Palladium-catalyzed C(sp3)-H arylation of diarylmethanes at room temperature: Synthesis of triarylmethanes via deprotonative-cross-coupling processes

Article abstract of DOI:10.1021/ja3047816

Although metal-catalyzed direct arylation reactions of non- or weakly acidic C-H bonds have recently received much attention, chemists have relied heavily on substrates with appropriately placed directing groups to steer reactivity. To date, examples of intermolecular arylation of unactivated C(sp³)-H bonds in the absence of a directing group remain scarce. We report herein the first general, high-yielding, and scalable method for palladium-catalyzed C(sp³)-H arylation of simple diarylmethane derivatives with aryl bromides at room temperature. This method facilitates access to a variety of sterically and electronically diverse hetero- and nonheteroaryl-containing triarylmethanes, a class of compounds with various applications and interesting biological activity. Key to the success of this approach is an in situ metalation of the substrate via C-H deprotonation under catalytic cross-coupling conditions, which is referred to as a deprotonative-cross-coupling process (DCCP). Base and catalyst identification were performed by high-throughput experimentation (HTE) and led to a unique base/catalyst combination [KN(SiMe₃)₂/Pd-NiXantphos] that proved to efficiently promote the room-temperature DCCP of diarylmethanes. Additionally, the DCCP exhibits remarkable chemoselectivity in the presence of substrates that are known to undergo O-, N-, enolate-, and C(sp²)-H arylation.

Full text of DOI:10.1021/ja3047816

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Article
Palladium-Catalyzed C(sp3)–H Arylation of Diarylmethanes
at Room Temperature: Synthesis of Triarylmethanes
via Deprotonative-Cross-Coupling Processes (DCCP)
Jiadi Zhang, Ana Bellomo, Andrea D. Creamer, Spencer D. Dreher, and Patrick J Walsh
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja3047816 • Publication Date (Web): 20 Jul 2012
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Palladium-Catalyzed C(sp3)–H Arylation of Diarylmethanes at Room
Temperature: Synthesis of Triarylmethanes via Deprotonative-
Cross-Coupling Processes (DCCP)
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Jiadi Zhang,a,c Ana Bellomo,a,c Andrea D. Creamer,a Spencer D. Dreher,*,b and Patrick J. Walsh*,a
aRoy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chem-
istry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States, bDepartment
of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States. c These
authors contributed equally.
Supporting Information Placeholder
ABSTRACT: Although metal catalyzed direct arylation reactions of non- or weakly acidic C–H bonds have recently received
much attention, chemists have relied heavily on substrates with appropriately placed directing groups to steer reactivity. To date,
examples of intermolecular arylation of unactivated C(sp3)–H bonds in the absence of a directing group remain scarce. We report
herein the first general, high-yielding, and scalable method for palladium-catalyzed C(sp3)–H arylation of simple diarylmethane
derivatives with aryl bromides at room temperature. This method facilitates access to a variety of sterically and electronically di-
verse hetero- and non-heteroaryl-containing triarylmethanes, a class of compounds with various applications and interesting biolog-
ical activity. Key to the success of this approach is an in situ metallation of the substrate via C–H deprotonation under catalytic
cross-coupling conditions, which is referred to as a deprotonative-cross-coupling process (DCCP). Base and catalyst identification
were performed by high throughput experimentation (HTE) and led to a unique base/catalyst combination [KN(SiMe3)2/Pd–
NiXantphos] that proved to efficiently promote the room-temperature DCCP of diarylmethanes. Additionally, the DCCP exhibits
remarkable chemoselectivity in the presence of substrates that are known to undergo O-, N-, enolate-, and C(sp2)–H arylation.
Directed C(sp3)–H Arylation (EDG=electron donating group,
1. INTRODUCTION
LG=leaving group).
Traditional approaches
This work
C.
Triarylmethane
derivatives
are
well-known
substructures in several areas, including leuco dye precursors,1
photochromic agents,2 and applications in materials science.3
They are also important in medicinal chemistry as
antitubercular,4 anticancer,5 and antiproliferative6 agents,
among others.7,8 For the past decade, advances in the catalytic
synthesis of triarylmethanes were largely based on two
A. Friedel-Crafts
C–H Functionalization
Ph
Ph
LG
+
Ar–EDG
H
H
Ar
Ar–X
+
Ph
Ph
Ph
Ph
B.
Cross-Coupling
Ph
Ph
OC(O)OR
approaches9:
(1)
Friedel-Crafts-type
arylations
of
Ar–B(OH)2
+
diarylmethanols or diarylmethylamines (Scheme 1A)10,11 and
(2) cross-coupling reactions between diarylmethyl carbonates
with arylboronic acids (Scheme 1B).12 Despite the popularity
of these methods, both have drawbacks. Friedel-Crafts-type
arylations typically have significant electronic and steric
limitations, being largely limited to electron-rich and
We recently introduced a novel approach toward the
catalytic synthesis of di- and triarylmethanes based on an η6-
arene-activation strategy. Initial studies employed readily
available (η6-PhCH2Z)Cr(CO)3 complexes (Z=Ph, H, OR,
NR2, eq 1).13
Arylations of η6-coordinated toluene,
unhindered nucleophiles.
Additionally, mixtures of
diphenylmethane, benzyl ethers, and benzyl amines were
readily achieved. Although proof-of-concept of this approach
was demonstrated, the stoichiometric use of chromium
precludes large-scale applications of this chemistry. As
outlined in Scheme 1C, we envisioned a chromium-free direct
arylation approach involving C(sp3)–H bonds of
diphenylmethane derivatives.
regioisomeric products are often obtained. Cross-coupling
methods require prefunctionalization of the coupling partners
and occasionally give moderate yield, complicated by
formation of homocoupling byproducts.12a
Scheme 1. Synthetic Approaches to Triarylmethanes: (A)
Friedel-Crafts Reaction, (B) Cross-Coupling, and (C) Non-
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most substrates (down to 1.2:1), and commercial availability
of Pd source and ligand.
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2. RESULTS AND DISCUSSION
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The first objective towards developing DCCPs is to
identify conditions for the deprotonation of diphenylmethane
(Ph2CH2). Diphenylmethane is weakly acidic, with a pKa of
32.3 in DMSO.18 The benzylic C–H’s in diphenylmethane
have traditionally been deprotonated with n-BuLi at –78 °C19
or NaNH2 and KNH2 in liquid ammonia.20,21 These conditions
were viewed as cumbersome and impractical because of the
low temperature and strongly basic media. We therefore fo-
cused on identifying conditions for the reversible in situ
deprotonation of diphenylmethane that would be mild and
compatible with the catalyst, reagents, and products in the
DCCP. The second challenge is the discovery of catalysts
suitable for cross-coupling processes at room temperature.
Prior reports on coupling with diarylmethane deriva-
tives have employed various activation strategies to decrease
the pKa of the substrates. As mentioned above, we activated
benzylic C–H’s through coordination to the Cr(CO)3 (eq
1).13,22 Miura has employed substrates bearing strong electron-
withdrawing groups on the aryl ring, as exemplified by 4-
nitrotoluene (pKa 20.4, eq 2).23 2-Benzyl- (eq 3) and 2-methyl
heteroarenes (eq 4) are significantly more acidic than diphe-
nylmethane, and have been successfully employed DCCPs.17a,c
Deprotonation of these substrates can be facilitated by binding
of the substrates’ nitrogen to Lewis acidic species in solution.
All three approaches required high temperatures (typically
130–150 °C). However, these methods fail with diarylme-
thane substrates such as 3-benzylpyridine and diphenylme-
thane itself.
Although metal catalyzed cross-coupling reactions to
form C–C bonds have become a mainstay in organic synthe-
sis,14 metal catalyzed direct arylation reactions of C(sp3)–H
bonds possess distinct advantages.15,16 Compared with tradi-
tional cross-coupling reactions with prefunctionalized partners
(Scheme 1B), C–H arylation reactions are efficient, atom-
economical, and minimize the costs of prefunctionalization.
Great progress has been made in direct arylations of activated
C(sp3)–H bonds alpha to electron-withdrawing groups, such as
ketones, esters, and amides, among others (Scheme 2A).15 In
contrast, much less success has been achieved with the more
challenging functionalization of non- or weakly acidic C(sp3)–
H bonds. To facilitate reactions at the unactivated C(sp3)–H
bonds (those with pKa > 3016d), chemists have relied heavily
on substrates with appropriately placed directing groups to
steer reactivity (Scheme 2B).16a–d Although this approach
avoids classical prefunctionalization of substrates, the addition
and removal of directing groups often offsets any gain in syn-
thetic efficiency provided by the direct C(sp3)–H functionali-
zation. To date, intermolecular arylation of C(sp3)–H bonds in
the absence of directing groups remains a formidable chal-
lenge.17
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Scheme 2. Catalytic C(sp3)–H Arylations
2.1.
Deprotonation/Benzylation of Diphenylmethane.
Development of Room-Temperature
We
To streamline the synthesis of triarylmethanes, we
set out to develop a general room-temperature directing
group-free method employing simple diarylmethane deriva-
tives. To increase the practicality and utility of the method,
we restricted our efforts to in situ metallation of the substrate
via C–H deprotonation under catalytic cross-coupling condi-
tions, and will refer to these transformations as deprotonative-
cross-coupling processes (DCCP) (Scheme 2C). Herein we
report a palladium-catalyzed DCCP that fulfills these require-
ments. The advantages of this method are: mild and reversible
substrate deprotonation simply by mixing diarylmethanes with
KN(SiMe3)2, good functional group tolerance and chemoselec-
tivity, nearly stoichiometric ratios of coupling partners for
decided to separate the challenges of identifying the
deprotonation conditions from the development and
optimization of the catalyst. We, therefore, first examined
diphenylmethane deprotonation step to determine the
suitability of the substrate/base combinations. As a surrogate
for the transmetallation step in the DCCP, we began with a
deprotonation/benzylation reaction employing benzyl chloride
(Scheme 3). A large number of variables for reagents and
conditions were to be simultaneously examined, including: (1)
base strength, (2) base nucleophilicity, (3) choice of main-
group counterion (M=Li, Na, K), (4) stoichiometry, (5)
solvent, (6) concentration and (7) temperature. Based on our
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previous experience with DCCP of (η6-PhCH2Z)Cr(CO)3
We initially evaluated the reaction of diphenylme-
complexes,13,22 the choice of base would be critical for both
deprotonation and cross-coupling. To perform this study in
the most efficient manner, we employed low-barrier
thane (1a) with 1-bromo-4-tert-butylbenzene (2a) using 112
sterically and electronically diverse, mono- and bidentate
phosphine ligands and different Pd(0) and Pd(II) sources on a
10 µmol scale at 110 °C (see Supporting Information for de-
tails). To our surprise, only one ligand from the entire collec-
tion, NiXantphos26 (see Table 1 for the structure), afforded an
excellent HPLC assay yield (AY) of the corresponding DCCP
product 3aa (93% AY from Pd(PPh3)2Cl2/NiXantphos and
100% AY from Pd(OAc)2/NiXantphos). These microscale
reactions were successfully translated to laboratory scale (0.1
mmol) under the same conditions.
microscale
high-throughput
experimentation
(HTE)
techniques.24
Using 12 diverse bases [LiN(SiMe3)2,
NaN(SiMe3)2, KN(SiMe3)2, LiO-t-Bu, NaO-t-Bu, KO-t-Bu,
LDA, LiH, KH, LiOH, KOH, and K2CO3] revealed that the
combination of 4 equiv of diphenylmethane and 4 equiv of
KN(SiMe3)2 with 1 equiv of benzyl chloride in dioxane at 110
°C was the most promising hit. Translation of this lead to
laboratory scale (0.1 mmol) under the same conditions showed
excellent reproducibility and rendered the benzylation product
in 92% yield (eq 5). Surprisingly, results of the HTE
experiments indicated the only base leading to in situ
deprotonation/benzylation product was KN(SiMe3)2. Neither
LiN(SiMe3)2, NaN(SiMe3)2 nor MO-t-Bu (M = Li, Na, K)
showed any reactivity (on both microscale or laboratory
scale). Decreasing the reaction temperature from 110 °C to 24
°C resulted in 78% yield of the benzylation product (eq 5).
Note that benzyl chloride did not react with bulky KN(SiMe3)2
on the timescale of the benzylation of diphenylmethane.
Unlike bases previously used to deprotonate diphenylmethane
(n-BuLi, NaNH2, and KNH2), KN(SiMe3)2 has a high
likelihood of compatibility with catalyst, reagents, and
products in catalytic DCCP (Scheme 3).25
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Although the combination of Pd(OAc)2 and
NiXantphos as precatalyst afforded the triarylmethane product
3aa in excellent yield in the presence of 4 equiv of diphenyl-
methane (1a), 1 equiv of aryl bromide (2a), and 3 equiv of
KN(SiMe3)2 in dioxane at 110 °C (Table 1, entry 1), further
optimization was desired to reduce the equivalents of diphe-
nylmethane and the reaction temperature.
Table 1. Optimization of Pd-Catalyzed DCCP of 1aa
Scheme 3. Benzylation Used as Surrogate for the Transmetal-
lation Step in DCCP
a
Reactions conducted on a 0.1 mmol scale using 1 equiv of
b
2a, 3 equiv of KN(SiMe3)2, and 1a at 0.1 M. Yield deter-
mined by 1H NMR spectroscopy of the crude reaction mixture.
c
d
Isolated yield after chromatographic purification.
assay yield of HTE conducted on a 10 µmol scale.
HPLC
Reducing the equivalents of diphenylmethane from 4
to 2 and 1.2 in dioxane at 110 °C resulted in a drop in triaryl-
methane yield from >95% to 77% (Table 1, entries 2–3). Fur-
thermore, the reaction at 24 °C gave moderate yield compared
with that at 110 °C (Table 1, entry 4 vs. 3). To reduce both the
equivalents of diphenylmethane and reaction temperature
without compromising the yield, 4 ethereal solvents [dioxane,
THF, 2-MeTHF and CPME (cyclopentyl methyl ether)] and 3
temperatures (24 °C, 50 °C, and 70 °C) were examined. The
best result was obtained when CPME was used as solvent,
where the triarylmethane 3aa was generated in >95% yield
from 1.2 equiv of diphenylmethane, 1 equiv of aryl bromide
2a, and 3 equiv of KN(SiMe3)2) at 24 °C (Table 1, entry 5).
The triarylmethane 3aa was ultimately isolated on laboratory
scale in 95% yield after flash chromatography (Table 1, entry
5).
2.2. Development and Optimization of Palladium-
Catalyzed DCCP of C(sp3)–H of Diarylmethanes. We next
turned our attention to the development of a Pd-catalyzed
DCCP of C(sp3)–H of diarylmethanes. Essential to accom-
plish this goal was the rapid identification of reagents and
conditions from HTE on a 10 µmol scale. These efforts are
summarized in Scheme 4, where the variables examined with
cumulative HTE are numbered (see Supporting Information
for details).
Scheme 4. HTE Variables in Pd-Catalyzed DCCP of Diaryl-
methanes
Control experiments conducted in the absence of any
reagent, ligand, or palladium from the reaction mixture above
resulted in no product. These optimized conditions were car-
ried forward in the next phase of the project, which focused on
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the determination of the scope of diarylmethane derivatives in
Pd-catalyzed DCCP.
THF) due to the low solubility of the substrates in CPME at 24
°C. In addition to nitrogen-containing substrates, 2-
benzylthiophene (1q) and 3-benzylthiophene (1r) underwent
DCCP at 24 °C to afford corresponding products 3qa and 3ra
in 99% and 77% yield, respectively. To summarize this meth-
od enables the synthesis of a variety of triarylmethanes from
diarylmethanes bearing ortho-substitution and with electron-
donating, electron-withdrawing, and heteroaryl groups.
2.3. Scope of Diarylmethanes in Palladium-
Catalyzed DCCP. The scope of the DCCP with various dia-
rylmethanes and 1-bromo-4-tert-butylbenzene (2a) is present-
ed in Table 2. These reactions were conducted at 24 °C, ex-
cept where noted. Substrates bearing various substituents on
the diarylmethane exhibited excellent reactivity. Alkyl groups
(3ba, 3ca, 3da), ortho-substituents (3da, 3ea), electron-
withdrawing (3fa, 3ga), and electron-donating groups (3ij)
were all well tolerated. Although 4-methoxydiphenylmethane
(1i) reacted with 2a to give >95% conversion to the desired
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Table 2. Scope of Diarylmethanes in Pd-Catalyzed DCCPa,b
Ar2
Ar2
5 mol % Pd(OAc)2
7.5 mol % NiXantphos
Br
+
Ar1
H
Ar = 4-tBu-C6H4
Ar1
Ar
KN(SiMe3)2 (3 equiv)
CPME, 24 oC, 12 h
tBu
1a-1r
2a
3aa-3ra
1
triarylmethane product 3ia (as determined by H NMR of the
crude reaction mixture), 3ia was inseperable from the starting
diarylmethane (1i) by flash chromatography. The reaction of
1i with 4-bromo-N,N-dimethylaniline (2j) afforded the desired
triarylmethane product 3ij in 97% isolated yield. Interesting-
ly, 4-benzylbenzoic acid (1h) proved to be suitable substrate
providing the corresponding product 3ha in 93% yield at 110
°C. In addition to increasing the temperature, an extra equiv
of KN(SiMe3)2 was necessary to convert the starting acid into
a potassium salt.
Ar
Ar
Ar
Ar
Ph
Ph
Ph
3aa 95%
3ba 81%
3ca 98%
3da 88%
Cl
F
HOOC
Ar
Ar
Ar
Ar
Ph
Ph
Ph
Ph
After demonstrating that our method was compatible
3ea 99%
3fa 89%
3ga 96%
3ha 93%c,d
with various diarylmethanes with different steric and electron-
ic properties, we examined cyclic diarylmethane analogues.
Both xanthene (1j) and fluorene (1k) proved to be good sub-
strates, with corresponding products isolated in 99% (3ja) and
87% (3ka) yield. Note that the reaction with fluorene (1k)
was run in THF at 85 °C due to solubility issues in CPME at
24 °C.
H3CO
H3CO
O
Ar
Ar
Ar
N(CH3)2
Ph
Ph
3ia >95%g
3ij 97%
3ka 87%e
3ja 99%
The next family of substrates examined was het-
H
N
N
N
eroaromatic diarylmethane derivatives, which are known for
their utility in medicinal chemistry.27 3-Benzyl-1H-indole did
not participate in the DCCP with 2a under the optimized con-
ditions, probably due to the decreased acidity of the benzylic
hydrogens after deprotonation of the free N–H.28a Fortunately,
DCCP proceeded with the N–Boc substrate in the presence of
4 equiv of KN(SiMe3)2 to furnish the indole-containing tri-
arylmethane product 3la in 89% isolated yield. Notably, 3la
was isolated in the deprotected 1H-indole form. The observed
reactivity of 3-benzyl-1H-indole and its N–Boc analogue sug-
gested that 3la was formed via DCCP with subsequent N–Boc
deprotection under the reaction conditions. Pyridine substrates
bearing benzyl groups on different position were also exam-
ined. Isomeric 2-, 3-, and 4-benzylpyridine substrates all un-
derwent DCCP smoothly to afford high yields of pyridine-
containing triarylmethane products (3ma, 3na, 3oa, 3pa).
Although 2- and 4-benzylpyridine were known to participate
in Pd-catalyzed DCCP at reflux in xylene, DCCP reactions
with 3-benzylpyridine failed in prior studies even under vigor-
ous conditions.17a The lack of reactivity of 3-benzylpyridine
under previously reported conditions is likely due to its higher
pKa (30.1) compared with 2- and 4-benzylpyridines (pKa =
28.2 and 26.7, respectively).28b It is noteworthy that 3-
benzylpyridine affords the product in 98% yield at 24 °C with
our procedure. In addition to 3-benzylpyridine, 3-(3,5-
difluorobenzyl)pyridine (1p) was successfully arylated to af-
ford 3pa in 93% isolated yield. Elevated temperatures were
required for 4-benzylpyridine to give 3na (110 °C in CPME)
and 3-(3,5-difluorobenzyl)pyridine to furnish 3pa, (85 °C in
N
Ar
Ar
Ar
Ar
Ph
Ph
Ph
Ph
3la 89%c
3ma 96%
3na 99%d
3oa 98%
N
S
S
Ar
Ar
Ar
F
Ph
Ph
F
3pa 93%e
3qa 99%f
3ra 77%
a
Reactions conducted on a 0.1 mmol scale using 1 equiv of
b
2a, 3 equiv of KN(SiMe3)2, and 1.2–3 equiv of 1 at 0.1 M.
Isolated yield after chromatographic purification. 4 equiv of
c
d
e
f
KN(SiMe3)2.
110 °C.
85 °C in THF.
1.5 equiv of
KN(SiMe3)2. Yield determined by 1H NMR spectroscopy of
g
the crude reaction mixture.
2.4. Scope of Aryl Bromides in Palladium-
Catalyzed DCCP. The scope of the DCCP with respect to
aryl bromides was next explored with diphenylmethane (1a)
(Table 3). Phenyl and 2-naphthyl bromides furnished 3ac and
3ad in 92% and 99% yield, respectively. Aryl bromides bear-
ing various substituents exhibited good to excellent reactivity.
Alkyl groups (3aa, 3ab), ortho-methyl (3ae), electron-
withdrawing groups (3af, 3ag, 3ah), and electron-donating
groups (3ai, 3aj, 3ak) were all well tolerated. 1-Bromo-4-
chlorobenzene (2g) reacted with 1a to produce 3ag as the ex-
clusive product in 71% isolated yield. No products derived
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from Ar–Cl oxidative addition were observed. The difference
To illustrate the practical utility of our method, we
examined its scalability by conducting the reaction of 1a with
2a on a 4 mmol scale, which afforded 1.14 grams of 3aa (95%
isolated yield, eq 6). We were also able to reduce the catalyst
loading to 1.0 mol % with only a minor drop in yield (eq 7).
in reactivity of C–Cl and C–Br bonds in 2g is in accordance
with previous studies on oxidative addition of haloarenes.29
To demonstrate the advantage of the mild conditions of our
method over the previous deprotonation conditions using n-
BuLi, NaNH2, and KNH2, we then tested substrates bearing
sensitive functional groups. As shown in Table 3 remarkable
chemoselectivity is observed with aryl bromides containing
acetal, amide, phenol, acetyl, and 1H-indole moieties, which
all underwent DCCP delivering the corresponding functional-
ized products in 78–96% yield (3al–3ap). Ketones are well
known to undergo 1,2-carbonyl addition reactions with reac-
tive organometallics. 4-Bromoacetophenone might be ex-
pected to participate in competitive aldol chemistry30 and α-
arylation of the enolate derived from deprotonation15 under the
basic conditions of the reaction (pKa of acetophenone in
DMSO: 24.731). Yet the triarylmethane 3ao was produced in
86% yield. Phenols are known to undergo O- and C(sp2)–H
arylation32 while 1H-indoles have been reported to react via N-
arylation (Buchwald-Hartwig coupling),33 C-2-, and C-3-
arylation34 in the presence of palladium catalysts and bases.
Our method exhibits orthogonal chemoselectivity with aryla-
tion taking place selectively at the benzylic C(sp3)–H’s. These
functional groups present opportunities to further functionalize
the triarylmethane products. It is noteworthy that for 4-
bromo-N-methylbenzamide (2m), 4-bromophenol (2n) and 5-
bromoindole (2p), an extra equiv of KN(SiMe3)2 as well as
elevated temperature (110 °C) were employed to raise the
yield to 82% (3am), 95% (3an) and 78% (3ap), respectively.
For substrates giving less than 80% yield in Table 3 (3ag, 3ah,
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3. SUMMARY AND OUTLOOK
We have developed the first general, high-yielding,
and scalable method for the palladium-catalyzed C(sp3)–H
arylation of diarylmethanes at room temperature. This method
circumvents the traditional low-temperature deprotonation
conditions with strong bases and the high temperature cross-
coupling conditions employed previously with more acidic,
activated diarylmethane substrates. Our DCCP affords a vari-
ety of triarylmethane derivatives, a class of compounds with
various applications and biological activity. Additionally, the
DCCP exhibits remarkable chemoselectivity in the presence of
substrates that are known to undergo O-, N-, enolate-, and
C(sp2)–H arylation.
1
3ap), H NMR of the reaction mixture after work-up and re-
moval of volatiles showed no byproduct formation. The
DCCP products were easily separated from the unreacted di-
phenylmethane by flash chromatography.
Table 3. Scope of Aryl Bromides in Pd-Catalyzed DCCPa,b
The development of the DCCP was accomplished by
solving two challenging interdependent problems: 1) to identi-
fy deprotonation conditions for diphenylmethane (pKa 32.3)
and related weakly acidic derivatives that would be amenable
to catalysis, and 2) to find a catalyst that would be compatible
with the deprotonation conditions and promote the cross-
coupling. Our approach to these two challenges was to sepa-
rate them by employing a deprotonation/benzylation protocol
as a surrogate for the deprotonation/transmetallation of the
desired catalytic cycle. Interestingly, only a single base,
KN(SiMe3)2, of the 12 examined, worked for the benzylation.
Once the base had been identified, a search for a catalyst was
conducted by screening 112 phosphine ligands and several
palladium sources. The use of the HTE tools enabled rapid
identification of the Pd(OAc)2/NiXantphos combination as an
excellent catalyst system for DCCP at room temperature. In
hindsight, it is unlikely that we would have identified a rea-
sonable catalyst system given that a single base/ligand combi-
nation was found to be successful. This translates to 1 out of
1344 combinations (12 bases × 112 ligands) of the two most
important variables.
a
Reactions conducted on a 0.1 mmol scale using 1 equiv of
aryl bromide, 3 equiv of KN(SiMe3)2, and 1.2–3 equiv of di-
phenylmethane at 0.1 M. b Isolated yield after chromatograph-
The broad scope and mild conditions of the DCCP
c
d
outlined herein make it a valuable contribution to applications
in non-directed transition metal-catalyzed arylation of C(sp3)–
H bonds for the synthesis of triarylmethanes. Mechanistic
studies to understand how the Pd(OAc)2/NiXantphos combina-
ic purification.
2 equiv of KN(SiMe3)2.
4 equiv of
KN(SiMe3)2. e 110 °C.
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tion promotes the room-temperature DCCP of diarylmethanes
are underway in our laboratory.
ꢀL, 0.12 mmol, 1.2 equiv) was added to the reaction mixture
followed by 1-bromo-4-tert-butylbenzene (17.3 ꢀL, 0.1 mmol,
1 equiv). Note that the diarylmethane or aryl bromide in a
solid form was added to the reaction vial prior to KN(SiMe3)2.
The reaction mixture was stirred for 12 h at 24 °C, quenched
with two drops of H2O, diluted with 3 mL of ethyl acetate, and
filtered over a pad of MgSO4 and silica. The pad was rinsed
with additional ethyl acetate, and the solution was concentrat-
ed in vacuo. The crude material was loaded onto a silica gel
column and purified by flash chromatography.
4. EXPERIMENTAL SECTION
Representative procedures are described herein. Full
experimental details and characterization of all compounds are
provided in the Supporting Information.
4.1. General Methods. All reactions were per-
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formed under nitrogen using oven-dried glassware and stand-
ard Schlenk or vacuum line techniques. Air- and moisture-
sensitive solutions were handled under nitrogen and trans-
ferred via syringe. Anhydrous CPME, dioxane, and 2-MeTHF
were purchased from Sigma-Aldrich and used as solvent with-
out further purification. Unless otherwise stated, reagents
were commercially available and used as purchased without
further purification. Chemicals were obtained from Sigma-
Aldrich, Acros, TCI America or Matrix Scientific, and sol-
vents were purchased from Fisher Scientific. The progress of
the reactions was monitored by thin-layer chromatography
using Whatman Partisil K6F 250 ꢀm precoated 60 Å silica gel
plates and visualized by short-wavelength ultraviolet light as
well as by treatment with ceric ammonium molybdate (CAM)
stain or iodine. Silica gel (230–400 mesh, Silicycle) was used
4.4. General Procedure C. HTE for Palladium-
Catalyzed DCCP of Diphenylmethane. Experiments were
set up inside a glovebox under a nitrogen atmosphere. A 96-
well aluminum block containing 1 mL glass vials was pre-
dosed with Pd(OAc)2 (0.5 ꢀmol) and NiXantphos (1 ꢀmol) in
THF. The solvent was evacuated to dryness using a Genevac
vacuum centrifuge, and KN(SiMe3)2 (30 ꢀmol) in THF was
added to the ligand/catalyst mixture. The solvent was re-
moved on the Genevac, and a parylene stir bar was then added
to each reaction vial.
1-Bromo-4-tert-butylbenzene (10
ꢀmol/reaction), diphenylmethane (12 ꢀmol/reaction) and bi-
phenyl (1 ꢀmol/reaction) (used as an internal standard to
measure HPLC yields) were then dosed together into each
reaction vial as a solution in CPME (100 ꢀL, 0.1 M). The 96-
well plate was then sealed and stirred for 18 h at 110 °C. Up-
on opening the plate to air, 500 ꢀL of acetonitrile was syringed
into each vial. The plate was then covered again and the vials
stirred for 20 min to extract the product and to ensure good
homogenization. Into a separate 96-well LC block was added
700 ꢀL of acetonitrile, followed by 40 ꢀL of the diluted reac-
tion mixtures. The LC block was then sealed with a silicon-
rubber storage mat, and mounted on HPLC instrument for
analysis.
1
for flash chromatography. The H NMR and 13C{1H} NMR
spectra were obtained using a Brüker AM-500 Fourier-
transform NMR spectrometer at 500 and 125 MHz, respective-
ly. Chemical shifts are reported in units of parts per million
(ppm) downfield from tetramethylsilane (TMS), and all cou-
pling constants are reported in hertz. The infrared spectra
were obtained with KBr plates using a Perkin-Elmer Spectrum
100 Series FTIR spectrometer. High resolution mass spec-
trometry (HRMS) data were obtained on a Waters LC-TOF
mass spectrometer (model LCT-XE Premier) using chemical
ionization (CI) or electrospray ionization (ESI) in positive or
negative mode, depending on the analyte. Melting points were
determined on a Unimelt Thomas-Hoover melting point appa-
ratus and are uncorrected.
ASSOCIATED CONTENT
Supporting Information. Procedures and full characterization of
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
4.2. General Procedure A. Room-Temperature
Deprotonation/Benzylation of Diphenylmethane. An oven-
dried 10 mL reaction vial equipped with a stir bar was charged
with KN(SiMe3)2 (79.8 mg, 0.40 mmol, 4 equiv) under a ni-
trogen atmosphere followed by 1 mL of dry dioxane, and the
reaction mixture was stirred for 5 min at 24 °C. Diphenylme-
thane (66.9 ꢀL, 0.40 mmol, 4 equiv) was added to the reaction
mixture followed by benzyl chloride (11.5 ꢀL, 0.1 mmol, 1
equiv). The reaction mixture was stirred for 12 h at 24 °C (or
110 °C). The reaction mixture was quenched with two drops
of H2O, diluted with 3 mL of ethyl acetate, and filtered over a
pad of MgSO4 and silica. The pad was rinsed with additional
ethyl acetate, and the solution was concentrated in vacuo. The
crude material was loaded onto a silica gel column and puri-
fied by flash chromatography.
AUTHOR INFORMATION
Corresponding Author
pwalsh@sas.upenn.edu
ACKNOWLEDGMENT
This manuscript is dedicated to Prof. Robert G. Bergman on his
70th birthday. We thank the NSF (CHE-0848467 and 0848460)
for partial support of this research. We also thank the NSF for an
X-ray diffractometer (CHE-0840438). We would also like to
thank Drs. Jason R. Schmink and Matthew Tudge (Merck) for
providing us with substrate 1p.
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4.3. General Procedure B. Pd-Catalyzed DCCP
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equipped with a stir bar was charged with KN(SiMe3)2 (59.8
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vial. After stirring for 5 min at 24 °C, diphenylmethane (20.1
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(31) pKa of acetophenone in DMSO: 24.7: Matthews, W. S.; Bares,
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7729.
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(34) For examples of Pd-catalyzed C-2- and C-3-arylation of in-
doles: (a) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897. (b) Lane,
B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050.
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Chem. Soc. 2006, 128, 4972. (d) Djakovitch, L.; Dufaud, V.; Zaidi, R.
Adv. Synth. Catal. 2006, 348, 715. (e) Toure, B. B.; Lane, B. S.;
Sames, D. Org. Lett. 2006, 8, 1979. (f) Wang, X.; Gribkov, D. V.;
Sames, D. J. Org. Chem. 2007, 72, 1476. (g) Bellina, F.; Benelli, F.;
Rossi, R. J. Org. Chem. 2008, 73, 5529. (h) Yang, S. D.; Sun, C. L.;
Fang, Z.; Li, B. H.; Li, Y. Z.; Shi, Z. J. Angew. Chem., Int. Ed. 2008,
47, 1473. (i) Zhao, J. L.; Zhang, Y. H.; Cheng, K. J. Org. Chem.
2008, 73, 7428. (j) Liang, Z. J.; Yao, B. B.; Zhang, Y. H. Org. Lett.
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