Polyaromatic ribbon/benzofuran fusion via consecutive endo cyclizations of enediynes

Article abstract of DOI:10.1021/ol302922t

The Sonogashira/5-endo-dig/6-endo-dig cascade fuses a polycyclic aromatic backbone to the electron-rich furan subunit. The transformation proceeds in modest yields as a one-pot reaction. Efficiency of the full cascade is increased by removal of base prior

Full text of DOI:10.1021/ol302922t

ORGANIC
LETTERS
2012
Vol. 14, No. 23
6032–6035
Polyaromatic Ribbon/Benzofuran
Fusion via Consecutive Endo
Cyclizations of Enediynes
Philip M. Byers, Julian I. Rashid, Rana K. Mohamed, and Igor V. Alabugin*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee,
Florida 32306-4390, United States
alabugin@chem.fsu.edu
Received October 23, 2012
ABSTRACT
The Sonogashira/5-endo-dig/6-endo-dig cascade fuses a polycyclic aromatic backbone to the electron-rich furan subunit. The transformation
proceeds in modest yields as a one-pot reaction. Efficiency of the full cascade is increased by removal of base prior to the addition of gold catalyst.
Under these conditions, conversion to the full cascade products is achieved in nearly quantitative yields without purification of the intermediate
products. Extension of the cascade toward triynes opens access to benzofuran-fused chrysene derivatives.
Alkynes are valuable precursors for the preparation of
carbon-rich materials1 due to their high carbon content,
modular assembly via reliable cross-coupling chemistry,
and propensity for participating in coordinated and effi-
cient cascade transformations leading to the construction
ofpolycyclic frameworks.2 Heteroatom incorporation into
polycyclic aromatic frameworks fine-tunes their electronic
properties, leadingtomajoradvancesinthe field of organic
materials. Annealing of donor heterocycles can expand
the utility of carbon-rich compounds in materials3,4 and
molecular devices.5
As a continuation of our work on alkyne cyclizations,6
we recently reported a cascade transformation of four
alkynes into extended polyaromatic structures through a
(4) Selected examples from special issue on organic electronics:
(a) Wakim, S.; Bouchard, J.; Simard, M.; Drolet, N.; Tao, Y.; Leclerc,
M. Chem. Mater. 2004, 16, 4386. (b) Chen, C.-T. Chem. Mater. 2004, 16,
4389. (c) Veres, J.; Ogier, S.; Lloyd, G.; Leeuw, D. Chem. Mater. 2004,
16, 4543.
(5) Collier, C. P.; Mattersteig, G.; Wong, E. W.; Luo, Y.; Beverly, K.;
Sampaio, J.; Raymo, F. M.; Stoddart, J. F.; Heath, J. R. Science 2000,
289, 1172.
(1) (a) Neenan, T. X.; Whitesides, G. M. J. Org. Chem. 1988, 53,
2489. (b) Haley, M. M., Tykwinski, R. R., Eds. Carbon-Rich Com-
pounds: From Molecules to Materials; Wiley-VCH: New York, 2006.
(c) Diederich, F., Stang, P. J., Tykwinski, R. R., Eds. Acetylene Chemistry:
Chemistry, Biology and Material Science; Wiley-VCH: Weinheim, 2005.
(d) Bunz, U. H. F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1073. (e) Tour,
J. M. Chem. Rev. 1996, 96, 537. (f) Gholami, M.; Tykwinski, R. R. Chem.
Rev. 2006, 106, 4997. (g) Shin, Y.; Fryxell, G. E.; Johnson, C. A., II;
Haley, M. M. Chem. Mater. 2008, 20, 981.
(2) (a) Curran, D. P. Synthesis 1988, 417, 489. (b) Jasperse, C. P.;
Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237. (c) Wang, K. K.
Chem. Rev. 1996, 96, 207. (d) Gansauer, A.; Bluhm, H. Chem. Rev. 2000,
100, 2771. (e) Renaud, P., Sibi, M. P., Eds. Radicals in Organic Synthesis;
Wiley-VCH: Weinheim, 2001. (f) Sibi, M. P.; Manyem, S.; Zimmerman J.
Chem. Rev. 2003, 103, 3263.
(6) Selected recent examples: (a) Alabugin, I. V.; Gilmore, K.; Patil,
S.; Manoharan, M.; Kovalenko, S. V.; Clark, R. J.; Ghiviriga, I. J. Am.
Chem. Soc. 2008, 130, 11535. (b) Vasilevsky, S. F.; Baranov, D. S.;
Mamatyuk, V. I.; Gatilov, Y. V.; Alabugin, I. V. J. Org. Chem. 2009, 74,
6143. (c) Baranov, D. S.; Vasilevsky, S. F.; Gold, B.; Alabugin, I. V. RSC
Adv. 2011, 1, 1745. (d) Gilmore, K.; Manoharan, M.; Wu, J.; Schleyer, P.
v.R.; Alabugin, I. V. J. Am. Chem. Soc. 2012, 134, 10584.
(7) Alabugin, I. V.; Gilmore, K.; Patil, S.; Manoharan, M.; Kova-
lenko, S. V.; Clark, R. J.; Ghiviriga, I. J. Am. Chem. Soc. 2008, 130,
11535. Intramolecular initiation via the “weak link” design: Byers,
P. M.; Alabugin, I. V. J. Am. Chem. Soc. 2012, 134, 9609.
(8) (a) Nevado, C.; Echavarren, A. M. Chem.;Eur. J. 2005, 11, 3155.
(b) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513. (c)
Alabugin, I. V.; Gilmore, K.; Manoharan, M. J. Am. Chem. Soc.
2011, 133, 12608.
(3) (a) Anthony, J. E. Chem. Mater. 2011, 23, 583. (b) Scharber,
€
M. C.; Muhlbacher, D.; Koppe, M.; Denk, P.; Waldauf, C.; Heeger,
A. J.; Brabec, C. J. Adv. Mater. 2006, 18, 789.
r
10.1021/ol302922t
Published on Web 11/28/2012
2012 American Chemical Society

sequence of four exo-dig radical cyclizations.7 The exclu-
sive exoselectivity in that reaction design relied on the
revised rules for alkyne cyclizations8 where, contrary to
the original Baldwin rules,9 the preferred approach of a
radical or a nucleophile follows the BurgiÀDunitz trajec-
tory (Figure 1).10
Scheme 1. Synthesis of Enediynes
Table 1. Optimization of the Catalyst System
entrya
catalyst (%)
product: yieldb (%)
1
PdCl2(PPh3)2 5% no Au
4a: 57%/5a:0%
Figure 1. Preferred trajectories for alkyne cyclizations and
the possible switch from the “all-exo” radical cascade to the
“all-endo” metal-assisted cascade.
effect of Au:
2
AuCl 5%
4a: 12%/5a: 0%
4a: 20%/5a: 0%
4a: 19%/5a: 0%
4a: 10%/5a: 0%
3
AuCl 10%
4
ClAuPPh3 10%
AuCl3 10%
Guided by stereoelectronic reasons (“the LUMO-
umpolung”) for the switch to endo selectivity in alkyne
cyclizations when an alkyne coordinates to an external Lewis
acid (“electrophile-assisted cyclizations”)8 and intrigued by
the expanding list of Au-mediated organic approaches toward
polycylic compounds,11 we investigated the feasibility of a
sequence which would involve only endo-dig cyclizations by
merging three metal-catalyzed steps: (1) Sonogashira cross-
coupling, (2) 5-endo-dig cyclization of o-alkynylphenols, and
(3) Au-catalyzed alkyne cyclizations. We also tested whether
this cascade can be expanded further via the participation of
additional alkynes. These tandem transformations would
allow benzofuran fusion to naphthalene, chrysene, and related
polyaromatic cores. Tandem Sonogashira cross-coupling/
5-endo-dig cyclization with a nucleophilic group at the
ortho-position (e.g., ÀOH) has ample literature precedents.12
5
effect of Ag:
6
7
AgOTF 10%
AuCl 10%
4a: 19%/5a: 0%
4a: 13%/5a: 1%
AgBF4 10%
AuCl 10%
8
4a: 32%/5a: 16%
4a: 22% /5a: 12%
4a: 57%/5a: 21%
AgOTf 10%
ClAuPPh3 10%
AgBF4 10%
ClAuPPh3 10%
AgOTf 10%
9
10
effect of base:
11c
ClAuPPh3 10%
AgOTf 10%
4a: 64%/5a: 11%
4a: 0%/5a: 0%
12d
ClAuPPh3 10%
AgOTf 10%
effect of metals:
13
ClAuPPh3 10%
AgOTF 10%
CuI 5%
4a: 18%/5a: 0%
14e
15e
ClAuPPh3 10%
AgOTf 10%
4a: 15%/5a: 0%
4a: 5%/5a: 0%
(9) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
€
(10) Burgi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron
1974, 30, 1563.
ClAuPPh3 10%
(11) (a) Zhou, Y.; Ji, X.; Liu, G.; Zhang, D.; Zhao, L.; Jiang, H.; Liu,
H. Adv. Synth. Catal. 2010, 352, 1711. (b) Song, X.-R.; Xia, X.-F.; Song,
Q.-B.; Yang, F.; Li, Y.-X.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2012, 14,
3344. (c) For a recent review of metal assisted alkyne cyclizations, see:
Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111, 2937.
(12) See, for example: (a) Ohtaka, A.; Teratani, T.; Fujii, R.; Ikeshita,
K.; Kawashima, T.; Tatsumi, K.; Shimomura, O.; Nomura, R. J. Org.
Chem. 2011, 76, 4052. (b) Wang, R.; Mo, S.; Lu, Y.; Shen, Z. Adv. Synth.
Catal. 2011, 353, 713. (c) Vasilevsky, S. F.; Gornostaev, L. M.;
Stepanov, A. A.; Arnold, E. V.; Alabugin, I. V. Tetrahedron Lett.
2007, 48, 1867.
a 0.1 M substrate in o-xylene and 2 equiv of triethylamine were used
unless stated otherwise. All reactions were run for 8 h. b Yields were
determined by 1H NMR except, for example, 9, where the product was
isolated. c 1 equiv of Et3N. d K2CO3 was used as a base. e Reaction was
run without PdCl2(PPh3)2.
Our challenge was in extending the cyclization process past
the initial 5-endo-dig cyclization toward annealing additional
Org. Lett., Vol. 14, No. 23, 2012
6033

Table 2. Tandem Sonogashira/Cascade of Substituted
Enediynes
Scheme 2. Au-Assisted 6-endo-dig Cyclization
hydroamination/hydroarylation cascades for the prepara-
tion of fused indoles and carbazoles.13 Wu et al. have
demonstrated the utility of similar cascades mediated by
iodine.14 Hashmi used Au(I) catalysis for the synthesis of
naphthalene derivatives from enediynes.15
The library of enediynes was prepared using the differ-
entiated reactivity of the two halogen atoms of 2-bromoio-
dobenzene in Sonogashira reactions. The aryl iodide was
coupled at room temperature under standard Sonogashira
conditions using PdCl2(PPh3)2 and CuI in triethylamine,
whereas subsequent coupling with the less reactive aryl
bromide necessitated Pd(PhCN)2Cl2/P(t-Bu)3 as catalyst
with the bulky electron-rich ligand (Scheme 1).16
Conditions for the cyclization cascades were optimized
using 3-((2-ethynylphenyl)ethynyl)thiophene as a model
substrate (Table 1). Inthe presenceof Au species, the use of
standard Sonogashira solvents (i.e., neat amines) gave low
yields of the monocyclized 5-endo product. Use of only 2
equiv of base along with o-xylene as a high-boiling solvent
increased the benzofuran yield to 57%. In the absence of Pd
the yields were dramatically decreased (entries 14 and 15).17
Formation of homocoupled products due to the Hay reac-
tion was minimized by utilizing Cu-free conditions. Although
addition of Au(I) and Au(III) species decreased the efficiency
of benzofuran formation, the addition of Ag salts restored the
reactivity.
(13) (a) Hirano, K.; Inaba, Y.; Takahashi, N.; Shimano, M.; Oishi,
S.; Fujii, N.; Ohno, H. J. Org. Chem. 2011, 76, 1212. (b) Hirano, K.;
Inaba, Y.; Takasu, K.; Oishi, S.; Takemoto, Y.; Fujii, N.; Ohno, H.
J. Org. Chem. 2011, 76, 9068. For the subsequent expansion to sub-
stituted naphthalenes, see: (c) Naoe, S.; Suzuki, Y.; Hirano, K.; Inaba,
Y.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2012, 77, 4907.
(14) Chen, C.-C.; Yang, S.-C.; Wu, M.-J. J. Org. Chem. 2011, 76,
10269.
(15) Hashmi, A. S. K.; Braun, I.; Rudolph, M.; Rominger, F.
Organometallics 2012, 31, 644.
a Isolated yield (%).
(16) (a) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C.
Org. Lett. 2000, 2, 1729. (b) Soheili, A.; Albaneze-Walker, J.; Murry,
J. A.; Dormer, P. G.; Hughes, D. L. Org. Lett. 2003, 5, 4191.
(17) The “Pd-free Sonogashira reactions” are likely due to Pd
impurities in the ClAuPPh3 catalyst. It has been estimated that as little
as 50 ppb of Pd impurity can be catalytically active. Livendahl, M.;
Espinet, P.; Echavarren, A. M. Platinum Metals Rev. 2011, 55, 212.
aromatic rings and extending the conjugated framework. In
our strategy, we were guided by the work of Ohno and co-
workers, which demonstrated the efficiency of Au-catalyzed
6034
Org. Lett., Vol. 14, No. 23, 2012

In the second part of the transformation, gold(I) acti-
vates the alkyne toward the 6-endo-dig cyclization where
the electron-rich furan moiety serves as a nucleophile
(Scheme 2). Because the catalytic Au(I) species are regen-
erated by proto-deauration of the cyclized intermediates,
the presence of base in the Sonogashira conditions may be
responsible for the relative inefficiency of the full cascade
by preventing protodemetalation.19 Alternatively, basic
amines may inhibit the addition step by directly coordinat-
ing at gold.20
Considering the two possible roles of the basic media, we
heated the monocyclized substituted benzofurans in o-xylene
with 10 mol % of ClAuPPh3/AgOTf in the absence of base.
Indeed, all intermediate products were converted into the full
cascade product in excellent yields.
In order to extend the Au-catalyzed transformation
further, triyne 8 was prepared from enediyne 3c. Reaction
of this triyne with 2-iodophenol under the Sonogashira
conditionsprovided only tracesofthe fullcascade product.
However, after removal of the base, the 5-endo product
underwent clean metal-assisted cascade ring closure in-
duced by ClAuPPh3/AgOTf in o-xylene. The intermediate
products corresponding to monocyclization of the 5-endo
product 9 were not observed (Figure 2).
In conclusion, cross-coupling of 2-iodophenol with a
terminal enediyne or triyne sets up an “all-endo” cascade
ofalkyne cyclizations. The fullcascade ismoreefficient ina
two-step procedure that removes base but does not require
further purification or isolation. The final alkyne cycliza-
tions are promoted by ClAuPPh3/AgOTf system in o-
xylene at 150 °C. Future work will optimize reaction
conditions for the cyclizations of extended o-alkyne oligo-
mers in these domino reactions.
Figure 2. Triyne synthesis and cascade reaction with 2-iodophe-
nol (A) and comparison of “all-exo” and “all-endo” strategies
toward the preparation of graphene ribbons (B).
The 10% ClAuPPh3/AgOTf system provided the first
evidence that the full cascade is viable, albeit in a low yield.
Better yields of the cascade products 5 were obtained when
enediyne, 2-iodophenol, Et3N, and PdCl2(PPh3)2 were allowed
to react in o-xylene for 1 h at room temperature before the
addition of ClAuPPh3/AgOTf and heating in a sealed tube.
The overall cascade merges the two metal-catalyzed
transformations. First, 2-iodophenol cross-couples with a
terminal alkyne via the classic Sonogashira path, followed
by 5-endo-dig attack of oxygen at the activated alkyne
(Table 2). In domino reactions of this nature, a variety of
soft Lewis acidic metals can activate alkynes for an in-
tramolecular nucleophilic attack.18
Acknowledgment. Support by National Science Foun-
dation (CHE-1213578) is gratefully acknowledged.
Supporting Information Available. Full synthetic pro-
cedures, 1H and 13C NMR spectra, and HRMS of all new
compounds; gHMBC and gHMQC data for compound
5a and 10; UV-absorbance data for 5aÀj and 10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128,
1798.
(18) Wang, R.; Mo, S.; Lu, Y.; Shen, Z. Adv. Synth. Catal. 2011, 353,
713.
(19) Lalonde, R. L.; Brenzovich, W. E.; Benitez, D.; Tkatchouk, E.;
Kelly, K.; Goddard, W. A.; Toste, F. D. Chem. Sci. 2010, 1, 226.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
6035