Convenient synthesis of heterobicycles by domino Heck-Diels-Alder reactions

Article abstract of DOI:10.1002/1099-0690(200105)2001:9<1673::AID-EJOC1673>3.0.CO;2-G

Palladium(0)-catalyzed intramolecular cross coupling of bromodialkenylamines, bromoalkenylalkenamides and bromodialkenyl ethers followed by in situ [4+2] cycloaddition with suitable dienophiles gave tetrahydroisoindolines (31-73%yield), tetrahydroisoindolin-1-ones (43-51%) and hexahydrobenzo[c]furans (35-55%), and hexahydro-1H-[2]pyrindines (66-75%), respectively, each in one-pot operations.

Full text of DOI:10.1002/1099-0690(200105)2001:9<1673::AID-EJOC1673>3.0.CO;2-G

FULL PAPER
Convenient Synthesis of Heterobicycles by Domino Heck؊Diels؊Alder
Reactions
Laxminarayan Bhat,[a] Arno G. Steinig,[a] Ruth Appelbe,[a] and Armin de Meijere*[a]
Dedicated to Professor Frank-Gerrit Klärner on the occasion of his 60th birthday
Keywords: Heck reaction, intramolecular / DielsϪAlder reaction / Tetrahydroisoindolines / Tetrahydroisoindolin-1-ones /
Hexahydrobenzo[c]furans / Hexahydro-1H-[2]pyrindines
Palladium(0)-catalyzed intramolecular cross coupling of bro- yield), tetrahydroisoindolin-1-ones (43−51%) and hexahy-
modialkenylamines, bromoalkenylalkenamides and bromo- drobenzo[c]furans (35−55%), and hexahydro-1H-[2]pyrin-
dialkenyl ethers followed by in situ [4+2] cycloaddition with
dines (66−75%), respectively, each in one-pot operations.
suitable dienophiles gave tetrahydroisoindolines (31−73%
Introduction
hexahydro-1H-[2]pyrindines. Although intramolecular
Heck couplings of bromodialkenylamines and bromodialk-
enyl ethers have been reported,[8,9] the subsequent
DielsϪAlder reactions of the resulting dienes have not been
explored in sufficient detail, especially not in sequential
one-pot operations.
Domino processes are particularly advantageous for the
construction of bi-, tri-, and higher oligocyclic skeletons, as
they allow the regio- and stereocontrolled formation of
more than two new bonds in a single synthetic operation.[1]
Important contributions to this area have been realized util-
izing a combination of cationic, anionic, radical, carbenoid,
and transition metal-catalyzed processes.[1a,2] Among these,
the Heck reaction has in recent years[3] become one of the
most important methods for carbonϪcarbon bond forma-
Results and Discussion
Initial studies were carried out on the easily accessible 2-
tion, since it allows the synthesis of a wide variety of com- bromo-4-aza-1,6-heptadienes 2aϪf with a variety of stand-
pounds using only catalytic amounts of palladium. Further- ard protecting groups on the nitrogen atom in order to ex-
more, it is compatible with a large variety of functional amine their influence on the outcome of the
groups. In earlier reports, we have described the facile con- HeckϪDielsϪAlder reaction. The substrates 2aϪe were
struction of bicyclo[4.3.0]nonenes and bicyclo[4.4.0]decenes prepared from the known allyl(bromoallyl)amine 1[8b] by
by a one-pot sequence consisting of an intramolecular Heck
coupling and a subsequent DielsϪAlder reaction.[4] Con-
sidering the important biological role of heterocyclic com-
pounds, it was logical to extend our earlier work towards
the synthesis of heterocycles having structural features re-
lated closely to those of biologically active natural products
such as illudins,[5] ptaquilosin,[6] and cytochalasins.[7] We
herein report on the palladium-catalyzed intramolecular
cross coupling of various 2-bromo-4-aza- and 2-bromo-4-
oxa-1,6-dienes leading to vicinal bis(methylene)pyrrolidines
and -tetrahydrofurans, which upon in situ [4ϩ2] cycloaddi-
tions with suitable dienophiles give substituted tetrahy-
droisoindolines, tetrahydroisoindolin-1-ones, and hexahy-
drobenzo[c]furans, respectively. We also report on the cor-
responding cyclization of an all-carbon 2-bromo-1,6-diene
followed by DielsϪAlder reaction with iminium ions to give
[a]
Institut für Organische Chemie der Georg-August-Universität
Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
Supporting information for this article is available on the
WWW under http://www.wiley-vch.de/home/eurjoc or from
the author.
Scheme 1. Synthesis of 2aϪf: A: HCO2Et, Et3N, TsOH·H2O, re-
flux, 24 h, 60%; B: Ac2O, Et3N, room temp., 2 d, 81%; C: (tBuO-
CO)2O, THF, reflux, 3 h, 54%; D: BnBr, Et3N, Et2O, 0 °C Ǟ room
temp., 12 h, 80%; E: TsCl, Et3N, THF, 0 °C Ǟ room temp., 5 h,
82%; F: K2CO3, DMF, room temp., 1 h, 98%
Eur. J. Org. Chem. 2001, 1673Ϫ1680
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0509Ϫ1673 $ 17.50ϩ.50/0
1673

L. Bhat, A. G. Steinig, R. Appelbe, A. de Meijere
FULL PAPER
acylation, alkylation, or sulfonylation, whereas the 4-nitro- tions of azabromodienes 2aϪf with dienophiles like methyl
benzenesulfonamide 2f[10a] was obtained by bromoallylation and tert-butyl acrylate (5a and b), di-tert-butyl maleate (5c),
of N-allyl-4-nitrobenzenesulfonamide (3),[10b] which was in acrylonitriles 5d,e also followed an analogous course to give
turn prepared by sulfonylation of allylamine in excellent the corresponding N-protected tetrahydroisoindolines
yield (Scheme 1. The Pd0-catalyzed intramolecular cross 6acϪfe in moderate to good yields (Entries 2Ϫ17, Table 1).
coupling of these terminally unsubstituted bromodienes Similarly, the treatment of 2aϪc and 2e with cyclopropylid-
2aϪf led to the corresponding symmetrical 3,4-bis(methy- eneacetates 5f,g[12,13] under identical reaction conditions af-
lene)-1-azacyclopentane derivatives. Upon in situ forded the tricyclic adducts 6afϪeg in 41Ϫ69% overall
DielsϪAlder reaction with symmetrically or unsymmet- yields (Entries 18Ϫ22, Table 1 and Scheme 2). Consistently,
rically substituted dienophiles, these cyclopentane derivat- the cycloadducts containing N-Boc as well as N-benzyl
ives all gave single cycloadducts (Scheme 2, Table 1).
groups were obtained in lower yields than those with N-
acetyl and N-formyl groups. The yields of the cycloadducts
were found to remain virtually constant when the reactions
were run on a tenfold scale.
In order to study the scope of this domino process, as
well as certain aspects of the regio- and stereochemistry, the
simple N-protected bromodiene system 2 was modified in
three features:
1) The nitrogen atom was replaced by oxygen; 2) a methyl
group was introduced either at the bromoethenyl or at the
ethenyl terminus; and 3) a carbonyl group was introduced
next to the nitrogen atom, i.e. acrylamides were used in-
stead of allylamines. In order to facilitate the analysis of
the regiochemistry and relative configurations of the
HeckϪDielsϪAlder products, methyl acrylate (5a) and
methyl 2-cyclopropylideneacetate (5f) were used as dien-
ophiles.
Scheme 2. HeckϪDielsϪAlder reactions of 2a؊f with dienophiles
5a؊g; for details see Table 1
In a typical experiment, a solution of the N-formylaza-
The methyl-substituted bromoallylamine 7 was prepared
bromodiene 2a (1.2 mmol), tert-butyl acrylate (5b) by allylation of N-benzyl-N-(2-bromo-2-butenyl)amine (8b)
(2.4 mmol), silver carbonate (1.49 mmol), palladium acetate in 78% yield (Scheme 3). Acylation of the bromodialkylam-
(5 mol-%), and 1,2-bis(diphenylphosphanyl)ethane[11] ines 8a,b with acryloyl chloride and crotonyl chloride gave
(dppe) (10 mol-%) in acetonitrile was heated at 80Ϫ85 °C the corresponding amides 9a,b and 10, respectively, in
for 24 h. The isolated product (54% yield) was characterized nearly quantitative yields (Scheme 3). The oxygen-con-
as N-formyltetrahydroisoindoline 6ab (Scheme 2). The reac- taining bromodienes 12 and 15 were prepared from the ap-
Table 1. HeckϪDielsϪAlder reactions of bromodialkenylamines 2aϪf with dienophiles 5a؊g
Entry[a]
Diene 2
Dienophile 5
Product 6
R1
R2
R3
R4
R5
Yield (%)
1
2
a
a
a
a
b
b
b
b
b
c
d
e
e
e
e
f
b
c
d
e
a
b
c
d
e
a
a
a
b
d
e
a
b
f
ab
ac
CHO
CHO
CHO
CHO
MeCO
MeCO
MeCO
MeCO
MeCO
Boc
H
H
H
Cl
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
Cl
Cl
Cl
Cl
CO2tBu
CO2tBu
CN
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
54
56
63
44
54
62
55
60
46
45
46
45
51
31
31
48
73
41
45
69
43
44
CO2tBu
3
ad
ae
H
H
4
CN
5
ba
bb
bc
CO2Me
CO2tBu
CO2tBu
CN
H
6
H
7
CO2tBu
H
8
bd
be
9
CN
H
10
11
12
13
14
15
16
17
18
19
20
21
22
ca
CO2Me
CO2Me
CO2Me
CO2tBu
CN
H
da
ea
Bn
H
Ts
H
eb
Ts
H
ed
Ts
H
ee
Ts
CN
H
fa[b,c]
fb[b]
af
pNbs[d]
pNbs
CHO
CHO
MeCO
Boc
CO2Me
CO2tBu
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
H
f
H
a
a
b
c
e
Ϫ(CH2CH2)Ϫ
g
g
g
g
ag
bg
cg
Ϫ(CH2CH2)Ϫ
Ϫ(CH2CH2)Ϫ
Ϫ(CH2CH2)Ϫ
Ϫ(CH2CH2)Ϫ
eg
Ts
[a]
Reaction conditions: 2 (1.2 mmol), 5 (2.4 mmol), Pd(OAc)2 (5 mol-%), dppe (10 mol-%), Ag2CO3 (1.49 mmol), MeCN, 80Ϫ85 °C,
[b]
[c]
[d]
24Ϫ36 h. Ϫ Reaction time 2 h. Ϫ PPh3 (10 mol-%) instead of dppe. Ϫ pNbs ϭ 4-NO2C6H4SO2.
1674 Eur. J. Org. Chem. 2001, 1673Ϫ1680

Convenient Synthesis of Heterobicycles by Domino HeckϪDielsϪAlder Reactions
FULL PAPER
propriate allyl alcohols 11 and 14, and allyl bromides 4 and by the terminal methyl group, preferring the quasi-ortho iso-
13 by simple alkylation using NaH in anhydrous THF or mer (Scheme 5). Reaction of the amide 9a with dienophile
basic phase transfer catalytic conditions for deprotonation 5a afforded two regioisomers in a 60:40 ratio in 43% yield.
of the alcohols, in 76 and 55% yields, respectively Thus, the amide group exerts a considerably weaker influ-
(Scheme 4).
ence on the regioselectivity of the final DielsϪAlder reac-
tion than the terminal methyl group. Interestingly, the
amide 10, having an amide and a methyl group on the same
side of the diene 17c, under identical reaction conditions
afforded only product 18c in 46% yield. Evidently, both
substituents ‘‘co-operate’’ to exert a decisive influence on
the regio- and stereochemistry of the product 18c. The
amide 9b, with the amide and the methyl group now on
opposite sides of the diene intermediate, afforded an insep-
arable mixture of two regioisomers 18d/19d and 20d/21d in
a 15:85 ratio (54% yield). The major regioisomer was a 4.4:1
mixture of diastereomers 20d and 21d (Scheme 5, Table 2).
Scheme 3. Synthesis of 7, 9, and 10: A: allyl bromide, Et2O, 0 °C
Ǟ room temp., 12 h, 78%; B: acryloyl chloride, Et3N, Et2O, 0 °C
Ǟ room temp., 3 h; C: crotonyl chloride, Et3N, Et2O, 0 °C Ǟ room
temp., 5 h, 89%
Scheme 5. HeckϪDielsϪAlder reactions of 16 (corresponding to
7, 9, 10, 12, and 15) with methyl acrylate (5a); ‘‘Pd’’: Pd(OAc)2,
dppe, Ag2CO3, MeCN, 80Ϫ85 °C; for further details see Table 2
Scheme 4. Synthesis of 12 and 15
The reaction of bromodialkenylamine 7 with methyl ac-
Treatment of the bromodialkenyl ether 12 with a palla-
rylate (5a) under HeckϪDielsϪAlder reaction conditions dium catalyst and methyl acrylate (5a) under
afforded an inseparable mixture of two pairs of regioiso- HeckϪDielsϪAlder conditions gave the hexahydroisoben-
meric diastereomers 18a/19a and 20a/21a in a 16:84 ratio zofuran 18e in 42% yield. The terminally monomethyl-sub-
and 41% yield. The major regioisomer was found to be a stituted ether 15, under identical reaction conditions, af-
5.8:1 mixture of diastereoisomers 20a and 21a, while the forded the expected mixture of four diastereomers 18fϪ21f
diastereomeric ratio of the minor regioisomer 18a/19a could in 55% yield. The major regioisomer was found to be a 4.2:1
not be determined from the 1H NMR spectrum of the mix- mixture of diastereomers 20f and 21f (Scheme 5, Table 2).
ture of these four diastereomers since the peaks were not Further, the domino HeckϪDielsϪAlder reactions of bro-
well resolved. Apparently, the regioselectivity of the [4ϩ2] modienes 7, 10, 12, and 15 with methyl cyclopropylidene-
cycloaddition of the intermediate diene from 7 is controlled acetate 5f also followed a similar course to give the corres-
Table 2. Domino HeckϪDielsϪAlder reactions of 16, bromodiene 7, 9, 10, 12, or 15 and methyl acrylate (5a)
Entry[a]
Bromodiene
Main product
Yield (%)
Diast. ratio[b] of major regioisomer
Regioisomer ratio[b] (18ϩ19)/(20ϩ21)
1
2
3
4
5
6
7
20a
18b
18c
20d
18e
20f
43
43
46
54
42
55
20a/21a, 5.8:1
16:84
60:40
Ϫ
15:85
Ϫ
9a
10
9b
12
15
Ϫ
18c
20d/21d, 4.4:1
Ϫ
20f/21f, 4.2:1
14:86
[a]
Reaction conditions: bromodiene (1.2 mmol), 5a (2.4 mmol), Pd(OAc)2 (5 mol-%), dppe (10 mol-%), Ag2CO3 (1.49 mmol), MeCN,
[b]
1
80Ϫ85 °C, 24Ϫ36 h. Ϫ The ratios were determined by integration of the relevant peaks in the H NMR spectra.
Eur. J. Org. Chem. 2001, 1673Ϫ1680
1675

L. Bhat, A. G. Steinig, R. Appelbe, A. de Meijere
FULL PAPER
ponding spirocyclopropane-annelated adducts 22Ϫ25 in influence on the Heck as well as the subsequent
31Ϫ49% overall yields (Scheme 6, Table 3). In those cases DielsϪAlder reaction.
where regio- and diastereomers could be formed, 5f consist-
Our previously reported HeckϪDielsϪAlder sequence
ently showed a higher selectivity than 5a (compare e.g. with the all-carbon bromodiene 29[4] could be extended to-
Table 2, Entry 1 with Table 3, Entry 1).
wards iminium ions as dienophiles to also give heterobi-
cycles (Scheme 8).[15] This, however, requires a two-step
procedure, yet still in one pot. Towards this end, after heat-
ing the bromodiene 29 with palladium acetate (6 mol-%),
triphenylphosphane (13 mol-%), and silver carbonate (52
mol-%) in acetonitrile to 80Ϫ85 °C for 45 min to form the
diene 30, the reaction mixture was diluted with the same
volume of water. Following this, aqueous formaldehyde so-
lution (10 equiv.) and the amine hydrochloride 31 (2 equiv.)
were added, and the reaction mixture was stirred for 4 d at
ambient temperature. The hexahydro-1H-[2]pyrindines 32-
R were isolated in 66Ϫ75% yield. These compounds possess
the ring system of tecomanine, which was reported to have
hypoglycemic properties,[16] and related skytanthine[17] al-
kaloids. A benzannelated analog of 32 showed high affinity
for the dopamine D2 receptor.[18]
Scheme 6. HeckϪDielsϪAlder reactions of 16 (corresponding to
7, 10, 12, and 15) with methyl cyclopropylideneacetate (5f); ‘‘Pd’’:
Pd(OAc)2, dppe, Ag2CO3, MeCN, 80Ϫ85 °C; for further details see
Table 3
Although tetrahydroisoindolin-1-ones could be prepared
by this route, an attempt to synthesize tetrahydrophthalides
by the same strategy was not successful. The required allyl
acrylates 26 and 28 were prepared by esterification[14] of
acrylic acid and bromoacrylic acid with 2,3-dibromoprop-
ene and allyl bromide, respectively, in the presence of potas-
sium fluoride in DMF in excellent yields. However, the es-
ters 26 and 28 failed to give any clear-cut products under
various reaction conditions (Scheme 7). From a mechanistic
point of view it was also quite interesting to examine these
systems under conditions of the HeckϪDielsϪAlder se-
quence since the alkenyl moiety of the bromodienes be-
comes increasingly electron deficient in the order of al-
lylamines, allyl ethers, α,β-unsaturated amides, and α,β-un-
saturated esters. This must be expected to have considerable
Scheme 8. Synthesis of 2,3,4,5,6,7-hexahydro-1H-[2]pyrindines 32:
A: Pd(OAc)2 (6 mol-%), PPh3 (13 mol-%), Ag2CO3 (0.52 equiv.),
MeCN, 85 °C, 45 min; B: H2O/MeCN 1:1, 20 °C, 4 d
Conclusion
A new one-pot synthesis of hitherto unknown hexahy-
dro-1H-[2]pyrindines, tetrahydroisoindolines, tetrahydroiso-
indolin-1-ones, and hexahydrobenzo[c]furans has been ac-
complished. Although the yields of the latter three types of
products are not very high, this approach is particularly
attractive as the bromodialkenyl amines, ethers, and bro-
moalkenylalkenamides can be prepared efficiently on a
large scale in good yields, and most of the cycloaddition
reactions are reasonably regio- and stereoselective.
Scheme 7. Attempted cyclization of bromodienes 26 and 28
Table 3. Domino HeckϪDielsϪAlder reaction of 16, bromodiene (7, 10, 12, or 15), and methyl cyclopropylideneacetate (5f)
Entry[a] Bromodiene Main product Yield (%) Diastereomer ratio[b] of major regioisomer Regioisomer ratio[b] (22ϩ23)/(24ϩ25)
1
2
3
4
7
24a
22c
22d
24e
40
49
31
41
24a/25a, 11.1:1
9:91
Ϫ
Ϫ
10
12
15
22b
Ϫ
24d/25d, 6.6:1
11:89
[a]
Reaction conditions: bromodiene (1.2 mmol), 5f (2.4 mmol), Pd(OAc)2 (5 mol-%), dppe (10 mol-%), Ag2CO3 (1.49 mmol), MeCN,
[b]
1
80Ϫ85 °C, 24Ϫ36 h. Ϫ The ratios were determined by integration of the relevant peaks in the H NMR spectra.
1676 Eur. J. Org. Chem. 2001, 1673Ϫ1680

Convenient Synthesis of Heterobicycles by Domino HeckϪDielsϪAlder Reactions
FULL PAPER
1.52 [s, 9 H, C(CH3)3], 3.75Ϫ3.96 (m, 2 H, CH2CHϭ), 3.98Ϫ4.15
(m, 2 H, CH2CBrϭ), 5.05Ϫ5.22 (m, 2 H, CHϭCH2), 5.08Ϫ5.83
(m, 3 H, CHϭCH2 and CBrϭCH2). Ϫ 13C NMR (62.9 MHz,
CDCl3); 2 rotamers: δ ϭ 27.3, 28.2 (CH3), 48.5, 49.0 (CH2CHϭ),
53.5 (CH2CBrϭ), 80.2, 85.1 [C(CH3)3], 116.6 (CHϭCH2), 117.2
(CBrϭCH2), 129.6 (CBrϭCH2), 133.3 (CHϭCH2), 146.7, 157.6
[CO2C(CH3)3]. Ϫ MS (EI, 70 eV), m/z (%) ϭ 221/219 (12/12) [Mϩ
Ϫ C4H8], 140 (80), 57 (100), 41 (28). Ϫ C11H18BrNO2: 275.0521
(HRMS).
Experimental Section
1H NMR and 13C NMR spectra were recorded with a Bruker AM
250 (250 MHz for 1H, 62.9 MHz for 13C) instrument at ambient
temperature in CDCl3 with TMS and the triplet of CDCl3 (δ ϭ
77.0), respectively, as internal standards. The line position or mul-
tiplets are given in ppm (δ) and the coupling constants (J) are given
as absolute values in Hertz, while the signal multiplicities are abbre-
viated as follows: s (singlet), brs (broad singlet), d (doublet), t (trip-
let), q (quadruplet), m (multiplet), mc (centered multiplet), AB (AB
system). The proportions of the minor products in inseparable mix-
tures were assigned from the NMR spectra of the mixtures.
Infrared spectra were recorded with a Bruker IFS 66 FT-IR instru-
ment. Ϫ Mass spectra were recorded using electron impact ioniza-
tion at 70 eV. High resolution mass spectra (HRMS) were recorded
using preselected ion peak matching at R ഠ 10000 to be within
Ϯ2 ppm. Ϫ All melting points were determined with a Reichert
microscopic hot stage apparatus and are uncorrected. Ϫ Elemental
analyses were carried out in the Mikroanalytisches Laboratorium
der Universität Göttingen, Germany. Ϫ Solvents and reagents were
dried and purified according to standard methods. All solvents for
chromatography or recrystallizations were distilled prior to use,
while dry diethyl ether and tetrahydrofuran (THF) were distilled
from sodium benzophenone ketyl under nitrogen immediately be-
fore use. N-(2-Bromo-2-propenyl)-N-(2-propenyl)amine (1), N-(2-
bromo-2-propen-1-yl)-N-(2-propenyl)acetamide (2b), 2-bromo-2-
propen-1-yl 2-propenyl ether (12),[8b] N-benzyl-N-(2-bromo-2-pro-
pen-1-yl)-N-(2-propenyl)amine (2d),[19] and diethyl (2-bromo-2-
propenyl)(2-propenyl)malonate (29)[4] were prepared according to
previously reported methods.
N-(2-Bromo-2-propen-1-yl)-N-(2-propen-1-yl)-4-toluenesulfonamide
(2e): To a stirred solution of 1 (3.52 g, 20 mmol) in THF (50 mL)
was added triethylamine (2.02 g, 20 mmol) at room temperature.
The reaction mixture was cooled to 0 °C, and a solution of p-
toluenesulfonyl chloride (3.81 g, 20 mmol) in THF (25 mL) was ad-
ded dropwise. The resulting mixture was stirred at room temper-
ature for 5 h. The reaction mixture was concentrated in a rotary
evaporator. The residue was dissolved in CH2Cl2 (100 mL), and the
solution washed with saturated aq. NaHCO3 solution (2 ϫ 15 mL)
and water (2 ϫ 25 mL), and dried with MgSO4. After evaporation
of the solvent, the crude product was purified by passing it through
a short silica gel column eluting with hexane to give 5.41 g (82%)
of 2e as a colorless viscous liquid. Ϫ IR (film): ν˜ ϭ 2922 cmϪ1
,
1629, 1597, 1494, 1347, 1305, 1159, 1092, 902. Ϫ 1H NMR
(250 MHz, CDCl3): δ ϭ 2.42, 2.48 (s, 3 H, CH3), 3.83 (brd, 2 H,
J ϭ 6.6 Hz, CH2CHϭ), 4.01 (s, 2 H, CH2CBrϭ), 5.09Ϫ5.23 (m, 2
H, CHϭCH2), 5.55Ϫ5.62 (m, 1 H, CHϭCH2), 5.59 (brs, 1 H,
CBrϭCH2), 5.84 (brs, 1 H, CBrϭCH2), 7.40 (d, 2 H, J ϭ 8.4 Hz,
Ar-H), 7.72 (d, 2 H, J ϭ 8.4 Hz, Ar-H). Ϫ 13C NMR (62.9 MHz,
CDCl3): δ ϭ 21.5 (CH3), 49.98 (CH2CHϭ), 53.8 (CH2CBrϭ),
119.3 (CHϭCH2), 119.9 (CBrϭCH2), 127.3, 129.7 (CHarom), 131.9
(CHϭCH2), 137.1 (CBrϭCH2), 143.5, 158.1 (Carom). Ϫ MS (EI,
70 eV), m/z (%) ϭ 331/329 (1/1) [Mϩ], 250 (100), 155 (35), 91 (52).
Ϫ C13H16BrNO2S: 329.0085 (HRMS); calcd. C 47.28, H 4.88, N
4.24; found C 47.53, H 4.87, N 4.00.
N-(2-Bromo-2-propen-1-yl)-N-(2-propen-1-yl)formamide (2a): A so-
lution of N-(2-bromo-2-propenyl)-N-(2-propenyl)amine (1) (8.79 g,
50 mmol), triethylamine (5.05 g, 50 mmol), p-toluenesulfonic acid
monohydrate (0.2 g), and ethyl formate (100 mL) was heated under
reflux for 24 h (monitored by TLC). After cooling to room temper-
ature, the reaction mixture was concentrated. The residue was dis-
solved in CH2Cl2 (100 mL), the solution washed with saturated aq.
NaHCO3 solution (2 ϫ 25 mL) followed by water (2 ϫ 50 mL).
Drying with MgSO4 and evaporation of the solvent yielded the
crude product, which was distilled under reduced pressure (b.p.
43 °C/0.1 Torr) to yield 6.09 g (60%) of 2a as a colorless oil. Ϫ
IR (film): ν˜ ϭ 2917 cmϪ1, 2867, 1679, 1642, 1397, 1283, 1217,
N-(2-Bromo-2-propen-1-yl)-N-(2-propen-1-yl)-(4-nitrobenzene)-
sulfonamide (2f): To a stirred solution of sulfonamide 3 (2.30 g,
9.49 mmol) and 2,3-dibromo-1-propene (4) (2.08 g, 10.4 mmol) in
DMF (20 mL) was added K2CO3 (2.62 g, 19.0 mmol) at room tem-
perature, and stirring was continued for 1 h. The reaction mixture
was worked up by adding water (30 mL), extracting with CH2Cl2
(4 ϫ 20 mL), washing the combined organic phases with brine
(30 mL), and drying with Na2SO4. The crude product obtained
after removal of CH2Cl2 contained much DMF, and therefore did
not crystallize. It was purified by chromatography on a silica gel
column eluting with CH2Cl2 to give 3.35 g (98%) of 2f as a colorless
1
1145, 978, 926. Ϫ H NMR (250 MHz, CDCl3); 2 rotamers: δ ϭ
3
3
3.87 (d, 1 H, J ϭ 5.9 Hz, CH2CHϭ), 3.94 (d, 1 H, J ϭ 6.1 Hz,
CH2CHϭ), 4.00 (s, 1 H, CH2CBrϭ), 4.20 (s, 1 H, CH2CBrϭ),
5.18Ϫ5.39 (m, 2 H, CHϭCH2), 5.71Ϫ5.85 (m, 3 H, CHϭCH2 and
CBrϭCH2), 8.14 and 8.20 (s, 1 H, CHO). Ϫ 13C NMR (62.9 MHz,
CDCl3); 2 rotamers: δ ϭ 43.5, 48.7 (CH2CHϭ), 48.9, 54.3
(CH2CBrϭ), 118.5, 119.0 (CHϭCH2), 119.2, 120.1 (CBrϭCH2),
127.0, 128.5 (CBrϭCH2), 131.4, 132.2 (CHϭCH2), 162.4, 162.5
(CHO). Ϫ MS (EI, 70 eV), m/z (%) ϭ 205/203 (2/2) [Mϩ], 124
(100), 41 (18). Ϫ C7H10BrNO: 202.9945 (HRMS); calcd. C 41.20,
H 4.94, N 6.86; found C 40.92, H 5.19, N 6.76.
solid, m.p. 58Ϫ59 °C. Ϫ IR (non-solidified melt): ν˜ ϭ 3105 cmϪ1
,
2983, 2924, 2868, 1937, 1810, 1629, 1606, 1531, 1477, 1421, 1402,
1351, 1312, 1265, 1165, 1108, 1091, 1062, 1013, 992, 909. Ϫ
1H NMR (250 MHz, CDCl3): δ ϭ 3.92 (d, 2 H, 3J ϭ 6.4 Hz,
CH2CHϭ), 4.12 (s, 2 H, CH2CBrϭ), 5.15Ϫ5.26 (m, 2 H, CHϭ
CH2), 5.62 (ddt, 1 H, 3J ϭ 16.7, 3J ϭ 10.4, 3J ϭ 6.4 Hz, CHϭ
2
2
CH2), 5.63 (d, 1 H, J ϭ 1.6 Hz, CBrϭCH2), 5.84 (dt, 1 H, J ϭ
tert-Butyl N-(2-Bromo-2-propen-1-yl)-N-(2-propen-1-yl)carbamate 1.6, 4J ϭ 1.3 Hz, CBrϭCH2), 8.01Ϫ8.07 and 8.33Ϫ8.39 (4 H,
(2c): To a stirred solution of 1 (3.52 g, 20 mmol) in THF (50 mL)
was added di-tert-butyl dicarbonate (4.36 g, 20 mmol) at room tem-
perature. The reaction mixture was heated under reflux for 3 h
(monitored by TLC), then the solvent was evaporated. The crude
product was purified by chromatography on silica gel, eluting with
AAЈBBЈ, Ar-H). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ 49.8
(CH2CHϭ), 53.9 (CH2CBrϭ), 120.6 (CBrϭCH2), 120.7 (CHϭ
CH2), 124.2 (CHarom), 127.1 (CBrϭCH2), 128.5 (CHarom), 131.2
(CHϭCH2), 146.0, 149.9 (Carom). Ϫ MS (70 eV), m/z (%) ϭ 362/
360 (1/1) [Mϩ], 335/333 (1/1), 281 (100), 255 (13), 241 (5), 186 (21)
pentane/diethyl ether (9:1) to give 3.0 g (54%) of 2c as a colorless 176/174 (7/7), 148/146 (4/4), 122 (35), 121/119 (7/7), 94 (16), 76 (9).
oil. Ϫ IR (film): ν˜ ϭ 2978 cmϪ1, 1710, 1640, 1455, 1404, 1366, Ϫ C12H13BrN2O4S (361.2): calcd. C 39.90, H 3.63, Br 22.12; found
1248, 1161. Ϫ 1H NMR (250 MHz, CDCl3); 2 rotamers: δ ϭ 1.46,
Eur. J. Org. Chem. 2001, 1673Ϫ1680
C 39.80, H 3.64, Br 21.92.
1677

L. Bhat, A. G. Steinig, R. Appelbe, A. de Meijere
FULL PAPER
General Procedure for the Domino Heck؊Diels؊Alder Reactions:
139.5 (Carom). Ϫ MS (EI, 70 eV), m/z (%) ϭ 227/225 (11/11) [Mϩ],
To a stirred solution of bromodiene (1.2 mmol) in acetonitrile 146 (26), 120 (32), 91 (100). Ϫ C10H12BrN: 225.0153 (HRMS).
(5 mL) in screw-cap Pyrex bottle were added dienophile
a
N-Benzyl-N-[(2E)-2-bromo-2-buten-1-yl]amine (8b): This compound
was prepared by alkylation of benzylamine (2.14 g, 20 mmol) with
1,2-dibromo-2-butene (4.28 g, 20 mmol) according to the procedure
applied for the amine 8a, and it was obtained as a colorless oil in
94% (4.5 g) yield. Ϫ IR (film): ν˜ ϭ 3328 cmϪ1, 3026, 2917,
2837, 1644, 1603, 1494. Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ
(2.4 mmol), Pd(OAc)2 (14 mg, 5 mol-%), dppe (48 mg, 10 mol-%),
and silver carbonate (410 mg, 1.49 mmol). The solution was purged
with argon and then stirred in the sealed bottle at 80Ϫ85 °C for
24Ϫ36 h (monitored by TLC). The reaction mixture was filtered
through a bed of charcoal and Celite, and the solvent was removed
under reduced pressure. The residue was purified by chromato-
graphy on silica gel eluting with a 10Ϫ100% gradient of pentane/
diethyl ether.
3
1.60 (d, 3 H, J ϭ 7.3 Hz, CH3), 1.82 (brs, 1 H, NH), 3.50 (s, 2 H,
CH2CBrϭ), 3.72 (s, 2 H, CH2C6H5), 6.15 (q, 1 H, 3J ϭ 7.3 Hz,
ϭCHCH3), 7.28Ϫ7.35 (m, 5 H, Ar-H). Ϫ 13C NMR (62.9 MHz,
CDCl3): δ ϭ 15.0 (CH3), 50.0 (CH2CBrϭ), 51.2 (CH2C6H5), 125.3
(CBrϭCHCH3), 127.0 (CBrϭCHCH3), 128.3, 128.4, 129.6
(CHarom), 139.7 (Carom). Ϫ MS (EI, 70 eV), m/z (%) ϭ 241/239 (10/
10) [Mϩ], 160 (23), 120 (17), 106 (30), 91 (100). Ϫ C11H14BrN:
239.0309 (HRMS).
tert-Butyl
2-Formyl-4,5,6,7-tetrahydroisoindoline-5-carboxylate
(6ab): Colorless oil, 54%. Ϫ IR (film): ν˜ ϭ 2931 cmϪ1, 1724, 1700,
1669, 1417, 1369. Ϫ 1H NMR (250 MHz, CDCl3); 2 rotamers: δ ϭ
1.45 [s, 9 H, C(CH3)3], 1.68Ϫ1.82 (brm, 1 H, 6-H), 1.99Ϫ2.12 [brm,
3 H, 6(7)-H], 2.17Ϫ2.22 (brm, 2 H, 4-H), 2.49Ϫ2.59 (brm, 1 H, 5-
H), 4.08, 4.20 [brs, 4 H, 1(6)-H], 8.29 (s, 1 H, CHO). Ϫ 13C NMR
(62.9 MHz, CDCl3); 2 rotamers: δ ϭ 22.1, 22.5 (C-6), 24.9, 25.0
(C-7), 25.3, 25.5 (C-4), 27.9 [C(CH3)3], 40.0 (C-5), 52.7, 52.8, 54.4,
54.5 [C-1(3)], 80.3 [C(CH3)3], 127.8, 128.6, 128.9, 129.7 [C-3a(7a)],
160.8 (CHO), 174.2 [CO2C(CH3)3]. Ϫ MS (EI, 70 eV), m/z (%) ϭ
251 (8) [Mϩ], 195 (100), 178 (20), 150 (53), 123 (44), 57 (38). Ϫ
C14H21NO3 (251.3): calcd. C 66.90, H 8.42, N 5.57; found C 66.69,
H 8.39, N 5.58.
N-Benzyl-N-(2-bromo-2-propen-1-yl)propenamide (9a): To a stirred
solution of 8a (2.26 g, 10 mmol) and triethylamine (1.05 g,
10 mmol) in diethyl ether (25 mL) was added dropwise acryloyl
chloride (0.90 g, 10 mmol) at 0 °C. The resulting mixture was
stirred at room temperature for 3 h. The reaction mixture was fil-
tered, and the precipitated triethylammonium hydrochloride was
washed with diethyl ether (2 ϫ 10 mL). The combined filtrates were
washed successively with saturated aq. NaHCO3 solution (10 mL)
and water (2 ϫ 25 mL). After drying with MgSO4 and evaporating
the solvent, the crude product was purified by passing it through a
short column of silica gel eluting with pentane/diethyl ether
(3:1) to yield 2.75 g (98%) of 9a as a colorless oil. Ϫ IR (film):
ν˜ ϭ 3030 cmϪ1, 1654, 1618, 1495. Ϫ 1H NMR (250 MHz,
CDCl3); 2 rotamers: δ ϭ 4.07, 4.32 (s, 2 H, CH2C6H5), 4.65 (s, 1
H, CH2CBrϭ), 4.67 (s, 1 H, CH2CBrϭ), 5.62Ϫ5.70 (m, 1 H, CHϭ
CH2), 5.71Ϫ5.83 (m, 2 H, CBrϭCH2), 6.45Ϫ6.59 (m, 2 H, CHϭ
CH2), 7.16Ϫ7.47 (m, 5 H, Ar-H). Ϫ 13C NMR (62.9 MHz, CDCl3);
2 rotamers: δ ϭ 48.4, 50.2 (CH2CBrϭ), 52.6, 54.1 (CH2C6H5),
117.9, 118.7 (CHϭCH2), 126.4, 127.0, 127.6, 127.8, 128.3, 128.7,
128.9 (CHϭCH2 and CHarom), 128.0 (CBrϭCH2), 129.5, 129.7
(CHϭCH2), 136.6 (Carom), 166.9 (CO). Ϫ MS (EI, 70 eV), m/z
(%) ϭ 281/279 (10/10) [Mϩ], 200 (30), 160 (12), 155 (27), 140 (22),
120 (8), 106 (38), 91 (78), 86 (100), 55 (86). Ϫ C13H14BrNO:
279.0258 (HRMS).
N-Benzyl-N-(2-bromo-2-buten-1-yl)-N-(2-propen-1-yl)amine (7): To
a stirred solution of 8b (2.40 g, 10 mmol) in diethyl ether (25 mL)
was added dropwise allyl bromide (0.60 g, 5 mmol) at 0 °C. The
resulting mixture was stirred overnight at room temperature. The
reaction mixture was filtered and the precipitate washed with di-
ethyl ether (2 ϫ 10 mL). The combined filtrates were washed with
water (2 ϫ 25 mL), dried with MgSO4, and the solvent was evapor-
ated. The crude product was purified by passing it through a short
column of silica gel and eluting with pentane to give 1.09 g (78%)
of 7 as a colorless oil. Ϫ IR (film): ν˜ ϭ 3026 cmϪ1, 2920, 2804,
1642, 1494. Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ 1.70 (d, 3 H, 3J ϭ
3
7.3 Hz, CH3), 3.13 (d, 2 H, J ϭ 6.3 Hz, CH2CHϭ), 3.33 (s, 2 H,
CH2CBrϭ), 3.62 (s, 2 H, CH2C6H5), 5.19Ϫ5.30 (m, 2 H, CHϭ
CH2), 5.88Ϫ6.07 (m, 1 H, CHϭCH2), 6.16 (q, 1 H, 3J ϭ 7.3 Hz, ϭ
CHCH3), 7.30Ϫ7.45 (m, 5 H, Ar-H). Ϫ 13C NMR (62.9 MHz,
CDCl3): δ ϭ 15.4 (CH3), 55.4 (CH2CHϭ), 55.9 (CH2CBrϭ), 57.2
(CH2C6H5), 117.0 (CHϭCH2), 123.7 (CBrϭCHCH3), 126.9, 128.1,
128.9 (CHarom), 130.5 (CHϭCH2), 135.5 (CBrϭCH2), 139.2 (Ca-
rom). Ϫ MS (EI, 70 eV), m/z (%) ϭ 281/279 (3/3) [Mϩ], 200 (7), 160
(30), 147 (20), 120 (10), 106 (15), 91 (100). Ϫ C14H18BrN:
279.0622 (HRMS).
N-Benzyl-N-[(2E)-2-bromo-2-buten-1-yl]propenamide (9b): This
compound was prepared by acylation of the amine 8b (2.40 g,
10 mmol) with acryloyl chloride (0.90 g, 10 mmol) according to the
procedure described for the amide 9a, as a colorless oil in 95%
(2.80 g) yield. Ϫ IR (film): ν˜ ϭ 2924 cmϪ1, 1653, 1615. Ϫ 1H NMR
(250 MHz, CDCl3); 2 rotamers: δ ϭ 1.53, 1.57 (2 d, 3 H, 3J ϭ
7.5 Hz, ϭCHCH3), 4.15, 4.39 (s, 2 H, CH2C6H5), 4.66 (brs, 2 H,
CH2CBrϭ), 5.69Ϫ5.80 (m, 1 H, ϭCHCH3), 6.12Ϫ6.19 (m, 1 H,
CHϭCH2), 6.38Ϫ6.71 (m, 2 H, CHϭCH2), 7.18Ϫ7.46 (m, 5 H,
Ar-H). Ϫ 13C NMR (62.9 MHz, CDCl3); 2 rotamers: δ ϭ 14.9,
19.0 (CH3), 46.3, 47.0 (CH2C6H5), 47.4, 50.0 (CH2CBrϭ), 119.8,
120.4 (CBrϭCHCH3), 125.6, 126.4, 127.6, 127.8, 128.0, 128.4,
128.7 (CBrϭCHCH3 and CHarom), 129.0, 130.5 (CHϭCH2), 131.6,
131.8 (CHϭCH2), 136.2, 136.6 (Carom), 166.9, 167.1 (CO). Ϫ MS
(70 eV), m/z (%) ϭ 295/293 (11/11) [Mϩ], 214 (65), 106 (46), 91
(100), 69 (91). Ϫ C14H16BrNO: 293.0415 (HRMS).
N-Benzyl-N-(2-bromo-2-propen-1-yl)amine (8a): To a stirred solu-
tion of benzylamine (2.14 g, 20 mmol) and triethylamine (2.02 g,
20 mmol) in diethyl ether (50 mL) was added dropwise a solution
of 2,3-dibromopropene (3.99 g, 20 mmol) in diethyl ether (10 mL).
The reaction mixture was stirred overnight at room temperature.
This was then filtered, and the precipitate washed with diethyl ether
(3 ϫ 15 mL). The combined filtrates were washed with water (2 ϫ
25 mL), dried with MgSO4, and the solvent was evaporated. The
crude product was chromatographed on silica gel eluting with hex-
ane to give 3.21 g (71%) of 8a as a colorless oil. Ϫ IR (film): ν˜ ϭ
3338 cmϪ1, 3027, 2833, 1625. Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ
1.81 (brs, 1 H, NH), 3.47 (s, 2 H, CH2CBrϭ), 3.74 (s, 2 H, (2E)-N-Benzyl-N-(2-bromo-2-propen-1-yl)-2-butenamide (10): This
CH2C6H5), 5.61 (d, 1 H, 2J ϭ 1.7 Hz, CBrϭCH2), 5.80 (d, 1 H,
amide was prepared by acylation of the amine 8a (2.26 g, 10 mmol)
2J ϭ 1.7 Hz, CBrϭCH2), 7.28Ϫ7.39 (m, 5 H, Ar-H). Ϫ 13C NMR with crotonyl chloride (1.05 g, 10 mmol) according to the proced-
(62.9 MHz, CDCl3): δ ϭ 51.4 (CH2CBrϭ), 56.5 (CH2C6H5), 117.9 ure applied for the amide 9a, as a light yellow viscous liquid in
(CBrϭCH2), 127.0, 128.2, 128.4 (CHarom), 133.4 (CBrϭCH2), 89% (2.62 g) yield. Ϫ IR (film): ν˜ ϭ 3029 cmϪ1, 2970, 2913, 1714,
1678
Eur. J. Org. Chem. 2001, 1673Ϫ1680

Convenient Synthesis of Heterobicycles by Domino HeckϪDielsϪAlder Reactions
FULL PAPER
3
4
1662, 1626, 1495. Ϫ 1H NMR (250 MHz, CDCl3); 2 rotamers: δ ϭ 1Ј-H), 5.30 (dq, 1 H, J ϭ 10.4, J ϭ 2J ϭ 1.2 Hz, 3Ј-H), 5.39 (dq,
1.91 (dd, 3 H, 3J ϭ 6.9, 4J ϭ 1.6 Hz, CH3), 4.06, 4.29 (s, 2 H, 1 H, 3J ϭ 17.2, 4J ϭ 2J ϭ 1.5 Hz, 3Ј-H), 5.96 (ddt, 1 H, 3J ϭ 17.2,
2
CH2C6H5), 4.65 (brs, 2 H, CH2CBrϭ), 5.63Ϫ5.79 (m, 2 H, CBrϭ
3J ϭ 10.4, 3J ϭ 5.7 Hz, 2Ј-H), 6.30 (d, 1 H, J ϭ 1.7 Hz, 3-HZ),
CH2), 6.12Ϫ6.32 (m, 1 H, CHϭCHCH3), 6.95Ϫ7.18 (m, 1 H, CHϭ 7.00 (d, 1 H, 2J ϭ 1.7 Hz, 3-HE). Ϫ 13C NMR (62.9 MHz, CDCl3):
CHCH3), 7.19Ϫ7.41 (m, 5 H, Ar-H). Ϫ 13C NMR (62.9 MHz, δ ϭ 67.1 (C-1Ј), 119.0 (C-3Ј), 121.1 (C-2), 130.9 (C-3), 131.2 (C-
CDCl3); 2 rotamers: δ ϭ 18.3 (CH3), 48.4, 50.0 (CH2CBrϭ), 52.5,
2Ј), 161.5 (CϭO). Ϫ C6H7BrO2 (191.0): calcd. C 37.73, H 3.69;
54.1 (CH2C6H5), 117.6, 118.3 (CBrϭCH2), 120.9, 121.1 (CHϭ found C 37.64, H 3.69.
CHCH3), 127.5, 127.7, 128.2, 128.6, 128.9 (CHarom), 127.9, 128.2
Diethyl 2-Methoxycarbonylmethyl-2,3,4,5,6,7-hexahydro-1H-[2]pyr-
(CBrϭCH2), 136.9, 138.3 (Carom), 143.6, 143.9 (CHϭCHCH3),
167.1 (CO). Ϫ MS (EI, 70 eV), m/z (%) ϭ 295/293 (4/4) [Mϩ], 214
(75), 174 (11), 106 (25), 91 (100), 86 (10), 69 (85), 41 (36). Ϫ
C14H16BrNO: 293.0415 (HRMS).
indine-6,6-dicarboxylate (32-CO2Me): Diethyl (2-bromo-2-propen-
1-yl)(2-propen-1-yl)malonate (29) (195 mg, 0.61 mmol) was treated
with Pd(OAc)2 (8 mg, 0.04 mmol), PPh3 (21 mg, 0.08 mmol), and
Ag2CO3 (88 mg, 0.32 mmol) in acetonitrile (5 mL) for 45 min at
85 °C in a thick-walled screw-cap Pyrex bottle. After cooling to
ambient temp., aq. formaldehyde solution (0.6 mL, 6 mmol, ap-
prox. 10 ), methyl glycinate hydrochloride (31-CO2Me) (153 mg,
1.22 mmol) and H2O (5 mL) were added, and the mixture was
stirred at ambient temp. for 4 d. The reaction mixture was filtered
through Celite, which was then washed with H2O (10 mL), and the
filtrate was extracted with Et2O (15 mL). The aqueous layer was
basified (pH ϭ 13) with 2  NaOH and extracted with Et2O
(4 ϫ 15 mL). The combined organic layers were washed with brine
(20 mL) and dried with Na2SO4. Purification by column chromato-
graphy on silica gel, eluting with petroleum ether/ether (1:2) gave
137 mg (66%) of 32-CO2Me as a pale yellow oil, Rf (petroleum
ether/ether 1:2) ϭ 0.17. Ϫ IR (film): ν˜ ϭ 2982 cmϪ1, 2906, 2839,
1733, 1444, 1389, 1366, 1257, 1177, 1103, 1068, 1017, 903, 860. Ϫ
1H NMR (250 MHz, CDCl3): δ ϭ 1.25 (t, 6 H, 3J ϭ 7.1 Hz,
(2E)-2-Bromo-2-buten-1-yl 2-Propen-1-yl Ether (15): To a stirred so-
lution of 2-bromo-2-butenol (14)[20] (3.02 g, 20 mmol) and allyl
bromide (3.0 g, 25 mmol) in CH2Cl2 (50 mL) was added cetyltri-
ethylammonium bromide (CETAB) (0.93 g, 2.5 mmol) followed by
50% aq. NaOH solution (25 mL). The resulting mixture was heated
under reflux for 2 h. After cooling to room temperature the organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2 (2 ϫ 25 mL). The combined filtrates were washed with
brine (2 ϫ 25 mL), dried with MgSO4, and concentrated. The crude
product was purified by passing it through a short silica gel column
eluting with pentane to give 2.10 g (55%) of 15 as a colorless oil.
Ϫ IR (film): ν˜ ϭ 2854 cmϪ1, 1640. Ϫ 1H NMR (250 MHz, CDCl3):
δ ϭ 1.74 (d, 3 H, 3J ϭ 6.9 Hz, CH3), 4.00 (d, 2 H, 3J ϭ 7 Hz,
CH2CHϭ), 4.22 (s, 2 H, CH2CBrϭ), 5.19Ϫ5.35 (m, 2 H, CHϭ
3
CH2), 5.87Ϫ6.05 (m, 1 H, CHϭCH2), 6.21 (q, 1 H, J ϭ 6.9 Hz,
CBrϭCHCH3). Ϫ 13C NMR (62.9 MHz, CDCl3): δ ϭ 15.3 (CH3),
68.6 (CH2CHϭ), 70.5 (CH2CBrϭ), 117.7 (CHϭCH2), 121.2
(CBrϭCHCH3), 131.7 (CBrϭCHCH3), 134.4 (CHϭCH2). Ϫ MS
(EI, 70 eV), m/z (%) ϭ 192/190 (2/2) [Mϩ], 148 (7), 134 (20), 111
(14), 93 (8), 69 (20), 53 (83), 41 (100). Ϫ C7H11BrO: 189.9993
(HRMS).
3
CH2CH3), 2.14 (very brs, 2 H, 4-H), 2.71 (t, 2 H, J ϭ 5.7 Hz, 3-
H), 2.95 (brs, 4 H, 5-H, 7-H), 3.08 (brs, 2 H, 1-H), 3.36 (s, 2 H,
NCH2CO2CH3), 3.74 (s, 3 H, CO2CH3), 4.19 (q, 4 H, 3J ϭ 7.1 Hz,
CH2CH3). Decoupling experiment: On irradiating the very broad
singlet at δ ϭ 2.14, the triplet at δ ϭ 2.71 becomes a singlet. Ϫ 13C
NMR (62.9 MHz, CDCl3, DEPT135): δ ϭ 13.9 (ϩ, CH2CH3), 25.6
(Ϫ, C-4), 41.8 and 43.3 (Ϫ, C-5, C-7), 49.6 (Ϫ, C-3), 51.6 (ϩ,
CO2CH3), 51.8 (Ϫ, C-1), 58.2 (Cquat, C-6), 58.5 (Ϫ, NCH2CO2),
61.4 (Ϫ, CH2CH3), 129.5 and 130.4 (Cquat, C-4a, C-7a), 170.9
(Cquat, CO2CH3), 172.1 (Cquat, CO2CH2CH3). The assignments of
the signals were confirmed by a C,H-COSY experiment. Ϫ MS (EI,
70 eV), m/z (%) ϭ 339 (35) [Mϩ], 294 (5), 280 (100), 266 (48), 234
(4), 206 (23), 192 (19), 177 (9), 167 (15), 134 (6), 125 (41), 105
(11), 91 (17), 55 (10), 43 (15), 42 (32). Ϫ C17H25NO6 (339.4): calcd.
C 60.16, H 7.42; found C 59.89, H 7.70.
2Ј-Bromo-2Ј-propen-1Ј-yl Propenoate (26): To a stirred suspension
of 2,3-dibromopropene (1.99 g, 10 mmol), KF (0.87 g, 15 mmol) in
DMF (25 mL), was added acrylic acid (0.72 g, 10 mmol). The re-
sulting mixture was heated at 80 °C for 2 h. After cooling to room
temperature, water (50 mL) was added, and the reaction mixture
was extracted with ether (3 ϫ 25 mL). The combined extracts were
washed with water (2 ϫ 20 mL), dried with MgSO4, and the solvent
was evaporated. The residue was passed through a short silica gel
column eluting with pentane to give 1.70 g (89%) of pure 26 as a
1
colorless oil. Ϫ IR (film): ν˜ ϭ 2941 cmϪ1, 1745, 1634. Ϫ H NMR
Diethyl 2-Benzyl-2,3,4,5,6,7-hexahydro-1H-[2]pyrindine-6,6-dicarb-
oxylate (32-Ph): Using benzylamine hydrochloride (31-Ph)
(175 mg, 1.22 mmol) under conditions otherwise identical to those
for the preparation of 32-CO2Me, 163 mg (75%) of 32-Ph was ob-
tained as a pale yellow, unstable oil, Rf (petroleum ether/ether
1:1) ϭ 0.23. Ϫ IR (film): ν˜ ϭ 3085 cmϪ1, 3062, 3027, 2980, 2906,
2805, 1733, 1602, 1494, 1454, 1256, 1178, 1096, 1067, 1016, 966,
4
(250 MHz, CDCl3): δ ϭ 4.79 (t, 2 H, J ϭ 1.1 Hz, 1Ј-H), 5.60 (dt,
1 H, 2J ϭ 2.0, 4J ϭ 1.1 Hz, 3Ј-H), 5.89 [m, 2 H, 3Ј(3)-H], 6.16 (dd,
3
1 H, 3J ϭ 18.3, 3J ϭ 10.4 Hz, 2-H), 6.52 (dd, 1 H, J ϭ 18.3, 2J ϭ
1.4 Hz, 3-H). Ϫ 13C NMR (62.9 Hz, CDCl3): δ ϭ 67.5 (C-1Ј), 119.0
(C-3Ј), 126.1 (C-2Ј), 127.7 (C-2), 131.9 (C-3), 165.1 (CϭO). Ϫ MS
(70 eV), m/z (%) ϭ 192/190 (2/2) [Mϩ], 159 (3), 135 (2), 119 (43),
55 (100). Ϫ C6H7BrO2: 189.9629 (HRMS).
1
907, 860, 808, 743, 700, 613, 543. Ϫ H NMR (250 MHz, CDCl3):
3
2Ј-Propen-1Ј-yl 2-Bromopropenoate (28): A stirred solution of 2-
bromopropenoic acid (0.75 g, 5.0 mmol), allyl bromide (0.52 mL,
0.72 g, 6.0 mmol), and KF (0.64 g, 11.0 mmol) in DMF (5 mL) was H), 3.61 (s, 2 H, NCH2Ph), 4.18 (q, 4 H, J ϭ 7.1 Hz, CH2CH3),
δ ϭ 1.24 (t, 6 H, J ϭ 7.1 Hz, CH2CH3), 2.08 (very brs, 2 H, 4-H),
2.57 (t, 2 H, 3J ϭ 5.7 Hz, 3-H), 2.90Ϫ3.00 (brm, 6 H, 1-H, 5-H, 7-
3
heated at 45 °C for 4 h. After cooling to room temperature, water
(20 mL) was added, and the aqueous phase was extracted with
ether (2 ϫ 20 mL). The combined ether phases were washed suc-
cessively with water (2 ϫ 20 mL), brine (20 mL), dried with
MgSO4, and the solvent was evaporated. The residue was purified
by column chromatography on silica gel eluting with petroleum
7.25Ϫ7.35 (m, 5 H, Ar-H). Decoupling experiment: On irradiating
the very broad singlet at δ ϭ 2.08, the triplet at δ ϭ 2.57 becomes
a singlet. Ϫ 13C NMR (62.9 MHz, CDCl3, DEPT135): δ ϭ 13.9
(ϩ, CH2CH3), 25.8 (Ϫ, C-4), 41.9 and 43.3 (Ϫ, C-5, C-7), 49.6 (Ϫ,
C-3), 52.5 (Ϫ, C-1), 58.1 (Cquat, C-6), 61.4 (Ϫ, CH2CH3), 62.5 (Ϫ,
NCH2Ph), 127.0, 128.2, 129.1 (ϩ, CHarom), 130.1 and 130.6 (Cquat
,
ether/ether (20:1) to yield 0.71 g (74%) of 28 as a colorless oil. Ϫ C-4a, C-7a), 138.2 (Cquat, Carom), 172.2 (Cquat, CO2CH2CH3). Ϫ
IR (film): ν˜ ϭ 3088 cmϪ1, 2955, 1733, 1650, 1610, 1456. Ϫ 1H MS (EI, 70 eV), m/z (%) ϭ 357 (100) [Mϩ], 312 (7), 284 (34), 283
NMR (250 MHz, CDCl3): δ ϭ 4.73 (dt, 2 H, 3J ϭ 5.7, 4J ϭ 1.4 Hz, (17), 266 (5), 255 (2), 238 (2), 210 (9), 185 (82), 164 (6), 136 (4),
Eur. J. Org. Chem. 2001, 1673Ϫ1680
1679

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