Straightforward synthesis of dihydrobenzo[a]fluorenes through Au(I)- catalyzed formal [3 + 3] cycloadditions

Article abstract of DOI:10.1021/ol3020682

Dihydrobenzo[a]fluorene derivatives have been prepared by a formal intramolecular [3 + 3] cycloaddition of o-alkynylstyrenes bearing a secondary alkyl group at the β-position of the styrene moiety. The process, catalyzed by a cationic gold(I) complex, involves a 1,2-hydride migration as the key step. 6,11-Dihydro-5H-benzo[a]fluorenes could be obtained from the initially generated 6,6a-dihydro-5H-benzo[a]fluorenes by subsequent heating of the reaction mixture under gold(I) or Bronsted acid catalysis or directly by conducting the reactions at high temperature.

Full text of DOI:10.1021/ol3020682

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4778–4781
Straightforward Synthesis of
Dihydrobenzo[a]fluorenes through Au(I)-
Catalyzed Formal [3 þ 3] Cycloadditions
†
ꢀ
´
´
Patricia Garcıa-Garcıa, Muhammad A. Rashid, Ana M. Sanjuan, Manuel A.
ꢀ
Fernandez-Rodrıguez, and Roberto Sanz*
´
ꢀ
Area de Quımica Organica, Departamento de Quımica, Facultad de Ciencias,
´
Universidad de Burgos, Pza. Misael Banuelos s/n, 09001-Burgos, Spain
ꢀ
´
~
rsd@ubu.es
Received July 26, 2012
ABSTRACT
Dihydrobenzo[a]fluorene derivatives have been prepared by a formal intramolecular [3 þ 3] cycloaddition of o-alkynylstyrenes bearing a
secondary alkyl group at the β-position of the styrene moiety. The process, catalyzed by a cationic gold(I) complex, involves a 1,2-hydride
migration as the key step. 6,11-Dihydro-5H-benzo[a]fluorenes could be obtained from the initially generated 6,6a-dihydro-5H-benzo[a]fluorenes by
subsequent heating of the reaction mixture under gold(I) or Brønsted acid catalysis or directly by conducting the reactions at high temperature.
Benzo[a]fluorene and, in particular, its polyhydro deri-
vatives are cores frequently found in diverse natural
products possessing biological activity (Figure 1). This
tetracyclic skeleton is present, for instance, in isopre-
kinamycin,1 veratramine,2 or nakiterpiosinone3 and is
the structural base of whole families of compounds
such as the dasyscyphins,4 walsuchocins,5 or fluostatins.6
Moreover, synthetic polyhydrobenzo[a]fluorenes have
also shown interesting properties, for example, as bone
loss inhibitors7 or estrogen receptors.8
† Present Address: Department of Chemistry and Biochemistry, Univer-
sity of Agriculture, Faisalabad-38040, Pakistan.
(1) Proteau, P. J.; Li, J.; Williamson, T. R.; Gould, S. J.; Laufer, R. S.;
Dmitrienko, G. I. J. Am. Chem. Soc. 2000, 122, 8325–8326.
(2) Johnson, W. S.; deJongh, H. A. P.; Coverdale, C. E.; Scott, J. W.;
Burckhardt, U. J. Am. Chem. Soc. 1967, 89, 4523–4526.
(3) Gao, S.; Wang, Q.; Huang, L. J.-S.; Lum, L.; Chen, C. J. Am.
Chem. Soc. 2010, 132, 371–383.
(4) (a) Mierau, V.; de la Parra, V. R.; Sterner, O.; Anke, T. J. Antibiot.
2006, 59, 53–56. (b) Liermann, J. C.; Kolshorn, H.; Anke, H.; Thines, E.;
Opatz, T. J. Nat. Prod. 2008, 71, 1654–1656.
(5) Zhou, Z.-W.; Yin, S.; Zhang, H.-Y.; Fu, Y.; Yang, S.-P.; Wang,
X.-N.; Wu, Y.; Tang, X.-C.; Yue, J.-M. Org. Lett. 2008, 10, 465–468.
Figure 1. Selected natural products containing the polyhydro-
benzo[a]fluorene skeleton.
€
(6) (a) Schneider, K.; Nicholson, G.; Strobele, M.; Baur, S.; Niehaus,
€
J.; Fiedler, H.-P.; Sussmuth, R. D. J. Antibiot. 2006, 59, 105–109.
(b) Baur, S.; Niehaus, J.; Karagouni, A. D.; Katsifas, E. A.; Chalkou,
K.; Meintanis, C.; Jones, A. L.; Goodfellow, M.; Ward, A. C.; Beil, W.;
On the other hand, transition-metal-catalyzed cycliza-
tion of functionalized unsaturated substrates has emerged
€
Schneider, K.; Sussmuth, R. D.; Fiedler, H.-P. J. Antibiot. 2006, 59, 293–
297.
(7) (a) Bryant, H. U.; Cullinan, G. J. Tetrahydrobenzo[a]fluorene
compounds and methods of use. Eur. Pat. Appl. EP0832883A1, 1998.
(b) Bryant, H. U.; Cullinan, G. J. Tetrahydrobenzo[a]fluorene compounds
and methods of use. U.S. Patent 5,821,253, 1998.
(8) Tedesco, R.; Youngman, M. K.; Wilson, S. R.; Katzenellenbogen,
J. A. Bioorg. Med. Chem. Lett. 2001, 11, 1281–1284.
r
10.1021/ol3020682
Published on Web 08/31/2012
2012 American Chemical Society

in recent years as a fundamental tool for the synthesis of a
wide array of cyclic structures not easily prepared by conven-
tional methodologies.9 Particularly interesting in this field are
gold- and platinum-catalyzed cycloisomerizations of enynes
that generally entail a rapid increase in structural complexity
from readily available precursors under mild conditions.10
In this regard, we have recently described a gold-cata-
lyzed cycloisomerization of o-alkynylstyrenes that provides
an easy enantioselective access to the indene skeleton and
is proposed to proceed via carbocation I (Scheme 1, via
route a).11 Continuing with our ongoing interest in imple-
menting new applications of gold-catalyzed reactions of
1,3-dien-5-ynes,12 we envisioned that those compounds
could be appropiate substrates for the development of a
new route to benzo[a]fluorene derivatives.13 Thus, we
considered that if a rearrangement of carbocation I by
hydride migration to the adjacent carbon would be possi-
ble, the trapping of the new intermediate II by intramole-
cular nucleophilic attack of an aromatic group could be
favored(Scheme1, viarouteb). Theoveralltransformation
would therefore lead to the formation of the dihydrobenzo-
[a]fluorene skeleton through a formal [3 þ 3] cycloaddi-
tion.14,15 The success of the proposed reaction would ob-
viously depend on the appropiate selection of groups R1 and
R2, which should be able to favor the formation of carbocation
II from the initially generated carbocation I.
To test our hypothesis, we selected as a model substrate
o-alkynylstyrene 1a (4:1 mixture of geometrical isomers),
having an isopropyl group linked to the double bond, that
would generate a rather favored tertiary carbocation upon
migration to form an intermediate of type II. At the outset,
we tested its reactivity in the presence of different cationic
gold complexes and solvents (Table 1). We were glad to
find that by performing the reaction in CH2Cl2 using 5 mol %
of AuPPh3Cl/AgSbF6 as catalyst a high selectivity to the
formation of the dihydrobenzo[a]fluorene products 2a and
iso-2a was obtained, with less than 10% of indene deriva-
tives 3a and iso-3a formed (entry 1). A minor influence of
the ligand of the gold complex was observed (entries 1ꢀ4),
while the counterion plays a crucial role in the outcome of
the reaction (entries 1 vs 5ꢀ9) as indene derivatives 3a and
iso-3a are primarily or even exclusively obtained with
triflate (entry 8) or tosylate (entry 9) counterions. The
solvent also has a significant influence in the selectivity of
the reaction (entries 1 vs 10ꢀ13) with CH2Cl2 being the best
for promoting the formal [3 þ 3] cycloaddition (entry 1),
whereas ethereal solvents lead mainly to the formation of
indene derivatives (entries 12 and 13). It is remarkable how
an appropriate selection of the reaction conditions allows
the selective isolation in good yields of either dihydrobenzo-
[a]fluorene (entry 1) or indene derivatives (entry 9).
Table 1. Effect of the Catalyst and the Solvent in the Selectivity
Scheme 1. Previously Reported Synthesis of Indenes and Pro-
posed Synthesis of Dihydrobenzo[a]fluorenes
2a þ iso-2a
3a þ iso-3a
entry
catalyst
solvent yielda (%)
yielda (%)
1 AuPPh3Cl/AgSbF6 CH2Cl2
94 (80)b
93
6
2 AuPEt3Cl/AgSbF6
3 IPrAuCl/AgSbF6
CH2Cl2
CH2Cl2
7
80
17
7
4 AuP(OPh)3Cl/AgSbF6CH2Cl2
91
€
(9) (a) Furstner, A. Chem. Soc. Rev. 2009, 38, 3208–3221. (b) Das, A.;
5 AuPPh3NTf2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
80
20
25
50
93
100 (78)
14
16
55
82
Sohel, S. M. A.; Liu, R.-S. Org. Biomol. Chem. 2010, 8, 960–979.
(c) Shapiro, N. D.; Toste, F. D. Synlett 2010, 675–691. (d) Rudolph,
M.; Hashmi, A. S. K. Chem. Commun. 2011, 47, 6536–6544.
(10) For reviews, see: (a) Zhang, L.; Sun, J.; Kozmin, S. A. Adv.
Synth. Catal. 2006, 348, 2271–2296. (b) Michelet, V.; Toullec, P. Y.;
6 AuPPh3Cl/AgBF4
7 AuPPh3Cl/AgPF6
8 AuPPh3Cl/AgOTf
9 AuPPh3Cl/AgOTs
75
45
7
^
ꢀ
Genet, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268–4315. (c) Jimenez-
ꢀ~
10 AuPPh3Cl/AgSbF6 MeNO2
11 AuPPh3Cl/AgSbF6 toluene
12 AuPPh3Cl/AgSbF6 DME
13 AuPPh3Cl/AgSbF6 THF
80
80
38
8
Nunez, E.; Echavarren, A. Chem. Rev. 2008, 108, 3326–3350.
ꢀ
(11) Martınez, A.; Garcıa-Garcıa, P.; Fernandez-Rodrıguez, M. A.;
Rodrıguez, F.; Sanz, R. Angew. Chem., Int. Ed. 2010, 49, 4633–4637.
ꢀ
(12) Garcıa-Garcıa, P.; Martınez, A.; Sanjuan, A. M.; Fernandez-
ꢀ
Rodrıguez, M. A.; Sanz, R. Org. Lett. 2011, 13, 4970–4973.
a Determined by 1H NMR of the crude mixture using 1,3,5-
trimethoxybenzene as internal standard; isolated yield shown in parenth-
eses. b 2a was obtained as a ca. 7:1 mixture of diastereoisomers.
(13) For recent syntheses of benzo[a]fluorene derivatives, see: (a) Liu,
W.; Buck, M.; Chen, N.; Shang, M.; Taylor, N. J.; Asoud, J.; Wu, X.;
Hasinoff, B. B.; Dmitrienko, G. I. Org. Lett. 2007, 9, 2915–2918.
(b) Chaudhuri, R.; Liao, H.-Y. M.; Liu, R.-S. Chem.;Eur. J. 2009,
15, 8895–8901. (c) Zhang, L.; Xie, X.; Liu, J.; Qi, J.; Ma, D.; She, X. Org.
Lett. 2011, 13, 2956–2958. See also refs 3 and 8. (d) For a recent gold-
catalyzed cascade cyclization that affords benzo[b]fluorenes, see: Chen,
Y.; Chen, M.; Liu, Y. Angew. Chem., Int. Ed. 2012, 51, 6493–6497.
Thus, the best conditions for accomplishing the formal
[3 þ 3] cycloaddition pathway consist of the use of
4779
Org. Lett., Vol. 14, No. 18, 2012

AuPPh3Cl/AgSbF6 as catalyst in CH2Cl2 as solvent. Un-
der these conditions, we were able to isolate 80% of a ca.
7:1 mixture of 6,6a-dihydro-5H-benzo[a]fluorene 2a and
6,11-dihydro-5H-benzo[a]fluorene iso-2a, differing in the
position of the double bond.16
According to these results and based on our experience
in the cycloisomerization of 1,3-dien-5-ynes we propose
the following mechanism (Scheme 3).
Gratifyingly, selective formation of either 2a or iso-2a
could be achieved by simply controlling the temperature of
the reaction (Scheme 2a). So, 75% of 2a was isolated as a
ca. 7:1 mixtureofdiastereoisomers17 when the reaction was
performed at 0 °C, whereas 79% of iso-2a was obtained at
80 °C in DCE. These results suggest that iso-2a could be
formed by a thermal rearrengment of 2a, which was
confirmed by the transformation in good yield of isolated
2a into iso-2a upon heating under the reaction conditions
or in the presence of a Brønsted acid (Scheme 2a). More-
over, we observed that when the reaction was carried out at
80°C not eventracesof indene derivatives 3aoriso-3awere
formed. Therefore, we checked out the possibility that
indene derivatives could cyclize under these reaction con-
ditions to afford iso-2a, which turned out to be the case
(Scheme 2b). However, no transformation of 3a/iso-3a was
observed in the presence of the cationic gold complex at
room temperature, which is evidence that these are not
intermediates in the synthesis of 2a at low temperature but
the result of a different reaction pathway.
Scheme 3. Proposed Mechanism
The reaction would be initiated by coordination of the
gold complex to the triple bond of the starting dienyne 1a
followed by an intramolecular 5-endo-dig nucleophilic
attack of the terminal olefin, leading to an intermediate
that can be represented as the contribution of two reso-
nance structures Ia and Ib. As previously proposed, elim-
ination of a proton in I (path a/a0) furnishes a vinyl gold
intermediate that after protodemetalation gives the indene
3a or iso-3a, depending on which proton has been elimi-
nated. On the other hand, intermediate I can undergo a
hydride migration giving rise to intermediate II (path b).
This new carbocation would be subsequently trapped by
nucleophilic attack of the aromatic ring, a FriedelꢀCrafts
alkylation,18 affording dihydrobenzo[a]fluorene derivative
III which after protodemetalation furnishes compound 2a
regenerating the catalytic species.19
Scheme 2. Effect of the Temperature in the Selectivity
Once we had established the optimum conditions for
directing the cycloisomerization of o-alkynylstyrenes 1 to
the [3 þ 3] cycloaddition pathway, we checked the poten-
tial of this methodology for the synthesis of a family of
dihydrobenzo[a]fluorenes 2 and iso-2. Gratifyingly, reac-
tion of easily accessible o-alkynylstyrenes 1aꢀk at 0 °C20
afforded 6,6a-dihydro-5H-benzo[a]fluorenes 2aꢀk in
good yields and with high diastereoselectivities (Table 2).
The method is compatible with the presence of both a
halogen (entry 1) and an electron-donating group (entry 2)
in the nucleophilic aromatic ring, which can also be
heteroaromatic (entry 3). Moreover, diverse substitution
paterns are well tolerated at the double bond of the starting
material, as long as one of the groups is a secondary alkyl
(14) It is worth noting that the unique properties of gold complexes
have allowed the disclosure of new types of cycloaddition reactions that
were previously unfeasible. For a recent revision on gold-catalyzed
ꢀ
~
cycloaddition reactions, see: Lopez., F.; Mascarenas, J. L. Beilstein J.
Org. Chem. 2011, 7, 1075–1094.
(15) For other gold-catalyzed cycloaddition reactions involving 1,3-
ꢀ
dien-5-ynes, see: (a) Barluenga, J.; Fernandez-Rodrıguez, M. A.;
Garcıa-Garcıa, P.; Aguilar, E. J. Am. Chem. Soc. 2008, 130, 2764–
ꢀ
ꢀ
2765. (b) Fernandez-Garcıa, J. M.; Fernandez-Rodrıguez, M. A.; Agui-
(18) For a mechanistically related gold-catalyzed reaction to give
fluorenes, see: Gorin, D. J.; Watson, I. D. G.; Toste, F. D. J. Am. Chem.
Soc. 2008, 130, 3736–3737.
(19) Proton elimination from intermediate II, which would lead to 3a
after protodemetalation, could also be possible.
(20) Reactions of 1b,eꢀh occurred at rt without significant formation
of iso-2 adducts, whereas increasing amounts of indenes 3 were observed
at 0 °C, and therefore these reactions were performed at rt.
lar, E. Org. Lett. 2011, 13, 5172–5175.
(16) Variable amounts of iso-2a were obtained for all entries in
Table 1 where the [3 þ 3] cycloaddition pathway was observed.
(17) The relative stereochemistry of the major isomer of 2a was
established by a NOESY experiment as syn. The same syn selectivity
was also observed and determined for cycloadducts 2bꢀh as described in
this paper. See the Supporting Information for details.
4780
Org. Lett., Vol. 14, No. 18, 2012

Scheme 4. Synthesis of 6,11-Dihydro-5H-benzo[a]fluorenea
Table 2. Synthesis of 6,6a-Dihydro-5H-benzo[a]fluorenes 2
entry
1
R1 R2 R3 R4
Ar
2
yielda (%) dr
1b 1b Me Me Me
H
H
H
H
p-ClC6H4
2b
81
79
75
68
75
71
70
72
67
76
5:1
2
3
1c Me Me Me
1d Me Me Me
p-MeOC6H4 2c
6:1
3-Th
Ph
2d
2e
2f
7:1
c
4b 1e Me Me Et
5b 1f Me ꢀ(CH2)5ꢀ H Ph
>20:1
5:1
6b 1g Et Me Me
7b 1h Ph Me Me
H
H
H
Ph
Ph
Ph
2g
2h
2i
>20:1
8
9
1i
1j
H
H
H
Me Me
ꢀ(CH2)5ꢀ H Ph
2j
10 1k
Me Me Br Ph
2k
a Isolated yield. b Reaction conducted at rt. c Obtained as a ca. 6:3:2:1
mixture of diastereoisomers.
a Reaction conducted at rt.
(entries 4ꢀ7). o-Alkynylstyrenes 1iꢀk, having a monosub-
stituted olefin, are also appropriate substrates for this
reaction (entries 8ꢀ10). In addition, further functionality
can also be introduced in the central aromatic ring of the
starting material (entry 10).
Scheme 5. Enantioselective Synthesis of Benzo[a]fluorenes iso-2
On the other hand reaction of selected o-alkynylstyrenes
1 at 80 °C allowed for the synthesis of 6,11-dihydro-5H-
benzo[a]fluorenes iso-2 with very good yields and again
with a wide scope regarding the substitution in all the
possible different positions (Scheme 4).
Finally, taking advantage of our previously reported
enantioselective synthesis of indenes by using dinuclear
chiral gold(I) catalysts,11,21 we explored the possibility
of obtaining enantioenriched dihydrobenzo[a]fluorenes.
Thus, under the best reaction conditions found,22 we
synthesized some dihydrobenzo[a]fluorenes iso-2 in an
enantioselective fashion in good yields although with
modest enantiomeric excess (Scheme 5).23
of o-alkynylstyrenes that could provide selective and
straightforward access to other relevant policyclic com-
pounds are currently underway.
In conclusion, we have developed an efficient synthesis
of dihydrobenzo[a]fluorenes through a novel gold-cata-
lyzed intramolecularformal [3 þ 3] cycloaddition of simple
o-alkynylstyrenes. Reactions take place through a tan-
dem 5-endo cyclizationꢀ[1,2]-hydride migrationꢀFriedelꢀ
Crafts alkylation to afford the corresponding cycloadducts
in good yields. Efforts to identify new reaction pathways
Acknowledgment. We are grateful to MICINN and
FEDER (CTQ2010-15358 and CTQ2009-09949/BQU)
ꢀ
and Junta de Castilla y Leon (BU021A09 and GR-172)
for financial support. A.M.S. thanks Junta de Castilla y
ꢀ
ꢀ
Leon (Consejerıa de Educacion) and Fondo Social Eur-
opeo for a PIRTU contract. M.A.R. thanks MEC for a
“Young Foreign Researchers” contract (SB2009-0186).
P.G.-G. and M.A.F.-R. thank MICINN for “Juan de la
(21) For gold(I)-catalyzed enantioselective cycloisomerizations of 1,
^
ꢀ
Cierva” and “Ramon y Cajal” contracts.
n-enynes see: (a) Chao, C.-M.; Vitale, M. R.; Toullec, P. Y.; Genet, J.-P.;
Michelet, V. Chem.;Eur. J. 2009, 15, 1319–1323. (b) Brazeau, J.-F.;
Zhang, S.; Colomer, I.; Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2012,
134, 2742–2749 and references therein. For reviews, see: (c) Marinetti, A.;
Jullien, H.; Voituriez, A. Chem. Soc. Rev. 2012, 41, 4884–4908. (d) Watson,
I. D. G.; Toste, F. D. Chem. Sci. 2012, DOI: 10.1039/c2sc20542d.
(22) See the Supporting Information for a detailed study.
(23) Compared with our previous results (ref 11), the observed
modest enantioselectivity could be partially explained considering that
the reaction that affords 2 is not totally diastereoselective.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
Copies of 1H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
4781