Intramolecular Huisgen-type cyclization of platinum-bound pyrylium ions with alkenes and subsequent insertion into a benzylic C-H bond

Article abstract of DOI:10.1002/anie.200802425

Access granted: The platinum-catalyzed cyclization of enynals 1, which contain an additional alkene bond in their side chain, through a [3+2] cycloaddition to give tetracyclic platinum-carbene complexes A was followed by C-H insertion at the δ position to afford highly complex products 2. These polycyclic compounds and related products of the title transformation are extremely difficult to access by other means. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200802425

Angewandte
Chemie
DOI: 10.1002/anie.200802425
Synthetic Methods
Intramolecular Huisgen-Type Cyclization of Platinum-Bound Pyrylium
À
Ions with Alkenes and Subsequent Insertion into a Benzylic C H
Bond**
Chang Ho Oh,* Ji Ho Lee, Su Jin Lee, Jae Il Kim, and Chang Seop Hong
The discovery of new and efficient synthetic routes to
polycycles containing a central seven-membered carbocycle
is still an important challenge for organic and medicinal
chemists, as numerous natural products, including taxol and
its analogues, have a core skeleton of this type.[1] Among the
various strategies for the construction of seven-membered
carbocycles, cycloaddition routes ([4+3] or [5+2]) are partic-
ularly attractive because of their inherent potential for
causing a rapid increase in skeletal complexity.[2] During the
course of our scientific endeavors to develop a general and
modular route to seven-membered-ring-containing natural
products, we observed a unique reactivity of platinum–
carbene complexes B (Scheme 1) formed through a Huis-
gen-type [3+2] cycloaddition between a metal-bound pyry-
lium ion and an alkene side chain.[3]
yne.[6] The versatility of catalytic reactions with substrate 1a
was explored under various conditions (Table 1).
Scheme 1. Three possible reaction pathways for the platinum–carbene
complex B.
Platinum–pyrylium intermediates Awith a double bond in
their side chain underwent [3+2] cycloaddition to form
platinum–carbene complexes B, the deprotonation of which
at the g position in the presence of a basic solvent, followed by
protodemetalation, provided dienes X. Alternatively, depro-
tonation at the g’ position (removal of a proton from the CH
center bonded to the oxygen atom) led to oxidative fragmen-
tation of the pyrylium ring, and subsequent protodemetala-
tion afforded ketones Y (Scheme 1).[4] In the light of these
previous investigations, we were prompted to consider the
insertion of the highly electron deficient carbene in complex
Table 1: Metal-catalyzed reactions of enynal 1a.[a]
Entry
Catalyst
Solvent
T [8C]
t [h]
Products
(yield [%])
1
2
3
4
5
6
7
8
9
PtCl2
PtCl4
PtCl2
PtCl2
[Pt(PPh3)4]
[PtCl2(PPh3)2]
[PtCl2(PPh3)2]
[PtCl2(PPh3)2]
[PtCl2(dppe)]
toluene
toluene
p-dioxane
DCE
toluene
toluene
p-dioxane
DCE
120
120
60
1
1
3
5
12
4
3
12
1
2a (25), 4a (35)
2a (20), 3a (40)
2a (35), 4a (10)
2a (20), 4a (40)
2a (20)
À
B into a specific C H bond. Herein we report a Pt-catalyzed
domino process involving a Huisgen-type [3+2] cyclization
and subsequent insertion of the proposed platinum–carbene
intermediate into a benzylic bond to form furans of type 2.
We designed the substrate 1a as a model compound to
80
120
120
60
80
120
2a (77)
2a (30), 4a (25)
2a (20), 3a (50)
2a (61), 3a (10)
À
study the trapping of the Pt–carbene complex by C H
toluene
insertion.[5] Substrate 1a with a benzyloxy substituent at the
propargylic position was prepared by the Sonogashira cou-
pling of 2-bromobenzaldehyde with 3-benzyloxy-7-octen-1-
[a] Catalyst loading: 5 mol%. Bn=benzyl, dppe=1,2-bis(diphenylphos-
phanyl)ethane.
[*] Prof. C. H. Oh, J. H. Lee, S. J. Lee
Department of Chemistry, Hanyang University
Sungdong-Gu, Seoul 133-791 (Korea)
Fax: (+82)2-2299-0762
When 1a was treated with PtCl2 at 1208C in toluene for
1 h, the reaction afforded two products, 2a and 4a, in 25 and
35% yield, respectively (Table 1, entry 1). In the presence of
PtCl4 under similar reaction conditions, 3a was isolated
instead of 4a in 40% yield, along with 2a (20%; Table 1,
entry 2). Interestingly, when PtCl2 was used as the catalyst in
p-dioxane, the insertion product 2a was formed as the major
product (35%; Table 1, entry 3), whereas 4a was obtained as
the major product (40%) when the reaction was carried out
with the same catalyst in 1,2-dichloroethane (DCE) at 808C
(Table 1, entry 4). The Pt0 complex [Pt(PPh3)4] showed very
weak catalytic activity, with product 2a formed in only in 20%
E-mail: changho@hanyang.ac.kr
Homepage: http://hychemistry.hanyang.ac.kr/gos
J. I. Kim, Prof. C. S. Hong
Department of Chemistry, Korea University
Sungbook-Gu, Seoul 136-704 (Korea)
[**] We thank the Korea Science and Engineering Foundation (R01-2007-
000-20315-0) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802425.
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yield (Table 1, entry 5). [PtCl2(PPh3)2]
proved to be the catalyst of choice: When
1a was treated with this catalyst in toluene
at 1208C, 2a was formed in excellent yield
(77%; Table 1, entry 6). In the solvents p-
dioxane and DCE, treatment with [PtCl2-
(PPh3)2] furnished 2a along with 4a and 3a,
respectively (Table 1, entries 7 and 8).
These results are similar to those observed
under the same conditions with PtC2
(Table 1, entries 3 and 4). Finally, [PtCl2-
(dppe)] also catalyzed this reaction to
afford 2a and 3a in 61 and 10% yield,
respectively.
The formation of 2a, 3a, and 4a can be
understood by considering two different
À
modes of C H insertion of the platinum–
carbene intermediates B1 and B2, which are
Scheme 2. A possible mechanism for the formation of 2a and 3a. PCC=pyridinium
presumably formed by
a Huisgen-type
chlorochromate.
[3+2] cyclization of a platinum-bound pyry-
lium ion with an alkene side chain
(Scheme 2). The platinum–carbene moiety
in the intermediate B2 can undergo inser-
À
tion into the benzylic C H bond to con-
struct the intermediate C, which would be
converted into the product 2a upon the
regeneration of the platinum catalyst.
Alternatively, if the platinum complex D
derived from B1 is taken into consideration
as an intermediate, the formation of the two
products 3a and 4a can be explained
simultaneously. Complex
D might be
formed through the opposite mode of
insertion of the Pt–carbene into the ben-
À
zylic C H bond. A base, expected to form
from the solvent at high temperature, might
abstract a proton from the benzylic position
of D. Fragmentation would follow to pro-
vide the benzoyl platinum complex E,
which could undergo transformation by
two possible pathways, depending on the
orientation of the PhCOPt group and the
activation energy available under the spe-
cific reaction conditions. The proximity
between the alkoxy oxygen atom (or its
protonated hydroxy group) and the benzoyl
Scheme 3. Products 2 of platinum-catalyzed cyclization, and the corresponding substrates
1. PDC=pyridinium dichromate, TBS=tert-butyldimethylsilyl.
group in a cis relationship would result in transfer of the
benzoyl group by path a and subsequent protolysis to provide
3a.[7] The other isomer of E with a trans relationship between
these two groups, however, could undergo internal SN2-type
attack by the oxygen nucleophile to furnish the product 4a
and benzaldehyde as a fragmentation product. The structure
of the unusual product 3a was confirmed by chemical
modification: The hydrolysis of 3a by aqueous NaOH,
followed by oxidation with PCC, gave the corresponding
ketone 5a.
substrates 1b and 1c, with two 4-pentenyl groups attached
to the propargylic carbon atom, were designed and prepared
to investigate competition between cyclopropanation and
insertion of the carbene.[8] These compounds were shown to
have a higher propensity to undergo insertion over cyclo-
propanation to afford 2b and 2c in 80 and 74% yield,
respectively. It is significant that non-aromatic cyclopentene-
linked substrate 1c was also transformed successfully. Sub-
strate 1d, with a 5-hexenyl group on the propargylic carbon
atom, also underwent a cyclization–insertion process to
produce 2d. However, the treatment of 1e, which contains a
3-butenyl group, under our optimized conditions provided
only the tricyclic benzoate ester 3e in 86% yield, rather than
Various substrates were subjected to the optimized
reaction conditions for the formation of 2a to explore the
scope and limitations of this process (Scheme 3). The
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Chemie
3.88 (t, J = 8.4 Hz, 1H), 3.39 (d, J = 10.0 Hz, 1H), 2.29–2.24 (m, 1H),
the product of carbene insertion. The present procedure can
be extended to similar systems. Thus, 1 f and 1g were
prepared according to known procedures[9] and converted
into the corresponding products 2 f and 2g (after desilylation
with tetrabutylammonium fluoride (TBAF) in THF) in 88 and
76% yield, respectively. Finally, 1h, a homologue of 1 f,
2.03–1.89 (m, 5H), 1.82–1.76 (m, 1H), 1.48–1.36 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d = 143.3, 139.0, 132.2, 130.8, 129.3,
127.3, 127.2, 125.8, 125.3, 122.2, 86.5, 84.0, 80.4, 75.7, 50.4, 42.3, 40.2,
31.8, 23.6, 23.3 ppm; HRMS: m/z calcd for C22H22NaO2: 341.1517
[M + Na]+; found: 341.1515.
À
underwent g’ elimination rather than C H insertion under
various conditions to give the ketone 5h in 80% yield; no
Received: May 24, 2008
Revised: June 21, 2008
Published online: August 19, 2008
À
product of C H insertion at the e position was observed.
Although these reactions involve a multistep process, all
products 2 were formed with high stereoselectivities and high
efficiency. To confirm the relative configuration of the
products, we oxidized 2g to the corresponding ketone 6g
with PDC. The X-ray crystal structure of 6g is shown in
Figure 1.[10]
Keywords: cyclization · homogeneous catalysis · insertion ·
platinum · pyrylium ions
.
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Figure 1. X-ray crystal structure of 6g.
In conclusion, enynals 1 with a terminal alkene double
bond in side chain underwent cyclization through a Huisgen-
type [3+2] cycloaddition in the presence of a platinum
catalyst to give a tetracyclic platinum–carbene complex of
type B (Scheme 2). This intermediate undergoes C H
insertion at the d position to afford highly complex products
of type 2 that are difficult to access by other means.
[4] a) N. Kim, Y. Kim, W. Park, D. Sung, A. K. Gupta, C. H. Oh,
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À
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Experimental Section
The enynal (1a–h; 0.10 mmol), [PtCl2(PPh3)2] (5 mol%), and the dry
solvent (0.5 mL) were placed in a new 5 mL test tube at 08C. The
reaction mixture was stirred under an argon atmosphere in a
preheated oil bath (60–1208C) for 1–12 h. Upon completion of the
reaction (as indicated by TLC), the solvent was removed under
vacuum. Flash column chromatography of the residue afforded the
pure product(s). In the case of product 2g, the reaction mixture was
cooled to 08C after completion of the reaction and treated with a
solution of TBAF (1.0m, 1.0 mmol) in THF. Extractive workup and
flash chromatography gave the desilylated compound 2g as a
diastereomeric mixture in 76% combined yield. To obtain a crystal
for X-ray crystallographic analysis, the alcohol 2g was oxidized with
PDC (2 equiv) in dichloromethane. Filtration over celite and flash
chromatography gave the ketone 6g (72%).
1
[7] The identity of all products was confirmed by FTIR, H NMR,
and 13C NMR spectroscopy and HRMS, and further supported
by the X-ray crystal structure of 6g. The structure of 3a was
confirmed further by chemical transformations.
[8] H. Kusama, H. Funami, N. Iwasawa, Synthesis 2007, 2014.
[9] For the preparation of 2-bromocycloalkenecarboxaldehydes
with PBr3/N,N-dimethylformamide, see: a) S. K. Mal, D. Ray,
J. K. Ray, Tetrahedron Lett. 2004, 45, 277; b) K. R. Buszek, Y.
Jeong, Synth. Commun. 1994, 24, 2461.
[10] CCDC 697658 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
2a: IR (NaCl): n˜ = 3024, 2932, 2853, 1488, 1453, 1075, 996 cmÀ1
;
1H NMR (400 MHz, CDCl3): d = 7.23–7.21 (m, 2H), 7.05–6.99 (m,
3H), 6.88–6.82 (m, 2H), 6.72 (td, J = 7.2, 2.0 Hz, 1H), 6.47 (d, J =
8.0 Hz, 1H), 5.35 (d, J = 10.0 Hz, 1H), 5.10 (dd, J = 6.0, 3.0 Hz, 1H),
Angew. Chem. Int. Ed. 2008, 47, 7505 –7507
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