Novel highly regioselective VO(acac)2/TBHP mediated oxidation of o-alkenyl phenols to o-hydroxybenzyl ketones

Article abstract of DOI:10.1021/jo026783j

A novel mild methodology for the preparation of o-hydroxybenzyl ketones is described starting from o-alkenyl phenols and based on the VO(acac)₂/TBHP (2 mol %/1.2 equiv) system. VO(acac)₂ first catalyzes the epoxidation of o-alkenyl phenols and then the rearrangement of the epoxyphenols to ketones via the selective benzylic C-O cleavage and 1,2 hydride migration. The protocol has also been applied to set up a useful and easy one-pot conversion of o-alkenyl phenols to benzo[b]furans by means of the sequential addition of TFA, after the generation of the intermediate o-hydroxybenzyl ketones.

Full text of DOI:10.1021/jo026783j

TABLE 1. VO(a ca c)2/TBHP Oxid a tion of o-P r op en yl
Novel High ly Regioselective VO(a ca c)2/
TBHP Med ia ted Oxid a tion of o-Alk en yl
P h en ols to o-Hyd r oxyben zyl Keton es
P h en ol 1a a
Alessandra Lattanzi,* Antonello Senatore,
Antonio Massa, and Arrigo Scettri
Dipartimento di Chimica, Universita’ di Salerno,
Via S. Allende, I- 84081, Baronissi, Salerno, Italy
entry solvent T (°C) t (h) yield of 2a (%)b yield of 2a (%)c
1
CH2Cl2
CH2Cl2
CH2Cl2
toluene
hexane
CCl4
rt
rt
40
rt
rt
rt
rt
4
4
2
4
4
4
4
86
88
88
68
66
65
82
55
55
56
31
2d
3
lattanzi@unisa.it
4
5
6
7
Received November 29, 2002
35
47
CH3CN
Abstr a ct: A novel mild methodology for the preparation of
o-hydroxybenzyl ketones is described starting from o-alkenyl
phenols and based on the VO(acac)2/TBHP (2 mol %/1.2
equiv) system. VO(acac)2 first catalyzes the epoxidation of
o-alkenyl phenols and then the rearrangement of the ep-
oxyphenols to ketones via the selective benzylic C-O cleav-
age and 1,2 hydride migration. The protocol has also been
applied to set up a useful and easy one-pot conversion of
o-alkenyl phenols to benzo[b]furans by means of the sequen-
tial addition of TFA, after the generation of the intermediate
o-hydroxybenzyl ketones.
a
b
Molar ratios: 1a /VO(acac)2/TBHP 1/0.02/1.2. Determined by
1H NMR analysis based on phenol 1a employed. c Isolated yield
after flash chromatography Reaction performed in the presence
of activated MS 4 Å (400 mg).
d
We recently reported the employment of VO(acac)2/
TBHP for the efficient epoxidation of a different class of
compounds, the o-(2-alkenyl) phenols.10 Furthermore, the
highly regio- and diastereoselective oxidative cyclization
to 2,3-dihydrobenzofuranols and 3-chromanols can be
accomplished in one pot, using catalytic loadings of
trifluoroacetic acid (TFA).11
In efforts to have a better insight into the reactivity of
the VO(acac)2/TBHP system on unsaturated phenols and
to eventually enlarge its synthetic utility, we investigated
the oxidation of o-alkenyl phenols, where the ortho C-C
double bond is directly bound to the phenyl ring.
The first runs were carried out on commercially avail-
able o-propenyl phenol 1a . On the basis of our previous
studies, 1a (1 mmol) was treated under mild conditions,
in the presence of a catalytic amount of VO(acac)2 (2 mol
%) and TBHP (1.2 mmol) in dichloromethane (4 mL)
under argon atmosphere at room temperature (Table 1,
entry 1). The presence of molecular oxygen had to be
avoided, because the VO(acac)2/O2 system has been
reported to promote the oxidative coupling of phenols.12
The development of catalytic and selective methods of
oxidation is extremely important in organic synthesis.
Among the several oxidizing reagents,1 the metal-
catalyzed methodologies2 have experienced ever increas-
ing growth and application over the years. One of the
best examples reported so far is the VO(acac)2/TBHP
system. First employed by Sharpless in the highly regio-
and stereoselective epoxidation of allylic alcohols,3 it has
been successfully exploited as a key step in many
synthetic sequences. The catalytic loadings of VO(acac)2
used (in general <10 mol %), the highly selective forma-
tion of the final compounds, and a mild oxidant such as
TBHP often constitute the main advantages over classical
reagents as for example m-chloroperoxybenzoic acid (m-
CPBA)4 and dioxiranes.5 The VO(acac)2/TBHP system6
promotes other useful transformations: oxidative cy-
clization of bis-homoallylic alcohols to tetrahydrofura-
nols,7 chemoselective dehydrogenation of acyclic and
cyclic secondary alcohols to the corresponding ketones,8
and oxidation of heteroatom-containing compounds.9
(4) (a) Bartlett, P. A. Rec. Chem. Prog. 1957, 18, 111. (b) Swern, D.
Organic Peroxides; Wiley-Interscience: New York, 1971; Vol. 2.
(5) (a) Murray, R. W. Chem. Rev. 1989, 89, 1187. (b) Adam, W.;
Curci, R.; Edwards, J . O. Acc. Chem. Res. 1989, 22, 205. (c) Frohn, M.;
Wang, Z.-X.; Shi, Y. J . Org. Chem. 1998, 63, 6425.
(6) For a general review on the employment of vanadium in organic
synthesis, see: Hirao, T. Chem. Rev. 1997, 97, 2707.
(7) (a) Fukuyama, T.; Vranesic, B.; Negri, D. P.; Kishi, Y. Tetrahe-
dron Lett. 1978, 31, 2741. (b) Hashimoto, M.; Kan, T.; Yanagiya, M.;
Shirahama, H.; Matsumoto, T. Tetrahedron Lett. 1987, 28, 5665. (c)
Hartung, J .; Schmidt, P. Synlett 2000, 3, 367. (d) Hartung, J .; Greb,
M. J . Organomet. Chem. 2002, 661, 67.
(1) (a) Lee, T. V. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Ley, S. V., Eds.; Pergamon: Oxford, UK, 1991; Vol. 7, p
291. (b) Ley, S. V.; Madin, A. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Ley, S. V., Eds.; Pergamon: Oxford, UK, 1991;
Vol. 7, p 251. (c) Ullmann’s Encyclopedia of Industrial Chemistry, 5th
ed.; Gerhartz, W., Yamamoto, Y. S., Kandy, L., Rounsaville, J . F.,
Schulz, G., Eds.; Verlag Chemie: Weinheim, Germany, 1987; Vol. A9,
p 531.
(8) Kaneda, K.; Kawanishi, Y.; J itsukawa, K.; Teranishi, S. Tetra-
hedron Lett. 1983, 24, 5009.
(2) (a) Mijs, W. J .; DeJ onge, C. R. H. I. Organic Synthesis with Metal
Compounds; Plenum: New York, 1986. (b) Sheldon, R. A.; Kochi, J .
K. In Metal-Catalyzed Oxidation of Organic Compounds; Academic
Press: New York, 1981. (c) Scheurer, A.; Mosset, P.; Spiegel, M.;
Saalfrank, R. W. Peroxide Chem. 2000, 320. (d) J acobsen, E. N. In
Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F.
G. A., Wilkinns, G., Eds.; Pergamon: Oxford, UK, 1995; Vol. 12;
Chapter 11.
(3) (a) Sharpless, K. B.; Michaelson, R. C. J . Am. Chem. Soc. 1973,
95, 6136. (b) Sharpless, K. B.; Verhoeven, T. R. Aldrichim. Acta 1979,
12, 63. (c) Mihelich, E. D.; Daniels, K.; Eickhoff, D. J . Am. Chem. Soc.
1981, 103, 7690.
(9) (a) Sheng, M. N.; Zajacek, J . G. J . Org. Chem. 1968, 33, 588. (b)
Howe, G. R.; Hiatt, R. R. J . Org. Chem. 1970, 35, 4007. (c) Curci, R.;
Di Furia, F.; Testi, R.; Modena, G. J . Chem. Soc., Perkin Trans. 2 1974,
752. (d) Takano, S.; Sugihara, Y.; Ogasawara, K. Heterocycles 1992,
34, 1519.
(10) Lattanzi, A.; Scettri, A. Synlett 2002, 6, 942.
(11) For previously reported use of the VO(acac)2/TBHP/TFA system,
see: (a) Morimoto, Y.; Iwai, T.; Kinoshita, T. J . Am. Chem. Soc. 2000,
122, 7124. (b) Morimoto, Y.; Kinoshita, T.; Iwai, T. Chirality 2002, 14,
578.
(12) Hwang, D.-R.; Chen, C.-P.; Uang, B.-J . Chem. Commun. 1999,
1207.
10.1021/jo026783j CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/05/2003
J . Org. Chem. 2003, 68, 3691-3694
3691

TABLE 2. Effect of Va r iou s Meta l Ca ta lysts in th e
Surprisingly, instead of the expected epoxide, 1-(o-hy-
droxyphenyl)propan-2-one (2a ) was obtained.13 From a
synthetic viewpoint this transformation has a practical
value: in fact, the preparation of unmasked o-hydroxy-
benzyl ketones lacks general methods.14 Gourges et al.15
reported the access to free o-hydroxybenzyl ketones using
CrCl2-mediated reductive transposition of an ester acyl
group in the o-O-acyl benzylic bromides. The reaction
conditions had to be finely tuned to obtain the ketones
in good yield, in fact to prevent the formation of side
products, a slow addition of the starting bromides to
CrCl2 in the THF solution was required. The major
drawback of this general approach to o-hydroxybenzyl
ketones is the use of 2.5 equiv of cromium(II) salt with
respect to the starting material and, in view of growing
environmental concerns and sustainable chemistry, the
development of a cleaner catalytic method is highly
desiderable.
Oxid a tion of o-P r op en yl P h en ol 1a a
entry
metal catalyst
t (h)
yield of 2a (%)b
1
2
3
4
Mo(CO)6 (10 mol %)
Ti(Oi-Pr)4 (10 mol %)
VO(Oi-Pr)3 (2 mol %)
VO(acac)2 (2 mol %)
18
18
4
3
7
83
89
4
a
b
Molar ratios: 1a /TBHP 1/1.2. Determined by 1H NMR
analysis based on phenol 1a employed.
TABLE 3. VO(a ca c)2/TBHP Oxid a tion of o-(Alk en yl)
P h en ols 1a
1
From H NMR analysis of the crude reaction mixture
a high conversion of 1a to 2a was determined (Table 1,
entry 1), but after flash chromatography the product was
recovered in 55% yield. This result can be ascribed to the
instability of o-hydroxybenzyl ketones, in fact, unavoid-
able losses of compounds of type 2, during the isolation
process, have been previously described.15,16 The conver-
sion to ketone 2a was not affected by the presence of
activated MS 4 Å,17 while a reduced reaction time was
observed at 40 °C to achieve a comparable yield of 2a
(entries 2-3). In other solvents (entries 4-7) such as
toluene, hexane, and CCl4, the yield of 2a decreased.
Other metal catalysts, commonly used in the epoxida-
tion of alkenes, were then screened under the conditions
reported in Table 1, entry 1. The results are summarized
in Table 2. Both Mo(CO)6 and Ti(Oi-Pr)4 complexes, even
after prolonged reaction time and in larger amounts (10
mol %), furnished low yields of 2a , leaving the starting
phenol 1a unreacted. VO(Oi-Pr)3, with the vanadium in
the higher (V) oxidation state, is an equally efficient
catalyst for the oxidation of 1a (compare entries 3 and
4), indicating that this transformation is peculiar to
oxovanadium metal complexes.
yield of yield of
entry
R
R1
R2
R3
1
t (h)
2 (%)b
3 (%)b
1
2
3
4
H
H
H
H
H
H
H
Me
Bu
s-Bu
t-Bu
Ph
Ph
t-Bu Me
H
H
H
H
H
H
Me
H
1a
1b
1c
1d
1e
1f
2
5
5
4
1
1.5
7
56
59
64
77
50
H
H
H
H
H
H
5
6c
7c
8d
82
80
1g
C7H15
H
OMe 1h 24
a
b
Molar ratios: 1/VO(acac)2/TBHP 1/0.02/1.2. Isolated yield.
c Reaction performed at -20 °C. Reaction performed at room
d
temperature.
mentioned conditions (Table 3). To understand if the
geometry of the C-C double bond could affect the process,
the reactivities of Z and E o-propenyl phenol 1a , synthe-
sized as the Z/E 55/45 mixture,19 were compared per-
forming the reaction at room temperature for 4 h. From
1H NMR analysis of the crude reaction mixture a high
conversion to 2a (88%) was observed and the same Z/E
ratio was determined in the unreacted phenol, demon-
strating that the two isomers showed comparable reac-
tivities. Longer chain alkyl substituted phenol 1b gave
a yield similar to that of model compound 1a (entry 2).
Increasing sterically demanding alkyl substituted phe-
nols 1c,d furnished higher yields of the ketones 2c,d
(entries 3 and 4). These results were particularly inter-
esting even because they outlined the complementary
nature of the VO(acac)2/TBHP system with respect to the
CrCl2-mediated methodology.15 In fact, in the last pro-
tocol, the efficiency of the transposition dramatically
decreased when a sterically encumbered group was
involved. As an example, the result was remarkable in
entry 4, where the bulky ketone 2d was isolated in fairly
good 77% yield, while the Cr(II)-based method completely
failed to give the same product. In the case of the phenyl-
To probe the general utility of this reaction, the stable
and cheap VO(acac)2 was chosen as catalyst and the
reactions were carried out in dichloromethane at 40 °C.
A variety of di- and trisubstituted C-C double bond
compounds of type 118 were then treated in the afore-
(13) The formation of ketone 2a in low yield (10%) has been reported
in the oxidation of 1a with m-CPBA, see: Tinsley, S. W. J . Org. Chem.
1959, 24, 1197.
(14) (a) Schulenberg, J . W.; Archer, S. J . Am. Chem. Soc. 1960, 82,
2035. (b) Royer, R.; Bisagni, E. Bull. Soc. Chim. Fr. 1960, 395. Some
examples of employment of phenol OH protected derivatives have been
reported: (c) Christiaens, L.; Renson, H. Bull. Soc. Chim. Belg. 1970,
79, 235. (d) Moengkramer, R. E.; Zimmer, H. J . Org. Chem. 1980, 45,
3994. (e) Beugelmans, R.; Ginsburg, H. J . Chem. Soc., Chem. Commun.
1980, 508.
(15) (a) Ledoussal, B.; Gorgues, A.; Le Coq, A. J . Chem. Soc., Chem.
Commun. 1986, 171. (b) Ledoussal, B.; Gorgues, A.; Le Coq, A.
Tetrahedron 1987, 43, 5841.
(16) When the crude reaction mixtures were purified over neutral
Al2O3, the yields of ketones were found to be inferior with respect to
the yields obtained with silica gel.
(17) The presence of molecular sieves in metal-catalyzed processes
has a beneficial effect in preserving the catalyst activity. In some cases
it has been reported a reaction rate enhancement ascribed to the ability
of molecular sieves to accelerate ligands exchange thus generating the
active catalytic complex, see: Mikami, K.; Motoyama, Y.; Terada, M.
J . Am. Chem. Soc. 1994, 116, 2812.
(18) (a) Compounds 1b-g were synthesized according to: Nguyen,
T.; Negishi, E. Tetrahedron Lett. 1991, 32, 5903. (b) Compound 1h was
synthesized according to: Yamaguchi, M.; Hayashi, A.; Hirama, M. J .
Am. Chem. Soc. 1995, 117, 1151.
(19) Z/E 55/45 mixture of 1a was synthesized according to: Seebach,
D.; Corey, E. J . J . Org. Chem. 1975, 40, 231.
3692 J . Org. Chem., Vol. 68, No. 9, 2003

SCHEME 1
and the transition metal-Lewis acid dual character of
the vanadium catalysts21,23 might be invoked as a plau-
sible explanation.
The hydride migration is an extremely fast process: in
fact no trace of the intermediate epoxide was detected
when the reaction was carried out on 1a at -20 °C after
a short reaction time (30 min), but only the presence of
10% of ketone 2a and unreacted starting phenol was
observed in the reaction mixture.24 In the case of trisub-
stituted epoxides 3f,g steric factors might prevent alkyl
or aryl migration.25 In the case of olefin 1h the final
rearranged product would be an aldehyde, which could
suffer VO(acac)2-catalyzed aldol condensation affording
side products.26
The coordination of the phenolic OH to the metal
catalyst accelerates the epoxidation of o-alkenyl phenols
and the following rearrangement of the chelated epoxides
intermediates could then be facilitated. It has to be noted
that the VO(acac)2/TBHP-mediated oxidation of o-alkenyl
phenols to o-hydroxybenzyl ketones is analogous to the
Wacker oxidation27 of vinylarenes to form carbonyl
compounds in a single step, but with the advantage of
being highly regioselective.
Ketones 2 are immediate synthetic precursors of benzo-
[b]furans, which are important natural structural units28
having interesting and several biological activities.29 We
therefore turned our attention to the possibility of
developing an easy one-pot methodology based on the
VO(acac)2/TBHP system as a suitable alternative proto-
col30 for the synthesis of benzo[b]furans.
On the grounds of literature reports,15 BF3‚(Et2O) was
initially chosen as the acid catalyst to perform the
intramolecular hemiketalization and dehydration of o-
hydroxybenzyl ketones to benzo[b]furans (Table 4, entries
1-3). The acid (0.5 equiv) was added to the reaction
mixture after the complete formation of intermediates 2
substituted compound 1e, an acceptable yield of the
ketone was attained (entry 5). The electron-rich trisub-
stituted C-C double bond compounds 1f,g were re-
acted under more controlled conditions and in this case
the epoxides 3f,g were isolated in very good yields
(entries 6 and 7). Additional experiments were carried
out on 1f,g. After the generation of the epoxides 3f,g
at -20 °C, the reaction mixture was slowly warmed to
room temperature and 1H NMR analysis showed the
presence of mixtures of unidentified products,20 while no
evidence of the formation of compounds of type 2 was
detected. In the last entry, the terminal olefin 1h reacted
slowly at room temperature, affording a complex reaction
mixture.
A reasonable mechanistic hypothesis to justify the
results obtained in the oxidation of o-alkenyl phenols
takes into account the transition metal-Lewis acid dual
character21 of the VO(acac)2 complex. First, the chelation
of the phenolic OH to the vanadium complex is essential
for the rate enhancement in the epoxidation of 1 accord-
ing to what is reported for the allylic alcohols.3 In fact,
when the reaction was performed on acetylated 1i, after
7 h the epoxide 3i was isolated in only 37% yield (Scheme
1).
Second, VO(acac)2 plays the role of Lewis acid, promot-
ing the rearrangement of the intermediate epoxides of
compounds 1a -e to ketones via selective benzylic C-O
cleavage, and 1,2 hydride migration affording a single
carbonyl compound. There have been a number of reports
on Lewis acid-catalyzed rearrangements of epoxides to
carbonyl compounds in the literature,22 but only a few
are catalytic and regioselective in nature. The constitu-
tion of the rearranged product is determined by the Lewis
acid used and the migratory aptitude of the epoxide
substituents. Interestingly, among them, VO(OR)Cl2
catalysts have been employed in the highly regioselective
rearrangement of epoxides to carbonyl compounds.23 In
this case, a greater and very fast migratory aptitude of
hydrogen compared to aryl and alkyl substituents has
been observed, a result that is in agreement with our
observations. This behavior is different with respect to
most of the Lewis acids reported for this transformation
(24) Another experiment was carried out to exclude that residual
acidity of silica gel, used in the workup, could be responsible for the
intermediate epoxide rearrangement to ketone. Compound 1a was
reacted with VO(acac)2/TBHP system, under argon atmosphere, at 0
°C in CDCl3 for 2.5 h. Then, the reaction mixture was directly analyzed
in an NMR tube and only ketone 2a (40%) and unreacted 1a were
detected.
(25) Steric factors in the Lewis acid complexed epoxide can be
involved preventing or favoring the alkyl or aryl migration.22c
(26) It has been previously reported that some acid-catalyzed
rearrangements of epoxides furnished very complex reaction mixtures,
whose separation afforded phenylacetaldehyde derivatives in low
yields.22d,g,h
(27) Keinan, E.; Seth, K. K.; Lamed, R. J . Am. Chem. Soc. 1986,
108, 3474.
(28) Donnelly, D. M. X.; Meegan, M. J . In Comprehensive Hetero-
cyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon:
Oxford, UK, 1984; Vol. 4, p 657.
(29) (a) Cagniant, P.; Cagniant, D. Adv. Heterocycl. Chem. 1975, 18,
343. (b) Kiyama, R.; Homna, T.; Hayashi, K.; Ogawa, M.; Hara, M.;
Fujimoto, M.; Fujishita, T. J . Med. Chem. 1995, 38, 2728. (c) Felder,
C. C.; J oyce, K. E.; Briley, E. M.; Glass, M.; Mackie, K. P.; Fahey, K.
J .; Cullinan, G. J .; Hunden, D. C.; J ohnson, D. W.; Chaney, M. O.;
Koppel, G. A.; Brownstein, M. J . Pharmacol. Exp. Ther. 1998, 284,
291. (d) Wyatt, P. G.; Allen, M. J .; Chilcott, J .; Foster, A.; Livermore,
D. G.; Mordaunt, J . E.; Scicinski, J .; Woollard, P. M. Bioorg. Med.
Chem. Lett. 2002, 12, 1399.
(30) (a) Brady, W. T.; Giang, Y. F. J . Org. Chem. 1986, 51, 2145. (b)
Banerjee, A.; Nayak, S. K. J . Chem. Soc., Chem. Commun. 1990, 150.
(c) Zubia`, E.; Luis, F. R.; Massanet, G. M.; Collado, I. G. Tetrahedron
1992, 48, 4239. (d) Hosokawa, T.; Ohkata, H.; Moritani, I. Bull. Chem.
Soc. J pn. 1975, 48, 1533. (e) Satoh, M.; Miyaura, N.; Suzuki, A.
Synthesis 1987, 373. (f) Kundu, N. G.; Pal, M.; Mahanty, J . S.; De, M.
J . Chem. Soc., Perkin Trans. 1 1997, 2815. (g) Arcadi, A.; Cacchi, S.;
Giuseppe, S. D.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4, 2409.
(20) The unidentified compounds obtained at the end of the reactions
presumably derived by the phenolic OH intra- and intermolecular
epoxide ring-opening.
(21) Bosnich, B. Aldrichim. Acta 1998, 31, 76.
(22) (a) House, H. O. J . Am. Chem. Soc. 1955, 77, 3070. (b) Rickborn,
B.; Gerkin, R. M. J . Am. Chem. Soc. 1971, 93, 1693. (c) Maruoka, K.;
Murase, N.; Bureau, R.; Ooi, T.; Yamamoto, H. Tetrahedron 1994, 50,
3663. (d) Sudha, R.; Malola Narasimhan, K. M.; Geetha Saraswathy,
V.; Sankararaman, S. J . Org. Chem. 1996, 61, 1877. (e) Kulasegaram,
S.; Kulawiec, R. J . J . Org. Chem. 1997, 62, 6547. (f) Ranu, B. C.; J ana,
U. J . Org. Chem. 1998, 63, 8212. (g) Anderson, A. M.; Blazek, J . M.;
Garg, P.; Payne, B. J .; Mohan, R. S. Tetrahedron Lett. 2000, 41, 1527.
(h) Bhatia, K. A.; Eash, K. J .; Leonard, N. M.; Oswald, M. C.; Mohan,
R. S. Tetrahedron Lett. 2001, 42, 8129.
(23) Mart´ınez, F.; del Campo, C.; Llama, E. F. J . Chem. Soc., Perkin
Trans. 1 2000, 1749.
J . Org. Chem, Vol. 68, No. 9, 2003 3693

TABLE 4. On e-P ot Syn th esis of Ben zo[b]fu r a n s by
general protocol for the preparation of o-hydroxybenzyl
ketones. Because of these notable features of the reaction,
this methodology competes well with that previously
reported, being the one to choose for the synthesis of
sterically hindered o-hydroxybenzyl ketones. Moreover,
starting from o-alkenyl phenols, a useful one-pot route
to benzo[b]furans has been easily developed based on VO-
(acac)2/TBHP/TFA. Efforts to elucidate the scope and
limitation of this oxidation system are underway.
VO(a ca c)2/TBHP /Acid Ca ta lysta
entry
R1
1
acid catalyst
t (h)c
yield of 4 (%)b
1
2
3
4
5
6
7
8
Me
Bu
Ph
Me
Bu
s-Bu
t-Bu
Ph
1a
1b
1e
1a
1b
1c
1d
1e
BF3(Et2O)
BF3(Et2O)
BF3(Et2O)
TFAd
2(3)
3(19)
1(2)
55
53
50
59
65
68
82
63
Exp er im en ta l Section
2(6)
TFAd
5(19)
3(19)
3(4)
Gen er a l P r oced u r e for 2 a n d 3. To a stirred solution of
dry CH2Cl2 (4 mL), under argon atmosphere, were added
VO(acac)2 (5.2 mg, 0.02 mmol) and 1 (1 mmol); then after 5 min
TBHP (212 µL, 1.2 mmol of a 5.5 M decane solution) was added.
The mixture was stirred at 40 °C for 1-7 h. At the end of the
reaction, the solvent of the crude reaction mixture was partially
removed in vacuo and the concentrated crude mixture was
filtered through a small pad of silica gel before 1H NMR analysis.
Then the reaction mixture was purified by flash chromatography
eluting with petrol-Et2O mixtures from 80:20 to 70:30.
Gen er a l P r oced u r e for 4. To a stirred solution of dry CH2Cl2
(4 mL), under argon atmosphere, were added VO(acac)2 (5.2 mg,
0.02 mmol) and 1 (1 mmol); then after 5 min TBHP (212 µL, 1.2
mmol of a 5.5 M decane solution) was added. The mixture was
stirred at 40 °C until the complete formation of 2 (TLC analysis).
Then, TFA (112 µL, 1.5 mmol) was added and the reaction
mixture was stirred for 2-19 h. At the end of the reaction, the
solvent was evaporated under reduced pressure and the crude
mixture was purified by flash chromatography eluting with
petrol-Et2O (99:1).
TFAd
TFAd
TFAd
1(2)
a
b
Molar ratios: 1/VO(acac)2/TBHP 1/0.02/1.2. Isolated yield.
c Numbers in parentheses refer to reaction time in the presence
of the acid catalyst. 1.5 equiv of TFA was added.
d
was monitored by TLC. Compounds 4a ,b,e were obtained
in moderate yields, but the presence of mixtures of
nonpolar products was detected at the end of the reaction.
BF3‚(Et2O) could competitively promote the aldol con-
densation of ketones 2, so, to favor the formation of the
desired products 4, the extent of aldol condensation had
to be limited by attempting more controlled reaction
conditions. When employing TFA, satisfying yields of
compounds 4 (entries 4-8) were indeed obtained. Better
yields were achieved with increasing bulkiness of the R1
substituent, according to the trend observed in the case
of ketones 231 (Table 3).
Ack n ow led gm en t. We acknowledge financial sup-
port from Ministero dell’Istruzione, Universita` e Ricerca
Scientifica (MIUR).
In conclusion, we have disclosed a novel reactivity of
the VO(acac)2/TBHP system with o-alkenyl phenols,
which led us to set up a mild, eco-safer, practical, and
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization for all compounds. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(31) All the yields of benzo[b]furans are higher than the yields of
the corresponding ketones 2 in Table 3; these results confirm the silica
gel induced decomposition of 2 during the purification process.
J O026783J
3694 J . Org. Chem., Vol. 68, No. 9, 2003