Selective Oxidation of Zirconocyclopentenes via Organoboranes

Article abstract of DOI:10.1021/ol036031r

(Equation presented) A new, convenient, one-pot protocol is described for oxidation of zirconocyclopent-2-enes selectively at the sp³ carbon by efficient transfer to electrophilic (^cHeX)₂BCl followed by oxidation with H

Full text of DOI:10.1021/ol036031r

ORGANIC
LETTERS
2004
Vol. 6, No. 1
67-70
Selective Oxidation of
Zirconocyclopentenes via
Organoboranes
Jeffrey S. T. Gorman, Scott T. Iacono, and Brian L. Pagenkopf*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
pagenkopf@mail.utexas.edu
Received October 16, 2003
ABSTRACT
A new, convenient, one-pot protocol is described for oxidation of zirconocyclopent-2-enes selectively at the sp3 carbon by efficient transfer
to electrophilic (cHex)2BCl followed by oxidation with H O /NaOH to afford 1-alkylidene-2-hydroxymethylcyclopentanes. Results with several
2
2
substrates show that overall reaction efficiencies for the zirconocene-mediated enyne cyclization, boron transmetalation, and oxidation sequence
are generally comparable to yields obtained from protonation of intermediate zirconocycles. The formation of E/Z olefin isomers from the
cyclization-oxidation sequence and an acid-catalyzed pinacol-type rearrangement of a vinylsilane are described.
In the 1980s several groups reported the reductive cyclization
of 1,7-enynes (and related systems) mediated by low valent
zirconocene that was generated in situ by the reduction of
Cp2ZrCl2.1,2 The most straightforward method for accessing
an equivalent “free zirconocene” (i.e., Cp2Zr) consists of
treating Cp2ZrCl2 with 2 equiv of n-BuLi at low tempera-
tures.2 These disclosures resulted in a subsequent flourish
of zirconocene research that ultimately led to widespread
adoption of zirconocene as a useful synthetic reagent for
many interesting transformations.3,4 Zirconocene has proved
surprisingly effective for converting various dienes and
enynes to zirconocyclopentanes and pentenes, and these
intermediates can be subsequently functionalized by ligand
transfer to reactive electrophiles.5 Selective functionalizations
of zirconocyclopentenes have been reported with preferential
reaction at the sp3 carbon (methanol,6-9 aldehydes,10 allenyl
carbenoids,11 halogens,7,8,12 chlorostannanes,7 isonitriles,7,13
and oxygen9) and at the sp2 carbon (enones,14 halogens,7,8,12
and allyl chloride15) often via transmetalation with Cu(I).16
However, the synthetic impact of Zr(II)-mediated enyne
(5) (a) Wipf, P.; Xu, W. J.; Smitrovich, J. H.; Lehmann, R.; Venanzi, L.
M. Tetrahedron 1994, 5I0, 1935. (b) Lootz, M. J.; Schwartz, J. J. Am. Chem.
Soc. 1977, 99, 8045. (c) Yoshifuji, M.; Loots, M. J.; Schwartz, J.
Tetrahedron Lett. 1997, 18, 1303.
(6) Takahashi, T.; Aoyagi, K.; Kondakov, D. Y. J. Chem. Soc., Chem.
Commun. 1994, 747.
(7) Aoyagi, K.; Kasai, K.; Kondakov, D. Y.; Hara, R.; Suzuki, N.;
Takahashi, T. Inorg. Chim. Acta 1994, 220, 319.
(8) Takahashi, T.; Aoyagi, K.; Hara, R.; Suzuki, N. J. Chem. Soc., Chem.
Commun. 1993, 1042.
(9) For reactions with zirconocyclopentenes derived from terminal
alkynes, see: Barluenga, J.; Sanz, R.; Fan˜ana´s, F. J. Chem. Eur. J. 1997,
3, 1324.
(10) Cope´ret, C.; Negishi, E.-i.; Xi, Z.; Takahashi, T. Tetrahedron Lett.
1994, 35, 695.
(11) (a) Gordon, G. J.; Whitby, R. J. Chem. Commun. 1997, 1321. (b)
Gordon, G. J.; Luker, T.; Tuckett, M. W.; Whitby, R. J. Tetrahedron 2000
56, 2113.
(12) Takahashi, T.; Aoyagi, K.; Kondakov, D. Y. J. Chem. Soc., Chem.
Commun. 1994, 747.
(13) Nigishi, E.-i.; Swanson, D. R.; Miller, S. R. Tetrahedron Lett. 1988,
29, 1631.
(1) RajanBabu, T. V.; Nugent, W. A.; Taber, D. F.; Fagan, P. J. J. Am.
Chem. Soc. 1988, 110, 7128.
(2) (a) Negishi, E.; Holmes, S. J.; Tour, M. J.; Miller, J. A. J. Am. Chem.
Soc. 1985, 107, 2568. (b) Negishi, E.; Cederbaum, F. E.; Takahashi, T.
Tetrahedron Lett. 1986, 27, 2829.
(3) (a) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cederbaum,
F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc. 1989, 111, 3336.
(b) Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124.
(4) For applications in natural product synthesis, see: (a) Wender, P.
A.; Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997, 119, 7897. (b)
Uesaka, N.; Saitoh, F.; Mori, M.; Shibasaki, M.; Okamura, K.; Date, T. J.
Org. Chem. 1994, 59, 5633. (c) Agnel, G.; Owczarczyk, Z.; Negishi, E.
Tetrahedron Lett. 1992, 33, 1543. (d) Agnel, G.; Negishi, E. J. Am. Chem.
Soc. 1991, 113, 7424.
(14) Lipshutz, B. H.; Wood, M. R. J. Am. Chem. Soc. 1994, 116, 11689.
10.1021/ol036031r CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/11/2003

cyclizations is constrained by the limited synthetic transfor-
mations available with which to functionalize the weakly
nucleophilic carbon-zirconium bonds.17
oxide were equally disappointing (entries 5-8). Molecular
oxygen caused decomposition (entry 9), in contrast to suc-
cessful oxidations of zirconocyclopentanes under identical
conditions.9,19a,20
We were interested in achieving a selective zirconocy-
clopentene oxidation (Scheme 1), but to the best of our
Zirconium alkyl and alkenyl ligands readily transfer to
boron and other main group elements.21 In synthetic studies
on borolanes, Cole elegantly demonstrated the viability of
oxidizing alkyl boranes generated by alkyl migration from
zirconium to boron.22 Our experimental results for the oxi-
dation of zirconocyclopentene 2b employing a similar trans-
metalation and oxidation strategy with a variety of electro-
philic boranes are summarized in Table 2. The transmeta-
Scheme 1
Table 2. Affect of Boron Reagent on Zirconocyclopentene
Transmetalation-Oxidationa
knowledge such a zirconocene-mediated transformation has
not been described.9,18 Oxidations of zirconocyclopentanes
or alkyl zirconium species generated by the Wailes-
Schwartz reaction have been reported that used molecular
oxygen or other chemical oxidants (e.g., H2O2, m-CPBA) to
produce alcohols or aldehydes.19 The malonate-derived enyne
1b was selected as a model substrate to evaluate the viability
of a direct oxidation of a carbon-zirconium bond generated
by reductive cyclization, and the results are summarized in
Table 1. Not surprisingly, hydroperoxides resulted primarily
isolated yield (ratio)b
entry
boron source
3b, oxidation
4b, protonation
1
2
3
4
5
6
7
BCl3
BBr3
5
0
11
75
8
62
79
59
8
Bu2BOTf
BrB(catechol)
9-BBNBr
(Ipc)2BCl
(cHex)2BCl
57
25
11
24
83
a Conditions: THF, rt to reflux. b Calibrated GC yields were within
(10%.
Table 1. Oxidation of Zirconocyclopentenesa
lation was monitored by GC analysis of an oxidized aliquot
(H2O2, NaOH), and the reaction was allowed to proceed until
no further change in the ratio of products was observed
(typically 4 h). Transmetalation efficiency proved to be
relatively insensitive to extended reaction times, excess boron
reagent, solvents, or lowered/elevated temperatures. Product
yields were similar whether H2O2 or NaBO3 was used to
oxidize the intermediate borane. In the reaction with BCl3
methyl ether cleavage accompanied transmetalation (entry
1), whereas no transmetalation appeared to occur with BBr3
(entry 2). Reaction with Bu2BOTf consistently gave the
alcohol 3b as the major product, but yields averaged only
57% (entry 3). Bromocatechol borane, 9-BBNBr, and di-
entry
oxidant
GC ratio 3:4:5:6
1
2
3
4
5
6
7
8
9
H2O2, NaOH
NaBO3
tBuOOH
m-CPBA
NMO
Me3NO
TEMPO
(BzO)2
4:96:0:0
4:96:0:0
19:81:0:0
20:80:0:0
21:72:7:0
5:95:0:0
5:95:0:0
2:90:8:0
decomposition
(17) For a recent review, see: Wipf, P.; Kendall, C. Chem. Eur. J. 2002,
8, 1778.
O2
(18) For a palladium-catalyzed variant, see: Galland, J.-C.; Savignac,
M.; Geneˆt, J.-P. Tetrahedron Lett. 1997, 38, 8695. For zirconocene-mediated
cyclization of a vinyl borane, see: Desurmont, G.; Dalton, S.; Giolando,
D. M.; Srebnik, M. J. Org. Chem. 1997, 62, 8907.
a Conditions: THF, rt to reflux.
(19) (a) Blackburn, T. F.; Labinger, J. A.; Schwartz, J. Tetrahedron Lett.
1975, 3041. (b) Gibson, T. Tetrahedron Lett. 1982, 23, 157.
(20) Taber, D. F.; Louey, J. P.; Wang, Y.; Nugent, W. A.; Dixon, D.
A.; Harlow, R. L. J. Am. Chem. Soc. 1994, 116, 9457.
(21) Fagan, P. J.; Nugent, W. A. J. Am. Chem. Soc. 1988, 110, 2310.
(b) Carr, D. B.; Schwartz, J. J. Am. Chem. Soc. 1977, 99, 638. (c) Cole, T.
E.; Quintanilla, R. J. Org. Chem. 1992, 57, 7366.
in protonation, with only 4-20% of oxidation products being
formed. Aprotic oxidants such as N-methylmorpholine N-
oxide, trimethylamine N-oxide, TEMPO, and benzoyl per-
(15) Kasai, K.; Kotora, M.; Suzuki, N.; Takahashi, T. J. Chem. Soc.,
Chem. Commun. 1995, 109.
(16) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 813.
(22) (a) Cole, T. E.; Gonzalez, T. Tetrahedron Lett. 1997, 38, 8487. (b)
Quintanilla, R.; Cole, T. E. Tetrahedron 1995, 51, 4297.
68
Org. Lett., Vol. 6, No. 1, 2004

isopinylcamphenylboron chloride gave the alcohol as the
minor product in each case (entries 4-6). Reaction with
dicyclohexylboron chloride gave the highest isolated yield
of alcohol 3b (83%, entry 7).
line hydrogen peroxide, and the product alcohol was isolated
by flash chromatography. It is important to note that securing
reproducible yields for this oxidation sequence necessitates
that freshly prepared (cHex)2BCl be employed.24
The generality of this new oxidation protocol was estab-
lished by successful reaction with a representative set of
enynes (Table 3). Reaction yields from separate protonolysis
Malonate-derived 1,6-enynes with either phenyl- or meth-
yl-substituted alkynes (entries 1 and 2) are excellent sub-
strates for the cyclization and oxidation sequence, as are the
geminal dimethyl substituted enynes in entries 3-5. In these
cases oxidation efficiency closely mirrors that observed from
protonation of the intermediate zirconocycles. In entry 5, a
1.5:1 ratio of diastereomers was obtained from both the
protonation and oxidation reaction sequences.20 The example
in entry 6 illustrates that a substrate lacking a propensity for
cyclization endowed by Thorpe-Ingold or reactive rotamer
effects can be successfully oxidized,25 but in this one case
the yield of the alcohol (64%) lagged behind that for
protonation (84%). Cyclization to form six-membered rings
was achieved in moderate yields (entry 7), but reassuringly,
oxidation efficiency (49%) was only slightly lower than for
simple protonation (56%).
Table 3. Oxidation or Protonation of Zirconocyclopentenesa
The product vinyl silane in entry 8 was not affected by
the conditions employed to oxidize the intermediate borane,
although conditions for concomitant Tamao-Fleming-type
oxidation are under investigation. Protonation results with
the enyne in entry 8 were peculiar in that yields greatly
depended upon the acid source employed (e.g., 95% with
1 M H2SO4, 64% with H2O, decomposition with 3 M
HCl).
In contrast to the preceding results, reaction of enyne 7
(Scheme 2 and Table 3, entry 9) under the boron transmeta-
lation-oxidation conditions with 1.5 equiv of (cHex)2BCl
resulted in formation of the expected Z product 8 (54%) along
with the unusual E isomer 9 (31%). The assignment of the
E configuration in 9 is based on single-crystal X-ray analysis
(Figure 1). The olefin configuration and trans ring substit-
uents of the remaining products were assigned on the basis
of NOE data. Additionally, cleavage of the silyl ether in 8
and 11 with HF‚pyridine gave the expected diols 10 and 9,
respectively, without E/Z isomerization.26 When the amount
of electrophilic borane was increased to 2.5 equiv, duplicate
experiments showed that none of the diols 9 or 10 formed
in the cyclization/oxidation reaction (Scheme 2).
(23) General Experimental Procedure. To a solution of Cp2ZrCl2 (1.05
mmol) in THF (3 mL) cooled to -78 °C was added n-BuLi (2.1 mmol),
and the dry ice bath was removed. The reaction mixture was allowed to
warm until homogeneous (∼0 °C), at which point the mixture was cooled
to -78 °C. A solution of enyne (1 mmol) in THF (1.5 mL) was added, and
the dry ice bath was replaced with an ice bath. After 1 h the ice bath was
removed, and the reaction was allowed to warm to room temperature. Neat
(cHex)2BCl was added 12-18 h later, and after 5 h the borane was oxidized
by treatment with aqueous NaOH (2 mL, 7.5 M, 15 mmol) and H2O2 (30%
aqueous solution, 2 mL), using a water bath to control the exotherm. The
resultant reaction mixture was then heated at 50 °C for 1 h; allowed to
cool; extracted with EtOAc; washed with 10% aqueous Na2S2O3 (2 × 10
mL), saturated aqueous NaHCO3, and brine; dried (MgSO4); filtered; and
purified by chromatography. See: Pagenkopf, B. L.; Lund, E. C.; Living-
house, T. Tetrahedron 1995, 51, 4421.
(24) (a) Brown, H. C.; Dhar, R. K.; Ganesan, K.; Singaram, B. J. Org.
Chem. 1992, 57, 499. (b) Soderquist, J. A.; Medina, J. R.; Huertas, R.
Tetrahedron Lett. 1998, 39, 6119. (c) Soderquist, J. A.; Huertas, R.; Medina,
J. R. Tetrahedron Lett. 1998, 39, 6123.
(25) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224.
(26) This isomerization will be described elsewhere.
a Zirconocycles generated in situ. b 1.5:1 ratio trans:cis. c 8:1 ratio. d 1
M H2SO4; H2O (64%); 3 M HCl (multiple products).
control experiments listed in Table 3 provide a reference
point for evaluating the impact of the transmetalation/
oxidation steps on overall reaction efficiency. Gratifyingly,
isolated yields of alcohols were within 10% of those obtained
from protonation in all cases examined but for one exception
(entry 6) in which oxidation was 20% less efficient.
A general procedure for oxidation was developed that
consisted of treating the zirconocyclopentene (prepared in
situ) in THF with (cHex)2BCl (1.5-2 equiv) at room
temperature.23 After 5 h the borane was oxidized with alka-
Org. Lett., Vol. 6, No. 1, 2004
69

Scheme 2
Transition metal catalyzed isomerizations of allylic alcohols
to carbonyl compounds have been extensively studied.28
In summary, a new method for the selective and efficient
oxidation of zirconocyclopentenes to 1-alkylidene-2-hydroxy-
methylcyclopentanes featuring ligand migration from zirco-
nium to boron has been described. The method is successful
with a variety of enynes representative of those typically
employed in zirconocene-mediated reductive cyclizations.
This new oxidation protocol enhances the synthetic utility
of reductive cyclizations by providing products with a
functional handle suitable for further synthetic manipulations.
Acknowledgment. We thank the Robert A. Welch Foun-
dation, donors of the American Chemical Society Petroleum
Research fund, the Texas Advanced Research Program
003658-0455-2001, and the DOD Prostate Cancer Research
Program DAMD17-01-1-0109 for partial financial support
of this research. We thank Dr. Karl Matos of Callery
Chemical Company for helpful discussions and Vincent
Lynch for determination of the X-ray structure.
Figure 1. X-ray structure of 9.
Scheme 3
Supporting Information Available: Characterization of
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL036031R
The diol 9 was prone to undergo an interesting silicon-
accelerated acid-catalyzed pinacol-type rearrangement (Scheme
3), and ketone 12 was obtained when a sample of vinylsilane
9 was stored in CDCl3 at room temperature for several days
(27) (a) Jung, M. E.; Piizzi, G. J. Org. Chem. 2002, 67, 3911. (b)
Blumenkopf, T. A.; Overman, L. E. Chem. ReV. 1986, 86, 857.
(28) For reviews, see: (a) Uma, R.; Crevisy, C.; Gree, R. Chem. ReV.
2003, 103, 27. (b) van der Drift, R. C.; Bouwman, E.; Drent, E. J.
Organomet. Chem. 2002, 650, 1.
1
(quantitative yield by H NMR, 92% isolated yield).27
70
Org. Lett., Vol. 6, No. 1, 2004