Unexpected dehomologation of primary alcohols to one-carbon shorter carboxylic acids using o-iodoxybenzoic acid (IBX)

Article abstract of DOI:10.1039/c3cc49160a

A novel and efficient transformation of primary alcohols to one-carbon shorter carboxylic acids using IBX is reported. Mechanistic studies revealed that the combination of IBX and molecular iodine produces a different active hypervalent iodine species.

Full text of DOI:10.1039/c3cc49160a

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Unexpected dehomologation of primary alcohols
to one-carbon shorter carboxylic acids using
o-iodoxybenzoic acid (IBX)†
Cite this: Chem. Commun., 2014,
50, 2758
Received 2nd December 2013,
Accepted 21st January 2014
Shu Xu,‡ Kaori Itto,‡ Masahide Satoh and Hirokazu Arimoto*
DOI: 10.1039/c3cc49160a
www.rsc.org/chemcomm
A novel and efficient transformation of primary alcohols to one-
carbon shorter carboxylic acids using IBX is reported. Mechanistic
studies revealed that the combination of IBX and molecular iodine
produces a different active hypervalent iodine species.
Scheme 1 Serendipitous observation of the IBX dehomologation reaction.
Tf = trifluoromethanesulfonyl, IBX = o-iodoxybenzoic acid.
The adjustment of carbon chain length is often crucial in organic
synthesis. Dehomologation, as the necessary complement to homo-
logation, is thus regarded as a fundamental reaction. However, usefulness of the transformation and our interest in the reaction
even the dehomologation of simple substrates sometimes requires mechanism, we next investigated the scope of the reaction.
tedious multi-step strategies. For instance, primary alcohols may be
In an initial study, using n-heptanol (2a) as the model substrate,
oxidized to carboxylic acids and then subjected to the Hunsdiecker IBX dehomologation in the presence or absence of I2 was explored
reaction to obtain the corresponding dehomologated alkyl halides. (Table S1, ESI†). When I2 was added to the reaction system, a shorter
To the best of our knowledge, the simple dehomologation of reaction time and a higher dehomologation ratio of n-hexanoic acid
primary alcohols has only been achieved using concentrated nitric (2c) to n-heptanoic acid (2d) were observed. Solvent screening then
acid1 or Cr(VI) reagents,2,3 and thus, both methods have limited disclosed that DMF yielded the best selectivity and the shortest
scope. Herein, we report a novel dehomologation of primary reaction time. While an oxygen atmosphere provided a better yield,
alcohols to the corresponding one-carbon shorter carboxylic excellent 2c/2d selectivity was retained even under an Ar atmosphere.
acids using o-iodoxybenzoic acid (IBX)4 as a mild oxidant.
With the optimized conditions in hand, we then investigated
In the course of our studies on total synthesis of natural the scope of the dehomologation reaction (Table 1). In all cases,
products, we attempted to prepare aldehyde 1b via oxidation of little, if any, unhomologated carboxylic acid was obtained, demon-
precursor alcohol 1a with IBX in refluxing EtOAc (Scheme 1). strating the high selectivity of the established conditions. Sub-
Surprisingly, the major product was one-carbon shorter carboxylic stituents including alkyl chloride (entry 2), cyclopropane (entry 3),
acid 1c, albeit in modest yield. The expected product 1b and its aryl bromide (entry 8), nitrile (entry 9), anisole (entry 10), naphtha-
overoxidized product (carboxylic acid without carbon loss5) were lene (entry 11), phenyl ether (entry 12), benzyl ether (entry 13), and
not detected. In fact, the above reaction conditions were originally benzoate (entry 14) groups were tolerated in the reaction. Even
reported to provide aldehydes.6 To the best of our knowledge, this 3-branched alcohols, including an adamantane subunit, gave
dehomologation is yet to be reported under similar conditions. It good yields. Thus, the bulkiness of neighboring groups had only
was thought that the partial decomposition of IBX to a lower valent a limited effect on the rate and yield of the reaction (entries 4–6).
iodine species may affect this surprising and interesting dehomo- In addition, both electron-donating and -withdrawing groups on
logation, because a light red color was observed as the reaction the benzene ring in aromatic substrates did not alter the yield
progressed, suggesting the generation of I2. Because of the potential (entries 8–10). However, in contrast to the results with 3-branched
alcohols (entries 5, 6 and 8–11), 2-branched alcohol 16a gave the
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira,
Sendai 980-8577, Japan. E-mail: arimoto@biochem.tohoku.ac.jp;
Fax: +81 22 217 6204; Tel: +81 22 217 6201
dehomologated ketone 16c in only 5.5% yield,7 together with
unhomologated carboxylic acid as the major product (entry 15).
To clarify the reaction mechanism, the dehomologation of 2a
in deuterated DMF (D7-DMF) was monitored via NMR analysis
(Scheme 2). The reaction mixture was first stirred at room tem-
perature for 1 h, and then the temperature was raised to 100 1C.
† Electronic supplementary information (ESI) available: Experimental proce-
dures, optimization of reaction conditions, and spectroscopic data. See DOI:
10.1039/c3cc49160a
‡ These authors contributed equally to this work and are co-first authors.
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Table 1 IBX dehomologation with various primary alcoholsa
Time
(h)
Yieldb
(%)
Substrate
Product
Entry
Scheme 3 IBX-mediated dehomologation of reaction intermediates 2b
and 5f.
1
2
3
2a
3a
4a
7
3
3
2c 74
3c 97
4c 99
of 2-iodoaldehyde 2f. Formation of 2b and 2f was also confirmed
via GC-MS analysis using authentic samples.8 After the reaction
temperature was raised to 100 1C, 2b was converted to 2f and then
further dehomologated to the carboxylic acid 2c. In independent
experiments (Scheme 3), aldehyde 2b and iodoaldehyde 5f were
treated under IBX–I2 conditions to afford the corresponding
dehomologated carboxylic acids 2c and 5c, respectively, in good
yields.9 These observations suggest the intermediacy of the
aldehyde and iodoaldehyde in the dehomologation of primary
alcohols. Moreover, the reaction of n-heptanoic acid (2d) under
optimal IBX–I2 conditions did not lead to the formation of
n-hexanoic acid, thus excluding the possibility of the genera-
tion of unhomologated carboxylic acid as an intermediate.
In addition, the generation of CO2 as a product was confirmed
via 13C-NMR analysis of the reaction of a 13C-labeled substrate
(Fig. S3, ESI†).
4
5
5a
6a
3
3
5c 73
6c 81
6
7
7a
8a
9
3
7c 69
8c 72
8
9
10
9a
10a
11a
3
3
3
9c 100
10c 100
11c 90
11
12a
3
12c 99
Additionally, NMR analysis of the reaction provided a clue to
the active species that actually mediates dehomologation. Speci-
fically, IBX was observed to be consumed via rapid reaction with I2
to generate a species designated as X, which was the major
detected hypervalent iodine species present during the conversion
of the aldehyde 2b to the carboxylic acid 2c. Therefore, it is
assumed that the newly formed compound X plays a key role in
the novel dehomologation process. X was isolated in a nearly pure
form as a colorless solid via filtration of an IBX–I2 mixture without
the added substrate alcohol. The NMR spectra of X are shown
along with those of IBX, o-iodosobenzoic acid (IBA), and
o-iodobenzoic acid (BA)10 in Fig. 1 (for IR spectra, see ESI†).
Notably, the aromatic H-3 proton in X is not observed in the
1H-NMR spectrum at room temperature, but can be seen in the
spectrum obtained at 80 1C.11 In addition, the melting point of X
was observed to be 238–240 1C (dec.) and is also different from
that of IBX (233 1C),4a IBA (234 1C),12a and BA (161.6–163 1C).12b
However, X-ray crystallographic analysis of X was not possible,
12
13
13a 18
13c 82
14c 57
14a
4
14
15a 21
16a
15c 91
16c 5.5
15c
3
a
Reaction conditions: a mixture of alcohol a (0.25 mmol), IBX
(2.0 mmol), and I2 (0.40 mmol) in DMF (3.6 mL) was heated at 100 1C
b
under an O2 atmosphere for the indicated time. The yield was
determined by GC-MS with n-nonanoic acid as the internal standard.
c
IBX (10 eq.) and I2 (1.1 eq.) were used and unhomologated carboxylic
acid (41%) was also detected.
The yield of 2c in this experiment was similar to that in Table 1
(entry 1). The 1H- and 13C-NMR analyses for the first 1 h indicated and therefore, its structure remains unclear at this time. A
the oxidation of 2a to aldehyde 2b and formation of a small amount tentative structure (Fig. 1a) is proposed based on the following
evidence: (1) X forms via the reduction of IBX with I2, and BA forms
via the reduction of X with I2, suggesting that the valence of the
iodine atom in X is lower than that in IBX and higher than that in
BA; (2) hydrolysis of X in aqueous DMF provided IBA at room
temperature. This observation suggests that the iodine atoms in X
and IBA may have the same oxidation level (data not shown); and
(3) the NMR spectra of X are very different from those of IBX and
BA but similar to those of IBA (Fig. 1).
We next turned our attention to the role of X in this trans-
formation (Scheme 4). As shown in Scheme 2, primary alcohols
Scheme 2 IBX-mediated dehomologation of 2a in D7-DMF.
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comparable to those obtained with IBX or species X. In fact, the
desired dehomologated product 2c was obtained in less than
20% yield with DMP and was not detected with PhI(OAc)2.
During the last decade, IBX has attracted intense interest,13
not only as a reagent for the oxidation of alcohols to aldehydes
and ketones,4b but also as a mild and selective reagent in other
surprisingly versatile transformations.13c–j Therefore, it has
been widely applied in the total synthesis of complex natural
products.13f The novel dehomologation of primary alcohols
conducted by us stands as a new member of this class of
reactions and will also be useful for the synthesis of functional
molecules.
In summary, a novel, highly selective dehomologation of
primary alcohols to their corresponding one-carbon shorter
carboxylic acids using the mild, hypervalent iodine reagent
IBX was developed. A stable hypervalent iodine species was
isolated and shown to be crucial for the dehomologation. Further
study of the reaction mechanism is currently underway.14
K. Itto thanks JSPS for a Research Fellowship for Young
Scientists. We thank Professor Yasunori Ohba and the late
Professor Seigo Yamauchi (Institute of Multidisciplinary
Research for Advanced Materials, Tohoku University) for helpful
discussions.
Fig. 1 Comparison of the 1H- and 13C-NMR spectra of X, IBX, IBA, and BA.
All spectra were recorded in D7-DMF at room temperature. (a) 1H-NMR
spectra (600 MHz, 7.3 to 8.7 ppm). (b) 13C-NMR spectra (150 MHz, 90 to
180 ppm). A a H.
Notes and references
1 (a) P. H. Washecheck, Chem. Abstr., 1972, 77, 113810; (b) C. Harald
and K. Manfred, Chem. Abstr., 1990, 112, 7044; (c) S.-B. Li, S.-M.
Zhang, K. Wu and Y.-L. Li, Huaxue Shiji, 1992, 14, 60.
2 (a) P. Bijoy and G. S. R. Subba Rao, Synth. Commun., 1993, 23,
2701–2708; (b) R. A. Fernandes and P. Kumar, Tetrahedron Lett.,
2003, 44, 1275–1278.
3 Dehomologation has been reported as a side reaction in Jones
oxidation, see: (a) G. Just, C. Luthe and H. Oh, Synth. Commun.,
1979, 9, 613–617; (b) J. T. Doi, G. W. Luehr, D. del Carmen and
B. C. Lippsmeyer, J. Org. Chem., 1989, 54, 2764–2767.
4 (a) C. Hartmann and V. Meyer, Ber. Dtsch. Chem. Ges., 1893, 26,
1727–1732; (b) M. Frigerio and M. Santagostino, Tetrahedron Lett.,
1994, 35, 8019–8022.
5 For IBX oxidation of alcohols to carboxylic acids without carbon
loss, see: A. P. Thottumkara, M. S. Bowsher and T. K. Vinod,
Org. Lett., 2005, 7, 2933–2936.
Scheme 4 Reactivity of the hypervalent iodine species X.
6 J. D. More and N. S. Finney, Org. Lett., 2002, 4, 3001–3003.
7 For examples of chromium reagent dehomologation of 2-branched
alcohols to the ketones, see ref. 2.
8 Aldehydes and alpha-iodoaldehydes were characterized as key inter-
mediates via GC-MS and NMR analyses. The characterization of
other reaction intermediates and the examination of their possible
involvement in this dehomologation are underway.
9 This result implied that our reaction conditions were also effective
for the dehomologation of aldehydes, and may be a promising
supplemental method for the Norrish I photocleavage and the
transition-metal catalyzed deformylation of aldehydes, while the
latter two methods usually could only produce the unfunctionalized
dehomologated alkanes.
10 IBA and BA have been reported as reduced species of IBX by I2 in
DMSO, see: J. N. Moorthy, K. Senapati and S. Kumar, J. Org. Chem.,
2009, 74, 6287–6290.
11 For attribution of NMR peaks of X and comparison of NMR spectra
of X at room temperature and 80 1C, see ESI†.
12 (a) J. G. Sharefkin and H. Saltzman, Anal. Chem., 1963, 35,
1428–1431; (b) W. J. Horton and D. E. Robertson, J. Org. Chem.,
1960, 25, 1016–1020.
13 For recent reviews, see: (a) V. V. Zhdankin, Chem. Rev., 2008, 108,
5299–5358; (b) M. Uyanik and K. Ishihara, Chem. Commun., 2009,
2086–2099; (c) V. Satam, A. Harad, R. Rajule and H. Pati,
are oxidized to their corresponding aldehydes and then deho-
mologated to the corresponding carboxylic acids. First, it was
determined that the addition of X to alcohol 2a did not provide
the corresponding aldehyde in the presence or absence of I2.
This implies that the aldehyde intermediate is generated via
IBX oxidation. On the other hand, aldehydes (e.g., 5b) react
smoothly with X to afford the corresponding 2-iodoaldehydes
(e.g., 5f), which are dehomologated to the corresponding
carboxylic acids at 100 1C. Notably, in the presence of a catalytic
amount of I2, the dehomologation with X is accelerated and
proceeds in higher yield. These results suggest that both X and
some inorganic iodine species may work together during the
carbon–carbon bond cleavage step. For comparison, the combi-
nation of molecular iodine with Dess–Martin periodinane
(DMP) or (diacetoxyiodo)benzene (PhI(OAc)2) was investigated
using n-heptanal (2b) as the dehomologation substrate.
Neither alternative hypervalent iodine species yielded results
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