Palladium-Catalyzed α-Arylation of Aryl Nitromethanes

Article abstract of DOI:10.1021/acs.orglett.5b02793

Catalytic conditions for the α-arylation of aryl nitromethanes have been discovered using parallel microscale experimentation, despite two prior reports of the lack of reactivity of these aryl nitromethane precursors. The method efficiently provides a variety of substituted, isolable diaryl nitromethanes. In addition, it is possible to sequentially append two different aryl groups to nitromethane. Mild oxidation conditions were identified to afford the corresponding benzophenones via the Nef reaction, and reduction conditions were optimized to afford several diaryl methylamines.

Full text of DOI:10.1021/acs.orglett.5b02793

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed α‑Arylation of Aryl Nitromethanes
Kelsey F. VanGelder and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
S
* Supporting Information
ABSTRACT: Catalytic conditions for the α-arylation of aryl
nitromethanes have been discovered using parallel microscale
experimentation, despite two prior reports of the lack of
reactivity of these aryl nitromethane precursors. The method
efficiently provides a variety of substituted, isolable diaryl
nitromethanes. In addition, it is possible to sequentially
append two different aryl groups to nitromethane. Mild
oxidation conditions were identified to afford the correspond-
ing benzophenones via the Nef reaction, and reduction conditions were optimized to afford several diaryl methylamines.
benzophenones.4,6 In addition, the requisite starting materials
he nitro group is highly versatile, as it can be transformed
1
are often difficult to access.
Tinto a variety of other functional groups.
Also, the
In 2002, the first catalytic α-arylation of nitroalkanes was
reported by Buchwald and co-workers.7 Under these Pd-
catalyzed conditions, further arylation of the product, that is the
aryl nitromethane, did not occur. Our laboratory subsequently
developed robust conditions for the arylation of more difficult
substrates including nitroacetates8 and nitromethane.9 A second
arylation at the α position was never observed under these
conditions, but a preliminary high-throughput experimentation
study showed that altering the phosphine ligand could result in
the second α-arylation. Studies were then initiated to efficiently
accomplish the previously unreported α-arylation of aryl
nitromethanes.
Initial studies revealed that both the diaryl nitromethane and
benzophenone products were produced. As reported by Mayr
and co-workers,6 some diaryl nitromethanes spontaneously
convert under air to the corresponding benzophenone. This
reactivity is primarily dictated by the electronic effects imparted
by the substituents on the aryl rings. In order to fully capture all
of the material that successfully underwent cross-coupling, we
elected to convert the initially formed diaryl nitromethane to
the benzophenone. Thus, preliminary efforts focused on the
second step of a two-step process, wherein the diaryl
nitromethanes were transformed via the Nef reaction to the
corresponding benzophenones (Table 1).
corresponding nitronate salts can be used as nucleophiles for
the formation of carbon−carbon bonds.1c,2,3 In this letter,
conditions for the palladium-catalyzed α-arylation of aryl
nitromethanes to afford the diaryl nitromethane products are
reported. The resultant products have been applied to the
synthesis of both benzophenone and diaryl methyl amine
derivatives.
Published methods for diaryl nitromethanes include the bis-
benzylic nitration (Scheme 1, eq 1),4 halide displacement by
nitrite (Scheme 1, eq 2),5 and rearrangement of the nitrite ester
(Scheme 1, eq 3).6 The methods are all low yielding, and most
afford a mixture of products, as some diaryl nitromethanes have
been reported to spontaneously convert to the corresponding
Scheme 1. Literature Precedent To Form Diaryl
Nitromethanes
Upon increasing the concentration from 0.1 to 0.2 M, it was
quickly found that the concentration of the cross-coupling
reaction was extremely important, as the Nef screening (Table
1) displayed higher overall yields with the higher concentration.
Using unoptimized cross-coupling conditions at 0.2 M, eight
conditions for the Nef reaction were screened. The most
effective version was a mild, oxidative method utilizing Oxone
(Table 1, entry 1).10,14
Received: September 25, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02793
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3). K2CO3 performed significantly better than the control,
K3PO4. Upon the addition of more equivalents of base,
however, the reaction slowed significantly.
Table 1. Optimization of Conditions for the Nef Reaction
Table 3. Optimization of Base for the Cross-Coupling
Reaction
isolated yield
a
b
entry
110
conditions
(%)
(1) NaOH, Na2HPO4, MeOH; (2) Oxone/H2O;
(3) 5 M HCl
44
211
38b
4
(1) TMSCl, DBU, CH2Cl2; (2) mCPBA
TBAF, KF, MeOH, MeI
40
40
36
34
(1) 5 M KOH, Et2O; (2) 5 M HCl, Et2O
a
512
(1) KOH, MeOH; (2) KMnO4, MgSO4;
(3) 5 M HCl
entry
base
HTE sum of products/IS
isolated yield (%)
1
4
2
3
5
K2CO3
K3PO4
KOH
1.05
1.00
0.96
1.01
0.99
94
80
71
6
(1) SiO2, MeOH, CDCl3, air; (2) KOH
(1) 2.0 M NaOH, MeOH; 5 M HCl
Bu4N+NO2−, benzene, MeOH
34
32
713
86
b
14
KHCO3
Cs2CO3
70
a
b
Conditions shown for the cross-coupling are unoptimized. Isolated
61
yields are for the two-step formation of the benzophenone.
a
b
Isolated yields are for the two-step formation of benzophenone. The
cross-coupling reaction time was 10 h.
After the Nef reaction was optimized, high-throughput
experimentation (HTE) was undertaken to optimize the
conditions of the first step, the coupling reaction. Twelve
ligands and eight solvents were examined with Pd2(dba)3 and
K3PO4 (Table 2). This screen resulted in three optimal ligands
and three optimal solvents, which were utilized in a lab scale
validation of the two-step process.
With these optimized conditions in hand, we shifted our
focus to the substrate scope of the reaction. However, we
discovered that some substrates were resistant to the Nef
reaction and gave rise to stable diaryl nitromethanes that could
be isolated (Scheme 2). Generally, more electron-poor and
Scheme 2. Exploration of Substrate Scope
Table 2. Optimization of Ligand and Solvent for the Cross-
Coupling Reaction
HTE sum of
a
isolated yield
b
entry
ligand
solvent
products/IS
(%)
1
2
t-BuXPhos
CPME
CPME
8.50
7.85
80
55
CataCXium
POMetB
3
4
5
6
Brett Phos
t-BuXPhos
BrettPhos
t-BuXPhos
CPME
7.60
7.11
6.61
8.38
49
42
41
38
benzene
benzene
dioxane
a
IS = internal standard. P = sum of diaryl nitromethane and
benzophenone products. High-Throughput Experimentation (the) was
b
performed using 4-bromoanisole. Isolated yields are for the two-step
formation of the benzophenone on larger scale experiments than the
HTE.
electron-neutral diaryl nitromethanes were more stable. Both
electron-neutral and electron-poor aryl bromides are coupled
effectively. Changing the electronic character of the aryl
nitromethane starting material is also well tolerated under the
optimized reaction conditions. A heterocyclic aryl halide
coupled in moderate yield (3ah). Unfortunately, ortho-
substituted aryl halides proved challenging and could not be
coupled. An ortho-substituent on the aryl nitromethane starting
material also had a deleterious effect. Longer reaction times and
higher temperatures proved ineffective for these resistant cases.
Previous work by both the Hartwig and Kozlowski
laboratories has shown that the proportion of base that was
soluble in the reaction medium was also very important in the
arylation of acidic substrates.8a,15 Thus, the top two ligands
from Table 2 were screened with 12 different bases.
CataCXium POMetB was inferior in this screen, so validation
was performed for five different bases with t-BuXPhos (Table
B
DOI: 10.1021/acs.orglett.5b02793
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Organic Letters
Letter
We propose that the reaction proceeds via a mechanism
similar to that reported for α-arylations of other acidic species
(Scheme 3).16−18 Furthermore, reactivity is compromised by
Scheme 5. Reduction of Diaryl Nitromethanes to Diaryl
Methylamines
a
Scheme 3. Proposed Mechanism for the α-Arylation of Aryl
Nitromethanes
a
Yields are for the two-step process from aryl nitromethane, 1.
Finally, a one-pot diarylation of nitromethane was accom-
plished. As shown in Scheme 6, the first arylation of
the presence of the nitro group. Specifically, deprotonation of
the acidic aryl nitromethane is likely facile, but the
correspondingly low nucleophilicity slows reaction with
intermediate B. In addition, the palladium can coordinate
either the benzylic carbon C or the nitro group D, but only the
former leads to product.18 Formation of species C is
disfavorable due to considerable steric hindrance from the
Ar2 group. Bulky ortho-substituents on either aryl ring further
exacerbate this problem.
Scheme 6. One-Pot Diarylation of Nitromethane
Next, a variety of diaryl nitromethanes were converted to the
corresponding benzophenones (Scheme 4), via the optimized
nitromethane can be accomplished with 2.0 equiv of nitro-
methane.9b The vial was then charged with the reagents for the
second arylation that we report herein, without changing
solvent. The second coupling can be accomplished efficiently,
with an overall yield of 53%, corresponding to an average step
yield of 73%.
Scheme 4. Nef Reaction of Diaryl Nitromethanes To Afford
Corresponding Benzophenones
a
In conclusion, the α-arylation of aryl nitromethanes has been
accomplished, permitting straightforward access to diaryl
nitromethanes. These conditions have the added benefit of
starting from widely available and easily differentiated aryl
halides. While these compounds can be difficult to work with
due to their stability, their high reactivity allows facile
generation of benzophenones and diaryl methyl amines.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02793.
a
Yields are for the two-step process from aryl nitromethane 1.
Experimental procedures and full characterization of new
compounds (PDF)
Nef conditions from Table 1. This one-pot sequence afforded a
diverse array of benzophenones, including a heterocyclic
example (4al). The reaction tolerated both electron-rich and
electron-poor aryl bromides and both electron-rich and
electron-neutral aryl nitromethanes.
The diaryl nitromethanes were also subjected to reduction
conditions. Of the conditions screened,8b,19−21 only sequential
addition of excess zinc dust resulted in reduction of the nitro
group with no over-reduction to the diaryl methane.8b Several
examples are shown in Scheme 5, including a naphthalenyl
diaryl methyl amine 5ag.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: marisa@sas.upenn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Institutes of Health
(GM087605) and the National Science Foundation
■
C
DOI: 10.1021/acs.orglett.5b02793
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(CHE1213230, CHE1464778) for financial support of this
research. The NSF provided funding of the High Throughput
Laboratory (GOALI CHE-0848460). Partial instrumentation
support was provided by the NIH for MS (1S10RR023444),
NMR (1S10RR022442), and HTE (S10OD011980). We thank
Dr. Simon Berritt (University of Pennsylvania) for his help on
high-throughput experimentation. We thank Hulbert Soh
(University of Pennsylvania) for his efforts.
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DOI: 10.1021/acs.orglett.5b02793
Org. Lett. XXXX, XXX, XXX−XXX