Controlled alcohol-carbonyl interconversion by nickel catalysis

Article abstract of DOI:10.1002/anie.201102092

All in one pot: A general synthetic platform allows the interconversion of alcohols and carbonyl compounds in a predictable and controlled fashion in one pot. Under the action of a Ni catalyst, PhCl, CsF, and arylboronates, several multistep alcohol-carbonyl interconversions have been achieved with good overall efficiency (see scheme). A one-pot nickel-catalyzed synthesis of flumecinol (a hepatic microsomal enzyme inducer) has also been demonstrated. Copyright

Full text of DOI:10.1002/anie.201102092

Communications
DOI: 10.1002/anie.201102092
Alkohol–Carbonyl Interconversion
Controlled Alcohol–Carbonyl Interconversion by Nickel Catalysis**
Takehisa Maekawa, Hiromi Sekizawa, and Kenichiro Itami*
The ability to transform one functional group into another lies
at the heart of organic chemistry. Such functional-group
interconversions do not involve carbon–carbon bond-forming
reactions and are thus seen as less efficient for the con-
struction of complex molecules, however, these interconver-
sions are often critical to “set up” a molecule for such a
transformation. The oxidation of primary and secondary
alcohols (1 and 3) to produce aldehydes (2) and ketones (4)
prior to the addition of organometallic species is a prime
example (Scheme 1). Although this reaction is often essential
alcohol-to-carbonyl transformations are oxidative, the
reverse processes such as carbonyl addition reactions are
reductive in nature. Herein, we report that [Ni(cod)2]/IPr
(cod = 1,5-cyclooctadiene, IPr= 1,3-bis(2,6-diisopropylphe-
nyl)imidazol-2-ylidene) serves as a general catalyst for the
controlled one-pot oxidation–addition of alcohols and car-
bonyl compounds. We demonstrate the feasibility of all
possible multistep transformations in alcohol–carbonyl inter-
conversions (Scheme 1). A one-pot nickel-catalyzed synthesis
of flumecinol (a hepatic microsomal enzyme inducer) is also
described.
As an important progress toward controlled carbonyl–
alcohol interconversions, we recently established that the
[Ni(cod)2]/IPr catalyst promotes the otherwise difficult inter-
molecular 1,2-addition of arylboronate esters to unactivated
ketones and aldehydes.[2] Among the various arylboron
reagents screened, arylboronic acid neopentyl glycol ester
ArB(neo) turned out to be the most reactive. The advantage
of our [Ni–IPr] catalytic system[2] over other transition-metal-
catalyzed organoboron-based 1,2-additions is obvious from
the viewpoint of the substrate scope. While other catalytic
systems are generally only applicable to aldehydes[3] and some
electronically and strain-activated ketones,[4] our [Ni–IPr]
catalysis shows good reactivity not only toward aldehydes but
also toward diaryl, alkyl aryl, and dialkyl ketones under mild
reaction conditions.[2] The high reactivity of our [Ni–IPr]
catalyst might be partly due to the unique Ni0/NiII mechanism
(right-hand catalytic cycle, Scheme 2).
Since many transition-metal complexes are able to
mediate the oxidation of alcohols to aldehydes or ketones,[5]
we envisioned that our nickel catalysis could be extended to a
controlled alcohol–carbonyl interconversion through a one-
pot oxidation–addition with an appropriate combination of
oxidant and organoboron compound. When identifiying a
suitable reagent pair that is capable of achieving this
synthetically useful process, we were particularly attracted
by the reports of Navarro and co-workers who described the
application of [Ni(cod)2]/IPr, which is identical to our
organoboronate addition catalyst, in the oxidation of secon-
dary alcohols to ketones by using chlorobenzene (PhCl) as an
oxidant and KOtBu as a promoter (left-hand catalytic cycle,
Scheme 2).[6–8]
Scheme 1. Interconversion of alcohols and carbonyl compounds
through oxidation and organometallic addition. The Ni/IPr catalyst
described here promotes all possible multistep transformations in one
pot (1!3, 1!4, 1!5, 2!4, 2!5, 3!5).
for the subsequent carbon–carbon bond-forming transforma-
tion, it does add an extra, linear step to the sequence. Thus, we
imagined that performing the two steps, oxidation and
addition, together would greatly simplify synthetic routes by
essentially eliminating the need to carry out a preliminary
oxidation before converting, for example, a primary alcohol
(1) into a secondary alcohol (3), or similarly 3 into a tertiary
alcohol (5).
Numerous practical advantages are associated with such
one-pot multistep alcohol–carbonyl interconversions,[1] but a
uniform methodology has not been developed, partly because
of the incompatibility of the reaction conditions. Whereas
[*] T. Maekawa, H. Sekizawa, Prof. Dr. K. Itami
Department of Chemistry, Graduate School of Science
Nagoya University
We must stress that the merging of these two catalytic
cycles (Scheme 2) is not as straightforward as we initially
surmised. At the outset, there are two critical hurdles to
overcome for our strategy to provide a synthetically useful
protocol for alcohol–carbonyl interconversions: 1) the oxida-
tion of primary alcohols to aldehydes must be achieved
(Navarro and co-workers reported that primary alcohols do
not undergo oxidation under the conditions that they
described)[6] and 2) unwanted side-reactions such as the
Chikusa, Nagoya 464-8602 (Japan)
Fax: (+81)52-788-6098
E-mail: itami.kenichiro@a.mbox.nagoya-u.ac.jp
Homepage: http://synth.chem.nagoya-u.ac.jp
[**] This work was financially supported by a Grant-in-Aid for Scientific
Research from MEXT and JSPS (Japan). We thank Dr. Jean Bouffard
and Prof. Cathleen M. Crudden for fruitful discussions and critical
comments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102092.
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yield). The key to this discovery is the use of both a toluene/
1,4-dioxane solvent system and an excess of 6a and CsF.
Although the issue of product selectivity (3aa/4aa) remained
to be addressed, we were delighted to observe the feasibility
of the desired one-pot process.
As already reported by Navarro and co-workers, a system
consisting of the [Ni–IPr] catalyst and PhCl cannot oxidize
primary alcohols.[6] We confirmed that the reaction of 1a in
the absence of boron reagent 6a does not give rise to 2a under
our conditions (Scheme 3). Therefore, the arylboronate is
likely to play a secondary role in the oxidation of primary
alcohols, but its mode of action is debatable and unclear at
present.[11]
Nevertheless, with a method for the oxidation–addition of
primary alcohols 1 established, we next investigated con-
ditions for making both secondary alcohols 3 and ketones 4 in
a controlled manner. The amounts of arylboronate, PhCl, and
CsF were examined in greater detail by using the oxidation–
phenylation of 2-methylpropanol (1b) as a model reaction
(Table 1). It was found that secondary alcohol 3ab could be
Table 1: Controlled one-pot synthesis of secondary alcohol 3ab and
ketone 4ab from primary alcohol 1b and arylboronate 6a.[a]
Scheme 2. Nickel catalysis for the interconversion of alcohols and
carbonyls.
Suzuki–Miyaura coupling of organoboron species with PhCl
must be suppressed.[9]
We first investigated conditions for converting primary
alcohols 1 to secondary alcohols 3 through oxidation–addition
using a single Ni catalyst. Gratifyingly, we were able to find
suitable conditions after extensive screening. The reaction of
benzyl alcohol (1a, 1.0 equiv) and PhB(neo) (6a, 3.0 equiv) in
the presence of [Ni(cod)2] (10 mol%), IPr·HCl (10 mol%),
PhCl (2.4 equiv), and CsF (6.0 equiv) in toluene/1,4-dioxane
at 608C furnished the desired secondary alcohol 3aa and
ketone 4aa in 51% and 32% yield, respectively (Scheme 3;
see Ref. [10] for details regarding the numbering of com-
pounds). The formation of benzaldehyde (2a) was not
observed under these conditions. Notably, the formation of
biphenyl resulting from the Suzuki–Miyaura coupling of 6a
and PhCl was suppressed under these conditions (< 2%
Entry
6a
[equiv]
PhCl
[equiv]
CsF
[equiv]
3ab
[%]
4ab
[%]
1
2
3
4
5
6
7
8
1.2
1.2
1.2
2.0
3.0
3.0
3.0
3.0
3.0
3.0
1.2
1.2
2.4
2.4
1.0
0
1.0
2.0
2.4
2.4
1.0
4.0
4.0
6.0
4.0
6.0
0
6.0
10
10
12
18
15
22
42
0
0
0
0
0
<5
14
11
32
0
0
0
77
83
74
9[b]
10[b,c]
[a] Conditions: 1b (0.25 mmol, 1.0 equiv), 6a, [Ni(cod)2] (25 mmol, 10
mol%), IPr·HCl (25 mmol, 10 mol%), PhCl, CsF, toluene (1 mL), 1,4-
dioxane (1 mL), 608C, 12–24 h. [b] 15 mol% of [Ni(cod)2] and 15 mol%
of IPr·HCl were employed. [c] PhB(OH)2 was employed instead of 6a.
selectively obtained when 1b (1.0 equiv) was treated with 6a
(3.0 equiv), PhCl (1.0 equiv), and CsF (4.0 equiv) in the
presence of [Ni–IPr] catalyst (10 mol%; Table 1, entry 5).[12,13]
Both PhCl and CsF are necessary for this reaction to occur
(Table 1, entries 6 and 7). By increasing the amounts of PhCl
(2.0–2.4 equiv) and CsF (6.0–10 equiv), ketone 4ab was
produced selectively (Table 1, entries 8 and 9).[13] We also
found that phenylboronic acid can be used as an arylating
agent in this catalytic reaction (Table 1, entry 10).
Encouraged by the success of the oxidation–addition and
oxidation–addition–oxidation sequences from primary alco-
hols 1, we next investigated the addition–oxidation and
addition–oxidation–addition sequences from aldehyde 2b
Scheme 3. a) Nickel-catalyzed oxidation–addition of primary alcohol 1a
with PhCl and 6a. b) Reaction without the boron reagent shows its
critical role in the oxidation step.
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(Scheme 4). By adjusting the amounts of phenylboronate 6a,
PhCl, and CsF, both ketone 4ab and tertiary alcohol 5aab
were selectively synthesized from 2b in good yields.[13]
We subsequently investigated the two-step oxidation–
addition reaction to form synthetically more challenging
tertiary alcohols 5 from secondary alcohols 3 (Scheme 5).[10]
By tuning the reaction temperature and the amounts of PhCl
and CsF, we were able to establish general conditions for this
challenging reaction. As shown in Scheme 5, a range of
structurally diverse tertiary alcohols 5 can be synthesized in
good yields. Aryl alkyl (acyclic and cyclic), diaryl, and dialkyl
(acyclic and cyclic) carbinols 3 are all potential substrates for
this present nickel-catalyzed reaction. Both electron-rich and
electron-deficient arylboronates 6 displayed good reactivity.
As an ultimate one-pot multistep reaction, we finally
investigated whether a four-step oxidation–addition–oxida-
tion–addition sequence to produce tertiary alcohols 5 from
primary alcohols 1 would be possible with the [Ni–IPr]
catalyst (Scheme 6).[10] We also tried to introduce two differ-
Scheme 4. Controlled one-pot synthesis of ketone 4ab and tertiary
alcohol 5aab from aldehyde 2b and arylboronate 6a.
Scheme 6. Controlled one-pot synthesis of tertiary alcohols 5 from
primary alcohols 1 and arylboronates 6.
ent aryl groups into the final tertiary alcohol structure by
applying two arylboronates 6 in a sequential fashion. Gratify-
ingly, the following procedure was identified to realize this
four-step transformation with reasonable efficiency. A pri-
mary alcohol 1 (1.0 equiv) was treated with an arylboronate 6
(3.0 equiv) in the presence of [Ni(cod)2] (15 mol%), IPr·HCl
(15 mol%), PhCl (2.4 equiv), and CsF (10 equiv) in toluene/
1,4-dioxane at 608C for 10 h to furnish the corresponding
arylated ketone 4 in situ.[12] Then, a second arylboronate 6
Scheme 5. Controlled one-pot synthesis of tertiary alcohols 5 from
secondary alcohols 3 and arylboronates 6.
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Commun. 2005, 1459; k) K. Hirano, H. Yorimitsu, K. Oshima,
Org. Lett. 2005, 7, 4689; l) T. Arao, K. Kondo, T. Aoyama,
Tetrahedron Lett. 2007, 48, 4115.
(3.0 equiv) was added to the same flask and the resultant
mixture was further heated at 808C for 14 h. After aqueous
workup, the target tertiary alcohol 5 was obtained in
reasonable overall yield (Scheme 6).[13] Moreover, to show-
case this unprecedented multistep transformation, we suc-
cessfully demonstrated the one-pot synthesis of flumecinol
(5ain), a hepatic microsomal enzyme inducer.[14]
In summary, we have developed a general synthetic
platform for the interconversion of alcohols and carbonyl
compounds in a predictable and controlled fashion in one pot.
Under the action of the [Ni–IPr] catalyst, PhCl, CsF, and
arylboronates, all possible multistep alcohol–carbonyl inter-
conversions (1!3, 1!4, 1!5, 2!4, 2!5, 3!5) have been
achieved with good overall efficiency.[15] An unexpected role
of arylboronates in the oxidation of primary alcohols has been
shown. Furthermore, we applied our methodology to the one-
pot synthesis of a hepatic microsomal enzyme inducer. These
fundamental yet previously unachieved one-pot multistep
interconversions of alcohols and carbonyl compounds should
greatly streamline chemical syntheses.
[4] For electronically activated ketones, see: a) P. He, Y. Lu, C.-G.
Dong, Q.-S. Hu, Org. Lett. 2007, 9, 343; b) R. Shintani, M. Inoue,
T. Hayashi, Angew. Chem. 2006, 118, 3431; Angew. Chem. Int.
Ed. 2006, 45, 3353; c) S. L. X. Martina, R. B. C. Jagt, J. G.
de Vries, B. L. Feringa, A. J. Minnaard, Chem. Commun. 2006,
4093; d) R. Motoki, D. Tomita, M. Kanai, M. Shibasaki,
Tetrahedron Lett. 2006, 47, 8083; for strain-activated ketones,
see: e) T. Matsuda, M. Makino, M. Murakami, Org. Lett. 2004, 6,
1257; for intramolecular additions, see: f) G. Liu, X. Lu, J. Am.
Chem. Soc. 2006, 128, 16504. B-to-Zn transmetalation: g) C.
Bolm, J. Rudolph, J. Am. Chem. Soc. 2002, 124, 14850; for rare
examples of intermolecular additions to unactivated ketones,
albeit limited in scope, see: h) K. Ueura, S. Miyamura, T. Satoh,
M. Miura, J. Organomet. Chem. 2006, 691, 2821; i) S. Facchetti, I.
Cavallini, T. Funaioli, F. Marchetti, A. Iuliano, Organometallics
2009, 28, 4150.
[5] a) J.-E. Bꢂckvall, Modern Oxidation Methods, Wiley-VCH,
Weinheim, 2004; b) M. J. Schultz, M. S. Sigman, Tetrahedron
2006, 62, 8227; c) J. Muzart, Tetrahedron 2003, 59, 5789.
[6] a) D. F. Brayton, C. Mocka, C. Berini, O. Navarro, Org. Lett.
2009, 11, 4244; b) C. Berini, O. H. Winkelmann, J. Otten, D. A.
Vicic, O. Navarro, Chem. Eur. J. 2010, 16, 6857.
[7] During the reviewing process of this manuscript, we became
aware that the group of Navarro also succeeded in merging their
reaction and our reactions. C. Berini, O. Navarro, Chem.
Commun. 2011, DOI: 10.1039/C1CC10826C.
[8] For selected examples of using haloarenes as oxidants for the
oxidation of alcohols, see: a) Y. Tamaru, Y. Yamamoto, Y.
Yamada, Z. Yoshida, Tetrahedron Lett. 1979, 20, 1401; b) X. Bei,
A. Hagemeyer, A. Volpe, R. Saxton, H. Turner, A. S. Guram, J.
Org. Chem. 2004, 69, 8626.
[9] For selected examples of nickel-catalyzed Suzuki–Miyaura
coupling, see: a) V. Percec, J.-Y. Bae, D. H. Hill, J. Org. Chem.
1995, 60, 1060; b) S. Saito, M. Sakai, N. Miyaura, Tetrahedron
Lett. 1996, 37, 2993; c) S. Saito, S. Ohtani, N. Miyaura, J. Org.
Chem. 1997, 62, 8024; d) S. B. Blakey, D. W. C. MacMillan, J.
Am. Chem. Soc. 2003, 125, 6046; e) J. Liu, M. J. Robins, Org.
Lett. 2004, 6, 3421; f) Z.-Y. Tang, Q.-S. Hu, J. Am. Chem. Soc.
2004, 126, 3058.
[10] In this study, we used alcohols, carbonyl compounds, and
boronates with various substituents. For simplicity, we assigned
letters to these substituents: phenyl (a), 2-propyl (b), 2-naphthyl
(c), methyl (d), 3,5-Me2C6H3 (e), 4-MeOC6H4 (f), 3-MeOC6H4
(g), 4-FC6H4 (h), 4-CF3C6H4 (i), 4-Me3SiC6H4 (j), 4-PhC6H4 (k),
butyl (l), heptyl (m), ethyl (n). Furthermore, capital letters
indicate that the carbon atom at the reaction center was part of a
cycle.
[11] We currently assume that the Lewis acid nature of arylboronate
(interaction of the boron atom with the oxygen atom of the
alcohol) is important in one of the elementary steps of the
oxidation catalytic cycle; namely the formation of a nickel
alkoxide or the b-hydrogen-elimination step. Related to this
assumption, we prepared PhCH2OB(neo) and subjected it to our
standard conditions. However, the expected oxidation product
(benzaldehyde) was not observed. More extensive mechanistic
studies to reveal why arylboronates together with PhCl are
necessary for the oxidation of alcohols are currently ongoing.
[12] An excess of arylboronate 6 is completely consumed under these
conditions.
Received: March 24, 2011
Revised: May 5, 2011
Published online: June 17, 2011
Keywords: alcohols · boronic acids · homogeneous catalysis ·
.
nickel · oxidation
[1] For reviews on one-pot multistep transformations, see: a) J.-C.
Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan, Chem. Rev. 2005,
105, 1001; b) C. J. Chapman, C. G. Frost, Synthesis 2007, 1; c) S. J.
Broadwater, S. L. Roth, K. E. Price, M. Kobaslija, D. T.
McQuade, Org. Biomol. Chem. 2005, 3, 2899; d) L. F. Tietze,
G. Brasche, K. M. Gericke, Domino Reactions in Organic
Synthesis, Wiley-VCH, Weinheim, 2006; e) K. C. Nicolaou,
D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118, 7292;
Angew. Chem. Int. Ed. 2006, 45, 7134; f) C. Grondal, M. Jeanty,
D. Enders, Nat. Chem. 2010, 2, 167. Selected examples: g) K.
Itami, T. Nokami, Y. Ishimura, K. Mitsudo, T. Kamei, J. Yoshida,
J. Am. Chem. Soc. 2001, 123, 11577; h) K. Itami, T. Kamei, J.
Yoshida, J. Am. Chem. Soc. 2003, 125, 14670; i) K. Itami, K.
Tonogaki, Y. Ohashi, J. Yoshida, Org. Lett. 2004, 6, 4093; j) K.
Itami, M. Mineno, N. Muraoka, J. Yoshida, J. Am. Chem. Soc.
2004, 126, 11778; k) H. Lebel, C. Ladjel, L. Brꢀthous, J. Am.
Chem. Soc. 2007, 129, 13321; l) H. Ishikawa, T. Suzuki, H. Orita,
T. Uchimaru, Y. Hayashi, Chem. Eur. J. 2010, 16, 12616; m) K.
Takahashi, M. Yamashita, T. Ichihara, K. Nakano, K. Nozaki,
Angew. Chem. 2010, 122, 4590; Angew. Chem. Int. Ed. 2010, 49,
4488.
[2] J. Bouffard, K. Itami, Org. Lett. 2009, 11, 4410.
[3] For Rh-based catalysts, see: a) M. Sakai, M. Ueda, N. Miyaura,
Angew. Chem. 1998, 110, 3475; Angew. Chem. Int. Ed. 1998, 37,
3279; b) R. A. Batey, A. N. Thadani, D. V. Smil, Org. Lett. 1999,
1, 1683; c) M. Ueda, N. Miyaura, J. Org. Chem. 2000, 65, 4450;
d) A. Fꢁrstner, H. Krause, Adv. Synth. Catal. 2001, 343, 343; for
Pd, see: e) M. Kuriyama, R. Shimazawa, R. Shirai, J. Org. Chem.
2008, 73, 1597; for Ru, see: f) Y. Yamamoto, K. Kurihara, N.
Miyaura, Angew. Chem. 2009, 121, 4478; Angew. Chem. Int. Ed.
2009, 48, 4414; for Fe, see: g) T. Zou, S.-S. Pi, J.-H. Li, Org. Lett.
2009, 11, 453; for Cu, see: h) D. Tomita, M. Kanai, M. Shibasaki,
Chem. Asian J. 2006, 1, 161; for Pt, see: i) Y.-X. Liao, C.-H. Xing,
P. He, Q.-S. Hu, Org. Lett. 2008, 10, 2509; for Ni, see: j) G.
Takahashi, E. Shirakawa, T. Tsuchimoto, Y. Kawakami, Chem.
[13] High selectivity in product distribution could be explained by the
following (assumed) characteristics of the reactions: 1) the four
key steps (oxidation of primary alcohol to aldehyde, addition to
aldehyde, oxidation of secondary alcohol to ketone, and addition
to ketone) each require one equivalent of arylboronate relative
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to the substrate; 2) the oxidation step requires one equivalent of
[15] Other organometallic reagents could be applied in the present
multistep alcohol–carbonyl interconversion. While attempts to
apply organozinc reagents were so far unsuccessful, some
Grignard reagents could be used, for example, in the synthesis
of tertiary alcohols from primary or secondary alcohols. How-
ever, the carbonyl addition steps are most likely not catalyzed by
nickel. Details will be reported in due course.
chlorobenzene relative to the substrate; 3) arylboronate addi-
tion to the ketone requires a reaction temperature of 808C;
4) arylboronate decomposes at 608C in parallel to its participa-
tion in oxidation and addition.
[14] J. T. Lahtela, B. Gachalyi, S. Eksymꢂ, A. Hꢂmꢂlꢂinen, E. A.
Sotaniemi, Br. J. Clin. Pharmacol. 1986, 21, 19.
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