Modulating N- versus O-arylation in pyrazolone-aryl halide couplings

Article abstract of DOI:10.1016/j.tetlet.2007.11.185

The regioselective, copper-catalyzed coupling of a tautomeric pyrazolone/pyrazole with 2-halopyridines was investigated. Conditions were developed to preferentially form either the N-aryl or O-aryl product.

Full text of DOI:10.1016/j.tetlet.2007.11.185

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 794–798
Modulating N- versus O-arylation in pyrazolone-aryl halide couplings
Jennifer E. Golden *, Shanina D. Sanders, Kristine M. Muller, Roland W. Burli
¨
Chemistry Research and Development, Amgen, Inc., One Amgen Center Dr. Thousand Oaks, CA 91320, United States
Received 27 November 2007; accepted 29 November 2007
Available online 4 December 2007
Abstract
The regioselective, copper-catalyzed coupling of a tautomeric pyrazolone/pyrazole with 2-halopyridines was investigated. Conditions
were developed to preferentially form either the N-aryl or O-aryl product.
Ó 2007 Elsevier Ltd. All rights reserved.
Pyrazolones are useful intermediates in the synthesis of
compounds possessing a broad range of pharmacological
activities.1a–d Within the scope of a medicinal chemistry
program, it was necessary to prepare pyrazolone 1 bearing
various heterocycles on the acyl ring nitrogen and a methyl
group on the adjacent amine (Scheme 1, R2 = Me). Cyclo-
condensations of aryl hydrazines with acetylenic or b-keto
esters are useful methods for installing the N-aryl group
regioselectively (1, R2 = H); however, this strategy required
preparation of commercially unavailable aryl hydrazines
and a subsequent methylation step for each compound in
our library.2a,b As an alternative approach, the Cu-medi-
ated coupling of aryl halides with an optimally substituted
NH-pyrazolone 2 was examined.
the N-phenyl product in 47% yield.3,4 Given the limited
scope of this reaction and several reports describing the
N-arylation of amides and acyl hydrazines, contemporary
copper-mediated conditions were applied to the coupling
of pyrazolone 3 and 2-bromopyridine (Scheme 2).5,6a–c
Two regioisomeric compounds were generated and char-
acterized as N-pyridyl pyrazolone 4a and O-pyridyl pyra-
zole 5a. Proton and 13C NMR data of 4a were consistent
with that reported for structurally similar N-aryl pyrazo-
lones.4 The 1H NMR data of the N-phenyl product
O
OH
cat. CuI, Cs2CO3,
1,10-phenanthroline
2-bromopyridine, 48 h
DMF or dioxane, 80 °C
NH
N
When this study was undertaken, prior art was limited
to one example of a regioselective SnAr N-arylation with
3-methylpyrazolin-5-one (2, R1 = Me, R2 = H) and an
electronically deactivated 2-fluorophenylnitrile to afford
N
N
Me
Me
3b
"hydroxy" form
3a
"oxo" form
O
O
Ar
Ar-halide
R = alkyl
O
N
N
NH
N
O
N
N
N
+
R1
R2
R1
R2
N
N
N
1
2
Me
Me
5a
-arylated
Scheme 1.
4a
-arylated
N
O
35%
55%
*
Corresponding author. Tel.: +1 805 313 5155; fax: +1 805 480 3016.
Scheme 2.
E-mail address: golden@amgen.com (J. E. Golden).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.185

J. E. Golden et al. / Tetrahedron Letters 49 (2008) 794–798
795
obtained from either Cu-promoted coupling with 3 or
cyclocondensation (using PhNHNH2, and subsequent
methylation step) were identical. Similarly, spectroscopic
data for 5a compared favorably with that of reported pyr-
result from a competing nucleophilic aromatic substitution
reaction between the 2-halopyridine and the ‘OH’ tautomer
3b, as even in the absence of catalyst, pyrazole 5a was
formed as the only product in 49% yield.7 Given the ease
of surveying this reaction from HPLC integration, the
generation of both products in good overall yield, and
the broad commercial availability of heterocyclic bromides,
2-bromopyridine was chosen as the substrate with
which further optimization was investigated, and a
more thorough study aimed at controlling the selective
formation of either product was undertaken.
1
azoles.8 Diagnostic shifts in H NMR signals and HPLC
retention times were found between 4a and 5a, and the rel-
ative product ratio could be determined from the crude
reaction mixture by integrating only those HPLC peaks
corresponding to each product. Notably, under these con-
ditions the reaction favored the formation of the less
desired O-aryl pyrazole. This product was speculated to
Table 1
Effect of changing the halopyridine on product ratio and yield in the O-arylation and N-arylation procedures with 3
Entry
Halopyridine
Conditionsa
HPLC ratiob 4a:5a
4a:5a Isolated (%)
Overall yield, isolated (%)
1
2
3
4
5
6
a
2-Chloropyridine
2-Chloropyridine
2-Bromopyridine
2-Bromopyridine
2-Iodopyridine
a
b
a
b
a
b
0:100
0
30:70
71:29
61:39
70:30
0:84
0
14:77
72:7
64:31
77:19
84
0
91
79
95
96
2-Iodopyridine
Reagents and conditions: (a) 0.50 g pyrazolone, halopyridine, 5 mol % CuCN, 11 mol % ethylenediamine, Cs2CO3, DMF, 110 °C, 48 h; (b) 0.50 g
i
pyrazolone, halopyridine, 5 mol % CuBr, 11 mol % 1,10-phenanthroline, K3PO4, PrOH, 110 °C, 48 h.
b
Ratio determined from the crude reaction mixture using reverse phase HPLC (5 min run, 0.1% formic acid in CH3CN/H2O) at 215 nm between peak
areas at ca. RT = 2.4 and ca. RT = 2.9 (4a and 5a, respectively). Other peaks, not integrated, may have been present, such as those corresponding to
starting material or ligand.
Table 2
Results of N-arylation study with 3 using optimized conditionsa
Entry
Halide
Product
Yield 4b (%)
Yield 5b (%)
Overall yield (%)
79
1
4a, 5a
72
7
N
Br
Me
2
3
4b, 5b
4c, 5c
70
68
5
75
83
N
Br
Br
MeO
15
N
OMe
4
4d, 5d
78
9
87
N
Br
NC
5
6
7
4e, 5e
4e, 5e
14
22
61
61
75
83
N
Br
NC
N
N
I
4f, 5f
80
51
10
47
90
98
Br
N
N
8
4g, 5g
Br
a
i
Reagents and conditions: 0.50 g pyrazolone, 1 equiv halide, 5 mol % CuBr, 11 mol % 1,10-phenanthroline, 1.4 equiv K3PO4, PrOH, 110 °C, 48 h.
Isolated yields.
b

796
J. E. Golden et al. / Tetrahedron Letters 49 (2008) 794–798
The influence of several parameters on the reaction
tions were used to study the effect of using 2-chloro- or 2-
iodopyridine instead of 2-bromopyridine (Table 1).
The formation of N-aryl product with 2-bromopyridine
was optimally achieved using CuBr and 1,10-phenanthro-
between 2-bromopyridine and 3 was examined. The choice
of copper catalyst (CuCl, CuBr, CuI, CuCN, CuOAc,
CuSO4, and CuSO4ꢀ5H2O), inorganic base (K3PO4 or
Cs2CO3), amine ligand (1,10-phenanthroline, 3,4,7,8-
tetramethylphenanthroline, ethylenediamine, and a few
examples with either N,N0-dimethylethylenediamine or
trans-1,2-diaminocyclohexane), and solvent (DMF, diox-
i
line in the presence of K3PO4 and PrOH for 48 h at
110 °C. This reagent combination provided 4a in 72% yield
with a 7% yield of pyrazole 5a (entry 4). Exchange of
2-chloropyridine for the bromide afforded neither product,
i
i
ane, and PrOH) were surveyed.9 From this preliminary
presumably due to a competitive side reaction with PrOH
screen, product distribution was determined to be pro-
foundly impacted by choice of solvent. A majority of reac-
tions in DMF resulted in near 1:1 production of 4a to 5a;
however, reagent combinations that resulted in significant
shifts in the product ratio away from 1:1 predominantly
favored pyrazole product 5a. Alternatively, reactions
(entry 2). The use of 2-iodopyridine resulted in an isolated
ratio of 4a:5a that was similar to that obtained when the
corresponding bromide was employed (entry 6).
Conditions were also identified that reversed the
observed ratio in favor of pyrazole 5a. Use of CuCN and
ethylenediamine in the presence of Cs2CO3 and DMF at
110 °C for 48 h afforded 5a in 77% yield and 4a in 14%
yield (entry 3). The N-aryl coupling predominated with
iodopyridine under these conditions; however, substituting
2-chloropyridine in this reaction exclusively provided the
pyrazole in 84% yield (entry 1), implying that the rate of
the aromatic substitution reaction is faster than the N-aryl
copper-mediated coupling with 2-chloropyridine. However,
it is important to note that copper plays an integral role in
accelerating or promoting the conversion to the O-aryl
product, since in the absence of catalyst the reaction with
i
employing PrOH generally favored pyrazolone 4a forma-
tion. Use of dioxane typically required longer heating times
(>90–120 h) to reach completion and did not offer advanta-
ges over other solvents. The use of ethylenediamine notably
shifted product ratios in favor of pyrazolone formation;
however, significant amounts of starting material remained
after 72–108 h, thus limiting the utility of this base due to
poor overall yield. Once conditions were identified that
promoted a product ratio in favor of either 4a or 5a, yields
were established by isolation and then the optimized condi-
Table 3
Results of O-arylation study with 3 using optimized conditionsa
Entry
1
Halide
Product
Yield 4b (%)
Yield 5b (%)
Overall yield (%)
84
4a, 5a
0
84
N
Cl
Me
2
3
4b, 5b
4c, 5c
0
0
17c
16
17
16
N
Cl
MeO
OMe
N
Cl
4
5
4d, 5d
4e, 5e
0
82
72
82
82
N
Cl
NC
10
N
Cl
Cl
6
7
4f, 5f
0
0
98
95
98
95
N
N
N
4g, 5g
Cl
Br
8
4h, 5h
0
84
84
N
Cl
a
Reagents and conditions: 0.50 g pyrazolone, 1.0 equiv halopyridine, 5 mol % CuCN, 11 mol % ethylenediamine, 1.4 equiv Cs2CO3, DMF, 110 °C, 48 h.
Isolated yields.
Heated for 72 h.
b
c

J. E. Golden et al. / Tetrahedron Letters 49 (2008) 794–798
797
2-chloropyridine gave only a marginal yield of 5a (41%,
single product after 48 h).
conditions were also developed to preferentially generate
the corresponding pyrazoles in good yield.12
With conditions in place that favored either product in a
controlled manner, the scope of each reaction was studied
mainly using 5-substituted, 2-halopyridines to ascertain
what effect electronic factors may have on the product
distribution. The conditions used to preferentially form
pyrazolone 4a were then applied to the substrates shown
in Table 2. The presence of a methyl or methoxy group
on the pyridine ring had little effect on the product ratio;
however, the introduction of an electron-withdrawing
group promoted the competitive substitution reaction such
that primarily the O-aryl product was formed (Table 2,
entry 5).
Acknowledgments
The authors thank Dr. Paul Schnier for acquiring exact
mass data for the compounds described herein. The
authors also wish to recognize Paul J. Reider for his sup-
port of the CR&D Amgen Student Internship Program
and this project. S.D.S. also thanks the National Physical
Science Consortium and Professor Jeff Johnson and his
group at the University of North Carolina for facilitating
her involvement in this program.
Having already determined experimentally in the preli-
minary screen that the use of iodopyridine predominately
led to the N-aryl pyrazolone regardless of what conditions
were used (Table 1, entries 5 and 6), 6-iodonicotinonitrile
was tested in an attempt to suppress pyrazole formation
(Table 2, entry 6). However, the bromo- and iodonicotino-
nitriles produced virtually identical results, indicating the
importance of the electronic nature of the substituent on
the prevalence of pyrazole formation. Use of 2-bromopyr-
azine (entry 8) likewise eroded the product ratio to nearly
1:1, presumably due to the inductively deactivating effect
of the second nitrogen in the ring. Surprisingly, 2-bromo-
quinoline10 showed good selectivity toward pyrazolone
formation despite the anticipated electron-withdrawing
effect of the conjugated fused ring system (entry 7).
Based on the results with 2-chloropyridine (Table 1), it
was expected that the analogous substituted 2-chloropyr-
idines would afford high yields of the corresponding pyr-
azoles. To test this idea, the conditions favoring O-aryl
product formation were then used with the substituted 2-
chloro heterocycles in Table 3. Experimentally, 2-chloro-
5-methylpyridine was found to be very unreactive, and a
substantial amount of starting material was recovered
unchanged (entry 2). In the case of entry 3, pyrazole 5c
was not stable to purification conditions, resulting in a
poor isolated yield; however, the 4-substituted methoxy
derivative delivered an acceptable yield of the expected pyr-
azole 5d. The presence of the strongly electron withdrawing
nitrile group (entry 5) only marginally affected the product
ratio such that a minor amount of pyrazolone product 4e
was formed; however, in all other cases only the expected
pyrazole was detected. Use of 2-chloroquinoline or 2-chloro-
pyrazine resulted in excellent yields of the correspond-
ing pyrazoles, and the 2-chloro-3-bromopyridine reacted
selectively at the 2-position in accordance with the pro-
posed mechanism.
Supplementary data
Summarized results from the preliminary screen of con-
ditions, experimental procedures, and full characterization
data for 4a–g and 5a–h are provided. Supplementary data
associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2007.11.185.
References and notes
1. (a) Burli, R. W.; Xu, H.; Zou, X.; Muller, K.; Golden, J.; Frohn, M.;
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Adlam, M.; Plant, M. H.; Wong, M.; McElvain, M.; Regal, K.;
Viswanadhan, V. N.; Tagari, P.; Hungate, R. Bioorg. Med. Chem.
Lett. 2006, 16, 3713–3718; (b) Banner, B.; Lester; B.; Joseph A.;
Fotouhi, N.; Gillespie, P.; Goodnow, R. A.; Hamilton, M. M.;
Haynes, N.-E.; Kowalczyk, A.; Mayweg, A.; Myers, M. P.; Pietra-
nico-Cole, S. L.; Scott, N. R.; Thakkar, K. C.; Tilley, J. W. U.S.
Patent Appl. 2,007,049,632, 2007; (c) Tripathy, R.; Ghose, A.; Singh,
J.; Bacon, E. R.; Angeles, T. S.; Yang, S. X.; Albom, M. S.; Aimone,
L. D.; Herman, J. L.; Mallamo, J. P. Bioorg. Med. Chem. Lett. 2007,
17, 1793–1798; (d) Balestra, M.; Bunting, H.; Chen, D.; Egle, I.;
Forst, J.; Frey, J.; Isaac, M.; Ma, F.; Nugiel, D.; Slassi, A.; Steelman,
G.; Sun, G.-R.; Sundar, B.; Ukkiramapandian, R.; Urbanek, R. A.;
Walsh, S. Patent Appl. WO 2006071730, 2006.
2. (a) Muller, A.; Kratzl, K.; Berger, K. P. Monatshe. Chem. 1958, 89,
23–35; (b) Hamper, B. C.; Kurtzweil, M. L.; Beck, J. P. J. Org. Chem.
1992, 57, 5680–5686.
3. Stabler, S. R.; Jahangir Synth. Commun. 1994, 24, 123–129.
4. More recently, an example of a Pd-catalyzed N-arylation of a
structurally related pyrazolidinone was reported Sibi, M. P.;
Manyem, S.; Palencia, H. J. Am. Chem. Soc. 2006, 128, 13660–13661.
5. Pyrazolone 3 was prepared according to a modified procedure. See
Supplementary data, and Ref. 2b.
6. For N-arylation of amides, see: (a) Klapars, A.; Antilla, J. C.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727–7729; (b)
Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421–7428. For N-arylation of acyl hydrazines, see: (c) Wolter, M.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803–3805.
7. The reaction of 2-chloropyridines with N-alkylated pyrazole deriva-
tives similar to 3 is known to afford the corresponding O-aryl
pyrazoles with CuI, DMF and heating at 100 °C. Importantly in this
example, only pyrazole O-aryl products can result, as the acyl ring
nitrogen is already alkylated; see: Morimoto, K.; Oonari, M.;
Furusawa, H.; Hatanaka, M.; Watanabe, J.; Kondo, Y.; Nawamaki,
T.; Ishikawa, K.; Shiojima, K.; Nakahira, K. Patent JP 07285962,
1995.
In conclusion, Cu-mediated coupling conditions have
been identified that promote the selective N-arylation of
a pyrazolone scaffold with 2-bromopyridines in reasonable
yields.11 We have demonstrated that a competing O-aryl-
ation pathway can be suppressed and that pyrazolone
product formation is sensitive to electronically deactivating
substituents on the heterocyclic bromide. Additionally,
8. Selwood, D. L.; Brummell, D. G.; Budworth, J.; Burtin, G. E.;
Campbell, R. O.; Chana, S. S.; Charles, I. G.; Fernandez, P. A.; Glen,
R. C.; Goggin, M. C.; Hobbs, A. J.; Kling, M. R.; Liu, Q.; Madge, D.

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J.; Millerais, S.; Powell, K. L.; Reynolds, K.; Spacey, G. D.; Stables,
J. N.; Tatlock, M. A.; Wheeler, K. A.; Wishart, G.; Woo, C.-K. J.
Med. Chem. 2001, 44, 78–93.
120.5, 117.8, 94.8, 36.5, 26.4, 21.7; EI-MS (M++H) m/z: calculated:
218.1, observed: 218.1; RT = 2.40; ESI-HRMS (M++H) m/z calcu-
lated: 218.1288, found: 218.1281.
9. Summarized results from the entire array of screened reactions can be
found in the Supplementary data.
12. Procedure for the O-arylation of 3: 2-(5-isopropyl-1-methyl-1H-
pyrazol-3-yloxy)pyridine, 5a: In a sealed tube was combined 3-
10. Schlosser, M.; Cottet, F. Eur. J. Org. Chem. 2002, 4181–4184.
11. Procedure for the N-arylation of 3: 3-isopropyl-2-methyl-1-(pyridin-
2-yl)-1,2-dihydropyrazol-5-one, 4a: In a sealed tube were combined
3-isopropyl-2-methyl-1,2-dihydropyrazol-5-one 3 (0.50 g, 3.6 mmol),
Cs2CO3 (1.63 g, 4.99 mmol), 1,10-phenanthroline (0.0707 g, 0.392
mmol), CuBr (0.026 g, 0.178 mmol), 2-bromopyridine (0.35 ml,
isopropyl-2-methyl-1,2-dihydropyrazol-5-one 3 (0.50 g, 3.6 mmol),
CuCN (0.016 g, 0.18 mmol), 2-chloropyridine (0.34 ml, 3.6 mmol),
Cs2CO3 (1.6 g, 5.0 mmol) and anhydrous DMF (7.5 mL). The vessel
was flushed with argon, sealed, and then ethylendiamine (0.026 ml,
0.39 mmol) was added via syringe through the sealed septum. The
reaction was heated for 48 h at 110 °C and then cooled to rt. LCMS
data were collected, and the reaction was concentrated under reduced
pressure to remove the solvent. At rt the solids were suspended in
EtOAc, adsorbed onto silica, and purified by flash chromato-
graphy (25–50% EtOAc/Hex) to afford 5a as a colorless oil (0.65 g,
84%). 1H NMR (300 MHz, chloroform-d) d ppm 8.16–8.27 (m, 1H)
7.58–7.73 (m, 1H) 6.90–7.06 (m, 2H) 5.81 (s, 1H) 3.74 (s, 3H) 2.81–
3.01 (m, 1H) 1.28 (d, J = 6.87 Hz, 6H); 13C NMR (75.5 MHz,
chloroform-d) d ppm 162.9, 156.7, 150.8, 147.6, 139.3, 118.7, 111.5,
91.9, 36.0, 25.9, 22.1; EI-MS (M++H) m/z: calculated: 218.1,
observed: 218.1; RT = 2.85; ESI-HRMS (M++Na) m/z calculated:
240.1107, found: 240.1102.
i
3.57 mmol) and PrOH (7.5 mL). The vessel was flushed with argon,
sealed, and heated for 48 h at 110 °C. After cooling to rt, LCMS data
were collected, and the reaction was concentrated under reduced
pressure to remove the solvent. At rt, the solids were suspended in
EtOAc, adsorbed onto silica, and purified by flash chromatography
(25%- 60% EtOAc/Hex) to afford 4a as a white solid (0.56 g, 72%) and
5a as a colorless oil (0.055 g, 7% yield). Data for 4a: 1H NMR
(400 MHz, chloroform-d) d ppm 8.44–8.52 (m, 1H), 7.91–7.98 (m,
1H), 7.76–7.84 (m, 1H), 7.10–7.17 (m, 1H), 5.36 (s, 1H), 3.27–3.42 (s,
3H), 2.74–2.91 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H); 13C NMR
(100.6 MHz, chloroform-d) d ppm 168.4, 166.3, 148.6, 148.1, 138.0,