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Synlett 2013; 24(9): 1150-1154
DOI: 10.1055/s-0033-1338433
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Tetrasubstituted Pyrazoles through Different Cyclization Strategies; Isosteres of Imidazole Fungicides

Raphael Dumeunier*
Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
,
Clemens Lamberth*
Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
,
Stephan Trah
Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
› Author Affiliations
Further Information

Publication History

Received: 07 March 2013

Accepted after revision: 28 March 2013

Publication Date:
18 April 2013 (online)

 
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Abstract

Formerly unknown 3-chloro-4,5-diaryl-1-methylpyrazoles have been prepared through two different synthesis pathways, one of which starts from 2,3-diarylacrylonitriles, the second from 3,3-dichloro-1,2-diarylpropenones. Both approaches rely on the cyclocondensation of diarylated three-carbon synthons with hydrazine derivatives and possess some unique features. One route uses a cyclization reaction, during which a chlorine atom is directly installed at the pyrazole ring that normally would be introduced in subsequent halogenation steps. The second pathway applies the Sandmeyer reaction to introduce this chloro substituent; an approach that is rarely described at the pyrazole nucleus. The obtained tetrasubstituted pyrazoles are isosteres of highly active imidazole fungicides and show good control of Uncinula necator (grape powdery mildew).


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Key words

pyrazole - heterocycles - cyclization - Sandmeyer reaction - fungicides

The tubulin polymerization promoters are a class of experimental fungicides that was discovered in the 1990s with the synthesis of special biheterocyclic compounds, such as trisubstituted [1,2,4]triazolo[1,5-a]pyrimidines[1] and pyrido[2,3-b]pyrazines.[2] More recently, similar substituted analogues with monoheterocyclic scaffolds have been the focus of agrochemical research, such as tetrasubstituted pyridazines[3] and imidazoles.[4] Imidazole 1 (Figure [1]) is highly active against a broad range of phytopathogens, such as Botrytis cinerea (grey mould), Uncinula necator (grape powdery mildew), Mycosphaerella graminicola (wheat leaf blotch) and Alternaria solani (potato and tomato early blight).[4] We decided to prepare pyrazole analogues with a similar substitution pattern because pyrazoles are well-known privileged structures in medicinal[5] and crop-protection chemistry[6] and are also regioisomeric diazole equivalents of imidazoles. Tremendous effort has already been invested in the preparation of a range of pyrazole derivatives,[7] and several tetrasubstituted pyrazoles have also been reported.[8] [9] However, when we started our research program, fully substituted pyrazoles bearing an alkyl group at one of the ring nitrogen atoms, two aryl or heteroaryl rings in positions 4 and 5 and a halogen substituent in position 3, such as 2, had not been described in the literature (Figure [1]). We therefore designed a new synthesis pathway to obtain the envisaged target compounds.

Zoom Image
Figure 1 Imidazole fungicide 1 and its pyrazole analogue 2

We realized that 3,3-dichloro-1,2-diarylpropenones, such as 7, are perfectly suited for heterocyclization to pyrazoles (Scheme [1]). The starting material 3,3-dichloro-2-(2,4,6-trifluorophenyl)acryloyl chloride (6), which we previously used for the synthesis of imidazo[2,1-b][1,3]thiazin-5-ones,[10] can be easily prepared by Corey–Fuchs type dichlorovinylation[11] of ethyl 2,4,6-trifluorophenylglyoxylate (4), subsequent ester saponification and acid chloride formation. The transformation of 6 with anisole in the presence of aluminum trichloride delivers the diaryl-substituted 3,3-dichloropropenone 7. Friedel–Crafts acylations of 3,3-dichloroacryloyl chlorides have never been described before. The next step required the heterocyclization of 7 with a hydrazine derivative. Hereby, one of the vinylic chlorine atoms in 7 is substituted during the ring closure reaction by a hydrazine nitrogen atom, the second remains in the molecule. We first attempted the conversion with methylhydrazine with the hope that it would directly deliver 11. Unfortunately, the undesired regioisomer 1-methyl-5-chloropyrazole 8 was the only product that could be isolated. We, therefore decided to apply a hydrazine derivative with a protecting group that could be cleaved after the heterocyclization. Our reagent of choice was benzylhydrazine dihydrochloride, which delivered the 1-benzyl-5-chloropyrazole 9. This cyclization product could be converted by removal of the benzyl protecting group under reductive conditions and subsequent methylation into 1-methyl-3-chloropyrazole 11, together with its regioisomer 8. Finally, regioselective replacement of the fluorine atom in the para-position of the phenyl ring by a methoxy group led to the desired target compound 12.[12] Although ring closure reactions with hydrazines have already been described with other 3,3-chloropropenones,[13] we succeeded in the first ring closure reactions of 1,2-diaryl-3,3-dichloropropenones to diarylated 3-chloropyrazoles.

Zoom Image
Scheme 1 Synthesis of the tetrasubstituted pyrazole 12 via 3,3-dichloro-1,2-diarylpropenone 7 (Method A)

On one hand, our synthesis route to 12 can be considered as efficient because it is one of the very few syntheses of 3-chloropyrazole derivatives in which the halogen atom is introduced simultaneously during the ring closure reaction without any need for a (subsequent) chlorination step. However, if the application of methylhydrazine could deliver the desired 1-methyl-3-chloropyrazole and not, as found, the regioisomeric 1-methyl-5-chloropyrazole 8, the last two steps of the reaction sequence (deprotection and alkylation) would not be required. Furthermore, the Friedel–Crafts acylation of 3,3-dichloro-2-arylacryloyl chlorides such as 6 seems to be limited to benzene derivatives with electron-donating substituents.

Zoom Image
Scheme 2 Synthesis of the tetrasubstituted pyrazole 2 via 2,3-diarylacrylonitrile 14 (Method B)

We therefore looked for an alternative synthesis to pyrazoles such as 2 that could be applicable in a more general manner. Instead of the 3,3-dichloro-1,2-diarylpropenones, we turned our attention to 2,3-diarylacrylonitriles as more appropriate starting materials. Such diarylated α,β-unsaturated nitriles can be easily prepared by base-catalyzed aldol condensation of an arylacetonitrile with an aromatic aldehyde.[14] This is demonstrated by the reaction of (2,4,6-trifluorophenyl)acetonitrile (13) with 4-chlorobenzaldehyde to give acrylonitrile 14, during which the fluorine atom in the para-position of the phenyl ring is also replaced by a methoxy group (Scheme [2]). This key intermediate is then transformed with methylhydrazine into the tetrasubstituted pyrazoline 15. This is the first example of a ring closure reaction of a 2,3-diarylacrylonitrile with a hydrazine to a pyrazoline derivative. Only two cases have been reported in which acrylonitriles have been cyclized with hydrazonoyl chlorides to completely different 5-cyanopyrazolines.[15] The aminopyrazoline 15 is then converted in two further steps by aromatization and subsequent chlorodediazoniation into the desired pyrazole 2. Such Sandmeyer type transformations of 3-aminopyrazoles via their diazonium salts into 3-chloropyrazoles have been only rarely described in the literature.[16]

Both approaches allowed the synthesis of several novel tetrasubstituted pyrazoles from diverse 3,3-dichloro-1,2-diarylpropenones and 2,3-diarylacrylo-nitriles (Table [1]). According to the structure-activity relationship requirements of the analogues imidazole fungicides, they all bear a methyl group in the 1-position, a chloro substituent in the 3-position and two aryl or heteroaryl rings in the 4- and 5-positions. Such benzene and pyridine rings are substituted by electron-donating as well as electron-withdrawing groups.

Table 1 Novel Tetrasubstituted Pyrazoles

Entry

Intermediate for heterocyclisation

Product

1H NMR (CDCl3)

LC-MS

Method

1

3.73 (s, 3 H), 3.76 (s, 3 H), 6.58 (t, J = 7.91 Hz, 2 H), 6.82 (d, J = 8.79 Hz, 2 H), 7.09 (d, J = 8.77 Hz, 2 H)

Rt  = 1.99 min; MS: m/z = 353 [M + 1]+, 355 [M + 3]+

A

2

3.77 (s, 3 H), 3.79 (s, 3 H), 3.82 (s, 3 H), 6.43 (d, J = 9.13 Hz, 2 H), 6.90 (d, J = 8.83 Hz, 2 H), 7.18 (d, J = 8.76 Hz, 2 H)

Rt  = 1.96 min; MS: m/z = 365 [M + 1]+, 367 [M + 3]+

A

3

3.79 (s, 3 H), 3.81 (s, 3 H), 6.43 (d, J = 9.2 Hz, 2 H), 7.19 (d, J = 8.49 Hz, 2 H), 7.46 (d, J = 8.48 Hz, 2 H)

Rt  = 2.12 min; MS: m/z = 369 [M + 1]+, 371 [M + 3]+

B

4

3.71 (s, 3 H), 3.74 (s, 3 H), 3.90 (s, 3 H), 6.37 (d, J = 9.15 Hz, 2 H), 6.69 (d, J = 8.48 Hz, 1 H), 7.38 (dd, J = 2.4, 8.59 Hz, 1 H), 8.00 (d, J = 2.2 Hz, 1 H)

Rt  = 1.93 min; MS: m/z = 366 [M + 1]+, 368 [M + 3]+

B

5

3.83 (s, 3 H), 3.94 (s, 3 H), 6.73 (d, J = 8.5 Hz, 1 H), 7.12 (d, J = 8.3 Hz, 1 H), 7.22 (dd, J = 2.1, 8.3 Hz, 1 H), 7.38 (dd, J = 2.4, 8.57 Hz, 1 H), 7.41 (d, J = 2.1 Hz, 1 H), 8.02 (d, J = 2.0 Hz, 1 H)

Rt  = 2.09 min; MS: m/z = 368 [M + 1]+, 370 [M + 3]+

B

6

3.83 (s, 3 H), 6.95 (d, J = 9.1 Hz, 1 H), 7.04 (d, J = 8.58 Hz, 2 H), 7.08–7.17 (m, 2 H), 7.32 (d, J = 8.51 Hz, 2 H)

Rt  = 2.12 min; MS: m/z = 355 [M + 1]+, 357 [M + 3]+

B

7

3.76 (s, 3 H), 7.11 (dd, J = 2.63, 8.12 Hz, 2 H), 7.19–7.23 (m, 4 H), 7.40–7.44 (m, 3 H)

Rt  = 1.18 min; MS: m/z = 303 [M + 1]+, 305 [M + 3]+

B

In conclusion, we have established two different reaction pathways for the preparation of novel 3-chloro-1-methyl-4,5-diarylpyrazoles, which are analogues of highly active imidazole fungicides.[17] Both approaches rely on the cyclocondensation of a diarylated three-carbon synthon with a hydrazine derivative. One type of reagent, 3,3-dichloropropenones, allows a ring closure reaction that directly leads to chlorinated pyrazoles, because only one of the two vinylic chlorine atoms is required for pyrazole formation. However, the condensation of 3,3-dichloropropenones with methyl hydrazine leads to the undesired 1-methyl-5-chloropyrazole. 2,3-Diarylacrylonitriles, the second kind of diarylated three-carbon synthons applied, facilitated a more direct approach to the desired fully substituted pyrazoles, because their transformation into the target compounds was possible in only three steps, the last one being a rarely described Sandmeyer reaction at a pyrazole nucleus. Several of the fully substituted pyrazoles described here showed excellent activity against Uncinula necator (grape powdery mildew) in whole-plant assays.


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  • References and Notes

  • 1 Montel F, Lamberth C, Jung PM. J. Tetrahedron 2008; 64: 6372
    CrossrefSearch in Google Scholar
  • 2 Crowley PJ, Lamberth C, Müller U, Wendeborn S, Nebel K, Williams J, Sageot O.-A, Carter N, Mathie T, Kempf H.-J, Godwin J, Schneiter P, Dobler MR. Pest Manage. Sci. 2010; 66: 178
    Search in Google Scholar
  • 3 Lamberth C, Trah S, Wendeborn S, Dumeunier R, Courbot M, Godwin J, Schneiter P. Bioorg. Med. Chem. 2012; 20: 2803
    CrossrefSearch in Google Scholar
  • 4 Lamberth C, Dumeunier R, Trah S, Wendeborn S, Godwin J, Schneiter P, Corran A. Bioorg. Med. Chem. 2013; 21: 127
    CrossrefSearch in Google Scholar

      • For some reviews on agrochemically active pyrazoles, see:
    • 6a Giornal F, Pazenok S, Rodefeld L, Lui N, Vors J.-P, Leroux FR. J. Fluorine Chem. 2012; in press,
    • 6b Lamberth C. Heterocycles 2007; 71: 1467
      CrossrefSearch in Google Scholar
  • 8 For a review on tetrasubstituted pyrazoles, see: Dadiboyena S, Nefzi A. Eur. J. Med. Chem. 2011; 46: 5258
    CrossrefPubMedSearch in Google Scholar
  • 10 Lamberth C, Querniard F. Tetrahedron Lett. 2008; 49: 2286
    CrossrefSearch in Google Scholar
  • 12 Dumeunier R, Lamberth C, Trah S. WO 2009/127612, 2009 (Syngenta AG): Chem. Abstr. 2009, 151, 491112.
    • 15a Zohdi HF, Rateb NM, Abdelhamid AO. Phosphorus, Sulfur Silicon Relat. Elem. 1998; 133: 103
      CrossrefSearch in Google Scholar
    • 15b Farag AM, Abbas IM, Abdallah MA, Kandeel ZE, Algharib MS. J. Chem. Res. 1994; 286
  • 17 Typical Procedures:
    (Z)-3-(4-Chlorophenyl)-2-(2,6-difluoro-4-methoxy-phenyl)acrylonitrile (14):     K2CO3 (2.42 g, 17 mmol) was added to a solution of (2,4,6-trifluorophenyl)-acetonitrile (2.5 g, 14 mmol) and 4-chlorobenzaldehyde (2.0 g, 14 mmol) in MeOH (30 mL). The reaction mixture was heated to reflux for 16 h, cooled, poured into H2O and filtered. The solid was washed twice with H2O and twice with heptane, and dried under vacuum to obtain 14 (1.28 g, 4.2 mmol, 30%). 1H NMR (CDCl3): δ = 3.84 (s, 3 H), 6.55 (d, J = 9.15 Hz, 2 H), 7.22 (s, 1 H), 7.43 (d, J = 8.51 Hz, 2 H), 7.82 (d, J = 8.74 Hz, 2 H). LC-MS: 1.69, 305 [M+], 307 [M++2]. 5-(4-Chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1H-pyrazol-3-ylamine (16): Et3N (0.16 g, 1.6 mmol) and methylhydrazine (0.75 g, 16 mmol) were added consecutively to a solution of 14 (0.5 g, 1.6 mmol) in MeOH (10 mL). The reaction mixture was heated to reflux for 72 h, then cooled and concentrated under reduced pressure to obtain 15 (0.44 g, 1.3 mmol), which was dissolved in CHCl3 (10 mL). MnO2 (1.1 g, 13 mmol) was added and the reaction mixture was stirred for 2 h at r.t., then diluted with EtOAc and filtered over Celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EtOAc–cyclohexane, 3:2), to deliver 16 (0.12 g, 0.35 mmol, 22% from 14). 1H NMR (CDCl3): δ = 3.69 (s, 3 H), 3.77 (s, 3 H), 6.41 (d, J = 9.08 Hz, 2 H), 7.15 (d, J = 8.9 Hz, 2 H), 7.33 (d, J = 8.45 Hz, 2 H). LC-MS: R t = 1.84 min; MS: m/z = 350 [M]+, 352 [M + 2]+. 3-Chloro-5-(4-chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1H-pyrazole (2): Compound 16 (60 mg, 0.17 mmol) was dissolved in concd HCl (0.5 mL) and cooled to 0 °C. A solution of NaNO2 (12 mg, 0.17 mmol) in H2O (0.1 mL) was then added dropwise. A solution of CuCl (17 mg, 0.17 mmol) in concd HCl (0.3 mL) was added and the reaction mixture was heated to 60 °C for 30 min, then the reaction mixture was neutralized by the addition of NaOH and diluted with EtOAc. The phases were separated and the aqueous phase was extracted twice with EtOAc and the combined organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc–hexane, 1:9), to deliver 2 (32 mg, 0.08 mmol, 51%).

  • References and Notes

  • 1 Montel F, Lamberth C, Jung PM. J. Tetrahedron 2008; 64: 6372
    CrossrefSearch in Google Scholar
  • 2 Crowley PJ, Lamberth C, Müller U, Wendeborn S, Nebel K, Williams J, Sageot O.-A, Carter N, Mathie T, Kempf H.-J, Godwin J, Schneiter P, Dobler MR. Pest Manage. Sci. 2010; 66: 178
    Search in Google Scholar
  • 3 Lamberth C, Trah S, Wendeborn S, Dumeunier R, Courbot M, Godwin J, Schneiter P. Bioorg. Med. Chem. 2012; 20: 2803
    CrossrefSearch in Google Scholar
  • 4 Lamberth C, Dumeunier R, Trah S, Wendeborn S, Godwin J, Schneiter P, Corran A. Bioorg. Med. Chem. 2013; 21: 127
    CrossrefSearch in Google Scholar

      • For some reviews on agrochemically active pyrazoles, see:
    • 6a Giornal F, Pazenok S, Rodefeld L, Lui N, Vors J.-P, Leroux FR. J. Fluorine Chem. 2012; in press,
    • 6b Lamberth C. Heterocycles 2007; 71: 1467
      CrossrefSearch in Google Scholar
  • 8 For a review on tetrasubstituted pyrazoles, see: Dadiboyena S, Nefzi A. Eur. J. Med. Chem. 2011; 46: 5258
    CrossrefPubMedSearch in Google Scholar
  • 10 Lamberth C, Querniard F. Tetrahedron Lett. 2008; 49: 2286
    CrossrefSearch in Google Scholar
  • 12 Dumeunier R, Lamberth C, Trah S. WO 2009/127612, 2009 (Syngenta AG): Chem. Abstr. 2009, 151, 491112.
    • 15a Zohdi HF, Rateb NM, Abdelhamid AO. Phosphorus, Sulfur Silicon Relat. Elem. 1998; 133: 103
      CrossrefSearch in Google Scholar
    • 15b Farag AM, Abbas IM, Abdallah MA, Kandeel ZE, Algharib MS. J. Chem. Res. 1994; 286
  • 17 Typical Procedures:
    (Z)-3-(4-Chlorophenyl)-2-(2,6-difluoro-4-methoxy-phenyl)acrylonitrile (14):     K2CO3 (2.42 g, 17 mmol) was added to a solution of (2,4,6-trifluorophenyl)-acetonitrile (2.5 g, 14 mmol) and 4-chlorobenzaldehyde (2.0 g, 14 mmol) in MeOH (30 mL). The reaction mixture was heated to reflux for 16 h, cooled, poured into H2O and filtered. The solid was washed twice with H2O and twice with heptane, and dried under vacuum to obtain 14 (1.28 g, 4.2 mmol, 30%). 1H NMR (CDCl3): δ = 3.84 (s, 3 H), 6.55 (d, J = 9.15 Hz, 2 H), 7.22 (s, 1 H), 7.43 (d, J = 8.51 Hz, 2 H), 7.82 (d, J = 8.74 Hz, 2 H). LC-MS: 1.69, 305 [M+], 307 [M++2]. 5-(4-Chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1H-pyrazol-3-ylamine (16): Et3N (0.16 g, 1.6 mmol) and methylhydrazine (0.75 g, 16 mmol) were added consecutively to a solution of 14 (0.5 g, 1.6 mmol) in MeOH (10 mL). The reaction mixture was heated to reflux for 72 h, then cooled and concentrated under reduced pressure to obtain 15 (0.44 g, 1.3 mmol), which was dissolved in CHCl3 (10 mL). MnO2 (1.1 g, 13 mmol) was added and the reaction mixture was stirred for 2 h at r.t., then diluted with EtOAc and filtered over Celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EtOAc–cyclohexane, 3:2), to deliver 16 (0.12 g, 0.35 mmol, 22% from 14). 1H NMR (CDCl3): δ = 3.69 (s, 3 H), 3.77 (s, 3 H), 6.41 (d, J = 9.08 Hz, 2 H), 7.15 (d, J = 8.9 Hz, 2 H), 7.33 (d, J = 8.45 Hz, 2 H). LC-MS: R t = 1.84 min; MS: m/z = 350 [M]+, 352 [M + 2]+. 3-Chloro-5-(4-chlorophenyl)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1H-pyrazole (2): Compound 16 (60 mg, 0.17 mmol) was dissolved in concd HCl (0.5 mL) and cooled to 0 °C. A solution of NaNO2 (12 mg, 0.17 mmol) in H2O (0.1 mL) was then added dropwise. A solution of CuCl (17 mg, 0.17 mmol) in concd HCl (0.3 mL) was added and the reaction mixture was heated to 60 °C for 30 min, then the reaction mixture was neutralized by the addition of NaOH and diluted with EtOAc. The phases were separated and the aqueous phase was extracted twice with EtOAc and the combined organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc–hexane, 1:9), to deliver 2 (32 mg, 0.08 mmol, 51%).

   Permissions and Reprints All articles of this category
Zoom Image
Figure 1 Imidazole fungicide 1 and its pyrazole analogue 2
Zoom Image
Scheme 1 Synthesis of the tetrasubstituted pyrazole 12 via 3,3-dichloro-1,2-diarylpropenone 7 (Method A)
Zoom Image
Scheme 2 Synthesis of the tetrasubstituted pyrazole 2 via 2,3-diarylacrylonitrile 14 (Method B)