Palladium-Catalyzed Regioselective C-Benzylation via a Rearrangement Reaction: Access to Benzyl-Substituted Anilines

Article abstract of DOI:10.1002/chem.201603941

An unprecedented C-benzylation rearrangement reaction, catalyzed by palladium, is reported. The reaction proceeds by rearrangement leading to the direct synthesis of para or ortho benzyl-substituted N-methylanilines. The product is obtained in high regioselectivity, without the need to use a ligand for the catalytic process.

Full text of DOI:10.1002/chem.201603941

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Accepted Article
Title: Palladium-Catalyzed Regioselective C-Benzylation via a Rearrangement Re-
action: Access to Benzyl-Substituted Anilines
´
´
Authors: Manuel Jose Amezquita; Howard Alper
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COMMUNICATION
Palladium-Catalyzed Regioselective C-Benzylation via a
Rearrangement Reaction: Access to Benzyl-Substituted Anilines
Manuel Amézquita-Valencia, and Howard Alper*
This paper is dedicated to Prof. Dr. Helmut Schwarz , Berlin, Germany, in celebration of his wonderful contributions to science, policy,
administration (A. von Humboldt Foundation), and to society. Integrity is his signature.
obtained in these reactions.[2a,6b-c] In particular, the ability to form
Abstract: An unprecedented C-benzylation rearrangement reaction,
benzyl-substituted anilines from N-alkyl or aryl anilines is
catalyzed by palladium, is reported in this contribution. The reaction
generally known as the Hofmann-Martius rearrangement
proceeds by rearrangement leading to the direct synthesis of para or
(Scheme 1C, Friedel-Crafts reaction via H-M rearrangement).[7]
ortho benzyl-substituted N-methylanilines. The reaction product is
In general, the reaction is
a thermal conversion of N-
obtained in high regioselectivity, without the need to use a ligand for
the catalytic process.
alkylanilines, involving the migration of an alkyl group in different
ways: dependent on the nature of the olefin, radical or
carbocation.[7b-d] Likewise, the H-M rearrangement can be
triggered by photo-irradiation.[8]
Benzyl-substituted anilines are important compounds
employed in the design of organic compounds and
pharmaceutical products.[1] Consequently, the development of
efficient and selective methods for the construction of amine
substituted diarylmethanes, is a worthwhile goal in organic
synthesis. An approach for the preparation of these type of
compounds involves C-benzylation via hydroarylation of anilines
with styrene (Scheme 1A).[2] There are very few examples of the
use of N-methyl anilines as substrates, for the synthesis of the
desired products.[3] Other strategies used include the reduction
of diaryl ketones containing the amino group in the structure,[4]
or cross coupling reactions catalyzed by transition metals
(Scheme 1B).[5]
In recent times, another way to address this issue is to use
benzyl alcohol as the reagent instead of alkyl or aryl halides
used traditionally in the FC reaction (Scheme 1C).[9] Despite
these achievements, we believe there are significant
opportunities to develop new synthetic methodologies for the
preparation of benzyl-substituted anilines. In addition, a practical
catalytic procedure that is both chemo- and regioselective is
meritorious. Herein, we wish to report a fascinating palladium-
catalyzed rearrangement under CO pressure in methylene
chloride, affording benzyl-substituted anilines in good yield and
excellent selectivity. This transformation is carried out under
catalytic conditions and the selectivity is sensitive to the amino
substitution pattern. To our knowledge, this type of reactivity has
never been reported before, and there only has been a report
where n-substituted carbazoles in presence of phenol and
H3PO4 resulted in the corresponding migration of a benzyl
group.[10]
Initially, 2-[((2-bromophenyl)methylamino)methyl]phenol 1a
was chosen as the model substrate for the rearrangement
reaction. The precursors for our study were easily obtained
based on the method of Mestichelli et al. via a four step
sequence in high overall yield, and only the final product was
purified by chromatography.[11] The optimization study was
initiated with 1 equivalent of K3PO4, and 2 mol % of palladium
precursor under CO pressure, with dichloromethane as the
solvent (Table 1). Initially, low product yield resulted when the
reaction was carried out with a monodentate phosphine ligand,
along with small amounts of byproducts (Entry 1-2). The reaction
was totally ineffective using a bidentate ligand [e.g., 1,4-
bis(diphenylphosphino)butane (dppb)], and the starting material
was recovered (Entry 3). We were gratified to find that the Pd-
catalyzed reaction occurred in the absence of a ligand, affording
the rearrangement product 1b in good yield and excellent
selectivity (entry 4). The structure of 1b was confirmed by single-
crystal X-ray diffraction.[12] Use of other solvents such as THF,
MeCN and toluene gave inferior results, and no reaction
occurred using coordinating solvents (Entries 5-7). Further
testing of the palladium catalyst revealed that Pd(OAc)2 is the
best choice. The use of Pd(dba)2 or PdCl2 gave the product 1b
in low yield, while the yield was moderate using Pd(tfa)2 (Entries
8-10).
Scheme 1. C/N-Benzylation of Anilines
One of the methods used to obtain diarylmethanes is via the
traditional Friedel-Crafts (FC) reaction, in which alkyl or aryl
halides and a Lewis acid are utilized.[6] However; amines are
incompatible here, due to nitrogen coordination to the Lewis acid
catalyst. In addition, mixtures of regioisomeric products are often
[*]
Dr. M. Amézquita-Valencia, Prof. H. Alper
Centre for Catalysis Research and Innovation, Department of
Chemistry and Biomolecular Sciences
University of Ottawa
Although the reaction yield is good using K3PO4, different
bases were examined to attempt to increase the yield of the
reaction. Organic bases facilitate the decomposition of the
substrate (Entries 12-15). Decreasing CO pressure proved
detrimental to the yield of the product. In contrast, the yield was
slightly enhanced when the pressure was increased to 600 psi
10 Marie Curie, Ottawa, Ontario, Canada, K1N 6N5
E-mail: howard.alper@uottawa.ca
Supporting information for this article is given via a link at the end of
the document.
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(entries 16-18). Lowering the reaction temperature from 120 to
100 degrees gave recovered starting material (entry 19). Control
experiments show that, in the absence of the palladium catalyst,
no reaction occurs; a similar result is obtained in the absence of
the base (entries 20-21).
withdrawing groups in the same position (7b-9b). Changing the
position of the substituent on the phenol moiety did not affect the
yield (10b-12b). In contrast, changing the position of halogen did
not give any product (13b/13c). On the other hand, absence of a
substituent on the amino moiety produced a mixture of para- and
ortho- isomers in low yields, 13% and 7% respectively
(14b/14c), and the product of double benzylation was observed
(14d). Changing the nature of the ortho substituent on the amino
moiety gave the expected products in excellent selectivity, and
in moderate yields (15b, 16b and 17b).
Table 1. Optimization of the reaction conditions[a]
Entry
1[c]
2[d]
3[e]
4
Catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
PdCl2
Base
Solvent
DCM
DCM
DCM
DCM
THF
Yield %[b]
40
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Na2CO3
CSF
32
s.m.
83
5
s.m.
s.m.
56
6
MeCN
toluene
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
7
8
36
9
23
10
12
13
14
15
16[f]
17[g]
18[h]
19[i]
20
21
Pd(tfa)2
47
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
62
s.m.
-
Et3N
DBU
-
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
-
67
65
85
s.m.
s.m.
13
Pd(OAc)2
[a] Reaction conditions: 1a (0.35 mmol), base 1 equivalent, 2 mol% [Pd]
(0.0068 mmol), 300 psi of CO, 5 mL of solvent at 120°C. [b]After column
chromatographyc. [c]PPh3 was used (4 mol%). [d]Cytop 292 was used (4
mol%). [e]dppb was used (1 mol%). [f]200 psi of CO. [g]100 psi of CO. [h]600
psi of CO. [i]Reaction at 100°C.
Scheme 2. Substrate Scope of N-Biaryl Derivatives..Reaction conditions:
2a-17a (0.35 mmol), 2 mol % of Pd(OAc)2 (0.0068 mmol), 1 equivalent of
K3PO4, CO (300 psi), DCM (5 mL), 120°C, 15h. [a]The reaction was carried out
at 600 psi of CO.
A set of experiments were carried out to explore the
participation of gases in the reaction. First, the desired product
was not formed in the absence of CO. Also, using carbon
dioxide instead of CO gave recovered starting material while
reaction under N2, afforded 1b in 27% yield (eq 1).
To explore the effect of the substituent on the amino
containing moiety, a variety of substrates were synthesized,
where the position of the methyl group around the aromatic ring
was changed. These substrates afforded the expected products
in moderate to good yields. The selectivity of the reaction was
sensitive to the substitution pattern (Scheme 3).
We found that the methyl group next to halide directly
influences the selectivity, affording a mixture of isomers in good
yield, but in moderate selectivity (18b/18c). Furthermore, the
substrate with an electron-donating methyl group on the
alcoholic arm gave the products in both good yield and
selectivity, 72%/8% (19b/19c), while an electron-withdrawing
group (e.g., Cl) afforded low product selectivity, 46%/29%
(20b/20c). In general, the selectivity of the reaction may be due
to the presence of two directing groups (-NRR´ and –Me) in the
same aromatic ring, generating competition in the benzylation
step. With the methyl group in the para position, only one
With optimum conditions in hand, we next explored the scope
of the palladium-catalyzed rearrangement. In all cases, the
reaction worked well using –Br or –Cl as a substituent on the
amino containing moiety (Scheme 2, 2b vs. 1b Table 1, entry 4).
For the N-biaryl compounds, bearing an electron-donating group
such as methyl or methoxy group at the para-position with
respect to the hydroxyl group, afforded the products in good
yield (3b-6b). Similar results were observed with electron-
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product was observed (21c-23c). Furthermore, the reaction with
meta-substituted anilines resulted in the formation of only one
regioisomer in good yield (24b-25b). Finally, the same result
was found with the methyl group in the ortho-position (26b). The
structures of the regioisomers 18b and 21c were confirmed by
single-crystal X-ray diffraction (Figure 1).
substrate coordination to the metal center. Furthermore,
changing the position of the substituents (OH and Br) on the
substrate failed to generate the rearrangement reaction;
identical results were obtained when the substituents were
removed. These experiments suggest that the position of the
hydroxyl group is very important for the formation of the initial
complex A.
An additional reaction was carried out using 8 mol% of PPh3
under standard conditions at 600 psi of CO. This reaction was
modestly effective for the rearrangement process, giving the
carbonylation product 27e (eq 4). This indicates that the
formation of the new compound is by CO insertion, which means
that the species C and C´ might be involved in the process.
Similar species have been reported for the functionalization of
vinyl phenols and alkenes.[13] In order to check if the process is
inter or intramolecular, the reaction was carried out using a
mixture of two different substrates 4a and 24a under optimized
reaction conditions. As shown in equation 5, four compounds
were detected by GC/MS (see Supporting Information, Figure
S1). It is conceivable that an intermolecular process is operative
here.
Scheme 3. Variation of the position of the methyl group on the amino
containing moiety. Reaction conditions: 18a-26a (0.35 mmol), 2 mol % of
Pd(OAc)2 (0.0068 mmol), 1 equivalent of K3PO4, CO (300 psi), DCM (5 mL),
120°C, 15h. [a]The product distribution is shown in brackets. [b]The reaction
was carried out at 600 psi of CO.
Although the precise mechanism for this migration reaction is
yet to be fully elucidated, on the basis of the above results, a
possible mechanism is outlined in Scheme 4. Initially, the
reaction between Pd(OAc)2 and substrate 1a may be chelation-
directed, resulting in the formation of complex A.[14]
Subsequently, the base removes the proton from the hydroxyl
group, releasing the ionic species B.[15] Simultaneously,
intermediates C and C´ may be formed, in which case they could
play a pivotal role in the reaction.[13,16] At this point, CO
coordination can help to stabilize different palladium species
present in the reaction. Under conditions shown in equation 4,
the formation of the palladacycle C´ followed by CO insertion
may afford the product 27e by cyclocarbonylation. The formation
of the carbonylation product is associated to excess ligand;
increasing electronic density in the metal center decreases the
possibility of a nucleophilic attack. Under standard conditions
(ligand free), the C-C bond formation might be derived from
Michael addition of C by the intermediate B, in which both para-
and ortho- carbon of B could act as nucleophile, affording the
rearrangement product 1b. In addition, the generation of ortho-
product might be obtained via stabilizing coordination of
nitrogen.
18b
21c
Figure 1. Crystallographic structures of compounds 18b and 21c.[12]
Several experiments were undertaken to gain some
mechanistic insight into the present transformation. First, under
standard reaction conditions using 1a, four mercury drops were
added in order to check the homogeneity of the reaction. The
result showed no inhibition of the process and no significant
differences in yield and selectivity were observed. This result is
consistent with a homogeneous process. In addition, the
presence of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) did
not inhibit the reaction, thus suggesting that a radical process is
not involved (eq 2). Notably, when a stoichiometric reaction
between Pd(OAc)2 and 3a was carried out under nitrogen at
room temperature, [Pd(3a)(OAc)]+ complex was found (eq 3).
The formulation of the new complex was based on the 1H-NMR
and ESI experiments. Several unsuccessful attempts were made
to fully characterize the complex, including growing suitable
crystals for X-Ray analysis. When the reaction was conducted
using complex A, the rearrangement product 3b was formed in
40% yield. The latter result may indicate a chelation-assisted
pathway. This behavior is supported by the results obtained in
Table 1 (entries 1-3 vs. 4), when a negligible amount of product
was formed by the action of the ligand in the reaction. The
phosphine was detrimental to the reaction; retarding the
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Scheme 4. Proposed Mechanism
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[11]
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In conclusion, we have developed a novel and efficient Pd-
catalyzed rearrangement of N-biaryl substrates for the direct
synthesis of benzyl-substituted N-methylamines under CO and
ligand-free conditions. In contrast, the presence of a ligand leads
to the formation of the carbonylation product. The selectivity of
the process can be controlled by the amino substitution pattern.
This reaction has significant synthetic utility, particularly as a
consequence of the high regioselectivity of the process.
[13]
[14]
Acknowledgements
We are grateful to the Natural Sciences and Engineering
Research Council (NSERC) for support of this work.
[15]
[16]
Keywords: Palladium • Rearrangement • Ligand free •
Regioselective • C-Benzylation
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COMMUNICATION
Amézquita-Valencia Manuel, Howard
Alper*
Page No. – Page No.
Palladium-Catalyzed Regioselective
C-Benzylation via a Rearrangement
Reaction: Access to Benzyl-
Substituted Anilines
Rearrangement Reaction: A new C-Benzylation reaction was developed using
Pd(OAc)2 and K3PO4 under a CO atmosphere. This transformation occurs in fine
yields and in excellent regioselectivity, and constitutes a new way to obtain para or
ortho benzyl-substituted N-methylanilines.
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