Synlett 2015; 26(01): 59-62
DOI: 10.1055/s-0034-1378937
cluster
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Trifluoromethylated Cycloheptatrienes from N-Tosylhydrazones: Transition-Metal-Free Büchner Ring Expansion

Zhikun Zhang
a  Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China   Fax: +86(10)62751708   Email: wangjb@pku.edu.cn
,
Jiajie Feng
a  Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China   Fax: +86(10)62751708   Email: wangjb@pku.edu.cn
,
Yan Xu
a  Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China   Fax: +86(10)62751708   Email: wangjb@pku.edu.cn
,
Songnan Zhang
a  Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China   Fax: +86(10)62751708   Email: wangjb@pku.edu.cn
,
Yuxuan Ye
a  Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China   Fax: +86(10)62751708   Email: wangjb@pku.edu.cn
,
Tianjiao Li
a  Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China   Fax: +86(10)62751708   Email: wangjb@pku.edu.cn
,
Xi Wang*
a  Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China   Fax: +86(10)62751708   Email: wangjb@pku.edu.cn
,
Jun Chen
b  Beijing Institute of Microchemistry, No.15 Xinjiangongmen Road, Haidian District, Beijing, 100091, P. R. of China
,
Yan Zhang
a  Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China   Fax: +86(10)62751708   Email: wangjb@pku.edu.cn
,
Jianbo Wang*
a  Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China   Fax: +86(10)62751708   Email: wangjb@pku.edu.cn
› Author Affiliations
Further Information

Publication History

Received: 30 September 2014

Accepted after revision: 21 October 2014

Publication Date:
18 November 2014 (online)

 


Abstract

A transition-metal-free Büchner reaction using trifluoromethylated N-tosylhydrazones as substrates is reported. A series of trifluoromethylated cycloheptatriene derivatives can be synthesized by this straightforward method.


#

Trifluoromethyl-bearing organic molecules have found wide applications in pharmaceuticals, agrochemicals, and functional materials.[1] However, trifluoromethyl-bearing organic molecules do not exist in the nature. Consequently, it is highly important to develop general and practical methods to synthesize trifluoromethyl-bearing compounds. Great efforts have devoted to this area and significant progress has been made in recent years.[2]

On the other hand, diazo compounds possess diverse reactivities and are highly useful in organic synthesis. In particular, diazo compounds have found extensive applications as metal carbene precursors in transition-metal-catalyzed reactions.[3] Thus, the diazo compounds bearing the trifluoromethyl group have become attractive for the synthesis of trifluoromethyl-containing organic compounds. For example, transition-metal-catalyzed cyclopropenation and ­cyclopropanation with 1-aryl-2,2,2-trifluorodiazoethanes have been reported by Davis[4] and Katsuki,[5] respectively (Scheme [1, a]). Recently, we[6] and Valdés[7] have independently reported the palladium-catalyzed cross-coupling reaction with 1-aryl-2,2,2-trifluoro ketone and 1-alkyl-2,2,2-trifluoro ketone N-tosylhydrazones. The diazo compounds could be generated in situ in these cases.[8] These reactions provide unique methods for the synthesis of trifluoromethylated alkenes and dienes (Scheme [1, b]).

Zoom Image
Scheme 1 Reactions with trifluoromethyl-bearing diazo compounds or N-tosylhydrazones

In connection to our interest in both carbene chemistry and trifluoromethylations, herein we report a transition-metal-free Büchner reaction using trifluoromethylated N-tosylhydrazones as the substrates (Scheme [1, c]). The rhodium(II)-catalyzed intramolecular Büchner reaction as an effective approach toward seven-membered carbocycles have been extensively studied by the groups of McKervey, Doyle, Moody, and others.[9] The intermolecular Büchner reaction without transition-metal catalysis usually suffers low selectivity due to other competing reaction pathways.[3b] The Büchner reaction with 1-aryl-2,2,2-trifluorodiazoethanes reported herein is not interfered by the aromatic sp2 C–H insertion side reactions, thus providing a convenient method for the synthesis of trifluoromethylated cycloheptatrienes.

The initial study was carried out with N-tosylhydrazone 1a (0.2 mmol) and benzene (2a, 2.0 mL) as the substrates, with Cs2CO3 (3.0 equiv) as the base at 80 °C. After three hours, the product 3a was isolated in 23% yield (Table [1], entry 1). To our delight, the direct C–H insertion product was not detected.[10] Next, the effect of temperature was examined. The yield could be slightly improved at high temperature (Table [1], entry 2). It was found that adding 4 Å molecular sieves (4 Å MS) as additive could further improve the yield (Table [1], entries 4 and 5). Besides, the concentration has marginal effect on the reaction (Table [1], entries 4–9). Finally, the effect of base was studied, and Cs2CO3 was found to afford the best result (Table [1], entries 10–14).

Table 1 Optimization of Reaction Conditionsa

Entry

Base (equiv)

Additive

Temp (°C)

2a (mL)

Yield (%)b

1

Cs2CO3 (3)

none

80

2

23

2

Cs2CO3 (3)

none

110

2

33c

3

Cs2CO3 (3)

4 Å MS

80

2

33c

4

Cs2CO3 (3)

4 Å MS

120

2

42

5

Cs2CO3 (3)

4 Å MS

80

1

20c

6

Cs2CO3 (3)

4 Å MS

120

3

51

7

Cs2CO3 (3)

4 Å MS

120

4

61

8

Cs2CO3 (3)

4 Å MS

120

5

51

9

Cs2CO3 (3)

4 Å MS

120

10

57

10

K2CO3 (3)

4 Å MS

2

2

25c

11

LiOt-Bu (3)

4 Å MS

4

4

30c

12

NaOt-Bu (3)

4 Å MS

4

4

55c

13

KOt-Bu (3)

4 Å MS

4

4

49

14

K3PO4 (3)

4 Å MS

4

4

53

a The reaction was carried in 0.2 mmol scale with 4 Å MS (50 mg). Reaction time is 3 h and the substances were reacted at a sealed tube.

b Unless otherwise noted, it refers to isolated yield.

c Yield determined by GC–MS.

With the optimized reaction conditions (Table [1], entry 7), the substrate scope of the reaction was investigated by using a series of N-tosylhydrazones.[11] As illustrated in Table [2, a] variety of N-tosylhydrazones 1al bearing different substituents on the aromatic rings were reacted smoothly with benzene, affording the desired products in moderate yields (3al). N-Tosylhydrazones bearing halogen substituents, such as fluoro, chloro, bromo, and iodo, all give the corresponding products in decent yields. In particular, active iodide 1e is compatible under the reaction conditions (Table [2], entry 5). The substrates bearing electron-withdrawing substituents, such as nitro and trifluoromethyl, gave the corresponding products in moderate yields (Table [2], entries 7 and 8).

However, the substrate with strong electron-donating 4-methoxy substituent only gave the product in low yield (Table [2], entry 11). Notably, the reaction also worked well with the substrate bearing the CF2CF2CF3 group instead of the trifluoromethyl group (Table [2], entry 12). The reaction seems to be significantly affected by the steric effect of the substituent, as the substrate bearing the 2-methyl group gave only trace amount of the expected product (Table [2], entry 13).

Table 2 Scope of N-Tosylhydrazones

Entry

Substrate 1al

Ar

Rf

Yield (%)a

1

1a

Ph

CF3

3a 61

2

1b

4-FC6H4

CF3

3b 57

3

1c

4-ClC6H4

CF3

3c 67

4

1d

4-BrC6H4

CF3

3d 68

5

1e

4-IC6H4

CF3

3e 62

6

1f

2-BrC6H4

CF3

3f 64

7

1g

4-F3CC6H4

CF3

3g 69

8

1h

3-O2NC6H4

CF3

3h 56

9

1i

4-MeC6H4

CF3

3i 52

10

1j

2-naphthyl

CF3

3j 51

11

1k

4-MeOC6H4

CF3

3k 27

12

1l

4-FC6H4

C3F7

3l 52

13

1m

2-MeC6H4

CF3

3m trace

a Isolated yield.

Furthermore, we proceeded to expand the substance scope of arenes and examined the reactions in several aromatic solvents. In these cases, the reaction will meet the problem of regioselectivity. Three aromatic solvents have been examined: anisole (4a), 1,3-dimethoxybenzene (4b), and mesitylene (4c).

In the case of anisole (4a), two regiosomeric products 5aa and 5ab were isolated in approximately equal amount (Scheme [2, a]). For 1,3-dimethoxybenzene (4b), attributed to the steric effects, the formal C–C bond insertion only occurs at the sterically less hindered sites, giving 5b as the sole product in moderate yield (Scheme [2, b]). For the symmetric substrate mesitylene (4c), the reaction afforded the expected product 5c, but in 27% yield due to steric hindrance (Scheme [2, c]).

Zoom Image
Scheme 2

In summary, we have reported herein the first Büchner reaction using N-tosylhydrazones as the substrates. This transition-metal-free reaction afforded trifluoromethylated cycloheptatrienes in moderate yields without aromatic sp2 C–H bond insertion by-products. This reaction demonstrates the unique reactivity of free carbene that is substituted by trifluoromethyl group. This property may be further explored for the synthesis of trifluoromethyl-­containing molecules.


#

Acknowledgment

The project is supported by the National Basic Research Program of China (973 Program, No. 2012CB821600) and the Natural Science Foundation of China (Grant 21272010 and 21332002).

Supporting Information

  • References and Notes


    • For selected reviews, see:
    • 2a Xu X.-H, Matsuzaki K, Shibata N. Chem. Rev. 2015; 115 in press; DOI: 10.1021/cr500193b
    • 2b Ni C, Hu M, Hu J. Chem. Rev. 2015; 115 in press; DOI: 10.1021/cr5002386
    • 2c Chu L, Qing F.-L. Acc. Chem. Res. 2014; 47: 1513
    • 2d Zhu W, Wang J, Wang S, Gu Z, Aceña JL, Izawa K, Liu H, Soloshonok VA. J. Fluorine Chem. 2014; 167: 37
    • 2e Chen P, Liu G. Synthesis 2013; 45: 2919
    • 2f Liang T, Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2013; 52: 8214
    • 2g Liu H, Gu Z, Jiang X. Adv. Synth. Catal. 2013; 355: 617
    • 2h Studer A. Angew. Chem. Int. Ed. 2012; 51: 8950
    • 2i Wu X.-F, Neumann H, Beller M. Chem. Asian J. 2012; 7: 1744
    • 2j Liu T, Shen Q. Eur. J. Org. Chem. 2012; 6679
    • 2k Macé Y, Magnier E. Eur. J. Org. Chem. 2012; 2479
    • 2l García-Monforte MA, Martínez-Salvador S, Menjón B. Eur. J. Inorg. Chem. 2012; 4945
    • 2m Tomashenko OA, Grushin VV. Chem. Rev. 2011; 111: 4475
    • 2n Zheng Y, Ma J.-A. Adv. Synth. Catal. 2010; 352: 2745
    • 2o Grushin VV. Acc. Chem. Res. 2009; 43: 160
    • 2p Cahard D, Ma J.-A. Chem. Rev. 2008; 108: PR1
    • 2q Kirk KL. Org. Process Res. Dev. 2008; 12: 305
    • 2r Shibata N, Mizuta S, Kawai H. Tetrahedron: Asymmetry 2008; 19: 2633
    • 2s Ma J.-A, Cahard D. J. Fluorine Chem. 2007; 128: 975
    • 2t Prakash GK. S, Hu J. Acc. Chem. Res. 2007; 40: 921
    • 2u Mizuta S, Shibata N, Hibino M, Nagano S, Nakamura S, Toru T. Tetrahedron 2007; 63: 8521
    • 2v Ma J.-A, Cahard D. Chem. Rev. 2004; 104: 6119
    • 2w Prakash GK. S, Yudin AK. Chem. Rev. 1997; 97: 757
  • 4 Denton JR, Sukumaran D, Davies HM. L. Org. Lett. 2007; 9: 2625
  • 5 Uehara M, Suematsu H, Yasutomi Y, Katsuki K. J. Am. Chem. Soc. 2011; 133: 170
  • 6 Wang X, Xu Y, Deng Y, Zhou Y, Feng J, Ji G, Zhang Y, Wang J. Chem. Eur. J. 2014; 20: 961
  • 7 Jiménez-Aquino A, Vega JA, Trabanco AA, Valdés C. Adv. Synth. Catal. 2014; 356: 1079
    • 8a Barluenga J, Valdés C. Angew. Chem. Int. Ed. 2011; 50: 7486
    • 8b Shao Z, Zhang H. Chem. Soc. Rev. 2012; 41: 560
    • 8c Xiao Q, Zhang Y, Wang J. Acc. Chem. Res. 2013; 46: 236
    • 9a Duddeck H, Kennedy M, McKervey MA, Twohig FM. J. Chem. Soc., Chem. Commun. 1988; 1586
    • 9b Moody CJ, Miah S, Slawin AM. Z, Mansfleld DJ, Richards IC. J. Chem. Soc., Perkin Trans. 1 1988; 4067
    • 9c Doyle MP, Ene DG, Forbes DC, Pillow TH. Chem. Commun. 1999; 1691
    • 9d Padwa A, Austin DJ, Price AT, Semones MA, Doyle MP, Protopopova MN, Winchester WR, Tran A. J. Am. Chem. Soc. 1993; 115: 8669
    • 9e Cordi AA, Lacoste J.-M, Hennig P. J. Chem. Soc., Perkin Trans. 1 1993; 3
    • 9f Merlic CA, Zechman AL, Miller MM. J. Am. Chem. Soc. 2001; 123: 11101
    • 9g Doyle MP, Hu W, Timmons DJ. Org. Lett. 2001; 3: 933
    • 9h Doyle MP, Phillips IM. Tetrahedron Lett. 2001; 42: 3155
    • 9i Kane JL, Shea KM, Crombie AL, Danheiser RL. Org. Lett. 2011; 3: 1081
  • 10 Brunner J, Serin H, Richards FM. J. Biol. Chem. 1980; 255: 3313
  • 11 General Procedure for the Büchner ReactionIn an oven-dried 20 mL Schlenk tube, N-tosylhydrazone (1, 0.2 mmol, 1.0 equiv), Cs2CO3 (0.6 mmol, 3 equiv), and 4 Å MS were added. Then the tube was sealed with a septum, and degassed by alternating vacuum evacuation and nitrogen backfill (3×) before benzene (4 mL) was added. The reaction was then stirred at 120 °C for 3 h. The reaction mixture was cooled to r.t. and filtered through a short plug of silica gel with Et2O as eluents. Solvent was then removed in vacuo to leave a crude mixture, which was purified by preparative TLC to afford pure products.7-Phenyl-7-(trifluoromethyl)cyclohepta-1,3,5-triene (3a) 1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 7.4 Hz, 2 H), 7.18–7.09 (m, 3 H), 6.44–6.42 (m, 2 H), 6.30–6.28 (m, 2 H), 5.72 (d, J = 9.3 Hz, 2 H). 13C NMR (101 MHz, CDCl3): δ = 134.9, 130.2, 129.8, 127.8, 127.1 (q, J = 281.9 Hz), 126.6, 126.6, 117.3, 53.2 (q, J = 25.0 Hz). 19F NMR (470 MHz, CDCl3): δ = –74.3 (s, 3 F). MS (EI): m/z (%) = 236 (66) [M+], 215 (15), 167 (100), 165 (60), 152 (28). IR (film): 1284, 1188, 1151, 978, 687 cm–1. HRMS (EI): m/z calcd for C14H11F3 [M]+: 236.0807; found: 236.0815.

  • References and Notes


    • For selected reviews, see:
    • 2a Xu X.-H, Matsuzaki K, Shibata N. Chem. Rev. 2015; 115 in press; DOI: 10.1021/cr500193b
    • 2b Ni C, Hu M, Hu J. Chem. Rev. 2015; 115 in press; DOI: 10.1021/cr5002386
    • 2c Chu L, Qing F.-L. Acc. Chem. Res. 2014; 47: 1513
    • 2d Zhu W, Wang J, Wang S, Gu Z, Aceña JL, Izawa K, Liu H, Soloshonok VA. J. Fluorine Chem. 2014; 167: 37
    • 2e Chen P, Liu G. Synthesis 2013; 45: 2919
    • 2f Liang T, Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2013; 52: 8214
    • 2g Liu H, Gu Z, Jiang X. Adv. Synth. Catal. 2013; 355: 617
    • 2h Studer A. Angew. Chem. Int. Ed. 2012; 51: 8950
    • 2i Wu X.-F, Neumann H, Beller M. Chem. Asian J. 2012; 7: 1744
    • 2j Liu T, Shen Q. Eur. J. Org. Chem. 2012; 6679
    • 2k Macé Y, Magnier E. Eur. J. Org. Chem. 2012; 2479
    • 2l García-Monforte MA, Martínez-Salvador S, Menjón B. Eur. J. Inorg. Chem. 2012; 4945
    • 2m Tomashenko OA, Grushin VV. Chem. Rev. 2011; 111: 4475
    • 2n Zheng Y, Ma J.-A. Adv. Synth. Catal. 2010; 352: 2745
    • 2o Grushin VV. Acc. Chem. Res. 2009; 43: 160
    • 2p Cahard D, Ma J.-A. Chem. Rev. 2008; 108: PR1
    • 2q Kirk KL. Org. Process Res. Dev. 2008; 12: 305
    • 2r Shibata N, Mizuta S, Kawai H. Tetrahedron: Asymmetry 2008; 19: 2633
    • 2s Ma J.-A, Cahard D. J. Fluorine Chem. 2007; 128: 975
    • 2t Prakash GK. S, Hu J. Acc. Chem. Res. 2007; 40: 921
    • 2u Mizuta S, Shibata N, Hibino M, Nagano S, Nakamura S, Toru T. Tetrahedron 2007; 63: 8521
    • 2v Ma J.-A, Cahard D. Chem. Rev. 2004; 104: 6119
    • 2w Prakash GK. S, Yudin AK. Chem. Rev. 1997; 97: 757
  • 4 Denton JR, Sukumaran D, Davies HM. L. Org. Lett. 2007; 9: 2625
  • 5 Uehara M, Suematsu H, Yasutomi Y, Katsuki K. J. Am. Chem. Soc. 2011; 133: 170
  • 6 Wang X, Xu Y, Deng Y, Zhou Y, Feng J, Ji G, Zhang Y, Wang J. Chem. Eur. J. 2014; 20: 961
  • 7 Jiménez-Aquino A, Vega JA, Trabanco AA, Valdés C. Adv. Synth. Catal. 2014; 356: 1079
    • 8a Barluenga J, Valdés C. Angew. Chem. Int. Ed. 2011; 50: 7486
    • 8b Shao Z, Zhang H. Chem. Soc. Rev. 2012; 41: 560
    • 8c Xiao Q, Zhang Y, Wang J. Acc. Chem. Res. 2013; 46: 236
    • 9a Duddeck H, Kennedy M, McKervey MA, Twohig FM. J. Chem. Soc., Chem. Commun. 1988; 1586
    • 9b Moody CJ, Miah S, Slawin AM. Z, Mansfleld DJ, Richards IC. J. Chem. Soc., Perkin Trans. 1 1988; 4067
    • 9c Doyle MP, Ene DG, Forbes DC, Pillow TH. Chem. Commun. 1999; 1691
    • 9d Padwa A, Austin DJ, Price AT, Semones MA, Doyle MP, Protopopova MN, Winchester WR, Tran A. J. Am. Chem. Soc. 1993; 115: 8669
    • 9e Cordi AA, Lacoste J.-M, Hennig P. J. Chem. Soc., Perkin Trans. 1 1993; 3
    • 9f Merlic CA, Zechman AL, Miller MM. J. Am. Chem. Soc. 2001; 123: 11101
    • 9g Doyle MP, Hu W, Timmons DJ. Org. Lett. 2001; 3: 933
    • 9h Doyle MP, Phillips IM. Tetrahedron Lett. 2001; 42: 3155
    • 9i Kane JL, Shea KM, Crombie AL, Danheiser RL. Org. Lett. 2011; 3: 1081
  • 10 Brunner J, Serin H, Richards FM. J. Biol. Chem. 1980; 255: 3313
  • 11 General Procedure for the Büchner ReactionIn an oven-dried 20 mL Schlenk tube, N-tosylhydrazone (1, 0.2 mmol, 1.0 equiv), Cs2CO3 (0.6 mmol, 3 equiv), and 4 Å MS were added. Then the tube was sealed with a septum, and degassed by alternating vacuum evacuation and nitrogen backfill (3×) before benzene (4 mL) was added. The reaction was then stirred at 120 °C for 3 h. The reaction mixture was cooled to r.t. and filtered through a short plug of silica gel with Et2O as eluents. Solvent was then removed in vacuo to leave a crude mixture, which was purified by preparative TLC to afford pure products.7-Phenyl-7-(trifluoromethyl)cyclohepta-1,3,5-triene (3a) 1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 7.4 Hz, 2 H), 7.18–7.09 (m, 3 H), 6.44–6.42 (m, 2 H), 6.30–6.28 (m, 2 H), 5.72 (d, J = 9.3 Hz, 2 H). 13C NMR (101 MHz, CDCl3): δ = 134.9, 130.2, 129.8, 127.8, 127.1 (q, J = 281.9 Hz), 126.6, 126.6, 117.3, 53.2 (q, J = 25.0 Hz). 19F NMR (470 MHz, CDCl3): δ = –74.3 (s, 3 F). MS (EI): m/z (%) = 236 (66) [M+], 215 (15), 167 (100), 165 (60), 152 (28). IR (film): 1284, 1188, 1151, 978, 687 cm–1. HRMS (EI): m/z calcd for C14H11F3 [M]+: 236.0807; found: 236.0815.

Zoom Image
Scheme 1 Reactions with trifluoromethyl-bearing diazo compounds or N-tosylhydrazones
Zoom Image
Scheme 2