Thermal intramolecular [2+2] cycloaddition of allenenes and allenynes: Diastereoselective access to bicyclic nitrogen heterocycles

Article abstract of DOI:10.1002/anie.200501413

Squaring the circle: A route to bicyclo-[4.2.0]octane derivatives has been developed by the [2+2] cycloaddition of allenenes or allenynes. The thermal intramolecular [2+2] cycloaddition of simple allenes 1 with an additional multiple bond leads to direct

Full text of DOI:10.1002/anie.200501413

Angewandte
Chemie
Synthetic Methods
ylates,[8] allenyl sulfones,[9] difluoroallenes,[10] b-lactam-teth-
ered allenes,[11] or diyne-diallenes.[12]
DOI: 10.1002/anie.200501413
In the course of our efforts toward the development of a
new methodology for the synthesis of heterocyclic com-
pounds by the transition-metal-catalyzed cyclization of
allenes,[4,13] we found that the thermal cycloaddition of
simple allenes with an additional multiple bond proceeds by
simply heating the allenenes or allenynes in the absence of
any catalyst. Herein, we present an intramolecular [2+2]
cycloaddition of unactivated allenes to form distal adducts of
type 3, which constitute an important class of compounds in
synthetic[14] and natural product chemistry.[15]
Thermal Intramolecular [2+2] Cycloaddition of
Allenenes and Allenynes: Diastereoselective
Access to Bicyclic Nitrogen Heterocycles**
Hiroaki Ohno,* Tsuyoshi Mizutani, Yoichi Kadoh,
Kumiko Miyamura, and Tetsuaki Tanaka*
Cycloaddition reactions that occur without the use of reagents
or catalysts and without creating any waste have attracted
much attention in recent years as an ideal process in terms of
atom economy.[1] Considerable research efforts have been
particularly focused on the development of cycloaddition of
allenes,[2] on account of the current interest in the reactions of
allenes with an additional multiple bond, including transition-
metal-catalyzed carbocyclizations.[3,4] The [2+2] cycloaddi-
tion reactions[5] between allenes and alkenes are extremely
useful for the synthesis of methylenecyclobutane deriva-
tives.[6] Especially, intramolecular cycloaddition constitutes a
versatile method for the stereoselective synthesis of a variety
of bicyclic compounds having a strained bicyclo[n.2.0] frame-
work (Scheme 1).[7] In most reported intramolecular [2+2]
Various allenenes 4–10 (Table 1) were prepared according
to the reported procedure[4d] and their thermal cycloaddition
reaction was investigated. First, the [2+2] cycloaddition of
Table 1: Thermal [2+2] cycloaddition of allenenes.[a]
Entry Substrate
t [h] Product
Yield [%][b]
1
2
65[c]
3
89
96
3
4
3
1
71
93
Scheme 1. Intramolecular [2+2] cycloaddition of allenenes.
5
6
2
73
82
cycloaddition reactions of simple unactivated allenes, the
proximal 2p component of the allene moiety participates in
the cycloaddition to form bicyclic products 2.[2] Only limited
examples of the intramolecular [2+2] reaction of the distal
allenic double bond to give 3 have been reported to date,
which used a special class of allenes such as allene carbox-
24[d]
7
8
19[d]
30
68
69
[*] Dr. H. Ohno
Graduate School of Pharmaceutical Sciences
Kyoto University
Sakyo-ku, Kyoto 606-8501 (Japan)
Fax: (+81)7-5753-4570
E-mail: hohno@pharm.kyoto-u.ac.jp
[a] Unless otherwise stated, reactions were carried out in DMF at 1508C.
[b] Yields of isolated products. [c] Reaction was carried out in dioxane
under reflux conditions. [d] Reaction was carried out in DMF under reflux
conditions. Mts=2,4,6-trimethylphenylsulfonyl.
T. Mizutani, Y. Kadoh, K. Miyamura, Prof. Dr. T. Tanaka
Graduate School of Pharmaceutical Sciences
Osaka University
1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-8214
E-mail: t-tanaka@phs.osaka-u.ac.jp
allenene 4 was examined under various reaction conditions.
Among the solvents employed, dioxane and dimethylforma-
mide (DMF) were the solvents of choice leading to 3-
azabicyclo[4.2.0]oct-5-ene derivative 11 in 89 and 96% yields,
respectively, as the sole isolable isomer (Table 1, entries 1 and
2). The structure and configuration of 11 were confirmed by
[**] We thank Dr. S. Aoki, Graduate School of Pharmaceutical Sciences,
Osaka University, for NMR spectroscopic analyses. This work was
supported by a Grant-in-Aid for Encouragement of Young Scientists
from the Ministry of Education, Culture, Sports, Science, and
Technology of Japan and Mitsubishi Chemical Corporation Fund,
which are gratefully acknowledged.
Angew. Chem. Int. Ed. 2005, 44, 5113 –5115
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heteronuclear multiple quantum correlation (HMQC) and
aryl group on the reactivity was not dramatic (Table 2,
entries 2–4). More important is the a substituent of the
allene: the reaction of the allenyne 22 bearing a smaller
substituent at the a position was complete in 8 h, whereas the
cycloaddition of a-unsubstituted allene derivative 23 required
a prolonged reaction time (117 h) to give 29 in 94% yield.
The related [2+2] thermal reactions of allenes are thought
to proceed by a two-step mechanism, that is, via a diradical
intermediate.[2,9b,c,16] In the present [2+2] cyclization of simple
allenenes and allenynes, the substituent on the double or
triple bond, which effectively stabilizes the radical intermedi-
ate, is essential for successful conversion: the corresponding
allenenes or allenynes without the radical-stabilizing group
were completely inert to the thermal [2+2] cycloaddition.
This experimental result supports the diradical mechanism;
however, further study is necessary to elucidate the reaction
mechanism.
NOESY analysis of the corresponding hydrogenated deriva-
tives. The reaction in dioxane under reflux was rather slow
(Table 1, entry 1), and therefore the cycloaddition of the
other allenenes 5–10 was conducted in DMF. All the allenenes
were successfully converted into the corresponding bicyclic
products in good to excellent yields, with complete regiose-
lectivity. The reaction of the allenene 5 bearing an electron-
donating aryl group gave 12 in relatively low yield (71%,
Table 1, entry 3), whereas the allenene 6 with an electron-
withdrawing group afforded 13 in 93% yield within a shorter
reaction time (1 h, Table 1, entry 4). Allene 7 with an a,b-
unsaturated ester group showed sufficient reactivity to give
the cycloadduct 14 in 73% yield. Allenene 8 with a geminal
dimethyl group on the olefinic carbon atom (Table 1, entry 6),
a-unsubstituted allene derived substrate 9 (Table 1, entry 7),
and dimethyl malonate derived allenene 10 (Table 1, entry 8)
gave the distal cycloadducts 15–17 in 68–82% yields, although
prolonged reaction times were required.
Next, the thermal cycloaddition of allenynes 18–23
(Table 2) was investigated, which were easily prepared by
the N-arylpropargylation of known amino allenes. In contrast
to the cycloaddition of allenenes 4 (Table 1, entries 1 and 2),
the reaction of the allenyne 18 was complete within 2 h in
dioxane under reflux conditions to give 3-azabicyclo-
[4.2.0]octa-1(8),5-diene derivative 24 in 92% yield (Table 2,
entry 1). In the reaction of N-tosylated allenyne derivatives
19–21, the effect of the electron-donating and -withdrawing
In conclusion,
a stereoselective route to bicyclo-
[4.2.0]octane derivatives has been developed by using thermal
[2+2] cycloaddition of allenes with an additional multiple
bond. This study first demonstrated that unactivated alle-
nenes and allenynes can regioselectively undergo intramo-
lecular [2+2] cycloaddition of the distal double bond of the
allene moiety. This simple and environmentally benign
process would extend the potential application of fused
bicyclic cyclobutane derivatives in synthetic and medicinal
chemistry.
Received: April 25, 2005
Published online: July 20, 2005
Table 2: Thermal [2+2] cycloaddition of allenynes.[a]
Yield [%][b]
92
Keywords: allenes · bicyclic compounds · cycloaddition ·
nitrogen heterocycles · regioselectivity
Entry Substrate
t [h] Product
.
1
2
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