Streamlined synthesis of the bippyphos family of ligands and cross-coupling applications

Article abstract of DOI:10.1021/op7002858

We describe the efficient preparation of Bippyphos, 1. The key precursor to Bippyphos, 5, was prepared via a one-pot bromination of diketone 2 followed by alkylation with pyrazole and condensation with phenylhydrazine. Lithiation of 5 and trapping with ditert-butylchlorophosphine afforded Bippyphos, 1. Using this approach we have prepared several derivatives of Bippyphos to probe the structure and activity relationships of this family of phosphine ligands. We also demonstrate the utility of these ligands in Pdcatalyzed amination reactions and other cross-coupling reactions.

Full text of DOI:10.1021/op7002858

Organic Process Research & Development 2008, 12, 480–489
Streamlined Synthesis of the Bippyphos Family of Ligands and Cross-Coupling
Applications
Gregory J. Withbroe, Robert A. Singer,* and Janice E. Sieser
Chemical Research and DeVelopment, Pfizer Global Research and DeVelopment, Groton Labs, Eastern Point Road,
Groton, Connecticut 06340, U.S.A.
Abstract:
Results and Discussion
A number of the steps in the synthesis of 1 (shown in
Scheme 1) appeared amenable to sequential processing without
isolation which we thought would alleviate the issue of unstable
isolated process intermediates leading up to the preparation of
5. Moreover, designing a one-pot process would also increase
the efficiency of material throughput and ultimately lower the
cost to prepare 1. Toward this end we evaluated the bromination
and subsequent alkylation in N-methyl-2-pyrrolidinone (NMP)
(Scheme 2). For the bromination, we studied a variety of
brominating reagents including bromine, pyridinium tribromide,
and N-bromosuccinimide. Using a slight excess (1.2 equiv) of
any of these reagents successfully pushed the bromination to
completion in NMP. The addition of bromine was exothermic
at the start of the reaction when preparing 3 and led to side
products if the rate of addition and temperature were not
controlled carefully. Once the bromination was complete,
pyrazole (3.5 equiv) was added to the solution to effect the
alkylation. The alkylation proceeded smoothly, although slowly
under ambient conditions as originally reported.5 We have now
found that heating to 40–50 °C enables the alkylation to reach
completion within 6-12 h.6 Once the alkylation to afford 4
was complete, acetic acid was added followed by a solution of
phenylhydrazine in methanol. Heating the reaction to about 40
°C allowed the condensation to reach completion within 10-16
h. After several hours, the product (5) began to precipitate from
the reaction mixture as a yellow suspension. Once the conden-
sation was complete, the reaction mixture was diluted with water
and stirred under ambient conditions. The crude product was
filtered and isolated as an NMP solvate. Washing the filtercake
with water helped remove excess NMP, while washing with
heptane significantly removed color. The crude bipyrazole 5,
was recrystallized by heating in toluene to achieve dissolution
of 5 and then adding heptane to promote crystal formation. The
recrystallization removed the NMP and produced crystals with
a low bulk density that were pure by NMR. The product was
typically isolated in 70-85% yield from this one-pot process
after the recrystallization. The lithiation of 5 was carried out
with n-butyllithium as reported in our prior communication.2a
For our kilo laboratory campaign at Pfizer we had conducted
the lithiation at -10 to -15 °C to enable use of conventional
glass-lined vessels. One important detail is that the trapping of
We describe the efficient preparation of Bippyphos, 1. The key
precursor to Bippyphos, 5, was prepared via a one-pot bromination
of diketone 2 followed by alkylation with pyrazole and condensa-
tion with phenylhydrazine. Lithiation of 5 and trapping with di-
tert-butylchlorophosphine afforded Bippyphos, 1. Using this ap-
proach we have prepared several derivatives of Bippyphos to probe
the structure and activity relationships of this family of phosphine
ligands. We also demonstrate the utility of these ligands in Pd-
catalyzed amination reactions and other cross-coupling reactions.
Introduction
Pd-catalyzed cross-couplings have found widespread utility
in industry.1 During our efforts to develop a Pd-catalyzed
amination reaction for a late-stage drug candidate intended for
the treatment of atherosclerosis, we embarked on development
of our own nonproprietary phosphine ligands. We have previ-
ously disclosed some of our advancements in this area, though
most notable is our work describing the utility of Bippyphos,
1.2 Bippyphos has been prepared by the four-step process shown
below (Scheme 1). Originally we used this route to prepare over
4 kg of 1 to enable development work at Pfizer with this ligand.3
While this route to 1 enables isolation of each intermediate, it
suffers from the overall length of the synthesis and from stability
issues with some of the process intermediates. In particular we
recognized that intermediate 4 could readily degrade under
alkaline or neutral conditions. Degradation was even observed
during storage of intermediate 4, further leading to concerns
around isolation of this intermediate. In addition, we recognized
that intermediate 3 was susceptible to debromination by
reducing agents.4 These observations prompted us to rethink
our original process route to 1 and to consider an approach that
would better enable the preparation of this family of ligands
for closer examination.
* Corresponding author. E-mail: robert.a.singer@pfizer.com.
(1) (a) Tsuji, J. Synthesis 1990, 739. (b) Buchwald, S. L.; Mauger, C.;
Mignani, G.; Scholz, U. AdV. Synth. Catal. 2006, 348, 23. (c) Farina,
V. AdV. Synth. Catal. 2004, 346, 1553. (d) Schlummer, B.; Scholz,
U. AdV. Synth. Catal. 2004, 346, 1599.
(2) (a) Singer, R. A.; Doré, M.; Sieser, J. E.; Berliner, M. A Tetrahedron
Lett. 2006, 47, 3727. (b) Singer, R. A.; Tom, N. J.; Frost, H. N.; Simon,
W. M. Tetrahedron Lett. 2004, 45, 4715. (c) Singer, R. A.; Caron, S.;
McDermott, R. E.; Arpin, P.; Do, N. M. Synthesis 2003, 1727.
(3) Bippyphos is commercially available through Digital Specialty
Chemicals or Sigma-Aldrich (catalogue number 676632).
(4) During our original work we found that quenching the bromination
with a reducing agent such as sodium thiosulfate led to debromination
of 3, converting the material back to 2. To avoid this problem, the
product, 3, was precipitated from solution prior to quenching with
the reducing agent.
(5) The alkylation requires 48 h to reach completion if carried out at room
temperature.
(6) We have even carried out the pyrazole alkylation of 3 at 55 °C without
issue. At 55 °C the alkylation to afford 4 is complete within 3–5 h.
Continued heating of the alkylation at 50–55 °C over 24 h only led to
low levels of side products (1–2%).
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Vol. 12, No. 3, 2008 / Organic Process Research & Development
10.1021/op7002858 CCC: $40.75
2008 American Chemical Society
Published on Web 03/20/2008

Scheme 1
Scheme 2
the chlorophosphine is highly exothermic and requires a slow
addition to maintain the temperature in range and to avoid side
products.
Scheme 3
During the condensation for the formation of 5, it was
important to add the acetic acid prior to the phenylhydrazine
to minimize side products that arise. Stability studies on 4
showed that addition of the acetic acid to maintain acidic
conditions helped to avoid decomposition to 2 or 6. It was also
recognized that 4 is stable to the acidic alkylation reaction
conditions under which it is produced (only buffered with excess
pyrazole), but once the phenylhydrazine is added, the retroaldol
side reaction or cleavage of pyrazole becomes more problem-
atic.7 Even the storage of 4 as a solid under ambient conditions
was found to lead to decomposition to 2 and 6!
Optimization of Pd-Catalyzed Amination
Having demonstrated a more efficient means of preparing
our family of ligands, we next sought to optimize the conditions
for use of Bippyphos in the Pd-catalyzed amination reaction.
Frequently we encounter heterocyclic substrates such as chlo-
ropyridines in our development work at Pfizer8 and require
optimization of reactions for this problematic substrate class.9
Secondary acyclic amines tend to be relatively more problematic
in the Pd-catalyzed amination reactions due to the greater
(7) We suspect that the retroaldol side reaction is suppressed under acidic
conditions due to the greater ease to protonate the tetrahedral
intermediate and to lose water in the condensation.
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481

Table 1. Screen of various bases for the coupling of 7 and 8
Table 2. Screen of various solvents
conversion
side product, 10
base used
(1.5 equiv)
conversion
conversion
b
at 16 h (%)a,c
(%)
entry
at 1 h (%)a,c
at 16 h (%)a,c
entry
solvent
toluene
dioxane
1
2
3
4
5
6
7
8
14
25
22
100
100
100
100
60
ND
1
2
3
4
5
6
7
8
KOH (88% pellets)
NaOH (99% pellets)
Cs2CO3
88
33
1
100
73
ND
THF or 2-Me-THF
tert-amyl alcohol
MeOH
20:1 THF/MeOH
sec-butanol
ND
29
ND
K2CO3
NaOtBu
0
0
42 (R ) Me)
14 (R ) Me)
22 (R ) sec-Bu)
ND
70
55
74
47
96
NaOH (5% water)b
NaOH (15% water)b
NaOH (33% water)b
90
100
100
NMP
a Reaction conditions: used 1.0 equiv 2-chloropyridine, 1.25 equiv N-benzylmethyl-
a Reaction conditions: used 1.0 equiv 2-chloropyridine, 1.25 equiv N-benzylmethyl-
amine, 1.5 equiv base, 0.005 equiv Pd2(dba)3, 0.02 equiv Bippyphos in tert-amyl
alcohol (1.25 M with respect to 2-chloropyridine) at reflux. b Amount of water is
by weight % based on total weight of base used. c GC measured conversion based
on integration of product relative to starting material.
amine, 1.5 equiv KOH, 0.005 equiv Pd2(dba)3, 0.02 equiv Bippyphos at reflux.
b Solvent concentration was 1.25
M
with respect to 2-chloropyridine. c GC
measured conversion based on integration of all products relative to starting
material.
propensity for ꢀ-hydride elimination.10 For this reason, we
elected to use 2-chloropyridine and N-benzylmethylamine (8)
in our trials.
using more water is that the reactions can remain homogeneous,
whereas in the absence of added water, the reactions become
heterogeneous from the generation of salt byproduct.
After demonstrating that hydroxide salts provided optimal
catalyst performance, solvents were evaluated. The higher
catalytic efficiency with alcohol solvents was consistent across
all substrate classes screened. Part of the reason for the increased
reactivity is likely to be the superior solubility of KOH in
alcohol over nonpolar solvents. The coupling between 4-bromo-
tert-butylbenzene and 8 showed almost no product formation
in toluene during the first hour, while the reaction was usually
complete in tert-amyl alcohol during this time. This reactivity
pattern was also observed with other amines such as 2,6-
dimethylaniline and phenethylamine in couplings with 4-bromo-
tert-butylbenzene. In couplings between pyridyl halides and
amines, this reactivity pattern also held (Table 2). For the
coupling between 2-chloropyridine (7) and N-benzylmethy-
lamine (8), nonpolar solvents such as toluene (Table 2, entry
1) or dioxane were inferior to alcohols, with tert-amyl alcohol
providing the cleanest purity profile (Table 2, entry 4). The more
polar alcohol solvents possessed the highest catalyst activity
but with some liabilities. Methanol appeared to be the best
solvent for reactivity, but it was observed that methanol would
couple with activated substrates, affording the methyl ether
adduct as a side product! In the case of 2-chloropyridine
coupling with N-benzylmethylamine, nearly a 1:1 ratio of
product to methyl ether side product was observed, but for
3-chloropyridine (a less activated substrate) only about 2% of
the methyl ether side product was observed. Using primary or
secondary alcohols also led to coupling and reduction side
products, with less hindered alcohols favoring coupling the most.
For these reasons tert-amyl alcohol remains as the ideal solvent
since side reactions are avoided,14 but in selected substrates
(electron-neutral systems) methanol could be a viable alternative.
Using water as a cosolvent with tert-amyl alcohol did not
We found that we could make minor adjustments to our
previously reported protocol to improve the success of couplings
with pyridyl halides. Simply raising the reaction temperature
from 80 to 90 °C to a reflux in tert-amyl alcohol (100–103 °C)
helped drive reactions further. The source of Pd did not appear
to impact performance of the Pd-catalyzed amination reactions
as Pd2(dba)3 and Pd(OAc)2 could be used interchangeably. We
reexamined bases while using tert-amyl alcohol as solvent and
confirmed that KOH pellets (88% assay)11 are ideal for the
process (Table 1, entry 1) as had been suggested previously in
the literature.12 As seen in Table 1, NaOH could perform equally
as well as KOH, but a small amount of water was required. In
addition, some water could be added to the process (up to 3%
based on the weight of the KOH charge); however, additional
water eventually led to a slower reaction, but still led to
complete conversion. The extent of inhibition by water does
eventually level out, and the process can be conducted as a
biphase in water and tert-amyl alcohol but requires longer
reaction times than if water is excluded.13 The advantage of
(8) (a) Pd-catalyzed amination reactions with pyridyl halides have been
previously reported, see: Shen, Q.; Shekhar, S.; Stambuli, J. P.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2005, 44, 1371. (b) Yin, J.;
Zhao, M. M.; Huffman, M. A.; McNamara, J. N Org. Lett. 2002, 4,
3481. (c) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald,
S. L J. Org. Chem. 2000, 65, 1158. (d) Wagaw, S.; Buchwald, S. L.
J. Org. Chem. 1996, 61, 7240.
(9) It has been shown that pyridyl substrates can displace phosphine
ligands on Pd, see: Paul, F.; Patt, J.; Hartwig, J. F. Organometallics
1995, 14, 3030.
(10) (a) Secondary acyclic amines have been shown to be more problematic
substrates, see: Wolfe, J. P.; Wagaw, S.; Buchwald, S. L J. Am. Chem.
Soc. 1996, 118, 7215. (b) Driver, M. S.; Hartwig, J. F. J. Am. Chem.
Soc. 1996, 118, 7217.
(11) The KOH pellets were used as supplied, without being ground to a
powder. Grinding of the pellets was found to potentially lead to inferior
performance, perhaps due to the ground pellets picking up water more
readily.
(12) (a) Potassium hydroxide has been previously established as one of
the most efficient bases for the Pd-catalyzed amination reaction, see:
Kuwano, R.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2002, 67,
6479. (b) Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org.
Chem. 2001, 66, 7729. (c) Huang, X.; Anderson, K. W.; Zim, D.;
Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
6653.
(13) The water was degassed with nitrogen to avoid oxidation of the
catalyst. Water is more effective at retaining dissolved oxygen than
organic solvents.
(14) Superior performance with tertiary alcohols as solvent or cosolvent
has been reported in Pd-catalyzed amination reactions, see: (a)
Reference 2c. (b) Huang, X.; Anderson, K.; Zim, D.; Jiang, L.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
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Table 3. Couplings of various amines and chloropyridines
blocks to better understand structure and activity relationships. In
general, substitution of the alkyl groups on phosphine appeared to
have the largest impact on performance. Exchanging tert-butyl
groups for cyclohexyl on the phosphine led to poorer performance
for couplings of primary amines (Table 4, entries 8 and 10). On
the other hand, secondary amines and anilines performed well with
the less hindered dicyclohexylphosphine derivative 11.17 Increasing
the steric environment further by substituting a tert-butyl group
for one of the two phenyls on the pyrazole moiety (ligand 12) led
to no substantial improvement in couplings with primary amines
(Table 4, entry 9).18 Attenuating the electron-donating ability of
the phosphine by exchanging the two alkyl groups for phenyl
groups (ligand 15) led to a relatively ineffective catalyst (Table 4,
entries 12 and 17).
catalyzed by Bippyphosa
Introducing a methoxy group on the distal phenyl group of
the pyrazole (through substitution on the phenylhydrazine
fragment) led to no discernible change in performance from
Bippyphos.19 This study suggests that substrates can be matched
with ligands based on the severity of the steric effects. Ideally,
the least hindered primary amines perform best with ligands 1,
12 or 14, while bulkier secondary amines perform better with
ligand 11. A clear diagonistic for the efficiency of the primary
amine couplings is the ratio of the desired mono-arylated adduct
to the bis-arylated adduct.
a Reaction conditions: used 1.0 equiv aryl halide, 1.25 equiv amine, 1.5 equiv
KOH, 0.005 equiv Pd2(dba)3, 0.02 equiv Bippyphos at reflux in tert-amyl alcohol
(1 M with respect to aryl halide) over 4 h. b Isolated yield.
typically lead to hydroxy-substituted side products in the manner
that alcohols would undergo coupling except in some cases
when attempting to couple secondary amines with highly
activated aryl halides.15 For electron-rich aryl halides, reduction
side products are more pronounced due to the slower reductive
elimination step which enables competitive ꢀ-hydride
elimination.16For example, when coupling 2-chloroanisole with
N-benzylmethylamine in methanol at a reflux, a 2:1 ratio of product
to reduction side product was observed. Reactions with NMP were
considerably slower than with alcohol solvents due to competitive
binding of the amide solvent blocking entry of the substrates to
the catalyst. Blending small amounts of NMP with tert-amyl
alcohol did not lead to noticeable inhibition and could be necessary
for dissolution of highly crystalline substrates. We demonstrated
that 2-chloropyridine and 3-chloropyridine could participate in the
Pd-catalyzed amination reaction with a standard set of amine
coupling partners. These results are shown in Table 3.
The less hindered ligands (11 and 13) have a relatively low
branching ratio, while the most hindered ligands (1, 12 and 14)
tend to suppress the bis-arylation, especially ligand 14. In
contrast, the coupling between N-benzylmethylamine and
2-bromo-6-methoxypyridine gave almost exclusively the desired
product using the less hindered dicyclohexylphosphines (Table
4, entries 14 and 16), while the di-tert-butylphosphine ligands
afforded a small percentage of the hydroxyl adduct as a side
product (Table 4, entries 13 and 15).
Preparation and Evaluation of Related Bipyrazole-Phosphine
Ligands
We wanted to exploit the modular synthesis of Bippyphos and
prepare analogues through substitution on the various building
(17) The diisopropylphosphine analogue of 11 was also prepared in a related
manner as described in the Experimental Section by lithiation with
n-BuLi and trapping with i-Pr2PCl. The diisopropylphosphine ligand
performed identically to the dicyclohexyl ligand 11. This diisopro-
pylphosphine ligand was highly crystalline as was 11 and conveniently
crystallized from isopropanol for isolation purposes.
(15) While 2-chloropyridine could undergo substitution with hydroxide,
this was not necessarily only Pd-catalyzed. Simply heating 2-chloro-
pyridine with a hydroxide salt enables nucleophilic aromatic substitu-
tion to occur as a side reaction. Use of LHMDS as a base in THF can
avoid this side reaction. To limit the Pd-catalyzed side reaction of
hydroxyl substitution, use of a less hindered ligand, such as 11, is
appropriate in couplings with secondary amines.
(18) We had attempted to prepare the di-tert-butylpyrazole analogue of
Bippyphos but found that the substrate (shown below)
(16) Hartwig, J. F.; Richards, S.; Barañano, D.; Paul, F. J. Am. Chem. Soc.
1996, 118, 3626.
did not easily undergo lithiation to introduce the phosphine.
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reductive elimination,16 and so we decided that couplings with
2-chloroanisole could serve as a valuable benchmark. For
couplings between 2-chloroanisole and amines other than 8 that
are not as prone to ꢀ-hydride elimination, ligand 11 performed
at least as well as Bippyphos (1) and in some cases appeared
to be superior (Table 5, entries 2 and 10). While primary amines
often have the liability of bis-arylation with less hindered ligands
such as 11, when coupling phenethylamine with 2-chloroanisole
(Table 5, entries 5 and 6) bis-arylated side products were not
observed, presumably due to the attenuated reactivity from the
electron-rich nature of 2-chloroanisole.
Table 4. Pd-catalyzed aminations with
2-bromo-6-methoxypyridine
We encountered a number of classes of substrates that did
not perform well with Bippyphos. While unhindered cyclic
secondary amines such as morpholine readily couple with aryl
halides, we found that the more sterically hindered cis-2,6-
dimethylpiperidine did not couple with either 2-chloroanisole
nor with the more reactive 2-bromo-6-methoxypyridine. We
also attempted couplings between amides and aryl halides which
typically gave only trace product.20 For example, the coupling
between benzamide or 2-pyrrolidinone with 4-bromo-tert-
butylbenzene only afforded about 2% product. Attempting these
amide couplings with 2-chloropyridine led to slight improve-
ment, but conversions of only about 10% was realized. Not
only did amides generally fail to couple, but other non-
nucleophilic heterocyclic amines failed to couple as well.
Heterocyclic amines such as pyrazole, imidazole and indole did
not produce any product with 4-bromo-tert-butylbenzene, nor
with electron-deficient aryl halides such as 4-chlorobenzotrif-
luoride. Only in the case of 2,6-dibromopyridine did pyrazole
couple to afford the desired product.
a Reaction conditions: used 1.0 equiv aryl halide, 1.2 equiv amine, 1.5 equiv
KOH, 0.005 equiv Pd(OAc)2, 0.02 equiv Bippyphos at reflux in tert-amyl alcohol
(1 M with respect to aryl halide) over 6 h. b Amount of desired product determined
by GC relative to side productes and starting material.
Table 5. Pd-catalyzed aminations with 2-chloroanisole using
various bipyrazole phosphine ligands
Ether Couplings
In an effort to better assess the side reactions with alcohols
and to potentially take advantage of this reaction as an intended
coupling, the scope of couplings between aryl halides and
alcohols was briefly examined. Coupling alcohols with aryl
halides is generally plagued with reduction side products due
to the ease of ꢀ-hydride elimination.21 Consequently, diaryl
ethers are formed much more readily by cross-coupling
methodology since they are not susceptible to ꢀ-hydride
elimination.22 In fact, bromo-tert-butylbenzene coupled cleanly
(19) We prepared methoxy-substituted derivatives of Bippyphos and
observed no change in reactivity. The methoxy derivatives did tend
to be more crystalline which could aid isolation. The structures are
shown below:
a Reaction conditions: used 1.0 equiv aryl halide, 1.2 equiv amine, 1.5 equiv
KOH, 0.01 equiv Pd(OAC)2, 0.02 equiv Bippyphos at reflux in tert-amyl alcohol
(1 M with respect to aryl halide) over 6 h. b Amount of desired product determined
by GC relative to side products and starting material.
.
(20) The Buchwald group has successfully designed phosphine ligands to
more generally catalyze couplings between aryl halides and amides
and other non-nucleophilic amines, see: Anderson, K. W.; Tundel,
R. E.; Ikawa, T.; Altman, R. A.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2006, 45, 6523–6527.
While ligand 11 outperformed Bippyphos for coupling
substrate 8 with an electron-deficient aryl halide (2-bromo-6-
methoxypryidine), we found that Bippyphos was more effective
at suppressing ꢀ-hydride elimination when attempting to couple
8 with an electron-rich aryl halide such as 2-chloroanisole (Table
5, entries 7 and 8). Generally, reactions with electron-rich aryl
halides are more prone to ꢀ-hydride elimination due to slower
(21) (a) Vorogushin, A. V.; Huang, X.; Buchwald, S. L J. Am. Chem. Soc.
2005, 127, 8146. (b) Torraca, K. E.; Huang, X.; Parrish, C. A.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 10770.
(22) For a recent review on diaryl ether cross-coupling methodology, see:
Frlan, R.; Kikelj, D. Synthesis 2006, 2271.
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Table 6. Pd-catalyzed couplings with aryl halides and
alcohols using Bippyphos (1)
Table 7. Pd-catalyzed Suzuki-Miyaura couplings
a Reaction conditions: used 1.0 equiv aryl halide, 1.5 equiv KOH, 0.005 equiv
Pd2(dba)3, 0.02 equiv Bippyphos at reflux in alcohol (1 M with respect to aryl
halide) over 3 h. b Amount of desired product determined by GC relative to side
products and starting material.
a Reaction conditions: used 1.0 equiv aryl halide, 1.2 equiv aryl boronic acid,
1.5 equiv K2CO3, 0.01 equiv Pd(OAc)2, 0.02 equiv ligand at reflux in tert-amyl
alcohol (1 M with respect to aryl halide) over 3 h. b Amount of desired product
determined by GC relative to side products and starting material. c Used 1.5 equiv
KOH in place of K2CO3.
with 1-napthol, p-cresol, and o-cresol when using Bippyphos
without any evidence of reduction products as expected.23
During our examination of alcohol couplings, electron-deficient
aryl halides such as 2-chloropyridine or 4-chlorobenzotrifluoride
performed optimally (Table 6, entries 1, 3, 4). Coupling
electron-neutral substrates with methanol tended to afford
30-50% dehalogenated byproduct while couplings with iso-
propanol showed even higher levels of dehalogenation due the
greater propensity for ꢀ-hydride elimination with a secondary
alcohol. Electron-rich aryl halides, such as 2-bromoanisole,
afforded solely reduction products (Table 6, entry 5). The steric
hindrance of Bippyphos is essential to the success of these
couplings to avoid reduction side products. As a comparison,
when coupling 4-bromo-tert-butylbenzene with methanol, Bi-
ppyphos provides the desired ether and reduction products in a
1:1 ratio (Table 6, entry 6), and related ligands 12 and 14
provided similar results. In contrast, the use of the dicyclo-
hexylphosphine analogue to Bippyphos (11) solely afforded the
reduction product with no trace of the desired methyl ether
product.
Suzuki-Miyaura Couplings
We examined Suzuki-Miyaura couplings with our ligands
and applied similar reaction conditions to what we had used
for the Pd-catalyzed amination reactions. Initially we examined
KOH and K2CO3 as activating agents for the coupling and found
no appreciable difference in performance (Table 7, entry 1);
however, we did see improved reaction rates in tert-amyl alcohol
over solvents such as dioxane. From this early optimization
work, we decided to conduct the screen of reactions using tert-
amyl alcohol and K2CO3. The source of Pd, whether Pd(OAc)2
or Pd2(dba)3, did not appear to impact the performance of the
couplings. While Bippyphos could efficiently catalyze reactions
between coupling partners with a single ortho substituent (Table
7, entry 1), substrates with two or more ortho substituents
performed better with 11 (Table 7, entries 5, 7, 9, 11, and 13).
In the coupling between 2,6-dimethylchlorobenzene and phe-
nylboronic acid, Bippyphos only achieved 35% conversion
while 11 afforded the product in 98% conversion. In a more
dramatic comparison, the coupling between 1-naphthylboronic
acid and 1-bromo-2-methoxynaphthalene only reached 5%
conversion with Bippyphos, whereas using 11 enabled 95%
conversion to the desired product (Table 7, entries 10 and 11).
We were pleased to find that when substituting KOH for K2CO3
(23) The diaryl ether couplings were carried out with Pd(OAc)2 and
Bippyphos in tert-amyl alcohol using 1.0 equiv arylbromide, 1.2 equiv
of the phenol and 1.5 equiv of K2CO3 at 100 °C over 8 h. Use of
Pd2(dba)3 in diaryl ether couplings appeared to result in poorer
reactivity.
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Table 8. Recommended applications for ligands 1 (Bippyphos) and 11 (Cy-Bippyphos)
ligand
reaction type
Bippyphos (1)
Cy-Bippyphos (11)
Pd-catalyzed amination reactions very general ligand, most effective with primary most effective with electron-deficient aryl
amines. Tends to suppress hydride elimination
for electron-rich aryl halides.
halides, anilines, and secondary amines (except
with electron-rich aryl halides where hydride
elimination occurs).
Suzuki-Miyaura couplings
most effective with unhindered aryl halides and
boronic acids
highly effective with hindered aryl halides and
boronic acids
in the couplings, the catalyst reactivity increased substantially.
A number of the couplings that performed only moderately with
K2CO3, provided excellent yields when switching to KOH
(Table 7, entries 7–9, 12, 13). Even more remarkable was the
successful coupling between 1-bromo-2-methoxynaphthalene
and 1,3,5-trimethylbenzeneboronic acid with ligand 11 (Table
7, entry 16). This demonstrates that couplings to afford tetra-
ortho-substituted biaryls are achievable with this ligand family.24
We also examined the performance of the diphenylphosphine
analogue of Bippyphos (15) and observed relatively poor
performance as was the case with the amination reactions. In
the coupling between 3-chloropyridine and 1-naphthalene
boronic acid, only 16% product formed (Table 7, entry 3).
General Procedure for Pd-Catalyzed Amination Reac-
tions. To a flask under nitrogen was added Pd2(dba)3 (24 mg, 0.005
equiv, note 0.01 equiv Pd), or Pd(OAc)2 (11 mg, 0.01 equiv), and
Bippyphos (51 mg, 0.02 equiv, note 2:1 ligand to Pd molar ratio)
in tert-amyl alcohol (5.0 mL). One can optionally add 0.10 mL of
water to maintain a homogeneous reaction. After 5–15 min of
stirring the dark purple reaction mixture (for Pd(OAc)2 the
reaction mixture was an orange color), KOH, 87–89% pellets
(478 mg, 1.5 equiv) and the amine (6.00 mmol, 1.2 equiv) were
added followed by the aryl halide (5.00 mmol, 1.0 equiv). The
resulting reaction mixture became an orange color and was
heated to ∼100 °C (reflux for tert-amyl alcohol is 100–103 °C).
After 3 h the reaction was usually complete (consumption of
aryl halide by GC). The reaction was cooled to rt and diluted
with MTBE (20 mL) (note: may need 2-methyl-THF for more
water-soluble substrates) and water (10 mL). The organic layer
was dried over sodium sulfate and concentrated in vacuo for
purification by silica gel chromatography.
General Procedure for Suzuki-Miyaura Reactions. To
a flask under nitrogen was added Pd(OAc)2 (11 mg, 0.01 equiv),
and 11 (56 mg, 0.02 equiv, note 2:1 ligand to Pd molar ratio)
in tert-amyl alcohol (5.0 mL). After 5–15 min of stirring the
orange reaction mixture, KOH (478 mg, 1.5 equiv), the aryl
boronic acid (6.00 mmol, 1.2 equiv) and the aryl halide (5.00
mmol, 1.0 equiv) were added. The resulting reaction mixture
was heated to ∼100 °C (reflux for tert-amyl alcohol is 100–103
°C). After 3 h the reaction was usually complete (consumption
of aryl halide by GC). The reaction was cooled to rt and diluted
with MTBE (20 mL) (note: may need 2-methyl-THF for more
water-soluble substrates) and water (10 mL). The organic layer
was dried over sodium sulfate and concentrated in vacuo for
purification by silica gel chromatography.
5-(Di-tert-butylphosphino)-1-(1,3,5-triphenyl-1H-pyrazol-
4-yl)-1H-pyrazole (1). Compound 5 (50.1 g, 138.3 mmol) was
dissolved in THF (400 mL) and cooled to -78 °C. A solution
of 2.5 M n-butyllithium in hexanes (66.0 mL, 166 mmol) was
added and the resulting reaction mixture was stirred at -78 °C
for 1.5 h (note: the lithiation may be carried out at -10 to -20
°C, see alternative preparation below). The reaction started as
an orange solution but after several minutes a suspension
formed. After this time, di-tert-butylchlorophosphine (32 mL,
166 mmol) was added. The reaction mixture was allowed to
gradually warm to 0 °C over 1 h and was stirred at 0 °C for an
additional hour (maintaining the reaction cold seems to help
with purity). The reaction was quenched with water (300 mL)
and was diluted with tert-butyl methyl ether (600 mL). The
organic layer was separated and washed with brine (200 mL).
The organic layer was then dried over anhydrous sodium sulfate
Conclusions
Bippyphos, 1, is generally an effective phosphine ligand for
Pd-catalyzed amination reactions, though the dicyclohexylphos-
phine analogue, 11, is slightly more effective for some
combinations of secondary amines and anilines with aryl halides
(Table 8). In particular, Bippyphos is highly effective at
suppressing ꢀ-hydride elimination which becomes more prob-
lematic in couplings involving secondary acyclic amines and
electron-rich aryl halides. More dramatic differences in ligand
performance were observed for Suzuki-Miyaura couplings,
especially those involving sterically challenged substrates. The
less hindered dicyclohexylphosphine ligand 11 outperformed
Bippyphos, 1, in all cases with substrates possessing multiple
substituents ortho to the biaryl bridge. Both Bippyphos and 11
(Cy-Bippyphos) performed optimally in the Suzuki-Miyaura
couplings with hindered substrates when using KOH as the base.
In general, Cy-Bippyphos (11) successfully catalyzed couplings
of aryl halides and boronic acids to afford tri-ortho-substituted
biaryls and even one example of a tetra-ortho-substituted biaryl.
Our modular design should enable us to continue to generate
new members of this ligand family and design ligands suited
to particular substrate combinations.
Experimental Section
All materials were purchased from commercial suppliers and
used without further purification. All reactions were conducted
under an atmosphere of nitrogen.
(24) (a) Biaryls with four ortho-alkyl substituents have been prepared
previously, see: Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L
J. Am. Chem. Soc. 2002, 124, 1162. (b) Walker, S. D.; Barder, T. E.;
Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43,
1871. (c) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S.
L J. Am. Chem. Soc. 2005, 127, 4685. (d) Jensen, J. F.; Johannsen, M
Org. Lett. 2003, 5, 3025. (e) Gereon, A.; Goddard, R.; Lehmann,
C. W.; Glorius, F J. Am. Chem. Soc. 2004, 126, 15195. (f) Demchuk,
O. M.; Yoruk, B.; Blackburn, T.; Snieckus, V Synlett 2006, 2908.
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and concentrated in vacuo to a total volume of about 200 mL.
The solution was diluted with tert-butyl methyl ether (400 mL)
and was concentrated to a volume of about 300 mL. Crystals
began to form, and the suspension was cooled to 0 °C to
crystallize more material. After stirring for 2 h, the mixture was
diluted with heptane (600 mL) to induce further crystallization,
and the slurry was stirred for 4 h before filtration. The filtercake
was washed with heptane to afford Bippyphos (1) as a white
near the end of the bromine dosing. Once reaction completion
to form 3 was confirmed by TLC or HPLC, pyrazole (53.1 g,
3.5 equiv) was added. The reaction was heated to 35-55 °C
and held for about 6-12 h. Once the reaction to form the
alkylation adduct, 4, was confirmed to be complete by HPLC,
the reaction mixture was diluted with acetic acid (150 mL, 3
mL/g LR). Heating was continued at 35-45 °C, and then a
solution of phenylhydrazine (36.2 g or 32.9 mL, 1.5 equiv) in
methanol (250 mL, 5 mL/g LR) was added. Once the pyrazole
condensation was nearly complete, the product precipitated from
solution as a yellow suspension. After about 10 to 16 h the
reaction was determined to be complete, and water (250 mL, 5
mL/g LR) was added to dilute the crystals. The crystals were
stirred for at least 2 h and filtered. The filtercake was washed
sequentially with water, then with cold methanol (to remove
water), and then with heptane (the methanol and heptane washes
removed color). The yellow solids were recrystallized by first
dissolving in hot toluene (250 mL, 5 mL/g LR) and then adding
heptane (500 mL, 10 mL/g LR) to the hot solution to promote
the formation of crystals. The resulting suspension was stirred
for at least 4 h and was filtered, washing the cake with heptane.
Isolated 1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1H-pyrazole (5) as
1
solid (59.0 g, 84%). Mp 191–193 °C; H NMR (CDCl3): δ
7.93 (d, J ) 1.7 Hz, 1H), 7.48–7.11 (m, 15H), 6.62 (d, J ) 1.7
Hz, 1H), 0.69 (d, J ) 12.5 Hz, 9H), 0.57 (d, J ) 12.5 Hz, 9H);
13C NMR (CDCl3): δ ) 150.0, 143.5 (d, J ) 26 Hz), 141.5,
140.4, 140.1, 132.3, 130.2, 129.0, 128.9, 128.8, 128.7, 128.5,
128.3, 127.8, 127.7, 125.8, 121.1, 113.9 (d, J ) 4.5 Hz), 32.1
(d, J ) 18 Hz), 32.1 (d, J ) 19 Hz), 30.0 (d, J ) 27 Hz), 29.8
(d, J ) 27 Hz). Anal. Calcd for C32H35N4P: C, 75.86; H, 6.96;
N, 11.06. Found: C, 75.62; H, 6.96; N, 10.86.
5-(Di-tert-butylphosphino)-1-(1,3,5-triphenyl-1H-pyrazol-
4-yl)-1H-pyrazole (1), Alternative Noncryogenic Process
Used for Scale Up. Compound 5 (2.00 kg, 5.52 mol) was
dissolved in THF (16 L) and cooled to -15 °C. A solution of
2.5 M n-hexyllithium in hexanes (2.68 L, 6.62 mol) was added
over about 45 min between -15 and -10 °C, and the resulting
reaction mixture was stirred at -15 °C for 1 h. The reaction
mixture remained as an orange solution at this temperature
range. After this time, di-tert-butylchlorophosphine (1.20 kg,
6.62 mol) was added over 1 h at -15 to -10 °C (could be
beneficial to add this reagent as a solution to help reduce
viscosity and minimize exotherm). The reaction mixture was
held for 1 h at this temperature range after the addition and
then allowed to gradually warm to ambient conditions. The
reaction mixture was stirred at ambient conditions for an
additional hour prior to the quench (note that maintaining the
reaction cold after the phosphine addition seems to help with
purity and the quench may proceed better at 0 °C than under
ambient conditions). The reaction was quenched with dilute
brine (7.2 L of water and 800 g of NaCl) and was further diluted
with tert-butyl methyl ether (20 L). The organic layer was
separated and was then dried over anhydrous sodium sulfate
(2.00 kg). The sodium sulfate was removed by filtration. The
organic solution was concentrated in vacuo to a total volume
of about 8 L. The solution was diluted with tert-butyl methyl
ether (20 L) and was concentrated to a volume of about 12 L.
Crystals began to form during the vacuum distillation and the
suspension was cooled to 0 °C to crystallize more material. After
stirring for 2 h, the mixture was diluted with heptane (24 L)
which was added over 30 min to induce further crystallization.
The slurry was stirred for 3 h at about 0 °C, then cooled to
-10 °C and stirred for another hour before filtration. The
filtercake was washed with heptane (4 L) and transferred to a
vacuum tray dryer held at 35 to 45 °C over 24 h to afford
Bippyphos (1) as a white solid (2.24 kg, 80%).
1
white crystals (64.7 g, 80%). Mp 168–169 °C; H NMR
(CDCl3): δ 7.75 (d, J ) 2.1 Hz, 1H), 7.44–7.11 (m, 16H), 6.33
(d, J ) 2.1 Hz, 1H); 13C NMR (CDCl3): δ ) 148.1, 141.2,
141.1, 140.0, 133.1, 131.1, 129.5, 129.3, 129.2, 128.7, 128.6,
128.1, 127.8, 127.0, 125.5, 121.2, 112.5, 107.1. Anal. Calcd
for C24H18N4: C, 79.54; H, 5.01; N, 15.46. Found: C, 79.16; H,
4.87; N, 15.30.
5-(Dicyclohexylphosphino)-1-(1,3,5-triphenyl-1H-pyrazol-
4-yl)-1H-pyrazole (11). Compound 5 (2.0 g, 5.3 mmol, 1.0
equiv) was dissolved in THF (20 mL) and cooled to -78 °C.
A solution of 2.5 M n-butyllithium in hexanes (2.6 mL, 6.4
mmol, 1.2 equiv) was added and the reaction allowed to stir at
-78 °C for 1.5 h. After this time, dicyclohexylchlorophosphine
(1.48 g, 6.38 mmol, 1.2 equiv) in THF (3 mL) was added. The
mixture was kept at -78 °C for 30 min, gradually warmed to
room temperature, and stirred overnight. The mixture was
quenched with 1 M NaOH (10 mL) and extracted into MTBE
(50 mL). The biphasic mixture was transferred to a separatory
funnel for phase separation. The MTBE layer was washed with
water (20 mL), dried with Na2SO4, filtered, and concentrated
under reduced pressure to give an oily foam, which solidified
upon standing. The solid was slurried in MTBE (10 mL) and
granulated for 1 h (as an alternative, this ligand could be
crystallized from isopropanol). The solids were filtered, rinsed
with MTBE (5 mL), and allowed to dry overnight in a vacuum
oven at 50–55 °C. This gave 11 as a white solid (1.5 g, 51%).
Mp 173–174 °C; 1H NMR (CDCl3): δ 7.94 (d, 1H), 7.47-7.14
(m, 15H), 6.42 (d, 1H), 1.5-0.2 (m, 22H); 13C NMR (CDCl3):
δ 149.6, 140.5, 140.2, 131.8, 129.8, 129.1, 128.8, 128.6, 128.5,
1-(1,3,5-Triphenyl-1H-pyrazol-4-yl)-1H-pyrazole (5). To
a solution of 1,3-diphenyl-1,3-propanedione, 2, (50 g, 223
mmol) in NMP (200 mL, 4 mL/g LR) was added bromine (42.7
g or 13.7 mL, 1.2 equiv). Note that pyridinium tribromide or
NBS may be used as alternatives to bromine for this step. The
sustained red color was a sign that the reaction was complete
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487

128.4, 127.8, 127.6, 125.5, 112.8, 33.6, 33.5, 29.7, 29.6, 28.8,
28.7, 28.4, 28.3, 27.2, 27.1, 27.0, 26.2. Anal. Calcd for:
C36H39N4P: C, 77.39; H, 7.04; N, 10.03. Found: C, 77.34; H,
7.01; N, 10.05.
for 30 min. at rt. The white solid was filtered off and discarded.
The filtrate, containing the product, was washed with aqueous
saturated NaHCO3 (50 mL), water (50 mL), dried with Na2SO4,
filtered, and concentrated under reduced pressure to give 17 as
a white solid (6.1 g, 97%). Mp 96–97 °C; 1H NMR (CDCl3):
δ 8.02-7.99 (d, 2H), 7.65-7.60 (m, 1H), 7.52-7.49 (m, 2H),
6.1 (s, 1H), 1.20 (s, 9H); 13C NMR (CDCl3): δ 202.8, 189.9,
134.4, 129.5, 129.2, 49.4, 45.0, 27.2. Anal. Calcd for:
C13H15BrO2: C, 55.14; H, 5.34. Found: C, 55.23; H, 5.38.
1-(3-tert-Butyl-1,5-diphenyl-1H-pyrazol-4-yl)-1H-pyra-
zole (19). Pyrazole (5.0 g, 74.3 mmol, 3.5 equiv) was added to
a solution of 17 (6.0 g, 21.2 mmol, 1.0 equiv) in NMP (18
o
mL) and warmed to 50 -55 °C overnight to give 18. Once
5-(Diphenylphosphino)-1-(1,3,5-triphenyl-1H-pyrazol-4-
yl)-1H-pyrazole (15). Compound 5 (2.0g, 5.3 mmol, 1.0 equiv)
was dissolved in THF (20 mL) and cooled to -78 °C. A
solution of 2.5 M n-butyllithium in hexanes (2.6 mL, 6.4 mmol,
1.2 equiv) was added and the reaction allowed to stir at -78
°C for 1.5 h. After this time, diphenylchlorophosphine (1.41 g,
6.38 mmol, 1.2 equiv) in THF (3 mL) was added. The mixture
was kept at -78 °C for 30 min., then gradually warmed to
room temperature, and stirred overnight. The mixture was
quenched with 1 M NaOH (10 mL) and extracted into MTBE
(50 mL). The biphasic mixture was transferred to a separatory
funnel for phase separation. The MTBE layer was washed with
water (20 mL), dried with Na2SO4, filtered, and concentrated
under reduced pressure to give an oily foam. MTBE (10 mL)
was added which gave an orange solution. Heptanes (2 mL)
was added and the mixture stirred 4 h. The resulting slurry was
filtered, rinsed with heptanes (5 mL), and allowed to dry
overnight in a vacuum oven at 50–55 °C. This gave 15 as a
yellow solid (2.1 g, 72%). Mp 150–151 °C; 1H NMR (CDCl3):
δ 7.79 (d, 1H), 7.40–6.99 (m, 21H), 6.86 (t, 2H), 6.75, (t, 2H),
6.02 (d, 1H); 13C NMR (CDCl3): δ 141.5, 133.4, 133.1, 133.0,
132.8, 129.7, 129.1, 129.0, 128.9, 128.6, 128.5, 128.4, 127.9,
127.1, 125.4, 114.7. Anal. Calcd for: C36H27N4P: C, 79.10; H,
4.98; N, 10.25. Found: C, 78.80; H, 4.87; N, 10.10.
reaction completion was confirmed by TLC or HPLC, the pot
was cooled to room temperature and diluted with acetic acid
(10 mL). A solution of phenylhydrazine (3.4 g, 31.8 mmol,
1.5 equiv) in methanol (10 mL) was added. The mixture was
warmed to 55–60 °C for 24 h. Once reaction completion was
confirmed by TLC or HPLC, the pot was cooled to room
temperature and concentrated under reduce pressure to remove
the methanol. The remaining orange solution was diluted with
water (20 mL) and MTBE (50 mL). The biphase was allowed
to stir for 1.5 h. The resulting precipitate was filtered, rinsed
with MTBE (10 mL), and allowed to dry overnight in the
vacuum oven. This gave 19 as a white solid (4.8 g, 66%). Mp
140–141 °C; 1H NMR (CDCl3): δ 7.78 (d, 1H), 7.49 (m, 5H),
7.20 (m, 5H), 6.41 (d, 1H), 1.0 (s, 9H); 13C NMR (CDCl3): δ
149.6, 147.9, 143.4, 140.5, 134.1, 131.2, 129.7, 129.2, 128.8,
128.6, 128.3, 127.0, 107.2, 33.6, 30.4. Anal. Calcd for:
C22H22N4: C, 77.16; H, 6.48; N, 16.36. Found: C, 76.70; H,
6.26; N, 16.23.
1-(3-tert-Butyl-1,5-diphenyl-1H-pyrazol-4-yl)-5-(di-tert-
butylphosphino)-1H-pyrazole (12). Compound 19 (1.2 g, 3.5
mmol, 1.0 equiv) was dissolved in THF (12 mL) and cooled to
-78 °C. A solution of 2.5 M n-butyllithium in hexanes (1.7
mL, 4.2 mmol, 1.2 equiv) was added and the reaction allowed
to stir at -78 °C for 1.5 h. At this time, di-tert-butylchloro-
phosphine (760 mg, 4.2 mmol, 1.2 equiv) in THF (2 mL) was
added. The mixture was kept at -78 °C for 2 h, gradually
warmed to room temperature, and stirred overnight. The mixture
was quenched with 1 M NaOH (10 mL) and extracted into
MTBE (40 mL). The biphasic mixture was transferred to a
separatory funnel for phase separation. The MTBE layer was
washed with water (20 mL), dried with Na2SO4, filtered, and
concentrated under reduced pressure to give an oily foam. The
oily foam was purified by flash chromatography (3:1 Heptane:
EtOAc). The fractions containing pure product were combined
and concentrated under reduced pressure to give 12 as a white
foam (740 mg, 43%). Mp 70–71 °C; 1H NMR (CDCl3): δ 7.82
(d, 1H), 7.53–7.46 (m, 5H), 7.29–7.27 (m, 2H), 7.15–7.13 (m,
3H), 6,71 (d, 1H), 1.23–1.20 (d, 9H), 1.09 (s, 9H), 0.74–0.71
(d, 9H); 13C NMR (CDCl3): δ 139.5, 129.5, 129.4, 128.9, 128.4,
128.2, 128.0, 31.4, 31.2, 30.3, 30.1, 30.0. Anal. Calcd for:
C30H39N4P: C, 74.04; H, 8.08; N, 11.51. Found: C, 73.47; H,
8.11; N, 11.02.
2-Bromo-4,4-dimethyl-1-phenylpentane-1,3-dione (17). N-
Bromosuccinimide (5.1 g, 28.6 mmol, 1.3 equiv) was added to
a solution of 4,4-dimethyl-1-phenyl pentane-1,3-dione (4.5 g,
22.0 mmol, 1.0 equiv) dissolved in CH3CN (23 mL). The
reaction was allowed to stir at 50 °C overnight. Once reaction
1-(3-tert-Butyl-1,5-diphenyl-1H-pyrazol-4-yl)-5-(dicyclo-
hexylphosphino)-1H-pyrazole (13). Compound 19 (1.2 g, 3.5
mmol, 1.0 equiv) was dissolved in THF (12 mL) and cooled to
completion was confirmed by TLC or HPLC, the solution was
cooled to rt and concentrated under reduced pressure to give a
white solid. The solid was slurried in MTBE (70 mL) and stirred
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-78 °C. A solution of 2.5 M n-butyllithium in hexanes (1.7
mL, 4.2 mmol, 1.2 equiv) was added, and the reaction was
allowed to stir at -78 °C for 1.5 h. After this time, dicyclo-
hexylchlorophosphine (760 mg, 4.2 mmol, 1.2 equiv) in THF
(2 mL) was added. The mixture was kept at -78 °C for 2 h,
gradually warmed to room temperature, and stirred overnight.
The mixture was quenched with 1 M NaOH (10 mL) and
extracted into MTBE (40 mL). The biphasic mixture was
transferred to a separatory funnel for phase separation. The
MTBE layer was washed with water (20 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure to
give a waxy yellow solid. To the solid was added isopropyl
ether (10 mL) and the mixture allowed to granulate for 1 h at
rt. The solid was filtered, rinsed with isopropyl ether (5 mL),
and allowed to dry overnight in the vacuum oven at 50–55 °C.
This gave 13 as a cream-colored solid (1.3 g, 71%). Mp
205–206 °C; 1H NMR (CDCl3): δ 7.82 (d, 1H), 7.47 (m, 5H),
7.19 (m, 5H), 6,46 (d, 1H), 0.50 – 2.0 (m, 31 H); 13C NMR
(CDCl3): δ 149.0, 143.0, 139.8, 132.2, 129.6, 129.2, 129.0,
128.7, 128.2, 127.5, 112.5, 33.6, 33.4, 30.6, 30.3, 27.2, 27.1,
27.0, 26.5, 26.1. Anal. Calcd for: C34H43N4P: C, 75.80; H, 8.05;
N, 10.40. Found: C, 75.41; H, 8.11; N, 10.26.
followed by a rinse with heptane (10 mL). The damp cake was
again charged to a clean flask. Toluene (28 mL) was added
and heated to 95 °C to give a yellow solution. Heptane (70
mL) was added dropwise. Once addition was complete, the pot
was slowly cooled to rt and stirred 1 h. The resulting slurry
was filtered, rinsed with heptane (10 mL), and dried in the
vacuum oven at 50–55 °C overnight. This gave 21 as a white
crystalline solid (3.7 g, 71% yield). Mp 198–199 °C; 1H NMR
(CDCl3): δ 7.55 (s, 1H), 7.45-7.14 (m, 15H), 7.09 (s, 1H),
2.04 (s, 3H); 13C NMR (CDCl3): δ 142.0, 131.6, 129.6, 129.2,
129.1, 128.7, 128.6, 128.0, 127.0, 125.5, 117.8, 9.5. Anal. Calcd
for: C25H20N4: C, 79.76; H, 5.35; N, 14.88. Found: C, 79.78;
H, 5.29; N, 14.94.
5-(Di-tert-butylphosphino)-4-methyl-1-(1,3,5-triphenyl-
1H-pyrazol-4-yl)-1H-pyrazole (14). Compound 21 (1.7 g, 4.4
mmol, 1.0 equiv) was dissolved in THF (25 mL) and cooled to
-78 °C. A solution of 2.5 M n-butyllithium in hexanes (2.1
mL, 5.3 mmol, 1.2 equiv) was added and the reaction allowed
to stir at -78 °C for 1.5 h. After this time, di-tert-butylchlo-
rophosphine (950 mg, 5.3 mmol, 1.2 equiv) in THF (2 mL)
was added. The mixture was kept at -78 °C for 2 h, gradually
warmed to room temperature, and stirred overnight. The mixture
was quenched with 1 M NaOH (10 mL) and extracted into
MTBE (50 mL). The biphasic mixture was transferred to a
separatory funnel for phase separation. The MTBE layer was
washed with water (20 mL), dried with Na2SO4, filtered, and
concentrated under reduced pressure to give a yellow foam.
The oily foam was purified by flash chromatography (3:1
heptane/EtOAc). The fractions containing pure product were
combined and concentrated under reduced pressure to give a
14 as a yellow foam (475 mg, 21%). Mp 95–96 °C; 1H NMR
(CDCl3): δ 7.72 (s, 1H), 7.51 (d, 2H), 7.40 (d, 2H), 7.33-7.15
(m, 11H), 2.24 (s, 3H), 0.73 (d, 9H), 0.61 (d, 9H); 13C NMR
(CDCl3): δ 142.6, 130.3, 129.0, 128.8, 128.5, 128.4, 128.2,
127.9, 127.6, 125.7, 30.8, 30.7, 13.5. Anal. Calcd for:
C33H37N4P: C, 76.13; H, 7.16; N, 10.76. Found: C, 76.05; H,
7.39; N, 10.54.
4-Methyl-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1H-pyra-
zole (21). N-Bromosuccinimide (3.2 g, 18.0 mmol, 1.3 equiv)
was added to a solution of 1,3-diphenyl-1,3-propanedione, 2,
(3.1 g, 13.9 mmol, 1.0 equiv) in NMP (12 mL) and allowed to
stir for 4 h at rt to give 3. Once reaction completion was
confirmed by TLC or HPLC, 4-methylpyrazole (4.0 g, 48.7
mmol, 3.5 equiv) was added. The resulting solution was allowed
to stir overnight at 50–55 °C to give the 4-methylpyrazole-
substituted intermediate, 20. Once reaction completion was
confirmed by TLC or HPLC, the pot was cooled to room
temperature and diluted with acetic acid (9 mL). A solution of
phenylhydrazine (2.2 g, 20.7 mmol, 1.5 equiv) in methanol (9
mL) was added. The reaction solution was allowed to stir at rt
overnight which resulted in an orange slurry. Once reaction
completion was confirmed by TLC or HPLC, the orange slurry
was filtered and rinsed with H2O (10 mL). The damp cake was
charged to a clean flask along with MeOH (15 mL) and H2O
(15 mL) where the slurry was allowed to granulate for 1 h at
rt. The slurry was filtered and rinsed with H2O (10 mL),
Acknowledgment
We thank Thomas Staigers, Jeff Haase, Bob Buckingham,
and Billy Buzon for assistance in the original scale up of
Bippyphos at Pfizer. We thank Scott Laneman for his help in
the commercial production of Bippyphos at Digital Specialty
Chemicals.
Received for review December 12, 2007.
OP7002858
Vol. 12, No. 3, 2008 / Organic Process Research & Development
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