Cu-catalyzed Allylic Perfluoroalkylation of Alkenes Using
Perfluoro Acid Anhydrides: Preparation of
N-(5,5,5-Trifluoro-2-penten-1-yl)phthalimide
Yuma Aoki, Shintaro Kawamura, and Mikiko Sodeoka1*
Catalysis and Integrated Research Group, RIKEN Center for Sustainable
Resource Science, and Synthetic Organic Chemistry Laboratory, RIKEN
Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama 351-0198,
Japan
Checked by Martina Drescher, Daniel Kaiser, and Nuno Maulide

cat. [Cu(CH3CN)]4PF6
O
N
O
F3C

O
O

O

urea·H2O2
CF3

CH2Cl20 °C, 1 h

CH2Cl240 °C, 4 h

O
1

CF3

N
O

2

Procedure (Note 1)
N-(5,5,5-Trifluoro-2-penten-1-yl)phthalimide (2). A stirring bar (7 x 50 mm)
is placed in a three-necked round-bottomed flask (500-mL size) (Note 2). The
flask is fitted with two glass stoppers and a reflux condenser is connected toa vacuum-argon manifold with a KOH trap in-between (Figure 1). After
addition of urea·H2O2 (4.85 g, 51.6 mmol, 1.2 equiv) (Note 3) to the flask, it isevacuated and backfilled with argon gas (>99.999%) three times and purged
with the gas very slowly during the reaction. Then, CH2Cl2 (100 mL) (Note 3)
is added from a 100-mL syringe fitted with PFA tubing (Note 2), after
replacing the two glass stoppers with a rubber septum and an internal
thermometer equipped with a Teflon® adapter. The slurry is cooled with an

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84

Published on the Web 4/2/2021
Ó 2021 Organic Syntheses, Inc.

ice-salt bath and is slowly stirred (150 rpm) (Note 4) until the temperature
falls to 2±1 °C (for ca. 1 h).

Figure 1. Reaction set-up (photo provided by submitters)
After cooling, trifluoroacetic anhydride (59.8 mL, 430 mmol, 10 equiv)(Note 3) is added to the mixture from a syringe fitted with PFA tubing(100-mL size) over ca. 5 min, temporarily leading to an increase of the internal
temperature of 5 °C. The rubber septum is replaced with a glass cap, and the
mixture is stirred at 2±1 °C for 1 h (Figure 2a). Then, N-(3-buten-1yl)phthalimide 1 (8.65 g, 43 mmol, 1.0 equiv) (Note 3) is added in one portion
via a funnel, followed by the addition of [Cu(CH3CN)4]PF6 (3.21 g, 8.6 mmol,
20 mol %) (Note 3) in one portion. After the addition of the copper catalyst,
the reaction mixture is warmed to 40 °C. The color of the solution changes
from colorless to aqua blue, and small bubbles of carbon dioxide appear(Figure 2b) (Note 5). The mixture is stirred for 4 h and completion of thereaction is confirmed by TLC analysis (Figure 3a) (Note 6).

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Figure 2. (a) Reaction of urea·H2O2 with trifluoroacetic anhydride (b)Color change after addition of Cu catalyst (photos provided bysubmitters)
The mixture is cooled to 2±1 °C and diluted with CH2Cl2 (200 mL) andtransferred to a 1 L round-bottomed flask. While further cooling, sat. K2CO3
aqueous solution (300 mL) is added while monitoring the appearance of
bubbles due to neutralization. Initially, this addition is performed drop wise,using a Pasteur pipette. After ~50 mL have been added in this manner, theremaining solution is slowly poured into the vigorously stirred mixture overthe course of 2 min. The mixture is further stirred at ambient temperature(22–25 °C) for 1 h and transferred to a separatory funnel (1-L size). The
aqueous layer is extracted with CH2Cl2 (3 x 200 mL), allowing the mixture to
stand for 10 min each time to ensure adequate separation of the phases. The
organic phases are combined in an Erlenmeyer flask (2-L size). The combinedorganic phase is washed with brine (50 mL) and dried over 50 g of anhydrous
Na2SO4. The absence of peroxides in the organic phase is confirmed by using
a peroxide detection strip (Figure 3b) (Notes 7 and 8). The organic phase isfiltered into a flask (2-L size) through a sintered glass filter (100-mL size), andthe filtrate is evaporated in a rotary evaporator (80 mmHg, 30 °C). The
obtained crude product (12.4 g) is purified by means of chromatography on
silica (Note 9). The product, containing a small amount of impurities, isobtained as a white solid (8.08 g) after concentration of the combined
fractions by removal of the solvent with a rotary evaporator (80 mmHg,
30 °C) and drying in vacuo (<6 mmHg) for 3 h.

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Figure 3. (a) TLC analysis of the reaction mixture (rxn) after 4 h (b)Detection of peroxide content in organic and aqueous phases after
extraction (photos provided by submitters)
Heptane (15 mL) is added to the white solid in a 50 mL round-bottomed
flask, and the white solid is roughly crushed with a spatula into pieces
smaller than ca. 0.5 cm (Figure 4). The liquid phase is decanted with the aidof a glass Pasteur pipette (ca. 1.5 mL, 9-inch size; Iwaki IK-PAS-9P). The
resulting white solid is further purified by repeating the crush-decantation
process three more times, and then drying the residue in vacuo (<6 mmHg)
for 3 h to give product 2 (5.66 g, 49% yield, 97% purity, E/Z = 88.5/11.5)(Notes 10, 11, 12, and 13) (Figure 5), which can be stored under ambientconditions.

Figure 4. Crushing lumps of the white solid with a spatula (photoprovided by submitters)

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Figure 5. Photograph of pure product 2 (photo provided by submitters)

Notes
1.

Prior to performing each reaction, a thorough hazard analysis and risk
assessment should be carried out with regard to each chemical substanceand experimental operation on the scale planned and in the context of thelaboratory where the procedures will be carried out. Guidelines forcarrying out risk assessments and for analyzing the hazards associatedwith chemicals can be found in references such as Chapter 4 of “Prudent
Practices in the Laboratory" (The National Academies Press, Washington,
D.C., 2011; the full text can be accessed free of charge athttps://www.nap.edu/catalog/12654/prudent-practices-in-thelaboratory-handling-and-management-of-chemical.
See
also“Identifying and Evaluating Hazards in Research Laboratories”(American Chemical Society, 2015) which is available via the associatedwebsite “Hazard Assessment in Research Laboratories” athttps://www.acs.org/content/acs/en/about/governance/committees/chemicalsafety/hazard-assessment.html. In the case of this procedure,
the risk assessment should include (but not necessarily be limited to) an
evaluation of the potential hazards associated with urea hydrogen
peroxide, trifluoroacetic anhydride, N-(3-buten-1-yl)phthalimide,
tetrakis(acetonitrile)copper(I) hexafluorophosphate, dichloromethane,potassium carbonate, heptane, and sodium sulfate. (Caution!) There is apossibility of explosions when handling bis(trifluoroacetyl)peroxide (BTFAP)

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2.

generated as a reactive intermediate in the present reaction. In particular, thephase transition from the liquid to the solid state must be avoided in accordancewith the literature.2 The peroxide must be carefully quenched with sat. K2CO3
aqueous as described in the procedure, and the peroxide content in the organic
phase after the extraction must be checked with a test paper as described in theprocedure before evaporation of the organic solvent.
All glassware used is dried in the oven before use. Very small amountsof grease or Teflon rings are used to seal glass joints and stopcocks. PTFE
tape is used to fix and seal connections between the flask and each PVC
tubing, septum, and thermometer. A syringe fitted with PFA tubing
instead of a metal-needle is used to avoid the possibility of contaminationof the peroxide solution with metals (see Figure 6). The vacuum/argon
gas manifold system is equipped with a bubbler containing liquidparaffin at the inlet and outlet, as shown in Figure 7.

Figure 6. Syringe fitted with PFA tubing (photo provided bysubmitters)

Figure 7. Vacuum/nitrogen gas manifold system (photo provided bysubmitters)
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3.

Urea·H2O2 (97%) was obtained from Aldrich Chemical Co., Inc. and used
as received. Anhydrous CH2Cl2 (<10 ppm of water and <1 ppm O2
contents) was obtained from Kanto Chemical Co., Inc. and further
purified by using a Glass Contour Solvent Filtration System equippedwith columns of alumina and a supported copper catalyst prior to use.
The checkers purchased dichloromethane (99.6%) from Acros Organics
and the solvent was used as received. Trifluoroacetic anhydride(>98.0%), N-(3-buten-1-yl)phthalimide (>98%), and [Cu(CH3CN)4]PF6(>97.0%) were obtained from Tokyo Chemical Industry Co., Ltd and used
as received. The checkers purchased [Cu(CH3CN)4]PF6 (>97.0%) from
Sigma Aldrich and the chemical was used as received.
4. Particles of urea·H2O2 are scattered and adhere to the surface of the flask
if stirring is vigorous. Thus, gentle stirring (ca. 150 rpm) is necessary.
5. The checkers observed the transient formation of a light blue precipitate.
Carbon dioxide (CO2) gas is released through the argon line under aslight positive flow of nitrogen gas.
6. The reaction is monitored by TLC analysis on Merck silica-gel 60 F254
plates with CH2Cl2 as the eluent. Spots on the TLC plate are visualizedwith a UV lamp (254 nm). The Rf values of 1 and 2 are 0.54 and 0.57,
respectively.
7. XploSens
PSTM
was
used
to
test
for
peroxides.
19
Bis(trifluoroacetyl)peroxide ( F NMR signal at –70.8 ppm in CDCl3)
could not be detected in the organic and water phases by 19F NMR
analysis. As shown in Figure 3, the test paper indicated no peroxide
content in the organic phase. Thus, we can conclude that no otherpotentially hazardous species, such as trifluoroacetoxy peracid, ispresent. In addition, 19F NMR analysis of the water phase shows only thesignal derived from trifluoroacetic acid, which suggests that the basic
workup sufficiently hydrolyzes diacyl peroxide to afford hydrogen
peroxide.
8. Peroxides in the water phase are quenched with sat. Na2S2O3 aqueous
solution.
9. Silica gel chromatography was performed using a column (5 x 30 cm)
containing 170 g of silica eluted with CH2Cl2 (3 L). Fraction sizes ofapproximately 95 mL were obtained using 100-mL test tubes. The
product (Rf = 0.57) (Note 6) was found in fractions 6–15.
10. Characterization of 2: mp (mixture of E- and Z-isomers, E/Z = 91/9) 83–
84 °C; 1H NMR (600 MHz, CDCl3) d: E-isomer: 2.75–2.87 (m, 2H), 4.30 (d,J = 5.9 Hz, 2H), 5.65– 5.69 (m, 1H), 5.81 (dt, J = 15.3, 5.8 Hz, 1H), 7.69–7.76
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(m, 2H), 7.82–7.89 (m, 2H); Z-isomer: 3.10–3.22 (m, 2H), 4.30 (overlap,
2H), 5.60–5.74 (overlap, 1H), 5.81 (overlap, 1H), 7.69–7.76 (m, 2H), 7.82–
7.89 (m, 2H); 13C NMR (151 MHz, CDCl3) d: E-isomer: 37.1 (q, J = 30 Hz),39.2, 122.3 (q, J = 3.9 Hz), 123.5 (2C), 125.7 (q, J = 276 Hz), 131.0, 132.2 (2C),
134.2 (2C), 167.9 (2C); Z-isomer: 32.5 (q, J = 30 Hz), 34.5, 122.2 (q,J = 3.9 Hz), 123.5 (2C), 126.1 (q, J = 277 Hz), 129.4, 132.2 (2C), 134.2 (2C),
167.9 (2C); 19F NMR (565 MHz, CDCl3): d: E-isomer: –66.29 (t, J = 10.6 Hz),
Z-isomer: –65.97 (t, J = 10.4 Hz). IR (neat, cm-1) 2934, 1771, 1711, 1489,
1430, 1397, 1350, 1337, 1293, 1264, 1245, 1172, 1147, 1128, 1098, 1047, 942,
721, 712; HRMS (ESI+) calc. for C13H10F3NO2 [M+Na]+ 292.0556, found292.0550.
11. The purity was determined to be 97% by quantitative 1H NMR
spectroscopy in CDCl3 using 53.8 mg of the compound 2 together with
13.9 µL of CH2Br2 as an internal standard.
12. A second run on half scale gave 2.79 g of an identical product (48%, 98%
purity, E/Z = 89/11).
13. The submitters reported a yield of 41% (4.80 g, 99% purity, E/Z = 91/9)
when using hexane in the crush-decantation process. Additional pureproduct 2 (2%, 0.21 g, 99% purity, E/Z = 85/15) was obtained byevaporation of the hexane washings followed by drying in vacuo(<6 mmHg) for 3 h. The total yield of 2 was 5.01 g (43%). The checkers
obtained no additional product from the residual heptane solutions.

Working with Hazardous Chemicals
The procedures in Organic Syntheses are intended for use only by persons
with proper training in experimental organic chemistry. All hazardous
materials should be handled using the standard procedures for work withchemicals described in references such as "Prudent Practices in the
Laboratory" (The National Academies Press, Washington, D.C., 2011; the full
text
can
be
accessedfreeofchargeat
http://www.nap.edu/catalog.php?record_id=12654). All chemical waste
should be disposed of in accordance with local regulations. For general
guidelines for the management of chemical waste, see Chapter 8 of Prudent
Practices.
In some articles in Organic Syntheses, chemical-specific hazards arehighlighted in red “Caution Notes” within a procedure. It is important toOrg. Synth. 2021, 98, 84-96

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recognize that the absence of a caution note does not imply that no significant
hazards are associated with the chemicals involved in that procedure. Prior
to performing a reaction, a thorough risk assessment should be carried outthat includes a review of the potential hazards associated with each chemicaland experimental operation on the scale that is planned for the procedure.
Guidelines for carrying out a risk assessment and for analyzing the hazards
associated with chemicals can be found in Chapter 4 of Prudent Practices.
The procedures described in Organic Syntheses are provided as publishedand are conducted at one's own risk. Organic Syntheses, Inc., its Editors, andits Board of Directors do not warrant or guarantee the safety of individuals
using these procedures and hereby disclaim any liability for any injuries ordamages claimed to have resulted from or related in any way to theprocedures herein.

Discussion
Fluoroalkyl group-containing molecules are of interest as drugcandidates, agrochemicals, and chemical probe molecules in chemical
biology research, because the fluorine-containing group often improves
pharmaceutical efficacy and can be used for bioisosteric replacement.3
Therefore, a practical fluoroalkylation method employing user-friendly
fluoroalkyl sources is highly desirable. Among various fluoroalkyl sources,
fluorine containing acid anhydride should be suitable because it is low-cost,
readily available, and applicable for a range of organic syntheses.4–9 In thiscontext, we developed allylic fluoroalkylations of simple alkenes by using theacid anhydrides as fluoroalkyl sources (Scheme 1).7,8 Specifically, diacyl
peroxide is generated in situ from acid anhydride and urea-hydrogen
peroxide and used as a reagent for allylic fluoroalkylation reaction of alkenes.
The key to success is to control the selectivity with the aid of a copper catalyst,
because a complex mixture is obtained in its absence. For perfluoroalkylation(Rf = CF3, C2F5, and C3F7), [Cu(CH3CN)]4PF6 is the optimal catalyst, affording
the desired product in up to 95% yield (Scheme 1a).7 The combination ofCu(O2CCF3)2 as the catalyst and pyridine as an additive enables efficientallylic chlorodifluromethylation using chlorodifluoroacetic anhydride(Scheme 1b).8

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(a)[Cu(CH3CN)]4PF6(10 mol %)O
Rfurea·H2O2(1.2 equiv)

O
Rf

O

CH2Cl20 °C, 1 h

(4.0–10 equiv)

R

O
Rf

O

Rf

O

O
diacyl peroxide

3
R

Rf
4
up to 95% yield(E/Z ~ 8/2)

CH2Cl240 °C, 3 h

Rf = CF3, C2F5, C3F7
(b)
O

O

ClF2C
O
CF2Cl
(5.0 equiv)

urea·H2O2(1.5 equiv)Cu(O2CCF3)2 (10 mol %)pyridine (2.0 equiv)
3

CH2Cl20 °C, 1 h

CH2Cl225 °C, 3 h

R

CF2Cl
4’
up to 92% yield(E/Z ~ 9/1)

Scheme 1. Cu-catalyzed allylic fluoroalkylations using acid anhydrides
Notably, as an exceptional case of successful fluoroalkylation of simple
alkenes using acid anhydrides in the absence of a Cu catalyst, an alkene
bearing a pendant aromatic ring 5 provides carbo-fluoroalkylation product 6
via intramolecular carbocycle formation (Scheme 2).7–9 Catalyst-controlledswitching between allylic and carbo-fluoroalkylations is possible and greatly
expands the scope of this method, as well as increasing the availability offluoroalkyl group-containing molecules. The present procedure is a powerful
synthetic tool to prepare fluoroalkyl group-containing molecules as a
candidate for pharmaceuticals and functional materials from commonly used
starting materials.

O
Rf

O

Rf

(4.0–10 equiv)

Rfurea·H2O2(1.2 equiv)

5

CH2Cl2–40 or 0 °C, 1 h

CH2Cl240 °C, 3 hOwithout catalyst

6

Rf = CF3 62%
Rf = C2F5 69%
Rf = C3F7 61%
Rf = CF2Cl 72%

Scheme 2. Carbo-fluoroalkylation of alkene without any catalyst

References
1.

Center for Sustainable Resource Science, RIKEN, 2-1 Hirosawa, Wako,
Saitama 351-0198, Japan, and Synthetic Organic Chemistry Laboratory,

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2.

3.

4.

5.

6.
7.
8.
9.

RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. E-mail:sodeoka@riken.jp. ORCID: https://orcid.org/0000-0002-1344-364X.
Acknowledgements: This work was supported by JSPS KAKENHI (No.
15K17860), and Project Funding from RIKEN.
Kopitzky, R.; Willner, H.; Hermann, A.; Oberhammer, H. Inorg. Chem.
2001, 40, 2693–2698. See also, Miller, W. T.; Dittman, A. L.; Reed, S. K.; US
Patent 1951, 2,580,0358.
Selected books: (a) Gouverneur, V.; Müller, K. Fluorine in Pharmaceuticaland Medicinal Chemistry: From Biophysical Aspects to Clinical Applications;
Imperial College Press: London, 2012. (b) Ojima, I. Fluorine in Medicinal
Chemistry and Chemical Biology; Wiley-Blackwell: Chichester, 2009.
Selected reports on perfluoroalkylation reactions using perfluoro acidanhydrides: (a) Yoshida, M.; Yoshida, T.; Kobayashi, M.; Kamigata, N. J.
Chem. Soc., Perkin Trans. 1. 1989, 909–914. (b) Zhong, S.; Hafner, A.;
Hussal, C.; Nieger, M.; Bräse, S. RSC Adv. 2015, 5, 6255–6258. (c) Beatty,
J. W.; Douglas, J. J.; Cole, K. P.; Stephenson, C. R. J. Nat. Commun. 2015, 6,
7919. (d) Valverde, E.; Kawamura, S.; Sekine, D.; Sodeoka, M. Chem. Sci.
2018, 9, 7115–7121.
Selected reports on chlorodifluoromethylation reactions using
chlorodifluorodifluoroacetic anhydrides: (a) Yoshida, M.; Morinaga, Y.;
Iyoda, M. J. Fluorine Chem. 1994, 68, 33–38. (b) McAtree, R. C.; Betty, J. W.;
McAtee, C. C.; Stephenson, C. R. J. Org. Lett. 2018, 20, 3491–3495.
Kawamura, S.; Sodeoka, M. Bull. Chem. Soc. Jpn. 2019, 92, 1245–1262.
Kawamura, S.; Sodeoka, M. Angew. Chem., Int. Ed. 2016, 55, 8740–8743.
Kawamura, S.; Henderson, C. J.; Aoki, Y.; Sekine, D.; Kobayashi, S.;
Sodeoka, M. Chem. Commun. 2018, 54, 11276–11279.
Kawamura, S.; Dosei, K.; Valverde, E. Ushida, K.; Sodeoka, M. J. Org.
Chem. 2017, 82, 12539–12553.

Appendix
Chemical Abstracts Nomenclature (Registry Number)
Urea hydrogen peroxide (urea·H2O2); (124-43-6)
Trifluoroacetic anhydride; (407-25-0)
N-Allyl-p-toluenesulfonamide; (50487-71-3)
Tetrakis(acetonitrile)copper(I) hexafluorophosphate; ([Cu(CH3CN)4]PF6);(64443-05-6)

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Yuma Aoki is received his B.E. M.E., and Ph. D.
degrees from Kyoto University under thesupervision of Professor Masaharu Nakamura.
Since 2018, he has worked in Professor Sodeoka’sgroup at RIKEN.

Shintaro Kawamura received his B.E. degree from
Doshisha University in 2007. He received his M.E.
and Ph. D. degrees from Kyoto University under
the supervision of Professor Masaharu Nakamura.
Since 2012, he has worked in Professor Sodeoka’sgroup at RIKEN. In 2017, he was promoted from a
postdoctoral researcher to a Research Scientist at
RIKEN.

Mikiko Sodeoka received her B.S., M.S., and Ph. D.
degrees from Chiba University. After working at
the Sagami Chemical Research Center, Hokkaido
University, Harvard University, and the
University of Tokyo, she became a Group Leader
at the Sagami Chemical Research Center in 1996.
She moved to the University of Tokyo as an
Associate Professor and then to Tohoku University
as a Full Professor in 2000. Since 2004, she has beena Chief Scientist at RIKEN.

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Martina Drescher is the lead technician of theMaulide group at the University of Vienna, where
she has worked with several group leaders overthe course of 38 years.

Daniel Kaiser received his Ph.D. at the Universityof Vienna in 2018, completing his studies under thesupervision of Prof. Nuno Maulide. After a
postdoctoral stay with Prof. Varinder K. Aggarwal
at the University of Bristol, he returned to Vienna
in 2020 to assume a position as senior scientist in
the Maulide group. His current research focusses
on the chemistry of destabilized carbocations andrelated high-energy intermediates.

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10.5

10.0

9.5

9.0

8.5

8.0

7.5

7.0

5.9

5.8

6.5

6.0

5.7

5.5

5.6

3.3

3.2

3.5

3.0

3.1

3.0

2.9

2.8

2.7

5.5

5.0
f1 (ppm)

4.5

4.0

2.5

2.0

1.5

1.0

0.5

0.0

210

200

190

180

170

160

150

140

130

120

110

100
f1 (ppm)

90

80

70

60

50

40

30

20

10

0

-10

-65.8

10

0

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100
-110
f1 (ppm)

-66.0

-120

-130

-66.2

-140

-150

-66.4

-160

-170

-180

-190

-200

-210

4.32
4.31

0.97

3.23
3.20
3.18
3.16
3.13
2.87
2.85
2.83
2.82
2.80
2.78

4.95

5.86
5.85
5.83
5.81
5.80
5.75
5.73
5.71
5.69
5.67
1.00

0.98

0.99

7.88
7.88
7.87
7.86
7.76
7.75
7.74
7.74