Trifluoromethylation of heterocycles in water at room temperature

Article abstract of DOI:10.1039/c3gc42119h

Using a reaction medium containing nanoparticles consisting of commercially available TPGS-750-M in water, a combination of Langlois' reagent and t-BuOOH can be used to effect trifluoromethylation of several heterocyclic arrays, including heteroaromatics. These reactions take place at ambient temperatures, and the aqueous medium can be recycled.

Full text of DOI:10.1039/c3gc42119h

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Trifluoromethylation of heterocycles in water at
room temperature†
Cite this: Green Chem., 2014, 16,
1097
James C. Fennewald and Bruce H. Lipshutz*
Received 11th October 2013,
Accepted 20th November 2013
DOI: 10.1039/c3gc42119h
www.rsc.org/greenchem
Using a reaction medium containing nanoparticles consisting of with solvent recycling, and (c) minimization of organic and/or
commercially available TPGS-750-M in water, a combination of aqueous waste being generated. In this report we describe a
Langlois’ reagent and t-BuOOH can be used to effect trifluoro- procedure for trifluoromethylation of heterocycles under very
methylation of several heterocyclic arrays, including hetero- mild and environmentally benign conditions: in water only,
aromatics. These reactions take place at ambient temperatures, and at ambient temperatures.
and the aqueous medium can be recycled.
We focused on trifluoromethylation that relies on substi-
tution at a C–H rather than C–X bond, thereby avoiding pre-
functionalization of the educt. For this approach, the impress-
ive method reported by Baran22 involving CF3 radicals seemed
especially attractive, utilizing commercially available Langlois’
reagent (NaSO2CF3) as the source of these radicals. That no
transition metal is needed is another positive feature. Our goal
thus became one of finding conditions that would (1) elimin-
ate use of a mixed aqueous solvent system that included a
chlorinated solvent (DCM); (2) reducing the amounts of
reagents involved; (3) improve yields; (4) be amenable to re-
cycling of the purely aqueous reaction medium, and (5) reduce
the level of organic waste being created, which is mainly
organic solvent in nature, manifested by reduction in the
associated E factors.23,24
As a test case using aqueous micellar conditions based on
our designer surfactant TPGS-750-M25 (Fig. 1), 4-t-butylpyri-
dine (1) was treated sequentially with NaSO2CF3 and then
t-butylhydroperoxide (TBHP), leading to an encouraging 84%
conversion to the anticipated trifluoromethylated product (2)
after 24 hours (Scheme 1), a result that is competitive with lite-
rature results on this particular educt.22
Introduction of the trifluoromethyl group onto heterocyclic
rings can often impart several desirable features associated
with physiologically active compounds (e.g., increased bioavail-
ability, membrane and metabolic stability, etc.).1,2 Indeed,
many of the top-selling drugs contain fluorine.1 Although
there is a rich history to this area of medicinal chemistry, e.g.,
using CF3Br or more commonly CF3I3 as precursors to CF3 radi-
cals, opportunities remain not only for improvements in exist-
ing technologies and development of new reagents, but also
for new processes that are more environmentally benign. Most
recent methods rely on transition metal-mediated C–CF3 bond
constructions, and while these typically offer good control of
regiochemistry, yields tend to be variable. Moreover, while pro-
cesses catalytic in transition metals are known (e.g.,
Cu(SO3CF3)2/t-BuOOH, LnPd/TESCF3 or TMSCF3,4–8 RuCl2(PPh3)3/
CF3SO2Cl,9,10 ReO3Me/Togni reagent,11,12 Ru(phen)3Cl2/
CF3SO2Cl, hv),13 several of the most recent procedures rely on
(super)stoichiometric quantities of transition metal complexes
(e.g., (MeCN)4CuPF6,14 CuCF3,15,16 CuX/TMS-CF3,17,18 AgX
TMSCF3 or CF3I,19 AgNO3/NaSO2CF320), which may well
present limitations in terms of both waste disposal and
cost.14,16
A screening of alternative surfactants showed that other
common nonionic amphiphiles led to inferior results
(Table 1). The top performing surfactant (global concentration
of 0.5 M) in the conversion of 1 to 2 was TPGS-750-M (entry 1),
consistent with the notion that its larger particles25 (ca.
50–60 nm) provide greater amounts of lipophilic material
Notably, every method for trifluoromethylation reported to
date has been developed without attention to its environ-
mental impact. That is, virtually no consideration has been
given to the twelve guiding principles of green chemistry21
insofar as these reactions being done (a) in green solvents; (b)
Department of Chemistry & Biochemistry, University of California, Santa Barbara
93106, USA. E-mail: lipshutz@chem.ucsb.edu
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3gc42119h
Fig. 1 Structure of designer surfactant TPGS-750-M.
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Table 3 Screening of the peroxide for the conversion of 1 to 2a
Entry
Peroxide
Yield (%)
1
2
3
4
TBHP
CHP
Bz2O2
H2O2
88
72
0
0
Scheme 1 Initial example of trifluoromethylation in water. Reaction
condition: substrate (1 mmol); NaSO2CF3 (3 equiv.); TBHP (5 equiv.);
TPGS-750-M (2 wt% in water).
a Conditions: substrate (0.1 mmol); NaSO2CF3 (3 equiv.); peroxide (5
equiv.); TPGS-750-M : water (2 wt%).
Table 1 Impact of the surfactant of the conversion of 1 to 2a
Table 4 Effects of metal salts on the yields of the annulated pyridine 3
and substituted indole 4a
Entry
Surfactanta
Conversionb (%)
1
2
3
4
5
6
7
8
TPGS-750-M25
PTS-60026
Cremophor EL
Triton X 100
Brij-30
84
54
36
22
22
19
18
17
TPGS-1000
PQS27
None
a Conditions: substrate (0.1 mmol); NaSO2CF3 (3 equiv.); TBHP (5 equiv.);
surfactant : water (2% w/w). b % conversion, by GC.
Yield (%)
Entry
Metal
None
3
4
1
2
3
4
5
6
7
8
9
73
51
0
53
54
52
42
47
45
64
42
0
49
Table 2 Impact of wt% of TPGS-750-M on the conversion of 1 to 2a
b
ZnCl2c
ZnCl2
Entry
Weight (%)
Conversionb (%)
CuI
CuOAc
CuBr·SMe2
NiCl2
NiI2(PPh3)2
Ni(COD)2
50
1
2
3
4
1
2
3
5
37
80
83
60
47
NDd
NDd
NDd
a Conditions: substrate (0.1 mmol); NaSO2CF3 (3 equiv.); TBHP (5
equiv.); TPGS-750-M : water (2 wt%). b % conversion, by GC.
a Conditions: substrate (0.15 mmol); metal salts (10 mol%) NaSO2CF3
(3 equiv.); TBHP (5 equiv.); TPGS-750-M : water (2 wt%). b TMEDA
(1 equiv.). c 1,10-Phen (1 equiv.). d Not determined.
within their inner cores, and thus, have greater binding con-
stants for substrate and reagent(s) thereby leading to hydrogen peroxide gave any of the desired trifluoromethylated
enhanced levels of conversion. The corresponding “on water” pyridine. Thus, the preferred peroxide was clearly TBHP,
reaction, where no surfactant was present, gave the lowest level affording 2 in 88% yield.
of conversion (entry 8).
Given that Langlois’ reagent contains various amounts of
The results from varying the amount of TPGS-750-M from trace metals,20 the potential for metal salts to facilitate single
one to five weight percent for the reaction of 1 to 2 are shown electron transfer from this source of CF3 was examined. Pro-
in Table 2. Both two and three weight percent afforded essen- ducts 3 and 4 (Table 4) result from an investigation of zinc(II),
tially the same extent of conversion, and hence, a two weight copper(I), and nickel(II) salts (10 mol%) containing varying
percent solution was used in all subsequent examples. This counterions. In all cases the isolated yields decreased. The
percentage also corresponds to that found in commercially effects of added ligands, such as TMEDA and 1,10-phenanthro-
available material (Aldrich catalog number 733857).
line, were also not productive, the latter amine completely
Several peroxide radical initiators were screened in this inhibiting the reaction.
same model reaction (1 to 2), and the results are shown in
Based on the results from these optimization studies, the
Table 3. In addition to TBHP, cumene hydroperoxide (CHP) procedure that emerged involves use of Langlois’ reagent in
was tested, as its c log P of 2.44 is much higher than that of combination with TBHP, both being added sequentially to the
TBHP (1.05). From previous work we anticipated that the far substrate in 2 weight% TPGS-750-M at room temperature.
greater lipophilicity of CHP would translate into a greater Several heterocyclic cases were then tested in an effort to estab-
amount of this reagent being localized within the micellar lish the scope of this new process. Many of the examples pre-
core.28 However, its high viscosity created difficulties in main- viously studied by Baran and co-workers22 were directly
taining a smoothly stirring reaction medium, with significant compared, as illustrated in Table 5. In all cases, the yields
clumping taking place. Neither dibenzoyl peroxide nor are improved, while reaction times are comparable. The
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Table 5 Direct comparisons with literature22 examples
Table 6 Recycling of the aqueous reaction mixture (1 to 2)a
Entry
Cycle
Yield (%)
1
2
3
4
5
1
78
79
73
68
62
2b
3b
4b
5b
a Conditions: substrate (1 mmol); NaSO2CF3 (3 equiv.); TBHP (5
equiv.); TPGS-750-M : water (2 wt%). b Extracted with EtOAc; aqueous
medium used for next reaction.
reaction mixture can be recycled. Results from a recycling
study for the conversion of 1 to 2 are shown in Table 6. The
drop in isolated yields associated with the 4th and 5th recycle is
likely due to continuous buildup of t-butanol in the reaction
mixture, which would help solubilize the product in the
aqueous layer. TLC indication of each recycle suggests that the
extent of conversion is also dropping, although the later reac-
tions are not any less clean than those done earlier in the
sequence.
This worka
Previous work
Entry Compound Yieldb (%)
Time (h) Yieldb (%)
Time (h)
1
2
3
4
5
6
7
8
3
4
5
6
7
8
9
10
73
64
62
84
55
54
43
47
43
44
28
23
44
51
38
52
43c
51
57
40
18
24
40
40
40
48
61
78
48c
50c
33c
43
To assess the “greenness” of this process, an E factor was
calculated23 based on organic solvent usage, since most
organic waste from organic reactions is attributable to this
reaction variable.23 Many reactions used by the pharmaceutical
industry tend to have E factors in the 25–100 range, while the
fine chemicals arena is usually in the 5–25 category.24 As
shown in Fig. 3, trifluoromethylation reactions carried out in
nanomicelles involve an E factor of only 5–6, given the com-
plete absence of any organic solvent in the reaction medium.
An E factor calculated on inclusion of water raises this value to
only 18.2, but with a single recycle this value is cut in half, in
line with our previous observations relating to cross-coupling
reactions performed within these recyclable nanoreactors.23
In conclusion, micellar catalysis has been found to be
amenable to radical-based trifluoromethylation of various
heterocyclic compounds. Nanoreactors composed of the
designer surfactant TPGS-750-M enable these substitution
reactions to be performed in water at room temperature in
modest to good yields. The aqueous reaction mixtures can be
recycled several times, and given the limited amounts of
organic solvent needed for product isolation, the associated E
factors imply that a considerably enhanced overall level of
greenness is realized using this technology.
a Conditions: substrate (1 mmol); NaSO2CF3 (3 equiv.); TBHP (5
equiv.); TPGS-750-M : water (2 wt%). b See ref. 20. c Required second
addition of reagents.
regiochemistry associated with product 7 was comparable to
that seen previously (C2 : C3 = 1.6 : 1). Noteworthy is that these
reactions were run using three equivalents of NaSO2CF3 and
five equivalents of TBHP in all cases. By contrast, in several of
the examples previously reported, twice as much of each
reagent was required.
Portion-wise addition of either Langlois’ reagent or TBHP
over time did not improve yields. Increasing the amounts of
reagents added initially (from 3 to 5 equiv. of NaSO2CF3, and
from 5 to 8.5 equiv. TBHP) led to lower yields of the desired
product. Additional examples (11,7,29 12,30 13, and 1429) are
illustrated in Fig. 2.
Workup of these trifluoromethylation reactions involves
addition of a minimal amount of a single organic solvent,
such as EtOAc, to the reaction vessel in order to extract the
product. The total amount of water invested in the entire
process is very modest, as reactions are run at 0.5 M and no
additional water need be added as part of the workup. Hence,
the eventual water waste stream drops to truly minimal levels.
The aqueous layer retains the surfactant and hence, the
Fig. 2 aConditions: substrate (1 mmol); NaSO2CF3 (3 equiv.); TBHP (5
equiv.); TPGS-750-M : water (2 wt%), bisolated yield, cNMR yield.
Fig. 3 E Factors associated with trifluoromethylations.
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