In situ generated (Hypo)iodite catalysts for the direct α-oxyacylation of carbonyl compounds with carboxylic acids

Article abstract of DOI:10.1002/anie.201101522

It′s the iodine: The intra- and intermolecular title reaction is catalyzed by an in situ generated ammonium (hypo)iodite species. Either H ₂O₂ or tert-butyl hydroperoxide (TBHP) can be used as an environmentally benign oxidant and a wide range of substrates react to give the corresponding α-acyloxycarbonyl compounds in good to excellent yields.

Full text of DOI:10.1002/anie.201101522

DOI: 10.1002/anie.201101522
Oxidation
In Situ Generated (Hypo)Iodite Catalysts for the Direct a-
Oxyacylation of Carbonyl Compounds with Carboxylic Acids**
Muhammet Uyanik, Daisuke Suzuki, Takeshi Yasui, and Kazuaki Ishihara*
a-Acyloxycarbonyl compounds, which are significant building
blocks in synthetic organic chemistry, can traditionally be
prepared by the substitution reaction of a-halocarbonyl
compounds with alkaline carboxylates[1] or the direct oxida-
tive coupling of carbonyl compounds with toxic heavy metal
oxidants (i.e. Pb(OAc)4, Tl(OAc)3, Mn(OAc)3, etc.).[2]
Recently, the chiral amine catalyzed enantioselective a-
oxybenzoylation of aldehydes with benzoyl peroxide has
also been reported.[3] However, the substrate scope is still
limited. Although hypervalent iodine compounds are envi-
ronmentally benign alternatives to rare or toxic heavy metal
oxidants, their use in catalytic amounts is still limited.[4] In
2005, the groups of Ochiai[5a] and Kita[5b] independently
reported the first iodosoarene (ArIL2)-catalyzed oxidative
coupling reactions using meta-chloroperbenzoic acid
(mCPBA) as a co-oxidant. In particular, Ochiai et al.
developed the a-oxyacetylation of ketones catalyzed by the
in situ generated iodine(III) in the presence of an excess
amount of BF3·Et2O in wet acetic acid [Eq. (1)].[5a] In 2007,
waste, and 4) excess amounts of carboxylic acids were
required.
We report here intra- [Eq. (3)] and intermolecular
[Eq. (4)] oxidative coupling reactions of carbonyl compounds
with carboxylic acids catalyzed by in situ generated tetra-
butylammonium (hypo)iodite with either hydrogen peroxide
or tert-butyl hydroperoxide (TBHP) as an environmentally
benign oxidant.[7,8] The most important features of the present
catalytic system are: 1) metal-free oxidation, 2) milder reac-
tion conditions, 3) high chemoselectivity, 4) wide range of
substrates, that is ketones, aldehydes, 1,3-dicarbonyl com-
pounds, and carboxylic acids, and 5) water or tert-butyl
alcohol is the only by-product derived from the co-oxidant
used.
Initially, we found that tetra n-butylammonium iodide
(nBu4NI) was highly effective as a pre-catalyst for the
oxylactonization of oxocarboxylic acids 1 with commercially
available 30% aqueous hydrogen peroxide even at room
temperature (Scheme 1).[9] These results are comparable with
our previous results using iodobenzene with mCPBA
[Eq. (2)].[6a] Importantly, no Baeyer–Villiger products were
obtained under the present reaction conditions. Both g-
arylcarbonyl-g-butyrolactones (2a–2e, 2k, and 2l) and g-
heteroarylcarbonyl-g-butyrolactones (2 f and 2i) were
obtained in high yield. However, g-alkylcarbonyl-g-butyro-
lactones (2g and 2j) and d-benzoyl-d-valerolactone (2h) were
obtained in moderate yields.
Huang and co-workers reported the same reaction under
similar conditions using peracetic acid (generated in situ from
Ac2O and H2O2) as a co-oxidant.[4c,5c] In 2009, we reported the
oxylactonization of oxocarboxylic acids to oxolactones cata-
lyzed by the in situ generated PhIL2 in the presence of a
catalytic amount of TsOH [Eq. (2)].[6] The major drawbacks
of these iodosoarene-catalyzed systems are: 1) harsh reaction
conditions were required, 2) low chemoselectivity was
observed (competing with Baeyer–Villiger oxidation),
3) meta-chlorobenzoic acid (mCBA) was generated as
[*] Dr. M. Uyanik, D. Suzuki, T. Yasui, Prof. Dr. K. Ishihara
Graduate School of Engineering, Nagoya University
Furo-cho, Chikusa-ku, Nagoya 464-8603 (Japan)
Fax: (+81)52-789-3222
E-mail: ishihara@cc.nagoya-u.ac.jp
Homepage: http://www.nubio.nagoya-u.ac.jp/nubio4/index.htm
Prof. Dr. K. Ishihara
Japan Science and Technology Agency (JST), CREST (Japan)
[**] Financial support for this project was provided by JSPS.KAKENHI
(20245022, 22750087), NEDO, the Society of Iodine Science, JSPS
Research Fellowships for Young Scientists (T.Y.), and the Global
COE Program of MEXT.
Next, we focused on the intermolecular coupling of
ketones with carboxylic acids. The oxidative coupling of
propiophenone (3a) with benzoic acid (4a) under reaction
conditions similar to those in Scheme 1 using a catalytic
amount of Bu4NI with 30% aqueous H2O2 at room temper-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101522.
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Communications
(entries 7 and 8). a-Acryloyloxy ketones are used industrially
as starting materials for the production of polymers.[10]
To explore the generality and scope of the present a-
oxyacylation, several ketones as well as 1,3-dicarbonyl com-
pounds were examined as substrates to react with benzoic
acid (4a) under the optimized reaction conditions
(Scheme 2). Propiophenones 3b—3h, which are substituted
with electron-donating or electron-withdrawing groups, gave
Scheme 1. Oxylactonization of oxocarboxylic acids 1. Reaction times
and yields of isolated 2 are shown. For details, see the Supporting
Information. [a] 2.5 equiv of H2O2 were used. [b] Reaction was per-
formed at 508C. [c] Toluene/H2O (2:1 v/v) was used as a solvent.
Np=napthyl, Py=pyridinyl.
ature or higher temperatures (up to 758C) gave a-benzoyloxy
ketone 5aa in low yield (up to 5%), and unreacted starting
materials were recovered. Fortunately, we found that a
commercial solution of TBHP in anhydrous nonane or
decane was much more effective than aqueous hydrogen
peroxide as
a
co-oxidant (Table 1).[9] Thus, equimolar
Table 1: a-Oxyacylation of propiophenone (3a) with carboxylic acids 4.[a]
Scheme 2. a-Oxybenzoylation of ketones (3b–3n) and 1,3-dicarbonyl
compounds (3o–3r). Reaction times and yields of isolated 5 are
shown. For details, see the Supporting Information. [a] 2.0 equiv of 3
were used. [b] 5 mol% of Bu4NI was used. [c] Yield was determined by
1H NMR analysis. [d] Reaction was performed at 508C. [e] Reaction
was performed at RT.
Entry
R (4)
5
t [h]
Yield [%][b]
1
Ph (4a)
Ph (4a)
Ph (4a)
4-MeC6H4 (4b)
4-NO2C6H4 (4c)
Me (4d)
5aa
5aa
5aa
5ab
5ac
5ad
5ae
5af
38
24
48
23
53
29
24
24
79 (84)[c]
99
2[d]
3[e]
4[d]
5[d]
6
76[c]
the corresponding a-benzoyloxy ketones 5ba—5ha in good to
excellent yields. However, the oxidative coupling of aceto-
phenone (3k) gave the desired product 5ka in only 30%
yield. Notably, a-benzoyloxy heteroaryl ketones (5la—5na)
were obtained in high yields. Oxidative coupling of 1,3-
diketones (5oa and 5pa), a ketoester (5qa), and dimethyl-
malonate (5ra) gave the corresponding a-benzoyloxy car-
bonyl compounds in good yields. In general, the reactivity was
increased by the excess use of ketones.
91
85
61
57 (72)[d]
61 (72)[d]
=
7
8
CH2 CH (4e)
=
CH2 C(Me) (4 f)
[a] Unless otherwise noted, an anhydrous solution of TBHP in decane or
nonane was used. For details, see the Supporting Information. [b] Unless
otherwise noted, yields of isolated 5 are shown. [c] Determined by
1H NMR analysis. [d] 2 equiv of 3a were used. [e] A 70% aqueous
solution of TBHP was used.
The a-oxyacylation of aldehydes was also examined
(Scheme 3). The oxidative coupling of 3-phenylpropanal
(6a) with 4a gave a messy reaction mixture under reaction
conditions identical to those used for the coupling of ketones
3. Self-aldol and oxidative dehydrogenation products were
obtained along with several unidentified products. We found
that the addition of a catalytic amount of piperidine was
effective as an additive under milder conditions (508C) for
enhancing product selectivity (Scheme 3).[9] Thus, equimolar
amounts of 6a and 4a were heated in the presence of
10 mol% Bu4NI, 5 mol% of piperidine, and 1.1 equivalents of
TBHP in EtOAc at 508C to give a-benzoyloxy aldehyde 7aa
in 89% yield. Several aldehydes (6) and acids (4) were
examined as substrates under the optimized reaction con-
ditions (Scheme 3). Interestingly, the oxidative coupling of 6a
with acetic acid (4d) gave the desired 7ad in higher yield than
ketone 3a (Scheme 3 versus entry 6 in Table 1). Acrylic acid
amounts of 3a and 4a were heated in the presence of
10 mol% Bu4NI and 2 equivalents of TBHP in EtOAc to give
5aa in 79% yield (entry 1). The use of 2 equivalents of 3a
gave 5aa quantitatively within a shorter reaction period
(entry 2). Commercially available 70% aqueous TBHP could
also be used instead of anhydrous TBHP (entry 3). The
oxidative coupling of 3a with p-toluic acid 4b also gave 5ab in
good yield (entry 4). However, the coupling reaction with p-
nitrobenzoic acid 4c was relatively slow (entry 5). The a-
oxyacetylation of 3a gave the corresponding product 5ad in
moderate yield (entry 6). Importantly, polymerizable acrylic
acid 4e and methacrylic acid 4 f could be used as substrates
under our reaction conditions, although the yields of the
corresponding coupling products 5ae and 5af were moderate
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the detailed reaction mechanism and achieve enantioselective
oxidative coupling are underway in our laboratory.
Received: March 2, 2011
Published online: May 3, 2011
Keywords: cyclization · heterocycles · hypervalent compounds ·
.
iodine · oxidation
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1376. Unfortunately, no intermolecular oxidative a-etherifica-
tion of carbonyl compounds with phenols occurred in the
presence of catalytic amounts of R4NI and stoichiometric
amounts of H2O2 or TBHP.
Scheme 3. a-Oxyacylation of aldehydes 6. Reaction times and yields of
isolated 7 are shown. For details, see the Supporting Information.
[a] 2 mol% of piperidine was used. [b] 20 mol% of Bu4NI was used.
Bn=benzyl, TBS=tert-butyldimethylsilyl, MOM=methoxymethyl.
(4e) and methacrylic acid (4 f) could be used as coupling
partners for 6a as well as 3a, and the corresponding 7ae and
7af were obtained in good yields. Several functional groups
such as terminal or internal alkenyl (7ae, 7af, 7ha, 7ia),
benzyloxy (7da), silyloxy (7ea), acetal (7 fa), halogen (7ga),
and ester (7ja) groups, were tolerated under these conditions.
Several control experiments were run to identify the
active iodine species under the present reaction conditions,[9]
and the results suggested that either ammonium hypoiodite
([Bu4N]+[IO]À) or iodite ([Bu4N]+[IO2]À), which should be
generated in situ from ammonium iodide (Bu4NI) and a co-
oxidant, might be the active species.[7,11] We conducted
additional control experiments to gain insight into the
reaction pathway using the well-established fragmentation
of cyclopropylmethyl radicals.[12] The reaction of diphenyl-
cyclopropyl ketone 8 with 4a under the present reaction
conditions gave the rearranged conjugated diene 9 and
benzophenone 10 in approximately 70% and 10% yield,
respectively, along with several unidentified side products
(Scheme 4). The desired a-benzoyloxy ketone was not
observed. Interestingly, 10 was obtained as the only isolated
product in the absence of 4a (Scheme 4).[13] These results
suggest that the reaction mechanism most likely includes a
radical intermediate.[12] Additional studies on the reaction
mechanism are underway.
[8] During the preparation of our manuscript, Nagano, Chan,
Hayashi, and co-workers reported the a-oxyacylation of ketones
using 30 mol% of Bu4NBr and 70% aqueous TBHP in acetic
acid at 1108C; see: a) T. Nagano, Z. Jia, X. Li, G. Liu, A. S. C.
Chan, T. Hayashi, Chem. Lett. 2010, 39, 929. Notably, no reaction
occurred under our milder reaction conditions using tetrabutyl-
ammonium bromide or chloride instead of tetrabutylammonium
iodide as a pre-catalyst. For comparisons of our “iodine”-
catalyzed oxidations with their “bromine”-catalyzed oxidations,
see the Supporting Information. We previously reported our
preliminary results: b) M. Uyanik, T. Yasui, K. Ishihara, Proc.
89th Ann. Meet. Jpn. Chem. Soc. 2009, 3G3 – 12; c) M. Uyanik,
D. Suzuki, K. Ishihara, Proc. 90th Ann. Meet. Jpn. Chem. Soc.
2010, 3F5 – 09.
Scheme 4. Control experiments with 8.
In conclusion, we developed a general intra- and inter-
molecular direct a-oxyacylation reaction catalyzed by an
in situ generated ammonium (hypo)iodite species using either
hydrogen peroxide or TBHP as an environmentally benign
oxidant. The oxidative coupling of several structurally diverse
ketones, aldehydes, and 1,3-dicarbonyl compounds with
carboxylic acids gave the corresponding a-acyloxycarbonyl
compounds in good to excellent yields. Studies to elucidate
[9] For details, see the Supporting Information.
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5333

Communications
[10] Two selected patents: a) T. Iwamoto, H. Kitamura, T. Fujimoto
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Chem. Soc. 1992, 114, 10915.
(Jpn. Kokai Tokkyo Koho), JP2009144071, July 2, 2009; b) J.
Hatakeyama, S. Tachibana, Y. Osawa (Jpn. Kokai Tokkyo
Koho), JP2009169406, July 30, 2009.
[11] Kirihara et al. reported the in situ generation of hypoiodite that
catalyzed oxidative homocoupling of thiols to disulfides with
hydrogen peroxide; see: a) M. Kirihara, Y. Asai, S. Ogawa, T.
Noguchi, A. Hatano, Y. Hirai, Synthesis 2007, 3286; for selected
reviews of iodine(I)-promoted reactions, see: b) A. Kirschning,
H. Monenschein, W. Wittenberg, Angew. Chem. 2001, 113, 670;
Angew. Chem. Int. Ed. 2001, 40, 650; c) A. N. French, S.
[13] The reaction of
9 under identical reaction conditions of
Scheme 4 gave 10, but only in ꢀ 10% yield. Shim et al. reported
that 10 was obtained from a similar substrate (1,1-diphenyl-2-
vinylcyclopropane) under photooxidation conditions, see: S. C.
Shim, J. S. Song, J. Org. Chem. 1986, 51, 2817. Thus, 10 might be
produced from 8 and/or 9 under the reaction conditions shown in
Scheme 4.
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