One-pot nitrile aldolization/hydration operation giving β-hydroxy carboxamides

Article abstract of DOI:10.1002/asia.201000921

Rhodium to the rescue: The formal aldol products of carboxamides (CONH ₂) were obtained by using a Rh^I(OR) (R=H, Me) catalyst under essentially neutral pH and ambient conditions. This novel aldol strategy is based on the catalytic al

Full text of DOI:10.1002/asia.201000921

COMMUNICATION
DOI: 10.1002/asia.201000921
One-Pot Nitrile Aldolization/Hydration Operation Giving b-Hydroxy
Carboxamides
Akihiro Goto,[a] Hiroshi Naka,[b] Ryoji Noyori,[a, b, c] and Susumu Saito*[a, c]
On the occasion of the 150th anniversary of the Department of Chemistry, The University of Tokyo
Carboxamide functionalities (CONH2) are versatile syn-
thetic intermediates or building blocks, and have been
widely used in the Hofmann rearrangement,[1] N-arylation,[2]
N-allylation,[3] and N-alkylation[4] reactions. In addition,
CONH2 is a useful protected form of carboxylic acid[5] and a
potent pharmacophore in many drug candidates.[6] There-
À
fore, a catalytic chemical transformation incorporating the
CR2CONH2 moiety (R=H or alkyl) into a molecular frame-
work through a carboxamide enolate, thus effecting a
À
carbon carbon bond-forming reaction would be of consider-
able practical importance. However, such a reaction has
thus far remained elusive, primarily due to the considerably
low acidity of the a-proton of carboxamide in comparison to
CONH2 (pKa =~25 in dimethyl sulfoxide).[7] The pKa value
Scheme 1. General scheme of the nitrile aldolization/hydration sequence.
of carboxamides in dimethyl sulfoxide is approximately 35,[7]
the highest value out of those reported for aldehydes and
ketones (pKa =~27 in dimethyl sulfoxide),[7] or for esters
type reaction (R=H, Me) of nitriles[8] (pKa =~31 in dimeth-
yl sulfoxide),[7] followed by in situ hydration of the nitrile
functionality.[9,10] This consecutive process was accommodat-
ed in a one-pot operation that minimized the amount and
different varieties of salt wastes.
(pKa =~31 in dimethyl sulfoxide).[7]
Herein, we report an alternative pathway to break out of
this problem (Scheme 1). The formal aldol products of car-
boxamides were obtainable by the RhIOR-catalyzed aldol-
First, the rhodium(I) catalyst was prepared by treatment
of [RhACTHNUTRGENNUG(OMe)ACHTUNGTERN(NGUN cod)]2 (cod=cycloocta-l,5-diene) with Cy3P
(1:2; Cy=cyclohexyl) in anhydrous tetrahydrofuran at 258C
for 15 minutes under argon. After removal of tetrahydrofur-
an and residual cycloocta-l,5-diene in vacuo, argon-filled
tert-butanol was added to yield a solution of rhodium cata-
lyst. Nitrile aldolization was carried out by using PhCHO
(1a) and acetonitrile (2a) with the rhodium(I) catalyst at
258C (Rh: 1.0ꢀ10À2 m). Subsequent removal of any volatile
components including excess acetonitrile gave a bright red/
orange slurry containing b-hydroxy nitrile 4aa. Addition of
argon-filled isopropanol, followed by treatment with
Na2CO3 and H2O at 258C, gave b-hydroxy carboxamide 3aa
in 96% yield.[11] Likely dehydration products, such as a,b-
unsaturated carboxamide and nitrile, were not detected.
Addition of a catalytic amount of Na2CO3 was critical for
this one-pot operation. In the absence of Na2CO3, little hy-
[a] Dr. A. Goto, Dr. R. Noyori, Dr. S. Saito
Department of Chemistry
Graduate School of Science
Nagoya University
Chikusa, Nagoya 464-8602 (Japan)
Fax : (+81)52-789-5945
E-mail: saito.susumu@f.mbox.nagoya-u.ac.jp
[b] Dr. H. Naka, Dr. R. Noyori
Research Center for Materials Science
Nagoya University
Chikusa, Nagoya 464-8602 (Japan)
[c] Dr. R. Noyori, Dr. S. Saito
Institute for Advanced Research
Nagoya University
Chikusa, Nagoya 464-8601 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000921.
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Chem. Asian J. 2011, 6, 1740 – 1743

Table 2. Catalytic aldolization of 2a with various aldehydes 1 and subse-
quent hydration of 4 in a one-pot operation.[a]
dration took place (3aa: <15%) even in the presence of
40–110 molar amounts of water in isopropanol (Rh: 1.0ꢀ
10À2–2.9ꢀ10À2 m). The requirement of a weak base is pre-
sumably related to the marginal but detrimental formation
of benzoic acid from 1a. In fact, a tiny amount of the acid
was detected by GC-MS after the aldolization or hydration
step. Benzoic acid was probably formed by side reactions,
such as the Cannizzaro and/or Tishchenko reaction during
the aldolization followed by hydrolysis. Indeed, the hydra-
tion was completely or partially suppressed when the rho-
dium(I)-promoted hydrations were performed separately
using benzonitrile as a standard model[10q] in the presence of
a small amount of benzoic acid or its ester (Table 1, en-
tries 2–4). In sharp contrast, addition of a catalytic amount
of Na2CO3 promoted the hydration reaction (entry 5).
Entry
Aldehyde
3 [%][b]
4 [%][c]
1
PhCHO (1a)
1a
o-MeOC6H4CHO (1b)
p-ClC6H4CHO (1c)
b-NaphCHO (1d)
p-CH3C6H4CHO (1e)
96
92
96
94
77
70
<1
7
<1
<1
<1
2
2[d]
3
4
5[e]
6
7[e,f]
(1 f)
84
6
8
ACHTUNGTNER(NUNG 1g)
65
3
9[d–f]
10[e]
1g
87
<1
<1
G
>99
11
CH
1i
(CH2)3CHO (1i)
70
38
94
91
13
10
<1
<1
Table 1. Detrimental effects of carboxylic acid and ester on nitrile hydra-
tion.[a]
12[d]
13
cHexCHO (1j)
tBuCHO (1k)
14[e,f]
[a] Unless otherwise specified, a molar ratio of 1:2a=1:38 was used. The
first step: [RhACTHUNGRTENNUG(OMe)ACHTUGNTRNE(NUGN cod)]2:Cy3P=0.02:0.08; tBuOH, 258C, 24 h (Rh:
6.5ꢀ10À3–1.0ꢀ10À2 m); the second step: H2O:Na2CO3 =40:0.1, iPrOH,
258C, 24–48 h (Rh: 2.3ꢀ10À2 m). [b] Yield of isolated purified 3. [c] Yield
Entry
Additive(s) [mol %]
Benzamide [%][b]
of isolated purified 4. [d] The first step: [Rh(OH)ACHTNUGTRNEN(UG cod)]2:Cy3P:K2CO3 =
0.02:0.08:0.1, tBuOH, 258C, 24 h (Rh: 1.0ꢀ10À2 m); the second step: H2O
(1:H2O=1:40), iPrOH, 258C, 24–48 h (Rh: 2.3ꢀ10À2 m). [e] Hydration
step: 1:H2O=1:80, 48 h. [f] Aldolization step: 1:2=1:77.
1
2
3
4
5
6
None
99
72
<1
<1
99
Benzyl benzoate (5%)
Benzoic acid (5%)
Benzoic acid (1%)
Benzoic acid (1%)/Na2CO3 (2.5%)
Benzyl alcohol (5%)
action conditions using [Rh(OH)
overall yield as the general reaction conditions using [Rh-
(OMe)(cod)]2. (5) Aliphatic aldehydes were well suited for
ACHTUNGTERN(NNUG cod)]2 gave as good an
98
[a] Rh:Cy3P:nitrile:H2O=1:2:100:2000; [Rh]=7.4ꢀ10À3 m. [b] Yield of
isolated purified product.
A
ACHTUNGTRENNUNG
the catalysis, because significant self-condensation was not
observed (entries 11 and 13). Indeed, the aldolization step in
the absence of an alkaline carbonate, performed under
more neutral pH, gave a better result for the valeraldehyde
transformation (entry 11 vs 12). A retro-aldol reaction was
nonobservable or negligible in all runs (Table 2). The
CONH2 groups, having rather acidic hydrogen atoms, did
not prevent the hydration from taking place. These observa-
tions suggest that more neutral pH conditions are advanta-
geous for generating the desired products.
A range of a-substituted nitriles are potentially capable of
undergoing the reaction sequence of aldolization/hydration.
Indeed, when a similar reaction sequence was applied to ni-
triles 2b and 2c, which have the elongated or branched
carbon chain, the corresponding carboxamides 3ab and 3ac
were obtained almost quantitatively (Scheme 2).
Other examples of this transformation are listed in
Table 2, which illustrate the broad applicability of the reac-
tion (see the footnote [a] of Table 2) with a range of alde-
hydes. There are several characteristic features in each of
the reaction steps: (1) The use of a polar solvent, such as di-
methyl sulfoxide, N,N-dimethylformamide, N,N-dimethyla-
cetamide, or 1,3-dimethyl-2-imidazolidinone (DMI), in place
of tert-butanol gave a faster reaction rate of aldolization;[8 h]
however, the second hydration step was barely detectable
when isopropanol and water (1a:H2O=1:40) were added to
the initial solvent (e.g., dimethyl sulfoxide), whereby a
mixed solvent system (Rh: 5.8ꢀ10À3 m) was prepared for the
second step. (2) Of the alcoholic solvents tested in this
study, the first and second steps of the reaction were best
performed in tert-butanol and isopropanol, respectively. In
fact, if the general reaction conditions were followed with
the exception of tert-butanol or isopropanol being used in
the second step or in the first step, respectively, yields of
3aa decreased. (3) Na2CO3 was the most effective alkaline
metal carbonate (amongst Li2CO3, K2CO3, and Cs2CO3) for
the hydration step, to obtain maximum conversion.
(4) When [Rh
(cod)]2, K2CO3 was the additive of choice for the aldoliza-
tion (entry 2). However, apart from entry 9, none of the re-
ACHTUNGTRENNUNG(OMe)ACHTUNGTERN(NUGN cod)]2 was replaced by [Rh(OH)-
ACHTUNGTRENNUNG
Scheme 2. Nitrile Aldolization/hydration using other nitriles. [a] Reaction
conditions were the same as described in footnotes [e] and [f] of Table 2.
Chem. Asian J. 2011, 6, 1740 – 1743
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S. Saito et al.
COMMUNICATION
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In summary, we have developed a straightforward method
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Experimental Section
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A 1.0m toluene solution of Cy3P (40 mL, 0.04 mmol) at 258C was added
to a solution of [RhACHTUNGTRENNUNG(OMe)ACHTUGNTREN(NUGN cod)]2 (4.8 mg, 0.01 mmol) in THF (0.5 mL)
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tBuOH (1 mL) was added to the resulting slurry, followed by sequential
addition of nitrile 2 (19–38 mmol) and aldehyde 1 (0.5 mmol). The reac-
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Acknowledgements
This work was supported by a Grant-in-Aid for Young Scientists (A) and
Basic Research (B) from JSPS, and Scientific Research on Priority Areas
“Advanced Molecular Transformations of Carbon Resource” from
MEXT, as well as Asahi Glass and the Sumitomo Foundation.
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Keywords: aldol reaction · catalysis · hydration · nitriles ·
rhodium
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One-Pot Aldol Reactions
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Received: December 22, 2010
Published online: March 17, 2011
Chem. Asian J. 2011, 6, 1740 – 1743
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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