DABCO-triggered mild cascade reaction of electron-deficient cyclopentadienone: Facile and efficient synthesis of condensed carbocycles

Article abstract of DOI:10.1016/j.tetlet.2011.09.002

2,5-Bis(methoxycarbonyl)-3,4-diphenylcyclopentadienone (1) reacts with 4-phenylbut-3-yn-2-one (2b) in the presence of DABCO to give the bicyclic carbocycles (6b) and the tetracyclic carbocycle (7b) under extremely mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2011.09.002

Tetrahedron Letters 52 (2011) 6082–6085
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
DABCO-triggered mild cascade reaction of electron-deficient
cyclopentadienone: facile and efficient synthesis of condensed carbocycles
⇑
Koki Yamguchi, Masashi Eto , Kenta Higashi, Yasuyuki Yoshitake, Kazunobu Harano
Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Kumamoto 860-0082, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2011
Revised 29 August 2011
Accepted 1 September 2011
Available online 10 September 2011
2,5-Bis(methoxycarbonyl)-3,4-diphenylcyclopentadienone (1) reacts with 4-phenylbut-3-yn-2-one (2b)
in the presence of DABCO to give the bicyclic carbocycles (6b) and the tetracyclic carbocycle (7b) under
extremely mild reaction conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopentadienone
But-3-yn-2-one
1,4-Diaza-bicyclo[2.2.2]octane
Cascade reaction
Pericyclic reaction
1. Introduction
(Scheme 1). In this reaction, DABCO acts as an efficient base to gen-
erate the alkoxide anion.
A cascade reaction, which consists of sequential chemical trans-
formations, is a useful synthetic method for the construction of com-
plex polycyclic systems. The transformations take place in one
synthetic operation under the same reaction conditions, without
adding additional reagents. The advantages are that the reaction is
generally fast and stereoselective owing to its intramolecular nature
and does not need the isolation of many intermediates generated in
the process.1–4 Studies on the application of a cascade reaction to
natural products synthesis have been widely reported.5 Addition-
ally, the synthetic method has become increasingly important from
the ecological and economical viewpoints.
On the basis of this connection, we considered that but-3-yn-2-
ones (2) would show a similar reaction behavior under the pres-
ence of DABCO resulting in carbon–carbon bond formation via an
enolate.
This Letter deals with the reaction of 1 with several but-3-yn-2-
ones (2) via the initial formation of the 1,4-adducts followed by the
ene reaction and/or the cascade pericyclic reactions.
Recently we reported a novel cyclization reaction of 2,5-
bis(methoxycarbonyl)-3,4-diphenylcyclopenta-dienone (1) with
2-alkynylamines and 2-alkynylalcohols via a cascade reaction
pathway.6–8
For example, the reaction of 1 with prop-2-yn-1-ol in the
presence of a catalytic amount of DABCO (1,4-diaza-bicyclo[2.2.2]
octane) gave the bicyclic heterocycle, which is derived from the
stepwise [2p+2p+2r] reaction (intramolecular ene reaction) of the
initial formation of 1,4-adduct. When 3-methyl- or 3-ethyl-prop-
2-yn-1-ol was used, the tetracyclic compound formed from the
intramolecular Diels–Alder (IMDA) reaction of the [1,5]-sigmatropic
rearrangement product of the 1,4-adduct, followed by the [1,5]-
sigmatropic rearrangement of hydrogen and by dehydrogenation
Scheme 1. Cyclization reaction of cyclopentadienone (1) with pop-2-yn-1-ol in the
presence of DABCO.
⇑
Corresponding author. Tel.: +81 96 326 4107; fax: +81 96 326 5048.
E-mail address: meto@ph.sojo-u.ac.jp (M. Eto).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.002

K. Yamguchi et al. / Tetrahedron Letters 52 (2011) 6082–6085
6083
Without DABCO, the reaction only gave the decarbonylated
Diels–Alder adduct (3a) with 72% yield, indicating that DABCO acts
as a trigger for altering the reaction behavior of 2a. Thus, the
expected carbocycles could not be obtained in the reaction of 1
and 2a.
Next, we tried to use 4-arylsubstituted-but-3-yn-2-one (2b–f)
as reactants. A mixture of 1 and 4-phenylbut-3-yn-2-one (2b) in
the presence of a catalytic amount of DABCO in benzene was al-
lowed to stand at room temperature for 3 days. After purification,
two major cyclization products 6b and 7b were obtained (Scheme
3).
The mass spectrum of 6b indicated a 1:1 adduct of 1 and 2b [m/
z 515 (M++Na)]. The 1H NMR spectrum showed a duplicated signal
pattern, suggesting that the product is a mixture of E- and Z-adduct
(E-6b and Z-6b). The 13C NMR spectrum of E-6b showed a charac-
teristic exocyclic vinyl group (d 143.5) and a low-field shift of
methylene group (d 47.7), supporting the formation of the bicyclic
compound. The methyl signals of the methoxycarbonyl groups are
d 2.84 and 3.83 for the E-form, showing the high field shift com-
pared to those in Z-6b (d 3.18 and d 3.77) (see Fig. 1). The upfield
2. Results and discussion
Based on the background described above, the reaction of 1
with but-3-yn-2-one (2a) was carried out first. A benzene solution
of 1 and an excess amount of 2a in the presence of a catalytic
amount of DABCO was allowed to stand at room temperature until
1 could not be recognized on the thin layer chromatogram (TLC).
Purification using normal phase column chromatography afforded
three cyclization products 3a, 4a, and 5a with 7%, 22%, and 18%
yields, respectively (Scheme 2 and Table 1).
Compound 3a exhibited an M+ ion peak at m/z 388 in the mass
spectrum, suggesting that the decarbonylated 1:1 cycloadduct is
obtained through the Diels–Alder reaction of 1 with the triple bond
of 2a followed by the aromatization.
The mass spectrum of 4a showed a 1:1 adduct (m/z 416) of 1
and 2a. The IR spectrum showed a conjugated carbonyl and an
ester carbonyl absorption band at 1766 and 1732 cmꢀ1. The 1H
NMR spectrum exhibited characteristic doublet signals at d 6.29
and d 6.74 (J 9.8 Hz ascribable to the cis olefin) (Fig. 1). The methyl
protons of a methoxycarbonyl group showed a high-field shift (d
3.20), suggesting that the methyl protons are shielded by the elec-
tronic ring current of the neighboring C3a-phenyl group. The struc-
ture of 4a was unambiguously confirmed by X-ray crystallographic
analysis.9
The mass spectrum of 5a showed an M+ ion peak at m/z 484,
suggesting that 1 reacts with twice the molar amount of 2a. The
1H NMR spectrum of 5a indicated the presence of the characteristic
five olefinic hydrogens and a methyl group derived from E-3-(1-
buten-3-yn-2-oxy)-buten-2-one (2a0). Ramanchandran et al., re-
ported that but-3-yn-2-one (2a) condenses itself in the presence
of a catalytic amount of DABCO providing 2a0 in high yield.10 The
13C NMR spectrum of 5a exhibited two sp3 carbon signals at d
72.1 and d 67.3, assignable to the tetrahedral carbons of the fused
ring position. These results strongly suggest the formation of bicy-
clic compound (5a) bearing a cyclobutene ring.11
Scheme 2. Cyclization reaction of 1 with but-3-yn-2-one (2a).
Figure 1. Characteristic 1H and 13C NMR Chemical Shifts (d) of 4a, 5a, E-6b, Z-6b,
and 7b.
Table 1
Reaction conditions and product ratio for the reaction of 1 with 4-substituted-but-3-
yn-2-one (2) in the presence of DABCO
Compd
Time (d)
Total yield (%)
Yield (%)
3
4
5
6a
7
2a
2b
2c
2d
2e
2f
3
3
4
7
3
7
47
68
37
86
48
58
7
22
—
—
—
—
—
18
—
—
—
—
—
—
—
—
—
49
—
—
42
24
32
48
47
26
13
5
—
11
a
Mixture of E- and Z-isomer.
Scheme 3. Cyclization Reaction of 1 with 4-arylsubstituted-but-3-yn-2-one (2b–f).

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K. Yamguchi et al. / Tetrahedron Letters 52 (2011) 6082–6085
shift of the OMe signal observed in E-6b is assigned to the aniso-
tropic effect of the neighboring cis-oriented C6a-phenyl and the
phenyl ring of the styrene moiety. Just after separation of 6b by
silica gel column chromatography, the E:Z ratio was 45:55. How-
ever, the amount of E-form increased with time, suggesting that
the isomerization from the Z-form to the E-form gradually takes
place in the solution (After 80 days, the E:Z ratio changed to 88:12).
Inspite of the isomerization, the mixture could be further sepa-
rated by reverse-phase HPLC. Both structures of the bicyclic carbo-
cycles E-6b and Z-6b were confirmed by X-ray analysis.9
The mass spectrum of 7b showed a dehydrogenated 1:1 adduct
of 1 and 2b [m/z 513 (M++Na)]. The 1H NMR spectrum exhibited
the absence of characteristic exocyclic vinyl group found in the
bicyclic compounds. The 1H detected heteronuclear multiple bond
connectivity (HMBC) spectrum and the numbers of aromatic pro-
tons (9H) suggested that the terminal alkynic carbon was con-
nected to the 2-position of the phenyl group. The methyl protons
of the methoxycarbonyl group showed high-field shift (d 3.15)
compared with another methyl group (d 3.93), suggesting that
the methyl group is located above the plane of the C2a-phenyl
group. The structure of 7b was confirmed as a tetracyclic carbocy-
cle by the X-ray analysis.
Similar reaction behavior was observed in 4-aryl-substituted-
but-3-yn-2-ones (2c–f). The reaction conditions and the product
distribution are summarized in Table 1.
The reaction of 1 with 2d gave the decarbonylated DA adduct
(3d) in 49% yield besides 6d and 7d. Increase in the DA cycloaddi-
tion reactivity can be explained in terms of the frontier molecular
orbital (FMO) theory.12 The
p-HOMO and p-LUMO energy levels of
2d are lowered by introducing the electron-withdrawing group on
the benzene ring, resulting in the fact that both HOMO–LUMO
interactions may be operative (i.e., neutral-type cycloaddition13).14
The highest yield of tetracyclic compounds (7) was obtained
when the unsubstituted phenyl derivative (2b) was used. The pres-
ence of either electron-withdrawing or -donating group on the
phenyl ring tends to decrease the yield.
Scheme 4. Possible pathway of cyclization reaction of 1 with 4-arylsubstituted-
but-3-yn-2-one (2).
Based on these structural features of the reaction products and
the reaction behavior of 1 toward propargyl alcohols8 and propar-
gyl amines6, we considered a possible reaction pathway of 1 and 2
as follows (Scheme 4).
Initially, DABCO catalyzed an enolization of 2, followed by a 1,
4-addition reaction of the enolate oxygen toward 1. Then, the
1,4-adduct rearranges to give the [1,5]-sigmatropic rearrangement
product. In this stage, there are two [3,3]-sigmatropic rearrange-
ment pathways that arise from the two olefines of the cyclopenta-
diene moiety.
The transition structures of the [3,3]-sigmatropic rearrangement
from the [1,5]-sigmatropic rearrangement product (I) were success-
fully located by semi-empirical MO (PM615) calculation (Fig. 2). The
estimated reaction barriers (DDHf) of I?II and I?III are 39.9 and
40.3 kcal/mol, respectively. These values are much lower than that
of the initial [1,5]-sigmatropic rearrangement (59.2 kcal/mol), sug-
gesting that the formation of tetra- and bicyclic compounds might
be formed via [3,3]-sigmatropic rearrangement.16
The tetracyclic compound 7 is considered to be formed from the
IMDA reaction (styrene as diene) of the [3,3]-sigmatropic rear-
rangement product (II), followed by the [1,5]-sigmatropic rear-
rangement of the hydrogen and dehydrogenation. In spite of the
loss of the aromatic resonance stabilization of the styrene moiety
at the initial step, the IMDA reaction takes place under extremely
mild conditions. The regaining of aromaticity of the benzene ring
seems to play an important role in the progress of subsequent
reactions.6
Figure 2. PM6-Transition structures and the reaction barriers for the [3,3]-
sigmatropic rearrangement of the [1,5]-sigmatropic rearrangement product (I).
When theacetylene terminusof 2 is free (i.e., 2a), 4a is considered
to be formed via sequential [1,5]- and [3,3]-sigmatropic rearrange-
ments of the initial 1,4-adduct, followed by the intramolecular
Michael addition of the enolate to the acetylene terminus of the
butynone moiety.17 The terminal acetylenic ketones tend to act as
efficient Michael acceptor18 with the result that the intramolecular
Michael addition of intermediate IV might occur prior to ene or
IMDA reactions.19
The bicyclic compounds 6 were considered to be derived from
the intramolecular [2
p+2p+2r] (ene) reaction of the [3,3]
-sigmatropic rearrangement product (III).6

K. Yamguchi et al. / Tetrahedron Letters 52 (2011) 6082–6085
6085
P21/n, a = 11.508 (3), b = 12.864 (4), c = 16.479 (6) Å, b = 97.68 (1)°, V = 2418 (2)
Å3, Dc = 1.348 g cmꢀ3 Do = 1.347 g cmꢀ3
Z = 4, R = 0.051, Rw = 0.086. CCDC
In summary, we have demonstrated that 1 reacts with but-3-
yn-2-ones (2) in the presence of DABCO to give the bicyclic (4, 5
and 6) and the tetracyclic carbocycles (7) under room temperature.
The reactions seem to provide a new synthetic method featuring
sequential carbon–carbon bond formation using organic amine
under extremely mild conditions.
,
,
reference number 831663. 4a; C25H20O6, M = 416.4, monoclinic, space group
P21/n, a = 8.543 (3), b = 16.115 (5), c = 15.571 (6) Å, b = 98.49 (2)°, V = 2120 (2)
Å3, Dc = 1.305 g cmꢀ3 Do = 1.304 g cmꢀ3
, , Z = 4, R = 0.050, Rw = 0.091. CCDC
reference number 831660.
10. Ramanchandran, P. V.; Rudd, M. T.; Reddy, M. V. R. Tetrahedron Lett. 1999, 40,
3819–3822.
11. Compound 5a is presumably formed via
pathway, that is, [2+2] cycloaddition of
rearrangement of the DA adduct.
12. Fukui. K. Chemical Reaction and Electron Orbitals, Maruzen, Tokyo, 1976.
13. Sustmann, R. Tetrahedron Lett. 1971, 2717–2720.
a
1
thermally forbidden reaction
Further experiments including the density functional theory
(DFT) calculations to elucidate the formation mechanisms of these
condensed carbocycles are in progress.
and 2a0, or 1,3-sigmatropic
14. PM6-calculated FMO energy levels are as follows:1:ꢀ9.93 eV (HOMO),
Acknowledgments
ꢀ2.05 eV (LUMO); 2b: ꢀ9.75 eV
(p
-HOMO), ꢀ0.84 eV
(p-LUMO); 2d:
ꢀ10.07 eV (p-HOMO), ꢀ1.34 eV (p-LUMO).
We thank Mr. K. Watanabe, Miss Y. Jikumaru and Miss E. Tanaka
for experimental assistance.
15. MOPAC2009: Stewart, J. J. P., Stewart Computational Chemistry, Version
9.062 M (http://OpenMOPAC.net)
16. (a) The PM6 calculated reaction barriers for Claisen rearrangements are ca. 20
kcal/mol higher than the actual values. We previously reported that PM3 and
MP2/6-31G(d)
calculated
reaction
barriers
for
[3,3]-sigmatropic
Supplementary data
rearrangement of A are 50.1 and 29.0 kcal/mol, respectively.16b The PM6 and
B3LYP/6-31G(d) calculations gave the similar results 48.9 and 27.9 kcal/mol,
respectively;
Supplementary data (experimental procedures, detailed charac-
terization data, copies of the spectral data, and ORTEP drawings)
associated with this Letter can be found, in the online version, at
doi:10.1016/j.tetlet.2011.09.002.
References and notes
1. Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006.
2. Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131–163.
3. Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
; (b) Jikyo, T.; Eto, M.; Harano, K. Chm. Pharm Bull. 1997, 45, 1961–1969.
17. (a) Lavalleé, J.-F.; Berthiaume, G.; Desiongchamps, P.; Grein, F. Tetrahedron Lett.
1986, 27, 5455–5458; (b) Deslongchamps, P.; Roy, C. L. Can. J. Chem. 1986, 64,
2068–2075.
4. Lecker, S. H.; Nguyen, N. H.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1986, 108, 856–
858.
5. Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
7134–7186.
6. Yoshitake, Y.; Yamaguchi, K.; Kai, C.; Akiyama, T.; Handa, C.; Jikyo, T.; Harano,
K. J. Org. Chem. 2001, 66, 8902–8911.
18. But-3-yn-2-one serves as a Michael addition donor as well as a Michael
acceptor and condenses with itself in the presence of DABCO providing E-3-(1-
buten-3-yn-2-oxy)-buten-2-one (2a0). 4-Phenylbut-3-yn-2-one (2b) did not
undergo self-condensation but serves as
a good Michael addition donor
reacting with but-3-yn-2-one to provide the cross-coupled product.10
7. Yamaguchi, K.; Kai, C.; Yoshitake, Y.; Harano, K. Eur. J. Org. Chem. 2004, 826–
834.
8. Yamaguchi, K.; Utsumi, K.; Yoshitake, Y.; Harano, K. Tetrahedron Lett. 2006, 47,
4235–4239.
9. All measurements were performed on a Rigaku RAXIS RAPID imaging plate area
detector with graphite-monochromated Mo-K
a radiation (k = 0.7107 Å). The
data were collected at a temperature of 23 1 °C to a maximum 2h value of 55°.
The structures were solved by direct method (SIR9220), and all hydrogen atoms
were located at calculated positions. The structure was refined by a full-matrix
least-squares technique using anisotropic thermal parameters for non-
hydrogen atoms and a riding model for hydrogen atoms. All calculations
were performed using the crystallographic software package Crystal
Structure.21 These X-ray crystallographic data have been deposited at the
Cambridge Crystallographic Data Centre (CCDC). Crystal Data of E-6b;
C
31H24O6, M = 492.5, orthorhombic, space group P212121, a = 9.294 (3),
19. The TS structure for the intramolecular Michael addition of IV is located by
PM6-calculation. The reaction barrier is 27.1 kcal/mol and the forming bond
distance is 1.813 Å.
20. SIR92: Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, M.; Giacovazzo, C.;
Guagliardi, A.; Polidori, G. J. Appl. Cryst. 1994, 27, 435–436.
21. CrystalStructure 4.0: Crystal Structure Analysis Package, Rigaku Corporation
(2000-2010). Tokyo 196-8666, Japan.
b = 15.894 (4), c = 16.704 (5) Å, V = 2468 (2) Å3, Dc = 1.326 gcm-3
,
Do = 1.325 g cmꢀ3
831661. Z-6b;
,
Z = 4, R = 0.036, Rw = 0.049. CCDC reference number
31H24O6, M = 492.5, monoclinic, space group P21/c,
C
a = 11.8334 (6), b = 12.9679 (8), c = 16.7754 (9) Å, b = 101.810 (1)° V = 2519.8
(3) Å3, Dc = 1.298 g cmꢀ3, Do = 1.300 g cmꢀ3, Z = 4, R = 0.077, Rw = 0.111. CCDC
reference number 831662. 7b; C31H22O6, M = 490.5, monoclinic, space group