Construction of multiring frameworks by metal-free cascade reactions of stable isochromenylium tetrafluoroborate

Article abstract of DOI:10.1021/jo902051g

(Chemical Equation Presented) Efficient methodologies for constructing several multiring frameworks have been developed utilizing the cascade reactions of air-stable isochromenylium tetrafluoroborates with olefins. Successive additions of two equivalents

Full text of DOI:10.1021/jo902051g

pubs.acs.org/joc
Construction of Multiring Frameworks by Metal-Free Cascade Reactions
of Stable Isochromenylium Tetrafluoroborate
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 September 23, 2009
Efficient methodologies for constructing several multiring frameworks have been developed utilizing the
cascade reactions of air-stable isochromenylium tetrafluoroborates with olefins. Successive additions of two
equivalents of styrene-type olefins to isochromenylium tetrafluoroborate (ICTB) 1 have been observed and
their mechanisms were proposed and discussed. Intramolecular capture of the early stage cationic intermediates
by predevised heteroatoms or Friedel-Crafts donors provided two different types of bridged-ring systems.
Introduction
activate the alkyne functionality and then to initiate the
subsequent intramolecular cyclization by the oxygen of the
carbonyl group. Such in situ produced isochromenylium
intermediates are very reactive to olefins, giving 1,2-dihy-
dronaphthalenes5d,7a (reaction a in Scheme 1) and oxa-bridged
Isochromenylium cations, a type of reactive intermediates,
have attracted great attention from organic chemists in
recent years.1-3 They have been reported to be involved in
many cascade transformations in constructing complex
multiring frameworks.4 Previously, isochromenyliums were
commonly produced in situ as inseparable intermediates by
treatment of o-alkynylbenzaldehyde precursors with metal
catalyst or promoters (AuX3,5 AgX,6 CuX2,7 PdX2,8 W,9
PtX2,10 etc.) or other electrophiles (IPy2BF4,11a-d I2,11e-g
TfOH,12 etc.). The catalysts or promoters are thought to
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DOI: 10.1021/jo902051g
r
Published on Web 10/28/2009
J. Org. Chem. 2009, 74, 8787–8793 8787
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SCHEME 1. Representative Reactions of Isochromenyliums with Olefins and Nucleophiles
frameworks9a-e (reaction b in Scheme 1) through a [4þ2]- or
a [3þ2]-cycloaddition process, respectively. In addition, they
are able to react with a variety of nucleophiles, affording
the corresponding 1H-isochromene products6a,11a,d,f (reaction
c in Scheme 1). Among these recent methodologies, due to
the excellent alkynophilicity, the gold-based alkyne activa-
tion has attracted special attention as a flexible catalytic
strategy for various efficient cascade transformations.13,14
However, optimization of those unsatisfactory cases is rather
difficult in the protocols using the in situ generated isochro-
menylium intermediates for many unknown factors associated
with inaccurate stoichiometry of reactants and reagents. For
the first time, we successfully prepared and characterized
a number of air- and moisture-stable and storable isochro-
menylium tetrafluoroborates (ICTBs) without using any
metals.15 Furthermore, these stable ICTBs could be used as
a regular reagent and retain the high reactivity with various
olefins (reaction d in Scheme 1).15 Unambiguously, the
isolation and application of the air- and moisture-stable
isochromenylium salts would greatly facilitate the discovery
of novel transformations and show the versatility of future
methodologies.
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TABLE 1. Reactions of Isochromenylium Tetrafluoroborate 1 with Styr-
enes and Allylsilanea
SCHEME 2. Direct Reaction of ICTB 1 with Styrene 2a
frameworks of biologically important natural products.17 In
this article, we wish to report our results in the development
of novel metal-free efficient cascade reactions suitable for
constructing polycyclic frameworks with the stable ICTBs.
Results and Discussion
Using the representative stable isochromenylium tetra-
fluoroborate 1 as the discovery platform, a wide range of
olefins were examined. More differently from our previous
observation,15 successive additions of 2 equiv of styrene-type
olefins and allylsilane to ICTB 1 were first observed in our
study (Table 1). For instance, reaction of 1 with styrene 2a
(2 equiv) afforded two products 3a (51%) and 3a0 (20%)
(Scheme 2), whose structures and relative configurations
were determined by the corresponding 2D NMR studies
and further confirmed by their X-ray crystallographic ana-
lyses (see the Supporting Information). Reducing the
amount of styrene 2a to 1.0 equiv did not significantly affect
the ratio of products 3a (21% yield of 3a basis on 1) and 3a0
(12%), except their relatively lower yields.
Similar results were also observed in other reactions with
styrenes 2b-e without strong electron-withdrawing
substituent(s) (Table 1, entries 2-5), as well as allyltrimethyl-
silane 2f (entry 6). In the latter case, two molecules of
allylsilane 2f were incorporated into the final product, and
one molecule of trimethylsilane, instead of a proton, was
eliminated at the final stage of the cascade process. Excep-
tionally, reactions with four styrenes 2n-q bearing a strong
electron-withdrawing group gave the monoadducts 4a-d
(entries 7-10), which were thought to follow our previously
proposed pathway.15 In addition, reactions with disubstitut-
ed or trisubstituted styrenes 2r and 2s also stopped at the
single-olefin-addition stage, affording 1,2-dihydronaphtha-
lenes 4e and 4f (entries 11 and 12).
As far as we know, few examples have been reported
incorporating 2 equiv of olefins in the cascade reactions
involving isochromenylium intermediates. According to
our above results, a mechanistic explanation is proposed as
Figure 1. At first, [4þ2]-cycloaddition takes place between
the isochromenylium oxa-diene 1 and styrene 2a, giving a
bridged oxonium intermediate A (Figure 1A). This inter-
mediate then counterpoises to the other open form B, which
is immediately trapped by the second molecule of styrene 2a
to afford a new intermediate C. At this stage, two pathways
compete with each other: In path a, a proton is eliminated
to give the olefin product 3a; while path b undergoes a
aA mixture of ICTB 1 (0.1 mmol) and olefin 2 (0.2 mmol) in
anhydrous MeCN (5 mL) was stirred at 25 °C for 1 h. b25 °C, 8 h.
cOther double-olefin-addition products were also isolated as an insepar-
able mixture of E- and Z-olefin isomers (∼30% yield based on 1,
detected by MS). dThe reaction time was 10 min. e60 °C, 1 h.
(17) (a) Don, M.-J.; Shen, C.-C.; Syu, W.-J.; Ding, Y.-H.; Sun, C.-M.
Phytochemistry 2006, 67, 497–503. (b) Xu, J.; Chang, J.; Zhao, M.; Zhang,
J.-S. Phytochemistry 2006, 67, 795–799. (c) Nimgirawath, S.; Udomputtimekakul,
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5, 831–834.
natural and unnatural functional molecules and useful build-
ing blocks of multiple-ring systems in organic synthesis.
Encouraged by our recent achievement in stable ICTBs,15
we extended our further methodology exploration to the new
cascade transformations building multiple ring-containing
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FIGURE 1. Proposed mechanism for reactions of ICTB 1 with various styrenes.
SCHEME 3. Reactions of ICTB 1 with Styrenes 2t and 2u
Friedel-Crafts reaction to afford a more complex tricyclic
compound 3a0. For those styrene substrates having electron-
withdrawing group(s) (Table 1, entries 7-10), the further
reaction with the second molecule of styrene is electronically
unfavorable (to give the less stable carbocation C-1, Figure 1B)
and thus less competitive in dynamics. In contrast, elimination
of a proton from the intermediate B-1 is a more favorable
pathway and results in a fast reaction providing the 1,2-
dihydronaphthalene products. In the reaction with (E)-1,2-
diphenylethene (Table 1, entry 11), approach of the second
molecule of (E)-1,2-diphenylethene to intermediate B-2 is
spatially unfavorable (Figure 1C). Such explanation is also
eligible to the last example in Table 1 (entry 12).
The above cascade chemistry of stable ICTBs unambigu-
ously provides us new insights into their potential applica-
tions in constructing novel multiring frameworks. To
further explore the kinetically favorable type of C-C
double bond between the terminal olefin and styrene, as
well as the possible prolonged cationic cascade with the
second olefin, two additional styrenes 2t and 2u were then
FIGURE 2. Design of cascade reactions for bridged-ring frame-
works P-1 and P-2.
designed and examined (Scheme 3). Under the same condi-
tions, the terminal olefin functionality in both cases did not
participate in the reactions, and no further extended cas-
cades were observed. Obviously, styrene-type olefins are the
preferred reaction partner for ICTB 1, providing 1,2-dihy-
dronaphthalenes 4g and 4h in 74% and 77% yield, respec-
tively.
Because intramolecular capture of the carbocation inter-
mediates by additional C-C double bonds failed (Scheme 3),
devising alternative suitable C-, O-, or N-based functionalities
was considered to intramolecularly receive the carbocation
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TABLE 2. Reaction of ICTB 1 with 2-Allylphenol 5fa
SCHEME 4. Reaction of ICTB 1 with o-Vinylaniline 7
intermediates at the stage of intermediates D and E
(Figure 2). If this new design works, two different types of
bridged-ring frameworks would be furnished after the cor-
responding cascade reactions.
o-Vinylaniline 7 was first examined to react with ICTB 1 in
MeCN. After treatment for 24 h at room temperature, the
reaction became very complicated and did not afford any
expected products. When the reaction temperature was
raised to 60 °C, after 1 h, a single benzophenanthridine
derivative 8 was afforded instead of the expected brid-
ged product (P-1, Figure 2) (Scheme 4). Undoubtedly,
benzophenanthridine 8 was produced via a [4þ2]-cycloaddi-
tion of ICTB 1 with styrene 7 followed by a dehydrative
imine-cyclization and an auto-oxidative aromatization.
To dismiss the undesired intramolecular imine-cycliza-
tion, olefin substrate 5f containing a phenol hydroxyl group
was then examined under the same conditions. Theoretically,
reaction of 1 with olefin-phenol 5f would give two possible
products 6f and 6f0 according to the analysis in Figure 2.
However, only [4.1.4]-bicyclic product 6f was afforded in this
reaction (Table 2). The structure and relative chemistries of
6f were confirmed by its X-ray single crystallographic study.
Optimization of the reaction conditions showed that MeCN
was the most suitable solvent for this type of cascade reaction
(Table 2), and increasing the amount of olefin 5f (to 2.4 equiv)
could not further accelerate the reaction and improve the yield
of product (entry 8). It is speculated that the transition state(s)
leading to [4.1.4]-bicyclic framework 6f might be more favor-
able in energy than that for the other theoretically possible
[4.1.5]-bicyclic product 6f0.
Prompted by the above achievement, a variety of olefin
substrates 5 were then examined under the above optimized
conditions (Table 2). All these reactions provided the corre-
sponding polycyclic structures 6 in excellent regio- and dia-
stereoselectivities and satisfactory yields (Table 3, 57-84%).
This unambiguously indicated that all these achieved cascade
reactions presented very high efficiency in the whole process.
Reactions of 1 with olefins 5b and 5c containing a phenol
functionality (entries 2 and 3) and olefins 5d and 5e having an
amide functionality (entries 4 and 5) afforded the P-1 products
(approach a, Figure 2), in which the carbocation intermediates
were finally captured by the corresponding intramolecular
heteroatoms. Alternatively, the P-2 products (Figure 2,
approach b) were generated in other examples where the
cascade pathways were terminated by an intramolecular
Friedel-Crafts reaction. In addition, excellent regioselectiv-
ities were observed in several examples (Table 3, entries 9, 13,
and 15). It is believed that all these regioselectivities were
determined by the favorable directions of the corresponding
Friedel-Crafts reactions. For the reactions with olefins 5i
(entry 9) and 5m (entry 13), the less hindered direction was
favored in the Friedel-Crafts cyclizations, while the regio
selectivity observed in the reaction with olefin 5o (entry 15) is
entry
solvent
temp [°C]
time [h]
product
yield [%]
1
2
3
MeCN
THF
toluene
1,2-DCE
DCM
MeCN
MeCN
MeCN
MeCN
60
60
60
60
40
25
80
60
60
5
24
24
24
24
24
5
6f
6f
6f
6f
6f
6f
6f
6f
6f
66
27
18
43
15
24
62
68
61
4
5b
6
7b
8c
9
5
24
aA mixture of ICTB 1 (0.1 mmol) and olefin 5f (0.12 mmol) in
anhydrous solvent (5 mL) was stirred for the indicated times. bThe
reaction was carried out under reflux. cOlefin 5f (0.24 mmol) was used.
more likely controlled by the electron factor of the substrate,
favorably occurring at the R-position of naphthalene. Unfor-
tunately, our further attempts failed to provide the [4.1.6]-
bicyclic frameworks and other larger medium-size rings.
Conclusions
In summary, new metal-free cascade reactions suitable for
the synthesis of several multiring frameworks have been
developed in this study, utilizing the air- and moisture-stable
isochromenylium tetrafluoroborates. Involvement of the
successive addition of 2 equiv of olefins was observed, and
their mechanisms were accordingly proposed and discussed.
New methodologies applying isochromenylium chemistry
were designed, explored, and optimized for efficient construction
of different bridged-ring frameworks by the intramolecular
capture of cationic intermediates with prefunctionalized
heteroatoms or Friedel-Crafts donors. Further application
of our newly developed methodology to target- and diver-
sity-oriented organic synthesis is currently under investiga-
tion in this laboratory.
Experimental Section
Synthesis of Compound 3a. To a solution of 1 (35 mg,
0.1 mmol) in dry CH3CN (5 mL) was added olefin 2a (0.2 mmol)
at room temperature under N2 atmosphere. After the starting
material was consumed, saturated aqueous NaHCO3 (5 mL)
was added. The mixture was extracted with ethyl acetate (3 ꢀ
10 mL). The combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, and concentrated. The residue
was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate=4:1) to give pure products 3a. Yellow oil;
1H NMR (CDCl3, 400 MHz) δ 7.78 (d, J=7.8 Hz, 2H), 7.49
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JOCArticle
TABLE 3. Reactions of ICTB 1 with Functionalized Alkenes 5a
aA mixture of ICTB 1 (0.1 mmol) and olefin 5 (0.12 mmol) in anhydrous MeCN (5 mL) was stirred at 60 °C for 5 h. bThe reaction time was 10 h.
(t, J=7.4 Hz, 1H), 7.30-7.41 (m, 6H), 7.12-7.25 (m, 6H), 6.76
(s, 1H), 6.41-6.53 (m, 3H), 4.88-4.90 (d, J=7.6 Hz, 1H), 3.83
(s, 3H), 3.67 (s, 3H), 3.60-3.65 (m, 2H), 2.28 (ddd, J=5.5, 9.7,
15.2 Hz, 1H), 2.17 (ddd, J=3.5, 5.3, 13.3 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 202.5, 148.1, 148.0, 143.5, 137.5, 137.4,
134.3, 132.8, 131.1, 130.5, 128.7, 128.6, 127.4, 127.3, 126.7,
126.6, 126.3, 112.6, 111.2, 55.9, 55.8, 54.4, 40,8, 40.3, 35.2; IR
(KBr) vmax 3057, 2962, 1672, 1515, 1260, 798, 692 cm-1; ESI-MS
(m/z) 497 [M þ Naþ]; HRMS (ESI) calcd for C33H30O3Na [M þ
Naþ] 497.2093, found 497.2084.
Syntheses of Compound 6a. To a solution of 1(35 mg, 0.1 mmol)
in dry CH3CN (5 mL) was added olefin 5a (0.12 mmol) at room
temperature under N2 atmosphere. The resulting mixture was
stirred at 60 °C until the starting material was consumed. Saturated
aqueous NaHCO3 (5 mL) was added and the mixture was extracted
with ethyl acetate (3 ꢀ 10 mL). The combined organic extracts were
washed with brine, dried over anhydrous Na2SO4, and concen-
trated. The residue was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate=4:1) to give pure products 6a.
White solid; mp 62-64 °C; 1H NMR (CDCl3, 300 MHz) δ
8.08-8.11 (m, 2H), 7.53-7.67 (m, 3H), 7.24-7.28 (m, 1H),
7.08-7.11 (m, 3H), 6.79 (s, 1H), 6.30 (s, 1H), 4.66 (s, 1H), 3.93
(s, 1H), 3.88 (s, 3H), 3.65 (s, 3H), 3.44 (dd, J=8.1, 17.7 Hz, 1H),
3.01 (d, J=18.0 Hz, 1H), 2.75-2.78 (m, 1H), 2.30-2.36 (m, 1H),
1.93-1.99 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 201.3, 148.1,
147.5, 142.4, 136.7, 135.4, 133.5, 133.2, 129.3, 128.9, 128.7, 127.3,
126.2, 125.9, 123.8, 112.8, 110.7, 55.9, 55.8, 53.7, 39.4, 36.6, 29.6,
25.9; IR (KBr) vmax 2931, 1682, 1515, 1448, 1259, 1221, 1124, 738,
699 cm-1; ESI-MS (m/z) 385 [M þ Hþ]; HRMS (ESI) calcd for
C26H25O3 [M þ Naþ] 385.1800, found 385.1798.
8792 J. Org. Chem. Vol. 74, No. 22, 2009

Hu et al.
Reaction of ICTB 1 with 2-Vinylaniline 7. To a solution of
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for C25H19NO2: C, 82.17; H, 5.24; N, 3.83. Found: C, 82.22;
H, 5.19; N, 3.64.
1 (35 mg, 0.1 mmol) in dry CH3CN (5 mL) was added olefin 7
(0.1 mmol) at room temperature under N2 atmosphere. The
resulting mixture was stirred at 60 °C until the starting
material was consumed. Saturated aqueous NaHCO3 (5 mL)
was added, and the mixture was extracted with ethyl acetate
(3 ꢀ 10 mL). The combined organic extracts were washed with
brine, dried over anhydrous Na2SO4, and evaporated.
The residue was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate = 2:1) to give 8 (27 mg,
76%). Yellw solid; mp 150-154 °C; 1H NMR (CDCl3,
300 MHz) δ 8.65 (d, J = 7.2 Hz, 1H), 8.58 (d, J = 8.7 Hz,
1H), 8.25 (d, J = 6.6 Hz, 1H), 8.08 (d, J = 8.7 Hz, 1H),
7.47-7.76 (m, 7H), 7.32 (s, 1H), 7.25 (s, 1H), 4.02 (s, 3H),
3.32 (s, 3H); IR (KBr) vmax 1611, 1515, 1472, 1218, 1047, 863,
796, 761, 516 cm-1; ESI-MS (m/z) 366 [M þ Hþ]. Anal. Calcd
Acknowledgment. This project was financially suppor-
ted by MOST (2010CB832200), MOH (2009ZX09501),
NSFC (20672128), CAS (KJCX2-YW-H08), and SHMCST
(08JC1422800). Y.Z.J. is a principal investigator of
the e-Institute of Chemical Biology of Shanghai Universi-
ties.
Supporting Information Available: Experimental details and
characterizations of new compounds, NMR copies of new
compounds (PDF), and X-ray crystal data of 3a, 3a0, and 6f
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 22, 2009 8793