Amidation of aldehydes and alcohols through α-iminonitriles and a sequential oxidative three-component strecker reaction/thio-michael addition/alumina-promoted hydrolysis process to access β-mercaptoamides from aldehydes, amines, and thiols

Article abstract of DOI:10.1002/chem.201202291

Mild and general alumina-promoted hydrolysis conditions for converting α-iminonitriles into carboxamides have been developed. In combination with the oxidative three-component Strecker reaction, the one-pot direct amidation of aldehydes and alcohols is reported. Subsequently, an Yb(OTf) ₃-catalyzed Michael addition of thiols to α,β-unsaturated α-iminonitriles is reported for the synthesis of β-mercapto-α- iminonitriles. The successful integration of an oxidative Strecker reaction, thio-Michael addition, and neutral-alumina-promoted hydrolysis of β-mercapto-α-iminonitriles into a three-component one-pot process allowed us to develop the direct conversion of amines, aldehydes, and thiols into β-mercaptoamides. All of these procedures were applicable to aromatic and aliphatic amines and aldehydes. First direct: The direct amidation reactions of aldehydes and alcohols were performed in combination with the oxidative three-component synthesis of α-iminonitriles. In addition, β-mercaptoamides were readily accessed from α,β-unsaturated aldehydes, amines, and thiols by a sequential process that involved a three-component Strecker reaction, Yb(OTf)₃-catalyzed thio-Michael addition, and hydrolysis of the resulting β-mercapto-α-iminonitriles (see scheme). Copyright

Full text of DOI:10.1002/chem.201202291

FULL PAPER
DOI: 10.1002/chem.201202291
Amidation of Aldehydes and Alcohols through a-Iminonitriles and a
Sequential Oxidative Three-Component Strecker Reaction/Thio-Michael
Addition/Alumina-Promoted Hydrolysis Process to Access b-
Mercaptoamides from Aldehydes, Amines, and Thiols
Jean-Baptiste Gualtierotti,[a] Xavier Schumacher,[a] Patrice Fontaine,[b]
Gꢀraldine Masson,[b] Qian Wang,[a] and Jieping Zhu*[a]
Abstract: Mild and general alumina-
promoted hydrolysis conditions for
converting a-iminonitriles into carbox-
amides have been developed. In combi-
nation with the oxidative three-compo-
nent Strecker reaction, the one-pot
direct amidation of aldehydes and alco-
hols is reported. Subsequently, an Yb-
thiols to a,b-unsaturated a-iminoni-
triles is reported for the synthesis of b-
mercapto-a-iminonitriles. The success-
ful integration of an oxidative Strecker
reaction, thio-Michael addition, and
neutral-alumina-promoted hydrolysis
of b-mercapto-a-iminonitriles into
a
three-component one-pot process al-
lowed us to develop the direct conver-
sion of amines, aldehydes, and thiols
into b-mercaptoamides. All of these
procedures were applicable to aromatic
and aliphatic amines and aldehydes.
Keywords: alumina
·
amides
·
Michael addition · multicomponent
reactions · Strecker reaction
ACHTUNGTRENNUNG(OTf)3-catalyzed Michael addition of
Introduction
with amines[13–17] have been developed into powerful alterna-
tives to classic peptide-coupling reactions.
Amide-bond formation is of great interest in organic synthe-
sis owing to the abundance of this functional group in natu-
ral products, pharmaceuticals, and polymers.[1] Such bonds
are generally formed from free carboxylic acids and amines
in the presence of a coupling reagent or by the prior conver-
sion of carboxylic acids into activated derivatives, such as
acid chlorides or anhydrides, followed by reaction with
amines.[2] Whilst these coupling reactions are remarkably ef-
fective, the waste production that is inherently associated
with the use of these coupling reagents and additives is also
significant. Therefore, new and “greener” conditions are
constantly being sought.[3–4] Among them, the Staudinger re-
action,[5] native chemical ligation,[6] a-ketoacid-hydroxyl-
In connection with our work on the isocyanide-based mul-
ticomponent synthesis of heterocycles,[18] we have reported a
one-pot homologation of aldehydes into amides and a-ke-
toamides.[11] As part of our continued efforts to develop new
multicomponent reactions,[19] we were interested in develop-
ing oxidative multicomponent reactions,[20–21] and we have
recently reported an oxidative three-component reaction of
aldehydes 1, amines 2, and trimethylsilyl cyanide (TMSCN)
for the synthesis of a-iminonitriles 3,[22] thus making these
ACHTUNGTRENNUNG
amine ligation,[7] alkyne–azide click reactions,[8] isocyanide-
mediated amidation,[9–11] the umpolung reaction of amino
acids,[12] and the oxidative coupling of aldehydes/alcohols
[a] J.-B. Gualtierotti, X. Schumacher, Dr. Q. Wang, Prof. Dr. J. Zhu
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304
1015 Lausanne (Switzerland)
Fax : (+41)21-6939740
E-mail: jieping.zhu@epfl.ch
[b] Dr. P. Fontaine, Dr. G. Masson
Centre de Recherche de Gif
Institut de Chimie des Substances Naturelles
CNRS, 91198 Gif-sur-Yvette Cedex (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202291.
Scheme 1. Chemistry of a-iminonitriles: from amines and aldehydes/alco-
hols to amides and b-mercaptoamides.
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Table 1. Survey of the reaction conditions for converting a-iminonitrile
3a into amide 4a.[a]
previously hard-to-obtain entities readily accessible (Sche-
me 1a).[23] Exploring the synthetic potential of this highly
functionalized structure,[24] we subsequently reported an
AlCl3-catalyzed [4+1] cycloaddition of a,b-unsaturated a-
iminonitriles and isocyanides for the synthesis of 2-amino-5-
cyanopyrroles.[25] Herein, we report an alumina-promoted
hydrolysis of a-iminonitriles 3 into amides 4 (Scheme 1b)
and a one-pot direct amidation of aldehydes 1 (Scheme 1c)
and alcohols 5 (Scheme 1d) by a process that involves the
tandem oxidation of alcohols/oxidative three-component
Strecker reaction/hydrolysis. Furthermore, by using a,b-un-
saturated aldehydes 6 as starting materials, we report an ef-
ficient one-pot synthesis of b-mercaptoamides 7 through a
sequence that involves: 1) an oxidative Strecker reaction,
Entry
Solvent
T [8C]
t [h]
3a [%]
4a [%]
1
2
3
4
CH2Cl2
toluene
toluene
toluene
20
20
24
24
24
1
100
41
42
0
0
59
39
130
MW[b]
100
[a] Reaction conditions: compound 3 (0.2 mmol), solvent (2.0 mL), basic
alumina (1.0 g, Brockmann I). [b] 300 W, 1308C, 1 h.
radation pathways (Table 1, entry 3). Thankfully, microwave
irradiation of the reaction mixture (toluene, 1.0 g of alumina
per 0.2 mmol of compound 3a) afforded amide 4a in quanti-
tative yield (Table 1, entry 4).
Having established optimal reaction conditions, the scope
of this reaction was examined next. As shown in Table 2, the
2) an YbACHTUNGTRENNUNG(OTf)3-catalyzed Michael addition of thiols to
a,b-unsaturated a-iminonitriles 8, and 3) an alumina-mediat-
ed hydrolysis of the resulting b-mercapto-a-iminonitriles
(Scheme 1e).
Results and Discussion
Table 2. Scope of the alumina-promoted hydrolysis of a-iminonitriles
into amides.[a]
Hydrolysis of a-iminonitriles into amides: a-Iminonitriles
can be considered as logical precursors of a-ketoacids[26] and
carboxamides.[27] However, these conversions have seldom
been studied, presumably owing to the lack of efficient syn-
thetic methods to access a-iminonitriles. To the best of our
knowledge, a two-step sequence that involves the methanol-
ysis of a-iminonitriles in the presence of a strong base
(NaOH) followed by hydrolysis (SiO2, MeOH) of the result-
ing imidates is the only reported method for the conversion
of a-iminonitriles into amides. However, the scope of this
procedure is limited and it is only applicable to a-iminoni-
triles that are derived from aniline and aromatic aldehydes.
In our initial studies on the synthesis of a-iminonitriles, di-
verse stationary phases, such as silica gel, silanized silica gel,
and alumina, were used as a support for the purification of
the relatively acid-labile products (by column chromatogra-
phy). With alumina as the support, a small percentage of the
corresponding amide was detected after purification, whilst
it was absent in the crude mixture. Knowing the challenges
that are associated with the hydrolysis of a-iminonitriles and
the potential synthetic applications of this transformation,
we set out to investigate the hydrolysis of a-iminonitriles in
detail by using alumina as a promoter.
By using purified (Z)-N-phenethylbenzimidoyl cyanide
(3a) as a test substrate and basic Brockmann I alumina as
an adsorbent, we investigated the reaction conditions by
varying the solvent and reaction temperature; representative
results are shown in Table 1. No reaction was detected in
CH2Cl2 after 24 h at room temperature, which only led to re-
covery of the starting iminonitrile 3a (Table 1, entry 1).
When toluene was used as the solvent under otherwise iden-
tical conditions, amide 4a was obtained in 59% yield togeth-
er with 41% of the recovered starting material (Table 1,
entry 2). Increasing the temperature (1308C) led to a lower
yield of the amide, most-probably owing to competitive deg-
Entry
R1
R2
4
Yield [%]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
PhCH2CH2
PhCH2
4a
4b
4c
4d
4e
4 f
4g
4h
quant.
quant.
63
quant.
quant.
quant.
quant.
quant.
4-MeOC6H4
PhCH2CH2
cyclopropyl
PhCH2CH2
PhCH2CH2
PhCH2CH2
4-MeOC6H4
PhCH=CH
PhCH=CH
MeCH=CH(Me)
PhCH2CH2
[a] Reaction conditions: 3 (0.2 mmol), solvent (2.0 mL), basic alumina
Brockmann I (1.0 g), 300 W, 1308C, 1 h. quant.=quantitative yield.
iminonitriles that were derived from aromatic, aliphatic, and
a,b-unsaturated aldehydes were hydrolyzed effectively into
their corresponding amides. Hydrolysis of both aniline and
aliphatic-amine-derived iminonitriles worked equally well.
The transformations proceeded essentially quantitatively,
except for the hydrolysis of 4-methoxyaniline-derived imino-
nitrile (Table 2, entry 3). In this way, N-cyclopropylamide
was obtained in quantitative yield (Table 2, entry 5). Inter-
estingly, alumina can trap the cyanide ion, thus rendering
this procedure less hazardous.[28]
One-pot synthesis of amides from aldehydes through a-imi-
nonitrile intermediates: After having established mild condi-
tions for the hydrolysis of a-iminonitriles, we turned our at-
tention to the direct amidation of aldehydes by using a se-
quence that involved an oxidative three-component Strecker
reaction and hydrolysis—without isolation—of the resulting
a-iminonitrile. By using 2-phenethylamine as a starting
amine, two procedures were developed that allowed for the
direct amidation of aldehydes. For reactions of aliphatic al-
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Amidation of Aldehydes and Alcohols and Synthesis of b-Mercaptoamides
FULL PAPER
dehydes, simply adding alumina to the reaction mixture of
Interestingly, in the absence of TMSCN, the reaction be-
the oxidative three-component Strecker reaction followed
by heating under microwave irradiation led to their corre-
sponding amides in excellent yields. As shown in Table 3,
both linear, a-branched, and a,b-unsaturated aldehydes
tween benzaldehyde and phenethylamine in the presence of
o-iodoxybenzoic acid (IBX) and tetrabutylammonium bro-
mide (TBAB) mainly afforded the corresponding imine and
2-phenylacetonitrile, which resulted from oxidation of the
primary amine.[29] Indeed, the corresponding N-phenethyl-
benzamide was obtained when five equivalents of benzalde-
hyde were used. However, the yield remained synthetically
insignificant and this procedure was only applicable to aro-
matic aldehydes.
Table 3. One-pot synthesis of amides from aldehydes and amines.[a]
From the point of view of diversity, the oxidative Strecker
reaction of aldehydes, amines, and TMSCN can now pro-
duce either a-iminonitriles or carboxamides by simply modi-
fying the work-up procedure.[30] Whilst aqueous work-up af-
forded a-iminonitriles, adsorption of the reaction mixture
onto the alumina surface prior to the purification directly
provided the carboxamides.
Entry
1
R1
Product
4
Yield [%]
quant.
Me2CH
4i
2
cyclohexyl
4j
97
Tandem oxidative amidation of alcohols through a-iminoni-
trile intermediates: Tandem oxidative processes (TOPs) in
which oxidation of the alcohols is combined with a subse-
quent elaboration of the carbonyl intermediates have been
developed into powerful synthetic tools.[31] Such tandem
processes, in addition to the avoidance of a purification step,
are particularly useful when the carbonyl intermediates are
unstable and, therefore, this field has attracted increased at-
tention among synthetic chemists.[32–33] Alcohols are readily
oxidized into aldehydes by using IBX and such oxidation re-
actions are generally performed in DMSO because it is the
only common solvent that is capable of solubilizing IBX.
However, More and Finney have shown that IBX-mediated
oxidation can be performed in different solvents with com-
parable efficiency.[34] This result prompted us to investigate
the direct conversion of alcohols into amides by using a se-
quence that involved oxidation of the alcohol into an alde-
hyde, followed by an oxidative Strecker reaction and hydrol-
ysis of the a-iminonitrile. After some experimentation, a
procedure that allowed the realization of the desired amida-
tion of alcohol starting materials was developed: Refluxing
3
4
5
6
MeCH=C(Me)
4g
4h
4a
4a
74
PhCH2CH2
73
Ph
Ph
76[b]
95[c]
[a] Reaction conditions: IBX (1.1 mmol) and TBAB (1.1 mmol) were
added to mixture of aldehyde (1.0 mmol), amine (1.1 mmol), and
a
TMSCN (1.1 mmol) in CH3CN. When the consumption of the aldehyde
was complete (followed by TLC), alumina (1.0 g) was added, and the reac-
tion mixture was placed under microwave irradiation (300 W, 1308C, 1 h).
[b] Alumina (2.0 g) was added, the volatile compounds were removed, and
the resulting powder was left to stand at room temperature. [c] Alumina
(6.0 g) was added, the volatile compounds were removed, and the resulting
powder was left to stand at room temperature.
were all tolerated in the reaction, thereby leading to their
corresponding amides in good to excellent yields (Table 3,
entries 1–4). Unfortunately, this procedure was not applica-
ble to aromatic aldehydes; only the corresponding a-imino-
nitriles were isolated after microwave irradiation. Reasoning
that this failure may arise from poor adsorption of the a-
iminonitriles on the alumina surface, the volatile compounds
were removed in vacuo after adding alumina. After being
left to stand at room temperature for a few hours, the result-
ing powder was deposited directly onto the silica-gel column
for purification. By applying this procedure, the yield of
compound 4a from benzaldehyde and phenethylamine was
76% when 2.0 g of alumina per 1.0 mmol of aldehyde were
added (Table 3, entry 5), which increased to 95% when the
amount of alumina was increased to 6.0 g per 1.0 mmol of
aldehyde (Table 3, entry 6). The second procedure was very
general in its scope and it was also applicable to a-iminoni-
triles that were derived from aliphatic aldehydes. More ex-
amples are presented below.
a
suspension of benzyl alcohol (1.0 mmol) and IBX
(3.0 equiv) in CH3CN for 25 min cleanly afforded the ben-
zaldehyde (monitored by TLC). After being cooled to room
temperature,
phenethylamine
(1.1 equiv),
TMSCN
(1.1 equiv), and TBAB (1.1 equiv) were added and the re-
sulting mixture was stirred at room temperature until the
starting materials had been completely consumed. The reac-
tion was filtered to remove IBX and 2-iodosobenzoic acid
(IBA), a reduced form of IBX, and the solid was rinsed with
toluene. Alumina was added to the filtrate and the volatile
compounds were evaporated. The resulting powder was left
to stand overnight and was purified by directly depositing it
onto the top of a short column of silica gel. In this manner,
compound 4a was isolated in 81% yield from benzyl alcohol
and phenethylamine.
The scope of this new amidation reaction was examined
next (Table 4). Benzyl alcohols that contained electron-rich-
and electron-poor aromatic rings were successfully convert-
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J. Zhu et al.
Table 4. One-step amidation of alcohols.[a]
remains unknown. With a method that allows easy access to
a,b-unsaturated a-iminonitriles[25] and their subsequent hy-
drolysis into amides in hand, we set out to develop a modu-
lar synthesis of b-mercaptoamides from amines, aldehydes
(alcohols), and thiols.
We began our investigation with the thio-Michael reaction
between ethanethiol (9a) and a,b-unsaturated a-iminonitrile
10a. No reaction took place at room temperature when
these two reactants were mixed in different solvents. How-
ever, in CH2Cl2, in the presence of a catalytic amount of
AlCl3 (0.1 equiv), Michael addition occurred to produce the
desired b-mercapto-a-iminonitrile 8a in 41% yield as a mix-
ture of the imine and its tautomeric enamine (structure not
shown). Partial degradation of b-mercapto-a-iminonitrile 8a
was observed during work-up and purification (Scheme 2).
Entry R1
R2
Product
4
Yield
[%]
1
2
Ph
Ph
PhCH2CH2
cyclopropyl
4a 81
4k 83
4-
3
4
Ph
4c 77
4d 76
MeOC6H4
4-MeOC6H4
PhCH2CH2
PhCH2CH2
5
2-IC6H4
4l 81
6
7
PhCH2CH2
PhCH2CH2
PhCH2CH2
4h 80
4m 77
Scheme 2. Synthesis of b-mercaptoamides from the thiol-Michael reac-
tion between a,b-unsaturated a-iminonitriles and ethanethiol, followed
by hydrolysis.
8
9
Me2CHCH2
cyclopropyl
PhCH2CH2
PhCH2CH2
4n 74
4o 84
Based on literature precedents for the Lewis acid cata-
lyzed thio-Michael addition of a,b-unsaturated carbonyl
compounds,[42] a range of Lewis acids were screened for the
reaction between compounds 9a and 10a. Although Cu-
[a] Reaction conditions: alcohol (1.0 mmol), IBX (3.0 mmol), CH3CN (c=
0.25m), 808C, 25 min; then, amine (1.0 mmol), TMSCN (1.1 mmol), and
TBAB (1.1 mmol) at room temperature; then, alumina (2.0 g) and evapo-
rate the volatile compounds.
A
ACHTNUGTRNENU(GN OTf)3, InBr3, ScAHCTNURGTEG(NNNU OTf)3, YbCATHNUGTRENN(UGN OTf)3, and
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ed into their corresponding amides with cyclopropylamine,
4-methoxyaniline, and phenethylamine as reaction partners
(Table 4, entries 1-5). Other, non-activated aliphatic alco-
hols, including linear, b-branched, and g-branched alcohols,
as well as cyclopropylmethanol, participated well in this
transformation, thus leading to their corresponding amides
in 73–84% yields (Table 4, entries 6–10).
for 2 h afforded compound 8a in 82% yield after rapid fil-
tration through a short pad of silica gel. Note that only the
imine (not the enamine) was isolated under these condi-
tions.
The hydrolysis of b-thio-a-iminonitriles into b-mercapto-
AHCTUNGTREGaNNNU mides was examined next. Applying the previously devel-
oped hydrolysis conditions to compound 8a afforded com-
pound 7a in a low yield (Table 5, entry 1). The presence of a
potentially labile thio group beta to the iminonitrile function
apparently rendered the hydrolysis of compound 7a as more
delicate. Reasoning that compound 7a might be prone to b-
elimination with basic alumina, different commercially avail-
able alumina materials were screened to optimize the hy-
drolysis conditions. Experimentally, we observed that adding
alumina to a solution of compound 8a in CH2Cl2 or toluene,
followed by heating or microwave irradiation, only led to
degradation of the starting material. However, hydrolysis
smoothly took place when the solvent was evaporated to
dryness after adding alumina, and the powder was left to
stand at room temperature. We also observed that removing
Thio-Michael addition of a,b-unsaturated-a-iminonitriles
and subsequent hydrolysis into b-mercaptoamides: Mercap-
toamides hold a special interest in medicinal chemistry
owing to their presence in a number of bioactive com-
pounds[35] that show anti-inflammatory,[36] antiviral and anti-
fungal,[37] antipsychotic,[38] antihypertensive,[39] and angina-
relieving activities, etc.[40] The thio-Michael addition reaction
is obviously one of the most direct ways to make this family
of compounds and both metal- and organocatalyzed Michael
additions of thiols to a,b-unsaturated carbonyl compounds
are well documented.[41] However, to the best of knowledge,
the thio-Michael addition to a,b-unsaturated a-iminonitriles
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Amidation of Aldehydes and Alcohols and Synthesis of b-Mercaptoamides
Table 5. Survey of reaction conditions for the hydrolysis of b-thio-a-imi-
FULL PAPER
phatic amines (PhCH2CH2, cyclopropyl) and aniline
(Table 6, entry 12) were tolerated. With regard to the nature
of the nucleophiles, benzenethiol, as well as aliphatic thiols,
including ethanethiol, benzylthiol, and sterically hindered
tert-butylthiol, were well tolerated as reactants. Excellent
chemoselectivity was observed with 2-mercaptoethanol:
only thio-Michael addition was observed at the expense of
the alternative oxa-Michael addition reaction. When N-Boc-
l-cystein methyl ester was used as a thiol donor (Table 6,
entry 7), the desired compound was obtained in 70% yield
as a mixture of two diastereomers. The same experiment
was performed with N-Boc-d-cysteine methyl ester to afford
another pair of diastereomers. Supercritical fluid chromatog-
raphy (SFC) analysis with a chiral stationary phase (col-
nonitrile into b-mercaptocarboxamide.[a]
Entry
Al2O3 type
Al2O3 [g]
t [h]
Yield [%]
1
2
3
4
5
6
7
8
9
basic Brockmann III
acidic Brockmann III
neutral Brockmann I
neutral Brockmann II
neutral Brockmann III
neutral Brockmann IV
neutral Brockmann I
neutral Brockmann I
neutral Brockmann I
neutral Brockmann I
1.0
1.0
1.0
1.0
1.0
1.0
0.15
0.5
0.75
1
36
36
18
24
36
25
84
98
84
66
67
36
45
90
98
36
0.5
0.5
18
10
4[b]
AHCTUNGTREGuNNUN mn IA, 15% MeOH) allowed us to conclude that no race-
[a] Reaction conditions: compound 7a (0.1 mmol) in CH2Cl2; then, addi-
tion of alumina, followed by removal of the solvent at room temperature
under vacuum. The powder was kept at room temperature. [b] The reac-
tion was performed at 408C.
mization occurred during this reaction sequence. Finally, we
noted that different functional groups, such as carboxylic
ester, N-Boc (Boc=tert-butoxycarbonyl), O-TBDPS, and
even free hydroxy groups, were well tolerated under these
conditions.
the solvent to adsorb the compound onto alumina had to be
performed at room temperature to avoid degradation.
Based on these initial observations, a survey of the reaction
conditions was performed by varying the type of alumina
used, as well as quantity and reaction time. As shown in
Table 5, both acidic and neutral alumina materials were ef-
fective as adsorbents to promote the desired hydrolysis reac-
tion (Table 5, entries 2 and 3), with the latter type being su-
perior. Therefore, neutral alumina was used for further opti-
mization. The water content of alumina adsorbents affected
the efficiency of the reaction, with neutral Brokmann I
being the best (Table 5, entries 3–6). The quantity of alumi-
na also played an important role in this reaction. Overall,
the optimal conditions consisted of 1.0 g of neutral alumina
per 1.0 mmol of the substrate. We also noticed that, once b-
mercaptoamide 7a had been adsorbed onto alumina, it was
no longer vulnerable and, therefore, the mixture could be
heated at 408C to shorten the reaction time (Table 5,
entry 10).
One-pot synthesis of b-mercaptoamides from aldehydes and
amines: Having established conditions for the direct conver-
sion of aldehydes into amides and for the one-pot synthesis
of b-mercaptoamides from a,b-unsaturated a-iminonitriles,
we briefly examined the possibility of integrating these two
reactions into an one-pot process.[43]
Cinnamaldehyde (1) and phenethylamine (2) were used
as test substrates. Surprisingly, when the reaction was run in
CH3CN or CH2Cl2, which were the solvents of choice for
the individual reactions, the desired product was not ob-
served. However, to our delight, when the one-pot reaction
was run in toluene, b-mercaptoamides 7b and 7c were ob-
tained from cinnamaldehyde, phenethylamine, and benzene-
thiol or benzylthiol in 63% and 75% yield, respectively
(Scheme 3).
With conditions for the thio-Michael reaction and for the
hydrolysis of b-thio-a-iminonitriles into b-mercaptoamides
in hands, a sequential one-pot process was examined. After
completion of the YbACHTNUTRGNE(NUG OTf)3-catalyzed thiol-Michael addi-
tion between compounds 9a and 10a, type I neutral Brock-
mann alumina was added to the reaction mixture and the
volatile compounds were removed under reduced pressure.
The resulting powder was gently heated at 408C for 4 h and
then purified directly to afford b-mercaptoamide 7a in 98%
yield (Table 6, entry 1).
Scheme 3. One-pot synthesis of b-mercaptoamides from a,b-unsaturated
aldehydes, primary amines, and thiols.
Conclusion
Next, the scope of this one-pot thiol-Michael addition/hy-
drolysis sequence was examined by varying the structure of
the a,b-unsaturated aldehydes, amines, and thiols (Table 6).
Pleasingly, we found that b-aryl- and b-alkyl-substituted a,b-
unsaturated a-iminonitriles with different electronic proper-
ties (R1 =Ph, 4-methoxyphenyl, 4-nitrophenyl, 4-bromo-
phenyl, Me) were appropriate substrates for this reaction.
The amine moiety could also be varied because both ali-
In summary, we have developed an unprecedented alumina-
mediated hydrolysis of a-iminonitriles to afford amides. By
combining this reaction with the TMSCN-mediated three-
component oxidative Strecker reaction that we have devel-
oped previously, procedures for the direct amidation of alde-
hydes and alcohols have been developed. We have also re-
ported the first examples of the Yb
ACHTUNGRTEN(NUNG OTf)3-catalyzed Michael
addition of thiols to a,b-unsaturated a-iminonitriles, thereby
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J. Zhu et al.
Table 6. Scope of the thio-Michael reaction of a,b-unsaturated a-iminonitriles.[a]
leading to b-thio-a-iminonitriles that can be subse-
quently hydrolyzed into b-mercaptoamides. Finally,
the feasibility of the one-pot condensation of an
a,b-unsaturated aldehyde, a primary amine, and a
thiol to afford b-mercaptoamides has been demon-
strated. Further expansion of the potential synthetic
utility of a-iminonitriles is currently underway in
our laboratory.
Entry R1
R2
R3
Product
7
Yield
[%][b]
1
2
3
4
Ph
Ph
Ph
Ph
PhCH2CH2 Et
PhCH2CH2 Bn
PhCH2CH2 Ph
PhCH2CH2 tBu
7a 98
7b 73
7c 69
7d 70
Experimental Section
Hydrolysis of a-iminonitriles: Alumina (6.0 g) was added to a
solution of a-iminonitrile (0.2 mmol) in toluene (10.0 mL, c=
0.02m), and the solvent was removed under reduced pressure.
The resulting powder was left to stand overnight before being
repeatedly rinsed with EtOAc by using a sintered-glass funnel.
The solvent was removed from the obtained solution under re-
duced pressure to afford the pure amide.
5
6
7
Ph
Ph
Ph
PhCH2CH2 HOCH2CH2
PhCH2CH2 TBDPSOCH2CH2
PhCH2CH2
7e 61
7 f 83
One-pot synthesis of amides from aldehydes and amines
through a-iminonitrile intermediates: IBX (1.0 mmol,
1.1 equiv) and tetrabutylammonium bromide (1.0 mmol,
1.1 equiv) were added to
a stirring solution of aldehyde
(1.0 mmol), amine (1.0 mmol, 1.1 equiv), and TMSCN
(1.1 mmol, 1.1 equiv) in CH3CN (1.0 mL, c=1.0m) at RT. Stir-
ring was maintained at RT (in a water bath) until the starting
materials had been completely consumed (by TLC); then, the
mixture was diluted with toluene (2.0 mL) and alumina (1.0 g)
was added. The suspension was irradiated with microwaves
(300 W, 1308C) for 1 h and the solvent was removed under re-
duced pressure. The resulting powder was purified by column
chromatography on silica gel (solid deposit; heptane/EtOAc,
7:3) to afford pure amide.
7g 70[c]
8
9
Me
Me
Me
PhCH2CH2 Ph
PhCH2CH2 Bn
PhCH2CH2 Et
7h 72
7i 76
7j 96
Tandem oxidative amidation of alcohols through a-iminonitrile
intermediates: IBX (3.0 mmol, 3.0 equiv) was added to a solu-
tion of alcohol (1.0 mmol) in CH3CN (4.0 mL, c 0.25m). After
heating at reflux for 25 min, the suspension was cooled to RT
and amine (1.0 mmol, 1.0 equiv), TMSCN (1.1 mmol,
1.1 equiv), and tetrabutylammonium bromide (1.1 mmol,
1.1 equiv) were added. After the starting materials had been
complete consumed (by TLC), the mixture was filtered and
rinsed with toluene (20.0 mL). Alumina was added to the fil-
trate and the volatile compounds were removed under reduced
pressure. The resulting powder was left to stand overnight
before purification by column chromatography on silica gel
(solid deposit; heptane/EtOAc, 7:3) to afford the pure amide.
10
11
12
13
cyclopropyl Ph
7k 58
7l 61
Ph
tBu
Thio-Michael addition of a,b-unsaturated-a-iminonitriles and
subsequent hydrolysis into b-mercaptoamides: YbACHTUNGTRENNUNG(OTf)3
(0.1 equiv) was added to a stirring solution of a-iminonitrile
(0.1 mmol) and thiol (0.5 mmol, 5 equiv) in CH2Cl2 (0.25 mL, c
0.4m) at 08C (ice bath). The mixture was left to stir at 08C
until the starting materials had been completely consumed (by
TLC). Then, the mixture was diluted with CH2Cl2 (2.0 mL)
and Al2O3 was added (1.0 g). The solvent was removed under
vacuum (water bath). The powder was kept at 408C for 4 h
before being filtered over Celite and washed with EtOAc. The
filtrate was evaporated under reduced pressure to give the b-
mercaptoamides. If necessary, the crude compound was puri-
fied by column chromatography on silica gel (petroleum ether/
EtOAc, 7:3) to afford the pure b-mercaptoamides.
Et
7m 80
14
PhCH2CH2 Bn
7n 86
[a] Reaction conditions: iminonitrile (0.1 mmol), thiol (0.5 mmol), YbACTHNURTGNE(NUG OTf)3
(0.01 mmol), CH2Cl2 (0.25 mL); then, addition of alumina, followed by removal of the
volatile compounds at room temperature under vacuum, and the mixture was warmed
at 408C for 4 h. [b] Yield of isolated product after column chromatography on silan-
ized silica gel. [c] Obtained as a 1:1 mixture of diastereoisomers. TBDPS=tert-butyldi-
phenylsilyl.
One-pot synthesis of b-mercaptoamides from aldehydes and
amines: IBX (0.10 mmol, 1.0 equiv) and tetrabutylammonium
bromide (0.10 mmol, 1.0 equiv) were added to a stirring solu-
tion of aldehyde (0.10 mmol), amine (0.11 mmol, 1.1 equiv),
and TMSCN (0.11 mmol, 1.1 equiv) in toluene (0.25 mL, c
0.4m) at RT. Stirring was maintained at RT until the starting
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Amidation of Aldehydes and Alcohols and Synthesis of b-Mercaptoamides
FULL PAPER
materials had been completely consumed. Then, the thiol was added
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3415.
5 min at the same temperature before Yb
(OTf)3 (0.1 equiv) was added.
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The mixture was left to stir at 08C until the starting materials had been
completely consumed. Then, the mixture was diluted with CH2Cl2
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moved under vacuum (water bath) and the resulting powder was left to
stand at 408C for 4 h before being filtered over Celite and washed with
EtOAc. The filtrate was evaporated under reduced pressure to give b-
mercaptoamides. If necessary, the crude compound was purified by
column chromatography on silica gel (petroleum ether/EtOAc, 7:3) to
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Acknowledgements
We thank the EPFL, the Swiss National Centre of Competence in Re-
search (NCCR), the Swiss National Science Foundation (SNSF), the
ICSN, and the CNRS (France) for financial support.
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Received: June 27, 2012
Published online: && &&, 0000
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Amidation of Aldehydes and Alcohols and Synthesis of b-Mercaptoamides
FULL PAPER
Multicomponent Reactions
J.-B. Gualtierotti, X. Schumacher,
P. Fontaine, G. Masson, Q. Wang,
J. Zhu* ......................... &&&& — &&&&
First direct: The direct amidation reac-
tions of aldehydes and alcohols were
performed in combination with the
oxidative three-component synthesis of
a-iminonitriles. In addition, b-mercap-
toamides were readily accessed from
a,b-unsaturated aldehydes, amines, and
thiols by a sequential process that
involved a three-component Strecker
reaction, YbACHTNUTRGNEU(GN OTf)3-catalyzed thio-
Michael addition, and hydrolysis of the
resulting b-mercapto-a-iminonitriles
(see scheme).
Amidation of Aldehydes and Alcohols
through a-Iminonitriles and a Sequen-
tial Oxidative Three-Component
Strecker Reaction/Thio-Michael Addi-
tion/Alumina-Promoted Hydrolysis
Process to Access b-Mercaptoamides
from Aldehydes, Amines, and Thiols
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
9
&
ÞÞ
These are not the final page numbers!