Zinc- and indium-promoted conjugate addition-cyclization reactions of ethenetricarboxylates with propargylamines and alcohol: Novel methylenepyrrolidine and methylenetetrahydrofuran syntheses

Article abstract of DOI:10.1021/jo0602118

A new zinc- and indium-promoted conjugate addition-cyclization reaction to afford nitrogen- and oxygen-containing five-membered heterocycles has been developed. Reaction of ethenetricarboxylates with propargylamines (1 equiv) in the presence of ZnBr₂ or InBr₃ afforded methylenepyrrolidines in high yields. The stoichiometric use of ZnBr₂ or InBr₃ at room temperature and the catalytic use of InBr ₃-Et₃N at 80°C were effective. Reaction of ethenetricarboxylates with propargyl alcohol in the presence of ZnBr₂ or InBr₃ afforded methylenetetrahydrofurans.

Full text of DOI:10.1021/jo0602118

Zinc- and Indium-Promoted Conjugate Addition-Cyclization
Reactions of Ethenetricarboxylates with Propargylamines and
Alcohol: Novel Methylenepyrrolidine and
Methylenetetrahydrofuran Syntheses
Satoshi Morikawa,†,‡ Shoko Yamazaki,*,† Yoshiteru Furusaki,† Naoya Amano,†
Kazumi Zenke,† and Kiyomi Kakiuchi‡
Department of Chemistry, Nara UniVersity of Education, Takabatake-cho, Nara 630-8528, Japan, and
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), Takayama,
Ikoma, Nara 630-0192, Japan
yamazaks@nara-edu.ac.jp
ReceiVed January 31, 2006
A new zinc- and indium-promoted conjugate addition-cyclization reaction to afford nitrogen- and oxygen-
containing five-membered heterocycles has been developed. Reaction of ethenetricarboxylates with
propargylamines (1 equiv) in the presence of ZnBr2 or InBr3 afforded methylenepyrrolidines in high
yields. The stoichiometric use of ZnBr2 or InBr3 at room temperature and the catalytic use of InBr3-
Et3N at 80 °C were effective. Reaction of ethenetricarboxylates with propargyl alcohol in the presence
of ZnBr2 or InBr3 afforded methylenetetrahydrofurans.
Introduction
propargylamines or allylamines leading to pyrrolidines have
been reported.5 In these examples, most substrates were
arylidenemalonates and the use of a primary propargylamine
was unsuccessful. nBuLi/Pd, Cu-promoted,6 and Zn-promoted7
reactions of alkylidenemalonates with excess amounts of
propargyl alcohol to give methylenetetrahydrofurans also have
been reported. Ethenetricarboxylate derivatives have been shown
to be highly electrophilic CdC components in Lewis acid-
promoted cycloadditions.8 Lewis acid-promoted intramolecular
Nitrogen- and oxygen-containing five-membered heterocycles
such as pyrrolidines, including proline and related amino acids,
and tetrahydrofurans are important core structures in organic
chemistry because of their presence in many natural products
and their biological activity.1,2 For this reason, mild and efficient
processes for the one-step construction of functionalized pyr-
rolidines3 and tetrahydrofurans4 are highly desirable. Recently,
nBuLi, NaH/Pd, and Cu-promoted one-pot reactions with
(4) For examples of synthesis of tetrahydrofurans, see: (a) Trost, B. M.;
Edstrom, E. D.; Carter-Petillo, M. B. J. Org. Chem. 1989, 54, 4489. (b)
Harada, T.; Muramatsu, K.; Fujiwara, T.; Kataoka, H.; Oku, A. Org. Lett.
2005, 7, 779. (c) Bassetti, M.; D’Annibale, A.; Fanfoni, A.; Minissi, F.
Org. Lett. 2005, 7, 1805.
(5) (a) Monterio, N.; Balme, G. J. Org. Chem. 2000, 65, 3223. (b) Dumez,
E.; Rodriguez, J.; Dulce´re, J.-P. Chem. Commun. 1997, 1831. (c) Clique,
B.; Monteiro, N.; Balme, G. Tetrahedron Lett. 1999, 40, 1301. (d) Clique,
B.; Vassiliou, S.; Monteiro, N.; Balme, G. Eur. J. Org. Chem. 1999, 40,
1301. (e) Azoulay, S.; Monteiro, N.; Balme, G. Tetrahedron Lett. 2002,
43, 9311. (f) Martinon, L.; Azoulay, S.; Monteiro, N.; Ku¨ndig, E. P.; Balme,
G. J. Orgnomet. Chem. 2004, 689, 3831.
† Nara University of Education.
‡ Nara Institute of Science and Technology.
(1) For examples of pyrrolidines, see: (a) Massiot, G.; Delaude, C. In
The Alkaloids: Chemistry and Pharmacology; Brossi, A., Ed.; Academic
Press: San Diego, CA, 1986; Vol. 27, Chapter 3, p 269. (b) Dewick, P. M.
Medicinal Natural Products; J. Wiley & Sons: Chichester, UK, 1997;
Chapter 6. (c) Nilsson, B. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem.
1990, 33, 580.
(2) For examples of tetrahydrofurans, see: Dean, F. M.; Sargent, M. V.
In ComprehensiVe Heterocyclic Chemistry; Katrizky, A. R., Rees, C. W.,
Eds.; Pergamon: Oxford, UK, 1984; Vol. 4, p 531.
(3) For examples of syntheses of pyrrolidines, see: (a) Felpin, F.-X.;
Girard, S.; Vo-Thanh, G.; Robins, R. J.; Villie´ras, J.; Lebreton, J. J. Org.
Chem. 2001, 66, 6305. (b) Xu, Y.-z.; Choi, J.; Calaza, M. I.; Turner, S. C.;
Rapoport, H. J. Org. Chem. 1999, 64, 4069. (c) Turner, S. C.; Zhai, H.;
Rapoport, H. J. Org. Chem. 2000, 65, 861. (d) Knight, D. W.; Salter, R.
Tetrahedron Lett. 1999, 40, 5915. (e) Schlummer, B.; Hartwig, J. F. Org.
Lett. 2002, 4, 1471.
(6) (a) Marat, X.; Monteiro, N.; Balme, G. Synlett 1997, 845. (b)
Cavicchioli, M.; Marat, X.; Monteiro, N.; Hartmann, B.; Balme, G.
Tetrahedron Lett. 2002, 43, 2609.
(7) Nakamura, M.; Liang, C.; Nakamura, E. Org. Lett. 2004, 6, 2015.
(8) (a) Srisiri, W.; Padias, A. B.; Hall, H. K., Jr. J. Org. Chem. 1994,
59, 5424. (b) Yamazaki, S.; Kumagai, H.; Takada, T.; Yamabe, S. J. Org.
Chem. 1997, 62, 2968.
10.1021/jo0602118 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/06/2006
3540
J. Org. Chem. 2006, 71, 3540-3544

Methylenepyrrolidine and Methylenetetrahydrofuran
t
t
TABLE 1. Stoichiometric Reaction of 1a (Y ) CO2 Bu) with
TABLE 2. Reaction of 1a (Y ) CO2 Bu) with
N-Methylpropargylamine 2a (R ) Me)a
N-Methylpropargylamine 2a (R ) Me) in Various Solvents
3a
4a
3a
4a
entry
MXn
(yield/%)
(yield/%)
entry
solvent
CH2Cl2
CH2Cl2
THF
toluene
toluene
CH2ClCH2Cl
CH2ClCH2Cl
no solvent
no solvent
MXn
(yield/%)
(yield/%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
ZnBr2
ZnCl2
ZnI2
Zn(OTf)2
InBr3
81
75
78
73
78
65
67
22
1
2
3
4
5
6
7
8
9
ZnBr2
InBr3
ZnBr2
ZnBr2
InBr3
ZnBr2
InBr3
ZnBr2
InBr3
81a
78a
96
32b
87
95
65b
InCl3
In(OTf)3
Cu(OTf)2
AlCl3
GaCl3
FeCl3
81
18b
31b
73b
61b
76
72
75
a Results in Table 1. b NMR yield.
SnCl4
b
b
Sn(OTf)2
Sc(OTf)3
TiCl4
94
86
in the absence of metal halides and triflates also gave 4a
quantitatively.11 Cyclization only occurred when zinc, indium,
and copper salts were used at room temperature, although copper
triflate gave 3a in lower yield. Treatment of the noncyclic adduct
4a with 1.2 equiv of ZnBr2 or InBr3 gave 3a in 60% and 66%
yields, respectively.
ZrCl4
97
a Reactions were carried out with 0.5 mmol of 1a, 0.5 mmol of 2a, and
1.2 equiv (0.6 mmol) of MXn and at 0.56 M for 1a in CH2Cl2 for 17-20
h at room temperature. b Decomposition.
Various solvents were examined for the reaction of 1a and
2a in the presence of ZnBr2 and InBr3 (1.2 equiv) at room
temperature (Table 2). Dichloromethane and 1,2-dichloroethane
are better solvents for formation of 3a.
cyclization of ethenetricarboxylate esters also has been studied.9
We have studied the reaction of highly reactive ethenetricar-
boxylate derivatives and related compounds with propargyl
substrates in this work. We have discovered stoichiometric (at
room temperature) and catalytic (at higher temperature) zinc-
and indium-promoted formal [3+2] cycloadditions of ethene-
tricarboxylates with 1 equiv of propargylamines (N-methyl and
primary) and propargyl alcohol to afford nitrogen- and oxygen-
containing five-membered rings (eq 1). No requirement for an
excess of the propargyl substrates and the mild conditions are
valuable features of this reaction.
Use of catalytic amounts of ZnBr2, InBr3, and In(OTf)3 at
room temperature gave 4a exclusively (entries 1, 3, and 4, Table
3). Catalytic amounts of Zn(OTf)2-NEt36 at room temperature
gave the mixture of 3a and 4a (entry 2). With 1,2-dichloroethane
as a solvent, the catalytic reaction at higher temperature (80
°C) was examined. With 0.2 equiv of ZnBr2, InBr3, ZnBr2-
Et3N, or Zn(OTf)2-Et3N, lower yields of 3a compared to
stoichiometric reactions at room temperature were obtained
along with small amounts of 4a and the starting material 1a
(entries 5-7, 9, and 10). With 0.2 equiv of InBr3-Et3N for 4
h, the yield of 3a was increased up to 74% (entry 8).12 The
reaction of 4a with InBr3-Et3N (0.2 equiv) at 80 °C for 4 h or
with Zn(OTf)2 (0.2 equiv) at 80 °C for 16 h gave 3a in 61%
and 71% yields, along with 1a (13% and 21%), respectively.
The reaction of 1a and N-propargylamine 2b with ZnBr2 or
t
InBr3 (1.2 equiv) also gave 3b (Y ) CO2 Bu, R ) H) as a major
Results and Discussion
product (Table 4). The reaction of 1a and N-propargylamine
2b in the absence of ZnBr2 or InBr3 or by their catalytic use
(0.2 equiv) at room temperature gave 4b exclusively. The
reaction of 1a and 2b in the presence of catalytic InBr3-Et3N
(0.2 equiv) at 80 °C for 4 h gave 3b in 75% yield (entry 5).
The reaction of various ethenetricarboxylate and related
ketone derivatives 1 with N-propargylamines 2 proceeded to
give proline derivatives (Table 5). Both stoichiometric (at room
temperature) and catalytic (at 80 °C) conditions are shown.
Other substrates, di-tert-butyl methylenemalonate (5),13 di-
ethyl ethylidenemalonate (6), and diethyl benzylidenemalonate
At first, reactions involving stoichiometric amounts of Lewis
acids (1.2 equiv) and substrates (1 equiv) were examined.
t
Triester 1a (Y ) CO2 Bu) and N-methylpropargylamine (2a)
reacted in the presence of ZnBr2 (1.2 equiv) in CH2Cl2 at room
temperature overnight to afford five-membered proline deriva-
tive 3a in 81% yield (eq 2, Table 1, entry 1). Various metal
(10) 4a is somewhat unstable to column chromatography (SiO2). Partial
decomposition of 4a to 1a possibly by retroconjugate addition was observed.
The instability is consistent with the reported results. (a) Bartoli, G.;
Bartolacci, M.; Giuliani, A.; Marcantoni, E.; Massaccesi, M.; Torregiani,
E. J. Org. Chem. 2005, 70, 169. (b) Bartoli, G.; Bosco, M.; Marcantoni,
E.; Petrini, M.; Sambri, L.; Torregiani, E. J. Org. Chem. 2001, 66, 9052.
(c) Toda, F.; Takumi, H.; Nagami, M.; Tanaka, K. Heterocycles 1998, 47,
467.
(11) The spontaneous 1,4-addition of amine was also reported for an
R,â-unsaturated oxazolidinone. Hamashita, Y.; Somei, H.; Shimura, Y.;
Tamura, T.; Sodeoka, M. Org. Lett. 2004, 6, 1861.
(12) The reaction also proceeds without Et3N. Et3N or unreacted
propargylamines may capture the transiently generated HBr in situ.
halides and triflates were examined. Interestingly, AlCl3, FeCl3,
GaCl3 Sn(OTf)2, Sc(OTf)3, and ZrCl4 gave exclusively 1,4-
t
adduct 4a (Y ) CO2 Bu, R ) Me).10 The reaction of 1a and 2a
(9) (a) Snider, B. B.; Roush, D. M. J. Org. Chem. 1979, 44, 4229. (b)
Yamazaki, S.; Yamada, K.; Yamabe, S.; Yamamoto, K. J. Org. Chem. 2002,
67, 2889. (c) Yamazaki, S.; Yamada, K.; Yamamoto, K. Org. Biomol. Chem.
2004, 2, 257. (d) Yamazaki, S.; Morikawa, S.; Iwata, Y.; Yamamoto, M.;
Kuramoto, K. Org. Biomol. Chem. 2004, 2, 3134.
J. Org. Chem, Vol. 71, No. 9, 2006 3541

Morikawa et al.
t
TABLE 3. Catalytic Reaction of 1a (Y ) CO2 Bu) with N-Methylpropargylamine 2a (R ) Me)a
reaction
MXn
3ab
4a
1a
entry
solvent
CH2Cl2
CH2Cl2
CH2Cl2
conditions
(0.2 equiv)
(yield/%)
(yield/%)
(yield/%)
1
2
3
4
5
6
7
8
9
rt, 16 h
rt, 16 h
rt, 16 h
rt, 16 h
80 °C, 16 h
80 °C, 4 he
80 °C, 16 h
80 °C, 4 he
80 °C, 4 h
80 °C, 16 h
ZnBr2
96b
41c
quantb
98b
19c
3c
Zn(OTf)2-Et3Nd
InBr3
35
15c
CH2Cl2
In(OTf)3
ZnBr2
InBr3
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
14
55
38
74
45
45
14c
10c
14c
ZnBr2-Et3Nd
InBr3-Et3Nd
Zn(OTf)2-Et3Nd
Zn(OTf)2-Et3Nd
19c
4c
13c
21c
10
a Reactions were carried out with 0.5 mmol of 1a, 0.5 mmol of 2a, and 0.2 equiv (0.1 mmol) of MXn-(Et3N) and at 0.56 M for 1a in CH2Cl2 or
CH2ClCH2Cl. b Isolated yield. c NMR yield. d Et3N (0.2 equiv) was added. e Longer reaction times decreased the yield.
t
TABLE 4. Reaction of 1a (Y ) CO2 Bu) with N-Propargylamine
2b (R ) H)
nitrogen of 2 to 1 and 5-7 leading to 1,4-adduct (4 and 11-
13) and simultaneous zinc (or indium) coordination to the diester
moiety gives intermediate A.14 Zinc (or indium) transfer to
alkyne and the following cyclization leads to intermediate B.
Protonation of the intermediate B furnishes the five-membered
rings 3 and 8-10. The successful cyclization by zinc and indium
reaction
3b
(yield/%)
4b
(yield/%)
entry
conditionsa
MXn
ZnBr2
InBr3
ZnBr2
equiv
1
2
3
4
5
rt, 16 h
rt, 16 h
rt, 16 h
1.2
1.2
0.2
0.2
0.2
54
82
82
71
rt, 16 h
InBr3
80 °C, 4 hb
InBr3-Et3Nc
75
a CH2Cl2 was used as solvent at rt and CH2ClCH2Cl was used at 80 °C.
b Longer reaction time decreased the yield. c Et3N (0.2 equiv) was added.
SCHEME 1
salts can be rationalized by the dual activation of the carbonyl
and alkyne moieties.15 The reversibility of the first 1,4-addition
step is suggested as follows. The B3LYP/6-31G* calculated
∆G298 of 4 (R ) Me, Y ) CO2Et) in the gas phase is 5 kcal/
mol less stable relative to 1b and 2a.16,17 ∆G298 of 13a (R )
Me, Y ) Ph) is 12.0 kcal/mol less stable relative to 7 and 2a.18
For the reaction of 7 (Y ) Ph), the reverse 1,4-addition seems
to be more preferred because of conjugation with the Ph group.19
The higher reactivity of ethenetricarboxylate 1 arises from
activation of the 2-position of 1 by the electron-withdrawing
ester group in the addition step.
(14) 1H NMR spectra of the mixture of 1a and 2a/2b in CDCl3 show
the immediate formation of adducts 4a/4b.
(15) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. Org.
Lett. 2005, 7, 1363.
(16) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. ReV. B 1998, 37, 785.
(7) were investigated to examine the effect of 2-substituents
(eq 3). Catalytic reaction of 5 with 2a proceeded even at room
(17) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Foresman,
K. Raghavachari, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision
C.02; Gaussian, Inc.:Wallingford CT, 2004.
(18) ∆G298 for 3c (R ) Me, Y ) CO2Et) relative to 1b and 2a is -35.3
kcal/mol and ∆G298 for 10a (R ) Me) relative to 7 and 2a is -25.9 kcal/
mol.
(19) Without Lewis acid, the reaction of 7 and 2a in CH2Cl2 at room
temperature for 17 h gave a ca. 1:1 mixture of 7 and a probable amine
adduct 13a. 13a could not be isolated and decomposed to give 7 by column
chromatography.
temperature (entries 6-8, Table 6). Treatment of the noncyclic
adduct 11a in CH2ClCH2Cl with InBr3-Et3N (0.2 equiv) at 80
°C for 4 h gave 8a in 73% yield. For the reaction of 6 and 7,
byproducts 14 and 15 (for 7) formed. The reaction of 7 with 2a
at 80 °C under the catalytic conditions gave a cyclized product
10a in 49% yield (entry 23).
The probable mechanism for formation of the five-membered
rings 3 and 8-10 is shown in Scheme 1. Conjugate addition of
(13) Ballesteros, P.; Roberts, B. W. Organic Syntheses; Wiley: New
York, 1990; Collect. Vol. VII, p 142.
3542 J. Org. Chem., Vol. 71, No. 9, 2006

Methylenepyrrolidine and Methylenetetrahydrofuran
TABLE 5. Reaction of 1 with N-Propargylamines 2a (R ) Me) and 2b (R ) H)
reaction
3
entry
1
2
conditionsa,b
MXn
ZnBr2
equiv
(yield/%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
1b (Y ) CO2Et)
2a
2a
2a
2b
2b
2b
2a
2a
2a
2b
2b
2a
2a
2a
2a
2a
2b
2a
2a
2a
2a
rt
1.2
1.2
0.2
1.2
1.2
0.2
1.2
1.2
0.2
1.2
0.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
3c (91)
3c (64)
3c (64)
3d (96)
3d (88)
3d (53)
3e (81)
3e (79)
3e (65)
3f (80)
3f (45)
3g (43)
3g (60)
3g (53)
3h (62)
3h (74)
3i (69)
3j (92)
3j (68)
3j (69)
3k (56)
1b (Y ) CO2Et)
rt
InBr3
1b (Y ) CO2Et)
80 °C, 4 h
rt
rt
80 °C, 4 h
rt
rt
80 °C, 4 h
rt
80 °C, 4 h
rt
InBr3-Et3Nc
ZnBr2
1b (Y ) CO2Et)
1b (Y ) CO2Et)
InBr3
1b (Y ) CO2Et)
InBr3-Et3Nc
ZnBr2
1c (Y ) CO2CH2Ph)
1c (Y ) CO2CH2Ph)
1c (Y ) CO2CH2Ph)
1c (Y ) CO2CH2Ph)
1c (Y ) CO2CH2Ph)
1d (Y ) CONMeCH2CtCH)
1d (Y ) CONMeCH2CtCH)
1d (Y ) CONMeCH2CtCH)
1e (Y ) CON-(CH2)5-)
1e (Y ) CON-(CH2)5-)
1e (Y ) CON-(CH2)5-)
1f (Y ) COPh)
InBr3
InBr3-Et3Nc
InBr3
InBr3-Et3Nc
ZnBr2
rt
InBr3
80 °C, 4 h
rt
rt
rt
rt
rt
InBr3-Et3Nc
ZnBr2
InBr3
InBr3
ZnBr2
1f (Y ) COPh)
InBr3
1f (Y ) COPh)
80 °C, 4 h
rt
InBr3-Et3Nc
InBr3
1g (Y ) CN)
a CH2Cl2 was used as a solvent at rt and CH2ClCH2Cl was used at 80 °C. b Reaction time is 15-17 h unless otherwise stated. c Et3N (0.2 equiv) was
added.
TABLE 6. Reaction of 5-7 with N-Propargylamines 2 (R ) Me, H)
reaction
entry
substrate
2
conditionsa,b
MXn
equiv
product (yield/%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
5
5
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
7
7
7
7
7
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2a
2a
2a
2b
2b
2b
2a
2a
2a
2a
2a
rt
rt
rt
rt
ZnBr2
ZnBr2
1.2
0.2
0.2
1.2
1.2
0.2
0.2
0.2
0.2
1.2
1.2
0.2
1.2
1.2
0.2
1.2
1.2
0.2
1.2
1.2
1.2
0.2
0.2
8a (89)
11a (86)
11a (89)
ZnBr2-Et3Ne
InBr3
8a (63)
8a (65)
8a (51)
8a (64)
8a (47)
8a (73)
8b (96)f
rt, 37 h
rt
rt, 46 h
rt
InBr3
InBr3
InBr3
11a (38)
11a (22)
11a (39)
InBr3-Et3Ne
InBr3-Et3Ne
ZnBr2
80 °C, 4 h
rt
rt 4 hd
InBr3
8b (100)f
8b (100)f
9a (72)
80 °C, 4 h
rt
rt
80 °C, 4 h
rt
rt
80 °C, 4 h
rt
rt
80 °C
80 °C
80 °C, 4 h
InBr3-Et3Ne
ZnBr2
InBr3
9a (73)
InBr3-Et3Ne
ZnBr2
9a (46)
9b (37)f,g
9b (47)f,g
9b (38)f,g
15 (63)
14 (50)
InBr3
InBr3-Et3Ne
ZnBr2
14 (5)g, 15 (3)g
14 (43), 7 (57)
7 (65)
InBr3
InBr3
10a (22)
10a (34)
7 (19)
Zn(OTf)2-Et3Ne
InBr3-Et3Ne
14 (47)g, 7 (47)g
14 (12), 7 (38)
10a (49)
a CH2Cl2 was used as a solvent at rt and CH2ClCH2Cl was used at 80 °C. b Reaction time is 15-17 h unless otherwise stated. c Isolated yield unless
otherwise stated. d Longer reaction time decreased the yield. e Et3N (0.2 equiv) was added. f Unstable to column chromatography. g NMR yield.
Formation of byproduct 14 in the reaction of 6 and 7 arises
from the reverse Knoevenagel reaction. Formation of 15 arises
from the conjugate addition reaction of 14 generated in situ
toward 6.
Methylenetetrahydrofuran Formation. These zinc- and
indium salt-promoted conditions were also found to be suitable
for methylenetetrahydrofuran formation. The reactions of ethene-
tricarboxylate derivatives with propargyl alcohol 16 were
examined (eq 4, Table 7). The reaction of tert-butyl ester 1a
and 16 in the presence of ZnBr2 or InBr3 did not give the
expected methylenetetrahydrofuran, probably because tert-butyl
cation generated in situ reacts with intermediates.20 On the other
hand, the reaction of triethyl ester 1b and 16 in the presence of
ZnBr2 or InBr3 (1.2 equiv) gave methylenetetrahydrofuran 17b
in 64% and 89% yields, respectively. The reaction of 1b and
16 in the presence of catalytic amounts of InBr3 with and without
Et3N at 80 °C gave 17b in 66% and 73% yields, respectively
(entries 6 and 7). The reaction of 1b and 16 without ZnBr2 or
InBr3 did not proceed. The different reactivity of propargyl-
amines and alcohol arises from the difference of nucleophilicity
of nitrogen and oxygen. The use of catalytic amounts of InBr3
(20) Yamazaki, S.; Ohmitsu, K.; Ohi, K.; Otsubo, T.; Moriyama, K. Org.
Lett. 2005, 7, 759.
J. Org. Chem, Vol. 71, No. 9, 2006 3543

Morikawa et al.
TABLE 7. Reaction of 1 with Propargyl Alcohol 16
reaction
entry
1
1
Y
conditiona,b
MXn
ZnBr2
equiv
1.2
product (yield)
17b (64%)
18 (trace) 19 (23%)
18 (63%)
recovered 1b (21%)
17b (38%)
recovered 1b (57%)
17b (89%)
1b
CO2Et
CO2Et
CO2Et
rt
2
3
1b
1b
rt
Zn(OTf)2-Et3Nc
Zn(OTf)2-Et3Nc
0.2
0.2
80 °C
4
5
6
7
8
1b
1b
1b
1b
1d
1e
1e
1e
1f
CO2Et
CO2Et
CO2Et
CO2Et
rt
rt
InBr3
InBr3
InBr3
1.2
0.2
0.2
0.2
1.2
1.2
1.2
0.2
1.2
1.2
0.2
18 (65%) 19 (8%)
17b (66%)
80 °C
80 °C, 4 h
rt
rt
rt
80 °C
rt
rt
80 °C
InBr3-Et3Nc
ZnBr2
ZnBr2
InBr3
17b (73%)d
CONMeCH2CtCH
CON-(CH2)5-
CON-(CH2)5-
CON-(CH2)5-
COPh
17d (60%) 20 (7%)
17e (64%)
17e (63%)
17e (88%)
17f (78%)
9
10
11
12
13
14
InBr3
ZnBr2
InBr3
1f
1f
COPh
COPh
17f (91%)
17f (78%)
InBr3
a CH2Cl2 was used as a solvent at rt and CH2ClCH2Cl was used at 80 °C. b Reaction time was 16-18 h unless otherwise stated. c 0.2 equiv of Et3N was
added. d A small amount of impurity could not be removed. Longer reaction times increased the impurity.
was added N-methylpropargylamine (35 mg, 43 µL, 0.5 mmol) and
ZnBr2 (130 mg, 0.58 mmol) at 0 °C. The mixture was allowed to
warm to room temperature and stirred overnight (17 h). The reaction
mixture was quenched by water (1.5 mL) and then saturated aqueous
NaHCO3. The mixture was extracted with dichloromethane and the
organic phase was washed with water, dried (Na2SO4), and
evaporated in vacuo. The residue was purified by column chro-
matography over silica gel with hexanes-ether as eluent to give
3a (138 mg, 81%).
(0.2 equiv) at room temperature leads to the formation of 1,4-
adduct 18 in 65% yield as a main product, along with the H2O
adduct 19 (8%) (entry 5).21 Formation of 18 is different from
the reported reaction of 7 with propargyl alcohol in the presence
of catalytic Zn(OTf)2-Et3N.7 Stoichiometric use of propagyl
alcohol is sufficient to lead to the satisfactory yields, in contrast
to the reaction of 7. These results arise from the high reactivity
of 1 toward propargyl alcohol as described for the reaction with
propargylamines similarly in the first 1,4-addition step, and the
reverse 1,4-addition is less favored than in the reaction of 7.
The ZnBr2-promoted reaction of amide derivative 1d with
16 gave methyleneterahydrofuran 17d in 60% yield, along with
δ-lactam 20 in 7% yield formed by internal propargyl amide
B (Table 3, Entry 1): To a solution of 1a (133 mg, 0.49 mmol)
in 1,2-dichloroethane (0.9 mL) was added N-methylpropargylamine
(34 mg, 41 µL, 0.49 mmol), Et3N (9.9 mg, 14 µL, 0.098 mmol)
and InBr3 (35 mg, 0.098 mmol). The mixture was heated to 80 °C
for 4 h. The reaction mixture was cooled to room temperature and
quenched by water (1.5 mL) and then saturated aqueous NaHCO3.
The mixture was extracted with dichloromethane and the organic
phase was washed with water, dried (Na2SO4), and evaporated in
vacuo. The residue was purified as above to give 3a (124 mg, 74%).
3a: Rf 0.8 (ether); pale yellow oil; 1H NMR (400 MHz, CDCl3)
δ (ppm) 1.26 (t, J ) 7.1 Hz, 3H), 1.27 (t, J ) 7.1 Hz, 3H), 1.47
(s, 9H), 2.46 (s, 3H), 3.39 (dt, J ) 13.0, 2.1 Hz, 1H), 3.67 (dt, J )
13.0, 2.1 Hz, 1H), 4.02 (s, 1H), 4.08-4.30 (m, 4H), 5.27 (t, J )
1.9 Hz, 1H), 5.46 (t, J ) 2.4 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3) δ (ppm) 13.89 (q), 13.94 (q), 28.1 (q), 39.1 (q), 59.1 (t),
61.8 (t), 62.2 (t), 66.7 (s), 72.9 (d), 81.7 (s), 111.5 (t), 143.1 (s),
167.1 (s), 168.2 (s), 168.4 (s). Selected HMBC correlations are
participation, which we have reported previously (entry 8).22
The reaction of piperidine amide 1e and ketone derivative 1f
with 16 in the presence of ZnBr2 or InBr3 (1.2 equiv) at room
temperature and InBr3 (0.2 equiv) at 80 °C (entries 9-14) also
gave methylenetetrahydrofurans 17e-f in 63-91% yield.
In summary, zinc- and indium-promoted reactions of ethene-
tricarboxylate derivatives 3 with N-propargylamines and alcohols
afford nitrogen- and oxygen-containing five-membered rings.
Stoichiometric and catalytic conditions were examined. The
present reaction to utilize highly electrophilic substrates provided
an efficient cyclization method. Because the obtained highly
functionalized heterocycle skeletons are biologically of interest,
further transformation of the products to potentially useful
compounds is ongoing.
t
between δ 4.02 (CHCO2 Bu) and δ 59.1 (NCH2), 66.7 (C(CO2-
Et)2), and 143.1 (CdCH2); IR (neat) 1742 cm-1; MS (FAB) m/z
342 (M + H)+; exact mass (M + H)+ 342.1920 (calcd for C17H28-
NO6 342.1917). Anal. Calcd for C17H27NO6: C, 59.81; H, 7.97;
N, 4.10. Found: C, 59.77; H, 8.11; N, 4.09.
Acknowledgment. This work was supported by the Ministry
of Education, Culture, Sports, Science, and Technology of the
Japanese Government. We thank Ms. Y. Nishikawa, Mr. S.
Katao, and Mr. F. Asanoma for assistance in obtaining HRMS
data and elemental analyses.
Experimental Section
Typical Experimental Procedure. A (Table 1, Entry 1): To
a solution of 1a (137 mg, 0.5 mmol) in dichloromethane (0.92 mL)
Supporting Information Available: Additional experimental
procedures, spectral data, and computational data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(21) The formation of 19 presumably arises from participation of
adventitious water in situ.20
(22) Yamazaki, S.; Inaoka, S.; Yamada, K. Tetrahedron Lett. 2003, 44,
1429.
JO0602118
3544 J. Org. Chem., Vol. 71, No. 9, 2006