ARTICLE Received 3 Feb 2017 | Accepted 9 May 2017 | Published 26 Jun 2017

DOI: 10.1038/ncomms15913

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A practical and catalyst-free trifluoroethylation reaction of amines using trifluoroacetic acid Keith G. Andrews1, Radmila Faizova1 & Ross M. Denton1

Amines are a fundamentally important class of biologically active compounds and the ability to manipulate their physicochemical properties through the introduction of fluorine is of paramount importance in medicinal chemistry. Current synthesis methods for the construction of fluorinated amines rely on air and moisture sensitive reagents that require special handling or harsh reductants that limit functionality. Here we report practical, catalyst-free, reductive trifluoroethylation reactions of free amines exhibiting remarkable functional group tolerance. The reactions proceed in conventional glassware without rigorous exclusion of either moisture or oxygen, and use trifluoroacetic acid as a stable and inexpensive fluorine source. The new methods provide access to a wide range of medicinally relevant functionalized tertiary b-fluoroalkylamine cores, either through direct trifluoroethylation of secondary amines or via a three-component coupling of primary amines, aldehydes and trifluoroacetic acid. A reduction of in situ-generated silyl ester species is proposed to account for the reductive selectivity observed.

1 School

of Chemistry, University Park, University of Nottingham, Nottingham NG7 2RD, UK. Correspondence and requests for materials should be addressed to R.M.D. (email: [email protected]).

NATURE COMMUNICATIONS | 8:15913 | DOI: 10.1038/ncomms15913 | www.nature.com/naturecommunications

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ARTICLE

NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15913

T

he incorporation of fluorine into potential medicines can be used to modify conformation, basicity, intrinsic potency, membrane permeability and pharmacokinetic properties1,2. For these reasons fluorinated entities are particularly important within drug discovery and development3,4. However, the use of fluorine in this field is currently limited to a small number of chemotypes with aryl fluorides being dominant5–9. Given the beneficial properties of fluorine, practical new methods that allow access to a more diverse range of medicinally relevant fluorinated building blocks are of particular importance10–26. For example, b-fluoroalkylamines are less basic than their hydrocarbon counterparts (pKaH 10.7 versus 5.7 for ethylamine and trifluoroethylamine respectively)27 and often exhibit decreased acute toxicity and increased metabolic stability rendering them very attractive in pharmaceutical contexts (for examples, see Fig. 1b)28–32. Unfortunately, while many C–H trifluoroethylation methods have been reported33–38, there are fewer reagents for the trifluoroethylation of amines (Fig. 1a, left)39,40. The most widely used method involves LiAlH4 or borane reduction of trifluoromethylamides generated using trifluoroacetic anhydride (Fig. 1a)41,42. The use of pyrophoric reductants requires special precautions, limits applicability on-scale and precludes substrates that contain other reducible functional groups. Alternatively,

a

O

O

F3 C

O F3 C

CF3

O

X F3 C

OTf I X=halogen

F3 C

OH F3C

N2

OTf

F3 C

OEt

F3 C Hartwig, 2015

Mes

O F3 C

NH 2

S

O

Zn

F3C with aryl halides

2

Typical amine trifluoroethylation O H

N

R1

F 3C

O O

O

CF3 F 3C

N

or borane

H/R2

H/R2 Limited FG tolerance

b

R1 LiAlH4

Pyrophoric reagents

F3 C

R1

N

H/R2 Two steps

CF3

F3C O O

NH CO2H NHAc

F

N

O

N

F

F

highly reactive trifluoroacetaldehyde (b.p.  18 °C) or derivatives can be used under milder reductive conditions43. Recent work by Hartwig and co-workers describes palladium-catalysed N-arylation reactions of fluoroalkylamines44. While this opens up an important new synthesis route the approach is inherently limited to fluoroalkylanilines. Herein we report a practical and catalyst-free method to access structurally diverse b-fluoroalkylamines using trifluoroacetic acid (TFA), which occurs through reduction of in situ-generated silyl ester intermediates. Results Reaction design. Seeking to develop a practical method for the fluoroalkylation of free amines, the direct use of TFA was attractive (Fig. 2), owing to its availability, low cost and stability. To the best of our knowledge reductive fluoroalkylation reactions using TFA have only been carried out in the presence of either platinum45 or borane46 catalysts under Schlenk conditions. Therefore, the development of a general and practical method with wide functional group tolerance would constitute a powerful new approach to the synthesis of fluorinated amines. Trifluoroethylation reactions of secondary amines. Trifluoroethylation reactions were performed in tetrahydrofuran, with 1.75 equivalents of TFA providing optimal results (Fig. 3; for optimization, see Supplementary Table 1). Importantly, the reactions were carried out in conventional laboratory glassware. Performing the reaction open to air in non-anhydrous solvent was not detrimental (Fig. 3; 1) highlighting the practicality of the method. The phenylsilane and TFA were used as supplied without purification. Acyclic and cyclic secondary amines could be trifluoroethylated in good to moderate isolated yields following flash column chromatography (conversions of 70–90% are typical). Additional moderately basic nitrogen atoms (2, 5) are tolerated as are silyl-protected alcohols (7) and free alcohols (9). In the case of the latter, the hydroxyl group undergoes silylation under the reaction conditions and the silyl group is cleaved upon workup with aqueous base. Most significantly, esters are not reduced under the reaction conditions (8). This transformation would not be possible using the conventional amidation/reduction protocol using LiAlH4 (ref. 43); nor could it be achieved using the Pt45 or borane-catalyzed reactions46. Anilines were relatively poor substrates, with N-methyl anilines typically giving less than 40% conversion to the desired amine (not shown).

N H

O

N

HN

F3C

F N Telcagepant intermediate (made using CF3 CH2OTf) CF3 O

OH

N

Cl

F3C

+

N

R1 R

H

H

PhSiH3

F3C

H 2N

N

N

Easily handled, inexpensive reagents/starting materials No catalyst, single step

N Me Ghrelin receptor antagonist (made using CF3 CH2OTf or CF3CHO)

R1 N R

N N

R1 N

R2 3° fluoroamine building blocks

O H

OH

PhSiH3

R Free amine

O F3C

R1 N 2

Carboxylic acid

Telcagepant CF3

N

H +

Reactions run in conventional glassware

F

Compatible with reducible FGs e.g. esters, alkenes, nitro

p38 kinase inhibitor

3 component coupling for functionalized 3° fluoroamines Novel mechanism - no amide intermediate

Figure 1 | Methods for the trifluoroethylation of amines. (a) Existing reagents for the trifluoroethylation of amines. (b) Examples of N-trifluoroethylamines in medicinal chemistry. 2

Figure 2 | This work. A practical and catalyst-free trifluoroethylation reaction using trifluoroacetic acid.

NATURE COMMUNICATIONS | 8:15913 | DOI: 10.1038/ncomms15913 | www.nature.com/naturecommunications

ARTICLE

NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15913

R1

H N

O R2

Me F3 C

PhSiH3 2.0 equiv.

F3 C

N

F3 C

2

Et 3: 70% a

2: 66%

N

Et

N

Me

Ph 1: 67% F3 C

N R1

N

N

R2

F3C

F3C OH THF, reflux, 2-4 h 1.75 equiv.

F3 C

F3 C

N

N O

NMe 4: 68% F3C

5: 47%

N

F3 C OTBS

b

6: 43% b F3C

N

N OH

EtO2C

7: 80%

9: 70% c

8: 83%

Figure 3 | Trifluoroethylation reactions of secondary amines. Isolated yields following chromatography. aIsolated as its HCl salt following aqueous work up. bProduct is volatile. cThe reaction was quenched with 1 M NaOH to desilylate the hydroxyl group (THF, tetrahydrofuran; TBS, tertbutyldimethylsilyl).

Three component trifluoroethylation reactions. We anticipated that we might be able to exploit the acidic, reductive conditions to perform a reductive amination of an aldehyde and a primary amine to form a secondary amine (Fig. 4; brackets), prior to the trifluoroethylation reaction. In this case, a complex, bespoke, b-fluorinated amine core could be generated. As before, these three-component couplings could be carried out in conventional laboratory glassware with moisture exclusion providing small yield gains. The functional group tolerance of this catalyst-free process allows the inclusion of reductively labile, but synthetically valuable, functional groups including alkenes (Fig. 4; 15, 21, 25, 27, 30, 31, 34), esters (16, 26, 39), nitro (11), nitrile (12), Boc-protected amines (33), amides (34), azides (see Supplementary Discussion) and aryl bromides (18, 26, 28, 29, 33, 35). Acid-sensitive functional groups, for example, furans are also tolerated (Fig. 4; 27, 28). The stereo-integrity of amino acid derivative 26 was preserved. Alkyl chloride 22 was prepared at gram-scale (5.00 mmol) from the HCl salt of the amine. The procedure was also amenable to ketones (36–39). Typically, an initial imine-forming period was followed by the standard reaction, with minor timing/temperature adjustments

O via OH 1.75 equiv.

F3 C O R1 NH 2

F3C

PhSiH 3 2.5 equiv.

R2

R1

toluene, 70 °C, 16 h

R1

HN R2

N

R2 OMe

F 3C

F3C Ph

NO2

Ph

N

N

F3 C

11: 78%a OAc

Ph

3

N 3

F3 C N

CN

Ph

3

10: 79%a

Ph

F3 C

Ph

15: 80%a

N

Me f

N 7

Br

Me

32: 34%b

N

Me 36: 42%d

Me

O

CF3 27: 43% f F3 C N

Ph

N

7

3

g

30: 70%

29: 46%

O

N H 33: 43%b

Me Me O

Me

O

a

31: 52% F3 C

Me N 2

Br

35: 61%

CF3 d

37: 20%

d

Me Cl CF3

38: 35%

O a

Me

Me N

O

N

Me

34: 52%b Me

N

Me

b,h

F3 C

N

O

N

CF3

CF3 N

23: 54%c

OMe

MeO

S

OMe CF3

CF3

Me

Br N

Me

28: 43%

N

O OMe CF3 26: 53% (>99% e.e.)

Br

F3 C

N

CF3

Me

Bn N

25: 65%b Me

CF3 O

Me Me

Cl

22: 67%e

N

Br

N

19: 55%a

CF3

CF3 OMe

N 3

MeO

21: 63%a

N

Cl

Ph OMe 18: 76%a

N

OMe 14: 57%a

F3 C

Br N 3

CF3

20: 50%a

N 3

F3 C Ph

17: 33%a

MeO

Me Me 24: 29%a

Ph

13: 83%a NMe2

16: 47%a

N

Me

12: 79%a

3

CF3

F3 C

N 3

N

3

O

OMe F3 C

Ph

F3C

N

F3 C

N

O OEt CF3

d

39: 41%

aTypically,

Figure 4 | Three-component trifluoroethylation reactions. amine (0.50 mmol) and aldehyde (0.50 mmol) were mixed neat, before adding toluene (0.5 ml) and PhSiH3 (0.25 mmol) and stirring for 10 min at 70 °C. Trifluoroacetic acid (0.875 mmol) and further PhSiH3 (2.0 mmol) were added and the reaction heated at 70 °C for 16 h. The products were purified by concentration, washing an ether solution of the crude material with sodium bicarbonate and chromatography. Slight timing/temperature modifications are described in Supplementary Methods for: bMethod B (alkyl aldehydes), cMethod C/D (hindered aldehydes), dMethod E (ketones). e5.00 mmol scale from HCl salt of amine, ftrifluoroacetic acid (1.50 mmol) used. gtrifluoroacetic acid (1.00 mmol) used, has mixture of 93:7 trans:cis alkenes. NATURE COMMUNICATIONS | 8:15913 | DOI: 10.1038/ncomms15913 | www.nature.com/naturecommunications

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NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15913

a O

O

TFA 1.75 equiv.

Bn F3 C F3C N N N PhSiH 3 2.0 equiv. Me Me THF, 60 °C, 4 h quantitative recovery 40 1.00 equiv. 41 73% An exogeneous amide is not reduced during a typical reaction.

HN

Bn

F3 C

O

b O F3 C

H OH

Product ratio depends on stoichiometry

Bn

N

PhSiH 3 , 2 equiv.

F3 C

THF, 60 °C, 3 h

Bn

N

F3C

c

O

O

H

EWG OH 2.00 equiv. F3 C

Me 40 54% 6%

Me 1 1.00 equiv. TFA 0% 1.75 equiv. TFA 80% Formation of amines requires excess acid. Amide forms if acid is limited. Me

Bn

N

N

Bn

PhSiH 3, 2 equiv. THF, 60 °C, 3 h

Me Bn

N Me 1: 67% 85:9

Cl 3C

N Me 42: 60% 62:9

Bn

N

EWG

EWG

Me Bn

HF2C

N Me 43: 44% 60:30

Bn

H 2ClC

N Me 44: 17% 30:60

Bn

Bn

N Me

Bn

Ph N N Me Me 46 45: 17%

A practical and catalyst-free trifluoroethylation reaction of amines using trifluoroacetic acid.

Amines are a fundamentally important class of biologically active compounds and the ability to manipulate their physicochemical properties through the...
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