Oxidative rearrangement of tertiary allylic alcohols employing oxoammonium salts

Article abstract of DOI:10.1021/jo800634r

(Chemical Equation Presented) Practical and highly efficient methods for oxidative rearrangement of tertiary allylic alcohols to β-substituted α,β-unsaturated carbonyl compounds employing oxoammonium salts are described. The methods developed are applicable to acyclic substrates as well as medium membered ring substrates and macrocyclic substrates. The counteranion of the oxoammonium salt plays crucial roles on this oxidative rearrangement.

Full text of DOI:10.1021/jo800634r

SCHEME 1. Cr(VI)-Mediated Oxidative Rearrangement of
Tertiary Allylic Alcohols
Oxidative Rearrangement of Tertiary Allylic
Alcohols Employing Oxoammonium Salts
Masatoshi Shibuya, Masaki Tomizawa, and
Yoshiharu Iwabuchi*
Department of Organic Chemistry, Graduate School of
Pharmaceutical Sciences, Tohoku UniVersity, Aobayama,
Sendai 980-8578, Japan
enables the facile and efficient oxidative rearrangement of a
variety of tertiary allylic alcohols.
An exploratory experiment was started by screening the
reactivity of readily available TEMPO-derived oxoammonium
salts with 1-phenylcyclohex-2-en-1-ol (1a) as the substrate
(Table 1).5i,8 It was found that TEMPO+ species carrying bulky,
poor nucleophilic anions, such as BF4- 2a or SbF6- 2b, exhibit
excellent reactivity to furnish 3-phenylcyclohex-2-en-1-one (1b)
in 95% yield within 3 min at room temperature (entries 1 and
iwabuchi@mail.pharm.tohoku.ac.jp
ReceiVed March 22, 2008
2). On the other hand, TEMPO+Br3 (2c) and TEMPO+Cl-
-
(2d) are completely ineffective for the same reaction (entries 3
and 4). It is important to point out that typical TEMPO oxidation
conditions with NaOCl, PhI(OAc)2, or Oxone as the co-oxidant
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Practical and highly efficient methods for oxidative rear-
rangement of tertiary allylic alcohols to ꢀ-substituted R,ꢀ-
unsaturated carbonyl compounds employing oxoammonium
salts are described. The methods developed are applicable
to acyclic substrates as well as medium membered ring
substrates and macrocyclic substrates. The counteranion of
the oxoammonium salt plays crucial roles on this oxidative
rearrangement.
The oxidative rearrangement of tertiary allylic alcohols to
ꢀ-substituted R,ꢀ-unsaturated carbonyl compounds is one of the
useful transformations in synthetic chemistry.1 Since the report
in the mid-70s that PCC, PDC, and Collins reagent exert the
one-pot allylic transposition-oxidation of a variety of tertiary
allylic alcohols, oxochromium(VI)-based reagents have been the
first-choice reagents and have played indispensable roles in
organic synthesis (Scheme 1 ).1–3 However, the ever-growing
demand for the development of green sustainable methodologies
has urged us to alternatives to hazardous oxochromium(VI)-
based reagents.4 On the basis of the speculation that the CrdO
motif plays a role in the rearrangement step, we took interest
in the potential use of organic oxoammonium ions
(R1R2N+dO),5 which are active species for the nitroxyl-radical
{e.g., TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy)6 and AZA-
DOs (2-azaadamantane N-oxyl)7 }-catalyzed oxidation of al-
cohols in promoting this particular oxidative transformation. We
now report a novel oxoammonium-salt-based method that
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4750 J. Org. Chem. 2008, 73, 4750–4752
10.1021/jo800634r CCC: $40.75 2008 American Chemical Society
Published on Web 05/24/2008

TABLE 1. Reaction Properties of Oxoammonium Salts of
TEMPO
TABLE 2. Scope of Oxoammonium-Mediated Oxidative
Rearrangementa
entry
X
time (min)
yield (%)
1
BF4 (2a)
SbF6 (2b)
Br3 (2c)
Cl (2d)
3
3
30
240
95
97
0b
0
2
3a
4
a CH2Cl2 was used as the solvent. b 2,3-Dibromo-1-phenylcyclohexanol
was produced quantitatively.
did not afford the product, although they are competent to
generate oxoammonium species.6,9,10
Experiments for probing the range of tertiary allylic alcohols
that undergo oxidative transformation are summarized in Table
2. The aryl- and alkyl-substituted six-membered substrates
3a-5a were smoothly converted to the corresponding transposed
products in high yields (entries 1-3). For medium to macro-
cyclic substrates,11 the reactions suffered from generation of
several byproduct including dimeric ethers. We found that H2O
addition in some cases greatly improves the productivity to allow
the spot-to-spot conversion in high yields (entries 4-7). We
conjecture that H2O aids the reactions in part to proceed in the
SN2′ pathway (vide infra). The tricyclic substrate 10a also
effectively yielded the desired product 10b (entry 8). The steroid
11a afforded the secondary allylic alcohol 11c in moderate yield,
due to considerable steric hindrance. Acyclic substrates also
smoothly underwent oxidative rearrangement in high yield,
although endo olefinic substrates need the addition of H2O
(entries 12 and 13).4 Unfortunately, the substrate 16a did not
yield the desired product 16b, instead an ene-like adduct was
obtained in moderate yield as a major product (entry 14).12 The
reaction of 13a to 13b with TEMPO+SbF6 was markedly
-
accelerated by warming the reaction mixture to 70 °C (entry
11). In these experiments, the TEMPO+SbF6 salt 2b as well
-
as TEMPO+ClO4 and TEMPO+PF6 tended to afford
-
-
13
better results than TEMPO+BF4
.
TEMPO+TfO- and
-
13
TEMPO+Tf2N- showed similar reactivity to TEMPO+BF4
.
-
Plausible reaction pathways are depicted in Scheme 2.
Considering the steric and electronic effect of the anion, it would
be reasonable to expect that the oxoammonium salt carrying a
bulkier counteranion, such as BF4- and SbF6-, should be more
electrophilic, due to the enhanced electrostatic potential, to allow
formation of the crucial adduct i under equilibrium. Once
formed, i could facilely proceed to give a rearranged product
iii via either allylic cation formation (path A) or concerted
intramolecular rearrangement (path B), which has been proposed
a Standard reaction conditions employed 1.5 equiv of oxoamonium
salts in MeCN at RT. b Isolated yield. c MeCN and H2O (1:1) solution
was used as the solvent. d E:Z ) 2:1. e Yield of allylic alcohol 11c. f E:Z
) 2.4:1. g E:Z ratio was not determined. h Reaction performed at 50 °C.
i Reaction performed at 40 °C. j Reaction performed at 70 °C. k E:Z )
3.5:1. l Ene-like adduct (67%) was obtained.
(9) (a) Anelli, P. L.; Banfi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1989,
54, 2970–2972. (b) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.;
Piancatelli, G. J. Org. Chem. 1997, 62, 6974–6977. (c) Bolm, C.; Magnus, A. S.;
Hidebrand, J. P. Org. Lett. 2000, 2, 1173–1175.
(10) Under the condition using NaClO or PhI(OAc)2, unreacted starting
material was recovered. Under the condition using Oxone, 1-phenylcyclohexa-
1,3-diene was produced as the major product with an accompanying small amount
(∼20%) of 1b.
(11) Tello-Aburto, R.; Ochoa-Teran, A.; Olivo, H. F. Tetrahedron Lett. 2006,
47, 5915–5917.
for PCC or IBX.1b,4 In the case that H2O addition plays
productive roles, we believe that mechanism C where H2O
attacks intermediate i in the SN2′ mode operates in part.
(12) Pradhan, P. P.; Bobbitt, J. M.; Bailey, W. F. Org. Lett. 2006, 8, 5485–
5487.
(13) See the Supporting Information.
J. Org. Chem. Vol. 73, No. 12, 2008 4751

SCHEME 2. Plausible Reaction Mechanism
SCHEME 4. Proposed Pathways for the Oxidation of
Benzyl Alcohol by TEMPO+Cl-
unsaturated carbonyl compounds employing oxoammonium
salts, which are alternatives to toxic oxochromium(VI)-based
reagents in organic chemistry. We found that counteranions are
important for the reactivity of the oxoammonium salts. Studies
toward the development of a catalytic version of this process
are under way.
SCHEME 3. Intermolecular Competitive Reactions
Experimental Section
Synthesis of TEMPO+BF4- (2a). TEMPO (10 g, 64 mmol) was
slurried with H2O (32 mL, 2 M) and 42% HBF4 (13.4 mL, 64
mmol) was slowly added dropwise over 1 h at room temperature.
After the solution turned to amber color, NaOCl (23 mL, 32 mmol)
was added over 1 h at 0 °C and stirred for an additional 1 h at 0
°C. The reaction mixture was filtered and the yellow crystalline
precipitate was washed with ice-cold 5% NaHCO3 (20 mL), water
(40 mL), and ice-cold Et2O (400 mL). The solid was dried over
-
24 h at 50 °C in vacuo to yield TEMPO+BF4 (2a) (12.1 g, 49.9
mmol, 78%) as the bright yellow solid, mp 162-163 °C (recrystal-
lized from H2O). Anal. Calcd for C9H18BF4NO: C, 44.47; H, 7.46;
N, 5.76. Found: C, 44.33; H, 7.12; N, 5.78.
-
Synthesis of TEMPO+SbF6 (2b). The same procedure with
65% HSbF6 instead of 42% HBF4 provided TEMPO+ SbF6 (2b).
Anal. Calcd for C9H18F6NOSb: C, 27.58; H, 4.63; N, 3.57. Found:
C,27.36; H, 4.60; N, 3.50.
To probe the reactive nature of oxoammonium salts, we
conducted intermolecular competition experiments with the
tertiary allylic alcohol 3a and benzyl alcohol (17a) (Scheme
3). On treatment with TEMPO+Cl- (2d), benzaldehyde (17b)
was rapidly produced and 3a was recovered. On the other hand,
General Procedure for the Oxidative Allylic Rearrange-
ment Reaction with TEMPO-Derived Oxoammonium Salts. To
a solution of 1-n-butyl-2-cyclohexenol 3a (200 mg, 1.3 mmol) in
-
MeCN (6.5 mL, 0.2 M) was added TEMPO+BF4 (474 mg, 1.95
mmol) at room temperature. The reaction mixture was stirred for
3 min and then diluted with Et2O. The organic layer was washed
sequentially with water and brine and then dried over MgSO4. The
solution was concentrated in vacuo and the residue was purified
by flash column chromatography (SiO2, 1:6 Et2O:hexane) to give
3-n-butyl-cyclohexenone 3b (185 mg, 1.22 mmol, 94%) as a
colorless oil.
treatment with TEMPO+SbF6 (2b) converted 3a into 3b
-
selectively. The treatment of 3a with 2d in the presence of an
equimolar amount of AgBF4 afforded almost the same result
as the reaction with 2b.14,15
The observed chemoselectivity would be rationalized by
considering the basicity of the counteranions (Scheme 4).16
Thus, in the case of TEMPO+Cl- (2d), the chloride anion can
act as a base that abstracts a proton from either the benzylic
(path a) or the OH proton (path b) giving an ammonium oxide
to bring about generation of 17b and 18. On the other hand,
less basic BF4- refrains for abstracting a proton, and thus slows
the oxidation.17,18
3-Butylcyclohex-2-en-1-one (3b). 1H NMR (400 MHz, CDCl3)
δ 5.87 (t, 1H, J ) 1.4 Hz), 2.35 (ddd, 2H, J ) 7.5, 6.7, 2.2 Hz),
2.29 (t, 2H, J ) 6.1 Hz), 2.21 (t, 2H, J ) 7.5 Hz), 2.05-1.95 (m,
2H), 1.53-1.45 (m, 2H), 1.39-1.29 (m, 2H), 0.92 (td, 3H, J )
7.3, 2.2 Hz). 13C NMR (100 MHz, CDCl3) δ 199.7, 166.5, 125.4,
37.7, 37.3, 29.6, 29.0, 22.7, 22.3, 13.8. IR (neat, cm-1) 1670. MS
m/z 152 (M+), 82 (100%). HRMS calcd for C10H16O 152.1201,
found 152.1180.
In summary, we disclosed a novel one-pot oxidative rear-
rangement of tertiary allylic alcohols to ꢀ-substituted R,ꢀ-
Acknowledgment. We thank Prof. Emeritus Kunio Ogasawara
of Tohoku University for his encouragement and helpful
discussion. This work was supported by JSPS and MEXT, Japan.
-
(14) It was assumed that TEMPO+BF4 was generated in situ.
(15) Gorin, D. J.; Toste, F. D. Nature 2007, 446–396.
(16) (a) Olah, G. A.; Prakash, G. K. S. Superacids; John Wiley and Sons:
New York, 1973. (b) Olah, G. A. J. Org. Chem. 2005, 70, 2413–2429.
(17) Bailey, W. F.; Bobbitt, J. M.; Wiberg, K. B. J. Org. Chem. 2007, 72,
4504–4509.
Supporting Information Available: Experimental proce-
dures and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) If the substrate possesses protons acidic enough (cf. allylic methine
proton in cyclohexenol), the proton would be abstracted by a solvent to afford
oxidized products.
JO800634R
4752 J. Org. Chem. Vol. 73, No. 12, 2008