"ligandless" Pentafluoroethylation of Unactivated (Hetero)aryl and Alkenyl Halides Enabled by the Controlled Self-Condensation of TMSCF3-Derived CuCF3

Article abstract of DOI:10.1021/acs.joc.9b02001

Pentafluoroethylation of unactivated C(sp²)-X bonds (X = I, Br) using a storable, "ligandless" CuC₂F₅ reagent prepared by controlled self-condensation of ready available TMSCF₃-derived CuCF₃ has been

Full text of DOI:10.1021/acs.joc.9b02001

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Article
“Ligandless” Pentafluoroethylation of Unactivated (Hetero)Aryl and Alkenyl
3
3
Halides Enabled by the Controlled Self-Condensation of TMSCF-Derived CuCF
Jordi Mestre, Sergio Castillón, and Omar Boutureira
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02001 • Publication Date (Web): 03 Oct 2019
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The Journal of Organic Chemistry
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“Ligandless” Pentafluoroethylation of Unactivated (Hetero)Aryl and
Alkenyl Halides Enabled by the Controlled Self‐Condensation of
TMSCF3‐Derived CuCF3
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Jordi Mestre, Sergio Castillón, and Omar Boutureira*
Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/ Marcel·lí Domingo 1, 43007 Tarra-
gona, Spain. *E-mail: omar.boutureira@urv.cat
Supporting Information Placeholder
Complex substrates
Divergent controlled synthesis & characterization
O
insertion
CuICF3
CuIC2F5
R
Br
NH
Cu=CF2
I
KF
CuBr
DMF
arenes
TMSCF3
N
O
HO
RO
RO
CuICF3
O
1:1 DMF/DMI
C2F5
O
Storable & ligandless CuC2F5
Low cost C2F5 source & scalable
Broad substratre scope (I,Br)
High functional group tolerance
OH
nucleosides
glycals
I
ABSTRACT: Pentafluoroethylation of unactivated C(sp2)–X bonds (X = I, Br) using a storable, “ligandless” CuC2F5 reagent pre-
pared by controlled self-condensation of ready available TMSCF3-derived CuCF3 has been developed. A thorough analysis by 19F
NMR and ESI–MS revealed the nature of this reagent in solution. The operational simplicity and robustness of this system enables
the efficient, late-stage incorporation of C2F5 units into a variety of (hetero)aryl and complex alkenyl halides such as glycals, nucle-
osides, and nucleobases.
Scheme 1. Syntheses of CuI-Pentafluoroethyl Reagents (up-
per panel) and This Work – Synthesis and Characterization
INTRODUCTION
In recent years, numerous reports highlight the importance of
incorporating fluorinated motifs into drug candidates to boost
their biophysical and/or pharmacological properties.1,2 Despite
the tremendous progress made in monofluorination3 and
trifluoromethylation,4 synthetic methods for the late-stage
introduction of longer perfluoroalkyl chains (Rf),5 and especially
the pentafluoroethyl motif (C2F5), remain underdeveloped. They
tyically involve nucleophilic,6 electrophilic,7 radical,8 or metal-
mediated/catalyzed transformations9,10 via the in situ generation
of Ln[CuC2F5] and subsequent cross-coupling with C(sp2)–X
bonds (X = I, Br) (Scheme 1a).10 Methods to generate CuC2F5
from C2F5-precursors use the expensive TMSC2F5,11 elevated
decarboxylation temperatures (>140 ºC) of hygroscopic
pentafluoropropionate salts (or esters),12 and the activation of
of Storable, “Ligandless” CuC2F5 by Controlled Self-
Condensation of TMSCF3-Derived CuCF3 (lower panel)
(a) Previous syntheses of CuC2F5 from C2F5-precursors
Expensive C2F5 sources
Difficult-to-handle precursors
C2F5CO2X
Harsh reaction conditions
(X=Na, K) (X=Et)
CuI, NMP CuCl, t-BuOK
>140 ºC Et3N·3HF, DMF
CuCl, t-BuOK
Et3N·3HF, DMF
CuI, KF
DMF
CuIC2F5
C2F5H
TMSC2F5
(b) Effect of ligands in trifluoromethylations with CuCF3
Stabilized CuCF3 (N- & P-ligands)
Selective trifluoromethylations
Non-stabilized CuCF3 (solvent as ligands)
Unselective perfluoroalkylations
insertionn
ArI
ArI
CuICF3
CuI(CF2)nCF3
Ar(CF2)nCF3
ArCF3
Cu=CF2
gaseous C2F5H,
hydrofluorocarbon (HFC-125).13 Moreover, the commercial
availability of CuC2F5 reagents is limited to
a
non-ozone depleting, greenhouse
(c) This work: storable, "ligandless" CuC2F5 from TMSCF3-derived CuCF3
Complex substrates
Pentafluoroethylator® [(Phen)CuC2F5]14 that is still considerably
air/moisture-sensitive and too expensive to be implemented in
large-scale operations (~83.000 $/mol).15 Alternatively, from as
early as 1986, Wiemers and Burton detected the formation of
CuC2F5 species produced after decomposition of non-stabilized
CuCF3.16 The formation of CuC2F5 and longer perfluoroalkyl
chains is widely accepted to occur by initial α-fluoride
elimination from CuCF3 and subsequent difluorocarbene
insertion into the Cu–CF3 bond to afford Cu(CF2)nCF3 species
(Scheme 1b).
insertion1
O
CuICF3
CuIC2F5
R
Br
Cu=CF2
NH
KF
I
DMF
TMSCF3
arenes
HO
CuBr
N
O
RO
RO
O
CuICF3
O
OH
nucleosides
1:1 DMF/DMI
I
glycals
Storable & ligandless CuC2F5
Low cost C2F5 source
Broad substrate scope (I,Br) & operational simplicity
Gram scale & high functional group tolerance
TMS = trimethylsilyl, NMP = N-methyl-2-pyrrolidone, DMF =
N,N-dimethylformamide, DMI = 1,3-dimethyl-2-imidazolidinone.
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Scheme 2. Synthesis and Characterization of “Ligandless” which is in the order CuCl>CuBr>CuI (Table 1, entry 2 vs. 3, 4
CuC2F5
a
1
vs. 5), promotes decomposition of CuCF3 by favoring the α-
fluoride elimination to difluorocarbene species that can insert
into Cu(CF2)nCF3 to produce Cu(CF2)n+1CF3 species (Scheme 2a
and SI, Scheme S1). To limit the production of CuC2F5, the
reaction was conducted at 0 ºC in 5:1 DMF/DMI to improve the
stability of CuCF3. Certainly, the yield of CuCF3 increased to
87% while that of CuC2F5 decreased to 8% providing an 11:1
CuCF3/CuC2F5 selectivity ratio (Table 1, entry 4). Under the
same conditions, the use of CuCl gave worse results in terms of
yield of CuCF3 (46%) with a 4.6:1 CuCF3/CuC2F5 ratio and also
afforded [Cu(CF3)4]− (Ic) in 11% yield. This can be explained
by the greater acidity of CuCl compared to CuBr (Table 1, entry
5). Using DMI and DMF/DMI mixtures with CuBr afforded
CuCF3 in 88% and 84% yield, respectively and reduced the
yield of CuC2F5 to ca. 1% (Table 1, entries 6 and 7). Finally,
after optimization (Table 1, entries 1–7), best results for CuCF3
were obtained using 1:1:1 TMSCF3/CuBr/KF system in 1:1
DMF/DMI as stabilizing solvent system at 0 ºC (Table 1, entry
8). 19F NMR showed signals at –27.3 ppm and –30.8 ppm,
typically assigned to neutral CuCF3 (Ia) and [Cu(CF3)2]– (Ib),
respectively (Scheme 2a). Since the anionic species that are
readily oxidized to [Cu(CF3)4]– (Ic) are indeed less effective
2
3
4
5
6
7
8
9
10
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towards trifluoromethylation reactions,23, a higher proportion
2
of neutral CuCF3 (Ia) is desired. While stability studies revealed
no detectable changes after storing the reagent solution at –30
ºC for at least 1.5 months, decomposition to CuC2F5 and higher
order CuRf species occurred at rt within days (Supporting
information (SI), Figure S3).
Next, we optimized this CuCF3-to-CuC2F5 conversion by
small adjustments on essential parameters (solvent, CuX, T, and
t). Thus, CuC2F5 was preferentially obtained conducting the
reaction in pure, non-deoxygenated DMF, adding a slight excess
of CuBr, and applying a gradient heating from rt to 55 ºC (Table
1, entry 9). The control of the temperature was crucial since a
too fast conversion of CuCF3 increase the yield of longer per-
fluoroalkyl CuRf species. Similarly, addition of >1.25 equiv of
CuBr also lowered the selectivity and longer perfluoroalkyl
chains were obtained. The amount of DMF was also relevant
since concentrated reaction mixtures resulted in the formation of
longer perfluoroalkyl chains and too diluted reactions slowed
down the conversion of CuCF3. The use of CuBr/TMSCF3/KF
in a 1:2:1 ratio (considering that two equivalents of CuCF3 are
required for the formation of one CuC2F5) delivered higher con-
centrations of CuCF3 and CuC3F7 presumably due to the slow
formation of CuCF3 and competing insertion of difluorometh-
ylene to CuC2F5 (Table 1, entry 10). We monitored the progress
by 19F NMR in DMF to confirm purity and selectivity, and 19F
COSY determined CF2–CF3 spin systems for each species
aSee the SI for details. BTB = 1,3-bis(trifluoromethyl)benzene.
This detrimental trifluoromethylation side reaction detected
with non-stabilized CuCF3 delivers unwanted perfluoroalkyl
byproducts.17 Although Yagupolskii18 reported the deliberate
access to CuC2F5 via decomposition of CuCF3, the resulting
organometallic species showed limited reactivity (<4% conv.)
with unactivated substrates. During the preparation of this man-
uscript,19 the controlled synthesis of a liganded CuC2F5 from
TMSCF3-derived CuCF3 was described by Hu and coworkers.20
Despite this progress, information regarding the nature of the
reagent and a broader evaluation of substrate scope focused on
using milder reaction conditions specially with more
sensitive/complex systems is still needed. To address this chal-
lenge, we envisioned a method for taming the uncontrolled gen-
eration of CuC2F5, yet balancing its stability/reactivity profile
without the necessary use of stoichiometric, conventional dative
ligands. The “ligandless”21 nature of CuRf is a key issue in late-
stage protocols since its effect in the reactivity/stability balance
of the organometallic system is often underestimated (Scheme
1c).
1
(Scheme 2b and SI, Figure S2). While H NMR only showed a
doublet (J = 7.5 Hz) at 0.22 ppm, which was assigned to TMSF,
13C{1H} NMR showed the characteristic multiplicity pattern
according to the fluoroalkyl moiety, a triplet of quartets (1J =
2
RESULTS AND DISCUSSION
285.0 Hz, J = 53.8 Hz) at 140.3 ppm and a quartet of triplets
(1J = 281.2 Hz, 2J = 29.8 Hz) at 124.2 ppm, assigned to CF2 and
CF3, respectively. Next, the nature and composition of the
complex was carefully evaluated by 19F diffusion-ordered
spectroscopy (DOSY) NMR (D = 8.06x10–10 m2 s–1 for IIa, D =
7.88x10–10 m2 s–1 for IIb) and ESI–MS (182.9213 Da for IIa
[M+H]–, 300.9168 Da for IIb [M]–) revealing the presence of
Optimization of the Synthesis and Characterization of
“Ligandless” CuC2F5. We started with the divergent preparation
of storable, “ligandless” CuCF3 and CuC2F5 reagents by pre-
generating CuCF3 from TMSCF3 (Scheme 2a and Table 1).
Although initial attempts with CuI, TMSCF3, and KF using
strong coordinating CH3CN hampered the formation of CuCF3,
the latter was smoothly afforded in 70% yield by conducting the
reaction in pure DMF (Table 1, entry 1 vs. 2). Grushin and co-
workers22 also noticed that increasing the Lewis acidity of CuX,
species with
a molecular weight compatible with the
coordination of ~3 DMF for IIa and ~2 DMF for IIb (Scheme
2b and SI, Table S1 and Figures S5–8).
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The Journal of Organic Chemistry
add Et3N·3HF to the CuCF3 and CuC2F5 reagent solutions ex-
pecting to promote precipitation of MF. After addition of the
acid, a white precipitate was instantaneously formed from both
reagents and, although the 19F NMR signals from CuC2F5 were
unchanged, CuCF3 resulted unstable under acidic conditions and
progressively evolved to CuC2F5. The solid was separated and
tried to redissolve in H2O but resulted poorly soluble and the
slurry gradually turned deep blue. Analysis by 19F NMR showed
no more signals than that from BTB, which was remarkably
broader than usual. Given that KF is highly soluble in water, the
precipitate was certainly composed of another fluoride salt. The
blue color appearance and the deterioration of the quality of the
spectra may be explained by the formation of CuII salts. Moreo-
ver, the presence of CuF2 could not be detected by 19F NMR
owing to its paramagnetic nature. Then, we presume that the
species involved in the equilibrium are those illustrated in eq. 2.
It should be noted that this equilibration is usually proposed in
recent reports27 and the composition of the species involved in
the equilibrium is related to those proposed by Vicic and co-
workers.24 Moreover, this behavior is also found in other Cu–Nu
species.28 The complexity of the system was evidenced after
observing the diversification of the species detected by 19F
NMR in different experiments and their apparent correlation
(SI, Figure S4 and Scheme S4). Thus, CuCF3 (Ia) equilibrates
with [Cu(CF3)2]− (Ib) (SI, Scheme S4a) and the same applies to
CuC2F5 (SI, Scheme S4b). Compounds CuC2F5 (IIa) and
[Cu(C2F5)2]− (IIb) are easily discernible by the difluorometh-
ylene moiety, which appears in this system at −112.8 ppm and
−117.2 ppm, respectively. Typically, the equilibrium is strongly
shifted towards the neutral organocopper reagent with, for ex-
ample, ca. 20:1 IIa/IIb ratio. Notably, after addition of
TMSCF3 and KF to a solution containing only CuC2F5, newly
formed CuCF3 was observed and meaningfully, the IIa/IIb ratio
was equilibrated to 1.2:1. Two new singlets appeared around
−30.6 ppm and −116.9 ppm (SI, Figure S4). This was also ob-
served in the following situations: (a) in intermediate stages
during conversion of CuCF3 to CuC2F5 and (b) after addition of
HF to a solution of CuCF3 and gradual formation of CuC2F5.
The common feature of these scenarios is the coexistence of
CuCF3 and CuC2F5, thus, their equilibration to give mixed
[Cu(CF3)(CF2CF3)]− (III) seems reasonable. Moreover, III
Table 1. Optimization of the Divergent Preparation of
CuCF3 and CuC2F5 from TMSCF3
a
1
2
3
4
5
6
7
8
entry solvent CuX
T
t
yield (%)b,c of CuRf
(v/v) (equiv) (ºC) (h)
d
e
CF3
C2F5
0
C3F7
1f
2
CH3CN CuI (1) rt
3
3
3
17(13)
70(44)
67(9)
0
0
0
9
DMF
DMF
CuI (1) rt
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
CuBr
rt
26
(1.25)
4
5
DMF/ CuBr
0
3
3
87(20)
8
0
0
DMI
(5:1)
(1.25)
DMF/ CuCl
0
46(5)g 10
88(26) <1
DMI
(5:1)
(1.25)
6
7
DMI
CuBr
0
0
3
3
0
0
(1.25)
DMF/ CuBr
86(20)
2
DMI
(1:1)
(1.25)
8
DMF/ CuBr
0
3
91(19) <1
0
DMI
(1:1)
(1)
9
DMF
CuBr
(1.25)
rt
→
55
33
10
0
2
87(4)
7h
10
DMF
CuBr
(0.5)
rt
→
55
74(15) 10h
aConducted in a Schlenk flask with TMSCF3 (1 equiv) and KF (1
equiv) in DMF (0.4 M) unless otherwise indicated (see the SI for
details). bAll Cu[(CF2)nCF3]m species Ia,b (n=0, m=1,2) and
c
IIa,b (n=1, m=1,2) included. Determined by 19F NMR using
1,3-bis(trifluoromethyl)benzene (BTB) as internal standard.
dYield of [Cu(CF3)2]– species (Ib, n=0, m=2) in round brackets.
eYield of [Cu(C2F5)2]– species (IIb, n=1, m=2) in round brackets.
f61% conversion of TMSCF3 determined by 19F NMR.
−
could be directly produced by the nucleophilic attack of CF3
liberated from TMSCF3/KF to neutral IIa, ultimately affecting
the initial IIa/IIb ratio (SI, Scheme S4c). The full picture can be
described as a series of comproportion/disproportion reactions.
h
g[Cu(CF3)4]– species (Ic, n=0, m=4) detected in 11% yield. The
selectivity defined as the molar ratio CuC2F5/CuC3F7 is ~10.
Optimization of the Pentafluoroethylation of 2‐
Iodoglycals. With our “ligandless” CuC2F5 in hand, we evalu-
ated its synthetic value starting with 2-iodoglycals29 as exam-
ples of complex/sensitive electron-rich alkenyl halides. 3,4,6-
Tri-O-benzyl-2-iodo-D-glucal 1a was selected for both optimi-
zation studies and comparison of Cu-mediated pentafluoroeth-
ylations (Table 2). We initially assessed the effect of the reac-
tion temperature and dilution (Table 2, entries 1–4). Raising the
temperature to 80 ºC was sufficient to afford 2a quantitatively
after 19 h, whereas moderate heating at 60 ºC provided the same
yield after 39 h (Table 2, entry 2 vs. 3). Dilution from 0.4 to
0.06 M of the CuC2F5 lowered the rate of the reaction and 2a
was afforded in 60% yield after 75 h (Table 2, entry 4). Alt-
hough traces of perfluoropropyl byproducts (3–5%) were occa-
sionally detected (19F NMR showed signals at ca. –80 ppm), the
absence of hydrodehalogenation30 and Ferrier31 side reactions
and the high purity of the crude reaction simplified isolation
steps (SI, Figure S9).
Equilibration of CuRf Species. Both monomeric compounds
CuRf and [Cu(Rf)X]− are in equilibrium with the corresponding
ionic form [Cu(Rf)2]−. The coordination sphere of neutral CuRf
species in ligand-free conditions has been mainly formulated in
the literature in two different forms: (a) MX·CuRf (metal halide
adduct), usually KBr·CuRf, and (b) LnCuRf (solvent stabilized
2
organocopper). Thus, KBr·CuRf adduct is expected to equili-
brate with ionic K+[Cu(Rf)2]− (eq. 1) whereas the solvent stabi-
lized LnCuRf will predictably equilibrate with LnCu+[Cu(Rf)2]−
(eq. 2).
To determine the presence of adducts in CuRf and the nature
of the counterion in M+[Cu(Rf)2]−, a precipitation test was per-
formed. Inspired by Grushin’s procedure for the stabilization of
CuCF3 by neutralization of t-BuOK with HF,2 we decided to
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3
2
Table 2. Optimization of Pentafluoroethylation of 1a and (t, JH,F = 2.4 Hz, 3F, CF3), −112.4 (d, JH,F = 273.6 Hz, 1F,
2
Comparison of Copper-Mediated Transformationsa
CF2a), and −113.38 (d, JH,F = 273.6 Hz, 1F, CF2b), the first as-
signed to CF3 and the other two signals to diastereotopic fluo-
rine atoms. Finally, C-1 and C-2 appeared in the 13C{1H} NMR
spectra as triplets at 149.7 ppm (3JC,F = 10.5 Hz) and 101.4 ppm
(2JC,F = 24.7 Hz), respectively, and two new quaternary carbon
signals corresponding to CF3 at 119.4 ppm (qt, 1JC,F = 286.0 Hz,
2JC,F = 39.6 Hz) and CF2 at 114.0 ppm (tq, 1JC,F = 254.9 Hz, 2JC,F
= 39.6 Hz) were also detected. Notably, the presence of C2F5
had an impact on the conformation adopted by 2-substituted-
glycals (from H5 in D-glucal to “inverted” H4 in 2a) as re-
vealed by analysis of diagnostic coupling constants J3,4 and J4,5
<2 Hz, probably due to the strong 1,2-allylic (A1,2 ) strain ob-
served with C2F5>CF3>I>H (SI, Figure S10).32
1
2
3
4
5
6
7
8
entry
1
CuC2F5
(equiv)
additive
(equiv)
T (ºC)
t (h) yield (%)b
4
5
9
TMSCF3-
derived
CuC2F5 (1.5)
–
rt
14
39
19
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
TMSCF3-
derived
CuC2F5 (1.5)
–
60
80
>95c
Comparison with Other Cu‐Systems. Next, the effect of
common ligands in Cu-mediated fluoroalkylations was ad-
dressed (Table 2, entries 5–8). Reactions in the presence of pyr-
idine, phenanthroline, bipyridine, and PPh3 ligands suffered
from very low yields (6–16%) after heating from 60 ºC to 80 ºC
for prolonged reaction times (up to 75 h in total) along with the
unproductive consumption of CuC2F5 to form C2F5H (Table 2,
entries 5–8). Finally, we also compared the performance of our
system with another “ligandless” reagent, the C2F5H-derived
CuC2F5 (Table 2, entries 9–11).13 No substantial differences
were observed when increasing from 0.33 to 0.53 equiv of
Et3N·3HF that afforded only traces of 2a. Collectively, these
3
TMSCF3-
derived
–
>95c
CuC2F5 (1.5)
4d,e
5d,e
6d,e
7d,e
8d,e
9
TMSCF3-
derived
CuC2F5 (1.5)
–
60 → 80 75
60 → 80 75
60 → 80 75
60 → 80 75
60 → 80 75
60(90)f
6(>98)f,g
TMSCF3-
derived
CuC2F5 (1.5)
Py (40)
Phen (1.5)
Bipy (1.5)
TMSCF3-
derived
CuC2F5 (1.5)
11(>98)f,g results suggest that our “ligandless” system performs better over
traditional Cu-based systems, especially with sensitive sub-
strates.
TMSCF3-
derived
CuC2F5 (1.5)
16(77)f,g
Substrate Scope. With the optimal conditions in hand, the
scope of this reaction was evaluated with a series of differently
protected (Bn, Ac, and Piv) 2-iodoglycals of different configu-
TMSCF3-
derived
CuC2F5 (1.5)
Phen (1.5)
PPh3 (1.5)
6(78)f,g
<5
rations (D-gluco, D-galacto) including disaccharides with acid-
labile linkages (D-lactose) and Neu5Ac2en, analog of the antivi-
ral zanamivir (Relenza®) (Scheme 3). All afforded pure C2F5-
derivatives 2a–f in high isolated yields (up to 97%, 92% in
gram scale for 2a). We next studied the scope with other elec-
tron-rich iodinated scaffolds (Scheme 3). Thus, the C2F5-analog
2g of the antiviral trifluridine33 (Viroptic®) was obtained in 79%
yield after only 6 h at 60 ºC in contrast to previous low-yielding
protocols based on radical perfluoroalkylations with
RfCO2H/XeF234 or Cu-mediated systems (Cu/C2F5I/HMPA).35 6-
C2F5-Pyrimidine derivative 2h (80%) was nicely obtained under
even milder conditions (50 ºC, 6 h), probably due to the facili-
tated oxidative addition at the more electron-deficient C-6 posi-
tion. Next, the regioselective preintroduction of iodine at elec-
tronically different positions (C-2 vs. C-3) enabled the selective
preparation of isomeric C2F5-indoles 2i (86%) and 2j (86%)
under very mild conditions (40−50 ºC), which provides a syn-
thetic alternative to perfluoroalkyl indoles obtained by cycliza-
tion of fluorinated building blocks.36 Of note is the fact that our
system is amenable to free OH and NH groups as demonstrated
with 2g and 2i. Finally, similar to 1a (Table 2, entries 9–11),
reactions of C2F5H-derived “ligandless” CuC2F5 with 1g and 1j
were unsuccessful at 60 ºC and only decomposition was ob-
served using excess of Et3N·3HF and higher temperatures. The
high performance of our system towards electron-rich
alkenyl/heterocyclic iodides prompted us to evaluate its reac-
tivity with aryl and heteroaryl iodides along with the more chal-
lenging bromides (Scheme 4). Thus, a series of p-substituted
aryl iodides and bromides afforded C2F5-derivatives 2k–p in
good yields (up to >98%) after 48 h at 60 ºC (X = I) and 90 ºC
(X = Br) regardless their electronic properties.
C2F5H-
derived
CuC2F5 (2)
Et3N·3HF
(0.33)h
60
60
60
24
24
24
10
11
C2F5H-
derived
CuC2F5 (2)
Et3N·3HF
(0.43)h
<5
C2F5H-
derived
Et3N·3HF
(0.53)h
<5i
CuC2F5 (2)
aConducted in a Schlenk flask with 1a (1 equiv) and CuC2F5 (1.5–2
equiv) in DMF (0.4 M for TMSCF3-derived and 0.7 M for C2F5H-
derived CuC2F5) unless otherwise indicated (see the SI for details).
bDetermined by 19F NMR using 1,3-bis(trifluoromethyl)benzene
c
(BTB) as internal standard. Isolated yields. dConducted in DMF
(0.06 M). e68 h at 60 ºC, 7 h at 80 ºC. fConversion of CuC2F5 indicat-
ed in round brackets. gDecomposition to C2F5H detected. hMol
i
Et3N·3HF/mol CuCl. Unidentified decomposition byproducts de-
tected after 40 h. Py = pyridine, Phen = 1,10-phenanthroline, Bipy =
2,2’-Bipyridine.
Identification and Conformational Analysis of 2a. While
2a was initially identified by ESI–MS analysis (I→C2F5, Δmass
1
−8 Da), H, 13C{1H}, and 19F NMR unequivocally proved the
introduction of the C2F5 unit at C-2. H-1 was shifted downfield
from 6.74 ppm in 1a to 7.02 ppm in 2a. Moreover, the 19F NMR
spectrum showed the appearance of three new signals at −84.4
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The Journal of Organic Chemistry
Scheme 3. Pentafluoroethylation of Electron-Rich Alkenyl Scheme 4. Pentafluoroethylation of Aryl and Heteroaryl
and Heterocyclic Iodidesa
Halidesa
1
2
3
4
5
O
O
N
RO
RO
RO
R1
R1
O
O
O
RO
N
N
I
F5C2
HO
O
C2F5
CuC2F5
DMF, 60 ºC
40 h
I
N
O
C2F5
HO
R2
R2
O
I
6
7
OH
OH
N
R3
N
R3
1a
j
2a j
8
9
O
BnO OBn
O
BnO
BnO
BnO
RO
RO
RO
F5C2
HO
O
O
NH
BnO
N
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
C2F5
2a, 96% (0.1 mmol scale)
92% (2.1 mmol scale)
<5% from C2F5H-derived CuC2F5
C2F5
C2F5
2d, 95%
O
2b, 97% (R=Ac)
2c, 95% (R=Piv)
OH
2g, 79% (6 h)
<5% from C2F5H-
derived CuC2F5
Trifluridine analog
(antiviral)
OAc
O
AcO
AcO
AcO AcO
AcO
O
H
O
CO2Me
C2F5
O
AcO
OAc
AcO
AcHN
O
N
C2F5
C2F5
2e, 89% (48 h)
OAc
2f, 95%
Zanamivir core
(antiviral)
F
F5C2
N
O
C2F5
N
N
aConducted in an NMR tube with 2k–v (1 equiv) and “ligandless”
CuC2F5 (1.5 equiv) in DMF (0.4 M) unless otherwise indicated. All
yields were determined by 19F NMR using 1,4-difluorobenzene (for
2k) or 1,3-bis(trifluoromethyl)benzene (for 2l–v) as internal stand-
ard. Deviation from standard conditions indicated in round brackets
(see the SI for details).
H
2h, 80% (50 ºC, 6 h)
Boc
2j, 86% (40 ºC, 16 h)
<5% from C2F5H-derived CuC2F5
2i, 86% (50 ºC, 6 h)
aConducted in a Schlenk flask with 1a–j (1 equiv) and “ligandless”
CuC2F5 (1.5 equiv) in DMF (0.4 M) unless otherwise indicated.
Isolated yields given. Deviation from standard conditions indicated
in round brackets. Reactions using C2F5H-derived CuC2F5 (2 equiv)
stabilized with Et3N·3HF (0.33–0.53 mol Et3N·3HF/mol CuCl) in
DMF (0.7 M) were conducted at 60 ºC, 24 h (see the SI for details).
Color code; electron-rich position (blue) and electron-deficient
(green). Piv = pivaloyl, Boc = tert-butoxycarbonyl.
EXPERIMENTAL SECTION
General Remarks. Proton (1H NMR), carbon (13C NMR),
and fluorine (19F NMR) nuclear magnetic resonance spectra
were recorded on a 400 MHz (for 1H), 100.6 MHz (for 13C) and
376.5 MHz (for 19F) spectrometer. Spectra were fully assigned
using COSY, HSQC, HMBC, and NOESY. Fluorine diffusion-
ordered spectroscopy (19F DOSY) experiments were recorded at
300 K operating at a proton frequency of 500.13 MHz using a 5
mm PBBO gradient probe. 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 = appar-
ent. Melting points (m.p.) were determined on a melting point
apparatus and are uncorrected. Infrared (IR) spectra were rec-
orded 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. Concen-
trations (c) are given in g/100 mL. High-resolution mass spectra
(HRMS) were recorded on a LC/MSD mass spectrometer with
electrospray ionization (ESI) or a GC/MSD apparatus with elec-
tronic impact ionization (EI, 70 eV). Nominal and exact m/z
values are reported in Daltons (Da). MS spectra of organometal-
lic complexes were acquired both in positive and negative ioni-
zation with a 6550-qTOF. 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 fol-
lowed 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). All rea-
gents and solvents (Analytical or HPLC grade) were used as
received from commercial suppliers. All reactions using anhy-
o-Isomers 2q–s also provided the expected products in nearly
quantitative yields under mild reaction conditions for both I and
Br, including the example of 2r (X = Br, >98%, rt, 48 h) in
which the so-called ortho-effect22 may be operative. Finally,
reaction with activated pyridines afforded 2u (X = Br, >98%)
and 2v (X = Br, 83%), including an example with a chloride that
yielded the same 2-C2F5-pyridine 2v in a fair 67% yield after 48
h at 120 ºC.
CONCLUSIONS
In summary, we have developed a selective method for the
preparation of a storable, “ligandless” CuC2F5 reagent from
ready available CuCF3. Evaluation of the nature and composi-
tion of this reagent in solution provided evidence of the species
involved in the subsequent cross-coupling reaction. Its high
reactivity enabled the efficient pentafluoroethylation of chal-
lenging alkenyl iodides and unactivated (hetero)aryl halides,
including ready available bromides (and an example with a 2-
Cl-pyridine). Collectively, our complex proves particularly ef-
fective for the late-stage incorporation of C2F5 units into com-
plex/sensitive products including sugars, nucleosides, and ni-
trogenous bases, along with the more robust (hetero)arenes
compared to other CuC2F5 systems bearing dative ligands.
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The Journal of Organic Chemistry
Page 6 of 11
drous conditions were performed using flame-dried apparatus and CuC2F5 (0.4 M in DMF, 10.3 mL, 4.14 mmol). After 40 h at
under an atmosphere of argon. Brine refers to a saturated solu- 60 ºC, standard workup and filtration through a short path of
tion of sodium chloride. Anhydrous sodium sulfate (Na2SO4) SiO2 (1:9 EtOAc/hexane) afforded 2a (1.024 g, 92%) as a color-
was used as drying agent after reaction work-up, as indicated. less syrup.
1
2
3
4
5
6
7
8
CuBr was stirred overnight under argon with an excess of gla-
cial acetic acid, and after filtration, the solid was washed with
1,5-Anhydro-3,4,6-tri-O-acetyl-2-deoxy-2-pentafluoroethyl-
D-arabino-hex-1-enitol (2b). The title compound was prepared
absolute ethanol, dry diethyl ether (Et2O), and the white CuBr
following the general procedure above, starting from 3,4,6-tri-
O-acetyl-2-iodo-D-glucal 1b29 (40 mg, 0.1 mmol) and CuC2F5
(0.4 M in DMF, 0.48 mL, 0.2 mmol). After 40 h at 60 ºC, stand-
was dried under vacuum at 60 ºC for at least 8 h and stored un-
der argon.
Preparation of “Ligandless” TMSCF3-Derived CuC2F5. ard workup and filtration through a short path of SiO2 (3:7
KF (1 mmol) and CuBr (1.25 mmol) were dried under vacuum EtOAc/hexane) afforded 2b (37.9 mg, 97%) as a colorless syr-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
overnight at 150 ºC and 80 ºC, respectively. The solids and a up. Rf (3:7 EtOAc/hexane): 0.38; [α]D –14.4 (c 0.25, CH2Cl2);
magnetic stir bar were added into a two-neck round-bottom 1H NMR (400 MHz, CDCl3) δ 7.12 (bt, J = 1.4 Hz, 1H), 4.50–
flask with PTFE stopcock and the system was evacuated under 5.47 (m, 1H), 5.14 (appt, J = 2.9 Hz, 1H), 4.60–4.54 (m, 1H),
vacuum and refilled with argon three times. Dry DMF (0.4 M) 4.45 (dd, J = 11.9 Hz, J = 7.8 Hz, 1H), 4.19 (dd, J = 11.9 Hz, J
was added under argon and the mixture vigorously stirred for 10 = 4.7 Hz, 1H), 2.09 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H); 13C{1H}
min. TMSCF3 (1 mmol) was slowly added via a syringe under NMR (100.6 MHz, CDCl3) δ 170.4, 169.3, 169.2, 151.3 (t, J =
argon while the reaction mixture was stirred at room tempera- 10.3 Hz), 119.0 (qt, J = 286.3 Hz, J = 40.4), 113.1 (tq, J = 252.6
ture. Next, the mixture was gradually warmed up to 55 ºC until Hz, J = 39.1 Hz), 99.8 (t, J = 24.3 Hz), 74.3, 65.4, 61.0, 60.7,
the
reaction
was
complete
(ca.
33
h).
1,3- 20.8, 20.8, 20.7; 19F NMR (376.5 MHz, CDCl3) δ –84.8 (t, J =
Bis(trifluoromethyl)benzene (BTB, 0.5 mmol) was added as 2.6 Hz, 3F), –113.4 (d, J = 276.0 Hz, 1F), –114.6 (d, J = 276.0
internal standard. After mixing well the components, the stirring Hz, 1F); FTIR–ATR (neat, νmax) 2965, 1746, 1655, 1371, 1196,
was stopped and the reaction was left undisturbed until all solids 1077, 1024, 906; HRMS (TOF ES+) m/z: [M+Na]+ Calcd for
settled on the bottom of the flask. An aliquot (0.7 mL) of the C14H15F5NaO7+ 413.0630; Found 413.0634.
supernatant was transferred under argon to a NMR tube for
1,5-Anhydro-3,4,6-tri-O-pivaloyl-2-deoxy-2-
pentafluoroethyl-D-arabino-hex-1-enitol (2c). The title com-
quantitative 19F NMR analysis.
General Procedure for the Pentafluoroethylation of Un- pound was prepared following the general procedure above,
activated (Hetero)aryl and Alkenyl halides. A Schlenk flask starting from 3,4,6-tri-O-pivaloyl-2-iodo-D-glucal 1c32 (23 mg,
charged with the corresponding (hetero)aryl/alkenyl halide 0.043 mmol) and CuC2F5 (0.4 M in DMF, 0.23 mL, 0.088
(0.1–0.17 mmol) was purged and backfilled with argon three mmol). After 40 h at 60 ºC, standard workup and filtration
times. TMSCF3-derived CuC2F5 solution (0.4 M, 0.15–0.26 through a short path of SiO2 (1:9 EtOAc/hexane) afforded 2c
mmol) and 1,3-bis(trifluoromethyl)benzene (BTB, 0.05–0.08 (21.5 mg, 95%) as a colorless syrup. Rf (1:9 EtOAc/hexane):
20
mmol) were sequentially added under argon and the Schlenk 0.36; [α]D –16.4 (c 1.13, CH2Cl2); 1H NMR (400 MHz,
flask was capped with a rubber septum. The reaction mixture CDCl3) δ 7.14 (bd, J = 1.9 Hz, 1H), 5.45 (bs, 1H), 5.08 (m, 1H),
was heated in a silicon oil bath at the indicated temperature and 4.60–4.51 (m, 2H), 4.06 (dd, J = 9.9 Hz, J = 2.2 Hz, 1H), 1.22
monitored by 19F NMR for quantitative analysis. The reaction (s, 9H), 1.21 (s, 9H), 1.18 (s, 9H); 13C{1H} NMR (100.6 MHz,
crude was extracted with Et2O, the solvent evaporated, support- CDCl3) δ 178.2, 176.7, 176.6, 151.2 (t, J = 10.8 Hz), 99.6 (dd, J
ed on SiO2 and filtrated through a short path of SiO2.
= 25.7, J = 22.75 Hz), 74.27, 65.14, 61.27, 60.64, 39.0, 39.0,
38.9, 27.3, 27.0, 27.0; 19F NMR (376.5 MHz, CDCl3) δ –84.70
(t, J = 2.3 Hz, 3F), –112.9 (d, J = 275.8 Hz, 1F), –114.8 (d, J =
275.8 Hz, 1F); FTIR–ATR (neat, νmax) 2975, 2936, 2875, 1737,
1657, 1481, 1278, 1201, 1115, 1031, 800; HRMS (TOF ES+)
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-pentafluoroethyl-
D-arabino-hex-1-enitol (2a). The title compound was prepared
following the general procedure above, starting from 3,4,6-tri-
O-benzyl-2-iodo-D-glucal 1a29 (57 mg, 0.105 mmol) and
CuC2F5 (0.4 M in DMF, 0.5 mL, 0.22 mmol). After 39 h at 60
ºC, standard workup and filtration through a short path of SiO2
+
m/z: [M+Na]+ Calcd for C23H33F5NaO7 539.2039; Found
539.2047.
(1:9 EtOAc/hexane) afforded 2a (54 mg, 96%) as a colorless
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-pentafluoroethyl-
20
syrup. Rf (1:9 EtOAc/hexane): 0.33; [α]D –21.9 (c 0.75, D-lyxo-hex-1-enitol (2d). The title compound was prepared fol-
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.41–7.17 (m, 15H), lowing the general procedure above, starting from 3,4,6-tri-O-
7.02 (bs, 1H), 4.64–4.57 (m, 1H), 4.56–4.38 (m, 6H), 4.02 (bs, benzyl-2-iodo-D-galactal 1d29 (43 mg, 0.079 mmol) and CuC2F5
1H), 3.87 (bs, 1H), 3.78 (dd, J = 10.4 Hz, J = 7.4 Hz, 1H), 3.63 (0.4 M in DMF, 0.37 mL, 0.16 mmol). After 40 h at 60 ºC,
(dd, J = 10.4 Hz, J = 5.5 Hz, 1H); 13C{1H} NMR (100.6 MHz, standard workup and filtration through a short path of SiO2 (1:9
CDCl3) δ 149.7 (t, J = 10.5 Hz), 137.8, 137.5, 137.4, 128.7, EtOAc/hexane) afforded 2d (40 mg, 95%) as a colorless syrup.
20
1
128.5, 128.2, 128.1, 128.0, 127.9, 127.9, 127.8, 119.4 (qt, J = Rf (1:4 EtOAc/hexane): 0.39; [α]D –56.4 (c 0.22, CH2Cl2); H
286.0 Hz, J = 39.6 Hz), 114.0 (tq, J = 254.9 Hz, J = 39.6 Hz), NMR (400 MHz, CDCl3) δ 7.40–7.22 (m, 15H), 6.86 (bs, 1H),
101.4 (t, J = 24.7 Hz), 76.5, 73.4, 72.2, 71.7, 70.3, 67.8, 67.8; 4.84–4.41 (m, 7H), 4.24 (bd, J = 2.6 Hz, 1H), 4.05–3.94 (m,
19F NMR (376.5 MHz, CDCl3) δ –84.4 (t, J = 2.8 Hz, 3F), – 2H), 3.90 (dd, J = 11.7 Hz, J = 2.0 Hz, 1H); 13C{1H} NMR
112.4 (d, J = 273.6 Hz, 1F), –113.38 (d, J = 273.6 Hz, 1F); (100.6 MHz, CDCl3) δ 149.4 (t, J = 10.5 Hz), 138.3, 138.0,
FTIR–ATR (neat, νmax) 3032, 2923, 2855, 1656, 1455, 1198, 137.4, 128.7, 128.5, 128.3, 128.2, 128.1, 127.9, 127.8, 127.7,
1069, 1027, 800, 736, 696; HRMS (TOF ES+) m/z: [M+Na]+ 127.6, 119.2 (qt, J = 286.4 Hz, J = 41.1 Hz), 113.6 (tq, J =
Calcd for C29H27F5NaO4+ 557.1722; Found 557.1724.
252.6 Hz, J = 38.8 Hz), 102.9 (t, J = 23.7 Hz), 76.4, 73.4, 73.4,
73.5, 72.4, 67.8, 67.8; 19F NMR (376.5 MHz, CDCl3) δ –84.5
(bs, 3F), –111.6 (d, J = 274.0 Hz, 1F), –112.8 (d, J = 274.0 Hz,
1F); FTIR–ATR (neat, νmax) 3064, 3032, 2920, 2865, 1773,
Large Scale Preparation of 2a. The title compound was
prepared following the general procedure above, starting from
3,4,6-tri-O-benzyl-2-iodo-D-glucal 1a29 (1.125 g, 2.074 mmol)
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Page 7 of 11
The Journal of Organic Chemistry
1724, 1651, 1455, 1196, 1071, 735, 697; HRMS (TOF ES+) 11.8 Hz, J = 2.5 Hz, 1H), 3.74 (d, J = 11.8 Hz, J = 2.5 Hz, 1H),
+
m/z: [M+Na]+ Calcd for C29H27F5NaO4 557.1722; Found 2.45 (m, 1H), 2.27 (m, 1H); 13C{1H} NMR (100.6 MHz,
1
2
3
4
5
557.1724.
CD3OD) δ 160.9, 151.3, 145.9 (t, J = 9.4 Hz), 120.5 (appdt, J =
285.0 Hz, 37.7 Hz), 103.0 (bs), 89.4, 87.7, 71.8, 62.1, 42.3; 19F
NMR (376.5 MHz, CD3OD) δ –85.6 (bs, 3F), –114.4 (m, 2F).
1,5-Anhydro-3,6-di-O-acetyl-2-deoxy-4-O-(2,3,4,6-tetra-O-
acetyl-β-D-galactopyranosyl)-2-pentafluoroethyl-D-arabino-
hex-1-enitol (2e). The title compound was prepared following
6-Pentafluoroethyl-1,3-dimethyluracil (2h). The title com-
the general procedure above, starting from 3,6-di-O-acetyl-2- pound was prepared following the general procedure above,
iodo-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-D-glucal starting from 6-iodo-1,3-dimethyluracil 1h38 (30.8 mg, 0.116
1e32 (59 mg, 0.086 mmol) and CuC2F5 (0.4 M in DMF, 0.39 mL, mmol) and CuC2F5 (0.4 M in DMF, 0.56 mL, 0.23 mmol). After
0.17 mmol). After 48 h at 60 ºC, standard workup and filtration 6 h at 50 ºC, standard workup and filtration through a short path
through a short path of SiO2 (1:1 EtOAc/hexane) afforded 2e of SiO2 (1:9 EtOAc/hexane) afforded 2h (24 mg, 80%) as a
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(52 mg, 89%) as a colorless syrup. Rf (1:1 EtOAc/hexane): colorless syrup. Rf (1:9 EtOAc/hexane): 0.16; H NMR (400
0.25; [α]D20 +4.6 (c 1.02, CHCl3); 1H NMR (400 MHz, CDCl3) δ MHz, CDCl3) δ 6.20 (s, 1H), 3.52 (t, J = 2.2 Hz, 3H), 3.38 (s,
7.09 (bs, 1H), 5.73 (bs, 1H), 5.37 (d, J = 3.4 Hz, J = 1.0 Hz, 3H); 13C{1H} NMR (100.6 MHz, CDCl3) δ 160.9, 152.0, 139.9
1H), 5.17 (dd, J = 10.4 Hz, J = 7.9 Hz, 1H), 5.01 (dd, J = 10.4 (t, J = 24.3 Hz), 118.2 (qt, J = 287.1 Hz, J = 40.1 Hz), 110.8 (tq,
Hz, J = 3.4 Hz, 1H), 4.70 (d, J = 7.9 Hz, 1H), 4.53–4.47 (m, J = 259.4 Hz, J = 40.1 Hz), 105.5 (t, J = 8.1 Hz), 33.6 (m), 28.7;
1H), 4.32 (dd, J = 12.0 Hz, J = 8.4 Hz, 1H), 4.21–4.07 (m, 3H), 19F NMR (376.5 MHz, CDCl3) δ –81.6 (bs, 3F), –111.4 (m, 2F);
4.02–3.97 (m, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 2.03 (s, 6H), 2.02 FTIR–ATR (neat, νmax) 3110, 2960, 2917, 1849, 1719, 1667,
(s, 3H), 1.97 (s, 3H); 13C{1H} NMR (100.6 MHz, CDCl3) δ 1440, 1369, 1200, 1146, 1078, 998, 938, 831, 744; HRMS
170.6, 170.5, 170.4, 170.2, 169.6, 169.2, 150.8 (t, J = 10.2 Hz), (QTOF EI+) m/z: [M]+ Calcd for C8H7F5N2O2+ 258.0428; Found
119.0 (qt, J = 286.6 Hz, J = 40.4 Hz), 113.2 (tq, J = 253.9 Hz, J 258.0430.
2-(Pentafluoroethyl)-1H-indole (2i).39 The title compound
was prepared following the general procedure above, starting
from 2-iodoindole 1i40 (26 mg, 0.107 mmol) and CuC2F5 (0.4 M
in DMF, 0.52 mL, 0.22 mmol). After 6 h at 50 ºC standard
workup and filtration through a short path of SiO2 (1:9
EtOAc/hexane) afforded 2i (21.5 mg, 86%) as a white solid. Rf
= 40.4 Hz), 101.7, 99.1 (t, J = 24.0 Hz), 74.8, 72.7, 71.3, 70.9,
68.9, 67.0, 61.4, 61.3, 61.2, 20.9, 20.8, 20.7, 20.7, 20.6; 19F
NMR (376.5 MHz, CDCl3) δ –84.7 (bs, 3F), –112.9 (d, J =
275.2 Hz, 1F), –115.6 (d, J = 274.3 Hz, 1F); FTIR–ATR (neat,
νmax) 2984, 1742, 1656, 1369, 1204, 1075, 1046, 1019, 956,
899, 736; HRMS (TOF ES+) m/z: [M+Na]+ Calcd for
C26H31F5NaO15+ 701.1475; Found 701.1476.
1
(1:9 EtOAc/hexane): 0.37; H NMR (400 MHz, CDCl3) δ 8.41
Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2,6-anhydro-3,5- (bs, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.46 (m, 1H), 7.35 (m, 1H),
dideoxy-3-pentafluoroethyl-D-glycero-D-galacto-non-2-enonate
7.22 (m, 1H), 6.98 (bs, 1H); 13C{1H} NMR (100.6 MHz,
(2f). The title compound was prepared following the general CDCl3) δ 136.1, 127.0, 125.0, 124.0 (t, J = 29.1 Hz), 122.2,
procedure above, starting from methyl 5-acetamido-4,7,8,9- 121.3, 119.0 (qt, J = 285.7 Hz, J = 38.9 Hz), 111.8, 111.0 (tq, J
tetra-O-acetyl-2,6-anhydro-3,5-dideoxy-3-iodo-D-glycero-α-D-
= 251.3 Hz, J = 38.9 Hz), 106.2 (t, J = 4.9 Hz); 19F NMR (376.5
galacto-non-2-enonate 1f32 (40 mg, 0.066 mmol) and CuC2F5 MHz, CDCl3) δ –84.5 (t, J = 3.2 Hz, 3F), –111.9 (m, 2F).
(0.4 M in DMF, 0.30 mL, 0.13 mmol). After 40 h at 60 ºC,
standard workup and filtration through a short path of SiO2 (7:3
tert-Butyl-5-fluoro-3-(pentafluoroethyl)-1H-indole-1-
carboxylate (2j). The title compound was prepared following
the general procedure above, starting from 1j41 (27 mg, 0.076
mmol) and CuC2F5 (0.4 M in DMF, 0.43 mL, 0.18 mmol). After
16 h at 40 ºC, standard workup and filtration through a short
path of SiO2 (hexane) afforded 2j (21 mg, 86%) as a white sol-
EtOAc/hexane) afforded 2f (38.1 mg, 95%) as a white foam. Rf
20
1
(EtOAc): 0.47; [α]D –14.4 (c 0.25, CH2Cl2); H NMR (400
MHz, CDCl3) δ 5.82 (d, J = 8.4 Hz, 1H), 5.76 (d, J = 6.5 Hz,
1H), 5.54 (dd, J = 6.0 Hz, J = 3.6 Hz, 1H), 5.22 (td, J = 6.0 Hz,
J = 3.0 Hz, 1H), 4.55–4.46 (m, 2H), 4.36 (dd, J = 12.5 Hz, J =
3.0 Hz, 1H), 4.11 (dd, J = 12.5 Hz, J = 6.0 Hz, 1H), 3.83 (s,
3H), 2.10 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.93
(s, 3H); 13C{1H} NMR (100.6 MHz, CDCl3) δ 170.7, 170.4,
169.8, 169.8, 161.2, 153.3 (dd, J = 7.1 Hz, J = 7.1 Hz), 118.8
(qt, J = 287.7 Hz, J = 40.2 Hz), 113.0 (dd, J = 256.9 Hz, J =
40.2 Hz), 101.2 (dd, J = 25.3 Hz, J = 21.8 Hz), 77.7, 69.8, 66.8,
65.1, 61.8, 53.5, 47.1, 23.1, 20.9, 20.8, 20.7, 20.6; 19F NMR
(376.5 MHz, CDCl3) δ –81.6 (bs, 3F), –106.1 (d, J = 281.0 Hz,
1F), –110.6 (d, J = 281.0 Hz, 1F); FTIR–ATR (neat, νmax) 3276,
1749, 1656, 1541, 1438, 1371, 1207, 1048, 1027, 965; HRMS
(TOF ES+) m/z: [M+Na]+ Calcd for C21H26F3NNaO12+ 564.1299;
Found 564.1307.
1
id. Rf (1:9 EtOAc/hexane): 0.50; mp 74–76 ºC; H NMR (400
MHz, CDCl3) δ 8.16 (bdd, J = 9.1 Hz, J = 4.4 Hz, 1H), 7.94 (bs,
1H), 7.33 (bd, J = 8.8 Hz, 1H), 7.10 (td, J = 9.1 Hz, J = 2.6 Hz,
1H), 1.69 (s, 9H); 13C{1H} NMR (100.6 MHz, CDCl3) δ 159.7
(d, J = 240.9 Hz), 148.7, 131.9, 128.7 (t, J = 8.1 Hz), 127.0 (dt,
J = 11.2 Hz, J = 2.6 Hz), 119.3 (qt, J = 285.7 Hz, J = 40.1 Hz),
116.8 (d, J = 9.3 Hz), 113.9 (d, J = 25.2 Hz), 113.0 (tq, J =
250.4 Hz, J = 40.1 Hz), 109.4 (td, J = 28.0 Hz, J = 4.1 Hz),
106.2 (d, J = 26.2 Hz), 85.8, 28.2; 19F NMR (376.5 MHz,
CDCl3) δ –84.8 (t, J = 2.7 Hz, 3F), –111.2 (bs, 2F), –118.63 (td,
J = 8.8 Hz, J = 4.7 Hz, 1F); FTIR–ATR (neat, νmax) 2984, 1751,
1479, 1454, 1385, 1256, 1203, 1152, 1067, 1026, 962, 854, 811,
+
738; HRMS (QTOF EI+) m/z: [M]+ Calcd for C15H13F6NO2
5-Pentafluoroethyl-2’-deoxyuridine (2g).37 The title com- 353.0850; Found 353.0848.
General Procedure for Quantitative 19F NMR Analysis.
An NMR tube charged with the corresponding solid (hetero)aryl
halide (0.171 mmol) was purged and backfilled with argon three
times. CuC2F5 (0.4 M in DMF, 0.4 mL, 0.26 mmol) and 1,3-
bis(trifluoromethyl)benzene (BTB, 13 µL, 0.084 mmol) were
sequentially added under argon and the NMR tube was capped
with a rubber septum. The reaction mixture was heated in a
silicon oil bath at the indicated temperature and monitored by
pound was prepared following the general procedure above,
starting from 5-iodo-2’-deoxyuridine 1g (44 mg, 0.124 mmol)
and CuC2F5 (0.4 M in DMF, 0.61 mL, 0.25 mmol). After 6 h at
60 ºC, standard workup and filtration through a short path of
SiO2 (9:1 CH2Cl2/MeOH) afforded 2g (34 mg, 79%) as a white
solid. Rf (9:1 CH2Cl2/hexane): 0.26; 1H NMR (400 MHz,
CD3OD) δ 8.82 (bs, 1H), 6.24 (t, J = 6.0 Hz, 1H), 4.41 (dd, J =
9.3 Hz, J = 4.0 Hz, 1H), 3.98 (bd, J = 2.8 Hz, 1H), 3.83 (dd, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
19F NMR for quantitative analysis. For liquid compounds, the
NMR tube was purged and backfilled with argon three times pound was prepared following the general procedure above,
2'-(Pentafluoroethyl)acetophenone (2r).43 The title com-
1
2
3
4
5
6
7
8
9
prior to the addition of all reagents.
starting from 2'-bromoacetophenone 1r (30.7 µL, 0.171 mmol),
CuC2F5 (0.4 M in DMF, 0.4 mL, 0.26 mmol), and 1,3-
bis(trifluoromethyl)benzene (BTB, 13 µL, 0.084 mmol). After
48 h at 90 ºC, quantitative 19F NMR analysis of the reaction
mixture indicated 2n was obtained in 98% yield. 19F NMR
(376.5 MHz, CDCl3) δ –83.9 (bs, 3F), –107.7 (bs, 2F).
2-(Pentafluoroethyl)-1,1'-biphenyl (2s).10 The title compound
was prepared following the general procedure above, starting
from 2-bromobiphenyl 1s (39.9 mg, 0.171 mmol), CuC2F5 (0.4
1-(Pentafluoroethyl)-4-(trifluoromethyl)benzene (2k).12 The
title compound was prepared following the general procedure
above, starting from 1-iodo-4-(trifluoromethyl)benzene 1k (25.1
µL, 0.171 mmol), CuC2F5 (0.4 M in DMF, 0.4 mL, 0.26 mmol),
and 1,4-difluorobenzene (17.5 L, 0.171 mmol). After 48 h at
60 ºC, quantitative 19F NMR analysis of the reaction mixture
indicated 2k was obtained in >98% yield. 19F NMR (376.5
MHz, CDCl3) δ –63.3 (s, 3F), –85.1 (bs, 3F), –115.2 (bs, 2F).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
M
in DMF, 0.4 mL, 0.26 mmol), and 1,3-
1-(Pentafluoroethyl)-4-nitrobenzene (2l).18 The title com-
pound was prepared following the general procedure above,
starting from 1-bromo-4-nitrobenzene 1l (34.9 mg, 0.171
mmol), CuC2F5 (0.4 M in DMF, 0.4 mL, 0.26 mmol), and 1,3-
bis(trifluoromethyl)benzene (BTB, 13 µL, 0.084 mmol). After
48 h at 90 ºC, quantitative 19F NMR analysis of the reaction
mixture indicated 2l was obtained in >98% yield. 19F NMR
(376.5 MHz, CDCl3) δ –84.9 (bs, 3F), –115.1 (bs, 2F).
4-(Pentafluoroethyl)benzaldehyde (2m).12 The title com-
pound was prepared following the general procedure above,
starting from 4-bromobenzaldehyde 1m (32.3 mg, 0.171 mmol),
CuC2F5 (0.4 M in DMF, 0.4 mL, 0.26 mmol), and 1,3-
bis(trifluoromethyl)benzene (BTB, 13 µL, 0.084 mmol). After
24 h at 90 ºC, quantitative 19F NMR analysis of the reaction
mixture indicated 2m was obtained in 86% yield. 19F NMR
(376.5 MHz, CDCl3) δ –85.0 (bs, 3F), –115.2 (bs, 2F).
4-(Pentafluoroethyl)-1,1'-biphenyl (2n).13 The title com-
pound was prepared following the general procedure above,
starting from 4-bromobiphenyl 1n (39.9 mg, 0.171 mmol),
CuC2F5 (0.4 M in DMF, 0.4 mL, 0.26 mmol), and 1,3-
bis(trifluoromethyl)benzene (BTB, 13 µL, 0.084 mmol). After
48 h at 90 ºC and 16 h at 110 ºC, quantitative 19F NMR analysis
of the reaction mixture indicated 2n was obtained in >98%
yield. 19F NMR (376.5 MHz, CDCl3) δ –85.2 (bs, 3F), –114.5
(bs, 2F).
1-Methoxy-4-(pentafluoroethyl)benzene (2o).13 The title
compound was prepared following the general procedure above,
starting from 1-bromo-4-methoxybenzene 1o (21.6 µL, 0.171
mmol), CuC2F5 (0.4 M in DMF, 0.4 mL, 0.26 mmol), and 1,3-
bis(trifluoromethyl)benzene (BTB, 13 µL, 0.084 mmol). After
48 h at 90 ºC and 16 h at 110 ºC, quantitative 19F NMR analysis
of the reaction mixture indicated 2n was obtained in 94% yield.
19F NMR (376.5 MHz, CDCl3) δ –85.4 (bs, 3F), –113.5 (bs, 2F).
1-Benzyloxy-4-(pentafluoroethyl)benzene (2p).42 The title
compound was prepared following the general procedure above,
starting from 1-benzyloxy-4-bromobenzene 1p (46.9 mg, 0.171
mmol), CuC2F5 (0.4 M in DMF, 0.4 mL, 0.26 mmol), and 1,3-
bis(trifluoromethyl)benzene (BTB, 13 µL, 0.084 mmol). After
48 h at 90 ºC and 16 h at 110 ºC, quantitative 19F NMR analysis
of the reaction mixture indicated 2p was obtained in >98%
yield. 19F NMR (376.5 MHz, CDCl3) δ –85.4 (bs, 3F), –113.6
(bs, 2F).
1-Methoxy-2-(pentafluoroethyl)benzene (2q).13 The title
compound was prepared following the general procedure above,
starting from 1-bromo-2-methoxybenzene 1q (22.0 µL, 0.171
mmol), CuC2F5 (0.4 M in DMF, 0.4 mL, 0.26 mmol), and 1,3-
bis(trifluoromethyl)benzene (BTB, 13 µL, 0.084 mmol). After
48 h at 90 ºC, quantitative 19F NMR analysis of the reaction
mixture indicated 2n was obtained in >98% yield. 19F NMR
(376.5 MHz, CDCl3) δ –84.2 (bs, 3F), –111.5 (bs, 2F).
bis(trifluoromethyl)benzene (BTB, 13 µL, 0.084 mmol). After
48 h at 90 ºC and 16 h at 110 ºC, quantitative 19F NMR analysis
of the reaction mixture indicated 2s was obtained in 94% yield.
19F NMR (376.5 MHz, CDCl3) δ –84.1 (bs, 3F), –106.3 (bs, 2F).
1-(Pentafluoroethyl)naphthalene (2t).13 The title compound
was prepared following the general procedure above, starting
from 1-iodonaphthalene 1t (25.7 µL, 0.171 mmol), CuC2F5 (0.4
M
in DMF, 0.4 mL, 0.26 mmol), and 1,3-
bis(trifluoromethyl)benzene (BTB, 13 µL, 0.084 mmol). After
48 h at 60 ºC, quantitative 19F NMR analysis of the reaction
mixture indicated 2t was obtained in >98% yield. 19F NMR
(376.5 MHz, CDCl3) δ –83.8 (bs, 3F), –108.2 (bs, 2F).
3-(Pentafluoroethyl)pyridine (2u).13 The title compound was
prepared following the general procedure above, starting from
3-bromopyridine 1u (16.6 µL, 0.171 mmol), CuC2F5 (0.4 M in
DMF, 0.4 mL, 0.26 mmol), and 1,3-bis(trifluoromethyl)benzene
(BTB, 13 µL, 0.084 mmol). After 24 h at 90 ºC and 24 h at 110
ºC, quantitative 19F NMR analysis of the reaction mixture indi-
cated 2u was obtained in >98% yield. 19F NMR (376.5 MHz,
CDCl3) δ –85.4 (bs, 3F), –115.7 (bs, 2F).
2-(Pentafluoroethyl)pyridine (2v).18 The title compound was
prepared following the general procedure above, starting from
2-bromopyridine 1v (16.6 µL, 0.171 mmol), CuC2F5 (0.4 M in
DMF, 0.4 mL, 0.26 mmol), and 1,3-bis(trifluoromethyl)benzene
(BTB, 13 µL, 0.084 mmol). After 16 h at 90 ºC, quantitative 19
F
NMR analysis of the reaction mixture indicated 2v was obtained
in 83% yield. 19F NMR (376.5 MHz, CDCl3) δ –83.4 (bs, 3F), –
116.8 (bs, 2F).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website. H, 13C{1H}, and 19F NMR spectra
1
for all new compounds, stability studies, and additional optimi-
zation experiments (PDF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: omar.boutureira@urv.cat
ACKNOWLEDGMENTS
We thank the Spanish Government-MCIU and the national agency
of investigation-AEI (CTQ2017-89750-R and CTQ2017-90088-R),
the European Regional Development Fund, and the Universitat
Rovira i Virgili (Martí Franquès Research Fellowship Programme;
2012BPURV-67 to J.M.) for financial support. We also thank Dr.
Vladimir V. Grushin for providing the C2F5H-derived CuC2F5 rea-
gent and Dr. Miguel A. Rodríguez (COS, URV-Eurecat) for the 19
F
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Page 9 of 11
The Journal of Organic Chemistry
DOSY NMR experiments. O.B. is a Ramón y Cajal Fellow (RYC-
2015-17705).
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