AuBr3- and Cu(OTf)2-catalyzed intramolecular [4 + 2] cycloaddition of tethered alkynyl and alkenyl enynones and enynals: A new synthetic method for functionalized polycyclic hydrocarbons

Article abstract of DOI:10.1021/jo0500434

(Chemical Equation Presented) Treatment of tethered alkynyl enynones 8, in which a carbon chain is attached to the carbonyl group, with a catalytic amount of AuBr₃in (ClCH₂)₂ gave the naphthyl ketones 9 in good to high yields (top-down approach). Analogously, the AuBr ₃-catalyzed benzannulations of 10, in which a carbon tether is extended from the alkynyl terminus, also proceeded smoothly, and the cyclized naphthyl ketones 11 were obtained in high yields (bottom-up approach). Similarly, when two kinds of tethered alkenyl enynones 12 and 14 were treated with Cu(OTf)₂ catalyst, the corresponding dihydronaphthyl ketone products 13 and 15 were obtained in high yields, respectively. The present formal [4 + 2] intramolecular cycloaddition proceeds most probably through the coordination of the triple bond at the ortho position of substrates to Lewis acids, the formation of benzopyrylium ate complex 16 via the nucleophilic addition of the carbonyl oxygen atom, the reverse electron demand type Diels-Alder addition of the tethered alkynes or alkenes to the ate complex, and subsequent bond rearrangement.

Full text of DOI:10.1021/jo0500434

AuBr3- and Cu(OTf)2-Catalyzed Intramolecular [4 + 2]
Cycloaddition of Tethered Alkynyl and Alkenyl Enynones and
Enynals: A New Synthetic Method for Functionalized Polycyclic
Hydrocarbons
Naoki Asao,* Kenichiro Sato, Menggenbateer, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
asao@mail.tains.tohoku.ac.jp; yoshi@yamamoto1.chem.tohoku.ac.jp
Received January 9, 2005
Treatment of tethered alkynyl enynones 8, in which a carbon chain is attached to the carbonyl
group, with a catalytic amount of AuBr3 in (ClCH2)2 gave the naphthyl ketones 9 in good to high
yields (top-down approach). Analogously, the AuBr3-catalyzed benzannulations of 10, in which a
carbon tether is extended from the alkynyl terminus, also proceeded smoothly, and the cyclized
naphthyl ketones 11 were obtained in high yields (bottom-up approach). Similarly, when two kinds
of tethered alkenyl enynones 12 and 14 were treated with Cu(OTf)2 catalyst, the corresponding
dihydronaphthyl ketone products 13 and 15 were obtained in high yields, respectively. The present
formal [4 + 2] intramolecular cycloaddition proceeds most probably through the coordination of
the triple bond at the ortho position of substrates to Lewis acids, the formation of benzopyrylium
ate complex 16 via the nucleophilic addition of the carbonyl oxygen atom, the reverse electron
demand type Diels-Alder addition of the tethered alkynes or alkenes to the ate complex, and
subsequent bond rearrangement.
Introduction
hydrocarbons. However, such a reaction often provides
products as a mixture of regioisomers due to the lack of
regioselective control on the Friedel-Crafts reaction.
Accordingly, an alternative method for regioselective
construction of functionalized polycyclic structures has
been highly desirable. Recently, we reported that the
AuX3-catalyzed intermolecular [4 + 2] benzannulation
between enynal units 1 and alkynes gave the naphthyl
ketones 2 in high yields.2-4 We also found that a similar
[4 + 2] cycloaddition between 1 and alkenes took place
in the presence of Cu(OTf)2 catalyst to give the 1,2-
Lewis acid-catalyzed cyclization reaction is one of the
most fundamental and important methods for the prepa-
ration of functionalized polycyclic hydrocarbons.1 Among
them, the intramolecular cyclization based on the Friedel-
Crafts reaction has been widely used as one of the most
effective preparative methods for functionalized polycyclic
* Corresponding author. Phone: +81-22-795-6581. Fax: +81-22-
795-6784.
(1) (a) Lewis Acids in Organic Synthesis: Yamamoto, H., Ed.; Wiley-
VCH: Weinheim, 2000; Vols. 1-2. (b) Lewis Acid Reagents; Yamamoto,
H., Ed.; Oxford University Press: New York, 1999. (c) Mahrwald, R.
Chem. Rev. 1999, 99, 1095-1120. (d) Santelli, M.; Pons, J. M. Lewis
Acids and Selectivity in Organic Synthesis; CRC Press: Boca Raton,
FL, 1996. (e) Shambayati, S.; Schreiber, S. L. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 1, pp 283-324. (f) Yamaguchi, M. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 1, pp 325-353.
(2) (a) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto,
Y. J. Am. Chem. Soc. 2002, 124, 12650-12651. (b) Asao, N.; Nogami,
T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 10921-10925.
(3) For reviews on the synthesis of naphthalenes, see: (a) de Koning,
C. B.; Rousseau, A. L.; van Otterlo, W. A. L. Tetrahedron 2003, 59,
7-36. (b) Katritzky, A. R.; Li, J.; Xie, L. Tetrahedron 1999, 55, 8263-
8293.
10.1021/jo0500434 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/02/2005
3682
J. Org. Chem. 2005, 70, 3682-3685

Lewis Acid-Catalyzed Intramolecular [4 + 2] Cycloaddition
TABLE 1. Lewis Acid-Catalyzed Intramolecular
Cyclization of 8a
SCHEME 1. Lewis Acid-Catalyzed Intermolecular
[4 + 2] Benzannulation and Cycloaddition
entry
8
R
n
Lewis acid conditions
9
yield (%)b
1
2
3d
4
5
6
7
8
8a Ph
8a Ph
8a Ph
8a Ph
8b Bu
3
3
3
3
3
3
3
4
AuCl3
AuBr3
AuBr3
rt, 3 h
rt, 3 h
rt, 3 h
9a
9a
9a
9a
9b
9c
9d
89c
92
91
84c
57
41
40
72
Cu(OTf)2 rt, 2 h
AuBr3
AuBr3
AuBr3
AuBr3
rt, 5 h
rt, 4.5 h
rt, 36 h
8c
H
8d TMS
8e Ph
80 °C, 5 h 9e
a Reaction was carried out using 8 (0.5 mmol) in the presence
of 5 mol % Lewis acid in (CH2Cl)2 unless otherwise noted.
b Isolated yields. c Yield was determined by 1H NMR using dibro-
momethane as an internal standard. d Reaction was conducted
using 1 g of 8a (2.9 mmol).
SCHEME 2. Lewis Acid-Catalyzed Intramolecular
[4 + 2] Benzannulation and Cycloaddition
reactions produced the corresponding polycyclic naph-
thalene derivatives 5 and 7 in good to high yields.9
Results and Discussion
First, we examined the reaction of 8 (type 1) under
several conditions (eq 1), and the results are summarized
in Table 1. When 8a (R ) Ph, n ) 3) was treated with 5
mol % AuCl3 in (CH2Cl)2 at rt for 3 h, the naphthyl ketone
9a was obtained in 89% yield (entry 1).10-11
dihydronaphthalene derivatives 3 in good to high yields
(Scheme 1).5-7 It occurred to us that the intramolecular
version of the [4 + 2] benzannulation and [4 + 2]
cycloaddition would produce a variety of polycyclic naph-
thalene and dihydronaphthalene derivatives and the
scope of the [4 + 2] benzannulation and cycloaddition
would be expanded very much because such products are
quite useful building blocks for the synthesis of natural
products such as tanshinones.8 In this paper, we wish to
report two different kinds of the intramolecular [4 + 2]
cycloaddition reactions; one is the top-down approach
using 4 (type 1), in which a carbon chain is attached to
the carbonyl group, and another is the bottom-up ap-
proach using 6 (type 2), in which a carbon tether is
extended from the alkynyl terminus (Scheme 2). Both
The chemical yield of 9a was increased up to 92% yield
by using AuBr3 catalyst instead of AuCl3 (entry 2). The
present benzannulation proceeded smoothly even when
1 g of 8a (2.9 mmol) was used and the corresponding
product 9a was obtained in 91% (entry 3). When we used
Cu(OTf)2 as a catalyst, 9a was obtained in 84% yield
together with 4-phenyl-2,3-dihydro-1H-cyclopenta[a]-
naphthalene (13% yield), which was produced by the
cleavage of benzoyl group (entry 4).2b The reaction
proceeded at high temperatures even in the absence of
Lewis acid catalyst; however, it was very sluggish at 80
°C, and the chemical yield of 9a was 34% even after 10
days. The AuBr3-catalyzed reaction of the other starting
materials 8b-d also proceeded smoothly, and the corre-
sponding products 9b-d were obtained in good to high
yields (entries 5-7). While the reaction of 8e, having a
tether chain consisting of four methylene groups (n ) 4),
did not proceed at rt, it proceeded at 80 °C and the
corresponding tetrahydrophenanthrene product 9e was
obtained in 72% yield (entry 8).
(4) For recent examples for naphthalene syntheses, see: (a) Iwasa-
wa, N.; Shido, M.; Maeyama, K.; Kusama, H. J. Am. Chem. Soc. 2000,
122, 10226-10227. (b) Wakasugi, K.; Nishi, Y.; Tanabe, Y. Tetrahedron
Lett. 2000, 41, 5937-5942. (c) Miura, T.; Iwasawa, N. J. Am. Chem.
Soc. 2002, 124, 518-519. (d) Huang, Q.; Larock, R. C. Org. Lett. 2002,
4, 2505-2508. (e) Viswanathan, G. S.; Wang, M.; Li, C.-J. Angew.
Chem., Int. Ed. 2002, 41, 2138-2141. (f) Yasukawa, T.; Satoh, T.;
Miura, M.; Nomura, M. J. Am. Chem. Soc. 2002, 124, 12680-12681.
(g) Viswanathan, G. S.; Li, C.-J. Synlett 2002, 1553-1555. (h) Ra-
makrishna, T. V. V.; Sharp, P. R. Org. Lett. 2003, 5, 877-879. (i)
Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. Org.
Lett. 2003, 5, 4121-4123. (j) Shen, H.-C.; Pal, S.; Lian, J.-J.; Liu, R.-
S. J. Am. Chem. Soc. 2003, 125, 15762-15763. (k) Kusama, H.;
Funami, H.; Takaya, J.; Iwasawa, N. Org. Lett. 2004, 6, 605-608.
(5) Asao, N.; Kasahara, T.; Yamamoto, Y. Angew. Chem., Int. Ed.
2003, 42, 3504-3506.
We next examined the type 2 reaction by using the
substrates 10 (eq 2), and the results are summarized in
(6) For reviews, see: Pape, A. R.; Kaliappan, K. P.; Ku¨ndig, E. P.
Chem. Rev. 2000, 100, 2917-2940.
(8) For examples, see: (a) Yagi, A.; Takeo, S. Yakugaku Zasshi 2003,
123, 517-532. (b) Takatsuki, A.; Sekino, Y.; Kadono, T.; Wakayama,
S. Jpn. Kokai Tokkyo Koho 11171765 A2 19990629, 1999.
(9) Dyker reported one example of the intramolecular acylnaphtha-
lene sysnthesis using bialkynylbenzil as the starting material; see:
Dyker, G.; Stirner, W.; Henkel, G.; Kockerling, M. Tetrahedron Lett.
1999, 40, 7457-7458.
(7) For recent examples for 1,2-dihydronaphthalene syntheses,
see: (a) Ahmed, A.; Clayden, J.; Rowley, M. Synlett 1999, 1954-1956.
(b) Shindo, M.; Koga, K.; Asano, Y.; Tomioka, K. Tetrahedron 1999,
55, 4955-4968. (c) Chatani, N.; Inoue, H.; Ikeda, T.; Murai, S. J. Org.
Chem. 2000, 65, 4913-4918. (d) Inoue, H.; Chatani, N.; Murai, S. J.
Org. Chem. 2002, 67, 1414-1417.
J. Org. Chem, Vol. 70, No. 9, 2005 3683

Asao et al.
TABLE 2. AuBr3-Catalyzed Intramolecular Cyclization
of 10a
proceeded smoothly, and the corresponding cyclization
products 13a and 13b were obtained in 88 and 72%
yields, respectively. Analogously, the phenanthrene de-
rivative 13c was produced from 12c in 81% yield.
Furthermore, the reactions of 14a and 14b, in which the
geometry of the olefin was Z and E, respectively, gave
15 as the sole product in 85 and 87% yields, respectively
(eq 4).
The present reaction most probably proceeds through
the formation of benzopyrylium-type intermediate 16,
followed by the intramolecular [4 + 2]-type cycloaddition
with alkynes or alkenes.2,5,12 In particular, the stereo-
selective formation of 15 is able to be explained as
follows: The pyrylium intermediate 17 gives the in-
tramolecular [4 + 2] adduct 18. The carbon-metal bond
of the ate complex 18 is displaced by carbon-hydrogen
bond by trapping the proton with retention of configu-
ration to give the cis product (15) as shown in Scheme 3.
entry
10
R
conditions
11
yield (%)b
1
2
3
4
5
6
7
8
10a
Ph
80 °C, 4 h
80 °C, 3 h
80 °C, 8 h
80 °C, 2 h
11a
11b
11c
11d
66
47
67
89
91
88
82
89
10b p-MeC6H4
10c
10d Bu
10e
10f
10g
10h
p-CF3C6H4
H
TIPS
50 °C, 1.5 h 11e
80 °C, 3 h
11f
11g
11h
(CH2)2OTIPS 80 °C, 1 h
I
80 °C, 1 h
a Reaction was carried out using 10 in the presence of 2 mol %
AuBr3 in (CH2Cl)2. b Isolated yields.
Table 2. When the reaction of 10a (R ) Ph) was carried
out in the presence of 2 mol % AuBr3 at 80 °C for 4 h,
the desired product 11a was obtained in 66% yield (entry
1). When a tolyl group was substituted at the terminus
of alkyne (10b), the chemical yield was decreased to 47%
yield (entry 2). On the other hand, the reaction of 10c,
bearing a p-CF3C6H4 group at the terminus, gave 11c in
67% yield, while 8 h was needed for the completion of
the reaction (entry 3). Other arylaldehydes such as
10d-h were also suitable as the starting materials for
the present reaction, and the corresponding 10-substituted-
2,3-dihydrophenanthrenones 11d-h were obtained in
high yields (entries 4-8).
SCHEME 3. Proposed Pathway for the
Cu(OTf)2-Catalyzed Reaction of 14
Conclusion
Since the intramolecular benzannulation of enynones
with tethers having an alkynyl group proceeded unex-
pectedly easily, we next turned our attention to the
cycloaddition reactions of the o-alkynyl-arylalkenyl ke-
tones. The requisite substrates 12a-c were easily pre-
pared and were treated with 2 mol % Cu(OTf)2 (eq 3),
because the intermolecular reaction of o-alkynyl-arylal-
dehydes and alkenes with Cu(OTf)2 catalyst, rather than
with AuX3, proceeded smoothly to give the corresponding
cycloaddition products in higher yields. The reactions of
12a and 12b, bearing three methylene groups as a tether,
We are now in a position to synthesize functionalized
polycyclic hydrocarbons from carbon-tethered alkynyl and
alkenyl enynons and enynals in good to high yields. By
choosing the reaction mode (type 1 and 2), a variety of
functionalized polycyclic hydrocarbons can be obtained,
which could potentially become an essential structural
framework for polycyclic natural products. Further stud-
ies to extend the scope of the reaction and to apply the
present methodology for the synthesis of natural products
are in progress in our laboratory.
Experimental Section
Lewis Acid-Catalyzed [4 + 2] Cycloaddition. The prepa-
ration of 9a is representative. To AuBr3 (11 mg, 5 mol %) was
added a solution of 8a (0.17 g, 0.5 mmol) in (ClCH2)2 (1.5 mL)
at rt under an Ar atmosphere. After the reaction mixture was
stirred for 3 h at rt, the resulting solution was filtered through
(10) For reviews on the gold catalyst, see: (a) Dyker, G. Angew.
Chem., Int. Ed. 2000, 39, 4237-4239. (b) Hashmi, A. S. K. Gold Bull.
2003, 36, 3-9.
(11) Gold-catalyzed benzannulation, see: (a) Hashmi, A. S. K.; Frost,
T. M.; Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553-11554. (b)
Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Org. Lett. 2001, 3, 3769-
3771. (c) Dankwardt, J. W. Tetrahedron Lett. 2001, 42, 5809-5812.
(d) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Catal. Today 2002, 72,
19-27.
(12) [3 + 2] cycloaddition of 16 with alkyne was proposed as another
possible mechanism for the intermolecular benzannulation; see: Straub,
B. F. Chem. Commun. 2004, 1726-1728.
3684 J. Org. Chem., Vol. 70, No. 9, 2005

Lewis Acid-Catalyzed Intramolecular [4 + 2] Cycloaddition
a short silica gel column. The solvent was removed under
reduced pressure to give the crude product. 1H NMR analysis
of the crude product, using CH2Br2 as an internal standard,
showed that 9a was produced in 98% yield. The product was
isolated as a white solid (0.16 g, 0.46 mmol) in 92% yield
by silica gel column chromatography using ether as an
eluent.
Supporting Information Available: Preparation meth-
ods of 8a, 10a, 12a, and 14a, and spectroscopic and analytical
data for 8a-e, 9a-e, 10a-h, 11a-h, 12a-c, 13a-c, 14a,b,
and 15. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
JO0500434
J. Org. Chem, Vol. 70, No. 9, 2005 3685