Osmium-catalyzed 7-endo heterocyclization of aromatic alkynols into benzoxepines

Article abstract of DOI:10.1002/anie.201000455

[Figure Presented] The wizard of Os: Regioselective osmiumcatalyzed 7-endo heterocyclization of aromatic alkynols affords benzoxepines in good yields. The proposed catalytic cycle involves the key formation of osmiumvinylidene complexes via an alkynyl-hydride-osmium(IV) complex from the starting alkynol.

Full text of DOI:10.1002/anie.201000455

Communications
DOI: 10.1002/anie.201000455
Heterocyclization
Osmium-Catalyzed 7-endo Heterocyclization of Aromatic Alkynols
into Benzoxepines**
Alejandro Varela-Fernꢀndez, Cristina Garcꢁa-Yebra, Jesffls A. Varela, Miguel A. Esteruelas,* and
Carlos Saꢀ*
Dedicated to Professor JosØ Barluenga on the occasion of his 70th birthday
The development of effective strategies for the synthesis of
heterocyclic compounds remains a very important challenge
for modern organic synthesis.[1] Molybdenum, tungsten,
ruthenium, and rhodium complexes that afford vinylidene
species have been among the most prominent catalytic
precursors employed in their synthesis.[2] The formation of
dihydrofurans and dihydropyrans by catalytic heterocycliza-
tion with molybdenum- and tungsten vinylidenes has been
pioneered by McDonald et al.,[3] and later by Trost and Rhee
using cationic ruthenium and rhodium complexes.[4] More
recently, the efficient preparation of indoles by the rhodium-
catalyzed cycloisomerization of 2-(ethynyl)anilines,[5] and the
smooth preparation of benzofurans and benzopyrans by the
ruthenium-catalyzed 5-endo and 6-endo heterocyclization
reactions of substituted (2-ethynyl)phenols and benzylic
alcohols, respectively, have been also described.[6,7] On the
other hand, the heterocyclization of alkynols into the seven-
membered oxepines, a framework commonly found in
complicated polycyclic marine natural products,[8] has only
been achieved from specific acetonide-protected alkynol
substrates via tungsten–vinylidene complexes.[9]
rhodium, promoting the 7-endo heterocyclization of aromatic
alkynols into benzoxepines that have biological interest
(Scheme 1).[12]
Scheme 1. Osmium-catalyzed 7-endo heterocyclization reactions of
aromatic alkynols.
Table 1 shows a series of complexes used for the hetero-
cyclization of 1a (R1, R2, R3 = H; R4 = Me) under several
catalytic conditions. The tungsten complex [W{=C-
(OMe)Me}(CO)5] is a relatively poor catalyst for the regio-
selective 7-endo cyclization of 1a into 3-benzoxepine 2a
(Table 1, entry 4).[13] Moderate activities were achieved with
ruthenium
species
[CpRu(PPh3)2Cl]
and
[CpRu-
(CH3CN)3]PF6 (Table 1, entries 6 and 8). The best results
were obtained with osmium complexes [CpNOs(CH3CN)2]PF6
(CpN = CpCH2CH2NHMe) and [CpOs(py)3]PF6 (Table 1,
entries 9 and 10). Although rhodium has a high tendency to
stabilize vinylidene compounds,[14] poor catalytic activity was
observed for the cyclization of 1a into 3-benzoxepine 2a
(Table 1, entries 1 and 2).
Osmium is more reducing than ruthenium, prefers to be
saturated by coordination, and redox isomers with more
[10]
À
metal carbon bonds.
These characteristics have been
argued to justify the versatility of stoichiometric osmium
chemistry and its poorer catalytic activity in comparison with
ruthenium.[11] Herein, we report that osmium promotes
catalysis more efficiently than ruthenium, tungsten, and
A closer look at the 7-endo heterocyclization of 1b (R1,
R3 = H; R2, R4 = Me) with ruthenium and osmium complexes
was then undertaken (Table 2). Regioselective 7-endo cycli-
zation occurred on heating a pyridine solution of 1b (0.15m)
in a sealed tube at 908C in the presence of 10 mol%
[CpRu(CH3CN)3]PF6 catalyst, giving a moderate yield of
the 3-benzoxepine 2b (Table 2, entry 1). Lower yields were
obtained when either preformed or in-situ-formed [CpRu-
(py)3]PF6 was used (Table 2, entries 2 and 3). The use of
ruthenium catalysts bearing CpN, a modified Cp ligand with a
coordinating side arm, gave low yields, even after prolonged
reactions times (Table 2, entries 4 and 5).[15a] As expected
from Table 1, more encouraging results were found using
osmium catalysts. A good yield of 2b was obtained in almost
24 hours when [CpNOs(CH3CN)2]PF6 was used (Table 2,
entry 6), and the reaction time could be reduced to only
3 hours when the catalyst was first heated in pyridine (Table 2,
entry 7), which is mandatory for the cyclization to take place
(Table 2, entry 8). Moreover, when the preformed
[CpNOs(py)2]PF6 catalyst was employed, the yield increased
[*] A. Varela-Fernꢀndez, Dr. J. A. Varela, Prof. C. Saꢀ
Departamento de Quꢁmica Orgꢀnica, Facultad de Quꢁmica
Universidad de Santiago de Compostela
15782 Santiago de Compostela (Spain)
Fax: (+34)98-159-5012
E-mail: carlos.saa@usc.es
Homepage: http://www.usc.es/gi1603/saa
Dr. C. Garcꢁa-Yebra, Prof. M. A. Esteruelas
Departamento de Quꢁmica Inorgꢀnica, Instituto de Ciencias de
Materiales de Aragꢂn, Universidad de Zaragoza-CSIC
50009 Zaragoza (Spain)
E-mail: maester@unizar.es
[**] We thank the MICINN (Spain) (CTQ2008-06557, CTQ2008-00810,
Consolider Ingenio 2010 (CSD2007-00006)), Xunta de Galicia
(2007/XA084 and INCITE08PXIB209024PR) and Diputaciꢂn Gen-
eral de Aragꢂn (E35). A.V-F. thanks USC and XUGA for a predoctoral
grant. C.G-Y. thanks MICINN for a Ramꢂn y Cajal research contract.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000455.
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Chemie
Table 1: Heterocyclization of alkynol 1a to 3-benzoxepine 2a.[a]
entries 4–8). However, nonterminal
alkynol 1i failed to cyclize with
either ruthenium or osmium cata-
lysts, indicating that the cyclization
occurs via a catalytic metal–vinyli-
dene complex.[2,11d]
Entry
Catalyst (mol%)
Base
Solvent
T
[8C]
t
[h]
Yield of 2a
[%][b]
1
2
[{Rh(cod)Cl}2] (1)
[{Rh(cod)Cl}2] (5)
(4-FC6H4)3P
(4 mol%)
(4-FC6H4)3P
DMF
DMF
85
85
24
10
s.m.
(25)
The superior capacity of [CpOs-
(py)3]PF6 as the catalyst for this
reaction is also shown in the chal-
lenging regioselective 7-endo heter-
ocyclization of benzylic-type alky-
nol 3. The pharmacologically inter-
esting 2-benzoxepine 4[12] can be
isolated in 40% yield after 12 hours
at 908C (Scheme 2). Under the
same conditions, the ruthenium
counterpart was totally inactive, as
(60 mol%)
3
4
5
6
7
8
9
10
[W{=C(OMe)Me}(CO)5] (10)
[W{=C(OMe)Me}(CO)5] (40)
[W{=C(OMe)Me}(CO)5] (40)
[CpRu(PPh3)2Cl] (10)
Et3N
Et3N
py
py
py
py
py
py
THF
THF
THF
–
–
–
60
60
60
130
90
90
90
90
24
2
24
24
24
1
s.m.
75(50)
s.m.
50(29)
s.m.
64(38)
76(62)
98(65)
[(h5-indenyl)Ru(PPh3)2Cl] (10)
[CpRu(CH3CN)3]PF6 (10)
[CpNOs(CH3CN)2]PF6 (10)
[CpOs(py)3]PF6 (10)
–
–
5
0.5
[a] [1a]=0.15m. [b] Yield determined by GC methods. Yield of isolated product given in parentheses.
cod=1,5-cyclooctadiene, Cp=cyclopentadienyl, s.m.=starting material, py=pyridine, DMF=N,N-
dimethylformamide.
Table 2: 7-endo Heterocyclization of alkynol 1b with [CpML3]PF6 and
Table 3: Osmium-catalyzed 7-endo heterocyclization of aromatic alky-
nols 1 into 3-benzoxepines 2.[a]
[CpNML2]PF6 catalysts.[a]
Entry
M
Cp
L
t
[h]
Yield of 2b
Entry
Alkynol 1
3-Benzoxepine 2
Yield [%][b]
[%][b]
1
2[c]
3
Ru
Ru
Ru
Ru
Ru
Os
Os
Os
Os
Os
Os
Cp
Cp
Cp
CH3CN
CH3CN
py
CH3CN
py
CH3CN
CH3CN
CH3CN
py
1
2
3
24
24
24
3
24
3
1
54 (31)
(15)
1
1a
1b
1c
1d
2a
2b
2c
2d
65
35 (19)
24 (21)[d]
21 (20)[d]
76 (53)
(52)
4
5
CpN
CpN
CpN
CpN
CpN
CpN
Cp
2
3
4
68
63
58
6[e]
7[c]
8[f]
9
s.m.
82 (57)
99 (68)
98 (68)
10
py
py
11[g]
Cp
5
[a] 10 mol% catalyst, [1b]=0.15m, py, 908C. [b] GC yields. Yield of
isolated product given in parentheses. [c] 10 mol% catalyst was heated
in pyridine for 1 hour before addition of 1b. [d] Recovered 1b (15–20%).
[e] Heating at 1108C. [f] [1b]=0.15m 1,2-dichloroethane. [g] 5 mol%
osmium catalyst.
5
1e
2e
56
6
7
1 f
2 f
60
60
(Table 2, entry 9). To understand the difference between
ruthenium and osmium, the heterocyclization of 1b at 808C in
the presence of [CpNM(py)2]PF6 (M = Ru, Os) was studied by
1H and 13C{1H} NMR spectroscopy. Whilst the osmium
catalysts selectively afforded 2b, the ruthenium analogue
gave a complex mixture of organic products containing 2b.
The optimal conditions were found when [CpOs(py)3]PF6 was
used, giving 2b in excellent yields (Table 2, entries 10 and
11).[15b]
1g
2g
8
1h
1i
2h
69
9[c]
s.m.
Under the optimized conditions, a variety of aromatic
alkynols 1 were converted into their corresponding 3-benzox-
epines 2 in good yields (Table 3, entries 1–8). The electronic
effects of substituents on the aromatic rings influenced the
reaction kinetics, as shown by the faster reaction of electron-
poor alkynol 1c than electron-rich aromatic 1b to give 3-
benzoxepines 2b and 2c, respectively (30 versus 60 minutes;
Table 3, entries 2 and 3). Other secondary alkynols, such as
benzylic alkynol 1d, cyclohexanol derivative 1e, the parent
and electron-rich primary alkynols 1 f and 1g, and even
tertiary alkynol 1h all smoothly afforded their corresponding
3-benzoxepines in times ranging from 30–90 minutes (Table 3,
[a] Typical conditions: 10 mol% [CpOs(py)3]PF6, 0.15m, pyridine, 908C,
0.5–1.5 hours. [b] Yield of isolated product. [c] 10 mol% [CpRu-
(CH3CN)3]PF6, 0.15m, py, 908C. s.m.=starting material.
Scheme 2. Osmium-catalyzed 7-endo heterocyclization of benzylic-type
alkynol 3 to 2-benzoxepine 4.
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Communications
was [Rh(cod)Cl]2 and [W{=C(OMe)Me}(CO)5] (for reaction
the regioselective 7-endo heterocyclization of aromatic alky-
nols into benzoxepines, suggesting that osmium can be a
promising alternative to the classical metal catalysts for these
reactions.[24] Additionally, the challenging regioselective 8-
endo heterocyclization of an aromatic alkynol could also be
achieved with osmium catalysts. Further studies to expand the
scope of these reactions are in progress.
conditions, see Table 1).[16]
Interestingly, even the more challenging regioselective
osmium-catalyzed 8-endo heterocyclization of aromatic alky-
nol 5 into 3-benzo[d]oxocine 6 was successfully achieved and
the product was isolated in moderate yield (40%), although in
this case the reaction did not proceed as cleanly (monitored
by GC methods) and harsher conditions were necessary
(Scheme 3).[17]
Experimental Section
Typical experimental procedure: A mixture of 1b (50 mg, 0.29 mmol)
and [CpOs(py)3]PF6 (0.018 mg, 0.029 mmol) in pyridine (2.0 mL) was
stirred in a sealed tube under argon for 1 hour at 908C (monitored by
GCMS). The reaction mixture was then cooled to room temperature
and extracted from saturated aqueous NH4Cl (2 mL) with diethyl
ether (3 ꢀ 2 mL). The combined organic extracts were dried with
anhydrous Na2SO4, filtered, and evaporated in vacuo. Purification by
flash column chromatography on silica gel using a gradient diethyl
ether/n-hexane (0.1:9.9 to 1:9) gave 3-benzoxepine 2b (34 mg, 68%)
as a yellowish oil. 1H NMR (300 MHz, CDCl3), d = 6.98–6.90 (m, 2H),
6.83 (s, 1H), 6.30 (d, J = 8.1 Hz, 1H), 5.31 (d, J = 8.1 Hz, 1H), 4.27–
4.18 (m, 1H), 2.94 (d, J = 3.8 Hz, 2H), 2.27 (s, 3H), 1.34 ppm (d, J =
6.4 Hz, 3H). 13C NMR, DEPT (75 MHz, CDCl3), d = 143.3 (CH),
137.3 (C), 134.9 (C), 132.4 (C), 129.6 (CH), 128.6 (CH), 127.0 (CH),
104.5 (CH), 75.9 (CH), 44.7 (CH2), 21.6 (CH3), 20.9 ppm (CH3). MS,
m/z (% relative intensity): 175 ([M + H]+, 100), 157 (79), 145 (31), 131
(20). HRMS (ESI) calculated for C12H15O [M + H]+: 175.1123; found:
175.1117.
Scheme 3. Osmium-catalyzed 8-endo heterocyclization of aromatic
alkynol 5 to 3-benzo[d]oxocine 6.
These heterocyclization reactions can be rationalized
according to the mechanism in Scheme 4. After dissociation
of py from the osmium precursor, unsaturated 16eÀ species I
Received: January 26, 2010
Revised: March 8, 2010
Published online: May 6, 2010
Keywords: alkynols · benzoxepines · cyclization · heterocycles ·
.
osmium
[1] Comprehensive Heterocyclic Chemistry III, (Eds.: A. R.
Katritzky, C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor),
Elsevier, Amsterdam, 2008.
[2] For reviews on the use of vinylidenes in catalysis, see: a) M. I.
Bruce, Chem. Rev. 1991, 91, 197 – 257; b) C. Bruneau, P. H.
Dixneuf, Angew. Chem. 2006, 118, 2232 – 2260; Angew. Chem.
Int. Ed. 2006, 45, 2176 – 2203; c) B. M. Trost, A. McClory, Chem.
Asian J. 2008, 3, 164 – 194.
[3] F. E. McDonald, K. S. Reddy, Y. Diaz, J. Am. Chem. Soc. 2000,
122, 4304 – 4309, and the references therein.
[4] a) B. M. Trost, Y. H. Rhee, J. Am. Chem. Soc. 2002, 124, 2528 –
2533; b) B. M. Trost, Y. H. Rhee, J. Am. Chem. Soc. 2003, 125,
7482 – 7483.
[5] B. M. Trost, Angew. Chem. 2007, 119, 2120 – 2123; Angew. Chem.
Int. Ed. 2007, 46, 2074 – 2077.
[6] A. Varela-Fernꢁndez, C. Gonzꢁlez-Rodrꢂguez, J. A. Varela, L.
Castedo, C. Saꢁ, Org. Lett. 2009, 11, 5350 – 5353.
[7] For carbocyclization reactions involving ruthenium catalysts,
see: a) J. A. Varela, C. Gonzꢁlez-Rodrꢂguez, S. G. Rubꢂn, L.
Castedo, C. Saꢁ, J. Am. Chem. Soc. 2006, 128, 9576 – 9577; b) C.
Gonzꢁlez-Rodrꢂguez, J. A. Varela, L. Castedo, C. Saꢁ, J. Am.
Chem. Soc. 2007, 129, 12916 – 12917.
[8] L. I. Belen’kii in Comprehensive Heterocyclic Chemistry III,
Vol. 3, Elsevier, Amsterdam, 2008, pp. 45 – 95, and the refer-
ences therein.
Scheme 4. Proposed catalytic cycle for the osmium-catalyzed hetero-
cyclization.
À
should be formed. Facile oxidative addition of the C(sp) H
bond of the terminal alkyne to the metal center could afford
hydride–OsIV–alkynyl intermediates II.[18] Removal of the
hydride as a proton by pyridine followed by re-protonation at
the Cb atom would afford the osmium–vinylidenes III.[18,19]
Then, the a-electrophilic[2a,20] center of the vinylidene could
be susceptible to intramolecular attack by the alcohol to give
the 2-oxacycloalkylidene osmium intermediates IV,[21] which,
in the presence of py would afford vinylic osmium species
V.[22] A related sequence has been proposed for the formation
of lactones from carboxylic acids that contain a triple bond in
the presence of catalytic amounts of a TpRu complex (Tp =
hydrotris(pyrazolyl)borate).[23] Finally, protonolysis of the
heterocyclic ligand would liberate the 3-benzoxepine 2 and
regenerate I.
In conclusion, osmium complexes are more efficient
catalysts than tungsten, ruthenium, and rhodium systems for
[9] The presence of the acetonide group in the alkynols is crucial to
give 7-endo cycloisomerizations; a) E. Alcazar, J. M. Pletcher,
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Chemie
F. E. McDonald, Org. Lett. 2004, 6, 3877 – 3880; b) B. Koo, F. E.
McDonald, Org. Lett. 2007, 9, 1737 – 1740.
[18] a) M. Baya, P. Crochet, M. A. Esteruelas, E. Gutiꢅrrez-Puebla,
A. M. Lꢃpez, J. Modrego, E. Oꢄate, N. Vela, Organometallics
2000, 19, 2585 – 2596; b) M. Baya, P. Crochet, M. A. Esteruelas,
A. M. Lꢃpez, J. Modrego, E. Oꢄate, Organometallics 2001, 20,
4291 – 4294.
[10] a) K. G. Caulton, J. Organomet. Chem. 2001, 617–618, 56 – 64;
b) M. A. Esteruelas, L. A. Oro, Adv. Organomet. Chem. 2001,
47, 1 – 59; c) M. A. Esteruelas, A. M. Lꢃpez, Organometallics
2005, 24, 3584 – 3613; d) M. A. Esteruelas, A. M. Lꢃpez, M.
Olivꢁn, Coord. Chem. Rev. 2007, 251, 795 – 840.
[11] a) M. A. Esteruelas, J. Herrero, A. M. Lꢃpez, M. Olivꢁn,
Organometallics 2001, 20, 3202 – 3205; b) N. Cobo, M. A.
Esteruelas, F. Gonzꢁlez, J. Herrero, A. M. Lꢃpez, P. Lucio, M.
Olivꢁn, J. Catal. 2004, 223, 319 – 327; c) R. Castarlenas, M. A.
Esteruelas, E. Oꢄate, Organometallics 2005, 24, 4343 – 4346;
d) M. A. Esteruelas, C. Garcꢂa-Yebra, E. Oꢄate, Organometal-
lics 2008, 27, 3029 – 3036; e) M. A. Esteruelas, C. Garcꢂa-Yebra,
M. Olivꢁn, E. Oꢄate, M. Valencia, Organometallics 2008, 27,
4892 – 4902.
[12] a) J. Liu, A. Steigel, E. Reininger, R. Bauer, J. Nat. Prod. 2000,
63, 403 – 405; b) J. R. Kesting, D. Staerk, M. V. Tejesvi, K. R.
Kini, H. S. Prakash, J. W. Jaroszewski, Planta Med. 2009, 75,
1104 – 1106.
[13] a) T. Sordo, P. Campomanes, A. Diꢅguez, F. Rodrꢂguez, F. J.
Faꢄanꢁs, J. Am. Chem. Soc. 2005, 127, 944 – 952; b) T. Nowroozi-
Isfahani, D. G. Musaev, F. E. McDonald, K. Morokuma, Orga-
nometallics 2005, 24, 2921 – 2929.
[19] For the formation of ruthenium vinylidenes, see: a) I. de los
Rꢂos, M. Jimꢅnez-Tenorio, M. C. Puerta, P. J. Valerga, J. Am.
Chem. Soc. 1997, 119, 6529 – 6538; b) E. Bustelo, M. Jimꢅnez-
Tenorio, M. C. Puerta, P. Valerga, Organometallics 1999, 18,
950 – 951; c) E. Bustelo, M. Jimꢅnez-Tenorio, M. C. Puerta, P.
Valerga, Organometallics 1999, 18, 4563 – 4573.
[20] M. C. Puerta, P. Valerga, Coord. Chem. Rev. 1999, 193–195, 977 –
1025.
[21] In the aliphatic series starting from 6-heptyn-1-ol, metal–
oxacycloheptylidenes (Ru, Os, Re) complexes have been
isolated in stoichiometric reactions. For ruthenium, see: a) M.
Gamasa, J. Gimeno, B. M. Martꢂn-Vaca, R. Isea, A. Vegas, J.
Organomet. Chem. 2002, 651, 22 – 33; b) S. Pavlik, K. Mereiter,
M. Puchbeger, K. Kirchner, J. Organomet. Chem. 2005, 690,
5497 – 5507; For osmium, see: c) J. Gimeno, M. Gonzꢁlez-Cueva,
E. Lastra, E. Pꢅrez-Carreꢄo, S. Garcꢂa-Granda, Inorg. Chim.
Acta 2003, 347, 99 – 106; For rhenium, see: d) C. Bianchini, A.
Marchi, N. Mantovani, L. Marvelli, D. Masi, M. Peruzzini, R.
Rossi, Eur. J. Inorg. Chem. 1998, 211 – 219.
[14] H. Werner, Coord. Chem. Rev. 2004, 248, 1693 – 1702.
[15] a) Metal [CpNM(py)2]PF6 complexes in pyridine are in equilib-
rium with [CpNM(py)3]PF6 (M = Ru, Os) that contain a free
pendant group. For thermodynamic data of these equilibria, and
b) for kinetic data of the formation of 2b, see the Supporting
Information.
[16] a) Smooth 6-exo cyclization occurred at room temperature with
1% PtCl2 (80% yield); for details, see the Supporting Informa-
tion. b) For alkynols 1, smooth 6-exo cyclization followed by
dimerization was observed.
[22] For the acid-base equilibria of alkylidene and alkenyl complexes,
see: a) W. G. Hatton, J. A. Gladysz, J. Am. Chem. Soc. 1983, 105,
6157 – 6158, and references therein; b) C. P. Casey, W. H. Miles,
H. Tukuda, J. Am. Chem. Soc. 1985, 107, 2924 – 2931, and
references therein.
[23] M. Jimꢅnez-Tenorio, M. C. Puerta, P. Valerga, F. J. Moreno-
Dorado, F. M. Guerra, G. M. Massanet, Chem. Commun. 2001,
2324 – 2325.
[24] Under typical conditions, the 7-endo heterocyclization of
aliphatic alkynols has so far been unsuccessful.
[17] a) Under the usual conditions (908C) the yield of isolated
product was 20%; b) No cyclization was observed with ruthe-
nium catalysts.
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