Tandem One-Pot Approach to N-Substituted Lactones by Carbon–Carbon Coupling Followed by 5-exo-dig or 6-endo-dig Cyclization: DFT Studies and Cyclization Mode

Article abstract of DOI:10.1002/ejoc.201901099

A one-pot approach has been developed for the preparation of a five or six-membered ring of unsaturated lactones bearing an amino group through a tandem coupling oxacyclization reaction. This tandem process involves Sonogashira-like cross-coupling followed by 5-exo-dig or 6-endo-dig intramolecular oxacyclization, according to the nature of the alkynes substituent. Furthermore, DFT calculations were performed to analyze the origin of this regioselectivity of cyclization.

Full text of DOI:10.1002/ejoc.201901099

DOI: 10.1002/ejoc.201901099
Full Paper
Intramolecular Oxacyclization
Tandem One-Pot Approach to N-Substituted Lactones by
Carbon–Carbon Coupling Followed by 5-exo-dig or 6-endo-dig
Cyclization: DFT Studies and Cyclization Mode
Atef Mayooufi,[a,b] Johan Jacquemin,[c,d] Julien Petrignet,[a] and Jérôme Thibonnet*[a]
Abstract: A one-pot approach has been developed for the like cross-coupling followed by 5-exo-dig or 6-endo-dig intra-
preparation of a five or six-membered ring of unsaturated lact- molecular oxacyclization, according to the nature of the alkynes
ones bearing an amino group through a tandem coupling oxa- substituent. Furthermore, DFT calculations were performed to
cyclization reaction. This tandem process involves Sonogashira- analyze the origin of this regioselectivity of cyclization.
Introduction
Five or six-membered lactones (butenolides, pyrones) bearing a
nitrogen-containing unit are important heterocyclic ring sys-
tems, which can be present in several natural products and
have a diverse range of biological properties. As shown in Fig-
ure 1, the natural compound Basidalin A is a novel butenolide
bearing an amino group at position 4, which seems to have
good antitumor activity against leukemia.[1] The Uncinine B,
which is based on a combination of the pyrrolidinone and
γ-alkylidenebutenolide fragments, exhibits cytotoxicity against
the Hep G2 cell line (IC50 6.1 μg/mL).[2] The synthetic γ-alkyl-
idenebutenolide C displays an antibacterial activity with a mini-
mum inhibitory concentration (MIC) value of 20 μg/mL against
Escherichia coli while γ-alkylidenebutenolide D exhibits cyto-
toxic activity against Ec9706 cells.[3] In addition, the α-pyranone
carboxamide E is reported as promising anti-hepatitis C
agent.[4] These skeletal motifs also feature as intermediates for
the synthesis of related heterocycles and complex natural prod-
ucts.[5]
Figure 1. γ-Alkylidenebutenolides and α-pyranone bearing an amino group
with biological properties.
In the light of their biological properties, different ap-
proaches have been then developed to synthesize these het-
erocycles.[6] Among them, the widely used approach is based
on an intramolecular cyclization between carboxylic acid and
alkyne functions, promoted by metal-catalyst, (Ag, Hg, Rh, Pd,
Cu, ...).[7] Such method can afford both five-membered lactones
through a 5-exo process and/or six-membered lactones result-
ing from a 6-endo process.[8] In the last decade, our group has
developed a selective approach for the preparation of such lact-
ones via a tandem coupling/cyclization reaction between ꢀ-
(di)halogeno-α,ꢀ-unsaturated acids and terminal alkynes in the
presence of catalytic amount of copper(I) catalyst (Scheme 1).[9]
During this work, we reported that the regioselectivity of the
cyclization was exclusively in favor of the 5-membered-ring lact-
one. This methodology was therefore extended to the prepara-
tion of natural compounds such as Nostoclides.[10] To further
explore the synthetic potential of ꢀ-iodo-α,ꢀ-unsaturated carb-
oxylic acid, we report herein an extension of our methodology
for the regioselective preparation of γ-alkylidenebutenolides
and pyranones bearing an amino group. Finally, DFT calcula-
tions have been carried out to support experimental data high-
[a] Laboratoire SIMBA, EA-7502, Université de Tours,
Faculté des Sciences et Techniques, Parc de Grandmont, 32 Av. Monge,
37200 Tours, France
E-mail: jerome.thibonnet@univ-tours.fr
[b] Laboratoire de Chimie Organique Structurale et Macromoléculaire,
Département de Chimie, Faculté des Sciences de Tunis, Campus
Universitaire El-Manar, Rue Béchir Salem Belkheiria, 2092 Tunis, Tunisie
[c] Laboratoire PCM2E, EA-6299, Université de Tours,
Faculté des Sciences et Techniques, Parc de Grandmont, 32 Av. Monge,
37200 Tours, France
[d] Materials Science and Nano-engineering, Mohammed VI Polytechnic
University,
Lot 660-Hay Moulay Rachid, Ben Guerir, Morocco
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901099.
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Scheme 1. Tandem Sonogashira coupling/oxacyclization.
lighting the impact of the nature of the alkyne on the regio-
selectivity.
3a and p-methoxyphenylacetylene were selected as the ref-
erence system to perform the optimized catalytic system for
the tandem coupling/5-exo-dig cyclization reaction (Table 1). In
the first approach, the reaction was performed with the cata-
lytic system previously discovered by our group.[9] Only the
starting materials were recovered after 12 h in such conditions
(Table 1, entry 1), even using different solvents, such as MeCN,
THF, and DMSO, (Table 1, entries 2–4). An increase of the tem-
perature from 55 °C to 100 °C led to ꢀ-elimination adducts
(Table 1, entry 5). Some traces of 4d were observed with a
stoichiometric amount of catalyst at 55 °C (Table 1, entry 6).
Pleasingly, the use of 1.2 equiv. of CuI led to the desired prod-
uct with 70 % yield (Table 1, entry 7). These data clearly indicate
that an excess of copper is required for this reaction. This result
could be explained by the presence of nitrogen atoms in the
starting material, such as the ꢀ-iodo-α,ꢀ-unsaturated carboxylic
acids 3a–b, which is able to complex the copper(I) catalyst and
prevent it reaching the reaction site.[14] Next, we focused on the
Results and Discussion
Firstly, we turned our attention to the preparation of ꢀ-iodo-
α,ꢀ-unsaturated carboxylic acid bearing an amino group ac-
cording to the sequence illustrated in Scheme 2. The synthesis
started with the tosylation of commercial allyl and butylamine
as reported in the literature,[11] followed by the propargylation
using propargyl bromide in the presence of K2CO3 as a base in
THF, afforded 1a and 1b with good yields.[12] Then, we prepared
the alkynoic acid 2a and 2b by carbonatation with EtMgBr/
CO2(ice). The resulting acids reacted with hydroiodic acid, using
conditions previously reported to obtain the corresponding (Z)-
3-iodovinylic acids 3a and 3b with good yields as single iso-
mers.[13] Furthermore, by following this procedure, each acid
was obtained on a multigram scale.
Scheme 2. Preparation of ꢀ-iodo-α,ꢀ-unsaturated carboxylic acids 3a and 3b.
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use of the palladium catalyst system for the tandem coupling/
cyclization process (Table 1, entries 8–12). We explored different
palladium sources in combination with CuI (Table 1, entries 8–
12), the best Pd salt was found to be Pd(PPh3)2Cl2 rather than
Pd(PPh3)4 or Pd(OAc)2. Further optimization revealed that the
catalyst loading could be reduced to 5 mol-% under the same
condition to obtain 4d in 70 % yields (Table 1, entry 11). A
decrease of the yields to traces was observed by decreasing the
temperature from 55 °C down to 25 °C (Table 1, entry 12) under
the same conditions.
Table 1. Optimization of γ-alkylidenebutenolide preparation.[a]
Entry Base
[equiv.]
Solvent Catalyst [equiv.]
T [°C] Yield
[%][b]
1
2
3
4
5
6
7
8
K2CO3 (2) DMF
K2CO3 (2) THF
K2CO3 (2) DMSO CuI (0.2)
K2CO3 (2) MeCN CuI (0.2)
K2CO3 (2) DMF
K2CO3 (2) DMF
K2CO3 (2) DMF
CuI (0.2)
CuI (0.2)
55
55
55
55
100
55
55
55
0[c]
0[c]
0[c]
0[c]
0[d]
10
70
54
60
72
CuI (0.2)
CuI (1)
CuI (1.2)
Pd(PPh3)4 (0.1) + CuI (0.2)
Et3N (3)
Et3N (3)
Et3N (3)
Et3N (3)
Et3N (3)
DMF
DMF
DMF
DMF
DMF
9
Pd(OAc)2 (0.1), + PPh3 (0.2) + CuI (0.2) 55
10
11
12
PdCl2(PPh3)2 (0.1) + CuI (0.2)
PdCl2(PPh3)2 (0.05) + CuI (0.2)
PdCl2(PPh3)2 (0.1) + CuI (0.2)
55
55
25
70
trace
[a] Reaction conditions: Substrate 3a (0.70 mmol), 4-methoxyphenylacetylene
(2 equiv.) in 20 mL of solvent. [b] Isolated yield after column chromatography.
[c] Starting material 3a. [d] Alkynoic acid 2a.
Finally, the reaction was performed using 10 mol-%
Pd(PPh3)2Cl2 with 20 mol-% CuI, in combination with Et3N
(3 equiv.) at 55 °C. In such conditions, 4d was obtained with a
good yield of 72 % (Table 1, entry 10).
We then focused on the scope and limitations of this cou-
pling/5-exo-dig oxacyclization process with various arylic alk-
ynes by using the optimal reaction conditions (i.e. 5 mol-%
Pd(PPh3)2Cl2 with 20 mol-% CuI, in combination with Et3N
(3 equiv.) at 55 °C). As shown in Scheme 3, the reaction afforded
the corresponding N-substituted butenolides 4a–m with mod-
erate to excellent yields (49–82 %).
Scheme 3. Substrate scope in Pd-catalyzed N-substituted γ-alkylidenebuten-
olide synthesis.
In contrast to aryl-substituted alkynes, the presence of linear
aliphatic or cyclohexyl-substituted alkynes affects the regio-
The regioselectivity and the stereochemistry of the double selectivity of the tandem process. On the one hand, at 55 °C
bond were unambiguously confirmed thanks to a single-crystal we obtained a mixture of 5-exo-dig and 6-endo-dig cyclization
X-ray diffraction study of compound 4j (Figure 2, for details see at an average ratio of 75:25 in favor of 6-endo-dig cyclization.
ESI).[15] The suitable single-crystal of 4j for X-ray diffraction was On the other hand, reactions performed at 35 °C with the same
obtained by crystallization from CH2Cl2.
Interestingly, a mixture of 4d with the corresponding pyran-
one was obtained in a 1:1 ratio when the reaction was per-
alkyne afforded only the 6-endo-dig cyclization product
(Scheme 4).
The results of this study show that the regiochemistry of
formed at 75 °C (see ESI). A further increase of the temperature intramolecular cyclization is greatly influenced by the nature
from 75 °C to 100 °C did however not improve this ratio in favor of the alkyne substituent. In short, the aryl-substituted alkynes
of the pyranone. At this stage, we assumed that a temperature undergo only 5-exo-dig cyclization to give N-substituted γ-alkyl-
below 55 °C is essential in order to obtain the expected N- idenebutenolides products, while linear aliphatic or cyclohexyl-
substituted butenolides as single isomers.
substituted alkynes give only 6-endo-dig cyclization and N-sub-
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in the carbon iodide bond, creating a Pd(II) intermediate B. This
intermediate could be further transformed into the cyclization
product by the catalysis of Pd(II) through the σ-vinyl-palladium
intermediate obtained by oxacyclization. The protodemetala-
tion with Et3NH+ of σ-vinyl-palladium intermediate could afford
the expected lactone and the Pd(0)L2 released in the Sonoga-
shira cross-coupling.
We also focused our attention to understanding the role of
the nature of alkyne in promoting the different cyclization
modes. Considering L = PMe3,[18] R2 = Ph and Cy respectively
as aromatic and aliphatic model, the relative formation energies
of intermediates I1, I2, I3, I4, I5, I6 and products 4 and 5 were
determined in-silico. Briefly, DFT calculations were performed in
DMF with a convergence criterion of 10–6 Hartree using Turbo-
mole 7.0 program package along with DFT/B3LYP/def-TZVP
level of theory calculations combining the COSMO-RS model
and the resolution of identity (RI) approximation. Cartesian co-
ordinates of investigated species are tabulated in SI2 along with
those determined for intermediate I1, reactants and products
as a function of R2 structure. Each ΔG (kcal mol–1) value, re-
ported in Scheme 5, corresponds to the Gibbs free energy of
the corresponding reaction step. Except for the products, all ΔG
values are positives with highest values for the protodemetala-
tion reactions which seem to the rate-determining step of the
entire transformation. However, by considering the Δ(ΔG) dif-
ferences between I3-Ph/I4-Ph (Δ(ΔG) = –2.4 kcal mol–1) and I3-
Cy/I4-Cy (Δ(ΔG) = +1.3 kcal mol–1), I5-Ph/I6-Ph (Δ(ΔG) =
–2.6 kcal mol–1) and I5-Cy/I6-Cy (Δ(ΔG) = +0.5 kcal mol–1), one
can appreciate that DFT results unambiguously corroborate the
influence of the nature of R2 on the cyclization mode during
Figure 2. X-ray single-crystal structure of 4j (thermal ellipsoids are draw at
50 % probability level).
stituted pyranones products. These results are in contrast to our
previous work, in which we highlighted that the structure of
the starting substrate affects the regioselectivity of the cycliza-
tion.[16a] Briefly, previously we demonstrated that 5-exo-dig was
mainly obtained with non-aromatic systems, while 6-endo-dig
was promoted in the case of heteroaromatic derivatives, and a
mixture of coumarin and phthalide was obtained when aro-
matic systems were used.[16b]
A plausible mechanism for this present tandem coupling/
cyclization was postulated (Scheme 5) in accordance with the
work of Burton et al.[17] Initially, we propose the formation of
carboxylate A followed by the oxidative insertion of the Pd(0)
Scheme 4. Substrate scope in Pd-catalyzed N-substituted pyranones synthesis.
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Scheme 5. Proposed mechanism for the tandem coupling/cyclization reaction along with energy profiles of intermediates I1–I6 and products with respect to
respective reactants (where ΔG, kcal mol–1, during the DFT calculations, done in the case of R2 = Ph or Cy, L = PMe3).
the oxacyclization step. Furthermore, this tendency was also carbon atom leading the 5-exo-dig reaction (denoted ꢀ in Fig-
confirmed by the natural population analysis of carbons in the ure 3) is positive on contrary of the other (denoted α in Fig-
alkyne group (Figure 3), showing that the local charge on the ure 3). This result agrees with observations made by Wang and
Burton,[17] and by Uchiyama et al. in basic conditions.[19] How-
ever, lower differences between the charges of these two
carbons are observed in the case of the linear aliphatic or cyclo-
hexyl-substituted alkynes, which may also explain why the 6-
endo-dig product is mainly obtained in this case, in contrary of
aryl-substituted alkynes. In the case of the linear aliphatic or
cyclohexyl-substituted alkynes, the temperature dependence in
the production of 5-exo-dig observed experimentally to in-
crease with the temperature (Scheme 4), could be related to the
relatively low differences, in comparison with aryl-substituted
alkynes, between charges on these carbons and also by be-
tween the formation energies observed in the case of the inter-
mediates I3 and I4 in the case of R2 = Cy.
Conclusions
In summary, we have developed a useful method for the syn-
thesis of ꢀ-iodo-α,ꢀ-unsaturated carboxylic acid bearing an
amino group in four steps from readily available primary amine.
We have then demonstrated that the resulting (Z)-4-(N-alkyl)-3-
iodobut-2-enoic acids afforded a novel series of N-substituted
pyranones and N-substituted γ-alkylidenebutenolides, prepared
Figure 3. Natural population analysis as a function of the nature of the alkyne
substituent.
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J = 6.8 Hz, 2H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3): δ (ppm) =
168.9, 144.2, 136.5, 131.5, 130.1, 127.4, 125.3, 120.8, 118.1, 60.2, 51.2,
21.7; HRMS (ESI): m/z calcd. for C14H17INO4S [M + H]+: 421.99175,
found 421.99126.
using a tandem coupling/cyclization reaction. We have also
studied the regiochemistry of this reaction as a function of the
nature of the alkynes substituent and temperature prior pro-
posing a mechanism for this tandem coupling/cyclization reac-
tion. A relationship between substituted alkynes and product (Z)-4-(N-butyl-4-methylphenylsulfonamido)-3-iodobut-2-enoic
acid (3b): Following the general procedure, 3b was prepared from
carboxylic acid 2b; 3b was isolated as a white solid (3.20 g, 74 %
yield). M.p. 117–119 °C; IR (ATR) νmax = 3156, 1694, 1619, 1598, 1495,
1457, 1418, 1398, 1332, 1273, 1197, 1156, 1009, 900, 759, 740, 696,
was then examined along with DFT calculations.
Experimental Section
659, 564, 512 cm–1 1H NMR (300 MHz, CDCl3): δ (ppm) = 8.8 (bs,
;
General procedure for the synthesis of carboxylic acids 2a–b:
1H), 7.70 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 6.75 (s, 1H),
4.18 (s, 2H), 3.14 (t, J = 7.3 Hz, 2H), 2.43 (s, 3H), 1.43 (quint, J =
7.3 Hz, 2H), 1.24 (sext, J = 7.3 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H); 13C
NMR (75 MHz, CDCl3): δ (ppm) = 169.0, 144.0, 136.3, 130.0, 127.3,
125.1, 118.5, 62.1, 49.3, 30.3, 21.6, 20.1, 13.7; HRMS (ESI): m/z calcd.
for C15H21INO4S [M + H]+: 438.02305, found 438.02406.
In a round-bottomed flask, N-propargylamine 1a–b (0.05 mol,
1 equiv.) was dissolved in THF (20 mL). A solution of EtMgBr 1
Et2O (60 mL, 0.6 mol) was slowly added at –15 °C. The mixture was
then stirred for 90 min at room temperature. Solid carbon dioxide
was added at 0 °C and the solution was vigorously stirred at room
temperature. After 15 min, the mixture was cooled to 0 °C and
M in
General Procedure for the preparation of lactones 4a-l and
5a-d:
acidified with HCl 1
M to obtain pH = 1. The resulting precipitate
was filtered and washed with hexane.
Method A:
4-(N-Allyl-4-methylphenylsulfonamido)but-2-ynoic acid (2a):
Following the general procedure, 2a was prepared from N-prop-
argylamine 1a; 2a was isolated as a yellow solid (10.88 g, 74 %
yield). M.p. 104–106 °C; IR (ATR) νmax = 2971, 2917, 2243, 1683, 1622,
A dry Schlenk tube with a Teflon-coated magnetic stirrer was
charged with carboxylic acid 3a–b (0.7 mmol, 1 equiv.) and Et3N
(212 mg, 2.1 mmol, 3 equiv.) in anhydrous DMF (20 mL). CuI (27 mg,
0.14 mmol, 0.2 equiv.) and PdCl2(PPh3)2 (25 mg, 0.035 mmol,
0.05 equiv.) were added, and the suspension was stirred for 15 min.
Then, the mixture was degassed at 0 °C for 10 min and backfilled
with argon. Alkyne (1.4 mmol, 2 equiv.) was added at room temper-
ature, and the reaction mixture was stirred at 55 °C for 12 h. The
medium was then cooled to 0 °C and was hydrolyzed with a satu-
rated NH4Cl aqueous solution (30 mL). Ethyl acetate (30 mL) was
added, and the mixture was filtered through a Celite pad. The pad
was washed with additional ethyl acetate (3 × 20 mL). The aqueous
layer was removed, and the organic layer was washed with water
(3 × 10 mL), dried with MgSO4 and concentrated under vacuum.
The crude material was purified by flash chromatography on silica
gel to give the desired product.
1598, 1411, 1341, 1283, 1208, 1157, 890, 748, 660, 543 cm–1 1H
;
NMR (300 MHz, CDCl3): δ (ppm) = 7.73 (d, J = 8.2 Hz, 2H), 7.32 (d,
J = 8.2 Hz, 2H), 5.58 (ddt, J = 17.0, 9.9, 6.8 Hz, 1H), 5.33–5.25 (m,
2H), 4.22 (s, 2H), 3.82 (d, J = 6.8 Hz, 2H), 2.42 (s, 3H); 13C NMR
(75 MHz, CDCl3): δ (ppm) = 156.3, 144.4, 135.1, 131.4, 129.9, 127.7,
120.8, 83.0, 49.7, 35.9, 21.6; HRMS (ESI): m/z calcd. for C14H16NO4S
[M + H]+: 294.07946, found 294.07905.
4-(N-Butyl-4-methylphenylsulfonamido)but-2-ynoic acid (2b):
Following the general procedure, 2b was prepared from N-prop-
argylamine 1b; 2b was isolated as a white solid (11.62 g, 75 % yield).
M.p. 98–100 °C; IR (ATR) νmax = 3355, 3262, 2969, 2659, 1732, 1706,
1599, 1414, 1330, 1244, 1159, 1094, 912, 815, 766, 661, 548 cm–1
;
1H NMR (300 MHz, CDCl3): δ (ppm) = 8.89 (s, 1H),7.71 (d, J = 8.2 Hz,
2H), 7.30 (d, J = 8.2 Hz, 2H), 4.25 (s, 2H),3.17 (t, J = 7.3 Hz, 2H), 2.40
(s, 3H), 1.53 (quint, J = 7.3 Hz, 2H), 1.35 (sext, J = 7.3 Hz, 2H), 0.92
(t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ (ppm) = 155.5, 144.1,
135.0, 129.8, 127.5, 82.5, 76.6, 46.6, 36.2, 29.4, 21.4, 19.6, 13.5; HRMS
(ESI): m/z calcd. for C14H20NO4S [M + H]+: 310.11130, found
310.11092.
Method B:
A dry Schlenk tube equipped with a Teflon-coated magnetic stirrer
was charged with K2CO3 (194 mg, 1.4 mmol, 2 equiv.) and carboxylic
acid 3a–b (0.7 mmol, 1 equiv.). Anhydrous DMF (30 mL) was added
and the suspension was stirred for 15 min. Then, the mixture was
degassed at 0 °C for 10 min and backfilled with argon. Alkyne
(1.4 mmol, 2 equiv.) and CuI (163 mg, 0.84 mmol, 1.2 equiv.) were
added at room temperature, and the reaction mixture was stirred
at 55 °C overnight. The reaction mixture was cooled to room tem-
perature and was partitioned between Et2O and saturated aqueous
NH4Cl. The organic portions were dried with MgSO4, filtered and
concentrated under vacuum. The crude material was purified by
flash chromatography on silica gel to give the desired γ-alkylidene-
butenolide.
General Procedure for the preparation of iodobut-2-enoic acids
3a–b:
In a two-necked round-bottomed flask, carboxylic acid 2a–b
(0.01 mol, 1 equiv.) was dissolved in 15 mL of Et2O. HI 57 % (1.6 mL,
0.012 mol) was added dropwise, and the mixture was stirred at
50 °C for 4 h. Then, a 20 % solution of Na2S2O3 (10 mL) was added
and the mixture was then stirred for 30 min. The mixture was rap-
idly extracted with Et2O (3 × 20 mL). The combined organic layers
were washed with brine (2 × 10 mL), dried with anhydrous MgSO4
and concentrated under vacuum. The crude solid was recrystallized
from CH2Cl2.
N-Allyl-N-((2-benzyl-1-butyl-2-hydroxy-5-oxo-2,5-dihydro-1H-
pyrrol-3-yl)methyl)-4-methylbenzenesulfonamide (4a): Follow-
ing the general procedure, 4a was prepared from carboxylic acid
3a; 4a was isolated as a white solid (194 mg, 70 % yield). M.p. 130–
132 °C; IR (ATR) νmax = 3095, 3052, 1757, 1660, 1602, 1573, 1419,
(Z)-4-(N-Allyl-4-methylphenylsulfonamido)-3-iodobut-2-enoic
acid (3a): Following the general procedure, 3a was prepared from
carboxylic acid 2a; 3a was isolated as a white solid (3.60 g, 85 %
yield). M.p. 110–112 °C; IR (ATR) νmax = 2905, 1696, 1622, 1598,
1351, 1317, 1288, 1225, 1175, 1148, 1121, 1091, 917, 817, 663 cm–1
1H NMR (300 MHz, CDCl3): δ (ppm) = 7.79–7.73 (m, 4H), 7.43–7.33
;
1410, 1340, 1283, 1207, 1156, 907, 819, 757, 659, 608 cm–1; 1H NMR (m, 5H), 6.20 (s, 1H), 6.03 (s, 1H), 5.56 (ddt, J = 16.9, 10.2, 6.6 Hz,
(300 MHz, CDCl3): δ (ppm) = 9.95 (bs, 1H), 7.72 (d, J = 8.3 Hz, 2H),
7.33 (d, J = 8.3 Hz, 2H), 6.72 (t, J = 16.9 Hz, 1H), 5.55 (ddt, J = 17.1,
10.3, 6.8 Hz, 1H), 5.19–5.10 (m, 2H), 4.18 (d, J = 1.3 Hz, 2H), 3.82 (d,
1H), 5.21–5.11 (m, 2H), 4.33 (s, 2H), 3.86 (d, J = 6.6 Hz, 2H), 2.45 (s,
3H); 13C NMR (75 MHz, CDCl3): δ (ppm) = 168.5, 155.0, 146.8, 144.3,
136.4,132.6, 131.8, 131.0, 130.2, 129.6, 129.0, 127.4, 120.7, 116.9,
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111.6, 51.1, 42.5, 21.7; HRMS (ESI): m/z calcd. for C22H22NO4S [M + isolated as a white solid (223 mg, 77 % yield). M.p. 164–166 °C; IR
H]+: 396.12641, found 396.12601.
(ATR) νmax = 3096, 1760, 1598, 1508, 1418, 1352, 1316, 1231, 1148,
1123, 944, 920, 883, 817, 664 cm–1 1H NMR (300 MHz, CDCl3): δ
;
(Z)-N-Allyl-4-methyl-N-((2-(4-methylbenzylidene)-5-oxo-2,5-di-
hydrofuran-3-yl)methyl)benzenesulfonamide (4b): Following the
general procedure, 4b was prepared from carboxylic acid 3a; 4b
was isolated as a white solid (186 mg, 65 % yield). M.p. 134–136 °C;
IR (ATR) νmax = 3094, 2921, 1759, 1652, 1599, 1513, 1419, 1318,
1148, 941, 883, 815, 665 cm–1; 1H NMR (300 MHz, CDCl3): δ (ppm) =
7.74 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz,
2H), 7.20 (d, J = 8.4Hz, 2H), 5.99 (s, 1H), 6.17 (s, 1H), 5.57 (ddt, J =
16.9, 10.2, 6.6 Hz, 1H), 5.21–5.10 (m, 2H), 4.33 (s, 2H), 3.86 (d, J =
6.2 Hz, 2H), 2.46 (s, 3H), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
(ppm) = 168.7, 154.8, 146.3, 144.3, 140.1, 136.4, 131.8, 131.0, 130.2,
129.8, 129.7, 127.4, 120.7, 116.5, 111.8, 51.0, 42.5, 21.7, 21.6; HRMS
(ESI): m/z calcd. for C23H24NO4S [M + H]+: 410.14206, found
410.14175.
(ppm) = 7.78 (dd, J = 8.8, 5.5 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.35
(d, J = 8.4 Hz, 2H), 7.09 (t, J = 8.7 Hz, 2H), 6.21 (s, 1H), 6.02 (s, 1H),
5.56 (ddt, J = 16.9, 10.3, 6.6 Hz, 1H), 5.20–5.10 (m, 2H), 4.32 (s, 2H),
3.86 (d, J = 6.4 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
(ppm) = 168.4, 163.2 (d, JC-F = 252.0 Hz), 154.8, 146.5 (d, JC-F
=
2.9 Hz), 144.4, 136.3, 133.0 (d, JC-F = 8.3 Hz), 131.7, 130.2, 128.9 (d,
JC-F = 3.4 Hz), 127.3, 120.8, 116.9, 116.1 (d, JC-F = 21.8 Hz), 110.5,
51.0, 42.5, 21.7; 19F NMR (282 MHz, CDCl3): δ (ppm) = –109.8; HRMS
(ESI): m/z calcd. for C22H21FNO4S [M + H]+: 414.11698, found
414.11658.
(Z)-N-Allyl-N-((2-(4-(dimethylamino)benzylidene)-5-oxo-2,5-di-
hydrofuran-3-yl)methyl)-4-methylbenzenesulfonamide (4g): Fol-
lowing the general procedure, 4g was prepared from carboxylic
acid 3a; 4g was isolated as a white solid (150 mg, 49 % yield). M.p.
122–124 °C; IR (ATR) νmax = 3091, 2919, 1747, 1650, 1606, 1589,
1521, 1445, 1430, 1347, 1319, 1239, 1187, 1149, 1120, 1093, 1061,
(Z)-N-Allyl-N-((2-(4-ethylbenzylidene)-5-oxo-2,5-dihydrofuran-
3-yl)methyl)-4-methylbenzenesulfonamide (4c): Following the
general procedure, 4c was prepared from carboxylic acid 3a; 4c was
isolated as a white solid (201 mg, 69 % yield). M.p. 138–140 °C; IR
(ATR) νmax = 3092, 3051, 2972, 3937, 1756, 1651, 1610, 1600, 1427,
1007, 921, 908, 876, 810, 777, 662, 628 cm–1 1H NMR (300 MHz,
;
CDCl3): δ (ppm) = 7.74 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H),
7.34 (d, J = 8.3 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 6.13 (s, 1H), 5.83 (s,
1H), 5.58 (ddt, J = 16.9, 10.3, 6.8 Hz, 1H), 5.19–5.10 (m, 2H), 4.32 (s,
2H), 3.85 (d, J = 6.8 Hz, 2H), 3.04 (s, 6H), 2.45 (s, 3H); 13C NMR
(75 MHz, CDCl3): δ (ppm) = 168.4, 155.0, 146.8, 144.3, 136.2, 132.5,
131.7, 130.9, 130.1, 129.5, 128.9, 127.3, 120.7, 116.8, 111.5, 53.5, 51.0,
42.5, 21.6; HRMS (ESI): m/zc alcd for C24H27N2O4S [M + H]+:
439.16860, found 439.16825.
1316, 1149, 938, 884, 813, 664 cm–1 1H NMR (300 MHz, CDCl3): δ
;
(ppm) = 7.74 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.35 (d, J =
8.3 Hz, 2H), 7.22 (d, J = 8.4Hz, 2H), 6.17 (s, 1H), 5.99 (s, 1H), 5.57
(ddt, J = 16.9, 10.1, 6.8 Hz, 1H), 5.21–5.10 (m, 2H), 4.32 (s, 2H), 3.86
(d, J = 6.6 Hz, 2H), 2.67 (q, J = 8.4 Hz, 2H), 2.46 (s, 3H), 1.24 (t, J =
8.4 Hz, 3H); 13C NMR (75 MHz, CDCl3):δ (ppm) = 168.7, 154.9, 146.3
(2 Cq), 144.3, 136.4, 131.8, 131.1, 130.2, 130.1, 128.5, 127.3, 120.7,
116.4, 111.8, 51.0, 42.5,28.9,21.7, 15.4; HRMS (ESI): m/z calcd. for
C24H26NO4S [M + H]+: 424.15771, found 424.15728.
(Z)-N-Allyl-N-((2-(2-fluorobenzylidene)-5-oxo-2,5-dihydrofuran-
3-yl)methyl)-4-methylbenzenesulfonamide (4h): Following the
general procedure, 4h was prepared from carboxylic acid 3a; 4h
was isolated as a white solid (229 mg, 79 % yield). M.p. 180–182 °C;
IR (ATR) νmax = 3095, 2924, 1769, 1758, 1654, 1599, 1487, 1452,
1419, 1351, 1318, 1175, 1148, 1121, 1090, 1011, 935, 919, 815, 776,
(Z)-N-Allyl-N-((2-(4-methoxybenzylidene)-5-oxo-2,5-dihydro-
furan-3-yl)methyl)-4-methylbenzenesulfonamide (4d): Following
the general procedure, 4d was prepared from carboxylic acid 3a;
4d was isolated as a white solid (208 mg, 70 % yield). M.p. 140–
142 °C; IR (ATR) νmax = 3091, 2971, 2936, 2254, 1754, 1648, 1600,
1512, 1442, 1427, 1344, 1303, 1253, 1152, 1090, 932, 906, 823, 813,
1
763, 664, 638 cm–1; H NMR (300 MHz, CDCl3): δ (ppm) = 8.20 (td,
J = 7.8, 1.6 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H),
7.31–7.28 (m, 1H), 7.19 (td, J = 7.5, 4.0 Hz), 1H), 7.11–7.04 (m, 1H),
6.37 (s, 1H), 6.13 (s, 1H), 5.60 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.20–
5.13 (m, 2H), 4.31 (d, J = 1.3 Hz, 2H), 3.87 (d, J = 6.6 Hz, 2H), 2.45
1
731, 662 cm–1; H NMR (300 MHz, CDCl3): δ (ppm) = 7.75–7.72 (m,
4H), 7.34 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.17 (s, 1H),
5.95 (s, 1H), 5.57 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.21–5.10 (m, 2H),
4.32 (s, 2H), 3.86 (d, J = 6.4 Hz, 2H), 3.85 (s, 3H), 2.45 (s, 3H); 13C
NMR (75 MHz, CDCl3): δ (ppm) = 168.8, 160.6, 154.8, 145.2, 144.2,
136.2, 132.6, 131.6, 130.1, 127.2, 125.3, 120.5, 115.6, 114.4, 111.5,
55.3, 50.9, 42.5, 21.5; HRMS (ESI): m/z calcd. for C23H24NO5S [M +
H]+: 426.13697, found 426.13635.
(s, 3H); 13C NMR (75 MHz, CDCl3): δ (ppm) = 168.3, 160.9 (d, JC-F
=
252.7 Hz), 155.6, 147.8, 144.3, 136.3, 131.8, 131.8 (d, JC-F = 1.6 Hz),
131.1 (d, JC-F = 8.3 Hz), 130.2, 127.4, 124.4 (d, JC-F = 3.6 Hz), 120.9,
120.7 (d, JC-F = 12.1 Hz), 117.3, 115.4 (d, JC-F = 22.0 Hz), 102.0 (d,
J
C-F = 7.8 Hz), 51.4, 42.6, 21.7; 19F NMR (282 MHz, CDCl3): δ (ppm) =
–116.0; HRMS (ESI): m/z calcd. for C22H21FNO4S [M + H]+: 414.11698,
found 414.11571.
(Z)-N-Allyl-N-((2-(4-(tert-butyl)benzylidene)-5-oxo-2,5-dihydro-
furan-3-yl)methyl)-4-methylbenzenesulfonamide (4e): Following
the general procedure, 4e was prepared from carboxylic acid 3a;
4e was isolated as a white solid (174 mg, 54 % yield). M.p. 155–
157 °C; IR (ATR) νmax = 3095, 3025, 2960, 2868, 1754, 1656, 1598,
(Z)-N-Allyl-N-((2-(2,4-difluorobenzylidene)-5-oxo-2,5-dihydro-
furan-3-yl)methyl)-4-methylbenzenesulfonamide (4i): Following
the general procedure, 4i was prepared from carboxylic acid 3a; 4i
was isolated as a white solid (247 mg, 82 % yield). M.p. 210–212 °C;
IR (ATR) νmax = 3098, 1766, 1645, 1601, 1499, 1435, 1418, 1337,
1275, 1215, 1157, 1142, 1091, 1013, 927, 866, 849, 812, 766, 658,
1418, 1349, 1323, 1297, 1150, 1126, 1093, 935, 922, 812, 661 cm–1
;
1H NMR (300 MHz, CDCl3): δ (ppm) = 7.74 (d, J = 8.4 Hz, 2H), 7.71
(d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H),
6.17 (s, 1H), 5.99 (s, 1H), 5.57 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.20–
5.10 (m, 2H), 4.33 (s, 2H), 3.86 (d, J = 6.6 Hz, 2H), 2.46 (s, 3H), 1.33
(s, 9H); 13C NMR (75 MHz, CDCl3): δ (ppm) = 168.7, 154.8, 153.2,
146.4, 144.3, 136.4, 131.8, 130.9, 130.2, 129.8, 127.4, 126.0, 120.7,
116.5, 111.6, 51.0, 42.5, 35.0, 31.2, 21.7; HRMS (ESI): m/z calcd. for
C26H30NO4S [M + H]+: 452.18901, found 452.18865.
647 cm–1 1H NMR (300 MHz, CDCl3): δ (ppm) = 8.22 (td, J = 8.9,
;
6.6 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4Hz, 2H), 6.98–
6.95 (m, 1H), 6.88–6.81 (m, 1H), 6.32 (s, 1H), 6.13 (s, 1H), 5.59 (ddt,
J = 16.9, 10.1, 6.8 Hz, 1H), 5.21–5.12 (m, 2H), 4.30 (d, J = 1.9 Hz, 2H),
3.86 (d, J = 6.8 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
(ppm) = 168.1, 163.4 (dd, JC-F = 254.3, 12.5 Hz), 161.1 (dd, JC-F
255.6, 12.0 Hz), 155.5, 147.5 (t, JC-F = 2.6, 4.0 Hz), 144.4, 136.2, 132.9
(dd, JC-F = 9.6, 3.0 Hz), 131.8, 130.2, 127.4, 120.9, 117.3, 117.3 (dd,
=
(Z)-N-Allyl-N-((2-(4-fluorobenzylidene)-5-oxo-2,5-dihydrofuran-
3-yl)methyl)-4-methylbenzenesulfonamide (4f): Following the
general procedure, 4f was prepared from carboxylic acid 3a; 4f was
JC-F = 11.3, 4.0 Hz), 112.4 (dd, JC-F = 21.2, 3.5 Hz), 104.0 (t, JC-F
=
25.8 Hz), 101.1 (dd, JC-F = 7.2, 1.9 Hz), 51.4, 42.6, 21.7; 19F NMR
Eur. J. Org. Chem. 0000, 0–0
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7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(282 MHz, CDCl3): δ (ppm) = –105.9 (d, J = 8.7 Hz), –111.5 (d, J =
8.7 Hz); HRMS (ESI): m/z calcd. for C22H20F2NO4S [M + H]+:
432.10756, found 432.10654.
(Z)-N-Allyl-4-methyl-N-((5-oxo-2-pentylidene-2,5-dihydrofuran-
3-yl)methyl)benzene sulfonamide (4n): Following the general
procedure, 4n was prepared from carboxylic acid 3a; 4n was iso-
lated as a white solid (50 mg, 19 % yield). M.p. 93–95 °C; IR (ATR)
νmax = 3072, 2771, 1756, 1648, 1612, 1573, 1495, 1453, 1433, 1515,
(Z)-N-Allyl-N-((2-(2-methoxybenzylidene)-5-oxo-2,5-dihydro-
furan-3-yl)methyl)-4-methylbenzenesulfonamide (4j): Following
the general procedure, 4j was prepared from carboxylic acid 3a; 4j
was isolated as a white solid (200 mg, 67 % yield). M.p. 160–162 °C;
IR (ATR) νmax = 3110, 3095, 3064, 2927, 2842, 1759, 1742, 1646,
1597, 1588, 1485, 1416, 1318, 1310, 1291, 1247, 1148, 1121, 1092,
1355, 1225, 1198, 1164, 1158, 1091, 1084, 938, 841, 615 cm–1 1H
;
NMR (300 MHz, CDCl3): δ (ppm) = 7.70 (d, J = 8.5 Hz, 2H), 7.33 (d,
J = 8.5 Hz, 2H), 5.94 (s, 1H), 5.53 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H),
5.42 (t, J = 7.8 Hz, 1H), 5.16–5.07 (m, 2H), 4.20 (d, J = 1.2 Hz, 2H),
3.80 (d, J = 6.7 Hz, 2H), 2.44 (s, 3H),2.36 (d, J = 7.3 Hz, 2H), 1.46–
1.30 (m, 4H), 0.90 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ
(ppm) = 168.6, 153.5, 148.2, 144.3, 136.3, 131.8, 130.1, 127.3, 120.6,
117.5, 115.3, 50.9, 42.4, 31.1, 26.1, 22.5, 21.7, 13.9, HRMS (ESI): m/z
calcd. for C20H26NO4S [M + H]+: 376.15771, found 376.15527.
1
935, 871, 811, 657, 605 cm–1; H NMR (300 MHz, CDCl3): δ (ppm) =
8.16 (dd, J = 7.9, 1.6 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.36–7.28 (m,
3H), 7.00 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.64 (s, 1H),
5.99–5.97 (m, 1H), 5.62 (ddt, J = 16.9, 10.3, 6.6 Hz, 1H), 5.21–5.12
(m, 2H), 4.36 (d, J = 1.6 Hz, 2H), 3.88 (s, 3H), 3.87 (d, J = 6.8 Hz, 2H),
2.45(s, 3H); 13C NMR (75 MHz, CDCl3): δ (ppm) = 168.8, 157.6, 155.7,
(Z)-N-Allyl-N-((2-(cyclohexylmethylene)-5-oxo-2,5-dihydro-
146.5, 144.1, 136.3, 131.8, 131.7, 130.9, 130.0, 127.2, 121.4, 121.0, furan-3-yl)methyl)-4-methyl benzenesulfonamide (4o): Follow-
120.6, 115.9, 110.6, 105.0, 55.6, 51.1, 42.5, 21.6; HRMS (ESI): m/z ing the general procedure, 4o was prepared from carboxylic acid
calcd. for C23H24NO5S [M + H]+: 426.13697, found 426.13549.
3a; 4o was isolated as a white solid (48 mg, 17 % yield). M.p. 103–
105 °C; IR (ATR) νmax = 3095, 3072, 2973, 2950, 2851, 1793, 1662,
1626, 1610, 1415, 1348, 1278, 1193, 1169, 1096, 1094, 988, 862,
(Z)-N-((2-Benzylidene-5-oxo-2,5-dihydrofuran-3-yl)methyl)-N-
butyl-4-methylbenzene sulfonamide (4k): Following the general
procedure, 4k was prepared from carboxylic acid 3b; 4k was iso-
lated as a white solid (207 mg, 72 % yield). M.p. 128–130 °C; IR (ATR)
νmax = 3092, 3052, 2953, 2930, 2871, 1766, 1658, 1602, 1574, 1493,
1452, 1423, 1315, 1223, 1199, 1148, 1091, 1054, 930, 814, 757, 687,
626 cm–1 1H NMR (300 MHz,CDCl3): δ (ppm) = 7.70 (d, J = 8.3Hz,
;
2H), 7.32 (d, J = 8.3 Hz, 2H), 5.94 (s, 1H), 5.23 (d, J = 9.7Hz, 1H), 5.54
(ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.17–5.06 (m, 2H), 4.18 (d, J = 1.1Hz,
2H), 3.76 (d, J = 7.0 Hz, 2H), 2.74–2.61 (m, 1H), 2.44 (s, 3H), 1.74–
1.63 (m, 4H), 1.37–1.08 (m, 6H); 13C NMR (75 MHz, CDCl3): δ (ppm) =
170.3, 162.9, 154.7, 144.1, 136.7, 131.6, 127.3, 120.6, 110.6, 100.7,
51.0, 49.4, 42.4, 30.5, 25.9, 25.8, 21.7; HRMS (ESI): m/z calcd. for
C22H28NO4S [M + H]+: 402.17336, found 402.17065.
649, 606 cm–1 1H NMR (300 MHz, CDCl3): δ (ppm) = 7.78 (d, J =
;
7.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.43–7.33 (m, 5H), 6.20 (s, 1H),
6.04 (s, 1H), 4.20 (s, 2H), 3.18 (t, J = 7.3 Hz, 2H), 2.45 (s, 3H), 1.46
(quint, J = 7.3 Hz, 2H), 1.25 (sext, J = 7.3 Hz, 2H), 0.85 (t, J = 7.3 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ (ppm) = 168.5, 155.5,146.8,144.2,
N-Allyl-N-((6-isopentyl-2-oxo-2H-pyran-4-yl)methyl)-4-methyl-
136.1, 132.6, 131.0, 130.1, 129.6, 129.0, 127.3, 116.7, 111.6, 49.1, 44.2, benzenesulfonamide (5a): Following the general procedure, 5a
30.5, 21.7, 20.0, 13.7; HRMS (ESI): m/z calcd. for C23H26NO4S [M +
was prepared from carboxylic acid 3a; 5a was isolated as a white
solid (134 mg, 49 % yield). M.p. 187–189 °C; IR (ATR) νmax = 2958,
2872, 1775, 1709, 1647, 1338, 1305, 1184, 1152, 1090, 813, 731,
H]+: 412.15771, found 412.15652.
(Z)-N-Allyl-4-methyl-N-((5-oxo-2-(4-(trifluoromethyl)benzyl-
idene)-2,5-dihydrofuran-3-yl)methyl)benzenesulfonamide (4l):
Following the general procedure, 4l was prepared from carboxylic
acid 3a; 4l was isolated as a white solid (214 mg, 66 % yield). M.p.
210–212 °C; IR (ATR) νmax = 3103, 2867, 1916, 1773, 1652, 1616,
1
663 cm–1; H NMR (300 MHz, CDCl3): δ (ppm) = 7.70 (d, J = 8.4 Hz,
2H), 7.33 (d, J = 8.4 Hz, 2H), 6.04 (s, 1H), 5.93 (s, 1H), 5.45 (ddt, J =
16.9, 10.3, 6.6 Hz, 1H), 5.13–5.04 (m, 2H), 4.03 (s, 2H), 3.76 (d, J =
6.6 Hz, 2H), 2.46 (t, J = 8.1 Hz, 2H), 2.44 (s, 3H), 1.63–1.48 (m, 3H),
0.92 (d, J = 6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ (ppm) = 166.7,
162.8, 154.7,144.1, 136.5, 131.5, 130.1, 127.2, 120.6, 110.4, 102.5,
51.0, 49.3, 35.9, 32.0, 27.8, 22.3, 21.6; HRMS (ESI): m/z calcd. for
1607, 1418, 1320, 1155, 1111, 1065, 928, 884, 830, 663 cm–1 1H
;
NMR (300 MHz, CDCl3): δ (ppm) = 7.87 (d, J = 8.4 Hz, 2H), 7.74 (d,
J = 8.3 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 6.27
(s, 1H), 6.11 (s, 1H), 5.56 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.20–5.12
(m, 2H), 4.33 (s, 2H), 3.86 (d,J = 6.5 Hz, 2H), 2.46 (s, 3H); 13C NMR
(75 MHz, CDCl3): δ (ppm) = 168.0, 154.9, 148.2, 144.5, 136.2, 136.0,
C
21H28INO4S [M + H]+: 390.17336, found 390.17281.
N-Allyl-N-((6-(3-chloropropyl)-2-oxo-2H-pyran-4-yl)methyl)-4-
methylbenzene sulfonamide (5b): Following the general proce-
dure, 5b was prepared from carboxylic acid 3a; 5b was isolated as
131.7, 131.0, 130.6 (q, JC-F = 33.6 Hz), 130.3, 127.4, 125.8 (q, JC-F
=
3.7 Hz), 124.0 (q, JC-F = 273.0 Hz), 120.9, 118.1, 109.7, 51.2, 42.6,
a white solid (144 mg, 52 % yield). M.p. 204–206 °C; IR (ATR) νmax
=
21.7; 19F NMR (282 MHz, CDCl3): δ (ppm) = –62.8; HRMS (ESI): m/z 3162, 2782, 1766, 1719, 1657, 1583, 1475, 1462, 1444, 1375, 1275,
calcd. for C23H21F3NO4S [M + H]+: 464.11379, found 464.11350.
1189, 1154, 1148, 1083, 1074, 939, 851, 715, 616 cm–1 1H NMR
;
(300 MHz, CDCl3): δ (ppm) = 7.71 (d, J = 8.3 Hz, 2H), 7.34 (d, J =
8.3 Hz, 2H), 6.10 (s, 1H), 5.99 (s, 1H), 5.48 (ddt, J = 16.8, 10.2, 6.9 Hz,
1H), 5.15–5.06 (m, 2H), 4.04 (s, 2H), 3.78 (d, J = 6.9 Hz, 2H), 3.57 (t,
J = 6.9 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 2.45 (s, 3H), 2.18–2.09 (m,
2H); 13C NMR (75 MHz, CDCl3): δ (ppm) = 164.2, 162.5, 154.7,144.1,
136.3, 131.5, 130.1, 127.2, 120.6, 110.9, 103.3, 51.1, 49.2, 43.7, 31.0,
29.5, 21.6; HRMS (ESI): m/z calcd. for C19H23ClNO4S [M + H]+:
396.10308, found 396.10293.
(Z)-N-Butyl-N-((2-(4-methoxybenzylidene)-5-oxo-2,5-dihydro-
furan-3-yl)methyl)-4-methylbenzenesulfonamide (4m): Follow-
ing the general procedure, 4m was prepared from carboxylic acid
3b; 4m was isolated as a white solid (192 mg, 67 % yield). M.p. 131–
133 °C; IR (ATR) νmax = 3145, 2991, 2362, 1784, 1678, 1620, 1561,
1452, 1477, 1335, 1243, 1199, 1137, 1091, 1022, 850, 824, 767, 639,
1
612 cm–1; H NMR (300 MHz, CDCl3): δ (ppm) = 7.76–7.71 (m, 4H),
7.33 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.17 (s, 1H), 5.96 (s,
1H), 4.31 (s, 2H), 3.86 (d, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.17 (t, J =
N-Allyl-N-((6-butyl-2-oxo-2H-pyran-4-yl)methyl)-4-methyl-
7.3 Hz, 2H), 2.44 (s, 3H), 1.45 (quint, J = 7.3 Hz, 2H), 1.25 (sext, J = benzenesulfonamide (5c): Following the general procedure, 5c
7.3 Hz, 2H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ
(ppm) = 168.8, 160.6, 155.3, 145.4, 144.1, 136.2, 132.8, 130.1, 127.3,
125.4, 115.6, 114.5, 111.7, 55.5, 49.0, 44.1, 30.5, 21.7, 20.0, 13.7;
HRMS (ESI): m/z calcd. for C25H28NO5S [M + H]+: 442.16107, found
442.16285.
was prepared from carboxylic acid 3a; 5c was isolated as a white
solid (158 mg, 60 % yield). M.p. 177–179 °C; IR (ATR) νmax = 3172,
2781, 1776, 1719, 1657, 1583, 1485, 1463, 1443, 1365, 1285, 1179,
1
1144, 1128, 1071, 1053, 928, 831, 715, 627cm–1; H NMR (300 MHz,
CDCl3): δ (ppm) = 7.65 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H),
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5.98 (s, 1H), 5.93 (s, 1H), 5.42 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.07–
5.00 (m, 2H), 3.99 (s, 2H), 3.72 (d, J = 7.4 Hz, 2H), 2.39 (s, 3H), 2.41
(t, J = 8.4 Hz, 2H), 1.56 (quint, J = 7.4 Hz, 2H), 1.30 (sext, J = 7.4 Hz,
2H), 0.87 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ (ppm) =
166.2, 162.7, 154.7, 143.9, 136.2, 131.4, 129.9, 127.0, 120.4, 110.2,
102.5, 50.9, 49.2, 33.4, 28.8, 22.0, 21.4, 13.6; HRMS (ESI): m/z calcd.
for C20H26NO4S [M + H]+: 376.15771, found 376.15511.
N-Allyl-N-((6-cyclohexyl-2-oxo-2H-pyran-4-yl)methyl)-4-methyl-
benzenesulfonamide (5d): Following the general procedure, 5d
was prepared from carboxylic acid 3a; 5d was isolated as a white
solid (152 mg, 54 % yield). M.p. 134–136 °C; IR (ATR) νmax = 3142,
2884, 1765, 1739, 1667, 1543, 1496, 1432, 1423, 1305, 1280, 1167,
1142, 1108, 1090, 1021, 958, 811, 805, 716, 634 cm–1 1H NMR
;
(300 MHz, CDCl3): δ (ppm) = 7.70 (d, J = 8.4 Hz, 2H), 7.32 (d, J =
8.3 Hz, 2H), 5.98 (bs, 1H), 5.93 (bs, 1H), 5.47 (ddt, J = 16.8, 10.1,
6.9 Hz, 1H), 5.13–5.04 (m, 2H), 4.03 (s, 2H), 3.77 (d, J = 6.9 Hz, 2H),
2.43 (s, 3H), 2.39–2.32 (m, 1H), 1.93–1.69 (m, 6H), 1.39–1.28 (m, 4H);
13C NMR (75 MHz, CDCl3): δ (ppm) = 168.6, 153.5, 148.2, 144.3,
136.3, 131.8, 130.1, 127.3, 120.6, 117.5, 115.3, 50.9, 42.4, 31.1, 26.1,
22.5, 21.7, 13.9, HRMS (ESI): m/z calcd. for C22H28NO4S [M + H]+:
402.17336, found 402.17073.
[8]
[9]
Acknowledgments
We acknowledge Dr. Frédéric Montigny (Analysis Department,
Tours University) for HRMS and Michel Giorgi (Spectropole of
Marseille) for all the performed RX analysis.
[10]
[11]
Keywords: Cyclization · Density functional calculations ·
Lactones · Regioselectivity · Synthetic methods
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Received: July 26, 2019
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Full Paper
Intramolecular Oxacyclization
A. Mayooufi, J. Jacquemin, J. Petrignet,
J. Thibonnet* .................................... 1–10
Tandem One-Pot Approach to N-
Substituted Lactones by Carbon–
Carbon Coupling Followed by 5-exo-
dig or 6-endo-dig Cyclization: DFT
Studies and Cyclization Mode
Five or six-membered unsaturated intramolecular oxacyclization, accord-
lactones bearing an amino group can ing to the nature of the alkynes sub-
be synthesized in one-pot reaction. stituent. Furthermore, DFT calculations
This tandem process involves a Sono- were performed to analyze the origin
gashira-like cross-coupling reaction of this regioselectivity of cyclization.
followed by 5-exo-dig or 6-endo-dig
DOI: 10.1002/ejoc.201901099
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