Additive effects on palladium-catalyzed deprotonative-cross-coupling processes (DCCP) of sp3 C-H bonds in diarylmethanes

Article abstract of DOI:10.1039/c2sc21673f

Palladium-catalyzed cross-coupling reactions have become one of the most useful tools in modern organic chemistry. Current methods to achieve direct functionalization of sp³ C-H bonds of arenes and heteroarenes often employ substrates with appropriately placed directing groups to enable reactivity. Examples of intermolecular arylation methods of weakly acidic sp³ C-H bonds in the absence of directing groups, however, are still limited. We describe herein a study on the use of additives in Pd-catalyzed deprotonative-cross-coupling processes (DCCP) of sp³ C-H bonds of diarylmethanes with aryl bromides at room temperature. These studies resulted in development of four new efficient Pd-catalyzed DCCP using additives that enabled the generation of a range of sterically and electronically diverse aryl- and heteroaryl containing triarylmethanes in good to excellent yields. Additive identification and optimization of all reaction conditions (additive loading, solvent and temperature) were performed using high-throughput experimentation (HTE). The approach outlined herein is expected to be generalizable to other C-H functionalization reactions involving the deprotonation of weakly acidic C-H bonds. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2sc21673f

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Additive Effects on Palladium-Catalyzed Deprotonative-Cross-Coupling
Processes (DCCP) of sp3 C−H Bonds in Diarylmethanes
Ana Bellomo, Jiadi Zhang, Nisalak Trongsiriwat and Patrick J. Walsh*
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
5
DOI: 10.1039/b000000x
Palladiumꢀcatalyzed crossꢀcoupling reactions have become one of the most useful tools in modern organic chemistry. Current methods
to achieve direct functionalization of sp3 C−H bonds of arenes and heteroarenes often employ substrates with appropriately placed
directing groups to enable reactivity. Examples of intermolecular arylation methods of weakly acidic sp3 C−H bonds in the absence of
directing groups, however, are still limited. We describe herein a study on the use of additives in Pdꢀcatalyzed deprotonativeꢀcrossꢀ
10 coupling processes (DCCP) of sp3 C−H bonds of diarylmethanes with aryl bromides at room temperature. These studies resulted in
development of four new efficient Pdꢀcatalyzed DCCP using additives that enabled the generation of a range of sterically and
electronically diverse arylꢀ and heteroaryl containing triarylmethanes in good to excellent yields. Additive identification and
optimization of all reaction conditions (additive loading, solvent and temperature) were performed using highꢀthroughput
experimentation (HTE). The approach outlined herein is expected to be generalizable to other C–H functionalization reactions involving
15 the deprotonation of weakly acidic C–H bonds.
diarylmethane is necessary in the majority of cases. The catalyst
system is very effective, providing an average yield of >90% for
1. Introduction
50 the 33 triarylmethanes synthesized in the initial study. High
Transitionꢀmetalꢀcatalyzed crossꢀcoupling reactions are among
throughput experimentation (HTE) techniques7 were used to
the most straightforward and versatile methods in organic
optimize parameters in this reaction leading to a unique
base/catalyst combination (Scheme 1C).
synthesis.1
These reactions typically involve two
20 prefunctionalized coupling partners, such as a vinyl or aryl halide
and an organometallic reagent. More recently, the synthetic
community has focused on direct functionalization of C−H bonds
of arenes and heteroarenes, because C−H functionalizations are
more atomꢀeconomical and minimize the costs of
25 prefunctionalization. Currently, much of this effort has been
concentrated on direct functionalization of sp3 C–H bonds.2
Despite this effort, the intermolecular arylation of weakly acidic
sp3 C−H bonds in the absence of directing groups remains
challenging.3
30
Our initial approach to direct functionalization and arylation of
weakly acidic benzylic sp3ꢀhybridized C–H bonds (ArCH2ꢀZ,
Z=H, Ph NR2, OR) relied on acidification of the benzylic C–H’s
by coordination of the arene substrates to Cr(CO)3 in the form of
(η6ꢀArCH2–Z)Cr(CO)3 complexes (Scheme 1A).4 This strategy
35 was amenable to the first catalytic asymmetric arylation of
benzylic amines (Scheme 1B).5 The novelty of this approach,
however, was moderated by the use of stoichiometric chromium.
To circumvent this issue, we recently reported the first palladiumꢀ
catalyzed deprotonativeꢀcrossꢀcoupling process (DCCP) for sp3
40 C−H arylation of unactivated diarylmethane derivatives in the
absence of chromium. This protocol enables the synthesis of a
variety of sterically and electronically diverse arylꢀ and heteroaryl
55
Scheme 1 Palladiumꢀcatalyzed sp3 C–H arylation approaches developed
by our group.
Surprisingly, of the 12 bases examined during the development
and optimization of this reaction,6 only KN(SiMe3)2 afforded the
containing triarylmethanes (Scheme 1C).6
Triarylmethane
60 desired DCCP products in good to excellent yields (Scheme 1C).
Related alkali metalꢀbis(trimethylsilyl)amide bases [MN(SiMe3)2,
M=Li, Na] as well as tertꢀbutoxide bases [MOꢀtꢀBu, M=Li, Na,
K] failed to show even trace conversion.
derivatives exhibit interesting applications in material science and
45 are also important in medicinal chemistry.6
It is noteworthy that the reaction can be conducted at room
temperature with most substrates and that only 1.2 equiv
We hypothesized that additives might influence the
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performance of LiN(SiMe3)2, NaN(SiMe3)2 and potentially other
participation of the palladium catalyst.
bases and turn on the DCCP to afford triarylmethane products
(Scheme 2). Additionally, we hoped the use of additives would
improve reaction yields of problematic substrates and result in
milder reaction conditions. A search of the additive literature led
to an unexpected result: despite the enormous number of
palladium catalyzed processes published in the last 20 years, we
were not able to find previous systematic studies on the use of
Lewis basic additives for the Pdꢀcatalyzed crossꢀcoupling
55
tBu
2a
Ph
Br
Cl
Ph
Ph
Ph
5
Ph
Ph
Ph
Ph
Pd(OAc)2/NiXantphos
CPME, rt, 12h
BASE
tBu
(3 equiv)
CPME, rt, 12h
BASE (3 equiv)
3aa
1a
pKa = 32.3
KN(SiMe3
)
KN(SiMe3)
2
>95% yield (1H NMR), 96% IYa
>95% yield (1H NMR)
N.R.
2
NaN(SiMe3
)
NaN(SiMe3)
2
N.R.
N.R.
2
10 processes with weakly acidic sp3 C−H bonds. Yet these reactions
are increasingly popular in the efficient and economical synthesis
of biologically active compounds.2a, 2e Thus, inspired by the use
of additives in different types of reactions, we set out to evaluate
the impact of additives on the DCCP in Scheme 2. We now
15 disclose four conditions with different additives and bases that
not only turn on the DCCP with previously unreactive
LiN(SiMe3)2 and NaN(SiMe3)2, but actually afford better reaction
conditions with certain challenging substrates relative to our
original additiveꢀfree conditions.6
60
LiN(SiMe3 2
)
LiN(SiMe3)
2
N.R.
Scheme 3 Deprotonation/benzylation and DCCP experiments with
diphenylmethane (1a). aIY: isolated yield.
65
To further test the hypothesis above, we compared KN(SiMe3)2
and
deprotonation/benzylation and DCCP experiments with 2ꢀ
benzylpyridine (1b, Scheme 4). The benzylic hydrogens of 2ꢀ
LiN(SiMe3)2
in
the
roomꢀtemperature
70 benzylpyridine are considerably more acidic (pKa=28.2)3g,
3k,
9
than those of diphenylmethane (pKa=32.3),10 which should
facilitate roomꢀtemperature deprotonation/benzylation process
with either of the two bases. In agreement with our expectations,
2ꢀbenzylpyridine underwent benzylation in excellent yield in the
75 presence of either KN(SiMe3)2 or LiN(SiMe3)2. Both of the
metallated 2ꢀbenzylpyridine species (organopotassium and
organolithium) also participated in the catalytic DCCP to furnish
20
Scheme 2 Study of additive effects on the DCCP for sp3 C−H arylation of
weakly acidic diarylmethanes.
the triarylmethane derivative 3ba in >95% yield.
These
experiments point to the reactivity of the base and the acidity of
80 the substrate as a key feature in the DCCP of diarylmethanes and
lead us to hypothesize that additives that increase the reactivity of
the base will have a beneficial impact on formation of the DCCP
product.
2. Results and discussion
25 2.1. Probing the Role of the Base in the Absence of Additives
Before selecting additives for use in the DCCP (Scheme 2), a
better understanding of the role of the base in roomꢀtemperature
(23 °C) Pdꢀcatalyzed DCCP was necessary. There are two
widely accepted pathways for the C–H cleavage step in transition
30 metalꢀcatalyzed C−H arylation reactions: (1) C–H activation via a
tBu
2a
Ph
Ph
Ph Br
Cl
Ph
Ph
Pd(OAc)2
NiXantphos
CPME, rt, 12h
CPME, rt, 12h
BASE (3 equiv)
N
N
N
tBu
baseꢀinduced, concerted metallationꢀdeprotonation (CMD)
1b
3ba
pKa = 28.2
BASE (3 equiv)
8
pathway2c,
and (2) C–H deprotonation by base without
>95% yield (1H NMR), 99% IY
>95% yield (1H NMR)
>95% yield (1H NMR)
>95% yield (1H NMR)
KN(SiMe3)2
LiN(SiMe3)2
KN(SiMe3)2
LiN(SiMe3)2
participation of the transition metal. The former is common for
unactivated sp3 C−H arylations while the latter is widespread for
35 activated sp3 C−H arylations.
85
To gain insight into the role of the base, we compared different
bases of the type MN(SiMe3)2 (M=Li, Na, K) by employing them
in the DCCP of diphenylmethane (1a) with 4ꢀtertꢀbutyl
bromobenzene (2a) (Scheme 3, left). Only KN(SiMe3)2 afforded
40 the DCCP product 3aa with excellent yield. In sharp contrast,
LiN(SiMe3)2 and NaN(SiMe3)2 showed no conversion. To
understand why these three alkali metal counterions exhibited
dramatic differences in the DCCP, we carried out
deprotonation/benzylation experiments with these three bases in
45 cyclopentylmethyl ether (CPME) at room temperature (Scheme 3,
right). Again, only KN(SiMe3)2 afforded the benzylation product
while LiN(SiMe3)2 and NaN(SiMe3)2 failed to produce detectable
amounts of product. The results in the room temperature
deprotonation/benzylation (Scheme 3) are consistant with the
50 roomꢀtemperature DCCP and suggest a reaction pathway for the
DCCP involving direct deprotonation of the substrate without the
Scheme 4 Deprotonation/benzylation and DCCP experiments with 2ꢀ
benzylpyridine (1b).
90
2.2. Additives Background
Several important contributions outlining the use of additives on
various processes guided our choice of starting points. In the past
decade, advances have been made in exploiting the use of
95 additives to improve synthetic performance in late transition
metalꢀcatalyzed reactions.11 In 2001 Beller’s group reported a
detailed study on the effect of halide additives on the Heck
reaction.12 Recently, the groups of Nakamura,13 Fürstner,14
Cahiez,15 Cossy16 and Jacobi von Wangelin17 have described the
100 use of N,N,N’,N’ꢀtetramethylethylenediamine (TMEDA) on the
2
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Feꢀcatalyzed crossꢀcoupling reactions between Grignard reagents 60 resulting lithium amide species.38
and alkyl halides while Hu18 reported its use in the Niꢀcatalyzed
sp3ꢀsp2 KumadaꢀCorriuꢀTamao crossꢀcoupling reaction. Evano et
al.19 as well as Shang and coꢀworkers20 also explored TMEDA in
5
crossꢀcoupling reactions using alkynylcopper reagents. We
employed
(PMDTA) and TMEDA in the enantioselective DCCP of (η6ꢀ
ArCH2–NR2)Cr(CO)3 Another diamine,
complexes.5
dimethylethylenediamine (DMEDA) has been described to
N,N,N’,N’’,N’’-pentamethyldiethylenetriamine
Scheme 5 Crown ether effect on the deprotonation/benzylation reaction
with diphenylmethane (1a) using LiN(SiMe3)2.
10 significant accelerate Cuꢀcatalyzed C–N crossꢀcoupling
reactions.21 In several of these systems the role of these additives
is unclear, although it has been suggested that in ironꢀcatalyzed
processes the TMEDA can function as the ligand for the iron
center22 while in Cuꢀcatalyzed processes the role of DMEDA has
15 been rationalized not only as acting as a ligand to copper but also
helping to solublize the base and possibly serving as reducing
agent.21b A Perspective published in 2010 by Buchwald23
discusses the use of diamine ligands in Cu catalysis. Myristic
acid24 as well as acetic acid25 were also reported by Buchwald as
20 additives; the first in Cuꢀcatalyzed C–N coupling methods and
the latter facilitating activation of the catalyst in Pdꢀcatalyzed Nꢀ
With these results in hand, we decided to determine the range of
65 additives that would increase the reactivity of LiN(SiMe3)2,
NaN(SiMe3)2 and potentially other bases and thus generate the
triarylmethane products starting from weakly acidic
diphenylmethane substrates.
Recently HTE techniques have emerged as a powerful
70 approach for the discovery of new and more active catalysts, and
milder reaction conditions, for a wide variety of transformations.
We, therefore, decided to examine the impact of additives in the
crossꢀcoupling reaction between 4ꢀtertꢀbutyl bromobenzene (2a)
and diphenylmethane (1a) against a range of bases and solvents
75 using HTE techniques. The additives were selected based on
their ability to coordinate to the mainꢀgroup counterions of the
bases.
arylation reactions.
Moreover, Buchwald highlighted the
remarkable effect of catalytic amounts of phenolic additives on
the Cuꢀcatalyzed αꢀarylation of malonates26 and ketone
25 enolates.27
As a starting point, we employed our previously optimized
additiveꢀfree conditions for the DCCP of 1a and 2a (5 mol %
80 Pd(OAc)2, 7.5 mol % NiXantphos in CPME at rt).6 In the present
Considering organolithium chemistry, Collum’s group has
studied the impact of diamines on organolithium and lithium
amide bases.28 Furthermore, they have outlined the beneficial
effect of LiCl in accelerating orthoꢀlithiation reactions.29
30 Knochel and coꢀworkers developed a new class of mixed
magnesium bisamides in combination with LiCl as active bases
for the direct magnesiation30 and zincation31 of arenes and
heteroarenes and they recently introduced the use of Lewis acids
to promote the deprotonation of a variety of aromatic and
35 heteroaromatic substrates for benzylic crossꢀcoupling reactions.32
In this same area, Hartwig’s research group had shown the
accelerating effect of Lewis acids in Pdꢀcatalyzed aminations33
and the effect of zinc additives34 and metal fluorides35 on
palladium complexes to catalyze the arylation of trimethylsilyl
40 enolates. Finally, Trost has also shown the beneficial effect of
Lewis acids like BF3•OEt2 in Pdꢀcatalyzed asymmetric allylic
study,
6
different bases [KN(SiMe3)2, LiN(SiMe3)2,
NaN(SiMe3)2, KOtBu, LiOtBu and NaOtBu] and 11 diverse
additives including crown ethers (12ꢀcrownꢀ4, 15ꢀcrownꢀ5, 18ꢀ
crownꢀ6) and various amines and nitrogenꢀcontaining ligands
85 [NEt3, TMEDA, N,N,N’,N’ꢀtetramethylꢀ1,3ꢀpropanediamine
(TMPDA),
N,N'ꢀdiisopropylethylenediamine,
N,Nꢀ
diethylethylenediamine, N,N’ꢀdibenzylethylenediamine (DBED),
PMDTA, 2,2’ꢀbipyridine (bipy), 1,10ꢀphenanthroline and 1,4ꢀ
diazabicyclo[2.2.2]octane (DABCO)] were screened (Scheme 6).
90
substitutions.36
These reports inspired our approach to
identification of additives for the DCCP in Scheme 2.
45 2.3. Examination of Additives in Deprotonation/Benzylation
Studies
Scheme 6. HTE study on the impact of additives in the crossꢀcoupling
reaction between 4ꢀtertꢀbutyl bromobenzene (2a) and diphenylmethane
95 (1a) against a range of bases.
To gain insight into the lack of reactivity of LiN(SiMe3)2 with
diphenylmethane in both the benzylation and DCCP (Scheme 3),
50 we decided to explore the use of additives, initially focusing on
crown ethers. It is wellꢀknown that 12ꢀcrownꢀ4 has a high
affinity for lithium cations.37 We, therefore, added 12ꢀcrownꢀ4 to
the reaction mixture of diphenylmethane (1a), LiN(SiMe3)2, and
benzyl chloride in CPME at room temperature (Scheme 5).
55 Under these conditions, the benzylation occurred in >95% assay
yield, indicating that binding the lithium cation by the crown
ether dramatically increased the kinetic basicity of LiN(SiMe3)2.
The enhanced reactivity in the presence of the crown ether is
presumably due to the reduced degree of aggregation of the
The 72ꢀreaction additive screening was carried out by dosing
diphenylmethane (1a, 12 ꢁmol), 4ꢀtertꢀbutyl bromobenzene (2a,
10 ꢁmol), and internal standard (biphenyl, 1 ꢁmol) in 100 ꢁL of
100 CPME into a 96 well plate containing 72ꢀ1 mL reaction vials.
The vials had been predosed with Pd(OAc)2 (5 mol %),
NiXantphos (10 mol %), base (30 ꢁmol) and additive (60 ꢁmol,
except for the control reactions). The plate was prepared inside a
glovebox under a nitrogen atmosphere and sealed for the reaction
105 period. The plate was then stirred for 12 h at room temperature
outside the glovebox, opened to air, diluted with acetonitrile and
the reaction mixtures subjected to HPLC analysis. The product
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standard, starting materials, and internal standard were previously 35 stoichiometry by employing 1, 2, 3, 6 and 8 equiv additive in the
analyzed to determine their retention times and UV/vis spectra. In
an effort to identify the most generalized set of conditions, we
focused our analysis on reactions generating coupled
triarylmethane product 3aa in ≥10% HPLC assay yield (AY,
Figure 1). These leads would then be further optimized in
subsequent experiments.
presence of LiN(SiMe3)2 and NaN(SiMe3)2. The effect of
temperature on AY was also examined. We found that the
loading of the crown ethers could be reduced from 6 equiv to 1
equiv at rt without dramatically impacting the reaction yield.
Reactions with amine additives performed better at high
temperature (110 °C compared to rt) using NaN(SiMe3)2 with 1
equiv PMDTA (45% AY) being more promising than 6 equiv
TMEDA (32% AY) and 6 equiv N,N'ꢀdiisopropylethylenediamine
(15% AY) (see Supporting Information for details).
5
40
The results of this study are illustrated graphically in Figure 1.
Reactions in column 1 are the control reactions conducted
10 without additive. Wells B1, C1, D1, E1 and F1 contained only
unreacted starting material and no triarylmethane product. In
contrast, KN(SiMe3)2 formed triarylmethane in >90% AY in the
absence of additive (A1). These results are consistent with our
earlier report.6 The combination of LiN(SiMe3)2/12ꢀcrownꢀ4
15 (B2) and NaN(SiMe3)2/15ꢀcrownꢀ5 (C2) rendered product 3aa in
45
Based on the observation that the triamine PMDTA was more
effective than the diamine TMEDA and the monoamine NEt3, we
decided
to
evaluate
the
tetramine
1,1,4,7,10,10ꢀ
hexamethyltriethylenetetramine (HMTETA). A new screen using
NaN(SiMe3)2 and several tetramine loadings in CPME at room
97% and 91% AY, respectively, whereas 18ꢀcrownꢀ6 was 50 temperature and 110 °C revealed that 6 equiv HMTETA at rt
detrimental to the AY with KN(SiMe3)2 (A1 vs. A2). Amines are
known to bind to lithium and increase the reactivity of lithium
bases such as LDA28 and LiN(SiMe3)2.38d, 39 Among the amine
20 additives examined, reactions with TMEDA (C4), N,N'ꢀ
resulted in generation of the desired product in good to excellent
yields (80% AY when 1.2 equiv of diphenylmethane was used
and 97% AY with 3 equiv; see Supporting Information for
details). Collectively, the results above indicate that the presence
diisopropylethylenediamine (C6) and PMDTA (C9) provided 55 of crown ethers and amine additives enhance reactivity in the
triarylmethane product in the presence of NaN(SiMe3)2, albeit in
low yield (10–12% AY). None of the other bases generated the
DCCP product with or without the additives (see Supporting
25 Information for details). It is interesting to note that all additives
DCCP with Liꢀ and NaN(SiMe3)2 bases.
With the successful identification of crown ethers as additives
with LiN(SiMe3)2 and NaN(SiMe3)2 bases, we decided to examine
solvents resembling crown ethers, such as DME (1,2ꢀ
employed in this initial study had a negative impact on reactions 60 dimethoxyethane) and diglyme. Thus, we screen the initial 6
with KN(SiMe3)2 relative to the control reaction.
bases at three temperatures (rt, 50 °C and 110 °C) in CPME,
DME and diglyme and in combination with various additive
loadings (see Supporting Information for details). The most
promising results obtained from HTE screen are summarized in
65 Table 1. The combination of 6 equiv of 12ꢀcrownꢀ4 with 3 equiv
of LiN(SiMe3)2 in CPME rendered the desire product in 97% AY
(95% isolated yield) at rt (Table 1, entry 2). Unfortunately, we
were not able to make the DCCP work as efficient with lower
loadings of 12ꢀcrownꢀ4 (Table 1, entries 3 and 4). The use of
70 substoichiometric amounts of 15-crown-5 (30 mol %) with
NaN(SiMe3)2, rendered the highest yield (quantitative AY, 96%
isolated yield) of the desired product in CPME at rt (Table 1,
entry 9). Attempts to decrease the additive loading to 15 mol %
or 3 mol % at rt was detrimental to the yield (Table 1, entries 11
75 and 14). When the reactions were conducted at 110 °C and the
amount of diphenylmethane was increased to 3 equiv, however,
better assay yields was obtained (Table 1, entries 13 and 16). The
use of 6 equiv HMTETA and NaN(SiMe3)2 at rt in CPME
rendered 80% AY (86% isolated yield, Table 1, entry 17). Of
80 significance, HMTETA is inexpensive and can be easily removed
from the reaction mixture during the purification of the product.
The coordinating solvent diglyme rendered good results (see
Supporting Information) but due to its reported toxicity (based on
the MSDS), we used it as an additive instead of solvent. Thus,
85 diglyme (6 equiv) with NaN(SiMe3)2 at rt was the most suitable
conditions, generating the desired product in 88% AY (78%
isolated yield, Table 1, entry 20). Bases MOꢀt-Bu did not show
promising results even in the presence of the additives explored
(see Supporting Information).
30
Fig. 1 Results of initial screen of additives. Column 1 is the control
reaction without additives.
90
It is of note that the microscale screening results (10 ꢀmol)
outlined above translated to laboratory scale (0.1 mmol) with
excellent reproducibility. The isolated yields are given in the last
column of Table 1 in parentheses.
After identification of the leads above, we performed
multiparallel screening in 1 mL reaction vials to evaluate additive
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C: [NaN(SiMe3)2/6 equiv HMTETA] and Conditions D:
NaN(SiMe3)2/6 equiv diglyme]). We were interested in testing
the substrate generality with these new Conditions A–D. We
20 investigated the DCCP of 5 aryl bromides (2a2e) bearing
electronꢀdonating and electronꢀwithdrawing groups as well as one
sterically hindered aryl bromide (2f) with four diphenylmethane
derivatives (1a–1d) under the four sets of conditions highlighted
in Table 1. The reactions were conducted in a 96 wellꢀplate,
25 worked up and assay yields (based on 1H NMR spectroscopy and
HPLC analysis) were obtained for all of the reactions. Table 2
outlines the results obtained for each combination of aryl bromide
and diarylmethane (see Supporting Information for details). One
of the triarylmethanes was prepared from two different sets of
30 coupling partners, giving a total of 23 unique triarylmethane
derivatives.
Overall, 21 of the 23 coupling combinations examined resulted
in generation of triarylmethane products in fair to excellent yields
(48–99%) with at least one of the conditions used. This is
35 particularly impressive because unactivated diphenylmethanes
were not viable substrates in the absence of additives with the
LiN(SiMe3)2 and NaN(SiMe3)2. More specifically, 12 of these 20
triarylmethanes (3aa, 3ad, 3ae, 3ba, 3bb, 3bd, 3be, 3bf, 3da,
3dd, 3de and 3df) were obtained in ≥90% yield using the
40 additives. pꢀBromobenzotrifluoride (2c) was reacted following
our previous conditions.6 A decrease in the amount of base along
with an increase in the nucleophile loading were essential to
avoid decomposition of the triarylmethane product formed.
Control reactions were conducted in the presence of
45 KN(SiMe3)2 in CPME at rt for all substrate combinations.
Comparison of the results in Table 2 with the control experiments
indicated that, in several cases the products were generated in
comparable yields with the additive Conditions A–D and with the
KN(SiMe3)2 control (see Supporting Information for details).
50 The most significant improvements were seen in the formation of
4 new compounds (3bb, 3bc, 3cb and 3db), which were accessed
in higher yields employing the additive systems than with the
controls with KN(SiMe3)2. Specifically, product 3bb was
Table 1 Selected results from HTE screen using different bases and
additive loadings. Isolated yields are shown in parenthesis for the best
conditions obtained.
5
Entry MN(SiMe3)2 Additive,
1a
AY (%) AY (%)
T (°C)
M=
loading
(equiv.) HTEa Lab scaleb
1
Li
ꢀ
23
1.2
NR
NR
2
12-crown-4, 23
6 equiv
1.2
97
97 (95)c
Li
Li
Li
3
4
12ꢀcrownꢀ4,
1 equiv
12ꢀcrownꢀ4,
1 equiv
ꢀ
23
50
1.2
1.2
79
78
70
70
5
6
7
8
Na
Na
23
50
1.2
1.2
3
NR
NR
35
NR
2
ꢀ
ꢀ
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
110
23
38
96
15ꢀcrownꢀ5,
6 equiv
1.2
91
9
15-crown-5, 23
30 mol %
3
102
quant.
(96)c
10
11
12
13
14
15
16
17
18
19
20
21
22
15ꢀcrownꢀ5,
30 mol %
15ꢀcrownꢀ5,
15 mol %
15ꢀcrownꢀ5,
15 mol %
50
23
50
1.2
1.2
1.2
3
90
41
74
79
NR
17
67
80
76
65
88
89
41
85
ꢀd
90
15ꢀcrownꢀ5, 110
15 mol %
ꢀd
15ꢀcrownꢀ5,
3 mol %
23
1.2
1.2
3
ꢀd
15ꢀcrownꢀ5,
3 mol %
50
ꢀd
15ꢀcrownꢀ5, 110
3 mol %
65
obtained in 99% isolated yield with Conditions
B
HMTETA,
23
1.2
1.2
1.2
1.2
1.2
1.2
89 (86)c
46
55 [NaN(SiMe3)2/30 mol 15ꢀcrownꢀ5] vs. 68% AY with
%
6 equiv
KN(SiMe3)2, 3bc was accessed in 78% isolated yield with
Conditions A [LiN(SiMe3)2/6 equiv 12ꢀcrownꢀ4] vs. 5% AY with
KN(SiMe3)2, 3cb was achieved in 51% isolated yield with
Conditions A [LiN(SiMe3)2/6 equiv 12ꢀcrownꢀ4] vs. 17% AY
60 with KN(SiMe3)2, and 3db was produced in 76% isolated yield
using Conditions A [LiN(SiMe3)2/6 equiv 12ꢀcrownꢀ4] vs. 50%
AY with KN(SiMe3)2 (see Supporting Information for details).
Importantly, scaleꢀup to laboratory scale using 0.1 mmol of
substrates were similar to those determined in microscale
65 experiments.
HMTETA,
3 equiv
50
HMTETA,
30 mol %
diglyme,
6 equiv
110
23
64
70 (78)c
72
diglyme,
50
3 equiv
diglyme,
30 mol %
110
43
Conditions: 5 mol % Pd(OAc)2, 10 mol % NiXantphos, base (3 equiv) in
CPME; aHPLC analysis on 10 ꢀmol scale; byield determined by 1H NMR
10 spectroscopy of the crude reaction mixture on a 0.1 mmol scale; cisolated
yield; dnot determined. NR: no reaction (SM unreacted).
As illustrated in Table 1 four promising sets of conditions
utilizing additives (Table 1, entries 2, 9, 17 and 20) were
15 discovered (Conditions A: [LiN(SiMe3)2/6 equiv 12ꢀcrownꢀ4];
Conditions B: [NaN(SiMe3)2/30 mol % 15ꢀcrownꢀ5]; Conditions
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Table 2 Scope of aryl bromides and diarylmethanes in the DCCP under
20
the four sets of conditions identified by HTE.a
2a
2b
2cb
2d
2e
2f
Br
Ar-Br
Diarylmethanes
Conditionsa
Results
A
B
C
D
LiN(SiMe3)2, 6 equiv 12ꢀCꢀ4
NaN(SiMe3)2, 30 mol % 15ꢀCꢀ5
NaN(SiMe3)2, 6 equiv HMTETA
NaN(SiMe3)2, 6 equiv diglyme
Product
87 (97)
96 (99)
80 (86)
88 (78)
3aa
6
54 (63)
25
12
3ab
76
25
18
4
106 (99)
118 (97)
2
28
3ad
66
105 (99)
2
23
3ae
9
91 (77)
36
19
3af
0
0
1a
3ac
81 (78)
A
B
LiN(SiMe3)2, 6 equiv 12ꢀCꢀ4
82
92
10
NaN(SiMe3)2, 30 mol % 15ꢀCꢀ5
26
73 (99)
21
19
112 (99)
99 (94)
73 (99)
C
D
NaN(SiMe3)2, 6 equiv HMTETA
NaN(SiMe3)2, 6 equiv diglyme
37
31
87
66
16
83
97
27
0
95 (99)
multiple
products
3bc
1b
1c
Product
3ba
3bb
3bd
3be
3bf
A
B
LiN(SiMe3)2, 6 equiv 12ꢀCꢀ4
61 (52)
39 (51)
multiple
products
multiple
products
0
0
3cc
12
8
59 (48)
48 (61)
55 (63)
NaN(SiMe3)2, 30 mol % 15ꢀCꢀ5
30
10
30
27
25
C
D
NaN(SiMe3)2, 6 equiv HMTETA
NaN(SiMe3)2, 6 equiv diglyme
Product
LiN(SiMe3)2, 6 equiv 12ꢀCꢀ4
NaN(SiMe3)2, 30 mol % 15ꢀCꢀ5
NaN(SiMe3)2, 6 equiv HMTETA
NaN(SiMe3)2, 6 equiv diglyme
Product
8
1
3ca
60
2
0
6
3
3cd
101
101 (99)
58
0
4
3ce
0
109 (99)
83
32
0
1
3cb
74 (76)
44
47
2
3cf
82 (88)
103
56
32
3df
A
B
C
D
6
73 (99)
49
3da
0
0
3dc
41
1d
3db
3dd = 3cb
3de
aAll reactions were conducted in CPME at rt. Numbers in brackets
correspond to isolated yields on laboratory scale. b3 equiv of
diarylmethane and 2 equiv of base were used with substrate 2c.
5
25
Figure 2 shows the most promising results obtained from the
HTE screen. We observed that pꢀbromobenzonitrile (2g) and 2ꢀ
bromopyridine (2i) rendered the desired product in good assay
30 yield (high ratio product/internal standard) with at least one set of
conditions used. The promising leads were then scaled to
laboratory scale. Conditions A [LiN(SiMe3)2/6 equiv 12ꢀcrownꢀ
4] with pꢀbromobenzonitrile (2g) was the most effective affording
67% isolated yield of the desired coupled product (3ag). In
35 contrast, 34% isolated yield was obtained with Conditions B
[NaN(SiMe3)2/30 mol % 15ꢀcrownꢀ5]. These results represented
a significant improvement over those of the control using
KN(SiMe3)2, which afforded the corresponding triarylmethane
3ag in only 16% isolated yield.
We next decided to probe the utility of the four sets of additive
conditions and explore the crossꢀcoupling reaction with six
10 challenging aryl bromides (2g–2l) that failed or gave very low
yields of desired products with diphenylmethane (1a) under the
original conditions using KN(SiMe3)2 in CPME.6 HTE in 1 mL
vials was used to screen these 24 reactions (Scheme 7).
40
Because functionalization of pyridines and related heterocycles
is very important in medicinal chemistry,32 we examined
heteroaryl bromide substrates 2i–2l. 2ꢀBromopyridine (2i)
successfully underwent DCCP affording 75% isolated yield of
desired product 3ai with Conditions A and 37% isolated yield
15
45 with Conditions B. No product was observed with the control,
KN(SiMe3)2 or in the absence of the palladium catalyst with
KN(SiMe3)2. In the case of pꢀBrꢀC6H4ꢀCO2Et (2h), the only
product observed in moderate yield corresponded to the attack of
the diphenylmethyl anion on the carbonyl group of ester. With
Scheme 7 DCCP of aryl bromides 2g–2l with 1a using Conditions A–D.
6
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substrates
3ꢀbromopyridine,
2ꢀbromothiophene,
or
3ꢀ
bromothiophene (2j–l), no triarylmethane products were observed
in the presence or absence of additives under our current DCCP
conditions and remain challenging.
ArBr
5
2i
2g
ArCH2Ar’
Conditionsa
Resultsb
A
LiN(SiMe3)2, 6 equiv 12ꢀCꢀ4
92
(86)
83
95
B
C
NaN(SiMe3)2, 30 mol % 15ꢀCꢀ5
NaN(SiMe3)2, 6 equiv HMTETA
83
107
(96)
69
D
NaN(SiMe3)2, 6 equiv diglyme
CONTROL ꢀ KN(SiMe3)2
54
20
44
74
1b
1c
Product
3bg
0
0
0
0
3bi
<6
0
0
0
0
3ci
83
(85)
A
B
C
D
LiN(SiMe3)2, 6 equiv 12ꢀCꢀ4
NaN(SiMe3)2, 30 mol % 15ꢀCꢀ5
NaN(SiMe3)2, 6 equiv HMTETA
NaN(SiMe3)2, 6 equiv diglyme
CONTROL ꢀ KN(SiMe3)2
Product
0
3cg
A
B
LiN(SiMe3)2, 6 equiv 12ꢀCꢀ4
0
NaN(SiMe3)2, 30 mol % 15ꢀCꢀ5
18
(26)
3
0
14
3dg
60
C
D
NaN(SiMe3)2, 6 equiv HMTETA
NaN(SiMe3)2, 6 equiv diglyme
CONTROL ꢀ KN(SiMe3)2
Product
0
0
0
1d
Fig. 2 Most promising results from HTE screen under different
conditions. Substrates 2g and 2i showed better reactivity than the control
reaction. aConditions A: LiN(SiMe3)2, 6 equiv 12ꢀcrownꢀ4, CPME, rt;
3di
aAll reactions were conducted in CPME at rt; bResults correspond to assay
35 yields based on 1H NMR of the crude mixture. Control results correspond
1
10 Conditions B: NaN(SiMe3)2, 30 mol % 15ꢀcrownꢀ5, CPME, rt; Conditions
to H NMR yields from the crude mixture on laboratory scale. Numbers
C: NaN(SiMe3)2,
6 equiv HMTETA, CPME, rt; Conditions D:
in brackets correspond to isolated yields on laboratory scale.
NaN(SiMe3)2, 6 equiv diglyme, CPME, rt. bIY: isolated yield on
laboratory scale.
The additive systems enabled access to four new products
40 (3bg, 3bi, 3dg and 3di) in good to excellent yields and in all
cases, superior results were obtained compared to control
conditions with KN(SiMe3)2 (see Table 3). pꢀBromobenzonitrile
(2g) showed excellent reactivity with diarylmethane 1b under
Conditions A and B. The product (3bg) was obtained in 86%
45 isolated yield using Conditions A. No reactivity was observed
when 2g was allowed to react with 1c while only Conditions B
rendered product 3dg although in poor yield (26% isolated yield).
Substrate 2i gave the corresponding product 3bi in high yield
under Conditions A–C with C being the most promising (96%
50 isolated yield). Product 3di was achieved in 85% isolated yield
using Conditions A but no desired product was observed for the
reaction of 2i with diarylmethane 1c. Substrate 1c is the least
acidic diarylmethane of those examined in this study.
15
Having proved that substrates 2g and 2i successfully
underwent DCCP with diphenylmethane (1a) under Conditions A
and B, we decided to explore their reactivity with diarylmethanes
1b–1d using Conditions A–D. HTE in 1 mL vials was employed
to screen these 24 reactions. Table 3 summarizes the results
1
20 obtained from this screening. Assay yields (based on H NMR
spectroscopy and HPLC analysis) were obtained for each
combination of aryl bromide and diarylmethane (see Supporting
Information for details).
25 Table 3 Crossꢀcoupling reaction of aryl bromides 2g and 2i with
diarylmethanes 1b–1d under Conditions AꢀD.
55
Overall, twenty six triarylmehtane derivatives were
synthesized in good to excellent yields using the additives. In
particular, ten of the compounds prepared showed better results
with the additive conditions than under the control conditions
using KN(SiMe3)2 in CPME in the absence of additive.6 This is
30
60 impressive when it is considered that in the original study of 33
substrate combinations with the KN(SiMe3)2, the triarylmethane
products were isolated with an average yield of 91%.
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funding.
Conclusions
Lewis basic additives can dramatically alter the outcome of
reactions by coordination to reagents that possess mainꢀgroup
metals. Despite the well known beneficial impact of additives in
a diverse range of chemical transformations, we are not aware of
thorough studies concerning the effect of Lewis basic additives
on metalꢀcatalyzed C–H arylation reactions involving
deprotonation of substrates possessing weakly acidic C–H bonds.
This class of reactions is very important and includes enolate Cꢀ
Notes and references
60 Roy and Diana Vagelos Laboratories, Penn/Merck High-Throughput
Experimentation Laboratory, Department of Chemistry, University of
Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-
6323, United States. Fax: +1-2155736743; Tel: +1-2155732875; E-mail:
pwalsh@sas.upenn.edu
5
65
† Electronic Supplementary Information (ESI) available: Data for new
compunds, experimental procedures, copies of H and 13C NMR spectra.
1
10 arylation processes and the DCCP of diarylmethanes, among
others.
See DOI: 10.1039/b000000x/
In this report, we have conducted a study on the use of
additives in the DCCP of sp3 C−H bonds of diphenylmethane
derivatives with aryl bromides to form synthetically useful
15 triarylmethanes. A number of potential monoꢀ and polydentate
Lewis basic additives were selected for examination. Highꢀ
throughput experimentation techniques were employed on
microscale to rapidly identify the most promising additives and
guide the optimization of the reaction conditions (additive
20 stoichiometry, base, solvent and temperature). These studies
have resulted in development of four efficient Pdꢀcatalyzed
procedures that rely on additives to enable the generation of a
range of arylꢀ and heteroaryl containing triarylmethanes. The
most useful additives discovered for this process are polydentate
25 ethers (12ꢀcrownꢀ4, 15ꢀcrownꢀ5, and diglyme), and the
tetradentate amine 1,1,4,7,10,10ꢀhexamethyltriethylenetetramine
(HMTETA). A benefit of these additives is that all are
70
1
a) A. de Meijere and F. E. Diederich, Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed., Wileyꢀ VCH: Weinheim, 2004;
b) F. Diederich and P. J. Stang, Metal-Catalyzed Cross-
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Miyaura, Cross-Coupling Reactions.
A Practical Guide,
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80
commercially available and relatively inexpensive.
It is
85
particularly noteworthy that the bases used in these new
30 procedures, LiN(SiMe3)2 and NaN(SiMe3)2, fail to promote
formation of detectable amounts of triarylmethane coupling
products with unactivated diarylmethanes in the absence of the
additives. Presumably these additives enhance the reactivity of
LiN(SiMe3)2 and NaN(SiMe3)2 by coordination to the main group
35 metal and reducing their aggregation state.38 It is interesting to
note that in the combination of NaN(SiMe3)2 with 15ꢀcrownꢀ5,
the crown ether is used in sub stoichiometric quantity (30 mol %).
In contrast to LiN(SiMe3)2 and NaN(SiMe3)2, the use of
KN(SiMe3)2 with additives gives inferior results relative to
40 reactions without additives. Finally, it is important to mention
90
3
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95
that the new procedures employing additives result in
a
significant improvement in the reaction yields with certain
substrates. In the most striking example, 2ꢀbromopyridine, which
failed to undergo DCCP under the original conditions with
45 KN(SiMe3)2, resulted in 75% yield with LiN(SiMe3)2 and 12ꢀ
crownꢀ4.
100
105
110
Because a variety of important C−H functionalizations involve
a
deprotonation step (Sonogashira reaction, αꢀarylation of
carbonyl compounds, benzylic C−H arylations of aromatics and
50 heteroaromatics, etc) we envision potential applications of the
additives outlined herein to facilitating these classes of reactions
and thus enabling increased access to chemical diversity and to
the discovery of new reactions.
4
5
Acknowledgements
G. I. McGrew, C. Stanciu, J. Zhang, P. J. Carroll, S. D. Dreher
and P. J. Walsh, Angew. Chem. Int. Ed., 2012, doi:
10.1002/anie.201201874.
55 We thank the National Science Foundation [CHEꢀ0848460,
(GOALI), 0848467 and 1152488 to PJW] for support of this
research. NT acknowledges Mahidol University (Thailand) for
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TABLE OF CONTENTS
Additive Effects on Palladium-Catalyzed Deprotonative-Cross-Coupling Processes
(DCCP) of sp3 C−H Bonds in Diarylmethanes
Ana Bellomo, Jiadi Zhang, Nisalak Trongsiriwat and Patrick J. Walsh*
Roy and Diana Vagelos Laboratories, Penn/Merck High-Throughput Experimentation
Laboratory
Department of Chemistry, University of Pennsylvania, 231 South 34th Street,
Philadelphia, Pennsylvania (United States)
E-mail: pwalsh@sas.upenn.edu
Phone: +1-2155732875; Fax: +1-2155736743
We describe the use of additives in Pd-catalyzed DCCP of unactivated sp3 C−H bonds
of diarylmethanes with aryl bromides.