Regio- and diastereoselective synthesis of trans-dihydrofuran-3carboxamides by radical addition of 1,3-dicarbonyl compounds to acrylamides using manganese(III) acetate and determination of exact configuration by X-ray crystallography

Article abstract of DOI:10.24820/ark.5550190.p009.855

In this study, we investigated the radical addition of 1,3-dicarbonyl compounds to acrylamide derivatives including phenyl, 2-thienyl and 5-methyl-2-furyl groups mediated by manganese(III) acetate. trans-3-Carboxamide-dihydrofurans were obtained in modarate to good yields, as well as regio- and diastereoselectievly. Structural analyses of these compounds were made by NMR techniques such as HMBC and NOSY spectra. Also, exact configuration and structures of these (7b, 7i and 7j) compounds were determined by X-ray crystallography.

Full text of DOI:10.24820/ark.5550190.p009.855

General Papers
ARKIVOC 2016 (vi) 79-91
Regio- and diastereoselective synthesis of trans-dihydrofuran-3-
carboxamides by radical addition of 1,3-dicarbonyl compounds to
acrylamides using manganese(III) acetate and determination of
exact configuration by X-ray crystallography
Mehmet Yilmaz,a* Ash Ustalar,a Bedriye Uçan,b and A. Tarık Pekelb
1Department of Chemistry, Faculty of Arts and Sciences, Kocaeli University, 41380
Umuttepe,Kocaeli, Turkey
2Department of Chemistry, Faculty of Science, Ankara University, 06100 Tandogan, Ankara,
Turkey
E-mail: mehmet.yilmaz@kocaeli.edu.tr
DOI: https://doi.org/10.24820/ark.5550190.p009.855
Abstract
In this study, we investigated the radical addition of 1,3-dicarbonyl compounds to acrylamide
derivatives including phenyl, 2-thienyl and 5-methyl-2-furyl groups mediated by manganese(III)
acetate. trans-3-Carboxamide-dihydrofurans were obtained in modarate to good yields, as well
as regio- and diastereoselectievly. Structural analyses of these compounds were made by NMR
techniques such as HMBC and NOSY spectra. Also, exact configuration and structures of these
(7b, 7i and 7j) compounds were determined by X-ray crystallography.
Keywords: Manganese(III) acetate, radical addition, cyclization, dihydrofuran-carboxamide, X-
ray analysis, diastereoselective
Introduction
Substituted dihydrofurans constantly occur as subunits for many medicinally important
compounds and biologically active natural compounds, such as clerodin, aflatoxin B1,
rocoglamide, austocystin A and fercoprolone.1-3 On the other hand, the carboxamide group is an
important structural moiety in many biologically active compounds and in some drugs, such as
acridine carboxamide (topoisomerase inhibitor), nicotineamide, pyrazineamide (a drug for
tuberclosis), dacarbazine (antineoplastic), valpromide (a drug for epilepsy). It was reported that
some dihydrofurans including carboxamide,4 and carbonitrile5 show antifungal and antibacterial
activity. Thus, development of effective synthetic methods to prepare polysubstituted
dihydrofurans has been focused on this area.
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Manganese(III) acetate6-10 and cerium(IV) ammonium nitrate (CAN)11-14 are widely used for
C-C bond formation and synthesis of polyfunctional organic compounds. It is well known that
Mn(OAc)3 or CAN mediated radical reaction of 1,3-dicarbonyl compounds with alkenes produce
dihydrofuran derivatives. Mn(OAc)3, CAN or Ag(I)/Celite mediated radical reactions of 1,3-
dicarbonyl compounds with unsymmetrically alkenes such as (1-pyridin-2-yl)-enones,9
unsaturated ketones,15,16 cinnamates,7,14 and unsaturated ether,11, 17 have been reported. Our
research group has focused on the radical reaction of 1,3-dicarbonyls and 3-oxopropanenitriles
with unsaturated systems.18-27 We first reported the reaction of (E)-2-styrylthiophene and (E)-2-
20
methyl-5-styrylfuran with 3-oxopropanenitriles,18,
fluorinated-1,3-dicarbonyls21 and 1,3-
diketones22, 23 lead to formation of 2-thienyl and 2-furylsubstituted trans-dihydrofurans (1 and 2).
Although there are two possible different cyclization routes with these reactions, we reported
that, this cyclization occurs only at the C-1 carbon (adjacent to thienyl or furyl groups)
regioselectively (Figure 1).18, 20
Figure 1
Previously, we obtained cis- and trans-diastereomer mixtures of dihydrofurans (3) from the
reaction of (E,E)-5-phenyl-2,4-pentandienamide with 3-oxopropanenitrile. We clearly reported
that coupling constants of the H2 and H3 vicinal protons of this compounds are Jcis 9.6-10.3 Hz
27
and Jtrans 6.8-7.5 Hz, respectively.19,
Based on the coupling constants of the trans-
diastereomers, we decided that 2,3-dihydrofuran-3-carboxamides (4) obtained from the reaction
of 3-oxopropanenitriles with (2E)-3-(2-thienyl)acrylamide and (2E)-3-(5-methyl-2-
furyl)acrylamide are in trans configuration (Fig 1).19
Depending on the substituents attached to dihydrofuran ring, coupling constant of the vicinal
protons can show some inequality. Hence, if both cis- and trans-diastereomers do not form in the
reaction of unsymmetrical alkenes, coupling constants of the vicinal protons or NOSY (or NOE-
DIFF) spectra may not be inadequate to determine configuration of the dihydrofurans in all
cases. The most exact proof of structure and configuration of the compounds can only be
obtained from X-ray crystallography. Thus, in the present study, we reported the radical addition
of acrylamide derivatives with various 1,3-dicarbonyl compounds using Mn(OAc)3, lead to
trans-3-carboxamide-substituted dihydrofurans as regio- and diastereoselectively. Absolute
structure and configuration of these compounds were determined by X-ray analysis.
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Results and Discussion
(2E)-3-Phenylacrylamide
5a,
(2E)-3-(2-thienyl)acrylamide
5b,
(2E)-3-(5-methyl-2-
furyl)acrylamide 5c and (2E)-3-(3-thienyl)acrylamide 5d were prepared by the reaction of
suitable acyl chloride and NH3/NaOH as described in literature.28, 19
Table 1. The reaction of 1,3-dicarbonyls (6a-d) with (2E)-3-phenylacrylamide 5a.
Entry 1,3-dicarbonyl
acrylamide dihydrofuran
yieldA, (%)
1
7a, 68
2
3
4
7b, 55
7c, 50
7d, 41
AYield of isolated product based on the conjugated amides 5a.
Treatments of (2E)-3-phenylacrylamide 5a with dimedone 6a and 1,3-cyclohexandione 6b in
the presence of Mn(OAc)3 in HOAc in a 2:1:3 molar ratio (1,3-dicarbonyl : acrylamide :
Mn(OAc)3) at 70 °C gave 2-phenyl-3-carboxamide-dihydrobenzofurans 7a in 68% and 7b in
1
55% yields (Table 1). In the H NMR spectra of these compounds, the H-2 and H-3 (C8-H and
C7-H in the x-ray graphic for 7b, respectively) protons of the dihydrobenzofurans 7a and 7b
appeared as two doublets with a vicinal coupling constant of J 6.0 Hz. The H-2 protons (δ 6.14
and 6.27 ppm) resonate at low field due to inductive effect of neighbouring etheric oxygen atom.
Since the HMBC spectra of 7a shows that the H-2 proton correlates with the ortho-carbon of
phenyl resonates at 125.3 ppm, phenyl group attached to the C-2 carbon in the
dihydrobenzofuran ring. Also, we verified absolute configuration and the assignment of regio-
and diastereoselectivity through X-ray analysis of 7b (2R, 3R) in Figure 2.
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Treatments of ethyl 3-oxobutanoate 6c and 2,4-pentanedione 6d with 5a gave trans-2,3-
dihydrofurans 7c and 7d in moderate yields, respectively. Compounds 7c and 7d show only two
doublets for two protons at C2- and C3-position with the coupling constants of 5.2 and 4.8 Hz,
which obviously indicated that these 2,3-dihydrofurans are in trans-configuration.
Figure 2. Molecular structure of the compound 7b.
It has been reported that the vicinal coupling constants of two methine protons in cis-
dihydrofuran are Jcis 8-11 Hz, while in trans-dihydrofurans vicinal coupling constants are Jtrans
2.5-7.5 Hz.18-27, 29, 30 Based on this information, the previously assigned cis-stereomer should
likely be the trans-stereomer for the dihydrofurans obtained from the Mn(OAc)3 mediated
radical reactions of 1,3-dicarbonyl compounds with chalcones,15 2-styrylthiophene10 and from
the radical reactions of 1,3-dicarbonyls with cinnamates,14 unsaturated ketones16 promoted by
CAN as these dihydrofurans had vicinal coupling constants of 5.8-7.2 Hz.
As seen in the Table 2, radical addition of dimedone 6a to 5b afforded trans-3-(2-thienyl)-
1
2,3-dihydrobenzofuran-3-carboxamide 7e which was characterized by H NMR, 13C NMR,
1
NOSY and HMBC spectra. In the H NMR spectrum of 7e, vicinal coupling constants of H-2
and H-3 are Jtrans 5.6 Hz. In the HMBC spectrum, H-3 proton resonated at 4.1 ppm correlates
with the thiophene carbon resonated at 142.5 ppm. These results show that 2-thienyl attached to
the C-2. Moreover, similar results were obtained by the radical reaction of 1,3-dicarbonyls 6b-d
with 5b forming trans-3-(2-thienyl)-dihydrofuran-3-carboxamides 7f-h with vicinal coupling
constants of 5.2 - 4.2 Hz appearing in corresponding 1H NMR spectra (Table 2, Entries 2-4). On
the other hand, trans-3-(5-methyl-2-furyl)dihydrobenzofuran-3-carboxamide 7i was obtained by
the treatment of dimedone 6a with (2E)-3-(5-methyl-2-furyl)acrylamide 5c in 80% yield.
Reaction of 6c and 6d with 5c afforded trans-2,3-dihydrofuran-3-carboxamides 7j (67%) and 7k
(70%) in good yields (Table 2, Entries 6 and 7). Also, the radical reaction of (2E)-3-(3-
thienyl)acrylamide 5d with 6a gave corresponding compound 7l in 36% yield. All dihydrofurans
were obtained in moderate to good yields.
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Related unsaturated amides used in radical reactions regained with column chromatography
from each crude products in 15-25 % yields. To accurately understand if there are any possible
compounds (especially cis- isomers) formed in this type of radical addition reactions , the crude
products from experiments 7a and 7e were analysed with LC-MS (without purification). The
results from these analyses showed that there are no isomers with same masses formed beside the
trans- products.
Table 2. Radical reaction of 1,3-dicarbonyl compounds 7a-d with 2c and 2d
entry 1,3-dicarbonyl acrylamide
dihydrofuran
yieldA (%)
1
7e, 55
2
3
7f, 54
7g, 46
4
5
7h, 52
7i, 80
6
7
7j, 67
7k, 70
8
7l, 36
A: Yield of isolated product based on the conjugated amides 5b and 5c. Moreover, structural
assignment of compounds 7i (2S, 3S) and 7j (2R, 3R) were further characterized by x-ray single
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crystal analysis (Figs 3 and 4), as a result of this, we can conclude that these vicinal protons are
definitely in trans-configuration.
Figure 3. Molecular structure of the compound 7i.
Figure 4. Molecular structure of the compound 7j. Displacement ellipsoids are drawn at the 50
% probability level. H-atoms are shown as small spheres of arbitrary radii.
The proposed mechanism for the formation of dihydrofuran-carboxamides is illustrated in
scheme 1. According to the mechanism, whilst Mn+3 reduces to Mn+2, a carbon radical forms on
the 1,3-dicarbonyl. The intermediate product A can be added to acrylamides with two ways. An
adduct intermediate B forms with pathway-i then structure B is oxidized to carbocation C with
Mn(OAc)3 and then enolizes to intermediate E. Dihydrofuran G is formed by intramolecular
cyclization of F. Dihydrofuran I which occurred by the cyclization of the other adduct
intermediate H obtained by pathway-ii. However, dihydrofuran I was not isolated, only
dihydrofurans G were obtained as sole products. The reason behind regioselective addition is
that intermediate B is being more stable than intermediate H. Also, diastereoselectivity can be
explained by intramolecular cyclization in structure F preferring trans-isomer which has less
steric hindrance and more thermodynamically stable.
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Scheme 1. Proposed
mechanism for the formation of trans-dihydrofuran-carboxamides.
Conclusions
We obtained 3-carboxamide-dihydrofurans in good yields as diastereoselectively by the
manganese(III) acetate mediated reaction of acrylamide derivatives and 1,3-dicarbonyl
compounds. It is seen that coupling constants of vicinal protons of the dihydrofurans in this work
are 1-1.5 Hz less than that of 3-cyano-carboxamides. These results show that the substituents
attached on the C=C double bond in the dihydrofuran rings significantly effect on the coupling
constants of vicinal protons. Our studies based on the X-ray analyses continue to determine
substituent effects on the coupling constant of vicinal protons and definite configurations of
some dihydofurans whose structure is open to debate.
Experimental Section
General. Melting points were determined on an electrothermal capillary melting point apparatus.
IR spectra (ATR) were obtained with a Bruker Tensor-27 400-4000 cm-1 range with 2 cm-1
1
resolution. H NMR, 13C NMR, HMBC, NOSY, spectra were recorded on a Bruker Avance
DPX-400 MHz and Varian Mercury-400 High performance Digital FT-NMR
spectrophotometers. High Resolution Mass Time-of-Flight spectra (TOF) were measured on a
Agilent 1200/6210 LC/MS spectrophotometer. Unit cell measurements and intensity data
collection was performed on an Bruker APEX II QUAZAR three-circle diffractometer using
monochromatized Mo Kα microfocus sealed-tube (λ = 0.71073 Å) using φ and ω technique at
120 K. Thin layer chromatography (TLC) was performed on Merck aluminum-packed silica gel
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plates. Purification of the products was performed by column chromatography on silica gel
(Merck silica gel 60, 40-63 mm) or preparative TLC on silica gel of Merck (PF254-366nm).
General procedure for dihydrofuran-carboxamides (7). A solution of manganese(III) acetate
dihydrate (3 mmol, 0.804 g) in 10 mL of glacial acetic acid was heated on oil bath under a
nitrogen atmosphere at 80 °C until it dissolved. After Mn(OAc)3 dissolved completely, the
solution was cooled down to 60 °C. A solution of 1,3-dicarbonyl compound (2 mmol) and
acrylamide (1 mmol) in 5 mL of acetic acid was added to this mixture and the temperature was
raised to 70 °C. The reaction was complete when the dark brown color of the solution
disappeared (monitoring by TLC). 30 mL water was added to the solution and extracted by
CHCl3 (3x20 mL). The combined organic extracts were neutralized with 10 mL of satd NaHCO3
solution, and dried over anhydrous Na2SO4 and evaporated. The crude products were purified by
column chromatography or preparative TLC (20x20 cm plates, 2 mm thickness) using n-
hexane/EtOAc (1:1) as eluent.
trans-6,6-Dimethyl-4-oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1-benzofuran-3-carboxamide
(7a). Colorless solid, yield 68%, 193 mg, mp 157-158 °C; IR (νmax, cm-1): 698, 761, 798, 1101,
1
1382, 1616 (C=C), 1683 (C=O), 2916, 2949, 3188, 3365; H NMR (400 MHz, CDCl3): δH 1.29
(6H, s, 2xMe), 2.43 (2H, s, H5), 2.71 (2H, s, H7), 3.97 (1H, d, JHH 6.0 Hz, H3), 6.14 (1H, d,
13
JHH 6.0 Hz, H2), 7.34 (1H, s, NH), 7.65-7.59 (5H, m, phenyl CH), 7.68 (1H, s, NH); C NMR
(100 MHz, CDCl3): δC 28.6 (Me), 28.8 (Me), 34.5, 38.3, 41.2, 53.2, 87.9 (C2), 110.3 (C3a),
126.1, 128.1 (2xCH), 129.3, 129.6, 140.8, 173.2 (C7a), 179.5 (C=O), 197.3 (C=O); HRMS
(ESI+): m/z (M+H)+ calcd for C17H20NO3: 286.14376; found: 286.14142.
trans-4-Oxo-2-phenyl-2,3,4,5,6,7-hexahydro-1-benzofuran-3-carboxamide (7b). Colorless
solid, yield 55%, 141 mg, mp 126-128 °C; IR (νmax, cm-1): 702, 754, 935, 1174, 1388, 1614
1
(C=C), 1647 (C=O), 1681 (C=O), 2939, 3186, 3381; H NMR (400 MHz, CDCl3): δH (400
MHz, CDCl3) 1.94 (2H, m, H6), 2.28 (2H, m, H5), 2.42 (2H, t, JHH 6.0 Hz, H7), 3.78 (1H, d,
JHH 6.0 Hz, H3), 5.34 (1H, s, NH), 6.27 (1H, d, JHH 6.0 Hz, H2), 7.21-7.08 (5H, m, phenyl
13
CH), 7.65 (1H, s, NH); C NMR (100 MHz, CDCl3): δC 21.4, 24.3, 36.6, 52.9 (3C), 97.1 (C2),
111.1 (C3a), 125.4 (2xCH), 128.6, 128.8 (2xCH), 139.9, 172.1 (C7a), 179.4 (C=O), 196.7(C=O);
HRMS (ESI+): m/z (M+Na)+ calcd for C15H15NO3Na: 280.09441; found: 280.09520.
trans-Ethyl 4-carbamoyl-2-methyl-5-phenyl-4,5-dihydrofuran-3-carboxylate (7c). Colorless
solid, yield 50%, 137 mg, mp 126-128 °C; IR (νmax, cm-1): 694, 748, 1095, 1263, 1649 (C=C),
1654 (C=O), 1701 (C=O), 2920, 2987, 3199, 3375; 1H NMR (400 MHz, CDCl3): δH 1.31 (3H, t,
3
5
JHH 7.2 Hz, -CH2CH3), 2.34 (3H, d, 5JHH 1.2 Hz, Me), 3.86 (1H, dq, JHH 5.2, JHH 1.2 Hz,
H4), 4.22 (2H, q, JHH 7.2 Hz, -OCH2CH3), 5.70 (1H, s, NH), 6.18 (1H, d, JHH 5.2 Hz, H5),
13
6.91 (1H, s, NH), 7.31-7.26 (2H, m), 7.39-7.33 (3H, m); C NMR (100 MHz, CDCl3): δC 14.3
(Me), 15.0 (Me), 56.0 (C4), 60.4170.2 (C2), 84.7 (C5), 101.3 (C3), 125.2 (2xCH), 128.4, 128.8
(2xCH), 140.4, 166.5 (C=O), 175.5 (C=O); HRMS (ESI+): m/z (M+Na)+ calcd for C15H17NO4Na:
298.10497; found: 298.10354.
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trans-4-Acetyl-5-methyl-2-phenyl-2,3-dihydrofuran-3-carboxamide (7d). Colorless solid,
yield 41%, 100 mg, mp 125-128 °C; IR (νmax, cm-1): 692, 748, 941, 1261, 1581 (C=C), 1660
(C=O), 1676 (C=O), 2848, 2914, 3186, 3348; 1H NMR (400 MHz, CDCl3): δH 2.53 (3H, s, Me),
2.56 (3H, s, Me), 4.15 (1H, d, JHH 4.81 Hz, H3), 5.80 (1H, s, NH), 6.38 (1H, d, JHH 4.83 Hz,
H2), 7.22 (1H, s, NH), 7.43 (2H, d, JHH 6.11 Hz, phenyl CH), 7.49 (3H, m, phenyl CH); 13C
NMR (100 MHz, CDCl3): δC 16.2 (Me), 29.3 (Me), 55.8 (3C), 84.4 (2C), 114.0 (4C), 125.2
(2xCH), 128.5 (2xCH), 128.8, 140.1, 169.9 (5C), 173.2 (C=O), 194.4 (C=O); HRMS (ESI+): m/z
(M+H)+ calcd for C14H16NO3: 246.11246; found: 246.11111.
trans-6,6-Dimethyl-4-oxo-2-(thiophen-2-yl)-2,3,4,5,6,7-hexahydro-1-benzofuran-3-
carboxamide (7e). Colorless solid, yield 55%, 160 mg, mp 153-155 °C; IR (νmax, cm-1): 613,
1
640, 713, 800, 1060, 1101, 1379, 1612 (C=C), 1685 (C=O), 2924, 2952, 3184, 3315; H NMR
(400 MHz, CDCl3): δH 1.14 (3H, s, Me), 1.15 (3H, s, Me), 2.34 (2H, s, H5), 2.40 (2H, d, JHH
2.0 Hz, H7), 4.11 (1H, d, JHH 5.60 Hz, H3), 5.39 (1H, s, NH), 6.68 (1H, d, JHH 5.60 Hz, H2),
6.99 (1H, dd, JHH 5.20, 3.60 Hz, thiophene CH), 7.11 (1H, d, JHH 3.2 Hz, thiophene CH), 7.30
13
(1H, d, JHH 4.8 Hz, thiophene CH), 7.75 (1H, s, NH); C NMR (100 MHz, CDCl3): δC 28.7
(2xMe), 34.6, 38.3, 51.2, 52.9 (C3), 83.9 (C2), 109.8 (C3a), 126.3, 126.6, 127.3, 142.5, 171.7
(C7a), 177.9 (C=O), 196.3 (C=O); HRMS (ESI+): m/z (M+Na)+ calcd for C15H17NO3SNa:
314.08213; found: 314.08170.
trans-4-Oxo-2-(thiophen-2-yl)-2,3,4,5,6,7-hexahydro-1-benzofuran-3-carboxamide
(7f).
Colorless solid, yield 54%, 142 mg, mp 100-103 °C; IR (νmax, cm-1): 705, 756, 837, 904, 1377,
1
1400, 1608 (C=C), 1670 (C=O), 1697 (C=O), 2902, 2947, 3192, 3315; H NMR (400 MHz,
CDCl3): δH 2.09 (2H, m, H6), 2.45 (2H, m, H5), 2.53 (2H, t, JHH 6.0 Hz, H7), 4.10 (1H, d, JHH
5.2 Hz, H3), 5.80 (1H, s, NH), 6.65 (1H, d, JHH 5.60 Hz, H2), 6.99 (1H, dd, JHH 4.8, 3.6 Hz,
thiophene CH), 7.11 (1H, d, JHH 3.2 Hz, thiophene CH), 7.31 (1H, dd, JHH 4.8, 1.2 Hz,
13
thiophene CH), 7.76 (1H, s, NH); C NMR (100 MHz, CDCl3): δC 21.6, 24.5, 36.7, 53.0 (C3),
83.6 (C2), 111.4 (C3a), 126.3, 126.6, 127.3, 142.3, 171.9 (C7a), 178.7 (C=O), 196.9 (C=O);
HRMS (ESI+): m/z (M+Na)+ calcd for C13H13NO3SNa: 286.05083; found: 286.05155.
trans-Ethyl 4-carbamoyl-2-methyl-5-(thiophen-2-yl)-4,5-dihydrofuran-3-carboxylate (7g).
Colorless solid, yield 46%, 129 mg, mp 82-86 °C; IR (νmax, cm-1): 696, 765, 975, 1095, 1201,
1
1649 (C=C), 1658 (C=O), 1701 (C=O), 2920, 2981, 3197, 3379; H NMR (400 MHz, CDCl3):
δH 1.36 (3H, t, JHH 7.12 Hz, Me), 2.30 (3H, d, JHH 1.20 Hz, Me), 4.04 (1H, dd, JHH 4.62, 1.24
Hz, H3), 4.27 (2H, q, JHH 7.13 Hz, -OCH2-),5.35 (1H, s, NH), 6.46 (1H, d, JHH 4.65 Hz, H2),
7.00 (1H, dd, JHH 5.03, 3.56 Hz, thiophene CH), 7.10 (1H, d, JHH 3.52 Hz, thiophene CH),
7.29 (1H, s, NH), 7.31 (1H, dd, JHH 5.07, 1.12 Hz, thiophene CH); 13C NMR (100 MHz,
CDCl3): δC 14.5 (Me), 15.4 (Me), 55.9, 60.8 (C4), 81.0 (C5), 101.7 (C3), 125.7, 126.1, 127.1,
143.0, 166.7 (C2), 169.7 (C=O), 172.9 (C=O); HRMS (ESI+): m/z (M+Na)+ calcd for
C13H15NO4SNa: 304.06139; found: 304.06149.
trans-4-Acetyl-5-methyl-2-(thiophen-2-yl)-2,3-dihydrofuran-3-carboxamide (7h). Yellow
oil, yield 52%, 130 mg; IR (νmax, cm-1): 704, 750, 935, 827, 1207, 1384, 1578 (C=C), 1670
(C=O), 2914, 3006, 3190, 3415; 1H NMR (400 MHz, CDCl3): δH 2.36 (3H, s, Me), 2.43 (3H, s,
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Me), 4.16 (1H, d, J HH 4.00 Hz, H3), 5.64 (1H, s, NH), 6.47 (1H, d, JHH 4.10 Hz, H2), 7.00
(1H, t, JHH 4.52 Hz, thiophene CH), 7.08 (1H, d, JHH 3.15 Hz, thiophene CH), 7.15 (1H, s,
NH), 7.30 (1H, d, J 5.09 Hz, thiophene CH); 13C NMR (100 MHz, CDCl3): δ C 16.5 (Me),
29.5 (Me), 55.7 (C3), 80.8 (C2), 114.0 (C4), 125.9, 126.2, 127.1, 142.5, 169.5 (C5), 172.9
(C=O), 194.6 (C=O); HRMS (ESI+): m/z (M+H)+ calcd for C12H14NO3S: 252.06889; found:
252.06908.
trans-6,6-Dimethyl-2-(5-methylfuran-2-yl)-4-oxo-2,3,4,5,6,7-hexahydro-1-benzofuran-3-
carboxamide (7i). Yellow solid, yield 80%, 231 mg, mp 143-145 °C; IR (νmax, cm-1): 621, 665,
781, 879, 1020, 1070, 1251, 1388, 1591 (C=C), 1614 (C=O), 1683 (C=O), 2920, 2964, 3175,
1
3383; H NMR (400 MHz, CDCl3): δH 1.11 (6H, s, Me), 2.26 (3H, s, Me), 2.32 (2H, d, JHH
1.60 Hz, H5), 2.35 (2H, d, JHH 1.20 Hz, H7), 4.25 (1H, d, JHH 6.0 Hz, H3), 5.53 (1H, s, NH),
5.94 (1H, dq, JHH 3.60, 0.40 Hz, furan CH), 6.34 (1H, d, JHH 3.2 Hz, furan CH), 6.35 (1H, d,
JHH 6.0 Hz, H2), 7.84 (1H, s, NH); 13C NMR (100 MHz, CDCl3): δC 13.9, 28.6, 28.8, 34.5,
38.3, 48.7, 51.1 (C3), 81.3 (C2), 106.9, 110.3, 111.0, 149.2, 154.1, 171.9 (C7a), 178.2 (C=O),
196.2 (C=O); HRMS (ESI+): m/z (M+H)+ calcd for C16H20NO4: 290.13868; found: 290.13923.
Ethyl
trans-3-carbamoyl-5,5'-dimethyl-2,3-dihydro-[2,2'-bifuran]-4-carboxylate
(7j).
Yellow solid, yield 67%, 186 mg, mp 133-135 °C; IR (νmax, cm-1): 653, 796, 962, 1124, 1217,
1
1319, 1381, 1635 (C=C), 1654 (C=O), 1678 (C=O), 2918, 2985, 3165, 3352; H NMR (400
MHz, CDCl3): δH 1.32 (3H, t, JHH 7.20 Hz, Me), 2.23 (3H, s, Me), 2.27 (3H, s, 5.84 (1H, s,
NH), Me), 4.14 (1H, d, JHH 5.60 Hz, H3´),4.23 (2H, q, JHH 7.20 Hz, –OCH2-),5.92 (1H, d,
JHH 3.20 Hz, furan CH), 6.08 (1H, d, JHH 5.60 Hz, H2´),6.28 (1H, d, JHH 3.20 Hz, furan CH),
13
6.95 (1H, s, NH); C NMR (100 MHz, CDCl3): δC 13.9 (Me), 14.6(Me), 15.3(Me), 52.1, 60.6,
78.6, 102.0, 106.7, 110.4, 149.8, 153.7, 166.8 (C=O), 169.8 (C5´), 173.3 (C=O); HRMS (ESI+):
m/z (M+Na)+ calcd for C14H17NO5Na: 302.09989; found: 302.10051.
trans-4-Acetyl-5,5'-dimethyl-2,3-dihydro-[2,2'-bifuran]-3-carboxamide (7k). Pale yellow
solid, yield 70%, 174 mg, mp 150-152 °C; IR (νmax, cm-1): 663, 796, 900, 943, 1213, 1392, 1595
1
(C=C), 1672 (C=O), 1681 (C=O), 2848, 2918, 3153, 3327; H NMR (400 MHz, CDCl3): δH
2.26 (3H, s, Me), 2.29 (3H, s, Me), 2.37 (3H, d, JHH 0.8 Hz, Me), 4.24 (1H, d, JHH 5.2 Hz,
H3´),5.70 (1H, s, NH), 5.91 (1H, dq, JHH 3.2, 0.8 Hz, furan CH), 6.11 (1H, d, JHH 5.2 Hz,
13
H2´),6.26 (1H, d, JHH 3.2 Hz, furan CH), 7.14 (1H, s, NH); C NMR (100 MHz, CDCl3): δC
13.9 (Me), 16.5 (Me), 29.6 (Me), 52.0, 78.4, 106.7, 110.5, 114.7, 149.6, 153.8, 169.9 (C5´),
173.1 (C=O), 194.5 (C=O); HRMS (ESI+): m/z (M+Na)+ calcd for C13H15NO4Na: 272.08932;
found: 272.08976.
trans-6,6-Dimethyl-4-oxo-2-(thiophen-3-yl)-2,3,4,5,6,7-hexahydrobenzofuran-3-
carboxamide (7l). Colorless solid, yield 36%, 104 mg, mp 148-150 °C; IR (νmax, cm-1): 700,
965, 1095, 1212, 1618 (C=C), 1675 (C=O), 1703 (C=O), 2920, 2983, 3194, 3362; 1H NMR (400
MHz, CDCl3): δH 1.14 (6H, s), 2.32 (2H, s), 2.42 (2H, s), 4.00 (1H, d, JHH 6.0 Hz, H3), 5.94
(1H, s, NH), 6.50 (1H, d, JHH 6.0 Hz, H2), 7.01 (1H, dd, JHH 4.8, 0.8 Hz, thiophene CH), 7.28
(1H, d, JHH 7.2 Hz, thiophene CH), 7.35 (1H, dd, JHH 5.2, 4.8 Hz, thiophene CH), 7.80 (1H, s,
NH); 13C NMR (100 MHz, CDCl3): δC 28.3, 28.6, 34.2, 38.1, 50.9, 51.8, 84.1, 109.6, 122.2,
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ARKIVOC 2016 (vi) 79-91
124.9, 127.3, 140.6, 171.9 (C=O), 178.1 (C7a), 196.0 (C=O); HRMS (ESI+): m/z (M+Na)+ calcd
for C15H17NO3SNa: 314.08213; found: 314.08881.
Acknowledgements
The authors are grateful to the Kocaeli University (BAP 2010/57 and 2012/28) Science Research
Foundations for financial support. Authors thank to Yunus Zorlu (GYTE) for X-ray
crystallography analyses. A. Ustalar thanks to TUBITAK for doctoral fellowship.
Supplementary Material
Copies of NMR spectra for all compounds, X-ray crystal data for compounds 7b, 7i and 7j
(CCDC nos. 997073, 997070 and 997071, respectively). Supplementary data and
crystallographic data associated with this article can be found in the online version, at
http://dx.doi.org/
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