A Passerini/Michael Pathway towards Butyrolactones

Article abstract of DOI:10.1002/ejoc.201800958

The Passerini adducts of aromatic aldehydes may act as nucleophiles in Michael additions with acrylonitrile. The reaction proceeds together with hydrolysis of the ester. The resulting γ-hydroxynitrile may be cyclized under acidic conditions to afford a three-steps synthesis of γ-butyrolactones from isocyanides.

Full text of DOI:10.1002/ejoc.201800958

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Accepted Article
Title: A Passerini/Michael pathway towards butyrolactones
Authors: Shuanglong Jia and laurent El Kaim
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10.1002/ejoc.201800958
European Journal of Organic Chemistry
COMMUNICATION
A Passerini/Michael pathway towards butyrolactones
Shuanglong Jia,[a] Laurent El Kaïm*[a]
Dedication ((optional))
Abstract: The Passerini adducts of aromatic aldehydes may act as
nucleophiles in Michael additions with acrylonitrile. The reaction
proceeds together with hydrolysis of the ester. The resulting -
hydroxynitrile may be cyclized under acidic conditions to afford a
three-steps synthesis of -butyrolactones from isocyanides.
onset of the study, acrylonitrile was chosen as Michael acceptor
due to its higher efficiency as electrophile in our previous study
on Ugi adducts.[2]h)
Introduction
Isocyanide based multicomponent reactions (IMCRs) are now
well established as efficient tools for the preparation of libraries
of heterocycles.[1] These syntheses are usually performed via
two-step procedures using first an Ugi reaction as the IMCR
affording the highest diversity and functional tolerance. The
heterocyclic core is then obtained in a second cyclization step
involving additional functionalities proper selected in the starting
materials. We recently started a program to evaluate the
potential of intermolecular reactions of Ugi adducts as a way to
expand the diversity and scope of heterocycles accessible by
these two-step procedures. In this direction, the peptidyl position
of Ugi adducts was selected due to the ability to tune its acidity
by proper selection of the aldehyde partner together with the
challenge of performing intermolecular reactions at a relative
hindered position.[2] Among the various solutions explored, we
discovered while attempting to performed Michael additions with
Ugi adducts as nucleophiles a [3+2] type cycloaddition of the
latter with acrylonitrile leading to pyrrole derivatives (Scheme 1).
Scheme 1. Addition of acrylonitrile on Ugi and Passerini adducts
When 1a was reacted under standard Michael addition reaction
(various amount of DBU, acetonitrile or THF at rt or reflux
conditions) we could not observe any reaction apart from partial
hydrolysis of the acetate. Microwave conditions were then
selected. When 1a was heated in methanol at 140°C in the
presence of diisopropylamine (0.5 equiv) and large excess of
acrylonitrile (6 equiv), nearly quantitative yield of alcohol 2a was
obtained after 30 min heating (Scheme 2). Replacing methanol
by acetonitrile didn’t change a behavior consistent with the
relatively sensitive ester moieties of Passerini adducts as
already observed in our recent conversion of Passerini adducts
of cinnamaldehyde into -ketoamides.[5] The nature of the base
and solvent were then varied working at the same temperature
until we gratifyingly observed a modest 33% isolated yield of
expected 3a when cesium carbonate was selected as base in
acetonitrile. Raising the amount of base to two equivalents led
[2]h)
Gratified by this coupling but still failing to observe any
Michael addition with Ugi adducts, we decided to explore the
behavior of Passerini adducts in similar reactions.[3] We now
wish to report a successful Passerini/Michael addition tandem
with acrylonitrile and its application to new -butyrolactone
preparation.
us to
a nice 81% isolated yield whereas lowering the
temperature to 130°C and the excess of acrylonitrile gave us the
best yield after 45 min of reaction (Scheme 2). These conditions
were selected for the rest of the study.
Results and Discussion
Our work as well as reports by others on cyclizations involving
the peptidyl position of Ugi adducts showed the importance of
selecting aromatic aldehydes for successful selective
deprotonation/alkylation strategies.[2] Thus, Passerini adduct 1a
was prepared in quantitative yield letting stoichiometric amount
of p-chlorobenzaldehyde, cyclohexylisocyanide and acetic acid
to react for two days under solvent free conditions.[4] At the
[a]
S. Jia, L. El Kaim
Laboratoire de Synthèse Organique (LSO), CNRS, Ecole
Polytechnique, ENSTA ParisTech-UMR 7652, Université Paris-
Saclay
828 Bd des Maréchaux, 91128 Palaiseau. France
E-mail: .laurent.elkaim@ensta-paristech.fr
Scheme 2. Optimized conditions for the formation of Michael adduct 3a.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201800958
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The formation of 3a most probably involves an initial
saponification followed by a Michael addition of the resulting
hydroxy derivative 2a. The presence of the aryl group in the
hydroxyl 2a allows a selective CH deprotonation induced by
Cs2CO3 (probably triggered by trace of water) followed by
Michael addition (Scheme 3). The closest Michael additions
reported in the literature involve the base triggered addition of
acrylates or acrylonitrile to benzoin derivatives.[6] Easy enolate
formation of the latter allows Michael additions to proceed under
mere treatment with DBU at room temperature. Such precedents,
easy formation of 2a when 1a was treated at lower temperature
and ability to convert isolated 2a into 3a in 89% isolated yield
under our optimized conditions bring further elements in support
for the proposed timing of the process.
Scheme 4. Cylization of 3a to butyrolactone 4a.
The scope of this two-step butyrolactone synthesis was then
evaluated on a set of different Passerini adducts prepared from
acetic acid under solvent less conditions. The results are
displayed in Table 1.
Table 1. scope of of -butyrolactone synthesis
Scheme 3. Probable mechanism for conversion of 1a into 3a .
Entry
1
R1
R2
1 (yield)[a] 3 (yield) [a] 4 (yield)[a]
1b (98%) 3b (90%) 4b (62%)
Even though the formation of alcohol 3a with loss of the acetate
moiety was not a good point in terms of diversity, it offers an
interesting opportunity for the preparation of butyrolactones
through cyclization of the alcohol onto the nitrile group.
Butyrolactones and their unsaturated butenolides analogues are
important scaffolds[7] appearing in many natural products and
associated with important biological activities such as
anticancer,[8] antibiotic[9] or anti-inflammatory activities.[10]
Butyrolactone synthesis from 4-hydroxynitriles is well
documented,[11] occurring under both acidic and basic conditions.
In most cases the imidate intermediate is not observed leading
directly to the butyrolactone.
Considering the literature on those cyclizations together with the
rather harsh basic conditions selected for our Michael addition,
the lack of cyclised products was rather a surprise in our case.
Thus, the ability of 3a to cyclize was directly tested under acidic
conditions. The few trials performed confirmed the relative
stability of 3a, nevertheless we could observe the expected
butylactone 4a in a good 75% isolated yield heating the alcohol
under microwave conditions in trifluoroethanol as solvent and in
the presence of a catalytic amount of zinc triflate (Scheme 4).
4-ClC6H4
t-Bu
2
3
4-ClC6H4
4-ClC6H4
1c (80%) 3c (95%) 4c (92%)
1d (84%) 3d (79%) 4d (86%)
4
5
4-FC6H4
4-NO2C6H4
Ph
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
1e (90%) 3e (95%)[b] 4e (87%)
1f (99%) 3f (39%) 4f (83%)
1g (82%) 3g (73%) 4g (72%)
1h (82%) 3h (66%) 4h (50%)
6
7
2-pyridyl
2-furyl
8
1i (78%)
1j (77%)
3i (99%)
3j (61%)
4i (20%)
4j (0%)
9
Stryryl
10
11
4-MeOC6H4
isobutyl
1k (72%) 3k (0%)
1l (88%) 3l (0%)
[a] Isolated yields after column chromatography on silica gel. [b] 110oC
was used.…
On the three steps of the overall procedure, the first Passerini
step has the wider scope and gives high yields for most
aldehydes and isocyanides tested. The synthetic sequence is
limited to aromatic aldehydes in agreement with the need of a
relatively acidic position for the Michael step to proceed. Indeed,
when Passerini adduct 1l (Table 1, entry 11) obtained in 88%
isolated yield from isovaleraldehyde was treated with
acrylonitrile under our optimized conditions for the Michael
addition step, we could not isolated any addition product and
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10.1002/ejoc.201800958
European Journal of Organic Chemistry
COMMUNICATION
only observed
a
saponification of the ester giving the
heteroaromatic aldehydes. This strategy significantly expands
the scope of the butyrolactones syntheses from benzoin
corresponding hydroxyamide in 96% isolated yield. This further
supports our mechanistic proposition of scheme 3 as for the
latter the OH group is now probably deprotonated faster
preventing the required carbanion formation for Michael addition.
The Passerini adduct of 4-methoxybenzaldehyde behaves
similarly probably due to more difficult deprotonation at the -
position. In the opposite direction, the use of 4-
nitrobenzaldehyde lead to quantitative formation of Passerini
adduct 1f (Table 1, entry 5) but the resulting anion is probably
too stabilized to give an efficient coupling with acrylonitrile
affording 3f only in a moderate 39% isolated yield. The furyl
derivative 1i gave us our best yield in the Michael addition step
(Table 1, entry 8), which was a bit surprising in light of the
electronrich nature of the ring and the failure of the 4-
methoxyaryl group to participate in the sequence. Finally, in the
case of cinnamaldehyde derived Passerini adduct 1j, we were
delighted to observe the formation of Michael addition product 3j
in moderate yield (Table 1, entry 9) as such conditions were
close to the one we proposed for the conversion of the same
Passerini adducts into a-ketoamides. Nevertheless, the resulting
nitrile 3j failed to cyclise in trifluoroethanol with Zn(OTf)2 as
catalyst.
derivatives
with
microwave
conditions
allowing
to
counterbalance the poorer electron-withdrawing group effect of
the amide moiety. Further work is under progress to raise the
diversity of the synthesis by performing the reaction on a larger
array of Michael acceptors.
Experimental Section
General Considerations
NMR spectra were recorded at 298 K using a Bruker AVANCE 400
spectrometer. 1H NMR spectra were recorded at 400 MHz and residual
solvent peaks were used as an internal reference (CDCl3 δ 7.26). Data
are reported as follows: chemical shift in ppm, apparent multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet or
overlap of nonequivalent resonances), coupling constants, integration.
13C NMR spectra were recorded at 100 MHz and residual solvent peaks
were used as an internal reference (CHCl3 δ 77.16). Data are reported as
follows: chemical shift in ppm, multiplicity deduced from DEPT
experiments (CH3, CH2, CH, Cq), apparent multiplicity, coupling
constants and integration where relevant. Analytical TLC was performed
with Merck silica gel plates, pre-coated with silica gel 60 F254 (0.2 mm).
Visualisation was effected by quenching of UV fluorescence (λmax = 254
nm or 360 nm) and by staining with p-anisaldehyde, potassium
permanganate or vanillin TLC stain solutions, followed by heating. Flash
chromatography employed VWR (230–400 mesh) silica gel. Reactions
were conducted under a positive pressure of dry nitrogen or argon in
oven-dried or flame dried glassware, and at ambient room temperature,
unless specified otherwise. Anhydrous solvents were either obtained
from commercial sources or dried with a MBRAUN Solvent Purification
System SPS-800. Petroleum ether refers to the 40-60 °C boiling fraction.
Commercially available chemicals were used as purchased, or where
specified, purified by standard techniques. IR spectra were recorded on a
Perkin Elmer Spectrum 65 FT-IR Spectrometer. Melting points were
To progress further on the mechanism of the reaction and
determine whether the Michael addition step could be observed
before the saponification of the ester, we prepared a Passerini
analogue of 1b using pivalic instead of acetic acid. When the
pivalate 1m was treated under microwave conditions with 6
equiv of acrylonitrile in acetonitrile, we couldn’t indeed isolate
any Michael adduct without loss of the pivalate moiety and 3b
was again obtained in a low 55% yield (Scheme 5). Lowering the
amount of base to 1 equiv afforded 3b in lower yields supporting
further the mechanistic propositions of scheme 3.
measured on
a Stuart SMP3 melting point apparatus and are
uncorrected. High resolution mass spectra were recorded on an Agilent
1100 series LC-MS (with a 6310 ion trap) under electrospray ionization
(ESI). For compounds containing bromine, the mass of 79Br was used.
Monowave 300 produced by Anton Paar was used for the microwave
conditions.
Synthesis of 1a to 1l
Scheme 5. Michael addition of pivalate ester 1m.
General procedure A:
In a round bottom flask under Argon was added the aldehyde (10 mmol,
1 equiv), glacial acetic acid (0.60 g, 0.57 ml, 10 mmol) and the
isocyanide (10 mmol, 1 equiv). The mixture was stirred at room
temperature for two days during which times it slowly solidifies. The pure
Passerini adducts 1a-1l were then obtained by column chromatography
on silica gel when the crude were not pure enough.
The Passerini/Michael/Cyclization sequence was next attempted
using different Michael acceptors. Starting from Passerini adduct
1a, we could not form any addition product using methyl acrylate
as Michael acceptor. DMF or acetonitrile as solvent and raising
the temperature up to 140°C led either to decomposition or sole
isolation of alcohol 2a. The same results were observed with
methyl vinyl ketone.
1-(4-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl
acetate
(1a):
Following general procedure A with para-chlorobenzaldehyde (1.4 g, 10
mmol) and cyclohexyl isocyanide (1.09 g, 1.24 ml, 10 mmol) gave 1a in
quantitative yield (3.07 g, 9.9 mmol, 99%). Aspect: white solid, m.p.
160.1-161.2 oC (after washing with an Et2O/PE = 5/5 mixture). Rf: 0.44
(EA:PE = 3:7). 1H NMR (400 MHz, CDCl3) δ 7.37-7.31 (m, 4H), 6.04-5.99
(m, 2H), 3.77 (tdt, J = 12.2, 8.1, 3.9 Hz, 1H), 2.18 (s, 6H), 1.91-1.88 (m,
2H), 1.71-1.59 (m, 3H), 1.40-1.30 (m, 2H), 1.21-1.09 (m, 3H).13C NMR
(101 MHz, CDCl3) δ 169.1, 166.9, 135.0, 134.5, 129.0, 128.9, 74.9, 48.4,
33.1, 33.0, 25.5, 24.9, 21.2. HRMS: calculated for C16H20ClNO3:
Conclusions
We have settled a two-step sequence for the preparation of -
butyrolactones from Passerini adducts of aromatic and
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10.1002/ejoc.201800958
European Journal of Organic Chemistry
COMMUNICATION
309.1132, found: 309.1133. IR (thin film): 3689, 3432, 2937, 2858, 1747,
1681, 1598, 1520, 1492, 1452, 1373, 1222, 1094, 1045, 1016 cm-1.
2H), 1.73-1.61 (m, 3H), 1.42-1.29 (m, 2H), 1.22-1.12 (m, 3H). 13C NMR
(101 MHz, CDCl3) δ 168.8, 166.1, 148.2, 142.9, 128.2, 124.0, 74.5, 48.6,
33.1, 33.0, 25.5, 24.9, 21.1. HRMS: calculated for C16H20N2O5: 320.1372,
not found, fragment: 195.0534. IR (thin film): 3692, 3433, 2938, 2858,
1751, 1682, 1608, 1524, 1452, 1373, 1350, 1217, 1049 cm-1
2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl acetate (1b): Following
general procedure A with para-chlorobenzaldehyde (1.4 g, 10 mmol) and
t-butyl isocyanide (0.83 g, 1.13 ml, 10mmol), the mixture was purified by
column chromatography on silica gel (eluent: PE:Et2O = 50:50) to afford
1b (2.78 g, 9.8 mmol, 98%). Aspect: white solid, m.p. 127.1-127.9 oC. Rf:
0.35 (Et2O:PE = 5:5). 1H NMR (400 MHz, CDCl3) δ 7.37-7.31 (m, 4H),
5.95 (s, 1H), 5.90 (s, 1H), 2.17 (s, 3H), 1.35 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ 169.1, 167.0, 134.9, 134.6, 129.0, 128.9, 75.0, 51.8, 28.8, 21.2.
HRMS: calculated for C14H18ClNO3: 283.0975, found: 283.0987. IR (thin
film): 3433, 2971, 1748, 1685, 1521, 1492, 1456, 1369, 1218, 1093, 1037,
1016 cm-1.
2-(cyclohexylamino)-2-oxo-1-phenylethyl acetate (1g): Following general
procedure A with benzaldehyde (1.06 g, 10 mmol) and cyclohexyl
isocyanide (1.09 g, 1.24 ml, 10 mmol), the mixture was purified by
column chromatography on silica gel (eluent:PE:EA = 70:30) to afford 1g
(1.65 g, 8.2 mmol, 82%). Aspect: white solid m.p. 133.9-140.5 oC. Rf:
0.46 (EA:PE = 4:6). 1H NMR (400 MHz, CDCl3) δ 7.43-7.40 (m, 2H),
7.38-7.33 (m, 3H), 6.03-6.01 (m, 2H), 3.83-3.73 (m, 1H), 2.17 (s, 3H),
1.91-1.87 (m, 2H), 1.71-1.58 (m, 3H), 1.40-1.29 (m, 2H), 1.21-1.08 (m,
3H). 13C NMR (101 MHz, CDCl3) δ 169.3, 167.3, 135.9, 129.0, 128.8),
127.5, 75.6, 48.3, 33.0, 25.5, 24.8, 21.2. HRMS: calculated for
C16H21NO3: 275.1521, found: 275.1530. IR (thin film): 3294, 3066, 2930,
2854, 1739, 1650, 1536, 1495, 1451, 1370, 1223, 1189, 1096, 1042,
1030 cm-1
1-(4-chlorophenyl)-2-((4-methoxybenzyl)amino)-2-oxoethyl acetate (1c):
Following general procedure A with para-chlorobenzaldehyde (1.4 g, 10
mmol) and 1-(isocyanomethyl)-4-methoxybenzene (1.47 g, 10 mmol), the
mixture was purified by column chromatography on silica gel (eluent:
PE:EA = 70:30) to afford 1c (2.78 g, 8.0 mmol, 80%). Aspect: white solid,
m.p. 97.1-98.2 oC. Rf: 0.32 (EA:PE=3:7). 1H NMR (400 MHz, CDCl3) δ
7.35-7.28 (m, 4H), 7.11-7.08 (m, 2H), 6.87-6.79 (m, 3H), 6.00 (s, 1H),
4.31 (qd, J = 14.7, 5.8 Hz, 2H), 3.76 (s, 3H), 2.11 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 169.3, 168.0, 159.1, 134.9, 134.2, 129.7, 129.0, 128.9,
128.8, 114.1, 74.8, 55.2, 42.8, 20.9. HRMS: calculated for C18H18ClNO4:
347.0924, not found, fragment: 287.0708(-HOAc). IR (thin film): 3295,
3072, 2935, 2836, 1742, 1657, 1612, 1512, 1490, 1463, 1438, 1369,
1300, 1222, 1175, 1090, 1033, 1015 cm-1
2-(cyclohexylamino)-2-oxo-1-(pyridin-2-yl)ethyl acetate (1h) : Following
general procedure A with picolinaldehyde (1.07 g, 10 mmol) and
cyclohexyl isocyanide (1.09 g, 1.24 ml, 10 mmol), the mixture was
purified by column chromatography on silica gel (eluent: PE:EA = 60:40)
to afford 1h (2.27 g, 8.2 mmol, 82%). Aspect: white solid, m.p. 95.2-96.3
oC. Rf: 0.38 (EA:PE = 4:6). 1H NMR (400 MHz, CDCl3) δ 8.52-8.51 (m,
1H), 7.70-7.66 (m, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.23-7.20 (m, 1H), 6.72
(d, J = 6.4 Hz, 1H), 6.05 (s, 1H), 3.74-3.66 (m, 1H), 2.20 (s, 3H), 1.87-
1.52 (m, 5H), 1.32-1.04 (m, 5H).13C NMR (101 MHz, CDCl3) δ 169.4,
166.0, 155.1, 149.1, 137.2, 123.5, 122.2, 75.7, 48.4, 32.7, 25.5, 24.7,
21.0. HRMS: calculated for C15H20N2O3: 276.1474, found: 276.1471. IR
(thin film): 3690, 3429, 3062, 3019, 2937, 2858, 1746, 1681, 1594, 1575,
1525, 1473, 1452, 1438, 1373, 1256, 1228, 1152, 1112, 1047 cm-1
1-(4-chlorophenyl)-2-((3,4-dimethoxyphenethyl)amino)-2-oxoethylacetate
(1d): Following general procedure A with para-chlorobenzaldehyde (1.4 g,
10 mmol) and 4-(2-isocyanoethyl)-1,2-dimethoxybenzene (1.91 g, 10
mmol), the mixture was purified by column chromatography on silica gel
(eluent:PE:EA = 80:20) to afford 1d (3.29 g, 8.4 mmol, 84%). Aspect:
white solid, m.p. 104.8-105.7 oC Rf: 0.43 (EA:PE = 4:6). 1H NMR (400
MHz, CDCl3) δ 7.32-7.27 (m, 4H), 6.77 (d, J = 8.1 Hz, 1H), 6.67-6.63 (m,
2H), 6.17 (s, 1H), 5.98 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.55-3.49 (m,
2H), 2.80-2.71 (m, 2H), 2.10 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.1,
167.9, 149.2, 147.9, 135.0, 134.1, 130.9, 129.0, 128.8, 120.8, 112.0,
111.3, 74.8, 56.0, 56.0, 40.6, 35.1, 21.0. HRMS: calculated for
C20H22ClNO5: 391.1187, found: 391.1187. IR (thin film): 3319, 2936,
2835, 1743, 1661, 1592, 1514, 1491, 1464, 1418, 1370, 1261, 1228,
1156, 1141, 1090, 1027, 1016 cm-1
2-(cyclohexylamino)-1-(furan-2-yl)-2-oxoethyl acetate (1i): Following
general procedure A with furan-2-carbaldehyde (0.96 g, 10 mmol) and
cyclohexyl isocyanide (1.09 g, 1.24 ml, 10 mmol), the mixture was
purified by column chromatography on silica gel (eluent: PE:EA = 70:30)
to afford 1i (2.07 g, 7.8 mmol, 78%). Aspect: white solid, m.p. 131.8-
132.6 oC. Rf: 0.44 (EA:PE = 4:6). 1H NMR (400 MHz, CDCl3) δ 7.37 (dd,
J = 1.8, 0.8 Hz, 1H), 6.45 (d, J = 3.2 Hz, 1H), 6.33 (dd, J = 3.3, 1.9 Hz,
1H), 6.14-6.11 (m, 2H), 3.84-3.75 (m, 1H), 2.13 (s, 3H), 1.94-1.86 (m,
2H), 1.71-1.56 (m, 3H), 1.39-1.28 (m, 2H), 1.23-1.09 (m, 3H). 13C NMR
(101 MHz, CDCl3) δ 169.1, 165.0, 148.3, 143.5, 111.2, 110.7, 68.8, 48.4,
32.9, 32.8, 25.5, 24.8, 20.9. HRMS: calculated for C14H19NO4: 265.1314,
found: 265.1312. IR (thin film): 3296, 2932, 2855, 1749, 1659, 1536,
1451, 1370, 1222, 1151, 1097, 1032, 1014 cm-1
2-(cyclohexylamino)-1-(4-fluorophenyl)-2-oxoethyl acetate (1e): Following
general procedure A with para-fluorobenzaldehyde (1.24 g, 10 mmol)
and cyclohexyl isocyanide (1.09 g, 1.24 ml, 10 mmol), the mixture was
purified by column chromatography on silica gel (eluent: PE:Et2O =
50:50) to afford 1e (2.64 g, 9.0 mmol, 90%). Aspect: white solid, m.p.
(E)-1-(cyclohexylamino)-1-oxo-4-phenylbut-3-en-2-yl
acetate
(1j) :
o
170.8-171.9 C. Rf: 0.22 (Et2O:PE = 5:5). 1H NMR (400 MHz, CDCl3) δ
Following general procedure A with cinnamaldehyde (1.32 g, 10 mmol)
and cyclohexyl isocyanide (1.09 g, 1.24ml, 10 mmol), the mixture was
purified by column chromatography on silica gel (eluent: PE:EA=70:30) to
afford 1j (2.71 g, 9.0 mmol, 90%). Aspect: white solid m.p. 141.8-142.6
oC. Rf: 0.49 (EA:PE = 4:6). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.4
Hz, 2H), 7.35-7.27 (m, 3H), 6.74 (d, J = 16.0 Hz, 1H), 6.28 (dd, J = 16.0,
6.9 Hz, 1H), 5.91 (d, J = 7.6 Hz, 1H), 5.72 (d, J = 6.9 Hz, 1H), 3.86-3.77
(m, 1H), 2.22 (s, 3H), 1.96-1.93 (m, 2H), 1.74-1.62 (m, 3H), 1.43-1.33 (m,
2H), 1.23-1.16 (m, 3H).13C NMR (101 MHz, CDCl3) δ 169.4, 167.2, 135.8,
134.9, 128.8, 128.5, 127.0, 122.8, 74.6, 48.4, 33.1, 25.6, 24.9, 21.3.
HRMS: calculated for C18H23NO3: 301.1678, found: 301.1678. IR (thin
film): 3288, 2931, 2854, 1743, 1659, 1546, 1449, 1371, 1230, 1031 cm-1
7.42-7.38 (m, 2H), 7.06-7.02 (m, 2H), 6.01 (s, 2H), 3.83-3.75 (m, 1H),
2.17 (s, 3H), 1.91 (bs, 2H), 1.72-1.60 (m, 3H), 1.44-1.28 (m, 2H), 1.25-
1.07 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 169.2, 167.2, 163.1(J = 246
Hz), 131.9, 129.5, 115.9, 115.7, 74.9, 48.4, 33.1, 25.5, 24.9, 21.2.
HRMS: calculated for C16H20FNO3: 293.1427, found: 293.1420. IR (thin
film): 3296, 2932, 2855, 1747, 1657, 1538, 1510, 1371, 1223, 1159, 1045
cm-1
2-(cyclohexylamino)-1-(4-nitrophenyl)-2-oxoethyl acetate (1f) : Following
general procedure A with para-nitrobenzaldehyde (1.51 g, 10 mmol) and
cyclohexyl isocyanide (1.09 g, 1.24ml, 10mmol), gave 1f in quantitative
yield (3.17 g, 99%). Aspect: white solid, m.p. 144.8-145.3 oC (after
washing the solid with an Et2O:PE = 5/5 mixture). Rf: 0.31 (EA:PE = 3:7).
1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.8 Hz,
2H), 6.14-6.10 (m, 2H), 3.81-3.72 (m, 1H), 2.23 (s, 3H), 1.93-1.87 (m,
2-(cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl
acetate
(1k):
Following general procedure A with para-methoxybenzaldehyde (1.36 g,
10 mmol) and cyclohexyl isocyanide (1.09 g, 1.24 ml, 10 mmol), the
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800958
European Journal of Organic Chemistry
COMMUNICATION
mixture was purified by column chromatography on silica gel (eluent:
mixture was purified by column chromatography on silica gel
(eluent:PE:EA = 70:30) to afford 3c (128 mg, 0.356 mmol, 95%). Aspect:
yellow oil. Rf: 0.49 (EA:PE = 5:5). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J
= 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.07-7.02 (m, 3H), 6.81-6.79 (m,
2H), 4.24 (qd, J = 14.6, 5.8 Hz, 2H), 4.16 (s, 1H), 3.77 (s, 3H), 2.64-2.54
(m, 1H), 2.35-2.23 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 172.5, 159.1,
139.6, 134.3, 129.4, 128.8, 128.7, 126.7, 119.7, 114.2, 77.5, 55.3, 43.0,
34.7, 12.0. HRMS: calculated for C19H19ClN2O3: 358.1084, found:
358.1093. IR (thin film): 3690, 3590, 3426, 3007, 2937, 2839, 1676, 1613,
1514, 1491, 1465, 1303, 1251, 1176, 1096, 1035, 1014 cm-1.
PE:EA = 70:30) to afford 1k (2.20 g, 7.2 mmol, 72%). Aspect: white solid,
1
m.p.162.5-163.4 oC. Rf: 0.33 (EA:PE=4:6). H NMR (400 MHz, CDCl3) δ
7.34-7.32 (m, 2H), 6.88-6.86 (m, 2H), 6.03-5.98 (m, 2H), 3.85-3.78 (m,
4H), 2.14 (s, 3H), 1.89-1.86 (m, 2H), 1.70-1.59 (m, 3H), 1.38-1.29 (m,
2H), 1.19-1.11 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 169.4, 167.6,
160.1, 129.1, 128.0, 114.2, 75.2, 55.4, 48.3, 33.0, 33.0, 25.5, 24.8, 21.2.
HRMS: calculated for C17H23NO4: 305.1627, found: 305.1623. IR (thin
film): 3299, 2931, 2854, 1742, 1650, 1611, 1535, 1512, 1450, 1370, 1227,
1176, 1031 cm-1
1-(cyclohexylamino)-4-methyl-1-oxopentan-2-yl acetate (1l): Following
general procedure A with isovaleraldehyde (0.86 g, 10 mmol) and
cyclohexyl isocyanide (1.09 g, 1.24 ml, 10 mmol), the mixture was
purified by column chromatography on silica gel (eluent:PE:Et2O = 50:50)
to afford 1l (2.25 g, 8.8 mmol, 88%). Aspect: white solid, m.p.87.2-88.6
2-(4-chlorophenyl)-4-cyano-N-(3,4-dimethoxyphenethyl)-2-hydroxybutan-
amide (3d): Following general procedure B with 1-(4-chlorophenyl)-2-
((3,4-dimethoxyphenethyl)amino)-2-oxoethyl acetate 1d (147 mg, 0.375
mmol), the mixture was purified by column chromatography on silica gel
(eluent:PE:EA = 80:20) to afford 3d (119 mg, 0.296 mmol, 79%). Aspect:
colourless oil. Rf: 0.48 (EA:PE = 4:6). 1H NMR (400 MHz, CDCl3) δ 7.39-
7.35 (m, 2H), 7.33-7.29 (m, 2H), 6.73-6.70 (m, 1H), 6.61 (d, J = 1.9 Hz,
1H), 6.58-6.48 (m, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 3.75 (s, 1H), 3.51-3.41
(m, 2H), 2.70-2.64 (m, 2H), 2.59-2.47 (m, 1H), 2.32-2.22 (m, 3H). 13C
NMR (101 MHz, CDCl3) δ 172.1, 149.1, 147.9, 139.4, 134.5, 130.7,
129.0, 126.7, 120.8, 119.7, 111.8, 111.4, 77.6, 56.0, 56.0, 40.8, 35.1,
35.0, 12.1. HRMS: calculated for C21H23ClN2O4: 402.1346, found:
402.1348. IR (thin film): 3691, 3593, 3427, 2938, 1676, 1594, 1516, 1491,
1262, 1238, 1158, 1142, 1028, 1014 cm-1.
1
oC. Rf: 0.32 (Et2O:PE = 5:5). H NMR (400 MHz, CDCl3) δ 5.86 (s, 1H),
5.12-5.09 (m, 1H), 3.77-3.69 (m, 1H), 2.11 (s, 3H), 1.92-1.86 (m, 2H),
1.71-1.56 (m, 6H), 1.37-1.28 (m, 2H), 1.15-1.11 (m, 3H), 0.98-0.88 (m,
6H). 13C NMR (101 MHz, CDCl3) δ 169.9, 169.3, 73.0, 47.9, 40.8, 33.0,
25.5, 24.8, 24.6, 23.2, 21.9, 21.1. HRMS: calculated for C14H25NO3:
255.1834, found: 255.1837. IR (thin film): 3288, 2930, 2855, 1744, 1648,
1536, 1450, 1370, 1224, 1063, 1028 cm-1
Synthesis of 3a to 3j
4-cyano-N-cyclohexyl-2-(4-fluorophenyl)-2-hydroxybutanamide
(3e):
General procedure B:
Following general procedure with 2-(cyclohexylamino)-1-(4-
B
To a dried microwave tube was added Passerini adduct 1 (0.375 mmol, 1
equiv), acetonitrile (1.5 ml) followed by acrylonitrile (60 mg, 1.125 mmol,
3 equiv), and Cs2CO3 (269 mg, 0.825 mmol, 2.2 equiv). The tube was
filled with Ar before heating under microwave condition to 130oC for 45
min. After completion, the solvent was removed under reduced pressure
and the crude mixture purified by column chromatography on silica gel to
afford the desired 3a- 3j.
fluorophenyl)-2-oxoethyl acetate 1e (110 mg, 0.375 mmol), the mixture
was purified by column chromatography on silica gel (eluent:PE:Et2O =
30:70) to afford 3e (108 mg, 0.356 mmol, 95%). Aspect: yellow oil. Rf: 44
1
(Et2O:PE = 7:3) H NMR (400 MHz, CDCl3) δ 7.49-7.47 (m, , 2H), 7.06-
7.02 (m, 2H), 6.57 (d, J = 7.5 Hz, 1H), 3.89 (s, 1H), 3.64 (bs, 1H), 2.63-
2.60 (m, 1H), 2.43-2.30 (m, 3H), 1.85-1.66 (m, 5H), 1.334-1.06 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 171.4, 162.7 (J = 246 Hz), 137.0, 127.1,
119.9, 115.8, 77.48, 48.7, 35.1, 33.0, 32.8, 25.5, 24.8, 12.3. HRMS:
calculated for C17H21FN2O2: 304.1587, found: 304.1583. IR (thin film):
3345, 2932, 2855, 1646, 1602, 1525, 1506, 1451, 1225, 1161, 1092 cm-1.
2-(4-chlorophenyl)-4-cyano-N-cyclohexyl-2-hydroxybutanamide
Following general procedure with 1-(4-chlorophenyl)-2-
(cyclohexylamino)-2-oxoethyl acetate 1a (116 mg, 0.375 mmol), the
mixture was purified by column chromatography on silica gel (eluent:
PE:EA = 70:30) to afford 3a (108 mg, 0.338 mmol, 90%). Aspect:
(3a):
B
4-cyano-N-cyclohexyl-2-hydroxy-2-(4-nitrophenyl)butanamide
(3f):
1
colorless oil. Rf: 0.31 (EA:PE = 3:7) H NMR (400 MHz, CDCl3) δ 7.46-
Following general procedure with 2-(cyclohexylamino)-1-(4-
B
7.43 (m, 2H), 7.35-7.32 (m, 2H), 6.51 (d, J = 8.2 Hz, 1H), 3.88 (s, 1H),
3.68-3.59 (m, 1H), 2.66-2.59 (m, 1H), 2.45-2.27 (m, 3H), 1.85-1.58 (m,
5H), 1.37-1.25 (m, 2H), 1.18-1.02 (m, 3H). 13C NMR (101 MHz, CDCl3) δ
171.2, 139.7, 134.5, 129.0, 126.7, 119.8, 77.5, 48.8, 35.1, 33.0, 32.8,
25.5, 24.8, 24.8, 12.3. HRMS: calculated for C17H21ClN2O2: 320.1292,
found: 320.1284. IR (thin film): 3591, 3417, 2937, 2858, 1671, 1598,
1519, 1491, 1452, 1401, 1350, 1253, 1206, 1096, 1014 cm-1.
nitrophenyl)-2-oxoethyl acetate 1f (120 mg, 0.375 mmol), the mixture
was purified by column chromatography on silica gel (eluent:PE:EA =
70:30) to afford 3f (48 mg, 0.146 mmol, 39%). Aspect: yellow oil. Rf: 0.53
(EA:PE = 4:6). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 9.0 Hz, 2H),
7.76 (d, J = 9.0 Hz, 2H), 6.71 (d, J = 8.3 Hz, 1H), 4.38 (s, 1H), 3.67-3.58
(m, 1H), 2.77-2.68 (m, 1H), 2.42-2.31 (m, 3H), 1.87-1.82 (m, 2H), 1.73-
1.57 (m, 3H), 1.37-1.01 (m, 5H). 13C NMR (101 MHz, CDCl3) δ 170.4,
148.4, 147.8, 126.4, 123.8, 119.6, 77.9, 48.9, 35.2, 33.0, 32.7, 25.4, 24.8,
24.7, 12.3. HRMS: calculated for C17H21N3O4: 331.1532, not found,
fragment: 248.0671. IR (thin film): 3691, 3589, 3417, 2937, 2858, 1674,
1606, 1524, 1452, 1350 cm-1.
N-(tert-butyl)-2-(4-chlorophenyl)-4-cyano-2-hydroxybutanamide
(3b):
Following general procedure with 2-(tert-butylamino)-1-(4-
B
chlorophenyl)-2-oxoethyl acetate 1b (111 mg, 0.375 mmol), the mixture
was purified by column chromatography on silica gel (eluent:PE:Et2O =
50:50 ) to afford 3b (99 mg, 0.338 mmol, 90%). Aspect: colorless oil. Rf:
0.44 (Et2O:PE=6:4). 1H NMR (400 MHz, CDCl3) δ 7.46-7.41 (m, 2H),
7.37-7.33 (m, 2H), 6.34 (s, 1H), 3.56 (s, 1H), 2.67-2.53 (m, 1H), 2.49-
2.23 (m, 3H), 1.29 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 171.2, 139.8,
134.6, 129.1, 126.7, 119.8, 77.6, 51.8, 35.1, 28.6, 12.3. HRMS:
calculated for C15H19ClN2O2: 294.1135, found: 294.1139. IR (thin film):
3691, 3590, 2971, 2935, 2260, 1678, 1598, 1519, 1491, 1457, 1394,
1368, 1268, 1223, 1096, 1014 cm-1.
4-cyano-N-cyclohexyl-2-hydroxy-2-phenylbutanamide (3g): Following
general procedure
B
with 2-(cyclohexylamino)-2-oxo-1-phenylethyl
acetate 1g (103 mg, 0.375 mmol), the mixture was purified by column
chromatography on silica gel (eluent:PE:EA = 70:30) to afford 3g (78 mg,
0.274 mmol, 73%). Aspect: white solid, m.p. 107.3-108.6 oC. Rf: 0.50
(EA:PE = 4:6). 1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.39-7.32
(m, 3H), 6.48 (d, J = 8.2 Hz, 1H), 3.77 (s, 1H), 3.68-3.61 (m, 1H), 2.64-
2.59 (m, 1H), 2.44-2.28 (m, 3H), 1.84-1.75 (m, 2H), 1.67-1.56 (m, 3H),
1.35-1.25 (m, 2H), 1.18-1.06 (m, 3H). 13C NMR (101 MHz, CDCl3) δ
171.6, 141.1, 129.0, 128.5, 125.2, 119.9, 77.8, 48.7, 35.1, 33.0, 32.8,
25.5, 24.8, 12.3. HRMS: calculated for C17H22N2O2: 286.1681, found:
2-(4-chlorophenyl)-4-cyano-2-hydroxy-N-(4-methoxybenzyl)butanamide
(3c): Following general procedure
B with 1-(4-chlorophenyl)-2-((4-
methoxybenzyl)amino)-2-oxoethyl acetate 1c (130 mg, 0.375 mmol) the
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10.1002/ejoc.201800958
European Journal of Organic Chemistry
COMMUNICATION
286.1681. IR (thin film): 3349, 2932, 2855, 1646, 1524, 1448, 1350, 1316,
1253, 1207, 1152, 1076 cm-1.
28.3, 25.4, 24.9, 24.8. HRMS: calculated for C17H20ClNO3: 321.1132, not
found, fragment: 295.0970. IR (thin film): 3422, 2937, 2858, 1788, 1677,
1598, 1521, 1490, 1452, 1403, 1351, 1286, 1255, 1222, 1186, 1173,
1156, 1095, 1061, 1015 cm-1.
4-cyano-N-cyclohexyl-2-hydroxy-2-(pyridin-2-yl)butanamide
(3h):
Following general procedure B with 2-(cyclohexylamino)-2-oxo-1-(pyridin-
2-yl)ethyl acetate 1h (104 mg, 0.375 mmol), the mixture was purified by
column chromatography on silica gel (eluent:PE:EA = 70:30) to afford 3h
(71 mg, 0.248 mmol, 66%). Aspect: light brown coloured oil. Rf: 0.51
(EA:PE = 4:6). 1H NMR (400 MHz, CDCl3) δ 8.50-8.48 (m, 1H), 7.91-7.88
(m, 1H), 7.79-7.75 (m, 1H), 7.32-7.29 (m, 2H), 6.33 (s, 1H), 3.71-3.61 (m,
1H), 2.58-2.51 (m, 1H), 2.38-2.23 (m, 3H), 1.88-1.85 (m, 1H), 1.76-1.55
(m, 5H), 1.40-1.25 (m, 2H), 1.22-1.06 (m, 3H). 13C NMR (101 MHz,
CDCl3) δ 171.1, 157.4, 147.2, 138.0, 123.7, 121.4, 119.5, 76.6, 48.6,
36.7, 33.0, 32.8, 25.5, 24.8, 12.2. HRMS: calculated for C16H21N3O2:
287.1634, not found, fragment: 161.0707. IR (thin film): 3405, 3287, 2937,
2858, 1670, 1593, 1573, 1517, 1468, 1452, 1437, 1395, 1350, 1253,
1214, 1154, 1137, 1094, 1052 cm-1.
N-(tert-butyl)-2-(4-chlorophenyl)-5-oxotetrahydrofuran-2-carboxamide
(4b): Following general procedure
C
with N-(tert-butyl)-2-(4-
chlorophenyl)-4-cyano-2-hydroxybutanamede 3b (111 mg, 0.375 mmol),
the mixture was purified by column chromatography on silica gel
(eluent:PE:Et2O = 80:20) to afford 4b (69 mg, 0.233 mmol, 62%). Aspect:
white solid, m.p. 94.2-95.7 oC. Rf: 0.48 (Et2O:PE=5:5). 1H NMR (400
MHz, CDCl3) δ 7.48-7.46 (m, 2H), 7.35-7.33 (m, 2H), 6.19 (s, 1H), 3.09-
3.02 (m, 1H), 2.65-2.39 (m, 3H), 1.29 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ175.0, 169.1, 137.6, 134.7, 128.9, 126.1, 87.7, 51.9, 33.6, 28.6,
28.3. HRMS: calculated for C15H18ClNO3: 295.0975, found: 295.0980. IR
(thin film): 3691, 3423, 2972, 2260, 1787, 1683, 1599, 1520, 1491, 1458,
1395, 1368, 1279, 1219, 1187, 1173, 1095, 1065, 1040 cm-1.
4-cyano-N-cyclohexyl-2-(furan-2-yl)-2-hydroxybutanamide (3i): Following
general procedure B with 2-(cyclohexylamino)-1-(furan-2-yl)-2-oxoethyl
acetate 1i (99 mg, 0.375 mmol), the mixture was purified by column
chromatography on silica gel (eluent:PE:EA = 70:30) to afford 3i (102 mg,
0.371 mmol, 99%). Aspect: white solid, m.p. 104.8-105.8 oC. Rf: 0.38
(EA:PE = 4:6). 1H NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 1.8, 0.8 Hz,
1H), 6.41-6.32 (m, 3H), 4.16 (s, 1H), 3.77-3.69 (m, 1H), 2.39-2.37 (m,
4H), 1.92-1.81 (m, 2H), 1.72-1.59 (m, 3H), 1.38-1.30 (m, 2H), 1.24-1.08
(m, 3H). 13C NMR (101 MHz, CDCl3) δ 169.8, 152.8, 142.9, 119.4, 111.2,
108.1, 74.0, 49.2, 34.7, 32.9, 32.8, 25.5, 24.7, 24.7, 12.0. HRMS:
calculated for C15H20N2O3: 276.1474, found: 276.1473. IR (thin film):
3691, 3594, 3418, 2937, 2858, 1675, 1602, 1525, 1452, 1375, 1350,
1317, 1253, 1221, 1150, 1128, 1066, 1006 cm-1.
2-(4-chlorophenyl)-N-(4-methoxybenzyl)-5-oxotetrahydrofuran-2-carbox-
amide (4c): Following general procedure C with 2-(4-chlorophenyl)-4-
cyano-2-hydroxy-N-(4-methoxybenzyl)butanamide 3c (135 mg, 0.375
mmol), the mixture was purified by column chromatography on silica gel
(eluent:PE:EA = 80:20) to afford 4c (124 mg, 0.345 mmol, 92%). Aspect:
white solid, m.p. 162.5-163.1 oC. Rf: 0.42 (EA:PE = 4:6). 1H NMR (400
MHz, CDCl3) δ 7.51-7.48 (m, 2H), 7.37-7.33 (m, 2H), 7.08-7.05 (m, 2H),
6.83-6.79 (m, 2H), 6.74 (s, 1H), 4.37-4.27 (m, 2H), 3.77 (s, 3H), 3.15-
3.08 (m, 1H), 2.65-2.45 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 174.8,
169.9, 159.3, 137.3, 134.9, 129.2, 129.1, 129.0, 126.2, 114.3, 87.5, 55.4,
43.3, 33.7, 28.2. HRMS: calculated for C19H18ClNO4: 359.0924, found:
359.0913. IR (thin film): 3691, 3431, 2958, 2937, 2839, 1789, 1682, 1613,
1514, 1491, 1442, 1303, 1250, 1224, 1176, 1113, 1094, 1065, 1036 cm-1.
(E)-2-(2-cyanoethyl)-N-cyclohexyl-2-hydroxy-4-phenylbut-3-enamide (3j):
Following general procedure B with (E)-1-(cyclohexylamino)-1-oxo-4-
phenylbut-3-en-2-yl acetate 1j (113 mg, 0.375 mmol), the mixture was
purified by column chromatography on silica gel (eluent:PE:EA=70:30) to
afford 3j (78 mg, 0.251 mmol, 67%). Aspect: yellow oil. Rf: 0.33 (EA:PE =
3:7). 1H NMR (400 MHz, CDCl3) δ 7.45-7.31 (m, 5H), 6.77 (d, J = 16.2 Hz,
1H), 6.55 (d, J = 8.1 Hz, 1H), 6.44 (d, J = 16.2 Hz, 1H), 3.82-3.75 (m, 1H),
3.27 (s, 1H), 2.57-2.38 (m, 3H), 2.22-2.14 (m, 1H), 1.97-1.87 (m, 2H),
1.81-1.65 (m, 3H), 1.45-1.36 (m, 2H), 1.28-1.16 (m, 3H). 13C NMR (101
MHz, CDCl3) δ 171.2, 135.7, 130.8, 129.7, 128.9, 128.5, 126.9, 119.9,
48.8, 35.2, 33.2, 33.0, 25.5, 24.9, 12.1. HRMS: calculated for
C19H24N2O2: 312.1838, not found, fragment (-C6H11CONH): 186.0914. IR
(thin film): 3387, 2932, 2855, 1642, 1525, 1449 cm-1.
2-(4-chlorophenyl)-N-(3,4-dimethoxyphenethyl)-5-oxotetrahydrofuran-2-
carboxamide (4d): Following general procedure
C
with 2-(4-
chlorophenyl)-4-cyano-N-(3,4-dimethoxyphenethyl)-2hydroxybutanamide
3d (151 mg, 0.375 mmol), the mixture was purified by column
chromatography on silica gel (eluent:PE:EA = 70:30) to afford 4d (130
mg, 0.323 mmol, 86%). Aspect: white solid, m.p. 101.1-102.4 oC. Rf: 0.50
(EA:PE = 4:6). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.7 Hz, 2H),
7.32 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 1.8 Hz, 1H),
6.54 (dd, J = 8.1, 1.8 Hz, 1H), 6.44 (s, 1H), 3.84 (s, 3H), 3.80 (s, 3H),
3.52-3.42 (m, 2H), 3.09-3.02 (m, 1H), 2.69 (t, J = 6.9 Hz, 2H), 2.49 (t, J =
7.9 Hz, 2H), 2.43-2.36 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 174.8,
167.0, 149.1, 147.8, 137.4, 134.8, 130.6, 128.9, 126.1, 120.8, 111.8,
111.3, 87.6, 56.0, 55.9, 40.8, 35.1, 33.5, 28.1. HRMS: calculated for
C21H22ClNO5: 403.1187, found: 403.1190. IR (thin film): 3691, 3606,
3432, 3009, 2938, 2839, 1788, 1683, 1599, 1516, 1491, 1466, 1263,
1237, 1158, 1142, 1095, 1028 cm-1.
Synthesis of 4a to 4i
General procedure C:
To a dried microwave tube was added 3 (0.375 mmol, 1 equiv), Zn(OTf)2
(14 mg, 10 mol%) and 2,2,2-trifluoroethanol (1.5 ml). The tube was filled
with Ar before heating under microwave condition to 110 C for 30 min.
After completion, the solvent was removed under reduced pressure and
N-cyclohexyl-2-(4-fluorophenyl)-5-oxotetrahydrofuran-2-carboxamide
(4e): Following general procedure C with 4-cyano-N-cyclohexyl-2-(4-
fluorophenyl)-2-hydroxybutanemide 3e (114 mg, 0.375 mmol), the
mixture was purified by column chromatography on silica gel
(eluent:PE:Et2O = 50:50) to afford 4e (99 mg, 0.326 mmol, 87%). Aspect:
colourless oil. Rf: 0.58 (Et2O:PE = 7:3). 1H NMR (400 MHz, CDCl3) δ
7.54-7.51 (m, 2H), 7.08-7.03 (m, 2H), 6.29 (d, J = 7.8 Hz, 1H), 3.67 (tdt, J
= 12.1, 8.1, 3.9 Hz, 1H), 3.10-3.03 (m, 1H), 2.65-2.45 (m, 3H), 1.91-1.88
(m, 1H), 1.74-1.56 (m, 4H), 1.38-0.99 (m, 5H). 13C NMR (101 MHz,
CDCl3) δ 175.1, 169.3, 162.9(d, J = 246 Hz), 134.8, 134.8, 126.7, 126.7,
115.8, 115.6, 87.6, 48.8, 33.7, 33.1, 32.7, 28.3, 25.4, 24.9, 24.8. HRMS:
calculated for C17H20FNO3: 305.1427, found: 305.1426. IR (thin film):
3348, 2931, 2855, 1784, 1666, 1603, 1506, 1451, 1225, 1182, 1152,
1106, 1060 cm-1.
o
crude mixture purified by column chromatography to afford 4a-4i.
2-(4-chlorophenyl)-N-cyclohexyl-5-oxotetrahydrofuran-2-carboxamide
(4a): Following general procedure C with 2-(4-chlorophenyl)-4-cyano-N-
cyclohexyl-2-hydroxybutanamide 3a (120 mg, 0.375 mmol), the mixture
was purified by column chromatography on silica gel (eluent:PE:EA =
90:10) to afford 4a (90 mg, 0.281 mmol, 75%). Aspect: white solid, m.p.
113.2-113.7 oC. Rf: 0.47 (EA:PE = 3:7). 1H NMR (400 MHz, CDCl3) δ
7.49 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 6.29 (d, J = 7.4 Hz, 1H),
3.70-3.63 (m, 1H), 3.11-3.04 (m, 1H), 2.65-2.43 (m, 3H), 1.90-1.88 (m,
1H), 1.71-1.57 (m, 4H), 1.37-1.00 (m, 5H). 13C NMR (101 MHz, CDCl3) δ
175.0, 169.1, 137.5, 134.8, 128.9, 126.2, 87.5, 48.9, 33.6, 33.0, 32.7,
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10.1002/ejoc.201800958
European Journal of Organic Chemistry
COMMUNICATION
N-cyclohexyl-2-(4-nitrophenyl)-5-oxotetrahydrofuran-2-carboxamide (4f):
Following general procedure C with 4-cyano-N-cyclohexyl-2-hydroxy-2-
(4-nitrophenyl)butanamide 3f (124 mg, 0.375 mmol), the mixture was
purified by column chromatography on silica gel (eluent:PE:EA = 90:10)
to afford 4f (103 mg, 0.311 mmol, 83%). Aspect: white solid, m.p. 151.2-
152.1 oC. Rf: 0.56 (EA:PE = 4:6). 1H NMR (400 MHz, CDCl3) δ 8.24-8.21
(m, 2H), 7.79-7.75 (m, 2H), 6.36 (d, J = 8.1 Hz, 1H), 3.71-3.62 (m, 1H),
3.21-3.14(m, 1H), 2.69-2.44 (m, 3H), 1.92-1.88 (m, 1H), 1.72-1.56 (m,
4H), 1.35-1.02 (m, 5H). 13C NMR (101 MHz, CDCl3) δ 174.4, 168.3,
148.1, 145.8, 125.9, 123.9, 87.2, 49.1, 33.8, 33.0, 32.6, 28.1, 25.4, 24.9,
24.8. HRMS: calculated for C17H20N2O5: 332.1372, not found, fragment:
206.0449. IR (thin film): 3691, 3421, 2938, 2858, 1803, 1680, 1606, 1525,
1494, 1453, 1352, 1184, 1170, 1155, 1062 cm-1.
[1]
For reviews on IMCRs, see: a) Multicomponent reactions; J. Zhu, H.
Bienaymé, Eds, Wiley-VCH, Weinheim, 2005; b) A. Dömling, I. Ugi,
Angew. Chem. Int. Ed. 2000, 39, 3168-3210; c) A. Dömling, Chem. Rev.
2006, 106, 17-89; d) A. Dömling, K. Wang, W. Wang, Chem. Rev. 2012,
112, 3083-3135; e) Multicomponent Reactions in Organic Synthesis, J.
Zhu, Q. Wang, M.-X. Wang, Eds., Wiley-VCH:Weinheim, Germany,
2014; f) G. Koopmanschap, E. Ruijter, R. V. A. Orru, Beilstein J. Org.
Chem. 2014, 10, 544-598: g) V. P. Boyarskiy, N. A. Bokach, K. V.
Luzyanin, V. Y. Kukushkin, Chem. Rev. 2015, 115, 2698-2779; h) A.
Varadi, T. C. Palmer, R. N. Dardashti, S. Majumdar, Molecules, 2016,
21, 19; i) M. M. Heravi, N. Nazari, Curr. Org. Chem. 2017, 21, 1440-
1529; j) J. Lei, J.P. Meng, D.Y. Tang, B. Frett, Z.Z. Chen, Z.G. Xu, Mol.
Divers. 2018, in press, DOI : 10.1007/s11030-017-9811-2.
[2]
For some intramolecular Ugi post-condensations involving the peptidyl
position see: a) R. Bossio, C. F. Marcos, S. Marcaccini, R. Pepino,
Synthesis 1997, 1389-1390; b) A. Salcedo, L. Neuville, J. Zhu, J. Org.
Chem. 2008, 73, 360-3603; c) L. El Kaïm, L. Grimaud, X. -F. Le Goff; M.
Menes-Arzate, L. D. Miranda Chem. Commun. 2011, 47, 8145-8147; d)
A. S. Trifilenkov, A. P. Ilyin, V. M. Kysil, Y. B. Sandulenko, A. V.
Ivachtchenko, Tetrahedron Lett. 2007, 48, 2563-2567; e) L. A.
Polindara-Garcia, L. D. Miranda, Org. Lett. 2012, 14, 5408-5411; f) M.
Ghandi, N. Zarezadeh, A. Abbasi, Org. Biomol. Chem. 2015, 13, 8211-
8220; g) Z.H. Li, A. Kumar, A. Peshkov, E. V. Van der Eycken,
Tetrahedron Lett. 2016, 57, 754–756; For some intermolecular
examples, see: h) A. Ben Abdessalem, R. Abderrahim, A. Agrebie, A.
Dos Santos, L. El Kaïm, A. Komesky, Chem. Commun. 2015, 51, 1116-
1119; i) A. Zidan, J. Garrec, M. Cordier, A. M. El-Naggar, N. E. A. Abd
El-Sattar, A. Khalil Ali, M. Ali Hassan, L. El Kaim, Angew. Chem. Int Ed.
2017, 56, 12179-12183; j) A. Zidan, J. Garrec, M. Cordier, A. M. El-
Naggar, N. E. A. Abd El-Sattar, A. Khalil Ali, M. Ali Hassan, L. El Kaim,
Org Lett. 2018, $, 12179-$.
N-cyclohexyl-5-oxo-2-phenyltetrahydrofuran-2-carboxamide
(4g):
Following general procedure C with 4-cyano-N-cyclohexyl-2-hydroxy-2-
phenylbutanamide 3g (107 mg, 0.375 mmol), the mixture was purified by
column chromatography on silica gel (eluent:PE:EA = 80:20) to afford 4g
(78 mg, 0.27 mmol, 72%). Aspect: light brown oil. Rf: 0.46 (EA:PE = 3:7).
1H NMR (400 MHz, CDCl3) δ 7.55-7.52 (m, 2H), 7.39-7.33 (m, 3H), 6.28
(d, J = 7.8 Hz, 1H), 3.71-3.64 (m, 1H), 3.11-3.06 (m, 1H), 2.63-2.50 (m,
3H), 1.92-1.88 (m, 1H), 1.74-1.56 (m, 4H), 1.35-1.02 (m, 5H). 13C NMR
(101 MHz, CDCl3) δ 175.3, 169.4, 139.0, 128.8, 128.7, 124.7, 88.1, 48.8,
33.5, 33.1, 32.7, 28.4, 25.5, 24.9, 24.8. HRMS: calculated for C17H21NO3:
287.1521, found: 287.1522. IR (thin film): 3349, 2931, 2854, 1783, 1666,
1518, 1449, 1224, 1183, 1153, 1109, 1085, 1054 cm-1.
N-cyclohexyl-5-oxo-2-(pyridin-2-yl)tetrahydrofuran-2-carboxamide (4h):
Following general procedure C with 4-cyano-N-cyclohexyl-2-hydroxy-2-
(pyridin-2-yl)butanamide 3h (108 mg, 0.375 mmol), the mixture was
purified by column chromatography on silica gel (eluent:PE:EA = 50:50)
to afford 4h (54 mg, 0.188 mmol, 50%). Aspect: white solid, m.p. 109.9-
110.5 oC. Rf: 0.34 (EA:PE = 5:5). 1H NMR (400 MHz, CDCl3) δ 8.62 –
8.60 (m, 1H), 7.74-7.69 (m, 1H), 7.52-7.50 (m, 1H), 7.29-7.26 (m, 1H),
6.72 (d, J = 7.7 Hz, 1H), 3.82-3.73 (m, 1H), 3.01-2.94 (m, 1H), 2.85-2.63
(m, 3H), 1.89-1.85 (m, 2H), 1.71-1.57 (m, 3H), 1.39-1.28 (m, 2H), 1.20-
1.11 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 175.9, 168.6, 157.3, 149.5,
137.3, 123.8, 120.6, 88.0, 48.6, 32.9, 31.9, 28.7, 25.5, 24.8. HRMS:
calculated for C16H20N2O3: 288.1474, found: 288.1476. IR (thin film):
3691, 3606, 3421, 2937, 2858, 1786, 1677, 1589, 1524, 1470, 1452,
1435, 1226, 1181, 1157, 1109, 1066 cm-1.
[3]
For reviews on Passerini reactions, see: a) L. Banfi, R. Riva, Org.
React. 2005, 65, 1-140; b) A.R. Kazemizadeh, A. Ramazani, Curr. Org.
Chem. 2012, 16, 418-450; For some selected applications of the
Passerini reaction, see: a) L. Banfi, G. Guanti, R. Riva, Chem. Commun.
2000, 985–986; b) L. Banfi, G. Guanti, R. Riva, A. Basso, E. Calcagno,
Tetrahedron Lett. 2002, 43, 4067-4069; c) A. Basso, L. Banfi, R. Riva,
P. Piaggio, G. Guanti, Tetrahedron Lett. 2003, 44, 2367-2370; d) L.
Banfi, A. Basso, G. Guanti, R. Riva, Mol. Diversity 2003, 6, 227-235; e)
S. Faure, T. Hjelmgaard, S. P. Roche, D. J. Aitken, Org. Lett. 2009, 11,
1167-1170. f) A. Dos Santos, L. El Kaïm, Synlett 2014, 1901-1903; g)
M. Cordier, A. Dos Santos, L. El Kaïm, N. Narboni, Chem. Commun.
2015, 51, 6411-6414
N-cyclohexyl-2-(furan-2-yl)-5-oxotetrahydrofuran-2-carboxamide
(4i):
[4]
a) D. Koszelewski, W. Szymanski, J. Krysiak, R. Ostaszewski, Synth.
Commun. 2008, 38, 1120-1127; b) T. Bousquet, M.. Jida, M. Soueidan,
R. Deprez-Poulain, F. Agbossou-Niedercorn, L. Pelinski, Tetrahedron
Lett. 2012, 53, 306-308.
Following general procedure C with 4-cyano-N-cyclohexyl-2-(furan-2-yl)-
2-hydroxybutanamide 3i (104 mg, 0.375 mmol), the mixture was purified
by column chromatography on silica gel (eluent:PE:Et2O = 80:20) to
afford 4i (21 mg, 0.075 mmol, 20%). Aspect: yellow oil. Rf: 0.42 (EA:PE =
[5]
[6]
A. Ben Abdessalem, R. Abderrahim, L. El Kaïm, Synlett 2015, 26,
2537-2540.
1
4:6). H NMR (400 MHz, CDCl3) δ 7.42-7.39 (m, 1H), 6.47-6.35 (m, 3H),
3.81 (tdd, J = 12.1, 8.2, 4.0 Hz, 1H), 2.87-2.74 (m, 3H), 2.68-2.55 (m, 1H),
1.97-1.89 (m, 2H), 1.76-1.61 (m, 3H), 1.42-1.32 (m, 2H), 1.24-1.16 (m,
3H). 13C NMR (101 MHz, CDCl3) δ 175.2, 167.4, 150.5, 143.8, 110.8,
109.5, 83.7, 48.9, 33.0, 32.9, 30.2, 28.6, 25.5, 24.9, 24.9. HRMS:
calculated for C15H19NO4: 277.1314, found: 277.1310. IR (thin film): 3361,
2931, 2855, 1757, 1710, 1663, 1529, 1451, 1347, 1259, 1185, 1154,
1098, 1067, 1009 cm-1.
For some examples, see: a) A. Miyashita, Y. Suzuki, Y. Okumura, T.
Higashino, Chem. Pharm. Bull. 1996, 44, 252-254; b) U. R. Seo, Y. K.
Chung, RSC Adv. 2014, 4, 32371-32374; c) Q. Zhao, B. Han, B. Wang,
H.-J. Leng, C. Peng, W. Huang, RSC Adv. 2015, 5, 26972-26976; d) C.
S. Buxton, D. C. Blakemore, J. F. Bower, Angew. Chem. Int. Ed. 2015,
127, 15079-15083. For an enantioselective approach, see: e) G. He, F.
Wu, W. Huang, R. Zhou, L. Ouyang, B. Han, Adv. Synth. Catal. 2014,
356, 2311-2319;
[7]
[8]
For reviews on the synthesis of butyrolactones, see: a) H. M. R.
Hoffman, J. Rabe, Angew. Chem., Int. Ed. Engl. 1985, 24, 94-110; b) M.
Seitz, O. Reiser, Curr. Opin. Chem. Biol. 2005, 9, 285-292; c) B. Mao,
M. Fananas-Mastral, B. L. Feringa, Chem. Rev. 2017, 117, 10502-
10566.
Acknowledgements
We thank the Chinese Scientific Council for the fellowship
of SJ
.
a) K. Nishio, T. Ishida, H. Arioka, H. Kurokawa, K. Fukuoka, T. Nomoto,
H. Fukumoto, H. Yokote, N. Saijo, Anticancer Res. 1996, 16, 3387-
3395; b) K.H. Lee, B. R. Huang, C. C. Tzeng, Bioorg. Med. Chem. Lett.
Keywords: Passerini • Michael addition • butyrolactone •
multicomponent reaction • acrylonitrile
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10.1002/ejoc.201800958
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COMMUNICATION
1999, 9, 241-244; c) S. Awale, J. Lu, S. K. Kalauni, Y. Kurashima, S.
Kadota, H. Esumi, Cancer Res. 2006, 66, 1751-1757.
2015, 63, 7958-7966; c) M. Liu, Q. Zhou, J. Wang, J. Liu, C. Qi, Y. Lai,
H. Zhu, Y. Xue, Z. Hu, Y. Zhang, RSC Adv., 2018, 8, 13040-13047;
[11] For some cyclizations to -lactones under basic conditions, see: a) K. M.
Sam, S. Auger, V. Luu-The, D. Poirier, J. Med. Chem. 1995, 38, 4518-
4528; b) C. A. Citron, C. J. Junker, B. Schulz, J. S. Dickschat, Angew.
Chem. Int. Ed. 2014, 53, 4346-4349; For a cyclization under acidic
conditions: P. Safar, S. Marchalin, M. Soral, J. Moncol, A. Daïch, Org.
Lett. 2017, 19, 4742-4745.
[9]
a) M. E.Cazar, G. Schmeda-Hirschmann, L. Astudillo, World J Microbiol
Biotechnol. 2005, 21, 1067-1075; b) J.-H. Xu, K.-B. Gu, D.-J. Zhang,
Y.-G. Li, L. Tian, J. Antibiot. 2017, 70, 733-736; c) S. Sukdolak, S.
Solujic, N. Vukovic, T. Milosevic, Turk. J. Chem. 2008, 32, 615-621.
[10] a) T. Hidaka, K. Hosoe, T. Yamashita, K. Watanabe, Y. Hiramatsu, H.
Fujimura, J. Pharm. Pharmacol. 1986, 38, 748-753; b) Y. N. Yang, X. Y.
Huang, Z. M. Fenq, J. S. Jiang, P. C. Zhang, J. Agric. Food Chem.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Multicomponent reaction*
Shuanglong Jia, Laurent. El Kaim*
Page No. – Page No.
A Passerini/Michael pathway towards
butyrolactones
Three-step access to butyrolactones built on the Passerini reaction
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