Tandem [4 + 2]/[2 + 2] cycloaddition reactions involving indene or benzofurans and arynes

Article abstract of DOI:10.1021/ol501579d

The reaction of arynes with indene/benzofurans has been developed. The arynes were generated from 2-(trimethylsilyl)aryl triflates by the fluoride-induced 1,2-elimination react with indene or various benzofurans proceeding via a cascade reaction involving

Full text of DOI:10.1021/ol501579d

Letter
pubs.acs.org/OrgLett
Tandem [4 + 2]/[2 + 2] Cycloaddition Reactions Involving Indene or
Benzofurans and Arynes
Sachin Suresh Bhojgude,† Manikandan Thangaraj,† Eringathodi Suresh,‡ and Akkattu T. Biju*,†
†Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune 411008, India
‡Analytical Department and Centralized Instrument Facility (CSIR-CSMCRI), Bhavnagar 364002, Gujarat, India
S
* Supporting Information
ABSTRACT: The reaction of arynes with indene/benzofur-
ans has been developed. The arynes were generated from 2-
(trimethylsilyl)aryl triflates by the fluoride-induced 1,2-
elimination react with indene or various benzofurans
proceeding via a cascade reaction involving the Diels−Alder
reaction and a [2 + 2] cycloaddition reaction. The tandem
process afforded functionalized dihydrobenzocyclobutaphenanthrenes in moderate to good yields. Moreover, the method has
been utilized for the one-pot synthesis of benzo[b]fluoranthene.
Scheme 1. Reaction of Arynes with Styrenes and Indene/
Benzofuran
ver since Wittig’s original demonstration on the Diels−
1,2 the synthetic utility of
EAlder reaction of furan with arynes,
arynes as a dienophile component in Diels−Alder reactions have
been widely used for the construction of benzo-fused carbocycles
and heterocycles.3 In many cases, the Diels−Alder reaction
employing arynes generated from conventional methods (such
as treating haloarenes with a strong base, halogen−metal
exchange of 1,2-dihalobenzenes with organolithium or -magne-
sium reagents, and decomposition of o-benzene diazonium
carboxylate) suffer from drawbacks including low yield of
products, incompatibility with various functional groups, and/or
harsh reaction conditions.4 The generation of arynes by the
fluoride induced 1,2-elimination of 2-(trimethylsilyl)aryl triflates
is a better alternative,5 and a wide range of cyclic and acyclic
dienes can be utilized as 4π-component in Diels−Alder reaction
with arynes generated using this method.6 In addition, the Diels−
Alder reaction of arynes can be coupled with other organic
transformations thereby leading to efficient cascade processes.7
We have recently reported the reaction of arynes with styrenes
leading to the synthesis of 9-aryldihydrophenanthrene deriva-
tives (Scheme 1, eq 1).8,9 The reaction proceeds via a cascade
process initiated by a Diels−Alder reaction of styrenes with
arynes followed by a selective ene reaction. In this context, we
envisioned that if the reaction of arynes is performed with cyclic
systems such as indenes or benzofurans, there is a possibility of
isolating the initial Diels−Alder adducts A (eq 2) as the ene
reaction can be avoided in this case. Surprisingly, however, the
reaction proceeds via a tandem [4 + 2]/[2 + 2] process.10
Notably, a single example on the reaction of benzofuran with
aryne generated by the thermolysis of o-benzene diazonium
carboxylate leading to the synthesis of cascade adduct in 32%
yield has been reported by Anthony and Wege.11 Herein, we
report the unexpected results of our studies on a [4 + 2]/[2 + 2]
cascade reaction involving indene or benzofurans, and arynes
resulting in the formation of dihydrobenzocyclobutaphenan-
threne derivatives in moderate to good yields and excellent
diastereoselectivity (eq 2). In addition, the application of this
method for the one-pot synthesis of benzo[b]fluoranthene has
been presented.
With a view to synthesize the Diels−Alder adduct of aryne and
indene, our present study was initiated by treating indene 2a with
aryne generated in situ from 2-(trimethylsilyl)aryl triflate 1a (1.2
equiv) using 2.4 equiv of CsF and CH3CN as the solvent.
Surprisingly, the expected Diels−Alder adduct 4a was not
isolated, but instead the dihydrobenzocyclobuta phenanthrene
3a was isolated in 48% yield and in excellent diastereoselectivity
of >20:1 (Scheme 2). The product 3a was formed by a tandem
Diels−Alder reaction between 2a and aryne generated from 1a
followed by a stereoselective [2 + 2] cycloaddition reaction of the
initially formed cycloadduct 4a with excess aryne. Interestingly,
when the reaction was carried out using 2.4 equiv of 1a and 4.8
equiv of CsF, 3a was formed in an improved yield of 86%
Received: June 2, 2014
© XXXX American Chemical Society
A
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Letter
Scheme 2. Reaction of Benzyne with Indene
maintaining the diastereoselectivity of >20:1.12 Notably, CsF was
found to be best fluoride source and CH3CN was found to be the
solvent of choice for this tandem process.
This tandem [4 + 2]/[2 + 2] cycloaddition reaction was found
to be quite general with various symmetrically substituted arynes
(Table 1). Electron-donating and -withdrawing groups at 4,5-
Figure 1. ORTEP diagram of 3c (35% probability factor for the thermal
ellipsoids).
+ 2]/[2 + 2] cascade product 6a in 65% yield and excellent
diastereoselectivity of >20:1 (Table 2, entry 1). Notably, the
a
Table 1. Tandem [4 + 2]/[2 + 2] Reaction: Scope of Arynes
Table 2. Tandem [4 + 2]/[2 + 2] Reaction of Benzofuran with
a
Arynes: Scope of Arynes
a
General conditions: 5a (0.50 mmol), 1 (1.50 mmol), CsF (6.0
equiv), CH3CN (2.0 mL), 30 °C and 24 h. Yields of the isolated
b
products are given. Reaction was run on 0.25 mmol scale.
a
General conditions: 1 (1.20 mmol), 2a (0.50 mmol), CsF (4.8
equiv), CH3CN (2.0 mL), 30 °C, and 12 h. Yields of the isolated
products are given. Reaction was run on 0.25 mmol scale.
b
reaction needs 3.0 equiv of aryne precursor 1a and 6.0 equiv of
CsF, and a longer reaction time of 24 h for better results. The
reaction was found to be working with electronically different
4,5-disubstituted arynes, and in all cases the expected product
was formed in moderate yields and in high diastereoselectivity
(entries 1−5). In the case of compound 6b, the structure and
stereochemistry was unambiguously confirmed by single-crystal
X-ray analysis (Figure 2).13 Additionally, the symmetrical 3,6-
dimethylaryne also furnished the bicyclic product 6f in 62% yield
(entry 6).
Then we examined the scope of the reaction with substituted
benzofuran derivatives (Scheme 3). Halogen substitution at a
different position in the carbocyclic ring of benzofuran is well
tolerated and the reaction furnished the [4 + 2]/[2 + 2] cascade
product in moderate yields (6g−i). Notably, the halogenated
cycloadducts are amenable for further derivatization by means of
traditional metal-catalyzed cross-coupling reactions. In addition,
positions of the arynes are well tolerated, and these reactions
afforded the expected dihydrobenzocyclobuta phenanthrene
derivatives 3b−e in moderate to good yields (entries 1−4). In the
case of compound 3c, the structure and stereochemistry was
unequivocally confirmed by single-crystal X-ray analysis (Figure
1).13 Moreover, the symmetrical 3,6-dimethylaryne and the
naphthalyne also afforded the expected products in moderate
yields (entries 5 and 6). Gratifyingly, in all cases, the desired
product was obtained in excellent diastereoselectivity of
>20:1.14−16
Inspired by the interesting results on the reaction of arynes
with indene, we then focused our attention on the reaction of
arynes with benzofurans. Treatment of aryne generated from 1a
using CsF with benzofuran 5a resulted in the formation of the [4
B
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Scheme 4. Synthesis of Benzo[b]fluoranthene
Figure 2. ORTEP diagram of 6b (40% probability factor for the thermal
ellipsoids).
Scheme 3. Scope of Benzofurans in the Tandem [4 + 2]/[2 +
2] Reaction
In conclusion, we have developed a facile and general reaction
of arynes with indene/benzofurans. The reaction took place via a
tandem [4 + 2]/[2 + 2] cycloaddition sequence resulting in the
formation of dihydrobenzocyclobutaphenanthrene derivatives in
moderate to good yields and in excellent diastereoselectivity.
Additionally, the application of this method has been
demonstrated by the one-pot synthesis of benzo[b]¯uoranthene.
Further studies on aryne Diels−Alder reactions with potential
dienes are ongoing in our laboratory.
a
ASSOCIATED CONTENT
* Supporting Information
■
S
Details on experimental procedures, characterization data of all
compounds, and single-crystal X-ray data of 3c and 6b. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Corresponding Author
■
a
General conditions: 5 (0.50 mmol), 1a (1.50 mmol), CsF (6.0
equiv), CH3CN (2.0 mL), 30 °C and 24 h. Yields of the isolated
products are given. Reaction was run on 0.25 mmol scale. 17% of [2
+ 2] adduct was also isolated.
*E-mail: at.biju@ncl.res.in.
Notes
b
c
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
the reaction of arynes with 9-bromonaphthofuran furnished the
cascade product 6j in 38% yield. In this case, 17% of [2 + 2]
adduct derived from aryne and the 9-bromonaphthofuran was
also isolated. In all other cases, the [2 + 2] adduct was formed in
<5% yield. Furthermore, the reaction of arynes with naphtho-
[1,2-b]furan resulted in the formation of the desired cycloadduct
in moderate to excellent yields (6k−m).17
Furthermore, the synthetic potential of this tandem [4 + 2]/[2
+ 2] cycloaddition reaction has been demonstrated by the one-
pot synthesis of benzo[b]fluoranthene, which is a potent
carcinogenic polynuclear aromatic hydrocarbon.18 The reaction
of benzofuran with aryne generated from 1a under the present
reaction conditions followed by the treatment of the reaction
mixture with BF3·OEt2 resulted in the one-pot synthesis of
benzo[b]fluoranthene 7 in 65% yield (Scheme 4).19 The product
formation can be rationalized by the initial formation of the
cycloadduct 6a followed by Lewis acid coordination to the
bicyclic system and subsequent opening of the benzocyclobutane
ring to generate intermediate 8. The intermediate 8 upon proton
loss and a release of a molecule of water furnished 7. It may be
mentioned in this context that the conversion of 5a to 7 in two
steps has been reported by Anthony and Wege.11
This activity was supported by CSIR-New Delhi (as part of the
XII Five Year plan program under ORIGIN-CSC0108). S.S.B.
and M.T. thank CSIR-New Delhi for the award of Research
Fellowships. We thank Dr. P. R. Rajamohanan (CSIR-NCL) for
the excellent NMR support and Dr. S. K. Asha (CSIR-NCL) for
extending the IR facility.
REFERENCES
■
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species.
(12) For details, see the Supporting Information.
(13) CCDC-1005419 (3c) and CCDC-1005420 (6b) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(14) The reaction of unsymmetrical arynes with indene is expected to
deliver four regioisomeric products. In view of the nonpolar nature of
the isomers, and its close Rf values, their purification has not been
attempted.
(15) It may be noted that the reaction of 2a with 1,3,5-trimethyl-2-
vinylbenzene afforded only the [2 + 2] cycloadduct in 40% yield. In this
case, the tandem [4 + 2]/[2 + 2] product was not observed.
(16) Notably, substituted indene derivatives such as 2-bromo-1H-
indene and 2-phenyl-1H-indene did not afford the desired product
under the optimized conditions. Moreover, 2-ethyl-1H-indene
furnished 13% of the cascade product under the present reaction
conditions.
(17) It may be noted that N-methylindole and benzothiophene did not
afford the [4 + 2]/[2 + 2] cascade product with arynes under the present
reaction conditions.
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