Palladium-catalyzed amination of chloromethylnaphthalene and chloromethylanthracene derivatives with various amines

Article abstract of DOI:10.1021/ja300164d

Palladium-catalyzed amination of chloromethylnaphthalene and chloromethylanthracene derivatives to produce naphthylamines and anthrylamines in satisfactory to good yields has been developed. The unprecedented amination reactions proceeded smoothly under mild conditions in the presence of Pd(PPh₃)₄ as a catalyst.

Full text of DOI:10.1021/ja300164d

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Amination of Chloromethylnaphthalene and
Chloromethylanthracene Derivatives with Various Amines
Sheng Zhang, Yi Wang, Xiujuan Feng, and Ming Bao*
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China
S
* Supporting Information
secondary amines occurred at the para position to afford a
1-amino-4-methylnaphthalene derivative.
ABSTRACT: Palladium-catalyzed amination of chloro-
methylnaphthalene and chloromethylanthracene deriva-
tives to produce naphthylamines and anthrylamines in
satisfactory to good yields has been developed. The
unprecedented amination reactions proceeded smoothly
under mild conditions in the presence of Pd(PPh3)4 as a
catalyst.
Initially, 1-chloromethylnaphthalene (1a) was used as a
starting material to determine the scope of amine substrates
under the optimized reaction conditions.10 The results are
shown in Table 1. The reaction of 1a with the five- and six-
membered cyclic amines pyrrolidine and piperidine proceeded
smoothly to give the corresponding products 2a and 2b in
moderate yields (62 and 66%, respectively). The use of the six-
membered cyclic amines morpholine and thiomorpholine led to
good yields of the corresponding products 2c and 2d (83 and
86%, respectively). Product 2e was obtained in only 40% yield
when the reaction of 1a with 1-methylpiperazine was
performed under the same reaction conditions (method A).
Gratifyingly, the yield of 2e was improved to 71% merely by
changing the solvent from tetrahydrofuran (THF) to 1,
2-dimethoxyethane (DME). Decomposition of 1a was observed
when the noncyclic aliphatic amine diisopropylamine was
examined (2f, 0%). However, the amination products 2g−i
were obtained in moderate to good yields when noncyclic
aromatic amines N-methylaniline, 4-methyl-N-methylaniline,
and 4-methoxy-N-methylaniline were tested (75, 81, and 65%,
respectively). The reaction of 1a with benzylamine, an aliphatic
primary amine, gave the desired amination product 2j in only
14% yield along with the normal nucleophilic substitution
product N-benzyl-1-(naphthalen-1-yl)methanamine (3) and
the dehalogenation product 1-methylnaphthalene (4) in yields
of 30 and 43%, respectively. Subsequent investigations revealed
that aromatic primary amines can be employed in this type of
amination reaction under modified reaction conditions
(method B). The product 2k was isolated in 74% yield when
a mixture of 1a and aniline in DME was treated at 45 °C for 24
h. A relatively low yield was observed for the reaction of 1a with
2-methylaniline (2l, 47%). The poor reactivity exhibited by
2-methylaniline was considered to be due to the steric effect
of the o-methyl group in the aniline substrate. However, a
m-methyl group in the aniline substrate did not influence the
reaction yield, as product 2m was obtained in 77% yield. A
m-methoxy group in the aniline substrate, unlike the m-methyl
group, strongly influenced the reaction process and resulted in
a low yield of 2n (45%). This result is perhaps due to the ability
of the methoxy group to coordinate to palladium.11 Product
2o was isolated in low yield (38%) from the reaction of 1a with
3-chloroaniline because 2o acted as an aromatic secondary
amine substrate that further reacted with 1a to give the
he development of convenient and efficient methods for
T
the synthesis of arylamines has attracted considerable
attention. Arylamines represent an interesting structural motif
that is frequently found in various bioactive molecules and
functional materials.1 Among C(aryl)−N bond-forming pro-
cesses, the transition-metal-mediated amination of aryl halides
with amines and amides using palladium,2 copper,3 nickel,4 and
iron5 catalysts has recently emerged as an extremely powerful
tool for the synthesis of aniline derivatives. As shown in eq 1,
the catalytic amination of aryl halides always occurs at the
aromatic carbon linked to a halogen atom no matter which kind
of catalyst is used. In addition, an excellent work reported by
Hartwig and co-workers revealed that the reductive elimination
reaction of a benzylpalladium amido complex containing the
chelating ligand 1,1′-bis(diphenylphosphanyl)ferrocene (dppf)
can easily occur to form a C(alkyl)−N bond in benzylamine.6
Palladium-catalyzed amination of aryl halides with amines,
namely, the Buchwald−Hartwig reaction, has been well-known
as an area of intense research in the recent literature.7,8 The
Buchwald−Hartwig reaction was successfully utilized as a key
reaction in natural product synthesis.9 Herein, an unprece-
dented palladium-catalyzed amination of chloromethylnaph-
thalene and chloromethylanthracene derivatives with various
amines is reported. As shown in eq 2, the palladium-catalyzed
amination of 1-chloromethylnaphthalene with primary and
Received: January 13, 2012
Published: March 12, 2012
© 2012 American Chemical Society
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Communication
were obtained when 4-chloro- and 4-bromoaniline were tested.
Products 2r and 2s were obtained in yields of 55 and 54%,
respectively, along with the byproducts N-(4-chlorophenyl)-4-
methyl-N-(naphthalen-1-ylmethyl)naphthalen-1-amine (6) and
N-(4-bromophenyl)-4-methyl-N-(naphthalen-1-ylmethyl)-
naphthalen-1-amine (7) in 21 and 26% yield, respectively. Finally,
dimethyl-substituted anilines 3,4-dimethylaniline and 3,5-dime-
thylaniline were examined, and the corresponding products 2t
and 2u were obtained in yields of 75 and 73%, respectively.
Table 1. Palladium-Catalyzed Regioselective Amination of
1-Chloromethylnaphthalene (1a) with Various Amines
ab
,
Next, morpholine was used as an amine substrate to
determine the scope of chloromethylnaphthalenes under the
optimized reaction conditions.10 The results are shown in Table 2.
Unlike the reaction of 1-(chloromethyl)-2-methoxynaphthalene
(1c) bearing a problematic o-methoxy group, the reactions of
1-(chloromethyl)-2-methylnaphthalene (1b) and 1-(chloro-
methyl)-3-methylnaphthalene (1d) proceeded smoothly to
give the corresponding products 8b and 8d in yields of 78
and 63%, respectively. Product 8c was isolated in 29% yield
along with the normal nucleophilic substitution product 4-((2-
methoxynaphthalen-1-yl)methyl)morpholine (9) in 64% yield.
1-Chloromethylnaphthalenes 1e−i with phenyl groups linked
at the benzylic position exhibited high reactivities, furnishing
the corresponding products 8e−i in moderate to good yields
(67−88%). Notably, the Cl and Br atoms linked to the
aromatic ring were maintained in the structures of the products
8g and 8i under the amination reaction conditions, suggesting
that further manipulation may produce useful compounds. The
applicability of 1-chloromethylnaphthalenes 1j−m with alkyl
groups linked at the benzylic position for this type of amination
reaction were subsequently investigated. Products 8j−l were
obtained in moderate yields (60, 62, and 55%, respectively)
along with β-hydride elimination products 10−12 in 27, 26,
and 36% yield, respectively.12 Surprisingly, 8m was obtained in
89% yield as the sole product from the reaction of 1-(1-chloro-
2-methylpropyl)naphthalene (1m) with morpholine. No
β-hydride elimination product could be observed.
a
Method A: 1a (0.5 mmol), amine (2.0 equiv), NaH (4.0 equiv), and
Pd(PPh3)4 (5 mol %) in THF (5 mL) at room temperature under a N2
atmosphere. Method B: 1a (0.5 mmol), amine (2.0 equiv), K3PO4 (2.0
equiv), and Pd(PPh3)4 (5 mol %) in DME (5 mL) at 45 °C under a
The success in obtaining naphthylamines via palladium-
catalyzed amination of chloromethylnaphthalenes encouraged
us to examine the reaction of 9-chloromethylanthracene (13)
with various amines, and the results are summarized in Table 3.
When the palladium-catalyzed amination reactions of 13 with
N-methylaniline, N-ethylaniline, N-allylaniline, 4-methyl-N-
methylaniline, and 4-methoxy-N-methylaniline were performed
in DME using NaOtBu as a base for 12 h (method D), the
corresponding amination products 14a−e were obtained in
moderate yields (48−55%). The cyclic secondary amine
morpholine exhibited higher reactivity than the N-alkyl-
substituted anilines, affording the desired product 14f in 60%
b
c
N2 atmosphere. Isolated yields are shown. DME was used as the
d
e
solvent. 1a decomposed. The normal substitution product 3 and
dehalogenation product 4 were isolated in 30 and 43% yield,
f
respectively. Byproducts 5, 6, and 7 were isolated in 39, 21, and
26% yield, respectively.
nucleophilic substitution product N-(3-chlorophenyl)-4-methyl-
N-(naphthalen-1-ylmethyl)naphthalen-1-amine (5) in 39% yield.
Products 2p and 2q were obtained in satisfactory yields using aniline
substrates bearing p-methyl or -methoxy groups (73 and 70%
yield, respectively). Results similar to those for 3-chloroaniline
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Table 2. Palladium-Catalyzed Regioselective Amination of
Chloromethylnaphthalene Derivatives with Morpholine
Table 3. Palladium-Catalyzed Regioselective Amination of
9-Chloromethylanthracene (13) with Various Amines
ab
,
a b
,
a
Method D: 13 (0.5 mmol), amine (1.2 equiv), NaOtBu (1.2 equiv),
and Pd(PPh3)4 (5 mol %) in DME (5 mL) at 60 °C under a N2
b
atmosphere. Isolated yields are shown.
Scheme 1. Palladium-Catalyzed Regioselective Amination of
1-(Chloro(phenyl)methyl)naphthalene (1e) with
Morpholine
Scheme 2. Proposed Mechanism for the Palladium-
Catalyzed Amination of Chloromethylnaphthalene and
Chloromethylanthracene Derivatives with Amines
a
Method A: 1b−i (0.5 mmol), amine (2.0 equiv), NaH (4.0 equiv),
and Pd(PPh3)4 (5 mol %) in THF (5 mL) at room temperature under
a N2 atmosphere. Method C: 1g−m (0.5 mmol), amine (1.2 equiv),
NaOtBu (1.2 equiv), and Pd(PPh3)4 (5 mol %) in THF or DMSO
b
(5 mL) at room temperature under a N2 atmosphere. Isolated yields
are shown. The normal nucleophilic substitution product 9 was
isolated in 64% yield. THF was used as the solvent. β-H elimination
products 10, 11, and 12 were also isolated in 27, 26, and 36% yield,
respectively. DMSO was used as the solvent.
c
d
e
f
yield. The relatively low yields of 14a−f obtained may be
attributed to the instability of 13 under the reaction conditions.
To explore the mechanism of this type of amination reaction,
a mixture of 1e and morpholine was treated under method A
conditions for a short time (1 h). The result is shown in
Scheme 1. As expected, an aminative dearomatization product,
15, was isolated in 30% yield. Product 15 was quite stable under
neutral and acidic conditions at room temperature but could
easily change into the isomer 8e (see Table 2) under strongly
basic conditions.
A plausible mechanism for the palladium-catalyzed amination
of chloromethylnaphthalene and chloromethylanthracene de-
rivatives with amines is shown in Scheme 2. The oxidative
addition of 1a to a Pd(0) species could produce the
η3-allylpalladium chloride intermediate A, which could isomerize
to η3-allylpalladium chloride intermediate B. The Tsuji−Trost-
type nucleophilic substitution reaction of intermediate B with
morpholine in the presence of NaH as a base could produce
dearomatization product C and regenerate the Pd(0) catalyst.13
The product C could undergo a 1,5-prototropic shift under basic
reaction conditions to give the para-aminated product 2c.14
In summary, we have developed a novel and general catalytic
method for the conversion of chloromethylnaphthalene and
chloromethylanthracene derivatives to naphthylamines and
anthrylamines using Pd(PPh3)4 as a catalyst. The methyl
group in the structures of products 2a−e, 2g−u, and 14a−f
should easily be transformed into various functional groups,
which would make these products more useful in organic
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Journal of the American Chemical Society
Communication
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theoretical explanation of the reaction mechanism and the
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and sulfur-containing nucleophiles are currently underway.
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Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
mingbao@dlut.edu.cn
■
(i) Schulz, T.; Torborg, C.; Enthaler, S.; Schaffner, B.; Dumrath, A.;
̈
Spannenberg, A.; Neumann, H.; Borner, A.; Beller, M. Chem.Eur. J.
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Notes
2009, 15, 4528.
The authors declare no competing financial interest.
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results are shown in the Supporting Information.
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coordinate to palladium, see: Walker, S. D.; Barder, T. E.; Martinelli,
J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871.
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β-hydride elimination often took place to give alkenes in preference to
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ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (20972021 and 21102012) for their financial support.
This work was also supported by the Specialized Research Fund
for the Doctoral Program of Higher Education (20090041110012).
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