Regioselective palladium-catalyzed C–H arylation of 4-alkoxy and 4-thioalkyl pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2017.10.047

A methodology for the palladium-catalyzed regioselective C–H arylation of electron rich pyrazoles has been developed. New ligands and mild conditions (70–90 °C) have been identified for this transformation. An intramolecular application of the methodology provided a novel synthetic route for the regioselective synthesis of 1,5-dihydroisochromeno[4,3-c]pyrazoles and 1,5-dihydroisothiochromeno[4,3-c]pyrazoles.

Full text of DOI:10.1016/j.tetlet.2017.10.047

Accepted Manuscript
Regioselective palladium-catalyzed C-H arylation of 4-alkoxy and 4-thioalkyl
pyrazoles
William F. Vernier, Laurent Gomez
PII:
S0040-4039(17)31339-4
https://doi.org/10.1016/j.tetlet.2017.10.047
TETL 49409
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 August 2017
6 October 2017
17 October 2017
Please cite this article as: Vernier, W.F., Gomez, L., Regioselective palladium-catalyzed C-H arylation of 4-alkoxy
and 4-thioalkyl pyrazoles, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.10.047
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Regioselective palladium-catalyzed C-H
arylation of 4-alkoxy and 4-thioalkyl
pyrazoles
Leave this area blank for abstract info.
William F. Vernier* and Laurent Gomez
Intermolecular:
Intramolecular:
X = Br
X = H
R1
X = H or Br
R1
SPhos or QPhos (7.5 mol%),
Pd(OAc)2 (5 mol%), Bu4NOAc,
Dioxane, 70-90 ºC
R1
R2
N
N
H
Ar(Het)
N
N
N
N
or
X
O
O
(Het)ArBr (when X = H)
O
R2
19-88%
34-93%
R2

1
Tetrahedron Letters
journal homepage: www.els evier.com
Regioselective palladium-catalyzed C-H arylation of 4-alkoxy and 4-thioalkyl
pyrazoles
William F. Vernier ∗ and Laurent Gomez
Discovery Chemistry, Dart Neuroscience, LLC, 12278 Scripps Summit Drive, San Diego, CA 92131
ARTICLE INFO
ABSTRACT
Article history:
Received
A methodology for the palladium-catalyzed regioselective C-H arylation of electron rich
pyrazoles has been developed. New ligands and mild conditions (70-90 °C) have been identified
for this transformation. An intramolecular application of the methodology provided a novel
synthetic route for the regioselective synthesis of 1,5-dihydroisochromeno[4,3-c]pyrazoles and
1,5-dihydroisothiochromeno[4,3-c]pyrazoles.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
C-H arylation
Pyrazoles
Sphos
Qphos
Palladium
Pyrazoles are widely used in the medicinal chemistry
community because of their good metabolic stability and
favorable physicochemical properties.1 Not surprisingly, this
heterocycle appears in numerous marketed therapeutics. In
particular, several drugs containing 5–aryl pyrazoles have
reached the market (Fig. 1). In addition, several 5–(het)aryl
pyrazoles are currently being investigated in clinical trials.2
Sames and co-workers next reported an application of the C-H
activation methodology to the synthesis of 5-aryl pyrazoles.7
Figure 1. Selected examples of 5–aryl pyrazoles that have reached
the market.
Pyrazoles have traditionally been synthesized by the
condensation of hydrazines and 1,3-bis-electrophiles leading to
poor regiochemical control in many cases.3 Methods have been
developed to improve the regiochemical control, but the
preliminary synthesis of organometallic derivatives is typically
−H
Scheme 1. Palladium-catalyzed C-H arylation of imidazoles and
pyrazoles.
needed.4 In recent years, transition-metal catalyzed
C
activation reactions have emerged as a powerful methodology to
straightforwardly introduce aryls to various heterocycles.5 In their
seminal paper, Miura and co-workers described the C-H arylation
of imidazoles at the 5-position with aryl bromides or iodides.6
More recently, the scope of this type of reaction has been
expanded and improved conditions have been identified.8
Although very useful, the existing conditions require high
temperatures with a limited choice of ligands and have not been
———
∗ Corresponding author. Tel.: +1-858-736-3162; e-mail: wvernier@dartneuroscience.com

2
Tetrahedron
applied to many heterocycles. Also, to the best of our
instead of Sphos as the ligand. However, the yields were still
moderate in the cases of 3g and 3j when using Qphos.
knowledge, direct C-H arylation has not been investigated with
electron rich pyrazoles. Herein, we report our research effort
aimed at identifying mild and general conditions for the direct
arylation of 4-alkoxy and 4-thio substituted pyrazoles. The
identified conditions were also applied to an expedient synthesis
Table 1. Optimization of the palladium-catalyzed C-H
arylation of alkoxypyrazolesa
of
1,5-dihydroisochromeno[4,3-c]pyrazoles
and
1,5-
dihydroisothiochromeno[4,3-c]pyrazoles via intramolecular
cyclization. This approach constitutes a novel and efficient
synthetic route to these biologically relevant heterocyclic
systems.
4-(Benzyloxy)-1-methyl-1H-pyrazole (1) was synthesized
according to literature procedures9 (see ESI) and selected as the
starting material for reaction optimization. We also wished to
investigate and develop reaction conditions that can easily be
applied to the synthesis of “druglike” molecules. Therefore, we
chose to conduct our optimization study with a heterocycle and
selected 5-bromo-2-methylpyridine (2). Traditionally, pyrazole
C-H arylation reactions have required the use of pivalic acid as a
co-catalyst and 1.5 eq. of the aryl bromide. In an initial round of
optimization, we observed that for our substrate, pivalic acid was
not necessary and led to increased formation of by-product 4a
(Table 1, entries 1 and 2). In addition, less than 1.5 eq. of the aryl
bromide could be used and Pd(OAc)2 was the superior Pd source
(see Table 1; and ESI S8). Finally, higher Pd and ligand loading
did not significantly improve the conversion. We focused next on
evaluating the influence of the base and solvent. Among the
bases investigated Bu4NOAc performed the best with complete
conversion and improved regiochemistry (Entries 2-5). This
result confirms the beneficial effect of this base as previously
observed by other groups.8a,8g For the solvent, NMP and dioxane
were far superior to DMA and toluene (Entries 2, 3, 6, 7; and 22
and 24, ESI S8). To further improve the methodology, the
temperature was decreased and 1.05 eq. of aryl bromide 2 was
used for the rest of the optimization. Under these milder
conditions, dioxane gave slightly better conversion than NMP
(Entries 9-10). These conditions also had the added benefit of
minimizing the formation of by-product 4a. With the optimized
solvent and base in hand, we next evaluated a set of ligands. We
were able to confirm that previously identified di(1-adamantyl)-
n-butylphosphine (PBuAd2, cataCXium A)7 and Davephos8a were
competent for this transformation (Entries 9 and 11). We also
identified three new ligands (BippyPhos,10 Sphos11 and Qphos12)
that gave conversions and isolated yields similar to the known
ligands (Entries 12, 13 and 15). For the rest of the study, we
selected dioxane as the solvent to simplify the work-up and
Sphos as the ligand due to lower cost and the fact that it has not
previously been studied for the C-H arylation of pyrazoles. It
should be noted that on a 1 mmol scale, the temperature and
reaction time needed to be increased to 80 °C and 72 h,
respectively, to obtain 3 in 77% isolated yield using the above
optimized conditions. In a few cases where the yield was not
satisfactory, Qphos was also examined.
Entry
1c,d
2d
3d
4d
Ligand
Base
Temp. (°C)
100
100
90
Conversion (3a/4a)b
75(69)/22(11)
79/16
PBuAd2
PBuAd2
PBuAd2
PBuAd2
PBuAd2
PBuAd2
PBuAd2
tBu2PMe
PBuAd2
PBuAd2
Davephos
K2CO3
K2CO3
Bu4NOAc
KOAc
90/10
90
48/0
5d
KF
90
52/0
6d,e
7d,f
8d
K2CO3
90
40/0
Bu4NOAc
K2CO3
90
46/0
90
66/1
9g
Bu4NOAc
Bu4NOAc
Bu4NOAc
70
94(78)/2
82/1
10g,h
11g
12g
13g
14g
15g
70
70
93(79)/2
93(82)/5
92(79)/5
52/0
BippyPhos Bu4NOAc
70
Sphos
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
70
Amphos
Qphos
70
70
95(82)/3
5/0
16g
Josiphos
70
a
Reactions were conducted on a 0.1 mmol scale for 18 h. The ratio of
1/2/catalyst/ligand/base was 1/1.05/0.075/0.05/3 unless otherwise noted.
b
Analysis by UPLC/MS using uncorrected AUC at 254 nM. Isolated yield
after column chromatography in parenthesis.
c t-BuCO2H (0.25 eq.) used as an additive.
d 2 (1.2 eq.) was used.
e DMA was used.
f Toluene was used.
g 16 h reaction time.
h NMP was used.
With the optimal reaction conditions in hand, we next studied
the substrate scope (Scheme 2). For the aryl bromide, electron
rich and electron deficient aryl groups were well tolerated (3d
and 3e). Various functional groups including chlorine, methoxy
and ester (3b, 3d and 3e) were also tolerated. Steric hindrance on
the aryl bromide was tolerated as compound 3c with an ortho-
substituent was obtained in 71% yield. However, steric hindrance
on the pyrazole seemed to be less tolerated as compounds 3i and
3j were obtained in lower yield. Pyrimidine and chloropyridine
were tolerated, although moderate yields were obtained (3f, 3g,
and 3h). In general, thioethers required higher temperatures and
longer reaction times compared to the ethers (3j and 3k). In the
case of 3h, the yield was greatly improved by using Qphos
Figure 2. Highly competent ligands used in this study.
We next investigated if this methodology could be applied to
an
dihydroisochromeno[4,3-c]pyrazoles
intramolecular
cyclization
to
afford
and
1,5-
1,5-
dihydroisothiochromeno[4,3-c]pyrazoles. Those analogs have
previously been investigated as inhibitors of the nicotinic
acetylcholine receptor13 and COX-2.14 Reported syntheses
involves the condensation of hydrazines with 1,3-diketone 7
(Scheme 3). The limitations of this synthetic route are the length
of synthesis and poor control of regiochemistry when R2
substituents are not electron withdrawing.

3
SPhos (7.5 mol%)a or
QPhos (7.5 mol%)b,
Pd(OAc)2 (5 mol%),
R1
N
SPhos (7.5 mol%)a or
QPhos (7.5 mol%)b,
Pd(OAc)2 (5 mol%),
N
Br
R
N
R
N
R2
R1
X
R2
N
N
Ar(Het)
Alk
Bu4NOAc (3 eq.),
Dioxane (0.4 M),
70-85 ºC
N
N
X
+
(Het)ArBr
Bu4NOAc (3 eq.),
Dioxane (0.4 M),
70-90 ºC
9
10
X = O or S
X = O or S
Alk
X
X
X = O or S
1.05 eq.
2a
3
1a
O
N
N
N
Cl
N
N
N
N
N
N
N
O
N
O
O
N
Cl
O
O
O
a
a
a
10a
10c
93%
61%
N
10b
73%
3b 80%a
3c 71%a
3d 88%a
Me3Si
O
O
N
N
N
N
N
N
N
O
N
N
N
N
Cl
N
N
N
O
a
O
N
O
O
O
O
O
a
10f
68%
a
10e
56%
10d
49%
75%a
52%a
47%a
52%b
78%b
3e
3f
3g
N
N
N
N
N
N
N
N
N
N
N
N
N
O
N
N
O
S
O
S
S
O
3h 35%a
86%b
3i 19%a
3j 35%a
37%b
a
a
a
10g
10h
10i
37%
49%
34%
N
14%b
Scheme 4. Synthesis of 1,5-dihydroisochromeno[4,3-c]pyrazoles and
1,5-dihydroisothiochromeno[4,3-c]pyrazoles via intramolecular
cyclization.
N
N
S
3k 48%a
To evaluate the generality of the methodology, we next applied
the optimized conditions to substrates that have been previously
studied by other groups (Fig. 3).8,15 Three pyrazoles that do not
bear an electron-rich substituent at the C4 position and one
imidazole were selected; it should be noted that the reactions
were run with less aryl bromide or azole and at lower
temperatures (for 3m-o) than previously reported. We were
pleased to find that the yields obtained were comparable to the
reported yields.
Scheme 2. Substrate scope for the C-H arylation of 4-alkoxy and 4-
thio pyrazoles.
Scheme 3. Synthesis of 1,5-dihydroisochromeno[4,3-c]pyrazoles via
condensation with hydrazines.
We were pleased to find that using our optimized conditions,
cyclized
4-((2-bromobenzyl)oxy)-1-methyl-1H-pyrazole
9
readily to give the desired 1,5-dihydroisochromeno[4,3-
c]pyrazoles 10 with complete control of the regiochemistry. The
substrate scope for this cyclization is shown in Scheme 4.
Electron donating and withdrawing substituents on the aryl
bromide were tolerated, as well as chlorine (10c-e). Unlike the
intermolecular cases, larger groups on the pyrazole were well
tolerated (10b and 10f). The methodology was also successfully
applied to the formation of a 7-membered ring to afford 10g in
moderate yield. For the thioethers, higher temperature was
required for the cyclization and lower yields were observed due
to increased decomposition and lower conversion (10h and 10i).
When using Qphos instead of Sphos as the ligand, the conversion
and the yield of 10d were improved. On the other hand, the yield
for 10i with the sterically demanding benzyl substituent was
lower when using the bulkier ligand.
Figure 3. Application of the optimized conditions to other
substrates.a
a Reaction conditions: azole (1 mmol), aryl bromide (1.05 eq.), Pd(OAc)2 (5
mol%), QPhos (7.5 mol%), Bu4NOAc (3 eq.), dioxane (0.4 M). Isolated yield
after column chromatography.
b
Yield was determined by 1H NMR analysis of the crude product using
CH2Br2 as the internal standard.
In conclusion, we have developed general and mild conditions
for the highly regioselective direct arylation of electron rich
pyrazoles. Three new ligands have been identified for this
transformation providing more options for reaction optimization
and future applications. The developed conditions show a
number of advantages, including the minimization of bisarylated
by-product formation, low cost of the catalytic system, and good
functional group tolerance. The methodology was successfully

4
Tetrahedron
Catal. 2010, 352, 2116–2120; (c) Beladhria, A.; Beydoun, K.; Ben
Ammar, H.; Ben Salem, R.; Doucet, H. Synthesis 2011, 2553–
2560; (d) Gaulier, S. M.; McKay, R.; Swain, N. A. Tetrahedron
Lett. 2011, 52, 6000–6002; (e) Yang, Y.; Kuang, C.; Jin, H.;
Yang, Q.; Zhang, Z. Beil. J. Org. Chem. 2011, 1656–1662; (f)
Yan, T.; Chen, L.; Bruneau, C.; Dixneuf, P. H.; Doucet, H. J. Org.
Chem. 2012, 77, 7659–7664; (g) Bellina, F.; Lessi, M.; Manzini,
C. Eur. J. Org. Chem. 2013, 5621–5630; (h) Smari, I.; Youssef,
C.; Yuan, K.; Beladhria, A.; Ben Ammar, H.; Ben Hassine, B.;
Doucet, H. Eur. J. Org. Chem. 2014, 1778–1786; (i) Iaroshenko,
V. O.; Gevorgyan, A.; Davydova, O.; Villinger, A.; Langer, P. J.
Org. Chem. 2014, 79, 2906–2915; (j) Takfaoui, A.; Zhao, L.;
Touzani, R.; Dixneuf, P. H.; Doucet, H. Tetrahedron Lett. 2014,
55, 1697–1701; (k) Kumpulainen, E. T. T.; Pohjakallio, A. Adv.
Synth. Catal. 2014, 356, 1555–1561; (l) Brahim, M.; Ben Ammar,
H.; Soule, J.-F.; Doucet, H. Tetrahedron 2016, 72, 4312–4320.
9. (a) Westaway, S. M.; Preston, A. G. S.; Barker, M. D.; Brown, F.;
Brown, J. A.; Campbell, M.; Chung, C.; Drewes, G.; Eagle, R.;
Garton, N.; Gordon, L.; Haslam, C.; Hayhow, T. G.; Humphreys,
P. G.; Joberty, G.; Katso, R.; Kruidenier, L.; Leveridge, M.;
Pemberton, M.; Rioja, I.; Seal, G. A.; Shipley, T.; Singh, O.;
Suckling, C. J.; Taylor, J.; Thomas, P.; Wilson, D. M.; Lee, K.;
Prinjha, R. K. J. Med. Chem. 2016, 59, 1370–1387; (b) Schultz-
Fademrecht, C.; Klebl, B.; Choidas, A.; Koch, U. J.; Eickhoff, J.;
Wolf, A.; Ullrich, A.; Max-Planck-Gesellschaft zur Förderung der
Wissenschaften E.V. Preparation of quinoline carboxamide
compounds as Axl inhibitors for treating hyperproliferative
disorders. WO2012028332, 2012.
applied to the synthesis of biologically relevant 1,5-
dihydroisochromeno[4,3-c]pyrazoles
dihydroisothiochromeno[4,3-c]pyrazoles via intramolecular
cyclization and should be highly valuable to medicinal chemists
wishing to install heteroaryl groups at the C5 position of
pyrazoles.
and
1,5-
Acknowledgments
We thank Dart Neuroscience for supporting this investigation
and Dr. Guy Breitenbucher for his assistance and feedback.
Supplementary Material
Starting material synthesis, additional table entries,
experimental procedures and spectra for all new compounds.
References and notes
1. (a) St. Jean, D. J.; Fotsch, C. J. Med. Chem. 2012, 55, 6002–6020;
(b) Ioannidis, S.; Lamb, M. L.; Almeida, L.; Guan, H.; Peng, B.;
Bebernitz, G.; Bell, K.; Alimzhanov, M.; Zinda, M. Bioorg. Med.
Chem. Lett. 2010, 20, 1669–1673.
2. Afuresertib (GSK2110183) an Akt inhibitor in phase 2,
Nelotanserin an inverse agonist of 5-HT2A in phase 2, and PF-
05180999 an inhibitor of cyclic nucleotide phosphodiesterase-2
(PDE2) discontinued after phase 1.
3. (a) Elguero, J. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds. Pergamon
Press: New York, 1996; Vol. 3, pp 58-61; (b) Fustero, S.; Román,
R.; Sanz-Cervera, J. F.; Simón-Fuentes, A.; Cuñat, A. C.;
Villanova, S.; Murguía, M. J. Org. Chem. 2008, 73, 3523–3529;
(c) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes,
A. Chem. Rev. 2011, 111, 6984–7034.
10. Singer, R. A.; Dore, M.; Sieser, J. E.; Berliner, M. A. Tetrahedron
Lett. 2006, 47, 3727–3731.
11. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685–4696.
12. (a) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem.
Soc. 2000, 122, 10718–10719; (b) Kataoka, N.; Shelby, Q.;
Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553–5566.
13. Herbert, B.; Schumacher, R.; Dai, G.; Xie, W.; Memory
Pharmaceuticals Corporation. Preparation of (1,4-
diazabicyclo[3.2.2]non-6-en-4-yl)-heterocyclyl-methanone ligands
for nicotinic acetylcholine receptors useful for the treatment of
disease. WO2009055437, 2009.
4. (a) Font-Sanchis, E.; Cespedes-Guirao, F. J.; Sastre-Santos, A.;
Fernandez-Lazaro, F. J. Org. Chem. 2007, 72, 3589–3591; (b)
Despotopoulou, C.; Klier, L.; Knochel, P. Org. Lett. 2009, 11,
3326–3329; (c) Kirkham, J. D.; Edeson, S. J.; Stokes, S.; Harrity,
J. P. A. Org. Lett. 2012, 14, 5354–5357; (d) Fricero, P.; Bialy, L.;
Brown, A. W.; Czechtizky, W.; Mendez, M.; Harrity, J. P. A. J.
Org. Chem. 2017, 82, 1688–1696.
14. (a) Talley, J. J.; Bertenshaw, S. R.; Graneto, M. J.; Rogier, D. J.;
G.D. Searle and Company. Benzopyranopyrazolyl derivatives for
the treatment of inflannation. WO1996009304, 1996; (b)
Bertenshaw, S. R.; Talley, J. T.; Rogier, D. J.; Graneto, M. J.;
Koboldt, C. M.; Zhang, Y. Bioorg. Med. Chem. Lett. 1996, 6,
2827–2830; (c) Metz, S.; Clare, M.; Crich, J. Z.; Hagen, T. J.;
Hanson, G. J.; Huang, H.; Houdek, S. J.; Stealey, M. A.; Vazquez,
M. L.; Weier, R. M.; Xu, X.; Pharmacia Corporation. Substituted
pyrazolo compounds for the treatment of inflammation.
WO2003024936, 2003.
5. (a) Alberico, D.; Scott, M.; Lautens, M. Chem. Rev. 2007, 107,
174–238; (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205;
(b) St. Jean, D. J.; Fotsch, C. J. Med. Chem. 2012, 55, 6002–6020;
(c) Joo, J. M.; Guo, P.; Sames, D. J. Org. Chem. 2013, 78, 738–
743; (d) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Adv. Synth.
Catal. 2014, 356, 17–117; (e) Rossi, R.; Lessi, M.; Manzini, C.;
Marianetti, G.; Bellina, F. Synthesis 2016, 48, 3821–3862.
6. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467–473.
15. We are thankful to the reviewer for this suggestion.
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7. Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009,
131, 3042–3048.
8. (a) Mateos, C.; Mendiola, J.; Carpintero, M.; Minguez, J. M. Org.
Lett. 2010, 12, 4924–4927; (b) Rene, O.; Fagnou, K. Adv. Synth.

5
Highlights
• New ligands and mild conditions for the C-H
arylation of electron rich pyrazoles.
• Synthesis of 1,5-dihydroisochromeno[4,3-
c]pyrazoles via intramolecular cyclization.
• The methodology can be applied to other
pyrazoles and imidazoles.