Catalytic Transfer Hydration of Cyanohydrins to α-Hydroxyamides

Article abstract of DOI:10.1021/jacs.8b12877

We report the palladium(II)-catalyzed transfer hydration of cyanohydrins to α-hydroxyamides by using carboxamides as water donors. This method enables selective hydration of various aldehyde- and ketone-derived cyanohydrins to afford α-mono- and α,α-disubstituted-α-hydroxyamides, respectively, under mild conditions (50 °C, 10 min). The direct conversion of fenofibrate, a drug bearing a benzophenone moiety, into a functionalized α,α-diaryl-α-hydroxyamide was achieved by means of a hydrocyanation-transfer hydration sequence. Preliminary kinetic studies and the synthesis of a site-specifically ¹⁸O-labeled α-hydroxyamide demonstrated the carbonyl oxygen transfer from the carboxamide reagent into the α-hydroxyamide product.

Full text of DOI:10.1021/jacs.8b12877

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Communication
Catalytic Transfer Hydration of Cyanohydrins to #-Hydroxyamides
Tomoya Kanda, Asuka Naraoka, and Hiroshi Naka
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12877 • Publication Date (Web): 27 Dec 2018
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Catalytic Transfer Hydration of Cyanohydrins to α-Hydroxyamides
Tomoya Kanda,† Asuka Naraoka,† and Hiroshi Naka#,*
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†Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
#Research Center for Materials Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
Supporting Information Placeholder
amino-analogs of cyanohydrins, but the applicability of this
ABSTRACT: We report the palladium(II)-catalyzed transfer
hydration of cyanohydrins to α-hydroxyamides by using
method to base-sensitive cyanohydrins remains unclear.14 In
particular, selective hydration of diarylcyanohydrins has been
hardly achieved (Figure 1A, (ii)). Thus, a universal method for
catalytic nitrile hydration that is capable of hydrating these
challenging substrates remains to be developed.
carboxamides as water donors. This method enables selective
hydration of various aldehyde- and ketone-derived
cyanohydrins to afford α-mono- and α,α-disubstituted-α-
hydroxyamides, respectively, under mild conditions (50 °C, 10
min). The direct conversion of fenofibrate, a drug bearing a
benzophenone moiety, into a functionalized α,α-diaryl-α-
hydroxyamide
was
achieved
by
means
of
a
hydrocyanation−transfer hydration sequence. Preliminary
kinetic studies and the synthesis of a site-specifically 18O-
labeled α-hydroxyamide demonstrated the carbonyl oxygen
transfer from the carboxamide reagent into the α-hydroxyamide
product.
The catalytic, chemoselective hydration of nitriles is one of
the most important issues in both laboratory and industrial
synthetic chemistry. Hydration of cyanohydrins (1) to α-
hydroxycarboxamides (2) represents a primary target in this
field (Figure 1A, (i)).1 Cyanohydrins are readily available
through (asymmetric) cyanation of aldehydes or ketones.2
Further, α-hydroxyamide substructures are found in various
bioactive compounds, and are easily convertible to α-hydroxyl
esters, α-hydroxycarboxylic acids, and acrylic analogs.3,4 The
hydration of acetone cyanohydrin by manganese oxide catalyst
is used in the industrial production of methyl methacrylates.5
Despite the utility of recently developed transition-metal
catalysts for nitrile hydration,6 however, hydration of
cyanohydrins by homogeneous catalysts is not straightforward,
firstly because cyanohydrins often decompose into carbonyl
compounds and hydrogen cyanide (HCN), especially at high
temperature or under basic conditions, and secondly, because
HCN often deactivates the metal catalysts (Figure 1A, (i)).1 The
hydration of aldehyde-derived cyanohydrins could be
effectively catalyzed by borates.7 Tyler et al. introduced a series
of elegant methods using Pt,8 Mo,8 and Ru9 complexes as well
as Pt and Ag nanoparticle catalysts.10 Very recently, Virgil,
Grubbs, et al. developed improved Pt complexes for catalytic
cyanohydrin hydration.11 Enzymatic methods have been also
developed.12 These catalytic methods are more atom-
economical than the conventional methods using stoichiometric
acid- or base-reagents. However, most of the existing catalysts
are far less effective in the hydration of ketone-derived
cyanohydrins than aldehyde-derived cyanohydrins due to the
lower stability of α,α-disubstituted cyanohydrins.13
Beauchemin et al. recently introduced an efficient
carbohydrate/base-promoted hydration of α-aminonitriles,
Figure 1. (A) Previous approaches, order of difficulty in nitrile
hydration, and (B) working hypothesis of this work.
In order to solve this problem, we report here the
palladium(II)-catalyzed transfer hydration of cyanohydrins to
α-hydroxyamides using carboxamides as a water donor (Figure
1B). We postulate this reaction as catalytic transfer hydration,
in which H2O is formally transferred from the H2O donor to
cyanohydrin through the activation of nitrile and amide by
cationic PdII catalysts, as inspired by the concept of transfer
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hydrogenation, in which H2 is formally transferred from
electron-deficient substituents were significantly less reactive,
as compared with linear alkyl substituents. The use of water21,22
and aldoxime23 as a H2O donor was ineffective under otherwise
identical conditions. Further details on the influences by
reaction parameters are shown in Tables S1−5 in Supporting
Information (SI). Acetic acid proved to be the best solvent for
the efficient transfer hydration of 1a, yet the reaction proceeded
in other carboxylic acids, alcoholic solvents, and mixed solvent
systems of water with THF, acetonitrile, or acetone albeit with
decreased yields (Table S3).
hydrogen donors to acceptors.15
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During the course of our recent study seeking efficient
methods for catalytic hydration of unsaturated organic
compounds,16 we found that the use of palladium chloride and
carboxamide17−19 allows the hydration of acetone cyanohydrin
(1a). The conversion of nitriles to amides by palladium chloride
and acetamide was initially described by Maffioli et al. as a
reverse reaction of the dehydration of amides to nitriles.17a After
a thorough examination of this transfer hydration of 1a, the
optimum reaction conditions were identified. The catalytic
transfer hydration of 1a (1.0 mmol) at 50 °C for 10 min using
n-hexanamide (4 equiv), Pd(NO3)2 (2 mol %), and acetic acid
(2 mL) gave 2a in an excellent isolated yield (Table 1A). The
reaction was stopped by adding a metal scavenger (R-cat-Sil-
AP, 50 mg). The rapid and efficient catalytic conversion of 1a
to 2a (94% yield in 10 min) was unprecedented, and the
calculated turnover frequency (TOF) of 280 h−1 is at least 15
times larger as compared with those reported for the hydration
of 1a [Pt complexes (TOF (h−1) of 0.02 and 18);8,11 a Mo
complex (0.07);8 Ru complexes (1.3);9 Pt nanoparticles
(0.51);10a Ag nanoparticles (0.70)].10b
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Table 2. Scope of the Catalytic Transfer Hydrationa
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Table 1. Catalytic Transfer Hydration of 1aa
aTypical conditions: 1a (1.0 mmol), acetamide (4.0 mmol),
Pd(NO3)2 [2 mol % for (B); 1 mol % for (C)], AcOH (2 mL),
mesitylene (0.34 mmol, internal standard for 1H NMR analysis), 50
b
ºC, 10 min, N2; metal scavenger (R-cat-Sil-AP, 50 mg). Isolated
yield. cNMR yield.
The catalyst effects are summarized in Table 1B. Cationic
palladium(II) catalysts effectively promoted the hydration of
1a.20 In contrast, catalysts bearing (pseudo)halogen ligands (Cl,
Br, I, and CN) were ineffective. The transfer hydration of 1a
scarcely proceeded with Pd0(dba)2 or in the absence of a Pd
catalyst. The reactivity of H2O donors was studied in the
presence of a decreased amount (1 mol %) of Pd(NO3)2 (Table
1C). The use of the amide reagent was found to be prerequisite:
the transfer hydration of cyanohydrin 1a did not proceed at all
in its absence. Carboxamide bearing a linear alkyl chain
afforded 2a in better yield (65−75%) than acetamide (42%). An
amide reagent bearing a longer alkyl chain (n-C11H23) was
poorly soluble in the reaction mixture and remained unreacted.
Amides bearing a sterically more demanding substituent and
b
c
aConditions analogous to Table 1A. Isolated yield. The R:S
ratio of (R)-2g = 91:9, as determined by chiral GC after acetylation
of the hydroxyl group. The R:S ratio of (R)-1g = 81:19.
The substrate scope of the Pd-catalyzed transfer hydration
was investigated under the optimized conditions (Table 2).24
The current transfer hydration of cyanohydrins proved to be
effective for the conversion of various cyanohydrins bearing
hydrogen or alkyl substituents. Glycolonitrile (1b) and
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lactonitrile (1c) underwent complete conversion in 10 min to and practical access to this class of products from the
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the corresponding hydroxyamides. Analogously to 1a, the
transfer hydration of dialkyl-substituted cyanohydrins 1d and
1e proceeded smoothly. Cyanohydrin 1f derived from ethyl
acetoacetate was hydrated to amide 2f without loss of the ester
functionality. In all these cases, products 2 were obtained in
excellent isolated yields (91−98%).
benzophenone analogs.
With the transfer hydration protocol on cyanohydrins in
hand, we next explored the direct derivatization of ketone
(Figure 2C). As a representative example, we chose fenofibrate
(an anti-hyperlipidemic drug), bearing a benzophenone moiety
with ester, ether, and chlorine functionalities. This ketone was
directly converted to the corresponding α,α-diaryl-α-
hydroxyamide 2n in 82% isolated yield for 2 steps by sequential
hydrocyanation and Pd-catalyzed transfer hydration.
Monoaryl-substituted cyanohydrins (R)-1g−1i were less
reactive and thermally less stable than the aliphatic analogs, but
could be successfully hydrated in 10 min to the corresponding
amides in good to excellent yields with 4 or 5 mol % Pd catalyst
(Table 2). A chiral cyanohydrin (R)-1g underwent the same
reaction to furnish the corresponding (R)-2g in 89% yield with
retention of the chirality around the α-carbon center. A
congested α,ß-dihydroxyamide 2i was produced from benzoin-
derived 1i, an intermediate of the benzoin condensation of
benzaldehyde with cyanide. The stereochemistry at the α- and
ß-carbons was completely retained to give the amide bearing an
anti-diol moiety exclusively (see SI).
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The transfer hydration protocol was also effective in the
synthesis of hydroxyamides regio-specifically 18O-labeled at
the carbonyl moiety. When 18O-labeled n-hexanamide25 was
used for the transfer hydration of cyanohydrin 1a, the labeled
α-hydroxyamide [18O]2a was obtained in 98% yield (Figure
3A). The degree of 18O labeling (90% 18O) was confirmed by
ESI-MS analysis (Figure 3B). The ratio of intensities for
[(18O)2a + Na]+ and [2a + Na]+ (90:10, Figure 3B (ii)) was
nearly identical to that for the 18O-labeled amide reagent. The
13C{1H} NMR and IR analyses confirmed that the 18O atom is
incorporated at the carbonyl group (see SI). Thus, this method
offers new opportunities for site-specific 18O-labeling of
carboxamide derivatives. At the same time, the result proved
that the oxygen atom in the amide reagent is unambiguously
transferred to the nitrile substrate without any oxygen-exchange
with water or acetic acid in the Pd-catalyzed transfer hydration
of nitriles. This reaction pattern is in marked contrast to the Pd-
catalyzed nitrile hydration using water21,22 and is similar to the
conversion of nitriles to amides using aldoximes.23
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Figure 2. (A) Gram-scale catalytic transfer hydration of 1j. (B)
Transfer hydration of O-acetylated cyanohydrin. (C) Direct drug
derivatization via hydrocyanation−transfer hydration sequence.
α,α-Diaryl-substituted cyanohydrins were highly unstable
and readily decomposed into the benzophenones upon storage
at room temperature. Nevertheless, these substrates were
hydrated quickly to afford 2j−m in 71−82% yields, without the
loss of the nitro (in 1k) or chlorine (in 2l) functionality (Table
2). Because aryl substituted products 2j−m were poorly soluble
to water, they could be purified without involving any
chromatographic procedures: the products were isolated by the
precipitation upon addition of water or recrystallization.
Furthermore, the current protocol was found to be gram-
scalable, as exemplified by the transfer hydration of
cyanohydrin 1j to 2j (Figure 2A). In addition, the presence of
the hydroxyl group in cyanohydrins is not prerequisite:
hydration of acetylated mandelonitrile smoothly proceeded to
give the corresponding amide in 97% yield (Figure 2B).
Overall, this transfer hydration strategy appears to offer general
Figure 3. (A) Transfer hydration of 1a using n-[18O]hexanamide
(90 atom % 18O). (B) ESI-MS spectra of (i) 2a and (ii) [18O]2a.
To better understand the catalytic profile, preliminary kinetic
studies were conducted (Figure 4). Monitoring of the Pd-
catalyzed transfer hydration of 1a with acetamide showed the
smooth reaction progress with 2 mol % of Pd(NO3)2 catalyst at
40 °C (Figure 4A). The pseudo-first-order plot indicated the
presence of two mechanistic periods (0−1 min and 1−10 min)
in the catalytic profile (Figure 4B). The reaction exhibited a
first-order dependence on [1a] in both periods, indicating the
participation of one molecule of 1a in the catalytic cycle. This
profile was observed in results with different catalyst
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concentrations ([Pd]0 = 5−25 mM). The reaction showed first
and second orders in [Pd]0 during t = 0−1 min (Figure 4C) and
1−10 min (Figure 4D), respectively. This result implies the
involvement of reactive mononuclear and less reactive
binuclear Pd species in these periods.26 Further mechanistic
studies are currently underway.
amides with PdCl2 in aqueous acetonitrile.17a Coproduction of
acetonitrile was confirmed by H NMR analysis (Figure S1).
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The incorporation of 18O atom to 2a from 18O-labeled n-
hexanamide in Figure 3 is in line with the proposed catalytic
cycle in Figure 5. High reactivity of electron-rich aliphatic
amides as H2O donors implies that the product yields are
affected by the equilibrium point depending on the relative
stability of starting materials and products. For example, the
transfer hydration of 1b with acetamide to 2b and acetonitrile is
exothermic by −29.4 kJ mol−1 in H and −26.2 kJ mol−1 in G
as estimated by DFT calculations (M06-2X/6-311++G**, T =
25 °C). This reaction pattern is also closely related to the shuttle
catalysis stated by Morandi et al.27
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In summary, we have developed a Pd-catalyzed transfer
hydration of cyanohydrins to afford α-hydroxyamides by using
carboxamides. This is the first example of a cyanohydrin
hydration reaction with a reasonably broad substrate scope,
including aromatic ketone-derived cyanohydrins. This catalytic
transfer hydration strategy should present a new approach for
inventing methods for challenging chemical transformations.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Tables S1−5, Figure S1, experimental procedures, and spectral data
(PDF); 1H and 13C NMR spectra (PDF).
AUTHOR INFORMATION
Corresponding Author
Figure 4. (A) Reaction time course and (B) Pseudo-first-order plot
of the transfer hydration of 1a using Pd(NO3)2 (2 mol %, 10 mM).
Dependence of the rate constant on [Pd]0 during (C) t = 0−1 min
and (D) 1−10 min. Conditions: [1a]0 = 0.50 M, [CH3CONH2]0 =
2.0 M, [Pd(NO3)2]0 = 5−25 mM, AcOH (2 mL), 40 °C.
*h_naka@nagoya-u.jp
ORCID
Asuka Naraoka: 0000-0001-6086-2700
Hiroshi Naka: 0000-0002-1198-6835
Funding Sources
H.N. is grateful for financial support from JSPS (KAKENHI
Grant Numbers JP15KT0141 and JP17K05859), IQCE, and
Toyota Physical and Chemical Research Institute (Toyota Riken).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Dr. J. Shimokawa (Kyoto U.) for his valuable
suggestions. We are grateful to Dr. K. Oyama (Nagoya U.) for his
technical support in MS and IR analyses. Generous support from
Profs. R. Noyori and S. Saito (Nagoya U.) is acknowledged.
REFERENCES
Figure 5. Proposed mechanism for catalytic transfer hydration of
1a with acetamide to give 2a and acetonitrile. n = 1 or 2; L = AcOH,
CH3CONH2, 1a, 2a, or CH3CN.
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availability.
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commercial suppliers or prepared by the hydrocyanation of aldehydes
or ketones. See SI for experimental procedures.
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(25) 18O-labeled hexanamide was prepared by the reaction of
hexanenitrile with H218O and trimethylsilyl chloride. The degree of 18
O
labeling (90%) was determined by ESI-MS analysis and showed good
agreement with the 13C{1H} NMR and IR data (see SI). See: Basu, M.
K.; Luo, F.-T. Efficient transformation of nitrile into amide under mild
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caused by the decomposition of 1a.
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(24) The amide reagents (R3CONH2) were selected according to the
polarity of the products in order to enable facile separation of the
products from excess amide reagents by precipitation or
chromatographic methods. Cyanohydrins were purchased from
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