Pd-catalyzed Negishi coupling of pyrazole triflates with alkyl zinc halides

Article abstract of DOI:10.1016/j.tetlet.2010.11.037

A mild, functional group tolerant palladium-catalyzed Negishi coupling of pyrazole triflates and nonaflates with alkyl, benzyl, and aryl zinc halides has been developed. It allows quick access to 3-substituted pyrazole analogs at late stage via common syn

Full text of DOI:10.1016/j.tetlet.2010.11.037

Tetrahedron Letters 52 (2011) 311–313
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Tetrahedron Letters
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Pd-catalyzed Negishi coupling of pyrazole triflates with alkyl zinc halides
Ting Zhang a, , Xiaodi Gao b, Harold B. Wood a
⇑
a Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
b Merck Summer Research Intern, University of Michigan, Ann Arbor, MI, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, functional group tolerant palladium-catalyzed Negishi coupling of pyrazole triflates and nona-
flates with alkyl, benzyl, and aryl zinc halides has been developed. It allows quick access to 3-substituted
pyrazole analogs at late stage via common synthetic intermediates.
Received 7 October 2010
Revised 4 November 2010
Accepted 8 November 2010
Available online 29 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Negishi coupling
Cross-coupling
Palladium catalysis
Pyrazole triflates
Organozinc reagents
Analog synthesis
1. Introduction
theless, there have been several recent reports on sp2–sp2, sp2–sp,
and benzylic sp2–sp3 cross-coupling reactions of pyrazole triflates.5
3-Substituted aryl pyrazoles are important structural motifs in
drug discovery. Traditionally, they are synthesized via condensa-
tion between prefunctionalized dicarbonyl compounds and aryl
hydrazines.1 Although reliable, such methods often generate
regioisomers and require custom synthesis of each different dicar-
bonyl compound at an earlier stage, which hampers the quick ac-
cess to a library of analogs via a common intermediate (Eq. 1). In
order to circumvent such drawbacks, we envisioned a late stage
Negishi coupling2 at the 3-position of a common pyrazole interme-
diate by only varying the commercially available organozinc part-
ner (Eq. 2).
However, a mild and reliable method for sp2–sp3 cross-coupling
reaction between pyrazole triflates and simple alkyl metal species
remains a challenge, particularly when b-hydride elimination is
a concern.5 Herein we report our success in accomplishing an
sp2–sp3 Negishi coupling reaction between pyrazole triflates and
organozinc reagents.
The investigation began with first optimizing the Pd source and
ligand (Table 1). The reactions were generally performed in THF as
Table 1
Catalyst screeninga
ð1Þ
Entry
Pd source
Ligand
Yieldb (%)
ð2Þ
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd2(dba)3
PdCl2
[Pd(allyl)Cl]2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
dppf
dppf
dppf
dppf
XPhos
RuPhos
SPhos
PCy3
94
58
49
20
99
87
80
0
Coupling reactions of halopyrazoles have been previously re-
ported in the literature,3 however their formation requires extre-
mely harsh conditions, (i.e., refluxing pyrazolone in POCl3 or
POBr3). Pyrazole triflates, on the other hand, are much easier to ac-
cess from pyrazolones. However, compared to pyrazole halides,
coupling reactions with pyrazole triflates have been much more
problematic, in part due to their propensity to hydrolyze.4 None-
PtBu3
0
a
Reaction conditions: 10 mol % Pd, 20 mol % ligand, 3 equiv BrZn(CH2)3CO2Et,
THF 0.1 M substrate), 50 °C, overnight.
b
Yields were determined by 1H NMR spectroscopy with 1 equiv 1,3,5-trime-
⇑
Corresponding author. Tel.: +1 732 594 3031; fax: +1 732 594 2840.
E-mail address: ting_zhang3@merck.com (T. Zhang).
thoxybenzene as internal standard.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.037

312
T. Zhang et al. / Tetrahedron Letters 52 (2011) 311–313
Table 3
the commercial zinc reagents are supplied as THF solutions. When
the ligand was held constant as dppf, Pd(OAc)2 gave the best con-
version compared to Pd2(dba)3, PdCl2 and [Pd(allyl)Cl]2 (entries
1–4) and thus was chosen as the Pd source for the reaction. Next,
ligand optimization was performed. XPhos was found to give a
near quantitative conversion (entry 5), whereas dppf, RuPhos, and
SPhos were also active but with a lower yield (entries 1, 6 and
7). Electron rich bulky phosphine ligands such as PCy3 and PtBu3
were ineffective (entries 8 and 9).6 It was also found that using
an excess amount of zinc reagent (3 equiv) and heating at 50 °C
overnight resulted in full consumption of the pyrazole triflate.
Table 2 summarizes the scope of the optimized Negishi cou-
pling between 1-phenyl pyrazole 3-triflates and commercial
organozinc halides. The chloro-substituted pyrazole 1b gave a low-
er yield of the desired product due to overreaction between the al-
kyl zinc bromide and the heteroaryl chloride (entry 2).
Functionalized primary alkyl zinc bromides generally afforded
good to excellent yields. It was found that ester, chloride, alkyne,
and acetal functional groups were all tolerated (entries 1 and 3–5).
Secondary and tertiary alkyl zinc bromides showed lower reac-
tivity toward the Negishi coupling reaction when paired with tri-
flate (entries 6 and 8). Knochel and Rottlander demonstrated that
compared to aryl triflates, aryl nonaflates have better stability,
Catalyst loadinga
Entry
Substrate (mmol)
Pd (mol %)
Ligand (mol %)
Yieldb (%)
1
2
3
0.342
0.684
1.369
10
5
2.5
20
10
5
80
92
96
a
Reaction conditions: 1 ꢀ mol % Pd, 2ꢀ mol % ligand, 3 equiv Zn reagent, THF
0.1 M substrate), 50 °C, overnight.
b
Isolated yield.
higher reactivity, and faster reaction time.7 Therefore these can
serve as nice alternatives to aryl triflates in cross-coupling reac-
tions. We therefore examined the reactions using pyrazole nona-
flate 1c in the two cases where pyrazole triflate 1a gave low
yields (entries 7 and 9). Indeed, both yields were improved quite
significantly (entry 7 vs entry 6, entry 9 vs entry 8); albeit the reac-
tivity of a tertiary alkyl zinc bromide was still moderate.
Delighted with the results of alkyl zinc halides, we extended our
methodology to benzyl zinc halides (entries 10 and 11). Gratify-
ingly, both electron rich and electron poor benzyl zinc chlorides re-
acted equally well.
While the primary focus was the more challenging sp2–sp3 cou-
pling reactions, we would like to demonstrate that our method is
also applicable in sp2–sp2 coupling reactions. Two representative
reactions between pyrazole triflate 1a and aryl zinc bromides were
examined which afforded satisfying results (entries 12 and 13).
Hence, we have broadened our reaction scope to both sp2–sp3
and sp2–sp2 coupling reactions.
Due to the relative small reaction scales, 10 mol % catalyst load-
ing was used in all cases. However, ideally we would like to reduce
the catalyst loading as the scale of the reaction increases. A scale-
dependant catalyst-loading investigation was carried out and the
results are summarized in Table 3. Each time we doubled the sub-
strate loading, we reduced the catalyst loading by half. To our de-
light, not only was the reactivity of the catalyst maintained, the
isolated yields of the reaction improved as the reaction scale in-
creased, presumably due to reduced material loss during workup
and purification.
Table 2
Substrate scopea
Entry
1
Substrate
Zn reagent
Product
Yieldb (%)
82 (99)
2a
1a
2
2b
59
1b
1a
1a
3
4
2c
67
2d
100
In conclusion, we have successfully developed a mild and ro-
bust sp2–sp3 Negishi coupling reaction between pyrazole triflates
and alkyl zinc halides to form 3-substituted pyrazoles with good
to excellent yields. The reaction is highly functional group tolerant
and easy to perform, offering quick access to a library of analogs by
late stage modification of a common intermediate. In addition, pyr-
azole nonaflates can serve as a nice alternative to pyrazole triflates
when using less reactive zinc reagents. Finally, we demonstrated
the coupling conditions are also applicable to benzyl and aryl zinc
halides with a wide range of electronic variations.
5
6
1a
1a
2e
2f
67c
55
7
2f
75
1c
1a
8
9
2g
2g
10
26
1c
1a
2. Experimental section
10
11
2h
2i
100
100
2.1. General procedure for the alkylation of pyrazole triflates:8
synthesis of 2a
1a
An 8 mL dram vial with a septum was charged with Pd(OAc)2
(7.7 mg, 0.034 mmol) and XPhos (33 mg, 0.068 mmol), then evacu-
ated and refilled with nitrogen three times. THF (0.5 mL) was
added and the mixture was stirred at room temperature for
15 min. To this mixture a solution of pyrazole triflate 1a (100 mg,
0.342 mmol) in THF (0.342 mL) and 4-ethoxy-4-oxobutyl zinc bro-
mide (0.5 M in THF, 2.05 mL) was added sequentially through the
septum.9 The vial was then capped under nitrogen and stirred
12
13
1a
1a
2j
80
2k
100
a
Reaction conditions: 10% Pd, 20% ligand, 3 equiv Zn reagent, THF 0.1 M sub-
strate), 50 °C, overnight.
Isolated yield (yield in parenthesis was determined by 1H NMR spectroscopy).
b
Trace amount of aldehyde product was observed in 1H NMR spectroscopy.
c

T. Zhang et al. / Tetrahedron Letters 52 (2011) 311–313
313
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overnight at 50 °C. The reaction was quenched with 1 N HCl
(0.5 mL) and back extracted with DCM. The combined organic lay-
ers were dried over MgSO4, filtered, and concentrated. Purification
by ISCO CombiFlash (4 g silica gel column, 0–30% ethyl acetate in
hexanes gradient) yielded 71 mg (80%) 2a as a colorless oil. 1H
NMR (500 Hz): d 7.82 (d, J = 2.4 Hz, 1H), 7.65 (m, 2H), 7.43 (m,
2H), 7.25 (m, 1H), 6.28 (d, J = 2.4 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H),
2.77 (t, J = 7.5 Hz, 2H), 2.41 (t, J = 7.6 Hz, 2H), 2.05 (quintet,
J = 7.6 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (125 Hz): d 173.5,
154.0, 140.2, 129.4, 127.3, 126.0, 118.9, 106.6, 60.3, 33.8, 27.7,
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Acknowledgments
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We are grateful to the Merck Future Talent Program. We also
would like to thank Drs. Ronald M. Kim, Qiang Tan and Shane W.
Krska (Merck) for helpful discussions, as well as Drs. Joie Garfunkle
and Alan Whitehead (Merck) for proofreading the manuscript.
4. Bourrain, S.; Ridgill, M.; Collins, I. Synlett 2004, 795.
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References and notes
8. Pyrazole triflate 1a and nonaflate 1c were synthesized in two-steps via literature
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Mueller, B.; Oberdorf, K.; EP Patent 680954A2, 1995. (b) Laggner, C.; Cuberes-
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Terreni, S.; Tonelli, F. WO Patent 2009130232, 2009. Formation of pyrazole
triflates: Castro Pineiro, J. L.; Collins, I. J.; Harrison, T. U.S. Patent 2005143369,
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Synlett 2004, 795.
1. (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley: UK, 2009. pp 494;
Alternatively, 3-substituted pyrazoles can be accessed via ortho-lithiation–
alkylation methods from unsubstituted pyrazoles, see: (b) Diez-Barra, E.; de la
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Am. Chem. Soc. 2004, 126, 13028; (b) Sase, S.; Jaric, M.; Metzger, A.; Malakhov, V.;
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9. All organozinc reagents were purchased from Rieke Metals as 0.5 M solutions in
THF.