One-pot synthesis of highly substituted allenylidene derivatives via palladium- or nickel-catalyzed tandem Michael addition-cyclization reaction

Article abstract of DOI:10.1002/adsc.200800582

A simple and tandem synthetic approach, which offers an efficient, direct route to highly substituted indenes, has been developed by palladiumor nickel-catalyzed cyclization of propargylic compounds and nitrogen nucleophiles. The reaction takes place unde

Full text of DOI:10.1002/adsc.200800582

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DOI: 10.1002/adsc.200800582
One-Pot Synthesis of Highly Substituted Allenylidene Derivatives
via Palladium- or Nickel-Catalyzed Tandem Michael Addition–
Cyclization Reaction
Yun Shi,a Jing Huang,a Yan-Fang Yang,a Lu-Yong Wu,a Yan-Ning Niu,a
Peng-Fei Huo,a Xue-Yuan Liu,a and Yong-Min Lianga,b,*
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Science,
b
Lanzhou 730000, Peopleꢀs Republic of China
Fax : (+86)-931-891-2582; phone: (+86)-931-891-2593; e-mail: liangym@lzu.edu.cn
Received: September 19, 2008; Revised: December 5, 2008; Published online: January 2, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800582.
Abstract: A simple and tandem synthetic approach,
which offers an efficient, direct route to highly sub-
stituted indenes, has been developed by palladium-
or nickel-catalyzed cyclization of propargylic com-
pounds and nitrogen nucleophiles. The reaction
takes place under mild conditions, and a possible
mechansim is proposed.
During the past decades, the Michael addition has re-
mained one of the most popular methods for the con-
struction of carbon-carbon and carbon-heteroatom
bonds. The synthesis of highly substituted annular
compounds through a one-pot or tandem Michael ad-
dition–cyclization process has attracted increasing at-
tention, due to its efficient and atom-economic meth-
odology.[3] Balme reported a Cu-mediated annulation
reaction of stabilized carbon with unactivated alkynes,
leading to highly substituted methylenecyclopentanes
[Scheme 1, Eq (1)].[4] However, few reports are
known concerning a one-pot cyclization strategy of
the stabilized carbon nucleophiles to propargylic com-
pounds. Such reactions were particularly challenging
Keywords: allenes; cyclization; nickel; palladium;
propargylic compounds
Tandem reactions involving a transition metal-pro- because the regio- and chemoselectivity of the organ-
moted step have emerged as a powerful tool to con- ometallic activation must be well controlled to avoid
struct cyclic and polycyclic structures.[1] Strategies the formation of intractable mixtures.
used in the design and synthesis of complex biologi-
The interesting reactivity of allenes originates
cally active compounds and natural products have re- mainly from their unique strained structure, and thus
ceived considerable attention in organic synthesis.[2] continuous efforts have been made to construct 1,2-
Scheme 1.
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141

Yun Shi et al.
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dienic moieties.[5] We have reported a novel palladi- nucleophile under Pd-tuned conditions, thus offering
um-catalyzed intermolecular reaction for the synthesis an efficient, direct route for the synthesis of allenylin-
of indene compounds including an allene functional dene derivative 3a. The starting materials could be
group with high regioselectivity and excellent yields.[6] easily obtained from propargyl aldehyde.[9] In this
Recently, Wu reported a effective cyclization process process, intermolecular nucleophilic attack happened
of indole with 2-[2-(alkynyl)benzylidene]malonate prior to the following intramolecular reaction. The ex-
mediated by t-BuOK [Scheme 1, Eq. (2)].[7] In con- periments were carried out by using 1.0 equiv. of ben-
nection with our research on carboannulation reac- zylidenemalonate 1a and 2.0 equiv. of aniline with 5
tions for the preparation of indene derivatives by mol% of PdACHTNURTGNE(UNG PPh3)4 under argon at room temperature.
transition metal catalysis,[8] we conceived that a In initial investigations, no reaction was observed
tandem annulation, in which both carbon-carbon and without base or when t-BuOK, NaOEt, NaH or Et3N
carbon-heteroatom bond were constructed, could pos- as the base was employed (Table 1, entries 1–5). The
sibly occur with suitable nucleophiles initiating an in- desired product 3a was obtained in 36% yield in the
termolecular Michael addition.
presence of K2CO3 (entry 6). t-BuOK furnished a
Fortunately, we discovered that diethyl 2-{2-[3- moderate isolated yield (entry 7). Remarkably,
(ethoxycarbonyloxy)prop-1-ynyl]benzylidene} malo- switching the base to Cs2CO3 led to the formation of
nate 1a undergoes a tandem reaction with aniline as target product in 76% yield and a shorter reaction
Table 1. Conditons screening for the transformations.[a]
Entry
Catalyst
–
Base
Solvent
Time [h]
Temp. [8C]
Yield [%][b] of 3a
1
2
3
4
5
6
7
8
t-BuOK
–
NaOEt
NaH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
1,4-dioxane
toluene
THF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
12
12
12
12
12
2
2
1
1
1
1
1
0.4
0.5
4
4
1
6
6
25
25
25
25
25
25
25
25
25
25
25
25
80
50
25
25
25
45
45
45
45
60
NR[c]
NR
NR
NR
NR
36
50
76
26
48
40
34
20
65
28
13
59
20
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
E
E
E
T
E
E
T
N
R
N
A
Et3N
K2CO3
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
U
Pd/C
NiCl2·6H2O[d]
Ni
Ni
Ni
Ni
(PO4)2·8H2O[d]
55
60
80
60
[d]
R
R
A
2
2
2
[d]
[a]
Conditions: 5 mol% of catalyst in 2.0 mL solvent using 1.0 equiv. of 1a, 2.0 equiv. of 2a and 3.0 equiv. of base under
argon.
Isolated yield.
NR=no reaction.
Experiments were carried out in air.
[b]
[c]
[d]
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One-Pot Synthesis of Highly Substituted Allenylidene Derivatives
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time (entry 8). Other solvents, for example, CH3CN, spectively (entries 2 and 3), whereas a relatively lower
1,4-dioxane, toluene and THF, were less effective (en- yield (55%) of product 3d was observed when the
tries 9–12). Higher temperatures accelerated the reac- methyl group was in the ortho-position probably due
tion but were not beneficial to the yield (entries 13 to steric hindrance (entry 4). Use of the Ni(II) cata-
and 14). Other catalyst systems, such as Pd
ACHTUNGTERN(NUG OAc)2/ lyst also afforded the desired products in good yields.
PPh3 and Pd2A(dba)3/dppf, were also screened and fur- Moderate results were generated when halogenated
CHTUNGTRENNUNG
nished low yields of the desired product (entries 15 anilines were utilized, such as chlorobenzenamine and
and 16). A better result was obtained when the cata- bromobenzenamine (entries 5–8) via Pd- and Ni-catal-
lyst was replaced by Pd/C (entry 17). On the other ysis. Interestingly, the electron-withdrawing nucleo-
hand, the inexpensive nickel catalyst could also cata- phile also gave rise to the product 3i smoothly
lyze this one-pot transformation, which was a good (entry 9). It has been found that other amines, such as
extension of our methodology.[10] Screening various benzylamine, naphthalen-2-amine and furan-2-amine
nickel catalysts, Ni
catalyst for this process (entry 21). However, none of tries 10 and 12). We have also investigated the reac-
other catalysts, such as NiCl2·6H2O, Ni3A(PO4) ·8H2O tions of substrates with various leaving groups, such
and Ni(acac)2 gave a higher yield than NiACTHNUTRGNEUNG(PPh3)2Cl2 as propargyl acetate 1b, propargyl benzoate 1c and
ACHTUGNTRENUN(GN PPh3)2Cl2 was found to be the best were also well tolerated under our conditions (en-
CTHUNGTRENNUNG
2
G
(entries 18–20). The higher reaction temperature propargyl acetate 1d afforded the desired products 3a
could not improve the yield (entry 22). Moreover, it in good yields (entries 13–15).
should be noted that all reactions catalyzed by nickel
could be carried out in air.
In addition, although the NMR spectroscopic data
support the formation of indenes 3 (see Supporting
With the optimized conditions established, the Information), the structure was definitively secured
scope of this reaction was then examined and the re- by an X-ray crystal structure analysis of compound 3a
sults are summarized in Table 2. The reaction went (Figure 1).[11]
well with methyl substituent groups such that m-tolui-
Phenol and diethyl malonate were found to be
dine and p-toluidine gave excellent yields with the Pd good nucleophiles to afford an allenylpalladium inter-
catalyst for the corresponding products 3b and 3c, re- mediate or p-propargyl palladium complex (an equi-
Table 2. Synthesis of indenes 3 by carboannulation of propargylic compounds 1 with amines 2.[a]
Entry
R1
R2
Pd
Time [h]
G
Ni
Time [h]
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COMe
COPh
CO2Me
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3a
3a
3a
1
2
2
2
1
1
1
1
1
1
4
1
1
1
1
76
78
81
55
55
49
61
46
58
65
45
60
72
65
69
2
3
3
3
2
2
2
2
2
3
5
3
2
2
2
80
68
70
50
40
44
53
40
59
50
40
56
70
55
60
4-CH3C6H4
3-CH3C6H4
2-CH3C6H4
4-ClC6H4
3-ClC6H4
4-BrC6H4
3-BrC6H4
2-NO2C6H4
benzyl
1-naphthyl
2-furyl
C6H5
C6H5
C6H5
9
10
11
12
13
14
15
[a]
PdACHTUNGTRENNUNG(PPh3)4-catalyzed reactions were carried out under argon at 258C; NiAHCTUNGTREN(NNGU PPh3)2Cl2-catalyzed reactions were carried out in
air at 458C.
[b]
Yields of isolated products based on the propargylic compounds.
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143

Yun Shi et al.
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Scheme 2.
may involve the following key steps. (i) Decarboxyla-
tion of propargylic compound 1 catalyzed by Pd(0)
generates an allenylpalladium complex 4[13] or the
Ni(II) species coordinates with the alkyne triple bond
of 1 to afford 6. (ii) Base mediates a Michael addition
which affords intermediate 5 or 7, respectively. (iii) 5
undergoes regioselective intramolecular stabilized
carbon nucleophilic attack to afford indene 3; on the
other hand, 7 could also undergo the same attack
with the activated triple bond to afford vinyl inter-
Figure 1. X-ray structure of compound 3a.
librium process) in the previous reports.[3,4,12] Howev- mediate 8 and then a-heteroatom elimination (a-
er, no intermolecular nucleophilic attack happened oxygen elimination) to form indene 3.
under the above conditions. Further raising the reac-
In summary, a simple and one-pot method for the
tion temperature, loading the amount of catalyst and synthesis of highly substituted indene derivatives in-
using stronger bases gave intractable mixtures cluding an allene functional group has been devel-
(Scheme 2).
oped through this addition–cyclization process under
On the basis of the above observations, the follow- mild conditions by Pd or Ni catalysis. The starting ma-
ing plausible reaction mechanism was proposed for terials are easily accessible. Applications to other
this novel casade transformation (Figure 2), which metal-catalyzed tandem transformations are currently
Figure 2. Proposed reaction mechanism for this cyclization.
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One-Pot Synthesis of Highly Substituted Allenylidene Derivatives
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Ma, N. Jiao, Angew. Chem. 2002, 114, 4931; Angew.
Chem. Int. Ed. 2002, 41, 4737.
being studied in our research group, and will be re-
ported in due course.
[3] a) B. M. Trost, Angew. Chem. 1986, 98, 1; Angew.
Chem. Int. Ed. Engl. 1986, 25, 1; b) C. Thebtaranonth,
Y. Thebtaranonth, Tetrahedron 1990, 46, 1385; c) L. F.
Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137;
Angew. Chem. Int. Ed. Engl. 1993, 32, 131; d) M. A.
Amputch, R. Matamoros, R. D. Little, Tetrahedron
1994, 50, 5591; e) D. Caine, Tetrahedron 2001, 57, 2643;
f) G. Balme, D. Bouyssi, N. Monteiro, Topics in Organ-
ometallic Chemistry, Springer Verlag, Berlin, Heidel-
berg, 2006, Vol. 19, p 115.
Experimental Section
Typical Experimental Procedure for Tandem Michael
Addition–Cyclization Reactions (3a)
To a solution of diethyl 2-{2-[3-(ethoxycarbonyloxy)prop-1-
ynyl]benzylidene}malonate 1a (75.8 mg, 0.20 mmol) in DMF
(2.0 mL) was added Cs2CO3 (197.6 mg, 0.60 mmol). After
[4] a) G. Balme, D. Bouyssi, N. Coia, Eur. J. Org. Chem.
2007, 19, 3158; b) D. Bouyssi, N. Monteiro, G. Balme,
Tetrahedron Lett. 1999, 40, 1297.
the mixture had been stirred for 10 min, PdACTHUNRTGNEUNG(PPh3)4 (22.5 mg,
0.01 mmol, 5 mol%) and the corresponding amine
(0.40 mmol) were added under the argon at 258C. When the
reaction was complete as monitored by TLC, the reaction
mixture was quenched with a saturated aqueous solution of
ammonium chloride, and the mixture was extracted with
EtOAc (3ꢂ15 mL). The combined organic extracts were
washed with water and saturated brine, dried over Na2SO4
and filtered. Solvents were evaporated under reduced pres-
sure. The residue was purified by chromatography on silica
gel using 80:1 hexanes/EtOAc to afford the corresponding
[5] For some of the most recent typical reactions about al-
lenes, see: a) S.-S. Ng, T. F. Jamison, J. Am. Chem. Soc.
2005, 127, 7320; b) J. D. Sieber, J. P. Morken, J. Am.
Chem. Soc. 2006, 128, 74; c) P. H. Lee, K. Lee, Y. Kang,
J. Am. Chem. Soc. 2006, 128, 1139; d) P. L. Lalonde,
B. D. Sherry, E. J. Kang, F. D. Toste, J. Am. Chem. Soc.
2007, 129, 2452; e) H.-T. Chang, T. T. Jayanth, C.-H.
Cheng, J. Am. Chem. Soc. 2007, 129, 4166; f) A. R.
Banaag, M. A. Tius, J. Am. Chem. Soc. 2007, 129, 5328;
g) A. S. K. Hashmi, Angew. Chem. 2000, 112, 3737;
Angew. Chem. Int. Ed. 2000, 39, 3590; h) A. S. K.
Hashmi, in: Modern Allene Chemistry, (Eds.: A. S. K.
Hashmi, N. Krause), Wiley-VCH, Weinheim, 2004,
p 877.
indene 3a. The reaction catalyzed by Ni3ACHTNUTRGNEU(GN PO4)2·8H2O was
carried ou in the same way except that the mixture was
stirred at 458C in air.
[6] H.-P. Bi, X.-Y. Liu, F.-R. Gou, L.-N. Guo, X.-H. Duan,
Y.-M. Liang, Org. Lett. 2007, 9, 3527.
Acknowledgements
[7] K. Gao, J. Wu, Org. Lett. 2008, 10, 2251.
We thank the NSF (NSF-20621091, NSF-20672049, NSF-
20732002) and China Scholarship Council for financial sup-
port.
[8] a) L.-N. Guo, X.-H. Duan, H.-P. Bi, X.-Y. Liu, Y.-M.
Liang, J. Org. Chem. 2006, 71, 3325; b) X.-H. Duan, L.-
N. Guo, H.-P. Bi, X.-Y. Liu, Y.-M. Liang, Org. Lett.
2006, 8, 3053; c) X.-H. Duan, L.-N. Guo, H.-P. Bi, X.-Y.
Liu, Y.-M. Liang, Org. Lett. 2006, 8, 5777; d) L.-N.
Guo, X.-H. Duan, H.-P. Bi, X.-Y. Liu, Y.-M. Liang, J.
Org. Chem. 2007, 72, 1538.
References
[9] See Supporting Information for details.
[10] F.-R. Gou, H.-P. Bi, L.-N. Guo, Z.-H. Guan, X.-Y. Liu,
[1] For reviews of tandem reactions, see: a) T.-L. Ho,
Tandem Organic Reactions, Wiley-Interscience, New
York, 1992; b) T.-L. Ho, Tactics of Organic Synthesis,
Wiley-Interscience, New York, 1994, p 79; c) L. F.
Tietze, F. Haunert, in: Stimulating Concepts in Chemis-
try, (Eds.: F. Vçgtle, J. F. Stoddart, M. Shibasaki),
Wiley-VCH, Weinheim, 2000, p 39; d) T. J. J. Mꢃller,
Topics in Organometallic Chemistry, Springer-Verlag,
Berlin, Heidelberg, 2006, Vol. 19, p 149.
[2] For recent selected examples of metal-promoted
tandem reactions, see: a) K.-T. Yip, M. Yang, K.-L.
Law, N.-Y. Zhu, D. Yang, J. Am. Chem. Soc. 2006, 128,
3130; b) X. Wei, J. C. Lorenz, S. Kapadia, A. Saha, N.
Haddad, C. A. Busacca, C. H. Senanayake, J. Org.
Chem. 2007, 72, 4250; c) H. Hamaguchi, S. Kosaka, H.
Ohno, N. Fujii, T. Tanaka, Chem. Eur. J. 2007, 13, 1692;
d) H. J. Bae, B. Baskar, S. E. An, J. Y. Cheong, D. T.
Thangadurai, I. C. Hwang, Y. H. Rhee, Angew. Chem.
2008, 120, 2295; Angew. Chem. Int. Ed. 2008, 47, 2263;
e) X.-Y. Liu, C.-M. Che, Angew. Chem. 2008, 120, 3865;
Angew. Chem. Int. Ed. 2008, 47, 3805; f) H. Ohno, K.
Miyamura, T. Mizutani, Y. Kadoh, Y. Takeoka, H. Ha-
maguchi, T. Tanaka, Chem. Eur. J. 2005, 11, 3728; g) S.
Y.-M. Liang, J. Org. Chem. 2008, 73, 3837.
[11] The molecular structure of the corresponding product
3a was determined by X-ray crystallography (Figure 1).
X-ray data for compound 3a: C23H23NO4, MW=377.42,
T=274 (2) K, l=0.71073 ꢄ, monoclinic space group,
triclinic, P-1, a=9.369 (12) ꢄ, b=10.308 (13) ꢄ, c=
10.606 (13) ꢄ, a=94.23(2)8, b=95.71(2)8, g=94.83(2)8,
V=1012(2) ꢄ3,
0.085 mmÀ1,
0.24 mm3, independent reflections 3639 [R
ACHTUNGTRENNUNG
Z=2,
(000)=400, crystal size 0.31ꢂ0.27ꢂ
(int)=
1cald =1.238 mgmÀ3,
m=
FACHTUNGTRENNUG
0.0223], reflections collected 4753, refinement method,
full-matrix least-squares on F2, goodness-of-fit on F2
1.013, final R indices [I> 2a(I)] R1 =0.0540, wR2 =
0.1361, R indices (all date) R1 =0.0986, wR2 =0.1747,
largest diff. peak and hole 0.231 and À0.216 eꢄÀ3.
CCDC 702185 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[12] a) C. F. Nguefack, P. Lhoste, D. Sinou, Synlett 1996,
553; b) M. Yoshida, H. Nemoto, M. Ihara, Tetrahedron
Adv. Synth. Catal. 2009, 351, 141 – 146
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
145

Yun Shi et al.
COMMUNICATIONS
Lett. 1999, 40, 8583; c) J. R. Labrosse, P. Lhoste, D.
Sinou, Tetrahedron Lett. 1999, 40, 9025; d) J. R. Lab-
rosse, P. Lhoste, D. Sinou, Org. Lett. 2000, 2, 527; e) Y.
Kozawa, M. Mori, Tetrahedron Lett. 2001, 42, 4869;
f) Y. Kozawa, M. Mori, Tetrahedron Lett. 2002, 43,
1499; g) H.-P. Bi, X.-Y. Liu, F.-R. Gou, L.-N. Guo, X.-
H. Duan, X.-Z. Shu, Y.-M. Liang, Angew. Chem. 2007,
119, 7198; Angew. Chem. Int. Ed. 2007, 46, 7068; h) H.-
P. Bi, L.-N. Guo, F.-R. Gou, X.-H. Duan, X.-Y. Liu, Y.-
M. Liang, J. Org. Chem. 2008, 73, 4713.
[13] a) Y. Kozawa, M. Mori, J. Org. Chem. 2003, 68, 8068;
b) M. Yoshida, Y. Morishita, M. Fujita, M. Ihara, Tetra-
hedron Lett. 2004, 45, 1861; c) M. Yoshida, Y. Morishi-
ta, M. Fujita, M. Ihara, Tetrahedron 2005, 61, 4381.
146
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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