Synthesis of β-hydroxyamides through ruthenium-catalyzed hydration/transfer hydrogenation of β-ketonitriles in water: Scope and limitations

Article abstract of DOI:10.1016/j.jorganchem.2019.05.016

A cascade process for the straightforward one-pot conversion of β-ketonitriles into β-hydroxyamides is presented. The process, that proceeds in water employing the arene-ruthenium(II) complex [RuCl₂(η⁶-p-cymene){P(4-C₆H₄F)₂Cl}] as catalyst in combination with sodium formate, involves the initial hydration of the β-ketonitrile substrates to generate the corresponding β-ketoamide intermediates, which subsequently undergo the transfer hydrogenation (TH) of the carbonyl group. Employing a family of forty different β-ketonitriles, featuring diverse substitution patterns, the scope and limitations of the process have been established.

Full text of DOI:10.1016/j.jorganchem.2019.05.016

Accepted Manuscript
Synthesis of β-hydroxyamides through ruthenium-catalyzed hydration/transfer
hydrogenation of β-ketonitriles in water: Scope and limitations
Rebeca González-Fernández, Pascale Crochet, Victorio Cadierno
PII:
S0022-328X(19)30205-0
DOI:
https://doi.org/10.1016/j.jorganchem.2019.05.016
JOM 20798
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 12 April 2019
Accepted Date: 17 May 2019
Please cite this article as: R. González-Fernández, P. Crochet, V. Cadierno, Synthesis of β-
hydroxyamides through ruthenium-catalyzed hydration/transfer hydrogenation of β-ketonitriles in
water: Scope and limitations, Journal of Organometallic Chemistry (2019), doi: https://doi.org/10.1016/
j.jorganchem.2019.05.016.
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ACCEPTED MANUSCRIPT
Synthesis of β-hydroxyamides through ruthenium-catalyzed
hydration/transfer hydrogenation of β-ketonitriles in water:
Scope and limitations
Rebeca González-Fernández, Pascale Crochet,* Victorio Cadierno*
Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al CSIC),
Centro de Innovación en Química Avanzada (ORFEO-CINQA), Departamento de
Química Orgánica e Inorgánica, IUQOEM, Universidad de Oviedo, Julián Clavería 8,
E-33006 Oviedo, Spain.
Dedicated to the memory of Professor Pascual Royo
______________________________________________________________________
Abstract
A cascade process for the straightforward one-pot conversion of β-ketonitriles into β-
hydroxyamides is presented. The process, that proceeds in water employing the arene-
ruthenium(II) complex [RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] as catalyst in
combination with sodium formate, involves the initial hydration of the β-ketonitrile
substrates to generate the corresponding β-ketoamide intermediates, which subsequently
undergo the transfer hydrogenation (TH) of the carbonyl group. Employing a family of
forty different β-ketonitriles, featuring diverse substitution patterns, the scope and
limitations of the process have been established.
Keywords: Ruthenium; Aqueous catalysis; Cascade processes; Nitrile hydration;
Transfer hydrogenation.
______________________________________________________________________
----------------------------------
* Corresponding authors. E-mail addresses: crochetpascale@uniovi.es (P. Crochet),
vcm@uniovi.es (V. Cadierno)
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1. Introduction
Catalytic cascade reactions, a concept that encompasses all those processes in
which two or more catalytic transformations occur sequentially in a single reaction
vessel [1], are of prime interest in contemporary chemistry since, in comparison with
classical multistep syntheses, they allow an easier, cheaper and cleaner access to a wide
variety of organic products [2]. In this context, in connection with our studies on the
metal-catalyzed hydration of nitriles [3], we recently communicated that this hydration
reaction can be combined in a concurrent manner with the transfer hydrogenation (TH)
of carbonyl compounds, thus opening a straightforward access to synthetically useful β-
hydroxyamides C from β-ketonitriles A, via the corresponding β-ketoamide
intermediates B (Scheme 1) [4]. Interestingly, this unprecedented cascade process
proceeds in water, without the need of any organic co-solvent, and making use of a
single metal source, i.e. the half-sandwich chlorophosphine ruthenium(II) complex
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (1), in combination with inexpensive sodium
formate (NaO2CH) [5,6].
Scheme 1. Access to β-hydroxyamides C by Ru-catalyzed hydration/TH of β-ketonitriles A.
At present, three general routes for the synthesis of β-hydroxyamides can be found
in the literature: (i) the amidation of β-hydroxy-esters and -acids [7], (ii) the aldol
addition of amide enolates to carbonyl compounds [8], and (iii) the reduction of β-
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ketoamides [9]. However, these protocols have been rarely employed in the preparation
of N-unsubstituted β-hydroxyamides C [7g,8d,9c,e,k]. The generation of such
compounds is usually achieved by hydration of the corresponding β-hydroxynitriles D
employing classical acid/base-promoted reactions [10] or enzymatic catalysis [11], but
problems associated with the overhydrolysis of the amides into carboxylic acids have
been in most cases observed. Surprisingly, the use of metal catalysts for the hydration of
β-hydroxynitriles D remains practically unexplored [12]. In this regard, the most
outstanding work in the field was published by Saito and co-workers, who developed a
straightforward procedure for the synthesis of β-hydroxyamides C from aldehydes and
nitriles through a sequential one-pot two-steps aldolization/hydration process, involving
compounds D as intermediates (Scheme 2) [13]. Both steps are catalyzed by the
rhodium(I) dimer [{Rh(µ-OMe)(cod)}2] (cod = 1,5-cyclooctadiene), with the hydration
of the C≡N bond of D requiring the addition of a base to the reaction medium. However,
although novel and appealing, a major drawback of this protocol is the large excess of
the nitrile partner employed (38-77 equiv.).
Scheme 2. Rhodium-catalyzed a nitrile aldolization/hydration process.
All these precedents, along with the ease of access to the starting β-ketonitriles A
(many are commercially available) [14], confer to the ruthenium-catalyzed tandem
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reaction depicted in Scheme 1 a high synthetic value [15,16]. In this regard, given that
in our preliminary communication we basically focused on the behavior of α-
unsubstituted aromatic β-ketonitriles, i.e. substrates of type ArC(=O)CH2C≡N, we
considered pertinent to carry out a broader study in order to outline the scope and
limitations of the process. Accordingly, a full report on this reaction is herein presented.
A family of forty different β-ketonitriles featuring diverse substitution patterns has been
employed along this study.
2. Experimental
2.1. General information
All the manipulations were performed under argon atmosphere using vacuum-line
and standard sealed-tube techniques. The ruthenium(II) catalyst [RuCl2(η6-p-
cymene){P(4-C6H4F)2Cl}] (1) was synthesized by following the method reported in the
literature [3e]. The β-ketonitriles 2a-n,o-p,af-ah,an were obtained from commercial
suppliers and used as received. The β-ketonitriles 2q-ae,ai-aj were synthesized by
acylation of the corresponding nitrile following the general procedure developed by
Trenkle and co-workers [17]. Compounds 2z,ab-ad have not been previously reported
(details on their synthesis and characterization are given below). The α-disubstituted β-
ketonitriles 2ak-am were prepared following the methods reported in the literature [18].
IR spectra were recorded on a Perkin-Elmer 1720-XFT spectrometer. NMR spectra
13
1
were obtained on Bruker DPX-300, AV-400 or AV600 spectrometers. C{1H} and H
chemical shifts were referenced to the residual signal of deuterated solvent. All data are
reported in ppm downfield from (CH3)4Si. For 19F{1H} NMR spectra, the chemical
shifts were referenced to the CFCl3 standard. All NMR measurements were carried out
at 25 °C. HRMS data were obtained on a ESI-q-TOF Bruker Impact II mass
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spectrometer. For column chromatography, Merck silica gel 60 (230-400 mesh) was
employed.
2.2. Synthesis and characterization of the novel β-ketonitriles 2z,ab-ad
These compounds were obtained by following the acylation procedure developed
by Trenkle and co-workers [17]:
To a solution of the corresponding nitrile R2CH2C≡N (4 mmol) in THF were
added dropwise, at 0 ºC and in an ice bath, 6.24 mL of a 1.7 M solution of KOtAmyl in
toluene (12 mmol). The corresponding ethyl ester R1CO2Et (16 mmol) was
subsequently added at 0 ºC, and the resulting mixture stirred at room temperature (R1 =
Ph) or 60 ºC (R1 = alkyl) till complete consumption of the starting nitrile (TLC
monitoring; ca. 4 h). Then, 100 mL of a 0.97 M solution of HCl in water and 100 mL of
EtOAc were added. The organic phase was separated, washed with water (2 x 50 mL)
and brine (2 x 50 mL), dried with anhydrous MgSO4 and filtered. Evaporation of the
organic solvents under vacuum led to a yellow oily residue which was purified by flash
column chromatography over silica gel using a mixture hexane/EtOAc (4:1) as eluent.
Characterization data for compounds 2z,ab-ad are as follows:
1
2-Benzoylheptanenitrile (2z): Colourless oil. Yield: 0.809 g (94%). H NMR
(CDCl3, 300 MHz): δ = 7.99-7.97 (m, 2H), 7.70-7.65 (m, 1H), 7.58-7.52 (m, 2H), 4.37
(dd, 1H, J = 7.5 and 6.6 Hz), 2.06-1.97 (m, 2H), 1.65-1.52 (m, 2H), 1.39-1.32 (m, 4H),
0.92 (t, 3H, J = 6.9 Hz) ppm. 13C{1H} NMR (CDCl3, 75 MHz): δ = 190.9, 134.4, 134.0,
129.1 (2C), 128.7 (2C), 117.4, 40.1, 31.1, 29.9, 26.8, 22.3, 13.9 ppm. IR (film): ν =
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2250 (C≡N), 1694 (C=O) cm-1. HRMS (ESI): m/z 238.120130, [M + Na+] (calcd for
C14H17NONa: 238.120235).
2-Benzoyl-4-phenylbutanenitrile (2ab): Colourless oil. Yield: 0.907 g (91%). 1H
NMR (CDCl3, 300 MHz): δ = 7.85-7.82 (m, 2H), 7.67-7.47 (m, 3H), 7.39-7.23 (m, 5H),
13
4.28 (dd, 1H, J = 7.2 and 7.2 Hz), 3.04-2.82 (m, 2H), 2.37-2.30 (m, 2H) ppm. C{1H}
NMR (CDCl3, 75 MHz): δ = 190.6, 139.2, 134.5, 133.8, 129.1 (2C), 128.9 (2C), 128.7
(2C), 128.6 (2C), 126.8, 117.1, 38.9, 32.9, 31.4 ppm. IR (film): ν = 2250 (C≡N), 1691
(C=O) cm-1. HRMS (ESI): m/z 272.104550, [M + Na+] (calcd for C17H15NONa:
272.104585).
2-(Cyclohexanecarbonyl)butanenitrile (2ac): Colourless oil. Yield: 0.645 g
1
(90%). H NMR (CDCl3, 300 MHz): δ = 3.47 (dd, 1H, J = 7.5 and 6.0 Hz), 2.79-2.72
13
(m, 1H), 1.98-1.70 (m, 6H), 1.42-1.25 (m, 6H), 1.10 (t, 3H, J = 7.5 Hz) ppm. C{1H}
NMR (CDCl3, 75 MHz): δ = 203.8, 117.5, 49.2, 43.7, 28.6, 28.3, 25.5, 25.3, 25.2, 22.5,
11.5 ppm. IR (film): ν = 2245 (C≡N), 1711 (C=O) cm-1. HRMS (ESI): m/z 202.120632,
[M + Na+] (calcd for C11H17NONa: 202.120235).
4-Cyclohexyl-2-ethyl-3-oxobutanenitrile (2ad): Colourless oil. Yield: 0.727 g
(94%). 1H NMR (CDCl3, 300 MHz): δ = 3.34 (dd, 1H, J = 7.8 and 6.0 Hz), 2.56 (d, 2H,
J = 6.6 Hz), 1.94-1.89 (m, 3H), 1.72-1.69 (m, 5H), 1.32-1.17 (m, 3H), 1.11 (t, 3H, J =
13
7.2 Hz), 1.02-0.94 (m, 2H) ppm. C{1H} NMR (CDCl3, 75 MHz): δ = 200.5, 117.5,
48.6, 45.9, 33.4, 33.0, 32.9, 26.0, 25.9 (2C), 22.6, 11.3 ppm. IR (film): ν = 2244 (C≡N),
1725 (C=O) cm-1. HRMS (ESI): m/z 216.136105, [M + Na+] (calcd for C12H19NONa:
216.135885).
2.3. General procedure for the catalytic conversion of β-ketonitriles into β-
hydroxyamides
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Under argon atmosphere, the corresponding β-ketonitrile 2 (1 mmol), water (3
mL), the ruthenium(II) complex 1 (0.028 g, 0.05 mmol; 5 mol%) and NaO2CH (1.360 g,
20 mmol) were introduced into a Teflon-capped sealed tube, and the reaction mixture
stirred at 100 °C for 24-48 h. The solvent was then removed under vacuum and the
resulting solid residue purified by flash column chromatography over silica gel using,
unless otherwise stated, a mixture of MeOH/EtOAc (1:10) as eluent. Characterization
data for the isolated β-hydroxyamides are as follows:
3-(4-Fluorophenyl)-3-hydroxypropanamide (4a) [7g]: Light brown solid. Mp
108-110 °C. Yield: 0.135 g (74%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.37 (dd, 2H, J
= 8.7 and 5.7 Hz), 7.30 (br, 1H), 7.14 (dd, 2H, J = 8.7 and 8.7 Hz), 6.84 (br, 1H), 5.43
13
(d, 1H, J = 4.5 Hz), 4.95 (m, 1H), 2.46-2.29 (m, 2H) ppm. C{1H} NMR (DMSO-d6,
100 MHz): δ = 172.6, 161.6 (d, J = 241.9 Hz), 142.0, 128.1 (d, 2C, J = 7.9 Hz), 115.1
(d, 2C, J = 21.2 Hz), 69.5, 45.8 ppm. 19F{1H} NMR (CD3OD, 282 MHz): δ = -117.5 (s)
ppm.
3-Hydroxy-3-phenylpropanamide (4b) [10c,e]: Light brown solid. Mp 117-119
1
°C (Lit. 120 °C). Yield: 0.135 g (82%). H NMR (DMSO-d6, 300 MHz): δ = 7.35-7.20
(m, 6H), 6.83 (br, 1H), 5.37 (d, 1H, J = 4.5 Hz), 4.94 (m, 1H), 2.51-2.29 (m, 2H) ppm.
13C{1H} NMR (DMSO-d6, 75 MHz): δ = 172.8, 145.9, 128.4 (2C), 127.2, 126.2 (2C),
70.1, 45.9 ppm.
3-(4-Chlorophenyl)-3-hydroxypropanamide (4c) [10a]: Light brown solid. Mp
129-131 °C (Lit. 130-131.5 °C). Yield: 0.176 g (88%). 1H NMR (DMSO-d6, 300 MHz):
δ = 7.37 (m, 4H), 7.31 (br, 1H), 6.85 (br, 1H), 5.48 (d, 1H, J = 3.3 Hz), 4.94 (m, 1H),
13
2.45-2.29 (m, 2H) ppm. C{1H} NMR (DMSO-d6, 75 MHz): δ = 172.5, 144.9, 131.7,
128.4 (2C), 128.1 (2C), 69.4, 45.7 ppm.
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3-(3-Chlorophenyl)-3-hydroxypropanamide (4d) [10a]: Light brown solid. Mp
133-135 °C (Lit. 134-135 °C). Yield: 0.139 g (70%). 1H NMR (DMSO-d6, 300 MHz): δ
= 7.38-7.26 (m, 5H), 6.85 (br, 1H), 5.53 (d, 1H, J = 4.5 Hz), 4.94 (m, 1H), 2.46-2.32
(m, 2H) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ = 172.4, 148.5, 133.2, 130.4,
127.2, 126.0, 124.9, 69.5, 45.6 ppm.
3-(2-Chlorophenyl)-3-hydroxypropanamide (4e) [10a]: Light brown solid. Mp
190-192 °C (Lit. 192.5-193 °C). Yield: 0.140 g (70%). 1H NMR (DMSO-d6, 300 MHz):
δ = 7.60 (dd, 1H, J = 7.8 and 7.8 Hz), 7.39-7.26 (m, 4H), 6.90 (br, 1H), 5.55 (d, 1H, J =
4.5 Hz), 5.29 (m, 1H), 2.38-2.23 (m, 2H) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ =
172.4, 143.1, 130.9, 129.4, 128.9, 128.0, 127.7, 66.7, 43.8 ppm.
3-(3,4-Dichlorophenyl)-3-hydroxypropanamide (4f): Light brown solid. Mp
1
140-142 °C. Yield: 0.171 g (73%). H NMR (DMSO-d6, 300 MHz): δ = 7.57 (m, 2H),
7.36-7.30 (m, 2H), 6.87 (br, 1H), 5.61 (d, 1H, J = 4.8 Hz), 4.94 (m, 1H), 2.46-2.33 (m,
13
2H) ppm. C{1H} NMR (DMSO-d6, 75 MHz): δ = 172.2, 147.1, 131.1, 130.7, 129.6,
128.2, 126.6, 69.0, 45.5 ppm. IR (KBr): ν = 3399 (O-H), 3294 (N-H), 3192 (N-H), 1655
(C=O) cm-1. HRMS (ESI): m/z 255.989536, [M + Na+] (calcd for C9H9Cl2O2NNa:
255.990255).
3-(4-Bromophenyl)-3-hydroxypropanamide (4g) [11b]: Light brown solid. Mp
137-139 °C. Yield: 0.207 g (85%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.50 (d, 2H, J =
8.1 Hz), 7.29 (d, 2H, J = 8.1 Hz), 6.82 (br, 1H), 5.47 (d, 1H, J = 4.5 Hz), 4.92 (m, 1H),
13
2.50-2.29 (m, 2H) ppm. C{1H} NMR (DMSO-d6, 75 MHz): δ = 172.5, 145.3, 131.3
(2C), 128.5 (2C), 120.2, 69.5, 45.7 ppm.
3-Hydroxy-3-(3-trifluoromethylphenyl)propanamide (4h): Light brown solid.
1
Mp 99-101 °C. Yield: 0.179 g (77%). H NMR (DMSO-d6, 300 MHz): δ = 7.69-7.53
(m, 4H), 7.32 (br, 1H), 6.88 (br, 1H), 5.62 (d, 1H, J = 4.5 Hz), 5.04 (m, 1H), 2.47-2.36
8

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(m, 2H) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ = 172.4, 147.3, 130.4, 129.5,
129.2 (q, J = 31.4 Hz), 124.8 (q, J = 272.4 Hz), 124.0 (q, J = 3.6 Hz), 122.6 (q, J = 3.5
Hz), 69.5 (s), 45.6 (s) ppm. 19F{1H} NMR (DMSO-d6, 282 MHz): δ = -61.0 (s) ppm. IR
(KBr): ν = 3391 (O-H), 3310 (N-H), 3195 (N-H), 1657 (C=O) cm-1. HRMS (ESI): m/z
256.055747, [M + Na+] (calcd for C10H10F3O2NNa: 256.055584).
3-Hydroxy-3-(4-methylphenyl)propanamide (4i) [11b]: Light brown solid.
1
Yield: 0.150 g (84%). Mp 136-138 °C. H NMR (DMSO-d6, 300 MHz): δ = 7.28 (br,
1H), 7.21 (d, 2H, J = 8.1 Hz), 7.11 (d, 2H, J = 8.1 Hz), 6.82 (br, 1H), 5.31 (d, 1H, J =
13
4.5 Hz), 4.90 (m, 1H), 2.51-2.27 (m, 2H), 2.27 (s) ppm. C{1H} NMR (DMSO-d6, 75
MHz): δ = 172.8, 142.9, 136.2, 129.0 (2C), 126.1 (2C), 69.9, 45.8, 21.1 ppm.
3-Hydroxy-3-(3-methylphenyl)propanamide (4j): Light brown solid. Mp 125-
127 °C. Yield: 0.147 g (82%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.29 (br, 1H), 7.22-
7.10 (m, 3H), 7.25 (d, 1H, J = 7.2 Hz), 6.83 (br, 1H), 5.33 (d, 1H, J = 4.5 Hz), 4.89 (m,
1H), 2.44-2.27 (m, 2H), 2.29 (s, 3H) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ =
172.8, 145.8, 137.4, 128.3, 127.8, 126.8, 123.3, 70.1, 45.8, 21.6 ppm. IR (KBr): ν =
3381 (O-H), 3303 (N-H), 3189 (N-H), 1657 (C=O) cm-1. HRMS (ESI): m/z 202.084358,
[M + Na+] (calcd for C10H13O2NNa: 202.083849).
3-Hydroxy-3-(4-methoxyphenyl)propanamide (4k) [10b]: Light brown solid.
Mp 179-181 °C (Lit. 184 °C). Yield: 0.166 g (85%). 1H NMR (DMSO-d6, 300 MHz): δ
= 7.28 (br, 1H), 7.25 (d, 2H, J = 8.7 Hz), 6.85 (d, 2H, J = 8.7 Hz), 6.81 (br, 1H), 5.28
(d, 1H, J = 4.5 Hz), 4.88 (m, 1H), 3.73 (s, 3H), 2.45-2.27 (m, 2H) ppm. 13C{1H} NMR
(DMSO-d6, 75 MHz): δ = 172.9, 158.6, 137.8, 127.3 (2C), 113.8 (2C), 69.7, 55.4, 45.8
ppm.
3-(3,5-Dimethoxyphenyl)-3-hydroxypropanamide (4l): Light brown solid. Mp
1
105-107 °C. Yield: 0.194 g (86%). H NMR (DMSO-d6, 400 MHz): δ = 7.28 (br, 1H),
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6.82 (br, 1H), 6.50 (d, 2H, J = 2.0 Hz), 6.34 (s, 1H), 5.36 (d, 1H, J = 4.4 Hz), 4.87 (m,
1H), 3.72 (s, 6H), 2.41-2.29 (m, 2H) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ =
172.8, 160.6 (2C), 148.5, 104.0 (2C), 98.9, 70.1, 55.5 (2C), 45.8 ppm. IR (KBr): ν =
3389 (O-H), 3370 (N-H), 3197 (N-H), 1651 (C=O) cm-1. HRMS (ESI): m/z 248.089455,
[M + Na+] (calcd for C11H15O4NNa: 248.089329).
3-Hydroxy-3-(5,6,7,8-tetrahydronaphthalen-2-yl)propanamide (3n): Light
brown solid. Mp 150-152 °C. Yield: 0.167 g (76%). 1H NMR (DMSO-d6, 300 MHz): δ
= 7.26 (br, 1H), 6.99 (m, 3H), 6.79 (br, 1H), 5.23 (d, 1H, J = 4.5 Hz), 4.84 (m, 1H), 2.68
(br, 4H), 2.38-2.27 (m, 2H), 1.71 (br, 4H) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ
= 172.9, 142.8, 136.4, 135.4, 128.9, 126.7, 123.4, 70.0, 45.8, 29.4, 28.9, 23.3 (2C) ppm.
IR (KBr): ν = 3400 (O-H), 3362 (N-H), 3214 (N-H), 1657 (C=O) cm-1. HRMS (ESI):
m/z 242.114808, [M + Na+] (calcd for C13H17O2NNa: 242.115149).
4-(3-Amino-1-hydroxy-3-oxopropyl)benzamide (4n): White solid. Mp 195-197
1
°C. Yield: 0.181 g (87%). H NMR (DMSO-d6, 300 MHz): δ = 7.94 (br, 1H), 7.82 (d,
2H, J = 8.3 Hz), 7.40 (d, 2H, J = 8.3 Hz), 7.33 (br, 1H), 7.31 (br, 1H), 6.84 (br, 1H),
5.51 (d, 1H, J = 4.5 Hz), 5.02-4.96 (m, 1H), 2.50-2.32 (m, 2H) ppm. 13C{1H} NMR
(DMSO-d6, 75 MHz): δ = 172.7, 168.3, 149.1, 133.2, 127.7 (2C), 125.9 (2C), 69.8, 45.6
ppm. IR (KBr): ν = 3383 (O-H and N-H), 3186 (N-H), 1653 (C=O) cm-1. HRMS (ESI):
m/z 231.074429, [M + Na+] (calcd for C10H12O3N2Na: 231.074013).
3-(2-Furyl)-3-hydroxypropanamide (4o) [13]: Light brown solid. Mp 121-123
°C. Yield: 0.124 g (80%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.56 (d, 1H, J = 1.8 Hz),
7.37 (br, 1H), 6.87 (br, 1H), 6.37 (dd, 1H, J = 3.0 and 1.8 Hz), 6.85 (d, 1H, J = 3.0 Hz),
13
5.45 (d, 1H, J = 5.4 Hz), 4.91 (m, 1H), 2.50 (m, 2H) ppm. C{1H} NMR (DMSO-d6,
75 MHz): δ = 172.2, 157.8, 142.2, 110.6, 105.7, 63.7, 42.2 ppm.
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3-Hydroxy-3-(2-thienyl)propanamide (4p): Light brown solid. Mp 94-96 °C.
Yield: 0.120 g (70%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.37 (m, 2H), 6.94 (m, 2H),
13
6.87 (br, 1H), 5.74 (d, 1H, J = 4.8 Hz), 5.18 (m, 1H), 2.56-2.41 (m, 2H) ppm. C{1H}
NMR (DMSO-d6, 75 MHz): δ = 172.3, 150.4, 127.0, 124.6, 123.1, 66.3, 45.9 ppm. IR
(KBr): ν = 3390 (O-H), 3303 (N-H), 3188 (N-H), 1658 (C=O) cm-1. HRMS (ESI): m/z
194.024385, [M + Na+] (calcd for C7H9O2NSNa: 194.024620).
4,4-Dimethyl-3-hydroxypentanamide (4q) [13]: Light brown solid. Mp 96-98
1
°C. Yield: 0.118 g (81%). H NMR (DMSO-d6, 300 MHz): δ = 7.31 (br, 1H), 6.84 (br,
1H), 4.69 (d, 1H, J = 4.8 Hz), 3.50 (m, 1H), 2.18 (dd, 1H, J = 14.4 and 2.7 Hz), 2.18
(dd, 1H, J = 14.4 and 10.2 Hz), 0.82 (s, 9H) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz):
δ = 174.8, 75.2, 38.1, 34.9, 26.2 ppm.
3-Hydroxy-4-methylpentanamide (4r) [19]: Light brown oil. Yield: 0.073 g
(56%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.27 (br, 1H), 6.80 (br, 1H), 4.57 (d, 1H, J
= 4.8 Hz), 3.63-3.56 (m, 1H), 2.14-2.01 (m, 2H), 1.59-1.48 (m, 1H), 0.82 (d, 3H, J = 6.6
Hz), 0.80 (d, 3H, J = 6.6 Hz) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ = 174.2,
72.3, 33.5, 19.2, 17.7 ppm.
3-Cyclohexyl-3-hydroxypropanamide (4s) [13]: Light brown solid. Mp 92-94
1
°C. Yield: 0.121 g (71%). H NMR (DMSO-d6, 300 MHz): δ = 7.26 (br, 1H), 6.80 (br,
1H), 4.55 (d, 1H, J = 5.1 Hz), 3.62-3.55 (m, 1H), 2.19-2.02 (m, 2H), 1.70-1.59 (m, 5H),
13
1.21-0.92 (m, 6H) ppm. C{1H} NMR (CDCl3, 75 MHz): δ = 175.7, 72.7, 43.4, 39.5,
28.8, 28.3, 26.4, 26.1, 26.0 ppm.
3-Cyclopropyl-3-hydroxypropanamide (4t) [11c]: Light brown oil. Yield: 0.067
g (52%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.27 (br, 1H), 6.79 (br, 1H), 4.67 (d, 1H,
J = 4.5 Hz), 3.36-3.23 (m, 1H), 2.22 (d, 2H, J = 6.3 Hz), 0.82-0.75 (m, 1H), 0.35-0.16
11

ACCEPTED MANUSCRIPT
(m, 4H) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ = 174.5, 71.1, 43.9, 17.8, 2.7, 2.3
ppm.
3-(Adamantan-1-yl)-3-hydroxypropanamide (4u): Light brown solid. Mp 169-
1
171 °C. Yield: 0.172 g (77%). H NMR (DMSO-d6, 300 MHz): δ = 7.28 (br, 1H), 6.81
(br, 1H), 4.55 (d, 1H, J = 4.8 Hz), 3.34-3.28 (m, 1H), 2.21-1.99 (m, 5H), 1.69-1.42 (m,
13
12H) ppm. C{1H} NMR (DMSO-d6, 75 MHz): δ = 175.0, 75.5, 38.1 (3C), 37.3 (3C),
36.7, 36.5, 28.2 (3C) ppm. IR (KBr): ν = 3380 (O-H), 3304 (N-H), 3177 (N-H), 1674
(C=O) cm-1. HRMS (ESI): m/z 246.145915, [M + Na+] (calcd for C13H21O2NNa:
246.146450).
4-Cyclohexyl-3-hydroxybutanamide (4v): White solid. Mp 93-95 °C. Yield:
1
0.154 g (83%). H NMR (DMSO-d6, 300 MHz): δ = 7.25 (br, 1H), 6.77 (br, 1H), 4.55
(d, 1H, J = 5.4 Hz), 3.94-3.84 (m, 1H), 2.12-2.09 (m, 2H), 1.77-1.63 (m, 5H), 1.42 (m,
1H), 1.24-1.16 (m, 5H), 0.91-0.78 (m, 2H) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ
= 173.7, 65.3, 45.2, 44.4, 34.2, 33.8, 32.7, 26.7, 26.4, 26.2 ppm. IR (KBr): ν = 3318 (O-
H and N-H), 3158 (N-H), 1673 (C=O) cm-1. HRMS (ESI): m/z 208.130494, [M + Na+]
(calcd for C10H19O2NNa: 208.130800).
3-Hydroxy-2-methyl-3-phenylpropanamide (4w) [20]: This compound was
obtained as a mixture of diastereoisomers which could be separated by column
chromatography using EtOAc as eluent. Syn diastereoisomer (Rf = 0.53): White solid.
1
Mp 132-135 °C (Lit. 134-136 °C). Yield: 0.070 g (39%). H NMR (DMSO-d6, 300
MHz): δ = 7.36-7.22 (m, 6H), 6.78 (br, 1H), 5.34 (d, 1H, J = 4.5 Hz), 4.52 (dd, 1H, J =
8.7 and 4.5 Hz), 2.48-2.43 (m, 1H), 0.70 (d, 3H, J = 6.9 Hz) ppm. 13C{1H} NMR
(DMSO-d6, 75 MHz): δ = 177.2, 144.5, 128.4 (2C), 127.5, 127.2 (2C), 75.5, 47.6, 15.3
ppm. Anti diastereoisomer (Rf = 0.35): White solid. Mp 87-90 °C (Lit. 84-85 °C).
Yield: 0.088 g (49%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.32-7.18 (m, 6H), 6.64 (br,
12

ACCEPTED MANUSCRIPT
1H), 5.29 (d, 1H, J = 4.8 Hz), 4.64 (dd, 1H, J = 7.2 and 4.8 Hz), 2.48-2.44 (m, 1H), 1.04
13
(d, 3H, J = 6.9 Hz) ppm. C{1H} NMR (DMSO-d6, 75 MHz): δ = 176.8, 144.7, 128.1
(2C), 127.1, 126.9 (2C), 74.2, 47.7, 13.9 ppm.
2-(Hydroxy(phenyl)methyl)butanamide (4x) [21]: This compound was obtained
as a mixture of diastereoisomers which could be separated by column chromatography
using EtOAc as eluent. Syn diastereoisomer (Rf = 0.30): White solid. Mp 130-133 °C.
Yield: 0.081 g (42%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.35-7.21 (m, 6H), 6.85 (br,
1H), 5.33 (d, 1H, J = 4.8 Hz), 4.51 (dd, 1H, J = 8.7 and 4.8 Hz), 2.29 (m, 1H), 1.32 (m,
1H), 0.90 (m, 1H), 0.71 (t, 3H, J = 7.2 Hz) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ
= 176.2, 144.9, 128.4 (2C), 127.5, 127.2 (2C), 74.9, 55.3, 22.7, 12.1 ppm. Anti
1
diastereoisomer (Rf = 0.59): White solid. Mp 119-122 °C. Yield: 0.064 g (33%). H
NMR (DMSO-d6, 300 MHz): δ = 7.31-7.15 (m, 6H), 6.63 (br, 1H), 5.27 (br, 1H), 4.55
(d, 1H, J = 8.1 Hz), 2.34 (m, 1H), 1.72 (m, 1H), 1.57 (m, 1H), 0.83 (t, 3H, J = 7.2 Hz)
13
ppm. C{1H} NMR (DMSO-d6, 75 MHz): δ = 175.6, 144.9, 128.1 (2C), 127.2 (3C),
74.2, 55.7, 21.9, 12.3 ppm. A Mp range of 117-118 °C was given in the literature for the
mixture of diastereoisomers.
2-(Hydroxy(phenyl)methyl)hexanamide (4y): This compound was obtained as a
mixture of diastereoisomers which could be separated by column chromatography using
EtOAc as eluent. Syn diastereoisomer (Rf = 0.37): White solid. Mp 104-106 °C. Yield:
1
0.095 g (43%). H NMR (DMSO-d6, 400 MHz): δ = 7.34-7.22 (m, 6H), 6.81 (br, 1H),
5.31 (d, 1H, J = 4.8 Hz), 4.49 (dd, 1H, J = 8.4 and 4.8 Hz), 2.39-2.33 (m, 1H), 1.38-1.30
(m, 1H), 1.14-1.07 (m, 4H), 0.85 (m, 1H), 0.72 (t, 3H, J = 6.0 Hz) ppm. 13C{1H} NMR
(DMSO-d6, 100 MHz): δ = 176.4, 145.0, 128.4 (2C), 127.5, 127.2 (2C), 75.1, 53.6,
29.5, 29.2, 22.5, 14.2 ppm. IR (KBr): ν = 3331 (O-H), 3283 (N-H), 3166 (N-H), 1685
(C=O) cm-1. HRMS (ESI): m/z 244.130570, [M + Na+] (calcd for C13H19O2NNa:
13

ACCEPTED MANUSCRIPT
244.130800). Anti diastereoisomer (Rf = 0.67): White solid. Mp 103-105 °C. Yield:
1
0.119 g (54%). H NMR (DMSO-d6, 300 MHz): δ = 7.31-7.20 (m, 5H), 7.12 (br, 1H),
6.59 (br, 1H), 5.24 (d, 1H, J = 4.4 Hz), 4.53 (dd, 1H, J = 7.6 and 4.4 Hz), 2.38 (m, 1H),
1.67 (m, 1H), 1.58-1.50 (m, 1H), 1.29-1.15 (m, 4H), 0.84 (t, 3H, J = 6.8 Hz) ppm.
13C{1H} NMR (DMSO-d6, 75 MHz): δ = 175.7, 144.8, 128.0 (2C), 127.1 (3C), 74.4,
54.1, 29.8, 28.5, 22.7, 14.4 ppm. IR (KBr): ν = 3359 (O-H), 3303 (N-H), 3178 (N-H),
1683 (C=O) cm-1. HRMS (ESI): m/z 244.130933, [M + Na+] (calcd for C13H19O2NNa:
244.130800).
2-(Hydroxy(phenyl)methyl)heptanamide (4z): This compound was obtained as
a mixture of diastereoisomers which could be separated by column chromatography
using EtOAc as eluent. Syn diastereoisomer (Rf = 0.33): Light brown solid. Mp 127-
1
129 °C. Yield: 0.066 g (28%). H NMR (DMSO-d6, 300 MHz): δ = 7.31-7.21 (m, 6H),
6.79 (br, 1H), 5.29 (d, 1H, J = 4.8 Hz), 4.48 (dd, 1H, J = 9.3 and 4.8 Hz), 2.39-2.30 (m,
1H), 1.31-1.22 (m, 2H), 1.16-1.04 (m, 6H), 0.76 (t, 3H, J = 5.7 Hz) ppm. 13C{1H} NMR
(DMSO-d6, 75 MHz): δ = 176.8, 145.4, 128.8 (2C), 127.9, 127.6 (2C), 75.5, 54.1, 32.0,
29.9, 27.3, 22.8, 14.7 ppm. IR (KBr): ν = 3376 (O-H), 3305 (N-H), 3164 (N-H), 1684
(C=O) cm-1. HRMS (ESI): m/z 258.146230, [M + Na+] (calcd for C14H21O2NNa:
258.146450). Anti diastereoisomer (Rf = 0.74): Light brown solid. Mp 102-104 °C.
Yield: 0.094 g (40%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.28-7.21 (m, 5H), 7.12 (br,
1H), 6.59 (br, 1H), 5.24 (d, 1H, J = 4.5 Hz), 4.51 (dd, 1H, J = 8.1 and 4.5 Hz), 2.41-2.34
(m, 1H), 1.68-1.47 (m, 2H), 1.23 (br, 6H), 0.83 (t, 3H, J = 5.9 Hz) ppm. 13C{1H} NMR
(DMSO-d6, 75 MHz): δ = 175.7, 144.8, 128.0 (2C), 127.1 (3C), 74.4, 54.1, 31.9, 28.8,
27.1, 22.5, 14.4 ppm. IR (KBr): ν = 3359 (O-H), 3313 (N-H), 3172 (N-H), 1682 (C=O)
cm-1. HRMS (ESI): m/z 258.146986, [M + Na+] (calcd for C14H21O2NNa: 258.146450).
14

ACCEPTED MANUSCRIPT
2-Benzyl-3-hydroxy-3-phenylpropanamide (4aa): This compound was obtained
as a mixture of diastereoisomers which could be separated by column chromatography
using EtOAc as eluent. Syn diastereoisomer (Rf = 0.77): Light brown solid. Mp 116-
118 °C. Yield: 0.145 g (57%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.37-7.12 (m, 10H),
6.93 (br, 1H), 6.46 (br, 1H), 5.47 (d, 1H, J = 4.8 Hz), 4.62 (dd, 1H, J = 7.5 and 4.8 Hz),
13
3.03-2.71 (m, 3H) ppm. C{1H} NMR (DMSO-d6, 75 MHz): δ = 174.4, 144.4, 140.9,
129.2 (2C), 128.4 (2C), 128.1 (2C), 127.3, 127.2 (2C), 126.1, 74.6, 56.1, 34.8 ppm. IR
(KBr): ν = 3399 (O-H and N-H), 3186 (N-H), 1653 (C=O) cm-1. HRMS (ESI): m/z
278.115523, [M + Na+] (calcd for C16H17O2NNa: 278.115149). Anti diastereoisomer (Rf
1
= 0.46): Light brown solid. Mp 60-63 °C. Yield: 0.038 g (15%). H NMR (DMSO-d6,
300 MHz): δ = 7.37-7.03 (m, 11H), 6.75 (br, 1H), 5.51 (d, 1H, J = 5.1 Hz), 4.58 (dd,
1H, J = 7.2 and 5.1 Hz), 2.82-2.67 (m, 2H), 2.29 (dd, 1H, J = 12.0 and 2.7 Hz) ppm.
13C{1H} NMR (DMSO-d6, 75 MHz): δ = 175.3, 144.6, 140.1, 129.1 (2C), 128.5 (4C),
127.6, 127.2 (2C), 126.2, 74.7, 55.1, 35.5 ppm. IR (KBr): ν = 3362 (O-H and N-H),
3156 (N-H), 1685 (C=O) cm-1. HRMS (ESI): m/z 278.115557, [M + Na+] (calcd for
C16H17O2NNa: 278.115149).
2-(Hydroxy(phenyl)methyl)-4-phenylbutanamide (4ab): This compound was
obtained as a mixture of diastereoisomers which could be separated by column
chromatography using EtOAc as eluent. Syn diastereoisomer (Rf = 0.41): Light brown
solid. Mp 128-130 °C. Yield: 0.097 g (36%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.41
(br, 1H), 7.28-7.11 (m, 8H), 7.00-6.95 (m, 3H), 5.39 (d, 1H, J = 4.8 Hz), 4.58 (dd, 1H, J
= 8.1 and 4.8 Hz), 2.49-2.43 (m, 2H), 2.34-2.28 (m, 1H), 1.67-1.61 (m, 1H), 1.19-1.11
(m, 1H) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ = 176.1, 144.7, 142.3, 128.7 (2C),
128.4 (4C), 127.5, 127.2 (2C), 126.1, 74.8, 53.7, 33.5, 31.7 ppm. IR (KBr): ν = 3318
(O-H and N-H), 3195 (N-H), 1684 (C=O) cm-1. HRMS (ESI): m/z 292.130825, [M +
15

ACCEPTED MANUSCRIPT
Na+] (calcd for C17H19O2NNa: 292.130800). Anti diastereoisomer (Rf = 0.74): Light
brown solid. Mp 139-142 °C. Yield: 0.124 g (46%). 1H NMR (DMSO-d6, 300 MHz): δ
= 7.29-7.12 (m, 11H), 6.71 (br, 1H), 5.32 (d, 1H, J = 4.5 Hz), 4.59 (dd, 1H, J = 7.8 and
4.5 Hz), 2.58-2.37 (m, 3H), 1.98-1.85 (m, 2H) ppm. 13C{1H} NMR (DMSO-d6, 75
MHz): δ = 175.3, 144.7, 142.7, 128.7 (2C), 128.5 (2C), 128.1 (2C), 127.2, 127.1 (2C),
126.1, 74.3, 54.1, 33.7, 31.0 ppm. IR (KBr): ν = 3384 (O-H and N-H), 3196 (N-H),
1653 (C=O) cm-1. HRMS (ESI): m/z 292.130540, [M + Na+] (calcd for C17H19O2NNa:
292.130800).
2-(Cyclohexyl(hydroxyl)methyl)butanamide (4ac) [22]: This compound was
obtained as an inseparable mixture of the syn and anti diastereoisomers in 1.4:1 ratio.
Light brown solid. Mp 160-163 °C (Lit. 164-165 °C). Yield: 0.121 g (61%). Syn
diastereoisomer: 1H NMR (DMSO-d6, 300 MHz): δ = 7.35 (br, 1H), 6.79 (br, 1H), 4.38
(d, 1H, J = 5.7 Hz), 3.26-3.16 (m, 1H), 2.24-2.12 (m, 1H), 1.67-1.09 (m, 13H), 0.81 (t,
13
3H, J = 7.2 Hz) ppm. C{1H} NMR (DMSO-d6, 75 MHz): δ = 176.7, 75.5, 51.2, 41.1,
30.7, 26.7, 26.6, 26.4, 25.8, 22.2, 12.4 ppm. Anti diastereoisomer: 1H NMR (DMSO-d6,
300 MHz): δ = 7.32 (br, 1H), 6.92 (br, 1H), 4.56 (d, 1H, J = 7.5 Hz), 3.26-3.16 (m, 1H),
13
2.24-2.12 (m, 1H), 1.67-1.09 (m, 13H), 0.85 (t, 3H, J = 7.5 Hz) ppm. C{1H} NMR
(DMSO-d6, 75 MHz): δ = 177.7, 75.7, 49.3, 41.7, 29.9, 27.9, 26.6, 26.4, 26.2, 23.4, 12.4
ppm.
4-Cyclohexyl-2-ethyl-3-hydroxybutanamide (4ad): This compound was
obtained as an inseparable mixture of the syn and anti diastereoisomers in 1.2:1 ratio.
Light brown solid. Mp 135-137 °C. Yield: 0.117 g (55%). IR (KBr): ν = 3350 (O-H),
3294 (N-H), 3174 (N-H), 1681 (C=O) cm-1. HRMS (ESI): m/z 236.161645, [M + Na+]
1
(calcd for C12H23O2NNa: 236.162100). Syn diastereoisomer: H NMR (DMSO-d6, 300
MHz): δ = 7.24 (br, 1H), 6.75 (br, 1H), 4.42 (d, 1H, J = 6.3 Hz), 3.51-3.43 (m, 1H),
16

ACCEPTED MANUSCRIPT
13
1.83-1.73 (m, 1H), 1.62-1.13 (m, 15H), 0.83 (t, 3H, J = 7.2 Hz) ppm. C{1H} NMR
(DMSO-d6, 75 MHz): δ = 176.4, 68.9, 55.5, 43.3, 34.7, 33.7, 32.2, 26.7, 26.5, 26.1,
1
22.1, 12.4 ppm. Anti diastereoisomer: H NMR (DMSO-d6, 300 MHz): δ = 7.24 (br,
1H), 6.85 (br, 1H), 4.48 (d, 1H, J = 6.9 Hz), 3.64-3.56 (m, 1H), 2.15-2.01 (m, 1H), 1.62-
13
1.13 (m, 15H), 0.80 (t, 3H, J = 7.5 Hz) ppm. C{1H} NMR (DMSO-d6, 75 MHz): δ =
176.9, 68.7, 53.7, 43.0, 34.5, 33.8, 32.5, 26.7, 26.5, 26.1, 22.2, 12.5 ppm.
2-Benzyl-3-hydroxypropanamide (4ae) [11d]: Light brown solid. Mp 122-125
°C (Lit. 127-130 °C). Yield: 0.090 g (50%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.28-
7.14 (m, 6H), 6.74 (br, 1H), 4.70 (t, 1H, J = 5.1 Hz), 3.57-3.50 (m, 1H), 3.40-3.33 (m,
1H), 2.54-2.78 (m, 3H) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ = 175.5, 140.6,
129.2 (2C), 128.5 (2C), 126.2, 62.8, 50.7, 34.9 ppm.
3-Hydroxy-2-(4-methoxyphenyl)-3-phenylpropanamide (4ai): This compound
was obtained as an inseparable mixture of the syn and anti diastereoisomers in 1.4:1
ratio (Rf = 0.49). Light brown solid. Mp 107-109 °C. Yield: 0.089 g (33%). IR (KBr): ν
= 3520 (O-H), 3415 (O-H), 3305 (N-H), 3169 (N-H), 1653 (C=O) cm-1. HRMS (ESI):
m/z 294.109547, [M + Na+] (calcd for C16H17O3NNa: 294.110064). Syn
diastereoisomer: 1H NMR (DMSO-d6, 300 MHz): δ = 7.39-7.22 (m, 8H), 6.86 (d, 2H, J
= 8.7 Hz), 6.54 (br, 1H), 5.11 (d, 1H, J = 5.1 Hz), 5.04-4.97 (m, 1H), 3.74 (s, 3H), 3.62
(d, 1H, J = 10.0 Hz) ppm. 13C{1H} NMR (DMSO-d6, 75 MHz): δ = 174.0, 158.4, 144.8,
130.2, 128.1 (2C), 127.5 (2C), 127.4 (2C), 127.4, 113.6 (2C), 74.3, 58.9, 55.5 ppm. Anti
diastereoisomer: 1H NMR (DMSO-d6, 300 MHz): δ = 7.45 (br, 1H), 7.39-7.22 (m, 7H),
6.80 (br, 1H), 6.68 (d, 2H, J = 8.7 Hz), 5.47 (d, 1H, J = 4.8 Hz), 5.04-4.97 (m, 1H), 3.69
13
(d, 1H, J = 8.4 Hz), 3.64 (s, 3H) ppm. C{1H} NMR (DMSO-d6, 75 MHz): δ = 174.7,
158.2, 144.2, 130.0, 128.0 (2C), 127.5 (2C), 127.3 (2C), 127.1, 113.6 (2C), 75.3, 59.0,
55.3 ppm. The amide 8 (Rf = 0.69) was also isolated in 10% yield (0.016 g).
17

ACCEPTED MANUSCRIPT
2-(3,4-Dimethoxyphenyl)-3-hydroxy-3-phenylpropanamide
(4aj):
This
compound was obtained as a mixture of diastereoisomers which could be separated by
column chromatography using EtOAc as eluent. Syn diastereoisomer (Rf = 0.32): White
solid. Mp 141-143 °C. Yield: 0.084 g (28%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.40-
7.20 (m, 6H), 7.04-6.86 (m, 3H), 6.57 (br, 1H), 5.11 (d, 1H, J = 5.1 Hz), 5.01 (dd, 1H, J
13
= 9.3 and 5.1 Hz), 3.74 (s, 6H), 3.66 (d, 1H, J = 9.3 Hz) ppm. C{1H} NMR (DMSO-
d6, 75 MHz): δ = 173.9, 148.5, 148.1, 144.7, 131.8, 128.1 (2C), 127.5 (2C), 127.3,
121.6, 113.1, 111.8, 74.3, 59.3, 56.0, 55.9 ppm. IR (KBr): ν = 3371 (O-H and N-H),
3191 (N-H), 1666 (C=O) cm-1. HRMS (ESI): m/z 324.120168, [M + Na+] (calcd for
C17H19O4NNa: 324.120629). Anti diastereoisomer (Rf = 0.64): White solid. Mp 150-
152 °C. Yield: 0.042 g (14%). 1H NMR (DMSO-d6, 300 MHz): δ = 7.45 (br, 1H), 7.15-
7.11 (m, 5H), 6.81 (br, 1H), 6.75-6.66 (m, 3H), 5.47 (d, 1H, J = 4.5 Hz), 5.02 (dd, 1H, J
13
= 8.4 and 4.5 Hz), 3.63 (s, 3H), 3.61 (s, 3H), 3.59 (d, 1H, J = 8.4 Hz) ppm. C{1H}
NMR (DMSO-d6, 75 MHz): δ = 174.6, 148.3, 147.8, 144.3, 130.7, 128.0 (2C), 127.4
(2C), 127.1, 121.2, 112.9, 111.5, 75.3, 59.4, 55.8, 55.7 ppm. IR (KBr): ν = 3398 (O-H
and N-H), 3195 (N-H), 1654 (C=O) cm-1. HRMS (ESI): m/z 324.121060, [M + Na+]
(calcd for C17H19O4NNa: 324.120629). The amide 9 (Rf = 0.77) was also obtained in
16% yield (0.031 g).
3-Hydroxy-2,2-dimethyl-3-phenylpropanamide (4ak) [10c]: Light brown solid.
1
Mp 132-134 °C (Lit. 134-136 °C). Yield: 0.116 g (60%). H NMR (DMSO-d6, 300
MHz): δ = 7.31-7.21 (m, 5H), 7.08 (br, 1H), 6.87 (br, 1H), 5.53 (d, 1H, J = 4.5 Hz),
4.77 (d, 1H, J = 4.5 Hz), 1.00 (s, 3H), 0.92 (s, 3H) ppm. 13C{1H} NMR (DMSO-d6, 75
MHz): δ = 179.1, 143.0, 128.1 (2C), 127.7 (2C), 127.2, 77.4, 47.0, 22.9, 21.1 ppm.
3-(4-Chlorophenyl)-3-hydroxy-2,2-dimethylpropanamide (4al): Light brown
solid. Mp 127-129 °C. Yield: 0.168 g (74%). IR (KBr): ν = 3345 (O-H), 3284 (N-H),
18

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3230 (N-H), 1663 (C=O) cm-1. 1H NMR (DMSO-d6, 400 MHz): δ = 7.35-7.29 (m, 4H),
7.06 (br, 1H), 6.88 (br, 1H), 5.60 (d, 1H, J = 4.4 Hz), 4.78 (d, 1H, J = 4.4 Hz), 1.00 (s,
13
3H), 0.90 (s, 3H) ppm. C{1H} NMR (DMSO-d6, 75 MHz): δ = 178.7, 142.0, 131.8,
129.8 (2C), 127.6 (2C), 76.5, 47.1, 22.3, 21.4 ppm. HRMS (ESI): m/z 250.060362, [M +
Na+] (calcd for C11H14O2ClNNa: 250.060527).
3-(3-Chlorophenyl)-3-hydroxy-2,2-dimethylpropanamide (4am): Light brown
solid. Mp 133-135 °C. Yield: 0.171 g (75%). IR (KBr): ν = 3344 (O-H), 3283 (N-H),
3243 (N-H), 1665 (C=O) cm-1. 1H NMR (DMSO-d6, 300 MHz): δ = 7.32-7.24 (m, 4H),
7.07 (br, 1H), 6.93 (br, 1H), 5.67 (br, 1H), 4.78 (br, 1H), 1.01 (s, 3H), 0.91 (s, 3H) ppm.
13C{1H} NMR (DMSO-d6, 75 MHz): δ = 178.6, 145.8, 132.6, 129.6, 127.7, 127.2,
126.7, 76.5, 47.1, 22.1, 21.6 ppm. HRMS (ESI): m/z 250.060264, [M + Na+] (calcd for
C11H14O2ClNNa: 250.060527).
3. Results and Discussion
In a previous study we demonstrated the utility of the arene-ruthenium(II)
complex [RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (1) as catalyst for the hydration of β-
ketonitriles A into β-ketoamides B in pure water [3e]. This fact along with known
ability of Ru(II) complexes to promote the TH of carbonyl compounds in aqueous
media, employing NaO2CH as the hydrogen source [6], led us to screening the potential
of the 1/NaO2CH combination for the one-pot conversion of β-ketonitriles into β-
hydroxyamides. Commercially available 3-(4-fluorophenyl)-3-oxopropanenitrile (2a)
was chosen as model substrate to monitor conveniently the course of the reactions by
19F{1H} NMR spectroscopy (see Table 1).
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Table 1. Metal-catalyzed hydration/transfer hydrogenation of the β-ketonitrile 2a: Optimization of the reaction conditions.a
Entry
Catalyst
Loading
NaO2CH
Temp.
Conv.b
Yield 3ab
Yield 4ab
Yield 5ab
1
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (1)
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (1)
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (1)
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (1)
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (1)
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (1)
[RuCl2(η6-p-cymene){P(4-C6H4F)2OH}]
[{RuCl(µ-Cl)(η6-p-cymene)}2]
[RuCl2(η6-p-cymene)(PPh3)]
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
1 equiv.
80 ºC
> 99%
> 99%
> 99%
> 99%
> 99%
> 99%
> 99%
> 99%
> 99%
98%
91%
67%
44%
24%
15%
0%
5%
0%
2
5 equiv.
80 ºC
27%
52%
71%
76%
92%
91%
0%
0%
3
10 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
20 equiv.
80 ºC
0%
4
80 ºC
0%
5
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
100 ºC
0%
6
0%
7
0%
0%
8
0%
62%
22%
18%
24%
34%
24%
75%
44%
0%
9
4%
0%
10
11
12
13
14
15
16
17
18
19
[RuCl2(η6-p-cymene){P(4-C6H4F)3}]
18%
3%
1%
[RuCl2(PPh3)3]
> 99%
> 99%
> 99%
95%
0%
[RuCl2(DMSO)4]
[RuCl(η5-C5Me5)(PPh3)2]
[RuCl(η5-Indenyl)(PPh3)2]
2%
1%
1%
0%
1%
0%
RuCl3·nH2O
> 99%
> 99%
> 99%
> 99%
> 99%
7%
5%
[RuCl2(η6-p-cymene)(PMe2OH)]
[RuCl2(η3:η3-C10H16)(PMe2OH)]
[OsCl2(η6-p-cymene)(PMe2OH)]
[PtH{(PMe2O)2H}(PMe2OH)]
0%
86%
34%
92%
91%
30%
0%
8%
0%
0%
0%
a Reactions performed under Ar atmosphere with 1 mmol of the β-ketonitrile 2a (0.33 M in water). b Determined by 19F{1H} NMR spectroscopy.
20

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Thus, in a first series of experiments solutions of 2a in water were treated with
complex 1 (2 mol%) at 80 ºC for 24 h in the presence of variable amounts of sodium
formate (from 1 to 20 equivalents; entries 1-4). In all the cases, complete consumption
of the starting β-ketonitrile took place as assessed by 19F{1H} NMR spectroscopy [23].
The major reaction products in the crude reaction mixtures were the β-ketoamide 3a and
the desired β-hydroxyamide 4a, increasing the amount of the latter with the quantity of
NaO2CH added (up to 71% yield with 20 equiv. of sodium formate; see entry 4). Minor
amounts of some unidentified products were also observed in the crudes, but in no case
the β-hydroxynitrile 5a resulting from the TH of 2a was present. These results clearly
indicate that the transfer hydrogenation step is the rate limiting one of the hydration/TH
cascade process, with the β-ketoamide intermediate 3a forming rapidly in the reaction
medium prior to the reduction of the carbonyl functionality [24]. Further experiments at
a higher temperature (100ºC) and with a higher ruthenium loading (5 mol%) allowed to
increase the yield of 4a from 71 to a maximum of 92% (entries 5-6). As shown in entry
6, employing 5 mol% of complex 1, 20 equivalents of sodium formate and a working
temperature of 100 ºC, the intermediate β-ketoamide 3a was not longer present in the
crude. From this experiment, the β-hydroxyamide 4a could be isolated in 74% yield
after solvent removal and subsequent chromatographic purification.
On the other hand, in complete accord with our previous findings indicating that,
when dissolved in water, hydrolysis of the chlorophosphine ligand in complex
[RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (1) readily takes place leading to the
phosphinous acid derivative [RuCl2(η6-p-cymene){P(4-C6H4F)2OH}] [3e], the direct
use of this latter compound as catalyst in the cascade process led to almost identical
results (entry 7). The key role played by the in situ formed phosphinous acid ligand in
the reaction was fully confirmed with the experiments collected in entries 8-15, where
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different commercially available or easily accessible ruthenium compounds lacking of
P-OH or hydrolizable P-Cl ligands where employed as potential catalysts [25]. Only
trace amounts of the desired β-hydroxyamide 4a were generated, and in most cases the
β-hydroxynitrile 5a resulting from the exclusive TH of 2a was the major product
present in the reaction crudes. Additional experiments were also performed employing
other transition-metal complexes bearing the phosphinous acid ligand PMe2OH (entries
16-19). All these compounds, that were successfully employed in previous reports as
nitrile hydration catalysts [3b,d,g,26], were able to generate 4a as the major reaction
product. Among them, the osmium(II) derivative [OsCl2(η6-p-cymene)(PMe2OH)]
(entry 18) and the Parkins-Ghaffar catalyst [PtH{(PMe2O)2H}(PMe2OH)] (entry 19)
showed an effectiveness and selectivity comparable to that of [RuCl2(η6-p-
cymene){P(4-C6H4F)2Cl}] (1). However, from a practical point of view, the use of these
compounds instead of 1 is less convenient given the higher price of Os and Pt in
comparison to Ru.
Having established the optimal reaction conditions, we next focused on the scope
of the process. To this end, the behavior of a broad family of α-unsubstituted β-
ketonitriles was firstly investigated (see Table 2). Thus, as observed for 2a (entry 1),
other aromatic systems 2b-m could be cleanly converted into the corresponding β-
hydroxyamides 4b-m, regardless of the substitution pattern and electronic properties of
the aromatic ring (entries 2-13). After appropriate chromatographic work-up, amides
4b-m were isolated in 70-88% yield and their identity confirmed by multinuclear NMR
spectroscopy, as well as IR and high resolution mass spectrometry (HRMS) in the case
of previously unreported examples (details are given in the Experimental section).
Interestingly, when 4-(2-cyanoacetyl)benzonitrile 2n was employed as substrate, the
corresponding diamide 4n was exclusively formed as the result of the hydration of the
22

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two nitrile functionalities plus the TH of the carbonyl group (87% isolated yield; entry
14). On the other hand, as exemplified with 2o and 2p, the present hydration/TH
process tolerates the use of heteroaromatic β-ketonitriles (entries 15 and 16). However,
we should note that a longer reaction time (48 vs 24 h) was needed to convert 3-oxo-(2-
thienyl)propanenitrile (2p) into 3-hydroxy-3-(2-thienyl)propanamide (4p) in high yield
(70%), due probably to the competing coordination of sulfur atom to the metal [27]. As
shown in entries 17-22, different β-ketonitriles containing aliphatic substituents 2q-v
could also be transformed into the corresponding β-hydroxyamides 4q-v in moderate to
good yields (52-82%) applying the standard reaction conditions, thus confirming the
wide scope of the process concerning the nature of the substituent of the carbonylic unit.
1
In all the reactions collected in Table 2 the only by-products detected by H NMR
spectroscopy in the crudes were the corresponding β-ketoamide intermediates (present
in ca. 3-10%).
Table 2. Ru-catalyzed synthesis of β-hydroxyamides 4a-v from β-ketonitriles 2a-v.a
Entry
1
β-Ketonitrile 2
β-Hydroxyamide 4
Yield (%)b
74
2
3
82
88
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4
5
6
70
70
73
7
85
8
9
77
84
10
11
82
85
12
86
13
14
76
87
15
80
70
16c
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17
18
19
81
56
71
20
21
52
77
22
82
a Reactions performed in a Teflon-capped sealed tube under Ar atmosphere with 1 mmol of the
c
corresponding β-ketonitrile (0.33 M in H2O). b Isolated yields after chromatographic work-up.
Reaction time 48 h.
To delineate more precisely the scope of the process, we next explored the
reactivity of a series of α-monosubstituted β-ketonitriles. In this regard, we were glad to
find that, under identical reaction conditions, the alkyl-, benzyl- and homobenzyl-
substituted substrates 2w-ae also participate in the hydration/TH cascade reaction
delivering the respective β-hydroxyamides 4w-ae in moderate to excellent yields (50-
97%; see Table 3). Only in the case of the sterically hindered ketonitrile 2ac the reaction
time had to be extended from 24 to 48 h to generate the amide product 4ac with a
satisfactory yield (entry 7). The result obtained with the β-formylnitrile 2ae merits to be
highlighted since it demonstrates that the process is not restricted to ketone substrates
(entry 9). On the other hand, during the hydration/TH reaction of compounds 2w-ad
two stereogenic carbons are generated, and consequently the final β-hydroxyamide
25

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products 4w-ad were isolated as mixtures of the corresponding syn and anti
diastereoisomers in ratios ranging from 3.8:1 to 1:1.4 (entries 1-8). In the case of
compounds 4w-ab, the two diastereoisomers could be separated by column
3
chromatography and their syn or anti nature determined by comparison of the JHH
coupling constants between the CHOH and CHR(=O)NH2 protons of both isomers,
assuming that, accordingly to previous studies on related systems [28], the syn
configuration gives rise to a larger coupling constant in comparison with the anti one
(the measured 3JHH values are given in Table 4).
Table 3. Ru-catalyzed synthesis of β-hydroxyamides 4w-ae from the α-substituted β-
ketonitriles 2w-ae.a
Entry
1
β-Ketonitrile 2
β-Hydroxyamide 4
Yield (%)b
88
syn/anti ratio
1:1.3
2
3
75
97
1.3:1
1:1.3
4
68
1:1.4
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5
6
72
3.8:1
1:1.3
82
7c
8
61
55
1.4:1
1.2:1
9
50
------
a Reactions performed in a Teflon-capped sealed tube under Ar atmosphere with 1 mmol of the
c
corresponding β-ketonitrile (0.33 M in H2O). b Isolated yields after chromatographic work-up.
Reaction time 48 h.
Table 4. Comparison of the coupling constants of the syn and anti diastereoisomers of
β-hydroxyamides 4w-ab.a
Entry
β-Hydroxyamide 4
JHaHb syn
JHaHb anti
1
2
3
4
5
4w (R1 = Ph; R2 = Me)
4x (R1 = Ph; R2 = Et)
4y (R1 = Ph; R2 = nBu)
4z (R1 = Ph; R2 = nPent)
4aa (R1 = Ph; R2 = Bn)
8.7 Hz
8.7 Hz
8.4 Hz
9.3 Hz
7.5 Hz
7.2 Hz
8.1 Hz
7.6 Hz
8.1 Hz
7.2 Hz
27

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6
4ab (R1 = Ph; R2 = CH2Bn)
8.1 Hz
7.8 Hz
a 1H NMR spectra recorded in DMSO-d6.
In contrast to 4w-ab, all attempts to separate the syn and anti diastereoisomers of
the aliphatic β-hydroxyamides 4ac-ad by column chromatography were unsuccessful,
1
and the overlapping of the CHOH and CHR(=O)NH2 signals of both isomers in the H
NMR spectra of the mixtures prevented to determine in a straightforward manner the
configuration of the major and minor isomers. In these cases, the assignments were
made indirectly by reducing first the β-ketonitriles 2ac-ad to the β-hydroxynitriles 5ac-
ad with NaBH4 in MeOH (Scheme 3). The syn and anti isomers of 5ac-ad could neither
be separated by column chromatography but, fortunately, no overlapping of the
1
respective CHOH and CHRC≡N signals was observed in the H NMR spectra, thus
allowing to assign a syn configuration to the major stereoisomer formed in both
reactions (as in the case of 4w-4ab, a Jsyn > Janti was assumed) [29,30]. Subsequent
hydration of 5ac-ad by means of complex [RuCl2(η6-p-cymene){P(4-C6H4F)2Cl}] (1)
generated the β-hydroxyamides 4ac-ad. As shown in Scheme 3, the hydration reactions
were performed under neutral and mild temperature conditions to avoid racemization
processes. To our delight, the isomeric ratios found for 4ac-ad were identical to those of
the starting nitriles 5ac-ad. In this way, comparison of the 1H NMR spectra recorded for
these experiments with those obtained in the hydration/TH reactions collected in Table
3 (entries 7 and 8) allowed to determine the syn/anti ratio of the products generated in
the latter.
28

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Scheme 3. Two-step synthesis of β-hydroxyamides 4ac-ad from β-ketonitriles 2ac-ad.
The behavior of different α-aryl-β-ketonitriles was also explored and the results
obtained brought to light an important limitation of the present Ru-catalyzed
hydration/TH cascade reaction. Thus, as shown in Scheme 4, when the phenyl-
substituted substrates 2af-ah were subjected to the combined action of complex 1 and
NaO2CH, in all the cases, 2-phenylacetamide 6 was the major reaction product that
could be isolated after the chromatographic work-up (77-91% yield). Formation of 6
can be rationalized in terms of the instability of the desired β-hydroxyamide products
4af-ah under the reaction conditions needed for the hydration/TH process to proceed. A
retro-aldol type reaction of compounds 4af-ah, facilitated by the NaO2CH base, could
explain the formation of 6. Inspection of the crude reaction mixtures before solvent
removal by gas chromatography indicated also the presence in solution of the
corresponding alcohols 7af-ah, resulting from TH of the retro-aldol aldehyde products
F. The marked differences in stability between the α-phenyl-β-hydroxyamides 4af-ah
and their alkyl-, benzyl- and homobenzyl-substituted counterparts 4w-ae (Table 3) is
probably related with the electronic delocalization of the negative charge in the amide
enolate intermediate E by conjugation with the aromatic ring, which would facilitate the
cleavage of the C-C bond of β-hydroxyamides 4af-ah.
29