A facile Zr-mediated multicomponent approach to arylated allylic alcohols and its application to the synthesis of highly substituted indenes and spiroindenes

Article abstract of DOI:10.1039/b804888f

An efficient and one-pot procedure for the synthesis of arylated and stereodefined allylic alcohols has been achieved through zirconium-mediated multicomponent coupling reactions of alkynes, aldehydes (or ketones), and aryl iodides. The subsequent intramo

Full text of DOI:10.1039/b804888f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A facile Zr-mediated multicomponent approach to arylated allylic alcohols
and its application to the synthesis of highly substituted indenes and
spiroindenes†
Shenghai Guo and Yuanhong Liu*
Received 25th March 2008, Accepted 16th April 2008
First published as an Advance Article on the web 16th May 2008
DOI: 10.1039/b804888f
An efficient and one-pot procedure for the synthesis of arylated and stereodefined allylic alcohols has
been achieved through zirconium-mediated multicomponent coupling reactions of alkynes, aldehydes
(or ketones), and aryl iodides. The subsequent intramolecular Friedel–Crafts reactions of these allylic
alcohols catalyzed by Brønsted or Lewis acids afford highly substituted indenes and spiroindenes under
extremely mild reaction conditions. This methodology also provided a highly efficient route to the
synthesis of spiroindenepiperidines.
via zirconium-mediated cross-coupling of alkynes, aldehydes or
Introduction
ketones, and alkynyl bromides in a one-pot procedure.12 The
Substituted indene derivatives including spiroindenes are attrac-
thus formed (Z)-enynols were easily converted to dihydrofurans
or furans via gold-catalyzed cyclizations.13 Based on this work,
tive compounds as they are versatile building blocks for functional
materials,1 biologically active substances,2 and nonsteroidal anti-
we envisioned that an arylated allylic alcohol with a stereode-
inflammatory drugs.3 They can also be used as ligands by
=
fined C C double bond might be formed by the coupling of
deprotonation for metallocene complexes utilized in the catalysis
of olefin polymerization.4 Despite their wide utility, their synthetic
oxazirconacycles with aryl iodides. These allylic alcohols can be
used for the synthesis of highly substituted indenes by a catalytic
routes are fewer than those for structurally similar heterocycles
protocol (Scheme 1). Now we’d like to report the details of these
such as benzofurans and indoles. The most important routes for
transformations.
the construction of indenes include the reduction/dehydration
of indanones,5 the cyclization of phenyl-substituted alkenes6 or
phenyl-substituted allylic alcohols,7 the ring-expansion of sub-
stituted cyclopropenes,8 metal-catalyzed protcols9 etc. Although
these methods are effective for the synthesis of indenes, they
have certain drawbacks, more or less, for example, the strong
acid medium or a stoichiometric amount of a Lewis acid that
is sometimes required, limited methods for the preparation of
starting materials, the moderate flexibility for the introduction
of different substitutents onto the indene rings. On the other
Scheme 1
hand, synthetic organic transformations based on a wide variety
of zirconacycles have been extensively developed in recent years
due to the following advantages of zirconacycles:10 (i) they are
easily prepared by reductive coupling of unsaturated compounds
such as alkynes, alkenes, nitriles, or ketones on a zirconocene
Results and discussion
equivalent, (ii) they are relatively stable under normal conditions,
Alkynes undergo selective intermolecular coupling with aldehydes
(iii) they have been proved as efficient precursors for a wide
or ketones using zirconocenes.14 Recently, we have developed
range of selective transformation reactions. An elegant synthesis of
an improved procedure for zirconium-mediated alkyne–aldehyde
multi-substituted indenes has been reported by Xi and Takahashi
coupling reactions under the “preactivated” conditions.12b The
et al11 through hydrolysis of oxazirconacycles derived from the
stereodefined allylic alcohols or 3-iodinated allylic alcohols were
coupling reactions of alkyl alkynes with aryl methyl ketone or
selectively formed via protonolysis or iodonolysis of the cor-
responding five-membered oxazirconacycles. The methodology
has also been successfully applied to the synthesis (Z)-enynols
through hydrolysis of zirconacyclopentadienes. We recently re-
ported an efficient synthetic approach to stereodefined (Z)-enynols
through three different component coupling reactions of alkynes,
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai,
200032, People’s Republic of China. E-mail: yhliu@mail.sioc.ac.cn
† Electronic supplementary information (ESI) available: Spectroscopic
characterization of 2b–i, 4b–4f, 5b–j, 8 and 9. Copies of 1H and 13C NMR
spectra of all new compounds. See DOI: 10.1039/b804888f
aldehydes and alkynyl bromides in a one-pot procedure. The
coupling reaction of aryl halides with organometals represents one
of the most powerful methods for C–C bond formation. Although
the coupling reactions of aryl iodides with various organozir-
conocenes such as vinyl zirconocenes, zirconacyclopentenes or
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zirconacyclopentadienes were known,15 there is no report for the
coupling of aryl iodides with oxazirconacycles. Here we found that
treatment of oxazirconacycle 1a (R1 = Pr, R2 = Ph) derived from
alkyne–aldehyde coupling with 1.3 equiv of CuCl and 1.2 equiv of
p-MeOC6H4I in the presence of 5 mol% Pd(PPh3)4 at 50 ◦C for 3 h
afforded arylated product 2a in 43% yield after hydrolysis (Table 1,
entry 1). The use of CuBr (1.3 equiv) afforded a similar yield (44%)
of 2a, however, in the case of CuI, only a low yield of 31% was
obtained. It was suggested that the first step of this reaction is
transmetalation of a Zr–C(sp2) bond to a Cu–C(sp2) bond to form
an alkenyl copper species, which is followed by coupling with
an arylpalladium intermediate generated from ArI and a Pd(0)
catalyst to form the desired arylated products.15 We next examined
the coupling reactions of oxazirconacyclopentenes with various
aromatic iodides. As shown in Table 1, alkyl, phenyl, and 2-thienyl-
substituted alkynes and alkyl, aryl aldehydes are all compatible
with coupling conditions, the corresponding allylic alcohols
were formed in 38–70% yields. Aryl iodides bearing electron-
donating or electron-withdrawing substituents could be used.
For example, the reaction between zirconacycles derived from
Table 1 Synthesis of multi-substituted allylic alcohols through oxazirconacycles
1
1
R2CHO
PhCHO
ArI
Product
Yield (%)a
43
≡
Entry
1
R C CR
≡
PrC CPr
p-MeOC6H4l
61b
55
43
62c
70
61
≡
2
3
4
5
6
7
PrC CPr
PhCHO
Phl
≡
PrC CPr
PhCHO
p-ClCC6H4l
p-MeC6H4l
Phl
≡
PrC CPr
PhCHO
≡
PhC CPh
PrCHO
≡
PhC CPh
PrCHO
p-MeOC6H4l
p-MeC6H4l
≡
PhC CPh
p-ClC6H4CHO
≡
≡
8
9
PhC CPh
Ph–C C–C6H4CHO
p-MeC6H4l
38
68
p-MeC6H4CHO
p-MeOC6H4l
a Isolated yields. b Containing ca. 3% 2E-1-phenyl-2-propyl-hex-2-en-1-ol, which could not be separated from the main product. c Containing ca. 8%
1E-1,2-diphenyl-hex-1-en-3-ol, which could not be separated from the main product. d Thi is a 2-thienyl group.
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bis(2-thienyl)acetylene and p-MeC6H4CHO with p-MeOC6H4I
resulted in the formation of 2i in 68% yield (Table 1, entry 9).
Next, we examined the coupling reactions of aryl iodides with
oxazirconacyclopentenes 3 derived from alkyne–ketone coupling
reactions, which may be used for the preparation of stereodefined
and fully substituted allylic alcohols. So far there are few methods
for the synthesis of fully substituted allylic alcohols. Initially, we
carried out the reaction under the same conditions employed
for the coupling of zirconacycles 1 with aryl iodides, however,
no expected products were observed. We envisioned that a facile
coordination of the magnesium salt produced in situ during the
exchange reaction of Cp2ZrCl2 and EtMgBr with the oxygen moi-
ety might occur, which may further increase the steric hindrance
around the reactive metal center. To our delight, it was found that
the desired allylic alcohols 4 could be formed through addition
of 0.4 mL 1,4-dioxane (to remove the magnesium salt). The
representative results are shown in Table 2. As shown in Table 2,
cyclic or acyclic ketones are all compatible under the controlled
reaction conditions, the corresponding fully substituted allylic
alcohols 4a–f were formed in 23–62% yields. When cyclohexenone
was employed, the coupling reaction with iodobenzene proceeded
smoothly to afford allylic alcohol 4d in 49% yield, while the double
bond in the cyclic ring was well tolerated during the reaction
(Table 2, entry 4).
(p-MeO, p-Me) and those without a substituent on the aromatic
ring (Table 4, entries 1–2, 4). However, when 2c substituted with
p-ClC6H4 was employed, the cyclization reaction was not clean
using TSOH·H2O as the catalyst; the desired product 5c was
obtained in 61% yield. The yield can be improved to 80% in the
presence of 2 mol% AuCl3 (Table 4, entry 3). The substituent effect
on the alcoholic carbon of allylic alcohols was also investigated.
Aryl, alkyl-substituted or phenyl, methyl-disubstituted substrates
were all compatible with cyclization conditions, and high yields of
the corresponding indenes were obtained in each case (Table 4,
entries 1–7). It should be noted that in the case of 2i, a 4H-
cyclopenta[b]thiophene derivative 5g was selectively obtained.
This result indicated that the cyclization can be easily controlled
by the electronic effects of the end groups, thus a highly reactive
thiophene ring under electrophilic attack would undergo Friedel–
Crafts cyclization more preferentially than an aryl ring (Table 4,
entry 7 and Scheme 2). Interestingly, this method could also be
used for the synthesis of spiroindenes 5h–j with high yields (Table 4,
entries 8–10).
With multi-substituted allylic alcohols in hand, we were in-
terested in exploring the feasibility of using 2 and 4 in indene
formation reactions. We began our investigation with allylic
alcohol 2a through a Friedel–Crafts cyclization. As we know,
the main drawback of classical Friedel–Crafts reactions is that
a strong acid medium or a stoichiometric amount of a Lewis acid
is sometimes required, therefore the method is not compatible
with sensitive functional groups. Recently, gold salt has emerged
as a useful catalyst for Friedel–Crafts reactions.16 We have also
reported a gold-catalyzed direct amination of allylic alcohols via
the formation of an allylic cation intermediate.17 We first examined
the reactivity of 2a in the presence of various gold catalysts.
Treatment of 2a with 5 mol% AuCl3 in CH2Cl2 or CH3CN at
room temperature for 1 h afforded the corresponding indene 5a
in 79% and 89% yields, respectively (Table 3, entries 1–2). AuCl
or Sc(OTf)3 worked well to generate 5a in excellent yields of
90% and 91%, respectively (Table 3, entries 4–5). Further studies
revealed that a Brønsted acid of TSOH·H2O18 showed excellent
catalytic activities to afford 92% yield of the desired product within
one hour (Table 3, entry 6).
Scheme 2
Compounds containing spiropiperdine backbones have at-
tracted much attention in pharmaceutical research due to their
significant biological activities.19 For example, they can be used
as an amine moiety of highly active chemokine CCR2 receptor
antagonists.20 The synthetic routes for these compounds usually
involve multistep procedures with low overall yields.19–20 As shown
in Scheme 3, spiroindenepiperidine derivatives could be efficiently
prepared using our methods. The precursor 8 for ring-closure
could be conveniently constructed through multicomponent cou-
pling of 4-octyne, tert-butyl 4-oxopiperidine-1-carboxylate and 4-
iodotoluene in 58% yield. Cyclization of 8 to spiropiperdine 9 was
achieved in 85% yield using 2% AuCl3 as the catalyst.
We chose TSOH·H2O as the catalyst for subsequent experi-
ments. The representative results are summarized in Table 4. The
electronic effect of substitution on the aromatic ring at C-3 of
allylic alcohols 2 was examined first. It was found that there
were no significant differences in the reaction times or the yields
between the allylic alcohols bearing an electron-donating group
Conclusion
In summary, we have succeeded in developing an efficient,
general, and one-pot procedure for the synthesis of arylated
and stereodefined allylic alcohols through zirconium-mediated
Scheme 3
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Table 2 Synthesis of fully substituted allylic alcohols through oxazirconacycles
1
1
R2R3CO
ArI
Product
Yield (%)a
62
≡
Entry
1
R C CR
≡
PhC CPh
p-MeC6H4l
≡
2
3
4
5
6
PrC CPr
p-MeC6H4l
Phl
62
61
49
23
45
≡
PhC CPh
≡
PhC CPh
Phl
≡
PrC CPr
p-MeC6H4l
Phl
≡
PhC CPh
PhCOMe
a Isolated yields.
Table 3 Optimization studies for the cyclization reaction of 2a
denes and spiroindenes under extremely mild reaction conditions.
This methodology also provided a highly efficient route to the
synthesis of spiroindenepiperidine derivatives. Further studies to
extend the scope of the synthetic utility for indene formations are
in progress in our laboratory.
Experimental
Entry
Catalyst (mol%)
Solvent
Yield (%)a
General methods
1
2
3
4
5
6
7
AuCl3 (5%)
AuCl3 (5%)
AuCl3 (2%)
AuCl (5%)
Sc(OTf)3 (5%)
TSOH·H2O (5%)
20% HClb
CH2Cl2
79
89
90
90
91
92
CH3CN
CH3CN
CH3CN
ClCH2CH2Cl
CH3CN
THF
All reactions using zirconocenes were carried out using standard
Schlenk techniques under nitrogen. THF was distilled from
sodium–benzophenone. CH3CN was distilled from CaH2. Unless
noted, all commercial reagents were used without further purifi-
cation. Zirconocene dichloride, aldehydes, ketones, and alkynes
were used as purchased. Benzaldehyde and butyroaldehyde were
distilled prior to use. Ethylmagnesium bromide (1.0 M solution
in THF) was used as purchased. Oxazirconacycles 112b and 314f
were prepared according to previously published procedures.
1H, and 13C NMR spectra were recorded on a Varian XL-
300 MHz spectrometer at 300, and 75.4 MHz, respectively,
and in CDCl3 (containing 0.03% TMS) solutions. 1H NMR
spectra were recorded with tetramethylsilane (d = 0.00 ppm) as
c
—
a Isolated yield. b 20% HCl solution was used. c The reaction was not
clean, the major products are the mixtures of butadienes derived from
dehydration of 2a.
multicomponent coupling reactions of alkynes, aldehydes/
ketones, and aryl iodides. The intramolecular Friedel–Crafts
reactions of a wide variety of multi-substituted allylic alcohols
catalyzed by Brønsted or Lewis acids afford highly substituted in-
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Table 4 Synthesis of substituted indenes and spiroindenes via the cyclization reaction of 2 or 4
Entry
1
Substrate
Product
Yield (%)a
92
2
3
4
5
86
80b
99
97
6
7
94
85
8
89
89
85
9
10
a Isolated yield. b AuCl3(2 mol%) was used as catalyst. c Thi is a 2-thienyl group.
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internal reference; 13C NMR spectra were recorded with CDCl3
(d = 77.00 ppm) as internal reference. 2D NMR experiments of
HMQC, gCOSY and HMBC spectra were recorded in CDCl3
solutions on a Varian XL-300 MHz spectrometer. Mass spectra
and high-resolution mass spectra were obtained by using a Waters
Micromass GCT mass spectrometer. Elemental analyses were
performed on an Italian Carlo-Erba 1106 analyzer.
solvent was evaporated in vacuo and the residue was purified
by chromatography on silica-gel to afford the arylated allylic
alcohols 4.
1-(1Z-1,2-Diphenyl-2-p-tolylvinyl)cyclohexanol (4a). Column
chromatography on silica-gel (petroleum ether–ethyl acetate = 20 :
1–15 : 1) afforded the title product as light yellow oil in 62% isolated
yield. 1H NMR (CDCl3, Me4Si) d 0.84–0.95 (m, 1H), 1.37–1.56 (m,
8H), 1.82 (d, J = 8.4 Hz, 2H), 2.30 (s, 3H), 6.79–7.32 (m, 14H);
13C NMR (CDCl3, Me4Si) d 21.08, 21.34, 24.98, 37.82, 75.56,
125.25, 125.85, 126.93, 127.31, 128.25, 128.76, 129.32, 130.84,
136.49, 139.82, 140.15, 140.74, 144.14, 148.35. HRMS (EI) calcd
for C27H28O [M]+: 368.2140, found 368.2135.
A general procedure for the preparation of arylated allylic alcohols
via the palladium-catalyzed coupling reactions of oxazircon-
acyclopentenes derived from alkyne–aldehyde coupling with aryl
iodides
To a solution of Cp2ZrCl2 (0.365 g, 1.25 mmol) in THF (5 mL) was
added EtMgBr (1.0 M THF solution, 2.5 mmol) at −50 ◦C. After
stirring for 1 h at the same temperature, alkyne (1 mmol) was
A general procedure for the preparation of indenes and spiroindenes
via TSOH·H2O or AuCl3-catalyzed cyclization of allylic alcohols
◦
added and the reaction mixture was warmed to 0 C and stirred
A solution of AuCl3 in MeCN (0.05 M) was prepared. The
reactions were carried out on a 0.25–0.4 mmol scale. To a 0.1 M
solution of allylic alcohol in CH3CN was added TSOH·H2O (p-
toluenesulfonic acid monohydrate, 5 mol%) or AuCl3 (2 mol%)
under a nitrogen atmosphere. The resulting solution was stirred at
room temperature until the reaction was completed as monitored
by TLC (1 h). The solvent was evaporated in vacuo and the residue
was purified by chromatography on silica-gel to afford the indene
products.
for 3 h. The thus formed zirconacyclopentene was heated up to
50 ◦C for a few minutes (ca. 5 min), followed by slow addition of
the corresponding aldehyde (1.2 mmol) at the same temperature.
After stirring for 1 h, CuCl (1.3 mmol), aryl iodide (1.2 mmol),
and Pd(PPh3)4 (5 mol%) were added successively. The reaction
mixture was stirred at 50 ◦C for 3 h, then quenched with 3 N HCl
solution (usually, within 2 minutes) and extracted with diethyl
ether. The extract was washed with NaHCO3, brine, and dried
over Na2SO4. The solvent was evaporated in vacuo and the residue
was purified by chromatography on silica-gel to afford the arylated
allylic alcohols 2.
6-Methoxy-1-phenyl-2,3-dipropyl-1H-indene
(5a). Column
chromatography on silica-gel (petroleum ether–ethyl acetate =
30 : 1) afforded the title product as yellow oil in 92% isolated
yield. 1H NMR (CDCl3, Me4Si) d 0.90 (t, J = 7.2 Hz, 3H),
1.04 (t, J = 7.2 Hz, 3H), 1.30–1.76 (m, 4H), 1.95–2.04 (m, 1H),
2.35–2.45 (m, 1H), 2.57 (t, J = 7.2 Hz, 2H), 3.75 (s, 3H), 4.41
(s, 1H), 6.76–6.85 (m, 2H), 7.04 (d, J = 6.9 Hz, 2H), 7.20–7.31
(m, 4H); 13C NMR (CDCl3, Me4Si) d 14.13, 14.28, 22.20, 23.08,
27.45, 28.68, 55.45, 56.69, 110.39, 111.68, 118.76, 126.47, 128.22,
128.55, 137.14, 138.82, 140.67, 144.85, 150.04, 157.50. HRMS
(EI) calcd for C22H26O [M]+: 306.1984, found 306.1980.
2Z-3-(4-Methoxyphenyl)-1-phenyl-2-propylhex-2-en-1-ol (2a).
Column chromatography on silica-gel (petroleum ether–ethyl
acetate = 20 : 1–10 : 1) afforded the title product as yellow oil in
43% isolated yield. 1H NMR (CDCl3, Me4Si) d 0.80 (t, J = 7.2 Hz,
3H), 0.88 (t, J = 7.2 Hz, 3H), 0.92–1.03 (m, 1H), 1.22–1.44 (m,
3H), 1.79 (s, 1H), 1.88–1.98 (m, 1H), 2.03–2.16 (m, 1H), 2.30–
2.36 (m, 2H), 3.78 (s, 3H), 5.38 (s, 1H), 6.86 (d, J = 8.4 Hz, 2H),
7.11 (d, J = 8.4 Hz, 2H), 7.17–7.37 (m, 5H); 13C NMR (CDCl3,
Me4Si) d 14.10, 14.82, 21.05, 24.28, 29.78, 36.50, 55.12, 73.71,
113.50, 125.64, 126.57, 127.86, 129.62, 134.54, 137.18, 140.53,
143.14, 158.04. HRMS (EI) calcd for C22H28O2 [M]+: 324.2089,
found 324.2086.
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant No. 20672133, 20732008), Chinese Academy of Science,
Science and Technology Commission of Shanghai Municipality
(Grant No. 07JC14063) and the Major State Basic Research
Development Program (Grant No. 2006CB806105) for financial
support.
A general procedure for the preparation of arylated allylic alcohols
via the palladium-catalyzed coupling reactions of oxazircon-
acyclopentenes derived from alkyne–ketone coupling with aryl
iodides
To a solution of Cp2ZrCl2 (0.365 g, 1.25 mmol) in THF (5 mL) was
added EtMgBr (1.0 M THF solution, 2.5 mmol) at −50 ◦C. After
stirring for 1 h at the same temperature, alkyne (1 mmol) was
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◦
added and the reaction mixture was warmed to 0 C and stirred
for 3 h. To this reaction mixture containing zirconacyclopentene
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CuCl (1.3 mmol), aromatic iodide (1.2 mmol), and Pd(PPh3)4
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stirred at 50 ◦C until the reaction was completed as monitored
by TLC or GC. Then the mixture was quenched with saturated
NH4Cl solution for 20 min and extracted with ether. The extract
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