Benzannulation from alkyne without metallic catalysts at room temperature to 100 °C

Article abstract of DOI:10.1021/ol902742u

(Figure presented) An efficient, novel metal-catalyst-free aminobenzannulation of 2-(prop-2-ynyl)(oxo)benzenes 1 with various dialkylamlnes 2 afforded a variety of 2-aminonaphthalenes 3 in good to excellent yields under mild reaction conditions at room temperature to 100 °C (at most).

Full text of DOI:10.1021/ol902742u

ORGANIC
LETTERS
2010
Vol. 12, No. 2
388-390
Benzannulation from Alkyne without
Metallic Catalysts at Room Temperature
to 100 °C
Tienan Jin,* Fan Yang, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity,
Sendai 980-8578, Japan and WPI-AIMR (WPI-AdVanced Institute for Materials Research),
Tohoku UniVersity, Sendai 980-8577, Japan
tjin@mail.tains.tohoku.ac.jp; yoshi@mail.tains.tohoku.ac.jp
Received December 1, 2009
ABSTRACT
An efficient, novel metal-catalyst-free aminobenzannulation of 2-(prop-2-ynyl)(oxo)benzenes 1 with various dialkylamines 2 afforded a variety
of 2-aminonaphthalenes 3 in good to excellent yields under mild reaction conditions at room temperature to 100 °C (at most).
Functionalized aromatics and polycyclic aromatics are
regarded as useful building blocks in organic synthesis,
medicinal chemistry, and materials chemistry. One of the
powerful strategies for the construction of these aromatics
is acetylene-incorporated aromatic annulation (benzannula-
tion) which was first reported by Berthelot in 1866 through
the thermal [2 + 2 + 2] cyclotrimerization of acetylene (400
°C).1a Since Reppe1b and Vollhardt1c developed the transi-
tion-metal-catalyzed version of this reaction at relatively
lower temperatures, a variety of benzannulation strategies
involving Lewis acid- and transition-metal-catalyzed trans-
formations, iodocyclization, and thermal cyclization have
been reported.2 Over the past 10 years, we developed several
novel palladium-, gold-, and copper-catalyzed benzannulation
reactions.2b,3 Our goal is to develop an entirely new method
for benzannulation with atom-economical and environmen-
tally friendly characteristics.4 Herein, we report an efficient,
unprecedented metallic catalyst-free benzannulation of the
2-(prop-2-ynyl)(oxo)benzenes 1 with dialkylamines 2 under
mild reaction conditions, producing various 2-dialkylami-
nonaphthalenes 3 in good to excellent yields (Scheme 1).
Scheme 1. Synthesis of 2-Aminonaphthalene Derivatives via
Aminobenzannulation without Metallic Catalysts
(1) (a) Berthelot, M. C. R. Acad. Sci. 1866, 62, 905–909. (b) Repee,
W.; Schweckendiek, W. J. Justus Liebigs Ann. Chem. 1948, 560, 104–116.
(c) Vollhardt, K. P. C. Angew. Chem., Int. Ed. 1984, 23, 539–556.
(2) For reviews, see: (a) Kotha, S.; Misra, S.; Halder, S. Tetrahedron
2008, 64, 10775–10790. (b) Saito, S.; Yamamoto, Y. Chem. ReV. 2000,
100, 2901–2915. (c) Dotz, K. H.; Tomuschat, P. Chem. Soc. ReV. 1999,
28, 187–198. (d) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96,
49–92. (e) Trost, B. M. Science 1991, 254, 1471–1477.
Recently, the amine-triggered benzannulation, so-called
aminobenzannulation, has been considered an attractive
strategy for the construction of the useful amino-substituted
(3) For reviews, see: (a) Gevorgyan, V.; Yamamoto, Y. J. Orgnomet.
Chem. 1999, 576, 232–247. (b) Yamamoto, Y. J. Org. Chem. 2007, 72,
7817–7831
.
(4) Horvath, I. T.; Anastas, P. T. Chem. ReV. 2007, 107, 2169–2173.
10.1021/ol902742u  2010 American Chemical Society
Published on Web 12/18/2009

aromatic rings and heterocycles. Since Merlic’s group
reported an aminobenzannulation method with chromium
dienylcarbene,5 the most common approach involves a
transition-metal- or Lewis acid-catalyzed enamine formation/
benzannulation reaction of 2-alkynylacetophenones.6 Wu¨rth-
wein and co-workers developed an interesting aminoben-
zannulation method based on deprotonation of 2-(1-
alkynyl)benzaldimines through a multistep rearrangement
cascade.7 However, these aminobenzannulation methods
were limited to the synthesis of 1-aminonaphthalenes. On
the other hand, 2-aminonaphthalenes are very important
structural frameworks in medicinal chemistry and materials
chemistry with a wide range of applications.8 To our
knowledge, the use of aminobenzannulation for the construc-
tion of the 2-aminonaphthalenes has been rarely explored.9
In the course of the study of the catalytic alkyne-carbonyl
metathesis,10 we uncovered that when 2-(prop-2-ynyl)-benzal-
dehyde 1a (0.4 mmol) was treated with diethylamine 2a as a
solvent (2 mL) in the presence of MS 4 Å (200 mg) at ambient
temperature for 2 h diethyl-naphthalen-2-yl-amine 3a was
obtained in 93% yield after recovery of the excess amount of
diethylamine by distillation followed by a short silica gel
chromatography (Table 1, entry 1). The reaction in the absence
of MS 4 Å gave 3a in variable yields of the range of 71-83%.
The reaction with the use of 1.5 equiv of Et2NH and MS 4 Å
in the following solvents gave lower yields (40-50%) of 3a:
CH2Cl2, CH3CN, toluene, THF, and MeOH.
Table 1. Benzannulation of 2-(Prop-2-ynyl)benzaldehydes with
Dialkylaminesa
entry
1
R2NH (2)
3 (h)
yield (%)b
1
2
3
4
5
6
7
8
1a Et2NH (2a)
3a (2)
3b (12)
3c (4)
93
86
71
78
74
79
84
76
71
83
77
68
93
86
88
1a Me2NH (2b)c
1a (n-Bu)2NH (2c)
1a (Me)(MeOCH2CH2)NH (2d) 3d (12)
1a (Me)(CHCCH2)NH (2e)
1a (Me)(CH2CHCH2)NH (2f)
1a pyrrolidine (2g)
1a piperidine (2h)
1a morpholine (2i)
1a thiomorpholine (2j)
1a N-methylpiperazine (2k)
1b Et2NH (2a)
3e (24)
3f (12)d
3g (2)
3h(4)e
3i (4)e
3j (24)f
3k (24)f
3l (14)
3m (5)
3n (5)
3o (3)
9
10
11
12
13
14
15
1b pyrrolidine (2g)
1c Et2NH (2a)
1c pyrrolidine (2g)
a General conditions: aldehydes 1 (0.4 mmol), dialkylamine 2 (2 mL,
0.2 M), MS 4 Å (200 mg), at room temperature. The reaction time is shown
in parentheses. b Isolated yields. c A 2.0 M THF solution. d 12 h at rt then
1 h at 60 °C. e 80 °C. f 100 °C.
The benzannulation of various acyclic and cyclic dialky-
lamines with 2-(prop-2-ynyl)benzaldehydes 1 is summarized
in Table 1. The reaction of the symmetric secondary amines,
dimethylamine and dibutylamine, gave the corresponding 2-di-
alkylaminonaphthalenes 3b and 3c in good yields at room
temperature (entries 2 and 3). Other acyclic dialkylamines with
a 2-methoxyethyl, propargyl, or allyl moiety could be used
similarly to give the expected 2-dialkylaminonaphthalenes 3d-f
in good yields with prolonged reaction times (entries 4-6). It
is noteworthy that methyl-naphthalen-2-yl-prop-2-ynylamine 3e
acts as a rat liver monoamine oxidase inhibitor.8a Cyclic
alkylamines were also suitable for this aminobenzannulation
reaction. The reaction of 1a with pyrrolidine gave the corre-
sponding 1-naphthalen-2-yl-pyrrolidine 3g in 84% yield under
mild reaction conditions (entry 7). Other cyclic amines, such
as piperidine, morpholine, thiomorpholine, and N-methylpip-
erazine, were also tolerated, giving the expected 2-aminonaph-
thalenes 3h-k in good to high yields under the elevated
temperatures (entries 8-11).8b The 2-(prop-2-ynyl)benzalde-
hydes substituted with an electron-donating (1b) or electron-
withdrawing group (1c) afforded the desired products, 3l-o,
in good to high yields (entries 12-15). A naphthalene derivative
(1d) reacted with either diethylamine or pyrrolidine at room
temperature, producing the corresponding 3-aminophenan-
threnes 3p and 3q in good yields (Scheme 2). Additional studies
(5) (a) Merlic, C. A.; Burns, E. E.; Xu, D.; Chen, S. Y. J. Am. Chem.
Soc. 1992, 114, 8722–8724. (b) Merlic, C. A.; Aldrich, C. C.; Albaneze-
Walker, J.; Saghatelian, A.; Mammen, J. J. Org. Chem. 2001, 66, 1297–
1309. (c) Merlic, C. A.; Xu, D.; Gladstone, B. G. J. Org. Chem. 1993, 58,
538–545.
(6) (a) Herndon, J. W.; Zhang, Y.; Wang, K. J. Organomet. Chem. 2001,
634, 1–4. (b) Belmont, P.; Belhadj, T. Org. Lett. 2005, 7, 1793–1795. (c)
Tiano, M.; Belmont, P. J. Org. Chem. 2008, 73, 4101–4109. (d) Facoetti,
D.; Abbiati, G.; Rossi, E. Eur. J. Org. Chem. 2009, 2872–2882.
(7) (a) Sagar, P.; Fro¨hlich, R.; Wu¨rthwein, E.-U. Angew. Chem., Int.
Ed. 2004, 43, 5694–5697. (b) Lyaskovskyy, V.; Fro¨hlich, R.; Wu¨rthwein,
E.-U. Synthesis 2007, 2135–2144.
Scheme 2. Formation of 3-Aminophenanthrenes
(8) (a) Tipton, K. F.; McCrodden, J. M.; Kalir, A. S.; Youdim, M. B. H.
Biochem. Pharmacol. 1982, 31, 1251–1255. (b) Dukat, M.; Abdel-Rahman,
A. A.; Ismaiel, A. M.; Ingher, S.; Teitler, M.; Gyermek, L.; Glennon, R. A.
J. Med. Chem. 1996, 39, 4017–4026. (c) Kabankin, A. S.; Kurlyandskii,
B. A. Pharm. Chem. J. 2001, 35, 257–259. (d) Agdeppa, E. D.; Kepe, V.;
Liu, J.; Flores-Torres, S.; Satyamurthy, N.; Petric, A.; Cole, G. M.; Small,
G. W.; Huang, S.-C.; Barrio, J. R. J. Neurosci. 2001, 21, RC189 1–5. (e)
Kim, H. M.; Jung, C. J.; Kim, B. R.; Jung, S.-Y.; Hong, J. H.; Ko, Y.-G.;
Lee, K. J.; Cho, B. R. Angew. Chem., Int. Ed. 2007, 46, 3460–3463. (k)
Saudan, C.; Balzani, V.; Gorka, M.; Lee, S.-K.; Maestri, M.; Vicinelli, V.;
Vogtle, F. J. Am. Chem. Soc. 2003, 125, 4424–4425.
revealed that, in contrast to the substrates with terminal alkynes
or dialkylamines, internal alkynes or less basic amines such as
secondary benzylamines and anilines did not undergo the
present aminobenzannulation.
Not only the substituted benzaldehydes but also the
acetophenone or benzophenone derivatives can be used as
(9) Gou, F.-R.; Huo, P.-F.; Bi, H.-P.; Guan, Z.-H.; Liang, Y.-M. Org.
Lett. 2009, 11, 3418–3421.
(10) (a) Jin, T.; Yamamoto, Y. Org. Lett. 2007, 9, 5259–5262. (b) Jin,
T.; Yamamoto, Y. Org. Lett. 2008, 10, 3137–3139. (c) Jin, T.; Yang, F.;
Liu, C.; Yamamoto, Y. Chem. Commun. 2009, 3533–3535.
Org. Lett., Vol. 12, No. 2, 2010
389

substrates for benzannulation. The reaction of 1e, 1f, or 1g
with pyrrolidine proceeded smoothly at 80 °C for 12 h, giving
the corresponding 2,4-disubstituted 2-aminonaphthalenes
3r-t in high yields (Table 2, entries 1-3). The acetophe-
formation/benzannulation stepwise reaction,6 in the present
reaction, the nucleophilic addition of amine to allene and
cycloaddition steps should occur simultaneously.
Table 2. Benzannulation of Acetophenone and Benzophenone
Derivativesa
A proposed reaction mechanism is shown in Scheme 4.11
Initially, rapid isomerization of 1a in the presence of
diethylamine leads to the allene A. Subsequent nucleophilic
entry
R1, R2 (1)
H, Me (1e)
R2NH (2)
3
yield (%)b
1
2
3
4
5
pyrrolidine (2g) 3rc
pyrrolidine (2g) 3s
85
87
99
78
99
H, Ph (1f)
4,5-(MeO)2, Me (1g) pyrrolidine (2g) 3t
5-Cl, Me (1h)
5-Cl, Me (1h)
Et2NH (2a)
3u
pyrrolidine (2g) 3vc
Scheme 4. Proposed Reaction Mechanism
a General conditions: ketones 1 (0.4 mmol), dialkylamine 2 (2 mL, 0.2
M), MS 4 Å (200 mg), at 80 °C for 12 h. b Isolated yields. c Room
temperature for 12 h.
nones having an electron-withdrawing group (1h) on the
benzene ring reacted with either diethylamine or pyrrolidine,
affording the expected multisubstituted 2-dialkylaminonaph-
thalenes 3u and 3v in good to excellent yields (entries 4 and
5). Interestingly, the acetophenones without substituents (1e)
or bearing an electron-donating group on the benzene ring
(1g) reacted with acyclic diethylamine under the same
reaction conditions, giving the 1-aminonaphthalenes 4w and
4x in high yields instead of forming 2-aminonaphthalenes
(Scheme 3).6 The reason is not clear.
addition of diethylamine to the central carbon of the allene
A followed by the cycloaddition onto the iminium moiety
probably forms the intermediate B. Finally, the aromatization
of the intermediate B through the elimination of amine
affords 2-diethylaminonaphthalene 3a.
In conclusion, we have developed an efficient and general
method for the synthesis of 2-dialkylaminonaphthalenes through
a novel aminobenzannulation reaction. The reaction proceeds
under mild reaction conditions without metal promoters and
catalysts. Compared to the previously reported benzannulation
protocols, the present approach has an obvious advantage from
the viewpoint of atom economy and environmental concern.
Further extension of this approach to the synthesis of the
biologically important amine-substituted heterocycles and ap-
plication to materials chemistry are in progress.
Scheme 3. Formation of 1-Aminonaphthalene Derivatives
To help clarify the reaction mechanism for the formation
of the 2-aminonaphthalenes, we performed the reaction with
4-(prop-2-ynyl)benzaldehyde 1i and diethylamine at room
temperature (eq 1). After 10 min, the allene 3b was obtained
predominantly, while after 2 h the hydroaminated internal
enamine 3c was observed as a major product together with
a small amount of the allene 3b and the hydrolyzed ketone
3d. When prop-2-ynyl-benzene 1j was subjected with
diethylamine, we never obtained the corresponding allene
or enamine product, and 1j was recovered cleanly (eq 2).
These experimental results suggest that the substrate 1i
having an electron-withdrawing group on the benzene ring
is readily converted into the corresponding allene. Addition-
ally, in contrast to the previously reported terminal enamine
Acknowledgment. We thank the faculty members of the
Instrumental Analysis Center at Tohoku University for the
measurement of NMR and mass spectra.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL902742U
(11) An alternative plausible reaction mechanism for the formation of
2-aminonaphthalenes is a 6-electrocyclization pathway as shown below.
390
Org. Lett., Vol. 12, No. 2, 2010