Cu-Promoted [2 + 2] cycloaddition of 1,4-bisallenes

Article abstract of DOI:10.1021/ol300096u

The thermal reaction of 1,4-bisallenes with the aid of Cu salt/amine significantly suppressed the formal [3,3] sigmatropic rearrangement resulting in the highly selective formation of the bicyclo[4.2.0]octadiene framework. This reaction could be applied to the one-pot synthesis of bicyclo[4.2.0]octadienes from 1,5-hexadiynes via the Crabbe homologation.

Full text of DOI:10.1021/ol300096u

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1366–1369
Cu-Promoted [2 þ 2] Cycloaddition
of 1,4-Bisallenes
Shinji Kitagaki,* Mikihito Kajita, Syu Narita, and Chisato Mukai*
Division of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
kitagaki@p.kanazawa-u.ac.jp; cmukai@kenroku.kanazawa-u.ac.jp
Received October 24, 2011
ABSTRACT
The thermal reaction of 1,4-bisallenes with the aid of Cu salt/amine significantly suppressed the formal [3,3] sigmatropic rearrangement resulting
in the highly selective formation of the bicyclo[4.2.0]octadiene framework. This reaction could be applied to the one-pot synthesis of bicyclo-
ꢀ
[4.2.0]octadienes from 1,5-hexadiynes via the Crabbe homologation.
The allene functionality is well-known to serve as a
powerful π-component in the [2 þ 2] czycloaddition.1 There
are many examples of efficient constructions of bicyclo-
[n.2.0] skeletons based on the thermal, photochemical,
or metal-catalyzed intramolecular [2 þ 2] cycloaddition
of alleneꢀalkenes2 and alleneꢀalkynes.3 The analogous
alleneꢀallenes (1,n-bisallenes) I (n = 3ꢀ7) selectively
produced bicyclo[n.2.0]alkadienes II or dimethylene-
bicyclo[n-2.2.0]alkanes III upon exposure to thermal or
metal-catalyzed conditions (Scheme 1).4ꢀ7 The 1,4-bisallene
(exemplified by 1a), however, has often been found
to provide the [2 þ 2] cycloadduct 3a in low yield under
thermal conditions due to the preferential formation of the
formal [3,3]-sigmatropic rearrangement product 4a via the
biradical intermediate 2a.8 Thus, it is obvious that no
(3) For recent examples of thermal reaction, see: (a) Brummond,
K. M.; Osbourn, J. M. Beilstein J. Org. Chem. 2011, 7, 601–605. (b)
Siebert, M. R.; Osbourn, J. M.; Brummond, K. M.; Tantillo, D. J. J. Am.
Chem. Soc. 2010, 132, 11952–11966. (c) Ovaska, T. V.; Kyne, R. E.
Tetrahedron Lett. 2008, 49, 376–378. (d) Mukai, C.; Hara, Y.; Miyashita,
Y.; Inagaki, F. J. Org. Chem. 2007, 72, 4454–4461. (e) Jiang, X.; Ma, S.
Tetrahedron 2007, 63, 7589–7595. (f) Oh, C. H.; Gupta, A. K.; Park,
D. I.; Kim, N. Chem. Commun. 2005, 5670–5672. For recent examples of
metal-catalyzed reaction, see: (g) Alcaide, B.; Almendros, P.; Aragoncillo, C.
Chem.;Eur. J. 2009, 15, 9987–9989. (h) Saito, N.; Tanaka, Y.; Sato, Y.
Org. Lett. 2009, 11, 4124–4126. (i) Oh, C. H.; Kim, A. Synlett 2008, 777–
781. (j) Matsuda, T.; Kadowaki, S.; Goya, T.; Murakami, M. Synlett
2006, 575–578. (k) Oh, C. H.; Park, D. I.; Jung, S. H.; Reddy, V. R.;
Gupta, A. K.; Kim, Y. M. Synlett 2005, 2092–2094. (l) Ohno, H.;
Mizutani, T.; Kadoh, Y.; Miyamura, K.; Tanaka, T. Angew. Chem.,
Int. Ed. 2005, 44, 5113–5115. (m) Cao, H.; Van Ornum, S. G.;
Deschamps, J.; Flippen-Anderson, J.; Laib, F.; Cook, J. M. J. Am.
Chem. Soc. 2005, 127, 933–943. (n) Shen, Q.; Hammond, G. B. J. Am.
Chem. Soc. 2002, 124, 6534–6535.
(4) For 1,3-bisallenes, see: (a) Garratt, P. J.; Neoh, S. B. J. Am.
Chem. Soc. 1975, 97, 3255–3257. (b) Bui, B. H.; Schreiner, P. R. Eur. J.
Org. Chem. 2006, 4187–4192.
(5) For 1,5-bisallenes, see: (a) Jiang, X.; Cheng, X.; Ma, S. Angew.
Chem., Int. Ed. 2006, 45, 8009–8013. (b) Lu, P.; Ma, S. Chin. J. Chem.
2010, 28, 1600–1606. (c) Hong, Y.-T.; Yoon, S.-K.; Kang, S.-K.; Yu,
C.-M. Eur. J. Org. Chem. 2004, 4628–4635. (d) Kim, S. M.; Park, J. H.;
Kang, Y. K.; Chung, Y. K. Angew. Chem., Int. Ed. 2009, 48, 4532–4535.
(6) For 1,6-bisallenes, see: Shimizu, T.; Sakamaki, K.; Kamigata, N.
Tetrahedron Lett. 1997, 38, 8529–8532. See also ref 5b.
(1) (a) Murakami, M.; Matsuda, T. Cycloadditions of Allenes. In
Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004; Vol. 2, pp 727ꢀ816. (b) Ma, S. Chem. Rev. 2005, 105,
2829–2872. (c) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Soc.
Rev. 2010, 39, 783–816. (d) Aubert, C.; Fensterbank, L.; Garcia, P.;
Malacria, M.; Simonneau, A. Chem. Rev. 2011, 111, 1954–1993.
(2) For recent examples of thermal reaction, see: (a) Ohno, H.;
Mizutani, T.; Kadoh, Y.; Aso, A.; Miyamura, K.; Fujii, N.; Tanaka, T.
J. Org. Chem. 2007, 72, 4378–4389. (b) Alcaide, B.; Almendros, P.;
Aragoncillo, C.; Redondo, M. C.; Torres, M. R. Chem.;Eur. J. 2006,
12, 1539–1546. (c) Hansen, T. V.; Skattebøl, L.; Stenstrøm, Y. Tetra-
hedron 2003, 59, 3461–3466. (d) Padwa, A.; Lipka, H.; Watterson, S. H.;
Murphree, S. S. J. Org. Chem. 2003, 68, 6238–6250. For recent examples
of photochemical reaction, see: (e) Lutteke, G.; Kleinnijenhuis, R. A.;
Jacobs, I.; Wrigstedt, P. J.; Correia, A. C. A.; Nieuwenhuizen, R.; Hue,
B. T. B.; Goubitz, K.; Peschar, R.; van Maarseveen, J. H.; Hiemstra, H.
Eur. J. Org. Chem. 2011, 3146–3155. (f) Miao, R.; Gramani, S. G.; Lear,
M. J. Tetrahedron Lett. 2009, 50, 1731–1733. (g) Winkler, J. D.; Ragains,
J. R. Org. Lett. 2006, 8, 4031–4033. For recent examples of metal-
ꢀ
catalyzed reaction, see: (h) Gulıas, M.; Collado, A.; Trillo, B.; Lopez, F.;
~
~
Onate, E.; Esteruelas, M. A.; Mascarenas, J. L. J. Am. Chem. Soc. 2011,
133, 7660–7663. (i) Alcarazo, M.; Stork, T.; Anoop, A.; Thiel, W.;
€
Furstner, A. Angew. Chem., Int. Ed. 2010, 49, 2542–2546. (j) Zhao, J.-F.;
Loh, T.-P. Angew. Chem., Int. Ed. 2009, 48, 7232–7235. (k) Luzung,
ꢀ
M. R.; Mauleon, P.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12402–
12403.
r
10.1021/ol300096u
Published on Web 02/24/2012
2012 American Chemical Society

PtCl2, and FeCl3 were also ineffective for this cycloaddi-
tion, except for the Cu salt. In fact, a solution of 1b in 1,4-
dioxane was refluxed in the presence of 1.2 equiv of CuBr2
for 1 h to produce the [2 þ 2] cycloadduct 3b in 31% yield
along with the tetraene 4b (6%) (Table 1, entry 1).
Scheme 1. [2 þ 2] Cycloaddition Reaction of 1,n-Bisallenes
Table 1. Cu-Mediated Reaction of Bisallene 1b
reliable method for the direct production of the bicyclo-
[4.2.0]octadiene skeleton 3a from 1,4-bisallene 1a is
available except for a few limited cases, in which the
benzocyclobutene derivatives were obtained from (i) ene-
bisallenes, in situ generated from (Z)-ethylene-bridged bis-
(propargyl alcohol)s,9,10 and (ii) 1,4-bisallenes having
an alkoxymethyl group at the C1 and C4 positions.11
We now report a new reliable method for the preparation
of the bicyclo[4.2.0] framework that involves the copper-
promoted, aromatization-independent [2 þ 2] cycloaddi-
tion of 1,4-bisallenes.
We first investigated the [2 þ 2] cycloaddition of
4,4-diphenylocta-1,2,7,8-tetraene (1b) using inexpensive
and easy to use transition metal complexes.12 The use of
Mo(CO)63m,n or PdCl2(PPh3)2,3k both of which have been
proven to catalyze the alleneꢀalkyne [2 þ 2] cycloaddition
reactions, in heated toluene afforded the corresponding
tetraene compound 4b as the only isolated product, and
the desired cycloadduct 3b could not be detected at all.
The reaction with Pd(PPh3)4 in the presence of K2CO3
and nBu4NI5a or with the cationic Au(I) complex,5d both
of which are known to convert the 1,5-bisallenes to the
corresponding [2 þ 2] cycloadducts, produced no desired
product. Several transition metal salts such as AuCl3,
product
(% yield)a
Cu
additive
(equiv)
entry
salt
solvent
dioxane
3b
4b
1
2
3
4
CuBr2
CuBr2
CuBr2
CuBr2
none
31
55
58
80
(81)b
74
54
73
77
77
51
6
iPr2NH (1.2) dioxane
iPr2NH (3.6) dioxane
iPr2NH (7.2) dioxane
11
12
17
(16)b
5
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
iPr2NH (10) dioxane
iPr2NH (3.0) dioxane
iPr2NH (6.0) dioxane
Cy2NH (7.2) dioxane
15
12
16
16
16
17
6c
7d
8
9
Et3N (7.2)
DABCO
(7.2)
dioxane
dioxane
10
11
12
CuBr2
CuBr2
nBuNH2
(7.2)
dioxane
dioxane
52
40
20
12
2,6-lutidine
(7.2)
13
14
15e
16
17
18
19
20
21
CuBr2
CuBr2
CuBr2
CuBr2
iPr2NH (7.2) toluene
iPr2NH (7.2) DCE
iPr2NH (7.2) DMF
iPr2NH (7.2) IPA
74
73
52
62
76
19
80
72
ꢀ
16
11
14
12
19
56
15
22
50
Cu(OAc)2 iPr2NH (7.2) dioxane
Cu(OTf)2 iPr2NH (7.2) dioxane
CuCl
CuI
iPr2NH (7.2) dioxane
iPr2NH (7.2) dioxane
(7) We have also observed the production of bicyclo[n.2.0] com-
pounds (n = 5ꢀ7) in the reaction of 1,n-bis(sulfonylallene)s in the
presence or absence of a Rh(I) complex. (a) Inagaki, F.; Narita, S.;
Hasegawa, T.; Kitagaki, S.; Mukai, C. Angew. Chem., Int. Ed. 2009, 48,
2007–2011. (b) Kawamura, T.; Inagaki, F.; Narita, S.; Takahashi, Y.;
Hirata, S.; Kitagaki, S.; Mukai, C. Chem.;Eur. J. 2010, 16, 5173–5183.
(c) Inagaki, F.; Kitagaki, S.; Mukai, C. Synlett 2011, 594–614.
(8) Production of 4a from 1a in the gas phase and in solution has been
reported. (a) Skattebøl, L.; Solomon, S. J. Am. Chem. Soc. 1965, 87,
4506–4513. (b) Roth, W. R.; Erker, G. Angew. Chem., Int. Ed. Engl.
1973, 12, 503–504. (c) Grimme, W.; Rother, H.-J. Angew. Chem., Int. Ed.
Engl. 1973, 12, 505–506. (d) Becher, G.; Skattebøl, L. Tetrahedron Lett.
1979, 20, 1261–1264. (e) Roth, W. R.; Scholz, B. P.; Breuckmann, R.;
Jelich, K.; Lennartz, H.-W. Chem. Ber. 1982, 115, 1934–1946.
none
none
dioxane
a Yields are estimated by 1H NMR spectra of the crude product
obtained after short column chromatography, which consisted of 3b and
4b, with tetrachloroethane as the internal standard. b Isolated yields.
c CuBr2 (0.5 equiv) was used. d CuBr2 (1.0 equiv) was used. e Reaction
was performed at 100 °C.
The effect of an amine additive was next examined for
the Cu-promoted reaction. The use of 1.2 equiv of iPr2NH
led to an improvement in the chemical yield of 3b (entry 2).
The best result was obtained when 7.2 equiv of iPr2NH
were used (entry 4). A decrease in the amount of Cu salt to
0.5 or 1.0 equiv led to a drop in the product yield (entries 6
and 7). Some primary to tertiary amines or an aromatic
amine (entries 8ꢀ12) also allowed the preparation of the
bicyclo[4.2.0]octadiene product 3b, and Cy2NH and Et3N
gave results comparable to iPr2NH (entries 8 and 9). With
the combination of CuBr2 and iPr2NH, we examined
several other solvents, which were less effective than
dioxane (entries 13ꢀ16). Other copper sources such as
Cu(II) acetate and Cu(I) halides worked as effectively as
(9) (a) Toda, F.; Tanaka, K.; Sano, I.; Isozaki, T. Angew. Chem., Int.
Ed. Engl. 1994, 33, 1757–1758. (b) Inanaga, J.; Sugimoto, Y.; Hanamoto, T.
Tetrahedron Lett. 1992, 33, 7035–7038. (c) Ezcurra, J. E.; Moore, H. W.
Tetrahedron Lett. 1993, 34, 6177–6180. (d) Braverman, S.; Duar, Y. J. Am.
€
Chem. Soc. 1990, 112, 5830–5837. (e) Hohn, J.; Weyerstahl, P. Chem. Ber.
1983, 116, 808–814. (f) Staab, H. A.; Draeger, B. Chem. Ber. 1972, 105,
2320–2333.
(10) (a) Kitagaki, S.; Okumura, Y.; Mukai, C. Tetrahedron 2006, 62,
10311–10320. (b) Kitagaki, S.; Okumura, Y.; Mukai, C. Tetrahedron
Lett. 2006, 47, 1849–1852. (c) Kitagaki, S.; Katoh, K.; Ohdachi, K.;
Takahashi, Y.; Shibata, D.; Mukai, C. J. Org. Chem. 2006, 71, 6908–
6914.
(11) Aubert, P.; Princet, B.; Pornet, J. Synth. Commun. 1997, 27,
2615–2625.
(12) For the metal-catalyzed [2 þ 2] cycloaddition, see: Lautens, M.;
Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49–92.
Org. Lett., Vol. 14, No. 6, 2012
1367

CuBr2 (entries 17, 19, and 20). Cu(OTf)2 was found to be
much less effective than CuBr2 (entry 18). A thermal reac-
tion in dioxane with neither a Cu source nor amine gave the
tetraene 4b as the only isolated product (entry 21).13
resulted in the production of a complex mixture including
dihydroanthracene 5, which would be obtained by the par-
ticipation of the phenyl group in the cyclization (eq 3). The
installation of a methyl group on both allene moieties did
not inhibit the cycloaddition. In this case, the bicyclo[4.2.0]
compounds 3k were obtained in 62% yield as a 5:1 mixture
of diastereomers (eq 4).
Encouraged by this initial result, we sought to explore the
generality of this process. A geminal substitution moiety
in the tether (e.g., 1b) generally tends to facilitate cycliza-
tion.14 1,4-Bisallene 1c possessing a monoalkyl group in the
tether still gave the corresponding cycloadduct 3c in an
acceptable yield with an extended reaction time (6 h) (Table
2, entry 1). 1,4-Bisallenes 1d and 1e with a vicinal dialkoxy
substitution led to the smooth conversion into bicyclo[4.2.0]
compounds (2.5ꢀ3 h, 63ꢀ69% yield: entries 2 and 3). The
trans-bisallene functionality of the dioxolane derivative 1f
caused inactivity regarding the ring closure (entry 4).
Scheme 2. Effect of the Substituent on the Allene Moietya
Table 2. Effect of the Substituent in the Tether
a Yields are estimated by 1H NMR data. bIsolated yields. cA mixture
of diastereomers, the ratio of which is not determined.
The obtained results indicated that the presence of both
a Cu salt and amine is critical for the preferential produc-
tion of the [2 þ 2] cycloadduct over that of tetraenes.
Although it is premature to discuss the mechanistic details,
the following interpretation that involves the initial for-
mation of Cu(I) or a related complex as the active catalyst,
followed by the process via the cupracyclopentane 6,1c,15
would be assumed (Scheme 3). More than 1 equiv of Cu
salt would be needed to overcome the undesired thermal
reaction leading to the formation of the tetraene or other
byproducts. The amine might not only reduce Cu(II)
to Cu(I)16 and dissociate the polymeric structure of the
complex17 but also stabilize the active species, and/or make
the oxidative addition more facile.
a Yields are estimated by 1H NMR data. Numbers in parentheses are
isolated yields. b iPr2NH (10 equiv) was used.
Further studies to survey the substrate scope are shown
inScheme 2. Thus, theeffectof the substituenton the allene
moiety was examined. The reaction of 3-benzylocta-
1,2,7,8-tetraene (1g) without any substituents in the alkyl
tether was completed within 2 h to produce the cycload-
duct 3g in good yield (eq 1). 3,6-Dibenzyl derivative 1h also
gavethe desiredproduct 3hin similar yield. Upon exposure
of the 1-benzyl derivative 1i, a regioisomer of 1g, to the
standard reaction conditions for 7 h, 3i was obtained in
52% yield along with the tetraene 4i (10%), and 1i was
recovered in 10% yield (eq 2). A prolonged reaction time
(16 h) completely consumed the starting material, but the
yield of 3i decreased to 23%. These results must reflect the
instability of the product 3i, which might be in accordance
with the low isolated yield (41%). Microwave irradiation
conditions at 160 °C for 10 min slightly improved the
chemical yield (56%). Reaction of 1-phenyl derivative 1j
(15) For example, in the Ni-catalyzed intermolecular [2 þ 2] cycloaddi-
tion of allenes and Fe-catalyzed intramolecular one of R,ω-dienes, the
mechanism involving a reductive elimination of the corresponding metal-
lacycle such as 6, which consists of a Csp3ꢀmetal bond, has been presented.
See: (a) Saito, S.; Hirayama, K.; Kabuto, C.; Yamamoto, Y. J. Am. Chem.
Soc. 2000, 122, 10776–10780. (b) Bouwkamp, M. W.; Bowman, A. C.;
Lobkovsky, E.; Chirik, P. J. J. Am. Chem. Soc. 2006, 128, 13340–13341.
For the mechanistic proposal involving a cupracyclopentene for the
intramolecular [2 þ 2] cycloaddition of allene-alkynes, see ref 3g.
(16) (a) Montaignac, B.; Vitale, M. R.; Ratovelomanana-Vidal, V.;
Michelet, V. Eur. J. Org. Chem. 2011, 3723–3727. (b) Paine, A. J. J. Am.
Chem. Soc. 1987, 109, 1496–1502.
(13) Only tetraene 4b was detected on TLC also in the reaction of 1b
with iPr2NH (7.2 equiv) in heated dioxane.
(14) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735–1766.
(17) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952–3015.
1368
Org. Lett., Vol. 14, No. 6, 2012

the steric hindrance of geminal phenyl groups in 3b. On
the other hand, 3h readily reacted with 10 to produce the
bridged polycyclic compound 11.
Scheme 3. Plausible Reaction Mechanism
Scheme 5. [4 þ 2] Cycloaddition Reaction of 3b and 3ha
The newly developed cycloaddition conditions nearly
ꢀ
overlapped with those of the Crabbe homologation
a Isolated yields are shown. bA mixture with 4h (3h:4h = 78:22) was
(conversion of alkynes to allenes).18 We expected that the
direct transformation of 1,5-diynes 7, precursors of the
bisallenes 1, into the bicyclo[4.2.0]octadienes 3 could be
realized. The preliminary results are shown in Scheme 4.
Treatment of 3,3-diphenylhexa-1,5-diyne (7b) with CuBr
(1.2 equiv), iPr2NH (10 equiv), and paraformaldehyde
(7 equiv) in refluxing dioxane for 7 h afforded the desired
cycloadduct 3b in 49% yield along with tetraene 4b in 7%
yield. The dialkoxylated hexadiyne 7d also gave the corre-
sponding bicyclo compound 3d in 46% yield.
used.
In conclusion, we have shown that 1,4-bisallenes, which
are well-known to be susceptible to [3,3] sigmatropic
rearrangement under thermal conditions, consistently un-
derwent [2 þ 2] cycloaddition in the presence of a Cu salt/
amine combination. This is the first successful example
of the selective synthesis of bicyclo[4.2.0]octadienes from
1,4-bisallenes. Wehave alsodemonstratedthat thisprocess
ꢀ
can be applied to the tandem Crabbe homologation and
[2 þ 2] cycloaddition of 1,5-hexadiynes. Further studies on
the scope of this novel process and the synthetic use of the
cycloadducts are currently underway.
Scheme 4. One-Pot Reaction Producing 3 from 7a
Acknowledgment. This work was supported in part by
a Grant-in Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan, for which we are thankful.
Supporting Information Available. Preparation and
characterization data for compounds 1, 3, and 11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Isolated yields are shown.
ꢀ
ꢀ
(18) (a) Crabbe, P.; Fillion, H.; Andre, D.; Luche, J.-L. J. Chem. Soc.,
Chem. Commun. 1979, 859–860. (b) Searles, S.; Li, Y.; Nassim, B.;
ꢀ
Lopes, M.-T. R.; Tran, P. T.; Crabbe, P. J. Chem. Soc., Perkin Trans. 1
1984, 747–751.
(19) (a) Becker, K. B. Synthesis 1980, 238–240. For examples of
reactions of 1,2-dimethylenecyclobutanes, see: (b) Heimbach, P.;
Schimpf, R. Angew. Chem., Int. Ed. Engl. 1969, 8, 206–208. (c) Hojo,
M.; Murakami, C.; Nakamura, S.; Hosomi, A. Chem. Lett. 1998,
331–332.
Finally, the diene reactivity in the [4 þ 2] cycloaddi-
tion of thus obtained bicyclo[4.2.0]octa-1,5-dienes was
investigated.19 3b underwent [4 þ 2] cycloaddition with
dimethyl acetylenedicarboxylate (8), followed by retro-
DielsꢀAlder reaction of the resulting cycloadduct to
produce benzocyclobutene 9 (Scheme 5). Reaction with
N-phenylmaleimide (10) did not proceed probably due to
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
1369