Palladium-catalyzed ring expansion reaction of 1-alkynylcyclobutanols with aryl iodides: An efficient route to 2-disubstituted methylenecyclopentanones

Article abstract of DOI:10.1016/S0040-4039(02)02581-9

The reaction of 1-alkynylcyclobutanols with aryl iodides in the presence of Pd(OAc)₂ and Et₃N in acetonitrile at 80°C for 24 h gives 2-disubstituted methylenecyclopentan-1-ones in modest to good yields. The tandem insertion-ring expansion process proceeds via the formation of an alkynyl π-complex, followed by migration of a carbon-carbon bond of the tert-alkanol to form the cyclopentanones stereoselectively.

Full text of DOI:10.1016/S0040-4039(02)02581-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 595–597
Palladium-catalyzed ring expansion reaction of
1-alkynylcyclobutanols with aryl iodides: an efficient route to
2-disubstituted methylenecyclopentanones
Li-Mei Wei,a,b Li-Lan Wei,a,b Wen-Bin Pana,b and Ming-Jung Wua,*
aSchool of Chemistry, Kaohsiung Medicial University, Kaohsiung, Taiwan
bFooyin University, Kaohsiung county, Taiwan
Received 31 July 2002; revised 31 October 2002; accepted 8 November 2002
Abstract—The reaction of 1-alkynylcyclobutanols with aryl iodides in the presence of Pd(OAc)2 and Et3N in acetonitrile at 80°C
for 24 h gives 2-disubstituted methylenecyclopentan-1-ones in modest to good yields. The tandem insertion-ring expansion process
proceeds via the formation of an alkynyl p-complex, followed by migration of a carbonꢀcarbon bond of the tert-alkanol to form
the cyclopentanones stereoselectively. © 2002 Elsevier Science Ltd. All rights reserved.
Palladium-promoted ring expansion reactions of 1-
alkenyl or 1-alkynyl cyclobutanols to the construction
of five-membered ring systems have been successfully
applied to the synthesis of biologically active natural
products.1,2 (Scheme 1) Ihara and Fukumoto et al. have
developed a cascade insertion-ring expansion reaction
of allenylcyclobutanols with aryl iodides.3 The reaction
generates a new carbon-carbon bond along with rear-
rangement of the four-membered ring system in a one-
close a new strategy for the synthesis of 2-arylidenecy-
clopentanones in a one-step process.
Tandem reactions were first studied using 1-[2-(4-
tolyl)ethynyl]cyclobutanol (1a)5 and iodobenzene
(2a).Treatment of 1a (0.3 mmol) and 2a (0.6 mmol)
with 5 mol% Pd(dba)2 and triethylamine (1.5 mmol) in
acetonitrile at 80°C for 24 h under nitrogen provided
the a-arylidenecyclopentanone 3aa in 50% yield (Table
1, entry 1).6
pot process, and constitutes
a potentially useful
synthetic method for the efficient synthesis of natural
products. Recently, we reported a powerful palladium-
catalyzed hydroarylation of aryl iodides with
trimethylsilylacetylenes and disubstituted alkynes to
give the diarylacetylenes and triarylethylenes.4 Our
approach to a tandem addition-ring expansion reaction
involves the application of the recently discovered
hydroarylation conditions employing Pd(0) or Pd(II) to
1-alkynylcyclobutanols and aryl iodides. Now, we dis-
When the catalyst was replaced by other palladium
catalysts,
such
as
Pd(OAc)2,
Pd(OCOCF3)2,
Pd(CH3CN)2Cl2, under the same reaction conditions,
the same product was isolated in 68, 40 and 48% yields,
respectively (entries 2–4). The results show that
Pd(OAc)2 is the most efficient catalyst for the successive
addition–rearrangement of 1-alkynylcyclobutanols. As
a solvent for this reaction, acetonitrile was found to be
more efficient than MeOH, THF, DMF and 1,4-diox-
ane. Triethylamine was the base of choice, and other
bases, such as K2CO3, NaOAc, Ag2CO3 and pyridine,
were found to be less efficient. Thus, various aryl
iodides were reacted with 1-[2-(4-tolyl)ethynyl]-
cyclobutanol 1a using Pd(OAc)2 as the catalyst and
triethylamine as the base to give the 2-arylidenecy-
clopentanones 3 in 50–75% yields. The results are sum-
marized in Table 1. 4-Tolyl iodide 2b and
4-methoxyphenyl iodide 2c afforded the corresponding
cyclopentanones 3ab and 3ac in 70 and 50% yields,
respectively (entries 5, 6). The reactions of 2-
Scheme 1.
Keywords: palladium and compounds; ring expansion; cyclopen-
tanones.
* Corresponding author.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02581-9

596
L.-M. Wei et al. / Tetrahedron Letters 44 (2003) 595–597
Table 1. Palladium-catalyzed sequential addition-rearrangement of 1-(2-substituted ethynyl)cyclobutanols with aryl iodides
Entry
1-Ethynylcyclobutanols
Aryl iodides
Pd catalyst
Productsa (yield, %)
1
2
3
4
5
6
7
8
1a (R=4-tolyl)
1a
1a
1a
1a
1a
1a
1a
1b (R=phenyl)
1b
1b
1b
2a (Ar=phenyl)
2a
2a
2a
2b (Ar=4-tolyl)
2c (Ar=4-methoxyphenyl)
2d (Ar=2-tolyl)
2e (Ar=2,3-dimethylphenyl)
2a
2b
2c
2d
2e
2b
Pd(dba)2
3aa (50%)
3aa (68%)
3aa (40%)
3aa (48%)
3ab (70%)
3ac (50%)
3ad (74%)
3ae (70%)
3ba (73%)
3bb (65%)
3bc (49%)
3bd (74%)
3be (75%)
3cb (30%b)
Pd(OAc)2
Pd(OCOCF3)2
Pd(CH3CN)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
9
10
11
12
13
14
1b
1c (R=n-butyl)
a Yields refer to isolated yields. All of the compounds gave satisfactory 1H, 13C NMR and MS spectra data.
b Reacted for 48 h.
tolyl iodide 2d and 2,3-dimethylphenyl iodide 2e pro-
duced 3ad and 3ae in 74 and 70% yields, respectively
(entries 7, 8), which indicated that steric hindrance has
little effect on this addition reaction. However, when
2-iodopyridine was used in this reaction, no reaction
took place and most of the starting materials were
recovered. 1-[2-(Phenyl)ethynyl]cyclobutanol (1b) was
prepared. The reaction of 1b with various aryl iodides
under the optimal reaction conditions gave the prod-
ucts in 49–75% yields. Iodobenzene gave the 2-disubsti-
tuted methylenecyclopentan-1-one 3ba in 73% yield
(entry 9). 4-Tolyl iodide and 4-methoxyphenyl iodide
afforded the corresponding cyclopentanones 3bb and
3bc in 65 and 49% yields, respectively (entries 10, 11).
2-Tolyl iodide and 2,3-dimethylphenyl iodide gave the
cyclopentanones 3bd and 3be in 74 and 75% yields,
respectively (entries 12, 13). The structure of 3bd was
unambiguously determined by X-ray crystallographic
analysis.7 It should be noted that the ring expansion
process proceeds in a stereoselective manner. 1-(1-
Hexynyl)cyclobutanol (1c) was also examined. The
reaction took place much slower and required 48 h to
give the product 3cb in only 30% yield (entry 14).
A mechanism for this cascade insertion-rearrangement
reaction is proposed in Scheme 2. The formation of the
product can be explained as follows; first, the oxidative
addition of the aryl iodide to a palladium complex gives
an arylpalladium intermediate, which coordinates to the
carbon–carbon triple bond of 1 to form a s-arylpalla-
dium complex and produce the h2-palladium complex.
Next, the ring transformation of 4 gives the s-alkylpal-
ladium complex 5 in a stereoselective fashion.3 Finally,
reductive elimination of Pd(0) from the resultant s-
alkylpalladium complex 5 provides the product 3.
In conclusion, the tandem insertion-ring expansion of
1-alkynylcyclobutanols provides a one-step synthesis of
a-disubstituted methylenecyclopentanones. This ring
expansion reaction proceeds in
manner.
a
stereoselective
Acknowledgements
We thank the National Science Council of the Republic
of China for financial support of this program.
Scheme 2.

L.-M. Wei et al. / Tetrahedron Letters 44 (2003) 595–597
597
References
CDCl3) l 7.34 (dd, 2H, J=8.0, 1.7 Hz), 7.10 (d, 2H,
J=8.4 Hz), 2.84 (b, 1H,), 2.37–2.53 (m, 4H), 2.34 (s, 3H),
1.82–1.91 (m, 2H); 13C NMR (50 MHz, CDCl3) l 138.2,
131.5, 128.9, 119.6, 91.9, 83.4, 68.2, 38.6, 21.3, 12.9;
EI(MS) m/z (rel. intensity) 186 (M+, 2), 158(89), 143(41),
115(100).
1. For some recent works on palladium-catalyzed ring expan-
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6. Typical experimental procedure for the addition-ring expan-
sion reaction. A slurry of the 1-alkynylcyclobutanol 1a (0.3
mmol), p-iodotoluene 2b (0.6 mmol), Pd(OAc)2 (5 mol%),
PPh3 (5 mol%), Et3N (1.5 mmol) in CH3CN (8 mL) was
stirred for 24 h at 80°C. The reaction mixture was filtered
through a short pad of silica gel to remove precipitated
inorganic salts. The silica gel pad was washed three times
with a small amount of EtOAc and the combined solution
was evaporated to dryness under reduced pressure. The
residue was chromatographed on silica gel using n-hex-
ane–EtOAc (20:1 v/v) as eluent to give the cyclopentanone
3ab (70%) as a light yellow solid. Mp: 149–150°C; 1H
NMR (200 MHz, CDCl3) l 7.10–7.14 (m, 4H), 7.07 (dd,
2H, J=6.4, 1.8 Hz), 7.00 (dd, 2H, J=6.4, 1.8 Hz), 2.80 (t,
2H, J=7.0 Hz), 2.36 (s, 3H), 2.36 (t, 2H, J=8.0 Hz), 2.35
(s, 3H), 1.91 (m, 2H); 13C NMR (50 MHz, CDCl3) l
206.6, 148.6, 139.2, 138.4, 137.6, 137.3, 133.6, 129.7, 129.5,
128.6, 128.5, 39.9, 33.2, 21.4, 21.3, 20.5; Anal. calcd. for
C20H20O: C, 86.92; H, 7.29. Found: C, 86.75; H, 7.36.
7. Crystal data for 3bd: C19H18O; M=262.33 g/mol, crystal
size: 0.40×0.30×0.25 mm, triclinic, space group P-1, u=
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as follows: to a dry 150-mL round-bottomed under nitro-
gen atmosphere was added the corresponding terminal
alkyne (15 mmol) and tetrahydrofuran (15 mL). The solu-
tion was cooled to −78°C and n-butyllithium (1.6 M in
hexane, 7.5 mL) was added dropwise by syringe. After
stirring for 30 min, a solution of cyclobutanone (10 mmol)
in THF (5 mL) was added dropwise and the mixture
stirred at the same temperature for 2 h. The reaction
mixture was quenched with saturated aqueous NH4Cl and
extracted with EtOAc. The combined organic extracts
were washed with brine. The residue upon workup was
chromatographed on silica gel, using n-hexane–EtOAc
(10:1 v/v) as eluent to give the cyclobutanols 1a–c as
colorless oils. Selected spectral data for 1-[2-(4-
tolyl)ethynyl]cyclobutanol: 1a, 1H NMR (200 MHz,
,
,
,
0.71073 A, a=9.3796(9) A, b=9.4887(9) A, c=9.5587(9)
,
A, a=87.687(2)°, i=85.472(2)°, k=60.466(2)°, V=
3
3
−1
,
737.87(12) A , Z=2, D=1.181 Mg/m . v=0.071 mm
,
T=295(2) K, q range: 2.14–27.5°, reflections collected:
7461, independent reflections: 3389 (Rint=0.0208), refine-
ment method: full-matrix least-square on F2, final R val-
ues[I>2|(I)]: R1=0.0746, wR2=0.2185. Diffractometer:
Bruker SMART APEX. Crystallographic data (excluding
structure factors) for this structure have been deposited at
the Cambridge Crystallographic Data centre as supple-
mentary publication no. CCDC-190286, and may be
obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223-
336-033; e-mail: deposit@ccdc.cam.ac.uk).