One-pot synthesis of highly substituted aromatic amine derivatives via Pd-catalyzed aminobenzannulation reaction

Article abstract of DOI:10.1021/ol901265b

A novel and convenient Pd(0)-catalyzed carboannulation with propargylic compounds for the synthesis of highly substituted aromatic amine derivatives in a one-pot operation was developed. In this process, a significant breakthrough in aminobenzannulation i

Full text of DOI:10.1021/ol901265b

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3418-3421
One-Pot Synthesis of Highly Substituted
Aromatic Amine Derivatives via
Pd-Catalyzed Aminobenzannulation
Reaction
Fa-Rong Gou,† Peng-Fei Huo,† Hai-Peng Bi,† Zheng-Hui Guan,† and
Yong-Min Liang*,†,‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou UniVersity,
Lanzhou 730000, People’s Republic of China, and State Key Laboratory of Solid
Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Science,
Lanzhou 730000, People’s Republic of China
liangym@lzu.edu.cn
Received June 5, 2009
ABSTRACT
A novel and convenient Pd(0)-catalyzed carboannulation with propargylic compounds for the synthesis of highly substituted aromatic amine
derivatives in a one-pot operation was developed. In this process, a significant breakthrough in aminobenzannulation is observed. Moreover,
the reaction appears to be very general and suitable for a variety of amines.
Transition metal-catalyzed annulation reactions represent an
effective and straightforward methodology for the synthesis
of cyclic and polycyclic structures, which has attracted much
attention during the past years.1 However, a drawback of
this methodology is that it is difficult to control the regio-
and chemoselectivity. Thus, the regio- and chemoselective
construction of cyclic compounds remains a challenging
problem in synthetic organic chemistry.
bonds.3 Herndon et al. reported a palladium-catalyzed
synthetic route to aminonaphthalenes using the coupling of
o-bromoacetophenone with monoalkyl acetylenes.4 The
excellent reactivity of o-alkynyl(oxo)benzenes led us to focus
on the development of a new type of cyclization. As a
continuation of our research on the carboannulation reaction
with propargylic compounds,5 we envisioned that the sub-
The synthetic potential of o-alkynyl(oxo)benzenes has
attracted great attention of organic chemists.2 Recently,
Tsukamoto and co-workers reported a series of Pd-catalyzed
annulations of alkynes with unsaturated carbon-heteroatom
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35, 1082. (b) Asao, N. Synlett 2006, 1645. For select examples, see: (c)
Yao, X.; Li, C.-J. Org. Lett. 2006, 8, 1953. (d) Asao, N.; Nogami, T.;
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2003, 42, 4399.
† Lanzhou University.
‡ Chinese Academy of Science.
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1998. (b) Palladium Reagents and
Catalysts: InnoVations in Organic Synthesis; Tsuji, J., Ed.; Wiley: Chich-
ester, UK, 1995. (c) Palladium Reagents in Organic Synthesis; Heck, R. F.,
Ed.; Academic Press: London, UK, 1985.
(3) (a) Tsukamoto, H.; Ueno, T.; Kondo, Y. J. Am. Chem. Soc. 2006,
128, 1406. (b) Tsukamoto, H.; Ueno, T.; Kondo, Y. Org. Lett. 2007, 9,
3033.
(4) Herndon, J. W.; Zhang, Y.; Wang, K. J. Organomet. Chem. 2001,
634, 1.
10.1021/ol901265b CCC: $40.75
Published on Web 07/08/2009
 2009 American Chemical Society

strate ethyl 3-(2-formylphenyl)prop-2-ynyl carbonate 1a
might act similarly to these o-alkynyl(oxo)benzenes to afford
indene or naphthalene derivatives.3b,4,6-8
Table 2. Pd-Catalyzed Cyclization of 1.0 Equiv of Propargylic
Compounds 1 with 1.5 Equiv of Amines 2a
Our preliminary study of the cyclization of 1a at 60 °C in
MeOH in the presence of a catalytic amount of Pd(PPh3)4
was unsuccessful. Further attempts, including increasing
temperature and using other solvents, exhibit no effect. We
then turned our attention to the introduction of amine
functionality. Instead of affording the preconceived products
under the above-mentioned condition in the presence of
Et2NH, an unexpected and interesting product ꢀ-naphthy-
lamine 3a was formed in 52% isolated yield (Table 1, entry
Table 1. Optimization of the Pd-Catalyzed Cyclization of 1.0
equiv of Propargylic Carbonate 1a with 1.5 equiv of Amine 2aa
entry
catalyst
solvent temp (°C) time (h) yield (%)b
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3/dppf EtOH
Pd(OAc)2/PPh3 EtOH
Pd(OAc)2/dppe EtOH
MeOH
MeCN
EtOH
THF
DMF
EtOH
60
60
60
60
60
60
60
60
60
40
80
100
2
2
2
2
2
6
4
2
4
5
1
0.5
52
45
61
n.r.c
22
trace
18
55
32
47
9
10
11
12
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
EtOH
EtOH
EtOH
68
73
a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of solvent
under argon with 1.0 equiv of 1a, 1.5 equiv of 2a, and 0.05 equiv of [Pd].
b Isolated yields. c n.r. ) no reaction.
1). The reaction should not proceed through iminium
formation but through high regio- and chemoselective
intramolecular nucleophilic attack, since formation of neither
indenamine or R-naphthylamine was observed.3b,4,7,8
a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of solvent
at 100 °C under argon with 1.0 equiv of 1, 1.5 equiv of 2, and 0.05 equiv
of [Pd]. b Isolated yields. c Decomposed. d n.r. ) no reaction.
To the best of our knowledge, few reports are known
concerning the direct formation of highly substituted naph-
thylamine derivatives via a net Pd-catalyzed aminobenzan-
nulation. This result encouraged us to extend our protocol
to investigate this novel cyclization. Consequently, we
investigated this reaction under various conditions. When
Pd(PPh3)4 was used as the catalyst, the reaction proceeded
smoothly in MeCN and EtOH (Table 1, entries 2 and 3).
Compared with other solvents such as THF and DMF, EtOH
gave the best yield (entries 4 and 5). During a survey of the
effect of different catalysts, it was determined that Pd(PPh3)4
was a superior catalyst than others (entries 6-9). And
significant improvement was achieved by conducting the
reaction at 100 °C. This means a higher temperature was
beneficial for both the rate and the yield of the reaction
(5) (a) Gou, F.-R.; Bi, H.-P.; Guo, L.-N.; Guan, Z.-H.; Liu, X.-Y.; Liang,
Y.-M. J. Org. Chem. 2008, 73, 3837. (b) Bi, H.-P.; Guo, L.-N.; Gou, F.-
R.; Duan, X.-H.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2008, 73, 4713.
(c) Guan, Z.-H.; Ren, Z.-H.; Zhao, L.-B.; Liang, Y.-M. Org. Biomol. Chem.
2008, 6, 1040. (d) Bi, H.-P.; Liu, X.-Y.; Gou, F.-R.; Guo, L.-N.; Duan,
X.-H.; Liang, Y.-M. Org. Lett. 2007, 9, 3527. (e) Guo, L.-N.; Duan, X.-H.;
Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2007, 72, 1538. (f) Duan,
X.-H.; Guo, L.-N.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2006, 8,
5777. (g) Bi, H.-P.; Liu, X.-Y.; Gou, F.-R.; Guo, L.-N.; Duan, X.-H.; Shu,
X.-Z.; Liang, Y.-M. Angew. Chem., Int. Ed. 2007, 46, 7068. (h) Guo, L.-
N.; Duan, X.-H.; Liu, X.-Y.; Hu, J.; Bi, H.-P.; Liang, Y.-M. Org. Lett.
2007, 9, 5425. (i) Shu, X.-Z.; Zhao, S.-C.; Ji, K.-G.; Zheng, Z.-J.; Liu,
X.-Y.; Liang, Y.-M. Eur. J. Org. Chem. 2009, 117. (j) Shi, Y.; Huang, J.;
Yang, Y.-F.; Wu, L.-Y.; Niu, Y.-N.; Huo, P.-F.; Liu, X.-Y.; Liang, Y.-M.
AdV. Synth. Catal. 2009, 351, 141
.
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Org. Lett., Vol. 11, No. 15, 2009
3419

good results were always obtained (entries 11 and 12). And
we tested the reactions with various amines. Among these,
cyclic secondary aliphatic amines 2b and 2c both led to
comparable yields of the products (entries 13 and 14). No
reaction was observed when the reaction was carried out by
using amines 2d and 2e. This might due to the nature of
their poor nucleophilicity (entries 15 and 16).
Table 3. Pd-Catalyzed Cyclization of 1.0 equiv of Propargylic
Compounds 1 with 1.5 equiv of Amines 2a
This methodology is also applicable to phenylketones. The
reaction of propargylic carbonate 1m with Et2NH afforded
naphthylamine 3j in 82% yield (Table 3, entry 1). In the
case of propargyl acetate 1n, the product 3j was also obtained
(entry 2). Various substituents of ketone carbonyl, such as
an alkyl or aryl group, were well tolerated (entries 3-6).
Secondary carbonates possessing phenyl substituted at the
propargylic position also worked well, affording the corre-
sponding product in moderate yield (entry 7). And the
reactivities of secondary amines were investigated. Both
cyclic and acyclic secondary aliphatic amines, even dim-
ethylamine in aqueous solution 2m or dimethylamine
hydrochloride 2n, are also applicable in this process and
provided naphthylamines 3p-x in moderate yields (entries
8-17). With the purpose of getting an asymmetric tertiary
amine, amine 2o was tested. Rewardingly, the reaction
furnished the desired product 3y in 59% yield (entry 18). It
is worth noting that tertiary amine 3y might be engaged in
post-transformation for constructing secondary amine by the
removal of the benzyl group.
We were very pleased to find that primary amine 2p could
efficiently react with propargylic carbonate 1m and furnish
secondary naphthylamine 4a in 77% yield exclusively (Table
4, entry 1). This was somewhat of a surprise, because the
Table 4. Pd-Catalyzed Cyclization of 1.0 equiv of Propargylic
Compounds 1 with 1.5 equiv of Amines 2a
a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of solvent
at 100 °C under argon with 1.0 equiv of 1, 1.5 equiv of 2, and 0.05 equiv
of [Pd]. b Isolated yields.
time
(h)
yield
(%)b
entry
1
2
4
1
2
3
4
1m
2p (t-BuNH2)
2
2
2
3
4a 77
4b 68
4c 72
4d 56
1m
2q (s-BuNH2)
(entries 10-12). Herein, the optimum reaction conditions
thus far developed employ 1.0 equiv of 1a, 1.5 equiv of
amine, and 5 mol % of Pd(PPh3)4 in EtOH at 100 °C under
argon.
1m
2r (cyclohexanamine)
2s (1-phenylethanamine)
1m
R1 ) H,
5
6
7
8
R2 ) Et (1t)
R1 ) H,
2p
2p
2
2
2
3
4e 75
R2 ) n-Pr (1o)
R1 ) H,
4f
71
Next, the substrate scope of propargylic compound 1 was
surveyed under the optimized reaction conditions. Generally,
the reaction of primary propargylic compounds proceeded
smoothly and led to the desired product 3a in moderate to
good yields (Table 2, entries 2-5). Various substituents at
the propargylic position, such as methyl, phenyl, naphthyl,
and electron-withdrawing aromatic, were well tolerated
(entries 6-9). However, aryl-substituted electron-rich sub-
strate decomposed quickly (entry 10). Furthermore, substit-
uents on the benzene ring did not affect the reaction, and
R2 ) n-Bu (1u) 2p
R1 ) H,
4g 66
4h 60
R2 ) n-Pent (1p) 2p
a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of solvent
at 100 °C under argon with 1.0 equiv of 1, 1.5 equiv of 2, and 0.05 equiv
of [Pd]. b Isolated yields.
reaction of propargylic carbonate 1a with various primary
amines did not provide any cyclized product. Next, a series
3420
Org. Lett., Vol. 11, No. 15, 2009

of primary amines were investigated, the most active amines
being shown in Table 4. Likewise, all of them resulted in
good yields of desired products (entries 2-4). The cyclization
reaction was sightly affected by the tether length of the
substituent of ketone carbonyl, and always led to moderate
yields of the desired products (entries 5-8).
Scheme 1
Although the NMR spectroscopic data support the forma-
tion of naphthylamines 3, the structure was unambiguously
confirmed through an X-ray crystal structure analysis of
compound 3n (Figure 1).9
generates allenylpalladium intermediate A; (b) nucleophile
attacks the center sp-carbon of A followed by 6-endo
cyclization, using the carbonyl group, to form alkenylpal-
ladium(II) intermediate B; (c) intramolecular delivery and
the iminium formation affords intermediate C; and (d)
elimination of palladium(II) gives the desired products 3 or
4 after dehydration of D.
In conclusion, we have developed a novel and convenient
Pd(0)-catalyzed aminobenzannulation with propargylic com-
pounds for the synthesis of highly substituted aromatic amine
derivatives. A variety of primary, secondary, and tertiary
amines are applicable in this process, affording various
products in moderate to good yields. In particular, a
carbon-nitrogen and a carbon-carbon bond are sequentially
formed in a single operative step. Moreover, the high regio-
and chemoselectivity makes this unprecedented transforma-
tion attractive in organic synthesis. The study of details of
the reaction mechanism is in progress.
Figure 1. Structure of 3n.
On the basis of our knowledge and combined with the
above observations,10-14 a plausible mechanism is proposed
in Scheme 1. It involves the following key steps: (a)
transformation of propargylic compound 1 by Pd(0) catalyst
Acknowledgment. We thank the NSF (NSF-20621091,
NSF-20672049) for financial support.
(9) Crystal data for 3n are listed in the Supporting Information.
(10) (a) Yoshida, M.; Morishita, Y.; Fujita, M.; Ihara, M. Tetrahedron
Lett. 2004, 45, 1861. (b) Yoshida, M.; Morishita, Y.; Fujita, M.; Ihara, M.
Supporting Information Available: Typical experimental
procedure, characterization data for all products, and X-ray
data for 3n, in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
Tetrahedron 2005, 61, 4381
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