A thermal dehydrogenative Diels-Alder reaction of styrenes for the concise synthesis of functionalized naphthalenes

Article abstract of DOI:10.1021/ol301938z

Functionalized naphthalenes are valuable building blocks in many important areas. A microwave-assisted, intramolecular dehydrogenative Diels-Alder reaction of styrenyl derivatives to provide cyclopenta[b]naphthalene substructures not previously accessible using existing synthetic methods is described. The synthetic utility of these uniquely functionalized naphthalenes was demonstrated by a single-step conversion of one of these cycloadducts to a fluorophore bearing a structural resemblance to Prodan.

Full text of DOI:10.1021/ol301938z

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4430–4433
A Thermal Dehydrogenative DielsꢀAlder
Reaction of Styrenes for the Concise
Synthesis of Functionalized Naphthalenes
Laura S. Kocsis, Erica Benedetti, and Kay M. Brummond*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260,
United States
kbrummon@pitt.edu
Received July 12, 2012
ABSTRACT
Functionalized naphthalenes are valuable building blocks in many important areas. A microwave-assisted, intramolecular dehydrogenative
DielsꢀAlder reaction of styrenyl derivatives to provide cyclopenta[b]naphthalene substructures not previously accessible using existing
synthetic methods is described. The synthetic utility of these uniquely functionalized naphthalenes was demonstrated by a single-step conversion
of one of these cycloadducts to a fluorophore bearing a structural resemblance to Prodan.
Designing and synthesizing small molecules for the
purpose of function enables advancement in fields ranging
from pharmaceuticals to pesticides.1 The DielsꢀAlder
(DA) reaction is one of the most powerful and robust
transformations for assembling cyclic molecular frame-
works, employing a plethora of diene (4π) and dienophile
(2π) components capable of delivering a rich diversity of
cyclic compounds poised for function.2 One structural
variant is the dehydro-DielsꢀAlder (DDA) reaction,
where one, two, or all three of the double bonds of the
classic diene and dienophile are replaced with triple bonds,
providing access to substituted aromatic compounds not
accessible using other chemistries.3 The energy price to
incorporate the high degree of precursor unsaturation
required for the formation of aromatic products can be
mitigated by the propensity of cyclohexadiene derivatives
to aromatize. Aromatic derivatives, in turn, can be pre-
pared from more saturated precursors via a two-step
process defined as a dehydrogenative DA reaction.4
A particularly problematic, but potentially useful, dehy-
drogenative DA reaction involves the use of styrene as the
diene component and an alkyne dienophile, affording a
cycloadduct that can aromatize under oxidative conditions
to give naphthalene derivatives (Scheme 1).5
Problems that can arise when using styrene as the diene
range from polymerizations6 to [2 þ 2] cycloaddition
reactions.5a,7 One solution, is to use very reactive dieno-
philes such as maleic anhydride or benzoquinone. How-
ever, the desired cycloadducts are typically obtained in low
yields because the reactivity of these dienophiles leads to a
second DA reaction with the newly formed diene of the
first cycloadduct.5a Lack of regioselectivity for the styrenyl
DA reaction is also a drawback, which can be overcome by
carrying out the reaction intramolecularly.4a,8 The intra-
molecular styrenyl DA reaction also suffers from low
yields and long reaction times, producing mixtures of
dihydronaphthalene and naphthalene products. Even so,
the intramolecular DielsꢀAlder (IMDA) reactions of
(1) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197–201.
(2) Takao, K.-I.; Munakata, R.; Tadano, K.-I. Chem. Rev. 2005, 105,
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5390–5393. (b) For an example of a dehydrogenative reaction that takes
place prior to the DielsꢀAlder reaction, see: Stang, E. M.; White, M. C.
J. Am. Chem. Soc. 2011, 133, 14892–14895.
(5) (a) For an extensive review on styrenyl DielsꢀAlder reactions,
see: Wagner-Jauregg, T. Synthesis 1980, 769–798. (b) For an early
example of styrene as a diene, see: Diels, O.; Alder, K. Justus Liebigs
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r
10.1021/ol301938z
Published on Web 08/22/2012
2012 American Chemical Society

styrenes and electron-deficient alkynes have resulted in the
occasional application of this reaction to the synthesis of
biologically relevant compounds.9
Our investigations differ from other methods for the
synthesis of naphthalene derivatives via the IMDA reac-
tion of styrenes, with most of the others sharing a few com-
mon features such as 1) the enyne precursors contain either
a heteroatom and/or a carbonyl group(s) within the tether
(mainly amides and esters); 2) limited functionality on the
terminus of the alkyne; 3) reaction conditions requiring
high temperatures and long reaction times; and 4) most
naphthalene products are contaminated with varying quan-
tities of dihydronaphthalene byproducts (Scheme 3).13
Moreover, our initial result shows that a TMS group on
the terminus of the alkyne is not essential for the exclusive
formation of the naphthalene over the dihydronaphtha-
lene product.4a
Scheme 1. Styrenyl Dehydrogenative DA Reaction
Continued interest in the development of an efficient
styrenyl DA reaction is driven by the need for functiona-
lized naphthalene compounds that can serve as valuable
building blocks for the synthesis of small molecules in
many important areas, such as pharmaceuticals, chiral
reagents, liquid crystals, and organic dyes.10,11 Moreover,
the intramolecular styrenyl DA reaction affords a unique
functionalization pattern on the resulting naphthalene
derivatives that complements other synthetic approaches.11
Recently, in our studies directed toward expanding the
scope of the thermal [2 þ 2] cycloaddition reaction of
allene-ynes,12 we obtained naphthalene 2 and none of the
anticipated [2 þ 2] cycloaddition product between the
allene and the alkyne of 1 upon microwave irradiation in
ortho-dichlorobenzene at 225 °C for 10 min (Scheme 2)!
While the 1H NMR and 13C NMR spectra of 2 contained
well-defined resonances in the aromatic region diagnostic
of a cyclopenta[b]naphthalene, verification of the structure
of compound 2 was confirmed by an X-ray crystal struc-
ture of para-toluenesulfonyl hydrazone 3. The outstanding
selectivity of this IMDA reaction for the naphthalene
product over the dihydronaphthalene product (1:0), the
high yield, and an overall interest in naphthalene deriva-
tives compelled us to study this reaction further.
Scheme 3. Previously Reported Dehydrogenative IMDA
Reaction
A concise synthesis of a dehydrogenative IMDA sty-
renyl precursor 5 was accomplished in three steps, and in a
manner entirely analogous to that used for the preparation
of 1 (Scheme 4). Aldehyde 4 is prepared by a PCC oxida-
tion of commercially available 5-hexyn-1-ol in 81% yield.
Next, reaction of the lithium salt of diethyl benzylpho-
sphonate with aldehyde 4 affords the styrene moiety of 5 in
68% yield. Deprotonation of the alkyne terminus with
n-BuLi followed by acetylation of the acetylide produces 5
in 69% yield. For the ensuing IMDA reaction, solvents
with lower boiling points were considered because of
difficulties in removing high boiling o-dichlorobenzene.
Scheme 2. Dehydrogenative IMDA Reaction
Scheme 4. IMDA Precursor Synthesis
(8) (a) Klemm, L. H.; Gopinath, K. W. Tetrahedron Lett. 1963, 19, 1243–
1245. (b) Klemm, L. H.; Hsu-Lee, D.; Gopinath, K. W.; Klopfenstein, C. E.
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Gopinath, K. W. J. Org. Chem. 1976, 41, 2571–2579. (d) Ruijter, E.; Garcia-
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Eagen, K.; Greenlee, W. J.; Lin, Y.; Tagat, J. R.; Tsai, H.; Xia, Y.; Ahn,
H.-S.; Agans-Fantuzzi, J.; Boykow, G.; Chintala, M.; Hsieh, Y.;
McPhail, A. T. Bioorg. Med. Chem. Lett. 2007, 17, 3647–3651. Toyota,
M.; Terashima, S. Tetrahedron Lett. 1989, 30, 829–832.
Microwave irradiation of styrene 5 in either 1,2-dichloro-
ethane (DCE) at 180 °C for 30 min or benzotrifluoride
(BTF) at 180 °C for 180 min afforded the cyclopenta-
[b]naphthalene derivative 6 in quantitative yield with no
(11) De Koning, C. B.; Rousseau, A. L.; van Otterlo, W. A. L.
Tetrahedron 2003, 59, 7–26.
(12) (a) Siebert, M. R.; Osbourn, J. M.; Brummond, K. M.; Tantillo,
D. J. J. Am. Chem. Soc. 2010, 132, 11952–11966. (b) Brummond, K. M.;
Chen, D. Org. Lett. 2005, 7, 3473–3476. (c) Alcaide, B.; Almendros, P.;
Aragonicillo, C. Chem. Soc. Rev. 2010, 783–816.
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(10) Lietzau, L.; Bremer, M.; Klassen-Memmer, M.; Heckmeier H.
Cyclopenta[b]naphthalene derivatives. U.S. Patent 7,612,243, Nov 3,
2009. Lietzau, L., Bremer, M.; Klassen-Memmer, M.; Heckmeier H.
Cyclopenta[b]naphthalene derivatives. U.S. Patent 7,291,366, Nov 6, 2007.
Naphthalene Derivatives. The Molecular Probes Handbook, A Guide to
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Org. Lett., Vol. 14, No. 17, 2012
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Table 1. Scope of the Microwave-Assisted Dehydrogenative DielsꢀAlder Reaction
a Yields are reported after flash chromatography on silica gel. b Crude yield, but no impurities by 1H NMR. c When purified by filtration through a
silica gel plug, 6a was obtained in 95% yield.
additional purification required of the final product
(entries 1 and 2, Table 1). It is interesting to note that heat-
ing 5b conventionally in a sealed tube at 180 °C required
48 h for the reaction to complete. With conditions for an
efficient and high yielding IMDA reaction utilizing a lower
boiling solvent in hand, we turned our attention to scope
and limitations investigations. First, substitution on the
aryl group was examined; exchanging a hydrogen atom for
a chlorine atom was deemed valuable, enabling access to a
wide-range of naphthalene derivatives via Pd-catalyzed
cross-coupling reactions. Moreover, Cl-atom is more stable
and accessible than other halides or groups used for cou-
pling, such as triflates. Styrenyl derivatives 5b, 5c, and 5d
werepreparedand subjectedtomicrowaveirradiation. The
p-chlorostyrene 5b gave 7-chloronaphthalene 6b in quantita-
tive yield after 200 min (entry 3). The o-chlorostyrene 5c also
produced only one product, the 5-chloronaphthalene 6c in
86% yield, even though two products are possible (entry 4).
The m-chlorostyrene 5d gave a 1.4:1 mixture of the 6-chloro-
and 8-chloronaphthalenes, 6d and 6d0 in 79% yield (entry 5).
Next, a number of functional groups on the terminus of
the alkyne were investigated in the IMDA reaction. Sub-
stitution of the alkyne with a phenyl methanone gave the
cycloadduct 6e in quantitative yield after 90 min (entry 6).
Reaction scale did notaffect the yield ofthis reaction, but it
did have an effect on the reaction time; for example, 50 mg
of 5e afforded 6e in 90 min, while 200 mg of 5e required a
reaction time of 130 min. Placement of the methylsulfonyl
and phenylsulfonyl groups on the terminus of the alkyne to
produce 5f and 5g resulted in a facile IMDA reaction to
give 6f and 6g in 78% and 89% yield, respectively (entries 7
and 8). Sulfoxide 5h gave a slightly lower yield but still
afforded the naphthalene product 6h selectively (entry 9).
Similarly, the diethyl phosphonate substituted alkyne 5i
produced 6i in quantitative yield in 150 min (entry 10).
Alkynal 5j affords the naphthalene 6j in 83% yield in 45 min
(entry 11). A substrate with a methyl ester on the alkyne
terminus, 5k, slowed the reaction considerably, requiring
600 min to obtain complete conversion to 6k in 76% yield
(entry 12). The reaction time could be shortened from 600 to
90 min by heating to 225 °C in o-dichlorobenzene; this also
resulted in an improved yield for 6k of 97% (entry 13).
Finally, structural changes in the tether were examined.
Extending the tether by one methylene unit gave precur-
sor 5l that required heating at 300 °C for 50 min in
o-dichlorobenzene but provided tetrahydroanthracene 6l
in quantitative yield (heating at 225 °C for 240 min resulted
in recovery of starting material). To the best of our knowl-
edge, this is the first successful styrenyl IMDA reaction
using a four-atom tether to provide a naphthalene fused to
a six-membered ring. Reaction of the precursor 5m with an
all-carbon tether possessing a diester moiety afforded only
6m in quantitative yield in 30 min (entry 15). Next, an ether
tether was used to connect the styrene and the alkyne. The
cycloaddition of 5n was complete in 30 min and gave a 2:1
ratio of the naphthalene 6n to the dihydronaphthalene 7n
(entry 16). The toluenesulfonamide substrate 5o also
afforded a mixture of products, but in a 2:1 ratio of the
dihydronaphthalene 7o to naphthalene 6o in 10 min in a
combined yield of 86% (entry 17). The case of the tolue-
nesulfonamide tether with a chloro group on the aromatic
ring also provided a 2:1 ratio of the dihydronaphthalene 7p
to naphthalene 6p in 10 min in a combined yield of 72%
(entry 18). When5pwas heatedto225 °C for 10min, nearly
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Org. Lett., Vol. 14, No. 17, 2012

(Scheme 5).16,17 Compound 8 was strongly fluorescent with
an absorption maximum of 377 nm and an emission max-
imum of 510 nm. The emission maximum was significantly
red-shifted from the structurally similar Prodan, which has
an emission maximum of 440 nm in dichloromethane.18
Moreover, a quantum yield of 99% was measured for
compound 8 in dichloromethane.19 In conclusion, a micro-
wave-assisted, dehydrogenative DielsꢀAlder reaction affords
13 different, functionalized naphthalenes in excellent yield.
Our study represents the first intramolecular dehydrogena-
tive DA reaction between styrene and electron-deficient
alkynes to produce functionalized naphthalenes without
contamination with the dihydronaphthalene product, for
the all-carbon containing tethers.
For the heteroatom-containing tether, dihydronaphtha-
lenes were obtained along with the naphthalene products.
Investigations are underway to understand the mechanism by
which these two products are formed. Finally, we have de-
monstrated the synthetic utility of this method by preparing a
highly fluorescent dye 8 that possesses other interesting
photophysical properties (see Supporting Information for
more details).
Scheme 5. Palladium-Catalyzed Cross Coupling Reaction of 6b
To Afford Fluorophore 8
a 10:1 ratio of naphthalene 6p to dihydronaphthalene 7p
was obtained in 65% yield (entry 19). For each of the
heteroatom-containing tethers, a mixture of products was
observed; furthermore, when the reaction time was ex-
tended to 120 min for entry 19, the ratio of naphthalene 6p
to internal standard did not change, but the dihydro-
naphthalene 7p was no longer evident by 1H NMR,
suggesting that dihydronaphthalene 7p is not converted
to 6p. Separation of dihydronaphthalene 7p and naphtha-
lene 6p could not be accomplished by column chromatro-
graphy, so attempts were made to oxidize the mixture to 6p
using cerric ammonium nitrate (CAN), dichlorodicyano-
benzoquinone (DDQ), Pd/C, or O2. All reactions gave
either complete decomposition of the naphthalene and
dihydronaphthalene products or selective decomposition
of the dihydronaphthalene.8d
Acknowledgment. We thank the National Science
Foundation (CHE0910597) and the National Institutes
of Health (NIGMS P50GM067082) for supporting this
work. We thank Professor Michael Trakselis (University
of Pittsburgh) for helpful discussions regarding quantum
yield measurements. We also thank Kristy Gogick and
Robin Sloan (University of Pittsburgh) for their assistance
in collecting fluorescence data for this manuscript.
We envision these naphthalene derivatives as potential
candidates for application to the ever-increasing field of
small molecule fluorescent probes.14,15
Consequently, reaction of 6b to a palladium-catalyzed
amination reaction using RuPhos precatalyst, lithium
hexamethyldisilylazide (LHMDS), and N,N-dimethyl-
amine afforded cyclopentanaphthalene 8 in 70% yield
Supporting Information Available. Detailed experimen-
tal procedures and characterization data are available
for all compounds listed in Table 1. This material is
available free of charge via the Internet at http://
pubs.acs.org.
(14) (a) Fernandez-Suarez, M; Ting, A. Y. Nat. Rev. 2008, 9, 929–
943. (b) Hell, S. W. Science 2007, 316, 1153–1158.
(15) Sinkeldam, R. W.; Greco, N. J.; Tor, Y. Chem. Rev. 2010, 110,
2579–2619.
(16) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27–50.
(17) Lee, B. K.; Biscoe, M. R.; Buchwald, S. L. Tetrahedron Lett.
2009, 50, 3672–3674.
(18) Weber, G.; Farris, F. J. Biochemistry 1979, 18, 3075–3078.
(19) Benedetti, E.; Kocsis, L. S.; Brummond, K. M. J. Am. Chem.
Soc. 2012, 134, 12418–12421.
The authors declare no competing financial interest.
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