Palladium-catalyzed approach to stereodefined ten-membered cycles from 1,5-bisallenes

Article abstract of DOI:10.1021/ol202074e

A three-component Pd(0)-catalyzed reaction of 1,5-bisallenes with organic halides in the presence of primary amines was observed to afford stereodefined not readily available ten-membered cyclic compounds highly chemo- and regioselectively. A mechanism in

Full text of DOI:10.1021/ol202074e

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5200–5203
Palladium-Catalyzed Approach to
Stereodefined Ten-Membered Cycles from
1,5-Bisallenes
Jiajia Cheng,† Xuefeng Jiang,† and Shengming Ma*,†,‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
P. R. China, and Shanghai Key Laboratory of Green Chemistry and Chemical Process
Department of Chemistry, East China Normal University, 3663 North Zhongshan Road,
Shanghai 200062, P. R. China
masm@sioc.ac.cn
Received August 1, 2011
ABSTRACT
A three-component Pd(0)-catalyzed reaction of 1,5-bisallenes with organic halides in the presence of primary amines was observed to afford
stereodefined not readily available ten-membered cyclic compounds highly chemo- and regioselectively. A mechanism involving two π-allylic
palladium intermediates was proposed to account for the observed regio- and stereoselectivity.
Most of the biologically active molecules are cyclic
compounds.1 However, medium-sized heterocycles includ-
ing ten-membered compounds are difficult to prepare due
to entropic and enthalpic reasons.2 Known methods
always require very special techniques, such as highly
diluted solutions.3 Thus, new methodologies for the effi-
cient synthesis of this medium-sized heterocycle are highly
desirable.
On the other hand, transition-metal-catalyzed reactions
of functionalized allenes have become one of the most
important tools for the synthesis of some biologically
important systems.4 With the development of multicom-
ponent reactions (MCRs), which have become efficient
synthetic methods to create complex molecules,5 novel
multicomponent reactions involving allenes as substrates
(4) For reviews, see: (a) Hashmi, A. S. K. Angew. Chem., Int. Ed.
2000, 39, 3590. (b) Marshall, J. Chem. Rev. 2000, 100, 3163. (c)
Brandsma, L.; Nedolya, N. A. Synthesis 2004, 735. (d) Sydnes, L. K.
Chem. Rev. 2003, 103, 1133. (e) Kim, H.; Williams, L. J. Curr. Opin. Drug
Disc. 2008, 11, 870. (f) Back, T. G.; Clary, K. N.; Gao, D. Chem. Rev.
2010, 110, 4498. (g) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria,
M.; Simonneau., A. Chem. Rev. 2011, 111, 1954. (h) Krause, N.; Winter,
C. Chem. Rev. 2011, 111, 1994.
† Chinese Academy of Sciences.
‡ East China Normal University.
(1) For reviews, see: (a) Majhi, T. P.; Achari, B.; Chattopadhyay, P.
Heterocycles 2007, 71, 1011. (b) Dietrich, B.; Viout, P.; Lehn, J. M.
Macrocyclic Chemistry; VCH: Weinheim, 1993. (c) Weber, E.; Vogtle, F.
Macrocycles; Springer: Berlin, 1992. (d) Evans, P. A.; Holmes, B. Tetra-
hedron 1991, 47, 9131.
€
(5) For reviews on multicomponent reactions: see: (a) Alba, A.;
Companyo, X.; Viciano, M.; Rios, R. Curr. Org. Chem. 2009, 13,
1432. (b) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions
(2) For related reviews, see: (a) Shiina, I. Chem. Rev. 2007, 107, 239.
(b) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(3) For reviews, see: (a) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39,
2073. (b) Molander, G. A. Acc. Chem. Res. 1998, 31, 603. (c) Parker, D.
Macrocycle synthesis: A practical approach; Oxford Univ. Press: Oxford,
1996. Selected examples: (a) Kitagaki, S.; Teramoto, S.; Mukai, C. Org. Lett.
2007, 9, 2549. (b) Ohno, H.; Hamaguchi, H.; Ohata, M.; Tanaka, T.
Angew. Chem., Int. Ed. 2003, 42, 1749. (c) Klapars, A.; Parris, S.;
Anderson, K. W.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 3529.
(d) Spring, D. R.; Krishnan, S.; Schreiber, S. L. J. Am. Chem. Soc. 2000,
122, 5656.
€
in Organic Synthesis; Wiley-VCH: Weinheim, 2006. (c) Domling, A. Chem.
ꢀ
Rev. 2006, 106, 17. (d) Zhu, J.; Bienayme, H. Multicomponent Reactions;
Wiley-VCH: Weinheim, 2005.
(6) For selected reports on Pd-catalyzed three-component reactions
of allenes, see: (a) Yang, F. Y.; Wu, M. Y.; Cheng, C. H. J. Am. Chem.
Soc. 2000, 122, 7122. (b) Ma, S.; J, N. Angew. Chem., Int. Ed. 2002, 41,
4737. (c) Huang, T. H.; Chang, H. M.; Wu, M. Y.; Cheng, C. H. J. Org.
Chem. 2002, 67, 99. (d) Shu, W.; Jia, G.; Ma, S. Angew. Chem., Int. Ed.
2009, 48, 2788.
r
10.1021/ol202074e
Published on Web 09/12/2011
2011 American Chemical Society

to construct complex structures have attracted much
attention.6
Scheme 1. Possible Reaction Pathways for Carbopalladation of
Allenes and Bisallenes
Pd-catalyzed carbopalladation of allenes may afford the
π-allyllic palladium species which would react with a
nucleophile to form the allylation product.7,8 Based on
this, we envisioned that the carbopalladation of 1,5-bisal-
lenes may affordtwo π-allylicPdintermediates, which may
be trapped by a NuH2-type of nucleophile sequentially to
give cyclic products.9 Nontheless, there are three types of
intermediates and each one has four reaction sites which
may lead to six types of products A to F (Scheme 1). It
should be mentioned that most of the known reports on the
trapping of two π-allyllic metal species by a NuH2-type of
nucleophile are prone to form 5- or 6-membered cyclic
compounds.10 Thus, in this reaction the control of regio-
and stereoselectivity would be a formidable challenge. Of
particular interest is the possible selective formation of the
ten-membered products A. Herein, we wish to disclose our
recent observation of the three-component cyclization for
the highly regioselective synthesis of ten-membered hetero-
cycles with two stereodefined CdC bonds.
Our initial work began with the cyclization of bis(2,3-
butadienyl)tosylamide 1a with phenyl iodide 2a in the
presence of benzylamine 3a as the NuH2-type of nucleo-
philes. Whenthe reactionwas carried out inN,N-dimethyl-
formamide (DMF) at 90 °C catalyzed by 5 mol %
Pd(PPh3)4 in the presence of 4.0 equiv of K2CO3, surpris-
ingly, the ten-membered cycloalkene 4a was obtained in
35% yield exclusively (Table 1, entry 1)! The structure and
configuration of the CdC bond was unambiguously es-
tablished by its X-ray diffraction study (Figure 1).11 It is
worth noting that other BꢀF types of regio- and
stereoisomers were not observed, indicating that this reac-
tion is highly regio- and stereoselective. The solvent effect
was examined with Pd(PPh3)4 as the catalyst, and DMF
was found to be the best for the reaction (Table 1, entries
1ꢀ5). No better results were observed by using catalyst
(7) For related reviews, see: (a) Shaw, B. L.; Stringer, A. J. Inorg.
Chim. Acta Rev. 1973, 7, 1. (b) Otsuka, S.; Nakamura, A. Adv.
Organomet. Chem. 1976, 14, 245. (c) Bowden, F. L.; Giles, R. Coord.
Chem. Rev. 1976, 20, 81. (d) Jones, W. M.; Klosin, J. Adv. Organomet.
Chem. 1998, 42, 147. (e) Bai, T.; Ma, S.; Jia, G. Coord. Chem. Rev. 2009,
253, 423.
(8) For a seminal report on the synthesis of medium-sized rings by
Pd-catalyzed allylic substitution, see: (a) Trost, B. M.; Verhoeven, T. R.
J. Am. Chem. Soc. 1977, 99, 3867. For related reviews, see:(b) Trost,
B. M. Angew. Chem., Int. Ed. 1989, 28, 1173. (c) Trost, B. M. ACS Adv.
Chem. Ser. 1992, 230, 463.
(9) For a highlight of 1,5-bisallenes, see: Chen, G.; Jiang, X.; Fu, C.;
Ma, S. Chem. Lett. 2010, 39, 78.
(10) For selected examples of π-allyllic palladium, see: (a) Huang, Y.;
Lu, X. Tetrahedron Lett. 1988, 29, 5663. For selected examples of
π-allyllic iridium, see:(b) Miyabe, H.; Yoshida, K.; Kobayashi, Y.;
Matsumura, A.; Takemoto, Y. Synlett 2003, 1031. (c) Welter, C.; Dahnz,
€
A.; Brunner, B.; Streiff, S.; Dubon, P.; Helmchen, G. Org. Lett. 2005, 7,
1239.
(11) Crystal data for 4a. C34H34N2O2S, MW = 534.69, monoclinic,
space group Pbca, final R indices [ I > 2σ(I)], R1 = 0.0697, wR2 =
0.1677, R indices (all data) R1 = 0.1590, wR2 = 0.1999, a = 13.1485(16)
˚
˚
˚
A, b = 16.858(2) A, c = 25.981(3) A, R = 90°, β = 90°, γ = 90°, V =
5758.7(12) A , T = 293 K, Z = 8, reflections collected/unique: 28914/
3
˚
5349 (Rint = 0.1070), number of observations [ I > 2σ(I)] 2161,
parameters:354. Supplementary crystallographic data have been depos-
ited at the Cambridge Crystallographic Data Center (CCDC 831646).
(12) Crystal data for 4u. C31H37Br2NO4, MW = 647.44, monoclinic,
space group Pbca, final R indices [ I > 2σ(I)], R1 = 0.0388, wR2
0.0840, R indices (all data) R1=0.0589, wR2=0.0939, a = 15.4711(9)
=
˚
˚
˚
A, b = 9.7718(6) A, c = 39.174(2) A, R = 90°, β = 90°, γ = 90°, V =
5922.3(6) A , T = 173 K, Z = 8, reflections collected/unique: 64554/
3
˚
5205 (Rint = 0.0637), number of observations [ I > 2σ(I)] 4012,
parameters:343. Supplementary crystallographic data have been depos-
ited at the Cambridge Crystallographic Data Center (CCDC 831645).
Figure 1. ORTEP drawings of (a) 4a and (b) 4u.
Org. Lett., Vol. 13, No. 19, 2011
5201

systems of Pd(dba)2/phosphorus or a nitrogen containing
ligand (Table 1, entries 6ꢀ7). A Pd(dba)2/N-heterocyclic
carbene (NHC) ligandcatalyst system failed to catalyzethe
reaction (Table 1, entry 8). When the same reaction was
carried out with Ag3PO4 as the halide scavenger, the yield
of 4a was very similar (36%) (Table 1, entry 9). Then, the
reaction was tested with different bases, such as K2CO3,
Cs2CO3, K3PO4, and Na3PO4. Among them K3PO4 was
shown to be the best with 4a being isolated in 43% yield
(Table 1, entries 13ꢀ16). Thus, Pd(PPh3)4 (5 mol %),
Ag3PO4 (0.7 equiv), and K3PO4 (1 equiv) in DMF at
90 °C were defined as the optimized reaction conditions
for further study. Based on the NMR analysis of the crude
reaction mixture formed under the optimized conditions
before separation, only one stereoisomer was formed.
structures of amines: substituted benzylamine with an
electron-donating group at the phenyl moiety gave poorer
results than benzylamine (Table 2, entry 2). Aliphatic
amines gave better results. In addition, the following issues
should be noted: (1) The yields of these reactions range
from 35% to 62%; (2) phenethylamine (Table 2, entry 6)
may also be used to afford the corresponding ten-mem-
bered rings with an excellent stereoselectivity.
Table 2. Pd(PPh3)4-Catalyzed Coupling Cyclization of 1a with
Different Amines under Standard Conditionsa
Table 1. Optimization of the Reaction Conditions for the
Pd-Catalyzed Three-Component Cyclization of 1a with
BnNH2 and PhIa
entry
R1NH2
Bn (2a)
yield of 4 (%)b
1
2
3
4
5
6
43 (4a)
35 (4b)
49 (4c)c
62 (4d)
48 (4e)c
56 (4f)
p-MeOC6H4CH2 (2b)
n-C4H9 (2c)
n-C6H13 (2d)
cyclopropyl (2e)
C6H4CH2CH2 (2f)
base or
yield
(%)b
1a
(%)c
entry
catalyst
additive
solvent/t (h)
a The reaction was conducted using 1a (0.1 M), R1NH2 (1.0 equiv),
PhI (3.0 equiv), Pd(PPh3)4 (5 mol %), K3PO4 (1.0 equiv), and Ag3PO4
(0.7 equiv) in DMF at 90 °C. b Yield of isolated product. c Amine (2.0
equiv) was used.
1
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dba)2/Le
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF/10
35
0
30
48
60
45
0
2
CH3CNd/16.5 28
3
THFd/10
toluene/17
dioxane/22
DMF/10
DMF/10
DMF/10
DMF/10
DMF/10
DMF/10
n.d.
4
n.d.
n.d.
n.d.
17
5
The scope of this reaction of differently tethered 1,5-
bisallenes 1 with different phenyl iodides to give ten-
membered rings has also been demonstrated (Table 3).
The phenyl ring in the aryl iodide could be substituted by
4-Me, 3-Me (Table 3, entries 1ꢀ2), 4-Cl (Table 3, entry 4),
p/m-Br (Table 3, entries 5ꢀ6), and the aryl group (Table 3,
entry 10). Polysubstituted phenyl iodides are also suitable
for this MCR process (Table 3, entry 3). Phenyl iodides
with electron-withdrawing and -donating substituents on
the phenyl ring are all good substrates (Table 3, entries
7ꢀ9). The reaction also proceeded smoothly with other
aliphatic amines (Table 3, entries 11 and 12). Moreover,
with differently tethered bisallene as the substrates, a ten-
membered ring was obtained in moderate yields (Table 3,
entries 13ꢀ15). The structure and configuration of the
CdC bonds of 4u were further confirmed by an X-ray
diffraction study (Figure 1).12 Finally, it is easy to conduct
the reaction to afford 4d in 62% yield in a gram scale
(Scheme 2).
6
7
Pd(dba)2/PPh3 K2CO3
0
8
Pd(dba)2/IPrf
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
K2CO3
n.d.
36
0
i
9
Ag3PO4
0
g
10
11
12
13
14
15
16
Ag2CO3
n.d.
n.d.
n.d.
28
25
0
h
AgNO3
AgOAch DMF/10
0
i
K2CO3
DMF/10.5
DMF/10
DMF/10
0
i
Cs2CO3
n.d.
45 (43j)
32
0
i
K3PO4
0
i
Na3PO4 DMF/10
0
a The reaction was carried out using 1a (0.1 M), BnNH2 (1.0 equiv),
PhI (3.0 equiv), base (1.0 equiv), additive (0.7 equiv), palladium complex
(5 mol %), and ligand (10 mol %) at 90 °C. b Determined by 1H NMR
analysis with mesitylene as the internal standard. n.d. = not detected.
c 1a recovered after the reaction. d The reaction was conducted under
reflux. e L = 2,20-bipyridine. f 6 mol % IPr was added. IPr = 1,3-bis(2,6-
diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene. g 1.0 equiv of
silver salt was added to the reaction mixture. h 2.0 equiv of silver salt
was added to the reaction mixture. i 0.7 equiv of Ag3PO4 was added.
j Isolated yield.
With the optimized conditions in hand, we turned to
examine the substrate scope of the reaction. We first
studied the cyclization reaction of bisallene 1a with
different amines under the optimized reaction conditions
(Table 2). The reaction is obviously influenced by the
The high regio- and stereoselectivity of this reaction
may be explained as follows: Carbopalladation of one
of the two allene groups in the substrate would favor
the formation of π-allylic Pd intermediate anti-7 due
to the steric interaction of the phenyl group R and the
5202
Org. Lett., Vol. 13, No. 19, 2011

Table 3. Pd(PPh3)4-Catalyzed Cyclization of 1 with Amines and
Organic Halides under Standard Conditionsa
Scheme 2. 1-g Scale Reaction of 1a
yield of
4(%)b
entry
Z
R1NH2/R2ArI
t (h)
Scheme 3. Rationale for the Selectivity Observed
1
TsN (1a)
TsN (1a)
TsN (1a)
TsN (1a)
TsN (1a)
TsN (1a)
TsN (1a)
TsN (1a)
TsN (1a)
TsN (1a)
TsN (1a)
TsN (1a)
n-C6H13 (2d)/4-Me (3b)
n-C6H13 (2d)/3-Me (3c)
n-C6H13(2d)/3,4-Me2 (3d)
n-C6H13 (2d)/4-Cl (3e)
n-C6H13 (2d)/4-Br (3f)
n-C6H13 (2d)/3-Br (3g)
n-C6H13 (2d)/4-F (3h)
n-C6H13 (2d)/4-EtOOC (3i)
n-C6H13 (2d)/4-MeO (3j)
n-C6H13 (2d)/4-C6H5 (3k)
n-C4H9 (2c)/4-Br (3f)
Bn (2a)/4-Br (3f)
16
10
10
10
10
10
10
10
10
9.5
10
8
50 (4g)
53 (4h)
61 (4i)
59 (4j)
51 (4k)
54 (4l)
61 (4m)
51 (4n)
44 (4o)
42 (4p)
54 (4q) c
45 (4r)
38 (4s)
33 (4t)
40 (4u)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
PhN (1b) n-C6H13 (2d)/4-EtOOC (3i)
10
10
10
X (1c)d
X (1c)d
n-C6H13 (2d)/H (3a)
n-C6H13 (2d)/4-Br (3f)
a The reaction was conducted at 90 °C in DMF with 1 (c = 0.1 M),
R1NH2 (1.0 equiv), R2ArI (3.0 equiv), K3PO4 (1.0 equiv), and Ag3PO4 (0.7
equiv) in the presence of Pd(PPh3)4 (5 mol %) at indicated time. b Yield of
isolated product. c Amine (2.0 equiv) was used. d X = C(CO2Me)2.
regio- and stereoselective, which involves two π-allylic Pd
intermediates and utilizes primary amines as dinucleo-
philes. Further studies in this area including the scope of
the bisallenes and other NuH2-types of nucleophiles are
being pursued in our laboratory.
substituent containing the other allene group in syn-7.
The regioselective intermolecular allylation of anti-7 would
lead to the formation of intermediate 8. Then carbopalladation
of the second allene moiety in the substrate would favor the
formation of π-allylic Pd intermediate anti-9. The regioselec-
tive intramolecular allylic substitution of anti-9 would lead to
the formation of the ten-membered product 4 (Scheme 3).
In conclusion, we have developed a highly efficient
methodology for the synthesis of challenging ten-mem-
bered rings from 1,5-bisallenes, amines, and organic ha-
lides. As a result of the challenge often encountered in the
synthesis of ten-membered rings, this Pd(0)-catalyzed
three-component coupling cyclization reaction is highly
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20732005) and
National Basic Research Program of China (2011CB808700)
is greatly appreciated. We thank Mr. Y. Qiu in this group for
reproducing the preparation of 4b in Table 2 and 4i, 4n, and 4t
in Table 3.
Supporting Information Available. General procedure
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
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