Intramolecular [4 + 2] Cycloaddition Reactions of Diarylacetylenes: Synthesis of Benzo[b]fluorene Derivatives via Cyclic Allenes

Article abstract of DOI:10.1021/ol991391t

(Equation Presented) 2-Propynyldiarylacetylenes undergo thermal intramolecular [4 + 2] cycloaddition to give benzo[b]fluorene derivatives in good yields. The hybridization of the tether connecting the reacting alkynes has a pronounced effect on the course

Full text of DOI:10.1021/ol991391t

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1497-1500
Intramolecular [4 + 2] Cycloaddition
Reactions of Diarylacetylenes:
Synthesis of Benzo[b]fluorene
Derivatives via Cyclic Allenes†
David Rodr´ıguez, Armando Navarro, Luis Castedo, Domingo Dom´ınguez,* and
Carlos Saa´*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC,
Facultad de Qu´ımica, UniVersidad de Santiago de Compostela.
15706 Santiago de Compostela, Spain
qocsaa@usc.es
Received December 22, 1999
ABSTRACT
2-Propynyldiarylacetylenes undergo thermal intramolecular [4 + 2] cycloaddition to give benzo[b]fluorene derivatives in good yields. The
hybridization of the tether connecting the reacting alkynes has a pronounced effect on the course of the reaction. Theoretical calculations and
isotopic labeling studies support a mechanism which involves the generation of a cyclic allene intermediate that evolves to the final benzo-
[b]fluorene.
We recently reported1 that the thermal cyclization of non-
conjugated benzotriynes 1a and 1b (Table 1) and benzodiyne
2a (Table 2)2 leads directly to the benzo[b]fluorene skeleton
(Scheme 1) which is a feature of a class of natural
compounds that exhibit interesting biological activity.3
Intramolecular [4 + 2] cycloadditions of alkynes with
arenynes,2,4 enynes,5 diynes,6 and arenenes7 are known
processes, some of them since the past century.
With a view to future synthetic applications, we investi-
gated how the reaction is affected by the nature of the tether
linking the diarylacetylene moiety to the other reacting
acetylene. We found that the hybridization of the tether has
a pronounced effect in terms of temperature requirements
and yield. Our theoretical calculations and isotopic labeling
† Dedicated to Prof. J. Barluenga on the occasion of his 60th birthday.
(1) Rodr´ıguez, D.; Castedo, L.; Dom´ınguez, D.; Saa´, C. Tetrahedron Lett.
1999, 40, 7701-7704.
(2) Thermolysis of 2a at 110 °C for 10 days to give the isomeric benzo-
[b]fluorenols 4a (44%) and 5a (13%) had been previously described:
Schmittel, M.; Strittmatter, M.; Schenk, W. A.; Hagel, M. Z. Naturforsch
1998, 53b, 1015-1020.
(5) (a) Danheiser, R. L.; Gould, A. E.; Ferna´ndez de la Pradilla, R.;
Helgason, A. L. J. Org. Chem. 1994, 59, 5514-5515. (b) Burrell, R. C.;
Daoust, K. J.; Bradley, A. Z.; DiRico, K. J.; Johnson, R. P. J. Am. Chem.
Soc. 1996, 118, 4218-4219. (c) Gonza´lez, J. J.; Francesch, A.; Ca´rdenas,
D. J.; Echavarren, A. M. J. Org. Chem. 1998, 63, 2854-2857.
(6) (a) Bradley, A. Z.; Johnson, R. P. J. Am. Chem. Soc. 1997, 119,
9917-9918. (b) Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Tetrahe-
dron Lett. 1997, 38, 3943-3946.
(3) Gould, S. J.; Melville, C. R.; Cone, M. C.; Chen, J.; Carney, J. R. J.
Org. Chem. 1997, 62, 320-324.
(4) (a) Michael, A.; Bucher, J. E. Chem. Ber. 1895, 28, 2511. (b) Baddar,
F. G.; El-Assal, L. S.; Doss, N. A. J. Chem. Soc. 1959, 1027. (c) Brown,
D.; Stevenson, R. J. Org. Chem. 1965, 30, 1759. (d) Klemm, L. H.;
Gopinath, K. W.; Lee, D. H.; Kelley, F. W.; Trod, E.; McGuire, T. M.
Tetrahedron 1966, 22, 1797. (e) Whitlock, H. W., Jr.; Wu, E.-M.; Whitlock,
B. J. J. Org. Chem. 1969, 34, 1857-1859.
(7) (a) Schmittel, M.; Maywald, M.; Strittmatter, M. Synlett 1997, 165-
166. (b) Frutos, O.; Echavarren, A. M. Tetrahedron Lett. 1997, 38, 7941-
7942.
10.1021/ol991391t CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/03/2000

We next examined whether the same effect occurred in
the benzodiyne series 2. When heated at 100 °C in toluene,
benzodiynone 2b (prepared in 90% yield by Dess-Martin
oxidation of 2a) gave a regioisomeric mixture of benzo[b]-
fluorenones 4b and 5b in almost quantitative combined yield
(Table 2).10 Once again, the temperature required was
Scheme 1
Table 2. Thermal Cyclization of Benzodiynes 2
X, Y
R
reactn time (h) T (°C)
products (%)
2a H, OH Ph
11
11
13
13
20
20
170 4a (70%) + 5a (26%)
100 4b (72%) + 5b (24%)
150 4c (85%)
150 4d (74%)
170
2b
2c
2d
O
O
O
Ph
TMS
H
2e H, OH TMS
2f H, OH
H
170
significantly less than for X ) H, Y ) OH, that is, the energy
of activation was reduced. Furthermore, heating solutions
of benzodiynone 2c11 and its desilylated derivative 2d11 in a
sealed tube at 150 °C smoothly produced the silylated benzo-
[b]fluorenone 4c and the parent benzo[b]fluoren-11-one 4d,12
whereas the corresponding alcohol derivatives (2e and 2f)
failed to cycloaromatize even under more severe conditions
(Table 2).1
The above results are plausibly explained by either of the
mechanisms depicted for the benzodiynes in Scheme 2. In
the first, rate-limiting thermal cyclization of the benzodiyne
affords the biradicals 6, which must then undergo fast
intramolecular radical coupling to furnish the strained cyclic
allene 8.13 Alternatively, the two new σ bonds in 8 might
arise in concert via transition state 7.5a To decide between
the two paths of Scheme 2, and to obtain energy data, we
performed DFT14 ab initio calculations15 using the hybrid
B3LYP,16-18 functional with a 6-31G* basis set.19 For triplet
states or singlets with biradical character, an unrestricted
formalism was used, allowing the R and â Kohn-Sham
studies support a mechanism which involves a cyclic
allene5a,b intermediate that evolves to the final benzo[b]-
fluorene.
We first studied the behavior of diarylacetylene 1c, the
silylated parent benzotriyne, which was prepared in 90%
yield by reduction of 1a with Et3SiH and TFA at room
temperature.8 Not unexpectedly, 1c was more recalcitrant
than 1a or 1b, with complete consumption requiring 20 h of
heating of a toluene solution in a sealed tube at 130 °C and
affording only a moderate 40% yield of benzo[b]fluorene
3c (Table 1). This result shows that the presence of an
Table 1. Thermal Cyclization of Benzotriynes 1
X, Y
R
reactn time (h) T (°C) product yield (%)
1a H, OH TMS
10
10
20
3
100
100
130
25
3a
3b
3c
3d
56
60
40
98
(10) Benzo[b]fluorenones 4b and 5b had been obtained previously as
byproducts when studying thermolysis of 2a at 110 °C. See ref 2.
(11) See Supporting Information for experimental details.
(12) Streitwieser, A., Jr.; Brown, S. M. J. Org. Chem. 1988, 53, 904-
906.
1b H, OH
1c H, H
H
TMS
TMS
1d
O
(13) For a theoretical study of 1,2,4-cyclohexatriene, a conjugated cyclic
allene, see: Janoschek, R. Angew. Chem., Int. Ed. Engl. 1992, 31, 476-
478.
(14) Parr, R. G.; Yang, W. Density Functional Theory of Atoms and
Molecules; Oxford University Press: New York, 1989.
electron-withdrawing group on the tether makes the transition
state more accessible, probably because of both conforma-
tional and electronic effects.9
(15) All calculations were performed with the Gaussian 98 and Gaussian
94 program packages. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;
Montgomery, J. A. Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam,
J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.;
Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Andres, J. L.; Gonza´lez, C.; Head-Gordon, M.; Replogle,
E. S.; Pople, J. A. Gaussian 98, Revision A.7, Gaussian, Inc., Pittsburgh,
PA, 1998.
Gratifyingly, while attempting to prepare diarylacetylene
1d by Dess-Martin oxidation of 1a in CH3CN at rt,
spontaneous cycloaddition took place, giving benzo[b]-
fluorenone 3d in 98% yield in only 3 h (Table 1). This
dramatic improvement in kinetics and yield seems likely to
be due to the carbonyl group favoring adoption of a
conformation in which the π orbitals of the alkynes interact
very easily in the transition state (see below).
(8) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633-
651.
(9) Sammes, P. G.; Weller, D. J. Synthesis 1995, 1205-1222.
(16) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
(17) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785.
1498
Org. Lett., Vol. 2, No. 11, 2000

Scheme 2
orbitals to break spin symmetry.20 Geometrical optimization
concerted transition structure led to a saddle point for
biradical formation.24 These results suggest that biradicals 6
are involved in the formation of cyclic allenes 8.
The most stable structures for intermediates 8d, 8f, and
8g correspond to singlet states. However, the unrestricted
Kohn-Sham MO determinant broke spin symmetry due to
the biradicaloid character of the strained allenes (Table 3).
of 2d, 2f, and 2g showed the alkynes to be much better
placed for cyclization in the most reactive conformation of
2d (1.7 kcal/mol above the minimum energy conformation)
than in those of 2f and 2g. Whereas the tethering carbons in
2f and 2g are tetrahedral, with CCC angles of 111.7° and
113.9°, respectively, the sp2 hybridization of the tethering
carbon of 2d imposes a CCC angle of 120.2° that not only
places the alkyne carbons to be linked closer than in 2f and
2g (2.962 Å apart, vs 3.223 Å in 2f and 3.347 Å in 2g) but
also makes the alkynes parallel, thereby facilitating π orbital
interactions.
Biradicals 6d,f,g adopt an angular geometry on the new
vinyl moieties, placing the unpaired electrons in sp2-like
orbitals. The most stable configuration of biradical 6d
(Scheme 2) is 22.4 kcal/mol above diyne 2d, whereas those
of 6f and 6g are 28.8 and 29.4 kcal/mol above the
corresponding diynes; this difference is attributable not only
to the above-mentioned conformational advantage of 2d over
2f and 2g but also to the carbonyl group of 2d which extends
the conjugation of the two new double bonds.21 Since
formation of the biradicals is endothermic, implying a late
transition state, these relative stabilities should be similar to
those of the transition states. The difference of 6.4 kcal/mol
may explain the total lack of reactivity of 2f.
Table 3. Energies Relative to Dibenzodiynes 2, and
Spin-Squared Expectation Values S2 , of Intermediates 6 and 8
biradical 6
E (kcal/mol)
allene 8
E (kcal/mol)
S2
S2
d
f
22.4
28.8
29.4
1.006
-0.3 (1A)
3.1 (3A)
6.7 (1A)
10.4 (3A)
6.0 (1A)
9.2 (3A)
0.527
2.037
0.438
2.038
0.548
2.038
0.954
0.958
g
The corresponding triplet states are higher in energy by about
3 kcal/mol. Note that formation of the allene is endothermic
for 2f and 2g but slightly exothermic for 2d (Table 3). All
To investigate the alternative concerted mechanism through
transition states 7, we performed B3LYP/6-31G* calculations
for the models (Z)-1-phenyl-3-heptene-1,6-diyne and (Z)-7-
phenyl-4-heptene-1,6-diyn-3-one. For the former, the con-
certed transition structure is very asynchronous, with NAO-
based22 Wiberg bond indexes23 of 0.58 for the C2-C6 and
0.22 for C2′-C7, and for the latter all attempts to locate a
(18) Although pure functionals have recently been used for description
of species with biradical character, we achieved better results using hybrid
functionals. Schreiner, P. R.; Prall, M. J. Am. Chem. Soc. 1999, 121, 8615-
8627 and references therein.
(19) Hehre, W.; Radom, W.; Schleyer, P. v. R.; Pople, J. A. Ab initio
Molecular Orbital Theory; Wiley: New York, 1986.
(20) Kohn, W.; Sham, L. J. Phys. ReV. 1965, 140, A1133-1138.
(21) The combination of these two factors was inferred using MCSCF
and B3LYP calculations for the models (Z)-4-heptene-1,6-diyn-3-one and
(Z)-3-heptene-1,6-diyne. Results to be published elsewhere.
(22) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV. 1988, 88,
899.
Figure 1. Highest occupied Kohn-Sham R molecular orbitals of
8d (top, HOMO; bottom, HOMO - 1).
(23) Wiberg, K. A. Tetrahedron 1968, 24, 1083-1096.
Org. Lett., Vol. 2, No. 11, 2000
1499

the singlet forms can be described as strained cyclic allenes
in which the π system is constructed of the p orbitals of all
three carbons and an sp2-like orbital placed on the central
carbon (Figure 1).
Strained allenes 8 might evolve to aromatic products 4
by an intramolecular hydrogen shift or by abstraction of
hydrogen from the solvent25 or from another molecule of
allene. To investigate the role of the solvent, we heated a
solution of benzotriyne 1a in toluene-d8; the absence of
deuterium in the final benzo[b]fluorene 3a (Scheme 3)
toluene/MeOH-d4. Heating a solution of 1a in this mixture
for 10 h in a sealed tube at 100 °C gave 3a-d1 in 85% yield,
an approximately 30% increase over the reaction in neat
toluene;26 more than 95% of the product was labeled at
position 5. These results show the involvement of the added
MeOH-d4 in the evolution of the intermediate allene 8a,
whether by hydrogen abstraction (the radical path) or proton
transfer (the ionic path). To distinguish between these
alternatives, we heated benzotriyne 1a in the presence of
CH3OD, which again gave a high yield of deuterated 3a-d1,
and in the presence of CD3OH, which led to no incorporation
of deuterium (Scheme 3). Since the methyl hydrogens of
methanol are much more susceptible to homolytic abstraction
than the hydroxyl hydrogen, we conclude that the ionic
mechanism is in operation here.
Scheme 3
In conclusion, we have found that two types of diaryl-
acetylene, benzotriynes 1 and benzodiynes 2, undergo
intramolecular [4 + 2] cycloaddition to give benzo[b]fluorene
derivatives in good yields. The hybridization of the tether
connecting the reacting alkynes has a pronounced effect on
the course of the reaction. Theoretical calculations and
isotopic labeling studies support a mechanism that involves
initial formation of a 1,4-vinyl biradical which then under-
goes fast intramolecular coupling to a strained cyclic allene
intermediate that evolves to the benzo[b]fluorene derivatives.
Application of this methodology to the synthesis of natural
benzo[b]fluorene antibiotics is in progress.
Acknowledgment. We thank the Direccio´n General de
Ensen˜anza Superior and the Xunta de Galicia for financial
support under Project PB98-0606. We thank the Centro de
Supercomputacio´n de Galicia (CESGA) for a generous
allocation of computational resources. D. Rodr´ıguez thanks
the Ministerio de Educacio´n y Ciencia (Spain) for a predoc-
toral grant.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds 1-4c,d and
details of deuteration experiments on 1a; Cartesian coordi-
showed that H5 of 3a came from allene 8a itself. Involve-
ment of the hydroxyl group of 1a was ruled out by the
finding that protected derivatives gave similar or even higher
yields.1
At this point we evaluated the influence of a proton source
on the course of the reaction by running it in 80:20 (v/v)
1
nates of 2, 6, and 8d,f,g; H and 13C NMR spectra for 1a,
2c, and 4c; and 1H NMR for 3a and 3a-d1. This material is
available via the Internet at http://pubs.acs.org.
OL991391T
(24) Results to be published elsewhere.
(25) This hypothesis had been suggested previously by Danheiser et al.
See ref 5a.
(26) Increased yield in the presence of a proton source (ArOH) has been
observed previously in intramolecular [4 + 2] cycloadditions. See ref 5a.
1500
Org. Lett., Vol. 2, No. 11, 2000