Palladium-catalysed biscyclisation of allenic bromoalkenes through a zipper-mode cascade

Article abstract of DOI:10.1039/b805845h

Treatment of allenic bromoalkenes bearing a nucleophilic moiety with a catalytic amount of palladium(0) in the presence of TBAF or Cs ₂CO₃ in MeCN affords bicyclic heterocycles in good to high yields, through zipper-mode cascade cyclisation. The Royal Society of Chemistry.

Full text of DOI:10.1039/b805845h

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Palladium-catalysed biscyclisation of allenic bromoalkenes through a
zipper-mode cascadew
Akinori Okano,a Tsuyoshi Mizutani,b Shinya Oishi,a Tetsuaki Tanaka,b Hiroaki Ohno*a
and Nobutaka Fujii*a
Received (in College Park, MD, USA) 7th April 2008, Accepted 5th May 2008
First published as an Advance Article on the web 20th June 2008
DOI: 10.1039/b805845h
Treatment of allenic bromoalkenes bearing a nucleophilic
moiety with a catalytic amount of palladium(0) in the presence
of TBAF or Cs2CO3 in MeCN affords bicyclic heterocycles in
good to high yields, through zipper-mode cascade cyclisation.
Palladium-catalysed cyclisation of allenic compounds has
become an extremely useful method for construction of het-
ero- and carbocycles of significant biological importance.1 It
has been well documented that carbopalladation of allenes
with an aryl- or alkenylpalladium halide easily occurs to afford
p-allylpalladium intermediates, which readily undergo inter-
Scheme 1 Reaction of allenes with aryl or alkenyl halides bearing a
nucleophilic moiety.
or intramolecular nucleophilic substitution with various nu-
cleophiles. Accordingly, the reaction of allenes 2 with aryl
halide derivatives 1, bearing a nucleophilic functional group
such as 2-halophenols/anilines, 2-halobenzyl alcohols/amines
and related compounds, provides a straightforward access to
benzene-fused heterocyclic compounds 4 (Scheme 1).2–4 In
contrast, the reaction of allenes with haloalkene derivatives
is relatively limited. Larock et al. reported regio- and stereo-
Scheme 2 Zipper-mode domino cyclisation of allenic haloalkenes.
selective annulation of cyclic or acyclic allenes 2 with vinylic
halides 5, possessing a nucleophilic hydroxy, amino, sulfona-
mide, or carboxylic group, to produce five- or six-membered
heterocycles 7.2b,c,5 However, there have been no precedents
for cascade intramolecular reaction of allenic haloalkene
derivatives with an internal nucleophile. We envisioned that
allenic haloalkenes 8, containing an appropriate nucleophilic
moiety, could undergo domino cyclisation by successive in-
tramolecular reactions (Scheme 2). Herein we wish to report
the zipper-mode cyclisation6 of allenic haloalkenylamine deri-
vatives 8 to produce diazabicycloalkene derivatives 10, which
include medium-sized rings (n = 1–3).7 The domino cyclisa-
tion involving oxygen and carbon nucleophiles is also
described.
butyldimethylsilyl (TBS)-protected (Z)-3,4-dibromobut-2-
en-1-ol9 and Mitsunobu-type amination.
We started our investigation with the domino cyclisation of
L-valine-derived allenic bromoalkenylamine 12a (Table 1). As
we expected, the reaction of 12a catalysed by Pd(PPh3)4
(10 mol%) in the presence of K2CO3 (2.5 equiv.) in MeCN
afforded the desired hexahydro-2,6-naphthyridine derivative
13a, although in low yield (37%, entry 1). Among palladium
catalysts examined (entries 1–4), Pd2(dba)3ÁCHCl3 (dba =
dibenzylideneacetone)proved promising, yielding 72% of 13a
with 5 mol% catalyst loading (entry 4). After experiments
using various bases (2.5 equiv., entries 5–7) and solvents
(entries 9–12), we found that a combination of tetrabutylam-
monium fluoride (TBAF)–MeCN gave the desired bicyclic
product 13a in 91% yield with 2.5 mol% of the palladium
catalyst (entry 8).
Requisite substrates for the biscyclisation were prepared
from protected known amino allene derivatives 11 (Scheme 3),
which, in turn, were readily obtained through diethylzinc-
mediated allene synthesis catalysed by palladium(0).8 Thus,
allenes 11 were converted to allenic bromoalkenylamines 12 by
a sequence of reactions including N-alkylation with tert-
Next, the domino cyclisation of several bromoalkenylamine
derivatives 12b–12e was investigated (Table 2). Results with
12a (91%, entry 1) and bis-tosylamide derivative 12b
a Graduate School of Pharmaceutical Sciences, Kyoto University,
Sakyo-ku, Kyoto 606-8501, Japan. E-mail: hohno@pharm.kyoto-
u.ac.jp. E-mail: nfujii@pharm.kyoto-u.ac.jp
b Graduate School of Pharmaceutical Sciences, Osaka University, 1-6
Yamadaoka, Suita, Osaka 565-0871, Japan
w Electronic supplementary information (ESI) available: Experimental
section and NMR spectra. See DOI: 10.1039/b805845h
Scheme 3 Preparation of allenic haloalkenylamines 12.
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Table 1 Domino cyclisation of 12a under various reaction condi-
tionsa
Table 2 Domino cyclisation of bromoalkenylamine derivativesa
Entry Substrate Time/ Product
h
(% yieldb)
Entry Pd catalyst
(mol%)
Solvent Base
Temperature/ Time/ Yield
1C
(%)b
1
2
3
4
12a (P1 = Mts, P2=Ts)
12b (P1 = P2 = Ts)
3.5
3.5
13a (P1 = Mts,
P2 = Ts; 91%)
13b (P1 = P2 = Ts;
89%)
h
1
2
3
4
Pd(PPh3)4 (10) MeCN K2CO3 70
Pd(OAc)2 (10) MeCN K2CO3 70
Pd(dppf)Cl2 (10) MeCN K2CO3 70
0.75 37
12c (P1 = Mts, P2 = Ns) 2.5
13c (P1 = Mts,
P2 = Ns; 91%)
2
16
53
43
Pd2(dba)3Á
CHCl3 (5)
Pd2(dba)3Á
CHCl3 (5)
Pd2(dba)3Á
CHCl3 (5)
Pd2(dba)3Á
CHCl3 (5)
Pd2(dba)3Á
CHCl3 (2.5)
Pd2(dba)3Á
CHCl3 (2.5)
Pd2(dba)3Á
CHCl3 (2.5)
Pd2(dba)3Á
CHCl3 (2.5)
Pd2(dba)3Á
CHCl3 (2.5)
MeCN K2CO3 70
MeCN Cs2CO3 70
MeCN NaOAc 70
MeCN TBAF 70
MeCN TBAF 50
0.6 72
3.5
5
0.1 71
6
42
Trace
12d
13d (90%)
13e (75%)
7
0.1 87
3.5 91
5
6
2.0
8
9
THF
Dioxane TBAF 50
DMF TBAF 50
EtOH TBAF 50
TBAF 50
5
Trace
10
11
12
2.5 77
12e
3.0
10
70
67
8
a
Abbreviations: Mts
1,1’-bis(diphenylphosphino)ferrocene. Isolated yields.
= 2,4,6-trimethylphenylsulfonyl; dppf =
b
14
15 (73%)
7
3.5
(89% yield, entry 2) were comparably successful. Similarly,
nosylamide 12c was smoothly cyclised into 13c in 91% yield
under identical reaction conditions. The substituent at the a-
position of the allenic moiety affects the reactivity of the
substrates. Thus, while the reaction of substrate 12d, bearing
a methyl group, afforded 13d in 90% yield (entry 4), a slightly
lower yield of the bicyclic product 13e was obtained in the
reaction of a-unsubstituted allene 12e (75%, entry 5). It should
be noted that this domino cyclisation is also applicable to
construction of fused medium-sized heterocycles 15 and 17,
containing seven (15, 73%, entry 6) and eight-membered rings
(17, 62%, entry 7).10
16
17 (62%)
a
All reactions were carried out using Pd2(dba)3ÁCHCl3 (2.5 mol%)
and TBAF (2.5 equiv.) in MeCN at 50 1C. Abbreviation: Ns =
2-nitrophenylsulfonyl. Isolated yields.
b
described previously (Scheme 3) from amino allene 11 (P1 =
Mts) and 2,3-dibromoprop-1-ene, derived from 2-aminoben-
zyl alcohol. The cyclisation of 22 using the standard procedure
cleanly gave the expected product 23 in 89% yield as the sole
isolable product.
The cyclisation using other nucleophiles (oxygen and car-
bon) was then examined (Scheme 4). Unfortunately, treatment
of bromoalkenol derivative 18 under the standard reaction
conditions employed with the amine substrates [Pd2(dba)3Á
CHCl3 and TBAF in MeCN at 50 1C] did not afford any
biscyclised product and led to a complete decomposition of the
substrate. In contrast, with the use of Cs2CO3 as the base, the
alcohol 18 was converted to the expected pyranopyridine
derivative 19 in 56% yield. Domino carbocyclisation of
malonate derivative 20 was successfully promoted using the
standard conditions, using TBAF as a base, to afford hexa-
hydroisoquinoline dicarboxylate 21 in 70% yield.
Finally, construction of a fused benzoazepine framework
using the domino cyclisation was investigated. Bromoalkenyl-
aniline 22 (Scheme 5) was prepared in a similar manner as
Scheme 4 Reaction involving oxygen and carbon nucleophiles.
Chem. Commun., 2008, 3534–3536 | 3535
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Eur. J. Org. Chem., 2001, 707–712; (d) K. Inamoto,
A. Yamamoto, K. Ohsawa, K. Hiroya and T. Sakamoto, Chem.
Pharm. Bull., 2005, 53, 1502–1507; (e) M. Chakoravarty and K. C.
K. Swamy, J. Org. Chem., 2006, 71, 9128–9138; (f) H.-P. Bi,
X.-Y. Liu, F.-R. Gou, L.-N. Guo, X.-H. Duan and Y.-M. Liang,
Org. Lett., 2007, 9, 3527–3529.
4. For cascade reactions with aryl halide derivatives, see: (a) S. Ma
and E. Negishi, J. Am. Chem. Soc., 1995, 117, 6345–6357;
Scheme 5 Construction of a fused benzoazepine framework.
(b) R. Grigg, I. Koppen, M. Rasparini and V. Sridharan, Chem.
¨
Commun., 2001, 964–965; (c) K. Hiroi, Y. Hiratsuka,
K. Watanabe, I. Abe, F. Kato and M. Hiroi, Synlett, 2001,
263–265; (d) K. Hiroi, Y. Hiratsuka, K. Watanabe, I. Abe,
F. Kato and M. Hiroi, Tetrahedron: Asymmetry, 2003, 13,
1351–1353; (e) K. Watanabe and K. Hiroi, Heterocycles, 2003,
59, 453–457.
In conclusion, we have developed a zipper-mode cascade
cyclisation of allenic bromoalkenes catalysed by palladium(0).
This reaction is widely applicable to cyclisations using nitro-
gen, oxygen, and carbon nucleophiles as well as the construc-
tion of fused medium-sized heterocycles. Further studies
directed toward the application of this method to the synthesis
of various heterocycles of biological importance is currently
underway.
5. R. C. Larock, Y. He, W. W. Leong, X. Han, M. D. Refvik and
J. M. Zenner, J. Org. Chem., 1998, 63, 2154–2160.
6. For our recent reports on zipper-mode cascade cyclisations, see:
(a) H. Ohno, K. Miyamura, Y. Takeoka and T. Tanaka, Angew.
Chem., Int. Ed., 2003, 42, 2647–2650; (b) H. Hamaguchi,
S. Kosaka, H. Ohno and T. Tanaka, Angew. Chem., Int. Ed.,
2005, 44, 1513–1517; (c) H. Ohno, M. Yamamoto, M. Iuchi and
T. Tanaka, Angew. Chem., Int. Ed., 2005, 44, 5103–5106;
(d) H. Hamaguchi, S. Kosaka, H. Ohno, N. Fujii and
T. Tanaka, Chem.–Eur. J., 2007, 13, 1692–1708; (e) H. Ohno,
M. Iuchi, N. Fujii and T. Tanaka, Org. Lett., 2007, 9,
4813–4815.
This work was supported in part by a Grant-in-Aid for
Encouragement of Young Scientists (A) and for Scientific
Research (B) from the Ministry of Education, Culture, Sports,
Science and Technology of Japan, and the Program for
Promotion of Fundamental Studies in Health Sciences of the
National Institute of Biomedical Innovation (NIBIO).
7. For a related medium-ring formation, see: R. C. Larock, C. Tu
and P. Pace, J. Org. Chem., 1998, 63, 6859–6866.
Notes and references
8. Chiral amino allenes 11 were prepared in an enantiomerically pure
form starting from L-amino acids, see: (a) H. Ohno, A.
Toda, S. Oishi, T. Tanaka, Y. Takemoto, N. Fujii and
T. Ibuka, Tetrahedron Lett., 2000, 41, 5131–5134; (b) H.
Ohno, K. Miyamura, T. Tanaka, S. Oishi, A. Toda,
Y. Takemoto, N. Fujii and T. Ibuka, J. Org. Chem., 2002, 67,
1359–1367.
9. The protected (Z)-3,4-dibromobut-2-en-1-ol was prepared by
Wittig olefination of 2-(tert-butyldimethylsiloxy)acetaldehyde
with Ph3PQC(Br)CO2Me followed by DIBAL-H reduction and
bromination with CBr4–PPh3–imidazole. See also A. G. Steinig
and A. de Meijere, Eur. J. Org. Chem., 1999, 1333–1344.
10. Formation of the five- or six-membered rings in the second
cyclisation of 14 and 16 was not observed. Such cyclisation would
be disfavoured because of highly restricted conformations of the
alkenylamine intermediates of the type 9.
1. For recent reviews, see: (a) R. Zimmer, C. U. Dinesh,
E. Nandanan and F. A. Khan, Chem. Rev., 2000, 100,
3067–3125; (b) A. S. K. Hashmi, Angew. Chem., Int. Ed., 2000,
39, 3590–3593; (c) R. W. Bates and V. Satcharoen, Chem. Soc.
Rev., 2002, 31, 12–21; (d) T. Mandai, in Modern Allene Chemistry,
ed. A. S. K. Hashmi and N. Krause, Wiley-VCH, Weinheim, 2004,
vol. 2, pp. 925–972; (e) S. Ma, Chem. Rev., 2005, 105, 2829–2871.
2. (a) R. C. Larock, N. G. Berrios-Pena and C. A. Fried, J. Org.
Chem., 1991, 56, 2615–2617; (b) R. C. Larock and J. M. Zenner,
J. Org. Chem., 1995, 60, 482–483; (c) J. M. Zenner and
R. C. Larock, J. Org. Chem., 1999, 64, 7312–7322.
3. (a) E. Desarbre and J.-Y. Merour, Tetrahedron Lett., 1996, 37,
´
43–46; (b) R. Grigg, W. S. Maclachlan, D. T. MacPherson,
V. Sridharan, S. Suganthan, M. Thornton-Pett and J. Zhang,
Tetrahedron, 2000, 56, 6585–6594; (c) R. Grigg and M. Kordes,
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3536 | Chem. Commun., 2008, 3534–3536