A convenient new method to construct 1-alkynyl cyclopropanol and its synthetic application to prepare trisubstituted dienones

Article abstract of DOI:10.1016/j.tetlet.2008.03.041

A new synthetic route was developed via the nucleophilic addition of lithium alkynylide to 1-arylsulfonyl cyclopropanol 1 to afford 1-alkynyl cyclopropanol, which then reacted with aryl iodide to construct trisubstituted cross-conjugated dienones through

Full text of DOI:10.1016/j.tetlet.2008.03.041

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3124–3128
A convenient new method to construct 1-alkynyl cyclopropanol
and its synthetic application to prepare trisubstituted dienones
Yan An, Jie Liu, Hai-Ying Jiang, Yahui Wang, Zili Chen *
Department of Chemistry, Renmin University of China, Beijing 100872, China
Received 16 December 2007; revised 5 March 2008; accepted 7 March 2008
Available online 18 March 2008
Abstract
A new synthetic route was developed via the nucleophilic addition of lithium alkynylide to 1-arylsulfonyl cyclopropanol 1 to afford
1-alkynyl cyclopropanol, which then reacted with aryl iodide to construct trisubstituted cross-conjugated dienones through a palladium-
catalyzed process, where the key steps included the regioselective carbopalladation of arylpalladium(II) intermediate across the triple
bond of 1-alkynyl cyclopropanol and the ring opening of the cyclopropyl group.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 1-Alkynyl cyclopropanol; Cyclopropanone surrogate; Dienone; Palladium-catalyzed process
The development of cyclopropanol chemistry in the past
decades has been quite fruitful. These compounds occupied
their own niche in synthetic practice as useful intermediates
in organic synthesis,1–7 and as substances possessing
important kinds of biological and pharmaceutical activi-
ties.8–10 Among a great variety of cyclopropanol deriva-
tives, 1-alkynyl substituted cyclopropanols are of great
interest due to the combination of highly reactive triple
bond and three-membered ring in one molecule.
X
O
Mg
Mg
R
O
O
+
Co2(CO)8
B
R
C
5
3
R
OTMS
O
D
A
HO
R
R
2
4
6
X
+
Scheme 1 gives an overview of the existing routes to con-
struct such compounds and some of its synthetic applica-
tions. The classical route to prepare these compounds is
the Simmon-Smith reaction (Route A, Scheme 1) of the
alkynyl enol ether 4,11 in which the tedious preparation
of the ether reactant is a disadvantage. Another route is
the reaction of arylacetylenic magnesium bromides with
O
R'I
O
S
ΗΟ
Li
Ar
O
R
R'
R'
1
7
Scheme 1. Synthetic routes to construct 1-alkynyl cyclopropanol and
some of its synthetic applications.
iodomagnesium 1-ethoxycyclopropylate
3 (Route B,
Scheme 1),12 where long reaction time under a reflux
condition is needed.
yl cyclopropanol 1 to construct 1-alkynyl cyclopropanol,
followed by a reaction with aryl iodide through a palla-
dium-catalyzed process to give trisubstituted cross-conju-
gated dienones. Unlike the well-known chemistry of
alkynyl cyclopropanol’s ring expansion to form a four-
(Route D, Scheme 1)13 or a five-(Route C, Scheme 1)11
membered ring, there has been no precedent, to the best
In this Letter, a new synthetic route is developed via the
nucleophilic addition of lithium alkynylide to 1-arylsulfon-
*
Corresponding author. Tel./fax: +86 10 62516660.
E-mail address: zilichen@ruc.edu.cn (Z. Chen).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.041

Y. An et al. / Tetrahedron Letters 49 (2008) 3124–3128
3125
Table 1
X
+
The reaction of 1 with lithium alkynilidea
R2
N
Ph
AuCl3
H2O
O
S
R1
R2
Yieldc (%)
+
Ar
ΗΟ
N
Entry
Alkyne 5
Product 2
R1
H
O
1a X=H
8
1b X=Me
1
2
87
78b
HO
Scheme 2. The coupling reaction of 1, phenylacetylene, and disubstituted
amine.
2a
2b
2c
of our knowledge, for its rearrangement to construct tri-
substituted dienone derivatives.
3
4
85
83b
HO
HO
In the previous studies, we documented well the synthe-
sis of 1-arylsulfonyl cyclopropanol 1,14 and its application
in preparing 1-alkynyl cyclopropylamine (Scheme 2). Com-
pound 1 acts as a cyclopropanone surrogate based on the
equilibrium between 1 and cyclopropanone, upon loss of
a benzenesulfinic acid. As the continued work of the previ-
ous study, herein we describe the reactions of compound 1
with different metal alkynylides in order to study the reac-
tivity of compound 1 and extend its synthetic utilities.
The reaction of compound 1a and phenylacetylene was
chosen as the model system for our initial investigation.
In preliminary studies, compound 1a underwent reaction
with lithium phenyl ethynilide at low temperature, provid-
ing 1-phenylethynyl cyclopropanol 2a in high yield
(Scheme 3). In contrast, phenyl ethynyl magnesium bro-
mide afforded the desired product only in 35% yield,
whereas the zinc alkynilide gave no product at all.
As shown in Table 1, a range of 1-alkynyl cyclopropa-
nols were readily obtained from the reaction of cycloprop-
anone equivalent 1a with the corresponding lithium
alkynilide.15 Both aromatic and aliphatic terminal alkynes
were able to undergo the nucleophilic addition to provide
the desired alkynyl cyclopropanols. Electron-rich aromatic
(Table 1, entries 3 and 5) and heteroaromatic alkynes
(Table 1, entry 9) displayed relatively high reactivity and
gave higher conversion. However, aryl alkynes (Table 1,
entries 6 and 7) substituted with electron-withdrawing
groups, such as chloro and bromo, exhibited relatively
low reactivity. The reaction of electron deficient 2-pyridinyl
ethyne (Table 1, entry 8) afforded the product in the lowest
yield. Aliphatic alkynes such as 3-phenyl-1-propyne and n-
hexyne also worked effectively in this reaction (Table 1,
entries 11 and 12). When 1-toluene sulfonyl cyclopropanol
O
O
5
6
7
8
90
76
75
44
Br
Br
HO
HO
2d
2e
Cl
Cl
N
HO
HO
N
S
2f
S
9
65
83
62
2g
10
HO
HO
2h
11
2i
a
Reaction conditions: unless noted, all reactions were carried out under
a nitrogen atmosphere using 1 equiv of 1a, 2.6 equiv of alkyne and
2.5 equiv of n-BuLi at À30 °C for 3 h.
b
1-(Toluenesulfonyl) cyclopropanol 1b as a substrate.
c
Isolated yield.
M
O
condition
1b, instead of 1a, was employed as an electrophile in this
reaction, the corresponding products were also obtained
in similar yields (Table 1, entries 2 and 4).
ΗΟ
S
O
+
HO
THF
1a
2a
We then explored the reaction of 1-phenylethynyl cyclo-
propanol 2a with iodobenzene by heating a mixture of 2a
(1 equiv), iodobenzene (2 equiv), Pd(OAc)2 (5 mol %),
PPh3 (10 mol %), NaOAc (2 equiv), and n-Bu4NCl
(1 equiv) in 5 mL of DMF for 6.5 h at 80 °C, compound
1,1,5-triphenylpenta-1,4-dien-3-one 7a was obtained in
30% yield (Table 1, entry 1).16 The effect of different
1, M = Li
2, M = Mg
3, M = Zn
86% a
35% b
0%
c
Scheme 3. The reaction of 1a with metal phenyl ethynilide. Reagents and
conditions: unless noted, all reactions were carried out under N2 with
1 equiv of 1a, 2 equiv of phenyl acetylene and 2.2 equiv of base in THF.
an-BuLi, À30 °C; bEtMgBr, À30 °C; Et2Zn, 0 °C.
c

3126
Y. An et al. / Tetrahedron Letters 49 (2008) 3124–3128
Table 2
The reaction of 2a, iodobenzene catalyzed by Pd(0)a
O
PhI
+
I
HO
Pd(0)
2a
7a
Entry
6 (equiv)
2 equiv
Base/additive
Temperature (°C/time)
Yieldb (%)
1
2
3
4
5
6
7
8
9
NaOAc (2 equiv)/nBu4NCl (1 equiv)
NaOAc (2 equiv)
Na2CO3 (2 equiv)
Cs2CO3 (2 equiv)
NaHCO3 (2 equiv)
K2CO3 (2 equiv)
Et3N (2.8 equiv)
No
K2CO3 (1 equiv)
K2CO3 (4 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
80/6.5 h
80/3 h
80/12 h
80/1 h
30
54
35
0
18
56
0
12c
47
31
33
44
70
45
53
80/2 h
80/40 min
80/12 h
80/12 h
80/1 h
80/30 min
40/6 h
10
11
12
13
14
15
a
60/3 h
100/20 min
120/16 min
100/30 min
2.5 equiv
Unless noted, all the reactions were carried out at 0.2 mmol scale with 1 equiv of 2a, 2–2.5 equiv of iodobenzene in DMF (4 mL).
Isolated yields.
A ring-opening product was obtained.17
b
c
reaction conditions on the yield of the dienone product was
iodides.18 As shown in Table 3, the reaction of iodo-
benzene, and electron-rich phenyl iodide with conjugated
1-alkynyl cyclopropanols such as 2a, 2b, or 2c gave positive
results (Table 3, entries 1–6). Among these, the best yield
was obtained in the reaction of 4-methyl phenyl iodide with
2b (Table 3, entry 5). However, coupling of nonconjugated
1-(4-phenylbut-1-ynyl) cyclopropanol 2h with iodobenzene
provided 7g in a relative low yield (Table 3, entry 7).
In consideration of the two double bonds existing in
these trisubstituted dienone derivatives, it was notable that
only one isomer was obtained in the reaction. The exami-
nation of the two alkene’s configuration was based on their
spectral data. E configuration of the first double bond (C1–
C2), which is on the right side to the carbonyl group, as
exemplified in compound 7g (Scheme 4), can be readily
determined from the high coupling constant of the two pro-
investigated. Other palladium catalysts and phosphine
ligands, such as Pd(OAc)2/dppe, Pd(Ph3P)4, or Pd(OAc)2/
PCy3, were found to be inactive in this transformation.
Removal of the chloride source (n-Bu4NCl) reduced the
reaction time and improved the yield somewhat (Table 2,
entry 2).
The choice of a base is critical to the reaction. In base-
screening experiments, K2CO3 was found to be superior
to other bases, which gave 56% yield of the desired dienone
in 40 min (Table 2, entry 6). Na2CO3 and NaHCO3 showed
low activity in the reaction (Table 2, entries 3 and 5);
Cs2CO3 and organic base, such as Et3N, and pyridine affor-
ded no product (Table 2, entries 4 and 7). Without any
base, a ring-opening product was obtained in low yield
(12% yield) (Table 2, entry 8).17 The amount of the base
was then examined. When 1 equiv K2CO3 was employed,
7a was obtained in 47% yield (Table 2, entry 9). Increasing
the amount of K2CO3 to 4 equiv was proved fruitless
(Table 2, entry 10).
Optimization of reaction temperature and the amount of
Pd(0) catalyst identified a set of best conditions (2a
(1 equiv), iodobenzene (2 equiv), Pd(OAc)2 (5 mol %),
PPh3 (10 mol %), K2CO3 (2 equiv), in 4 mL of DMF for
20 min at 100 °C, Table 2, entry 13) to give the desired
product in 70% yield. Increasing the amount of iodo-
benzene (2.5 equiv) slightly lowered the yield (Table 2,
entry 15).
1
tons attached to it (JH1ÀH2 = 16 Hz). H–1H Noesy spec-
trum of compound 7g was then studied to investigate the
configuration of its second double bond (C4–C5). There
was a strong NOE correlation that existed between the pro-
tons on C(4) and C(6) at chemical shifts 6.74 and 3.42 ppm,
indicating that these protons were in a ‘syn’ relationship
(on the same side of the alkene). Thus, the bis-alkenes sys-
tem in dienone 7g was proved to be (1E,4Z)-configuration,
from which the exact structures of all the other dienone
derivatives can be deduced.
A plausible mechanism for this reaction was provided
(Scheme 5). The arylpalladium(II) intermediate, generated
by oxidative addition of the aryl iodide to a palladium(0)
species, undertook a regioselective carbopalladation across
the triple bond of compound 2 to give alkenyl palladium
With this standard procedure in hand, we explored the
scope and limitations of the reaction by examining other
alkynyl cyclopropanols, and different substituted aryl

Y. An et al. / Tetrahedron Letters 49 (2008) 3124–3128
3127
Table 3
JH1-H2 = 16 Hz
H1
Coupling reaction of 1-alkynyl cyclopropanol 2, Aryl iodide catalyzed by
Pd(0)a
O
Entry Aryl iodide
2
Product
Yieldb
(%)
H6 H6
H4
H2
3.42ppm
6.74ppm
NOE correlation
O
1
2
PhI
2a
70
63
Scheme 4. Determination of the configuration of the two alkenes in
compound 7g.
7a
OH
R
OH
R
ArPdI
ring
R
OH
Ar
p-CH3PhI
2a
O
carbopalladation
opening
Ar
PdILn
PdILn
2
A
B
7b
O
O
OMe
Ar
O
β-elimination
ArPdI
1
R
R
Ar
Pd
4
2
R
Ar
D
Ar
3
p-MeOPhI
2a
53
O
ILn
C
Scheme 5. A plausible mechanism for the palladium induced reaction of
compound 2 with aryl iodide.
7c
OMe
reacted with another arylpalladium(II) species in Heck
condition to afford the final product. The complexation
of Pd(II) with the alkene bond in intermediates B and C,
as illustrated in Scheme 5, led to the formation of a ‘syn’
relationship between H(4) and group R.
In summary, a novel synthetic route was developed via
the nucleophilic addition of lithium alkynylide to 1-aryl-
sulfonyl cyclopropanol 1 to afford a range of 1-alkynyl
cyclopropanols, which was then used to react with aryl
iodide to construct trisubstituted cross-conjugated dienon-
es through a palladium-catalyzed process. Further study on
the applications of compound 1 either as a cyclopropanone
equivalent or as a new synthetic subunit is in progress.
O
4
5
PhI
2b
56
79
7d
p-CH3PhI
2b
O
7e
O
6
7
PhI
PhI
2c
51c
Acknowledgments
7f
MeO
Support of this work by a starter grant from Renmin
University of China and a grant from the National Sciences
Foundation of China (No. 20502033) is gratefully
acknowledged.
O
2h
27d
7g
Unless noted, all the reactions were carried out at 0.2 mmol scale with
References and notes
a
1 equiv of 1-alkynyl cyclopropanol 2, 2 equiv of aryl iodide, 5 mol % of
Pd(OAc)2, 10 mol % of PPh3, and 2 equiv of K2CO3 in 4 mL DMF at
100 °C.
1. De Puy, C. H. Acc. Chem. Res. 1968, 1, 33.
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M.; Robson, M. J. Angew. Chem., Int. Ed. Engl. 1975, 14, 473.
b
Isolated yields.
Reaction temperature is 60 °C.
c
4. Salaun, J. Top. Curr. Chem. 1988, 144, 1.
¨
d
Reaction temperature is 80 °C.
5. Salaun, J. In The Chemistry of the Cyclopropyl Group; Rappoport, Z.,
¨
Ed.; Wiley: London, 1987; p 809.
6. Salaun, J. Chem. Rev. 1989, 89, 1247.
7. Kulinkovich, O. G. Pol. J. Chem. 1997, 71, 849.
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Rappoport, Z., Ed.; Wiley: London, 1987; p 959.
¨
intermediate A. Upon ring opening of the cyclopropyl
group and b-hydrogen elimination, intermediate A was
transformed into the disubstituted dienone D, which then

3128
Y. An et al. / Tetrahedron Letters 49 (2008) 3124–3128
17. The product in this condition is
9. Salaun, J.; Baird, M. S. Curr. Med. Chem. 1995, 2, 511.
¨
O
10. Salaun, J. Top. Curr. Chem. 2000, 207, 1.
¨
11. Iwasawa, N.; Matsuo, T.; Iwamoto, M.; Ikeno, T. J. Am. Chem. Soc.
1998, 120, 3903.
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¨
Chem. 1980, 45, 4129.
13. Markham, J. P.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 9708.
18. General procedure for Pd(0) catalyzed reaction of 1-alkynyl cyclopro-
panol 2, Aryl iodide to provide trisubstituted dienone derivatives: Aryl
iodide (0.4 mmol, 2 equiv), 1-alkynyl cyclopropanol 2 (0.2 mmol,
1 equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), K2CO3 (2 equiv), and
4 mL of DMF were placed in a 20 mL reaction vial, which was heated
in an oil bath at a given temperature with TLC monitoring. After the
reaction was completed, the reaction mixture was cooled, diluted with
EtOAc, washed with saturated NH4Cl, dried over anhydrous Na2SO4,
and filtered. The solvent was evaporated under reduced pressure and
the product was isolated by chromatography (PE/EA = 40/1). The
spectral data of (E)-1,1,5-triphenylpenta-1,4-dien-3-one 7a: Obtained
as a yellow solid in 70% yield (Rf = 0.2, PE/AcOEt = 30/1). 1H NMR
(CDCl3, Me4Si) d 6.42 (d, J = 16 Hz, 1H), 6.77 (s, 1H), 7.25–7.31 (m,
7H), 7.37–7.41 (m, 8H), 7.50 (d, J = 16 Hz, 1H). 13C NMR (CDCl3) d
126.5, 127.5, 128.1, 128.3, 128.4, 128.5, 128.6, 128.7, 128.9, 129.4,
130.0, 130.2, 135.0, 139.1, 141.1, 141.8, 154.2, 191.4. MS m/z (%) 310
(M+, 75), 309 (M+À1, 100), 191 (16), 178 (31), 165 (6), 152 (8), 131
(13), 103 (22), 77 (24), 51 (10). HRMS (EI) calcd for C23H18O:
310.1358; found: 310.1352.
14. Liu, J.; An, Y.; Jiang, H.-Y.; Chen, Z. Tetrahedron Lett. 2008, 49, 490.
15. General procedure for the reaction of 1a with lithium alkynilide: To a
solution of 1 mmol arylacetylene in THF (10 mL) was added
1.1 mmol of n-butyl lithium (0.69 mL, 1.6 M) via a syringe. The
reaction mixture was maintained at À30 °C for 30 min, and then a
solution of 1-(benzenesulfonyl) cyclopropanol 1a (99 mg, 0.5 mmol)
in THF (5 ml) was added dropwise. 2 h later, 10 ml saturated NH4Cl
was added slowly to stop the reaction. After the usual workup and
removal of solvents, flash chromatograph over SiO2 gave the desired
1-(arylethyny1)cyclopropanol (PE/EA = 30/1). The spectral data of
1-(phenylethynyl) cyclopropanol 2a: Obtained as a colorless solid in
87% yield (Rf = 0.25, PE/AcOEt = 20/1). 1H NMR (CDCl3, Me4Si) d
1.07–1.11 (m, 2H), 1.17–1.22 (m, 2H), 2.76 (br s, 1H), 7.28–7.31 (m,
3H), 7.40–7.43 (m, 2H). 13C NMR (CDCl3) d 17.7, 46.0, 82.4, 90.8,
122.8, 128.2, 128.3, 131.6. MS m/z (%) 158 (M+, 25), 129 (100), 115
(27), 103 (11), 78 (28), 55 (21).
16. The initial reaction condition was adopted from Tian, Q.; Larock, R.
C. Org. Lett. 2000, 2, 3329.