Cycloisomerization of aromatic homo and bis-homopropargylic alcohols via catalytic ru vinylidenes: Formation of benzofurans and isochromenes

Article abstract of DOI:10.1021/ol902212h

Ru-catalyzed cycloisomerizations of aromatic homo- and bis-homopropargylic alcohols effectively afford benzofurans and isochromenes. These processes proved to be chemo- and regioselective (5-, and 6-endo cyclizations) derived from key Ru vinylidene intermediates. The presence of an amine/ammonium base-acid pair is crucial for the catalytic cycle.

Full text of DOI:10.1021/ol902212h

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5350-5353
Cycloisomerization of Aromatic Homo-
and Bis-homopropargylic Alcohols via
Catalytic Ru Vinylidenes: Formation of
Benzofurans and Isochromenes
Alejandro Varela-Ferna´ndez, Carlos Gonza´lez-Rodr´ıguez, Jesu´s A. Varela,
Luis Castedo, and Carlos Saa´*
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad de Santiago
de Compostela, 15782 Santiago de Compostela, Spain
carlos.saa@usc.es
Received September 24, 2009
ABSTRACT
Ru-catalyzed cycloisomerizations of aromatic homo- and bis-homopropargylic alcohols effectively afford benzofurans and isochromenes. These
processes proved to be chemo- and regioselective (5-, and 6-endo cyclizations) derived from key Ru vinylidene intermediates. The presence
of an amine/ammonium base-acid pair is crucial for the catalytic cycle.
The development of effective strategies for the synthesis of
a large structural diversity of heterocyclic compounds is a
very important challenge for modern organic synthesis.1
Convenient synthetic approaches involving heterocyclizations
of functionalized alkynes have been developed in which
catalytic metal vinylidenes have been invoked as key
intermediates.2 Pioneer work using Mo and W vinylidenes
has been developed by McDonald when homo- and bis-
homopropargylic alcohols cycloisomerized to dihydrofurans
and dihydropyrans, respectively, in moderate to good yields.3
Other seminal studies were carried out by Trost using cationic
Ru vinylidenes as catalytic species (from CpRuCl(PAr3)2/
N-hydroxysuccinimide/n-Bu4NPF6, and NaHCO3) in oxida-
tive cyclizations of homo- and bis-homopropargylic alcohols
to γ-butyro- and δ-valerolactones4 and cycloisomerizations
of bis-homopropargylic alcohols to dihydropyrans,5 but no
Ru-catalyzed cycloisomerization of homopropargylic alco-
hols to dihydrofurans has been described under these
conditions (Scheme 1, eq 1). However, cycloisomerizations
of both alcohols with catalytic Rh vinylidenes (from [Rh-
(cod)Cl]2/PAr3) showed better chemoselectivities and turn-
overs than Ru vinylidenes.6 More recently, successful
cycloisomerizations of 2-(ethynyl)anilines and phenols (aro-
matic homopropargylic alcohols) to indoles and benzofurans,
respectively, have been achieved under the same Rh condi-
tions that require relatively large amounts of phosphine
ligands.7 Herein, we now describe a fruitful simple combina-
(1) ComprehensiVe Heterocyclic Chemistry III; Katritzky, A. R., Rams-
den, C. A., Scriven, E. F. V., Taylor, R. J. K. , Eds.; Elsevier: New York,
2008.
(2) For reviews of metal vinylidenes in catalysis, see: (a) Bruce, M. I.
Chem. ReV. 1991, 91, 197. (b) Bruneau, C.; Dixneuf, P. H. Acc. Chem.
Res. 1999, 32, 311. (c) Trost, B. M. Acc. Chem. Res. 2002, 35, 695. (d)
Bruneau, C.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2006, 45, 2176. (e)
Trost, B. M.; McClory, A. Chem. Asian J. 2008, 3, 164.
(3) (a) McDonald, F. E.; Connolly, C. B.; Gleason, M. M.; Towne, T. B.;
Treiber, K. D. J. Org. Chem. 1993, 58, 695. (b) McDonald, F. E.; Schultz,
C. C. J. Am. Chem. Soc. 1994, 116, 9363. (c) McDonald, F. E.; Bowman,
J. L. Tetrahedron Lett. 1996, 37, 4675. (d) McDonald, F. E.; Gleason, M. M.
J. Am. Chem. Soc. 1996, 118, 6648. (e) McDonald, F. E.; Zhu, H. Y. H.
Tetrahedron 1997, 53, 11061. (f) McDonald, F. E.; Zhu, H. Y. H. J. Am.
Chem. Soc. 1998, 120, 4246. (g) McDonald, F. E.; Reddy, K. S.; Diaz, Y.
J. Am. Chem. Soc. 2000, 122, 4304.
(4) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 1999, 121, 11680.
(5) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 2528.
(6) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125, 7482.
(7) Trost, B. M.; McClory, A. Angew. Chem., Int. Ed. 2007, 46, 2074.
10.1021/ol902212h CCC: $40.75
Published on Web 10/27/2009
 2009 American Chemical Society

A variety of aromatic bis-homopropargylic alcohols 1 were
converted into the corresponding isochromenes 2 in good
yields using the optimized conditions for both amine solvents
(Table 2). Both electron-poor and electron-rich substrates
Scheme 1. Ru-Catalyzed Cycloisomerization of Aliphatic and
Aromatic Homo- and Bis-homopropargylic Alcohols
Table 2. Cycloisomerization of Bis-homopropargylic Alcohols 1
into Isochromenes 2
8
tion of CpRuCl(PPh3)2 and amines (n-BuNH2 or Py) to
accomplish new cycloisomerizations of aromatic homo- and
bis-homopropargylic alcohols to benzofurans and isoch-
romenes,9 respectively, through formation of cationic Ru
vinylidenes as key catalytic intermediates (Scheme 1, eq 2).10
First, the amine solvent and other reaction parameters of the
ruthenium-catalyzed cycloisomerization (6-endo cyclization) of
aromatic bis-homopropargylic alcohol 1a was optimized (Table
1). Heating an n-butylamine solution of 1a (0.15 M) in a sealed
Table 1. Optimization of Ru-Catalyzed Cycloisomerization of
Bis-homopropargylic Alcohol 1a
entry
amine
time (h)
temp (°C)
yielda (%)
1
2
3
n-BuNH2
Py
Py
6
3
4
48
24
24
90
90
130
90
90
90
86
42
60
4b
5c
6d
n-BuNH2
dec
a [1a] ) 0,15 M. b Without Ru catalyst. c DMF as solvent. d DMF/NaHCO3
(2 equiv).
tube at 90 °C in the presence of 10% CpRuCl(PPh3)2 as catalyst
gave an excellent 86% yield of isochromene 2a (entry 1),
whereas in pyridine it gave only a 42% yield (entry 2). Heating
at a higher temperature in pyridine (130 °C) gave an improved
60% yield (entry 3). Control experiments showed that both Ru
catalyst and amine solvent were essential (entries 4 and 5) as
well as the use of amine as organic base (entry 6).11,12
a Typical conditions: 10% CpRuCl(PPh3)2, n-BuNH2, 90 °C. b 10%
CpRuCl(PPh3)2, Py, 130 °C. c Without catalyst. d 90 °C. Dec ) decomposition.
(8) CpRuCl(PPh3)2 has been previously used in stoichiometric reactions
with homo- and bis-homopropargylic alcohols to give stable cyclic
oxacarbene Ru complexes: Bruce, M. I.; Swincer, A. G.; Thomson, B. J.;
Wallis, R. C. Aust. J. Chem. 1980, 33, 2605.
1b and 1c gave good yields of the corresponding isoch-
romenes 2b and 2c (entries 2 and 3). Interestingly, the alcohol
functionality in 1 was mandatory for achieving 6-endo
cyclizations by C-O bond formation since the 2-ethynyl-
benzoic acid 3 was smoothly converted by a 5-exo cyclization
into 2-benzofuran-1-one 4 in an excellent yield (entry 4).13
(9) For isochromenes with interesting biological properties, see: (a)
Biber, B.; Muske, J.; Ritzan, M.; Graft, U. J. Antibiot. 1998, 51, 381. (b)
Maruse, N.; Goto, M. J. Antibiot. 1998, 51, 545. (c) Wang, W.; Breining,
T.; Li, T.; Milbum, R.; Attardo, G. Tetrahedron Lett. 1998, 39, 2459, and
references cited therein.
Org. Lett., Vol. 11, No. 22, 2009
5351

On the other hand, benzylic alcohols must have terminal
2-alkynyl substituents in order to be cyclized since 1d gave
decomposition (entry 5), that seems to indicate that the
cyclization is not produced by simple alkyne activation by
the catalyst. Smooth 6-endo cyclizations occurred when
secondary and even tertiary benzylic alcohols 1e-g were
cycloisomerized to isochromenes 2e-g in quite good yields
(entries 6-8). For the sake of comparison, when our new
conditions were applied to aliphatic bis-homopropargylic
alcohol 5, smooth cycloisomerization took place to dihy-
dropyran 6 in 60% yield,14 whereas the double bis-homopro-
pargylic alcohol 7, with favorable Thorpe-Ingold effect,15
gave spirodihydropyran 8 in a high 80% yield (entries 9 and
10).
The presence of phenolic OH group was mandatory for
C-O bond formation since 1-ethynyl-2-methoxybenzene
11 gave no cycloisomerized but dimeric linear enyne
product 12 (entry 5).21
Having in mind all the precedents of C-O bond formation
involving metal vinylidenes, these results may be satisfac-
torily explained according to the proposed mechanism shown
in Scheme 2. After Cl- dissociation from the starting Ru
Scheme 2
.
Proposed Catalytic Cycle for the Ru-Catalyzed
Cycloisomerization
Finally, the regioselectivity of the cyclization (6-endo
vs 5-endo) was probed with substrate 9a, which possesses
benzylic and phenolic OH groups, obtaining exclusively
the benzofuran 10a (5-endo) in an excellent 82% yield,16
showing the possibility of performing ruthenium-catalyzed
cycloisomerizations of aromatic homopropargylic alcohols
to benzofuran (Table 3, entry 1).17 Thus, 9b was smoothly
Table 3. Ru-Catalyzed Cycloisomerization of Homopropargylic
Alcohols 9 into Benzofurans 10
precatalyst and coordination to the alkyne 1a, the key Ru
vinylidene intermediate I could be formed.22 This process
could be suggested from isotopic labeling which shows
(10) For a general review of Ru-catalyzed reactions, see: Trost, B. M.;
Frederiksen, M. U.; Rudd, M. T. AngewChem., Int. Ed. 2005, 44, 6630.
For reviews of Ru-vinylidenes, see ref 2. For books, see: (a) Murahashi,
S.-I., Ed. Ruthenium in Organic Synthesis; Wiley-VCH: Weinheim, 2004.
(b) Bruneau, C., Dixneuf, P. H., Eds. Topics in Organometallic Chemistry;
Springer: Berlin, 2004; Vol. 11.
(11) Solvent (DMF) and base (NaHCO3) were used for cycloisomer-
ization of bis-homopropargyl alcohols. See ref 5.
(12) Other Ru(II) catalysts and amines failed or gave lower yields. See
the Supporting Information for details.
(13) The same result was obtained without catalyst by heating in
pyridine: Kanazawa, C.; Terada, M. Tetrahedron Lett. 2007, 48, 933.
(14) Yield comparable to the one obtained using other Ru catalytic
conditions (64%) and using Rh catalysts (61%). See refs 5 and 6 for more
details.
(15) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,
107, 1080. (b) Ingold, C. K. J. Chem. Soc. 1921, 119, 305. (c) Ingold,
C. K.; Sako, S.; Thorpe, J. F. J. Chem. Soc. 1922, 121, 1117. (d) Hammond,
G. In Steric Effects in Organic Chemistry; Newman, M. S., Ed.; Wiley:
New York, 1956; pp 462-470. (e) Kanetis, J.; Kirby, A. J.; Koedjikov,
A. H.; Pojarlieff, I. G. Org. Biomol. Chem. 2004, 2, 1098.
(16) The 5-endo is probably preferred on the basis of the driving force
of forming a new aromatic furan ring when the phenolic OH reacts.
(17) To the best of our knowledge, only Ru-catalyzed oxidative
cyclization of homopropargylic alcohols to γ-butyrolactones has been
described. See refs 4 and 5.
a 10% CpRuCl(PPh3)2, Py, 90 °C. b 130 °C.
converted in only 2 h to the benzofuran derivative 10b in
an excellent 84% yield (entry 2). Challenging function-
alized benzofuranes 10c,d, important cores in organic
materials18 and pharmaceuticals,19 could be directly
achieved in relatively good yields, in spite of nucleophi-
licity of phenols 9c,d being reduced (entries 3 and 4).20
(18) Friedman, M. R.; Toyne, K. J.; Goodby, J. W.; Hird, M. J. Mater.
Chem. 2001, 11, 2759.
(19) Saitoh, M.; Kumitomo, J.; Kimura, E.; Hayase, Y.; Kobayashi, H.;
Uchiyama, N.; Kawamoto, T.; Tanaka, T.; Mol, C. D.; Dougan, D. R.;
Textor, G. S.; Snell, G. P.; Itoh, F. Biorg. Med. Chem. 2009, 17, 2017.
5352
Org. Lett., Vol. 11, No. 22, 2009

deuterium incorporation at the vinylic position of the final
isochromene 2a.23 Nucleophilic attack by the pendant alcohol
to the vinylidene with concurrent removal of a proton by
the amine then provides the alkenyl Ru species II, which
after protonolysis by the ammonium salt formed could
provide the final isochromene 2a with regeneration of the
active catalyst.
from key Ru vinylidene intermediates. The presence of an
amine/ammonium base-acid pair is crucial for the catalytic
cycle. The synthesis of benzofurans and isochromenes from
the cycloisomerization of aromatic homo- and bis-homopro-
pargylic alcohols by C-O bond formation significantly
increases the scope of metal vinylidene intermediates in
catalytic processes.24
In summary, Ru-catalyzed cycloisomerizations of aromatic
homo- and bis-homopropargylic alcohols to benzofurans and
isochromenes have been developed. These processes proved
to be chemo- and regioselective (5- and 6-endo cyclizations)
Acknowledgment. We thank the MICINN (Spain)
(CTQ2008-06557), Consolider Ingenio 2010 (CSD2007-
00006), and the Xunta de Galicia (2007/XA084 and
INCITE08PXIB209024PR). A.V.-F. thanks the USC for a
predoctoral contract. C.G.-R. thanks Xunta de Galicia for a
postdoctoral Anxeles Alvarin˜o contract.
(20) On the other hand, the aliphatic homopropargylic alcohol 1,1-
diphenylbut-3-yn-1-ol could be cycloisomerized to 2,2-diphenyl-2,3-
dihydrofuran in 30% yield. See the Supporting Information for de-
tails.
Supporting Information Available: Typical experimental
procedure and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) This type of alkyne dimerization has been observed before; see:
Bassetti, M.; Pasquini, C.; Raneri, A.; Rosato, D. J. Org. Chem. 2007, 72,
4558.
(22) (a) Touchard, D. Haquette, P. Pirio, N. Toupet, L. Dixneuf, P. H.
Organometallics 1993, 12, 3132. (b) Bustelo, E. Carbo, J. J. Lledo´s,
A. Mereiter, K. Puerta, M. C. Valerga, P. J. Am. Chem. Soc. 2003, 125,
3311. (c) Wakatsuki, Y. J. Organomet. Chem. 2004, 689, 4092. See also
ref 10.
OL902212H
(23) The deuteration experiment was performed with a 3:7 mixture of
deuterated alkyne (shown in Scheme 2) and deuterated alcohol (not shown).
See the Supporting Information for details.
(24) Initial results with aromatic alkynyl amines and amides are
promising (C-N bond formation) and will be the subject of future
reports.
Org. Lett., Vol. 11, No. 22, 2009
5353