5-endo-dig Cyclization of O-Propargyl Mandelic Acid Amides towards 2,5-Dihydrofurans

Article abstract of DOI:10.1002/ejoc.201901397

5-endo-dig cyclization of O-propargyloxyamides, obtained through a Passerini reaction mediated by boric acid and subsequent propargylation, affords 2,5-dihydrofurans in the presence of tert-butylate. The mechanism of the reaction was studied by using DFT calculations and the results were compared with the behavior of analogous N-propargylamide derivatives.

Full text of DOI:10.1002/ejoc.201901397

DOI: 10.1002/ejoc.201901397
Full Paper
Cyclization Reactions
5-endo-dig Cyclization of O-Propargyl Mandelic Acid Amides
towards 2,5-Dihydrofurans
Lilia Ben Gaied,[a] Nicolas Fincias,*[b] Julian Garrec,*[b] and Laurent El Kaïm*[b]
Abstract: 5-endo-dig cyclization of O-propargyloxyamides, ob- studied by using DFT calculations and the results were com-
tained through a Passerini reaction mediated by boric acid and
subsequent propargylation, affords 2,5-dihydrofurans in the
presence of tert-butylate. The mechanism of the reaction was
pared with the behavior of analogous N-propargylamide deriva-
tives.
Introduction
Compared to 2,3-dihydrofurans, tetrahydrofurans or furans, 2,5-
dihydrofurans are certainly the least represented in terms of
biological activity as well as occurrence in natural products.[1]
However, the interest for these compounds has grown signifi-
cantly in the last twenty years and 2,5-dihydrofurans now ap-
pear as major synthetic intermediates for the preparation of
other members of the furan family. They can be easily isomer-
ized to their more stable 2,3-isomer,[2] converted to tetrahydro-
furans[3] or oxidized either to furans[4] or butyrolactones,[5]
a
skeleton widely encountered in natural products. The wealth of
this chemistry is mainly associated with the disclosure of direct
accesses to these compounds thanks to the development of
metathesis reactions of alkenyl ethers[6] (Scheme 1). Besides this
ruthenium carbenoid based transformation, many other prepa-
rations of 2,5-dihydrofurans are associated with metal triggered
cyclization of alkyne or allenyl derivatives. These transforma-
tions take advantage of the π-Lewis electrophilic properties of
various metals in order to activate nucleophilic attacks on dou-
ble and triple bonds. Thus many silver or gold-catalyzed forma-
tions of 2,5-hydrofurans from both hydroxyallenes and hydroxy-
alkynes have been reported.[7] The interaction of diazo com-
pounds with propargylic alcohols affords as well a direct access
to dihydrofuran under palladium or gold catalysis.[8] Alterna-
tively, 2,3-dihydrofurans can be arylated towards substituted
2,5-dihdyrofurans under Heck type reactions.[9] (Scheme 1).
Though the formation of 2,5-dihydrofurans through anionic
5-endo-dig cyclization of O-propargylic ethers (which may be
considered as an example of Conia-ene cyclization)[10] appears
as a very attractive method due to an easy formation of prop-
Scheme 1. Usual approaches towards 2,5-dihydrofurans.
argylic ethers, the scope of nucleophiles that can be involved
in the cyclization is often limited by the use of a Lewis acid as
catalyst in order to raise the electrophilicity of the alkyne. In-
deed while O-propargyl hydroxypyrimidinediones could cyclize
[11]
[12]
in a 5-endo mode in the presence of AgSbF6
or FeCl3
(Scheme 2), more simple O-propargyl keto esters failed to cy-
clize in a tandem Rh2(esp)2/ZnI2 addition-cyclization sequence
from diazo compounds (in contrast to the related O-homo-
propargyl keto ester which led to efficient formation of tetrahy-
drofurans via 5-exo-dig Conia-ene cyclization).[13] Besides these
metal triggered cyclizations, few anionic 5-endo-dig cyclizations
have been described on propiolate esters.[14] In these cases, the
reaction is favored by the electron-poor nature of the triple
bond. For simple alkynes and more reactive O-propargyl anionic
species formed in the absence of π-electrophilic Lewis acids,[1,2]
or [2,3]-Wittig rearrangement towards hydroxy alkynes and all-
enes are usually observed (Scheme 2).[15]
[a] Laboratoire de physico-chimie des microstructures et microsystèmes,
Institut Préparatoire aux Etudes Scientifiques et Techniques, La Marsa,
B.P. 51, 2070 La Marsa, Tunis – Tunisie
[b] Laboratoire de Synthèse Organique (LSO), CNRS, Ecole Polytechnique,
ENSTA Paris-UMR 7652, Institut Polytechnique de Paris, 828 Bd des
Maréchaux, 91128 Palaiseau, France
E-mail: laurent.elkaim@ensta-paristech.fr
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901397.
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Scheme 3. O-alkylative Passerini procedures.[20]
While no reaction occurred at room temperature using
tBuOK (0.5 equiv.) in acetonitrile, we could observe the ex-
pected cyclization with the same basic conditions heating at
50 °C for 12 hours (Scheme 4). Cs2CO3 which gave quantitative
yields in the alkylation step was not basic enough to trigger the
cyclization. Raising the amount of base to 1.5 equiv. afforded a
slight increase in yields. Sodium hydride as well as other sol-
vents (DMF, toluene, EtOH, DMSO) all proved less efficient or
convenient than the tBuOK/CH3CN couple. These conditions
could be easily adapted to offer a one-pot two-step conversion
of 1a into 3a. After room temperature propargylation of 1a in
the presence of 1.2 equiv. of tBuOK in CH3CN, further base was
added after 4 hours and the temperature raised at 50 °C for the
following 12 hours to afford 3a in 63 % isolated yield. These
conditions were selected to perform the preparation of the vari-
ous 2,5-dihydrofurans displayed in Table 1.
Scheme 2. 5-endo-dig cyclization of propargyl ethers.
Considering these limitations and the low number of metal-
free 5-endo-dig cyclizations of O-propargyl ethers,[16] we de-
cided to start a combined experimental and theoretical ap-
proach towards anionic cyclization of O-propargyl-mandelic
secondary amides enolate. Indeed, the ability to obtain these
compounds from benzaldehyde in a 2-step Passerini/O-prop-
argylation sequence opens the way for easy preparation of vari-
ous aryl analogs allowing better tuning of the reactivity of the
anions (Scheme 2).
Results and Discussion
The Passerini reaction is a convenient three-component access
to α-acyloxy amides from aldehydes, isocyanides, and carb-
oxylic acids.[17] Though the preparation of the requisite O-prop-
argyl amide derivatives could be envisioned using a three-step
one-pot Passerini/saponification/alkylation procedure settled
by Basso et al. (Scheme 3),[18] we preferred to form directly the
starting α-hydroxyamides using a previously reported boronic
acid triggered Passerini coupling.[19] Thus, following a slightly
modified procedure (working at 50 °C in DMF instead of r.t.),
we could obtain hydroxyamide 1a in 87 % isolated yield from
4-chlorobenzaldehyde and tert-butyl isocyanide (Scheme 3).
Due to an internal hydrogen bonding, these amides are ex-
pected to be more acidic than simple secondary alcohols and
their O-alkylation is known to proceed efficiently under basic
conditions (NaH/DMF or KOH in dichloromethane/water mix-
ture under phase-transfer conditions).[21] With the objective of
reaching a potential one-pot alkylation/cyclization procedure,
various conditions were tested for the O-propargylation of 1a.
tBuOK or Cs2CO3 which afforded an almost quantitative yield of
2a in acetonitrile (Scheme 3), were then evaluated as bases for
the following step.
Scheme 4. Optimized formation 2,5-dihydrofuran 3a.
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Table 1. Scope of 2,5-dihydrofuran synthesis.
Scheme 5. Attempted O-propargylation/cyclization sequence for 1k and 1l.
hydrofurans. Whereas for the nitrogen analogs, the potential
2,3-Wittig reaction is not an issue, the formation of 2,3-pyrrol-
ines as major regioisomers is even more puzzling in the light of
our results. In order to gain further indications on the reaction
mechanism, O-propargyl Passerini adduct 1a was treated under
our optimized cyclization conditions using tBuOK as a base but
replacing CH3CN by deuterated acetonitrile. Under these condi-
tions, the trideuterated dihydrofuran 3m was obtained in 58 %
yield (Scheme 6).
[a] Isolated yields after column chromatography on silica gel. [b] A 50 % con-
version was observed. [c] The isomeric 2,3-dihydrofuran 3j′ was also obtained
in 29 % yield.
Scheme 6. 5-endo cyclization of 2a in deuterated acetonitrile.
This last example gives some good indications on the mech-
anism probably involved in the cyclization step. Starting 2a pos-
sesses several acidic centers, besides the NH amide and the CH
benzylic positions, one can also imagine the potential deproto-
nation of the terminal CH alkyne as well as the two propargylic
CH bonds. From the reaction performed in deuterated aceto-
nitrile and the fact that the cyclization works efficiently with
less than one equivalent of base, it may be reasoned that the
three monoanionic species A, B, and C exist in equilibrium after
treatment with tBuOK (Scheme 7). Even if no deuterium ex-
change has been observed at this position, anion D might be
also expected to be formed as an intermediate towards allene
derivatives. While A and B may lead to proton exchanges with
the solvent, C may cyclize in a 5-endo-dig fashion to form the
vinyl anion E which is protonated either by the solvent or
tBuOH from the added base to form 3a. A further experiment
made placing 3a in deuterated acetonitrile under the cycliza-
For most reactions of Table 1, the alkylation step was almost
quantitative (checked by an NMR of an aliquot before adding
more base and heating) and the cyclization led to the dihydro-
furans 3 in moderate to good yield. Except for phenyl-substi-
tuted O-propargyl amide 1j, which led to an equimolar mixture
of 2,3 and 2,5-dihydrofurans 3j and 3j′, all amides 1 afforded
2,5-dihydrofurans without any trace of 2,3 isomer visible in the
NMR of the crude mixture (Table 1, entries 1–9). No other side
product could be isolated. The reaction seems to be strongly
affected by the electronic nature of the starting aldehyde. The
cyclization was less effective with an electron-rich aromatic al-
dehyde. In the case of 4-methoxy-substituted Passerini adduct
1l, the expected dihydrofuran was not isolated but we could
recover oxazolinone 4a obtained in a 60 % isolated yield
(Scheme 5). The analogous oxazolinone 4b was also formed
when the Passerini/Propargylation/Cyclization sequence was at-
tempted with isobutyraldehyde (Scheme 5). Both 4a and 4b
were isolated as single diastereomers but their stereochemistry
could not be determined.
The formation of 2,3 and 2,5 regioisomeric dihydrofurans
together with oxazolinones according to the nature of the
starting aldehyde is indicative of the importance of the depro-
tonation step under basic treatment. The most related cycliza-
tions displaying similar potential competing deprotonations
have been reported using N-propargyl Ugi adducts instead of
Passerini ones.[22] Pyrrolines were then formed instead of di-
Scheme 7. Anionic species involved in the reaction mechanism.
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Table 2. Relative energies (kcal/mol) of the four different anionic species for
O-propargyloxyamide with different substituents (R). Energy of anion A was
set as reference for easier comparison.
tion conditions showed that the terminal alkyne position fully
exchanges its proton with deuterium before the cyclization step
(no deuteration of the vinyl positions of 3a but conversion of
the NH into ND).
Whenever the benzylic position becomes less acidic either
by using electron-rich starting aromatic aldehydes (Passerini ad-
duct 1k) or when the anion is less stabilized by conjugation
(Passerini adduct 1l made from an aliphatic aldehyde), the for-
mation of anionic intermediate C together with its cyclization
become less efficient and the O-propargyl moiety may ulti-
mately isomerize into an allenyl ether which is probably in-
volved in the cyclization process towards 4a and 4b as well as
the formation of the regioisomeric 2,3-dihydrofuran 3j′ (Table 1,
entry 10).
To confirm these elements, molecular modeling employing
density functional theory (DFT) calculations was undertaken to
examine the relative energies of the various anions presented
above in CH3CN together with the feasibility of the 5-endo-dig
cyclization.
pound C is too high for efficient deprotonation at this position
in the presence of the NH-amide unless a dianionic species is
involved. This analysis is further confirmed with the lack of
5-endo cyclization observed with both 1k and 1l.
The higher acidity of the NH-amide raises further questions
on the reaction mechanism. Indeed, amide anion A could be
expected to cyclize onto the alkyne moiety in a 6-exo-dig fash-
ion to afford morpholine derivatives. Related 6-exo-dig cycliza-
tions have been recently reported by Miranda et al. working on
N-propargyl Ugi adducts derived from aliphatic aldehydes and
aromatic isocyanides.[24]
The relative stability of different carbanions that may be gen-
erated during the deprotonation of O-propargyloxyamide was
evaluated by comparing their energy in acetonitrile as a solvent
cage (Table 2).
Amide anions A appear as the most stable in most of the
substitution patterns examined. As expected, the relative stabil-
ity of species C leading to the 5-endo cyclization adduct is
greatly influenced by the substitution of the enolic position.
When this carbon is substituted with a phenyl or a p-chloro-
phenyl group, anion C and anion A have close energies indicat-
In order to answer these questions, we have modeled the
full 5-endo and 6-exo reaction pathways.[25]
The chosen structural model was compound 1j. The corre-
ing that both compounds may be present in solution. However, sponding potential energy surfaces (PES) are represented in Fig-
the higher stability of C for the chloro substituted analog is ure 1. For both mechanisms, deprotonation before cyclization
associated with an exclusive formation of the 2,5-isomer in simi- and reprotonation after cyclization are always facile processes
lar amount. In the case of the phenyl ring, the lower amount of (thermodynamically favorable) with energy drops in the range
C in the medium probably gives more space for the propargyl- [–18, –14] kcal/mol. It is worth stressing that these energy val-
allenyl isomerization to occur leading to important amount of ues are pretty independent of the mechanism considered. The
the 2,3-isomer.[23] When the enolic carbon is substituted with a main difference in the energetics of the two chemical pathways
p-methoxybenzene or a methyl group, the energy of com- lies in the cyclization step itself. The 5-endo cyclization is clearly
Figure 1. Comparison of the potential energy surfaces of the 5-endo and 6-exo mechanisms in acetonitrile, depicted in red and blue, respectively. Optimized
molecular structures derived from compound 1a′ are represented for all stationary points of the two pathways. H-atoms the Ar and tBu groups are hidden
for the sake of clarity. On each energy level, B– and BH correspond to, respectively, a deprotonated and normal acetonitrile molecule taken at infinite
separation. Deprotonation and protonation steps are shown as dashed lines on the pathways. Cyclization steps are represented with plain lines. Anionic sites
on meta-stable structures are highlighted with a green arrow.
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more favorable, both on the kinetic and thermodynamic point ester analog 6, a one-pot version was directly attempted as
of view, with a barrier of Δ5-endo cycl.E‡ ≈ 15 kcal/mol and an described previously for our NH-amides 1. While the substitu-
energy difference between cyclized and uncyclized forms of tion pattern of 9 is close to the one of 1k, to our surprise we
Δ5-endo cycl.E ≈ –10 kcal/mol. The corresponding values for the didn't observe any 2,5-dihydrofuran but the sole formation of
6-exo pathway are Δ6-exo cycl.E‡ ≈ 22 kcal/mol and Δ6-exo cycl.E ≈ the 2,3-dihydrofuran 11 isolated in
+7 kcal/mol, respectively. Hence, the differences in activation (Scheme 9).
and reaction energies between the two cyclization steps are
a good 72 % yield
Δ
5-endo→6-exoΔcycl.E‡ ≈ 7 kcal/mol and Δ5-endo→6-exoΔcycl.E ≈
17 kcal/mol, respectively. This is consistent with our experimen-
tal observation that only dihydrofurans are formed from com-
pound 1j.
A close inspection of our optimized transition state struc-
tures reveals that the preference for the 5-endo mechanism
originates from a steric conflict involving the tBu group at-
tached to the amide group of 1j in the case of the 6-exo
approach. Indeed, the 6-exo cyclization requires the terminal
carbon atom of the alkyne moiety to get very close to the tBu
group, which is detrimental to the energetics of the chemical
step. We provide more detailed molecular representations
showing this specific steric hindrance in the supporting infor-
mation part together with a comparison of the 5-endo/6-exo
cyclization of the N–Me analog showing that the latter cycliza-
tion may become easier (ref SI in Fig. S1).
While the use of the Passerini reaction affords a fast synthetic
pathway towards dihydrofurans, our study clearly shows that
the presence of a secondary amide moiety may complicate the
cyclization due to competing deprotonations. Thus, we decided
to examine the behavior of alternative starting materials replac-
ing secondary amides by tertiary amides or esters. Due to
poorly efficient O-propargylation of ethyl mandelate under our
conditions, we decided to prepare O-propargyl ester 6 using a
BF3 triggered reaction of diazoester 5 as reported by Just et
al. (Scheme 8).[26] When 6 was treated under our optimized
cyclization conditions, the expected 2,5-dihydrofuran 7 was not
formed but we could isolate out of the complex mixture the
2,5-dihydrofuran 8 obtained in a low 12 % yield (Scheme 8).
The formation of 8 demonstrates the sensitivity of the ester
moiety to the reaction conditions. Indeed, the latter may un-
dergo a nucleophilic attack of the acetonitrile derived anion
after cyclization. A potential formation of a ketene from 6 may
be also considered.
Scheme 9. Cyclization of amide 9.
According to the trend observed in our study and confirmed
by the modeling with NH amides, this behavior should be indic-
ative of a less acidic α-amide CH position. Indeed, the presence
of two alkyl groups on the nitrogen should prevent the amide
benzylic anion C (Table 3) to reach a flat geometry leading to
a higher energy of the latter and thus more time for the prop-
argyl-allene isomerization to occur. In opposition to this analy-
sis, the modeling of the geometry[27] and energies of the vari-
ous anions potentially formed from 10 failed to bring convin-
cing elements to explain the more selective formation of 2,3-
dihydrofuran as anion C is more stabilized for the pyrrolidone
moiety than for the NHtBu group. A more detailed study on the
isomerization of the propargyl moiety will probably be required
for a better understanding of this effect.
Table 3. Relative energies (kcal/mol) of the different anionic species in aceto-
nitrile generated from 9 and 1k. Energies of anion B were set to 0 kcal.mol–1
for relative energy comparison.
Conclusions
We have performed a combined experimental and theoretical
study on the formation of 2,5-dihydrofuran under basic treat-
ment of O-propargyl amides. The formation of dihydrofurans
under transition metal-free cyclization of O-propargyl deriva-
tives is much less documented than the related cyclization of
the nitrogen analogs towards pyrrolidines due to the potential
competing 2,3-Wittig rearrangement well described in the liter-
ature. While the 2,3-Wittig rearrangement is not observed with
our substrates, we have explained and confirmed with DFT
modeling the selectivity of the process. Most noteworthy is the
ability to extend these cyclizations to other substrates than
Scheme 8. Cyclization of ester 6.
The hydroxy amide 9 was next prepared (Scheme 9). As its Passerini adducts as shown by our last cyclizations performed
propargylation could be achieved much more easily than the with ester 6 or tertiary amide 9.
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N-(tert-Butyl)-2-(4-chlorophenyl)-2-hydroxyacetamide (1a): Fol-
lowing general procedure with p-chlorobenzaldehyde and tert-
butyl isocyanide. 1a was obtained as a white solid (m.p. 150–153 °C)
in 87 % isolated yield (421 mg, 1.74 mmol) after column chromatog-
raphy (PE/EtOAc = 80:20 to 70:30). 1H NMR (400 MHz, CDCl3) δ =
7.27 (d, J = 9.0 Hz, 2H), 7.23 (d, J = 9.0 Hz, 2H), 5.90 (s, 1H), 4.79 (d,
J = 3.7 Hz, 1H), 3.78 (d, J = 3.7 Hz, 1H), 1.24 (s, 9H). 13C NMR
(101 MHz, CDCl3) δ = 170.8, 138.4, 134.4, 129.0, 128.2, 73.5, 51.6,
28.7. HRMS: expected: 241.0870, found 241.0870. IR (thin film) cm–1
3363, 3233, 2969, 1644, 1535, 1407, 1284, 1229, 1189, 1103, 1087,
1068, 842.
Experimental Section
Computational Methods: All electronic structure calculations were
performed by means of density functional theory (DFT) using the
M062X functional[28] with the 6-31G(d,p) basis set.[29–31] as imple-
mented in the Gaussian 09 suite of programs[32] The molecular sys-
tem was embedded in a dielectric cavity mimicking the acetonitrile
solvent (polarizable continuum model (PCM)[33]).
All relevant reactants, products, and transition states (TS) geome-
tries were optimized then and characterized by standard normal
mode analysis. For each TS, the single mode corresponding to an
imaginary frequency was used to define an intrinsic reaction coordi-
nates (IRC)[34] and proceed downhill toward the reactants an prod-
ucts of the elementary step. It is worth noting that we did not
attempt to search transition states corresponding to proton trans-
fers as all relevant protonation/deprotonations steps in the various
chemical pathways where all highly exothermic and thus consid-
ered as rather facile processes (see main text for discussion).
2-(4-Chlorophenyl)-N-cyclohexyl-2-hydroxyacetamide (1b): Fol-
lowing general procedure with p-chlorobenzaldehyde and cyclo-
hexyl isocyanide. 1b was obtained as a white solid (m.p. 126–
128 °C) in 85 % yield (455 mg, 1.70 mmol) after column chromatog-
raphy (PE/EtOAc = 80:20 to 70:30). 1H NMR (400 MHz, CDCl3) δ =
7.25 (s, 4H), 6.01 (d, J = 8.3 Hz, 1H), 4.87 (s, 1H), 3.65 (tdd, J = 10.7,
6.7, 4.1 Hz, 1H), 3.65 (s br, 1H), 1.87–1.70 (m, 2H), 1.69–1.44 (m, 3H),
1.39–1.16 (m, 2H), 1.04 (ddt, J = 18.0, 10.9, 3.4 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ = 170.7, 138.2, 134.43, 129.0, 128.2, 73.4, 48.5,
32.9, 32.9, 25.4, 24.8, 24.7. HRMS: expected: 267.1026, found
Graphical representations of the molecules were made with the
software VMD.[35]
General Considerations: NMR spectra were recorded at 298 K us-
ing a Bruker AVANCE 400 spectrometer. 1H NMR spectra were re-
corded 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 = dou-
blet, t = triplet, q = quartet, p = pentuplet, m = multiplet or overlap
of non-equivalent 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 re-
ported as follows: chemical shift in ppm, multiplicity deduced from
DEPT experiments (CH3, CH2, CH, Cq), apparent multiplicity, cou-
pling 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 performed using UV fluorescence
(λmax = 254 nm or 360 nm) and staining with p-anisaldehyde, potas-
sium permanganate or vanillin TLC stain solutions, followed by
heating. Flash chromatography employed VWR (230–400 mesh) sil-
ica 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 an 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 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 micro-
wave conditions.
267.10.23. IR (thin film): ν = cm–1 3291, 2929, 2854, 1746, 1647,
˜
1529, 1489, 1089, 736.
2-(4-Chlorophenyl)-N-(3,4-dimethoxyphenethyl)-2-hydroxy-
acetamide (1c): Following general procedure with para-chloro-
benzaldehyde and 4-(2-isocyanoethyl)-1,2-dimethoxybenzene, 1c
was obtained as a dark yellow oil in 95 % yield (665 mg, 1.90 mmol)
after column chromatography (CH2Cl2/MeOH = 100:0 to 95:5). 1H
NMR (400 MHz, CDCl3) δ = 7.36 (d, J = 8.6 Hz, 2H), 7.30 (d, J =
8.6 Hz, 2H), 6.78 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 6.58 (dd,
J = 8.1, 2.0 Hz, 1H), 6.26 (d, J = 5.3 Hz, 1H), 4.99 (s, 1H), 3.91 (s, 3H),
3.87 (s, 3H), 3.66–3.44 (m, 2H), 2.76 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ = 171.6, 149.0, 147.7, 138.0, 134.4, 129.0, 128.1, 120.7,
111.7, 111.2, 73.4, 55.9, 55.9, 40.7, 35.1. HRMS: expected: 349.1081,
found 349.1085. IR (thin film): ν = cm–1 3336, 3059, 2933, 2835,
˜
1652, 1511, 1258, 1233, 1142, 1083, 1021.
N-(tert-Butyl)-2-(4-fluorophenyl)-2-hydroxyacetamide (1d): Fol-
lowing general procedure with p-fluorobenzaldehyde and tert-butyl
isocyanide. 1d was obtained as a white solid (m.p. 154–156 °C) in
80 % yield (360 mg, 1.60 mmol) after column chromatography (EP/
EtOAc = 80:20 to 70:30). 1H NMR (400 MHz CDCl3) δ = 7.34–7.23
(m, 2H), 7.04–6.93 (m, 2H), 5.85 (s, 1H), 4.80 (d, J = 3.6 Hz, 1H), 3.70
(d, J = 3.6 Hz, 1H), 1.25 (s, 9H). 13C NMR (101 MHz, CDCl3) δ = 171.0,
162.8 (d, J = 247.0 Hz), 135.8 (d, J = 3.1 Hz), 128.6 (d, J = 8.2 Hz),
115.8 (d, J = 21.7 Hz), 73.5, 51.6, 28.7. HRMS: expected: 225.1165,
found 225.1154. IR (thin film): ν = cm–1 3361, 3237, 2972, 1641,
˜
1536, 1508, 1219, 846.
N-Cyclohexyl-2-(4-fluorophenyl)-2-hydroxyacetamide (1e): Fol-
lowing general procedure with p-fluorobenzaldehyde and cyclo-
hexyl isocyanide, 1e was obtained as a white solid (m.p. 92–95 °C)
in 96 % yield (482 mg, 1.92 mmol) after column chromatography
(PE/EtOAc = 90:10 to 70:30). 1H NMR (400 MHz CDCl3) δ = 7.25–
7.15 (m, 2H), 6.90 (m, 2H), 6.54 (s, 1H), 4.78 (s, 1H), 4.68 (s, 1H), 3.75–
3.35 (m, 1H), 1.81–1.46 (m, 5H), 1.33–0.92 (m, 5H). 13C NMR
(101 MHz, CDCl3) δ = 171.5, 162.6 (d, J = 246.6 Hz), 135.8 (d, J =
3.1 Hz), 128.5 (d, J = 8.2 Hz), 115.4 (d, J = 21.5 Hz), 73.3, 48.2, 32.9,
32.8, 25.4, 24.7. HRMS: expected: 251.1322, found 251.1332. IR (thin
General Procedure for the Synthesis of α-Hydroxyamides: The
corresponding aldehyde (2.00 mmol), isocyanide (1.00 equiv.) and
boric acid (1.00 equiv.) were dissolved in 0.4 mL of DMF and the
resulting mixture was stirred at 50 °C for 24 h. The crude solution
was then diluted with 10 mL of EtOAc and washed with 80 mL of
brine. The aqueous solution was further extracted with 2 × 10 mL
of EtOAc; the combined organic layers were washed one last time
film): ν = cm–1 3296, 2930, 2855, 1647, 1604, 1508, 1223, 1071, 839.
˜
with 60 mL of brine, dried with MgSO4 and the solvent was re- N-(tert-Butyl)-2-hydroxy-2-(pyridin-3-yl)acetamide (1f): Follow-
moved under reduced pressure. α-Hydroxyamides were purified by
ing general procedure with pyridine-3-carboxaldehyde and tert-
flash column chromatography with the corresponding eluent.
butyl isocyanide, 1f was obtained as a yellow oil in 82 % yield
Eur. J. Org. Chem. 0000, 0–0
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Full Paper
(342 mg, 1.64 mmol) after column chromatography (CH2Cl2/
MeOH = 100:0 to 95:5). 1H NMR (400 MHz CDCl3) δ = 8.38 (d, J =
2.2 Hz, 1H), 8.29 (dd, J = 4.9, 1.6 Hz, 1H), 7.80–7.60 (m, 1H), 7.20
(ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 6.79 (s, 1H), 4.84 (s, 1H), 1.26 (s, 9H).
13C NMR (101 MHz, CDCl3) δ = 170.9, 148.4, 147.6, 136.8, 135.0,
123.8, 71.8, 51.2, 28.7. HRMS: expected: 208.1212, found 209,1287
4.91 (d, J = 3.2 Hz, 1H), 3.87 (t, J = 1.4 Hz, 3H), 3.69 (t, J = 2.7 Hz,
1H), 1.38 (t, J = 1.4 Hz, 9H). 13C NMR (101 MHz, CDCl3) δ = 171.6,
159.8, 132.1, 128.3, 114.3, 73.8, 55.4, 51.5, 28.7. HRMS: expected:
237.1365, found 237.1365. IR (thin film): ν = cm–1 3380, 2966, 1652,
˜
1510, 1245, 1174, 1065, 1032, 734.
N-(tert-Butyl)-2-hydroxy-4-methylpentanamide (1l): Following
general procedure with isobutyraldehyde and tert-butyl isocyanide,
1l was obtained as a white solid (m.p. 83–85 °C) in 88 % yield
(330 mg,1.76 mmol) after column chromatography (PE/EtOAc =
90:10 to 70:30. 1H NMR (400 MHz CDCl3) δ = 6.11 (s, 1H), 3.94 (ddd,
J = 9.7, 5.2, 3.4 Hz, 1H), 2.61–2.37 (m, 1H), 1.76 (dddd, J = 13.3, 11.5,
6.6, 3.3 Hz, 1H), 1.61–1.36 (m, 2H), 1.30 (s, 9H), 0.90 (d, J = 3.0 Hz,
3H), 0.88 (d, J = 2.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ = 173.4,
70.9, 51.0, 44.1, 28.8, 24.6, 23.6, 21.5. HRMS: expected: 187.1572,
[M + H]. IR (thin film): ν = cm–1 3296, 2967, 2929, 1879, 1654, 1521,
˜
1221, 1077, 709.
N-Cyclohexyl-2-hydroxy-2-(pyridin-3-yl)acetamide (1g): Follow-
ing general procedure with pyridine-3-carboxaldehyde and cyclo-
hexyl isocyanide, 1g was obtained as a yellow oil in 86 % yield
(403 mg, 1.72 mmol) after column chromatography (CH2Cl2/
1
MeOH = 100:0 to 95:5). H NMR (400 MHz CDCl3) δ = 8.41 (s, 1H),
8.25 (d, J = 4.8 Hz, 1H), 7.71 (dt, J = 7.9, 1.8 Hz, 1H), 7.17 (dd, J =
7.9, 4.8 Hz, 1H), 7.06 (d, J = 8.5 Hz, 2H), 4.93 (s, 1H), 3.61 (td, J = found 187.1562. IR (thin film): ν = cm–1 3356, 3252, 2955, 1642,
˜
14.4, 7.0 Hz, 1H), 1.88–1.45 (m, 6H), 1.36–0.92 (m, 5H). 13C NMR
(101 MHz, CDCl3) δ = 171.0, 148.2, 147.5, 136.8, 135.0, 123.7, 71.44,
48.1, 32.9, 32.9, 25.4, 24.8, 24.8.HRMS: expected: 234.1368, found
109.0523 (M + H-C(O)NHCy). IR (thin film): cm–1 3271, 2928, 2853,
1647, 1589, 1523, 1077, 1029, 708.
1533, 1229, 1085.
General Procedure for the Synthesis of O-Propargyloxy-acet-
amides 2a: N-(tert-Butyl)-2-(4-chlorophenyl)-2-hydroxyacetamide
1a (1.00 mmol) was dissolved in 2.0 mL of MeCN, and tBuOK
(1.20 equiv.) was added. The solution was stirred at r.t. for 20 min
and alkylating reagent (1.20 equiv.) was added dropwise. The solu-
tion was kept stirring at r.t. for 2 h. The reaction mixture was
quenched with sat. NH4Cl solution and the aqueous solution was
extracted with 3 × 10 mL of EtOAc. The organic layer was washed
with 20 mL of brine, dried with MgSO4 and the solvent was re-
moved under reduced pressure. The crude residue was purified by
N-(3,4-Dimethoxyphenethyl)-2-hydroxy-2-(pyridin-3-yl)acet-
amide (1h): Following general procedure with pyridine-3-carbox-
aldehyde and 4-(2-isocyanoethyl)-1,2-dimethoxybenzene, 1h was
obtained as a red solid (m.p. 93–95 °C) in 82 % yield (519 mg,
1.64 mmol) after column chromatography (CH2Cl2/MeOH = 98:2 to
90:10). 1H NMR (400 MHz CDCl3) δ = 8.35 (d, J = 2.1 Hz, 1H), 8.29
(dd, J = 4.9, 1.6 Hz, 1H), 7.61 (dt, J = 8.0, 1.9 Hz, 1H), 7.17 (dd, J = flash column chromatography (PE/EtOAc= 95:05 to 80:20).
7.9, 4.8 Hz, 1H), 6.92 (t, J = 6.0 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.64–
N-(tert-Butyl)-2-(4-chlorophenyl)-2-(prop-2-yn-1-yloxy)acet-
6.53 (m, 2H), 4.94 (s, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.44 (qd, J = 7.0,
amide (2a): Following general procedure using propargyl bromide
3.3 Hz, 2H), 2.68 (td, J = 7.0, 1.7 Hz, 2H). 13C NMR (101 MHz, CDCl3)
as alkylating reagent, 2a was obtained as a yellow solid (m.p. 93–
δ = 171.6, 149.0, 148.8, 147.7, 147.7, 136.2, 134.8, 131.0, 123.8, 120.7,
96 °C) in 96 % yield (269 mg, 0.96 mmol) after column chromatogra-
111.9, 111.4, 71.7, 55.9, 55.9, 40.5, 35.2. HRMS: expected: 316.1423,
1
phy. H NMR (400 MHz, CDCl3) δ = 7.26 (s, 4H), 6.51 (s, 1H), 4.81 (s,
found 316.1419. IR (thin film): ν = cm–1 3284, 3054, 2936, 2835,
˜
1H), 4.18 (dd, J = 15.8, 2.4 Hz, 1H), 3.92 (dd, J = 15.8, 2.4 Hz, 1H),
1657, 1511, 1458, 1421, 1259, 1233, 1024, 730, 706.
2.43 (t, J = 2.4 Hz, 1H), 1.30 (s, 9H). 13C NMR (101 MHz, CDCl3) δ =
N-Cyclohexyl-2-(furan-2-yl)-2-hydroxyacetamide (1i): Following
general procedure with furan-2-carbaldehyde and cyclohexyl iso-
cyanide, 1i was obtained as a brown solid (m.p. 85–87 °C) in 72 %
yield (322 mg, 1.44 mmol) after column chromatography (PE/
EtOAc = 100:00 to 85:15). 1H NMR (400 MHz CDCl3) δ = 7.33 (dd,
J = 1.8, 0.9 Hz, 1H), 6.32 (dt, J = 3.3, 0.8 Hz, 1H), 6.29 (dd, J = 3.3,
1.8 Hz, 1H), 6.03 (d, J = 8.3 Hz, 1H), 5.00 (d, J = 3.7 Hz, 1H), 3.81–
3.65 (m, 2H), 1.94–1.74 (m, 1H), 1.73–1.46 (m, 2H), 1.43–0.97 (m, 6H).
13C NMR (101 MHz, CDCl3) δ = 168.7, 152.0, 143.0, 110.7, 108.5, 67.6,
48.7, 32.9, 32.9, 25.4, 24.7, 24.7. HRMS: expected: 223.1208, found
223.1201. IR (thin film): cm–1 3292, 2928, 2853, 1646, 1529, 1448,
1146, 1057, 734.
168.7, 135.4, 134.5, 128.9, 128.8, 79.9, 78.2, 75.9, 56.4, 51.2, 28.8.
HRMS: expected: 279.1026, found 179.0264 (M – C(O)NHtBu). IR
(thin film): ν = cm–1 3408, 3298, 2968, 1673, 1518, 1489, 1083.
˜
General Procedure for the One-pot Synthesis of 2,5 Dihydro-
furans and Isoxazoles: The corresponding α-hydroxyamide
(0.50 mmol) was dissolved in 1.00 mL of acetonitrile, tBuOK
(1.20 equiv.) was added and the solution was stirred for 20 min.
Then, propargyl bromide (1.20 equiv.) was added and the solution
was stirred for another 2 h at r.t. To the previous solution was added
an extra amount of tBuOK (1.50 equiv.) and the solution was stirred
for 22 h at 50 °C. The reaction mixture was quenched with sat.
NH4Cl solution and the aqueous solution was extracted with 3 ×
N-(tert-Butyl)-2-hydroxy-2-phenylacetamide (1j): Following gen- 10 mL of EtOAc. The organic layer was washed with 20 mL of brine,
eral procedure with benzaldehyde and tert-butyl isocyanide, 1j was
obtained as a white solid (m.p. 89–93 °C) in 70 % yield (290 mg,
1.40 mmol) after column chromatography (PE/EtOAc = 100:00 to
85:15). 1H NMR (400 MHz CDCl3) δ = 7.51–7.35 (m, 5H), 5.88 (s, 1H),
4.94 (d, J = 3.5 Hz, 1H), 3.77 (d, J = 3.2 Hz, 1H), 1.37 (s, 9H). 13C NMR
(101 MHz, CDCl3) δ = 171.2, 139.9, 129.0, 128.6, 126.9, 74.2, 51.6,
dried with MgSO4 and the solvent was removed under reduced
pressure. The crude residue was purified by flash column chroma-
tography with the suited eluent.
N-(tert-Butyl)-2-(4-chlorophenyl)-2,5-dihydrofuran-2-carbox-
amide (3a): Following general procedure with N-(tert-butyl)-2-(4-
chlorophenyl)-2-hydroxyacetamide, 3a was obtained as a colourless
oil in 61 % yield (85 mg, 0.31 mmol) after column chromatography
(PE/EtOAc = 95:05 to 80:20). 1H NMR (400 MHz, CDCl3) δ = 7.43–
7.34 (m, 2H), 7.24–7.18 (m, 2H), 6.73 (s, 1H), 6.17 (dt, J = 6.1, 2.5 Hz,
1H), 5.92 (dt, J = 6.1, 1.6 Hz, 1H), 4.88–4.63 (m, 2H), 1.27 (s, 9H). 13C
NMR (101 MHz, CDCl3) δ = 170.8, 139.9, 133.7, 130.6, 128.4, 127.2,
28.7. HRMS: expected: 207.1259 found: 207.1253. IR (thin film): ν =
˜
cm–1 3353, 3243, 2965, 2921, 1638, 1530, 1451, 1229, 735.
N-(tert-Butyl)-2-hydroxy-2-(4-methoxyphenyl)acetamide (1k):
Following general procedure with p-methoxy benzaldehyde and
tert-butyl isocyanide, 1k was obtained as a white solid (m.p. 94–
96 °C) in 82 % yield (389 mg, 1.64 mmol) after column chromatogra- 126.7, 94.1, 76.0, 50.9, 28.8. HRMS: expected: 279.1026, found
phy (PE/EtOAc = 90:10 to 70:30). 1H NMR (400 MHz, CDCl3) δ = 7.34
(dd, J = 9.0, 2.5 Hz, 2H), 6.95 (dd, J = 9.0, 2.5 Hz, 2H), 5.85 (s, 1H),
279.1014. IR (thin film): ν = cm–1 3397, 2966, 2923, 2860, 2195, 1665,
1511, 1488, 1223, 1073, 757.
˜
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2-(4-Chlorophenyl)-N-cyclohexyl-2,5-dihydrofuran-2-carbox-
amide (3b): Following general procedure with 2-(4-chlorophenyl)-
N-cyclohexyl-2-hydroxyacetamide, 3b was obtained as a pale yellow
oil in 63 % yield (96 mg, 0.32 mmol) after column chromatography
(PE/EtOAc = 95:05 to 80:20). 1H NMR (400 MHz, CDCl3) δ = 7.43–
7.36 (m, 2H), 7.26–7.20 (m, 2H), 6.92–6.68 (m, 1H), 6.18 (dt, J = 6.1,
2.5 Hz, 1H), 5.93 (dt, J = 6.1, 1.6 Hz, 1H), 4.75 (td, J = 2.7, 1.6 Hz,
2H), 3.78–3.42 (m, 1H), 1.88–1.72 (m, 2H), 1.71–1.47 (m, 3H), 1.42–
0.98 (m, 5H). 13C NMR (101 MHz, CDCl3) δ = 170.5, 139.7, 133.7,
130.5, 128.4, 127.2, 126.8, 94.1, 76.0, 47.9, 33.1, 33.0, 25.5, 24.8, 24.8.
HRMS: expected: 305.1183, found 179.0259 (M – C(O)NHCy). IR (thin
133.6, 130.2, 127.1, 123.1, 93.1, 76.1, 51.0, 28.7. HRMS: expected:
246.1368, found 146.0601 (M – C(O)NHtBu). IR (thin film): ν = cm–1
˜
3411, 2946, 2893, 1775, 1669, 1511, 1074, 710.
N-Cyclohexyl-2-(pyridin-3-yl)-2,5-dihydrofuran-2-carboxamide
(3g): Following general procedure with N-cyclohexyl-2-hydroxy-2-
(pyridin-3-yl) acetamide 3g was obtained as a dark yellow solid
(m.p. 118–121 °C) in 52 % yield (71 mg, 0.26 mmol) after column
1
chromatography (PE/EtOAc= 85:15). H NMR (400 MHz, CDCl3) δ =
8.69 (d, J = 2.3 Hz, 1H), 8.55–8.39 (m, 1H), 7.79 (dt, J = 7.9, 2.0 Hz,
1H), 7.18 (dd, J = 8.0, 4.8 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.20 (dt,
J = 6.1, 2.5 Hz, 1H), 5.97 (dt, J = 6.1, 1.6 Hz, 1H), 4.93–4.65 (m, 2H),
3.63 (dddd, J = 10.6, 8.5, 6.7, 4.2 Hz, 1H), 1.93–1.41 (m, 5H), 1.41–
0.96 (m, 5H). 13C NMR (101 MHz, CDCl3) δ = 170.1, 149.0, 147.2,
136.8, 133.6, 130.0, 127.2, 123.1, 93.0, 76.1, 47.9, 33.0, 33.0, 25.5,
24.8, 24.8. HRMS: expected: 272.1525 found: 272.1530. IR (thin film):
film): ν = cm–1 3406, 3329, 2927, 2852, 1658, 1507, 1488, 1071.
˜
2-(4-Chlorophenyl)-N-(3,4-dimethoxyphenethyl)-2,5-dihydro-
furan-2-carboxamide (3c): Following general procedure with 2-(4-
chlorophenyl)-N-(3,4-dimethoxyphenethyl)-2-hydroxyacetamide, 3c
was obtained as a yellow oil in 47 % yield (82 mg, 0.24 mmol) after
column chromatography (PE/EtOAc = 85:15). 1H NMR (400 MHz
CDCl3) δ = 7.42–7.26 (m, 2H), 7.26–7.11 (m, 2H), 6.92 (t, J = 6.0 Hz,
1H), 6.68 (d, J = 8.7 Hz, 1H), 6.60–6.55 (m, 2H), 6.15 (dt, J = 6.1,
2.4 Hz, 1H), 5.89 (dt, J = 6.1, 1.6 Hz, 1H), 4.64 (qdd, J = 13.2, 2.5,
1.6 Hz, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.40 (dp, J = 16.5, 6.6 Hz, 2H),
2.66 (t, J = 6.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ = 171.6, 149.0,
147.7, 139.5, 133.8, 131.2, 130.2, 128.4, 127.1, 126.9, 120.8, 111.9,
111.3, 94.1, 76.0, 55.9 (d, J = 10.6 Hz), 40.3, 35.2. HRMS: expected:
ν = cm–1 3403, 3318, 3043, 2927, 2853, 1655, 1580, 1510, 1072, 707.
˜
N-(3,4-Dimethoxyphenethyl)-2-(pyridin-3-yl)-2,5-dihydrofuran-
2-carboxamide (3h): Following general procedure with N-(3,4-di-
methoxyphenethyl)-2-hydroxy-2-(pyridin-3-yl) acetamide 3h was
obtained as a light brown colored oil in 44 % yield (78 mg,
0.22 mmol) after column chromatography (PE/EtOAc= 85:15 to
65:35). 1H NMR (400 MHz, CDCl3) δ = 8.73–8.65 (m, 1H), 8.43 (dd,
J = 4.8, 1.7 Hz, 1H), 7.72 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.16 (ddd,
J = 7.9, 4.8, 0.8 Hz, 1H), 6.99 (t, J = 6.1 Hz, 1H), 6.73–6.66 (m, 1H),
6.64–6.52 (m, 2H), 6.19 (dt, J = 6.1, 2.4 Hz, 1H), 5.94 (dt, J = 6.1,
1.6 Hz, 1H), 4.90–4.59 (m, 2H), 3.77 (s, 3H), 3.74 (s, 3H), 3.42 (ddd,
J = 12.7, 6.9, 5.8 Hz, 2H), 2.68 (t, J = 6.9 Hz, 2H). 13C NMR (101 MHz,
CDCl3) δ = 171.1, 149.0, 148.9, 147.7, 147.1, 136.6, 133.6, 131.1,
127.3, 123.1, 120.7, 111.9, 111.3, 93.1, 76.2, 55.9, 55.8, 40.3, 35.2.
387.1237 found: 387.1243. IR (thin film): ν = cm–1 3406, 3055, 2933,
˜
2857, 1665, 1510, 1260, 1234, 1022, 732.
N-(tert-Butyl)-2-(4-fluorophenyl)-2,5-dihydrofuran-2-carbox-
amide (3d): Following general procedure with N-(tert-butyl)-2-(4-
fluorophenyl)-2-hydroxyacetamide 3d was obtained as a colourless
oil in 31 % yield (41 mg, 0.16 mmol) after column chromatography
(PE/EtOAc= 100:0 to 85:15). 50 % of starting material was recovered
HRMS: expected: 354.1580, found 354.1580. IR (thin film): ν = cm–1
˜
3353, 2937, 2836, 1663, 1510, 1260, 1234, 1024, 730.
1
after column chromatography. H NMR (400 MHz CDCl3) δ = 7.51–
7.33 (m, 2H), 6.94 (m, 2H), 6.86–6.69 (m, 1H), 6.18 (dt, J = 6.1, 2.4 Hz,
1H), 5.93 (dt, J = 6.1, 1.6 Hz, 1H), 4.91–4.60 (m, 2H), 1.28 (s, 9H). 13C
NMR (101 MHz, CDCl3) δ = 171.0, 162.4 (d, J = 246.0 Hz), 137.2 (d,
J = 3.1 Hz), 130.8, 127.5 (d, J = 8.2 Hz), 126.6, 115.1 (d, J = 21.4 Hz),
94.2, 75.9, 50.9, 28.8. HRMS: expected: 263.1322, found 163.0555 (M
N-Cyclohexyl-[2,2′-bifuran]-2(5H)-carboxamide (3i): Following
general procedure with N-cyclohexyl-2-(furan-2-yl)-2-hydroxyacet-
amide 3i was obtained as a brown solid (m.p. 113–116 °C) in 62 %
yield (82 mg, 0.31 mmol). 1H NMR (400 MHz, CDCl3) δ = 7.30 (dd,
J = 1.8, 0.9 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 6.24 (qd, J = 3.3, 1.4 Hz,
2H), 6.09 (dt, J = 6.1, 2.4 Hz, 1H), 6.04 (dt, J = 6.1, 1.5 Hz, 1H), 4.75
(qdd, J = 13.1, 2.4, 1.6 Hz, 2H), 3.71 (tdt, J = 10.6, 8.1, 3.9 Hz, 1H),
1.98–1.48 (m, 5H), 1.43–1.00 (m, 5H). 13C NMR (101 MHz, CDCl3) δ =
168.7, 152.8, 142.8, 128.5, 128.0, 110.4, 108.2, 90.5, 76.1, 47.9, 33.0,
25.5, 24.8, 24.8. HRMS: expected: 261.1365, found 261.1357. IR (thin
– C(O)NHtBu). IR (thin film): ν = cm–1 3401, 2970, 1775, 1677, 1506,
˜
1227, 836.
N-Cyclohexyl-2-(4-fluorophenyl)-2,5-dihydrofuran-2-carbox-
amide (3e): Following general procedure with N-cyclohexyl-2-(4-
fluorophenyl)-2-hydroxyacetamide 3e was obtained as a yellow oil
in 67 % yield (84 mg, 0.34 mmol) after column chromatography (PE/
EtOAc = 95:05 to 80:20). 1H NMR (400 MHz, CDCl3) δ = 7.52–7.17
(m, 3H), 7.04–6.89 (m, 2H), 6.78 (d, J = 8.6 Hz, 1H), 6.20 (dt, J = 6.1,
2.5 Hz, 1H), 5.95 (dt, J = 6.1, 1.6 Hz, 1H), 4.76 (dt, J = 2.7, 1.3 Hz,
2H), 3.77–3.53 (m, 1H), 1.91–1.43 (m, 7H), 1.42–0.98 (m, 3H). 13C
NMR (101 MHz, CDCl3) δ = 170.7, 162.5 (d, J = 246.2 Hz), 137:0,
130.6, 127.6 (d, J = 8.3 Hz), 126.7, 115.2 (d, J = 21.5 Hz), 94.2, 75.9,
47.8, 33.1, 33.1, 25.5, 24.9, 24.8. HRMS: expected: 289.1478, found
film): ν = cm–1 3353, 2928, 2854, 1658, 1514, 1154, 1062, 757, 738.
˜
N-(tert-Butyl)-2-phenyl-2,5-dihydrofuran-2-carboxamide (3j'):
Following general procedure with N-(tert-butyl)-2-hydroxy-2-phen-
ylacetamide 3j was obtained as a colourless oil in 25 % yield (32 mg,
0.13 mmol) after column chromatography (contaminated with
around 10 % of an inseparable impurity). The 2,3-hydrofuran 3j′
isomer was also isolated as a colourless oil in 29 % isolated yield
(35 mg, 0.14 mmol).
163.0555 (M – C(O)NHCy). IR (thin film): ν = cm–1 3407, 3332, 2927,
˜
1
3j: H NMR (400 MHz, CDCl3) δ = 7.49–7.39 (m, 2H), 7.29–7.23 (m,
2853, 2321, 1773, 1659, 1501, 1229, 1069, 833.
2H), 7.23–7.16 (m, 1H), 6.77 (s, 1H), 6.22 (dt, J = 6.1, 2.5 Hz, 1H), 5.93
(dt, J = 6.0, 1.6 Hz, 1H), 4.82–4.68 (m, 2H), 1.28 (s, 9H). 13C NMR
(101 MHz, CDCl3) δ = 171.2, 141.3, 130.8, 128.4, 127.8, 126.5, 125.7,
94.7, 75.9, 50.9, 28.8.
N-(tert-Butyl)-2-(pyridin-3-yl)-2,5-dihydrofuran-2-carboxamide
(3f): Following general procedure with N-(tert-butyl)-2-hydroxy-2-
(pyridin-3-yl) acetamide, 3f was obtained in 56 % yield (69 mg,
0.28 mmol) after column chromatography (PE/EtOAc = 85:15). 1H
NMR (400 MHz CDCl3) δ = 8.79 (dd, J = 2.4, 0.9 Hz, 1H), 8.56 (dd,
J = 4.7, 1.7 Hz, 1H), 7.88 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 7.29 (ddd,
J = 8.0, 4.8, 0.9 Hz, 1H), 6.86 (s, 1H), 6.30 (dt, J = 6.1, 2.5 Hz, 1H),
6.08 (dt, J = 6.1, 1.6 Hz, 1H), 4.89 (qdd, J = 13.2, 2.5, 1.6 Hz, 2H),
1.38 (s, 9H). 13C NMR (101 MHz, CDCl3) δ = 170.3, 149.0, 147.2, 136.9,
1
3j′: H NMR (400 MHz, CDCl3) δ = 7.53–7.42 (m, 2H), 7.31–7.23 (m,
2H), 7.24–7.16 (m, 1H), 6.52 (s, 1H), 6.33 (q, J = 2.4 Hz, 1H), 4.92 (q,
J = 2.6 Hz, 1H), 3.48 (dt, J = 16.0, 2.5 Hz, 1H), 2.78 (dt, J = 15.9,
2.4 Hz, 1H), 1.24 (s, 9H). 13C NMR (101 MHz, CDCl3) δ = 172.2, 143.1,
142.1, 128.3, 127.7, 125.0, 101.0, 90.2, 51.0, 41.1, 28.6. HRMS: ex-
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pected: 245.1416, found 245.1414. IR (thin film): ν = cm–1 3414,
2967, 2868, 1675, 1511, 1451, 1226, 1046, 698.
tBuOK (1.10 equiv.) in DMF (1.00 mL). The solution was stirred for
24 h at 50 °C. The solution was quenched with water diluted with
15 mL EtOAc, and the organic layer was washed with 3 × 20 mL of
water, dried with MgSO4, the solvent was removed under vacuum
and the crude was purified by column chromatography (PE/EtOAc =
100:00 to 85:15) affording 3 ethyl 2-phenyl-2,5-dihydrofuran-2-carb-
oxylate as a colourless oil in 12 % yield (13 mg, 0.06 mmol). 1H NMR
(400 MHz, CDCl3) δ = 7.41 (tt, J = 5.8, 1.4 Hz, 2H), 7.33–7.18 (m, 3H),
6.15 (ddt, J = 23.9, 6.1, 2.5 Hz, 1H), 6.07–5.95 (m, 1H), 4.91–4.69 (m,
2H), 4.27–3.97 (m, 2H), 1.17 (td, J = 7.1, 2.3 Hz, 4H). 13C NMR
(101 MHz, CDCl3) δ = 171.9, 140.5, 129.0, 128.5, 128.5, 128.1, 125.4,
˜
3-(tert-Butyl)-5-(4-methoxyphenyl)-2-vinyloxazolidin-4-one
(4a): Following general procedure with N-(tert-butyl)-2-hydroxy-2-
(4-methoxyphenyl)acetamide, 4a was obtained as a colourless oil
in 64 % yield (88 mg, 0.32 mmol) after column chromatography (PE/
EtOAc = 100:00 to 85:15). 1H NMR (400 MHz, CDCl3) δ = 7.37 (m,
2H), 7.05–6.88 (m, 2H), 6.07 (ddd, J = 17.1, 10.1, 7.7 Hz, 1H), 5.78
(dd, J = 7.7, 1.6 Hz, 1H), 5.57 (d, J = 17.1 Hz, 1H), 5.48 (d, J = 10.2 Hz,
1H), 5.21 (d, J = 1.5 Hz, 1H), 3.85 (s, 3H), 1.52 (s, 9H). 13C NMR
(101 MHz, CDCl3) δ = 170.4, 159.9, 136.8, 129.1, 128.2, 119.8, 114.1,
90.2, 78.7, 55.3, 54.8, 28.0. HRMS: expected 275.1521, found
93.8, 76.1, 61.6, 14.2. IR (thin film): ν = cm–1 3097, 2996, 2917, 2852,
˜
1776, 1731, 1234, 1095, 1032, 695.
175.0747 (M – C(O)NHtBu). IR (thin film): ν = cm–1 2932, 2855, 1698,
˜
1512, 1248, 1175, 1031, 732.
3-Oxo-3-(2-phenyl-2,5-dihydrofuran-2-yl)propanenitrile (8):
Ethyl 2-phenyl-2-(prop-2-yn-1-yloxy)acetate (0.50 mmol) was
treated with tBuOK (1.10 equiv.) in MeCN (1.00 mL). The solution
was stirred for 24 h at 50 °C. The solution was quenched with water
diluted with 15 mL EtOAc, and the organic layer was washed with
3 × 20 mL of water, dried with MgSO4, the solvent was removed
under vacuum and the crude was purified by column chromatogra-
phy (PE/EtOAc = 100:00 to 85:15) affording 3-oxo-3-(2-phenyl-2,5-
dihydrofuran-2-yl)propanenitrile as a dark red oil in 10 % yield
(11 mg, 0.05 mmol) as a dark red oil. 1H NMR (400 MHz, CDCl3) δ =
7.41–7.35 (m, 2H), 7.36–7.23 (m, 3H), 6.14 (dt, J = 6.1, 2.5 Hz, 1H),
6.01 (dt, J = 6.1, 1.6 Hz, 1H), 5.00–4.72 (m, 2H), 3.83 (d, J = 19.7 Hz,
1H), 3.53 (d, J = 19.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ = 198.3,
138.4, 129.0, 128.6, 128.5, 128.3, 124.9, 113.6, 98.3, 76.4, 28.2. HRMS:
expected: 213.0790, found 145.0653 (M – C(O)CH2CN). IR (thin film):
3-(tert-Butyl)-5-isobutyl-2-vinyloxazolidin-4-one (4b): Following
general procedure with N-(tert-butyl)-2-hydroxy-4-methylpentan-
amide 4b was obtain as a colourless oil in 57 % yield (64 mg,
0.29 mmol) after column chromatography (PE/EtOAC = 100:00 to
85:15). 1H NMR (400 MHz, CDCl3) δ = 5.95 (ddd, J = 17.1, 10.1,
7.7 Hz, 1H), 5.56–5.51 (m, 1H), 5.46 (dt, J = 17.1, 0.8 Hz, 1H), 5.38
(dt, J = 10.1, 0.7 Hz, 1H), 4.29 (ddd, J = 9.3, 3.3, 1.5 Hz, 1H), 1.94–
1.79 (m, 1H), 1.70 (ddd, J = 14.1, 8.7, 3.3 Hz, 1H), 1.57–1.47 (m, 1H),
1.45 (s, 9H), 1.01–0.85 (m, 5H). 13C NMR (101 MHz, CDCl3) δ = 172.3,
136.7, 119.2, 89.8, 75.6, 54.4, 41.0, 27.9, 24.7, 23.3, 21.8. HRMS: ex-
pected: 225.1729, found 225.1730. IR (thin film): ν = cm–1 2957,
˜
2872, 1699, 1394, 1366, 1215, 936.
Ethyl 2-Phenyl-2-(prop-2-yn-1-yloxy)acetate (6): Ethyl 2-oxo-2-
phenyl acetate (4.00 mmol) was treated with p-toluenesulfonyl-
hydrazide (1.05 equiv.) in 20 mL of MeOH. The solution was stirred
at r.t. for 12 h, the solvent was removed under reduced pressure
giving a pale yellow oil which was dissolved in 20 mL of EtOAc and
washed with 3 × 10 mL of water to remove the remaining hydraz-
ide. The organic layer was dried with MgSO4 and the solvent was
removed under reduced pressure affording the ethyl-2-phenyl-2-(2-
tosylhydrazineylidene)acetate quantitatively. Hydrazone was en-
gaged in the next step without purification.
ν = cm–1 3062, 2918, 2861, 1730, 1308, 1067, 741, 699.
˜
2-Hydroxy-2-phenyl-1-(pyrrolidin-1-yl)ethan-1-one (9): Methyl
2-hydroxy-2-phenyl acetate (2.00 mmol) was treated with pyrrol-
idine (1.50 equiv.) in presence of p-toluenesulfonic acid (0.10 equiv.)
in toluene (10 mL, 2.0
M). The solution was stirred at 100 °C over-
night. Solvent was removed under vacuum and the crude solid was
dissolved in 30 mL EtOAc and washed with 3 × 10 mL of water. The
organic layer was dried with MgSO4, the solvent was removed un-
der vacuum affording 2-hydroxy-2-phenyl-1-(pyrrolidin-1-yl)ethan-
1-one as a white solid (96–99 °C) in 90 % yield (369 mg, 1.80 mmol).
1H NMR (400 MHz, CDCl3) δ = 7.34–7.21 (m, 5H), 4.97 (d, J = 5.9 Hz,
1H), 4.69 (d, J = 6.0 Hz, 1H), 3.63–3.23 (m, 3H), 2.91–2.63 (m, 1H),
1.90–1.55 (m, 4H). 13C NMR (101 MHz, CDCl3) δ = 170.7, 139.0, 128.9,
128.5, 127.8, 72.7, 46.6, 45.9, 25.9, 23.8. HRMS: expected: 205.1103,
Ethyl (E)-2-phenyl-2-(2-tosylhydrazineylidene)acetate was treated
with triethylamine (1.20 equiv.) in dichloromethane (20 mL, 0.40 M)
for 24 h. 40 mL Were then added to the solution and the organic
layer was washed with 3 × 20 mL, dried with MgSO4 and the solvent
was removed under reduced pressure to give ethyl 2-diazo-2-
phenyl acetate, which was directly engaged in next step.
found 205.1102. IR (thin film): ν = cm–1 3390, 2972, 2878, 1632,
˜
1450, 1382, 1190, 1067, 702.
To a solution of ethyl 2-diazo-2-phenyl acetate in dichloromethane
(40 mL, 0.1 M) was added propargyl alcohol (10.00 equiv.) and the
solution was stirred for 5 min. Boron trifluoride diethyl etherate
complex (0.10 equiv.) was then added: the solution started to bub-
ble gently: the reaction was stirred for 2 h at r.t. until no more
bubbling was observed. The reaction was quenched with 10 mL of
water, the organic layer was washed with 3 × 20 mL of water, dried
with MgSO4 and the solvent was removed under vacuum to afford
a yellow oil which was purified by column chromatograph giving
ethyl 2-phenyl-2-(prop-2-yn-1-yloxy)acetate as a deep yellow oil in
67 % yield (585 mg, 2.67 mmol). 1H NMR (400 MHz, CDCl3) δ =
7.55–7.47 (m, 2H), 7.47–7.35 (m, 3H), 5.24 (s, 1H), 4.41–4.12 (m, 4H),
2.54 (t, J = 2.4 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ = 170.3, 135.5, 129.0, 128.7, 127.6, 78.7, 75.7, 61.4, 56.2,
(2-Phenyl-2,3-dihydrofuran-2-yl)(pyrrolidin-1-yl)methanone (11):
2-Hydroxy-2-phenyl-1-(pyrrolidin-1-yl)ethan-1-one (0.50 mmol) was
treated with tBuOK (1.10 equiv.) in MeCN (1.00 mL). The solution was
stirred for 24 h at 50 °C. The solution was quenched with water
diluted with 15 mL EtOAc, and the organic layer was washed with
3 × 20 mL of water, dried with MgSO4, the solvent was removed
under vacuum and the crude was purified by column chromatogra-
phy (PE/EtOAc = 100:00 to 85:15) affording (2-phenyl-2,3-dihydro-
furan-2-yl)(pyrrolidin-1-yl)methanone as a colorless oil in 72 % yield
(88 mg, 0.36 mmol). 1H NMR (400 MHz, CDCl3) δ = 7.35–7.14 (m, 5H),
6.32 (q, J = 2.5 Hz, 1H), 4.86 (q, J = 2.6 Hz, 1H), 3.99 (dt, J = 16.0,
2.5 Hz, 1H), 3.60–3.31 (m, 3H), 2.93 (ddd, J = 11.5, 7.5, 4.3 Hz, 1H),
2.47 (dt, J = 15.9, 2.4 Hz, 1H), 1.78–1.40 (m, 4H). 13C NMR (101 MHz,
CDCl3) δ = 169.3, 142.9, 142.5, 128.6, 127.4, 124.1, 100.1, 91.3, 47.5,
47.1, 42.3, 26.4, 23.4. HRMS: expected: 243.1259, found 243.1258. IR
14.1. HRMS: expected: 218.0943, found 218.0946. IR (thin film): ν =
˜
cm–1 3284, 2983, 2902, 1737, 1206, 1178, 1094, 1024, 695.
Ethyl 2-Phenyl-2,5-dihydrofuran-2-carboxylate (7): Ethyl 2-
phenyl-2-(prop-2-yn-1-yloxy)acetate (0.50 mmol) was treated with
(thin film): ν = cm–1 3395, 2968, 2871, 1637, 1423, 1146, 1042, 965,
˜
700.
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Acknowledgments
The authors gratefully acknowledge the Ministry of Higher Edu-
cation and Scientific Research (MHESR) for the financial support
given to L. Ben Gaied through the Project CMCU 17G1207.
Keywords: 5-endo dig cyclization · Alkynes ·
Dihydrofuran · Passerini adducts · DFT modelling
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Received: September 20, 2019
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Cyclization Reactions
L. B. Gaied, N. Fincias,* J. Garrec,*
L. E. Kaïm* ......................................... 1–11
5-endo-dig Cyclization of O-Prop-
argyl Mandelic Acid Amides towards
2,5-Dihydrofurans
5-endo-dig cyclization of O-propargyl- ied by using DFT calculations and the
oxyamides in the presence of tert- results were compared with the be-
butylate affords 2,5-dihydrofurans. The havior of analogous N-propargylamide
mechanism of the reaction was stud- derivatives.
DOI: 10.1002/ejoc.201901397
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