Oxidation of benzylic alcohols and ethers to carbonyl derivatives by nitric acid in dichloromethane

Article abstract of DOI:10.1002/ejoc.200390090

Nitric acid in dichloromethane may be successfully employed for the oxidation of benzylic alcohols and ethers to the corresponding carbonyl compounds. The proposed method proved to be of general applicability, affording very good yields of aldehydes and ketones and showing interesting chemoselectivity in many instances, allowing competitive aromatic nitration to be avoided, as well as - in the case of aldehydes - any further oxidation to carboxylic acids. The reaction probably proceeds by a radical mechanism, the active species in the oxidation process being NO₂. Competitive formation of nitro esters was observed in some cases, whereas poor results were obtained with allylic and non-benzylic substrates. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390090

FULL PAPER
Oxidation of Benzylic Alcohols and Ethers to Carbonyl Derivatives by Nitric
Acid in Dichloromethane
Paolo Strazzolini*[a] and Antonio Runcio[a]
Keywords: Alcohols / Aldehydes / Ketones / Oxidations / Radical reactions
Nitric acid in dichloromethane may be successfully employed
for the oxidation of benzylic alcohols and ethers to the corres-
ponding carbonyl compounds. The proposed method proved
to be of general applicability, affording very good yields of
further oxidation to carboxylic acids. The reaction probably
proceeds by a radical mechanism, the active species in the
oxidation process being NO2. Competitive formation of nitro
esters was observed in some cases, whereas poor results
aldehydes and ketones and showing interesting chemoselec- were obtained with allylic and non-benzylic substrates.
tivity in many instances, allowing competitive aromatic nitra- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
tion to be avoided, as well as − in the case of aldehydes − any Germany, 2003)
Introduction
Results and Discussion
In the course of our studies concerning the synthetic ap-
plications of the HNO3/CH2Cl2 system, previously found
to be very effective in ortho-oriented nitrations of some
benzylic substrates (chaperon effect),[1] as well as a useful
heterolytic (nitrolytic) reagent suitable for the deprotection
of N-Boc derivatives,[2] tert-butyl and 1-adamantyl carb-
oxylates,[3] we set out to explore the synthetic potential im-
plicit in our initial observation[1] that methyl phenylmethyl
ether (1a) underwent a rapid and quantitative transforma-
tion into benzaldehyde (2a), thus preventing any occurrence
of ring nitration[4] and without undergoing further oxida-
tion to benzoic acid (3, Scheme 1).[5] Such behaviour ap-
peared particularly noteworthy in view of the fact that com-
pound 1a was reported to meet a completely different fate
under classical nitration conditions.[6] Although a plethora
of methods to achieve the oxidation of alcohols (and ethers
as well) to the corresponding carbonyl compounds are
described in the literature,[7] this investigation was deemed
worthy of attention thanks to its straightforwardness of
operation and the easy availability[8] and low cost of the
chemicals to be employed.
We first considered benzylic primary substrates
(Scheme 2, compounds 1 and 4, G2 ϭ H) on the basis of
the well-known capability of HNO3 to effect their oxidation
to carbonyl compounds,[9] and taking account of the ad-
vantages of operating in an organic solvent.[10] Initially, we
set out to establish reasonably good conditions for the ox-
idation of PhCH2OCH3 (1a) at room temperature, after ini-
tial mixing of the reagents at 0 °C. The results of different
HNO3/1a ratios at identical substrate concentration (see
Exp. Sect.) are collected in Table 1, and show that a faster
reaction can be achieved Ϫ without the occurrence of aro-
matic nitration Ϫ by increasing the ratio, a strategy useful
to apply in the case of substrates sensitive in other locations
to long exposures to this environment. We therefore decided
to employ an excess of 3 mol of HNO3 per mol of substrate
to perform a number of experiments suitable to evaluate the
applicability of the method, so as to obtain a comparative
view of the behaviour of benzylic alcohols and ethers under
these conditions. The obtained results are collected in
Table 2.
Scheme 1
Scheme 2
[a]
Department of Chemical Sciences and Technologies, University
of Udine,
Via del Cotonificio 108, 33100 Udine, Italy
Fax: (internat.) ϩ 39-0432/55-8870
E-mail: strazzolini@dstc.uniud.it
For most of the tested ethers that did not bear additional
α-alkyl groups (1, G2 ϭ H), the conversion into the corres-
526
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0203Ϫ0526 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 526Ϫ536

Oxidation of Benzylic Alcohols and Ethers to Carbonyl Derivatives
FULL PAPER
the occurrence of an ECO-like, acid-catalysed elimination
mechanism[13] as proposed in some instances, in which high
temperatures were usually required.[14] This inference was
confirmed when 7 was treated under otherwise identical
conditions but with an equivalent amount of trifluoroacetic
acid (TFA) in place of HNO3. This produced a very slug-
gish reaction; no products were detectable after 1 h, and
only 15% of 2a was formed after 24 h (Scheme 4), thus in-
dicating that an ionic pathway of elimination of HNO2 is
indeed possible, but slow (Scheme 5).
Table 1. Optimization of the HNO3/1a ratio in the oxidation reac-
tion to 2a (Scheme 1)
Entry
1a [mol]
HNO3
[mol]
Reaction
time [h]
Conversion [%][a]
1
2
3
4
1.0
1.0
1.0
1.0
2.0
2.0
2.5
3.0
1
24
1
68
Ͼ 99
82
1
Ͼ 99
[a] Determined by 1H NMR (see Exp. Sect.). Benzaldehyde (2a) was
the sole product.
On the other hand, a long induction period associated
with a slower reaction was observed for the isomeric nitro
alcohols 4m and 4n, this behaviour having been taken as an
ponding aldehydes was quantitative within 1 h at room tem- indication of the involvement of a radical mechanism[15]
perature (Table 2). We observed that the process is acceler- with NO2 acting as the active species,[16] whereas an ionic
ated by relatively mild electron-releasing substituents, with- process[17] appears unlike under the current conditions. In
out suffering any significant activation towards competitive fact, 4-nitrobenzyl nitrate (10) proved to be completely un-
aromatic nitration, and slowed down by the presence of reactive under these conditions, its reactivity being totally
electron-withdrawing substituents. On the other hand, inhibited by the electron-withdrawing nitro groups, both to-
strongly electron-releasing substituents present in the ben- wards oxidation and towards further aromatic nitration. In
zene ring caused the unavoidable incursion of aromatic elec- this context, the comparative behaviour of the 3-methoxy
trophilic substitution. Indeed, when 3-methoxy derivative (1p, 4p) and 3-phenoxy (1q and 4q) derivatives under the
1p was the substrate, concomitant ring nitration was evident usual reaction conditions is noteworthy (Table 2). 3-Me-
(Scheme 3), resulting in the formation of a consistent thoxybenzyl alcohol (4p) gave a predominant oxidation pat-
amount (58%) of a mixture of isomeric nitro ethers (5). In- tern (66% 3-methoxybenzaldehyde, 2p), whereas the corres-
terestingly enough, the observed complete absence of nitro ponding methyl ether 1p, less prone to oxidation, reacted
aldehydes 6 in the reaction mixture was a good indication competitively to give 42% aldehyde 2p and 58% ring nitra-
both of the deactivation of aromatic nitration exerted by tion products (Scheme 3). The electron-releasing action of
the formyl substituent and of the inhibition of the oxidative the PhO group is much reduced, allowing the oxidation of
process caused by the presence of the nitro function in de- 3-phenoxybenxyl alcohol (4q) to the corresponding alde-
rivatives 5. When dibenzyl ether (1z) was the substrate and hyde 2q as the sole and quantitative process taking place,
the amount of HNO3 was adjusted appropriately, almost whereas methyl 3-phenoxybenzyl ether (1q), which would
complete conversion into 2 mol of benzaldehyde (2a) was be expected to react more slowly in the oxidation process,
achieved, showing some remarkable improvement over a re- indeed gave a final pattern similar to 1p. In line with
cently reported method.[11] In addition, benzyl ethers with the above observations, (4-hydroxyphenyl)methanol (15) is
an alkyl counterpart other than methyl (1aaϪdd) behaved believed[3b] to undergo faster aromatic nitration under the
normally, affording PhCHO (2a) in almost quantitative conditions employed for the oxidation. In fact, even the less
yield (Table 2).
activated 4-methoxy derivative 4r gave only 44% of the cor-
Benzylic alcohols with a variety of ring substituents were responding benzaldehyde 2r, undergoing prevalent compet-
also tested and found to be more reactive than the corres- itive ring nitration. Nevertheless, when the phenolic func-
ponding ethers,[12] as confirmed by an appropriate compet- tion was selectively protected with the easily removable, but
itive experiment involving PhCH2OH (4a) vs. PhCH2OCH3 under these conditions quite stable,[3b] phenylmethoxy-
(1a), in which a 1:1 mixture of the substrates was treated carbonyl group as in 4s, the oxidation of the alcoholic func-
with an insufficient amount of HNO3. Compound 1a tion took place without any undesired ring nitration, affor-
proved to be by and large preferentially oxidized to PhCHO ding the aldehyde 2s in high yield, thus circumventing some
(2a). Treatment of alcohols, however, although easier than previously reported drawbacks.[18]
treatment of ethers, may result in faster esterification by
When an alcohol was the substrate, the product balance
HNO3, a competitive side process not eventually producing of the oxidation process had to be inorganic in nature, but
oxidation products under these conditions, as evidenced for in the case of ethers an organic counterpart was to be ex-
4m and 4n, to the point of becoming a convenient route to pected. In order to cast more light on the reaction mechan-
nitro esters in some cases.
ism, this point was carefully investigated. The substrate se-
Mechanistically, a nitric ester could be a candidate inter- lected for the purpose was benzyl hexyl ether (1aa), which
mediate in our benzylic oxidations of alcohols (and possibly underwent smooth oxidation under our conditions to af-
of ethers, following nitrolysis). When, though, benzyl ni- ford, besides the expected quantity of PhCHO (2a), a 70%
trate (7) was treated with HNO3 in CH2Cl2, only ring nitra- yield of hexyl nitrite (11), accompanied by its likely prod-
tion to afford the three nitro derivatives 8, 9, and 10 was ucts of hydrolysis[19] (hexanol, 12, 6%) and oxidation[20]
observed after 1 h at room temperature, with only traces of (hexanal, 13, 18%), together with hexyl nitrate (14, 6%), the
PhCHO (2a) being formed (Scheme 4). This result ruled out latter probably originating from direct esterification of 12
Eur. J. Org. Chem. 2003, 526Ϫ536
527

P. Strazzolini, A. Runcio
FULL PAPER
Table 2. Oxidation of benzylic alcohols and ethers with HNO3 in CH2Cl2 (Scheme 2)
Entry
Substrate
G1
G2
G3
Product[a]
Conversion [%][b]
Yield [%][c]
1
2
3
4
5
6
7
8
9
1a
4a
4b
1c
1d
4d
1e
1f
4f
1g
1h
4h
1j
1k
1m
4m
1n
4n
1p
4p
1q
4q
4r
CH3
H
H
CH3
CH3
H
CH3
CH3
H
CH3
CH3
H
CH3
CH3
CH3
H
CH3
H
CH3
H
CH3
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH2Ph
(CH2)5CH3
CH2CH2Ph
cyclopentyl
C(CH3)3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2a
2b
2c
2d
2d
2e
2f
2f
2g
2h
2h
2j
2k
2m
2m
2n
2n
2p
2p
2q
2q
2r
2s
2t
2u
2v
2w
2x
2y
2a
2a
2a
2a
2a
2ee
2ee
2ff
2gg
2hh
2hh
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99
Ͼ 99[d]
59[e]
83
91
92
87
87
90
86
82
85
2-CH3
3-CH3
4-CH3
4-CH3
4-C(CH3)3
2-Cl
2-Cl
3-Cl
4-Cl
4-Cl
2,4-Cl2
2-NO2
3-NO2
3-NO2
4-NO2
4-NO2
3-OCH3
3-OCH3
3-OPh
3-OPh
4-OCH3
4-OCOOCH2Ph
4-CH2OCH3
4-COOH
4-COOCH3
4-COOC(CH3)3
4-CH2Cl
4-CH2OOCCH3
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
78
86
91
81
59[b]
78
95[f]
Ͼ 99[g]
69[h]
75[b]
69[b]
76[b]
42[b]
66[b]
56[b]
82
Ͼ 99[i]
Ͼ 99[j]
Ͼ 99[k]
98[k]
Ͼ 99
Ͼ 99[k]
Ͼ 99
Ͼ 99[l]
98
44[b]
94
79
88
86
4s
4t
1u
1v
1w
1x
1y
1z
1aa
1bb
1cc
1dd
1ee
4ee
4ff
4gg
1hh
4hh
98[m]
97[n]
0
91
Ͼ 99
98
80
Ͼ 99
184[o]
81
H
H
H
H
H
H
H
H
97[p]
H
H
H
CH3
CH3
CH2Ph
COPh
Ph
Ph
99[q]
57[b]
83
Ͼ 99
99[r]
88
Ͼ 99[s]
Ͼ 99[t]
Ͼ 99[u]
43[v]
69
70[b]
40[b]
0
H
H
CH3
H
H
H
Ͼ 99[w]
Ͼ 99[x]
86
85
[a]
The reactions were carried out with 3.0 mol of HNO3 per mol of substrate for 1 h at room temperature, and reaction products were
isolated after distillation or crystallization from a suitable solvent. Unless otherwise indicated, the carbonyl compound 2 was the sole
[b]
1
[c]
[d]
[e]
reaction product. Determined by H NMR (see Exp. Sect.). Isolated product.
After 24 h; 76% after 1 h. After 24 h; 2% after
1 h. [f] After 24 h; 34% after 1 h. After 1 h the reaction mixture contained 55% of aldehyde 2m and 45% of the nitro ester 9; after 24 h,
[g]
[h]
[i]
75% of 2m and 25% of 9.
After 24 h; 3% after 1 h. After 1 h, the reaction mixture contained 76% of aldehyde 2n and 24% of the
[j]
nitro ester 10; no change after 24 h. The reaction mixture contained 42% of aldehyde 2p and 58% of a mixture of three isomeric
[k]
products (in the ratio 58:32:10) generated by aromatic nitration of 1p.
The reaction mixture consisted of the expected aldehyde,
[l]
[m]
accompanied by various ring nitration products. The reaction mixture contained some 8% of terephthalaldehyde (27).
After 24 h;
[n]
[o]
40% after 1 h. The sole product formed was the acid 1u, which was isolated in 91% yield. 4.0 mol of HNO3 was employed; 1.0 mol
of substrate gave 2.0 mol of benzaldehyde (2a). [p] The reaction mixture contained, besides the expected amount of 2a (1H NMR analysis):
[q]
hexyl nitrite (11, 70%), hexanol (12, 6%), hexanal (13, 18%) and hexyl nitrate (14, 6%). The reaction mixture contained 2-phenylethyl
nitrite (23, 33%) and phenylacetaldehyde (24, 10%). [r] The reaction mixture also contained 1,1-dimethylethyl nitrate (25) and 1,1-dimethyl-
[s]
ethyl nitrite (26) in a ratio of 59:41. The reaction mixture contained 2ee (85%), accompanied by some (15%) 1-phenylethyl nitrate (17).
[t]
After 1 h, the reaction mixture contained 2ee (33%), accompanied by 67% of 1-phenylethyl nitrate (17); after 24 h, the ratio was 70:30.
[u]
The reaction mixture contained 2ff (40%), accompanied by 60% of 1,2-diphenylethyl nitrate (18). After 24 h, the ratio was unchanged,
whereas some aromatic nitration set in. [v] No oxidation took place: 2-oxo-1,2-diphenylethyl nitrate (19) was the only product formed (7%
after 1 h; 43% after 24 h). [w] After 1 h, the degree of conversion was 83% and the reaction mixture contained 27% of 2hh, accompanied by
[x]
56% of diphenylmethyl nitrate (22); after 24 h, the ketone 2hh was the sole product present.
2hh, accompanied by 96% of diphenylmethyl nitrate (22); after 24 h, the ketone 2hh was the sole product present.
The reaction mixture contained 4% of
rather than metathetic exchange and/or direct oxidation[21] tion. Nevertheless, some attack by HNO3 might indeed oc-
of 11 (vide infra). Such behaviour clearly points to the cur on the alkyl side, being responsible for part of the
nitroso ester 11 as the likely cleavage partner in the oxida- formation of aldehyde 13, but in this case and according to
528
Eur. J. Org. Chem. 2003, 526Ϫ536

Oxidation of Benzylic Alcohols and Ethers to Carbonyl Derivatives
FULL PAPER
making the homolytic abstraction of the α-hydrogen atom
more difficult.
Scheme 3
Scheme 4
Scheme 5
the above interpretation, phenylmethyl nitrite (16) should
also be formed, and this, as we observed in an ad hoc ex-
periment, goes on to produce 2a quantitatively under
these conditions.
Scheme 6
The presence of α-alkyl groups, facilitating the produc-
When carefully degassed HNO3 was used, a definite in- tion of the intermediate cations, as in compounds 1ee, 4ee,
duction time for the reactions was clearly observable in and 4ff, depressed the yields of carbonyl products owing to
some experiments, made evident by subsequent sudden and the competitive reaction affording nitric acid esters (17 and
rapid evolution of nitrous gas. Our working procedure ruled 18), which are stable products under the reaction conditions
out the formation of significant amounts of NO2 by the (Table 2).[25] In addition, when the formation of the nitrate
spontaneous decomposition of HNO3[22] in CH2Cl2, the ob- ester 18 slowed down the oxidative process, as in the case
served actual induction time being definitively shorter. This of compound 4ff, the deactivating effect on potential ring
pattern may be viewed as an additional hint of a reaction nitration was not equivalent, so that some occurrence of
mechanism radical in nature, although ruling out the initial nitro derivatives was found to take place.[25] On the other
operation of a single-electron-transfer reaction to form an hand, the presence of a carbonyl substituent (4gg), strong
ϩ
unlikely NO2 ion.[23] A possible alternative is outlined in enough to prevent any ring nitration, suppressed the oxida-
Scheme 6, in which HNO3 itself is proposed as the initiator tion reaction completely and the nitrate ester 19 was the
of the oxidative process, in turn generating the active species only product formed. When Ph2CHOH (4hh) and the cor-
NO2 responsible for the rapid transformation of the sub- responding methyl ether (1hh) were the substrates, we ob-
strates into the corresponding carbonyl compounds, in line served that, although the overall conversion into Ph2CO
with a number of previously reported observations.[24] Ac- (2hh) was in both instances quantitative after 24 h, the reac-
cordingly, the superior reactivity of alcohols relative to tion of the alcohol 4hh was significantly faster (Scheme 7).
ethers in the oxidation reaction could probably be attrib- Nevertheless, the protonated alcohol (20) gave rise to the
uted to the higher basicity of the latter compounds, which rapid formation of the organic cation 21, readily intercepted
Ϫ
are preferentially protonated in the reaction environment, by NO3 to give the ester 22, representing kinetic control
Eur. J. Org. Chem. 2003, 526Ϫ536
529

P. Strazzolini, A. Runcio
FULL PAPER
of the process; the irreversible oxidative route eventually benzylic ethers, and resulted in quantitative conversion of
leads to 2hh.
1dd with production of 2a, accompanied by the formation
of 1,1-dimethylethyl nitrate (25) and 1,1-dimethylethyl ni-
trite (26) in a ratio of 59:41. The nitrolytic reaction there-
fore appears to be an intrinsically easier and fast process.
In fact, although the aromatic product of the nitrolysis
[phenylmethanol (4a)], which was not intercepted, would be
bound to be rapidly oxidized to the corresponding aldehyde
2a, the 25/26 ratio can be taken as a good representation of
the outcome of the whole reaction, since we have shown
that under the conditions employed, both the metathetic
transformation and the oxidation of 26 to 25 are definitively
much slower reactions.
Scheme 7
The oxidation reaction was found to be highly chemose-
lective for the benzylic position and of higher velocity than
a potential aromatic nitration, as shown by the behaviour
of 2-phenylethyl phenylmethyl ether (1bb, Table 2) in which,
in addition to ring nitration, a non-benzylic competitive re-
action might be envisaged (Scheme 8). The system ran
smoothly to give quantitative conversion into benzaldehyde
(2a), accompanied by a close to stoichiometric amount of
the expected 2-phenylethyl nitrite (23). Only minor amounts
of phenylacetaldehyde (24) were detected, showing that the
direct attack at the ether benzylic position (Scheme 8, path
a) is largely prevalent, if not even exclusive. In fact, the al-
ternative competitive reaction (Scheme 8, path b) would
have yielded 24, which, however, is also the product of de-
composition of the nitrite 23 under acidic conditions. In
any case, the absence of the implicit partner in path b,
phenylmethyl nitrite (16), in the reaction mixture is due to
its known prompt further reaction to afford 2a.
Scheme 9
The simultaneous presence of both alcoholic and ether
benzylic functions in the substrate, as in [4-(methoxymethyl)-
phenyl]methanol (4t), allowed the chemoselectivity of the
oxidation reaction to be better appreciated. Compound 4t
was attacked almost exclusively at the alcoholic site, with
the formation of only a very minor amount of terephthalal-
dehyde (27), affording 4-(methoxymethyl)benzaldehyde (2t)
in very good yield (Table 2). It was also of interest to ob-
serve the behaviour of other functions attached to a
benzylic carbon atom when exposed to the oxidative condi-
tions, with a view to obtaining simple polyfunctional chem-
icals by easy and inexpensive routes. It is known that
HNO3, at various concentrations and temperatures, rapidly
converts phenylmethyl halides[26] and esters[27] into the cor-
responding carbonyl compounds in high yields, it being
suggested that the intermediate in the oxidation process is
the hydrolysis product, the corresponding phenylmethanol.
When the substrate was phenylmethyl chloride (28,
Scheme 10), our system was totally ineffective in per-
Sdheme 8
Comparison of the reactivities observed for the methyl forming this reaction, giving exclusive electrophilic ring
(1v) and 1,1-dimethylethyl (1w) esters of 4-(methoxymethyl)- substitution to afford the three nitro isomers 29. When,
benzoic acid (1u) with the HNO3/CH2Cl2 system under though, 4-(methoxymethyl)benzyl chloride (1x) was sub-
strictly comparable conditions is worth noting (Table 2). jected to identical conditions, it afforded 4-(chloromethyl)-
The former compound reacted more slowly, exclusively pro- benzaldehyde (2x) as the sole reaction product, in quantit-
viding the expected aldehyde 2v, whereas the acid-sensitive ative yield (Scheme 11). Carboxylic esters proved to be
1w exclusively underwent nitrolysis[3a] to give 1,1-dimethyl- equally resistant towards nitric oxidation in CH2Cl2. In
ethyl nitrate (25) and the acid 1u, thus indicating that the fact, benzyl acetate (30) was found to undergo only ring
nitrolytic process was easier than the oxidative one. We nitration, affording the isomeric mixture 31 (Scheme 10), as
therefore studied the reaction between 1,1-dimethylethyl did the bulkier phenylmethyl 2,2-dimethylpropanoate (32),
phenylmethyl ether (1dd) and HNO3 in order to evaluate which underwent exclusive nitration to give 33 in a similar
the relative impact of the nitrolysis vs. direct benzylic oxida- fashion, though in a slower reaction. Consistently, the bi-
tion (Scheme 9). The experiment was performed with the functional compound 4-(methoxymethyl)benzyl acetate (1y)
equivalents of HNO3 usually employed in the oxidation of underwent selective oxidation to 4-(acetoxymethyl)benzal-
530
Eur. J. Org. Chem. 2003, 526Ϫ536

Oxidation of Benzylic Alcohols and Ethers to Carbonyl Derivatives
FULL PAPER
dehyde (2y) in quantitative yield under the usual condi-
tions (Scheme 11).
Scheme 10
Scheme 12
Scheme 11
3,4-Dihydro-1H-isochromene (34) is a benzylic substrate
in which the ether function is part of a ring condensed to
benzene. Our conditions resulted in exclusive α-oxidation
to give the corresponding lactone 35, any other product Ϫ
particularly 2-(2-formylphenyl)ethyl nitrite (36) Ϫ being
totally absent. This result contrasts with the behaviour of
benzyl 2-phenylethyl ether (1bb), which, as discussed above,
afforded benzaldehyde (2a) and 2-phenylethyl nitrite (23).
Mechanistically, the divergent outcome of the two reactions
may be explained as follows (Scheme 12). Formed NO2,
Scheme 13
after abstracting a benzylic hydrogen atom from the ether mol of substrate), appears difficult to control and marred
substrate, reacts further to afford a covalent bond with by considerable amounts of side products, in part a con-
either N and C (37) or O and C (38) to give species in sequence of the presence of enolizable α-hydrogen atoms.[28]
equilibrium, an internal reaction by 38 eventually produ- Indeed, when the reaction was performed on 2,2-dimethyl-
cing the lactone 35. Such behaviour might find an explana- propanol (44), the corresponding aldehyde 45 was formed
tion in a stereochemical consideration: the distance between in 66% yield, accompanied by minor amounts of 2,2-di-
C-3 and the NO oxygen atom in both the bicyclic interme- methylpropyl nitrite (46, 9%), 2,2-dimethylpropyl nitrate
diates 37 and 38 is too long to allow the reaction observed (47, 10%) and 2,2-dimethylpropanoic acid (48, 15%).[29]
for 1bb. This inference is supported by the reaction of 1,3- This behaviour highlights the important role played by con-
dihydro-2-benzofuran (39), which under identical condi- jugation with the benzene ring in stabilizing the aldehyde
tions underwent the comparable transformations to the di- towards further oxidation to the corresponding carboxylic
aldehyde 40 and the lactone 41 (Scheme 13), the stereo- acid.[5] Such a stabilizing effect had previously been attrib-
chemical problem inhibiting route a being at least partially uted to the formation of a stable adduct between HNO3
removed. The intermediate nitroso ester 42, which would and the carbonyl compound,[30] though this was never ob-
be expected to undergo rapid and quantitative oxidation to served in our reaction mixtures. The presence of an elec-
give phthalaldehyde (40) by path a, was not detected in the tron-withdrawing α-Cl atom in the substrate, as in 2-chloro-
reaction mixture; moreover, no further oxidation of lactone 2-methylpropanol (49), still allowed the formation of the
41 to phthalic anhydride (43) occurred at all, pointing to corresponding aldehyde (50, 9%) but slowed down the
the protecting effect on the benzylic position exerted by the whole process (79% conv. after 1 h, Ͼ 99% after 24 h), thus
ester function.
favouring the competitive and predominant formation of
An attempt was made to extend the application of the large amounts of nitroso (51, 30%) and nitro (52, 40%) es-
oxidation procedure to allylic and to non-benzylic, fully ali- ters of 49, together with some 2-chloro-2-methylpropanoic
phatic substrates, but the obtained results proved quite un- acid (53, 21%). The presence of additional α-positioned Cl
satisfactory. With non-benzylic substrates, the oxidation re- substituents, as in 2,2-dichloropropanol (54) and 2,2,2-
action employing HNO3 in CH2Cl2, though very rapid even trichloroethanol (55), completely inhibited the oxidation,
after the excess of acid is reduced (2.0 mol of HNO3 per causing the exclusive formation of the corresponding nitro
Eur. J. Org. Chem. 2003, 526Ϫ536
531

P. Strazzolini, A. Runcio
FULL PAPER
(50 and 58)[34] in 82% (6.65 g) and 61% (7.85 g) yields, respectively,
by a described procedure.[35] 1,2-Diphenylethanol (4ff, 5.23 g,
88%)[36] was obtained from deoxybenzoin (2ff) in a similar way.[37]
1-(Iodomethyl)-2-nitrobenzene (59),[38] 1-(iodomethyl)-3-nitroben-
zene (60),[39] and 1-(iodomethyl)-4-nitrobenzene (61)[40] were pre-
pared in 88% (5.79 g), 77% (5.06 g), and 78% (5.13 g) isolated
yields, respectively, by simply mixing of solutions of the corres-
ponding chlorides in acetone (18.0 mmol in 4.0 mL) and NaI in
the same solvent (18.0 mmol in 15.0 mL), by a described proced-
ure.[41] The following alkyl and arylalkyl nitrites were prepared by
esters 56 and 57 in a slow reaction (82 and 72% conv. after
24 h at room temperature, respectively).
In conclusion, the oxidation of benzylic alcohols and
ethers to the corresponding carbonyl compounds may be
easily achieved by the use of HNO3 in CH2Cl2, avoiding
further oxidation, aromatic nitration and formation of un-
wanted side products, with some limitations. The reaction,
most probably proceeding by a radical mechanism, failed in
the case of allylic substrates and gave coherent but poor
results with non-benzylic ones. The proposed method is a known general method:[20] hexyl nitrite (11, 3.93 g, 60%),[42]
simple, environmentally friendly and economically conveni-
phenylmethyl nitrite (16, 4.93 g, 72%).[43]
ent, offering interesting chemoselectivity in many instances
and thus representing a valuable alternative to the existing
2,2-Dimethylpropyl Nitrite (46): Yield: 3.50 g (48%); pale yellow li-
quid, b.p. 32 °C/17332 Pa. 1H NMR (200 MHz, CDCl3, 25 °C):
δ ϭ 0.96 (s, 9 H, CH3), 4.47 (s, 2 H, CH2) ppm. 13C NMR
(50 MHz, CDCl3, 25 °C): δ ϭ 26.46 (CH3), 31.91(CMe3), 78.18
(CH2). IR (film): ν˜max ϭ 2963 s, 1653 s, 1609 w, 1370 s, 1018 w,
978 m, 922 m, 796 s, 749 w, 643 m cmϪ1. MS (EI): m/z (%) ϭ 71
(66), 57 (100), 41 (97), 39 (50), 30 (63). C5H11NO2 (117.15): calcd.
C 51.26, H 9.47, N 11.96; found C 51.18, H 9.49, N 11.95.
approaches, on both the laboratory and the industrial scale.
In addition, owing to its operation in organic solvent, with
alcoholic substrates particularly resistant to oxidation it
may represent a convenient, straightforward and simple al-
ternative route to the corresponding nitro esters.
2-Chloro-2-methylpropyl Nitrite (51): Because of the poor stability
of the alcohol 49[32a] the nitroso ester 51 was not prepared, but
its presence in the oxidation reaction mixture was inferred by the
observation in the 1H NMR spectrum of a signal [δ ϭ 4.90 ppm
(s)] attributable to ϪCH2ONO.
Experimental Section
General Remarks: Unless otherwise specified, reagents and solvents
were commercially available (Aldrich Italia, Milano, Italy) and used
as received. Commercial 100% HNO3 (d ϭ 1.51)[24] was purchased
from Hydro Chemicals France (Nanterre, France) and kept at 4 °C
in the dark to avoid decomposition; the acid was freshly distilled
and its titre, averaging ca. 24 , alkalimetrically checked prior to
use. TLC analyses and column chromatography were performed on
silica gel 60 from Merck (Darmstadt, Germany). The courses of all
the described reactions were monitored by TLC when suitable, and
2-Phenylethyl Nitrite (23): Yield: 2.95 g (65%); pale yellow liquid,
1
b.p. 73 °C/1600 Pa. H NMR (200 MHz, CDCl3, 25 °C): δ ϭ 2.99
(t, J ϭ 7.1 Hz, 2 H, PhCH2), 4.87 (t, J ϭ 7.1 Hz, 2 H, ONOCH2),
7.13Ϫ7.36 (m, 5 H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3, 25
°C): δ ϭ 35.53 (PhCH2), 68.71 (ONOCH2), 126.70, 128.56, 128.90,
137.19 ppm. IR (film): ν˜max ϭ 3439 w, 3026 w, 2943 w, 1650 m,
1610 w, 1385 s, 1217 m, 1039 w, 759 s, 700 w cmϪ1. MS (EI): m/z
(%) ϭ 151 (Ͻ 1) [Mϩ], 122 (9), 105 (7), 92 (25), 91 (100), 65 (5).
C8H9NO2 (151.17): calcd. C 63.57, H 6.00, N 9.27; found C 63.45,
H 6.02, N 9.25.
1
by a parallel accurate H NMR quantitative evaluation. Analyses
were performed after simple dilution of the reaction mixture
(0.2 mL) with CDCl3 (0.3 mL); in addition, 0.2 mL of the same
mixture was admixed with CDCl3 (0.5 mL), washed with 10%
aqueous Na2SO4, dried with anhydrous Na2SO4, filtered, suitably
1,1-Dimethylethyl nitrate (47) has been reported in a previous pa-
per.[44] Alkyl and arylalkyl nitrates were prepared by known general
methods.[45] Hexyl nitrate (14, 2.44 g, 83%),[46] phenylmethyl nitrate
(7, 2.33 g, 76%),[47] (2-nitrophenyl)methyl nitrate (8, 3.13 g,
79%),[48] (4-nitrophenyl)methyl nitrate (10, 3.13 g, 79%),[48] and di-
phenylmethyl nitrate (22, 3.85 g, 84%),[47] were prepared by treat-
ment of CH3CN solutions of the appropriate halides (chloride in
the case of 22, bromide for 7, iodide for 14, 8, 9, and 10; 20.0 mmol
in 5.0 mL) with a solution of AgNO3 in the same solvent
(25.0 mmol in 5.0 mL), by a known procedure (Method A).[49]
1
concentrated, and subjected to H NMR analysis. Melting points
were determined in open-ended capillary tubes with a Mettler FP
61 automatic apparatus and are uncorrected. Elemental analyses
were obtained by use of a Carlo Erba CHN/OS 1106 analyser and
found to be satisfactory. IR spectra were recorded with a Nicolet
FTIR Magna 550 spectrophotometer by the KBr technique. Unless
otherwise indicated, 1H and 13C NMR spectra were recorded in
CDCl3 with a Bruker AC 200 spectrometer at 200 and 50 MHz,
respectively (s: singlet, d: doublet, t: triplet, q: quadruplet, m: mul-
tiplet, br: broad, sym: symmetrical). The proton chemical shifts are
reported in ppm on the δ scale relative to TMS as an internal refer-
(3-Nitrophenyl)methyl Nitrate (9): Yield: 2.97 g (75%, Method A);
1
ence (δ ϭ 0.00 ppm); the carbon chemical shifts are reported in yellowish solid, m.p. 44 °C. H NMR (200 MHz, CDCl3, 25 °C):
ppm relative to the centre line of the CDCl3 triplet (δ ϭ 77.00 δ ϭ 5.56 (s, 2 H, CH2), 7.57Ϫ7.71 (m, 1 H, Ar-H), 7.73Ϫ7.85 (m,
ppm) or, when [D6]Me2SO was the solvent, the centre line of the
corresponding septuplet (δ ϭ 39.50 ppm). The coupling constants
1 H, Ar-H), 8.21Ϫ8.33 (m, 2 H, Ar-H) ppm. 13C NMR (50 MHz,
CDCl3, 25 °C): δ ϭ 72.83 (CH2), 123.53, 124.13, 129.96, 134.41,
are given in Hz. MS measurements were carried out with a Fisons 134.57, 148.28 ppm. IR (KBr): ν˜max ϭ 3090 w, 2893 w, 1695 s,
TRIO-2000 apparatus, working in the positive-ion electron impact
mode (70 eV), by direct introduction of the sample into the ion
source and heating from 50 up to 300 °C. The five most intense
peaks and the molecular peak for each individual compound are
reported, with intensity values in parentheses.
1535 s, 1087 s, 987 s, 892 m, 749 w, 714 m, 670 w cmϪ1. MS (EI):
m/z (%) ϭ 198 (7) [Mϩ], 151 (100), 150 (78), 136 (65), 94 (68), 77
(55). C7H6N2O5 (198.13): calcd. C 42.43, H 3.05, N 14.14; found
C 42.36, H 3.05, N 14.11.
2,2-Dimethylpropyl nitrate (25, 9.71 g, 73%),[50] 2-chloro-2-methyl-
propyl nitrate (52, 6.42 g, 38%),[51] 1-phenylethyl nitrate (17,
11.36 g, 68%),[52] 1,2-diphenylethyl nitrate (18, 10.2 g, 42%),[37] and
2-(nitrooxy)-1,2-diphenylethanone (19, 16.45 g, 64%)[53] were pre-
pared by treatment of CH2Cl2 solutions of the corresponding alco-
Synthesis of Intermediates and Substrates: Phenylmethyl 2,2-di-
methylpropanoate (32) was prepared by a reported method.[31] 2-
Chloro-2-methylpropanol (49)[32] and 2,2-dichloropropanol (53)[33]
were prepared by NaBH4 reduction of the corresponding aldehydes
532
Eur. J. Org. Chem. 2003, 526Ϫ536

Oxidation of Benzylic Alcohols and Ethers to Carbonyl Derivatives
FULL PAPER
hols (100.0 mmol in 5.0 mL) with a mixture of HNO3 (200.0 mmol) phenylmethyl bromide),[67] [(cyclopentyloxy)methyl]benzene (1cc,
and H2SO4 (100.0 mmol), by a reported procedure (Method B).[54]
15.14 g, 86% from cyclopentanol and phenylmethyl bromide),[68]
and (1-methoxyethyl)benzene (1ee, 12.92 g, 95% from 1-phenyle-
thanol and Me2SO4).[69]
2,2-Dichloropropyl Nitrate (56): Yield: 11.00 g (63%, Method B);
colourless liquid, b.p. 63 °C/3333 Pa. 1H NMR (200 MHz, CDCl3,
25 °C): δ ϭ 2.17 (s, 3 H, CH3), 4.86 (s, 2 H, CH2) ppm. 13C NMR
(50 MHz, CDCl3, 25 °C): δ ϭ 33.75 (CH3), 78.13 (CH2), 82.98
(CCl2) ppm. IR (film): ν˜max ϭ 2925 m, 1800 m, 1743 w, 1646 s,
1376 s, 1284 m, 1126 w, 856 s, 744 s, 581 w cmϪ1. MS (EI): m/z
(%) ϭ 101 (12), 99 (65), 97 (100), 63 (15), 61 (41). C3H5Cl2NO3
(173.98): calcd. C 20.71, H 2.90, Cl 40.76, N 8.05; found C 20.67,
H 2.91, Cl 40.87, N 8.03.
1-(Methoxymethyl)-3-phenoxybenzene (1q): Yield: 19.69 g (92%,
Method B, from the corresponding alcohol and Me2SO4); colour-
1
less liquid, b.p. 104 °C/8 Pa. H NMR (200 MHz, CDCl3, 25 °C):
δ ϭ 3.36 (s, 3 H, OCH3), 4.41 (s, 2 H, ArCH2), 6.87Ϫ7.13 (m, 6
H, Ar-H), 7.23Ϫ7.38 (m, 3 H, Ar-H) ppm. 13C NMR (50 MHz,
CDCl3, 25 °C): δ ϭ 58.09 (OCH3), 74.15 (OCH2), 117.86, 117.92,
118.84, 122.29, 123.17, 129.62, 129.66, 140.25, 157.07, 157.32 ppm.
IR (film): ν˜max ϭ 3441 w, 2928 w, 2359 m, 1587 w, 1383 s, 1254 w,
1216 m, 1101 w, 760 s, 682 w cmϪ1. MS (EI): m/z (%) ϭ 214 (100)
[Mϩ], 213 (15), 184 (51), 183 (38), 181 (24). C14H14O2 (214.26):
calcd. C 78.48, H 6.59; found C 78.31, H 6.62.
2,2,2-Trichloroethyl Nitrate (57): Yield: 13.77 g (71%, Method B);
colourless liquid, b.p. 80 °C/6666 Pa. 1H NMR (200 MHz, CDCl3,
25 °C): δ ϭ 5.15 (s, 2 H, CH2) ppm. 13C NMR (50 MHz, CDCl3,
25 °C): δ ϭ 79.31 (CH2), 93.10 (CCl3) ppm. IR (film): ν˜max
ϭ
[(2-Phenylethoxy)methyl]benzene (1bb): Yield: 18.23 g (86%,
Method B, from 2-phenylethanol and phenylmethyl bromide); col-
ourless liquid, b.p. 96 °C/13 Pa. 1H NMR (200 MHz, CDCl3, 25
°C): δ ϭ 2.91 (t, J ϭ 7.2 Hz, 2 H, PhCH2), 3.66 (t, J ϭ 7.2 Hz, 2
H, OCH2), 4.49 (s, 2 H, PhCH2O), 7.16Ϫ7.32 (m, 10 H, Ar-H)
ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ ϭ 36.27 (PhCH2),
71.12 (OCH2), 72.81 (PhCH2O), 126.06, 127.39, 127.45, 128.21
(two overlapped signals), 128.81, 138.32, 138.86 ppm. IR (film):
3437 w, 2934 w, 1668 s, 1385 s, 1282 m, 1218 w, 1060 w, 828 m,
759 s, 613 w cmϪ1. MS (EI): m/z (%) ϭ 121 (30), 119 (100), 117
(97), 76 (42), 46 (26). C2H2Cl3NO3 (194.40): calcd. C 12.36, H 1.04,
Cl 54.71, N 7.21; found C 12.32, H 1.04, Cl 54.78, N 7.20.
Benzyl methyl ethers were almost exclusively prepared by the clas-
sical Williamson synthesis, by treatment of an MeOH solution of
the appropriate halide (100.0 mmol in 100 mL) with MeONa in
MeOH (200 mmol in 100 mL), by a described procedure (Method
A).[55] 1-(Methoxymethyl)-3-methylbenzene (1c, 11.02 g, 81% from
the chloride),[56] 1-(1,1-dimethylethyl)-4-(methoxymethyl)benzene
(1e, 14.60 g, 82% from the bromide),[57] 1-chloro-2-(methoxyme-
thyl)benzene (1f, 11.70 g, 75% from the chloride),[58] 1-chloro-3-
(methoxymethyl)benzene (1g, 12.48 g, 80% from the chloride),[58]
1-chloro-4-(methoxymethyl)benzene (1h, 12.17 g, 78% from the
chloride),[59] 1,3-dichloro-4-(methoxymethyl)benzene (1j, 17.57 g,
92% from the chloride),[60] 1-(methoxymethyl)-2-nitrobenzene (1k,
12.53 g, 75% from the iodide),[61] 1-(methoxymethyl)-3-nitroben-
zene (1m, 13.03 g, 78% from the iodide),[62] 1-(methoxymethyl)-4-
nitrobenzene (1n, 12.69 g, 76% from the iodide),[62] and di-
phenylmethyl methyl ether (1hh, 17.62 g, 89% from the chloride)[63]
were prepared by Method A. [(1,1-Dimethylethoxy)methyl]ben-
zene[64] (1dd, 7.22 g, 44%) was prepared in a similar way, from
benzyl bromide and potassium tert-butoxide. The remaining ethers
were prepared by alkylation of the corresponding alcohols by a
known procedure,[65] with minor modifications (Method B, see be-
low).
νmax ϭ 3440 w, 3024 w, 2861 w, 2399 w, 2359 w, 1483 w, 1382 s,
1215 m, 1104 m, 760 s cmϪ1. MS (EI): m/z (%) ϭ 212 (51) [Mϩ],
182 (14), 106 (12), 92 (16), 91 (100). C15H16O (212.29): calcd. C
84.87, H 7.60; found C 84.65, H 7.61.
˜
4-(Hydroxymethyl)phenyl Phenylmethyl Carbonate (4s): Benzyl
chloroformate (6.0 mL, 40.0 mmol) was added dropwise, at 0 °C
and with vigorous stirring, to a solution of (4-hydroxyphenyl)me-
thanol (4.96 g, 40.0 mmol) in NaOH (4 , 10.0 mL, 40.0 mmol),
while the pH was kept between 9 and 11 by careful addition of
NaOH (4 ). After the addition was complete, the reaction mixture
was allowed to reach room temperature, kept overnight whilst stir-
ring, diluted with H2O (100 mL) and extracted with Et2O (3 ϫ
50 mL), and the combined organic phases were washed with 10%
aqueous Na2SO4 (2 ϫ 50 mL), filtered, and concentrated to dry-
ness. The obtained oily residue was purified by column chromato-
graphy (SiO2), affording compound 4s. Yield: 4.33 g (42%); pale
yellow solid, m.p. 56 °C. 1H NMR (200 MHz, CDCl3, 25 °C): δ ϭ
2.35 (t, J ϭ 4.5 Hz, 1 H, OH), 4.57 (d, J ϭ 4.5 Hz, 2 H, ArCH2O),
5.24 (s, 2 H, PhCH2O), 7.08Ϫ7.16 (m, 2 H, Ar-H), 7.26Ϫ7.46 (m,
7 H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ ϭ 64.31
(HOCH2), 70.28 (OCH2), 120.95, 127.92, 128.43, 128.60, 128.68,
General Procedure for the Synthesis of Some Ethers (Method B): A
solution of the selected alcohol in diglyme (100.0 mmol in 15.0 mL)
was added dropwise, over 15 min and underan inert gas, to a previ-
ously heated (55 °C) stirred suspension of NaH (125.0 mmol, 60%
dispersion in mineral oil) in diglyme (70 mL). After the addition
was complete, the obtained mixture was stirred for an additional
30 min at 55 °C. Subsequently, the temperature was raised to 90
°C and a solution of the appropriate amount (135.0 mmol) of the
alkylating agent in diglyme (15.0 mL) was introduced dropwise.
Stirring was continued at 90 °C for 2 h, and the reaction mixture
was then allowed to cool to room temperature, poured into H2O
(250 mL) and extracted with Et2O (3 ϫ 100 mL). The combined
organic phases were dried with anhydrous Na2SO4 and filtered, and
the solvent was evaporated off. The obtained residue was fraction-
134.63, 138.75, 150.29, 153.62 (OCOO) ppm. IR (KBr): ν˜max
ϭ
3310 s (br), 2926 w, 1753 s, 1382 m, 1272 s, 1242 s, 1214 m, 913 w,
698 m, 526 w cmϪ1. MS (EI): m/z (%) ϭ 258 (Ͻ 1) [Mϩ], 214 (4),
92 (9), 91 (100), 77 (4), 65 (8). C15H14O4 (258.27): calcd. C 69.76,
H 5.46; found C 69.68, H 5.47.
4-(Methoxymethyl)benzoic acid (1u)[70] was prepared by a reported
method.[71] The corresponding methyl ester (1v) was obtained by
careful treatment (Ϫ30 °C) of MeOH (100 mL) with SOCl2 (40.0 g,
336.0 mmol), followed by addition at room temperature of acid 1u
(8.3 g, 50.0 mmol), stirring for 4 h at room temperature, solvent
evaporation and distillation of the residue.
ally distilled and the desired product was purified as convenient. Methyl 4-(Methoxymethyl)benzoate (1v): Yield: 7.83 g (87%); col-
The following ethers were prepared by Method B: 1-(methoxyme-
thyl)-4-methylbenzene (1d, 10.88 g, 80% from the corresponding al-
cohol and Me2SO4),[59] 1-methoxy-3-(methoxymethyl)benzene (1p,
12.77 g, 84% from the corresponding alcohol and Me2SO4),[66]
ourless oil, b.p. 109 °C/133 Pa. 1H NMR (200 MHz, CDCl3, 25
°C): δ ϭ 3.40 (s, 3 H, OCH3), 3.90 (s, 3 H, COOCH3), 4.49 (s, 2
H, OCH2), 7.35Ϫ7.43 (m, 2 H, Ar-H), 7.97Ϫ8.06 (m, 2 H, Ar-H)
ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ ϭ 51.86 (ester CH3),
(hexyloxymethyl)benzene (1aa, 10.56 g, 55% from hexanol and 58.21 (OCH3), 73.84 (OCH2), 127.00, 129.20, 129.53, 143.41,
Eur. J. Org. Chem. 2003, 526Ϫ536 533

P. Strazzolini, A. Runcio
FULL PAPER
166.73 (CϭO) ppm. IR (film): ν˜max ϭ 2952 m, 1723 s, 1610 w, 5.28 (s, 2 H, PhCH2O), 7.31Ϫ7.48 (m, 7 H, Ar-H), 7.86Ϫ7.94 (m,
1434 m, 1416 w, 1382 s, 1278 s, 1108 s, 966 w, 757 m cmϪ1. MS (EI): 2 H, Ar-H), 9.97 (s, 1 H, CHO) ppm. 13C NMR (50 MHz, CDCl3,
m/z (%) ϭ 180 (19) [Mϩ], 165 (91), 149 (88), 133 (75), 121 (100), 25 °C): δ ϭ 70.67 (PhCH2O), 121.62, 128.53, 128.69, 128.87,
89 (44). C10H12O3 (180.20): calcd. C 66.65, H 6.71; found C 66.60,
H 6.71.
131.17, 134.04, 134.34, 152.69, 155.42 (OCOO), 190.68 (CHO)
ppm. IR (KBr): ν˜max ϭ 3066 w, 2855 w, 1754 s, 1700 m, 1272 s,
1218 s, 962 w, 860 m, 739 m, 700 w cmϪ1. MS (EI): m/z (%) ϭ 256
(Ͻ 1) [Mϩ], 92 (10), 91 (100), 89 (2), 77 (3), 65 (6). C15H14O4
(256.26): calcd. C 70.31, H 4.72; found C 70.11, H 4.74.
The 1,1-dimethylethyl ester 1w was obtained by treatment of a solu-
tion of the corresponding acid 1u in CH2Cl2 (1.66 g, 10.0 mmol in
25 mL) with an excess of liquid 2-methylpropene (ca. 20 mL), fol-
lowed by addition of a catalytic amount of H2SO4 (0.3 mL) and
stirring of the mixture at room temperature for 24 h. After evapora-
tion of the solvent, dissolution of the residue in Et2O (50 mL),
washing with 5% aqueous NaHCO3 (20.0 mL), drying with
Na2SO4, filtration and concentration to dryness, the oily residue
was chromatographed on SiO2 to afford pure 1w.
Reaction between 3,4-Dihydro-1H-isochromene (34) and HNO3 in
CH2Cl2: A solution of 3,4-dihydro-1H-isochromene (34, 3.35 g,
25.0 mmol) in CH2Cl2 (5.0 mL) was treated as described in the gen-
eral oxidation procedure (Ͼ 99% conv. after 1 h), affording 3,4-
dihydro-1H-isochromen-1-one (35)[78] in 81% (3.00 g) isolated
yield.
1,1-Dimethylethyl 4-(Methoxymethyl)benzoate (1w): Yield: 1.58 g
(71%); colourless oil, b.p. 65 °C/106 Pa (extensive decomposition).
1H NMR (200 MHz, CDCl3, 25 °C): δ ϭ 1.59 [s, 9 H, C(CH3)3],
3.39 (s, 3 H, OCH3), 4.50 (s, 2 H, OCH2), 7.33Ϫ7.41 (m, 2 H, Ar-
H), 7.93Ϫ8.01 (m, 2 H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3,
25 °C): δ ϭ 28.10 (ester CH3), 58.17 (OCH3), 73.97 (OCH2), 80.81
(CMe3), 126.95, 129.43, 131.17, 142.85, 165.51 (CϭO) ppm. IR
(film): ν˜max ϭ 2979 s, 1711 s, 1616 w, 1460 w, 1293 s, 1165 m,
1112 s, 1020 w, 851 m, 760 m cmϪ1. MS (EI): m/z (%) ϭ 222 (2)
[Mϩ], 167 (100), 149 (88), 133 (39), 121 (38), 57 (32). C13H18O3
(222.28): calcd. C 70.25, H 8.16; found C 70.41, H 8.18.
Reaction between 1,3-Dihydro-2-benzofuran (39) and HNO3 in
CH2Cl2:
A solution of 1,3-dihydro-2-benzofuran (39, 3.00 g,
25.0 mmol) in CH2Cl2 (5.0 mL) was treated as described in the gen-
eral oxidation procedure. After 1 h at room temperature, a quantit-
ative conversion was observed and the reaction mixture was found
to contain (1H NMR analysis) phthalaldehyde (40, 61%) and 2-
benzofuran-1(3H)-one (41, 39%).
Competitive Oxidation of Phenylmethanol (4a) and (Methoxyme-
thyl)benzene (1a):
75.0 mmol) in CH2Cl2 (5.0 mL) was added dropwise, at 0 °C and
with stirring, to solution of phenylmethanol (4a, 2.70 g,
A solution of HNO3 (d ϭ 1.51, 4.73 g,
a
[4-(Methoxymethyl)phenyl]methanol[72] (4t, 5.72 g, 94%) was pre-
pared by reduction of methyl ester 1v (40.0 mmol) with LiAlH4
(40 mmol) in Et2O (80.0 mL). 1-(Chloromethyl)-4-(methoxymethyl)-
benzene[73] (1x, 1.51 g, 89%) was prepared by treatment of the alco-
hol 4t (10.0 mmol) with SOCl2 (11 mmol) in CH2Cl2 (10.0 mL). 4-
(Methoxymethyl)benzyl acetate[72] (1y, 1.63 g, 84%) was obtained
by direct acetylation of alcohol 4t (10.0 mmol) with excess Ac2O
(106 mmol).
25.0 mmol) and (methoxymethyl)benzene (1a, 3.05 g, 25.0 mmol)
in CH2Cl2 (5.0 mL). After the addition was complete, the homo-
geneous reaction mixture was allowed to reach room temperature
and stirring was continued for 1 h. After this time, the reaction
mixture (0.2 mL) was diluted with CDCl3 (0.3 mL), washed with
10% aqueous Na2SO4 (0.5 mL), dried with Na2SO4, and concen-
trated to dryness, and the residue was dissolved in CDCl3 and sub-
jected to 1H and 13C NMR analysis. Complete conversion of the
alcohol 4a into the corresponding aldehyde 2a was observed,
whereas the ether 1a was found essentially unchanged in the reac-
tion mixture.
General Procedure for the Oxidation of Benzylic Alcohols and Ethers
to the Corresponding Carbonyl Compounds: A solution of HNO3
(d ϭ 1.51, 4.73 g, 75.0 mmol) in CH2Cl2 (5.0 mL) was added drop-
wise, at 0 °C and with stirring, to a solution of the selected sub-
strate (25.0 mmol) in CH2Cl2 (5.0 mL). After the addition was
complete, the homogeneous reaction mixture was allowed to reach
room temperature and stirring was continued for 1 h or, when
necessary, prolonged to 24 h. Evolution of brown fumes of nitrogen
oxides was observed in association with the beginning of the oxida-
tion reaction, after variable induction times: in some cases efficient
chilling of the mixture was required to control the reaction. In or-
der to monitor the composition of reaction mixtures, aliquots
(0.2 mL) were withdrawn at suitable times, diluted with CDCl3
(0.3 mL) and subjected to 1H and 13C NMR analysis. The analyses
were also repeated after the sample solution had been washed with
aqueous Na2SO4 (10%, 0.5 mL) and dried with Na2SO4, the solvent
had been carefully evaporated, and the residue had been taken up
in CDCl3. After the completion of the oxidation, the reaction mix-
ture was diluted with CH2Cl2 (50.0 mL), washed with 10% aqueous
Na2SO4 (2 ϫ 30.0 mL), dried with Na2SO4, filtered, and concen-
trated to dryness. When suitable, the obtained reaction products
were conveniently isolated by standard techniques (Table 2): 4-(me-
thoxymethyl)benzaldehyde (2t, 2.96 g, 79%),[74] methyl 4-formyl-
benzoate (2v, 3.53 g, 86%),[75] 4-(chloromethyl)benzaldehyde (2x,
3.50 g, 91%),[76] and 4-[(acetyloxy)methyl)]benzaldehyde (2y,
3.56 g, 80%).[77]
Reaction between Phenylmethyl Nitrate (7) and HNO3 in CH2Cl2:
A solution of HNO3 (d ϭ 1.51, 4.73 g, 75.0 mmol) in CH2Cl2
(5.0 mL) was added dropwise, at 0 °C and with stirring, to a solu-
tion of phenylmethyl nitrate (7, 3.83 g, 25.0 mmol) in CH2Cl2
(5.0 mL) and the resulted homogeneous reaction mixture was
stirred at room temperature and analysed by NMR in the usual
way. After 1 h, the observed degree of conversion was 64% and the
reaction mixture consisted of an isomeric mixture of (nitro-
phenyl)methyl nitrates (8, 9, and 10, 59%), accompanied by traces
(5%) of benzaldehyde (2a). The experiment was repeated with an
equivalent amount of TFA in place of HNO3; no reaction was evid-
ent after 1 h at room temperature; after 24 h, only 15% conversion
into 2a was observed.
Reaction between (4-Nitrophenyl)methyl Nitrate (10) and HNO3 in
CH2Cl2: The title compound was recovered unchanged after 24 h
of treatment with HNO3 under the usual conditions.
Reaction between Phenylmethyl Nitrite (16) and HNO3 in CH2Cl2:
The title compound was quantitatively converted into aldehyde 2a
(NMR analysis) after 1 h of treatment with HNO3 under the
usual conditions.
Reaction between 1,1-Dimethylethyl Nitrite (26) and HNO3 in
4-Formylphenyl Phenylmethyl Carbonate (2s): Yield: 6.02 g (94%);
CH2Cl2: Compound 26 (0.515 g, 5.0 mmol), when exposed to the
yellow solid, m.p. 54 °C. 1H NMR (200 MHz, CDCl3, 25 °C): δ ϭ oxidative treatment according to the general procedure, underwent
534
Eur. J. Org. Chem. 2003, 526Ϫ536

Oxidation of Benzylic Alcohols and Ethers to Carbonyl Derivatives
FULL PAPER
Weyl), 4th ed., G. Thieme Verlag, Stuttgart, 1981, vol. IV/1a,
(Oxidation), pp. 703Ϫ704.
only 33% conversion into the corresponding nitrate ester 25 after
1 h at room temperature (NMR analysis).
[6]
S. R. Hartshorn, R. B. Moodie, K. Schofield, J. Chem. Soc. B
1971, 2454Ϫ2461 and references cited therein.
Reaction between Phenylmethyl Chloride (28) and HNO3 in CH2Cl2:
A solution of HNO3 (d ϭ 1.51, 4.73 g, 75.0 mmol) in CH2Cl2
(5.0 mL) was added dropwise, at 0 °C and with stirring, to a solu-
tion of phenylmethyl chloride (28, 3.17 g, 25.0 mmol) in CH2Cl2
(5.0 mL) and the resulted homogeneous reaction mixture was
stirred at room temperature and analysed by NMR in the usual
way. After 1 h, the observed degree of conversion was 92% and the
only products detected in the reaction mixture were an isomeric
mixture of (nitrophenyl)methyl chlorides (29); no trace of aldehyde
2a was present.
[7] [7a]
O. Bayer, Methoden der Organischen Chemie (Houben-
Weyl), 4th ed., G. Thieme Verlag, Stuttgart, 1954, vol. VII/1
(Aldehyde), pp. 159Ϫ193. [7b] K.-D. Bode, D. Dieterich, B. Eis-
tert, R. Gipp, H. Henecka, H. Herlinger, R. Jira, D. Kramer,
H.-J. Kabbe, A. Lüttringhaus, M. Regitz, C.-W. Schellhammer,
H. Söll, H. Stetter, H. Wilms, F. Wingler, Methoden der Or-
ganischen Chemie (Houben-Weyl), 4th ed., G. Thieme Verlag,
[7c]
Stuttgart, 1973, vol. VII/2a (Ketone), pp. 699Ϫ777.
J.
Bracht, W. Friedrichsen, K. Krohn, H. Kropf, M. Maher-
Detweiler, P. Margaretha, P. Messinger, G. Ohloff, E. Schaum-
ann, Methoden der Organischen Chemie (Houben-Weyl), 4rth
Reaction between Phenylmethyl Acetate (30) and HNO3 in CH2Cl2:
A solution of HNO3 (d ϭ 1.51, 4.73 g, 75.0 mmol) in CH2Cl2
(5.0 mL) was added dropwise, at 0 °C and with stirring, to a solu-
tion of phenylmethyl acetate (31, 3.75 g, 25.0 mmol) in CH2Cl2
(5.0 mL) and the resulted homogeneous reaction mixture was
stirred at room temperature and analysed by NMR in the usual
way. After 1 h, the observed degree of conversion was 26%, exclus-
ively affording an isomeric mixture of (nitrophenyl)methyl acetates
(31); no oxidation took place.
ed., G. Thieme Verlag, Stuttgart, 1984, vol. VI/1b (Alkohole
[7d]
III), pp. 878Ϫ896.
A. H. Haines, Best Synthetic Methods.
Methods for the Oxidation of Organic Compounds (Alcohols,
Alcohols Derivatives), Academic Press, London, UK, 1988, pp.
5Ϫ238. [7e] M. Hudlicky, Oxidations in Organic Chemistry, ACS
Monograph 186, American Chemical Society, Washington,
[7f]
DC, USA, 1990, pp. 114Ϫ150.
M. B. Smith, J. March,
March’s Advanced Organic Chemistry. Reactions, Mechanisms
and Structure, 5th ed., John Wiley & Sons, Inc., Chichester,
[7g]
UK, 2001, pp. 1514Ϫ1517.
R. C. Larock, Comprehensive
Organic Transformations. A Guide to Functional Group Prepara-
tion, 2nd ed., Wiley-VCH, Chichester, UK, 1999, pp.
1230Ϫ1250.
P. Strazzolini, A. G. Giumanini, A. Runcio, Tetrahedron Lett.
2001, 42, 1387Ϫ1389.
Reaction between Phenylmethyl 2,2-Dimethylpropanoate (32) and
HNO3 in CH2Cl2: Ester 32 (4.80 g, 25.0 mmol) was treated as
above, undergoing exclusive ring nitration to give the three isomers
33 (12% conv. after 1 h, 33% conv. after 24 h); no oxidation was ob-
served.
[8]
[9]
O. Buddenberg, Methoden der Organischen Chemie (Houben-
Weyl), 4th ed., G. Thieme Verlag, Stuttgart, 1981, vol. IV/1a
(Oxidation), pp. 678Ϫ680.
General Procedure for the Oxidation of Non-Benzylic Alcohols and
Ethers: A solution of HNO3 (d ϭ 1.51, 3.15 g, 50.0 mmol) in
CH2Cl2 (5.0 mL) was added dropwise, at 0 °C and with stirring, to
a solution of the selected substrate (25.0 mmol) in CH2Cl2
(5.0 mL). After the addition was complete, the homogeneous reac-
tion mixture was allowed to reach room temperature and stirring
was continued for 1 h or, when necessary, prolonged for 24 h. In
order to monitor the composition of reaction mixtures, aliquots
(0.2 mL) were withdrawn at suitable times, diluted with CDCl3
(0.3 mL) and subjected to 1H and 13C NMR analysis. The analyses
were also repeated after the diluted sample solution had been
washed with 10% aqueous Na2SO4 (0.5 mL) and dried with
Na2SO4, the solvent had been evaporated and the residue had been
taken up in CDCl3. After the completion of the reaction, the re-
sulting mixture was diluted with CH2Cl2 (50.0 mL), washed with
10% aqueous Na2SO4 (2 ϫ 30.0 mL), dried with Na2SO4, filtered,
and concentrated to dryness. When suitable, the obtained reaction
products were conveniently isolated by fractional distillation.
[10] [10a]
O. Bayer, Methoden der Organischen Chemie (Houben-
Weyl), 4th ed., G. Thieme Verlag, Stuttgart, 1954, vol. VII/1
[10b]
(Aldehyde), pp. 181Ϫ182.
O. Buddenberg, Methoden der
Organischen Chemie (Houben-Weyl), 4th ed., G. Thieme Ver-
lag, Stuttgart, 1981, vol. IV/1a (Oxidation), p. 652.
S. R. Joshi, S. B. Sawant, J. B. Joshi, Org. Process Res. Dev.
2001, 5, 152Ϫ157.
A. H. Haines, Best Synthetic Methods. Methods for the Oxida-
tion of Organic Compounds (Alcohols, Alcohols Derivatives),
Academic Press, London, UK, 1988, p. 184.
J. W. Baker, A. J. Neale, J. Chem. Soc. 1955, 608Ϫ615.
S. D. Ross, E. R. Coburn, M. Finkelstein, J. Org. Chem. 1968,
33, 585Ϫ587.
[11]
[12]
[13]
[14]
[15]
J. W. Baker, T. G. Heggs, J. Chem. Soc. 1955, 616Ϫ630.
[16] [16a] P. Gray, A. D. Yoffe, Chem. Rev. 1955, 55, 1069Ϫ1154. [16b]
P. Gray, A. D. Yoffe, Quart. Rev. (London) 1955, 9, 362Ϫ390.
[16c]
O. Buddenberg, Methoden der Organischen Chemie
(Houben-Weyl), 4th ed., G. Thieme Verlag, Stuttgart, 1981,
vol. IV/1a (Oxidation), p. 651.
H. Suzuki, T. Takeuchi, T. Mori, Bull. Chem. Soc. Jpn. 1997,
70, 3111Ϫ3115.
A. McKillop, M. E. Ford, Synth. Commun. 1972, 2, 307Ϫ313.
E. Iglesias, L. Garcia-Rio, J. R. Leis, M. E. Pena, D. L. H.
[17]
[18]
Acknowledgments
[19]
This work was supported in part by research grants to P. S. from
the University of Udine (FURD, 1999Ϫ2000), Udine, Italy. We are
indebted to Prof. G. Verardo for MS data collection and to Dr. P.
Martinuzzi for recording the NMR spectra.
Williams, J. Chem. Soc., Perkin Trans. 2 1992, 1673Ϫ1679.
[20]
W. A. Noyes, in: Organic Syntheses, Collective Vol. 2, John
Wiley & Sons, Inc., New York, 1943, pp. 108Ϫ109.
[21]
I. Sakai, N. Kawabe, M. Ohno, Bull. Chem. Soc. Jpn. 1979,
52, 3381Ϫ3383.
[22]
S. A. Stern, J. T. Mullhaupt, W. B. Kay, Chem. Rev. 1960, 60,
185Ϫ207.
L. Eberson, Electron Transfer Reactions in Organic Chemistry,
[1]
P. Strazzolini, A. G. Giumanini, A. Runcio, M. Scuccato, J.
[23]
Org. Chem. 1998, 63, 952Ϫ958.
[2]
P. Strazzolini, T. Melloni, A. G. Giumanini, Tetrahedron 2001,
Springer-Verlag, Heidelberg, 1987, p. 91.
[24] [24a]
57, 9033Ϫ9043.
Y. Ogata, Y. Sawaki, J. Am. Chem. Soc. 1966, 88,
[3] [3a]
[24b]
P. Strazzolini, M. G. Dall’Arche, A. G. Giumanini, Tetra-
5832Ϫ5837.
54, 1531Ϫ1535.
Chem. 1990, 55, 5606Ϫ5609.
J. Chem. Soc., Chem. Commun. 1990, 1607Ϫ1608.
K.-D. Bode D. Dieterich, B. Eistert, R. Gipp, H. Henecka, H.
T. Nishiguchi, F. Asano, J. Org. Chem. 1989,
[3b]
[24c]
hedron Lett. 1998, 39, 9255Ϫ9258.
P. Strazzolini, M. Scuc-
T. Nishiguchi, M. Bougauchi, J. Org.
[24d]
cato, A. G. Giumanini, Tetrahedron 2000, 56, 3625Ϫ3633.
D. G. Markees, Helv. Chim. Acta 1973, 56, 1382Ϫ1384.
O. Buddenberg, Methoden der Organischen Chemie (Houben-
T. Nishiguchi, H. Okamoto,
[4]
[5]
[25]
Eur. J. Org. Chem. 2003, 526Ϫ536
535

P. Strazzolini, A. Runcio
FULL PAPER
[49]
[50]
Herlinger, R. Jira, D. Kramer, H.-J. Kabbe, A. Lüttringhaus,
M. Regitz, C.-W. Schellhammer, H. Söll, H. Stetter, H. Wilms,
F. Wingler, Methoden der Organischen Chemie (Houben-Weyl),
4th ed., G. Thieme Verlag, Stuttgart, 1973, vol. VII/2a (Ke-
tone), p. 765.
A. F. Ferris, K. W. McLean, I. G. Marks, W. D. Emmons, J.
Am. Chem. Soc. 1953, 75, 4078.
G. B. Bachman, N. W. Connon, J. Org. Chem. 1969, 34,
4121Ϫ4125.
L. Henry, C. R. Acad. Sci. 1906, 142, 493Ϫ497.
R. J. Lewis, R. B. Moodie, J. Chem. Soc., Perkin Trans. 2
1997, 563Ϫ567.
A. McKillop, B. P. Swann, M. E. Ford, E. C. Taylor, J. Am.
Chem. Soc. 1973, 95, 3641Ϫ3645.
S. M. Tsang, A. P. Paul, M. P. DiGiaimo, J. Org. Chem. 1964,
29, 3387Ϫ3390.
N. C. Deno, N. H. Potter, J. Am. Chem. Soc. 1967, 89,
3550Ϫ3554.
B. Ortiz, F. Walls, F. Yuste, H. Barrios, R. Sanchez-Obregon,
L. Pinelo, Synth. Commun. 1993, 23, 749Ϫ756.
S. Torii, T. Inokuchi, S. Takagishi, H. Horike, H. Kuroda, K.
Uneyama, Bull. Chem. Soc. Jpn. 1987, 60, 2173Ϫ2188.
B. Halton, C. J. Randall, G. J. Gainsford, W. T. Robinson, Aust.
J. Chem. 1987, 40, 475Ϫ489.
[51]
[52]
[26] [26a]
O. Bayer, Methoden der Organischen Chemie (Houben-
Weyl), 4th ed., G. Thieme Verlag, Stuttgart, 1954, vol. VII/1
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[26b]
(Aldehyde), p. 194.
O. Buddenberg, Methoden der Or-
ganischen Chemie (Houben-Weyl), 4th ed., G. Thieme Verlag,
Stuttgart, 1981, vol. IV/1a (Oxidation), pp. 672Ϫ673.
O. Bayer, Methoden der Organischen Chemie (Houben-Weyl),
4th ed., G. Thieme Verlag, Stuttgart, 1954, vol. VII/1 (Alde-
hyde), p. 181.
K.-D. Bode, D. Dieterich, B. Eistert, R. Gipp, H. Henecka, H.
Herlinger, R. Jira, D. Kramer, H.-J. Kabbe, A. Lüttringhaus,
M. Regitz, C.-W. Schellhammer, H. Söll, H. Stetter, H. Wilms,
F. Wingler, Methoden der Organischen Chemie (Houben-Weyl),
4th ed., G. Thieme Verlag, Stuttgart, 1973, vol. VII/2a (Ke-
tone), p. 763.
D. G. Kundiger, G. F. Morris, J. Am. Chem. Soc. 1958, 80,
5988Ϫ5990.
O. Bayer, Methoden der Organischen Chemie (Houben-Weyl),
4th ed., G. Thieme Verlag, Stuttgart, 1954, vol. VII/1 (Alde-
hyde), p. 180.
[27]
[28]
C. Imrie, T. A. Modro, E. R. Rohwer, C. C. P. Wagener, J. Org.
Chem. 1993, 58, 5643Ϫ5649.
[29]
[30]
D. V. Carter, P. T. Charlton, A. H. Fenton, J. R. Housley, B.
Lessel, J. Pharm. Pharmacol. 1958, 10, suppl. 149TϪ159T.
B. Wladislaw, A. Giora, J. Chem. Soc. 1964, 1037Ϫ1040.
P. Wan, S. Muralidharan, I. McAuley, C. A. Babbage, Can. J.
Chem. 1987, 65, 1775Ϫ1783.
[61]
[62]
[31]
J. W. Hilborn, E. MacKnight, J. A. Pincock, P. J. Wedge, J.
Am. Chem. Soc. 1994, 116, 3337Ϫ3346.
[63] [63a]
H. Ishikawa, T. Mukaiyama, S. Ikeda, Bull. Chem. Soc.
[63b]
[32] [32a]
Jpn. 1981, 54, 776Ϫ780.
R. Popielarz, D. R. Arnold, J.
E. L. Eliel, C. Herrmann, J. T. Traxler, J. Am. Chem. Soc.
[32b]
Am. Chem. Soc. 1990, 112, 3068Ϫ3082.
N. Hartz, G. K. Surya Prakash, G. A. Olah, Synlett 1992,
569Ϫ572.
K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa, O. Yonemitsu,
Tetrahedron 1986, 42, 3021Ϫ3028.
H. Tomioka, K. Tabayashi, Y. Ozaki, Y. Izawa, Tetrahedron
1985, 41, 1435Ϫ1440.
B. H. Lipshutz, D. Parker, J. A. Kozlowski, J. Org. Chem. 1983,
48, 3334Ϫ3336.
M. Ochiai, T. Ito, H. Takahashi, A. Nakanishi, M. Toyonari,
T. Sueda, S. Goto, M. Shiro, J. Am. Chem. Soc. 1996, 118,
7716Ϫ7730.
E. C. Brown, J. T. Kurek, M.-H. Rei, K. L. Thompson, J. Org.
Chem. 1984, 49, 2551Ϫ2557.
T.-X. Xiang, B. D. Anderson, J. Pharm. Sci. 1994, 83,
1511Ϫ1518.
O. Exner, J. Jonas, Collect. Czech. Chem. Commun. 1962, 27,
2296Ϫ2306.
T.-A. Kobayashi, M. Tanaka, J. Mol. Catal. 1988, 47, 41Ϫ49.
T.-A. Kobayashi, F. Abe, M. Tanaka, J. Mol. Catal. 1988, 45,
91Ϫ109.
M. Eikawa, S. Sakaguchi, Y. Ishii, J. Org. Chem. 1999, 64,
4676Ϫ4679.
S. K. Sharma, M. Tandon, J. W. Lown, Eur. J. Org. Chem.
2000, 2095Ϫ2103.
M. E. Pierce, G. D. Harris, Q. Islam, L. A. Radesca, L. Storace,
R. E. Waltermire, E. Wat, P. K. Jadhav, G. C. Emmet, J. Org.
Chem. 1996, 61, 444Ϫ450.
1956, 78, 1193Ϫ1198.
E. L. Eliel, T. J. Prosser, J. Am.
[64]
[65]
[66]
[67]
[68]
Chem. Soc. 1956, 78, 4045Ϫ4049.
[33]
[34]
C. R. Dick, J. Org. Chem. 1962, 27, 272Ϫ274.
F. Bellesia, L. De Buyck, F. Ghelfi, E. Libertini, U. M. Pag-
noni, F. Roncaglia, Tetrahedron 2000, 56, 7507Ϫ7511.
A. Salgado, T. Huybrechts, L. De Buyck, J. Czombos, A. Tka-
chev, N. De Kimpe, Synth. Commun. 1999, 29, 57Ϫ63.
K. Itami, T. Kamei, J. Yoshida, J. Am. Chem. Soc. 2001, 123,
8773Ϫ8779.
C. J. Easton, A. J. Ivory, C. A. Smith, J. Chem. Soc., Perkin
Trans. 2 1997, 503Ϫ507.
M. A. Smith, B. Weinstein, F. D. Greene, J. Org. Chem. 1980,
45, 4597Ϫ4602.
J. M. Aizpurua, B. Lecea, C. Palomo, Can. J. Chem. 1986,
64, 2342Ϫ2347.
T. Imamoto, T. Matsumoto, T. Kusumoto, M. Yokoyama, Syn-
thesis 1983, 460Ϫ461.
J. H. Clark, J. M. Miller, K.-H. So, J. Chem. Soc., Perkin Trans.
1 1978, 941Ϫ946.
S. Oae, Y. H. Kim, D. Fukushima, K. Shinhama, J. Chem.
Soc., Perkin Trans. 1 1978, 913Ϫ917.
R. G. Gillis, J. Org. Chem. 1956, 21, 805Ϫ808.
P. Strazzolini, M. G. Dall’Arche, A. G. Giumanini, Tetrahedron
Lett. 1998, 39, 9255Ϫ9258.
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[43]
[44]
[45]
[46]
[47]
[48]
R. Boschan, R. T. Merrow, R. W. Van Dolah, Chem. Rev. 1955,
55, 485Ϫ510.
G. A. Olah, Q. Wang, X. Li, G. K. Surya Prakash, Synthesis
1993, 207Ϫ208.
P. Fr øyen, Phosphorus, Sulfur, Silicon Relat. Elem. 1997, 129,
[77]
[78]
C. Gennari, S. Ceccarelli, U. Piarulli, K. Aboutayab, M.
Donghi, I. Paterson, Tetrahedron 1998, 54, 14999Ϫ15016.
N. A. Noureldin, D. Zhao, D. G. Lee, J. Org. Chem. 1997,
62, 8767Ϫ8772.
89Ϫ97.
H. Suzuki, T. Murashima, I. Kozai, T. Mori, J. Chem. Soc.,
Perkin Trans. 1 1993, 1591Ϫ1597.
Received July 26, 2002
[O02428]
536
Eur. J. Org. Chem. 2003, 526Ϫ536