Continuous Flow Homolytic Aromatic Substitution with Electrophilic Radicals: A Fast and Scalable Protocol for Trifluoromethylation

Article abstract of DOI:10.1002/chem.201604579

We report an operationally simple and rapid continuous flow radical C?C bond formation under Minisci-type reaction conditions. The transformations are performed at or below room temperature employing hydrogen peroxide (H₂O₂) and dimethylsulfoxide (DMSO) as reagents in the presence of an Fe^IIcatalyst. For electron-rich aromatic and heteroaromatic substrates, C?C bond formation proceeds satisfactorily with electrophilic radicals including^.CF₃,^.C₄F₉,^.CH₂CN, and^.CH₂CO₂Et. In contrast, electron-poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF₃I and C₄F₉I as reagents proceed exceedingly fast with high conversion for selected substrates in residence times of a few seconds. The attractive features of the present process are the low cost of the reagents and the extraordinarily high reaction rates. The direct application of the protocol to dihydroergotamine, a complex ergot alkaloid, yielded the corresponding trifluoromethyl ergoline derivative within 12 seconds in a continuous flow microreactor on a 0.6 kg scale. The trifluoromethyl derivative of dihydroergotamine is a promising therapeutic agent for the treatment of migraines.

Full text of DOI:10.1002/chem.201604579

A Journal of
Accepted Article
Title: Continuous Flow Homolytic Aromatic Substitution with
Electrophilic Radicals - A Fast and Scalable Protocol for
Trifluoromethylation
Authors: Julia L Monteiro, Paula F Carneiro, Petteri Elsner, Dominique
Roberge, Peter G. M. Wuts, Kathrin Kurjan, Bernhard
Gutmann, and C. Oliver Kappe
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201604579
Link to VoR: http://dx.doi.org/10.1002/chem.201604579
Supported by

10.1002/chem.201604579
Chemistry - A European Journal
FULL PAPER
Continuous Flow Homolytic Aromatic
Substitution with Electrophilic Radicals – A Fast
and Scalable Protocol for Trifluoromethylation
Júlia L. Monteiro,[a] Paula F. Carneiro,[a] Petteri Elsner,[b] Dominique M.
Roberge,[b] Peter G. M. Wuts,+[c] Katherine C. Kurjan,[d] Bernhard Gutmann,*[a,e]
and C. Oliver Kappe*[a,e]
[a]
J. L. Monteiro, Dr. P. F. Carneiro, Dr. B. Gutmann, Prof. Dr. C. O. Kappe
Institute of Chemistry, University of Graz, NAWI Graz
Heinrichstrasse 28, A-8010 Graz (Austria)
Homepage: http://goflow.at
E-mail: bernhard.gutmann@uni-graz.at; oliver.kappe@uni-graz.at
Dr. P. Elsner, Dr. D. M. Roberge
Chemical Manufacturing Technologies
Lonza AG, CH-3930 Visp (Switzerland)
Dr. P. G. M. Wuts
Kalexsyn, Inc.
4502 Campus Drive Kalamazoo, MI 49008 (USA)
K. C. Kurjan
[b]
[c]
[d]
[e]
[+]
Allergan plc
2525 Dupont Drive Irvine, CA 92612 (USA)
Dr. B. Gutmann, Prof. Dr. C. O. Kappe
Research Center Pharmaceutical Engineering (RCPE)
Inffeldgasse 13, 8010 Graz (Austria)
Present Address: Wuts Chemistry Consulting
5287 Saddle Club Drive
Kalamazoo, MI 49009 (USA)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.xxxxxxxx.
1
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Abstract: Herein, we report an operationally simple and rapid continuous flow radical C─C bond
formation under Minisci-type reaction conditions. The transformations are performed at or below
room temperature employing hydrogen peroxide (H2O2) and dimethylsulfoxide (DMSO) as
reagents in the presence of an Fe(II) catalyst. For electron rich aromatic and heteroaromatic
substrates C─C bond formation proceeds satisfactorily with electrophilic radicals including ·CF3,
·C4F9, ·CH2CN and ·CH2CO2Et. In contrast, electron poor substrates exhibit minimal reactivity.
Importantly, trifluoromethylations and nonafluororobutylations using CF3I and C4F9I as reagents
proceed exceedingly fast with high conversion for selected substrates in residence times of a few
seconds. The attractive features of the present process are the low cost of the reagents and the
extraordinary high reaction rates. The direct application of the protocol to dihydroergotamine, a
complex ergot alkaloid, yielded the corresponding trifluoromethyl ergoline derivative within a
reaction time of 12 seconds in a continuous flow microreactor on a 0.6 kg scale. The
trifluoromethyl derivative of dihydroergotamine is a promising therapeutic agent for the treatment
of migraine.
Introduction
An increasing number of new drugs and drug candidates as well as a number of agrochemicals
contain a trifluoromethyl moiety.[1] Indeed, fluorinated and trifluoromethylated compounds are
routinely evaluated in drug-discovery and drug-development programs. The incorporation of
fluorine into a pharmaceutical ingredient frequently increases metabolic stability and improves
lipophilicity, membrane permeability and bioavailability.[1] Considerable efforts have been
devoted towards the development of new methods for the selective introduction of the CF3-
moiety into organic molecules. Traditional techniques for the generation of aryl-CF3 compounds
have been limited to deoxofluorination of carboxylic acids and to perchlorination of aromatic
methyl groups with subsequent exchange of chloride by fluoride.[2] In the last decades, however,
a range of reagents and protocols for the direct introduction of the CF3 group into aromatic and
heteroaromatic compounds have been developed.[2] Typically, the introduction of the CF3 moiety
is accomplished by transition-metal-mediated cross-coupling of suitably functionalized aromatic
compounds with either nucleophilic or electrophilic CF3-sources.[3] Furthermore, methods for the
direct CH-trifluoromethylation of unactivated aromatic and heteroaromatic precursors by
2
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homolytic aromatic substitution have become available.[4] The generation of perfluoroheptyl
radicals by thermal homolysis of the C-I bond of perfluoroheptyliodide in an autoclave at 250 °C
was reported by Tiers in 1960.[5] The thermally generated radical could be utilized to convert
simple aromatic substrates, such as benzene, toluene, naphthalene and halobenzenes, to the
perfluoroalkyled products.[5] More recently, reagents including Na2S2O4,[6] Et3B/O2,[7] and
Me3Al,[8] have been used to initiate radical trifluoromethylation under mild reaction conditions.
Baran and co-workers introduced an effective protocol using CF3SO2Na (Langlois reagent) and
tBuOOH as a source for the trifluoromethyl radical in biphasic solutions.[9] The method allowed
the trifluoromethylation of a variety of electron-deficient and electron-rich heteroaromatic
systems after reaction times of 3 to 24 h at room temperature.[9] Moreover, various researchers
have demonstrated that photoredox catalysis allows the efficient generation of the CF3 radical
from various CF3-sources under reaction conditions compatible with a wide range of functional
groups.[10,11]
The generation of alkyl radicals from alkyl iodides, hydrogen peroxide, DMSO and Fe(II)
as catalyst was described by Minisci and co-workers in 1988 (Scheme 1).[12,13] Simple alkyl
iodides form nucleophilic radicals which add to electron-poor olefins and heteroaromatic bases
with good regio- and chemo-selectivity.[13] On the other hand, electrophilic radicals generated
from halides with electron-withdrawing groups in the α-position, such as ICH2CO2R, ICH2CN, or
ICH(CO2R)2, show the potential to add to electron-rich aromatic compounds and olefins.[14]
Importantly, Baciocchi and Muraglia demonstrated the applicability of Minisci-type reaction
conditions for the perfluoroalkylation of pyrroles starting from perfluoroalkyl iodides.[15] The
reaction was further explored by Minisci,[16] and Yamakawa.[17] Moreover, Yamakawa and
coworkers demonstrated that these conditions are suitable for the production of 5-
trifluoromethyluracil from uracil and CF3I on a 50 kg scale in a 600 L stirred tank reactor.[18]
Due to the extreme reaction speed and exothermicity of Minisci-type alkylation reactions,
hydrogen peroxide typically has to be dosed dropwise over a period of hours to a cooled, well-
stirred reaction mixture to keep the reaction under control.[12-18] Microreactors provide
significantly improved control over reaction conditions, and reactions often can be performed
under conditions which would be infeasible or impossible to use in batch reactors.[19] Fast mixing
can be achieved in microfluidic devices with dedicated mixing structures, and the high surface-
to-volume ratio allows rapid dissipation of excess heat.[19] Thus, mass and energy transport
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limitations can be eliminated even for fast and highly exothermic reactions and the intrinsic
reaction kinetics can be fully exploited.[20]
Herein we disclose a continuous flow protocol for the radical CH-trifluoromethylation of
unactivated aromatic compounds using hydrogen peroxide/DMSO/iron as the radical source.[12,13]
Importantly, this protocol allows the direct transformation of unprotected dihydroergotamine
mesylate 1a to the corresponding trifluoromethyl derivative 1b within residence times of only
seconds in a continuous flow microreactor (Scheme 1). Dihydroergotamine, a semi-synthetic
form of ergotamine, is a well-established pharmaceutical product, with over 70 years of use in the
treatment of migraine.[21] However, since dihydroergotamine causes several negative side effects,
such as nausea, its use has recently declined and it has become increasingly replaced by more
selective (and generally significantly more expensive) 5-HT agonists (e.g. sumatriptan).[21] Newer
receptor activity studies have suggested that the fluoro derivatives of ergotamines are promising
therapeutic agents for the treatment of migraine. In particular, the trifluoromethyl derivative of
dihydroergotamine (1b) is active against receptors responsible for antimigraine effects while
exhibiting reduced activity against receptors responsible for side-effects.[22] An economic and
selective strategy for the late-stage trifluoromethylation of dihydroergotamine 1b is thus of
significant interest.
Scheme 1. Perfluoroalkylations under Minisci-type conditions.
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Results and Discussion
The addition of H2O2 to a solution of substrate, perfuoroalkyl iodide and Fe(II) in DMSO as
solvent starts a complex, but fairly selective and well-understood series of redox reactions
(Scheme 1).[13] The intermediate reactions are very fast and exothermic, with some reaction rates
close to the diffusion-controlled limit. The sequence starts with the fast reduction of H2O2 by
Fe(II) to a hydroxyl radical and a hydroxide ion (Fenton reaction). The extreme reactivity of the
hydroxyl radical is controlled by the use of DMSO as the solvent. The hydroxyl radical quickly
adds to DMSO to form a (CH3)2SO2H· radical, and unselective reactions of the hydroxyl radical
with other reagents, substrate or product are thus prevented.[13] The radical adduct of the OH
radical with DMSO subsequently decomposes to methylsulfinic acid and a methyl radical. The
highly reactive methyl radical further reacts with the alkyl iodide in an equilibrium reaction. This
reaction is very fast as well, and successfully competes with other potential side-reactions, such
as addition of the methyl radical to the substrate.[13] The alkyl radical finally adds to the double
bond of the substrate, the intermediate radical is oxidized by Fe(III), and the catalytic cycle in Fe
is thus closed (Scheme 2).[13]
Scheme 2. Mechanism for Minisci-type C─C bond formation.[12,13]
A crude kinetic model using the mechanism shown in Scheme 2 and rate constants derived from
those reported in the literature, revealed that the whole reaction sequence ought to proceed to
conversions >90% in a fraction of a second (see Figure S3 in the Supporting Information). As
5
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mentioned above, this reactivity cannot be harnessed in traditional stirred tank reactors due to
limited mass and heat transfer, and slow addition of the H2O2 to the reaction mixture is necessary
to avoid severe concentration gradients and to control reaction temperature.[12-18] Thus a
continuous flow microreactor setup was assembled. The flow setup for the first experiments
consisted of a continuous syringe pump to introduce a solution containing substrate, reagents and
catalyst (feed A; cf. Table 1), and a second syringe pump to introduce the hydrogen peroxide
(feed B). The two feed solutions were mixed in a standard Y-connector (thru hole: 0.5 mm; 1.7
µL), at 0 °C, and the combined mixture went through a short residence tubing at 0 °C
(perfluoroalkoxy alkanes (PFA), 0.8 mm i.d., 500 µL internal volume). Initial experiments were
performed with 3-methylindole 2a as a model substrate and CF3I as reagent with stoichiometries
close to those reported by Yamakawa and co-workers.[17] Trifluoroiodomethane is a
comparatively cheap, non-toxic, gaseous CF3 source (b.p. -23 °C),[23] and has been previously
used in continuous flow processes.[11c-e] For the flow reactions, the desired amount of CF3I was
condensed into a vessel cooled to ~ -60 °C, and the remaining reagents dissolved in
DMSO/MeCN 2:1 as solvent were added (feed A). This solution was loaded into the sample loop
of a 6-port injection valve. When the reaction was started, the injection valve was switched to
connect the sample loop in line with the carrier stream (DMSO/MeCN). The feed solution A was
carried into the mixer with a flow rate of 4.7 mL/min, where it was combined with the 30%
aqueous hydrogen peroxide feed pumped with a flow rate of 0.3 mL/min (feed B).[19e] The
yellowish feed solution immediately turned deep-red upon contact with the hydrogen peroxide.
The mixture went through the residence tubing at 0 °C and was collected into a quench solution
of aqueous sodium bicarbonate and ethyl acetate (6 s nominal residence time). The best
conversion and selectivity was obtained with 0.4 equiv of FeSO4·7H2O, 0.8 equiv of H2SO4, 1.2
to 1.6 equiv of CF3I and 1.6 equiv of H2O2 (see Table S1 to S3 in the Supporting Information). A
conversion of 92% and a selectivity of 84% for the 2-trifluoromethylated product were attained
according to HPLC-UV/Vis peak area integration at 215 nm. The main side-product was a bis-
trifluoromethylated 3-methylindole (~7%). The position of the trifluoromethyl groups could not
be unequivocally established. Additionally, further mono- and bis-trifluoromethylated isomers
could be detected in the crude reaction mixture in small quantities by GC-MS analysis (see
Figure S4 in the Supporting Information). Minisci-type reactions are usually performed with an
H2O2 amount larger than stoichiometric, since it is consumed in various, poorly understood, side
reactions.[12,13] Also the iron is consumed by side reactions, and the use of close-to-stoichiometric
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amounts is common.[13] An increase of the amount of FeSO4·7H2O above ~0.4 equiv or a larger
excess of H2O2 did not increase the conversion further (see Table S1 and S3 in the Supporting
Information). Sulfuric acid increased the solubility of the iron sulfate and prevented quick
oxidation of Fe(II) to Fe(III) in the feed solution by atmospheric oxygen. However, the
concentration of sulfuric acid had little effect on the trifluoromethylation reaction (Table S2 in
the Supporting Information). Furthermore, longer reaction times or heating did not drive the
reaction to completion. It has been frequently observed that Minisci-type reactions proceed only
to a certain point and then stop.[12] Often this is indeed the main limitation of Minisci reactions.
To further explore the effect of reaction time, residence tubes of various residence
volumes were connected to the Y-mixer, and a quench solution of Na2S2O3 was mixed into the
reaction mixture after the residence tube using a second Y-shaped mixer (Table 1).[24] With a
total flow rate of 5 mL/min and a PFA residence tube with a length of 6.4 cm (0.4 i.d., internal
volume of 8 µL), the nominal residence time was reduced to 100 ms. Even with this short
residence time, no appreciable decrease in conversion was observed (Table 1).
Table 1. Continuous flow trifluoromethylation under Minisci-type conditions.[a]
Entry
CF3I
[equiv]
reactor
[µL]
flow rate
A/B
rt
[s]
conv.
[%][b]
sel.
[%][b]
[mL/min]
4.75/0.25
4.75/0.25
9.5/0.5
4.75/0.25
4.75/0.25
4.75/0.25
4.75/0.25
4.75/0.25
1
2
3
4
6
7
8
9
1.2
1.2
1.2
1.2
1.6
1.6
1.6
1.6
125
41
41
17
170
87
41
8
1.5
0.5
0.25
0.2
2.0
1.0
0.5
0.1
89
90
79
93
95
88
70
91
85
83
88
87
81
80
87
77
[a] Conditions: Feed A: 3.2 mL of 0.32 M solution of 2-methylindole 2a, CF3I, FeSO4·7H2O (0.4 equiv)
and H2SO4 (0.8 equiv) in DMSO/MeCN 2:1 as solvent; Feed B: 30% aqueous H2O2 (1.6 equiv). [b]
Conversion and selectivity was determined by HPLC peak area integration at 215 nm. rt = nominal
residence time; SL = sample loop; M1, M2 = Y connectors.
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Slightly higher selectivities but similar conversions were obtained for reactions using
nonafluororoiodobutane as reagent (Table 2). The reaction proceeded to conversions of around
90% after residence times of 1 s. Lower reaction times resulted in reduced conversions (entries 2
and 3 in Table 2). Further experiments were performed with microreactors of various designs.
Microreactors typically incorporate channels with active mixing geometries to ensure efficient
turbulent mixing of reaction streams, and they show superior performance when the diffusional
mixing provided by simple Y connectors is too slow. However, the results obtained in the tested
microreactors were similar to those obtained with a combination of Y connectors and tube
reactors. For instance, the employed Chemtrix microreactor had 3 reagent inputs and a total
volume of 19 µL.[25] The feed solutions A and B (H2O2) were pumped into the microreactor by
two syringe pumps. The feed solutions were pre-cooled in the channels of the microreactor before
they were mixed in the SOR-mixing zone (staggered oriented ridge).[25]
Table 2. Continuous flow nonafluoromethylation under Minisci-type conditions.[a]
Entry
C4F9I
[equiv]
reactor (vol
[µL])
Flow
rt
[s]
conv.
[%][b]
sel.
Rates A/B
[mL/min]
4.75/0.25
4.75/0.25
4.75/0.25
[%][b]
1
2
3
4
5
6
7
8
9
1.2
1.2
1.2
1.6
1.6
1.6
1.6
1.6
1.6
tubing (87)
tubing (8)
tubing (4)
1.0
0.1
0.045
4.0
22
93
61
51
84
95
94
93
92
95
94
96
96
93
92
94
95
94
93
tubing (330) 4.75/0.25
chip (1800)[c] 4.75/0.25
chip (1800)[c]
chip (19)[d]
chip (19)[d]
chip (19)[d]
9.5/0.5
0.95/0.05
1.9/0.1
11
2.7
0.6
0.3
3.8/0.2
[a] Conditions: Feed A: 3.2 mL of 0.31 M solution of 2-methylindole 2a, C4F9I, FeSO4·7H2O (0.4 equiv)
and H2SO4 (0.8 equiv) in DMSO/MeCN 2:1 as solvent; Feed B: 30% aqueous H2O2 (1.6 equiv). [b]
Conversion and selectivity was determined by HPLC peak area integration at 215nm. [c] Uniqsis glass
static mixer [ref. 26]. [d] Chemtrix glass static mixer [ref. 25]. rt = nominal residence time; SL = sample
loop; M1, M2 = Y connectors.
8
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After mixing, the combined stream passed through the residence time channel. The processed
mixture was then combined with the quench solution of Na2S2O3 in the second SOR-mixing zone
and left the reactor through the outlet. A conversion of 95% after a nominal residence time of 0.3
s was obtained for this reaction (entry 9 in Table 2).
Under the optimized conditions, we examined the trifluoromethylation and
nonafluorobutylation of various aromatic and heteroaromatic compounds. The reactions shown in
Figure 1 were performed in a glass static mixer with 1.8 mL mixing volume (Uniqsis).[26] With
flow rates of 4.75 and 0.25 mL/min for feed A and feed B, respectively, a residence time of 22 s
was obtained. The CF3 radical is a highly reactive, electrophilic radical with a low-lying
SOMO.[4] Accordingly, reactions with electron-rich heteroaromatics such as pyrroles and indoles
progressed to high conversions. As expected, the reaction with indole 3a formed a mixture of
trifluoromethylated products. In contrast, pyrrole 4a was alkylated at the 2-postion with high
selectivity and the products 4b and 4c were isolated in good to excellent yields after column
chromatography. Furthermore, reactions with strongly electron-rich aromatic compounds
proceeded satisfactorily. However, due to the extraordinary reactivity of the CF3 radical, no or
only modest regioselectivity was observed for substrates with two or more positions of similar
reactivity. The CH-trifuoromethylation of dihydroxybenzene 6a yielded a mixture of mono- and
bis-substituted products. Reducing the reaction time had almost no effect on the selectivity.
Similarly, trifluoromethylation of the particularly electron-rich aniline 7a furnished a roughly 1:1
mixture of mono- and bis-substituted products, regardless of the chosen reaction time.
Importantly, reactions with 2,6-dichloroaniline (8a) proceeded to acceptable conversions (~60%)
and afforded the p-CF3 derivative with a selectivity of ~80% (see Table S4 in the Supporting
Information for further details). The product 8b is the key-structure in various widely used
pesticides of the phenylpyrazole family, including the insecticide fipronil and its derivatives
acetoprole and ethiprole (Figure 1). Reactions with substrates without a strongly activating
substituent generally stopped before acceptable conversions were obtained, while electron-poor
substrates did not give any reaction (see Table S5 in the Supporting Information for further
details). Attempts to further optimize the reaction were mostly fruitless. Nevertheless, the
obtained yields compare well with those reported in the literature for related batch radical
reactions.[17] Reactions with nonafluororobutyliodide (C4F9I) under the standard reaction
conditions usually proceeded to higher conversions and yielded the products with better
selectivities compared to reactions with CF3I (Figure 1).
9
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Figure 1. Continuous flow C-C bond formation with electrophilic radicals. Yields correspond to isolated
and fully characterized products. [a] Conditions: Feed A: substrate, CF3I of C4F9I (1.6 equiv), FeSO4·7H2O
(0.4 equiv) and H2SO4 (0.8 equiv) in DMSO/MeCN 2:1 as solvent; Feed B: 30% aqueous H2O2 (1.6
equiv); residence time: 22 s. [b] See Experimental Section and Table S4 in the Supporting Information for
details. [c] Conditions: Feed A: substrate (10.0 equiv), ICH2CN or ICH2CO2Et, FeSO4·7H2O (0.4 equiv) in
DMSO as solvent; Feed B: 30% aqueous H2O2 (12.0 equiv); residence time 12 min.
10
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In contrast, CH-functionalization with iodoacetonitrile was significantly slower than reactions
with perfluoroalkyl iodides. The reaction of pyrroles with iodoacetontirile required 12 equiv of
H2O2 and a reaction time of 12 min to attain conversions of ~90%. To get sufficient residence
time, a 10 mL PFA tube reactor was connected to the outlet of the glass static mixer. The best
results were obtained in DMSO as solvent without the addition of sulfuric acid. No in-line
quench was performed for these reactions and the product was directly collected into a solution of
H2O/Et2O. With 1-phenylpyrrole as the substrate, the 2-substituted product 4d was formed with a
selectivity of 50% with 1.6 equiv of iodoacetontirile. The main side product was the bis-
substituted compound. In contrast, a high selectivity was obtained with phenylpyrrole in excess
(10 equiv), and the product was isolated in 44% yield after column chromatography (yield with
respect to iodoacetonitrile). Similarly, reactions with 1-methylpyrrole (10 equiv) afforded 1-
methyl-2-pyrroleacetonitrile 10d with a selectivity > 90%. However, the low boiling point of the
product caused significant losses during isolation. CH-Functionalization of 1-methyl-pyrrole with
ethyl iodoacetate afforded the corresponding pyrrole-2-acetate 10e in 65% yield. The pyrrole-2-
acetic acid structure is contained in a wide variety of molecules of pharmaceutical interest, most
notably non-steroidal anti-inflammatory drugs including tolmetin and ketorolac (Figure 1).
Traditional methods for the generation of this important structural motif involve Friedel–Crafts
acylation of pyrrole with ethyl oxalyl chloride and subsequent reduction of the glyoxalate
ester,[27] or alternatively reaction of pyrrole with explosive ethyl diazoacetate in the presence of
Cu catalysts.[28] The generation of pyrrol-2-acetic acids by a radical mediated CH-
functionalization under Minisci-type conditions was first reported by Baciocchi and coworkers in
1992,[14] and the value of this transformation for the generation of natural products and
pharmaceuticals has been demonstrated.[29] For the original batch procedure, hydrogen peroxide
was slowly dropped to the reaction mixture containing 15 to 75 equiv of substrate, and the
pyrrole acetates were isolated in yields comparable to those reported herein for the continuous
flow reactions.[14]
The extraordinary high reaction rate of the radical CH-perfuoroalkylation allows the
generation of large amounts of material in a microreactor of small volume. To demonstrate the
scalability of the reaction, the injection loop was removed and the feed A solution was directly
introduced into the glass microreactor by two continuous syringe pumps at a combined flow rate
of 19 mL/min. In the microreactor the solution was mixed with H2O2 at a flow rate of 1 mL/min.
After the residence unit the mixture was again quenched with aqueous Na2S2O3. With a
11
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microreactor of 1.8 mL residence volume a residence time of ~ 6 s was obtained. With this setup
10 mmol of a 0.32 M solution of 1-phenylpyrrole were processed within only 1.6 min (Scheme
3). Both the reaction with CF3I and with C4F9I proceeded with extraordinary selectivity (92% and
99%; see Figure S5 in the Supporting Information). The trifluoromethylated and
nonafluorobutylated pyrroles were isolated in yields of respectively 63% (0.81 g/min) and 83%
(1.82 g/min) after column chromatography (Scheme 3).
Scheme 3. Continuous flow C─H perfluoroalkylation (see Experimental Section for details).
Finally the reaction conditions were used to convert dihydroergotamine mesylate 1a to the
corresponding trifluoromethyl derivative (Scheme 4). This and related fluoroergoline analogs are
explored as less toxic ergoline derivatives to treat and/or prevent primary headache disorders
such as migraine.[22] Preliminary batch experiments revealed Minisci-type trifluoromethylation as
a promising strategy for the selective late-stage functionalization for this complex alkaloid.
However, the yield for the batch experiments was unsatisfactory and the reaction poorly
reproducible. For the continuous flow reactions, dihydroergotamine mesylate (1a), FeSO4·7H2O
and H2SO4 in DMSO/MeCN 2:1 as solvent were charged into a jacketed three-neck flask
equipped with a mechanical stirrer (see Figure S6 in the Supporting Information). The mixture
was cooled to -10 °C and the respective amounts of CF3I were introduced into the flask under
stirring through an immersion tube. The continuous flow reactions were performed using the
Modular MicroReaction System from Ehrfeld Mikrotechnik BTS (MMRS).[30] MMRS is a
modular, continuous flow platform which allows multiple unit operation elements, including
mixers, residence time modules, heat exchangers and back-pressure regulators, to be mounted on
a common base plate.[30] The reaction mixture was directly pumped from the flask into the flow
system by a syringe pump. Hydrogen peroxide was delivered by a second syringe pump. Both
feed solutions were pre-cooled in a heat-exchanger (1.2 mL internal volume) before they were
12
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Chemistry - A European Journal
combined in the mixer. As reactor for the initial optimization reactions we explored the Lonza
FlowPlate® Lab with a curvature-based mixing geometry and 0.4 mL internal volume (Lonza
FlowPlate® SZ or TG).[31] With 2 equiv of CF3I and 0.2 equiv of FeSO4·7H2O, conversions of
98% and selectivities up to 85% were obtained at a reaction temperature of -10 °C (HPLC-
UV/Vis analysis at 270 nm). Again, increasing the residence time did not further improve the
conversion and virtually identical results were obtained with residence times ranging from 10 s to
4 s (Figure 2).
O
N
HO
O
N
FeSO4·7H2O
H2SO4, CF3I
in DMSO/MeCN
O
NH
N
HO
O
N
O
H
2.9 - 6.8 mL/min
0.53 mL
O
O
quench
NH
HN
H
1a
N
H2O2
-10 °C
4 - 10 s
O
H
HN
F3C
0.14 - 0.33 mL/min
N
1b
H
Scheme 4. Trifluoromethylation of dihydroergotamine mesylate 1a under Minisci conditions.
90%
80%
product 1b
70%
60%
2 equiv
H2O2
50%
40%
30%
20%
10%
0%
sum side-products
DHE 1a
2,00
3,00
4,00
5,00
6,00
7,00
8,00
total flow rate [mL/min]
Figure 2. Trifluoromethylation of dihydroergotamine mesylate (DHE, 1a) at various flow rates (residence
time of 10 to 4 s). Conditions: Feed A: substrate 1a, CF3I (2 equiv), FeSO4·7H2O (0.2 equiv) and H2SO4
(0.75 equiv) in DMSO/MeCN 2:1 as solvent; Feed B: 33% aqueous H2O2 (4.0 equiv); see Experimental
Section for reaction details.
13
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The main side-product of this reaction was a bis-trifluoromethylated derivative of not yet fully
elucidated structure. Apart from this, the trifluoromethylation under Minisci conditions exhibited
remarkable functional group tolerance and no protection of OH or NH groups was required.
Increasing the stoichiometry of CF3I above 2 equiv pushed the reaction to conversions beyond
98% at the cost of reaction selectivity, due to the formation of bis-trifluoromethylated side-
products. Indeed, the best selectivity for the desired product was obtained with 1.5 equiv of CF3I
and 2 equiv of H2O2 (Figure S7 in the Supporting Information). A slightly reduced selectivity was
obtained at 0 °C instead of -10 °C.
For the generation of larger amounts of material, a reactor consisting of 4 plates of A6
format was installed (FlowPlate® A6; total volume: 16.5 mL; see Figure 3). Neat CF3I was
pumped into the reactor as a separate feed from a cooled pump reservoir at a flow rate of 284
µL/min (1.5 equiv). The solution of dihydroergotamine mesylate (1a), FeSO4·7H2O (0.25 equiv)
and H2SO4 (0.7 equiv) in DMSO/MeCN, and H2O2 (34.5%; 2 equiv) were pumped at flow rates
of 15.1 mL/min and 439 µL/min, respectively. Both the substrate feed and the H2O2 feed were
pre-cooled to -10 °C in a heat-exchanger (Figure 3). The substrate feed was first combined with
CF3I in a SZ-mixer of 2.05 mL internal volume, before the resulting mixture was merged with
H2O2 in a second mixer (3.08 mL internal volume; Figure 3), resulting in an overall residence
time of 12 s. The processed mixture was finally quenched with aqueous Na2SO3 in a continuous
stirred tank reactor. In total, the reactor was operated continuously for 5 h. A sample of 600 g of
dihydroergotamine mesylate (1a) was processed during this time. The product was formed with a
stable conversion of 98% and a product selectivity of 85 to 86% (HPLC peak area integration at
270 nm). 10.5 kg of the effluent biphasic product mixture were collected for work-up. Extraction
with ethyl acetate and evaporation of the solvent provided the crude product as the sulfate salt in
87% yield, according to 19F-NMR with trifluorobenzene as internal standard (see Experimental
Section for details).
14
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Figure 3. Reaction in a Lonza FlowPlate® A6 rack on a 0.6 kg scale. CF3I and the substrate feed
were combined in a mixer at -10 °C before the mixture was merged with H2O2 in a second mixer.
The combined stream then went through a residence module at -10 °C. HKK = heating/cooling
circuit.
Conclusion
In conclusion we have demonstrated a scalable continuous flow protocol for the CH-
functionalization of various aromatic and heteroaromatic compounds with CF3I, C4F9I, ICH2CN
and ICH2CO2Et under Minisci-type reaction conditions. Though rarely used, radical reactions
with alkyl iodides and H2O2/DMSO/Fe(II) constitute a broadly applicable and valuable method to
generate carbon─carbon bonds. The distinguishing feature of this reaction is its experimental
15
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simplicity, the mild reaction conditions, the availability of a large number of inexpensive radical
precursors that can be successfully applied, and the particularly low price of H2O2 and Fe(II)
salts. No prefunctionalization of the substrate is needed. The main limitation arises from the
possibility of generating undesired isomers if more than one position is amenable to substitution.
Furthermore, the reaction frequently does not proceed to completion and isolated yields are often
modest. However, even with these genuine limitations, Minisci reactions are extremely useful.
The continuous flow process reported herein allows this reaction to be performed with
extraordinary efficiency. Due to the exceptional heat and mass transfer capacity of microreactors,
the reaction could be performed within reaction times of a few seconds or less. The short reaction
time, in turn, allows the production of large amounts of material in reactors of small volume.
Thus, the process reported herein appears to be especially appealing for industrial applications
where reaction time and reactor cost are important economic factors. Importantly, the reaction
exhibits remarkable functional group tolerance. Dihydroergotamine mesylate, a complex
semisynthetic ergot alkaloid, could be directly converted under mild conditions to the
corresponding trifluoromethyl derivative without the need of protection groups. High conversions
and good selectivities were obtained within reaction times of only 12 seconds on a 0.6 kg scale.
Experimental Section
General Remarks. All compounds and solvents were obtained from standard commercial
1
13
vendors and used without further purification. H-NMR and C spectra were recorded on a 300
or 400 MHz instrument using CDCl3 or DMSO-d6 as solvent. Chemical shifts (δ) are expressed in
ppm downfield from TMS as internal standard. The letters s, d, t, q, qt and m are used to indicate
a singlet, doublet, triplet, quadruplet, quintuplet and multiplet, respectively. Melting points were
determined on a standard melting point apparatus. Analytical HPLC analysis was carried out on a
C-18 reversed-phase (RP) analytical column (150 × 4.6 mm, particle size 5 μm) at 37 °C using a
mobile phase A (water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B (MeCN + 0.1 % TFA) at a
flow rate of 1.5 mL/min. The following gradient was applied: linear increase from solution 30%
B to 100% B in 8 min, hold at 100% solution B for 2 min. For new compounds, HRMS
experiments were performed on a TOF LC/MS instrument equipped with an APCI ion source
(positive ionization mode).
General Experimental Procedure for the Continuous Flow Trifluoromethylation of 1a (kg
Scale) . For a Scheme of the flow setup see Figure 3. The reactor consisted of Lonza FlowPlates®
16
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of A6 format (total volume: 16.5 mL). Neat CF3I was pumped into the reactor from a cooled
pump reservoir at a flow rate of 284 µL/min (1.5 equiv; Teledyne Isco syringe pump). Neat CF3I
was pumped into the reactor from a cooled pump reservoir at a flow rate of 284 µL/min (1.5
equiv; Teledyne Isco syringe pump). For these experiments, the CF3I was condensed into the pre-
cooled cylinder of the Isco pump (-25 °C). The liquefied CF3I was then pushed by the plunger of
the Isco pump into the continuous flow reactor. The solution of dihydroergotamine mesylate 1a
(10.5 wt%), FeSO4·7H2O (0.25 equiv) and H2SO4 (0.7 equiv) in DMSO/MeCN 2:1 was pumped
via a gear pump controlled by a Coriolis mass flow meter at a flow rate of 15.1 mL/min.
Hydrogen peroxide (34.5%, 2 equiv) was delivered at a flow rate of 439 µL/min by a syringe
pump (SyrDos). The substrate feed and the H2O2 feed were pre-cooled in a heat-exchanger to -10
°C (6.2 mL and 5.13 mL, respectively). CF3I and the substrate feed were combined in a SZ-mixer
(2.05 mL) before the mixture was merged with H2O2 in a second mixer (TAN-mixer; 3.08 mL).
The mixture was finally quenched with aqueous Na2S2O3 in a continuous stirred tank reactor
(10% aqueous Na2S2O3 at 12.5 g/min and ethyl acetate at 12.5 g/min). In total, the reactor was
operated continuously for 5 h. A sample of 600 g of dihydroergotamine mesylate was processed
during this time. 10.5 kg of the effluent biphasic product mixture were collected for work-up.
Extraction with ethyl acetate and evaporation of the solvent provided the crude product as the
sulfate salt in 87% yield according to 19F-NMR with trifluorobenzene as internal standard.
Redissolution of the organic residue in ethyl acetate and extraction with aqueous Na2CO3 yielded
the crude free base as an oil after concentration. The free base was precipitated from
acetonitrile/water mixtures. The crude solid was redissolved in ethanol (50 °C) and the product
was precipitated by the addition of ethanolic HCl (1.25 M). Recrystallization of the precipitate
1
from ethanol yielded the product as the hydrochloride salt in 97% purity (HPLC at 270 nm). H
NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 11.54 (s, 1H), 9.75 (s, 1H), 7.38 – 7.33 (m, 2H),
7.31 – 7.29 (m, 2H), 7.21 (t, J = 7.5 Hz, 2H), 7.12 (t, J = 7.3 Hz, 1H), 7.05 – 7.02 (m, 1H), 6.51
(d, J = 1.6 Hz, 1H), 4.54 – 4.50 (m, 1H), 3.79 – 3.53 (m, 5H), 3.44 – 3.15 (m, 5H), 3.09 – 2.91
(m, 5H), 2.01-1.97 (m, 3H), 1.77-1.60 (m, 2H), 1.53 (s, 3H). 13C NMR (126 MHz, DMSO-d6,
carbons lost in the background noise) δ 173.76, 166.16, 164.80, 139.15, 134.13, 130.20, 128.26,
126.44, 124.40, 122.44 (q, JC-F = 268.0 Hz), 118.74 (q, JC-C-F = 38.2 Hz), 114.71, 110.97, 103.30,
86.41, 64.27, 60.23, 56.66, 46.25, 38.99, 30.19, 26.36, 24.26, 22.20, 14.56. 19F NMR (376 MHz,
DMSO) δ -56.89.
17
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General Experimental Procedure for Continuous Flow Trifluoromethylation (2b-7b’, Lab
Scale). For a detailed description of the flow setup see Figure S1 in the Supporting Information.
Feed A: Trifluoroiodomethane (1.6 equiv) was condensed into a vessel cooled in a 2-
proponal/liquid N2 bath. Substrate (2.0 mmol, 0.32 M), FeSO4·7H2O (0.4 equiv. 0.222g), and
H2SO4 (0.8 equiv, 43.0 μL) dissolved in DMSO/MeCN (5.4 mL, 2:1) were added. The solution
was introduced into the injection loop. H2O2 (30%, 1.6 equiv) was pumped into the Uniqsis
microchip (1.8 mL internal volume) at a flow rate of 0.25 mL/min (feed B). DMSO/MeCN was
pumped into the reactor via pump A at a flow rate of 4.75 mL min–1. When the flow system was
stable, the reaction mixture was carried from the injection loop into the reactor. The mixture
leaving the microchip was quenched into a solution of Na2S2O3 (1 M) at flow rate of 5.00 mL
min–1. The products were collected in an open flask and the residue was purified by flash
chromatography to afford the desired compounds in analytical purity.
3-Methyl-2-(trifluoromethyl)-1H-indole (Figure 1, 2b). Substrate: 3-methlyindole. Isolation by
flash chromatography with petroleum ether/ethyl acetate as eluent (0 to 4%) afforded the title
compound in 60 % yield (237 mg, 1.19 mmol) as a colorless solid. Mp: 65.9-68.7°C (lit.[32] 73.0-
1
74.0 °C). H NMR (300 MHz, CDCl3) δ 8.18 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.35 (ddd, J =
13
11.3, 8.9, 4.5 Hz, 2H), 7.20 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 2.45 (q, J = 1.8 Hz, 3H). C NMR
(75 MHz, CDCl3) δ 135.2, 128.1, 124.8, 121.5 (q, JC-C-F = 37.1 Hz), δ 122.12 (q, JC-F = 268.4
Hz), 120.4, 120.1, 114.2 (q, JC-C-C-F = 3.0 Hz), 111.6, 8.3. 19F NMR (282 MHz, CDCl3) δ -58.63
(s, 3F).
2-(Trifluoromethyl)-1H-indole (Figure 1, 3b). Substrate: indole. Isolation by flash
chromatography with petroleum ether/ethyl acetate as eluent (0 to 10%) afforded the title
compound in 30 % yield (111 mg, 0.60 mmol) as a colorless solid. Mp: 94.2-95.8 °C (lit.[32]
107.0-108.0 °C). 1H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.48
(d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.4 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.01 (s, 1H). 13C NMR (75
MHz, DMSO-d6, CF3-carbon lost in the background noise) δ 136.7, 125.9, 124.8 (q, JC-C-F = 38.3
Hz), 124.2, 121.7, 120.4, 112.3, 103.1 (q, JC-C-C-F = 3.4 Hz). 19F NMR (282 MHz, DMSO-d6) δ -
58.82 (s, 3F).
1-Phenyl-2-(trifluoromethyl)-1H-pyrrole (Figure 1, 4b). Substrate: 1-phenylpyrrole. Isolation by
flash chromatography with petroleum ether afforded the title compound in 66 % yield (278 mg,
1.31 mmol) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.48 – 7.42 (m, 3H), 7.41 – 7.36 (m,
2H), 6.89 (dd, J = 2.5, 2.1 Hz, 1H), 6.74 (ddd, J = 3.7, 1.7, 0.8 Hz, 1H), 6.30 – 6.25 (m, 1H). 13C
18
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NMR (75 MHz, CDCl3, C-CF3carbon lost in the background noise) δ 139.2, 129.1, 128.6, 127.4,
19
126.7, 121.3 (q, JC-F = 266.9 Hz), 112.9 (q, JC-C-C-F = 3.4 Hz), 108.4. F NMR (282 MHz,
CDCl3) δ -55.94 (s, 3F).
Methyl 5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (Figure 1, 5b). Substrate: methyl 2-
pyrrolecarboxylate. Isolation by flash chromatography with petroleum ether/ethyl acetate as
eluent (0 to 10%) afforded the title compound in 53 % yield (207 mg, 1.07 mmol) as a white
1
solid. Mp: 95.2-96.8 °C. H NMR (300 MHz, DMSO-d6) δ 13.23 (s, 1H), 6.88 – 6.80 (m, 1H),
6.68 (ddd, J = 3.7, 2.5, 0.9 Hz, 1H), 3.81 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ 160.3, 125.7,
123.8 (q, JC-C-F = 39.4 Hz), 120.6 (q, JC-F = 267.3 Hz), 114.6, 110.7 (q, JC-C-C-F = 3.0 Hz), 51.7.
19F NMR (282 MHz, DMSO-d6) δ -58.44 (s, 3F).
Methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (Figure 1, 5b’). Side product of the
preparation of methyl 5-(trifluoromethyl)-1H-pyrrole-2-carboxylate. Isolation by flash
chromatography with petroleum ether/ethyl acetate as eluent (0 to 10%) afforded the title
1
compound in 7.5 % yield (28.9 mg, 0.15 mmol) as a white solid. Mp: 89.6-91.2 °C. H NMR
(300 MHz, DMSO-d6) δ 12.69 (s, 1H), 7.10 (t, J = 2.8 Hz, 1H), 6.53 (t, J = 2.5 Hz, 1H), 3.82 (s,
3H). 13C NMR (75 MHz, DMSO-d6) δ 159.0, 123.1 (q, JC-F = 266.8 Hz), 122.8, 119.6 (q, JC-C-C-F
= 3.1 Hz), 117.4 (q, JC-C-F = 37.0 Hz), 109.6 (q, JC-C-C-F = 4.0 Hz), 51.8. 19F NMR (282 MHz,
DMSO-d6) δ -55.51 (s, 3F).
2-(Trifluoromethyl)benzene-1,4-diol (Figure 1, 6b). Substrate: hydroquinone. Isolation by flash
chromatography with petroleum ether/ethyl acetate as eluent (0 to 40%) afforded the title
compound in 34 % yield (121 mg, 0.68 mmol) as a brown solid. Mp: 96.0-97.7 °C. 1H NMR (300
MHz, DMSO-d6) δ 9.69 (s, 1H), 9.20 (s, 1H), 6.92 – 6.76 (m, 3H). 13C NMR (75 MHz, DMSO-
d6) δ 149.3, 148.0 (q, J = 1.9 Hz), 123.9 (q, JC-F = 272.0 Hz), 120.4, 118.0, 115.41 (q, J
29.8 Hz), 112.16 (q, JC-C-C-F = 5.1 Hz). 19F NMR (282 MHz, DMSO-d6) δ -60.91 (s, 3F).
=
C-C-F
3,4,5-Trimethoxy-2-(trifluoromethyl)aniline (Figure 1, 7b). Substrate: 3,4,5-trimethoxyaniline.
Isolation by flash chromatography with petroleum ether/diethyl ether (0 to 10%) afforded the title
compound in 18.0 % yield (90.4 mg, 0.36 mmol) as a yellow oil. 1H NMR (300 MHz, DMSO-d6)
δ 6.23 (s, 1H), 5.36 (s, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.62 (s, 3H). 13C NMR (75 MHz, DMSO-
d6) δ 156.4, 152.67 (q, J = 1.8 Hz), 143.8, 132.7, 125.6 (q, JC-F = 272.2 Hz), 97.10 (q, JC-C-F
=
28.1 Hz), 95.9, 61.2, 60.5, 55.4. 19F NMR (282 MHz, DMSO-d6) δ -52.19 (s, 3F). HRMS (APCI):
m/z: calcd for C10H12F3NO3 [(M+H)]+: 252.084204, found: 252.083851.
19
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3,4,5-Trimethoxy-2,6-bis(trifluoromethyl)aniline (Figure 1, 7b’). Side product of the
preparation of 3,4,5-trimethoxy-2-(trifluoromethyl)aniline. Isolation by flash chromatography
with petroleum ether/diethyl ether (0 to 10%) afforded the title compound in 15 % yield (28.9
mg, 0.15 mmol) as a yellow oil.1H NMR (300 MHz, DMSO-d6) δ 5.51 (s, 2H), 3.88 (s, 6H), 3.70
13
(s, 3H). C NMR (75 MHz, DMSO-d6) δ 157.3, 141.9, 136.7, 124.6 (q, JC-F = 274.0 Hz), 102.6
(q, JC-C-F = 27.7 Hz), 61.6, 60.8.19F NMR (282 MHz, DMSO-d6) δ -53.34 (s, 3F). HRMS (APCI):
m/z: calcd for C11H11F6NO3 [(M+H)]+: 318.057036, found: 318.057609.
3-Methyl-2-(perfluorobutyl)-1H-indole (Figure 1, 2c). Substrate: 3-methlyindole. Isolation by
flash chromatography with petroleum ether/ethyl acetate as eluent (0 to 4%) afforded the title
compound in 71 % yield (494 mg, 1.41 mmol) as a yellow solid. Mp: 70.0-71.1°C (lit.[33] 67.1-
1
68.8 °C). H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.44 – 7.30 (m,
13
2H), 7.21 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 2.45 (t, J = 2.2 Hz, 3H). C NMR (75 MHz, CDCl3,
C4F9-carbons lost in the background noise) δ 136.1, 128.5, 125.1, 120.5, 120.2, 119.6 (t, JC-C-F
=
28.4 Hz), 116.9 (t, JC-C-C-F = 3.4 Hz), 111.7, 8.7 (d, J = 1.4 Hz). 19F NMR (282 MHz, CDCl3) δ -
80.99 (tt, J = 9.7, 2.6 Hz, 3F), -108.76 – -108.93 (m, 2F), -122.93 – -123.18 (m, 2F), -125.85 – -
126.11 (m, 2F).
2-(Perfluorobutyl)-1H-indole (Figure 1, 3c). Substrate: indole. Isolation by flash
chromatography with petroleum ether/ethyl acetate as eluent (0 to 10%) afforded the title
1
compound in 34 % yield (230 mg, 0.69 mmol) as a yellow solid. Mp: 43.2-44.8 °C. H NMR
(300 MHz, DMSO-d6) δ 12.20 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.3, 0.8 Hz, 1H),
13
7.30 (t, J = 7.6 Hz, 1H), 7.14 (ddd, J = 8.0, 7.1, 0.9 Hz, 1H), 7.04 (s, 1H). C NMR (75 MHz,
DMSO-d6, C4F9-carbons lost in the background noise) δ 137.3, 126.3, 124.3, 122.9 (t, JC-C-F
=
19
29.7 Hz), 121.7, 120.5, 112.4, 105.3 (t, JC-C-C-F = 4.7 Hz). F NMR (282 MHz, DMSO-d6) δ -
80.53 (ddd, J = 12.4, 6.2, 3.0 Hz, 3F), -107.12 (t, J = 12.1 Hz, 2F), -122.02 – -123.17 (m, 2F), -
124.99 – -125.99 (m, 2F).
2-(Perfluorobutyl)-1-phenyl-1H-pyrrole (Figure 1, 4c). Substrate: 1-phenylpyrrole. Isolation by
flash chromatography with petroleum ether afforded the title compound in 90 % yield (645 mg,
1.78 mmol) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.46 – 7.40 (m, 3H), 7.38 – 7.31 (m,
2H), 6.91 – 6.86 (m, 1H), 6.77 – 6.71 (m, 1H), 6.33 (dd, J = 3.7, 2.9 Hz, 1H). 13C NMR (75
MHz, CDCl3, C4F9-carbons lost in the background noise) δ 139.8, 129.2 (m), 128.8, 127.5, 121.3,
19
120.2 (t, JC-C-F = 29.7 Hz), 115.2 (t, JC-C-C-F = 5.4 Hz), 108.8. F NMR (282 MHz, CDCl3) δ -
20
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Chemistry - A European Journal
81.09 (tt, J = 9.8, 2.9 Hz, 3F), -101.15 (t, J = 13.3 Hz, 2F), -121.30 – -121.59 (m, 2F), -125.79 – -
125.98 (m, 2F).
2-(Perfluorobutyl)benzene-1,4-diol (Figure 1, 6c). Substrate: hydroquinone. Isolation by flash
chromatography with petroleum ether/ethyl acetate as eluent (0 to 40%) afforded the title
1
compound in 52 % yield (342 mg, 1.04 mmol) as a yellow solid. Mp: 84.4-86.1 °C. H NMR
(300 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.22 (s, 1H), 6.89 (dd, J = 8.9, 2.7 Hz, 1H), 6.84 (d, J = 8.8
Hz, 1H), 6.76 (d, J = 2.7 Hz, 1H). 13C NMR (75 MHz, DMSO-d6, C4F9-carbons lost in the
background noise) δ 149.6, 149.3 (t, JC-C-C-F = 3.1 Hz), 121.1, 118.5, 113.7 (t, JC-C-C-F = 8.8 Hz),
19
113.0 (t, J C-C-F = 22.4 Hz). F NMR (282 MHz, DMSO-d6) δ -80.48 (tt, J = 9.7, 2.7 Hz, 3F), -
107.41 (td, J = 13.3, 2.5 Hz, 2F), -121.76 (h, J = 9.6 Hz, 2F), -125.70 (dq, J = 19.9, 9.9 Hz, 2F).
HRMS (APCI): m/z: calcd for C10H5F9O2 [(M+H)]+: 327.007307, found: 327.007136.
2,5-Dimethoxy-4-(perfluorobutyl)aniline (Figure 1, 9c). Substrate: 2,5-dimethoxyaniline.
Isolation by flash chromatography with petroleum ether/dichloromethane as eluent (0 to 50%)
afforded the title compound in 56 % yield (417 mg, 1.12 mmol) as a brown solid. Mp: 53.9-55.2
°C. 1H NMR (300 MHz, DMSO-d6) δ 6.73 (s, 1H), 6.46 (s, 1H), 5.58 (s, 2H), 3.72 (s, 3H), 3.68
(s, 3H). 13C NMR (75 MHz, DMSO-d6, C4F9-carbons lost in the background noise) δ 153.8 (t, JC-
= 3.0 Hz), 143.6, 139.5, 110.2 (t, JC-C-C-F = 9.0 Hz), 99.5 (t, JC-C-F = 23.7 Hz), 98.1, 56.0,
C-C-F
55.9. 19F NMR (282 MHz, DMSO-d6) δ -80.51 (t, J = 9.7 Hz, 3F), -104.35 (td, J = 12.9, 1.6 Hz,
2F), -121.72 (h, J = 9.0 Hz, 2F), -125.57 – -125.90 (m, 2F). HRMS (APCI): m/z: calcd for
C12H10F9NO2 [(M+H)]+: 372.064059, found: 372.064469.
General Experimental Procedure for the Continuous Flow Synthesis of 2,6-Dichloro-4-
(trifluoromethyl)aniline (Figure 1, 8b). Feed A consisting of a mixture of 2,6-dichloroaniline
(2.0 mmol, 0.28 M), FeSO4.7H2O (1.6 equiv, 0.888 g), H2SO4 (3.2 equiv, 342 µL), and
trifluoroiodomethane (1.6 equiv, 251.0 µL) dissolved in a 5% solution of DMSO in H2O (5.4
mL), and feed B containing H2O2 (30%, 4.0 equiv) were pumped, at room temperature, into a
Uniqsis microchip (1.8 mL internal volume) by two syringe pumps (Asia Syrris) at flow rates of
4.150 mL min–1 and 0.850 mL/min, respectively. The mixture leaving the microchip was
quenched into a solution of diethyl ether/ H2O out line. The product was collected in an open
flask and the residue was purified by flash chromatography to afford the desired compound in
analytical purity. Substrate: 3,4,5-Trimetoxyaniline. Isolation by flash chromatography with
petroleum ether/diethyl ether (0 to 5%) afforded the title compound in 32 % yield (166 mg, 0.72
1
13
mmol) as a yellow oil. H NMR (300 MHz, DMSO-d6) δ 7.59 (m, 2H), 6.21 (s, 2H). C NMR
21
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10.1002/chem.201604579
Chemistry - A European Journal
(75 MHz, DMSO-d6) δ 145.2, 125.5 (q, JC-C-C-F = 3.7 Hz), 124.0 (q, JC-F = 270.8 Hz), 118.0,
116.8 (q, JC-C-F = 33.7 Hz). 19F NMR (282 MHz, DMSO-d6) δ -59.56.
General Experimental Procedure for the Continuous Flow Synthesis of Acylpyrroles
(Figure 1, 4d, 10d and 10e). Feed A consisting of a mixture of the substrate (10.0 equiv),
FeSO4.7H2O (0.4 equiv, 0.222g) and iodoacetonitrile or ethyl iodoacetate (2.0 mmol, 0.26M, 1.0
equiv) dissolved in DMSO (5.4 mL), and feed B containing H2O2 (30%, 12.0 equiv) were
pumped, at room temperature, into a Uniqsis microchip (1.8 mL internal volume) connected by a
T mixer to a coil (10 mL internal volume) by two syringe pumps (Asia Syrris) at flow rates of
0.700 mL min–1 and 0.300 mL/min, respectively. After 12 min of residence time, the mixture
leaving the coil was quenched into a solution of diethyl ether/ H2O out line. The product was
collected in an open flask and the residue was purified by flash chromatography to afford the
desired compounds in analytical purity.
2-(1-Phenyl-1H-pyrrol-2-yl)acetonitrile (Figure 1, 4d). Substrate: 1-phenylpyrrole. Isolation by
flash chromatography with petroleum ether/ethyl acetate as eluent (0 to 10%) afforded the title
1
compound in 44 % yield (160 mg, 0.88 mmol) as a yellow solid. Mp: 48.7-49.8 °C. H NMR
(300 MHz, DMSO-d6) δ 7.91 – 7.83 (m, 2H), 7.81 – 7.72 (m, 3H), 7.33 (dd, J = 2.7, 2.0 Hz, 1H),
6.60 (dd, J = 2.9, 2.1 Hz, 1H), 6.54 (t, J = 3.2 Hz, 1H), 4.34 (s, 2H). 13C NMR (75 MHz, DMSO-
d6) δ 139.2, 130.1, 128.1, 125.8, 124.0, 121.8, 118.4, 110.4, 109.0, 16.2.
2-(1-Methyl-1H-pyrrol-2-yl)acetonitrile (Figure 1, 10d). Substrate: N-methylpyrrole. Isolation
by flash chromatography with petroleum ether/diethyl ether as eluent (0 to 40%) afforded the title
compound in 62 % yield (151 mg, 1.25 mmol) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ
6.75 – 6.70 (m, 1H), 6.03 – 5.95 (m, 1H), 5.96 – 5.89 (m, 1H), 4.02 (s, 2H), 3.56 (s, 3H). 13C
NMR (75 MHz, DMSO-d6) δ 123.2, 121.1, 118.1, 107.8, 106.6, 33.3, 14.8.
Ethyl 2-(1-Methyl-1H-pyrrol-2-yl)acetate (Figure 1, 10e). Substrate: N-methylpyrrole. Isolation
by flash chromatography with petroleum ether/ethyl acetate as eluent (0 to 10%) afforded the title
1
compound in 70 % yield (234 mg, 1.40 mmol) as a yellow oil. H NMR (300 MHz, CDCl3) δ
6.60 (d, J = 1.9 Hz, 1H), 6.10 – 6.07 (m, 1H), 6.05 (d, J = 2.7 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H),
13
3.62 (s, 2H), 3.59 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). C NMR (75 MHz, CDCl3) δ 170.6, 125.0,
122.5, 108.7, 107.0, 61.0, 33.9, 32.7, 14.2.
22
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10.1002/chem.201604579
Chemistry - A European Journal
Acknowledgements
C.O.K acknowledges the Brazilian Science without Borders program (CNPq, CAPES) for a
“Special Visiting Researcher” fellowship. J. L. M. thanks FAPESP for a scholarship
(2014/21319-8) and P. F. C. thanks CNPq for a postdoctoral scholarship (200566/2014-8/PDE).
We thank Microinnova Engineering GmbH for the loan of a Labtrix Start reactor (Chemtrix). We
also acknowledge the valuable input of Michael Bittel (Lonza AG) to this work.
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Chemistry - A European Journal
TOC Graphic
Trifluoromethylation in seconds: Radical C─C bond formation with CF3I, H2O2,
dimethylsulfoxide and Fe(II) as catalyst yields trifluoromethylated products within reaction times
of seconds in a continuous flow microreactor. The reaction proceeds satisfactory with selected
electrophilic radicals, including ·C4F9, ·CH2CN and ·CH2CO2Et. The protocol allowed the
trifluoromethylation of dihydroergotamine on a 0.6 kg scale.
Keywords: Trifluoromethylation • Fenton reagent • Minisci reaction • Radical reactions • Flow
chemistry
26
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