Catalytic and chemoselective oxidation of activated alcohols and direct conversion of diols to lactones with in situ-generated bis-IBX catalyst

Article abstract of DOI:10.1002/ejoc.201201699

The twisted 3,3′-diiodo-2,2′,6,6′-tetramethoxybiphenyl-4, 4′-dicarboxylic acid (DIDA) was designed and synthesized for the in situ generation of Bis-IBX and catalytic oxidations. The seemingly better solubility of the in situ-generated Bis-IBX and the attenuated reactivity arising from its unique structural features and methoxy substituents allowed the catalytic oxidation of activated alcohols selectively using DIDA/oxone. Chemoselective oxidations were demonstrated for substrates containing two different hydroxy groups. Furthermore, the unique reactivity of DIDA was demonstrated for sequential oxidation reactions of 1,4- and 1,6-diols to give lactones catalytically in respectable yields.

Full text of DOI:10.1002/ejoc.201201699

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DOI: 10.1002/ejoc.201201699
Catalytic and Chemoselective Oxidation of Activated Alcohols and Direct
Conversion of Diols to Lactones with In Situ-Generated Bis-IBX Catalyst
Saona Seth,[a] Samik Jhulki,[a] and Jarugu Narasimha Moorthy*[a]
Dedicated to Professor Mariappan Periasamy (University of Hyderabad) on the occasion of his 60th birthday
Keywords: Hypervalent compounds / Oxidation / Alcohols / Lactones / Chemoselectivity / Homogeneous catalysis
The twisted 3,3Ј-diiodo-2,2Ј,6,6Ј-tetramethoxybiphenyl-4,4Ј-
oxidation of activated alcohols selectively using DIDA/
dicarboxylic acid (DIDA) was designed and synthesized for oxone. Chemoselective oxidations were demonstrated for
the in situ generation of Bis-IBX and catalytic oxidations. The
seemingly better solubility of the in situ-generated Bis-IBX
and the attenuated reactivity arising from its unique struc-
tural features and methoxy substituents allowed the catalytic
substrates containing two different hydroxy groups. Further-
more, the unique reactivity of DIDA was demonstrated for
sequential oxidation reactions of 1,4- and 1,6-diols to give
lactones catalytically in respectable yields.
the remarkable reactivity of o-iodoxybenzenesulfonic acid
(IBS, Scheme 1), generated in situ from o-iodobenzene-
sulfonic acid and oxone.[5d] Recently, we showed that
TetMe-IBX (Scheme 1), generated in situ from its precursor
tetramethyl-o-iodobenzoic acid, is a good reagent for the
oxidation of a variety of primary and secondary aliphatic
and benzylic alcohols.[5e] The non-planarity introduced into
the structure by a steric relay between four consecutive
methyl groups results in an enhancement of the reactivity
and solubility of this reagent over IBX. In a continuation
of these investigations, we surmised that o-iodobenzoic ac-
ids that lead, upon oxidation with oxone, to pentavalent
iodanes with enhanced solubility and attenuated reactivity
should be appealing from the point of view of achieving
chemoselectivity in oxidations.[4b] In particular, we envis-
aged that the oxidation of activated benzylic alcohols in the
presence of aliphatic alcohols could possibly be ac-
complished catalytically. We thus designed tetramethoxy-
substituted bis-iodoxybenzoic acid (Scheme 1), referred to
as Bis-IBX for convenience, as a modified IBX derivative,
whose precursor, i.e., 3,3Ј-diiodo-2,2Ј,6,6Ј-tetramethoxybi-
phenyl-4,4Ј-dicarboxylic acid (DIDA), could be used cata-
lytically in the oxidations. The rationale behind the design
of Bis-IBX are as follows: i) the methoxy groups at the ortho
positions render the two aryl rings orthogonal; in general,
the molecular systems characterized by orthogonal planes
lead to packing difficulties in the solid state such that one
may expect better solubility; ii) the four methoxy groups
may aid solubility in common organic solvents; and
iii) while the electron-rich methoxy groups in each of the
iodobenzene rings may promote oxidation in the presence
of oxone for ready generation of IV species, they decelerate
Introduction
Over the past decade or so, o-iodoxybenzoic acid (IBX)
has emerged as a very powerful oxidation reagent.[1] Aside
from advantages such as its low cost and ready availability,
environmentally-benign characteristics, non-toxicity, etc., a
myriad of facile transformations that continue to be re-
ported render this reagent virtually indispensable in con-
temporary organic oxidation chemistry.[1] Unfortunately,
IBX is explosive[2] and highly insoluble in common organic
solvents, so that solvents such as DMSO are normally used
for oxidations using this reagent.[3] Considerable efforts
have been directed towards devising modified reagents that
would overcome these serious drawbacks.[4] The develop-
ment of catalytic oxidation protocols using precursor iodo-
acids that allow the in situ generation of hypervalent IV
species in the presence of a terminal oxidant such as oxone
is a new dimension to the oxidation chemistry based on
IBX.[5]
It was Vinod et al. who first developed a catalytic proto-
col for the oxidation of alcohols using the oxidant-precur-
sor, o-iodobenzoic acid, as a catalyst (30 mol-%) in the pres-
ence of oxone in a water/acetonitrile biphasic mixture.[5a]
Giannis et al. subsequently reported similar catalytic
oxidations with o-iodobenzoic acid in water/EtOAc mix-
tures.[5b] These studies highlight the possibility of avoiding
the isolation of explosive IBX. Ishihara et al. demonstrated
[a] Department of Chemistry, Indian Institute of Technology,
Kanpur 208016, India
E-mail: moorthy@iitk.ac.in;
Homepage: http://home.iitk.ac.in/~moorthy/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201699
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FULL PAPER
the rate of oxidation of alcohols, as is evident from mechan-
istic studies.[4,5] This latter point is an important criterion
for chemoselective oxidations. In this paper, we show that
the precursor of Bis-IBX, i.e., DIDA, can indeed be used
catalytically in the presence of oxone for the oxidation of
primary alcohols either to the corresponding aldehydes or
to the acids, and of secondary alcohols to ketones. Capi-
talizing on the ability of the in situ generated hypervalent
iodine species to oxidize only activated alcohols, i.e., benz-
ylic alcohols, we demonstrate chemoselective oxidation at
the benzylic site for substrates containing two hydroxy func-
tionalities. Furthermore, we show that DIDA uniquely
brings about the conversion of 1,4- and 1,6-diols into the
corresponding lactones by two consecutive oxidation reac-
tions.
Scheme 2. Synthetic route to 3,3Ј-diiodo-2,2Ј,6,6Ј-tetramethoxybi-
phenyl-4,4Ј-dicarboxylic acid (DIDA).
(2 equiv.) (Table 1). The solvents tested included tert-buta-
nol, ethyl acetate, ethyl formate, acetonitrile, acetonitrile/
water, DMF, nitromethane, etc., and the catalyst loading
was between 1 and 5 mol-%. The reaction conditions in-
volving acetonitrile/water (1:1, v/v) at 50 °C and using
5 mol-% of the catalyst were judged to be best for the oxi-
dation of alcohols to the corresponding acids; of course, it
is well known that oxone oxidizes aldehydes to acids in
DMF at room temperature.[6] Furthermore, the screening
results also revealed that the oxidation with DIDA (5 mol-
%) in nitromethane led selectively to the aldehyde at room
temp. (Table 1). Encouraged by these results, the oxidation
of a variety of primary and secondary alcohols was exam-
ined using DIDA (5 mol-%) and oxone (2 equiv.) in acetoni-
trile/water (1:1) (Table 2). While the reactions were carried
out at 50 °C for primary alcohols, the oxidation of second-
ary alcohols was performed at room temp. The oxidation
reactions of primary alcohols were carried out at elevated
temperature to reduce the reaction times; the primary
alcohols could be converted into the carboxylic acids at
room temperature when the reactions were run for a longer
duration (Table 1).
Scheme 1. Structures of the in situ-generated modified IBXs and
Bis-IBX.
Results and Discussion
Synthesis of 3,3Ј-Diiodo-2,2Ј,6,6Ј-tetramethoxybiphenyl-
4,4Ј-dicarboxylic Acid, DIDA
Synthesis of the target twisted Bis-IBX was approached
starting from 5-methylresorcinol dimethyl ether, which was
subjected to o-lithiation with BuLi, followed by treatment
with iodine to give the mono-iodinated product (Scheme 2).
Ullmann coupling of this product, followed by double io-
dination of the biphenyl with NIS under acidic conditions,
and subsequent oxidation of the two methyl groups using
KMnO4 in basic medium, led to the target diiodo-diacid,
i.e., DIDA. Persistent efforts to isolate Bis-IBX by oxidation
either with oxone or with KBrO3/dilute H2SO4 were unsuc-
cessful.
As can be seen from Table 2, the reaction yields were
excellent for all the benzylic alcohols examined (Table 2, en-
Catalytic Oxidation of Alcohols
In light of our failure to isolate the Bis-IBX, the oxi- tries 1–5). The secondary alcohols were found to undergo
dation of alcohols using in situ generated IBX from DIDA smooth oxidation at room temp. to give the ketones in very
in the presence of oxone was attempted with p-bromobenzyl good yields (Table 2, entries 6–8, 11, 15–16), with the excep-
alcohol as a representative case in a range of solvents and tion of some ketones that underwent complicated reactions.
with different catalyst loadings in the presence of oxone Although 1-indanol gave the expected oxidation product,
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Catalytic Oxidation of Activated Alcohols
Table 1. Optimization of the conditions for the oxidation of p-bromobenzyl alcohol with DIDA as a catalyst in the presence of oxone.
the yield was poor (Table 2, entry 9). A possible reason for ylbutane-1,3-diol and p-bromophenylethylene glycol was
this is the known reactivity of oxone towards benzylic C– examined. Remarkable selectively was observed in both
H bonds.[7] A vicinal diol, 1,2-diphenylethane-1,2-diol, gave cases, and β-hydroxybutyrophenone and 4-bromo-α-hy-
benzil as the major oxidation product (Table 2, entry 10). droxyacetophenone, respectively, were formed in very good
Aliphatic alcohols were found not to undergo oxidation. isolated yields (Table 3, entries 7 and 8). In contrast, 1,2-
Consequently, cholestanol was recovered quantitatively, and diphenylethane-1,2-diol gave a mixture of benzoin and ben-
3-phenylpropanol was recovered in 84% yield after 24 h zil, which suggests that the selective oxidation of benzylic
(Table 2, entries 12 and 13). The small loss of the starting vicinal diols to the corresponding acyloin is difficult to con-
material in the latter case is attributed to reactions induced trol (Table 3, entry 9).
by oxone.[7] Notably, 2-hydroxy-2-phenylacetic acid under-
went decarboxylative oxidation to give benzoic acid in to the corresponding dialdehyde[4b] using DIDA/oxone in
quantitative yield (Table 2, entry 14). nitromethane at room temp., we stumbled on the observa-
During our attempts to oxidize 1,2-phenylenedimethanol
Based on the selective conversion of p-bromobenzyl tion that the corresponding lactone, namely, isobenzofuran-
alcohol to the corresponding aldehyde in nitromethane dur- 1(3H)-one, was formed in excellent yield (Table 4, entry 1).
ing the screening experiments (Table 1, entry 10), the oxi- Buoyed by this observation, the oxidation of a number of
dation of primary and secondary alcohols was investigated aryldimethanols with DIDA (5 mol-%) and oxone (2 equiv.)
with DIDA at room temp. in the presence of oxone. The was examined. As can be seen from the results in Table 4,
oxidation of benzylic alcohols occurred selectively to give increasing the number of electron-withdrawing groups led
the corresponding aldehydes in 10–20 h (Table 3, entries 1– to reduced yields of the lactones, and virtually no reaction
5), while primary and secondary aliphatic alcohols such as at all was seen (Table 4, entries 1, 4, and 7). Significantly,
cholestanol and 3-phenylpropanol remained unreactive. An 2,2Ј-biphenyldimethanol was found to undergo lactoniz-
allylic alcohol, cinnamyl alcohol, was found to undergo oxi- ation to give the product in 82% isolated yield (Table 4,
dation rather slowly (Table 3, entry 6). The unreactivity of entry 5). Inexplicably, naphthalene-1,8-dimethanol was
aliphatic alcohols under the conditions used for the oxi- found to be unreactive, even after heating at 100 °C
dation of benzylic alcohols prompted us to investigate the (Table 4, entry 8). It is noteworthy that the catalytic conver-
possibility of chemoselectivity in oxidations. Thus, the sion of diols into lactones using IV reagents is unprece-
chemoselective benzylic oxidation of diols such as 1-phen- dented.[8]
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Table 2. Oxidation of primary[a]and secondary[b] alcohols using DIDA/oxone in CH3CN/H2O (1:1).
[a] At 50 °C. [b] At room temp. [c] Isolated yields. [d] Oxidation with o-iodobenzoic acid (10 mol-%) as the catalyst led to the acid and
aldehyde in 83 and 12% yields, respectively after 36 h. [e] The formation of an unidentified polar compound was observed, which seemed
to account for the poor yield. [f] Benzoic acid (23%) and benzoin (10%) were isolated as by-products. [g] The starting material was
recovered quantitatively. [h] Starting material (82%) was recovered, the remainder was an intractable material.
Catalytic Activity and Mechanistic Implications
tive oxidations involving an initial alcohol-to-aldehyde con-
version followed by a lactol-to-lactone oxidation.[9] This lat-
The results of the oxidations shown in Tables 2, 3, and 4 ter result is remarkable in the light of the reported failure of
clearly demonstrate the new catalytic activity of DIDA. this conversion by Corey et al. using IBX in stoichiometric
Thus, the selective oxidation of activated primary alcohols amounts.[10]
to aldehydes, as well as over-oxidation to acids, can be read-
To establish the fact that the structural attributes in-
ily performed depending on the choice of solvent. Further- herent to DIDA impart superior reactivity, control experi-
more, the catalytic protocol is amenable to the chemoselec- ments were performed using o-iodobenzoic acid under iden-
tive oxidation of substrates that contain two or more hy- tical conditions. Such control experiments are pertinent to
droxy functionalities, in that only the hydroxy groups at the evaluating the efficacy of the catalytic oxidations with
benzylic positions are oxidized under very mild reaction DIDA in the light of the following considerations: i) oxone
conditions. It should be noted that catalytic chemoselective is known to oxidize benzylic alcohols, albeit at higher tem-
oxidation based on IBX is unprecedented. Furthermore, it peratures;[7] and ii) simple o-iodobenzoic acid (20–40 mol-
was shown that DIDA can be used catalytically to ac- %) has also been reported to be an effective catalyst for the
complish the conversion of diols into lactones by consecu- oxidation of benzylic alcohols in the presence of oxone
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Catalytic Oxidation of Activated Alcohols
Table 3. Catalytic oxidation of primary and secondary alcohols using DIDA/oxone in CH3NO2 at room temp. (30–35 °C).
[a] Isolated yields. [b] Oxidation with o-iodobenzoic acid led to the aldehyde in 73% yield after 36 h. [c] Benzil (39%) was isolated.
(0.8–1.5 equiv.) in acetonitrile/water medium.[5a] Thus, the oxidation of the alcohols to the corresponding aldehydes or
catalytic oxidation of p-bromobenzyl alcohol, a representa- ketones. To gain some insight into this, the oxidation of
tive case, was carried out with o-iodobenzoic acid (10 mol- DIDA in the presence of oxone in a D2O/CD3CN (2:1) mix-
1
%) and DIDA (5 mol-%) under identical experimental con- ture was monitored by 500 MHz H NMR spectroscopy.
ditions by using oxone (2 equiv.) in CH3CN/H2O (1:1) and The initially turbid solution gradually turned clear over a
nitromethane solvents at 50 °C and room temp., respec- period of 24 h. The multiple substitution of the aromatic
tively. In acetonitrile/water, the reaction with DIDA was rings of DIDA greatly simplifies the spectral analysis. Thus,
complete within 7.5 h, leading to p-bromobenzoic acid in the singlet for the equivalent aromatic protons at δ =
93% isolated yield, whereas the reaction with o-iodobenzoic 7.16 ppm gradually disappeared, with concomitant appear-
acid as the catalyst went on for 36 h, providing the acid in ance of several signals. These in turn disappeared with time,
83% yield together with the aldehyde in 12% yield. For the leading finally to a singlet at δ = 7.58 ppm (Figure 1). The
oxidation in nitromethane at room temp., the aldehyde was number of singlets that appeared as the oxidation pro-
obtained in 96% isolated yield with DIDA after 10.2 h, gressed can be accounted for by assuming sequential oxi-
whereas it was isolated in only 73% yield after 36 h with o- dation of the two iodines initially to IIII and eventually to
iodobenzoic acid. Furthermore, a similar control experi- IV species. Attempts to isolate the presumed IV compound
ment using o-iodobenzoic acid for the oxidation of benz- led to the recovery of the starting material, which suggests
ene-1,2-dimethanol led to the corresponding lactone in that it is too labile to be isolated. Similar monitoring of the
72% yield after 48 h, while the same reaction was ac- oxidation by 13C NMR spectroscopy was thwarted by the
complished with DIDA in 15 h, providing the lactone in concentration being too low to allow rapid spectral acqui-
1
96% isolated yield. Indeed, this oxidation was incomplete sition. Although the H NMR analysis does point towards
when o-iodobenzoic acid was used as the catalyst, even after the in situ generation of the IV species, unambiguous evi-
48 h. These results clearly attest to the unique reactivity of dence was unfortunately not obtained. Nonetheless, the fact
DIDA for catalytic oxidations.
that the species is indeed Bis-IBX can be substantiated from
To explain the reactivity of DIDA, let us first focus on the following considerations. Zhdankin et al. have shown
the nature of the in situ generated species that is responsible that an o-methoxy group stabilizes IV iodyl species, i.e.,
for the observed oxidations. As mentioned at the outset, the –IO2, with weak I···O interactions leading to so-called pseu-
pentavalent λ5-iodane, i.e., Bis-IBX, could not be isolated docyclic IBX-ethers;[11] indeed, such species have been
when either oxone or KBrO3 was used as an oxidant. Thus, shown to be effective for the oxidation of alcohols when
one wonders what the species is that is responsible for the used in stoichiometric amounts in refluxing chloroform.[11]
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Table 4. Oxidation of diols to lactones using DIDA/oxone in mechanism of the oxidation of alcohols with IBX reagents
CH3NO2 at room temp. (30–35 °C).
has been thoroughly established in several investiga-
tions,[5d,5e] and is not considered by us any further.
Figure 1. 1H NMR (500 MHz) spectroscopic monitoring of the oxi-
dation of DIDA in CD3CN/D2O (1:2): (a) at the beginning of the
reaction, (b) after 2 h, (c) after 4 h, and (d) after 24 h.
The questions that still remain are: why is the Bis-IBX
unstable, and why do the oxidations occur more rapidly
with DIDA than with the simple o-iodobenzoic acid. We
believe that the o-methoxy group in some way imparts steric
constraints to destabilize the λ5-iodane species. The reason
why oxidations occur more rapidly must be to do with the
[a] Isolated yields. [b] Oxidation with o-iodobenzoic acid as the cat-
better solubility of the in situ generated Bis-IBX in the reac-
alyst led to the corresponding lactone in 72% yield after 48 h.
tion medium than that of the parent IBX. Otherwise, faster
[c] Isolated as a mixture of 5-bromoisobenzofuran-1(3H)-one and
reactions with the reagent with attenuated reactivity cannot
be rationalized. We believe that the presence of orthogonal
aromatic planes precludes aggregation of in situ formed Bis-
IBX, and thus improves its solubility. In the realm of supra-
molecular chemistry, molecules with such features function
effectively as inclusion host compounds by virtue of the fact
that they cannot pack efficiently except in the presence of
guest molecules of suitable shape and size.[12]
6-bromoisobenzofuran-1(3H)-one in a 1:2.5 ratio, as determined by
1H NMR spectroscopy. [d] The starting material was recovered in
30% yield. [e] The starting material was recovered quantitatively.
Notably, they are very much less reactive than IBX. Cata-
lytic oxidations with iodo compounds that yield pseudocy-
clic IBX-ethers/esters/amides by in situ oxidations using
oxone/KBrO3 are unknown before now. Based on the estab-
lished reactivity pattern of the pseudocyclic IBX-ethers, the
reasonably rapid oxidations observed in our work with
catalytic amounts of DIDA (5 mol-%) should be better
understood based on the formation of Bis-IBX species. Af-
Conclusions
A variety of modified IBXs with improved attributes that
ter all, why such a Bis-IBX should not be formed is incom- address the disadvantages associated with poor solubility
prehensible. The fact that the iodyl species is unlikely to and explosive characteristics continue to be reported. The
be involved is further supported from the absence of any development of catalytic oxidation protocols based on the
reactivity of an analogous derivative, i.e., 3,3Ј-diiodo- in situ generation of IBX is appealing from the point of
2,2Ј,6,6Ј-tetramethoxybiphenyl, which is devoid of the car- view of cost economy and simplicity. To the best of our
boxy groups. This convincingly points to the operation of knowledge, only a few instances of catalytic oxidations are
λ5-iodane species in the observed oxidations. Of course, the known to date,[5a–5e] and protocols that permit modulation
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Catalytic Oxidation of Activated Alcohols
(500 MHz, CDCl3): δ = 2.39 (s, 6 H), 3.71 (s, 12 H), 6.48 (s, 4 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 22.3, 56.1, 105.5, 109.5,
138.6, 158.2 ppm. HRMS (EI+): calcd. for C18H22O4 [M]+
302.1518; found 302.1517.
of the reactivity of in situ-generated IBX for catalytic
chemoselective oxidations are virtually unprecedented. We
have designed a tetramethoxybiphenyl-based molecular sys-
tem that leads, upon in situ oxidation, to Bis-IBX, which
is characterized by perpendicular aromatic planes. Bis-IBX
derived from such a twisted biphenyl scaffold presumably
undergoes inefficient aggregation, which results in good sol-
ubility and facile oxidation. The solubility, in conjunction
with the attenuated reactivity arising from the presence of
the methoxy groups, allows the catalytic oxidation of reac-
tive activated alcohols only. Primary alcohols are converted
catalytically to the corresponding aldehydes selectively (in
CH3NO2 at room temp.), or to the acids (in CH3CN/H2O
3,3Ј-Diiodo-2,2Ј,6,6Ј-tetramethoxy-4,4Ј-dimethylbiphenyl (4): TFA
(0.2 mL) was added slowly to a mixture of 2,2Ј,6,6Ј-tetramethoxy-
4,4Јdimethylbiphenyl (0.50 g, 1.65 mmol) and NIS (0.81 g,
3.64 mmol) in CH3CN (8 mL). The resulting reaction mixture was
stirred at room temp. for 3 h, and was subsequently quenched by
the addition of crushed ice. The colorless solid that formed was
filtered off to give 4 (0.89 g, 98%); m.p. 201–212 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.53 (s, 6 H), 3.47 (s, 6 H), 3.72 (s, 6 H),
6.72 (s, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 29.3, 56.0,
60.4, 88.6, 108.6, 115.4, 142.9, 158.17, 158.21 ppm. HRMS (EI+):
(1:1) at 50 °C). These results are remarkably different from calcd. for C18H20I2O4 [M]+ 553.9451; found 553.9459.
those reported with other reagents[5a–5e] used catalytically,
in the sense that aliphatic alcohols are untouched under
the reaction conditions, which means that the oxidation of
3,3Ј-Diiodo-2,2Ј,6,6Ј-tetramethoxy-4,4Ј-biphenyldicarboxylic Acid
(DIDA): KMnO4 (19.1 g, 120.8 mmol) was added in several por-
tions at regular intervals over a period of 5 d to a solution of
benzylic alcohols can occur selectively. The diiodo-diacid, 3,3Ј-diiodo-2,2Ј,6,6Ј-tetramethoxy-4,4Ј-dimethylbiphenyl (5.58 g,
10.07 mmol) in pyridine/water (4:1 v/v; 100 mL) heated at reflux.
After completion of the reaction, the pyridine and most of the
water were removed in vacuo, and the brown solid was filtered off.
The filtrate was acidified with concd. HCl and the resulting precipi-
tate was collected by filtration to give DIDA (3.68 g, 60%) as a
colorless solid, which was stable up to 250 °C, but decomposed
i.e., DIDA, can also be used for cascade oxidations in which
diols are sequentially converted to lactones.
Experimental Section
at 256–258 °C with the liberation of iodine. IR (KBr): ν = 2939,
˜
4-Iodo-3,5-dimethoxytoluene (2): nBuLi (1.4 m in hexane; 8.5 mL,
11.84 mmol) was added dropwise to a solution of 3,5-dimeth-
oxytoluene (1.5 g, 9.87 mmol) in dry THF (20 mL) at 0 °C over a
period of 15 min. The reaction mixture was stirred for 1.5 h at 0 °C,
by which time the reaction mixture had turned yellow. A solution
of of iodine (3.01 g, 11.84 mmol) in dry THF (20 mL) was added
using a dropping funnel. The resulting reaction mixture was al-
lowed to reach room temp. slowly, and was allowed to stir at this
temperature for another 30 min. At the end of this period, the reac-
tion mixture was quenched with ice, the THF was removed under
reduced pressure, and the product was extracted with chloroform.
The combined chloroform extracts were washed with sodium thio-
sulfate solution and dried with anhydrous Na2SO4. The solvent was
removed in vacuo to give the crude product, which was further
purified by column chromatography to give 2 (2.6 g, 95%), m.p.
1705 cm–1. 1H NMR (500 MHz, [D6]acetone): δ = 3.49 (s, 6 H),
3.81 (s, 6 H), 7.27 (s, 2 H) ppm. 13C NMR (125 MHz, [D6]DMSO):
δ = 56.6, 60.6, 81.4, 108.4, 119.6, 141.0, 158.34, 158.38, 169.3 ppm.
HRMS (ESI–): calcd for C18H15I2O8 [M – H]– 612.8856; found
612.8857.
Procedure for the Catalytic Oxidation of Alcohols: In a typical ex-
periment, the alcohol (0.5–1.0 mmol), DIDA (5 mol-%), and oxone
(2 equiv.) were added to CH3CN/water (1:1; 4–6 mL). The resulting
mixture was stirred at room temp. for the oxidation of secondary
benzylic alcohols, or heated at 50 °C for primary benzylic alcohols.
After completion of the reaction, as judged from TLC analysis, a
little water was added to dissolve the inorganic salts, and then the
organic matter was extracted with ethyl acetate. The combined ex-
tracts were washed with brine, dried with anhydrous Na2SO4, and
concentrated in vacuo. Filtration over a short pad of silica gel gave
the pure oxidation product.
1
87–89 °C. H NMR (500 MHz, CDCl3): δ = 2.35 (s, 3 H), 3.86 (s,
6 H), 6.34 (s, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 21.9,
56.4, 73.5, 105.2, 140.3, 159.1 ppm. HRMS (EI+): calcd. for
C9H11IO2 [M]+ 277.9804; found 277.9809.
For oxidations in CH3NO2, a procedure similar to that described
above was followed, with the reactions all being conducted at room
temp.
2,2Ј,6,6Ј-Tetramethoxy-4,4Ј-dimethylbiphenyl (3): This compound
was prepared following a modified Ullmann reaction reported for
the synthesis of 2,2Ј,6,6Ј-tetramethoxybiphenyl.[13] Accordingly,
3,5-dimethoxytoluene (0.28 g, 1.80 mmol) was subjected to ortholi-
thiation in THF as described above. After 1.5 h, cuprous iodide
(0.38 g, 1.98 mmol) was introduced in 2–3 portions. The resulting
reaction mixture was allowed to stir at 0 °C for 1 h, during which
time the reaction mixture turned grayish-black. Subsequently, a
solution of 4-iodo-3,5-dimethoxytoluene (0.5 g, 1.80 mmol) in dry
pyridine (7 mL) was added dropwise to the reaction mixture, which
was then heated at reflux for 72 h. At the end of this period, the
pyridine and THF were removed under reduced pressure, the resi-
due was neutralized with dilute HCl, and the organic matter was
extracted with chloroform three times. The combined organic ex-
tracts were washed with brine and dried with anhydrous Na2SO4,
and the solvent was removed in vacuo. The crude residue was puri-
fied by column chromatography to obtain biphenyl product 3
(0.41 g, 75%) as a colorless solid, m.p. 136–138 °C. 1H NMR
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for the intermediates, target com-
pound, and the products of oxidations.
Acknowledgments
J. N. M. is thankful to the Department of Science and Technology
(DST) for generous financial support. S. S. and S. J. gratefully
acknowledge SPM and junior research fellowships, respectively,
from the Council of Scientific and Industrial Research (CSIR), In-
dia.
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Date: 06-03-13 15:59:24
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S. Seth, S. Jhulki, J. N. Moorthy
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Received: December 16, 2012
Published Online: ᭿
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Date: 06-03-13 15:59:24
Pages: 9
Catalytic Oxidation of Activated Alcohols
Catalytic Oxidations
The twisted 3,3Ј-diiodo-2,2Ј,6,6Ј-tetrameth-
oxybiphenyl-4,4Ј-dicarboxylic acid (DIDA),
used catalytically, permits the in situ gener-
ation of a Bis-IBX, and promotes the
chemoselective oxidation of activated al-
cohols.
S. Seth, S. Jhulki, J. N. Moorthy* .... 1–9
Catalytic and Chemoselective Oxidation of
Activated Alcohols and Direct Conversion
of Diols to Lactones with In Situ-Gener-
ated Bis-IBX Catalyst
Keywords: Hypervalent compounds / Oxi-
dation / Alcohols / Lactones / Chemoselec-
tivity / Homogeneous catalysis
Eur. J. Org. Chem. 0000, 0–0
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www.eurjoc.org
9