Dehydrogenative diels-alder reaction

Article abstract of DOI:10.1021/ol202283d

The dehydrogenative cycloaddition of dieneynes, which possess a diene in the form of a styrene moiety and a dienophile in the form of an alkyne moiety, produces naphthalene derivatives when heated. It was found that a key requirement of this process is th

Full text of DOI:10.1021/ol202283d

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5390–5393
Dehydrogenative DielsꢀAlder Reaction
Takuya Ozawa, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoto 615-8510, Japan
tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp; matsubar@orgrxn.mbox.media.kyoto-u.
ac.jp
Received August 23, 2011
ABSTRACT
The dehydrogenative cycloaddition of dieneynes, which possess a diene in the form of a styrene moiety and a dienophile in the form of an alkyne
moiety, produces naphthalene derivatives when heated. It was found that a key requirement of this process is the presence of a silyl group
attached to the alkyne moiety, which forces a dehydrogenation reaction to occur.
The DielsꢀAlder reaction is undoubtedly one of the
most fundamental and useful reactions available to organ-
ic chemists. It is used widely to form carbocyclic and
heterocyclic frameworks as precursors for constructing
complex organic molecules such as natural products.1ꢀ3
Therefore, the quest to discover new variants of the
DielsꢀAlder reaction remains important.4ꢀ7 Herein, we
report a dehydrogenative DielsꢀAlder reaction. Com-
pounds that possess a diene in the form of a styrene moiety
and a dienophile in the form of an alkyne moiety facilitate
the production of naphthalene derivatives through the
DielsꢀAlder reaction and a retro-DielsꢀAlder reaction
that occurs via dehydrogenation. It was found that a key
requirement of this process is the presence of a silyl group
attached to the alkyne moiety, which forces a dehydro-
genation reaction to occur.
We evaluated the reaction of 1a in DMF at 160 °C for 48
h under an Ar atmosphere. The reaction afforded 2a in
22% yield (Table 1, entry 1). While 77% of unreacted 1a
was recovered, the formation of byproducts such as cy-
cloadduct 2a0 that were produced via the DielsꢀAlder
reaction and subsequent aromatization was not observed.
Microwave irradiation at 200 °C did not promote the
occurrence of the reaction (entry 2). A 34% yield of 2a
was achieved without using a solvent (entry 3). We then
assumed that, in other types of medium, the reaction might
occur more efficiently.8 Therefore, we examined the effect
of the type of solvent on the reaction. When xylene was
used as the reaction medium, the desired cycloadduct 2a
was obtained in 80% yield (entry 4). We also found that
(1) Diels, O.; Alder, K. Ann. Chem. 1928, 460, 98.
(2) For related reviews on the DielsꢀAlder reaction, see: (a) Kagan,
H. B.; Riant, O. Chem. Rev. 1992, 92, 1007. (b) Martin, J. G.; Hill, R. K.
Chem. Rev. 1961, 61, 537. (c) Reymond, S.; Cossy, J. Chem. Rev. 2008,
108, 5359. (d) Brieger, G.; Bennett, J. N. Chem. Rev. 1980, 80, 63. (e)
Winkler, J. D. Chem. Rev. 1996, 96, 167. (f) Pindur, U.; Lutz, G.; Otto, C.
Chem. Rev. 1993, 93, 741.
(3) For reviews on the synthetic application of the DielsꢀAlder
reaction, see: (a) Nicolaou, K. C.; Synder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668. (b) Takao,
K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105, 4779.
(4) For some recent development of DielsꢀAlder type reactions, see:
(a) Kim, W. H.; Lee, J. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2009,
131, 12576. (b) Momiyama, N.; Tabuse, H.; Terada, M. J. Am. Chem.
Soc. 2009, 131, 12882. (c) Li, P.; Yamamoto, H. J. Am. Chem. Soc. 2009,
131, 16628. (d) Schotes, C.; Mezzetti, A. J. Am. Chem. Soc. 2010, 132,
3652. (e) Tambar, U. K.; Lee, S. K.; Leighton, J. L. J. Am. Chem. Soc.
2010, 132, 10248. (f) Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2010,
132, 11004. (g) Lee, J. H.; Zhang, Y.; Danishefsky, S. J. J. Am. Chem.
Soc. 2010, 132, 14330. (h) Sakaki, T.; Danheiser, R. L. J. Am. Chem. Soc.
2010, 132, 13203.
(5) For reviews on the hetero-DielsꢀAlder reaction, see: (a) Corey,
E. J. Angew. Chem., Int. Ed. 2002, 41, 1650. (b) Jørgensen, K. A. Angew.
Chem., Int. Ed. 2000, 39, 3558. (c) Johnson, J. S.; Evans, D. A. Acc.
Chem. Res. 2000, 33, 325. (d) Tietze, L.-F.; Kettschau, G.; Gewart, J. A.;
Schuffenhauer, A. Curr. Org. Chem. 1998, 2, 19.
(6) For reviews on the retro-DielsꢀAlder reaction, see: (a) Ichihara,
A. Synthesis 1987, 207. (b) Kwart, K.; King, K. Chem. Rev. 1968, 68, 415.
(c) Rickborn, B. Org. React. 1998, 52, 1. (d) Rickborn, B. Org. React.
1998, 53, 223. (e) Klunder, A. J. H.; Zhu, J.; Zwanenburg, B. Chem. Rev.
1999, 99, 1163.
(7) For reviews on the dehydro-DielsꢀAlder reaction, see: Wessig,
€
P.; Muller, G. Chem. Rev. 2008, 108, 2051.
(8) (a) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816.
(b) Otto, S.; Engberts, J. B. F. N. Pure Appl. Chem. 2000, 72, 1365. (c)
Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275.
r
10.1021/ol202283d
Published on Web 09/09/2011
2011 American Chemical Society

polar solvents retarded the reaction (entries 5ꢀ8). Thus,
xylene was the best solvent for the reaction. To further
elucidate the factors that affect the reaction rate, the
reaction temperature and time were also evaluated. We
found that a reaction temperature of 160 °C was essential
for achieving a good yield of 2a; a lower yield was observed
when the reaction was carried out at 130 °C (entry 9). The
reaction time was also examined, and the results indicated
that the yields of 2a increased gradually from 22% to 80%
when the reaction time was prolonged from 12 to 48 h
(entries 4, 10, and 11). It was found that the reaction under
air resulted in the decomposition of 1a (entry 12).9
Scheme 1. Scope of Dehydrogenative DielsꢀAlder Reactiona
Table 1. Dehydrogenative DielsꢀAlder Reaction of 1aa
yield (%)
temp
time
(h)
entry
solvent
DMF
(°C)
2a
2a0
1
160
200b
160
160
160
100
100
100
130
160
160
160d
48
1
22
8
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
2
DMF
3
ꢀ
48
48
48
48
48
48
48
12
24
48
34
4
xylene
1,4-dioxane
MeCN
AcOEt
H2O
80 (78)c
18
a All reactions were carried out using 1 (0.2 mmol) in 1.6 mL of xylene
(160 °C) under an Ar atmosphere for 48 h unless otherwise noted.
bIsolated yields. c2f-H; Protodesilylated cycloadduct. dReaction tem-
perature: 250 °C (neat).
5
6
<1
7
<1
8
<1
9
xylene
xylene
xylene
xylene
3
polyaromatic cycloadduct 2e in 92% yield. The reaction of
1f, which possessed a 2-naphthyl component, produced 2f
in 72% yield along with protodesilylated cycloadducts
2f-H in 23% yield. The molecular structure of 2f was
confirmed by carrying out X-ray crystal structure analysis
(Figure 1).
10
11
12
22
56
<1
a All reactions were carried out using 1 (0.2 mmol) in 1.6 mL of
solvent under an Ar atmosphere unless otherwise noted. b Microwave
irradiation. c Isolated yield. d Reaction was carried out under air.
Even though it was necessary to carry out the reaction at
a high temperature and for a long period of time to bring
about its completion, we believed that this was reasonable in
terms of producing polycyclic aromatic compounds without
yielding byproducts considering that the constituents of the
reaction were a styrene moiety and an alkyne. We therefore
further examined the details of this type ofcycloaddition to
demonstrate its synthetic utility. We first examined various
dieneynes 1 that possessed various functional groups; the
results for these dieneynes are summarized in Scheme 1.
The reactions of fluoro- and trifluoro-substituted die-
neynes 1b and 1c afforded correspondingly substituted
cycloadducts 2b and 2c in 87% and 85% isolated yields,
respectively. Methoxy-substituted 1d also produced cy-
cloadduct 2d in 67% yield. Dieneyne 1e, which contained
a naphthyl ring, participated in the reaction and afforded
Figure 1. ORTEP drawing of 2f.
The effects of the presence of a tether group were also
examined. Not only a tosyl group but also mesitylsulfonyl
and trifluoromethanesulfonyl groups remained intact un-
der the reaction conditions to afford the corresponding
cycloadducts 2g and 2h. The ether tether 1i also reacted to
give the desired product 2i in 73% yield. The expected
cycloadduct 2k was not obtained through the reaction of
carbon-tethered dieneyne 1k under the standard condi-
tions used thus far. However, the desired product 2k was
obtained in 86% yield at an elevated reaction temperature
(9) The reaction of 1a in both the presence and absence of radical
initiator azobisisobutyronitrile (5 mol %) under the standard conditions
provided cycloadduct 2a in the same yields (78%).
Org. Lett., Vol. 13, No. 19, 2011
5391

of 250 °C. The effects of double bond geometry on the
reaction were evaluated using the cis form of 1a. The low
yield of 2a (29%) suggested that a double bond trans-
configuration geometry was essential for the cycloaddition
to occur (Scheme 2).
yield (entry 8). In addition, dimethylphenylsilyl-substi-
tuted dieneyne 1q also afforded 2q as the sole product in
63% yield (entry 9). To further evaluate this dehydrogena-
tive DielsꢀAlder reaction, we examined it with respect to
the participation of dieneyne 4 (Scheme 3). The reaction of
4 under optimized reaction conditions produced Dielsꢀ
Alder cycloadduct 500 in 68% yield. Not even a trace
amount of isomerized product 50 or dehydrogenated cy-
cloadduct 5 was observed. Thus, the aromatic moiety that
was present in dieneyne 1 was also critical for carrying out
the dehydrogenative DielsꢀAlder reaction.
Scheme 2. Effects of Double Bond Geometry on Reaction
Scheme 3. Reaction of Dieneyne 4
We next examined effects of substituents on alkynes to
gaininsightintohow thecycloadditionproceedsselectively
to provide dehydrogenated cycloadduct 2 with a silyl-
substituent. The results of this investigation are summar-
ized in Table 2. We found that substituents such as H, Ph,
and CO2Et produce cycloadducts 20 as major products and
that desirable dehydrogenated cycloadducts 2 were ob-
tained as minor products (entries 1, 5, and 6). Dehydroge-
nated cycloadducts 2 were not obtained as a major product
even with prolonged reaction time (entries 2 and 7). At an
elevated reaction temperature of 250 °C, 1l was decom-
posed (entry 3). It is worth pointing out that the reaction of
methyl-substituted dieneyne 1m did not provide dehydro-
genated cycloadduct 2m or cycloadduct 2m0 (entry 4). On
the other hand, the reaction of dieneyne 1p, which pos-
sessed a bulky triisopropylsilyl group, resulted in the
formation of the dehydrogenated cycloadduct 2p in 13%
While the mechanism of this reaction has not been
elucidated completely, we propose the following reaction
pathway based on the results that we observed (Scheme 4).
The interaction between a styrene moiety and an alkyne
moiety of dieneyne 1 to give cycloadduct 200 is initiated by
the DielsꢀAlder reaction.10 In thecaseofdieneyne1with an
alkylsilane group (e.g., R = SiMe3), the dehydrogenative
retro-DielsꢀAlder reaction of 200 will proceed owing to a
potent thermodynamic driving force that originates from
the simultaneous dual aromatization; this will result in the
production of polyaromatic cycloadducts with higher ther-
modynamic stability (path A).11 We also presume that the
intermediate cycloadduct 200 has a 1,4-cyclohexadine moiety
with a strained boat conformation that originated from its
benzannulated structure and steric repulsive effects due to
its bulky trimethylsilyl group. Accordingly, two hydrogen
atoms are in spatial proximity, and thus, a facile dehydro-
genative retro-DielsꢀAlder reaction may proceed under the
reaction conditions.12 For dieneynes 1 with another term-
inal substituent such as H, Ph, and COOEt, cycloadduct 20 is
produced via the isomerization of 200, which is converted
gradually to 2 under the reaction conditions (path B).
Table 2. Evaluation of Silyl-Substituent Effectsa
yield (%)
time
entry
1
R
(h)
2
20
1
2
1l
H
48
96
48
48
48
48
96
48
48
48
6
37
66
<1
<1
56
65
59
<1
<1
<1
(10) (a) Goldstein, E.; Beno, B.; Houk, K. N. J. Am. Chem. Soc. 1996,
118, 6036. (b) Khuong, K. S.; Jones, W. H.; Pryor, W. A.; Houk, K. N. J.
Am. Chem. Soc. 2005, 127, 1265.
(11) For detailed energy profiles of the reactions and corresponding
molecular structures, see Supporting Information.
(12) The reaction of deuterium-labeled dieneyne 1a produced 2a with
50% deuterium labeling (vide infra). Therefore, the H/D kinetic isotope
effect was not observed.
1l
H
11
<1b
<1
14
29
35
13
63
80
3
1l
H
4
1m
1n
1o
1o
1p
1q
1a
Me
Ph
5
6
CO2Et
CO2Et
SiiPr3
7
8
9
SiMe2Ph
SiMe3
10
a All reactions were carried out using 1 (0.2 mmol) in 1.6 mL of
solvent under an Ar atmosphere. b Reaction temperature: 250 °C (neat).
5392
Org. Lett., Vol. 13, No. 19, 2011

Scheme 4. Plausible Reaction Pathways
Scheme 5. Utility of Silyl Group for Transformation of 2
Scheme 6. Cross-Coupling To Form Binaphthyl Frameworks
the addition of a Lewis acid, transition metal, or oxidant.
Further efforts to expand the scope of this type of chem-
istry and its applications for synthesizing complex mole-
cules are now in progress.
Additional experiments were performed to show the silyl
group on the cycloadducts 2 obtained through the dehy-
drogenative DielsꢀAlder reaction can be utilized for further
chemical transformation (Scheme 5). For example, the
halogenation of 2a with iodine chloride or NBS pro-
duced 6a or 7a, respectively, both in 94% yields. The
treatment of 2a with TBAF afforded 2l in 90% yield.
Furthermore, Negishi cross coupling of 7b and 6a, which
were synthesized from 2i and 2a, respectively, also resulted
in the production of binaphthyl compound 8ba in 83% yield
(Scheme 6).
In summary, we have developed a dehydrogenative
DielsꢀAlder reaction through which we can use dieneynes
to produce polyaromatic cycloadducts. A silyl substituent
on an alkyne moiety directs the reaction toward producing
dehydrogenated cycloadducts in a selective manner. Aside
from the challenge of linking a styrene as a conjugated
diene with an alkyne via dearomatization and dehydro-
genation, the process is simple; that is, it does not require
Acknowledgment. This work was supported by MEXT,
Japan. T.K. also acknowledges the support from Asahi
Glass Foundation, Kansai Research Foundation, and
Toyota Physical and Chemical Research Institute.
Supporting Information Available. Experimental pro-
cedures, analytical data of new compounds. CIF file of
2a, 2b, 2d, and 2f. Computational results, energies and
Cartesian coordinates of stationary points, full citations
of Gaussian 03 program. This material is available free of
charge via the Internet at http://pubs.acs.org.
Note Added after ASAP Publication. The graphic in table
2 has been corrected along with a production error
involving the graphic in Table 1. The revised version
reposted September 13, 2011.
Org. Lett., Vol. 13, No. 19, 2011
5393