Tetrahedron Letters 55 (2014) 5801–5804

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Tetrahedron Letters

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Preparation of 5-chloropyrazoles via tandem Meyer–Schuster/vonAuwers rearrangements

http://dx.doi.org/10.1016/j.tetlet.2014.08.1070040-4039/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Tel.: +41 628660271.E-mail address: raphael.dumeunier@syngenta.com (R. Dumeunier).

� This Letter reports part of S.J. diploma work for HFP (Höhere Fachprüfung) School,CH-4132 Muttenz, Switzerland.

R = Ar'

R = Me, EtRef. 7

R = Alkyl, Aryl

RNHNH2

WhenAr = R = Ph

PPh3, CCl4

Ref. 5, 6

Ref. 7

1

2

23

4

Ph

Ph

RNN Ar

ClR

O

O

ArO

Cl

ClCl

R

ArCl

Cl

O

R

ArCl

Cl

O

Scheme 1. The only reported accesses to ketones 2.

Raphaël Dumeunier ⇑, Simon Jaeckh �, Rebekka GoebelSyngenta Crop Protection, Schaffhauserstrasse, CH-4332 Stein, Switzerland

a r t i c l e i n f o

Article history:Received 9 July 2014Revised 7 August 2014Accepted 27 August 2014Available online 2 September 2014

Keywords:RearomatizationRearrangementvon AuwersSemi-benzeneMeyer–Schuster

a b s t r a c t

A new, practical preparation of b,b-dichloroenones in three to four steps allows for a straightforward syn-thesis of 5-chloropyrazoles. Addition of various propargyl anions to commercially available 4-methyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-one gives high yields of the corresponding propargyl alcohols.These are then transformed, in a single step, via two consecutive rearrangements, a Meyer–Schusterand a (sometimes spontaneous) von Auwers rearomatizing rearrangement, to deliver a,a-aryl-trichlo-romethylketones. After elimination of HCl, cyclization of the b,b-dichloroenones with various hydrazinesdelivers 5-chloropyrazoles. The four to five step sequence to 5-chloropyrazoles is very atom economical,expelling only water and two molecules of HCl from all the building blocks.

� 2014 Elsevier Ltd. All rights reserved.

Introduction

Reported syntheses of 4-aryl-5-halopyrazoles 1 are stillrelatively scarce, but remain of high interest. Indeed, most of thearticles and patents describe those as being biologically activecompounds. Nowadays, 4-aryl-5-chloropyrazoles are accessedalmost exclusively via the transformation of pre-existing pyrazolerings: by the introduction of the 4-aryl with Pd coupling1 or by theintroduction of the 5-chloro via Sandmeyer reaction,2 POCl3 onpyrazolone3 or electrophilic chlorination.4 Cyclizing a fully substi-tuted pyrazole ring with the 5-chloro atom already present in theprecursor is rarer still. Indeed, only our past synthesis of biologi-cally active 4-aryl-5-halopyrazoles can be found in the literature.5,6

This can be ascribed to the fact that the obvious precursors to 1,namely 3,3-dichloro-1-(Alk/Ar)-2-(Ar0)-prop-2-en-1-one such as 2,are mainly unknown (Scheme 1). Indeed, apart from our reports, asingle article only7 describes the bis-phenyl 3,3-dichloro-1-(phe-nyl)-2-(phenyl)-prop-2-en-1-one (2, R = Ar = Ph, as the symmetryof diketone 3 allows for a Wittig reaction with CCl4) as well astwo b,b-dichloroenones made by the addition of MeZnI or EtZnIonto acid chloride 4 (Ar = Ph).

Our previous efforts to access ketones 2 bearing two differentaromatic groups (R = Ar0) required a long route of 5 steps, restricted

to good Friedel–Crafts partners for Ar0.5,6 In the present Letter, wedisclose a new, shorter preparation of b,b-halogenoenones such as2 (R being Aryl or Alkyl) by making use of the radical, rearomatiza-tion chemistry from Karl von Auwers (Scheme 2).8,9

Δ, hν or

spont.

X is H or Cl5 6Cl ClX

R

R

Cl

ClX

Scheme 2. A radical chain transfer, rearomatizing [1,5]-von Auwers rearrangement.

5802 R. Dumeunier et al. / Tetrahedron Letters 55 (2014) 5801–5804

We envisaged that adding anions of methyl-ketones tocommercially available 4-methyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-one 7 would deliver, after dehydration and [1,5]-vonAuwers rearrangement, the corresponding a-trichloro-methyl-ketones 9 (Scheme 3). Those should easily be further transformedinto 5-chloropyrazoles via 2.

Due to the easiness of dehydration and [1,5]-shifts as alreadyexperienced by von Auwers himself, in the addition of Grignardreagents to 7,9 one can reasonably expect this sequence to takeplace in a single operation. This would amount to the remarkablesum of two difficult C–C bonds being formed in a single step,a to the ketone. The first bond formation would correspond to a

7 8aO R

HOCl

ClC

O

ClCl

Cl

R

O

Scheme 3. Our proposed

LiHMDS, THF, -78

then 726%

34%

11

13

LiHMDS, THF, -78

then 7

OF

F

OFF

F

Scheme 4. Direct addition o

nBuLi, THF, -78 °

then 7

15 R1,R2=OMe,H16 R1,R2=H, F17 R1,R2=H,OMe

21 83%

nBuLi, THF, -78 °

then 7

R1

R2

Scheme 5. Direct addition of al

noble-metal free a-arylation, and the second one, to a close tounknown10 a-trichloromethylation of a ketone.

Such rearrangement approaches to structures similar to 2 arenot without precedents. Esters or acid derivatives (R = OR or OHin 2) have indeed been obtained by a von Auwers rearrangement,as described by Karl von Auwers himself11,12 or by MelvinNewman.13

Results and discussion

Dienone 7 can be bought or prepared easily, following theimprovements by M. Newman14 on the Zincke and Shul reaction.15

The direct addition of the anion of acetophenones onto 7 provedhowever disappointingly difficult. Our initial attempt with 2,4-difluoro-acetophenone 11 gave directly the rearranged compound12, albeit with only 26% yield. With 3-trifluoromethyl-acetophe-none 13, the semi-benzene intermediate 14 was isolated with34% yield (Scheme 4). As can be seen from these reactions, eventhough the addition of acetophenones proved to be a problematicstep, the dehydration (both cases) and subsequent rearrangement(first case) were spontaneous, which was very encouraging.

i) - H2O

ii) [1,5]-von Auwers 9Cl ClCl

R

Ol

access to ketones 9.

°C

12

14

°C

F

O

ClCl Cl

F

OClCl

ClF F

F

f ketone enolates to 7.

C

22

C

18 >99% (R1,R2=OMe,H)19 >99% (R1,R2=H, F)20 68% (R1,R2=H,OMe)

R1

R2

OH

ClCl

Cl

Cl

ClCl

OH

kyne anions onto ketone 7.

Not efficient

7

7

Base

Base

- H2O

H+ cat.

Formally,-H2O 8c

8b

8a

9Cl ClCl

R

O

O R

OHCl

ClCl

ClCl

Cl

RO

R

OH

Cl

ClCl

R

O R

Scheme 6. Alternative to inefficient enolate addition to 7.

pTSA (5%)EtOH:H2O

thentoluene, 60 °C

18, 19, 22

23 47% (R is oMeOC6H4-)24 70% (R is pFC6H4-)25 71% (R is cPr-)

R

O

ClCl Cl

Cl

ClCl

OHR

Scheme 7. Meyer–Schuster rearrangements towards 23–25.

Table 1Conversion of ketones 9 to 5-chloropyrazoles

MeOH, 65 °C

K2CO3

CH3CN

H2N-NHR2

29-3326-2823-25

R2

RNN

Cl

R

O

ClCl

R

O

ClCl Cl

Entry Ketone R Enone (yield (%)) R2 (hydrazine) Pyrazole (yield (%))

1 23

O26 (>99)

Ph29 (67)

2 24 F 27 (84) Ph 30 (49)

3 25 28 (98) Ph 31 (40)

4 23

O26 (>99) 32 (75)

5 23

O26 (>99)

H

p-Tol

R NN

H

H33 (17)

R. Dumeunier et al. / Tetrahedron Letters 55 (2014) 5801–5804 5803

We thought that a problem in the addition of enolates to 7might be the reversibility of the first step, with the equilibriumlying in favour of the starting materials. We then got inspirationfrom the chemistry of M. Newman,13 offering a convenientalternative access to enones such as 14 via a Meyer–Schuster rear-rangement. Fortunately, the addition of anions of aryl-acetylenes15–17 proved to be very efficient, as well as the anion ofcyclopropyl-acetylene 21 (Scheme 5).

Terminal alkynes may be seen, formally as dehydrated methylketones. Therefore, as depicted in Scheme 6, the loss of waterrequired from 8a, to form semi-benzenes 8c, has then to bereplaced by a Meyer–Schuster reorganization of alcohols 8b.

The propargyl alcohols 18, 19 and 22 were therefore takenthrough Meyer–Schuster rearrangements by stirring at room tem-perature in EtOH (2 mL/mmol) in the presence of pTSA (5 mol %)and 5 equiv of water. After work-up, the analysis showed a mixture

34

2-3 steps

no transition metal ROH

Scheme 8. Dearomatization/functionalization/re-aromatization as a powerful toolfor C–C (R-Ar) bond formation.

5804 R. Dumeunier et al. / Tetrahedron Letters 55 (2014) 5801–5804

of intermediate semi-benzenes 8c and a-trichloromethylketones 9.The crudes were then dissolved in toluene, and concentratedslowly under vacuum (rotavap) at 60 �C. This simple operationwas enough to convert quantitatively the remaining semi-benzenes into the desired products 23–25 (Scheme 7).

Ketones 23–25 were submitted to the action of K2CO3 inacetonitrile to deliver the b,b-dichloroenones 26–28, which werein turn converted to 5-chloropyrazoles by reaction with varioushydrazines (Table 1). Notably, when substituted hydrazines wereused (entries 1–4) only one isomer of the pyrazole was formed(assigned by NOE 1H NMR). When hydrazine was used (entry 5),the dechlorinated pyrazole was the only product that could beisolated, albeit with a very poor yield.

The four step sequence from 7 to pyrazoles is extremely atomeconomical, a significant process quality brought naturally by theuse of rearrangements. Indeed, from the three building blocksrequired to assemble the pyrazoles (ketone 7, alkyne and hydra-zine), only two molecules of HCl and one molecule of water containall the atoms wasted in the sequence.

Conclusion

The chemistry of K. von Auwers offers a convenient access tounsymmetrical (Ar/Ar0) 3,3-dichloro-1-(Ar)-2-(Ar0)-prop-2-en-1-ones 2, which behave in turn as good bis-electrophiles in thepresence of bis-nucleophiles such as hydrazines. We would likehowever to highlight the general transformation disclosed inScheme 8.

We reported indeed in this Letter a transition metal-free, Car-bon to Aryl bond formation in only two steps from a phenol (34to ketone 12), first by dearomatization (delivering reactive speciessuch as 7), followed by functionalization and further rearomatiza-tion, via spontaneous dehydration and von Auwers rearrangement.

Since von Auwers’s discovery, in 1884, of the abnormalReimer–Tiemann to dearomatize,16 and in 1903, of the radical

[1,5]-sigmatropic rearomatizing rearrangement,8 many otherdearomatization17–21 and rearomatization22–25 reactions havebeen discovered as well. Even though they are usually reportedindependently of each other, it is our belief that combined in thealready exemplified,26–29 three step principle summarized inScheme 8, they will continue to prove synthetically useful in manyoriginal ways.

Acknowledgments

The authors would like to acknowledge Stephan Bachmann andTheodor Stoll for their role as examiners for the diploma work ofS.J.

References and notes

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