Efficient synthesis of heterocyle-fused β-naphthylamines via intramolecular addition to a cyano group initiated by nucleopalladation of alkynes

Article abstract of DOI:10.1021/ol5031074

A palladium(II)-catalyzed efficient synthesis of heterocycle-fused-naphthylamines was accomplished via nucleophilic addition of a carbon-palladium bond to the intramolecular cyano group initiated by nucleopalladation (oxypalladation or aminopalladation) o

Full text of DOI:10.1021/ol5031074

Letter
pubs.acs.org/OrgLett
Efficient Synthesis of Heterocyle-Fused β‑Naphthylamines via
Intramolecular Addition to a Cyano Group Initiated by
Nucleopalladation of Alkynes
Guoqin Xia, Xiuling Han,* and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai, 200032, China
S
* Supporting Information
ABSTRACT: A palladium(II)-catalyzed efficient synthesis of hetero-
cycle-fused β-naphthylamines was accomplished via nucleophilic
addition of a carbon−palladium bond to the intramolecular cyano
group initiated by nucleopalladation (oxypalladation or amino-
palladation) of alkynes.
Scheme 1. Strategy for the Synthesis of Heterocycle-Fused β-
Naphthylamines
he carbon−palladium bond is generally considered to be
Telectrophilic in traditional palladium chemistry and can
undergo various carbon−carbon or carbon−heteroatom bond
forming processes.1 Early examples of the nucleophilic addition
of a carbon−palladium bond to the carbonyl group were from
the pioneer works of Heck2 and Larock.3 In 1996, Vicente’s
group first reported a direct stoichiometric nucleophilic
addition of vinylpalladium species to benzaldehyde.4 Since
then, the nucleophilic addition reaction of the carbon−
palladium bond to the carbon−heteroatom multiple bonds
has become a new strategy for the carbon−carbon bond
formation.5
The cyano group is one of the most accessible carbon−
heteroatom multiple bonds, and it is widely used in synthetic
organic chemistry. Generally, the cyano group is inert in
palladium chemistry; e.g., acetonitrile could be used as a ligand
or solvent in some palladium-catalyzed reactions. Nevertheless,
several research groups have reported the nucleophilic addition
of the carbon−palladium bond to the cyano group in the past
decade.6 We were interested in the nucleophilic addition of
carbon−palladium bonds to carbon−heteroatom multiple
bonds, including the cyano group.7 From these works, it was
demonstrated that the vinyl carbon−palladium bonds gen-
erated from nucleopalladation of alkynes could add to the
cyano group conveniently.7a,d And very recently, a new strategy
by exploring the tandem cyclization mode of this reaction to
synthesize some heterocycle-fused indoles was also carried out
successfully (Scheme 1).8 Inspired by this result, we then
changed the positions of nucleophiles and the cyano group to
try to find a new tandem cyclization for the synthesis of
heterocycle-fused β-naphthylamines (Scheme 1).
this consideration, we wish to investigate these kinds of
reactions initiated by oxypalladation using an alcohol as the
nucleophile to synthesize some heterocycle-fused β-naphthyl-
amines. As we know, β-naphthylamines are widely used in
dyestuff industry and are also found to have some applications
in the synthesis of axial chiral ligands.9 In addition, some of the
derivatives of heterocycle-fused β-naphylamines were also
target molecules in medicinal chemistry.10 However, in general,
these heterocycle-fused β-naphthylamines are not easily
available.10a,11 Thus, we wonder if these compounds could be
prepared from some substituted benzenes via a tandem
cyclization reaction developed by our group.
Furthermore, in our previous work, the nucleophiles used in
the addition reactions to the nitriles were acetic acid and the
NHTs group; we then wondered whether alcohols can also be
used as the nucleophile due to its electromeric effect. Based on
Received: October 23, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5031074 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Initially, substrate 1a was used to study the reaction
conditions. It was found that only starting material was
recovered using Pd(OAc)2/bpy as the catalyst in dioxane at 100
°C (Table 1, entry 1). This preliminary result indicated that the
benzene ring gave good to excellent yields, and the site of the
substitution did not affect the yield obviously (Scheme 2, 2b-
Scheme 2. Substrate Scope of Oxypalladation-Initiated
a
Tandem Cyclization Reaction
a
Table 1. Optimization of the Reaction Conditions
b
entry
additives
solvents
dioxane
temp (°C) yield (%)
1
2
3
4
5
6
7
8
9
−
100
0
Cs2CO3
dioxane
100
0
Et3N
dioxane
100
0
K2CO3
DMF/H2O (10:1)
dioxane/HOAc (4:1)
dioxane
100
0
−
100
0
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
100
83
86
82
94
0
dioxane
80
dioxane
60
THF
reflux
reflux
reflux
reflux
reflux
c
10
THF
d
11
THF
0
e
12
THF
0
f
13
THF
0
a
Reaction conditions: Pd(OAc)2 (5 mol %), bpy (10 mol %), 1a (0.3
mmol), and additives (2 equiv) were dissolved in 2.0 mL of the
indicated solvents, and then the reaction mixture was stirred for 4 h
b
c
under the indicated temperature. Isolated yield. No Pd(OAc)2 was
d
e
a
added. No bpy was added. Sc(OTf)3 was used as the catalyst.
Cu(OTf)2 was used as the catalyst.
Reaction conditions: Pd(OAc)2 (5 mol %), bpy (10 mol %),
f
substrate (0.3 mmol), and TsOH·H2O (2 equiv) were dissolved in 2.0
b
mL of THF, and the reaction mixture was refluxed for 4 h. The
reaction time was 8 h.
oxypalladation probably could not occur under the neutral
conditions. Several bases were then tried using the same
catalyst, since some of the oxypalladations reported in literature
were under basic conditions.12 Unfortunately, none of these
conditions worked and only starting material was recovered
besides some unidentified products (Table 1, entries 2−4). In
our previous works, it was found that the Brønsted acid could
activate the cyano group and make it react with the carbon−
palladium bond successfully.8 Thus, we turned our attention to
the acidic conditions. When acetic acid was used as the
cosolvent, no expected product was detected (Table 1, entry 5).
To our delight, when TsOH·H2O was used, the β-
naphthylamine 2a was formed successfully in 83% yield
(Table 1, entry 6), and the reaction could also proceed
smoothly without a significant change in the yield even after
decreasing the temperature from 100 to 60 °C (Table 1, entries
7 and 8). A higher yield (94%, Table 1, entry 9) could be given
in THF. In the absence of palladium acetate or bpy, the
reaction was completely blocked (Table 1, entries 10 and 11),
indicating that the palladium(II) catalyst and bpy are crucial to
the reaction. In addition, some Lewis acids such as Sc(OTf)3 or
Cu(OTf)2 could not catalyze this reaction under the same
conditions. Finally, the optimal conditions were chosen as
follows: Pd(OAc)2 (5 mol %), bpy (10 mol %), substrate (0.3
mmol), and TsOH·H2O (2 equiv) were dissolved in 2.0 mL of
THF, and the reaction mixture was refluxed for 4 h.
2d). Surprisingly, the yield decreased dramatically when the
substitution was a methoxy group, and we are unable to give a
reasonable explanation for this at present (Scheme 2, 2e).
Substrates with an electron-withdrawing group such as CF3 also
gave a high yield (Scheme 2, 2g), and this reaction was also
suitable for the naphthalene-fused substrate (Scheme 2, 2f).
Substrates with halogen atoms such as Cl, Br, and F gave good
to excellent yields (Scheme 2, 2h−2k), and similarly the site of
the halogen on the benzene ring did not affect the yields too
much. Finally, we tried to extend the fused-heterocycle in the
product from a five-membered to six-membered or even to a
seven-membered ring system. Fortunately, it worked well for a
six-membered ring when the corresponding substrate was
reacted under similar conditions for 8 h (73% yield, Scheme 2,
2l), but for a seven-membered ring, only a 37% yield was
achieved under the same conditions (Scheme 2, 2m).
In our previous work, it was found that a nitrogen atom α to
the vinyl C−Pd bond could also promote the nucleophilic
addition to the cyano group.8 So we continued to investigate
this kind of reaction initiated by aminopalladation. With this
purpose, substrates 3a−3c were applied to the reaction and all
of them gave the corresponding products in moderate to good
yields (Scheme 3, 4a−4c).
Having established the optimal conditions, we then set out to
investigate the substrate scope of this reaction. A series of
substituted substrates were tested under the optimal conditions.
The results showed that substrates with a methyl group on the
In addition, we also examined the reaction of substrate 5, in
which the tert-butyl ester could also be used for the
oxypalladation reaction in literature.13 To our delight,
naphthylamine 6 was formed successfully in 98% yield. The
B
dx.doi.org/10.1021/ol5031074 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope of Aminopalladation-Initiated
Tandem Cyclization Reaction
Scheme 5. Study for the Role of the α-H in the Reaction
a
a
Scheme 6. Proposed Mechanism
Reaction conditions: Pd(OAc)2 (5 mol %), bpy (10 mol %),
substrate (0.3 mmol), and TsOH·H2O (2 equiv) were dissolved in 2.0
mL of THF, and then the reaction mixture was refluxed for 4 h.
similar skeleton of compound 6 was found to be the core
structure in antibiotics such as the lambdamycin (Scheme 4).14
Scheme 4. Tandem Cyclization Using tert-Butyl Ester as the
Nucleophile
ization from imine to enamine), which may cause the tandem
cyclization to occur successfully.
In conclusion, we have developed a new tandem cyclization
mode for the synthesis of a series of heterocycle-fused β-
naphthylamines via an intramolecular nucleophilic addition of a
carbon−palladium bond to the cyano group. This is a reaction
which can be initiated by either oxypalladation or amino-
palladation of alkynes without the necessity of a redox system.
The existence of the hydrogen atom α to the cyano group is
crucial to the reaction, probably because it provides the
potential to undergo aromatization. This reaction should have
some applications in synthetic chemistry and pharmaceutics
due to the special skeleton of the products.
In this reaction, all the substrates bear the hydrogen atom α
to the cyano group and it seems that it is indispensable for the
formation of β-naphthylamines as seen from Scheme 1. In
order to investigate the role of the hydrogen atom, compounds
7 and 9 were tested under the optimal conditions. Product 8
was formed successfully in 71% yield using 7 as the substrate,
while the reaction became disordered and no expected product
was detected when substrate 9 was used (Scheme 5). This
result indicated that the existence of the hydrogen atom α to
the cyano group is crucial to the success of this reaction.
Finally, a proposed mechanism is outlined in Scheme 6.
Using substrate 1a as an example, the carbon−carbon triple
bond in the substrate coordinates with the palladium(II)
catalyst in the first stage of the reaction, and then trans-
oxypalladation occurs to generate the intermediate B. The
nucleophilic addition to the cyano group generates C, and the
protonolysis of C results in the formation of the imine D. Then
D undergoes aromatization to generate the final product 2a.
From the mechanism, it can be seen that the existence of a
hydrogen atom α to the cyano group can initiate the
aromatization of intermediate D to β-naphthylamines (isomer-
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, compounds characterization data,
and copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: xylu@mail.sioc.ac.cn.
*E-mail: xlhan@mail.sioc.ac.cn.
Notes
The authors declare no competing financial interest.
C
dx.doi.org/10.1021/ol5031074 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China
(2011CB808706), National Natural Science Foundation of
China (21232006, 21272249), and Chinese Academy of
Sciences for financial support.
REFERENCES
■
(1) For reviews, see: (a) Negishi, E., de Meijere, A., Eds. Handbook of
Organopalladium Chemistry for Organic Synthesis; John Wiley & Sons,
Inc.: New York, 2002; Vol. 1, p 17. (b) Crabtree, R. H. The
Organometallic Chemistry of the Transition Metals, 5th ed.; John Wiley
& Sons, Inc.: NJ, 2009; pp 252−254.
(2) Tao, W.; Silverberg, L. J.; Rheingold, A. L.; Heck, R. F.
Organometallics 1989, 8, 2550.
(3) Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem. 1993, 58,
4579.
(4) Vicente, J.; Abad, J.-A.; Gil-Rubio, J. Organometallics 1996, 15,
3509.
(5) For reviews, see: (a) Yamamoto, Y.; Nakamura, I. Top.
Organomet. Chem. 2005, 14, 211. (b) Sole,
Chem. Res. 2014, 47, 168.
́ ́
D.; Fernandez, I. Acc.
(6) (a) Zhou, C.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 2302.
(b) Zhou, C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551. (c) Zhao, B.;
Lu, X. Org. Lett. 2006, 8, 5987. (d) Lindh, J.; Sjoberg, P. J. R.; Larhed,
̈
M. Angew. Chem., Int. Ed. 2010, 49, 7733. (e) Liu, J.; Zhou, X.; Rao,
H.; Xiao, F.; Li, C.-J.; Deng, G.-J. Chem.Eur. J. 2011, 17, 7996.
(f) Ma, Y.; You, J.; Song, F. Chem.Eur. J. 2013, 19, 1189. (g) Jiang,
T.-S.; Wang, G.-W. Org. Lett. 2013, 15, 788. (h) Jiang, T.-S.; Wang, G.-
W. Adv. Synth. Catal. 2014, 356, 369.
(7) (a) Zhao, L.; Lu, X. Angew. Chem., Int. Ed. 2002, 41, 4343.
(b) Zhao, B.; Lu, X. Org. Lett. 2006, 8, 5987. (c) Zhao, B.; Lu, X.
Tetrahedron Lett. 2006, 47, 6765. (d) Xia, G.; Han, X.; Lu, X. Adv.
Synth. Catal. 2012, 354, 2701.
(8) Xia, G.; Han, X.; Lu, X. Org. Lett. 2014, 16, 2058.
̌
́
̌ ̌ ̌
(9) For reviews, see: (a) Kocovsky, P.; Vykocil, S.; Smrcina, M. Chem.
Rev. 2003, 103, 3213. (b) Telfer, S. G.; Kuroda, R. Coord. Chem. Rev.
2003, 242, 33.
(10) For some examples, see: (a) Alvarez-Fitz, P.; Alvarez, L.;
Marquina, S.; Luna-Herrera, J.; Navarro-Garcia, V. M. Molecules 2012,
17, 8464. (b) Ferreira, S. B.; Salomao, K.; De Carvalho Da Silva, F.;
̃
Pinto, A. V.; Kaiser, C. R.; Pinto, A. C.; Ferreira, V. F.; De Castro, S. L.
Eur. J. Med. Chem. 2011, 46, 3071. (c) Silva, R. S. F.; Pinto, F. R.;
Goulart, M. O. F.; De Souza Filho, J. D.; Neves, I., Jr.; Lourenco, M. C.
S.; Pinto, A. V. Eur. J. Med. Chem. 2009, 44, 2334. (d) Perez-Sacau, E.;
Diaz-Penate, R. G.; Estevez-Braun, A.; Ravelo, A. G.; Garcia-
Castellano, J. M.; Pardo, L.; Campillo, M. J. Med. Chem. 2007, 50,
696. (e) Don, M. J.; Shen, C. C.; Lin, Y. L.; Syu, W. J.; Ding, Y. H.;
Sun, C. M. J. Nat. Prod. 2005, 68, 1066.
(11) (a) Pan, C.; Abdukader, A.; Han, J.; Cheng, Y.; Zhu, C. Chem.
Eur. J. 2014, 20, 3606. (b) Sallenave, X.; Delbaere, S.; Vermeersch, G.;
Pozzo, J.-L. J. Phys. Org. Chem. 2007, 20, 872. (c) Tominaga, Y.;
Castle, L. W.; Raymond, N. J. Heterocycl. Chem. 1993, 30, 845.
(d) Kamel, M.; Allam, M. A.; Abou-Zeid, N. Y. Tetrahedron 1967, 23,
1863.
(12) (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L. M.
Tetrahedron 2003, 59, 4661. (b) Cacchi, S.; Fabrizi, G.; Goggiomani,
A. Heterocycles 2002, 56, 613. (c) Hosokawa, T.; Murahashi, S.-I.
Heterocycles 1992, 33, 1079.
(13) (a) Wang, H.; Han, X.; Lu, X. Tetrahedron 2013, 69, 8626.
(b) Zhao, P.; Chen, D.; Song, G.; Han, K.; Li, X. J. Org. Chem. 2012,
77, 1579. (c) Speranca, A.; Godoi, B.; Pinton, S.; Back, D. F.; Menezes,
P. H.; Costa, M. D.; Zeni, G. J. Org. Chem. 2011, 76, 6789. (d) Yao, T.;
Larock, R. C. J. Org. Chem. 2003, 68, 5936.
(14) Fleck, W.; Strauss, D.; Prauser, H.; Jungstand, W.; Heinecke, H.;
Gutsche, W.; Wohlrabe, K. Z. Allg. Mikrobiol. 1976, 16, 521.
D
dx.doi.org/10.1021/ol5031074 | Org. Lett. XXXX, XXX, XXX−XXX