One pot synthesis of indene through copper(i)-catalyzed three-components coupling and cyclization reaction

Article abstract of DOI:10.1039/c2ob07071e

A new and efficient synthesis of substituted indene has been achieved via copper(i)-catalyzed domino three-component coupling and cyclization reaction in moderate to good yield.

Full text of DOI:10.1039/c2ob07071e

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 3636
www.rsc.org/obc
PAPER
One pot synthesis of indene through copper(I)-catalyzed three-components
coupling and cyclization reaction†
Xiang-Chuan Wang,a Mei-Jin Zhonga and Yong-Min Liang*a,b
Received 11th December 2011, Accepted 5th March 2012
DOI: 10.1039/c2ob07071e
A new and efficient synthesis of substituted indene has been achieved via copper(I)-catalyzed domino
three-component coupling and cyclization reaction in moderate to good yield.
In connection with our ongoing project on the carboannulation
Introduction
reaction,11 we expected that secondary amine and paraformalde-
The indene is an important class of compounds that exists
widely in nature and has numerous applications in medicine.1
Consequently, a number of approaches to the synthesis of the
indene ring system have been developed, including classic
methods such as the reduction/dehydration of indanones,2 the
cyclization of phenyl-substituted allylic alcohols,3a–c 2-substi-
tuted ethynylmalonates,3d acetylenic malonates3e and 1-alkyl-2-
ethynylbenzenes3f, and the ring expansion of substituted cyclo-
propenes.4 Recently, Larock et al. reported synthesis of indenes
by Pd-catalyzed or Cu-catalyzed carboannulation of alkynes.5
Our group have described a convenient approach to the synthesis
of 2-substituted indenes by palladium-catalyzed carboannulation
of propargylic carbonates and nucleophiles.6 To expand the
method for the synthesis of indenes, we developed a copper(I)-
catalyzed domino three-component coupling and cyclization
reaction to construct the structure of indene.
Multicomponent reactions (MCRs) involve a domino process
with at least three different simple substrates. It has emerged as a
powerful strategy.7 This methodology allows molecular complex-
ity and diversity to be created by the facile formation of several
new covalent bonds in a one-pot transformation. Thus it is quite
closely approaches the concept of an ideal synthesis.8 A catalytic
domino reaction including a MCR would be more attractive to
achieve this goal.9 Recently, Fujii et al. reported a convenient
method for the preparation of functionalized indoles by the
copper-catalyzed multicomponent reaction of N-(2-ethynylphe-
hyde could react with diethyl 2-(2-ethylphenyl)malonate under
copper catalysis to give the 2-substituted indene (Scheme 2).
Results and discussion
Our initial study began with the 0.2 mmol diethyl 2-(2-ethylphe-
nyl)malonate (1a), 2.0 equiv of disopropylamine, 2.0 equiv of
paraformaldehyde, 1.2 equiv of t-BuOK, and 5 mol% equiv of
CuI in THF at 60 °C for 20 min. However, the desired product
diethyl 2-((diispropylamino)methyl)-1-H-indene-1,1-dicarboxy-
late (5aa) was not obtained. Only the Mannich reaction product
diethyl 2-(2-(but-1-yl) phenyl)malonate (4a)12 and the cycliza-
tion reaction product diethyl 1H-indene-1,1-dicarboxylate (6a)
were observed (Scheme 3).
However, when the Mannich reaction finished, CuI (5 mol%)
was added to the reaction mixture and stirred for 8 h, to our
delight, the desired product was obtained. We suppose water was
produced as a by-product, which had a disadvantageous effect
Scheme 1
Scheme 2
nyl)-4-methybenzenesulfonamid
with
paraformaldehyde
(Scheme 1).10 A catalytic domino reaction including a MCR
would be more attractive to achieve this goal.
aState Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou 730000, P.R. China. E-mail: liangym@lzu.edu.cn;
Fax: +86-931-8912582; Tel: +86-931-8912593
bLaboratory of Solid Lubrication, Lanzhou Institute of Chemical
Physics, Chinese Academy of Science, Lanzhou 730000, P.R. China.
†Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/c2ob07071e
Scheme 3
3636 | Org. Biomol. Chem., 2012, 10, 3636–3641
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 2 Copper-catalyzed three-components coupling and cyclization
reaction of 2-(2-ethylphenyl)malonate and paraformaldehyde with
aminea
on the copper catalyst. Therefore, the molecular sieve was added
to the reaction mixture to absorb the water generated by reaction.
Fortunately, the desired product was obtained, though 6a was
produced as a by-product simultaneously. In order to avoid the
by-product 6a, we first added 1a (0.2 mmol), 2.0 equiv of diiso-
propylamine, 2.0 equiv of paraformaldehyde, 0.2 g 4 Å molecu-
lar sieve and 5 mol% of CuI in THF at 60 °C for 20 min. Then
we added 1.2 equiv of t-BuOK. The product was isolated in 55%
yield.
The base effect on the cyclization reaction was then evaluated.
In all bases we examined, t-BuOLi was the best choice (entry 6).
Other solvents, such as CH3CN, dioxane and DMSO were also
tested in the reaction, however, no superior results were obtained
(entries 7–9). The efficiency with CuBr, CuCl, CuCl·Me2S or
Cu(PPh3)2Br was much lower than that with CuI (entries
14–17). Thus, we chose the following reaction conditions as
optimum for all subsequent cyclization: 1.0 equiv of 1, 2.0 equiv
of 2, 2.0 equiv of 3 and 0.2 g 4 Å molecular sieve and 5 mol%
equiv of CuI in THF at 60 °C under argon. When the first step
finished, 1.2 equiv of t-BuOLi was added (Table 1).
Entry Alkyne
1
Amines
t (h) Products Yieldb
(i-Pr)2NH 3a
2
5aa
79
2
3
4
5
1a
1a
1a
1a
Et2NH 3b
2.5
3
4.5
2
5ab
5ac
5ad
5ae
70
69
68
82
(n-Pr)2NH 3c
(n-Bu)2NH 3d
Dioctylamine 3e
6
1a
2
5af
80
To extend the general applicability of this three-component
coupling and cyclization reaction, the reaction of diethyl malo-
nate alkyne and paraformaldehyde with various amines under
the optimized conditions was investigated. The results are sum-
marized in Table 2. The volatile amine such as Et2NH with 1a
and paraformaldehyde result in 70% yield (entry 2).11b (n-
Pr)2NH and (n-Bu)2NH were also excellent amine components
in this reaction (entries 3 and 4). Even when the long-chain ali-
phatic amine dioctylamine (entry 5) was used, the reaction
7
1a
5
5ag
81
8
9
1a
1a
3
2
5ah
5ai
71
82
10
11
12
1a
1a
1a
4
3
3
5aj
5ak
5al
62
64
45
Table 1 Optimization of the copper-catalyzed three-components
coupling and cyclization reaction of 2-(2-ethylphenyl)malonate,
disopropylamine and paraformaldehydea
13
14
1a
5
5
5am
5ba
56
68
3a
15
16
17
18
1b
1b
1b
3b
3f
3h
3a
6
8
7
6
5bb
5bf
5bh
5ca
51
55
57
45
Entry
Base
Solvent
Copper
t (h)
Yieldc
a Reaction conditions: 0.20 mmol of 1, 2.0 equiv of 2, 2.0 equiv of 3,
5 mol% of CuI and 0.2 g 4 Å MS in 3 mL THF at 60 °C under argon.
When the first step finished, added 1.2 equiv of t-BuOLi for the
specified period of time. b Yield = isolated yield (%).
1
2
3
4
5
6
t-BuOK
CH3ONa
NaH
K2CO3
t-BuOLi
EtOLi
THF
THF
THF
THF
THF
THF
CuI
CuI
CuI
CuI
CuI
CuI
8
2
5
5
2
2
55
42
45
n.r.b
79
55
7
8
9
10
11
12
13
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
CH3CN
Dioxane
DMSO
THF
THF
THF
CuI
CuI
CuI
CuBr
CuCl
CuCl·Me2S
Cu(PPh3)2Br
2
18
7
61
15
26
57
10
Trace
15
proceeded very well (82% yield). The cycle secondary amine
such as pyrrolidine, piperidine, 4-methylpipeidine and 1-methyl-
piperazine (entries 6–9)11b also afforded the desired products in
good yields. The asymmetric secondary amines 3j and 3k
(entries 10 and 11) also afforded the corresponding products in
64% and 62% yields, respectively. For 3l (entry 12), a moderate
yield (45%) was obtained which can be explained by the steric
effects. In addition, piperazine (entry 13) was then employed in
this reaction. The corresponding product 5am was isolated in
56% yield (Scheme 4).
6
18
15
36
THF
a Reactions conditions: 0.20 mmol of 1a, 2.0 equiv of 2, 2.0 equiv of 3
and 5 mol% of copper catalysts and 0.2 g 4 Å MS in 3 mL solvent at
60 °C under argon. When the first step finished, added 1.2 equiv of base
for the specified period of time. b n.r. = no reaction. c Yield = isolated
yield (%).
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3636–3641 | 3637

View Article Online
Scheme 4
Encouraged by the above results, we further investigated the
reactivity of two other malonates. To our delight, various sec-
ondary amines such as (i-Pr)2NH, Et2NH, pyrrolidine, 4-methyl-
pipeidine could react with diethyl 2-(2-entynylbenzyl)malonate
(1b) or dimethyl 2-(2-entynylbenzyl) malonate (1c) to give the
desired products in moderate yields (entries 14–18). What’s
more, the symmetrical structure 5am was obtained when we
used amine 3m react with 1a and 2 (Scheme 4).
Scheme 5
Typical procedure for the preparation of propargylic
trimethylsilane
Diethyl 2-(2-(2-(trimethylsilyl)entynyl)phenyl)malonate. To
a
solution of diethyl (2-iodophenyl)malonate (1.81 g, 5.0 mmol)
and ethynyltrimethylsiane (0.58 g, 6 mmol) in Et2NH (20.0 mL)
was added Pd(PPh3)4 (57.5 mg, 0.5 mol%). The mixture was
stirred for 5 min and CuI (9.5 mg, 1 mol%) was added. The
resulting mixture was then stirred under an argon atmosphere at
room temperature for 3 h. The ammonium salt was removed by
filtration. The solvent was removed under reduced pressure and
the residue was purified by column chromatography on silica get
to afford 1.53 g (92%) as an oil.
A plausible mechanism accounting for the formation of the
indenes is depicted in Scheme 5.6,10
The reaction may undergo the following key steps: (1) The
reaction of 1 and 2 with 3 though a Mannich-type mechanism to
get the intermediate 4a, (2) 4a reacts with base, to afford a carba-
nion, (3) coordination of the alkynyl moiety of 4a to CuI to gen-
erate the complex A, (4) the carbanion attacks the alkyne carbon
activating the triple bond, leading to the indene 5a and a regener-
ated copper catalyst, which then enters the next cycle.
Diethyl
2-(2-(2-(trimethylsilyl)entynyl)benzyl)malonate. This
was prepared by the same method, but employing diethyl-(2-
iodobenzyl)malonate (1.88 g, 5.0 mmol) and (0.58 g, 6 mmol)
for 3 h afforded 1.54 g (89%) as an oil.
Dimethyl 2-(2-(2-(trimethylsilyl)entynyl)benzyl)malonate. This
was prepared by the same method, but employing dimethyl-(2-
iodobenzyl)malonate (0.72 g, 2.0 mmol) and (0.17 g, 2.4 mmol)
for 3 h afforded 0.54 g (90%) as an oil.
Conclusions
In summary, we have developed a mild and efficient CuI cataly-
tic method for the synthesis of indene. A variety of secondary
amines undergo this process, giving the desired products in mod-
erate to good yields.
Typical procedure for the preparation of 1a–c. To a solution
of
diethyl
2-(2-(2-(trimethylsilyl)entynyl)phenyl)malonate
(0.66 g, 2.0 mmol) in THF (10 mL) was added TBAF at −78 °C
(0.76 g, 2.4 mmol). After stirring for 10 min the reaction
mixture was diluted with CH2Cl2. The CH2Cl2 solution was
washed with water, dried over anhydrous sodium sulfate, and
concentrated. The residue was purified by column chromato-
graphy on silica gel to afford the corresponding product 1a
0.44 g (85%) as an oil.
Experimental
General remarks
1
Column chromatography was carried out on silica gel. H NMR
spectra were recorded on 400 MHz in CDCl3 and 13C NMR
spectra were recorded on 100 MHz in CDCl3 using TMS as
internal standard. IR spectra were recorded on a FT-IR spec-
trometer and only major peaks are reported in cm−1. Melting
points were determined on a microscopic apparatus and were
uncorrected. All new compounds were further characterized by
elemental analysis; copies of their 1H NMR and 13C NMR
spectra are provided in the ESI†. Unless otherwise stated, all
amines were purchased from commercial suppliers and used
without further purification.
1a: 1H NMR (400 MHz, CDCl3) δ 7.52–7.55 (m, 2H),
7.37–7.39 (m, 1H), 7.27–7.32 (m, 1H), 5.33 (s, 1H), 4.23–4.26
(m, 4H), 3.25 (s, 1H), 1.26–1.27 (t, J = 7.2 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 167.9, 135.2, 132.7, 129.1, 128.7, 127.9,
122.6, 82.2, 81.9, 61.9, 55.5, 13.9; IR (neat, cm−1): 2956, 2252,
1631, 1309, 1248, 1146, 1045; Anal. Calcd for C15H16O4: C
69.22; H 6.20 Found: C 69.08; H 6.33.
Diethyl 2-(2-entynylbenzyl)malonate. The 1b was prepared by
the above method, but employing diethyl 2-(2-(3-hydroxyprop-
1-ynyl)benzyl)malonate (0.58 g, 2.0 mmol) and methyl chloro-
formate afforded 1b 0.61 g (87%) as an oil.
Starting materials
1
Diethyl (2-iodophenyl)malonate was prepared according to the
literature.13
1b: H NMR (400 MHz, CDCl3) δ 7.46–7.48 (d, J = 7.2 Hz,
1H), 7.18–7.20 (m, 2H), 4.12–4.18 (m, 4H), 3.87–3.91 (t, J =
7.6 Hz, 1H), 3.37–3.39 (d, J = 7.6 Hz, 2H), 3.32 (s, 1H),
1.15–1.18 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
Diethyl (2-iodobenzyl)malonate and dimethyl (2-iodobenzyl)-
malonate were prepared according to the literature.11
3638 | Org. Biomol. Chem., 2012, 10, 3636–3641
This journal is © The Royal Society of Chemistry 2012

View Article Online
168.8, 140.2, 132.9, 129.7, 128.8, 126.7, 121.8, 81.8, 81.5,
61.3, 52.1, 33.4, 13.9; IR (neat, cm−1): 2923, 2167, 1676, 1331,
1234, 1167, 1045; Anal. Calcd for C22 H31O4: C 70.06; H 6.61.
Found: C 70.08; H 6.63.
N 3.69. HRMS (ESI) Calcd for C22H31NO4: M + H = 374.2326.
Found: 374.2351.
5ab: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 48.3 mg (70%) of the indicated
1
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.49–7.51
Dimethyl 2-(2-entynylbenzyl) malonate. The 1c was prepared by
the above method, but employing dimethyl 2-(2-(2-(trimethylsi-
lyl)entynyl)benzyl)malonate (0.58 g, 2.0 mmol) and methyl
chloroformate afforded 1c 0.61 g (87%) as an oil.
(d, J = 7.2 Hz, 1H), 7.10–7.21 (m, 3H), 6.82 (s, 1H), 4.09–4.15
(m, 4H), 3.414–3.418 (d, J = 1.6 Hz, 2H), 2.48–2.53 (q, J = 7.2
Hz, 4H), 1.27–1.21 (t, J = 7.2 Hz, 6H), 1.06–1.01 (t, J = 7.2 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 168.1, 146.2, 144.1, 141.4,
131.6, 128.5, 125.3, 124.8, 120.5, 70.7, 61.8, 52.3, 47.2, 13.9,
11.9; IR (neat, cm−1): 3424, 2972, 1731, 1464, 1234, 1050;
Anal. Calcd for C20H27NO4: C 69.54; H 7.88; N 4.05. Found: C
69.48; H 7.84; N 3.96. HRMS (ESI) Calcd for C20H27NO44:
M + H = 346.2013. Found: 346.2019.
1c: 1H NMR (400 MHz, CDCl3) δ 7.46–7.48 (m, 1H),
7.17–7.28 (m, 3H), 3.91–3.95 (t, J = 7.6 Hz, 1H), 3.69 (s, 6H),
3.38–3.40 (d, J = 7.6 Hz, 2H), 3.33 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 169.8, 140.6, 133.1, 129.7, 128.9, 126.8,
121.8, 81.9, 81.4, 52.4, 51.8, 33.5; IR (neat, cm−1): 2956, 2223,
1667, 1354, 1268, 1123; Anal. Calcd for C14H14O4: C 68.28; H
5.73. Found: C 68.25; H 5.78.
5ac: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 52.3 mg (52%) of the indicated
4a: 1H NMR (400 MHz, CDCl3) δ 7.41–7.52 (m, 1H),
7.23–7.33 (m, 3H), 5.35 (s, 1H), 4.15–4.28 (m, 4H), 3.70 (s,
2H), 3.23–3.29 (m, 2H), 1.24–1.28 (t, J = 7.2 Hz, 6H),
1.14–1.16 (d, J = 6.8 Hz, 12H); 13C NMR (100 MHz, CDCl3) δ
168.2, 134.4, 132.1, 128.0, 127.8, 124.2, 94.1, 81.2, 61.7, 55.4,
48.4, 34.7, 20.7, 14.0; IR (neat, cm−1): 3437, 2982, 2232, 1671,
1301, 1228, 1154, 1032; Anal. Calcd for C22 H31NO4: C 70.75;
H 8.37; N 3.75. Found: C 70.77; H 8.35; N 3.68. HRMS (ESI)
Calcd for C22 H31NO4: M + H = 374.2326. Found: 374.2345.
1
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.56–7.58
(m, 1H), 7.14–7.29 (m, 3H), 6.90 (s, 1H), 4.15–4.23 (m, 4H),
3.45 (s, 2H), 2.41–2.45 (t, J = 7.6 Hz, 4H), 1.40–1.50 (m, 4H),
1.18–1.27 (m, 6H), 0.85–0.89 (t, J = 7.6 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 168.2, 144.2, 140.9, 139.6, 131.4, 128.5,
125.3, 124.8, 120.8, 70.7, 61.8, 56.5, 53.3, 13.9, 11.9; IR (neat,
cm−1): 3434, 2981, 1726, 1459, 1239, 1047; Anal. Calcd for
C22H31NO4: C 70.75; H 8.37; N 3.75. Found: C 70.79; H 8.35;
N 3.70. HRMS (ESI) Calcd for C22H31NO4: M + H = 374.2326.
Found: 374.2350.
1
6a: H NMR (400 MHz, CDCl3) δ 7.64–7.62 (d, J = 7.2 Hz,
1H), 7.17–7.26 (m, 3H), 6.82–6.84 (d, J = 5.6 Hz, 1H),
6.49–6.50 (d, J = 5.6 Hz, 1H), 4.10–4.18 (m, 4H), 1.16–1.22
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 167.6, 143.6, 139.8,
134.7, 133.4, 128.6, 126.3, 125.4, 121.5, 70.4, 62.12, 13.9; IR
(neat, cm−1): 2986, 1671, 1301, 1228, 1154, 1032; Anal. Calcd
for C15H16O4: C 69.22; H 6.20. Found: C 69.25; H 6.31. HRMS
(ESI) Calcd for C15H16O4: M + H = 261.1121. Found:
261.1144.
5ad: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 54.5 mg (68%) of the indicated
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.61–7.59
1
(d, J = 7.2 Hz, 1H), 7.19–7.31 (m, 3H), 6.93 (s, 1H), 4.19–4.23
(m, 4H), 3.47 (d, J = 1.6 Hz, 2H), 1.36–1.48 (m, 4H), 1.27–1.34
(m, 4H), 1.21–1.25 (m, 6H), 0.90–0.94 (t, J = 7.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 168.2, 146.5, 144.2, 141.0, 131.2,
128.5, 125.32, 124.8, 120.8, 70.8, 61.8, 54.3, 53.3, 29.5, 20.6,
14.1, 13.9; IR (neat, cm−1): 3434, 2972, 1731, 1464, 1234,
1050; Anal. Calcd for C24H35NO4: C 71.79; H 8.79; N 3.49.
Found: C 71.81; H 8.77; N 3.45. HRMS (ESI) Calcd for
C24H35NO4: M + H = 402.2639. Found: 402.2645.
General procedure for the preparation of indenes or dihydro-
naphthalene (5). A mixture of (1, 0.20 mmol), paraformalde-
hyde (2, 0.40 mmol), amine (3, 0.04 mol), CuI (1.9 mg, 5.0 mol
%), 0.2 g 4 Å MS, THF (3.0 mL) was placed under argon atmos-
phere in a 10 mL flask. The resulting mixture was then heated at
60 °C. When it was considered that the first step of the reaction
was complete (as determined by TLC analysis) t-BuOLi
(19.2 mg, 0.24 mmol) was added, then when the reaction was
considered complete as determined by TLC analysis, the reaction
mixture was allowed to cool to room temperature. The reaction
mixture was concentrated under reduced pressure and the residue
was purified by chromatography on silica gel to afford the corre-
sponding 2-substituted indenes 5a.
5ae: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 86.4 mg (82%) of the indicated
1
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.58–7.60
(d, J = 7.2 Hz, 1H), 7.23–7.30 (m, 2H), 7.14–7.18 (m, 1H), 6.91
(s, 1H), 4.12–4.22 (m, 4H), 3.45–3.46 (d, J = 1.6 Hz, 2H),
2.45–2.48 (t, J = 7.6 Hz, 4H), 1.46 (s, 4H), 1.19–1.28 (m, 26H),
0.85–0.89 (t, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
168.2, 146.5, 144.2, 141.0, 131.2, 128.5, 125.32, 124.8, 120.7,
70.8, 61.8, 54.5, 53.3, 31.8, 29.6, 29.3, 27.5, 27.3, 22.6, 14.0,
13.9; IR (neat, cm−1): 3451, 2980, 1736, 1468, 1254, 1038;
Anal. Calcd for C33H55NO4: C 75.10; H 10.12; N 2.65. Found:
C 75.12; H 10.06; N 2.63. HRMS (ESI) Calcd for C33H55NO4:
M + H = 528.4073. Found: 528.4056.
5aa: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 59 mg (79%) of the indicated
1
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.49–7.51
(d, J = 7.2 Hz, 1H), 7.14–7.20 (m, 2H), 7.05–7.18 (m, 1H), 6.19
(s, 1H), 4.09–4.19 (m, 4H), 3.441–3.448 (d, J = 2 Hz, 2H),
3.00–3.03 (t, J = 6.8 Hz, 2H), 1.15–1.18 (t, J = 7.2 Hz, 6H),
0.91–0.96 (d, J = 6.8 Hz, 12H); 13C NMR (100 MHz, CDCl3) δ
169.2, 140.1, 131.8, 130.0, 128.4, 126.8, 122.3, 96.7, 81.8,
61.6, 58.6, 52.5, 33.9, 24.2, 13.9; IR (neat, cm−1): 3437, 2982,
1732, 1371, 1301, 1228, 1154, 1032; Anal. Calcd for
C22H31NO4: C 70.75; H 8.37; N 3.75. Found: C 70.78; H 8.33;
5af: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 54.8 mg (80%) of the indicated
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.59–7.61
(d, J = 8.0 Hz, 1H), 7.24–7.32 (m, 2H), 7.17–7.21 (m, 1H), 6.88
(s, 1H), 4.15–4.23 (m, 4H), 3.59 (s, 2H), 2.60–2.63 (t, J = 6.4
Hz, 4H), 1.78–1.81 (m, 4H), 1.22–1.30 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 168.1, 145.2, 144.0, 140.9, 131.7, 128.5,
125.5, 124.9, 120.9, 71.0, 61.8, 54.5, 54.4, 23.7, 13.9; IR (neat,
1
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3636–3641 | 3639

View Article Online
cm−1): 3402, 2964, 1731, 1463, 1234, 1050; Anal. Calcd for
C20H25NO4: C 69.95; H 7.34; N 4.08. Found: C 69.86; H 7.38;
N 3.99. HRMS (ESI) Calcd for C20H25NO4: M + H = 344.1856
Found: 344.1837.
1.06–1.10 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
168.1, 145.1, 143.9, 141.0, 139.5, 132.0, 128.7, 128.6, 125.5,
124.8, 120.9, 70.8, 62.3, 61.9, 56.3, 42.5, 13.9; IR (neat, cm−1):
3435, 2939, 1738, 1465, 1238, 1047; Anal. Calcd for
C25H29NO4: C 73.68; H 7.17; N 3.44. Found: C 73.36; H 7.18;
N 3.45. HRMS (ESI) Calcd for C25H29NO4: M + H = 408.2169.
Found: 408.2187.
5ag: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 53.6 mg (81%) of the indicated
1
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.59–7.60
(d, J = 7.6 Hz, 1H), 7.25–7.31 (m, 2H), 7.16–7.20 (m, 1H), 6.85
(s, 1H), 4.16–4.23 (m, 4H), 3.39 (s, 2H), 2.46 (s, 4H), 1.56–1.60
(m, 4H), 1.44–1.45 (d, J = 4.4 Hz, 1H), 1.22–1.26 (t, J = 6.8
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 168.1, 144.5, 143.9,
141.1, 132.1, 128.5, 125.5, 124.8, 120.8, 70.8, 61.9, 57.6, 55.0,
26.1, 24.4, 13.9; IR (neat, cm−1): 3431, 2934, 1731, 1465, 1236,
1049; Anal. Calcd for C21H27NO4: C 70.56; H 7.61; N 3.92.
Found: C 70.36; H 7.67; N 3.78. HRMS (ESI) Calcd for
C21H27NO4: M + H = 358.2013. Found: 358.2033.
5al: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 34.1 mg (45%) of the indicated
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.62–7.64
1
(d, J = 7.6 Hz, 1H), 7.15–7.28 (m, 8H), 7.76–7.78 (m, 2H), 6.58
(s, 1H), 3.44–3.45 (d, J = 1.6 Hz, 2H), 4.13–4.11 (m, 4H), 3.07
(s, 3H), 1.27–1.30 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 167.8, 143.4, 143.1, 140.9, 131.3, 129.1, 128.7, 125.6,
125.0, 121.0, 116.2, 111.7, 70.4, 62.34, 52.2, 38.5, 13.9; IR
(neat, cm−1): 3453, 2949, 1756, 1467, 1055; Anal. Calcd for
C23H25NO4: C 72.80; H 6.64; N 3.69. Found: C 72.86; H 6.67;
N 3.68. HRMS (ESI) Calcd for C23H25NO44: M + H =
380.1856. Found: 380.1863.
5ah: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 52.7 mg (71%) of the indicated
1
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.59–7.60
(d, J = 7.6 Hz, 1H), 7.23–7.30 (m, 2H), 7.16–7.20 (m, 1H), 6.85
(s, 1H), 4.15–4.23 (m, 4H), 3.996–3.999 (d, J = 1.2 Hz, 2H),
2.95–2.96 (d, J = 11.6 Hz, 2H), 1.94–2.00 (m, 2H), 1.59–1.62
(d, J = 12.8 Hz, 2H), 1.27–1.38 (m, 1H), 1.18–1.28 (m, 7H),
0.90–0.93 (t, J = 5.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
168.1, 144.6, 143.9, 141.1, 132.1, 128.5, 125.4, 124.8, 120.8,
70.8, 61.8, 57.3, 54.3, 34.6, 30.8, 21.9, 13.9; IR (neat, cm−1):
3432, 2936, 1732, 1464, 1237, 1047; Anal. Calcd for
C22H29NO4: C 71.13; H 7.83; N 3.77. Found: C 71.16; H 7.87;
N 3.79. HRMS (ESI) Calcd for C22H29NO4: M + H = 372.2169.
Found: 372.2154.
5am: The reaction mixture was chromatographed using
EtOAc to afford 53.6 mg (56%) of the indicated compound as a
solid: mp 146–148 °C; 1H NMR (400 MHz, CDCl3) δ
7.59–7.61 (d, J = 7.6 Hz, 2H), 7.17–7.31 (m, 6H), 6.85 (s, 2H),
4.16–4.23 (m, 8H), 3.45 (s, 4H), 2.56 (s, 8H), 1.19–1.15 (t, J =
7.2 Hz, 12H); 13C NMR (100 MHz, CDCl3) 168.0, 144.0,
143.8, 141.0, 132.4, 128.5, 125.6, 124.9, 120.9, 70.8, 61.9,
56.8, 13.9; IR (neat, cm−1): 3435, 2939, 1738, 1465, 1238,
1047; Anal. Calcd for C36H42N2O8: C 68.55; H 6.71; N 4.44.
Found: C 68.48; H 6.67; N 4.47. HRMS (ESI) Calcd for
C36H42N2O8: M + H = 631.3014. Found: 631.3061.
5ai: The reaction mixture was chromatographed using 1 : 1
CH3OH–EtOAc to afford 53.6 mg (82%) of the indicated com-
pound as an oil: H NMR (400 MHz, CDCl3) δ 7.52–7.53 (d, J
5ba: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 53.4 mg (69%) of the indicated
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.52–7.53
1
1
= 7.6 Hz, 1H), 7.12–7.22 (m, 3H), 6.78 (s, 1H), 4.11–4.13 (m,
4H), 3.385–3.389 (d, J = 1.6 Hz, 2H), 2.52 (s, 8H), 1.19–1.15
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 167.9, 143.7, 143.6,
141.0, 132.4, 128.5, 125.6, 124.8, 120.9, 70.8, 61.9, 56.6, 55.2,
53.0, 45.9, 13.9; IR (neat, cm−1): 3435, 2939, 1738, 1465, 1238,
1056; Anal. Calcd for C21H28N2O4: C 69.72; H 7.58; N 7.52.
Found: C 69.75; H 7.62; N 7.49. HRMS (ESI) Calcd for
C21H28N2O4: M + H = 373.2122. Found: 373.2123.
(d, J = 7.6 Hz, 1H), 7.12–7.22 (m, 3H), 6.78 (s, 1H), 4.13–4.11
(m, 4H), 3.385–3.389 (d, J = 1.6 Hz, 2H), 2.52 (s, 8H),
1.19–1.15 (t, J = 7.2 Hz, 6H), 1.02–1.03 (d, J = 6.8 Hz, 12H);
13C NMR (100 MHz, CDCl3) 170.8, 137.9, 133.1, 132.1, 127.1,
126.9, 126.8, 126.0, 125.0, 61.5, 58.7, 48.0, 47.5, 20.7, 14.0; IR
(neat, cm−1): 3432, 2923, 1743, 1463, 1248, 1056; Anal. Calcd
for C23H33NO4: C 71.29; H 8.58; N 3.61. Found: C 71.36; H
8.57; N 3.68. HRMS (ESI) Calcd for C23H33NO4: M + H =
388.2482. Found: 388.2514.
5aj: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 48.7 mg (62%) of the indicated
5bb: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 36.6 mg (51%) of the indicated
1
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.52–7.53
1
(d, J = 7.6 Hz, 1H), 7.19–7.38 (m, 8H), 7.00 (s, 1H), 4.10–4.20
(m, 4H), 3.60–3.62 (d, J = 10.4 Hz, 2H), 3.48–3.52 (m, 2H),
2.24 (s, 3H), 1.18–1.21 (t, J = 7.2 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 168.1, 145.1, 143.9, 141.0, 139.5, 132.0,
128.7, 128.6, 125.5, 124.8, 120.9, 70.8, 62.3, 61.9, 56.3, 42.5,
13.9; IR (neat, cm−1): 3435, 2939, 1738, 1465, 1238, 1042;
Anal. Calcd for C24H27NO4: C 72.36; H 6.92; N 3.56. Found: C
72.38; H 7.01; N 3.58. HRMS (ESI) Calcd for C24H27NO4:
M + H = 394.2013. Found: 394.2041.
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.07–7.26
(m, 4H), 6.71 (s, 1H), 4.06–4.22 (m, 4H), 3.45 (s, 2H),
3.30–3.33 (d, J = 1.6 Hz, 2H), 2.53–2.60 (m, 4H), 1.19–1.23 (t,
J = 7.2 Hz, 6H), 0.99 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
170.6, 139.6, 132.4, 130.6, 128.5, 128.2, 127.2, 126.8, 126.1,
61.4, 57.9, 46.03, 36.2, 14.0, 13.9, 10.9; IR (neat, cm−1): 3436,
2949, 1768, 1467, 1238, 1087; Anal. Calcd for C21H29NO4: C
70.17; H 8.13; N 3.90. Found: C 70.16; H 8.17; N 3.98. HRMS
(ESI) Calcd for C21H29NO4: M + H = 360.2169. Found:
360.2197.
5ak: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 52.1 mg (64%) of the indicated
5be: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 41.4 mg (56%) of the indicated
1
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.52–7.53
1
(d, J = 7.6 Hz, 1H), 7.19–7.38 (m, 8H), 7.00 (s, 1H), 4.08–4.18
(m, 4H), 3.67–3.62 (s, 2H), 3.51–3.50 (d, J = 1.6 Hz, 2H),
2.55–2.60 (q, J = 7.2 Hz, 4H), 1.16–1.20 (t, J = 7.2 Hz, 6H),
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.07–7.16
(m, 4H), 6.04 (s, 1H), 4.06–4.20 (m, 4H), 3.46 (s, 2H), 3.39 (s,
2H), 2.49 (s, 4H), 1.75 (s, 4H), 1.20–1.24 (m, 6H); 13C NMR
3640 | Org. Biomol. Chem., 2012, 10, 3636–3641
This journal is © The Royal Society of Chemistry 2012

View Article Online
A. Lee, B. Y. Lee and Y. K. Chung, J. Organomet. Chem., 2005, 690,
1822.
(100 MHz, CDCl3) δ 170.8, 132.7, 132.5, 127.3, 127.2, 126.9,
126.8, 61.51, 59.6, 57.7, 53.8, 36.1, 23.9, 23.7, 13.9; IR (neat,
cm−1): 3454, 2980, 1743, 1455, 1239, 1043; Anal. Calcd for
C21H27NO4: C 70.56; H 7.61; N 3.92. Found: C 70.36; H 7.67;
N 3.78. HRMS (ESI) Calcd for C21H27NO4: M + H = 358.2013.
Found: 358.2037.
3 (a) J. Prough, A. Alberts, A. Deanna, J. Gilfillian, R. Huff, J. Smith and
J. Wiggins, J. Med. Chem., 1990, 33, 758; (b) S. Ikeda, N. Chatani,
Y. Kajikawa, K. Ohe and S. Murai, J. Org. Chem., 1992, 57, 2;
(c) C. Becker and M. McLaughlin, Synlett, 1991, 642; (d) Z. A. Khan
and T. Wirth, Org. Lett., 2009, 11, 229; (e) C. Zheng and R. H. Fan,
Chem. Commun., 2011, 47, 12221; (f) M. Tobisu, H. Nakai and
N. Chatani, J. Org. Chem., 2009, 74, 5471.
4 W. Miller and C. Pittman, J. Org. Chem., 1974, 39, 1955.
5 D. H. Zhang, Z. J. Liu and R. C. Larock, J. Org. Chem., 2007, 72, 251.
6 F. R. Gou, H. P. Bi, L. N. Guo, Z. H. Guan, X. Y. Liu and Y. M. Liang, J.
Org. Chem., 2008, 73, 3837.
7 (a) P. Appukkuttan, W. Dehaen, V. V. Fokin and V. Eycken, Org. Lett.,
2004, 6, 4223; (b) F. Liéby-Muller, T. Constantieux and J. Rodriguez, J.
Am. Chem. Soc., 2005, 127, 17176; (c) G. Byk and E. J. Kabahn, J.
Comb. Chem., 2004, 6, 596; (d) S. Marcaccini, D. Miguel, T. Torroba and
M. G. Valverge, J. Org. Chem., 2003, 68, 3315. For some recent reviews
of MCRs, see (e) D. J. Ramon and M. Yus, Angew. Chem., Int. Ed.,
2005, 44, 1602; (f) H. Bienaymé, C. Hulme, G. Oddon and P. Schmitt,
Chem.–Eur. J., 2000, 6, 3321; (g) A. Domling and I. Ugi, Angew. Chem.,
Int. Ed., 2000, 39, 3168; (h) J. Zhu, Eur. J. Org. Chem., 2003, 68, 1133;
(i) Y. Ohta, H. Chiba, S. Oishi, N. Fujii and H. Ohno, J. Org. Chem.,
2009, 74, 7052.
5ca: The reaction mixture was chromatographed using
10 : 1 hexanes–EtOAc to afford 53.4 mg (69%) of the indicated
1
compound as an oil: H NMR (400 MHz, CDCl3) δ 7.06–7.16
(m, 4H), 6.97 (s, 1H), 3.74 (s, 6H), 3.45 (s, 2H), 3.27–3.28 (d, J
= 1.6 Hz, 2H), 3.05–3.12 (m, 2H), 1.01–1.03 (d, J = 6.8 Hz,
12H); 13C NMR (100 MHz, CDCl3) 171.4, 137.6, 132.9, 131.9,
127.1, 127.0, 126.1, 125.5, 58.6, 48.5, 47.6, 36.5, 20.7; IR (neat,
cm−1): 3435, 2939, 1738, 1465, 1238, 1047; Anal. Calcd for
C21H29NO4: C 70.17; H 8.13; N 3.90. Found: C 70.26; H 8.17;
N 3.98. HRMS (ESI) Calcd for C21H29NO4: M+H = 360.2169.
Found: 360.2190.
8 A. Meijere, H. Nüske, M. Es-Sayed, T. Labahn, M. Schroen and S. Bräse,
Angew. Chem., Int. Ed., 1999, 38, 3669.
Acknowledgements
9 For recent reviews, see: H. Ohno, Chem. Pharm. Bull., 2005, 53, 1211.
10 H. Ohno, Y. Ohta, S. Oishi and N. Fujii, Angew. Chem., 2007, 119, 2345.
11 (a) X. H. Duan, L. N. Guo, H. P. Bi, X. Y. Liu and Y. M. Liang, Org.
Lett., 2006, 8, 5777; (b) L. N. Guo, X. H. Duan, H. P. Bi, X. Y. Liu and
Y. M. Liang, J. Org. Chem., 2007, 72, 1538; (c) L. N. Guo, X. H. Duan,
H. P. Bi, X. Y. Liu and Y. M. Liang, J. Org. Chem., 2006, 71, 3325;
(d) H. P. Bi, L. N. Guo, X. H. Duan, F. R. Gou and Y. M. Liang, Org.
Lett., 2007, 9, 397; (e) H. P. Bi, L. N. Guo, X. H. Duan, F. R. Gou and Y.
M. Liang, J. Org. Chem., 2008, 73, 4713.
12 (a) S. Searles, Y. Li, B. Nassim, M. T. R. Lopes, P. T. Tran and P. Crabbe,
J. Chem. Soc., Perkin Trans. 1, 1984, 747; (b) C. Fischer and E.
M. Carreira, Org. Lett., 2001, 3, 4319; (c) C. J. Li and C. Wei, Chem.
Commun., 2002, 268; (d) C. Wei and C. J. Li, J. Am. Chem. Soc., 2002,
124, 5638.
We thank the National Science Foundation (NSF-20732002,
NSF-20090443 and NSF-20872052) for financial support.
Notes and references
1 (a) T. Kikuchi, K. Tottori and Y. Uwahodo, PCT Int. Appl. 9621449996;
T. Kikuchi, K. Tottori and Y. Uwahodo, Chem. Abstr., 1996, 125, 204–
539; (b) W; Mederski, D. Dorsch, C. Wilm and M. Osswald, Chem.
Abstr., 1998, 129, 275905; (c) C. Senanayake, F. E. Roberts, L. Di
Michele, K. Ryan, J. Liu, L. Fredenburgh and B. Foster, Tetrahedron
Lett., 1995, 36, 3993.
2 (a) W. Spaleck, M. Antberg, V. Dolle, R. Klein, J. Rohmann and
A. Winter, New J. Chem., 1990, 14, 499; (b) P. Foster, J. C. W. Chien and
M. D. Rausch, Organometallics, 1996, 15, 2404; (c) D. H. Kim, J.
13 D. H. Zhang, E. K. Yum, Z. Liu and R. C. Larock, Org. Lett., 2005, 7,
4963.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3636–3641 | 3641