Aminotrifluoromethylation of Olefins via Cyclic Amine Formation: Mechanistic Study and Application to Synthesis of Trifluoromethylated Pyrrolidines

Article abstract of DOI:10.1021/jacs.5b02046

(Chemical Equation Presented). We examined the mechanism of our previously reported aminotrifluoromethylation reaction, which proceeds via intramolecular cyclization of alkenylamines in the presence of the combination of copper catalyst and Togni reagent (1). Kinetic studies revealed that the initial rate of the reaction was first order with respect to Togni reagent and CuI, as well as the substrate. Changes of the ¹⁹F NMR chemical shift of Togni reagent during the reaction suggested the existence of a dynamic equilibrium involving coordination of not only Togni reagent, but also the substrate amine and the product aziridine to copper. ESI-MS analysis provided evidence of involvement of reactive Cu(II) intermediates in the catalytic cycle. Overall, our results indicate that the reaction proceeds at the hypervalent iodine moiety of Togni reagent, which is activated by Cu(II) species acting as a Lewis acid catalyst. On the basis of these mechanistic considerations, we developed an efficient synthesis of trifluoromethylated pyrrolidine derivatives. This transformation exhibited a remarkable rate enhancement upon addition of Et₃N.

Full text of DOI:10.1021/jacs.5b02046

Article
pubs.acs.org/JACS
Aminotrifluoromethylation of Olefins via Cyclic Amine Formation:
Mechanistic Study and Application to Synthesis of
Trifluoromethylated Pyrrolidines
Shintaro Kawamura,†,‡,§ Hiromichi Egami,†,§,∥ and Mikiko Sodeoka*,†,‡,§
†Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
‡RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
§Sodeoka Live Cell Chemistry Project, ERATO, Japan Science and Technology Agency, 2-1 Hirosawa, Wako, Saitama 351-0198,
Japan
S
* Supporting Information
ABSTRACT: We examined the mechanism of our previously reported aminotrifluoromethylation reaction, which proceeds via
intramolecular cyclization of alkenylamines in the presence of the combination of copper catalyst and Togni reagent (1). Kinetic
studies revealed that the initial rate of the reaction was first order with respect to Togni reagent and CuI, as well as the substrate.
Changes of the 19F NMR chemical shift of Togni reagent during the reaction suggested the existence of a dynamic equilibrium
involving coordination of not only Togni reagent, but also the substrate amine and the product aziridine to copper. ESI-MS
analysis provided evidence of involvement of reactive Cu(II) intermediates in the catalytic cycle. Overall, our results indicate that
the reaction proceeds at the hypervalent iodine moiety of Togni reagent, which is activated by Cu(II) species acting as a Lewis
acid catalyst. On the basis of these mechanistic considerations, we developed an efficient synthesis of trifluoromethylated
pyrrolidine derivatives. This transformation exhibited a remarkable rate enhancement upon addition of Et3N.
forming reactions emerged as the next focus of research.5 In
INTRODUCTION
■
2011, Buchwald,9a Liu,9b and Wang9c independently reported
Trifluoromethylated compounds have attracted much attention
as candidate agrochemicals and pharmaceuticals because of
Cu-catalyzed deprotonative trifluoromethylation of olefins by
using electrophilic trifluoromethylating reagents such as Togni
reagent and Umemoto reagent. Qing achieved the reaction with
their unique biological activities, high hydrophobicity, lip-
ophilicity, and metabolic stability.1,2 Trifluoromethylated cyclic
the combination of Ruppert−Prakash reagent (CF3SiMe3) and
amines are especially important, not only as core structures of
oxidant in 2012.9d We and Gouverneur also independently
bioactive compounds,3 but also as potential synthetic
precursors of β-trifluoromethylated alkylamine derivatives.4
reported the reaction of allylsilanes with Togni reagent to afford
trifluoromethylated exomethylenes, trisubstituted alkenes, and
Thus, efficient and convenient synthetic methods to access
vinylsilane derivatives, which are synthetically important
these compounds are desirable.
building blocks.10 Difunctionalization of olefins via trifluor-
Catalytic trifluoromethylations have been well studied in the
past decade.5 In 1989, Chen and Wu reported the first copper-
omethylation is an important goal in this field, because this
approach offers direct access to synthetically significant
catalyzed trifluoromethylation with 2,2-difluoro-2-(fluorosufo-
compounds.5,10−19 In 2012, catalytic oxytrifluoromethylation
nyl)acetate (DFSA).6a,b Amii6c and Inoue6d independently
developed the efficient catalytic trifluoromethylation of
aromatic compounds with trialkyltrifluoromethylsilane in
2009,6 and various types of aromatic trifluoromethylation
have since been reported.5 In 2011, Hartwig isolated a Cu−
CF3-diamine complex and demonstrated its reactivity for
aromatic trifluoromethylation.7,8 After the establishment of
trifluoromethylation of aromatic compounds, Csp3−CF3 bond-
of styrene derivatives with Togni reagent was independently
reported by us11a and Szabo,11b
enabling direct introduction of
́
both 2-iodobenzoate and trifluoromethyl groups. Buchwald
developed intramolecular oxytrifluoromethylation leading to
Received: February 25, 2015
© XXXX American Chemical Society
A
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cyclic ethers or lactones, and also reported an asymmetric
version of the reaction.11c,d Synthetically useful intra- and
intermolecular oxytrifluoromethylations have also been devel-
oped.12 The first example of catalytic carbotrifluoromethylation
was reported by Liu in 2012.13 The reaction proceeded under
oxidative trifluoromethylation conditions using CF3SiMe3 and
Pd(II) catalyst, affording trifluoromethylated oxindoles from
α,β-unsaturated amides. In 2013, we developed a copper-
catalyzed electrophilic carbotrifluoromethylation of simple
olefins, through which both carbo- and heterocycles such as
indane, tetralin, indoline, and tetrahydroquinoline were
successfully constructed.14a,b Trifluoromethylated oxindole
synthesis by electrophilic carbotrifluoromethylation has been
extensively studied and achieved under various reaction
conditions.14−16 However, despite the rapid progress of
difunctionalizing trifluoromethylations,17 aminotrifluoromethy-
lation is still rare.18,19 Akita and Cho independently achieved
aminotrifluoromethylation by using Ru-bipyridyl complexes as
photoredox catalysts. Akita developed a Ritter-type reaction of
styrene derivatives with Umemoto reagent,19b and Cho
demonstrated the perfluoroalkylation of N-allylanilines with
perfluoroalkyl iodide, providing trifluoromethylated aziridines
in up to 65% yield.19c At around the same time, we
independently reported an efficient aminotrifluoromethylation
of alkenylamines with the combination of Togni reagent 1 and
CuI as a catalyst; this provided a method for selective and high-
yielding synthesis of trifluoromethylated aziridines (Scheme
1).19a In the same report, we showed that selective synthesis of
enable synthesis of trifluoromethylated pyrrolidines (Scheme
2).
Scheme 2. This Work
RESULTS AND DISCUSSION
■
Mechanistic Study. To our knowledge, two types of
possible key reactive species have been proposed in related
work on Cu-catalyzed trifluoromethylations of olefins with
Togni reagent 1 (Scheme 3). One of the proposed mechanisms
Scheme 3. Proposed Key Intermediates
Scheme 1. Cu-Catalyzed Aminotrifluoromethylation of
Allylamines 2 with Togni Reagent 1 to Obtain β-
Trifluoromethyl Amines
requires generation of trifluoromethyl radical as a key
intermediate, which either reacts directly with olefins or is a
precursor of Cu−CF3 species.20 The other proposed
mechanism involves activated Togni regent as the reactive
species, in which the electrophilicity of the hypervalent iodine is
enhanced by copper as a Lewis acid. The latter is based on
Togni’s originally proposed mechanism of trifluoromethylation
of alcohols in the presence of zinc salts.21 However, there is no
decisive evidence regarding the mechanism of Cu-catalyzed
olefin trifluoromethylation. In this context, we first planned to
identify the reactive species of the aminotrifluoromethylatio-
n.19a As shown in Scheme 3(a), highly reactive free CF3 radical
could be generated by the reaction of Togni reagent 1 with
Cu(I) salt. If the resulting CF3 radical plays a major role in the
aminotrifluoromethylation reaction, preincubation of copper
salt with 1 in the absence of the substrate should have negative
effects on the reaction. Therefore, the influence of pretreatment
of the copper salt with Togni reagent 1 on the reaction was
examined (Scheme 4, Figure 1). Less reactive allylamine
bearing an ethylbenzoate group 2 was selected as a model
substrate for the study. In procedure A, CuI was pretreated with
Togni reagent 1 in CH2Cl2 at 40 °C for 30 min, and the
substrate was then added to the mixture. In procedure B,
substrate and Togni reagent 1 were mixed first, and then CuI
was added. No conversion was observed when a mixture of
substrate and Togni reagent 1 was simply warmed to 40 °C
without the copper catalyst. Under these conditions, we traced
the formation of the trifluoromethylated aziridine 3 and N-
migratory oxytrifluoromethylated product 4. It was found that
not only did the reaction rate increase, but also the product
selectivity of 3 was improved by the pretreatment. These
N-migratory oxytrifluoromethylation products could also be
achieved by solvent switching. Furthermore, we successfully
transformed the in situ-generated aziridine to various β-
trifluoromethylated amines via Lewis acid-catalyzed ring
opening with various nucleophiles, such as n-BuOH, PhOH,
PhNH2, DecSH, p-TolSH, and indole. Although this method is
an efficient and convenient strategy for preparing β-
trifluoromethyl amines, the reaction mechanism remained
unclear. We also reported in the same paper that the reaction
conditions were applicable to the synthesis of trifluoromethy-
lated pyrrolidines, albeit with limited substrate scope. Here, we
present a mechanistic study of our aminotrifluoromethylation
and we also describe an extension of the substrate scope to
B
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increased the solubility by coordination, thereby accelerating
the reaction.22 Indeed, a dilute condition (0.08 M) showed an
almost linear time course at the initial stage of the reaction.
Therefore, further investigation of the kinetics was performed
under a dilute condition (Figures 3−5). The dependence of the
Scheme 4. Procedures for Aminotrifluoromethylation
Figure 3. Plots of d[aziridine 3]/dt vs initial concentration of (a)
Togni reagent 1 and (b) CuI.
Figure 1. Effect of preactivation of Cu catalyst with Togni reagent 1
on the reaction of allylamine 2.
initial rate on the concentrations of Togni reagent 1, CuI, and
allylamine 2 was examined (Figures 3 and 4).23As shown in
observations suggested formation of a reactive species during
the pretreatment of CuI with 1 (Figure 1). Thus, using
procedure A, we conducted a kinetic study of the reaction, and
the yield of aziridine 3 was plotted against the reaction time
(Figure 2, blue line; 0.20 M). An induction period was observed
at the initial stage of the reaction, despite the preactivation of
CuI. We speculated that low solubility of copper species caused
the induction period, and the substrate amine possibly
Figure 4. Plot of turnover frequency (TOF) vs initial concentration of
allylamine 2.
Figure 3, first-order relationships of the initial rates with the
concentrations of both Togni reagent 1 and CuI were observed.
Furthermore, the turnover frequency (TOF) of the catalyst was
found to depend on the initial concentration of allylamine 2
with a first-order relationship (Figure 4). These observations
suggested that not only Togni reagent 1 and the reactive
copper species, but also the substrate are involved in the
turnover-limiting step. The possibility of product inhibition was
also investigated by external addition of aziridine 3 to the
reaction mixture (Figure 5). The rate of conversion of starting
material 2 decreased with increasing amount of externally
added aziridine 3, and the plot showed an inverse first-order
Figure 2. Reaction rate under the previously reported optimized
conditions for aminotrifluoromethylation (blue) and under the diluted
condition used for kinetic study (red).
C
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Complex 5a provided the desired aziridine 3 in 66% yield,
despite slow conversion (entry 2) compared to the reaction
with CuI (entry 1). Extension of the reaction time increased the
amount of N-migratory oxytrifluoromethylated product 4
(entry 3). In order to investigate the influence of the
coordinating solvent, Cu2(O2CAr)4·2THF (5b) was employed
in the reaction (entry 4). The THF complex 5b provided the
desired products 3 and 4 in only 14 and 7% yield,
respectively.26 Furthermore, catalytic amount of MeOH was
externally added to the reaction using CuI, and the rate was
found to be decreased to the similar level of the reaction using
5a (entries 2 and 5) indicating the coordinating solvent
decreases the catalytic reactivity. These data suggest that the
Cu(II) 2-iodobenzoate species27 dominantly catalyzes the
aminotrifluoromethylation reaction with the pretreatment
procedure.28
Figure 5. Product inhibition.
relationship. Thus, aziridine 3 probably inhibits the reaction by
coordination to a copper center of an intermediate in the
catalytic cycle.
Next, we attempted to identify the reactive copper species
generated by preincubation of Togni reagent 1 and CuI. The
mixture of CuI and Togni reagent 1 showed a green color
regardless of the solvent. Fortunately, green crystals of 5a
generated from the reaction mixture of CuI and Togni reagent
1 in MeOH were successfully isolated, and the crystal structure
was solved by X-ray single-crystal analysis.24 No trifluoromethyl
group was contained in the complex 5a, and it was found to be
a Cu(II) dimer bridged by four 2-iodobenzoates with two
solvent molecules as additional ligands (Figure 6).25 This result
The trifluoromethyl group in the reaction mixture was then
traced by means of 19F NMR spectroscopy. First, CuI and
complex 5a were each reacted with Togni reagent 1 in CD2Cl2,
and the 19F NMR spectra were compared (Figure 7). The 19F
Figure 7. 19F NMR analysis of the mixtures of Cu precursors and
Togni reagent in CD2Cl2.
Figure 6. Structure of Cu2(O2CAr)4·2MeOH (5a) (Ar = 2-IC6H4)
Thermal ellipsoids are shown at 50% probability in the X-ray crystal
structure. Selected bond lengths (Å): Cu1−O1, 1.986(2); Cu1−Cu2,
2.6040(6); Cu1−O2, 2.111(2).
NMR signal derived from Togni reagent 1 (−34.6 ppm) was
shifted to lower magnetic field after addition of the copper salt,
and the two mixtures gave almost the same chemical shifts
(−32 ppm).29 Notably, the signal of Togni reagent 1 itself
completely disappeared, despite its excess amount. This can be
explained in terms of rapid ligand exchange of intermediates.
Only CuI as the precursor gave signals with low intensity at
−25.9 and −3.4 ppm that should be derived from side-products
generated during the oxidation of CuI.30 For further
comparison of the mixtures, ESI-MS spectra were obtained
(Figure 8). We found that the ESI-MS spectra obtained from
the two mixtures were almost identical, which indicated that the
same intermediates were formed from the different copper
precursors by reaction with Togni reagent 1. In addition to the
signal corresponding to the Togni reagent, several signals
derived from copper species were observed by ESI-MS analysis,
although a single major signal was observed in the 19F NMR
spectra of the mixtures, which suggested the existence of rapid
equilibria between the various copper complexes. The intense
signals of copper-containing species were assigned as described
in Figure 9.31−33 ESI-MS signals of copper species were easily
distinguished because of the unique isotope pattern of copper.
The strongest signal A was assigned as a cationic monomeric
copper species with Togni reagent 1, and an Na+ adduct of
neutral diiodobenzoate complex B, a potential parent
compound of A, was also detected as a weak signal. Signal C
suggested that Togni reagent 1 can oxidize Cu(I) to Cu(II)
species under the reaction conditions. Having the copper
complex 5a in hand, we examined its catalytic reactivity in the
aminotrifluoromethylation (Table 1). According to procedure
A shown in Scheme 4, allylamine 2 was reacted with Togni
reagent 1 in the presence of 5a in CH2Cl2 at 40 °C for 1 h.
Table 1. Aminotrifluoromethylation with Cu(II)-2-
Iodobenzoate Complexes As the Precursor
b
yield (%)
a
b
entry
Cu cat.
3
4
recovery of 2 (%)
d
1
2
CuI
92
66
71
14
64
2
5
Cu2(O2CAr)4·2MeOH (5a)
Cu2(O2CAr)4·2MeOH (5a)
Cu2(O2CAr)4·2THF (5b)
CuI + MeOH (20 mol %)
4
29
13
70
25
c
3
16
7
4
5
10
a
Reactions were conducted on 0.25 mmol scale for 1 h according to
b
procedure A in Scheme 4. Yields were determined by 1H NMR
analysis with dibromomethane as an internal standard. The reaction
was conducted for 3 h. Isolated yield.
c
d
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Figure 10. 19F NMR traces of the reaction of allylamine 2 with Togni
reagent 1 by using Cu catalyst 5a in CD2Cl2. Expanded views from (a)
−34.7 to −31.7 ppm and (b) −65.4 to −64.5 ppm are shown in the
boxes.
Figure 8. ESI-MS analysis of mixtures of Cu catalysts and Togni
reagent 1 in MeOH (a: CuI + 1, b: 5a + 1).
The results of the above mechanistic studies led us to the
following conclusions. The Cu(II) species generated by
oxidation of CuI with Togni reagent 1 serves as a Lewis acid
catalyst, and the desired reaction involves rapid equilibria that
include product inhibition. A plausible catalytic cycle is shown
in Figure 11. CuI is first oxidized by Togni reagent 1 to provide
Figure 9. Possible structures of the copper species detected by ESI-MS
analysis in the mixtures of copper precursors and Togni reagent (Ar =
2-IC6H4).
was characterized as a cationic copper species involving two
Togni reagent molecules.
Next, the substrate allylamine 2 was added to the equilibrated
mixture of Togni reagent 1 and 5a, and the mixture was
monitored using 19F NMR (Figure 10). As presented in Figure
7, a signal derived from the reactive species formed from 5a
with Togni reagent 1 was detected at −32.0 ppm. As soon as
the substrate 2 was added to the reaction mixture, the 19F NMR
signal shifted to −34.0 ppm, and a broad signal, probably
derived from aziridine 3, was detected at −64.9 to −65.0 ppm.
As the reaction proceeded, the signal at −34.0 ppm gradually
shifted to lower magnetic field and its intensity decreased. On
the other hand, the signal of aziridine 3 increased as the other
major signal at ca. −33 to −34 ppm decreased. After overnight
reaction, a very tiny signal was detected at −33.6 ppm and the
signal derived from the aziridine was slightly shifted to lower
magnetic field.34 In addition, a signal at −63.6 ppm derived
from the N-migratory oxytrifluoromethylation product was
detected. These observations help us to understand the
dynamic equilibrium during the reaction. The chemical shift
changes observed for the first and second 19F NMR signals can
be explained in terms of coordination of the starting material 2
and the product aziridine 3 to the copper center coordinating
Togni reagent 1, respectively.35
Figure 11. Proposed catalytic cycle.
Cu(II) species during the pretreatment. Although CF3 radical
would be cogenerated by this oxidation step, it is likely to be
decomposed in the absence of the substrate.35 The Lewis-acidic
Cu(II) species forms an intermediate I, detected as a fragment
ion by ESI-MS analysis.36 The O−I bond of Togni reagent 1 is
activated by the Cu(II) species and the electrophilicity of the
hypervalent iodine is enhanced by formation of intermediate II.
This intermediate II is in equilibrium with intermediates I and
also III in the presence of allylamine 2. Intermediates II or III
reacts with nucleophilic allylamine 2 or Togni reagent 1 on the
activated hypervalent iodine moiety, respectively. We consid-
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ered this step to be the turnover-limiting step, based on the
first-order kinetic relationships of Togni reagent, CuI, and
allylamine (Figures 3 and 4). The transformation of
intermediate I to IV37 should be affected by the concentrations
of copper catalyst, Togni reagent 1, and allylamine 2 because of
the rapid equilibriums. Intermediate I is regenerated via ligand
coupling38 with formation of the desired aziridine 3 and 2-
iodobenzoic acid. After the second cycle, aziridine can inhibit
the reaction by coordination to the copper center.
Table 2. Substrate Scope for Synthesis of
Trifluoromethylated Pyrrolidines
Application to Synthesis of Trifluoromethylated
Pyrrolidines. In our previous report on aminotrifluoromethy-
lation, we demonstrated that this reaction was applicable to the
systhesis of not only trifluoromethylated aziridines, but also
pyrrolidines.19a Recently, Tan and Liu reported an intra-
molecular aminotrifluoromethylation with five-membered ring
formation, in which 10−50 mol % of CuI and higher
temperature were required.39 They also noted that our
previously reported conditions for aminotrifluoromethylation
(with CuI, in t-BuOH (0.2 M)) provided better results for
some of their substrates. However, in some cases poor results
were obtained. For instance, when N-(4-pentenyl)aniline 6a
was employed as a substrate, the desired pyrrolidine 7a was
obtained in only 38% yield due to formation of uncyclized
byproducts (Scheme 5). On the basis of the present
Scheme 5. Pyrrolidine Ring Formation by
Aminotrifluoromethylation of Alkenylamine 6a with Togni
Reagent 1
mechanistic findings, we speculated that protonation of the
substrate amine by the coexisting 2-iodobenzoic acid prevents
nucleophilic C−N bond formation. Thus, trapping the acid
with an appropriate base should accelerate the ring formation
and improve the yield of the desired product. We conducted
additive screening, and found that Et3N as a cocatalyst
dramatically improved the reaction, affording 7a in 73%
yield.40 After further optimization, the reaction in CH2Cl2
(0.4 M) was found to give the best result under mild
conditions, and the desired pyrrolidine 7a was obtained in 89%
yield.41 We then examined the substrate scope of the reaction
under the optimized conditions (Table 2). Both electron-rich
and deficient aniline tolerated available for the reaction (entries
1−5). Alkenylamine 6b bearing a 4-methoxy group on the
aromatic ring showed high reactivity, as did 6a, although the
yield was slightly decreased due to competing trifluoromethy-
lation of the aromatic ring (entry 1). Halogen groups are
completely tolerated under these conditions, and the desired
product was obtained in 72−78% yield (entries 2−5). 2-Me-4-
MeO-phenyl substrate 6g provided the desired product 7g in
82% yield (entry 6). Naphthylamine 6h afforded the
corresponding pyrrolidine 7h in 42% yield (entry 7). The o-
allylaniline 6i efficiently gave the indoline derivative 7i in 82%
yield under the conditions with Et3N (entry 8). In addition, the
catalyst loading could be reduced to 1 mol % without decrease
a
Reactions were conducted under the optimal conditions described in
b
Scheme 5. The yields without Et3N are shown in parentheses. The
reaction was conducted at 40 °C. 1 mol % of CuI was used. t-BuOH
was used as the solvent. The reaction was conducted for 3 h. The
reaction was conducted at 75 °C for 24 h. Without Et3N. 0.3 mol %
of CuI was used.
c
d
e
f
g
h
of the yield. Alkenylamine 6j, possessing a methyl side chain,
could also be employed in the reaction (entry 9). The desired
product 7j was obtained in 55% yield (trans/cis = 64/36).
F
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J. Fluorine Chem. 2006, 127, 992. (f) Jeschke, P. ChemBioChem 2004,
5, 637.
(2) Selected books: (a) Kirsch, P. Modern Fluoroorganic Chemistry:
Aliphatic substrates bearing cyclohexyl (6k) and benzyl (6l)
groups afforded the desired products 7k and 7l in 45% and 56%
yields, respectively (entries 10 and 11). In the case of the much
less nucleophilic tosylated alkenylamine 6m, the reaction
proceeded at 75 °C in t-BuOH to afford the desired product
7m in 81% yield (entry 12). Furthermore, with 0.3 mol %
catalyst, the cyclized product was obtained in 80% yield. The
internal alkenylamine 6n also showed high reactivity under
these conditions (entries 13 and 14). The desired pyrrolidine
7n was obtained in 43% and 40% yields from (E)-6n and (Z)-
6n, respectively, albeit with no diastereoselectivity.42
Synthesis, Reactivity, Applications, 2nd ed.; Wiley-VCH: Weinheim,
2013. (b) Gouverneur, V.; Muller, K. Fluorine in Pharmaceutical and
̈
Medicinal Chemistry: From Biophysical Aspects to Clinical Applications;
Imperial College Press: London, 2012. (c) Ojima, I. Fluorine in
Medicinal Chemistry and Chemical Biology; Wiley-Blackwell: Chi-
́ ́
chester, 2009. (d) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and
Medicinal Chemistry of Fluorine; Wiley-VCH: Weinheim, 2008.
(e) Hiyama, T. Organofluorine Compounds: Chemistry and Applications;
Springer: Berlin, 2000.
(3) For selected papers on bioactive β-trifluoromethylamines, see:
(a) Jackel, C.; Salwiczek, M.; Koksch, B. Angew. Chem. 2006, 118,
̈
CONCLUSION
■
4305; Angew. Chem., Int. Ed. 2006, 45, 4198. (b) Chiu, H.-P.; Suzuki,
Y.; Gullickson, D.; Ahmad, R.; Kokona, B.; Fairman, R.; Cheng, R. P. J.
Am. Chem. Soc. 2006, 128, 15556. (c) Chiu, H.-P.; Kokona, B.;
Fairman, R.; Cheng, R. P. J. Am. Chem. Soc. 2009, 131, 13192.
(d) Buer, B. C.; Chugh, J.; Al-Hashimi, H. M.; Marsh, E. N. G.
Biochemistry 2010, 49, 5760. (e) Hopkins, C. R. ACS Chem. Neurosci.
2012, 3, 3.
In conclusion, we examined the mechanism of our amino-
trifluoromethylation reaction, which provides various trifluor-
omethylated cyclic amines, by means of kinetic studies, NMR
and ESI-MS analyses. In our aminotrifluoromethylation
conditions, Cu(II) complex generated by oxidation of CuI
during the pretreatment plays major role. Several Cu(II)
species are in rapid dynamic equilibrium through ligand
exchanges. The turnover limiting step of this reaction involves
copper, Togni reagent 1, and allylamine. Cu(II) ion serves as a
Lewis acid catalyst to activate Togni reagent and enhances the
electrophilicity of its hypervalent iodine. In addition, use of
triethylamine as a cocatalyst improved the yield of the
aminotrifluoromethylation in the synthesis of trifluoromethy-
lated pyrrolidines. The substrate scope of this reaction is broad,
including internal alkenylamines, and catalytic efficiency is
excellent. We expect that this reaction will prove useful in
synthetic organic and medicinal chemistry.
(4) For selected reviews on transformations of aziridines, see:
́
(a) Stankovic, S.; D’hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.;
Van Speybroeck, V.; De Kimpe, N.; Ha, H.-J. Chem. Soc. Rev. 2012, 41,
643. (b) Lu, P. Tetrahedron 2010, 66, 2549.
(5) For recent reviews on trifluoromethylation reactions, see:
(a) Charpentier, J.; Fruh, N.; Togni, A. Chem. Rev. 2014, 115, 650.
̈
(b) Egami, H.; Sodeoka, M. Angew. Chem., Int. Ed. 2014, 53, 8294.
(c) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598. (d) Liu, X.;
Xu, C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683. (e) Chu, L.;
Qing, F.-L. Acc. Chem. Res. 2014, 47, 1513. (f) Xu, J.; Liu, X.; Fu, Y.
Tetrahedron Lett. 2014, 55, 585. (g) Zhang, C. Adv. Synth. Catal. 2014,
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ASSOCIATED CONTENT
■
S
* Supporting Information
Additional results, experimental details, procedures, spectra for
characterization of new compounds, and crystallographic data
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
2012, 51, 5048. (s) Mace,
2012, 2479.
́
Y.; Magnier, E. Eur. J. Org. Chem. 2012,
AUTHOR INFORMATION
■
(6) (a) Chen, Q.-Y.; Wu, S.-W. J. Chem. Soc., Chem. Commun. 1989,
11, 705. (b) Su, D.-B.; Duan, J.-X.; Yu, A.-J.; Chen, Q.-Y. J. Fluorine
Chem. 1993, 65, 11. (c) Oishi, M.; Kondo, H.; Amii, H. Chem.
Commun. 2009, 1909. (d) Inoue, M.; Araki, K., Kawada, K. JP 2009−
234921, 2009. See also, Pd-catalyzed trifluoromethylation of aryl
chlorides reported by Buchwald: (e) Cho, E. J.; Senecal, T. D.; Kinzel,
T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science 2010, 328, 1679.
Early reports on catalytic direct trifluoromethylation of indoles:
(f) Shimizu, R.; Egami, H.; Nagi, T.; Chae, J.; Hamashima, Y.;
Sodeoka, M. Tetrahedron Lett. 2010, 51, 5947. (g) Wiehn, M. S.;
Vinogradova, E. V.; Togni, A. J. Fluorine Chem. 2010, 131, 951.
(h) Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem.Eur. J. 2011, 17, 6039.
(i) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224.
(7) (a) Mormino, M. G.; Fier, P. S.; Hartwig, J. F. Org. Lett. 2014, 16,
1744. (b) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F.
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Corresponding Author
*sodeoka@riken.jp
Present Address
∥School of Pharmaceutical Sciences, University of Shizuoka,
52−1 Yada, Suruga-ku, Shizuoka 422−8526, Japan.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research was supported in part by a Grant-in-Aid for
Young Scientists (B) from JSPS (No. 23750116), JST, and by
Project Funding from RIKEN. We also thank Dr. Hashizume
(RIKEN) for conducting the X-ray single-crystal analysis. DFT
calculation was conducted on the RIKEN Integrated Cluster of
Clusters (RICC). We dedicate this paper to Prof. Iwao Ojima
on the occasion of his 70th birthday.
́
Pathipati, S. R.; Szabo, K. J. J. Org. Chem. 2013, 78, 7330.
(d) Lishchynskyi, A.; Grushin, V. V. J. Am. Chem. Soc. 2013, 135,
12584. (e) Zanardi, A.; Novikov, M. A.; Martin, E.; Benet-Buchoolz, J.;
Grushin, V. V. J. Am. Chem. Soc. 2011, 133, 20901. (f) Tomashenko,
́
O. A.; Escudero-Adan, E. C.; Belmonte, M. M.; Grushin, V. V. Angew.
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For experimental procedure, see Supporting Information.
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1
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in Supporting Information.
(29) Weakly coordinating MeOH derived from 5a may affect the
chemical shift and also the reactivity of the catalyst due to its
participation in the dynamic equilibrium.
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shown in the Supporting Information.
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(31) The structure was decided by analogy with the X-ray single-
crystal structure of [Zn(1)2(4-NO2C6H4CH2OH)2(H2O)2](NTf2)2
reported by Togni. For details, see ref 21a.
(32) DFT calculation of Togni reagent indicated that the carbonyl
oxygen makes a major electronic contribution to the HOMO. Thus we
show the structures with carbonyl coordination. For details, see
Supporting Information.
(33) A dimeric Cu species (m/z = 1182.5563) was also detected and
assigned as complex D shown below. The complex is also a potential
reactive species, but the monomeric species were considered as the
major catalytically active species on cycle for the reasons discussed in
the text.
(34) At the late stage of the reaction, increased acidity due to 2-
iodobenzoic acid production may affect the chemical shift of the signal
derived from the aziridine 3.
(35) The presented data suggested the Cu(II) species as a Lewis acid
catalyst mainly contributed in the reaction with the pretreated CuI. If
CF3 radical was generated by the oxidation of CuI in the presence of
the substrate, it may partly contribute to the production of 3. Further
discussion is shown in Supporting Information.
(36) ESI-MS of the reaction mixture and assignment of the signals
are described in Supporting Information; a Cu species coordinating
Togni reagent 1, the substrate, and/or the aziridine was detected.
(37) In the conversion from TS to IV, C−I and C−N bond
formation may proceed either in concerted or stepwise mechanism via
cation intermediate formation.
(38) Selected paper, see: Ochiai, M.; Kitagawa, Y.; Toyonari, M.
ARKIVOC 2003, vi, 43.
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X.-Y. Chem.Eur. J. 2014, 20, 1332. See also: (b) Lin, J.-S.; Liu, X.-
G.; Zhu, X.-L.; Tan, B.; Liu, X.-Y. J. Org. Chem. 2014, 79, 7084.
(40) In the absence of Et3N, several unidentified products were also
obtained in addition to the uncyclized allylic and hydrotrifluorome-
thylation products.41 Et3N improved the product selectivity of the
reaction.
(41) For details of additive screening and optimization, see
Supporting Information.
(42) The stereochemical outcome may suggest the stepwise
mechanism for the pyrrolidine formation.
I
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