrich alkenes (upper panel) and this work
– metalꢀmediated halogenꢀguided with fluoroformꢀderived “ligandless” CuCF3 (lower panel).
Consequently, the development of an effective, mild approach for the
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regioselective preparation of CF3ꢀcontaining electronꢀrich alkenes using this
interesting CuCF3 reagent is particularly attractive. We propose a general twoꢀstep
methodology for the selective introduction of CF3 units into a predefined position of
electronꢀrich alkenes via metalꢀmediated crossꢀcoupling with fluoroformꢀderived
“ligandless” CuCF3 (Scheme 1c). The overall transformation (from the parent, nonꢀ
halogenated electronꢀrich alkene) would allow to program the introduction of a CF3
group based on the availability of wellꢀestablished methods for the selective
introduction of iodine in both carbons and the specificity of Cuꢀmediated crossꢀ
couplings with C(sp2)–I bonds.
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RESULTS AND DISCUSSION
Optimization of the trifluoromethylation of iodoglycals. We started our study
by exploring the selective incorporation of the CF3 moiety into carbohydrate
scaffolds reacting fluoroformꢀderived “ligandless” CuCF3 reagent (CuCF3ꢀnHF)
with 2ꢀiodoglycals23 as representative examples of building blocks derived from
structurally complex natural sources. 3,4,6ꢀTriꢀOꢀbenzylꢀ2ꢀiodoꢀDꢀglucal 1a was
selected for the optimization studies (Table 1). Treatment of 1a with stabilized
CuCF3 in DMF afforded expected coupling product 2a in 57% yield after 27 h at
room temperature (Table 1, entry 1). In an attempt to improve yield, the effect of
“extra” Et3N·3HF (TREATꢀHF)16–19 was evaluated, being the addition of 0.2 “extra”
equiv optimal (81%) in terms of balance between reagent‘s reactivity and stability
(Table 1, entries 2–4). No significant differences were observed when moving from
1.2 to 2 equiv of CuCF3ꢀ0.6HF (Table 1, entries 5–7). Increasing the temperature up
to 50 ºC substantially accelerated the reaction rate (Table 1, entries 8–11). While the
use of 1.2 equiv of CuCF3ꢀ0.6HF afforded 2a in 92% yield after 5 h (Table 1, entry
8) and the same reaction with 1.6 equiv resulted in nearly quantitative yield after 13
h (Table 1, entry 9), optimal conditions with 2 equiv reduced the time to 7 h (Table
1, entry 10). The yield and stability of the final vinylꢀCF3ꢀproduct was not
compromised upon extending the reaction time from 7 to 13 h once the reaction is
completed (Table 1, entry 11). Notably, the formation of undesired byꢀproducts such
as those found in many metalꢀmediated reactions with glycals (e.g. Ferrier)24 and 2ꢀ
iodoglycals (e.g. hydrodehalogenation)23 is suppressed. These findings, together
with the fact that microwaveꢀassisted trifluoromethylation at 100 ºC (Table 1, entry
12) reduced the time to only 10 min while maintaining practical yields (81%),
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Table 1. Optimization of trifluoromethylation of 1aa
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entry CuCF3ꢀnHF
(equiv)
“Extra”
(equiv)b
T (ºC) t (h)
yield
(%)c
Et3N·3HF
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1
CuCF3 (2)d
–
rt
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5
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2
CuCF3ꢀ0.3HF (2)
CuCF3ꢀ0.6HF (2)
CuCF3ꢀ0.9HF (2)
0.1
0.2
0.3
rt
73
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rt
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rt
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CuCF3ꢀ0.6HF (1.2) 0.2
CuCF3ꢀ0.6HF (1.6) 0.2
rt
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rt
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CuCF3ꢀ0.6HF (2)
0.2
rt
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CuCF3ꢀ0.6HF (1.2) 0.2
CuCF3ꢀ0.6HF (1.6) 0.2
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100
92
9
13
7
>95
>95
>95
81
10
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12e
CuCF3ꢀ0.6HF (2)
CuCF3ꢀ0.6HF (2)
CuCF3ꢀ0.6HF (2)
0.2
0.2
0.2
13
10
aReactions were performed in a sealed NMR tube with CuCF3ꢀnHF
(up to 2 equiv) in DMF and 2ꢀiodoglucal 1a (1 equiv) unless
b
otherwise indicated. Mol Et3N·3HF/mol CuCl added to stabilized
CuCF3. cDetermined by 19F NMR of the crude reaction mixture using
1,3ꢀbis(trifluoromethyl)benzene as internal standard. dSoꢀcalled
e
stabilized CuCF3. The reaction mixture was microwave irradiated in
a sealed tube at 100 ºC for 10 min using a CEMꢀDiscover™ singleꢀ
mode synthesizer (temperature control, fixed hold time off, normal
absorption mode, 300 W).
Table 2. Trifluoromethylation of 1a using wellꢀestablished copper
systems
entry reaction conditions (equiv)
yield
(%)a,b
1
2
3
FSO2CF2CO2Me (2), CuI (2), DMF, 80 ºC, 8 h
FSO2CF2CO2Me (2), CuI (2), DMF, 100 ºC, 8 h
51(55)
84(100)c
76(92)d
TMSCF3 (2), Phen (2), CuCl (2), tBuOK (2)
DMF, 50 ºC, 24 h
4
TMSCF3 (2), CuBr (2), KF (2), 1:1 DMF/DMI
50 ºC, 20 h
31(45)e
aDetermined by 19F NMR of the crude reaction mixture using 4ꢀ
fluoroacetophenone
(entries
1
and
2)
or
1,3ꢀ
bis(trifluoromethyl)benzene (entries 3 and 4) as internal standard (see
SI for details). bConversion in round brackets. Unidentified byꢀ
c
products
detected.
dHydrodehalogenation
detected.
ePentafluoroethylation detected. Phen = 1,10ꢀphenanthroline, DMI =
1,3ꢀdimethylꢀ2ꢀimidazolidinone.
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reinforces the potential application of this strategy as
a
lateꢀstage
trifluoromethylation protocol suitable, for example, in the preparation of challenging
18Fꢀradiolabelled carbohydrates with [18F]CuCF3.25 This is further supported by the
operational simplicity of the purification step (only an aqueous extraction and/or
filtration through a short path of SiO2 was sufficient to afford 2a in highꢁpurity) (SI,
Figure S11) and the scalability of this reaction as demonstrated for 2e and 2u, which
also makes our protocol using fluoroformꢀderived “ligandless” CuCF3 amenable for
gramꢀscale applications. The identity of the resulting product was first confirmed by
MS analysis, which showed a mass shift (from 542 to 484 Da) corresponding to the
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loss of I and the addition of a single CF3 unit (ꢁmass –58 Da). As expected, H, 13C,
19
and F NMR analysis revealed the trifluoromethylation proceed at Cꢀ2. Besides the
characteristic CF3 peak at –62.6 ppm in the 19F NMR and the presence of two
2
1
quaternary centres corresponding to Cꢀ2 (q, JC,F = 30.7 Hz) and CF3 (q, JC,F
=
269.9 Hz) in the 13C NMR, 2DꢀHMBC experiments also showed key H1ꢀCꢀ2/CF3
crossꢀpeaks that unequivocally confirms the structure of 2a. Finally, the impact of
the CF3 group in the conformation of 2a was evaluated analysing the characteristic
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3
coupling constants J3,4 and J4,5 ~ 3.2 Hz. These small values are indicative of a 2ꢀ
5
substituted Dꢀglucal adopting the “inverted” H4 conformation,26 probably due to the
destabilizing 1,2ꢀallylic (A1,2) strain introduced by the bulky CF3 group (supporting
information (SI), Figures S12–15).
Comparision with other trifluoromethylation systems. Trifluoromethylation of
1a was also compared with wellꢀestablished Cuꢀmediated protocols (Table 2). The
FSO2CF2CO2Me/CuI/KF system afforded 2a in up to 84% yield upon increasing the
temperature from 50 to 100 ºC, which may compromise the stability of sensitive
substrates, as confirmed by the presence of unidentified byꢀproducts (Table 2,
entries 1 and 2).27 The in situ preparation of PhenCuCF3 gave 2a (76%), although
hydrodehalogenation was also detected (Table 2, entry 3).28 Finally, reaction with
TMSCF3/CuBr/KF29 yielded 2a (31%) after 20 h at 50 ºC together the formation of
undesired pentafluoroethyl byꢀproducts due to CuCF3 decomposition (Table 2, entry
4).30 Collectively, these results suggest a slight benefit of the “ligandless” system
used herein over traditional Cuꢀbased protocols in terms of mildness and/or reduced
byꢀproducts profile.
Substrate scope. With the optimal conditions in hand, the scope of this
transformation was evaluated with a series of haloglycals featuring representative
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protecting groups (Bn, Ac, Piv, and TIPS), multiple stereocenters/configurations (Dꢀ
gluco, Dꢀgalacto, etc.), and high degree of complexity (disaccharides) (Scheme 2).
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Scheme 2. Trifluoromethylation scope with haloglycals and control reactions. Isolated yields given
a
(see SI for details). Reactions conducted with 3,4,6ꢀtriꢀOꢀbenzyl and 3,4,6ꢀtriꢀOꢀacetylꢀ
D
ꢀglucal 4a
and 4b, respectively. bSome degradation of 1j observed. X1 and X2 refer to I, Br or H and the
superscript indicates position. NR = no reaction, Piv = pivaloyl, TIPS = triisopropylsilyl. ORTEP
drawing of 2c with thermal ellipsoids drawn at the 50% probability level (H atoms omitted for
clarity).
CF3ꢀproducts 2a–j were consistently obtained in high isolated yields and purity.
Benzyl 2ꢀiodoglycals 1a (DꢀGlc) and 1b (DꢀGal) afforded 2a and 2b in good yields
(up to 85%). Unlike protocols using nucleophilic R3SiCF3 reagents that can react
with the electrophilic C(sp2) of carbonyl moieties,21 the combination of mild
reaction conditions and specific crossꢀcoupling allowed CuCF3 to react in the
presence of acetyl and pivaloyl esters 2c–e and 2h,i (up to 93%), even in gram scale
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for 2e (93%). Diagnostic coupling constants J3,4 and J4,5 in 2ꢀCF3ꢀDꢀgalactals 2b,c
and 2e ranged from 4.3 to 3.0 Hz,26,31, indicating certain ringꢀflattening induced by
4
5
the 2ꢀCF3 (distorted between H5 and H4) as evidenced by Xꢀray analysis of 2c.32
Acidꢀsensitive isopropylidene moiety was also well tolerated in 2f (77%). Indeed,
this represents a successful example of a complex carbohydrate CF3ꢀbuilding block
that contains the core structure of important heptosides found in bacterial glycolipids
such as the epimers of 3ꢀdeoxyꢀDꢀmannoꢀ2ꢀoctulosonic acid (Kdo) and LꢀglyceroꢀDꢀ
mannoꢀheptopyranose (heptose).33
We next evaluated the reactivity (I vs. Br) and selectivity (Cꢀ1 vs. Cꢀ2) of this
transformation. 2ꢀBromoglucals 3a–c were unreactive under the conditions used for
iodides in contrast to what is observed with vinyl13 and styryl14,15 halides where both
I and Br react. Moreover, the selective introduction of I at Cꢀ1 enables access to 1ꢀ
CF3ꢀglucal 2g in 88% yield. The method also tolerates fluorideꢀlabile silyl ethers
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(TIPS) as protecting groups. Controls to further confirm the importance of I using Dꢀ
glucals 4a and 4b resulted in recovery of the starting materials. Again, no Ferrier
products were observed with neither iodoglycals nor glycals. Collectively, the
synthetic flexibility of the overall transformation has been validated with 2ꢀCF3 2a,d
and 1ꢀCF3 2g since this strategy allows the selective preparation of complementary
1ꢀ and 2ꢀCF3ꢀregioisomers from a single/commonꢀconfiguration precursor in a
diversityꢀoriented manner. Of benefit is also the smooth preparation of complex Dꢀ
lactose 2h (80%) with an acidꢀsensitive glycosidic linkage and Neu5Ac2en 2i
(85%), containing the core structure of the antiviral zanamivir (Relenza®). The fast
kinetics for 2i under very mild conditions (without “extra” TREATꢀHF, rt, 1 h),
probably due to the strongly coordinating and/or electronꢀwithdrawing ester at Cꢀ
2,19,34 and the fast product isolation (filtration through a short path of SiO2) suggests
a good potential for largeꢀscale operations.
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Finally, a key advantage of our method is the specificity of the crossꢀcoupling
between the CuCF3/C(sp2)–I pair that prevents, unlike methods using
electrophilic/radicalꢀCF3 sources, the generation of reactive glycosyl oxocarbenium
ions incompatible with many free nucleophiles (OH, NH2), which are indeed
frequent in many lateꢀstage protocols.35 Thus, trifluoromethylation of unprotected 2ꢀ
iodogalactal 1j afforded 2j albeit in 25% yield. However, the inertness of 2ꢀbromo
3c and the successful results with unprotected nucleosides 2k and 2m suggest the
reduced yield is due to the instability of the starting unprotected vinyl iodide moiety
under the conditions tested.
Derivatization of 2ꢀtrifluoromethylglycals. A second round of scaffold
elaboration further demonstrated the synthetic value of the vinylꢀCF3 motif (Scheme
3). While conventional Zemplén deacetylation afforded 2j in excellent yield (98%),
consecutive hydrogenation (10% Pd/C, 10 atm H2) and deacetylation yielded 1,5ꢀ
anhydroꢀ2ꢀCF3ꢀ2ꢀdeoxy alditol 5e (89%) as sole diastereoisomer (1C4 conformation)
as indicated by the analysis of diagnostic coupling constants and key NOE signals.
Scheme 3. Elaboration of 2e. Conditions: (a) NaOMe, MeOH, rt, 12 h, 98%; (b) H2 (10 atm), 10%
Pd/C, MeOH, rt, 72 h.
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Trifluoromethylation of iodinated nucleosides and nitrogenous bases. Having
established conditions for the efficient siteꢀselective trifluoromethylation of
iodoglycals, we next extended the scope of this approach to iodinated nucleosides
and nitrogenous bases (Scheme 4). Since CF3ꢀnucleosides are attractive antiviral
compounds, our trifluoromethylation strategy with commercially available 5ꢀ
iodonucleosides represents an interesting alternative to methods using radical
reactions (e.g. CF3SO2Na – Langlois reagent). Thus, the antiviral trifluridine 2k
(Viroptic®) used in the treatment of herpes simplex virusꢀ1 and ꢀ2 (HSVꢀ1 and ꢀ2)36
and its precursor 2l were obtained in 62% and 84% yield, respectively and 5ꢀCF3ꢀ2’ꢀ
deoxycytidine 2m, which displays activity against certain tumours37 was prepared in
a fair 71% yield. Indeed, our results are in line with classic radical strategies (62%
vs. 57% for 2k and 71 vs. 73% for 2m).10,38 Finally, our method allowed the
preparation in excellent yields (up to 97%) of the two regioisomers of trifluoroꢀ1,3ꢀ
dimethyluracil 2n,o and the rare bisꢀtrifluoromethyl derivative 2p (92%) obtained
from its diiodinated precursor 1p.
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Scheme 4. Trifluoromethylation of iodinated nucleosides and nitrogenous bases. Isolated yields
given (see SI for details). X5 and X6 refer to I or H and the superscript indicates position.
Trifluoromethylation of iodinated benzoꢀfused heterocycles. Next, the method
was extended to iodinated benzoꢀfused heterocycles (Scheme 5). Unlike that
observed with iodoglycals and nucleosides, preliminary experiments with 3ꢀ
iodoindole 1q using optimized conditions (CuCF3ꢀ0.6HF, 50 ºC) resulted in the
formation of small amounts of hydrodehalogenation products (<15%) (SI, Table S1).
Gratifyingly, this side reaction was nearly suppressed by conducting reactions at
room temperature and without the addition of “extra” TREATꢀHF. Thus, 2ꢀCF3
indole 2t (94%) and 3ꢀCF3ꢀindoles 2q–s were obtained in good yields (up to 86%)
after 2 h at room temperature regardless the electronic properties of their
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substituents (e.g. F vs. OMe). Unlike previous reactions with unprotected indoles
1q–s that proceed smoothly at room temperature, trifluoromethylation of NꢀBoc 1u
required heating up to 50 ºC to afford 2u in 87% yield (up to 95% in gram scale,
suitable for Xꢀray).32 This together with the in situ 19F NMR monitoring of the
reaction with 1q, which indicates a putative N–Cu(I) coordination, suggest this
event plays a role in the enhancement of the trifluoromethylation rate with
unprotected indoles (SI, Scheme S1). Finally, the versatility of this protocol to
access advanced heterocyclic CF3ꢀbuilding blocks was demonstrated with the
preparation of 2v (80%), a fluorinated analog containing the vitamin p core
(chromone), using 0.2 equiv of “extra” TREATꢀHF.
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Scheme 5. Trifluoromethylation of iodinated benzoꢀfused heterocycles. Isolated yields given (see SI
a
b
for details). Conducted from room temperature up to 50 ºC, 24 h. CuCF3ꢀ0.6HF, rt, 15 h. X2 and X3
refer to I or H and the superscript indicates position. Boc=tertꢀbutoxycarbonyl. ORTEP drawing of
2u with thermal ellipsoids drawn at the 50% probability level (H atoms and the minor disordered
part are omitted for clarity).
CONCLUSION
In summary, we have implemented a flexible metalꢀmediated strategy for the precise
introduction of CF3 units into a predefined position of electronꢀrich alkenes using
fluoroformꢀderived “ligandless” CuCF3. The present transformation enables the
preparation of all regioisomers by combining the possibility of selective introduction
of iodine at both carbons using wellꢀestablished methods and the specificity of the
reaction with “ligandless” CuCF3. Given the broad substrate scope (sugars,
nucleosides, and heterocycles) and functional group tolerance (including the
presence of free nucleophilic/chelating moieties) together with other “practical”
aspects such as mildness (reduced sideꢀreactions profile), scalability, and
processability (only an aqueous extraction and/or filtration through a short path of
SiO2), we expect this strategy to be broadly applicable to other homogeneous lateꢀ
stage metalꢀmediated fluorinations and crossꢀcouplings with electronꢀrich alkenes
bearing C(sp2)–I bonds in the fields of agrochemistry,39 medicinal chemistry, and
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EXPERIMENTAL SECTION
General remarks. Proton (1H NMR), carbon (13C NMR), and fluorine (19F NMR)
1
nuclear magnetic resonance spectra were recorded on a 400 MHz (for H), 100.6
9
MHz (for 13C) and 376.5 MHz (for 19F) spectrometer. Spectra were fully assigned
using COSY, HSQC, HMBC, and NOESY. All chemical shifts are quoted on the δ
scale in ppm using the residual solvent as internal standard (1H NMR: CDCl3 = 7.26,
CD3OD = 3.31 and 13C NMR: CDCl3 = 77.16, CD3OD = 49.0). Coupling constants
(J) are reported in Hz with the following splitting abbreviations: s = singlet, d =
doublet, t = triplet, q = quartet, quin = quintet, and app = apparent. Melting points
(m.p.) were determined on a melting point apparatus and are uncorrected. Infrared
(IR) spectra were recorded on a FTIR–ATR spectrophotometer. Absorption maxima
(νmax) are reported in wavenumbers (cm–1). Optical rotations were measured on a
polarimeter with a path length of 1.0 dm and are reported with implied units of 10–1
deg cm2 g–1. Concentrations (c) are given in g/100 mL. Highꢀresolution mass spectra
(HRMS) were recorded on a LC/MSD mass spectrometer with electrospray
ionization (ESI). Nominal and exact m/z values are reported in Daltons (Da). Thin
layer chromatography (TLC) was carried out using commercial aluminium backed
sheets coated with silica gel. Visualization of the silica plates was achieved using a
UV lamp (λmax = 254 nm) and/or staining with a 6% H2SO4 in EtOH or cerium
molybdate solution dip followed by heating. Flash column chromatography was
carried out using silica gel (230–400 mesh). Mobile phases are reported in relative
composition (e.g., 1:1 EtOAc/hexane v/v). HPLC grade dichloromethane (CH2Cl2)
and tetrahydrofuran (THF) were dried using standard methods, acetonitrile was dried
using activated 3Å molecular sieves, and anhydrous DMF was stored over freshly
calcined 4 Å molecular sieves in a glove box. All other solvents were used as
supplied (Analytical or HPLC grade), without prior purification. All reagents were
used as received from commercial suppliers. All reactions using anhydrous
conditions were performed using flameꢀdried apparatus under an atmosphere of
argon. Brine refers to a saturated solution of sodium chloride. Anhydrous sodium
sulfate (Na2SO4) was used as drying agent after reaction workꢀup, as indicated.
1,5ꢀAnhydroꢀ3,4,6ꢀtriꢀOꢀpivaloylꢀ2ꢀdeoxyꢀ2ꢀiodoꢀDꢀlyxoꢀhexꢀ1ꢀenitol (1c). Nꢀ
iodosuccinimide (NIS) (423 mg, 1.88 mmol) was added to a solution of 3,4,6ꢀtriꢀOꢀ
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pivaloylꢀDꢀgalactal41 (500 mg, 1.25 mmol) in 10:1 (v/v) CH3CN/H2O (22 mL) at 0 ºC.
The reaction mixture was warmed up to room temperature and stirred for 3 h. The crude
was then diluted with EtOAc and washed with saturated aqueous Na2S2O3, saturated
aqueous NaHCO3, and brine. The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was azeotropically dried
with toluene and used in the next step without further purification. The crude was
dissolved in dry CH2Cl2 (12 mL) and treated with a mixture of Ph2SO (758 mg, 3.75
mmol), 2,4,6ꢀtriꢀtertꢀbutylpyrimidine (TTBP) (932 mg, 3.75 mmol), and 4 Å molecular
sieves (0.8 g) in dry CH2Cl2 (12 mL) at –78 ºC for 30 min. Tf2O (0.25 mL, 1.5 mmol)
was then added and the reaction gradually warmed up to room temperature and stirred
for 5 h. The reaction mixture was quenched with Et3N and the solvent evaporated. The
residue was purified by column chromatography (1:20 EtOAc/hexane) to afford 1c (344
mg, 52% over two steps) as a pale yellow solid. Rf (1:9 EtOAc/hexane): 0.51; m.p: 53–
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55 ºC; [α]D +17.7 (c 9.1, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 6.72 (d, J = 1.5 Hz,
20
1H), 5.57 (dd, J = 4.4 Hz, J = 1.5 Hz, 1H), 5.46 (dd, J = 4.4 Hz, J = 2.5 Hz, 1H), 4.46–
4.43 (m, 1H), 4.26 (dd, J = 12.0 Hz, J = 8.2 Hz, 1H), 4.06 (dd, J = 12.0 Hz, J = 5.0 Hz,
1H), 1.20 (s, 9H), 1.17 (s, 9H), 1.15 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 178.0,
177.0, 176.7, 148.7, 73.3, 67.0, 64.4, 61.2, 60.4, 39.1, 39.0, 38.8, 27.3, 27.14, 27.12;
FTIR–ATR (neat, νmax) 2972, 2934, 2871, 1739, 1624, 1480, 1280, 1138, 1036; HRMS
+
(TOF ES+) m/z: [M+Na]+ Calcd for C21H33INaO7 547.1163; Found 547.1149.
1,5ꢀAnhydroꢀ3,4,6ꢀtriꢀOꢀpivaloylꢀ2ꢀdeoxyꢀ2ꢀiodoꢀDꢀarabinoꢀhexꢀ1ꢀenitol (1d). NIS
(110 mg, 0.44 mmol) was added to a solution of 3,4,6ꢀtriꢀOꢀpivaloylꢀDꢀglucal42 (110
mg, 0.28 mmol) in 10:1 (v/v) CH3CN/H2O (5.5 mL) at 0 ºC. The reaction mixture was
warmed up to room temperature and stirred for 3 h. The crude was then diluted with
EtOAc and washed with saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and
brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was azeotropically dried with toluene and used in
the next step without further purification. The crude was dissolved in dry CH2Cl2 (7
mL) and treated with a mixture of Ph2SO (190 mg, 0.92 mmol), 2,4,6ꢀtriꢀtertꢀ
butylpyrimidine (TTBP) (230 mg, 0.92 mmol), and 4 Å molecular sieves (0.5 g) in dry
CH2Cl2 (5 mL) at –78 ºC for 30 min. Tf2O (78 µL, 0.46 mmol) was then added and the
reaction gradually warmed up to room temperature and stirred for 5 h. The reaction
mixture was quenched with Et3N and the solvent evaporated. The residue was purified
by column chromatography (1:60 EtOAc/hexane) to afford 1d (15 mg, 10% over two
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steps) as a pale yellow solid. Rf (1:9 EtOAc/hexane): 0.68; m.p: 104–105 ºC; [α]D
+53.5 (c 2.5, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 1.1 Hz, 1H), 5.57–
5.55 (m, 1H), 5.27 (dd, J = 7.9 Hz, J = 5.8 Hz, 1H), 4.38 (ddd, J = 7.9 Hz, J = 5.5 Hz, J
= 2.8 Hz, 1H), 4.30 (dd, J = 12.3 Hz, J = 5.5 Hz, 1H), 4.19 (dd, J = 12.3 Hz, J = 2.8 Hz,
1H), 1.23 (s, 9H), 1.20 (s, 9H), 1.17 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 178.1,
177.3, 176.4, 149.6, 74.6, 70.6, 67.2, 67.0, 61.1, 39.2, 39.0, 38.9, 27.4, 27.2, 27.1;
FTIR–ATR (neat, νmax) 2960, 2923, 2852, 1742, 1480, 1280, 1135; HRMS (TOF ES+)
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m/z: [M+Na]+ Calcd for C21H33INaO7 547.1163; Found 547.1156.
+
1,5ꢀAnhydroꢀ3,6ꢀdiꢀOꢀacetylꢀ2ꢀdeoxyꢀ4ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀacetylꢀβꢀDꢀ
galactopyranosyl)ꢀ2ꢀiodoꢀDꢀarabinoꢀhexꢀ1ꢀenitol (1h). NIS (224 mg, 0.99 mmol) and
AgNO3 (42 mg, 0.25 mmol) were added under argon atmosphere to a solution of 3,6ꢀdiꢀ
Oꢀacetylꢀ4ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀacetylꢀβꢀDꢀgalactopyranosyl)ꢀDꢀglucal
(470
mg,
0.83 mmol) in dry CH3CN (2 mL) at room temperature. The reaction mixture was
warmed up to 80 ºC and stirred for 4 h. The crude was filtered through a short path of
Celite 545 and the solvent evaporated. The residue was purified by column
chromatography (1:1 EtOAc/hexane) to afford 1h (385 mg, 68%) as a white solid. Rf
(1:1 EtOAc/hexane): 0.25; m.p: 43–45 ºC; [α]D +5.5 (c 0.14, CHCl3); 1H NMR (400
20
MHz, CDCl3) δ 6.76 (bs, 1H), 5.59 (d, J = 4.4 Hz, 1H), 5.38 (d, J = 3.3 Hz, 1H), 5.19
(dd, J = 10.7 Hz, J = 7.8 Hz, 1H), 5.00 (dd, J = 10.7 Hz, J = 3.3 Hz, 1H), 4.62 (d, J =
7.8 Hz, 1H), 4.37–4.31 (m, 2H), 4.24 (dd, J = 12.8 Hz, J = 7.9 Hz, 1H), 4.17–4.01 (m,
2H), 4.02 (appt, J = 4.4 Hz, 1H), 4.94 (appt, J = 6.5 Hz, 1H), 2.17 (s, 3H), 2.13 (s, 3H),
2.11 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 1.98 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ
170.6, 170.5, 170.4, 170.2, 169.8, 169.3, 148.8, 101.5, 75.4, 74.2, 71.1, 71.0, 70.8, 68.9,
66.9, 65.5, 61.3, 61.2, 21.1, 20.94, 20.88, 20.83, 20.81, 20.7; FTIR–ATR (neat, νmax
)
2979, 1740, 1368, 1215, 1170, 1046; HRMS (TOF ES+) m/z: [M+NH4]+ Calcd for
C24H35INO15+ 704,1046; Found 704.1035.
Methyl
5ꢀAcetamidoꢀ4,7,8,9ꢀtetraꢀOꢀacetylꢀ2,6ꢀanhydroꢀ3,5ꢀdideoxyꢀ3ꢀiodoꢀDꢀ
glyceroꢀαꢀDꢀgalactoꢀnonꢀ2ꢀenonate (1i). NIS (105 mg, 0.47 mmol) and AgNO3 (18.3
mg, 0.107 mmol) were added under argon atmosphere to a solution of methyl 5ꢀ
acetamidoꢀ4,7,8,9ꢀtetraꢀOꢀacetylꢀ2,6ꢀanhydroꢀ3,5ꢀdideoxyꢀDꢀglyceroꢀαꢀDꢀgalactoꢀnonꢀ
2ꢀenonate (170 mg, 0.359 mmol) in dry CH3CN (2 mL) at room temperature. The
reaction mixture was warmed up to 80 ºC and stirred for 6 h. A second batch of NIS
(105 mg, 0.47 mmol) and AgNO3 (18.3 mg, 0.107 mmol) was added and the mixture
stirred at 80 ºC for 6 h. The crude was filtered through a short path of Celite 545 and
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the solvent evaporated. The residue was purified by column chromatography (4:1
20
EtOAc/hexane) to afford 1i (100 mg, 46%) as a white foam. Rf (EtOAc): 0.42; [α]D
–
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0.96 (c 6.4, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 6.30–6.21 (m, 1H), 5.68–5.62 (m,
1H), 5.47–5.41 (m, 1H), 5.25–5.17 (m, 1H), 4.54 (dd, J = 12.5 Hz, J = 2.7 Hz, 1H),
4.49–4.42 (m, 2H), 4.07 (dd, J = 12.5 Hz, J = 6.9 Hz, 1H), 3.78 (s, 3H), 2.10 (s, 3H),
2.07 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H), 1.85 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ
170.7, 170.5, 170.3, 170.1, 169.9, 161.3, 145.9, 77.0, 75.3, 73.7, 70.6, 67.1, 61.9, 52.8,
47.7, 22.9, 20.9, 20.8, 20.7, 20.6; FTIR–ATR (neat, νmax) 3274, 3058, 2956, 1739, 1662,
1535, 1436, 1370, 1210, 1029, 734; HRMS (TOF ES+) m/z: [M+Na]+ Calcd for
C20H26INNaO12+ 622.0392; Found 622.0394.
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1,5ꢀAnhydroꢀ2ꢀdeoxyꢀ2ꢀiodoꢀDꢀlyxoꢀhexꢀ1ꢀenitol (1j). 3,4,6ꢀtriꢀOꢀacetylꢀ2ꢀiodoꢀDꢀ
galactal43 1e (78 mg, 0.195 mmol) was dissolved in MeOH (2 mL) and NaOMe (8.5
mg, 0.16 mmol) was added at room temperature. The reaction mixture was stirred at the
same temperature for 5 h and neutralized with Dowex® (H+ 50WX8ꢀ200). The ion
exchanger was filtered off and washed with MeOH. The resulting solution was
concentrated under reduced pressure and the residue purified by column
chromatography (1:9 MeOH/CH2Cl2) to afford 1j (45 mg, 85%) as a white solid. Rf (1:9
20
1
MeOH/CH2Cl2): 0.13; m.p: 135–137 ºC; [α]D +31.5 (c 1.2, MeOH); H NMR (400
MHz, CD3OD) δ 6.71 (d, J = 1.5 Hz, 1H), 4.18–4.16 (m, 1H), 4.09–4.03 (m, 2H), 3.81
(dd, J = 11.6 Hz, J = 6.9 Hz, 1H), 3.74 (dd, J = 11.6 Hz, J = 5.1 Hz, 1H); 13C NMR
(100.6 MHz, CD3OD) δ 149.3, 79.6, 77.5, 69.3, 67.6, 62.0; FTIR–ATR (neat, νmax
)
3343, 2926, 1736, 1627, 1373, 1227, 1164, 1022; HRMS (TOF ES+) m/z: [M+Na]+
+
Calcd for C6H9INaO4 294.9438; Found 294.9434.
Synthesis of stabilized CuCF3 with “extra” Et3N·3HF. The fluoroformꢀderived
reagent CuCF3 stabilized with Et3N·3HF (TREATꢀHF) was prepared in a 0.1 mol scale
in DMF using the following reported procedure.16b In a glove box, CuCl (1.5 g, 15
mmol) was added to a solution of tꢀBuOK (3.54 g, 30.6 mmol) in DMF (20 mL). The
reaction mixture was stirred at room temperature for 30 min and KCl precipitated. The
solid was filtered off and washed with additional DMF (10 mL). The DMF solution was
transferred to a 3ꢀoz Fischer–Porter tube equipped with a pressure gauge, a needle
valve, and a Teflonꢀcoated magnetic stirꢀbar. The tube was sealed, brought out, and
quickly evacuated under vacuum to ~1 mm Hg. Next, fluoroform was introduced to ~50
psi at vigorous stirring followed by a rapid drop of pressure to 5–10 psi. After 5 min, a
solution of TREATꢀHF (0.83 mL, 5 mmol) in DMF (3 mL) was added under vigorous
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stirring. The tube was introduced to the glove box and unsealed. Next, the suspension
was left on standing for 1 h to allow KF to precipitate. Finally, the pale yellow
supernatant (~6 mL) was carefully separated by a syringe and the solution of CuCF3
stored at –30 ºC. At the moment of use, the concentration of the reagent (referred to as
CuCF3) was 0.34 M. CuCF3 reagents with “extra” TREATꢀHF were prepared as follows.
In a glove box, three different vials were charged with 5 mL of the CuCF3 solution and
different volumes of TREATꢀHF (purity 99%) were added to the vials. TREATꢀHF (35
µL, 0.215 mmol) to obtain CuCF3ꢀ0.3HF, TREATꢀHF (70 µL, 0.430 mmol) to obtain
CuCF3ꢀ0.6HF, and TREATꢀHF (105 µL, 0.645 mmol) to obtain CuCF3ꢀ0.9HF. All
reagents were stored at –30 ºC and left undisturbed for several hours prior to use.
Optimization experiments for the trifluoromethylation of 1a. In a glove box, the
corresponding CuCF3 TREATꢀHF reagent was added to 3,4,6ꢀtriꢀOꢀbenzylꢀ2ꢀiodoꢀDꢀ
glucal23a 1a (54 mg, 0.1 mmol) in an NMR tube. The tube was sealed, brought out of the
glove box, and 1,3ꢀbis(trifluoromethyl)benzene (internal standard; 0.05 mmol, 7.7 µL)
was added. The reaction was monitored by 19F NMR at the selected temperature and
quenched by extraction with Et2O. The solvent was evaporated under reduced pressure
and the crude analyzed by 1H NMR to determine the conversion.
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Trifluoromethylation using the FSO2CF2CO2Me/CuI system. To a flameꢀdried
Schlenk flask equipped with a magnetic stir bar was added CuI (38 mg, 0.2 mmol)
under argon. DMF (1.5 mL), FSO2CF2CO2Me (25.4 ꢀL, 0.2 mmol) and 1a (54 mg, 0.1
mmol) were consecutively added and the resulting mixture was stirred at the indicated
temperature for 8 h. 4′ꢀFluoroacetophenone (internal standard; 36.4 µL, 0.3 mmol) was
added to the crude mixture and an aliquot was transferred to an NMR tube for
quantitative 19F NMR analysis.
Trifluoromethylation using the in situ generated (Phen)CuCF3. In a glove box, to
a vial equipped with a magnetic stir bar was added CuCl (35 mg, 0.35 mmol), tBuOK
(39 mg, 0.35 mmol) phenanthroline (63 mg, 0.35 mmol) and DMF (0.7 mL). The
resulting red mixture was stirred 30 min at room temperature followed by addition of
TMSCF3 (51.7 ꢀL, 0.35 mmol). After stirring 1 h at room temperature, 1a (95 mg,
0.175 mmol) was added, the vial was capped with a rubber septum and taken out of the
glove box and the reaction mixture was heated 24 h at 50 ºC without stirring. 1,3ꢀ
Bis(trifluoromethyl)benzene (internal standard; 13.6 µL, 0.087 mmol) was added to the
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crude mixture and an aliquot was transferred to an NMR tube for quantitative F NMR
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Trifluoromethylation using the TMSCF3/KF/CuBr system. Dry KF (12 mg, 0.2
mmol) and CuBr (30 mg, 0.2 mmol) were added to a Schlenk flask and the reaction
vessel was evacuated and refilled with argon three times. DMF (0.2 mL) and 1,3ꢀ
dimethylꢀ2ꢀimidazolidinone (DMI, 0.2 mL) were then added followed by addition of
TMSCF3 (29.6 ꢀL, 0.2 mmol) at 0 ºC and the reaction mixture was stirred at this
temperature for 3 h. Then 1a (54 mg, 0.1 mmol) was added and the reaction mixture
was heated for 24 h at 50 ºC without stirring. 1,3ꢀBis(trifluoromethyl)benzene (internal
standard; 7.7 µL, 0.05 mmol) was added to the crude mixture and an aliquot was
transferred to an NMR tube for quantitative 19F NMR analysis.
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General procedure for the trifluoromethylation of electronꢀrich vinyl iodides. In
a glove box, CuCF3ꢀ0.6HF (0.34 M, 0.59 mL, 0.2 mmol) was added at room temperature
to a vial containing the corresponding vinyl iodide (0.1 mmol). The concentration of
CuCF3ꢀ0.6HF at the moment of use ranged between 0.33–0.38 M. The vial was sealed,
brought out of the glove box, and stirred at 50 ºC for 7 h. The crude was extracted with
1
Et2O, the solvent evaporated, and the crude analyzed by H NMR. The residue was
purified using chromatographic techniques.
1,5ꢁAnhydroꢁ3,4,6ꢁtriꢁOꢁbenzylꢁ2ꢁdeoxyꢁ2ꢁtrifluoromethylꢁDꢁarabinoꢁhexꢁ1ꢁenitol
(2a).9b The title compound was prepared following the general procedure above, starting
from 3,4,6ꢀtriꢀOꢀbenzylꢀ2ꢀiodoꢀDꢀglucal23a 1a (200 mg, 0.36 mmol) and CuCF3ꢀ0.6HF
(2.2 mL, 0.74 mmol). After standard workꢀup, the crude was purified by column
chromatography (1:15 EtOAc/hexane) to afford 2a (139 mg, 80%) as a colorless syrup.
20
1
Rf (1:4 EtOAc/hexane): 0.43; [α]D –11.2 (c 1.26, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 7.40–7.21 (m, 15H), 7.07 (bq, J = 1.5 Hz, 1H), 4.59–4.44 (m, 7H), 4.10 (bs,
1H), 3.90 (appt, J = 3.2 Hz, 1H), 3.78 (dd, J = 10.5 Hz, J = 6.9 Hz, 1H), 3.67 (dd, J =
10.5 Hz, J = 5.1 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 148.1 (q, J = 7.2 Hz), 137.8,
137.6, 137.4, 128.7, 128.6, 128.5, 128.4, 128.2, 128.11, 128.06, 128.0 127.9, 127.8,
125.0 (q, J = 269.9 Hz), 103.6 (q, J = 30.7 Hz), 76.5, 73.4, 72.4, 72.2, 71.2, 68.9, 71.2,
19
68.9, 67.7; F NMR (376.5 MHz, CDCl3,) δ –62.6 (s); FTIR–ATR (neat, νmax) 3030,
2866, 1667, 1497, 1454, 1323, 1213, 1109; HRMS (TOF ES+) m/z: [M+Na]+ Calcd for
+
C28H27F3NaO4 507.1754; Found 507.1752.
1,5ꢁAnhydroꢁ3,4,6ꢁtriꢁOꢁbenzylꢁ2ꢁdeoxyꢁ2ꢁtrifluoromethylꢁDꢁlyxoꢁhexꢁ1ꢁenitol (2b).9b
The title compound was prepared following the general procedure above, starting from
3,4,6ꢀtriꢀOꢀbenzylꢀ2ꢀiodoꢀDꢀgalactal23a 1b (63.4 mg, 0.12 mmol) and CuCF3ꢀ0.6HF
(0.71 mL, 0.23 mmol). After standard workꢀup, the crude was purified by column
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chromatography (1:15 EtOAc/hexane) to afford 2b (49.6 mg, 85%) as a colorless syrup.
Rf (1:4 EtOAc/hexane): 0.53; [α]D20 –20.7 (c 2.1, CH2Cl2); 1H NMR (400 MHz, CDCl3)
δ 7.40–7.21 (m, 15H), 7.07 (bq, J = 1.5 Hz, 1H), 4.59–4.44 (m, 7H), 4.10 (bs, 1H), 3.90
(appt, J = 3.2 Hz, 1H), 3.78 (dd, J = 10.5 Hz, J = 6.9 Hz, 1H), 3.67 (dd, J = 10.5 Hz, J =
13
5.1 Hz, 1H); C NMR (100.6 MHz, CDCl3) δ 147.9 (q, J = 7.1 Hz), 138.2, 138.0,
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137.7, 128.6, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 124.7 (q, J = 269.6 Hz), 104.8 (q,
J = 30.8 Hz), 76.6, 74.2, 73.5, 72.9, 72.7, 68.5, 67.8; 19F NMR (376.5 MHz, CDCl3) δ –
62.1 (s); FTIR–ATR (neat, νmax) 3063, 3031, 2867, 1662, 1497, 1454, 1326, 1211, 1108,
+
1063, 1027; HRMS (TOF ES+) m/z: [M+Na]+ Calcd for C28H27F3NaO4 507.1754;
Found 507.1750.
1,5ꢁAnhydroꢁ3,4,6ꢁtriꢁOꢁpivaloylꢁ2ꢁdeoxyꢁ2ꢁtrifluoromethylꢁDꢁlyxoꢁhexꢁ1ꢁenitol (2c).
The title compound was prepared following the general procedure above, starting from
1c (54 mg, 0.10 mmol) and CuCF3ꢀ0.6HF (0.57 mL, 0.20 mmol). After standard workꢀ
up, the crude was purified by column chromatography (1:9 EtOAc/hexane) to afford 2c
(43 mg, 92%) as a white solid. Rf (1:9 EtOAc/hexane): 0.50; m.p: 96–98 ºC; [α]D20 +6.0
(c 0.17, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.09 (bs, 1H), 5.86 (bdq, J = 4.1 Hz, J
= 0.9 Hz, 1H), 5.46 (dd, J = 4.1 Hz, J = 3.3 Hz, 1H), 4.49 (m, 1H), 4.41 (dd, J = 11.8
Hz, J = 8.9 Hz, 1H), 4.18 (dd, J = 11.8 Hz, J = 4.1 Hz, 1H), 1.22 (s, 9H), 1.21 (s, 9H),
1.20 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 178.2, 177.2, 176.8, 149.0 (q, J = 7.1
Hz), 123.8 (q, J = 271.6 Hz), 103.0 (q, J = 31.5 Hz), 74.0, 63.5, 61.3, 61.2, 39.1, 39.0,
38.9, 27.2, 27.2, 27.1; 19F NMR (376.5 MHz, CDCl3) δ –62.5 (s); FTIR–ATR (neat,
ν
max) 2975, 1738, 1666, 1481, 1280, 1111; HRMS (TOF ES+) m/z: [M+Na]+ Calcd for
+
C22H33F3NaO7 489.2071; Found 489.2072.
1,5ꢁAnhydroꢁ3,4,6ꢁtriꢁOꢁpivaloylꢁ2ꢁdeoxyꢁ2ꢁtrifluoromethylꢁDꢁarabinoꢁhexꢁ1ꢁenitol
(2d). The title compound was prepared following the general procedure above, starting
from 1d (15 mg, 0.028 mmol) and CuCF3ꢀ0.6HF (0.16 mL, 0.056 mmol). After
standard workꢀup, the crude was purified by column chromatography (1:40
EtOAc/hexane) to afford 2d (9.1 mg, 70%) as a pale yellow syrup. Rf (1:9
EtOAc/hexane): 0.57; [α]D20 –13.3 (c 0.1, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.18
(bs, 1H), 5.56 (bd, J = 3.3 Hz, 1H), 5.13 (bd, J = 3.3 Hz, 1H), 4.53–4.43 (m, 2H), 4.05
13
(dd, J = 17.6 Hz, J = 7.9 Hz, 1H), 1.23 (s, 9H), 1.20 (s, 9H), 1.19 (s, 9H); C NMR
(100.6 MHz, CDCl3) δ 178.1, 176.8, 176.6, 149.3 (q, J = 6.6 Hz), 124.0 (q, J = 271.8
19
Hz), 102.3 (q, J = 31.8 Hz), 74.6, 65.6, 61.3, 61.0, 38.98, 38.97, 38.96, 27.3, 27.0; F
NMR (376.5 MHz, CDCl3) δ –62.5 (s); FTIR–ATR (neat, νmax) 2978, 2963, 1740, 1669,
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1327, 1279, 1122; HRMS (TOF ES+) m/z: [M+Na]+ Calcd for C22H33F3NaO7
489.2071; Found 489.2092.
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1,5ꢁAnhydroꢁ3,4,6ꢁtriꢁOꢁacetylꢁ2ꢁdeoxyꢁ2ꢁtrifluoromethylꢁDꢁlyxoꢁhexꢁ1ꢁenitol (2e).9b
The title compound was prepared following the general procedure above, starting from
3,4,6ꢀtriꢀOꢀacetylꢀ2ꢀiodoꢀDꢀgalactal43 1e (1.58 g, 3.97 mmol) and CuCF3ꢀ0.6HF (20.9
mL, 7.94 mmol).. After standard workꢀup, the crude was purified by column
chromatography (1:4 EtOAc/hexane) to afford 2e (1.25 g, 93%) as a white solid. Rf (1:4
EtOAc/hexane): 0.41; m.p: 54–56 ºC; [α]D20 +23.5 (c 0.2, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.06 (bs, 1H), 5.80 (d, J = 4.3 Hz, 1H), 5.41 (dd, J = 4.3 Hz, J = 3.0 Hz, 1H),
4.43 (m, 1H), 4.34 (dd, J = 11.9 Hz, J = 8.1 Hz, 1H), 4.23 (dd, J = 11.9 Hz, J = 4.1 Hz,
1H), 2.08 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 170.5,
169.8, 169.7, 149.3 (q, J = 6.9 Hz), 123.6 (q, J = 270.0 Hz), 102.9 (q, J = 31.5 Hz),
73.8, 63.5, 61.3, 60.8, 20.7, 20.5; 19F NMR (376.5 MHz, CDCl3) δ –62.7 (s); FTIR–
ATR (neat, νmax) 2940, 1747, 1666, 1455, 1371, 1328, 1213, 1151, 1112, 1046; HRMS
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+
(TOF ES+) m/z: [M+Na]+ Calcd for C13H15F3NaO7 363.0662; Found 363.0658.
1,5ꢁAnhydroꢁ2ꢁdeoxyꢁ2ꢁtrifluoromethylꢁ3,4:6,7ꢁdiꢁOꢁisopropylideneꢁDꢁglyceroꢁDꢁ
taloꢁheptꢁ1ꢁenitol (2f). The title compound was prepared following the general
procedure
above,
starting
from
1,5ꢀanhydroꢀ2ꢀdeoxyꢀ2ꢀiodoꢀ3,4:6,7ꢀdiꢀOꢀ
isopropylideneꢀDꢀglyceroꢀDꢀtaloꢀheptꢀ1ꢀenitol23b 1f (24 mg, 0.06 mmol) and CuCF3ꢀ
0.6HF (0.34 mL, 0.12 mmol).. After standard workꢀup, the crude was purified by
column chromatography (1:8 EtOAc/hexane) to afford 2f (15 mg, 77%) as a pale
yellowish oil. Rf (1:8 EtOAc/hexane): 0.37; [α]D20 +0.55 (c 0.2, CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 6.96 (bq, J = 1.5 Hz, 1H), 4.86 (d, J = 6.2 Hz, 1H), 4.54 (dd, J = 6.2 Hz,
J = 1.0 Hz, 1H), 4.41 (ddd, J = 8.1 Hz, J = 6.1 Hz, J = 4.6 Hz, 1H), 4.13 (dd, J = 9.1 Hz,
J = 6.1 Hz, 1H), 4.08 (dd, J = 9.1 Hz, J = 4.6 Hz, 1H), 3.84 (bd, J = 8.1 Hz, 1H), 1.44
(s, 3H), 1.43 (s, 3H), 1.42 (s, 3H), 1.38 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 148.3
(q, J = 6.7 Hz), 124.6 (q, J = 270.0 Hz), 111.7, 109.9, 107.0 (appd, J = 30.5 Hz), 76.2,
73.8, 71.5, 67.0, 66.6, 29.9, 27.8, 27.0, 25.3; 19F NMR (376.5 MHz, CDCl3) δ –62.5 (s);
FTIR–ATR (neat, νmax) 2986, 2933, 2361, 2331, 1774, 1724, 1668, 1373, 1334, 1225,
1146, 1115, 1043, 993, 844; HRMS (TOF ES+) m/z: [M+Na]+ Calcd for C14H19F3NaO5
+
347.1077; Found 347.1082.
1,5ꢁAnhydroꢁ2ꢁdeoxyꢁ1ꢁtrifluoromethylꢁ3,4,6ꢁtrisꢁOꢁ(triisopropylsilyl)ꢁDꢁarabinoꢁ
hexꢁ1ꢁenitol (2g). The title compound was prepared following the general procedure
above, starting from 1ꢀiodoꢀ3,4,6ꢀtrisꢀOꢀ(triisopropylsilyl)ꢀ Dꢀglucal44 1g (74.1 mg, 0.10
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mmol) and CuCF3ꢀ0.6HF (0.57 mL, 0.20 mmol).. After standard workꢀup, the crude
was purified by column chromatography (hexane) to afford 2g (60 mg, 88%) as a glassy
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6
syrup. Rf (hexane): 0.74; [α]D –7.9 (c 0.28, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
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7
8
9
5.47 (dd, J = 5.6 Hz, 1H), 4.45–4.42 (m, 1H), 4.15 (bs, 1H), 4.09–3.86 (m, 1H), 3.99
(dd, J = 11.4 Hz, J = 7.5 Hz, 1H), 3.88 (dd, J = 11.4 Hz, J =4.8 Hz, 1H), 1.13–0.96 (m,
63H); 13C NMR (100.6 MHz, CDCl3) δ 142.0 (q, J = 35.0 Hz), 119.9 (q, J = 273.2 Hz),
100.9 (q, J = 3.7 Hz), 82.2, 69.4, 65.0, 61.4, 18.2–18.1, 12.6, 12.4, 12.1; 19F NMR
(376.5 MHz, CDCl3) δ –72.9 (s); FTIR–ATR (neat, νmax) 2944, 2867, 1735, 1463, 1370,
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+
1192, 1103, 882; HRMS (TOF ES+) m/z: [M+NH4]+ Calcd for C34H73F3NO4Si3
700.4794; Found 700.4782.
1,5ꢁAnhydroꢁ3,6ꢁdiꢁOꢁacetylꢁ2ꢁdeoxyꢁ4ꢁOꢁ(2,3,4,6ꢁtetraꢁOꢁacetylꢁβꢁDꢁ
galactopyranosyl)ꢁ2ꢁtrifluoromethylꢁDꢁarabinoꢁhexꢁ1ꢁenitol (2h).9b The title compound
was prepared following the general procedure above, starting from 1h (60.9 mg, 0.087
mmol) and CuCF3ꢀ0.6HF (0.45 mL, 0.17 mmol). The reaction mixture was stirred at 50
ºC for 16 h. After standard workꢀup, the crude was purified by column chromatography
(1:1 EtOAc/hexane) to afford 2h (44 mg, 80%) as a white solid. Rf (1:1 EtOAc/hexane):
20
0.15; m.p: 50–52 ºC; [α]D +1.9 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.13
(bq, J = 1.5 Hz, 1H), 5.59 (bs, 1H), 5.37 (dd, J = 3.6 Hz, J = 1.0 Hz, 1H), 5.18 (dd, J =
10.5 Hz, J = 7.5 Hz, 1H), 5.01 (dd, J = 10.5 Hz, J = 3.6 Hz, 1H), 4.69 (d, J = 7.5 Hz,
1H), 4.46 (m, 1H), 4.31 (dd, J = 12.0 Hz, J = 8.1 Hz, 1H), 4.18 (dd, J = 12.0 Hz, J = 4.8
Hz, 1H), 4.15 (dd, J = 11.4 Hz, J = 6.7 Hz, 1H), 4.11 (dd, J = 11.4 Hz, J = 6.5 Hz, 1H),
4.02–3.96 (m, 2H), 2.14 (s, 3H), 2.10 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H),
2.00 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 170.6, 170.5, 170.4, 170.2, 169.7, 169.2,
149.0 (q, J = 6.5 Hz), 124.2 (q, J = 271.8 Hz), 101.7, 101.1 (q, J = 31.3 Hz), 74.9, 73.2,
19
71.4, 70.9, 68.9, 67.0, 61.4, 61.3, 61.1, 20.9, 20.84, 20.78, 20.77, 20.7, 20.6; F NMR
(376.5 MHz, CDCl3) δ –64.0 (s); FTIR–ATR (neat, νmax) 2980, 1740, 1667, 1369, 1328,
+
1211, 1115, 1047, 1020; HRMS (TOF ES+) m/z: [M+Na]+ Calcd for C25H31F3NaO15
651.1507; Found 651.1509.
Methyl
5ꢁAcetamidoꢁ4,7,8,9ꢁtetraꢁOꢁacetylꢁ2,6ꢁanhydroꢁ3,5ꢁdideoxyꢁ3ꢁ
trifluoromethylꢁDꢁglyceroꢁαꢁDꢁgalactoꢁnonꢁ2ꢁenonate (2i).9b The title compound was
prepared following the general procedure above, starting from 1i (40 mg, 0.067 mmol)
and CuCF3ꢀ0.6HF (0.36 mL, 0.13 mmol). The reaction mixture was stirred at room
temperature for 1 h. After standard workꢀup, the crude was purified by column
chromatography (1:4 EtOAc/hexane) to afford 2i (30.7 mg, 85%) as a white foam. Rf
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(1:1 EtOAc/hexane): 0.23; [α]D +9.0 (c 0.62, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
5.87 (d, J = 7.5 Hz, 1H), 5.73 (d, J = 9.2 Hz, 1H), 5.48 (dd, J = 6.9 Hz, J = 2.7 Hz, 1H),
5.25 (ddd, J = 6.9 Hz, J = 6.0 Hz, J = 2.9 Hz, 1H), 4.48 (dd, J = 9.7 Hz, J = 2.7 Hz, 1H),
4.44–3.35 (m, 2H), 4.09 (dd, J = 12.5 Hz, J = 6.0 Hz, 1H), 3.86 (s, 3H), 2.11 (s, 3H),
2.08 (s, 3H), 2.04 (s, 3H), 1.92 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 170.72,
170.70, 170.6, 170.0, 169.8, 161.0, 151.2 (q, J = 3.8 Hz), 122.5 (q, J = 272.3 Hz), 104.9
(q, J = 33.0 Hz), 77.45, 69.8, 66.7, 66.2, 61.8, 53.6, 47.3, 23.2, 20.92, 20.85, 20.80,
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19
20.78; F NMR (376.5 MHz, CDCl3) δ –58.6 (s); FTIR–ATR (neat, νmax) 3273, 3060,
2961, 1746, 1663, 1540, 1370, 1208, 1131, 1008; HRMS (TOF ES+) m/z: [M+Na]+
Calcd for C21H26F3NNaO12+ 564.1299; Found 564.1307.
Deacetylation of 2e. 1,5ꢀAnhydroꢀ3,4,6ꢀtriꢀOꢀacetylꢀ2ꢀdeoxyꢀ2ꢀtrifluoromethylꢀDꢀ
lyxoꢀhexꢀ1ꢀenitol 2e (20 mg, 0.058 mmol) was dissolved in MeOH (0.5 mL) and
NaOMe (1.6 mg, 0.03 mmol) was added at room temperature. The reaction mixture was
stirred at the same temperature for 12 h and neutralized with Dowex® (H+ 50WX8ꢀ200).
The ion exchanger was filtered off and washed with MeOH. The resulting solution was
concentrated under reduced pressure to afford 2j (12.2 mg, 98%) as a white solid. Rf
20
(1:9 MeOH/CH2Cl2): 0.55; m.p: 93–95 ºC; [α]D +8.0 (c 0.1, MeOH); 1H NMR (400
MHz, CD3OD) δ 7.03 (bs, 1H), 4.46 (bdq, J = 4.4 Hz, J = 0.9 Hz, 1H), 4.08 (m, 1H),
3.99 (dd, J = 4.4 Hz, J = 2.5 Hz, 1H), 3.90 (dd, J = 12.0 Hz, J = 6.8 Hz, 1H), 3.80 (dd, J
= 12.0 Hz, J = 4.6 Hz, 1H); 13C NMR (100.6 MHz, CD3OD) δ 149.4 (q, J = 7.6 Hz),
126.4 (q, J = 269.2 Hz), 107.0 (q, J = 29.0 Hz), 80.1, 66.3, 63.4, 61.4; 19F NMR (376.5
MHz, CD3OD) δ –63.0 (s); FTIR–ATR (neat, νmax) 3537, 3349, 3185, 1669, 1346,
1214, 1103, 1040; HRMS (TOF ES+) m/z: [M+Na]+ Calcd for C7H9F3NaO4 237.0345;
+
Found 237.0341.
5ꢀTrifluoromethylꢀ2’ꢀdeoxyuridine (2k).9c To a vial containing 5ꢀiodoꢀ2’ꢀ
deoxyuridine 1k (47 mg, 0.13 mmol), three portions of CuCF3ꢀ0.6HF (0.36 mL, 0.13
mmol) was added every 2 h and stirred at 50 ºC. After 2 h from the last addition, the
residue was azeotropically dried with toluene and the crude purified by column
chromatography (1:9 MeOH/CH2Cl2) to afford 2k (23.8 mg, 62%) as a white solid. Rf
1
(4:1 EtOAc/hexane): 0.38; H NMR (400 MHz, CD3OD) δ 8.80 (bs, 1H), 6.24 (t, J =
6.2 Hz, 1H), 4.42 (m, 1H), 3.97 (m, 1H), 3.84 (dd, J = 11.9 Hz, J = 2.9 Hz, 1H), 3.75
(dd, J = 11.9 Hz, J = 2.9 Hz, 1H), 2.37 (ddd, J = 13.7 Hz, J = 6.3 Hz, J = 4.4 Hz, 1H),
2.27 (m, 1H); 13C NMR (100.6 MHz, CD3OD) δ 161.2, 151.3, 143.8 (q, J = 5.9 Hz),
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123.9 (q, J = 268.8 Hz), 105.3 (q, J = 32.9 Hz), 87.3, 87.5, 71.7, 62.1, 42.1; F NMR
(376.5 MHz, CD3OD) δ –64.5 (s).
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5ꢁTrifluoromethylꢁ3’,5’ꢁdiꢁOꢁacetylꢁ2’ꢁdeoxyuridine (2l).45 The title compound was
prepared following the general procedure above, starting from 3’,5’ꢀdiꢀOꢀacetylꢀ5ꢀiodoꢀ
2’ꢀdeoxyuridine46 1l (43 mg, 0.10 mmol) and CuCF3ꢀ0.6HF (0.55 mL, 0.20 mmol). The
reaction mixture was stirred at 50 ºC for 4 h. After standard workꢀup, the crude was
purified by column chromatography (1:30 MeOH/CH2Cl2) to afford 2l (32 mg, 84%) as
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a white solid. Rf (4:1 EtOAc/hexane): 0.38; H NMR (400 MHz, CDCl3) δ 8.08 (bs,
1H), 6.27 (dd, J = 8.1 Hz, J = 5.5 Hz, 1H), 5.23 (appdt, J = 6.2 Hz, J = 2.1 Hz, 1H),
4.42 (dd, J = 11.2 Hz, J = 2.3 Hz, 1H), 4.36–4.28 (m, 2H), 2.62 (ddd, J = 14.5 Hz, J =
5.5 Hz, J = 2.1 Hz, 1H), 2.22–2.07 (m, 7H); 13C NMR (100.6 MHz, CDCl3) δ 170.5,
170.3, 158.3, 149.4, 140.1 (q, J = 5.9 Hz), 121.8 (q, J = 269.8 Hz), 105.9 (q, J = 33.2
Hz), 86.2, 83.2, 74.1, 63.8, 38.7, 21.0, 20.6; 19F NMR (376.5 MHz, CDCl3) δ –63.5 (s).
5ꢁTrifluoromethylꢁ2’ꢁdeoxycytidine (2m).38 The title compound was prepared
following the general procedure above, starting from 5ꢀiodoꢀ2’ꢀdeoxycytidine 1m (16
mg, 0.045 mmol) and CuCF3ꢀ0.6HF (0.55 mL, 0.20 mmol). The reaction mixture was
stirred at 50 ºC for 4 h. The residue was azeotropically dried with toluene and the crude
purified by column chromatography (from 1:20 to 1:4 MeOH/CH2Cl2) to afford 2m (9.5
mg, 71%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.83 (bs, 1H), 6.19 (appt, J =
J = 5.9 Hz, 1H), 4.38 (m, 1H), 3.97 (m, 1H), 3.86 (dd, J = 12.0 Hz, J = 2.9 Hz, 1H),
3.74 (dd, J = 12.0 Hz, J = 2.9 Hz, 1H), 2.44 (ddd, J = 13.6 Hz, J = 6.3 Hz, J = 5.0 Hz,
1H), 2.21 (m, 1H); 13C NMR (100.6 MHz, CD3OD) δ 162.5, 157.0, 144.7 (q, J = 6.1
Hz), 124.7 (q, J = 268.9 Hz), 98.0 (q, J = 34.5 Hz), 89.2, 88.3, 71.1, 61.9, 42.6; 19F
NMR (376.5 MHz, CD3OD) δ –63.8 (s).
5ꢁTrifluoromethylꢁ1,3ꢁdimethyluracil (2n).47 The title compound was prepared
following the general procedure above, starting from 5ꢀiodoꢀ1,3ꢀdimethyluracil48 1n (30
mg, 0.11 mmol) and CuCF3ꢀ0.6HF (0.59 mL, 0.22 mmol). The reaction mixture was
stirred at 50 ºC for 3 h. After standard workꢀup, the crude was purified by column
1
chromatography (3:7 EtOAc/hexane) to afford 2n (21.1 mg, 92%) as a white solid. H
NMR (400 MHz, CDCl3) δ 7.68 (bs, 1H), 3.48, 3.36 (s, 6H); 13C NMR (100.6 MHz,
CDCl3) δ 158.8, 151.0, 143.2 (q, J = 5.9 Hz), 122.1 (q, J = 268.8 Hz), 104.1 (q, J = 32.9
Hz), 37.9, 28.1; 19F NMR (376.5 MHz, CDCl3) δ –63.9 (s).
6ꢁTrifluoromethylꢁ1,3ꢁdimethyluracil (2o).49 The title compound was prepared
following the general procedure above, starting from 6ꢀiodoꢀ1,3ꢀdimethyluracil48 1o (84
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mg, 0.31 mmol) and CuCF3ꢀ0.6HF (1.66 mL, 0.62 mmol). The reaction mixture was
stirred at room temperature for 5 h. After standard workꢀup, the crude was purified by
column chromatography (1:4 EtOAc/hexane) to afford 2o (63 mg, 97%) as a white
solid. 1H NMR (400 MHz, CDCl3) δ 6.22 (s, 1H), 3.49 (q, J = 1.3 Hz, 3H), 3.34 (s, 3H;
13C NMR (100.6 MHz, CDCl3) δ 161.1, 151.7, 140.6 (q, J = 34.3 Hz), 119.6 (q, J =
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275.1 Hz), 102.7 (q, J = 5.6 Hz), 32.6 (q, J = 3.6 Hz), 28.5 (CH3); F NMR (376.5
MHz, CDCl3) δ –66.0 (s).
5,6ꢁbis(Trifluoromethyl)ꢁ1,3ꢁdimethyluracil (2p). The title compound was prepared
following the general procedure above, starting from 5,6ꢀdiiodoꢀ1,3ꢀdimethyluracil48 1p
(22 mg, 0.056 mmol) and CuCF3ꢀ0.6HF (0.59 mL, 0.22 mmol). The reaction mixture
was stirred at 50 ºC for 5 h. After standard workꢀup, the crude was purified by column
chromatography (3:7 EtOAc/hexane) to afford 2p (14.3 mg, 92%) as a yellowish syrup.
1H NMR (400 MHz, CDCl3) δ 3.57 (q, J = 2.6 Hz, 3H), 3.39 (s, 3H); 13C NMR (100.6
MHz, CDCl3) δ 157.1, 150.1, 144.2 (q, J = 37.0 Hz), 121.0 (q, J = 273.5 Hz), 119.2 (q,
J = 279.6 Hz), 107.9 (q, J = 33.7 Hz), 35.8 (m), 29.0 (appd, J = 2.1 Hz); 19F NMR
(376.5 MHz, CDCl3) δ –56.53 (q, J = 14.8 Hz), –58.45 (qq, J = 14.6, J = 2.15 Hz);
FTIR–ATR (neat, νmax) 2960, 2923, 2852, 1732, 1670, 1442, 1366, 1200, 1160; HRMS
(EI) m/z: [M]+ Calcd for C8H6F6N2O2 276.0333; Found 276.0339.
+
3ꢁ(Trifluoromethyl)ꢁ1Hꢁindole (2q).12d The title compound was prepared following
the general procedure above, starting from 3ꢀiodoꢀ1Hꢀindole50 1q (37 mg, 0.15 mmol)
and CuCF3 (0.82 mL, 0.3 mmol). The reaction mixture was stirred at room temperature
for 2 h. After standard workꢀup, the crude was purified by column chromatography (1:9
1
EtOAc/hexane) to afford 2q (24 mg, 86%) as a white solid. H NMR (400 MHz,
CDCl3,) δ 8.36 (bs, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.56–7.52 (m, 1H), 7.44 (d, J = 8.1
Hz, 1H), 7.35–7.23 (m, 2H); 13C NMR (100.6 MHz, CDCl3) δ 135.9, 124.4 (q, J = 5.3
Hz), 124.3 (q, J = 265.9 Hz), 123.68, 123.66 (q, J = 2.1 Hz), 121.7, 119.6, 111.7, 107.9
19
(q, J = 36.9 Hz); F NMR (376.5 MHz, CDCl3) δ –57.4 (s); FTIR–ATR (neat, νmax
)
2940, 1747, 1666, 1455, 1371, 1328, 1213, 1151, 1112, 1046.
5ꢁMethoxyꢁ3ꢁ(trifluoromethyl)ꢁ1Hꢁindole (2r). The title compound was prepared
following the general procedure above, starting from 5ꢀmethoxyꢀ3ꢀiodoꢀ1Hꢀindole50 1r
(69 mg, 0.25 mmol) and CuCF3 (1.6 mL, 0.5 mmol). The reaction mixture was stirred at
room temperature for 2 h. After standard workꢀup, the crude was purified by column
chromatography (1:9 EtOAc/hexane) to afford 2r (40 mg, 75%) as a brownish solid.
1
M.p: 62–65 ºC; H NMR (400 MHz, CDCl3) δ 8.30 (bs, 1H), 7.51–7.48 (m, 1H), 7.31
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(d, J = 8.9 Hz, 1H), 7.17 (bs, 1H), 6.95 (dd, J = 8.9 Hz, J = 2.4 Hz, 1H), 3.88 (s, 3H);
13C NMR (100.6 MHz, CDCl3,) δ 155.4, 130.9, 124.8 (q, J = 5.2 Hz), 124.5 (q, J =
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265.9 Hz), 124.2 (q, J = 1.9 Hz), 114.4, 112.6, 107.5 (q, J = 36.8 Hz), 100.7, 55.9; F
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NMR (376.5 MHz, CDCl3) δ –57.5 (s); FTIR–ATR (neat, νmax) 3325, 2950, 2843, 1734,
1631, 1595, 1559, 1492, 1450, 1374, 1284, 1216, 1116, 1072, 993, 924, 727; HRMS
(TOF ES+) m/z: [M+H]+ Calcd for C10H9F3NO+ 216.0631; Found 216.0632.
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5ꢁFluoroꢁ3ꢁ(trifluoromethyl)ꢁ1Hꢁindole (2s). The title compound was prepared
following the general procedure above, starting from 5ꢀfluoroꢀ3ꢀiodoꢀ1Hꢀindole50 1s (26
mg, 0.1 mmol) and CuCF3 (0.56 mL, 0.2 mmol). The reaction mixture was stirred at
room temperature for 2 h. After standard workꢀup, the crude was purified by column
chromatography (1:9 EtOAc/hexane) to afford 2s (15.6 mg, 77%) as a yellowish solid.
M.p: 62–64 ºC; 1H NMR (400 MHz, CDCl3) δ 8.41 (bs, 1H), 7.59–7.55 (m, 1H), 7.44–
7.39 (m, 1H), 7.36 (dd, J = 8.9 Hz, J = 4.3 Hz, 1H), 7.06 (td, J = 9.0 Hz, J = 2.5 Hz,
1H); 13C NMR (100.6 MHz, CDCl3) δ 158.8 (d, J = 237.5 Hz), 132.4, 125.9 (q, J = 5.1
Hz), 124.2 (dq, J = 10.6 Hz, J = 2.2 Hz), 124.1 (q, J = 266.0 Hz), 112.6, 112.5 (d, J =
36.6 Hz), 108.1 (appdd, J = 37.3 Hz, J = 4.7 Hz), 104.9 (d, J = 25.0 Hz); 19F NMR
(376.5 MHz, CDCl3) δ –57.7 (s, 3F), –121.7 (td, J = 9.2 Hz, J = 4.3 Hz, 1F); FTIR–
ATR (neat, νmax) 3363, 2977, 1735, 1370, 1096, 992, 801; HRMS (TOF ES–) m/z:
[M+H]– Calcd for C9H4F4N– 202.0285; Found 202.0285.
tertꢁButylꢁ2ꢁ(trifluoromethyl)ꢁ1Hꢁindoleꢁ1ꢁcarboxylate (2t).51 The title compound was
prepared following the general procedure above, starting from tertꢀbutylꢀ2ꢀiodoꢀ1Hꢀ
indoleꢀ1ꢀcarboxylate52 1t (46 mg, 0.13 mmol) and CuCF3 (0.73 mL, 0.32 mmol). The
reaction mixture was stirred at room temperature for 16 h. After standard workꢀup, the
crude was purified by column chromatography (hexane) to afford 2t (36 mg, 94%) as a
colorless syrup. 1H NMR (400 MHz, CDCl3) δ 8.29 (bdq, J = 8.6, J = 0.8 Hz, 1H), 7.62
(d, J = 7.8 Hz, 1H), 7.49–7.42 (m, 1H), 7.33–7.27 (m, 1H), 7.14 (s, 1H), 1.68 (s, 9H);
13C NMR (100.6 MHz, CDCl3) δ 148.7, 137.8, 127.1, 127.0 (q, J = 39.2 Hz) 126.6,
123.7, 122.1, 120.9 (q, J = 267.8 Hz), 116.2, 113.6 (q, J = 5.1 Hz), 85.6, 28.0; 19F NMR
(376.5 MHz, CDCl3) δ in ppm: –58.2 (s).
tertꢁButylꢁ5ꢁfluoroꢁ3ꢁ(trifluoromethyl)ꢁ1Hꢁindoleꢁ1ꢁcarboxylate (2u). The title
compound was prepared following the general procedure above, starting from tertꢀ
butylꢀ5ꢀfluoroꢀ3ꢀiodoꢀ1Hꢀindoleꢀ1ꢀcarboxylate50 1u (1.88 g, 5.2 mmol) and CuCF3 (22
mL, 8.32 mmol). The reaction mixture was stirred 16 h at room temperature and 8 h at
50 ºC. After standard workꢀup, the crude was purified by column chromatography
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(hexane) to afford 2u (1.50 g, 95%) as a white solid. M.p: 81–83 ºC; H NMR (400
MHz, CDCl3) δ 8.13 (dd, J = 9.1 Hz, J = 4.5 Hz, 1H), 7.97 (bd, J = 1.2 Hz, 1H), 7.34–
7.28 (m, 1H), 7.10 (td, J = 9.1 Hz, J = 2.6 Hz, 1H), 1.71 (s, 9H); 13C NMR (100.6 MHz,
CDCl3) δ 159.7 (d, J = 241.2 Hz), 148.7, 131.8, 127.5 (q, J = 5.4 Hz), 126.3 (dq, J =
10.5 Hz, J = 1.8 Hz), 123.2 (q, J = 267.1 Hz), 116.8 (d, J = 9.2 Hz), 113.7 (d, J = 25.2
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Hz), 111.4 (qd, J = 37.3 Hz, J = 4.2 Hz), 105.4 (d, J = 25.2 Hz), 85.6, 28.1; F NMR
(376.5 MHz, CDCl3) δ –59.5 (s, 3F), –118.7 (m, 1F); FTIR–ATR (neat, νmax) 3133,
2982, 1739, 1454, 1371, 1251, 1138, 1093, 844; HRMS (EI) m/z: [M]+ Calcd for
+
C14H13F4NO2 303.0882; Found 303.0872.
6ꢁFluoroꢁ3ꢁ(trifluoromethyl)ꢁ4Hꢁchromenꢁ4ꢁone (2v). The title compound was
prepared following the general procedure above, starting from 6ꢀfluoroꢀ3ꢀiodoꢀ4Hꢀ
chromenꢀ4ꢀone 1v (54 mg, 0.186 mmol) and CuCF3ꢀ0.6HF (0.98 mL, 0.36 mmol). The
reaction mixture was stirred at room temperature for 15 h. After standard workꢀup, the
crude was purified by column chromatography (1:9 EtOAc/hexane) to afford 2v (34.5
1
mg, 80%) as a white solid. M.p: 80–82 ºC; H NMR (400 MHz, CDCl3) δ 8.32 (q, J =
1.3 Hz, 1H), 7.91 (dd, J = 7.9 Hz, J = 3.0 Hz, 1H), 7.55 (ddd, J = 9.2 Hz, J = 4.2 Hz, J =
0.4 Hz, 1H), 7.48 (ddd, J = 9.2 Hz, J = 7.9 Hz, J = 3.0 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3) δ 172.2, 160.3 (q, J = 249.6 Hz), 156.0 (q, J = 6.8 Hz), 152.3 (d, J = 2.1 Hz),
125.8 (d, J = 6 Hz), 123.2 (d, J = 25.5 Hz), 122.2 (q, J = 272.3 Hz), 120.7 (d, J = 8.2
19
Hz), 115.6 (appd, J = 31.1Hz), 111.3 (d, J =24.2 Hz); F NMR (376.5 MHz, CDCl3) δ
–64.5 (s, 3F), –112.7 (m, 1F); FTIR–ATR (neat, νmax) 3086, 2925, 1655, 1479, 1389,
+
1333, 1139, 1101, 961, 831, 716; HRMS (TOF ES+) m/z: [M+H]+ Calcd for C10H5F4O2
233.0220; Found 233.0217.
Hydrogenation/deacetylation of 2e. 10% Pd/C (90 mg, 0.08 mmol Pd) was added to
a solution of 2e (55 mg, 0.162 mmol) in dry and deoxygenated methanol (1mL) at room
temperature. The mixture was stirred under H2 (10 atm) at the same temperature for 72
h, filtered through a short path of Celite 545, and concentrated under reduced pressure.
The crude was redissolved in MeOH (2 mL) and NaOMe (4.32 mg, 0.08 mmol) was
added at room temperature. The reaction mixture was stirred at the same temperature for
12 h and neutralized with Dowex® (H+ 50WX8ꢀ200). The ion exchanger was filtered off
and washed with MeOH. The crude material was purified by column chromatography
(1:9 MeOH/EtOAc) to afford 1,5ꢀanhydroꢀ2ꢀdeoxyꢀ2ꢀtrifluoromethylꢀDꢀtalitol 5e (31.0
mg, 89% over two steps) as a white solid. Rf (1:9 MeOH/CH2Cl2): 0.15; m.p: 137–139
ºC; [α]D20 +49.3 (c 0.1, MeOH); 1H NMR (400 MHz, CD3OD) δ 4.81 (appt, J = 3.2 Hz,
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1H), 4.15 (dd, J = 12.7 Hz, J = 8.6 Hz, 1H), 4.03 (dd, J = 11.4 Hz, J = 10.4 Hz, 1H),
3.87 (ddd, J = 8.6 Hz, J = 6.1 Hz, J = 2.8 Hz, 1H), 3.79 (dd, J = 6.1 Hz, J = 3.2 Hz, 1H),
3.73 (dd, J = 12.7 Hz, J = 2.8 Hz, 1H), 3.64 (dd, J = 11.4 Hz, J = 4.1 Hz, 1H), 4.63–
4.56 (m, 1H); 13C NMR (100.6 MHz, CD3OD) δ 125.2 (q, J = 280.1 Hz), 79.3, 66.6,
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69.3 (q, J = 2.3 Hz), 59.1, 55.9 (q, J = 3.1 Hz), 45.8 (q, J = 25.8 Hz); F NMR (376.5
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MHz, CD3OD) δ –68.0 (d, J = 9.3 Hz); FTIR–ATR (neat, νmax) 3366, 2926, 1664, 1398,
1325, 1262, 1110, 1036; HRMS (TOF ES+) m/z: [M+Na]+ Calcd for C7H11F3NaO4
+
239.0502; Found 239.0506.
ASSOCIATED CONTENT
1
13
19
Supporting Information. H, C, and F NMR spectra for all new compounds and
additional optimization and Cu(I) coordination experiments with 3ꢀiodoindole 1q.
Xꢀray crystallographic analysis of 2c and 2u. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: omar.boutureira@urv.cat
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We thank the European Commission (Marie Curie CIG to O.B.), the Spanish
Government (CTQ2014ꢀ58664ꢀR and RYCꢀ2015ꢀ17705), the European Regional
Development Fund, and the Universitat Rovira i Virgili (Martí Franquès Research
Fellowship Programme to J.M.) for financial support. We also thank Dr. Vladimir V.
Grushin for providing the fluoroformꢀderived CuCF3 reagent and for helpful
discussions and Dr. Eddy Martin (ICIQ) for the crystallographic studies. O.B. is a
Ramón y Cajal Fellow.
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