Transformation of reactive lsochromenylium intermediates to stable salts and their cascade reactions with olefins

Article abstract of DOI:10.1021/ol9019524

Transformation of reactive isochromenylium intermediates to the corresponding storable and stable reagents has been achieved, and a number of isochromenylium tetrafluoroborates (ICTBs, 1) have been conveniently prepared and characterized. Direct metal-fre

Full text of DOI:10.1021/ol9019524

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4676-4679
Transformation of Reactive
Isochromenylium Intermediates to Stable
Salts and Their Cascade Reactions with
Olefins
Zhi-Long Hu,† Wen-Jian Qian,† Sheng Wang,‡ Shaozhong Wang,‡ and
Zhu-Jun Yao*,†,‡
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China, and Nanjing National Laboratory of Microstructures, School
of Chemistry and Chemical Engineering, Nanjing UniVersity, 22 Hankou Road,
Nanjing, Jiangsu 210093, China
yaoz@mail.sioc.ac.cn; yaoz@nju.edu.cn
Received August 23, 2009
ABSTRACT
Transformation of reactive isochromenylium intermediates to the corresponding storable and stable reagents has been achieved, and a number
of isochromenylium tetrafluoroborates (ICTBs, 1) have been conveniently prepared and characterized. Direct metal-free treatment of
isochromenylium tetrafluoroborate 1a with olefins afforded a variety of polycyclic frameworks 4 via mild cascade reactions. Starting from the
prefunctionalized o-alkynylbenzaldehydes, a one-pot metal-free procedure of intramolecular cascade annulation to 2,3-dihydrophenanthren-
4(1H)-one derivatives was also developed.
Isochromenyliums, a type of reactive intermediate, have
attracted great attention of organic chemists in recent
years.1-3 They are commonly produced in situ as inseparable
intermediates in the treatment of o-alkynylbenzaldehydes
with certain metal catalysts (AuX3,4 AgX,5 CuX2,6 PdX2,7
W,8 PtX2,9 etc.) or some electrophiles (IPy2BF4, I2,10 TfOH,11
(4) (a) Asao, N.; Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002,
124, 12650–12651. (b) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am.
Chem. Soc. 2003, 125, 10921–10925. (c) Asao, N.; Aikawa, H.; Yamamoto,
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D.; Liu, J. H. Angew. Chem., Int. Ed. 2003, 42, 4399–4402. (e) Patil, N. T.;
Yamamoto, Y. Chem. ReV. 2008, 108, 3395–3442. (f) Arcadi, A. Chem.
ReV. 2008, 108, 3266–3325. (g) Li, Z. G.; Brouwer, C.; He, C. Chem. ReV.
2008, 108, 3239–3265. (h) Jin, T. N.; Yamamoto, Y. Org. Lett. 2007, 9,
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† Chinese Academy of Sciences.
‡ Nanjing University.
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Nava, E. M.; Merritt, A. T.; Wills, M. J. Org. Chem. 2001, 66, 3284–
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Yao, Z.-J. J. Am. Chem. Soc. 2007, 129, 6400–6401. (c) Wei, W.-G.; Zhang,
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Gowin, K. M.; Pettus, T. R. Org. Lett. 2006, 8, 3481–3483. (e) Zhu, J. L.;
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10.1021/ol9019524 CCC: $40.75
Published on Web 09/18/2009
 2009 American Chemical Society

etc.). Roles of the catalysts or promoters are thought to
activate the alkyne and initiate the subsequent intramolecular
cyclization by the oxygen of a carbonyl group. However,
few have been involved in deeply understanding the chemical
properties of isochromenyliums (salts or intermediates)
including their physical characterizations. Although the
present in situ protocols of generating isochromenyliums with
assistance of metal catalysts or promoters simplify the
experimental operations in many successful reactions, uses
of the reactants and reagents are usually inaccurate in
stoichiometry and highly dependent on the experience of
researchers. In some multistep cascade transformations
involving isochromenyliums, optimization of conditions in
those unsatisfactory cases is rather difficult. Therefore,
thorough understanding of isochromenyliums is of great
value for broadening their further applications in organic
synthesis. Undoubtedly, acquirement of isochromenylium
intermediates as a stable and storable form will be a shortcut
to resolve all of these questions. Unfortunately, such storable
isochromenyliums have remained challenging for several
decades.12 In this work, we report our recent achievement
on the air- and moisture-stable isochromenylium salts,
including their preparation and full characterizations as well
as their use in the cascade reactions with variously substituted
olefins.
stable reagents, for example, Me3OBF4,13 tetrafluoroboric
acid was thus employed to our experiments. To our delight,
simple treatment of o-alkynylbenzaldehydes 2a with tet-
rafluoroboric acid in acetic acid gave a yellow solid 1a in a
high yield (Scheme 1). This solid is considerably stable in
Scheme 1
.
Preparation of Stable Isochromenylium
Tetrafluoroborates 1
To obtain a stable isochromenylium salt for NMR mea-
surements, our initial attempts focused on the optimiziation
of the literature conditions. However, the known
procedures2b,c,3 could not afford a qualified sample for a
clean NMR spectrum. Instead, rather complicated mixtures
1
were often indicated by the corresponding H NMRs. To
the open air and can be stored in the laboratory for more
than a year at room temperature. No decomposition and other
transformations have been observed when exposured to air
even at 60-100 °C (either in the solution or in the solid
state) after one day. Its 19F NMR shows a typical signal of
BF4 at -151.2 ppm, and its H NMR unambiguously
indicates an identical isochromenylium structure. Isochrome-
nylium tetrafluoroborate (ICTB) 1a was further characterized
by 13C NMR, IR, mass spectrum, and elemental analysis,
and finally confirmed by the X-ray crystallographic analysis
(see Supporting Information).14
improve the stablility of reactive isochromenylium species,
introduction of a suitable counterion was thus considered.
Treatment of o-alkynylbenzaldehyde 2a with Brønsted acids
HCl, TFA, and HClO4 were examined, respectively. Unfor-
tunately, all of the produced solid precipitations were unstable
when they were exposed to the air at room temperature.
-
1
-
Because tetrafluoroborate (BF4 ) has been frequently used
as a counterion to stabilize oxoniums in some chemically
Chem. 1996, 61, 5804–5812. (c) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org.
Chem. 2004, 69, 1126–1136.
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Chem. Soc. 2002, 124, 764–765. (b) Li, J. J.; Gribble, G. W. Palladium in
Heterocyclic Chemistry; Pergamon: New York, 2000.
To examine the structural scope, a number of other
isochromenylium tetrafluoroborates with different substitu-
ents were accordingly prepared. Using the substrates (2a-2e)
bearing 3,4-dimethoxyl functionalities on their corresponding
phenyl ring, satisfactory yields of the expected salts (1a-1e)
were achieved (Scheme 1). In all these examples, the nature
of alkyne-substituent of substrates 2 affects little on the
corresponding results. A naphthalene-derived substrate 2g
also afforded good yield of isochromenylium salt 1g.
Existence of a phenol hydroxyl group (2f) does not affect
the formation of the corresponding salt 1f. Advantageously,
all of these isochromenylium tetrafluoroborates could be
(8) (a) Kusama, H.; Funami, H.; Shido, M.; Iwasawa, N. J. Am. Chem.
Soc. 2005, 127, 2709–2716. (b) Maeyama, K.; Iwasawa, N. J. Am. Chem.
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Iwasawa, N. Angew. Chem., Int. Ed. 2008, 47, 4903–4905.
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J. Am. Chem. Soc. 2003, 125, 9028–9029. (b) Barluenga, J.; Va´zquez-Villa,
H.; Ballesteros, A.; Gonza´lez, J. M. AdV. Synth. Catal. 2005, 347, 526–
530. (c) Barluenga, J.; Va´zquez-Villa, H.; Merino, I.; Ballesteros, A.;
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Larock, R. C. J. Org. Chem. 2007, 72, 9643–9647.
(11) (a) Singh, V.; Krishna, U. M.; Vikrant, V.; Trivedi, G. K.
Tetrahedron 2008, 64, 3405–3428. (b) Tovar, J. D.; Swager, T. M. J. Org.
Chem. 1999, 64, 6499–6504. (c) Goldfinger, M. B.; Crawford, K. B.;
Swager, T. M. J. Am. Chem. Soc. 1994, 116, 7895–7896.
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3559–3563.
(13) Me3OBF4 is a commercial available reagent. Tetrafluoroborate anion
was frequently utilized as counterion to stabilize the oxoniums and
ammoniums.
(14) Crystal sample of 1a for X-ray single crystallographic study was
obtained from a mixed solvent of acetonitrile and petroleum ether.
Org. Lett., Vol. 11, No. 20, 2009
4677

conveniently prepared at room temperature in a scale up to
100 g. Simple filtration and solvent washes (to remove the
unreacted substrates and excess reagents) in the open air are
sufficient to afford the qualified samples for analyses.
However, under the same conditions, those substrates 2
having electron-withdrawing group(s) and/or halogen(s) on
their phenyl ring failed to provide the corresponding isoch-
romenylium salts; instead, a dimerization reaction happened.
In those metal-catalyzed reactions with olefins, the substrates
bearing electron-withdrawing group(s) also could not afford
corresponding products.4-6,8 Fortunately, the phenol and/or
phenol methyl ethers existing in the above stable ICTBs
would make future further transformations (of the obtained
products after their reactions) possible to more diverse
functionalities including the carboxylic ester, amide, aniline,
cyanid, and aryl halide through the corresponding intermedi-
ates ArOTf.
density markedly. In addition, fluorines of tetrafluoroborate
anions are found to serve as the hydrogen bonding acceptors
in the crystal.
Because ring B presents weak Hu¨ckel aromaticity in
crystal 1a, ICTBs 1 are likely suitable oxa-dienes for the [4
+ 2] cycloadditions. A simple olefin 1-heptene (3a) was thus
chosen as the substrate to examine the corresponding reaction
with ICTB 1a (Table 1). Screening of reaction conditions
Table 1. Screening of Conditions for the Reaction of ICTB 1a
with 1-Hepatene 3aa
The crystal structure of ICTB 1a (Figure 1) shows that
all three rings A/B/C are approximately in the same plane
entry
solvent
temp. (°C)
time (h)
yield (%)b
1
2
3
4
5
6
7
8
THF
THF
25
60
25
60
25
60
25
60
48
48
48
48
24
7
2
<10
16
<10
14
73
72
toluene
toluene
1,2-DCE
1,2-DCE
MeCN
MeCN
76
75
40 min
a Mixture of isochromenylium tetrafluoroborate 1a (0.1 mmol) and
1-hepatene 3a (0.2 mmol) was stirred in the indicated solvents (5 mL,
anhydrous) at room temperature or at 60 °C. b Isolated yields of 4a.
showed that MeCN was the best solvent. Under the optimized
conditions, 1,2-dihydronaphthalene 4a was afforded in
75-76% yield in shorter reaction times (Table 1, entries
7-8).
Figure 1. ORTEP drawing of isochromenylium tetrafluoroborate
Under the optimized conditions, substrate scope of olefins
3 were further investigated (Table 2). Reactions of 1a usually
took place rapidly in MeCN at 25 °C with the monosubsti-
tuted, disubstituted, and trisubstituted olefins, as well as the
cyclic olefins 3g and 3h, affording satisfactory yields of
diverse 1,2-dihydronaphthalenes 4 (Table 2, entries 1-2 and
5-9). The relative configurations of products 4 were
confirmed by corresponding NOESY experiments. However,
reaction of 1a with 3-buten-1-ol (3d), which contains both
terminal olefin and hydroxyl functionalities, afforded the
acetal product 4d only. Obviously, reaction of the “unusual”
carbonyl functionality of 1a with the hydroxyl group of olefin
substrate 3d is much faster than the corresponding [4 + 2]
reaction with terminal olefin of 3d (entry 4). In the production
of 4i (entry 9), a 1,2-alkyl migration was involved prior to
the final proton elimination. To our surprise, reaction of 1a
with R,ω-diene 3j stopped at the mono-olefin addition stage
(entry 10). It is inferred that further reactions with the second
terminal olefin of 3j are unfavorable by either intramolecular
or intermolecular ways. Indole (3k) was also a good substrate
for this cascade reaction, affording tetracyclic product 4k in
43% yield (entry 11). Although indole was frequently used
as the electron-donating agent, no addition of 3k was detected
to the C-1 position of 1a in this reaction.
1a and the bond lengths (red digitals).
so that the positive charge of the oxygen (O1) could be
delocalized to the best extent. This provides a large electronic
conjugated system and makes ICTB 1a sufficiently stable.
Unsymmetrical distribution of carbon-carbon bonds in the
pyrylium ring B of crystal 1a indicates that it is an unusual
aromatic system.15 Ring C is also affected by ring B. The
lengths of C2-C3 and C1-C5 are more close to a double
bond, while the lengths of C3-C4 and C4-C5 show the
tendency to a single bond. The difference of bond lengths
of O1-C1 (1.32 Å, ring B) and O1-C2 (1.37 Å) suggests
that C1-O1 is more likely an activated carbonyl group. The
contact forces are also found between different layers of
ICTB 1a in the crystal. Complex inter- and intramolecular
hydrogen bonding networks are observed in the crystal cell
parameters (for a summary, see Supporting Information).
Such interactions of hydrogen bondings not only help to
stabilize energetic compounds substantially but also help to
pile up the molecules orderly and thus increase the crystal
(15) In a typical aromatic ring system, each carbon-carbon bond length
is almost equal due to the π-electron delocalization effects.
4678
Org. Lett., Vol. 11, No. 20, 2009

provides a new straightforward metal-free access to the 2,3-
dihydrophenanthren-4(1H)-one skeleton, which represents the
tricyclic core structure of a number of biologically interesting
natural products such as danshenxinkun B16 and bisprioterone
C.17 Isochromenylium 5′ is thought to be the intermediate
involved in this cascade process (Scheme 2).
Table 2. Reactions of ICTB 1a with Olefins 3a
Scheme 2. HBF4-Promoted One-Pot Construction of
2,3-Dihydrophenanthren-4(1H)-one
In summary, a number of air- and moisture-stable isoch-
romenylium tetrafluoroborates were conveniently prepared
and characterized for the first time. These solid materials
could be stored in the laboratory without any protection and
used as regular laboratory reagents. Direct metal-free reac-
tions of representative ICTB 1a with olefins were studied,
and a variety of multiple-ring-containing frameworks were
afforded via efficient cationic cascade pathways. In addition,
a one-pot procedure for the synthesis of 2,3-dihydrophenan-
thren-4(1H)-one derivatives under metal-free conditions was
also developed in this work.
Acknowledgment. This project was financially supported
byMOST(2010CB832200,2009ZX09501),NSFC(20672128,
20621062),CAS(KJCX2-YW-H08),andSHMCST(08JC1422800,
07DZ22001). Y.Z.J. is a principle investigator of e-Institute
of Chemical Biology of Shanghai Universities.
a Mixture of isochromenylium tetrafluoroborate 1a (0.1 mmol) and olefin
3 (0.2 mmol) was stirred in anhydrous MeCN (5 mL) at 25 °C for 1 h.
b Isolated yields of 4. c Reaction temperature is 60 °C. d Reaction time is
8 h. e Olefin 3 (4.0 equiv) was used. f Reaction time is 10 min. g Reaction
time is 18 h.
Supporting Information Available: Experimental details
and charaterizations of new compounds, NMR copies of new
compounds, and X-ray crystal data of 1a. This material is
available free of charge via the Internet at http://pubs.acs.org.
With the above results (Table 2), we deduced that the
cycloisomerizations would be possible using an intramo-
lecular cascade reaction by direct treatment with HBF4. A
prefunctionalized acetylene-aldehyde substrate, 2-alkynyl-
benzaldehyde 5, was thus prepared. To our delight, direct
treatment of 5 with HBF4 in acetic acid ar room temperature
afforded 43% yield of the expected tricyclic product 6. This
OL9019524
(16) Don, M.-J.; Shen, C.-C.; Syu, W.-J.; Ding, Y.-H.; Sun, C.-M.
Phytochemistry 2006, 67, 497–503.
(17) Xu, J.; Chang, J.; Zhao, M.; Zhang, J.-S. Phytochemistry 2006,
67, 795–799.
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