Diversity in platinum-catalyzed hydrative cyclization of trialkyne substrates to form tetracyclic ketones

Article abstract of DOI:10.1021/jo701458b

(Chemical Equation Presented) We report a one-pot synthesis of tetracyclic ketones via PtI₂-catalyzed hydrative cyclization of trialkyne functionalities. These triyne substrates bear an electron-rich aryl group at the outer alkyne to direct the

Full text of DOI:10.1021/jo701458b

SCHEME 1
Diversity in Platinum-Catalyzed Hydrative
Cyclization of Trialkyne Substrates To Form
Tetracyclic Ketones
Hsu-Kai Chang, Yen-Chen Liao, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity,
Hsinchu, Taiwan, ROC 30043
rsliu@mx.nthu.edu.tw
ReceiVed July 5, 2007
SCHEME 2
We report a one-pot synthesis of tetracyclic ketones via PtI2-
catalyzed hydrative cyclization of trialkyne functionalities.
These triyne substrates bear an electron-rich aryl group at
the outer alkyne to direct the initial hydration occurring at
the adjacent alkynyl carbon. This tandem catalysis is pro-
posed to comprise two alkyne hydrations, an alkyne insertion
and an intramolecular aldol condensation.
more rapidly than 1-propynylbenzene.7 In this spiroketone syn-
thesis, the initial hydration occurs exclusively at the central
diphenyl alkynes to form R-ketonyl platinum species A, which
subsequently forms intermediate B via an alkyne insertion and
the second alkyne hydration.6 To demonstrate the diversity of
this tandem cyclization, we report here a remarkable hydrative
cyclization of trialkyne substrates via an initial hydration at the
outer alkyne, which ultimately gives varied tertacyclic ketones
efficiently.
The synthesis of complex polycarbocyclic molecules from
metal-catalyzed multicomponent coupling reactions1-2 is fas-
cinating because multiple carbon-carbon bonds can be formed
simultaneously. Regiocontrolled hydrative cyclization of an
alkyne with another functionality is particularly notable as this
approach provides complex oxygenated carbocyclic molecules
from readily available alkynes. Most of the reported examples
are restricted to two-component couplings that yield only mono-
cyclic ring products.3-5 To achieve a more complex framework,
we recently reported6 hydrative cyclization of trialkyne func-
tionalities to produce bicyclic spiroketones using PtCl2/CO as
the catalyst; the protocol appears in Scheme 1. The design of
this cyclization is based on kinetic differentiation such that
diphenyl acetylene undergoes PtCl2-catalyzed hydration much
Scheme 2 shows the relative rates in the PtCl2/CO8-catalyzed
hydrations of the two diphenyl acetylenes 1a and 1b in a 1:1
reaction mixture; ketone products 2a and 2b were obtained in
a molar ratio of 1:2.9 at 60% conversion relative to species 1b.
This information is indicative of the hydration preference for
1b, likely due to platinum stabilizing the vinyl cationic character
in the π-alkyne bonding.9 To verify this hypothesis, an experi-
ment with catalytic hydration of unsymmetric internal alkyne
1c gave ketone 2c10 exclusively via selective hydration at the
MeOC6H4Ct carbon.
(1) For general reviews, see: (a) Ho, T.-L. Tactics of Organic Synthesis;
Wiley-Interscience: New York, 1994: p 79. (b) Tietze, L. F. Chem. ReV.
1996, 96, 115. (c) Winkler, J. D. Chem. ReV. 1996, 96, 167. (d) Denmark,
S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137.
Accordingly, we prepared triyne 3 bearing a 4-methoxyphenyl
group at the outer alkyne to facilitate hydration at the adjacent
alkynyl carbon. Table 1 shows the hydrative cyclization of triyne
(2) (a) Hegedus, L. S. In Transition Metals in the Synthesis of Complex
Organic Molecules, 2nd ed.; University Science Books: Sausalito, Cali-
fornia, 1999. (b) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003,
42, 1364. (c) de Meijere, A.; von Zezschwitz, P.; Bra¨se, S. Acc. Chem.
Res. 2005, 38, 413.
(3) For hydrative cyclization of 1,n-diynes, see selected examples: (a)
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2003, 125, 11516. (b) Trost,
B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763. (c) Odedra, A.;
Wu, C.-J.; Pratap, T. B.; Huang, C.-W.; Ran, Y.-F.; Liu, R.-S. J. Am. Chem.
Soc. 2005, 127, 3406.
(7) Treatment of a 1:1 mixture of diphenyl acetylene and 1-propynyl-
benzene with PtCl2/CO (10 mol%) and water (1 equiv) in hot 1,4-dioxone
(100 C, 12 h) gave a mixture of phenyl benzyl ketone (47%), phenyl ethyl
ketone (2%), benzyl methyl ketone (1%), and recovered 1-propynylbenzene
(45%).
(4) For yne-enone, see: Trost, B. M.; Brown, R. E.; Toste, F. D. J.
(8) This catalytic system is proposed to form PtCl2(CO)n; see (a) Fu¨rstner,
A.; Davies, P. W.; Gress, T. J. Am. Chem. Soc. 2005, 127, 8244. (b) Fu¨rstner,
A.; A¨ıssa, C. J. Am. Chem. Soc. 2006, 128, 6306. (c) Fu¨rstner, A.; Davies,
P. W. J. Am. Chem. Soc. 2005, 127, 15024. (d) Taduri, B. P.; Ran, Y.-F.;
Huang, C.-W.; Liu, R.-S. Org. Lett. 2006, 8, 883. (e) Lo, C.-Y.; Lin,
C.-C.; Cheng, H.-M.; Liu, R.-S. Org. Lett. 2006, 8, 3153.
Am. Chem. Soc. 2000, 122, 5877.
(5) For 1,5-enynes, see: Chen, Y.; Ho, D. M.; Lee, C. J. Am. Chem.
Soc. 2005, 127, 12184.
(6) Chang, H.-K.; Datta, S.; Das, A.; Odedra, A.; Liu, R.-S. Angew.
Chem., Int. Ed. 2007, 46, 4744.
10.1021/jo701458b CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/21/2007
J. Org. Chem. 2007, 72, 8139-8141
8139

TABLE 1. Hydrative Cyclization of Triyne Species 3 over Various
Catalysts
TABLE 2. PtI2-Catalyzed Hydrative Cyclization of Triyne Species
yield (%)a
entry
catalyst
10% PtCl2/CO
10% Ptl2/CO
5% Ptl2/CO
10% HPF6
10% AuCl
time (h)
3
4
1
2
3
4
5
6
7
6
3.5
18
18
18
18
12
-
-
-
92
88
87
91
76b
83b
62b
-
tracec
tracec
-
10% AuCl3
5% AuClPPh3/5% AgOTf
a Yields were reported after separation from silica column. b 1,4-dioxane,
[triyne] ) 0.15 M. c [Triyne] ) 0.075 M.
3 catalyzed with PtCl2/CO (10 mol %) in wet 1,4-dioxane (100
°C, 6 h) (Table 1, entry 1), giving in 76% yield tetracyclic ketone
4 that was characterized by an X-ray diffraction study.11 Among
common π-Lewis acids, we found that PtI2 (10 mol %) exhibited
the best cyclization activity at a brief period to increase the yield
of ketone 4 to 83% (entry 2). A low loading of PtI2 (5 mol %)
attained a decreased yield (62%, entry 3). The same reactions
using HPF6, AuCl, AuCl3, and AuPPh3OTf only led to exclusive
recovery of starting triyne 3 (entries 4-7).
a 100 ˚C, 1,4-dioxane, [triyne] ) 0.075 M. b Yields were reported after
separation from silica column. c [Triyne] ) 0.15 M.
SCHEME 3
Table 2 summarizes the results of the extension of this
hydrative cyclization to various triynes 5-16 bearing three
inequivalent internal alkynes. These triynes include an electron-
rich aryl group to enhance the hydration at the tCAr carbon.
The catalytic reactions were performed by using 10 mol % PtI2
in wet 1,4-dioxane at 100 °C; the duration of the reaction (1-6
h) enables the complete consumption of triynes 5-16. Entries
1-4 show the variation of the aryl substituents; triyne 8 bearing
a phenyl group is much less efficient for the cyclization than
other triynes 5-7 containing an electron-rich phenyl substituent
such as methyl, 3,4-dimethoxy, and methylenedioxy, which gave
desired tetracyclic ketones 17-19 with 74-85% yields. In the
case of phenyl substrate 8, a mixture of products were obtained,
from which desired tetracyclic ketone 20 was obtained in only
12% yield; the poor performance with species 8 demonstrates
the importance of an electron-rich aryl substituent for the
cyclization. The 2-thiophene and 2-furan derivatives 9 and 10
also exhibited reasonable activity; their corresponding tetracyclic
ketones 21 and 22 were obtained in 62% and 57% yield,
respectively (entry 5-6). Entries 7-10 show the applicability
of this cyclization to triynes 11-14 bearing a terminal alkyne
(R ) H); the corresponding ketone products 23-26 were
obtained in 61-72% yields. This hydrative cyclization worked
satisfactory with triynes 15 and 16 bearing an R ) n-butyl
group, affording cyclized ketones 27-28 in 43-62% yields.
As depicted in Scheme 3, this cyclization is extensible to
triyne 29 bearing a bridging cyclohexenyl group, giving
tetracyclic ketone 30 in 33% yield using the PtI2/CO/H2O
1
system; H NOE effects confirmed its structure.12 This case
shows the applicability of this cyclization to construction of a
complex carbocyclic framework.
This work demonstrates the diversity of hydrative cyclization
of trialkyne substrates, which might provide tetracyclic ketones
or bicyclic spiroketones (Scheme 1). For starting triyne 3, the
outer MeOC6H4Ct carbon appears to be more active for hy-
drolysis based on our observations in Scheme 2. We propose a
mechanism involving an initial attack of H2O at the MeOC6H4Ct
carbon of triyne 3 to form R-carbonyl platinum species D
(Scheme 4), which then undergoes alkyne insertion and hydro-
demetalation to form indene species E. After a second hydration
at the remaining alkyne of species E, the resulting diketone
species F undergoes a subsequent aldol condensation to form
an initial product bearing a central [5.3.0]decenol core rather
than a strained [3.3.0]octenol structure.
In summary, we report a new regioselective hydrative cycliza-
tion of triynes to give tetracyclic ketones with satisfactory yields.
The cyclization is proposed13 to proceed via an initial attack of
H2O at the outer alkyne, followed by an alkyne insertion, a
second hydration, and an ultimate aldol condensation. This work
demonstrates the diversity of hydrative cyclization of trialkynes14
bearing a suitable directing group.
(9) In a π-alkyne moiety, the phenyl group is expected to stabilize the
adjacent vinyl cation via extensive resonance forms.
(10) Spectra data of compound 2c was identical to those reported in
literature; see: Wang, D.; Zhang, Z. Org. Lett. 2003, 5, 4645.
(11) The X-ray crystallographic data of compound 4 are provided in the
Supporting Information.
(12) 1H NOE map of key compounds is provided in Supporting
Information.
8140 J. Org. Chem., Vol. 72, No. 21, 2007

SCHEME 4
0.22 mmol), CuI (85.7 mg, 0.45 mmol), and degassed triethylamine
under nitrogen atmosphere; to this mixture were added (2-
iodophenyl)ethynyl]trimethylsilane (3.37 g, 11.2 mmol) and species
S-1 (1.63 g, 12.3 mmol) under nitrogen. The reaction mixture was
stirred at 60 °C for 6 h. Triethylamine was removed under reduced
pressure, and the residues were partitioned between ethyl acetate
and water. The solution was extracted with ethyl acetate (30 mL
× 2), washed with saturated aqueous NaCl, dried over MgSO4,
and concentrated under reduced pressure. Column chromatography
on silica gel with hexane afforded a yellow oil, which further
afforded S-2 (yellow oil, 2.19 g, 9.43 mmol) following the
desilylation procedure as described in preceding section. 1H NMR
(400 MHz, CDCl3): δ 7.55-7.52 (m, 4 H), 7.30 (td, J ) 8.0, 1.6
Hz, 1 H), 7.25 (td, J ) 8.0, 1.6 Hz, 1 H), 6.87 (d, J ) 8.0 Hz, 2
H), 3.78 (s, 3 H), 3.41 (s, 1 H); 13C NMR (100 MHz, CDCl3): δ
159.7, 133.1 (2 × CH), 132.4, 131.4, 128.4, 127.5, 126.5, 124.2,
115.1, 113.9 (2 × CH), 93.7, 86.6, 82.3, 81.0, 55.1; HRMS calcd
for C17H12O: 232.0888, found: 232.0884.
Experimental Section
General Procedures for the Synthesis of 1-[(4-Methoxyphen-
yl)ethynyl]-2-[(2-(1-propynyl)phenyl)ethynyl]benzene
(3). (a) Synthesis of 4-Methoxyphenylacetylene (S-1).
(c) Synthesis of 1-[(4-methoxyphenyl)ethynyl]-2-[(2-(1-pro-
pynyl)phenyl) ethynyl]benzene (3). Into a two-necked flask was
placed Pd(PPh3)4 (218 mg, 0.19 mmol), CuI (71.8 mg, 0.38 mmol),
and degassed triethylamine under nitrogen atmosphere, and to this
reaction mixture was added 1-iodo-2-(1-propynyl)benzene (2.51 g,
10.4 mmol) and compound S-2 (2.19 g, 9.43 mmol) under nitrogen.
The reaction mixture was stirred at 60 °C for 6 h, and triethylamine
was removed under reduce pressure; the residues were partitioned
between ethyl acetate and water. The solution was extracted with
ethyl acetate (30 mL × 2), washed with saturated aqueous NaCl,
dried over MgSO4, and concentrated under reduced pressure. Col-
umn chromatography on silica gel with hexane afforded compound
3 as a yellow oil (2.45 g, 7.07 mmol, 75%). IR (neat, cm-1): 3100
1
(s), 2115 (m), 1600 (w); H NMR (400 MHz, CDCl3): δ 7.57-
7.50 (m, 5 H), 7.43-7.41 (m, 1 H), 7.30-7.22 (m, 4 H), 6.85 (d,
J ) 8.0 Hz, 2 H), 3.81 (s, 3 H), 1.97 (s, 3 H); 13C NMR (100
MHz, CDCl3): δ 159.7, 133.2 (2 × CH), 132.1, 131.9, 131.8, 131.5,
128.0 (2 × CH), 127.5, 127.2, 126.5, 126.0, 125.7, 125.5, 115.3,
113.9 (2 × CH), 93.6, 92.3, 91.7, 90.6, 87.1, 78.4, 55.3, 4.4; HRMS
calcd for C26H18O: 346.1358, found: 346.1355.
Into a two-necked flask was placed Pd(PPh3)2Cl2 (180 mg, 0.26
mmol), CuI (100.0 mg, 0.52 mmol), and degassed triethylamine
under a nitrogen atmosphere; to this mixture were added 4-iodo-
anisole (3.0 g, 12.8 mmol) and trimethylsilylacetylene (2.2 mL,
15.4 mmol) under nitrogen. The reaction mixture was stirred at 60
°C for 3 h; triethylamine was removed under reduced pressure, and
the residues were partitioned between ethyl acetate and water. The
solution was extracted with ethyl acetate (30 mL × 2), washed
with saturated aqueous NaCl, dried over MgSO4, and concentrated
under reduced pressure. Column chromatography on silica gel with
hexane afforded (4-methoxyphenyl)ethynyltrimethylsilane as yellow
oil. This silyl compound was then dissolved in dichloromethane
(100 mL) and methanol (50 mL), added with K2CO3 (3.54 g, 25.6
mmol); the mixture was stirred at 23 °C for 2 h before the addition
of water (100 mL). The solution was extracted with ethyl acetate
(30 mL × 2), washed with saturated aqueous NaCl, dried over
MgSO4, and concentrated under reduced pressure. Column chro-
matography on silica gel with hexane afforded S-1 (1.63 g, 12.3
mmol, 96%, two steps) as a yellow oil. 1H NMR (400 MHz,
CDCl3): δ 7.39 (d, J ) 8.0 Hz, 2 H), 6.78 (d, J ) 8.0 Hz, 2 H),
3.71 (s, 3 H), 3.01 (s, 1 H); 13C NMR (100 MHz, CDCl3): δ 159.7,
133.3 (2 × CH), 114.0, 113.7 (2 × CH), 83.5, 77.3, 54.8; HRMS
calcd for C9H8O: 132.0575, found: 132.0571.
General Procedures for Catalytic Reaction. A long tube
containing PtI2 (13 mg, 0.03 mmol) was dried in vacuo for 1 h;
vacuum was released with CO gas using a CO balloon before the
tube was charged with triyne 3 (100 mg, 0.3 mmol), water (41.6
µL, 2.3 mmol), and 1,4-dioxane (2.0 mL, 0.15 M). The mix-
ture was stirred at 23 °C for 30 min and heated at 100 °C for
3.5 h. The solution was concentrated and eluted through a silica
column (hexane/ethyl acetate) to afford compound 4 (87.0 mg,
0.24 mmol, 83%) as a yellow solid; mp 172.8-173.4 °C; IR
1
(neat, cm-1): 3075 (s), 1670 (s), 1630 (m), 1600 (w); H NMR
(400 MHz, CDCl3): δ 7.85-7.80 (m, 2 H), 7.66 (t, J ) 8.0 Hz, 1
H), 7.54 (t, J ) 8.0 Hz, 1H), 7.43 (d, J ) 8.0 Hz, 1H), 7.22 (d, J
) 8.0 Hz, 2 H), 7.08 (t, J ) 8.0 Hz, 1 H), 6.94-6.89 (m, 3 H),
6.22 (d, J ) 8.0 Hz, 1 H), 4.10 (s, 2 H), 3.85 (s, 3 H), 2.20 (s, 3
H); 13C NMR (100 MHz, CDCl3): δ 198.7, 159.2, 145.0, 142.9,
141.8, 139.7, 138.7, 138.1, 137.7, 133.5, 132.2, 131.3, 131.1 (2 ×
CH), 128.9, 128.4, 127.1, 126.2, 125.2, 123.5, 123.4, 113.8 (2 ×
CH), 55.2, 41.0, 18.7; HRMS calcd for C26H20O2: 364.1463,
found: 364.1459.
(b) Synthesis of 1-Ethynyl-2-[(4-methoxyphenyl)ethynyl]ben-
zene (S-2). Into a two-necked flask was placed Pd(PPh3)4 (260 mg,
(13) The proposed mechanism in Scheme 4 suggests that this catalytic
sequence is accomplished by both PtX2 (X ) Cl, I) and H+. We propose
that the superior activity of PtI2 versus PtCl2 is attributed to its easy
hydrolysis to release more protons. In the presence of 2,6-lutidine, treatment
of triyne 3 with PtI2 (10 mol %) in wet and hot dioxane (100 °C, 3 h) only
led to exclusive recovery of starting 3. The role of H+ is evident here.
(14) In Tables 1 and 2, we did not observe isomeric products because
our substrates were designed for initial hydration at the outer diphenyl
alkyne, which is more active than the remaining two internal alkynes in
the alkyne hydration (see Scheme 2 and reference 4).
Acknowledgment. We thank the National Science Council,
Taiwan, for supporting this work.
Supporting Information Available: Spectra data and NMR
1
spectra for compounds 3-30; H NOE map of key compounds;
X-ray data for compound 4. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO701458B
J. Org. Chem, Vol. 72, No. 21, 2007 8141