Introducing CF3 Groups on
Nitrogen Atoms
Literature Seminar
M1 Kimihiro Miyauchi
2022/10/21

1

Contents• IntroductionØBackgroundØElectrophilic trifluoromethylation reagent• Constructing N-CF3 via prefucnctionalizationØSchohenebeck’s work
ØXu’s work

• Summary2

Importance of F atom in medicinal chemistry• Improvement of metabolic stability
CF3OH N

CF3OH NNHNN

F3C OH N
N
H<NN

CLp = 110 mL/min/kg

NH

<N
N

CLp = 52 mL/min/kg

CLp = 20 mL/min/kg

Lin, S. L., et al., ACS Med. Chem. Lett. 2011, 2, 43–47• Improvement of inhibitory activity
FFFF

NH2 O
NNF

NH2 ONN

NNFN

Et
DPP4 IC50 = 37 nM

DPP4 IC50 = 18 nM

N
CF3Weber, A. E., et al., Bioorg. Med. Chem. Lett. 2007, 17, 3373– 3377
Meanwell, N. A., J. Med. Chem. 2018, 61, 5822−5880

Introducing F atom improves affinity, lipophilicity, metabolic stability, andother properties of drug molecules.
Demand for synthetic methodology is growing.

3

Conventional N-trifluoromethylation
Et2N SCF3

S
Et2NS

Et

NEt2

S70˚C, 20 min.

S

CF3N
Et70%

Kirsanov, A. V., et al., Synthesis 1973,12, 787-789

ORN
RSF4, KF
HR

150˚C, 48 hr

CF3N
R
90%

Dmowski, W., & Kamiński, M., J. Fluor. Chem. 1983, 23, 207-218

R

CF2Br2, TMAE
NH
R

sulfolane, rtR

CF3N
R
37~50%

Pawelke, G., J. Fluor. Chem. 1991, 52, 229-234•

Lacking safe, general and high yielding methodology
4Electrophilic N-trifluoromethylation•Typical alkylation

R I +I- + Nu R

Nu-H
HH

•C+ I 𝛿𝛿

Perfluorolkylation

RfI +Rf- + Nu I

NuF
𝛿-FCFI

𝛿+Umemoto, T. Chem. Rev. 1996, 96, 1757–1778

Ø Trimethylation(perfluoroalkylation) does not proceed like nonfluorinated alkylation.
5Electrophilic N-trifluoromethylation: Umemoto’s reagent•

S-CF3 dibenzothiophene

S
CF3OO

CF3OO
PPh3n-C12H25 SNa

F3C PPh3n-C12H25 S CF3
NH2NH2F3C

•

NH2
CF3

N-CF3 bond formation was not reported
Umemoto, T. & Ishihara, S., J. Am. Chem. Soc. 1993, 115, 2156–2164
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Electrophilic N-trifluoromethylation: Umemoto’s reagent•Thermally unstable CF3-oxionium saltt-BuO
CF3NH2H
N

NH
NH
N

CF3N
CF3N

NH2N
HN

CF3

CF3N
HNN
CF3CF3NH

CF3

Ø Unstable above room temperature
Umemoto, T., et al., J. Org. Chem. 2007, 72, 6905–6917
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Electrophilic N-trifluoromethylation: Togni’s reagent
CF3IO
Togni’s reagent• Ritter-type trifluoromethylation

Togni. A., et al., Angew. Chem., Int. Ed. 2011, 50, 1059-1063• Synthesizing N-CF3 azoles

Togni. A., et al., Angew. Chem., Int. Ed. 2012, 51, 6511-6515

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Contents• IntroductionØBackgroundØElectrophilic trifluoromethylation reagent• Constructing N-CF3 via prefucnctionalizationØSchohenebeck’s work
ØXu’s work

• Summary9N-trifluoromethylation via prefunctionalization
CF3N

prefunctionalization

NH2

CF3N
AG
CF3N
H

CF3N
O

X
O

CF3N

etc…

derivatization10

N-trifluoromethylation via prefunctionalization• Functionalization of amine under mild conditions (Schohenebeck’s work)

Schohenebeck, F., et al., Angew. Chem., Int. Ed. 2017, 56, 221-224

Ø Proposed mechanism
FS
R

H
N

R1(Me4N)SCF3S
FF

R

N

AgF
R1

CF3S-CF3N
R
R111

Schohenebeck’s work: Substrate scope•

Tolerant to various functional group

12Schohenebeck, F., et al., Angew. Chem., Int. Ed. 2017, 56, 221-224

Synthesis of N-CF3 amide• Safer, more robust and versatile methodology.

•Schoenebeck, F., et al., Nature 2019, 573, 102−107.
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Drawbacks in constructing N-CF3 amide• Coupling is not applicable due to instability of secondary N-CF3 amine.

RHNO
CF3+1R

OH

H
NR
F

couple-HF

FFRN

FF

Kloeter, G. & Seppelt, K. J. Am. Chem. Soc. 1979, 101, 347–349
Burger, H. & Pawelke, G., J. Chem. Soc., Chem. Commun. 1988, 105–106• Conventional methods need hazardous reagent.
RN

EtSHCSSRN
HR’COOHSEtO
RN
R’
CS2Et

BrF3

OR

NR’
CF3F FRNR’
CF3Rozen, S., et al., J. Org. Chem. 2009, 74, 8578-8582
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Strategy
prefunctionalization

derivatization
carbamateamide

thiocarbamate

urea
Schoenebeck, F., et al., Nature 2019, 573, 102−107.
15

Substrate Scope: Carbamoyl fluoride

Schoenebeck, F., et al., Nature 2019, 573, 102−107.
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Substrate Scope: Carbamoyl fluoride
chiral amino acidsdrug molecules•

High functional group tolerance was shown.

•Stereochemistry was also retained.
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Schoenebeck, F., et al., Nature 2019, 573, 102−107.

Mechanistic studies: Proposed mechanism

generated byAgF

O
Cl3C

CCl3O
F

F

Schoenebeck, F., et al., Nature 2019, 573, 102−107.
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Mechanistic studies: IR spectra

AgF

CNN

C

BTC
SF

O
CN
N

F
C
F
F

6CN
NC
F

F

(I)
19
Schoenebeck, F., et al., Nature 2019, 573, 102−107.

Mechanistic studies: IR spectra

CNNC

AgF onlyS

Schoenebeck, F., et al., Nature 2019, 573, 102−107.

NCNFN

CF3CN(III)CNN(I)

CFF
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Substrate Scope: Constructing amide

21

Schoenebeck, F., et al., Nature 2019, 573, 102−107.

Substrate Scope: Constructing amidesi) Pd(OAc)2 (10 mol%)/ BINAP (15 mol%), Cs2CO3, toluene, 110 °C, 3 h; (ii) step 1: trifluoroacetic acid,dichloromethane, RT, 2 h; step 2: HBTU, DIPEA, amino acid, RT, 16 h.

• Stereochemistry was retained.
• Compatible with further derivatization
Schoenebeck, F., et al., Nature 2019, 573, 102−107.
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Substrate Scope: Constructing ureaOFH 2N
N
CF3DCM, DIEA
DMAP (cat.)

Schoenebeck, F., et al., Nature 2019, 573, 102−107.
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Substrate Scope: Constructing carbamate
OFHON
CF3DCM, DIEA
DMAP (cat.)

Schoenebeck, F., et al., Nature 2019, 573, 102−107.
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Substrate Scope: Constructing thio- and selenocarbamateOFNa+ -NuN
CF3•

THF

Carbamoylfluoride could be transformed to urea, carbamate, andthio(seleno-)carbamate
Schoenebeck, F., et al., Nature 2019, 573, 102−107.
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Short summary
RNCSAgFBTC• Safe and simple methodology to construct N-CF3 amide• Accessible to urea, carbamate and thiocarbamate

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Contents• IntroductionØBackgroundØElectrophilic trifluoromethylation reagent• Constructing N-CF3 via prefucnctionalizationØSchohenebeck’s work
ØXu’s work

• Summary27

Constructing N-CF3 by Prefunctionalizing hydroxylamine derivatives

Xu, X., et al., J. Am. Chem. Soc. 2022, 144, 1962−1970• Strategy
HNOLG

CF3NLGOIr cat.

CF3N28

Constructing N-CF3 hydroxylamine• Previous work

Xu, X., et al., Org. Lett. 2015, 17, 5048–5051

Ø Applied to N-trifluoromethylation of hydroxylamine• Proposed mechanismTMSCF3

AgOTf, KF

Ag(I) CF3

selectfluor

2-fluoropyridine-AgF
F3CNu

Nu Ag(III)FAg(III) Nu
F3CNu-FXu, X., et al., Angew. Chem., Int. Ed. 2015, 54, 11839-11842
Xu, X., et al., J. Org. Chem. 2017, 82, 3702–3709

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Constructing N-CF3 hydroxylamine• Conversion proceeded in moderate ~ good yield.
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Inserting N-CF3 to C-H: Optimizationa Reaction conditions: 5a (0.1 mmol), reagent 2 or 4 (0.15 mmol), photocatalyst (0.002 mmol), solvent (1.0 mL), white LEDs, under N2, rt, 18 h. b Yields weredetermined by 19F NMR spectroscopy using trifluoromethylbenzene as an internal standard. c 5a (0.15 mmol), reagent 2 (0.1 mmol). d Note: reagent 2f was selected31
because the Cbz is easily deprotected under mild conditions. e No light.

Xu, X., et al., J. Am. Chem. Soc. 2022, 144, 1962−1970

Substrate scope

Xu, X., et al., J. Am. Chem. Soc. 2022, 144, 1962−1970

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Substrate scope

Xu, X., et al., J. Am. Chem. Soc. 2022, 144, 1962−1970
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Substrate scope•Deprotection and further functionalization with Schoenebeck’ssystem*.
Xu, X., et al., J. Am. Chem. Soc. 2022, 144, 1962−1970* Schoenebeck, F., et al., Nature 2019, 573, 102−107.
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Constructing N-CF3 amide•

Boc-protected amine afforded cyclized compound
Xu, X., et al., J. Am. Chem. Soc. 2022, 144, 1962−197035

Constructing unprecedented ynamide

unprecedented

N-CF3 alkynamide (reported)• Succeeded in synthesizing unprecedented ynamide
Xu, X., et al., J. Am. Chem. Soc. 2022, 144, 1962−1970
N-CF3 alkynamide: Schoenebeck, F., et al., J. Am. Chem. Soc. 2021, 143,13029–13033
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Contents• IntroductionØBackgroundØElectrophilic trifluoromethylation reagent• Constructing N-CF3 via prefucnctionalizationØSchohenebeck’s work
ØXu’s work

• Summary37

Perspective• Recent reports on N-CF3 compound

Schohenebeck, F., et al., J. Am. Chem. Soc. 2022, 144, 6100–6106

BrN

C

S

Et3SiH
AgF

CF3N
H

S
O O

AgOTf

CF3N
SO O

Yi. W., et al., Angew. Chem., Int. Ed. 2022, accepted

Synthetic methodologies for various N-CF3 compounds are now
developed.
Lead to elucidating unique bioactivity
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Summary• Electrophilic direct N-trifluoromethylation is still difficult.
• CF3 incorporation and derivatization is major strategy toconstruct N-CF3 moiety.
• More simple and versatile methodology for N-CF3 isemerging.
• Biological activity of N-CF3 molecule will be elucidated in
the future.

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