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

Article abstract of DOI:10.1016/j.tetlet.2012.09.136

Two syntheses of 7-trifluoromethylpyrazolo[1,5-a]pyridine dicarboxylate have been described. Approach A utilizes a nucleophilic addition of a trifluoromethyl group to N-p-toluenesulfonyliminopyridinium ylide followed by aromatization and subsequent cycloaddition with diethyl acetylenedicarboxylate to give 1b in 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 good yield. The process in approach B has been successfully demonstrated on scale.

Full text of DOI:10.1016/j.tetlet.2012.09.136

Tetrahedron Letters 53 (2012) 6786–6788
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
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, USA
b Product Development, Early Development Sciences, GlaxoSmithKline, 5 Moore Drive, Durham, NC 27709, USA
c Product Development, API Chemistry & Analysis, GlaxoSmithKline, 5 Moore Drive, Durham, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Two syntheses of 7-trifluoromethylpyrazolo[1,5-a]pyridine dicarboxylate have been described. Approach
A utilizes a nucleophilic addition of a trifluoromethyl group to N-p-toluenesulfonyliminopyridinium ylide
followed by aromatization and subsequent cycloaddition with diethyl acetylenedicarboxylate to give 1b
in modest yield. Approach B involves a selective zincation of pyrazolopyridine dicarboxylate at the C7
position with (TMP)2ZnÁ2LiClÁ2MgCl2 followed by iodination and trifluoromethylation to give 1b in good
yield. The process in approach B has been successfully demonstrated on scale.
Received 14 September 2012
Revised 26 September 2012
Accepted 30 September 2012
Available online 13 October 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Pyrazolopyridine
Trifluoromethylation
Metalation
N-Iminopyridinium ylide
7-Trifluoromethylpyrazolo[1,5-a]pyridinedicarboxylate 1 is an
important intermediate for a drug candidate in our drug discovery
program.
CF3 addition/
rearomatization
CF3
N+
NH2
NH2
N+
I-
A
CF3
N
3
[3+2]
2
N
CF3
CO2R
N
N
regioselective
metalation
CO2R
B
I
CO2R
: R = Me
N
N
N
1a
1b: R = Et
N
CO2R
CO2R
CO2R
CF3
coupling
1a
1b R = Et
R = Me
CO2R
: R = Me
4b: R = Et
CO2R
: R = Me
4a
5a
5b: R = Et
Scheme 1. New approaches to pyrazolo[1,5-a]pyridine 1a and 1b.
The original synthesis of this intermediate entailed a problem-
atic N-amination step, which was not amenable to scale up due
to its low yield and in particular the use of the thermally unstable
reagent, O-mesitylsulfonylhydroxylamine (MSH).1 The more ther-
mally stable hydroxylamine O-sulfonic acid (HOSA) did not achieve
the desired N-amination. Therefore, we needed to identify a new
synthetic approach to 7-trifluoromethylpyrazolo[1,5-a]pyridine 1
that would facilitate the delivery of multi-kilogram quantities of
material to support our drug discovery program.
After evaluating a number of different possibilities, we decided
to concentrate our efforts on two main approaches (Scheme 1). In
both cases, we sought to introduce a trifluoromethyl group into the
starting materials with the N–N bond already incorporated. Thus,
the need to use highly energetic reagents such as MSH on scale
would be obviated. These starting materials are commercially
available as they are readily prepared using the thermally stable
HOSA. 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 could
be prepared by nucleophilic addition of trifluoromethylation re-
agents such as Ruppert’s reagent (CF3SiMe3)2 to the commercially
available N-aminopyridinium iodide (3), followed by rearomatiza-
tion of the resultant N-aminodihydropyridine.3 In approach B, we
envisioned that the C7 position of the pyrazolo[1,5-a]pyridine
dicarboxylate 4 could undergo selective metalation followed by
iodination to generate iodide 5.4 Subsequently, metal-catalyzed
trifluoromethylation could afford 1.5 Herein we describe our efforts
on these two new approaches to prepare 1.
⇑
Corresponding author. Tel.: +1 919 483 8165; fax: +1 919 483 3706.
E-mail address: bing.b.liu@gsk.com (B. Liu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.136

P. Chong et al. / Tetrahedron Letters 53 (2012) 6786–6788
6787
CF3TMS,
I
TsCl,
CF3
CF3
N
N-Ts
CuI,
CsF,
NaOH (aq)
THF
NH2
O O
NHTs
N
N
N+
N
DMF, 80 °C
DMF/H2O
N+
N
S
CO2Me
CO2Et
I-
+
CO2Et
F
89%
79%
84%
F F
CO2Et
CO2Et
6
3
7
5b
10
1b
CF3
N
CF3
EtO2C
CO2Et
DDQ,
THF
N
N-Ts
Scheme 3. Trifluoromethylation of iodide 6b.
Na2CO3, EtOH, 70 °C
CO2Et
N+
25%
60%
CO2Et
(TMP: 2,2,6,6-tetramethylpiperidine) could alleviate this problem.9
Indeed, upon addition of the commercially available (TMP)2Zn
Á2MgCl2Á2LiCl to a solution of dimethyl pyrazolo[1,5-a]pyridine
dicarboxylate (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 95:5
ratio (Table 1).10 Zincation and iodination of diethyl dicarboxylate
4b led to a similar ratio of products (96:4) at room temperature.
The partial hydrolysis of ester increased when the solid iodine was
used directly to quench the metalated species instead of the iodine
THF solution. Lower reaction temperature reduced the amount of
dealkylation. Thus, zincation and iodination of 4b at À10 °C
suppressed the dealkylation nearly completely to give iodide 5b
in 95% AUC by HPLC. It was interesting to note that zincation/
iodination of the more bulky t-butyl ester 4c at room temperature
also 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 of
CsF and copper (I) idodide gave 1b; however, the reaction was
not 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 of
1 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 the
presence of sub-stoichiometric amounts of CuI (0.75 equiv) with-
out substantially affecting yield or purity although the reaction
took longer to reach completion (10 h). The zincation/iodination
and trifluoromethylation have been carried out on 300 g of pyraz-
olopyridine dicarboxylate successfully. We have also shown that
these two steps could be telescoped without isolation of iodide
5b to give 1b in 86% yield over two steps on 6 L scale.
1b
8
Scheme 2. The approach A to pyrazolo[1,5-a]pyridine 1b.
We initially focused our efforts on approach A. We were encour-
aged by literature examples in which N-alkylpyridinium6 and
N-aminopyridinium7 species have been reported to undergo nucle-
ophilic attack at the 2-position. While reactions on substrate 3 were
rather messy, we found that protecting the exocyclic nitrogen as the
highly crystalline p-toluenesulfonamide 6, followed by treatment
with Ruppert’s reagent (CF3SiMe3) and CsF, led to the formation
of dihydropyridine 7 with exclusive regioselectivity (Scheme 2).
Among a number of possible rearomatization conditions, we found
that treatment of 7 with dichlorodicyanobenzoquinone (DDQ)
cleanly generated the N-p-toluenesulfonyliminopyridinium ylide
moiety 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 the
desired 7-trifluoromethyl pyrazolopyridine 1b in 25% yield. There
were many byproducts in the reaction mixture. We observed three
major byproducts on LC–MS. Two compounds have the same
molecular weight as the initial cycloadduct, presumably formed
from 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 another
molecule of acetylenedicarboxylate. Attempts to optimize the reac-
tion by screening bases and solvents proved fruitless as the initial
cycloadduct was prone to these unproductive pathways.8
Next we turned our attention to approach B. There are precedents
of selective metalation of pyrazolopyridine in the literature.4 How-
ever, lithiation or magnesiation of pyrazolopyridine 4a followed
by iodination led to decomposition under a variety of conditions
without the formation of the desired iodide 5a. We suspected that
decomposition was attributable to functional group intolerance of
metalation reagents or the resulting metalated pyrazolopyridine. A
more selective metalation reagent such as (TMP)2ZnÁ2MgCl2Á2LiCl
In conclusion, we have studied two synthetic routes to make
7-trifluoromethylpyrazolo[1,5-a]pyridine 1b that eliminate the
use of the highly energetic reagent MSH. Approach A utilizes a
nucleophilic addition of a trifluoromethyl group to N-p-toluene-
sulfonyliminopyridinium ylide followed by aromatization and
Table 1
Selective zincation and iodination of pyrazolo[1,5-a]pyridine dicarboxylates 4
I
I
(TMP)2Zn•2MgCl2•2LiCl,
N
N
N
N
THF; I2
N
N
+
CO2R
CO2R
CO2R
CO2R
CO2R
CO2H
, R = Me
4a,
R = Me
9a
5a
, R = Me
4b, R = Ev
9b, R = Et
5b, R = Et
4c, R = t-Bu
9c, R = t-Bu
5c, R = t-Bu
Substrate
Conditions
Ratio ester 5:acid 9
Yielda (%)
4a
4b
4c
4b
4b
(TMP)2ZnÁ2MgCl2Á2LiCl (0.7 equiv), rt
(TMP)2ZnÁ2MgCl2Á2LiCl (0.7 equiv), rt
(TMP)2ZnÁ2MgCl2Á2LiCl (0.7 equiv), rt
(TMP)2ZnÁ2MgCl2Á2LiCl (0.7 equiv), 0 °C
(TMP)2ZnÁ2MgCl2Á2LiCl (0.7 equiv), À10 °C
95:5
89b
85b
92
90
95
96:4
82:18c
89:11c
99:1
a
b
c
Sum of HPLC percent area under the curve (AUC) for both ester 5 and acid 9.
Isolated yield.
Quenched by adding iodine solids instead of iodine THF solution.

6788
P. Chong et al. / Tetrahedron Letters 53 (2012) 6786–6788
8. Possible structures of three major byproducts:
CF3
subsequent cycloaddition with diethyl acetylenedicarboxylate to
give 1b in modest yield. Approach B involves a selective zincation
of pyrazolopyridine dicarboxylate at the C7 position with (TMP)2Zn
Á2MgCl2Á2LiCl followed by iodination and trifluoromethylation to
give 1b in good yield. We have successfully demonstrated the
approach B processes in our scale-up equipment.
CF3
N
NTs
N
NHTs
CO2Et
CO2Et
CO2Et
CO2Et
References and notes
CF3
N
EtO2C
EtO2C
NTs
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 for
MSH 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.
CO2Et
CO2Et
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 carboxylic
acid is more reactive as the decarboxylation occurred at the C3 position when
pyrazolopyridine-2,3-dicarboxylic acid was heated in
hydrobromic acid and acetic acid.
11. Chen, Q. Y.; Wu, S. W. J. Chem. Soc., Chem. Commun. 1989, 11, 705.
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.
a
mixture of