Copper-catalyzed bis(methoxycarbonyl)carbene reactions of α,β-unsaturated carboxamides

Article abstract of DOI:10.1002/hlca.201000384

The [Cu(acac)₂]-catalyzed reactions of α,β- unsaturated carboxamides with dimethyl diazomalonate yielded dihydrofuran derivatives by a 1,5-electrocyclic reaction at C(β), and butadiene derivatives by carbene addition reaction at C(α) (Schemesa

Full text of DOI:10.1002/hlca.201000384

Helvetica Chimica Acta – Vol. 94 (2011)
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Copper-Catalyzed Bis(methoxycarbonyl)carbene Reactions of
a,b-Unsaturated Carboxamides
by GçkÅe Merey and Olcay AnaÅ*
Istanbul Technical University, Faculty of Science and Letters, Department of Chemistry, 34460 Maslak,
TR-Istanbul (phone: þ 90-212-2853229; fax: þ 90-212-2856386, e-mail: anac@itu.edu.tr)
The [Cu(acac)2]-catalyzed reactions of a,b-unsaturated carboxamides with dimethyl diazomalonate
yielded dihydrofuran derivatives by a 1,5-electrocyclic reaction at C(b), and butadiene derivatives by
carbene addition reaction at C(a) (Schemes 4 and 5; Table). Phenyl substituents at the N-atom of the
amides seem to be effective on the reaction pathways (Table).
Introduction. – Carbene transfer to appropriate substrates is a highly versatile tool
for the construction of carbon frameworks with increased functional and structural
complexity. The formal [2 þ 1], [4 þ 1], and [6 þ 1] annulations [1][2] of a,b,g,d-
unsaturated carbonyl compounds have been widely applied in the enantioselective
construction of rings such as oxiranes [3], cyclopropanes [4], dihydrofurans [5],
dioxoles [6], dihydrobenzoxepines [7], and other possible derivatives of them. These
ring-closure reactions lead to structures frequently occurring in biologically active
compounds [8] and extremely useful synthetic intermediates [9] since they can be
readily converted to highly functionalized derivatives.
We previously reported on [Cu(acac)2]-catalyzed reactions of dimethyl diazomal-
onate (¼dimethyl 2-diazopropanedioate; E2C¼N2) with aminoenones (acac ¼ pentane-
2,3-dionato). These reactions resulted in 1,5-cyclization and formal C(a)ꢀH insertion
products (see 2 and 3 in Scheme 1). In the case of anilino derivatives (R1 or R2 ¼ Ph),
products 4 dominated the reaction resulting from an unusual formal insertion to the
benzoyl moiety [10]. A probable mechanism for the formation of this novel 3-anilino-
naphthalen-1(4H)-one compounds 4 [10] might be realized by a ring-opening reaction
of the present benzoyl-substituted push-pull cyclopropane and participation of the
present phenyl ring by subsequent loss of two H-atoms. It was the first time that we
obtained a product with the loss of two H-atoms. Its final structure 4 was revealed by a
crystallographic analysis.
Scheme 1
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 94 (2011)
On the other hand, in a study with vinylidene- or benzylidene-containing ketones or
esters 5 [11], we found furofuran 7 and b-bis[methoxycarbonyl)methyl] derivatives 8 as
second-step products derived from dihydrofurans 6 (Scheme 2).
Scheme 2
In a recent investigation with 2-benzylidene-1,3-dicarbonyl compounds 9 [12], we
obtained dihydrobenzoxepine derivatives 11 by 1,7-electrocyclization and dihydrofuran
derivatives 10 by 1,5-electrocyclization in varying ratios (Scheme 3); other possible
reaction products were not observed in these experiments.
Scheme 3
Results and Discussion. – In the present study, we explored the copper-catalyzed
bis(methoxycarbonyl)carbene reaction of a,b-unsaturated carboxamides 12a – 12i with
three reaction sites (N, C(a), and O) for the attack of electrophiles beside the carbene
addition at the double bond. Due to the presence of various possible reaction pathways,
the chemoselectivity of a carbene becomes an important issue that constitutes a
recurrent theme over the last three decades, especially in transition-metal-catalyzed
carbene-transfer reactions. The reaction of E2C¼N2 with carboxamides 12a – 12i

Helvetica Chimica Acta – Vol. 94 (2011)
1055
permits to study the formation of new dihydrofurans and its expected derivatives by
carbonyl ylide (¼oxonium ylide) reaction, and also to investigate the possibility of the
formation of products by a probable ammonium ylide or insertion reaction.
In the [Cu(acac)2]-catalyzed reactions of 12a – 12i with E2C¼N2, we observed the
formation of a mixture of adducts with either 1 mol-equiv. or 2 mol-equiv. of carbene,
i.e., first- and second-step products (Scheme 4). Attempts to obtain only or predom-
inantly the first- or the second-step products failed, and approximately the same
product distributions were found in all attempts. No reaction by intervention of an
ammonium ylide was observed. The yield of all identified first- and second-step
products of carboxamides 12a – 12i with E2C¼N2 are given as GC-determined values in
the Table. Thus, from most of the carboxamides, mixtures of two to five products were
obtained, some of which, i.e., 15 and 16, being certainly related to hydrolytic
transformations of the postulated first formed dihydrofuran 13. As expected, the
electron-rich dihydrofuran 13, which is a cyclic ketene O,N-acetal, is prone to
hydrolysis and was not isolated or spectroscopically observed under our reaction
conditions (Scheme 4). All the reactions, except for that of 12i, yielded a compound 15
as a result of water addition to 13 and subsequent ring opening of 14. The source of the
g-lactone derivative 16 was also the water addition product 14, via protonation at the N-
atom of 14 and H2O elimination. It is remarkable that the percentage of 15 was
noticeably high in the reactions of 12a – 12d with phenyl substituent(s) at the N-atom.
This might be due to a positive-charge resonance stabilization by the phenyl
Scheme 4a)

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Helvetica Chimica Acta – Vol. 94 (2011)
Table. Product Composition from the Reaction of Carboxamides 12a – 12i with Dimethyl Diazomalonate
R1
R2
R3
Yield [%]a)
15
16
17
18
19
12a
12b
12c
12d
12e
12f
12g
12h
12i
Ph
Me
Ph
Me
Ph
Ph
Me
Ph
Me
Ph
Ph
Ph
Ph
Et
Ph
Ph
Me
Me
Et
75
77
43
75
6
3
8
6
–
8
–
21
18
19
8
6
9
7
–
–
4
–
–
3
–
–
–
–
–
–
–
–
19
6
47
65
68
61
75
–
24
19
3
24
6
ꢀ(CH2)4ꢀ
ꢀ(CH2)4ꢀ
ꢀ(CH2)5ꢀ
ꢀ(CH2)5ꢀ
a) Percentages determined by GC/MS analyses; see Schemes 4 and 5 for structures.
substituent(s) at the N-atom of the hydroxylated tetrahydrofuran derivatives 14a – 14i;
the preferential protonation of the ring O-atom of 14a – 14d yields then 15a – 15d.
1
The H-NMR spectrum of the major product 15a from the reaction of 12a shows
three different dd, each counting for one H-atom at d(H) 4.31, 2.90, and 2.62 with
coupling constants of 10.1 and 4.7, 15.0 and 10.1, and 15.1 and 4.7 Hz, respectively.
These data represent the ABX spin system CHꢀCH2. The ca. 15.0 Hz value for Jgem
indicates an open-chain arrangement. The structure of 15a was also determined by an
X-ray crystal-structure analysis (Fig. 1)1).
In the reactions of 12c and 12f, the familiar [13] second-step products 17c and 17f
were obtained via 17’ which were formed by addition of a second molequiv. of E2C¼N2
to the initially formed dihydrofuran derivative 13 by a zwitterionic mechanism, albeit in
minor amounts (Scheme 4).
On the other hand, in the reactions of carboxamides 12e, 12f, and 12h, a-
[bis(methoxycarbonyl)methyl],b-hydroxy-substituted amides 18 were obtained. These
products might be formed by carbene addition to C(a) followed by water addition
(Scheme 5). Another plausible mechanism for the formation of 18 may involve
cyclopropane derivatives although cyclopropanation itself could not be observed under
our conditions. Since the probable cyclopropanes of the studied carboxamides have
acceptor groups, they might behave as homo-Michael systems, which readily undergo
nucleophilic ring opening by H2O [14].
Unexpected butadiene derivatives with four ester groups and an amide function,
i.e., compounds 19, were also isolated (Scheme 5). The molecular masses of these
derivatives showed the absence of two H-atoms per mol-equiv. of carboxamide by
involvement of 2 mol-equiv. of carbene. Under our reaction conditions, we also
obtained saturated carbene dimers [15], which might originate from compounds of type
19 with two missing H-atoms. It is also noteworthy that the percentages of 19e – 19i
1
)
CCDC-764748 (15a) and CCDC-764749 (19e) contain the supplementary crystallographic data for
this article. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/
cif.

Helvetica Chimica Acta – Vol. 94 (2011)
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Fig. 1. X-Ray crystal structure of 15a (R1 ¼ R2 ¼ R3 ¼ Ph). Arbitrary atom numbering.
(with no Ph group at N) were apparently higher than those of 19c and 19d (with one Ph
group at N) (see Table). However, compounds 19 were found in the reactions of 12a
and 12b (with two Ph groups at N). Since compounds 18 were only formed in the
reaction of carboxamides without Ph groups at the N-atom (see Path a), we suggest a
mechanism for the formation of compounds 19 by carbene addition to C(a) as
postulated in Scheme 5 (Path b). The formation of some of the dihydrofuran derivative
15 in the reactions of 12e – 12h also allows to formulate alternative procedures for the
formation of compounds 19 as shown in Scheme 6.
The 1H-NMR spectrum of 19e showed four different s at d(H) 3.81, 3.78, 3.73, and
3.44 for the methyl ester groups and also the signals for the H-atoms of the Et2N and Ph
group. Since no other H-signals were observable, we proposed a highly unsaturated
structure for 19e. The exact structure of 19e was finally confirmed by an X-ray crystal-
structure analysis (Fig. 2)1).
Conclusions. – The reactions of a,b-unsaturated carboxamides and [bis(methoxy-
carbonyl)carbene]copper mainly led to the novel butadiene derivatives 19 if there is no
Ph group at the N-atom of the carboxamides, in contrast to our previous results with
a,b-conjugated ketones [13b,c], aminoenones [10], and esters [11]. This finding allows
an efficient synthesis of methoxycarbonyl- and amido-substituted novel butadiene

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Scheme 5a)
Scheme 6a)

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1059
Fig. 2. X-Ray crystal structure of 19e (R1 ¼ Ph, R2 ¼ R3 ¼ Et). Arbitrary atom numbering.
derivatives applying 2 mol-equiv. of bis(methoxycarbonyl)carbene to 1 mol-equiv. of
N,N-dialkyl-substituted a,b-unsaturated carboxamide. The new compounds are
promising derivatives due to their wide variety of functional groups at the butadiene
moiety. In addition, as already previously observed, novel dihydrofuran derivatives are
obtained in variable yields (maximum for N-phenylated amides).
The authors thank the Istanbul Technical University Research Fund (No. 32039).
Experimental Part
General. Flash chromatography (FC): silica gel. M.p.: Gallenkamp apparatus; uncorrected. IR
Spectra (neat): Perkin-Elmer Spectrum One; in cmꢀ1. NMR Spectra: Varian Unity Inova 500 and Bruker
AC 250; if not otherwise stated, at 250 (1H) and 60 MHz; (13C); in CDCl3; d in ppm rel. to Me4Si as
internal standard, J in Hz. GC/MS: 6890 Hewlett-Packard GC instrument with HP-1 capillary column
(24 m) packed with cross-linked (phenylmethyl)siloxane; 5973 HP mass detector; column temp.
program: isothermal at 1008 for 5 min, heating to 2908 with a rate of 208/min, and staying isothermal for
10 min; tR in min. EI-MS and MR-EI-MS: HP5973 mass detector and Micromass Autospec Ultima, resp.;
in m/z (rel. %).
Carboxamides 12a – 12i: General Procedure. To a soln. of secondary amine (0.05 mol) in CH2Cl2
(25 ml) was added pyridine (0.05 mol) and the a,b-unsaturated acyl chloride (0.055 mol) at 08. After
stirring for 15 min at 08, the mixture was allowed to warm to r.t. and was stirred for an additional 2 h. The
resulting mixture was washed with H2O, 5% HCl soln., 5% NaOH soln., and brine and dried (Na2SO4).
After evaporation of the solvent, the residue was subjected to FC: carboxamide 12.
N,N-Diphenylcinnamamide ( ¼ (2E)-N,N,3-Triphenylprop-2-enamide; 12a): Yield 98%. Pale blue
1
solid. M.p. 1638. IR: 3052, 1734, 1657, 1613, 1351, 1288. H-NMR: 7.79 (d, J ¼ 15.6, 1 H); 7.27 – 7.43 (m,
15 H); 6.51 (d, J ¼ 15.6, 1 H). 13C-NMR: 166.2; 142.8; 142.6; 135.2; 129.7; 129.2; 128.7; 128.0; 127.6; 126.8;

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119.9. GC/MS: tR 16.40. EI-MS: 299 (40, Mþ), 222 (5), 169 (80), 131 (100), 103 (60), 77 (25). HR-EI-MS:
300.1391 (Mþ, C21H17NOþ; calc. 300.1388).
(2E)-N,N-Diphenylbut-2-enamide (12b): Yield 83%. Light orange solid. M.p. 112 – 1138. IR: 3060,
2350, 1664, 1488, 1343, 1287, 1250. 1H-NMR: 7.38 – 7.20 (m, 10 H); 7.02 (dq, J ¼ 15.0, 7.0, 1 H); 5.86 (dq,
J ¼ 15.1, 1.7, 1 H); 1.77 (dd, J ¼ 7.0, 1.7, 3 H). 13C-NMR: 166.1; 142.9; 142.4; 129.2; 127.6; 126.7; 123.9; 18.0.
GC/MS: tR 12.06. EI-MS: 237 (65, Mþ), 169 (100), 144 (5), 115 (5), 77 (10), 69 (70). HR-EI-MS: 238.1235
(Mþ, C16H15NOþ; calc. 238.1232).
N-Methyl-N-phenylcinnamamide ( ¼ (2E)-N-Methyl-N,3-diphenylprop-2-enamide; 12c): Yield 96%.
Yellow oil. IR: 3075, 3030, 2900, 2360, 1653, 1615, 1364 1239. 1H-NMR: 7.67 (d, J ¼ 15.6, 1 H); 7.57 – 7.20
(m, 10 H); 6.36 (d, J ¼ 15.6, 1 H); 3.40 (s, 3 H). 13C-NMR: 166.1; 143.7; 141.7; 135.2; 129.6; 129.5; 128.7;
127.8; 127.6; 127.3; 118.8; 37.5. GC/MS: tR 13.63. EI-MS: 237 (45, Mþ), 160 (15), 131 (100), 107 (45), 103
(45), 77 (35). HR-EI-MS: 238.1236 (Mþ, C16H15NOþ; calc. 238.1232).
(2E)-N-Methyl-N-phenylbut-2-enamide (12d): Yield 75%. Yellow oil. IR: 3060, 2900, 2359, 1663,
1
1627, 1495, 1373, 1127. H-NMR: 7.36 – 7.21 (m, 3 H); 7.09 (dd, J ¼ 7.7, 1.1, 2 H); 6.84 (dq, J ¼ 15.0, 6.9,
1 H); 5.68 (d, J ¼ 15.0, 1 H); 3.25 (s, 3 H); 1.64 (d, J ¼ 6.9, 3 H). 13C-NMR: 165.9; 143.7; 140.8; 129.4;
127.6; 122.7; 37.2; 17.8. GC/MS: tR 9.85. EI-MS: 175 (60, Mþ), 160 (7), 107 (100), 69 (65), 51 (8). HR-EI-
MS: 176.1072 (Mþ, C11H13NOþ; calc. 176.1075).
N,N-Diethylcinnamamide ( ¼ (2E)-N,N-Diethyl-3-phenylprop-2-enamide; 12e): Yield 81%. Pale
yellow solid. M.p. 688. IR: 2965, 2350, 1646, 1593, 1458, 1365, 1219, 1145. 1H-NMR: 7.70 (d, J ¼ 15.5, 1 H);
7.54 – 7.21 (m, 2 H); 7.40 – 7.35 (m, 3 H); 6.82 (d, J ¼ 15.5, 1 H); 3.53 – 3.43 (m, 4 H); 1.26 (t, J ¼ 7.2, 3 H);
1.18 (t, J ¼ 7.1, 3 H ) . 13C-NMR: 165.7; 142.3; 135.6; 129.4; 128.7; 128.1; 127.7; 117.9; 42.3; 41.1; 15.0; 13.2.
GC/MS: tR 16.58. EI-MS: 203 (90, Mþ), 188 (50), 174 (12), 131 (100), 126 (40), 103 (90), 77 (58). HR-EI-
MS: 204.1391 (Mþ, C13H17NOþ; calc. 204.1388).
(2E)-3-Phenyl-1-(pyrrolidin-1-yl)prop-2-en-1-one (12f): Yield 83%. White solid. M.p. 1238. IR:
2969, 2873, 2360, 1650, 1592, 1429, 1196. 1H-NMR: 7.69 (d, J ¼ 15.5, 1 H); 7.54 – 7.51 (m, 2 H); 7.35 – 7.34
(m, 3 H); 6.72 (d, J ¼ 15.5, 1 H); 3.62 (t, J ¼ 6.6, 2 H); 3.58 (t, J ¼ 6.7, 2 H); 2.06 – 1.84 (m, 4 H). 13C-NMR:
164.7; 141.7; 135.4; 129.5; 128.7; 127.8; 119.0; 46.6; 46.0; 26.1; 24.3. GC/MS: tR 13.28. EI-MS: 201 (85, Mþ),
131 (100), 103 (65), 77 (30), 70 (15). HR-EI-MS: 202.1238 (Mþ, C13H15NOþ; calc. 202.1232).
(2E)-1-(Pyrrolidin-1-yl)but-2-en-1-one (12g): Yield 79%. Yellow oil. IR: 2970, 2871, 2359, 1663,
1603, 1507, 1418, 1227. 1H-NMR: 6.72 (dq, J ¼ 15.1, 6.8, 1 H); 5.96 (d, J ¼ 15.1, 1 H); 3.34 (t, J ¼ 5.8, 4 H);
1.86 – 1.66 (m, 4 H); 1.70 (d, J ¼ 6.7, 3 H). 13C-NMR: 164.5; 140.1; 123.1; 46.2; 45.4; 25.9; 24.1; 17.7. GC/
MS: tR 8.91. EI-MS: 139 (50, Mþ), 124 (100), 98 (5), 69 (98). HR-EI-MS: 140.1080 (Mþ, C8H13NOþ; calc.
140.1075).
(2E)-3-Phenyl-1-(piperidin-1-yl)prop-2-en-1-one (12h): Yield 87%. White solid. M.p. 1038. IR: 2934,
1
1643, 1585, 1441, 1248, 1222, 1018. H-NMR: 7.63 (d, J ¼ 15.5, 1 H); 7.52 – 7.50 (m, 2 H); 7.36 – 7.34 (m,
3 H); 6.89 (d, J ¼ 15.5, 1 H); 3.65 – 3.58 (m, 4 H); 1.70 – 1.51 (m, 6 H). 13C-NMR: 165.4; 142.1; 135.6;
129.3; 128.7; 127.6; 117.9; 47.0; 43.3; 26.7; 25.6; 24.6. GC/MS: tR 13.40. EI-MS: 215 (100, Mþ), 214 (55),
138 (40), 131 (90), 103 (50), 84 (22), 77 (25). HR-EI-MS: 216.1393 (Mþ, C14H17NOþ; calc. 216.1388).
(2E)-1-(Piperidin-1-yl)but-2-en-1-one (12i): Yield 65%. Yellow oil. IR: 2935, 2359, 1661, 1607, 1435,
1217. 1H-NMR: 6.18 (d, J ¼ 15.1, 1 H); 6.72 (dq, J ¼ 15.1, 6.8, 1 H); 3.64 – 3.38 (m, 4 H); 1.76 (d, J ¼ 6.8,
3 H); 1.54 – 1.45 (m, 6 H). 13C-NMR: 165.3; 140.4; 121.9; 46.6; 42.9; 26.5; 25.5; 24.5; 17.9. GC/MS: tR 9.15.
EI-MS: 153 (10, Mþ), 138 (100), 110 (5), 84 (15), 69 (40). HR-EI-MS: 153.1158 (Mþ, C9H15NOþ; calc.
153.1154).
Catalytic Reactions of Carboxamides 12 with Dimethyl Diazomalonate (E2C¼N2): General
Procedure. To a soln. of one of the carboxamides 12a – 12i (6.6 mmol) in benzene (10 ml) was added
[Cu(acac)2] (0.02 mmol), and the mixture was heated under reflux. A soln. of E2C¼N2 (3.3 mmol) in
benzene (5 ml) was added dropwise over 3 h. When the IR spectrum indicated total consumption of
E2C¼N2 (absence of the characteristic diazo band at 2130 cmꢀ1), the mixture was concentrated and the
residue subjected to FC. The crude mixture contained varying amounts of unidentified compounds (max.
20% by GC/MS).
Dimethyl 2-[3-(Diphenylamino)-3-oxo-1-phenylpropyl)-2-hydroxypropanedioate (15a): Yield 68%.
1
Colorless solid. M.p. 2038. IR: 3490, 3060, 2956, 1742, 1666, 1491, 1266, 1136. H-NMR: 7.26 – 6.82 (m,
15 H); 4.31 (dd, J ¼ 10.1, 4.7, 1 H); 4.02 (s, 1 OH); 3.81 (s, 3 H); 3.52 (s, 3 H); 2.90 (dd, J ¼ 15.0, 10.1, 1 H);

Helvetica Chimica Acta – Vol. 94 (2011)
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2.62 (dd, J ¼ 15.1, 4.7, 1 H). 13C-NMR: 171.0; 170.0; 142.7; 138.2; 129.6; 129.2; 128.1; 127.5; 126.9; 81.8;
53.5; 53.2; 47.1; 36.2. GC/MS: tR 19.98. EI-MS: 447 (5, Mþ), 388 (4), 279 (5), 169 (100), 121 (15), 77 (5).
HR-EI-MS: 448.1766 (Mþ, C26H25NO6þ ; calc. 448.1760).
Dimethyl 2-[3-(Diphenylamino)-1-methyl-3-oxopropyl]-2-hydroxypropanedioate (15b): Yield 71%.
1
Colorless oil. IR: 3483, 2956, 1742, 1665, 1592, 1493, 1243, 1156, 1083. H-NMR: 7.52 – 6.80 (m, 10 H);
4.29 (s, OH); 3.77 (s, 3 H); 3.71 (s, 3 H); 3.14 – 3.04 (m, 1 H); 2.35 (dd, J ¼ 15.9, 4.9, 1 H); 2.26 (dd, J ¼
15.9, 8.0, 1 H); 0.98 (d, J ¼ 6.8, 3 H). 13C-NMR: 171.8; 168.5; 166.8; 142.8 (2 C); 130.6 – 120.8 (10 C);
82.0; 53.8; 53.2; 36.8; 35.7; 14.6. GC/MS: tR 14.97. EI-MS: 385 (3, Mþ), 326 (5), 217 (3), 169 (100), 157
(8), 129 (12), 77 (5), 59 (10). HR-EI-MS: 386,1600 (Mþ, C21H23NO6þ ; calc. 386,1604).
Dimethyl 2-Hydroxy-2-{3-[methyl(phenyl)amino]-3-oxo-1-phenylpropyl}propanedioate (15c): Yield
41%. Yellow oil. IR: 3492, 2926, 1803, 1747, 1437, 1265, 1049. 1H-NMR: 7.64 – 7.21 (m, 8 H); 6.96 (d, J ¼
6.4, 2 H); 4.25 (dd, J ¼ 9.4, 4.8, 1 H); 4.7 (br. s, OH); 3.81 (s, 3 H); 3.50 (s, 3 H); 3.10 (s, 3 H); 2.69 (dd,
J ¼ 15.3, 9.4, 1 H); 2.43 (dd, J ¼ 15.9, 4.8, 1 H). 13C-NMR (100 MHz, CDCl3): 169.7; 169.0; 168.9; 142.7;
137.5; 128.4; 128.3; 127.7; 127.6; 127.5; 127.1; 127.0; 126.9; 126.4; 126.3; 81.0; 52.5; 52.1; 45.7; 34.4; 28.7. GC/
MS: tR 15.65. EI-MS: 385 (2, Mþ), 367 (5), 326 (15), 279 (3), 239 (15), 107 (100), 77 (15), 59 (6). HR-EI-
MS: 386.1600 (Mþ, C21H23NOþ6 ; calc. 386.1604).
Dimethyl 2-Hydroxy-2-{1-methyl-3-[methyl(phenyl)amino]-3-oxopropyl}propanedioate (15d): Yield
70%. Dark red oil. IR: 3490, 2958, 1800, 1743, 1437, 1211, 1193, 1081. 1H-NMR: 7.62 – 7.31 (m, 3 H); 7.13
(d, J ¼ 7.04, 2 H); 4.65 (br. s, OH); 3.75 (s, 3 H); 3.71 (s, 3 H); 3.23 (s, 3 H); 3.00 (dd, J ¼ 12.5, 6.5, 1 H);
2.14 – 2.07 (m, 2 H); 0.88 (d, J ¼ 6.7, 3 H). 13C-NMR (100 MHz, CDCl3): 172.4; 170.7; 169.7; 142.8; 128.9
(2 C); 128.2; 127.0; 126.3; 86.6; 52.5; 52.2; 35.3; 34.7; 34.1; 14.3. GC/MS: tR 13.85. EI-MS: 323 (7, Mþ), 264
(12), 217 (3), 204 (11), 157 (11), 129 (15), 107 (100), 77 (10), 59 (12). HR-EI-MS: 324.1442 (Mþ,
C16H21NOþ6 ; calc. 324.1447).
Dimethyl 2-[3-(Diethylamino)-3-oxo-1-phenylpropyl]-2-hydroxypropanedioate (15e): Yield 3%.
1
Orange oil. IR: 3492, 2955, 1741, 1634, 1435, 1221, 1134. H-NMR: 7.37 – 7.16 (m, 5 H); 4.42 (s, OH);
4.27 (dd, J ¼ 9.1, 4.8, 1 H); 3.86 (s, 3 H); 3.51 (s, 3 H); 3.26 – 3.14 (m, 4 H); 2.92 (dd, J ¼ 15.3, 9.2, 1 H);
2.64 (dd, J ¼ 15.3, 4.8, 1 H); 1.05 (t, J ¼ 7.2, 3 H); 0.91 (t, J ¼ 7.1, 3 H ) . 13C-NMR: 170.11 (2 C); 169.8;
138.8; 129.2; 128.5; 128.0; 127.3; 82.2; 53.5; 53.1; 46.6; 42.0; 42.3; 34.4; 14.3; 12.8. GC/MS: tR 13.25. EI-
MS: 351 (7, Mþ), 333 (20), 292 (60), 274 (55), 205 (30), 131 (25), 100 (100), 72 (40), 59 (10). HR-EI-MS:
352.1757 (Mþ, C18H25NOþ6 ; calc. 352.1760).
Dimethyl 2-Hydroxy-2-[3-oxo-1-phenyl-3-(pyrrolidin-1-yl)propyl]propanedioate (15f): Yield 2%.
Orange oil. IR: 3397, 2973, 1798, 1741, 1624, 1436, 1231, 1048. 1H-NMR: 7.37 – 7.18 (m, 5 H); 4.26 (dd, J ¼
8.9, 4.9, 1 H); 3.80 (s, 3 H); 3.84 (s, OH); 3.49 (s, 3 H); 3.38 – 3.17 (m, 4 H); 2.85 (dd, J ¼ 15.4, 9.1, 1 H);
2.64 (dd, J ¼ 15.4, 4.7, 1 H); 1.86 – 1.65 (m, 4 H). 13C-NMR (125 MHz, CDCl3): 170.0; 169.2 (2 C); 139.0;
129.2 (2 C); 128.1 (2 C); 127.3; 82.2; 53.5; 53.1; 46.7; 46.2; 45.6; 36.4; 26.0; 24.3. GC/MS: tR 15.22. EI-MS:
349 (5, Mþ), 331 (12), 290 (90), 272 (50), 230 (25), 203 (35), 131 (15), 98 (100), 70 (25), 59 (7). HR-EI-
MS: 350.1659 (Mþ, C18H23NOþ6 ; calc. 350.1604).
Dimethyl 2-Hydroxy-2-[1-methyl-3-oxo-3-(pyrrolidin-1-yl)propyl]propanedioate (15g): Yield 6%.
Dark red oil. IR: 3492, 2956, 1801, 1739, 1621, 1435, 1226, 1042. 1H-NMR: 3.82 (s, OH); 3.79 (s, 3 H); 3.76
(s, 3 H); 3.45 (t, J ¼ 6.8, 2 H); 3.38 (t, J ¼ 6.8, 2 H); 3.11 – 2.98 (m, 1 H); 2.42 – 2.24 (m, 2 H); 1.95 – 1.79
(m, 4 H); 0.97 (d, J ¼ 6.7, 3 H). 13C-NMR: 170.8; 170.6; 170.1; 82.2; 53.3; 53.2; 46.9; 45.8; 36.4; 35.1; 26.0;
24.3; 14.5. GC/MS: tR 13.41. EI-MS: 287 (10, Mþ), 228 (70), 168 (68), 140 (100), 98 (45), 59 (15). HR-EI-
MS: 288.1442 (Mþ, C13H21NOþ6 ; calc. 288.1447).
Dimethyl 2-Hydroxy-2-[3-oxo-1-phenyl-3-(piperidin-1-yl)propyl]propanedioate (15h): Yield 5%.
Dark yellow oil. IR: 3472, 2952, 1782, 1735, 1634, 1436, 1259, 1142, 1023. 1H-NMR: 7.37 – 7.20 (m, 5 H);
4.24 (dd, J ¼ 9.2, 4.5, 1 H); 3.84 (s, OH); 3.81 (s, 3 H); 3.51 (s, 3 H); 3.42 – 3.32 (m, 4 H); 2.97 (dd, J ¼ 15.1,
9.2, 1 H); 2.64 (dd, J ¼ 15.3, 4.4, 1 H); 1.54 – 1.30 (m, 6 H). 13C-NMR (125 MHz, CDCl3): 172.4; 169.1;
169.0; 137.7; 128.2; 127.7; 127.1; 127.0; 126.4; 81.2; 52.5; 52.2; 45.8; 45.5; 41.8; 33.3; 25.3; 24.4; 23.5. GC/
MS: tR 15.47. EI-MS: 363 (10, Mþ), 345 (25), 304 (100), 286 (75), 244 (30), 217 (35), 126 (30), 112 (95),
84 (30), 59 (10). HR-EI-MS: 364.1756 (Mþ, C19H25NO6þ ; calc. 364.1760).
Dimethyl Dihydro-5-oxo-3-phenylfuran-2,2(3H)-dicarboxylate (16a ¼ 16c ¼ 16e ¼ 16f ¼ 16h): Yield
4% (for 16a), 20% (for 16c), 15% (for 16e), 4% (for 16f), and 5% (for 16h). Yellow oil. IR: 2956, 2359,
1801, 1741, 1435, 1240, 1157, 1071. 1H-NMR: 7.30 – 7.25 (m, 5 H); 4.45 (t, J ¼ 8.7, 1 H); 3.84 (s, 3 H); 3.82

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Helvetica Chimica Acta – Vol. 94 (2011)
(s, 3 H); 3.07 (dd, J ¼ 17.5, 8.7, 1 H); 2.98 (dd, J ¼ 17.5, 8.7, 1 H). 13C-NMR (125 MHz, CDCl3): 172.4;
165.5; 164.7; 134.3; 127.7 (2 C); 127.5; 127.0 (2 C); 87.6; 52.7; 51.7; 44.9; 33.0. GC/MS: tR 12.67. EI-MS: 278
(50, Mþ), 246 (5), 218 (70), 191 (80), 131 (55), 104 (100), 77 (20), 59 (20). HR-EI-MS: 279.0865 (Mþ,
C14H14NOþ6 ; calc. 279.0869).
Dimethyl Dihydro-3-methyl-5-oxofuran-2,2(3H)-dicarboxylate (16d ¼ 16g ¼ 16i): Not isolated in
pure form. GC/MS: tR 9.80. EI-MS: 216 (2, Mþ), 173 (2), 157 (75), 129 (77), 101 (25), 69 (19), 59 (100).
Dimethyl Dihydro-4-[2-methoxy-1-(methoxycarbonyl)-2-oxoethyl]-5-oxo-3-phenylfuran-2,2(3H)-
dicarboxylate (17c ¼ 17f): Yield 2% (for 17c) and 1% (for 17f): Dark red oil. IR: 2957, 1798, 1743,
1435, 1259, 1233, 1102, 1025. 1H-NMR: 7.35 – 7.25 (m, 5 H); 4.78 (d, J ¼ 12.0, 1 H); 3.94 (d, J ¼ 5.0, 1 H);
3.86 (s, 3 H); 3.82 (dd, J ¼ 12.0, 5.0, 1 H); 3.64 (s, 3 H); 3.34 (s, 3 H); 3.20 (s, 3 H). 13C-NMR (125 MHz,
CDCl3): 171.9; 166.2; 165.7; 165.2; 165.0; 132.1; 128.8; 128.1; 127.7; 127.6 (2 C); 86.0; 52.6; 52.0; 51.9; 51.4;
48.7; 42.0; 28.7. GC/MS: tR 14.98. EI-MS: 408 (2, Mþ), 345 (7), 317 (8), 277 (100), 257 (10), 229 (23), 201
(6), 171 (7), 115 (25), 59 (8). HR-EI-MS: 409.1141 (Mþ, C19H20NO1þ0 ; calc. 409.1135).
Dimethyl 2-{2-(Diethylamino)-1-[hydroxy(phenyl)methyl]-oxoethyl}propanedioate (18e): Yield
1
18%. Yellow oil. H-NMR (500 MHz, CDCl3): 7.21 – 7.16 (m, 5 H); 3.79 (s, OH); 3.76 – 3.73 (m, 1 H);
3.70 (s, 3 H); 3.49 (q, J ¼ 7.1, 2 H); 3.43 – 3.36 (m, 1 H); 3.42 (s, 3 H); 3.24 (d, J ¼ 7.7, 1 H) 3.18 (q, J ¼ 7.0,
2 H); 1.23 (t, J ¼ 7.1, 3 H); 1.04 (t, J ¼ 7.1, 3 H ) . 13C-NMR (125 MHz, CDCl3): 168.2; 165.8; 165.4; 132.7;
129.3; 127.5; 127.4; 127.3; 126.5; 87.5; 51.9; 51.8; 47.5; 43.1; 41.3; 39.8; 13.6; 11.9. GC/MS: tR 13.84. EI-MS:
333 (5, [M ꢀ H2O]þ), 302 (15), 274 (100), 258 (5), 233 (90), 212 (65), 173 (50), 145 (10), 113 (35), 100
(45), 72 (25), 59 (5). HR-EI-MS: 352.1764 (Mþ, C18H25NO6þ ; calc. 352.1760).
Dimethyl 2-[2-Hydroxy-2-phenyl-1-(pyrrolidin-1-ylcarbonyl)ethyl]propanedioate (18f): Yield 15%.
Colorless oil. IR: 3467, 2954, 2925, 1743, 1790, 1646, 1436, 1258, 1012. 1H-NMR (500 MHz, CDCl3): 7.36 –
7.17 (m, 5 H); 3.80 (s, OH); 3.74 (s, 3 H); 3.69 – 3.61 (m, 2 H); 3.68 (t, J ¼ 7.7, 2 H); 3.65 (d, J ¼ 9.5, 1 H);
3.45 – 3.39 (m, 1 H); 3.42 (s, 3 H); 3.21 (d, J ¼ 7.7, 1 H); 1.98 – 1.92 (m, 2 H); 1.87 – 1.80 (m, 2 H).
13C-NMR (125 MHz, CDCl3): 166.0; 165.4; 164.5; 132.7; 127.5; 127.4; 127.3 (2 C); 126.5; 86.3; 52.0; 51.7;
45.9; 45.2; 42.9; 34.5; 25.0; 23.4. GC/MS: tR 14.85. EI-MS: 331 (7, [M ꢀ H2O]þ), 300 (12), 272 (100), 233
(90), 210 (50), 173 (40), 145 (10), 115 (27), 98 (55), 70 (6), 59 (3). HR-EI-MS: 350.1609 (Mþ,
C18H23NOþ6 ; calc. 350.1604).
Dimethyl 2-[2-Hydroxy-2-phenyl-1-(piperidin-1-ylcarbonyl)ethyl]propanedioate (18h): Yield 21%.
Dark yellow oil. IR: 3467, 3060, 2955, 1792, 1742, 1666, 1491, 1266, 1229, 1136. 1H-NMR (500 MHz,
CDCl3): 7.40 – 7.15 (m, 5 H); 3.81 (s, OH); 3.77 – 3.69 (m, 5 H); 3.60 – 3.55 (m, 1 H); 3.72 (s, 3 H); 3.60 –
3.55 (m, 1 H); 3.42 (s, 3 H); 3.29 (d, J ¼ 7.8, 1 H); 1.63 – 1.41 (m, 6 H). 13C-NMR (125 MHz, CDCl3):
168.2; 165.4; 163.9; 132.7; 129.3; 127.5; 127.4; 127.3; 126.5; 87.5; 51.9; 51.8; 47.5; 45.8; 42.7; 42.4; 25.4; 24.5;
23.5. GC/MS: tR 15.07. EI-MS: 345 (7, [M ꢀ H2O]þ), 314 (15), 286 (100), 233 (90), 224 (65), 173 (50), 145
(14), 114 (30), 112 (35), 84 (15), 69 (18), 59 (5). HR-EI-MS: 364.1765 (Mþ, C19H25NO6þ ; calc. 364.1760).
Tetramethyl 2-{[Methyl(phenyl)amino]carbonyl}-3-phenylbuta-1,3-diene-1,1,4,4-tetracarboxylate
(19c): Yield 16%. Yellow oil. IR: 2956, 1731, 1651, 1434, 1222, 1160, 1003. 1H-NMR (500 MHz, CDCl3):
7.39 – 7.11 (m, 10 H); 3.83 (s, 3 H); 3.79 (s, 6 H); 3.72 (s, 6 H). 13C-NMR (125 MHz, CDCl3): 167.7; 167.5
(2 C); 165.8 (2 C); 164.5; 163.5; 146.4; 133.8; 128.7 – 126.6 (12 C); 55.4; 53.0; 52.9; 52.1; 37.5. GC/MS: tR
18.09. EI-MS: 495 (10, Mþ), 464 (12), 436 (20), 404 (30), 380 (27), 361 (12), 329 (100), 301 (6), 106 (13),
77 (15), 59 (10). HR-EI-MS: 496.1611 (Mþ, C26H25NO9þ ; calc. 496.1608).
Tetramethyl 2-Methyl-3-{[methyl(phenyl)amino]carbonyl}buta-1,3-diene-1,1,4,4-tetracarboxylate
(19d): Not isolated in pure form. GC/MS: tR 15.35. EI-MS: 433 (1, Mþ), 402 (18), 374 (35), 342 (20),
327 (55), 295 (60), 263 (100), 235 (12), 207 (10), 134 (8), 106 (16), 77 (20), 59 (12).
Tetramethyl 2-[(Diethylamino)carbonyl]-3-phenylbuta-1,3-diene-1,1,4,4-tetracarboxylate (19e):
1
Yield 46%. Colorless solid. M.p. 1878. IR: 2923, 2390, 1731, 1639, 1444, 1218, 1085. H-NMR: 7.41 –
7.25 (m, 5 H); 3.78 (s, 3 H); 3.77 (s, 3 H); 3.73 (s, 3 H); 3.44 (s, 3 H); 3.41 (q, J ¼ 7.06, 2 H); 3.17 (q,
J ¼ 7.05, 2 H); 0.97 (t, J ¼ 7.01, 3 H); 0.86 (t, J ¼ 7.06, 3 H). 13C-NMR: 165.4; 164.6; 163.5 (2 C); 163.3;
148.7; 147.7; 134.5; 129.7; 128.7; 128.5; 128.1; 52.7 (2 C); 52.3 (2 C); 42.0; 39.0; 13.3; 11.8. GC/MS: tR
15.72. EI-MS: 461 (10, Mþ), 430 (30), 402 (100), 358 (65), 329 (28), 298 (33), 271 (15), 100 (30), 72
(100), 59 (7). HR-EI-MS: 462.1769 (Mþ, C23H27NO9þ ; calc. 462.1764).
Tetramethyl 2-Phenyl-3-(pyrrolidin-1-ylcarbonyl)buta-1,3-diene-1,1,4,4-tetracarboxylate (19f): Yield
63%. Yellow oil. IR: 2954, 2990, 1732, 1638, 1434, 1226, 1089. 1H-NMR: 7.35 – 7.25 (m, 5 H); 3.76 (s, 6 H);

Helvetica Chimica Acta – Vol. 94 (2011)
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3.74 (s, 3 H); 3.45 (s, 3 H); 3.28 (t, J ¼ 6.1, 2 H); 3.23 (t, J ¼ 5.9, 2 H); 1.25 – 1.19 (m, 4 H). 13C-NMR
(125 MHz, CDCl3): 164.3; 163.4; 162.7; 162.3; 161.5; 147.2; 146.4; 133.8; 128.7; 127.8; 127.4; 127.3; 126.8;
52.0; 51.8; 51.7; 51.4; 46.1; 45.0; 24.9; 22.9. GC/MS: tR 16.85. EI-MS: 459 (7, Mþ), 428 (20), 358 (40), 329
(15), 298 (30), 272 (10), 203 (6), 153 (7), 129 (7), 98 (15), 55 (12). HR-EI-MS: 460.1612 (Mþ,
C23H25NOþ9 ; calc. 460.1608).
Tetramethyl 2-Methyl-3-(pyrrolidin-1-ylcarbonyl)buta-1,3-diene-1,1,4,4-tetracarboxylate (19g): Not
isolated in pure form. GC/MS: tR 14.79. EI-MS: 397 (3, Mþ), 366 (65), 338 (100), 299 (70), 164 (65), 232
(60), 205 (25), 98 (70), 70 (60), 59 (20).
Tetramethyl 2-Phenyl-3-(piperidinyl-1-carbonyl)buta-1,3-diene-1,1,4,4-tetracarboxylate (19h): Yield
60%. Yellow oil. IR: 2951, 2360, 1731, 1712, 1633, 1429, 1221, 1091. 1H-NMR: 7.42 – 7.32 (m, 5 H); 3.80 (s,
3 H); 3.79 (s, 3 H); 3.77 (s, 3 H); 3.46 (s, 3 H); 3.36 (t, J ¼ 4.8, 2 H); 3.25 (t, J ¼ 4.9, 2 H); 1.48 – 1.37 (m,
4 H); 1.18 – 1.08 (m, 2 H). 13C-NMR: 165.1; 164.3; 163.5; 163.3; 162.6; 148.5; 146.6; 134.7; 130.3; 129.5;
128.7; 128.6; 128.3; 127.8; 127.2; 53.8; 52.8; 52.7; 52.3; 47.0; 42.8; 25.3; 25.2; 24.2. GC/MS: tR 17.29. EI-MS:
473 (3, Mþ), 442 (15), 414 (100), 358 (65), 298 (35), 271 (10), 112 (10), 64 (15), 59 (6). HR-EI-MS:
474.1761 (Mþ, C24H27NOþ9 ; calc. 474.1764).
Tetramethyl 2-Methyl-3-(piperidin-1-ylcarbonyl)buta-1,3-diene-1,1,4,4-tetracarboxylate (19i): Not
isolated in pure form. GC/MS: tR 14.99. EI-MS: 411 (3, Mþ), 380 (50), 352 (100), 299 (50), 264 (55),
232 (47), 205 (20), 177 (10), 112 (50), 84 (52), 59 (14).
REFERENCES
[1] A. H. Li, L. X. Dai, V. K. Aggarwal, Chem. Rev. 1997, 97, 2341; L. X. Dai, X. L. Hou, Y. G. Zhou,
Pure Appl. Chem. 1999, 71, 369; M. J. Gaunt, C. C. Johansson, Chem. Rev. 2007, 107, 5596.
[2] S. Son, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 1046; J. Schnaubelt, E. Marks, H. U. Reissig, Chem.
Ber. 1996, 129, 73; J. L. Loebach, D. M. Bennett, R. L. Danheiser, J. Am. Chem. Soc. 1998, 120, 9690;
W. Cao, G. Chen, J. Chen, R. Chen, Synth. Commun. 2005, 35, 527.
[3] E. M. McGarrigle, E. L. Myers, O. Illa, M. A. Shaw, S. L. Riches, V. K. Aggarwal, Chem. Rev. 2007,
´
´
107, 5841; A. Solladie-Cavallo, L. Bouerat, M. Roje, Tetrahedron Lett. 2000, 41, 7309; V. K.
Aggarwal, I. Bae, H. Y. Lee, J. Richardson, D. T. Williams, Angew. Chem., Int. Ed. 2003, 42, 3274.
[4] V. K. Aggarwal, E. Alonso, G. Y. Fang, M. Ferrara, G. Hynd, M. Porcelloni, Angew. Chem., Int. Ed.
2001, 40, 1433; H. Lebel, J. F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev. 2003, 103, 977;
W. W. Liao, K. Li, Y. Tang, J. Am. Chem. Soc. 2003, 125, 13030; C. D. Papageorgiou, M. A. Cubillo de
Dios, S. V. Ley, M. J. Gaunt, Angew. Chem., Int. Ed. 2004, 43, 4641; N. Bremeyer, S. C. Smith, S. V.
Ley, M. J. Gaunt, Angew. Chem., Int. Ed. 2004, 43, 2681; V. K. Aggarwal, E. Grange, Chem. – Eur. J.
2006, 12, 568.
[5] A. M. Bernard, A. Frongia, P. P. Piras, F. Secci, M. Spiga, Org. Lett. 2005, 7, 4565; H. M. L. Davies, G.
Ahmed, R. L. Calvo, M. R. Churchill, D. G. Churchill, J. Org. Chem. 1998, 63, 2641; D. A. Evans,
Z. K. Sweeney, T. Rovis, J. S. Tedrow, J. Am. Chem. Soc. 2001, 123, 12095.
[6] M. E. Alonso, M. C. Garcia, A. W. Chitty, J. Org. Chem. 1985, 50, 3445; A. Padwa, S. F. Hornbuckle,
Chem. Rev. 1991, 91, 263.
[7] M. Lautens, J. F. Paquin, S. Piguel, J. Org. Chem. 2002, 64, 3972; S. B. Polovsky, R. W. Franck, J. Org.
Chem. 1974, 39, 3010.
[8] B. M. Fraga, Nat. Prod. Rep. 1992, 9, 217; A. T. Merrit, S. V. Ley, Nat. Prod. Rep. 1992, 9, 243; D. S.
Mortensen, A. L. Rodriguez, K. E. Carlson, J. Sun, B. S. Katzenellenbogen, J. A. Katzenellenbogen,
J. Med. Chem. 2001, 44, 3838; T. G. Kilroy, T. P. OꢂSullivan, P. J. Guiry, Eur. J. Org. Chem. 2005, 36, 4929.
[9] B. H. Lipshutz, Chem. Rev. 1986, 86, 795; M. M. Faul, B. E. Huff, Chem. Rev. 2000, 100, 2407; F.
Garzino, A. Meou, P. Brun, Synthesis 2003, 598; J. D. Pettigrew, P. D. Wilson, Org. Lett. 2006, 8, 1427.
[10] F. S. Gungor, O. Anac, O. Sezer, Tetrahedron Lett. 2007, 48, 4883.
[11] O. Anac, F. S. Gungor, G. Merey, Helv. Chim. Acta 2006, 89, 1231.
[12] O. Anac, O. Sezer, O. Candan, F. S. Gungor, M. S. Cansever, Tetrahedron Lett. 2008, 49, 1062.
[13] a) O. Anac, A. Daut, Liebigs Ann. Recl. 1997, 1249; b) O. Anac, A. Daut, O. Sezer, Helv. Chim. Acta
2003, 86, 290; c) O. Anac, F. S. Gungor, C. Kahveci, M. S. Cansever, Helv. Chim. Acta 2004, 87, 408.

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[14] D. Agrawal, V. K. Yadav, Chem. Commun. 2008, 6471.
[15] D. S. Wulfman, B. W. Pearce, R. S. McDaniel Jr., Tetrahedron 1976, 32, 1251.
Received October 18, 2010