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Arkivoc 2017, part i, 67-83

Application of fluoroform in trifluoromethylation and difluoromethylation reactions Cai Zhang Department of Architecture and Environment, Chongqing Vocational Institute of Safety Technology, Chongqing 404 020, People’s Republic of China E-mail: [email protected] Received 09-18-2016

Accepted 12-10-2016

Published on line 03-12-2017

Abstract Recent development in the trifluoromethylation and difluoromethylation of organic compounds employing fluoroform is reviewed. Eight approaches to trifluoromethylation and difluoromethylation are summarized: (i) trifluoromethylation or difluoromethylation of carbonyl compounds, (ii) trifluoromethylation of sulfonyl fluorides, (iii) trifluoromethylation of epoxides, (iv) nucleophilic trifluoromethylation of silicon, boron, and sulfur-based compounds, (v) CuCF3 derived from fluoroform for the trifluoromethylation of aryl or heteroaryl halides, aryl boronic acids, arenediazonium salts and alkynes, (vi) difluoromethylation of alkynes, (vii) difluoromethylation of phenols, thiophenols and heterocyclic compounds, and (viii) difluoromethylation of nitriles.

HCF3 strong base

-CF3

decompose

: CF2

+

F

-

trifluoromethylation difluoromethylation

Keywords: Trifluoromethylation, difluoromethylation, fluoroform, CuCF3

DOI: http://dx.doi.org/10.3998/ark.5550190.p009.884

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Table of Contents 1. 2.

3. 4. 5.

Introduction Application of Fluoroform in Trifluoromethylation and Difluoromethylation 2.1 Trifluoromethylation or difluoromethylation of carbonyl compounds 2.2 Trifluoromethylation of sulfonyl fluorides 2.3 Trifluoromethylation of epoxides 2.4 Nucleophilic trifluoromethylation of silicon, boron, and sulfur-based compounds 2.5 CuCF3 derived from fluoroform for the trifluoromethylation of aryl or heteroaryl halides, aryl boronic acids, arenediazonium salts and alkynes 2.6 Difluoromethylation of alkynes 2.7 Difluoromethylation of phenols, thiophenols and heterocyclic compounds 2.8 Difluoromethylation of nitriles Conclusions Acknowledgements References

1. Introduction In recent years, the organic fluorine compounds, such as trifluoromethylated and difluoromethylated molecules, have been widely concerned in pharmaceutical and agrochemical research,1-3 because the trifluoromethyl and difluoromethyl groups can improve the binding selectivity, lipophilicity and metabolic stability of these compounds.4 Recently, a series of fluorine reagents, such as Umemoto’s reagents,5-10 NaSO2CF3,11-15 CF3SiMe3,16 Togni’s reagents,17-19 and TMSCF2H,20,21 were employed in the transformations of these fluorine functional groups. However, reports on the application of fluoroform (a cheap, nontoxic and not an ozone-depleting gas22) in trifluoromethylation and difluoromethylation reactions are rare.23 This review provides an overview of trifluoromethylation and difluoromethylation using fluoroform over the period from 2010 to the present. Several approaches will be reviewed and divided into (i) trifluoromethylation or difluoromethylation of carbonyl compounds, (ii) trifluoromethylation of sulfonyl fluorides, (iii) trifluoromethylation of epoxides, (iv) nucleophilic trifluoromethylation of silicon, boron, and sulfur-based compounds, (v) CuCF3 derived from fluoroform for the trifluoromethylation of aryl or heteroaryl halides, aryl boronic acids, arenediazonium salts and alkynes, (vi) difluoromethylation of alkynes, (vii) difluoromethylation of phenols, thiophenols and heterocyclic compounds, and (viii) difluoromethylation of nitriles. On the basis of a large amount of research literature,24-26 a proposed mechanism for trifluoromethylation and difluoromethylation reactions employing fluoroform is depicted in Scheme 1. Due to the weak acidity of HCF3,27 in the presence of the strong bases, such as t-BuOK, [(Me2N)3PN]3PNCMe3, MeSOCH2K, n-BuLi and so on, fluoroform can produce the trifluoromethyl anion (CF3-), which is a very important intermediate in trifluoromethylation reactions.16 The trifluoromethyl anion, as an unstable intermediate, can undergo decomposition to generate fluoride anion (F-) and difluorocarbene,28 which can then react with substrates to afford difluoromethylated products.29,30

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-CF3

decompose

: CF2

+

F

-

trifluoromethylation difluoromethylation

Scheme 1. A proposed mechanism for trifluoromethylation and difluoromethylation reactions employing fluoroform.

2. Application of Fluoroform in Trifluoromethylation and Difluoromethylation 2.1. Trifluoromethylation or difluoromethylation of carbonyl compounds As early as 1998-2000, an effective nucleophilic trifluoromethylation of carbonyl compounds employing fluoroform as a CF3 source in the presence of a common base [t-BuOK, MeSOCH2K, electrogenerated or silicon-containing base] was developed by the research groups of Roques, Normant, Troupel and Langlois.26,3134 A series of aldehydes and ketones were tested for trifluoromethylation, and gave moderate to good yields of the target products 2 in most cases. [(Me2N)3PN]3PNCMe3 THF, -30 oC, 2 h 52-92% Shibata's group [(Me2N)3PN]3PNCMe3 THF, -40 oC, 3 h 48-99% Mikami's group

O R1

1

R2

+

HCF3

KHMDS or t-BuOK THF or ether 0-81% Prakash's group

tBu N N N N P N P N P N N N N N P N HO CF3 N R1 R2 [(Me2N)3PN]3PNCMe3 2 K N

Si Si 1)[(Me2N)3 PN]3PNCMe3 N(SiMe3)3 KHMDS THF, RT, 2-19 h 2) TBAF, THF, RT 64-99% Shibata's group R1 = 2-Naphthyl, Ph, 3- and 4-CH3C6 H4, 4-BrC6H4, 4-NO2C6H4, 9-Anthracyl, 2-Thienyl, (CH3)3C, n-C6H13, cyclohexyl, 4-CH3OC6H4, 4-FC6H4, 2-C5 H4N, 2-, 3- and 4-ClC6H4 R2 = H, CH=CHPh, Ph, 4-ClC6H4, CH3, (CH3)3C, 4-CH3 OC6H4, 2-C5H4N

Scheme 2. Trifluoromethylation of aldehydes and ketones. In 2012, 2013 and 2015, some new type bases, such as [(Me2N)3PN]3PNCMe3 and KHMDS, applied in the nucleophilic trifluoromethylation of aldehydes, ketones, carboxylic acid esters or halides were developed by the research groups of Prakash, Shibata and Mikami (Schemes 2 and 3).24,35-37 In these studies, various carbonyl compounds were scrutinized, giving moderate to good yields of products 2, 4 or 5 in most cases. Prakash et al. showed that all the trifluoromethylation reactions, performed in THF or ether instead of DMF as solvent in the presence of fluoroform as a CF3 source and KHMDS or t-BuOK as a base, afforded the desired Page 69

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products 2 in 0-81% yields (Scheme 2).35 When the chalcone containing a nitro group in the para position of the benzoyl group was employed for this transformation, however the target product 2 was not obtained.35 The other two research groups, such as Shibata and Mikami, both reported that in the effect of [(Me2N)3PN]3PNCMe3 as base, fluoroform was used for difluoromethylation reaction at lower temperature (30 oC or -40 oC) or room temperature, and produced the compounds 2 in moderate to excellent yields (Shibata: 52-92% and 64-99%, Mikami: 48-99%, respectively).24,36,37 In addition, the carboxylic acid esters and halides 3 were also employed for trifluoromethylation by Mikami and co-workers (Scheme 3).36 It is very interesting that when benzoyl chloride and 1.2 equiv [(Me2N)3PN]3PNCMe3 were used for this transformation, the reaction time had no effect on the yield of the product 4 (72% yield). However, in the presence of 2.4 equiv. [(Me2N)3PN]3PNCMe3, as the reaction time was prolonged, the yield of the product 4 decreased gradually, while the yield of the product 5 gradually increased. O

O X

3 X= X= X= X= X= X=

Cl Cl Cl Cl Cl OMe

+

HCF3

[(Me2N)3PN]3PNCMe3 (Y equiv)

Y= 1.2 Y= 1.2 Y= 2.4 Y= 2.4 Y= 2.4 Y= 1.2

THF, -40

CF3 CF3

CF3 +

oC

1.5 h 3h 1h 10 h 24 h 24 h

HO

4 72% 72% 81% 13% 0% 58%

5 trace 14% 7% 60% 90% 0%

Scheme 3. Trifluoromethylation of the carboxylic acid esters and halides. A proposed catalytic cycle for the trifluoromethylation using fluoroform as a CF3 source in the presence of [(Me2N)3PN]3PNCMe3 and N(SiMe3)3, was described by Shibata and co-workers,37 as shown in Scheme 4. The stabilized ion pair A, arising from the reaction between substrate 1 and fluoroform in the presence of [(Me2N)3PN]3PNCMe3, reacted with N(SiMe3)3 to produce the ion pair C and intermediate B, which underwent a process of removing TMS to afford the desired product 2 in the effect of TBAF. The fluoroform, as a weak acid, would suffer a deprotonation reaction in the presence of the ion pair C to produce the trifluoromethyl anion (CF3-), which can react with compound 1 and H[[(Me2N)3PN]3PNCMe3]+ also to give the stabilized ion pair A. In the entire reaction, H[[(Me2N)3PN]3PNCMe3]+ should play an important role in the trifluoromethylation.37

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Zhang, C. HCF3

R2

[(Me2N)3PN]3PNCMe3

H[[(Me2N)3PN]3PNCMe3]+

1

O

CF3

R1

R2

stabilized ion pair A

N(SiMe3)3

H[[(Me2N)3PN]3PNCMe3]+ N(SiMe3)2

Me3SiO R1

TBAF

R2

HO R1

B

C

CF3 2

R2

N(SiMe3)3 HCF3

O R1

CF3

H[[(Me2N)3PN]3PNCMe3 ]+

R2

O

CF3

R1

R2

stabilized ion pair A

Scheme 4. A proposed catalytic cycle for the trifluoromethylation using fluoroform. In 2013, Vugts and co-workers reported an efficient method for the synthesis of [18F] trifluoromethylcontaining compounds 7 via a trifluoromethylation process using [18F] fluoroform in the presence of t-BuOK as a base (Scheme 5).38 A series of aldehydes and ketones were found to undergo the desired transformations to give moderate to excellent yields of the corresponding products 7 in most cases. However, when the substrates 6 bearing an electron-withdrawing group such as 4-NO2 and 3-NO2 in the aromatic ring, only trace amounts of the desired products 7 were afforded under the action of a smaller amount of t-BuOK. O R2

HO R1

+

HCF218F

R1

t-BuOK

R2 up to 99%

6 R1 = H, 4-OMe, 4-CF3, 4-F, 4-NO2, 3-NO2 R2 = H, Ph, CH3

CF218F

7

Scheme 5. An efficient method for the synthesis of [18F] trifluoromethyl containing compounds. In 2012, a direct α-difluoromethylation of ketones for the synthesis of α-difluoromethyl products 9 using fluoroform as a difluoromethylating reagent in the presence of LHMDS was developed by Mikami and coworkers (Scheme 6).39 Not only protected lactams 8a, b, d-f but also the lactones 8g-i, ketone 8j and acyclic substrates 8k-m were all examined for α-difluoromethylation, and afforded the α-difluoromethyl products 9 in moderate to excellent yields (9a-b: 45-69%, 9d-f: 37-64%, 9g-i: 33-47%, 9j: 36%, 9k-m: 35-82%). However, the α-difluoromethylation of the α-unsubstituted lactam 8c did not proceed well with 99% of the raw material 8c being recovered.

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X R2

O CF2H Bn TsN

TsN 9a 69% O

BocN

O

9c 0

O

O CF2H O CO2Et

CF 2H

CF2H 9k 78%

CF2H

O EtO

Bn

MeO

9i 33%

EtO MeO CF2H 9l 35%

CF2H Bn

Bn

O

EtO

9e 57% O

9d 64%

9h 47%

9g 47%

Me

R 9 up to 82% yield O O CF2H CF2H TsN Bn BocN

CF2H allyl TsN

9b 45% O O CF2H CF2H Bn O Bn O

9f 37%

CF2H 1 2R

X

2) HCF3 (ca. 5 equiv) 0 oC or RT.

8 O

O

1) LHMDS (2 equiv) THF, 0 oC, 30 min

9j 36%

O

OEt Me CF2H 9m 82%

Scheme 6. A direct α-difluoromethylation of ketones using fluoroform. 2.2. Trifluoromethylation of sulfonyl fluorides In 2015, Shibata and co-workers developed an effective trifluoromethylation of sulfonyl fluorides 10 employing N(SiMe3)3 and excess HCF3, in the presence of a catalytic amount of [(Me2N)3PN]3PNCMe3 (Scheme 7).37 A series of sulfonyl fluorides 10a-g bearing an electron-withdrawing or electron-donating group located on the aromatic ring, underwent the desired transformations, and afforded the aryl triflones 11 in good to high yields (11a-g: 50-84%). Beyond that, the naphthyl-substituted sulfonyl fluorides 10h,i were also employed for the synthesis of aryl triflones, and give 60-78% yields of the the desired products 11h, i.

Ar SO2F 10

N(SiMe3)3 (1.5 equiv) DMF, 0 oC, 5-17 h

SO2CF3 Br

SO2CF 3 Cl 11a 84%

HCF3 (excess) [(Me2N)3PN]3PNCMe3

Ar SO2CF3 11 50-84% Br

SO2CF3 11c 62%

11b 57%

SO2CF3 I 11d 50%

SO 2CF3 11e 79%

SO2CF3 SO2CF3 SO2CF3 11f 54%

SO 2CF3 11g 78%

11h 78%

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Scheme 7. Trifluoromethylation of sulfonyl fluorides. 2.3. Trifluoromethylation of epoxides In 2013, an organocatalysis approach to trifluoromethylation of epoxides with fluoroform at 40 ºC was developed by Mikami and co-workers (Scheme 8).36 The epoxides 12 or 14 containing not only electronwithdrawing but also electron-donating groups, afforded the internal or terminal trifluoromethylation products 13 or 15 in 37-69% yields. A suggested reaction mechanism, shown in Scheme 9, for the trifluoromethylation of epoxides was proposed by Mikami and co-workers.36 First of all, the [(Me2N)3PN]3PNCMe3 reacts with epoxides 12 at the terminal carbon to afford the intermediates A, which would undergo a hydrogen transfer process to produce methyl ketones B. Then the ketones B are attacked by trifluoromethyl anion (CF3-), arising from the reaction between fluoroform and [(Me2N)3PN]3PNCMe3, to give the intermediates C, which finally form the observed products 13, by proton transfer from H[[(Me2N)3PN]3PNCMe3]+. H3C OH

O +

HCF3

X 12

[(Me2 N)3PN]3PNCMe3

CF3

o

THF, 40 C, overnight 37-69%

H3C OH

X 13

H3C OH

CF3

CF3 F3C

13a 51%

H3C OH CF3 MeO

13b 69%

13c 37%

O +

HCF3

CF 3 OH

[(Me2N)3PN]3PNCMe3 THF, 40 oC, overnight

14

CH3 15

53%

Scheme 8. Trifluoromethylation of of epoxides. O

O

O

+ P4 N13C22H63

+ [(Me2N) 3PN]3PNCMe3

H X

X

X 12

[(Me2N)3PN]3PNCMe3

B

A

CF3 H[[(Me2N)3PN]3PNCMe3]+

H[[(Me2 N)3PN]3PNCMe3]+

CF3 HCF3

X 13

-

H3C O

H3C OH

X

CF3

[(Me2N)3PN]3PNCMe3

C

Scheme 9. A suggested reaction mechanism for the trifluoromethylation of epoxides.

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2.4. Nucleophilic trifluoromethylation of silicon, boron, and sulfur-based compounds In 2012, Prakash and co-workers also reported a nucleophilic trifluoromethylation of silicon, boron, and sulfurbased compounds with HCF3 in the presence of KHMDS as base (Scheme 10).35 It was found that when CF3H was used for trifluoromethylation of silicon-based substrates 16, the desired products 17 were obtained in 4280% yields. In the effect of KHMDS, the boron-based compounds 18 can react with fluoroform, then followed by 48% aqueous HF to afford CF3BF3K 19 in 53% or 66% yield. The trifluoromethanesulfonic acid (CF3SO3H) 20, a widely used and widely available organic acid, can be obtained in modest 18% conversion, in the presence of CF3H, S8, KHMDS, 30% H2O2 and H2SO4.35 Because of low conversion rate of this synthesis procedure, we think that this preparation method of trifluoromethanesulfonic acid is not going to be economically viable. R R Si Cl R 16

HCF3

+

KHMDS (1 equiv) Toluene or ether -78 oC to rt 4 to 6 h 42-80%

HCF3

+ B(OR)3

1) KHMDS, THF -5 oC to rt 2) 48% aq. HF 53-66%

18

R R Si CF3 R 17

CF3 F B F K F 19

R= Me, n-Bu

HCF3

CH3 H3C Si CF3 CH3 17a 80%

+

S8

KHMDS (2 equiv) o

THF, -78 C 3 h to rt

CF3Sn

-

18% by 19 F NMR

30% H2O2 CF3 SO3H H2SO4 20 100% by 19F NMR based on CF3Sn

Si CF3

Si CF3

Si CF3

Si CF3

17b 58%

17c 71%

17d 78%

17e 42%

Si Si Si CF3 Si 17f 68%

CF3 Si CF3 17g 44%

Scheme 10. Nucleophilic trifluoromethylation of silicon, boron, and sulfur-based compounds. 2.5. CuCF3 derived from fluoroform for the trifluoromethylation of aryl or heteroaryl halides, aryl boronic acids, arenediazonium salts and alkynes In 2011, 2013, 2014 and 2016, CuCF3 derived from fluoroform for the trifluoromethylation of aryl boronic acids, arenediazonium salts, alkynes, aryl and heteroaryl halides was developed by the research groups of Grushin, Daugulis and Tsui (Scheme 11).40-45 All these research groups showed that HCF3 can react with CuCl in the presence of t-BuOK and DMF, or zinc bis-2,2,6,6-tetramethylpiperidide (TMP)2Zn, 1,3dimethylpropyleneurea (DMPU) and phenanthroline to produce fluoroform-derived CuCF3, which was a good

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trifluoromethylating reagent for the trifluoromethylation,5,46,47 and afforded the desired products 25-27 in moderate to excellent yields.40-45 CF3 X1

Het

Het HCF3 21

CuCl a) Grushin's t-BuOK and Tsui's DMF groups

X1

R1 +

22 N2+ F-

R1

CF3

R1

26 27-99%

HCF3

23 R2

CuCF3 CuCl TMP2Zn b) Daugulis's group DMPU

25 30-99%

X2

R2

CF3

27 40-96%

24 X1 =

Br, I, B(OH)2 R1= 4-Ac, 3-CHO, 2-CONH2, 4-Br, 2-Br, 2-CO2H, 4-Ph, 2-CO2Et, H, 4-CH3 , 4-Cl, 4-CH3O, 4-F, 4-CO2H, 4-NO2, 4-NHCOCH3, 4-COCH3, 4-CO2CH3, 4-I, 3-NO2, 3-I, 2-CO2CH3, 2-COCH3, 2-Cl, 2-CO2H X2 = H, TMS R2= 2-naphthyl, 4-CH3OC6H4, 4-CH3C6H4, 4-C6H4CO2Et, 4-CF3C6H4, Ph, 4-FC6H4, 4-BrC6H4, 4-IC6H4, 4-TMSC6H4, 3-CH3OC6H4, 2-CH3OC6H4 , 2-CH3C6H4, 2-NH2C6H4, 3-C5H4N, n-C10H21, C6H5CH2OCH2

Scheme 11. Trifluoromethylation of aryl or heteroaryl halides, aryl boronic acids, arenediazonium salts and alkynes. In 2014, a valuable method for the [18F] trifluoromethylation of aryl iodides and aryl boronic acids in situ by use of HCF218F as the precursor of CuCF218F was described by Vugts and co-workers (Scheme 12).48 Under the optimized reaction conditions, a broad range of aryl iodides and aryl boronic acids can be converted successfully into the desired products 28 in moderate to excellent yields in many cases. From the experimental results, it can be seen that electronic effects seem to have no influence on the yields. However, the unprotected alcohol, carboxylic acid and amine did not perform well for the [18F] trifluoromethylation reaction, and gave poor yields of the products 28k-m. When the substrates 28n, 28p, 28q and 29h were employed for the [18F] trifluoromethylation, only 2-41% yields of the [18F] trifluoromethyl arenes 30n, 30p, 30q and 30h were obtained.

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HCF218F

Method A 28 Ar-I 130 oC, 10 min

1) CuBr, KOtBu 2) Et3N.3HF DMF, 20 oC, 2 min

CuCF218F

Ar-B(OH)2

ArCF218F 30 up to 99%

29

air, 20 oC, 1 min Method B

CF218F

CF3 CF 218F F3C

F3C 30a 30b A: 61% ± 2% A: 79% ± 7% B: 94% ± 1% B: 84% ± 8% CF218F MeO

CF218F

HO

30k A: 13% ± 4% B: 75% ± 5%

30o A: 62% ± 13% B: 97% ± 1%

30i A: 89% ± 2% B: 87% ± 4%

H2N

HO2C

30m A: 48% ± 4%

30l A: 3% ± 1% B: 0% ± 0%

CF218F

BocHN 30p A: 34% ± 6% B: 94% ± 5%

CF218F

H3COC

30j A: 61% ± 2% B: 92% ± 5%

CF218F

CF218F

CF218F MeO2C

OHC

30h A: 73% ± 6% B: 4% ± 2%

CF218F

30e A: 86% ± 4% B: 91% ± 5%

CF218F

CF218F I

30g A: 70% ± 5% B: 95% ± 1%

CF218F

O 2N

30d A: 79% ± 5% B: 96% ± 3%

30c A: 82% ± 5% B: 95% ± 2%

Br

30f A: 54% ± 3% B: 94% ± 2%

CF218F

CF218F

CF218F

AcO

30n A: 30% ± 3%

CF218F

H3COCHN

30q A: 40% ± 1% B: 94% ± 1%

N

CF218F

30r A: 89% ± 4%

Scheme 12. [18F] trifluoromethylation of aryl iodides and aryl boronic acids. 2.6. Difluoromethylation of alkynes In 2015 and 2016, an effective difluoromethylation of alkynes under a fluoroform atmosphere in the presence of t-BuOK or LHMDS as base was developed by the research groups of Shibata and Mikami (Scheme 13).49,50 A variety of arynes bearing either electron-donating or electron-withdrawing groups, such as methoxy (31a, 31e, 31g, 31k), phenyl 31c, dimethylamino 31b, bromo 31d, benzyloxy 31f and ester 31m were all tolerated, and afforded the desired products 32a-g, 32k, 31m in moderate yields. The heterocyclic alkynes 31h and 31n were also examed, and gave the products 32h, 32n in 48% and 45% yields. In addition, the aliphatic alkynes 31l and 31o have also been well transformed to the difluoromethylated compounds (32l: 38%, 32o: 72%).

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R

H 31

CF2H

CF 2H

HCF3 (excess) tBuOK (10 equiv) n-decane (0.1 M) 36-73% a) Shibata's group

R

LHMDS

CF2H

CF2H

Si

32

HCF3 (balloon) LHMDS (2 equiv) THF, -78 oC, 2 h 43-72% b) Mikami's group

CF2H

Si

CF2H

Li N

CF 2H

CF 2H

CF2H

OMe OMe Ph NMe2 Br OMe 32c 32e 32b 32d 32a 61% 36% 54% 50% 60% Shibata Shibata Shibata Shibata Shibata

32f 57% Shibata

S

OBn 32g 44% Shibata

32h 48% Shibata

CF2 H CF2H

CF2H

CF2 H

CF2H

CF2H

CF2H

MeO N

32i

32j 73% 42% 57% Shibata Mikami Shibata

OMe 32k 32l 48% 38% 43% Shibata Mikami Shibata

TIPS

CO2 Me 32m 63% Mikami

32n 45% Mikami

32o 72% Mikami

Scheme 13. Difluoromethylation of alkynes. 2.7. Difluoromethylation of phenols, thiophenols and heterocyclic compounds In 2013 and 2014, the conversion of a series of substrates such as phenols, thiophenols, imidazoles, benzotriazoles and hydroxypyridines into their difluoromethylated derivatives 34, 36 and 38, with fluoroform as a difluorocarbene source in the presence of KOH as base, was demonstrated by the research group of Dolbier (Scheme 14).51,52 They showed that the phenols and thiophenols 33 containing either electron withdrawing or electron donating groups, performed well under the conditions of synthetic methods A and B, and afforded the products 34 in moderate to excellent yields.51 Dolbier and co-workers found that, under the conditions of method B, difluoromethylation of heterocyclic compounds, such as imidazoles, benzimidazoles, indazoles and benzotriazoles (35) and hydroxypyridines (37), proved satisfactory, with moderate to good yields of the difluoromethylated products 36, 38 being obtained.52

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XH Method A: HCF3, KOH H2O/Dioxane, 50 oC

1

R

XCF2H 1

R

Method B: HCF3, KOH, H2O/MeCN, RT.

R2 R2 33 34 40-90% X= O, S R1= H, 4-Cl, 4-CH3O, 4-CH3, 2-CH3, 4-Ph, 4-CN, 4-NO2, 2-NO2, 3-NO2, 3,4-OCH2O R2= H, 4-Cl, 2-CH3 CF2H H Method B: HCF3, KOH, N N H2O/MeCN, RT. R3 R3 R4 R4 N N 42-93% 35 36 OCF2H OH Method B: HCF3, KOH, 5 5 H2O/MeCN, RT. Het R Het R 48-65% 37 38 CF2H CF2H CF2H CF2H CF2H N N N N N SMe NO2 N N N N N 36a 36d 36c 36e 36b 50% 71% 42% 99% 45% MeO N N N N N CF2H 36f

67% 1:1 ratio

36h

36g

N

N 38b 51%

Cl

N CF2H

N

N

N CF2H

N CF2H

Cl

N

36l 95% 2:1 ratio OCF2H OCF2H

N 38c 53%

Br

N

OCF2H

N 38a 50%

36k

OCF2H

36i

66% 1:1 ratio

Cl

Cl

36j 72%

N CF2H

N MeO CF2H

N CF2H

F

38d 54%

N

Cl

Cl 38e 65%

OCF2H

OCF2H N 38f 48%

Scheme 14. Difluoromethylation of phenols, thiophenols and heterocyclic compounds. 2.8. Difluoromethylation of nitriles In 2015, Mikami and co-workers reported a valuable difluoromethylation of nitrile compounds with fluoroform as a CF2H source in the presence of nBuLi as base (Scheme 15).53 It was found that higher yields (40a-f: 75-96%) were generally observed for the substrates 39a-f containing either an electron withdrawing or electron donating group in the position of the benzene ring. However, when the acyclic or cyclic α-monoalkylated and Page 78

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vinylic substituted nitriles 39h-n were employed for the difluoromethylation reactions, the difluoromethylated products 40h-n were obtained in moderate yields (39-53%). CN R1

nBuLi (1.1 equiv) HCF3 (2 equiv)

R2 39

40b 79%

40a 96%

NC CF2H

NC CF2H

R1

THF, -78 39-96%

NC CF2H

NC CF2H

NC CF2H

oC

R2 40

NC CF2H

NC CF2H

OMe F

F

40c 92%

NC CF2H

Cl

40d 94%

NC CF 2H

NC CF2H

40h 53%

40i 58%

Cl Cl 40f 75%

40e 87% NC CF2H

NC CF H 2

40g 41% NC CF2H

NC CF2H NC CF2H

40j 50%

40k 48%

40l 52%

40m 39%

40n 50%

Scheme 15. Difluoromethylation of nitriles.

3. Conclusions In summary, recent developments in trifluoromethylation and difluoromethylation by use of fluoroform are presented. In the presence of the strong bases, fluoroform can produce the trifluoromethyl anion, which is an unstable intermediate undergoing a decomposition reaction to generate difluorocarbene. Both the trifluoromethyl anion and difluorocarbene are very important intermediates in the trifluoromethylation or difluoromethylation reactions. In this review, we classified trifluoromethylation and difluoromethylation reactions under eight headings: (i) trifluoromethylation or difluoromethylation of carbonyl compounds, (ii) trifluoromethylation of sulfonyl fluorides, (iii) trifluoromethylation of epoxides, (iv) nucleophilic trifluoromethylation of silicon, boron, and sulfur-based compounds, (v) CuCF3 derived from fluoroform for the trifluoromethylation of aryl or heteroaryl halides, aryl boronic acids, arenediazonium salts and alkynes, (vi) difluoromethylation of alkynes, (vii) difluoromethylation of phenols, thiophenols and heterocyclic compounds, and (viii) difluoromethylation of nitriles. In most cases, the trifluoromethylated or difluoromethylated products were obtained in moderate to excellent yields. Compared with Umemoto’s reagents, NaSO2CF3 and Togni’s reagents, fluoroform is a non-toxic and harmless gas, and not easy to operate in the reactions. However, it can be converted to other stable CF3 reagents, such as CuCF3 and CF3SiMe3, which are relatively Page 79

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easy to operate in industrial production of the trifluoromethylated or difluoromethylated compounds. In spite of this, we also expect that the application of fluoroform in trifluoromethylation and difluoromethylation reactions will continue.

4. Acknowledgements We would like to thank all authors whose names are listed in the references for their contributions to the organic fluorine chemistry described in this review. We also gratefully acknowledge the financial support by the research project (143144, AQJK15-08) from Chongqing Education Commission and Chongqing Vocational Institute of Safety Technology.

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Author’s Biography

Cai Zhang was born in Anhui Province, P. R. of China. He received his BSc degree from Huaibei normal University (P. R. of China) in 2005, and obtained his MSc degree at Southwest University, Chongqing, P. R. of China, in 2009. From 2009 to 2013, he conducted Active Pharmaceutical Ingredient (API) research, such as cholesterol absorption inhibitors, antiplatelet drugs and antidiabetic drugs at pharmaceutical enterprises. In 2013 he moved to Chongqing Vocational Institute of Safety Technology, where he is engaged in the work of teaching and scientific research. His current research interests focus on the development of novel synthetic methodologies, such as hypervalent iodine reagents for application in organic synthesis, C–H bond activation and fluorine chemistry.

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