PtCl2-catalyzed hydrative cyclization of trialkyne functionalities to form bicyclic spiro ketones

Article abstract of DOI:10.1002/anie.200700022

(Chemical Equation Presented) Triple rounds: A regioselective hydrative cyclization of triynes has been developed to give bicyclic β-hydroxy spiro ketones, which undergo subsequent dehydration to give the β,γ- unsaturated ketones (see scheme). Model reactions suggest that this platinum catalysis includes two selective hydrations, an alkyne insertion, and an aldol condensation.

Full text of DOI:10.1002/anie.200700022

Communications
DOI: 10.1002/anie.200700022
Synthetic Methods
PtCl2-Catalyzed Hydrative Cyclization of Trialkyne Functionalities to
Form Bicyclic Spiro Ketones**
Hsu-Kai Chang, Swarup Datta, Arindam Das, Arjan Odedra, and Rai-Shung Liu*
The metal-catalyzed coupling of multifunctional groups[1–4] is
Table 1: Hydrative cyclization of triyne species 1 with PtCl2.
synthetically useful because two or more carbon–carbon and
carbon–heteroatom bonds can be formed simultaneously in a
one-pot operation. Regiocontrolled hydrative cyclization of
an alkyne with another functional group is particularly
notable, as this procedure provides complex oxygenated
carbocyclic molecules from readily available alkynes.[2–4] The
Entry Substrate[a] Catalyst
n
t
Product (yield [%])[b]
reported examples are restricted to two-component cycliza-
tions, including hydrative cyclization of 1,n-diynes (n = 5, 6),[2]
1-yne-5-enones,[3] and 1-en-5-ynes.[4] Nucleophilic hydration
of internal alkynes is seldom used in such cyclizations[2c]
because the resulting ketones are generally inactive in the
subsequent coupling with unactivated alkynes and alkenes.[5]
Herein we report a new cyclization of triynes initiated by a
PtCl2-catalyzed nucleophilic hydration of internal alkynes.
This coupling reaction yields bicyclic spiro ketones with
remarkable regioselectivity, even for triynes with three
inequivalent internal alkynes.
1
2
3
4
5
6
1
1
1
1
2a
2b
[TpRu][a]
PtCl2
PtCl2/CO
PtCl2/CO
PtCl2/CO
PtCl2/CO
6
6
6
6
24 h 2b (3)
24 h 2b (56)
24 h 2b (78)
5 h
2a (28), 2b (54)[c]
0.6 20 h 2b (88, 76[d])
6
24 h 2b (78)
[a] [TpRu]=[TpRuPPh3(CH3CN)2]PF6, 1008C, 1,4-dioxane, [triyne]=
0.2m. [b] Yields are given after purification by column chromatography
on silica gel. [c] The d.r. ratio for 2a is 14:1. [d] This 76% yield
corresponds to 6 equiv of water.
We previously reported the catalytic cyclization of ene-
diynes with water and other nucleophiles in the presence of
[TpRuPPh3(CH3CN)2]PF6 (Tp = tris(1-pyrazolyl)borate) to
produce functionalized benzene derivatives regioselective-
ly.[2c] Hydrative cyclization of triyne 1 with this ruthenium
species (8 mol%) in hot, wet 1,4-dioxane (6H2O, 1008C, 24 h)
gave a complex mixture of products, from which spiro ketone
2b was isolated in 3% yield (Table 1, entry 1). After screening
the catalytic activity of common p-Lewis acids,[6] we found
that only PtCl2[7] (8 mol%) showed reasonable activity to give
a 56% yield of spiro ketone 2b (entry 2); the yield was further
increased to 78% in the presence of CO (1 atm).[7] After a
brief reaction (5 h, entry 4), we isolated p-ketonyl alcohol 2a
(14:1 d.r.) in 28% yield as well as the desired ketone 2b
(54%). Alcohol 2a was verified to be the precursor of spiro
ketone 2b because it underwent facile dehydration when
catalyzed by PtCl2/CO in the presence or absence of water
(entry 5). In contrast, ketone 2b was recovered in hot, wet 1,4-
dioxane (entry 6). Spiro ketone 2b was characterized through
an X-ray diffraction analysis,[8] while alcohol 2a was identified
according to the crystal structure of its analogue 28a.[8]
We extended this hydrative cyclization to symmetric
triynes 3–10 containing two inequivalent internal alkynes
(Table 2). Entries 1–4 show the results of the reaction when
the Y substituents, which are in the para position to the prop-
Table 2: PtCl2-catalyzed hydrative cyclization of symmetric triynes.
Entry
Triyne[a]
Product
Yield [%][b]
1
2
3
4
X=H, Y=OMe (3)
X=H, Y=Me (4)
X=H, Y=F (5)
11b
12b
13b
14a[c]
14b
15b
16b
17b
18b
35
62
65
53
12
81
70
35
69
[*] H.-K. Chang, Dr. S. Datta, A. Das, Dr. A. Odedra, Prof. Dr. R.-S. Liu
Department of Chemistry
X=H, Y=CF3 (6)
National Tsing-Hua University
Hsinchu, 30043 (Taiwan)
Fax: (+886)3571-1082
E-mail: rsliu@mx.nthu.edu.tw
5
6
7
8
X=OMe, Y=H (7)
X=Me, Y=H (8)
X=F, Y=H (9)
X=Y=ÀOCH2O- (10)
[**] We thank the National Science Council, Taiwan, for support of this
work.
[a] 1008C, 1,4-dioxane, [triyne]=0.20m, 24 h. [b] Yields are given after
purification by column chromatography on silica gel. [c] The d.r. ratio for
14a is 10:1.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
1-ynyl group, were varied; the methoxy substituent 3 is less
efficient in the cyclization compared to its methyl-, fluoro-,
and trifluoromethyl analogues 4–6. The alcohol 14a was
obtained as the major product (in entry 4) because of its
relative stability in aqueous 1,4-dioxane. Entries 5–7 show the
results when the X substituents, which lie para to the inner
alkyne, were varied. In these cases, this hydrative
cyclization was found to be unfavorable for fluoro
derivative 9, relative to its methoxy and methyl
analogues 7 and 8. When triyne 10, which contains
a methylenedioxy group, was used, its correspond-
ing cyclized ketone 18b was obtained in 69% yield
(entry 8).
indene ring. Transformation of alcohols 25a–28a into their
spiro ketones 25b–28b proceeded efficiently (83–89% yields)
in hot and anhydrous 1,4-dioxane in the presence of a PtCl2/
CO catalyst (8 mol%).
Scheme 1 shows the model reactions carried out to
simulate the mechanism of cyclization. PtCl2-catalyzed hydra-
The value of this hydrative cyclization is
reflected by its applicability to unsymmetric triynes
19–24, which contain three inequivalent internal
alkynes; the cyclization proceeded highly regiose-
lectively to yield bicyclic spiro products of only one
family (Table 3). The duration of the reactions in
entries 1–5 and 7 (7–24 h) indicates the complete
consumption of triynes 19–24.[9] The 1H NOE
spectra of species 25a and 26a[8] reveal that the
tertiary alcohol is situated on the cyclohexanone
ring rather than the cyclopentane ring. This
structural assignment was confirmed by an X-ray
Scheme 1. Model reactions to simulate the cyclization mechanism.
diffraction study of alcohol 28a, of which the major
diastereomer has the 2R*,3S* configuration.[8] In
the cyclized products 25–30, the more electron-rich
C6H4X ring forms a spiro cyclohexanone ring whereas the
remaining electron-deficient C6H4Y ring generates a spiro
tion of alkyne species 31 in hot, wet 1,4-dioxane (6H2O,
1008C, 12 h) produced cyclized indene species 32 in a yield of
up to 91%. We also prepared ketone species 33, which was
shown to be unrelated to the formation of indene compound
32 because it gave a mixture of products in dry 1,4-dioxane,
and gave 1-naphthol 34 in 31% yield in wet conditions. These
observations suggest that indene 32 is derived from an alkyne
insertion in to intermediate I, followed by hydrodemetalation
of intermediate II. Catalytic hydration of alkyne species 35 by
PtCl2 is rapid and complete in a short time (1,4-dioxane,
1008C, 30 min) to give a-tetralone 36a and 1-naphthol 36b in
yields of 63% and 25%, respectively; the common inter-
mediate is thought to be diketone IV. The hydration
Table 3: PtCl2-catalyzed hydrative cyclization of unsymmetric triynes.
ꢀ
selectivity occurs at the C CMe carbon atom rather than
[10,11]
ꢀ
the expected PhC C carbon atom.
Transformation of
species 35 into 1-naphthol 36b was also conducted effectively
by wet HPF6 (10 mol%) in hot 1,4-dioxane (1008C, 2 h;
Scheme 1).
Entry
1
Triyne[a]
t
Product
Yield [%][b]
The fact that alcohol species 26a was verified as the
primary product strongly indicates the participation of
intermediate E in the cyclization mechanism (Scheme 2).
According to the model reactions in Scheme 1, we envisage
that hydration of triyne 20 occurs more readily at the inner
diphenyl alkyne to give a-ketonyl platinum species C, of
which the ketone group facilitates the second catalytic
hydration at its ortho-alkynyl C(2’) carbon atom to produce
diketone species D. This species undergoes a subsequent
alkyne insertion and hydrodemetalation to form indene
compound F, of which the CHCO hydrogen atom is highly
acidic and activates aldol condensation to give the observed
bicyclic alcohol 26a.
X=OMe,
Y=CF3 (19)
X=Me,
Y=CF3 (20)
X=H,
Y=CF3 (21)
X=Me,
Y=F (22)
X=Me,
Y=H (23)
X=Me, Y=H (23)
X=OMe, Y=F (24)
12 h
25a (9.0:1 d.r.)
25b
26a (11:1 d.r.)
26b
27a (12.9:1 d.r.)
27b
28a (7.3:1 d.r.)
28b
54
17
44
36
23
38
47
26
51
26
76
61
2
3
4
5
24 h
24 h
18 h
7 h
29a (>20 d.r.)
29b
29b
6
7
36 h
8 h
30b
[a] 1008C, 1,4-dioxane, [triyne]=0.20m. [b] Yields are given after
purification by column chromatography on silica gel.
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Communications
The understanding of the preceding cycli-
zation mechanism is very helpful for the design
of new hydrative cyclizations of triynes; one
example is shown in Scheme 3. The PtCl2/CO-
catalyzed hydrative cyclization of triynes 37
and 38 provided a one-pot synthesis of new
bicyclic ketones 39 and 40 in yields of 56% and
78%, respectively; the structure of compound
40 has been characterized by an X-ray diffrac-
tion study.[8] In this catalysis, H2O initially
ꢀ
attacks at the outer MeOC6H4C C carbon
atom to form acylplatinum species I, which
then undergoes alkyne insertion and hydro-
demetalation to form indene species J. After a
second hydration at the remaining alkyne of J,
Scheme 2. A proposed mechanism for the formation of spiro ketones.
the resulting diketone species K undergoes a
The selective hydrations of alkyne 35 to diketone IV and
of C to D are crucial for the formation of the observed spiro
ketones. The observed selectivity is contrary to literature
reports[10] and our separate experiments[11] that p-Lewis acids
subsequent aldol condensation to initially form the
[5.3.0]octenol species rather than the strained [3.3.0]octenol
product.
In summary, we have reported a regioselective hydrative
cyclization of triynes[13,14] to give bicyclic spiro ketones in
good yields. According to our model reactions, this cyclization
is proposed to proceed by two initial selective hydrations,
followed by an alkyne insertion and aldol condensation.
Further application of this catalysis to the synthesis of
bioactive molecules is under investigation.
ꢀ
prefer to add water at the PhC CR carbon atom (R = alkyl).
The C(2)-selectivity for the hydration of alkyne 35 is
attributed to an initial PtCl2- or proton-catalyzed 6-endo-
cyclization of p-alkyne species G[12] to form benzo[c]pyrylium
H, which produces diketone IV upon hydrolysis of this
intermediate [Eq. (1)].
Received: January 3, 2007
Published online: May 18, 2007
Keywords: alkynes · cyclization · homogeneous catalysis ·
.
platinum · spiroketones
[1] For selected examples, see a) A. de Meijere, P. von Zezschwitz,
S. Bräse, Acc. Chem. Res. 2005, 38, 413; b) S. Kamijo, T. Jin, Z.
Huo, Y. Yamamoto, J. Am. Chem. Soc. 2003, 125, 7786; c) S. J.
Patel, T. F. Jamison, Angew. Chem. 2003, 115, 1402 – 1405;
Angew. Chem. Int. Ed. 2003, 42, 1364 – 1367; d) H. Yoshida, H.
Fukushima, J. Ohshita, A. Kunai, Angew. Chem. 2004, 116,
4025 – 4028; Angew. Chem. Int. Ed. 2004, 43, 3935 – 3938; e) Y.
Tamaru, K. Yasui, H. Takanabe, S. Tanaka, K. Fugami, Angew.
Chem. 1992, 104, 662 – 664; Angew. Chem. Int. Ed. Engl. 1992,
31, 645 – 646.
The preceding proposed mechanism also rationalizes the
effects of X and Y substituents in Table 2. A low yield was
obtained with Y= OMe (Table 2, entry 1) because it favors
ꢀ
the second hydration at the C CMe carbon atom rather than
ꢀ
the desired C CMe carbon atom. A similarly low yield with
X = F (Table 2, entry 7) arises from its slow hydration at the
inner alkyne carbon atom because of its high electronegativ-
ity.
[2] For selected examples of the hydrative cyclization
of 1,n-diynes, see a) B. M. Trost, M. T. Rudd, J.
Am. Chem. Soc. 2003, 125, 11516; b) B. M. Trost,
M. T. Rudd, J. Am. Chem. Soc. 2005, 127, 4763;
c) A. Odedra, C.-J. Wu, T. B. Pratap, C.-W.
Huang, Y. F. Ran, R.-S. Liu, J. Am. Chem. Soc.
2005, 127, 3406.
[3] For yne-enones, see B. M. Trost, R. E. Brown,
F. D. Toste, J. Am. Chem. Soc. 2000, 122, 5877.
[4] For 1,5-enynes, see Y. Chen, D. M. Ho, C. Lee, J.
Am. Chem. Soc. 2005, 127, 12184.
[5] Only highly enolizable ketones can be cyclized
onto alkynes[5a] and alkenes[5b] by using suitable
catalysts, see, for example a) J. J. Kennedy-Smith,
S. T. Staben, F. D. Toste, J. Am. Chem. Soc. 2004,
126, 4526; b) H. Qian, R. A. Widenhoefer, J. Am.
Chem. Soc. 2003, 125, 2056.
[6] The data obtained with catalyst screening, addi-
tives, effect of water and time-dependent product
Scheme 3. One-pot synthesis of new bicyclic [5.3.0]ketones.
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Chemie
distribution are provided in Table S1 and Figure S1 of the
Supporting Information.
[14] PtCl2-catalyzed hydration of ketone species 43 gave bicyclic
compound 44 (81%) rather than the desired spiro ketone 2b.
Both species 43 and its tris-ketone intermediate M can be
excluded from being the reaction intermediate in this spiro
ketone synthesis. Spectra data of compounds 43 and 44 are
provided in the Supporting Information.
[7] This system is proposed to form PtCl2(CO)n; see a) A. Fürstner,
P. W. Davies, T. Gress, J. Am. Chem. Soc. 2005, 127, 8244; b) A.
Fürstner, C. Aïssa, J. Am. Chem. Soc. 2006, 128, 6306; c) A.
Fürstner, P. W. Davies, J. Am. Chem. Soc. 2005, 127, 15024.
[8] CCDC-631140 (2b), CCDC-631139 (28a), and CCDC-632066
(40) contain the supplementary crystallographic data. These data
can be obtained free of charge from the Cambridge Crystallo-
graphic Data Center via www.ccdc.cam.ac.uk/data request/cif.
[9] Triynes 19–22 gave the following products (and yields) after a
reaction period of 36 h: 25a (28%)/25b (39%) for entry 1; 26a
(31%)/26b (42%) for entry 2; 27a (11%)/27b (46%) for
entry 3; 28a (21%)/28b (45%) for entry 4.
[10] For selected examples of metal-catalyzed hydration of alkynes,
see a) W. Hiscox, P. W. Jennings, Organometallics 1990, 9, 1997;
b) W. Baidossi, M. Lahav, J. Blum, J. Org. Chem. 1997, 62, 669;
c) Y. Fukuda, K. Utimoto, J. Org. Chem. 1991, 56, 3729; d) E.
Mizushima, K. Sato, T. Hayashi, M. Tanaka, Angew. Chem. 2002,
114, 4745 – 4747; Angew. Chem. Int. Ed. 2002, 41, 4563 – 4565.
[11] Treatment of prop-1-ynylbenzene with PtCl2/CO (10 mol%) and
water (25 equiv) in hot 1,4-dioxone gave a mixture of phenyl
ethyl ketone a and benzyl methyl ketone b (a/b 1.8).
[15] This new cyclization can be extended to triyne 45 bearing a
bridging alkene group; the yield of spiro ketone 46 was 41%
using PtCl2/CO and HPF6 as an additive. Spectroscopic data of
compounds 45–46 are provided in the Supporting Information.
[12] For this 6-endo-dig cyclization, see a) N. Asao, K. Takahashi, S.
Lee, T. Kasahara, Y. Yamamoto, J. Am. Chem. Soc. 2002, 124,
12650; b) N. Asao, H. Aikawa, Y. Yamamoto, J. Am. Chem. Soc.
2004, 126, 7458.
[13] Blum and co-workers[10b] used PtCl4/CO (200 psi) to catalyze the
hydrative cyclization of triyne 41 in wet THF (5% water) to
obtain indenone 42 (91% yield) by a two-component coupling,
and this ketone product is obtained from aldol condensation of
the tris-ketone intermediate L. The active catalytic intermediate
is proposed to be HPtCl(CO)2.
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