Metal-catalyzed chemoselective cycloisomerization of cis-2,4-dien-1-als to 3-cyclopentenones and 4-alkylidene-3,4-dihydro-2H-pyrans

Article abstract of DOI:10.1021/ol061248h

PtCl₂ (5 mol %) catalyst effected cycloisomerization of cis-2,4-dien-1-al (1) to 3-cyclopentenone (3) efficiently in hot toluene. In the presence of p-TSA, this PtCl₂ catalysis gave 2-cyclopentenone (5) exclusively because of the secondary isomerization reaction. Although the 1-2 equilibrium state greatly favors aldehyde (1), PdCl₂(PhCN) ₂ (5 mol %) catalyzed cycloisomerization of aldehyde (1) to 4,6,7,8-tetrahydro-3H-isochromene (4) smoothly in hot toluene. A plausible mechanism is proposed on the basis of reaction observation and isotope-labeled experiment.

Full text of DOI:10.1021/ol061248h

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3153-3156
Metal-Catalyzed Chemoselective
Cycloisomerization of cis-2,4-Dien-1-als
to 3-Cyclopentenones and
4-Alkylidene-3,4-dihydro-2H-pyrans
Ching-Yu Lo, Chung-Chang Lin, Hsin-Mei Cheng, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity, Hsinchu, Taiwan, 30043,
Republic of China
rsliu@mx.nthu.edu.tw
Received May 22, 2006
ABSTRACT
PtCl2 (5 mol %) catalyst effected cycloisomerization of cis-2,4-dien-1-al (1) to 3-cyclopentenone (3) efficiently in hot toluene. In the presence
of p-TSA, this PtCl2 catalysis gave 2-cyclopentenone (5) exclusively because of the secondary isomerization reaction. Although the 1 2 equilibrium
−
state greatly favors aldehyde (1), PdCl2(PhCN)2 (5 mol %) catalyzed cycloisomerization of aldehyde (1) to 4,6,7,8-tetrahydro-3H-isochromene (4)
smoothly in hot toluene. A plausible mechanism is proposed on the basis of reaction observation and isotope-labeled experiment.
Metal-catalyzed cycloisomerization of an acyclic molecule
to more than one cyclic structure is challenging and useful
in organic synthesis. One prominent example is the cyclo-
isomerization of 1,6- and 1,7-enynes with suitable catalysts
to produce various carbocyclic and heterocyclic compounds.1
A cis-2,4-dien-1-al functionality is often encountered in
organic synthesis, and this species is prone to thermally
reversible 6-π-electrocyclization to give 2H-pyran as depicted
in Scheme 1 (eq 1).2,3 The state of this equilibrium depends
on the nature of its substituents. This thermal cyclization
has been employed as a key step to construct complex
polycyclic frameworks.3 Metal-catalyzed cycloisomerization
of cis-2,4-dien-1-als has been studied extensively;4,5 such
reactions produce 2-cyclopentenones exclusively via two
Scheme 1
(1) (a) Ma, S.-M.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200.
(b) Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328. (c) Aubert, C.;
Buisine, O.; Malacria, M. Chem. ReV. 2002, 102, 813. (d) Mendez, M.;
Mamane, V.; Fu¨rstner, A. Chemtracts 2003, 16, 397.
(2) Okamura, W. H.; De Lera, A. R. ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 5, p 699.
(3) For selected examples, see: (a) Tambar, U. K.; Kano, T.; Stoltz, B.
M. Org. Lett. 2005, 7, 2413. (b) Lumb, J.-P.; Trauner, D. Org. Lett. 2005,
7, 5865. (c) Shoji, M.; Imai, H.; Shiina, I.; Kakeya, H.; Osada, H.; Hayashi,
Y. J. Org. Chem. 2004, 69, 1548.
10.1021/ol061248h CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/17/2006

distinct pathways: (1) initial Lewis acid-catalyzed π4a +
π2a or Nazarov-type cyclization to give cyclopentadiene
epoxide I intermediates4 or (2) initial formation of rhodium-
hydride species II via oxidative addition.5 Here, we report
new metal-catalyzed chemoselective cyclization of cis-2,4-
dien-1-als to 3-cyclopentenones and 4-alkylidene-3,4-dihy-
dro-2H-pyran, respectively, in addition to the expected
3-cyclopentenones.
tenone 3 to its conjugated isomer 5. Notably, PdCl2(PhCN)2
(5 mol %) produced 4,6,7,8-tetrahydro-3H-isochromene 4
in 87% yield under optimum conditions. Among other
π-alkyne activators (entries 4-7), only AgOTf (5 mol %)
was catalytically efficient in hot toluene and gave 2-cyclo-
pentenone 5 in 91% yield.
The value of this catalytic cyclization is manifested by
formation of not only the expected 2-cyclopentenone 5, but
also the unprecedented 3-cyclopentenone 3 and 4-alkylidene-
3,4-dihydro-2H-pyran 4. Table 2 shows additional examples
Table 1. Cyclization of cis-2,4-Dien-1-al 1 over Various
Catalystsa,b
Table 2. PtCl2-Catalyzed Chemoselective Cycloisomerization
of cis-2,4-Dien-1-als to 3-Cyclopentenones
catalysts
(1) -
(2) PtCl2
solvents
conditions
products
1 (81%)
toluene
toluene
100 °C, 54 h
100 °C, 30 min 3 (92%)
100 °C, 30 min 5 (88%)
(3) PtCl2+ p-TSA toluene
(3) PdCl2(PhCN)2 toluene
100 °C, 12 h
4 (87%)
(4) AgOTf
toluene
100 °C, 20 min 5 (91%)
(5) AuCl
benzene 100 °C, 17 h
benzene 100 °C, 11 h
1 (25%), 4 (63%)
1 (56%), 4 (32%)
3 (15%)
(6) AuClPPh3
(7) AuClPPh3 +
AgSbF6
CH2Cl2
23 °C, 20 min
a 5 mol % catalyst, [substrate] ) 0.25 M. b Product yields are given after
separation from a silica column.
As shown in Table 1, cis-2,4-dien-1-al 1 was selected as
the studied molecule because similar aldehydes will not form
2H-pyran 2 at elevated temperatures.6 We undertook a
theoretic calculation (B3LYP/6-31G**) of the relative ener-
gies of its four possible cycloisomerization species 2-5. The
ease of formation of 2-cyclopentenone in most catalytic
reactions is attributed to its conjugated stabilization energy,
ca. 15-28 kcal/mol less than four other species. Heating
aldehyde 1 alone in hot toluene (100 °C, 54 h) led to its
exclusive recovery although 2H-pyran 2 has enthalpy 5 kcal/
mol less than aldehyde 1 (entry 1).6,7 Cyclization of this
aldehyde with PtCl2 (5 mol %) catalyst in hot toluene (100
°C, 30 min) gave 3-cyclopentenone 3 efficiently (92%, entry
2), whereas this catalyst produced 2-cyclopentone 5 in the
presence of p-toluenesulfonic acid (p-TSA, 5 mol %, entry
3). The role of p-TSA is the isomerization of 3-cyclopen-
a 5% PdCl2(PhCN)2, toluene, [substrate] ) 0.25 M, 100 °C, 12 h for
entries 6 and 8, 14 h for entry 10, 16 h for entry 5, 18 h for entries, 1, 3-4,
and 11, and 24 h for entries 2, 7, and 9. b Yields of products are given after
separation from a silica column.
to generalize the catalytic cycloisomerization of various cis-
2,4-dien-1-als 6-20 to corresponding 3-cyclopentenones
21-35 with PtCl2 catalyst (5 mol %); the resulting yields
were as high as 81-92% except for 18, which gave desired
33 (72%) in addition to 4-alkylidene-3,4-dihydro-2H-pyran
51 (see Table 3) in 17% yield.8 These catalytic reactions
were completed in hot toluene (100 °C) within 30-50 min,
except for entry 15, which requires a longer period (6 h).
3-Cyclopentenone 25 was obtained in two isomeric forms
(dr ) 1.10) from aldehyde 10 bearing a trans-hexene
substituent (entry 5). In entry 14, aldehyde 19 equilibrates
with its thermally 6-π-cyclized 2H-pyran species (aldehyde:
(4) To the best of our knowledge, there is only one example for catalytic
cycloisomerization of cis-2,4-dien-1-als to 2-cyclopentenones with use of
Lewis acids, see: Miller, A. K.; Banghart, M. R.; Beaudry, C. M.; Suh, J.
M.; Trauner, D. Tetrahedron 2003, 59, 8919 and reference therein.
(5) Kundu, K.; McCullagh, J. V.; Morehead, A. T., Jr. J. Am. Chem.
Soc. 2005, 127, 16042.
(6) Tekevac, T. N.; Louie, J. Org. Lett. 2005, 7, 4037.
(8) Formation of 2H-pyran 51 is attributed the acidity of the O-CH2 of
cis-2,4-dien-1-al 18. This hypothesis is verified by treatment of alcohol 18
with PtCl2 (5 mol %) and 2,6-lutidine (5 mol %) in hot toluene (100 °C, 14
h), which increased the yield of 2H-pyran 51 to 85%.
(7) The absence of 2H-pyran 2 in this thermal equlibrium is attributed
to the negative entropy change because acyclic 2,4-dien-1-al 1 is more
conformationally flexible.
3154
Org. Lett., Vol. 8, No. 14, 2006

aldehydes 36-38 with PtCl2 (5 mol %) in hot toluene (100
°C) for 2 h gave two isomeric products 39-41(A) and 39-
41(B) which were not separable from silica column. 3-Cy-
clopententones 39-41(A) are related to their isomeric forms
39-41(B) by a 1,3-migration of the oxygen atom.
Table 3. PtCl2-Catalyzed Chemoselective Cycloisomerization
of cis-2,4-Dien-1-als to 3-Cyclopentenones
Table 3 shows the generalization of the PdCl2-catalyzed
synthesis of 4-alkylidene-3,4-dihydro-2H-pyran derivatives
42-52 with use of the same cis-2,4-dien-1-als 8 and 10-
19. Synthesis of such 2H-pyrans is extendable to aldehydes
10-11, and gave desired products 42 and 43 in 77% and
75% yields, respectively. In entries 3-5, cyclization of
aldehydes 12-13 and 8 by using PdCl2(PhCN)2 catalyst (5
mol %) produced preferably 3-cyclopentenones 27-28 and
23, rather than the desired 2H-pyrans 44-46. This chemose-
lectivity problem was circumvented by using 2,6-lutidine
(5%), and in such cases 2H-pyrans 44-46 were produced
exclusively (75-78%). For the remaining aldehydes 14-
18, PdCl2 maintains high cyclization efficiencies toward
formation of 2H-pyrans 47-51 with 75-83% yields in the
absence of 2,6-lutidine additives. Cyclization of aldehyde
19 requires 2,6-lutidine (5%) and PdCl2(PhCN)2 to furnish
2H-pyran 52 in 61% yield.
cis-2,4-dien-1-ala
additive
product (yields)b
(1) R1 ) H, R2 ) nBu
-
-
-
42 (77%)
X ) CH2 (E-isomer, 10)
(2) R1 ) H, R2 ) iPr
43 (75%)
X ) CH2 (E/Z ) 2.34, 11)
(3) R1 ) Me, R2 ) Et
X ) CH2, (E/Z ) 1.39, 12)
(4) R1 ) Me, R2 ) nPr
X ) CH2 (E/Z ) 1.10, 13)
(5) R1, R2 ) -(CH2)4-
X ) CH2, (8)
44 (21%), 27 (58%)
5% 2,6-lutidine 44 (78%)
-
45 (11%), 28 (69%)
5% 2,6-lutidine 45 (75%)
-
46 (13%), 23 (72%)
5% 2,6-lutidine 46 (75%)
(6) R1, R2 ) Me
-
-
-
-
-
47 (82%)
48 (75%)
49 (85%)
50 (83%)
51 (83%)
X ) CH(tBu) (14)
(7) R1 ) H, R2 ) nPr
X ) CH(tBu) (E/Z ) 2.25, 15)
(8) R1, R2 ) Me
X ) O (16)
(9) R1 ) Me, R2 ) nPr
X ) O (E/Z ) 1.20, 17)
2
We also prepared H- and 13C-labeled samples 1 and 37
(10) R1, R2 ) -(CH2)4-
X ) O (18)
to elucidate the mechanism of formation of 3-cyclopenten-
ones. As shown in Scheme 3, species 1 bearing a deuterated
(11) R1, R2 ) Me
5% 2,6-lutidine 52 (61%)
X ) -(CH2)2- (19)
a 5% PdCl2(PhCN)2, toluene, [substrate] ) 0.25 M, 100 °C, 12 h for
entries 6 and 8, 14 h for entry 10, 16 h for entry 5, 18 h for entries 1, 3-4,
and 11, and 24 h for entries 2, 7, and 9. b Yields of products are given after
separation from a silica column.
Scheme 3
2H-pyran ) 12:88), and such an equilibrium mixture can
be transformed into 3-cyclopentenone 34 (81%) efficiently
with PtCl2. This catalytic reaction is further compatible with
an acyclic 2,4-dien-al 20 and gave the expected 3-enone 35
in 81% yield.
The PtCl2-catalyzed synthesis of 3-cyclopentenones in-
volves unusual skeletal rearrangement for special cis-2,4-
dien-1-als 36-38 bearing a bulky tert-butyl and phenyl group
at the C(2)-carbon. As shown in Scheme 2, treatment of
aldehyde produced 3-enone 3 with a 1,2-deuterium migration.
In contrast, we did not observe an oxygen migration for
3-enone 3 produced from species 1 bearing a 10% 13C-
enriched alkenyl C(1) carbon. Cyclization of cis-2,4-dien-al
37 bearing a deuterated aldehyde gave two 3-enones 40(A)
and 40(B) bearing a deuterium at their C(2)Ph and dC(4)
carbons, respectively, and no loss of deuterium occurred.
The 1,3-oxygen migration shown by 3-cyclopentenones
39-41(B) (Scheme 2) excludes a conventional Lewis-
catalyzed c4a + c2a cyclization mechanism.4,9 Nazarov-type
cyclization4,10,11 is also unlikely to occur because cis-2,4-
dien-1-al 10 bearing a trans-hexenyl substituent gave two
Scheme 2
(9) (a) Ireland, C.; Faulkner, D. J.; Solheim, B. A.; Clardy, J. J. Am.
Chem. Soc. 1972, 94, 6767. (b) George, M. V.; Mitra, A.; Sukumaran, K.
B. Angew. Chem., Int. Ed. 1980, 19, 973.
(10) Habermas, K. L.; Denmark, S. E.; Jones, K. T. Org. React. 1994,
45, 1.
a 5% PtCl2, [substrate] ) 0.25 M, toluene, 100 °C, 10 h for entries
b
1 and 2 h for entries 2 and 3. Yields of products are given after
separation from a silica column.
Org. Lett., Vol. 8, No. 14, 2006
3155

isomers of 3-cyclopentenone 25 in equal population (see
Table 2, entry 5), inconsistent with the expected trans isomer
according to Nazarov cyclization. Scheme 4 shows a
For cis-2,4-dien-1-al 12, the use of 2,6-lutidine (5%) to
alter the cyclization chemoselectivity in the PdCl2-based
catalysis (Table 3, entries 3) is informative about the relation
of the two new cyclizations. This observation indicates that
an equilibrium exists between A and E as depicted in Scheme
5. With PdCl2 catalyst, most cis-2,4-dien-als follow the A
Scheme 4
Scheme 5
plausible pathway to rationalize the oxygen migration and
isotopic labeling experiments. The formation of 3-cyclopen-
tenone is initiated with an intramolecular ene-aldehyde
condensation12 to form an OPt(IV)-allyl species B. This
species preferably generates cyclopentadiene epoxide D via
reductive elimination, leading to 3-cyclopentenone 40A with
a 1,2-deuterium migration.13 In the case of a bulky R1 group,
species B likely undergoes reductive elimination to form
oxabicyclic alkene species C reversibly. The reversible nature
of this transformation allows the formation of a second OPt-
(IV)-allyl intermediate B′, and ultimately gave the isomeric
3-cyclopentenone 40B via intermediate D. Most cis-2,4-dien-
1-als with a moderate size R1 substituent are expected to
give 3-cyclopentenone such as species 40A without oxygen
migration.14 The feasibility of the interconversion between
intermediates B and C, as well as C and B, was recently
proposed in a ruthenium-based catalysis.15
f E f F f G pathway except for alcohol such as 12, which
gave 3-cyclopentenone 27 as major products unless 2,6-
lutidine is present. We envision that this pyridine base
accelerates the deprotonation reaction of intermediate F and
preferably gives 2H-pyrans 44 with alternation of chemose-
lectivity.
In summary, we have achieved chemoselective cyclo-
isomerization of cis-2,4-dien-1-als to 3-cyclopentenones and
4-alkylidene-3,4-dihydro-2H-pyrans using PtCl2 and PdCl2-
(PhCN)2, respectively. In the presence of p-TSA catalyst,
PtCl2 also led to formation of conjugated 2-cyclopentenones.
These new metal-catalyzed reactions highlight the synthetic
utility of cis-2,4-dien-1-als with the availability of various
carbocyclic and oxygen heterocyclic compounds. The use
of cis-2,4-dien-1-al as a building block to construct a complex
molecular framework will be more attractive than before.
(11) In the Nazarov-type cyclization, the cyclization follows the conro-
tatory mode to give epoxide opposite to the n-propyl substituent. PtCl2-
catalyzed rearrangement of this vinyl epoxide is expected to give trans-3-
cyclopentenone via a 1,2-hydrogen shift.
Acknowledgment. This work was supported by the
National Science Council, Taiwan.
Supporting Information Available: Experimental pro-
cedures, spectral data, and NMR spectra of key compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Review: Snider, B. In The Prins Reaction and Carbonyl Ene
Reactions; Trost B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon Press:
New York, 1991; Vol. 2, pp 527-561.
(13) For metal-catalyzed transformation of vinyl epoxides into 3-en-1-
ones, see: (a) Suzuki, M.; Oda, Y.; Noyori, R. J. Am. Chem. Soc. 1979,
101, 63. (b) Rosenberger, M.; Jackson, W.; Saucy, G. HelV. Chim. Acta
1980, 63, 1665.
OL061248H
(14) The gem-dialkyl group of the alkenyl substituent of 2,4-dien-1-al
is expected to block this oxygen transfer process, and this hypothesis is
supported by a high A/B ratio (A/B ) 2.0) of species 38 compared to that
(A/B ) 0.58) of its vinyl analogue 37.
(15) Villeneuve, K.; Tam, W. J. Am. Chem. Soc. 2006, 128, 3514.
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Org. Lett., Vol. 8, No. 14, 2006