Regioselective synthesis of 5-alkylidene and 5-(iodoalkylidene)-pyrrol- 2(5H)-ones by halolactamisation of (2Z,4E)-dienamides and (Z)-alk-2-en-4- ynamides

Article abstract of DOI:10.1016/j.tetlet.2004.01.063

Stereo- and regioselective synthesis of 5-alkylidene (arylidene) and 5-(iodoalkylidene)-pyrrol-2(5H)-ones was achieved from (2Z,4E)-dienamides and (Z)-alk-2-en-4-ynamides by halocyclisation reaction. Selectivity was found to be highly dependent on the nat

Full text of DOI:10.1016/j.tetlet.2004.01.063

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2063–2066
Regioselective synthesis of 5-alkylidene and 5-(iodoalkylidene)-
pyrrol-2(5H)-ones by halolactamisation of (2Z,4E)-dienamides
and (Z)-alk-2-en-4-ynamides
a
a,b
a
b
ꢀ ^
^
Khalil Cherry, Jerome Thibonnet, Alain Duchene, Jean-Luc Parrain
and Mohamed Abarbria,*
aLaboratoire de Physicochimie des Interfaces et des Milieux Rꢀeactionnels, Facultꢀe des Sciences de Tours, Parc de Grandmont,
37200 Tours, France
bLaboratoire de Synthꢁese Organique, UMR 6009, Facultꢀe des Sciences de Saint Jꢀer^ome, 13397 Marseille Cedex 20, France
Received 18 December 2003; revised 14 January 2004; accepted 16 January 2004
Abstract—Stereo- and regioselective synthesis of 5-alkylidene (arylidene) and 5-(iodoalkylidene)-pyrrol-2(5H)-ones was achieved
from (2Z,4E)-dienamides and (Z)-alk-2-en-4-ynamides by halocyclisation reaction. Selectivity was found to be highly dependent on
the nature of the substituents and on the temperature.
ꢀ 2004 Elsevier Ltd. All rights reserved.
acids from b-iodovinylic acids and vinyltins and alky-
nylzinc reagents, respectively.9 This methodology was
then applied to the synthesis of 5-alkylidene (arylidene)-
furan-2(5H)-ones.10
2
O
N
R
In connection with our studies on the synthesis of oxy-
gen- and nitrogen-containing heterocycles, we wish to
report the electrophilic cyclisation of dienamides and
enynamides with ICl as regioselective method for syn-
thesising 5-alkylidene and 5-(iodoalkylidene)-pyrrol-
2(5H)-ones, respectively. We first examined the reaction
of our (2Z,4E)-dienamides 1 using several electrophilic
halogen sources (ICl, I2, I2/KI, NBS, . . .). The dien-
amides 1 were obtained in excellent yields by treatment
of the corresponding (2Z,4E)-dienoic acids9d with oxalyl
chloride followed by addition of primary amine.11 ICl
was found to be the best reagent to obtain fair to good
yields of 5-alkylidene pyrrol-2(5H)-ones 2. The use of
other sources of halogen (NIS, NBS, I2/KI, . . .) led to
lower yields. A number of solvents were examined
including ether, THF, acetonitrile, toluene and dichlo-
romethane. The latter gave the best results, which we
think may be due to a greater ability to solubilise ICl.
Interestingly, the cyclisation is followed by in-situ
dehydrohalogenation leading to 5-alkylidene pyrrol-
2(5H)-ones 2a–g. This takes place without any addition
of base (Scheme 1 and Table 1), as opposed to what was
observed previously when we prepared c-alkylidene
butenolides by halolactonisation of dienoic acids, where
5-Ylidene pyrrol-2(5H)-one structural unit 2 is found in
a range of biologically important natural products
including holomycin,1 pukeleimide,2 isoampullicin3 and
the bile pigment bilirubin.4 Although extensive meth-
odology has been developed for the construction of 5-
ylidene furan-2(5H)-ones and 4-ylidene tetronic acids,5
only a few examples are reported for the preparation of
5-ylidene pyrrol-2(5H)-ones 2.6 Nevertheless, although
Z-selectivity of the exocyclic double bond is relatively
easy to control, clean access to the (E)-stereoisomer still
remains a challenge for organic chemists. We recently
reported the regioselective synthesis of a-pyrones and a-
pyridones under palladium complex catalysis by cou-
pling tributylstannylallenes with (Z)-iodovinylic acids or
(Z)-iodovinylic amides.7;8 We have also previously
described the synthesis of dienoic acids and enynoic
Keywords: Pyrrolones; Halolactamisation.
* Corresponding author. Tel.: +33-2-47-36-73-59; fax: +33-2-47-36-69-
60; e-mail: abarbri@univ-tours.fr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.063

2064
K. Cherry et al. / Tetrahedron Letters 45 (2004) 2063–2066
R1
R1
R1
R1
ICl, CH2Cl2, 3 h
R3
R3
o
+
O
O
O
N
N
N
to
0 °C
25 °C
R2
R2
HN
R2
O
R3
R3
R2
1a-g
(Z )-2a-g
(Z )-2a-g
(E)-2b-g
Scheme 1.
Table 1. Synthesis of 5-alkylidene (arylidene)-pyrrol-2(5H)-ones 2a–g
Entry
R1
R2
R3
Ph
Pyrrol-2(5H)-one Yield (%)
Z/Ea
Z/Eb
1
Ph
Bn
2a
2b
2c
2d
2e
2f
55
80
77
58
78
50
51
100/0
10/90
5/95
6/94
3/97
5/95
7/93
100/0
100/0
100/0c
78/22
100/0
100/0
100/0
2Ph
3
Bn
ꢀ Me
3Si
Ph
(CH3)2CH–CH–CH3
PhCH(CH3)
Bn
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
4
H
CH3
5
6
CH3
CH3OCH2
m-CH3O–C6H4
m-CH3O–C6H4
7
2g
a Before isomerisation reaction.
b After a spontaneous isomerisation.
25
D
c
½aŠ þ 29ꢁ (c ¼ 2%, CH2Cl2).
it was necessary to use a base such as the DBU to form
the exocyclic double bond.10 The results are summarised
in Table 1.
compared to (E)-2a where the extensive interaction of
the ortho hydrogens of the phenyl group and the phenyl
substituent prevents conjugation. As shown in Table 1,
we obtained optically pure c-silylmethylidene pyrrol-
2(5H)-ones 2c from the available optically active amide
1c (entry 3), and in all cases the c-alkylidene pyrrol-
2(5H)-ones 2 were obtained without any trace of 2-
pyridone. It should be noted that the alkylidene pyrrol-
2(5H)-ones were not stable and gradually decomposed
upon heating or exposure to air. It was also necessary to
neutralise silica during chromatography using a base
such as triethylamine to avoid their decomposition.
As expected, the selectivity observed was largely in
favour of the (E)-stereochemistry of the exocyclic double
bond. Nevertheless, selectivity was highly dependent on
temperature and the nature of the substituent. For the
first time, c-silylmethylidene pyrrol-2(5H)-ones 2b–g
were obtained with mainly E stereochemistry for the
exocyclic double bond, which was confirmed by NOESY
experiments. It should be noted that at room tempera-
ture 2b–g isomerised quickly (after few hours) largely in
favour of Z stereochemistry. In the case of the forma-
tion of 2a, the desired benzylidene pyrrol-2(5H)-one was
obtained only with a complete (Z)-configuration of the
exocyclic double bond. This can be explained by the
greater thermodynamic stability of the (Z)-isomer of 2a
We next chose to extend our method by investigating
similar cyclisation of (Z)-alk-2-en-4-ynamides 3a–e.
Alk-2-en-4-ynamides 3a–e were prepared via the Sono-
gashira cross-coupling reaction12 of terminal alkynes
with (Z)-3-iodoalk-2-enamides (Scheme 2). The mild
R1
R1
PdCl2(PPh3)2 (2.5 mol%), CuI (5 mol%)
Et3N, DMF, 25 °C
R2
I
+
R2
HN
Bn
3a-e (69-81%)
O
HN
Bn
O
Scheme 2.
R1
R1
R1
ICl, CH2Cl2, 6 h
0 °c 25 °C
R2
I
O
+
O
N
Bn
R2
N
Bn
R2
I
Bn-HN
O
(Z )-4a-e
(E)-4a-e
3a-e
Scheme 3.

K. Cherry et al. / Tetrahedron Letters 45 (2004) 2063–2066
2065
Pd(PPh3)4, toluene/EtOH
Na2CO3, 50 °C, 12 h
R
I
R-B(OH)2
+
O
O
N
Bn
N
Bn
Ph
Ph
5a-e
4b
5a:R = p.CH3-C6H4, E/Z = 90/10(71%); 5b: R = 3-thienyl,E/Z = 75/25(65%);
5c:R = tert.butylvinyl, 5E/5Z = 10/90(62%); 5d: R = p.Br-C6H4, E/Z = 88/12
(67%); 5e:R = m.Cl-C6H4, E/Z = 85/15(60%).
Scheme 4.
Table 2. Synthesis of (iodoalkylidene)-pyrrol-2(5H)-ones 4a–e
References and notes
Entry
R1
H
R2
Product
E/Z
Yield (%)
1. Celmer, W. D.; Solomons, I. A. J. Am. Chem. Soc. 1955,
77, 2861.
2. (a) Simmons, C. J.; Marner, F.-J.; Cardellina, J. H., II;
Moore, R. E.; Seff, K. Tetrahedron Lett. 1979, 20, 2003;
(b) Cardellina, J. H., II; Moore, R. E. Tetrahedron Lett.
1979, 20, 2007.
1
2CH
Ph
Ph
4a
4b
4c
4d
4e
90/10
65/35
55/45
85/15
90/10
65
79
80
75
70
3
3
4
5
Ph
Ph
Me3Si
HOC(CH3)2
CH3
CH3
3. Abdullaev, N. D.; Samikov, K.; Antsupova, T. P.;
Yagudaev, M. R.; Yunusov, S. Yu. Khim. Prir. Soedin.
1987, (5), 692[ Chem. Nat. Compd. (Engl. Transl.), 1987,
23, 576].
4. (a) Falk, H.; Grubmayr, K.; Herzig, U.; Hofer, O.
Tetrahedron Lett. 1975, 16, 559; (b) Lightner, D. A.;
Park, Y.-T. J. Heterocycl. Chem. 1977, 14, 415.
experimental conditions of the reaction resulted in
excellent yields of (Z)-enynamides and no polymerisa-
tion products were detected.
Indeed, treatment of (Z)-alk-2-en-4-ynamides 3a–e by
ICl in CH2Cl2 gave good yields of regioselective
5-(iodoalkylidene or arylidene)-pyrrol-2(5H)-ones 4a–e
(Scheme 3 and Table 2).13 In our case, this iodocycli-
sation reaction proceeded via the 5-exo process, and the
corresponding six-membered ring lactams were not
observed in either case. The exocyclic double bond
formed had mainly the E configuration except in the
case of 4b and 4c (Table 2, entries 2 and 3), where a
significant amount of Z-isomer were observed.
€
5. For recent synthesis see: (a) Bruckner, R. Curr. Org.
Chem. 2001, 5(6), 679; (b) Rossi, R.; Bellina, F. Targets
€
Heterocycl. Syst. 2001, 5, 169; (c) Bruckner, R. Chem.
€
Commun. 2001, 141; (d) Hanisch, I.; Bruckner, R. Synlett
2000, 374; (e) Bruckner, R.; Ohe, F. v. d. New J. Chem.
€
€
2000, 659; (f) Siegel, K.; Bruckner, R. Synlett 1999, 1227;
(g) Xu, C.; Negishi, E.-I. Tetrahedron Lett. 1999, 40, 431;
€
(h) Ma, S.; Shi, Z. J. Org. Chem. 1998, 63, 6387; (i) Gorth,
F. C.; Umland, A.; Bruckner, R. Eur. J. Org. Chem. 1998,
€
1055; (j) Rossi, R.; Bellina, F.; Biagetti, M.; Mannina, L.
Tetrahedron Lett. 1998, 39, 7799; (k) Rossi, R.; Bellina, F.;
Biagetti, M.; Mannina, L. Tetrahedron Lett. 1998, 39,
7599; (l) Rossi, R.; Bellina, F.; Mannina, L. Tetrahedron
Lett. 1998, 39, 3017; (m) Rossi, R.; Bellina, F.; Bechini, C.;
Mannina, L.; Vergamini, P. Tetrahedron 1998, 54, 135; (n)
Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org.
Chem. 1997, 62, 367; (o) Kotora, M.; Negishi, E.-I.
Synthesis 1997, 121;; (p) Negishi, E.-I.; Kotora, M.
Tetrahedron 1997, 53, 6707; (q) Marshall, J. A.; Wolf,
M. A. J. Org. Chem. 1996, 61, 3238; (r) Marshall, J. A.;
Wallace, E. M. J. Org. Chem. 1995, 60, 796.
Finally, Suzuki cross-coupling14 of 4b with vinyl or aryl
boronic acids using toluene as solvent, ethanol as
co-solvent and 3 mol % of tetrakis(triphenylphos-
phine)palladium(0) as catalyst allowed the stereoselec-
tive synthesis of desired products 5a–e (Scheme 4).15 The
use of (E)-tertiobutyl vinyl boronic acid reagent per-
mitted the transfer of a vinyl group with retention of the
configuration of the double bond, and no polymerisa-
tion products were observed.
€
6. (a) Wuckelt, J.; Doring, M.; Langer, P.; Beckert, R.;
Gorls, H. J. Org. Chem. 1999, 64, 365; (b) Yoshimatsu,
€
In conclusion, we describe here efficient and general
syntheses of 5-alkylidene (or arylidene) and 5-
(iodoalkylidene or arylidene)-pyrrol-2(5H)-ones by
halolactamisation of unsaturated amides. Further stud-
ies are currently in progress aimed at broadening the
application of iodoalkylidene lactams to the synthesis of
natural alkylidene pyrrolones.
M.; Machida, K.; Fuseya, T.; Shimizu, H.; Kataoka, T. J.
Chem. Soc., Perkins Trans. 1996, 1839; (c) Abell, A. D.;
Oldham, M. D.; Taylor, J. M. J. Chem. Soc., Perkin
Trans. 1 1995, 953; (d) Murakami, M.; Hayashi, M.; Ito,
Y. J. Org. Chem. 1994, 59, 7910; (e) Gill, G. B.; James, G.
D.; Oates, K. V.; Pattenden, G. J. Chem. Soc., Perkin
Trans. 1 1993, 23, 2567; (f) Fiorenza, M.; Reginato, G.;
Ricci, A.; Taddei, M. J. Org. Chem. 1984, 49, 551; (g)
Walton, H. M. J. Org. Chem. 1957, 22, 315.
^
7. Rousset, S.; Abarbri, M.; Thibonnet, J.; Duchene, A.;
Parrain, J.-L. Chem. Commun. 2000, 1987.
8. Cherry, K.; Abarbri, M.; Parrain, J.-L.; Duchene, A.
Tetrahedron Lett. 2003, 44, 5791.
9. (a) Abarbri, M.; Parrain, J.-L.; Kitamura, M.; Noyori, R.;
^
Acknowledgements
We thank MESR and CNRS for providing financial
support and the Ôservice dÕanalyse chimique du vivant de
toursÕ for recording NMR and mass spectra.
^
Duchene, A. J. Org. Chem. 2000, 65, 7475; (b) Thibonnet,
J.; Abarbri, M.; Duchene, A.; Parrain, J.-L. Synlett 1999,
141; (c) Thibonnet, J.; Abarbri, M.; Parrain, J.-L.;
^

2066
K. Cherry et al. / Tetrahedron Letters 45 (2004) 2063–2066
Duchene, A. Synlett 1997, 771; (d) Abarbri, M.; Parrain,
^
J.-L.; Cintrat, J.-C.; Duchene, A. Synthesis 1996, 82; (e)
NMR (CDCl3, 200 MHz) d (ppm): 2.55 (s, 3H), 4.46 (s,
2H), 6.47 (s, 1H), 7.22–7.56 (m, 10H); 13C NMR (CDCl3,
50 MHz) d (ppm): 19.0, 52.5, 74.3, 127.1, 127.2, 128.3 (2C),
128.5 (2C), 128.8 (2C), 129.8, 130.3 (2C), 140.5, 141.6,
147.2, 152.3, 157.7; MS (70 eV, EI) m=z (%): 401 (M, 0.4),
127 (6), 91 (100), 65 (18), 64 (17), 48 (11). (Z)-4b: 1H NMR
(CDCl3, 200 MHz) d (ppm): 2.61 (s, 3H), 4.51 (s, 2H), 6.34
(s, 1H), 7.22–7.56 (m, 10H); 13C NMR (CDCl3, 50 MHz) d
(ppm): 19.5, 54.6, 74.2, 126.9, 127.2, 128.0 (2C), 128.6
(2C), 128.8 (2C), 129.3, 130.5 (2C), 140.4, 141.1, 146.1,
151.9, 157.6.
^
Abarbri, M.; Parrain, J.-L.; Duchene, A. Tetrahedron
^
Lett. 1995, 36, 2469; (f) Duchene, A.; Abarbri, M.;
^
Parrain, J.-L.; Kitamura, M.; Noyori, R. Synlett 1994,
524.
10. Rousset, S.; Thibonnet, J.; Abarbri, M.; Duchene, A.;
Parrain, J.-L. Synlett 2000, 260.
11. Abarbri, M.; Parrain, J.-L.; Duchene, A. Synth. Commun.
1998, 28, 239.
12. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467; (b) Sonogashira, S. In Metal-
Catalyzed Cross-Coupling Reactions; Stang, P. J., Diede-
rich, F., Eds.; Wiley-VCH: Weinheim, 1998; p 203; (c)
Sonogashira, K. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Coupling reactions between
sp2 and sp carbon centers; Pergamon: Oxford, 1991; Vol. 3,
p 521.
13. Typical procedure: Preparation of 2a–g or 4a–e. Iodine
monochloride (1.7 g, 10.5 mmol) in dry dichloromethane
(10 mL) was added dropwise at 0 ꢁC to dieneamide 1 (or
enynamide 3) (10 mmol). Stirring was then maintained for
3 h at room temperature in darkness, the mixture was
hydrolysed by dropwise addition of a 5% solution of
sodium thiosulfate until the solution became clear. The
solution was then extracted with CH2Cl2 (3 · 15 mL) and
dried with MgSO4. After evaporation of the solvent, the
products were obtained after purification by flash column
chromatography on silica (petroleum ether/diethyl ether/
triethylamine; 80/19/1) or by crystallisation in diethyl ether
to yield alkylidene pyrrol-2(5H)-one 2 or iodoalkylidene
pyrrol-2(5H)-one 4. For example: Compound (Z)-2e: IR
(neat): 2954, 1672, 1611; 1H NMR (CDCl3, 200 MHz) d
(ppm): 0.21 (s, 9H), 1.98 (s, 3H), 4.64 (s, 2H), 4.85 (s, 1H),
6.18 (s, 1H), 7.19–7.31 (m, 5H); 13C NMR (CDCl3,
50 MHz) d (ppm): )0.04 (3C), 12.3, 52.2, 103.5, 122.3,
127.2, 128.4 (2C), 128.9 (2C), 139.8, 147.5, 161.6, 164.3;
MS (70 eV, EI) m=z: 271 (M, 4), 243 (22), 91 (100), 73 (16),
65 (20). (E)-4b: IR (neat): 3065, 2964, 1677, 1603; 1H
^
^
14. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
15. Typical procedure: Preparation of 5a–e. An oven-dried
Schlenk flask was evacuated and back-filled with argon
and charged with ethanol (8 mL), toluene (10 mL), pyrro-
lone 4b (5 mmol), and aryl boronic acid (6 mmol). The
flask was evacuated and back-filled with argon and then
0.6 mL of 1 M solution of Na2CO3 and Pd(PPh3)4 (173 mg,
0.15 mmol, 3 mol %), were added. The reaction mixture
was stirred at 50 ꢁC for 12h, the solution was filtered
through a Celite pad and the solvents were evaporated.
The residue was extracted with diethylether, and dried
over anhydrous MgSO4. Products 5a–e were obtained
after purification by flash column chromatography on
silica (petroleum ether/diethyl ether/triethylamine; 80/19/
1). For example: (E)-1-benzyl-4-methyl-5(phenyl-p-tolyl-
methylene)-pyrrol-2(5H)-one 5a. (E)-5a: IR (neat): 3028,
1
2964, 1673, 1604; H NMR (CDCl3, 200 MHz) d (ppm):
1.53 (d, J ¼ 1:4 Hz, 3H), 2.45 (s, 3H), 4.74 (s, 2H), 6.29
(q, J ¼ 1:4 Hz, 1H), 7.23–7.46 (m, 14H); 13C NMR
(CDCl3, 50 MHz) d (ppm): 15.8, 21.8, 52.5, 115.8, 124.4,
127.1, 127.9, 128.3 (2C), 128.4 (2C), 128.8 (2C), 129.5
(2C), 130.6 (2C), 131.6 (2C), 135.3, 138.5, 139.3, 141.0,
148.0, 150.5, 160.1; MS (70 eV, EI) m=z (%): 365 (M, 35),
275 (21), 274 (100), 165 (17), 105 (22), 65 (24), 39 (13).
(Z)-5a: 1H NMR (CDCl3, 200 MHz) d (ppm): 1.55 (s, 3H),
2.44 (s, 3H), 4.73 (s, 2H), 6.34 (br s, 1H), 7.20–7.49 (m,
14H).