Tetrahedron Letters 53 (2012) 6786–6788

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Tetrahedron Letters

journal homepage: www.elsevier .com/ locate / tet let

Synthesis of 7-trifluoromethylpyrazolo[1,5-a]pyridinedicarboxylate

Pek Chong a, Roman Davis b, Vassil Elitzin c, Mark Hatcher c, Bing Liu c,⇑, Matthew Salmons c, Elie Tabet b

a Infectious Disease CEDD, HCV Discovery Performance Unit, GlaxoSmithKline, 5 Moore Drive, Durham, NC 27709, USAb Product Development, Early Development Sciences, GlaxoSmithKline, 5 Moore Drive, Durham, NC 27709, USAc Product Development, API Chemistry & Analysis, GlaxoSmithKline, 5 Moore Drive, Durham, NC 27709, USA

a r t i c l e i n f o

Article history:Received 14 September 2012Revised 26 September 2012Accepted 30 September 2012Available online 13 October 2012

Keywords:PyrazolopyridineTrifluoromethylationMetalationN-Iminopyridinium ylide

0040-4039/$ - see front matter � 2012 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.tetlet.2012.09.136

⇑ Corresponding author. Tel.: +1 919 483 8165; faxE-mail address: bing.b.liu@gsk.com (B. Liu).

a b s t r a c t

Two syntheses of 7-trifluoromethylpyrazolo[1,5-a]pyridine dicarboxylate have been described. ApproachA utilizes a nucleophilic addition of a trifluoromethyl group to N-p-toluenesulfonyliminopyridinium ylidefollowed by aromatization and subsequent cycloaddition with diethyl acetylenedicarboxylate to give 1bin modest yield. Approach B involves a selective zincation of pyrazolopyridine dicarboxylate at the C7

position with (TMP)2Zn�2LiCl�2MgCl2 followed by iodination and trifluoromethylation to give 1b in goodyield. The process in approach B has been successfully demonstrated on scale.

� 2012 Elsevier Ltd. All rights reserved.

N N

CF3

CO2R

CO2R

1a: R = Me1b: R = Et

N+

CF3NH2 N+

NH2

N NCO2R

CO2R

N NCO2R

CO2R

I

CF3 addition/rearomatization

A

regioselectivemetalation

B

CF3coupling

2 3

I-

5a: R = Me5b: R = Et

4a: R = Me4b: R = Et

[3+2]

Scheme 1. New approaches to pyrazolo[1,5-a]pyridine 1a and 1b.

7-Trifluoromethylpyrazolo[1,5-a]pyridinedicarboxylate 1 is animportant intermediate for a drug candidate in our drug discoveryprogram.

N N

CF3

CO2R

CO2R

1a R = Me1b R = Et

The original synthesis of this intermediate entailed a problem-atic N-amination step, which was not amenable to scale up dueto its low yield and in particular the use of the thermally unstablereagent, O-mesitylsulfonylhydroxylamine (MSH).1 The more ther-mally stable hydroxylamine O-sulfonic acid (HOSA) did not achievethe desired N-amination. Therefore, we needed to identify a newsynthetic approach to 7-trifluoromethylpyrazolo[1,5-a]pyridine 1that would facilitate the delivery of multi-kilogram quantities ofmaterial to support our drug discovery program.

After evaluating a number of different possibilities, we decidedto concentrate our efforts on two main approaches (Scheme 1). Inboth cases, we sought to introduce a trifluoromethyl group into thestarting materials with the N–N bond already incorporated. Thus,the need to use highly energetic reagents such as MSH on scale

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would be obviated. These starting materials are commerciallyavailable as they are readily prepared using the thermally stableHOSA. In approach A, we anticipated that 1 could be obtained via[3 + 2] cycloaddition of 2 with the dipolarophile acetylenedicar-boxylate. The requisite 2-trifluoromethylpyridinium 2 ylide couldbe prepared by nucleophilic addition of trifluoromethylation re-agents such as Ruppert’s reagent (CF3SiMe3)2 to the commerciallyavailable N-aminopyridinium iodide (3), followed by rearomatiza-tion of the resultant N-aminodihydropyridine.3 In approach B, weenvisioned that the C7 position of the pyrazolo[1,5-a]pyridinedicarboxylate 4 could undergo selective metalation followed byiodination to generate iodide 5.4 Subsequently, metal-catalyzedtrifluoromethylation could afford 1.5 Herein we describe our effortson these two new approaches to prepare 1.

N+NH2

I-

TsCl,NaOH (aq)THF

84%

N+N-Ts

CF3TMS,CsF,DMF/H2O

79%N

NHTsCF3

DDQ,THF

60%

N+N-Ts

CF3 CO2EtEtO2CNa2CO3, EtOH, 70 °C

N N

CF3

CO2Et

CO2Et1b

3 6 7

8

25%

Scheme 2. The approach A to pyrazolo[1,5-a]pyridine 1b.

N N

CF3

CO2Et

CO2Et1b

N NCO2Et

CO2Et

I

FS CO2Me

F F

CuI,DMF, 80 °C

105b

+89%

O O

Scheme 3. Trifluoromethylation of iodide 6b.

P. Chong et al. / Tetrahedron Letters 53 (2012) 6786–6788 6787

We initially focused our efforts on approach A. We were encour-aged by literature examples in which N-alkylpyridinium6 andN-aminopyridinium7 species have been reported to undergo nucle-ophilic attack at the 2-position. While reactions on substrate 3 wererather messy, we found that protecting the exocyclic nitrogen as thehighly crystalline p-toluenesulfonamide 6, followed by treatmentwith Ruppert’s reagent (CF3SiMe3) and CsF, led to the formationof dihydropyridine 7 with exclusive regioselectivity (Scheme 2).Among a number of possible rearomatization conditions, we foundthat treatment of 7 with dichlorodicyanobenzoquinone (DDQ)cleanly generated the N-p-toluenesulfonyliminopyridinium ylidemoiety to give 8. Finally, [3 + 2] cycloaddition with diethyl acety-lenedicarboxylate (DEAD), and concomitant aromatization by elim-ination of sulfinic acid in the presence of base (Na2CO3), gave thedesired 7-trifluoromethyl pyrazolopyridine 1b in 25% yield. Therewere many byproducts in the reaction mixture. We observed threemajor byproducts on LC–MS. Two compounds have the samemolecular weight as the initial cycloadduct, presumably formedfrom the cycloadduct via N-N-cleavage and 1,5-sigmtropic rear-rangement. The other major byproduct was derived from the[4 + 2] cycloaddition of the initial [3 + 2] cycloadduct with anothermolecule of acetylenedicarboxylate. Attempts to optimize the reac-tion by screening bases and solvents proved fruitless as the initialcycloadduct was prone to these unproductive pathways.8

Next we turned our attention to approach B. There are precedentsof selective metalation of pyrazolopyridine in the literature.4 How-ever, lithiation or magnesiation of pyrazolopyridine 4a followedby iodination led to decomposition under a variety of conditionswithout the formation of the desired iodide 5a. We suspected thatdecomposition was attributable to functional group intolerance ofmetalation reagents or the resulting metalated pyrazolopyridine. Amore selective metalation reagent such as (TMP)2Zn�2MgCl2�2LiCl

Table 1Selective zincation and iodination of pyrazolo[1,5-a]pyridine dicarboxylates

N NCO2R

CO2R

(TMP)2Zn•2MgCl2•2LiCl,THF; I2

4a, R = Me4b, R = Ev4c, R = t-Bu

Substrate Conditions

4a (TMP)2Zn�2MgCl2�2LiCl (0.7 equiv), rt4b (TMP)2Zn�2MgCl2�2LiCl (0.7 equiv), rt4c (TMP)2Zn�2MgCl2�2LiCl (0.7 equiv), rt4b (TMP)2Zn�2MgCl2�2LiCl (0.7 equiv), 0 �C4b (TMP)2Zn�2MgCl2�2LiCl (0.7 equiv), �10 �C

a Sum of HPLC percent area under the curve (AUC) for both ester 5 andb Isolated yield.c Quenched by adding iodine solids instead of iodine THF solution.

(TMP: 2,2,6,6-tetramethylpiperidine) could alleviate this problem.9

Indeed, upon addition of the commercially available (TMP)2Zn�2MgCl2�2LiCl to a solution of dimethyl pyrazolo[1,5-a]pyridinedicarboxylate (4a) in THF at room temperature, followed by quench-ing with a solution of iodine in THF, led to the desired methyl carbox-ylate 5a accompanied with des-methyl carboxylic acid 9a in 95:5ratio (Table 1).10 Zincation and iodination of diethyl dicarboxylate4b led to a similar ratio of products (96:4) at room temperature.The partial hydrolysis of ester increased when the solid iodine wasused directly to quench the metalated species instead of the iodineTHF solution. Lower reaction temperature reduced the amount ofdealkylation. Thus, zincation and iodination of 4b at �10 �Csuppressed the dealkylation nearly completely to give iodide 5bin 95% AUC by HPLC. It was interesting to note that zincation/iodination of the more bulky t-butyl ester 4c at room temperaturealso generated the acid 9c.

With the 7-iodo derivative 5b in hand, we then went on to ex-plore the trifluoromethylation reaction. Initial work using CF3TMS(Ruppert’s reagent) as a trifluoromethyl donor in the presence ofCsF and copper (I) idodide gave 1b; however, the reaction wasnot clean. After screening a number of trifluoromethylation re-agents and conditions, we found that methyl fluorosulfonyldifluo-roacetate (10)11 reacted cleanly with iodide 5b in the presence of1 equiv of copper (I) iodide in DMF to give 1b in 89% yield in 2 h(Scheme 3). The trifluoromethylation could be carried out in thepresence of sub-stoichiometric amounts of CuI (0.75 equiv) with-out substantially affecting yield or purity although the reactiontook longer to reach completion (10 h). The zincation/iodinationand trifluoromethylation have been carried out on 300 g of pyraz-olopyridine dicarboxylate successfully. We have also shown thatthese two steps could be telescoped without isolation of iodide5b to give 1b in 86% yield over two steps on 6 L scale.

In conclusion, we have studied two synthetic routes to make7-trifluoromethylpyrazolo[1,5-a]pyridine 1b that eliminate theuse of the highly energetic reagent MSH. Approach A utilizes anucleophilic addition of a trifluoromethyl group to N-p-toluene-sulfonyliminopyridinium ylide followed by aromatization and

4

N NCO2R

CO2H

I

N NCO2R

CO2R

I

+

5a, R = Me5b, R = Et5c, R = t-Bu

9a, R = Me9b, R = Et9c, R = t-Bu

Ratio ester 5:acid 9 Yielda (%)

95:5 89b

96:4 85b

82:18c 9289:11c 9099:1 95

acid 9.

N

CF3

CO2EtCO2Et

NTs N

CF3

CO2EtCO2Et

NHTs

NEtO2C

EtO2C

CF3NTs

CO2EtCO2Et

6788 P. Chong et al. / Tetrahedron Letters 53 (2012) 6786–6788

subsequent cycloaddition with diethyl acetylenedicarboxylate togive 1b in modest yield. Approach B involves a selective zincationof pyrazolopyridine dicarboxylate at the C7 position with (TMP)2Zn�2MgCl2�2LiCl followed by iodination and trifluoromethylation togive 1b in good yield. We have successfully demonstrated theapproach B processes in our scale-up equipment.

References and notes

1. For the original synthesis, see: Pek, C.; Shotwell, J. B.; Catalano, J.; Miller, J.; Tai,V. W.-F.; Fang, J.; Banka, A.; Roberts, C.; Zhang, H.; Xiong, P.; Mathis, A.; Pouliot,J.; Hamatake, R.; Price, D.; Seal, J.; Stroup, L.; Creech, K.; Spaltenstein, A.; Furst,A.; Peat, A. manscript submitted to J. Med. Chem. The onset temperature forMSH was reported to be at 41.5 �C. For the safe handling of MSH, see: Mendiola,J.; Rincón, J. A.; Mateos, C.; Soriano, J. F.; Frutos, O.; Niemeier, J. K.; Davis, E. M.Org. Proc. Res. Dev. 2009, 13, 263. For an incident with the storage of MSH, see:Ning, R. Y. Chem. Eng. News 1973, 51, 36.

2. Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25, 2195.3. For a recent review on nucleophilic trifluoromethylation of C@N bond, see:

Dilman, A. D.; Levin, V. V. Eur. J. Org. Chem. 2011, 831.4. (a) Aboul-Fadl, T.; Lober, S.; Gmeiner, P. Synthesis 2000, 1727; (b) Finkelstein, B.

L. J. Org. Chem. 1992, 57, 5538.5. For a recent review on trifluoromethylation, see: Furuya, T.; Kamlet, A. S.;

Ritter, T. Nature 2011, 473, 470.6. Loska, R.; Majcher, M.; Makosza, M. J. Org. Chem. 2007, 72, 5574.7. Legault, C.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 6360.

8. Possible structures of three major byproducts:

For the unproductive pathways of the initial cycloadduct, see: (a) Zhao, J.; Li, P.;Wu, C.; Chen, H.; Ai, W.; Sun, R.; Ren, H.; Larock, R. C.; Shi, F. Org. Biomol. Chem.1922, 2012, 10; (b) Chen, Z.; Su, M.; Yu, X.; Wu, J. Org. Biomol. Chem. 2009, 7,4641; (c) Sundberg, R. J.; Ellis, J. E. J. Heterocyclic Chem. 1982, 19, 573.

9. (a) Dong, Z.; Clososki, G. C.; Wunderlich, S. H.; Unsinn, A.; Li, J.; Knochel, P.Chem. Eur. J. 2009, 15, 457; (b) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int.Ed. 2007, 46, 7685.

10. The structure of 10a was assigned by the assumption that the C3 carboxylicacid is more reactive as the decarboxylation occurred at the C3 position whenpyrazolopyridine-2,3-dicarboxylic acid was heated in a mixture ofhydrobromic acid and acetic acid.

11. Chen, Q. Y.; Wu, S. W. J. Chem. Soc., Chem. Commun. 1989, 11, 705.