Asymmetric synthesis of pyrrolo[2,1-a]isoquinoline derivatives by 1,3-dipolar cycloadditions of stabilized isoquinolinium N-ylides with sulfinyl dipolarophiles

Article abstract of DOI:10.1021/jo200191c

Enantiomerically pure pyrrolo[2,1-a]isoquinoline derivatives are obtained by 1,3-dipolar reactions of isoquinolinium azomethine ylides with enantiopure 3-p-tolylsulfinylacrylonitriles, tert-butyl (2E)-4,4-diethoxy-2-p- tolylsulfinylbut-2-enoate, and 5-eth

Full text of DOI:10.1021/jo200191c

ARTICLE
pubs.acs.org/joc
Asymmetric Synthesis of Pyrrolo[2,1-a]isoquinoline Derivatives by
1,3-Dipolar Cycloadditions of Stabilized Isoquinolinium N-Ylides with
Sulfinyl Dipolarophiles
Josꢀe Luis García Ruano,* Alberto Fraile, M. Rosario Martín,* Gemma Gonzꢀalez, Cristina Fajardo, and
Ana María Martín-Castro
Departamento de Química Orgꢀanica, Universidad Autꢀonoma de Madrid, Cantoblanco, 28049-Madrid, Spain
S Supporting Information
b
ABSTRACT: Enantiomerically pure pyrrolo[2,1-a]isoquinoline
derivatives are obtained by 1,3-dipolar reactions of isoquinoli-
nium azomethine ylides with enantiopure 3-p-tolylsulfinylacry-
lonitriles, tert-butyl (2E)-4,4-diethoxy-2-p-tolylsulfinylbut-2-
enoate, and 5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones. Reac-
tions evolve through the anti conformation of the ylide with
complete regioselectivity. The facial selectivity is completely
controlled by the configuration of the sulfinyl sulfur for acyclic dipolarophiles, whereas it is high (dr 83/17 or 89/11) but controlled
by the C-5 configuration for sulfinylfuranones. Complete endo selectivity is observed with cyclic dipolarophiles and substituted
acrylonitriles, but it is low with butenoate. The sulfinyl group also exerts a positive influence on the dipolarophilic reactivity toward
these ylides.
’ INTRODUCTION
the endo/exo and π-facial selectivities of the cycloadditions.14
These features prompted us to use activated acyclic (3ꢀ6)15 and
cyclic (7)15b vinyl sulfoxides (Figure 1) as dipolarophiles in the
[3 þ 2] cycloadditions with stabilized isoquinolinium ylides 1
and 2.16 The results obtained in this study are herein reported.
The comparison of the results obtained in reactions of 7 with
those from racemic furanone 8,17 which are also reported in this
paper, allowed us to establish the role of the sulfinyl group at C-3
on the course of these reactions.
Pyrrolo[2,1-a]isoquinoline moieties1 are present in alkaloid
families, such as erythrina2 and lamellarin,3 and in more simple
pyrrolo[2,1-a]isoquinoline derivatives,4,5 all of them exhibiting
diverse biological activities. Additionally, the importance of these
heterocyclic systems is further enhanced by their utility as
advanced intermediates for the synthesis of alkaloids.1 Conse-
quently, plenty of attention has been paid to the synthesis of
these systems. Three main strategies have been developed for the
asymmetric construction of polyhydro derivatives, the key steps
of which employ N-acyliminium cyclization,6 Mitsunobu reac-
tion of optically pure 3-(tetrahydroisoquinolin-1-yl)propan-1-
oles,7 and asymmetric hydrogenation of prochiral iminium salts
with a chiral Ru complex preformed from chiral amines.8 How-
ever, the most straightforward way to obtain this moiety, which
involves the [3 þ 2] cycloadditions of stabilized isoquinolinium
or 3,4-dihydroisoquinolinium ylides with proper chiral dipolar-
ophiles (Scheme 1), has never been explored to our knowledge,
despite the fact that asymmetric [3 þ 2] cycloadditions are
among the most efficient reactions for the construction of
enantiopure five-membered heterocycles.9
Asymmetric cycloaddition of azomethine ylides derived from
imino esters leading to pyrrolidines has been extensively
studied.9,10 In contrast, the use as the dipole of heteroaromatic
N-ylides for preparing optically pure polycyclic products has
been scarcely exploited. In this field we have reported some
reactions of acyclic N-metalated azomethine ylides11 and of
thiazolium N-ylides12 with activated vinyl sulfoxides,13 which
evidenced that the incorporation of the sulfinyl group to the
dipolarophilic double bonds improves their reactivity as well as
’ RESULTS AND DISCUSSION
The reaction of ylide 1, generated in situ by treatment of 1-
HBr with base, with sufinylacrylonitrile 3 in acetonitrile, at room
temperature using a 1:1.4:1.2 ratio of dipolarophile 3:1-HBr:
DBU, afforded a mixture of two adducts (Scheme 2). The major
one (endo-9)18 was isolated pure in 80% yield by filtration of the
crude mixture. The minor adduct (exo-9)18 was separated by
flash column chromatography, but it could not be isolated as a
pure compound, because it rapidly transformed into ethyl
1-cyanopyrrolo[2,1-a]isoquinoline-3-carboxylate (12)19,20 by
elimination of sulfenic acid and further aromatization.
Ylide 1 reacted with substituted acrylonitriles 4 and 5 more
slowly than with 3, but with complete stereoselectivity, yielding
only endo-10 and endo-11 adducts,18 respectively (Scheme 2).
The moderate yield of endo-11 is due to its partial transformation
into the corresponding 2,3-dehydroisoquinoline 13 (isolated in
Received: January 26, 2011
Published: March 07, 2011
r
2011 American Chemical Society
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19% yield) on the silica gel during its purification by column
chromatography.
stable than endo-11 (it is only partially desulfinylated), presum-
ably due to steric reasons.
The easy decomposition of the primary adducts 9ꢀ11 de-
picted in Scheme 2 could be ascribed to the presence of the
enamine group. In order to avoid this problem, we studied the
cycloaddition of dipole 2 (generated from 2-HBr) to sulfinyla-
crylonitriles. As can be seen in Scheme 3, the reactions of 2 with 3
and 4 are completely stereoselective, yielding the endo adducts18
(14 and 15, respectively). Reaction of 2 with 5 only yields
compound 16, resulting from the spontaneous desulfinylation of
the corresponding undetected endo adduct, which must be less
Next, we performed the reaction of tert-butyl (2E)-4,4-
diethoxy-2-p-tolylsulfinylbut-2-enoate (6) with isoquinolinium
1-HBr in acetonitrile at room temperature, using DBU as base.
This reaction yielded a mixture of three products, two primary
cycloadducts (endo- and exo-17)18 and compound 18 in a ratio
of 59:36:5 (Scheme 4).21 Unfortunately, primary adducts 17
and acetal 18 are unstable in silica gel. Chromatographic separa-
tion of the mixture only provided the major endo-17 as a pure
compound, in 30% yield, along with a 51% of pyrroloisoquinoline
19, derived from adducts 17 by elimination of sulfenic acid and
subsequent aromatization and acetal hydrolysis. Compound 19
was also formed by hydrolysis of 18 during the chromatographic
separation. Both the composition of the reaction mixture before
chromatography and the isolated yields of endo-17 and 19 (30
and 51%, respectively) are indicative that 19 results from the
evolution of endo- and exo-17, which requires that the two
primary adducts exhibit the same regiochemistry.
Scheme 1. 1,3-Dipolar Approach to Enantiomerically Pure
Polyhydropyrrolo[2,1-a]isoquinolines
The 1,2,3,10b-tetrahydro- or 1,2,3,5,6,10b-hexahydropyrrolo-
[2,1-a]isoquinoline framework of the primary adducts obtained
from acyclic vinyl sulfoxides 3ꢀ6 was mainly determined by
NMR (1H-, 13C- and NOESY experiments). Cycloadduct exo-9
was chemically correlated with ethyl 1-cyanopyrrolo[2,1-a]-
isoquinoline-3-carboxylate (12)19 (Scheme 2). The NOE
effects observed in compound 10 [H-5/H-3 (d) and H-10/
H-10b (s)] and 15 (H-10 and singlet at 4.29 ppm of H-10b)
support the regiochemistry indicated in Figure 2 and
Schemes 2 and 3. Finally, the NOE effect observed in the
NOESY experiment of endo-17 between the singlet at 5.81 (H-
1
10b) and H-10 (Scheme 4) and the H chemical shift of the
tert-butyl group of ester 17 allow assignment of the structure
proposed for this compound.22 The so-assigned regiochem-
istry agrees with the complete control of the regioselectivity
reported by Tsuge et al.16b,23 for cycloadditions of 1 with
alkenes bearing one electron-withdrawing group.
Figure 1. Dipoles and dipolarophiles used in this study.
Scheme 2. Reaction of Isoquinolinium Ylide 1 with (Z,RS)-3-p-Tolylsulfinylacrylonitriles 3ꢀ5
Scheme 3. Reaction of Isoquinolinium Ylide 2 with (Z,RS)-3-p-Tolylsulfinylacrylonitriles 3ꢀ5
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Scheme 4. Reaction of Isoquinolinium Ylide 1 with tert-Butyl (2E)-4,4-Diethoxy-2-p-tolylsulfinylbut-2-enoate (6)
Figure 2. Significant NOE effects supporting the structure of adducts.
Figure 3. Favored conformations of dipole and dipolarophiles.
The configuration of the major or exclusive adduct obtained in
these reactions was assigned by assuming that the stereochem-
istry of the dipolarophiles is maintained in the adducts and
that they must be formed by attack of the anti conformation
of the dipole,24 stabilized by intramolecular hydrogen bonding
(Figure 3a), to the less hindered face of the dipolarophiles
(Figure 3b) in their most stable conformations from an
electrostatic point of view (s-trans in 3ꢀ5 and s-cis in 6). The
absolute configuration of endo-17, determined by X-ray diffrac-
tion analysis,25 confirms the above hypotheses.
The endo approach of the anti-dipoles 1 or 2 to the less
hindered face of the dipolarophiles 3ꢀ5 will be favored with
respect to the exo approach due to the destabilizing interactions
CO2Et/SOTol and R/isoquinoline (Scheme 5). Consequently,
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Scheme 5. Stereochemical Course of the Cycloaddition of Azomethine Ylide 1 to Vinyl Sulfoxides 3ꢀ5
Scheme 6. Stereochemical Course of the Cycloaddition of Azomethine Ylide 1 to Vinyl Sulfoxide 6
the endo adducts are obtained as the major 9 or exclusive (10, 11,
14, and 15) ones. Additionally, in the endo approach there is an
attractive interaction between the isoquinolinium ring and the
cyano group.26 The NOE effects H-2/H-10b and H-3/Tol
(ortho protons) observed in adducts 10 and 15 (Figure 2)
support the assignment of the proposed structures for the
adducts.
Table 1. Reactions of 5-Methoxyfuran-2(5H)-one [(()-8]
with Isoquinolinium Ylide 1
The endo/exo selectivity of the reaction of 1 with 6 was lower
than that observed with 3 (Scheme 2). This result can be justified
by taking into account that the interactions destabilizing the exo
approach [mainly CO2Et/CH(OEt)2] are partially balanced by
the electrostatic interactions involving the sulfinyl oxygen
(attractive in the exo approach and repulsive in the endo one,
Scheme 6). The absolute configuration of the major adduct 17
shows that interaction destabilizing the exo approach [CO2Et/
CH(OEt)2] is larger than the interaction existing in the endo
approach (CO2Et/SOTol).
reaction time
(min)
anti-endo-
entry
solvent
temperature
20:syn-endo-20 ratio
1
2
3
4
CH3CN
CH2Cl2
toluene
CH3CN
5
15
90
30
rt
80:20
65:35
60:40
80:20
rt
rt
ꢀ40 °C
The main conclusions deduced from the results obtained in
the cycloadditions of isoquinolinium azomethine ylides 1 and 2
with acyclic sulfoxides 3ꢀ6 are (a) the reactions are completely
regioselective, with the carbon bonded to the alkoxycarbonyl
group of dipole generating a bond with the β-carbon of the
dipolarophile. (b) The π-facial selectivity is complete and con-
trolled by the configuration of the sulfinyl group. (c) The endo-
selectivity is complete in reactions with 4 and 5, very high with 3
(86:14 endo:exo), and moderate with 6 (62:38 endo:exo). It is
dependent on the sulfinyl configuration and its interactions with
the groups present at the dipoles. These results indicate that the
sulfinyl group confers excellent properties to the double bonds
for being used as dipolarophiles in asymmetric [3 þ 2] cycload-
ditions with ylides 1 and 2, opening a new straightforward route
for the preparation of polyhydropyrrolo[2,1-a]isoquinolines in
their optically pure form.
At this point, we reasoned that adducts obtained from cyclic
dipolarophiles would be less prone to desulfinylation than the
previously obtained from acyclic dipolarophiles, which prompted
us to study the reactions of sulfinylfuranones 7 and 8 (Figure 1)
with ylide 1. In order to evaluate the influence of the alkoxy group
at C-5 at the furanone ring, we first studied the reaction
of racemic 5-methoxyfuran-2(5H)-one [(()-8] with 1-HBr
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Scheme 7. Stereochemical Course of the Endo-Cycloaddi-
tion of Ylide 1 to 5-Methoxyfuranone (()-8
Scheme 8. Cycloaddition of Isoquinolinium Ylide 1 to Sul-
finylfuranones 7
is associated with the anti and endo character of the adducts,
whereas those larger than 6.9 Hz are characteristic of the
synperiplanar arrangement, present in the syn and exo stereo-
isomer. The absolute configuration of adducts 21 was initially
assigned as indicated in Scheme 8 on the assumption that the
configurations at C-5 of the starting furanones 7a and 7b
remained unaltered in the course of these reactions and that
the anti-dipole was the only reactive species. These assignments
were confirmed by X-ray diffraction analyses29 of compounds
anti-endo-21a, syn-endo-21a, and anti-endo-21b.
As we can see, all these cycloadditions evolve with a complete
control of the regioselectivity and the endo selectivity, from the
anti conformation of dipole 1. This could be explained making
use of the same reasons previously indicated for compound 8,
lacking of the sulfinyl group. The high but not complete facial
selectivity observed in these reactions is also similar to that found
from 8 (anti/syn ratio 80:20) with slightly better dr, mainly for
7b (anti/syn ratio is 89:11). This fact suggests a moderate
contribution of the sulfinyl group in the facial selectivity, which
could be associated with the fact that steric effects of the sulfinyl
group in the most stable conformation of 7b (the tolyl and the
ethoxy groups are positioned toward the same face of the double
bond) reinforce the steric tendency imposed by the OMe group
at C-5 at the furanone ring.30
(Table 1). This reaction afforded an 80:20 mixture of anti-endo-
2027 and syn-endo-20 in acetonitrile at rt (entry 1, Table 1).28
This composition was not altered at ꢀ40 °C, whereas stereo-
selectivity decreased in less polar solvents such as dichloro-
methane (entry 2) or toluene (entry 3), which also caused an
increase in the reaction times.
From these results we can conclude that reaction of (()-8
with isoquinolinium ylide 1 is completely regioselective, with the
generation of a bond between the negative extreme of the dipole
and the β-carbon of the conjugated system, which suggests a
significant contribution of the electrostatic interactions in the
control of the favored approach. The endo selectivity is also
complete (both adducts display H-4 and H-11b in a trans
arrangement), which could be explained by the favorable elec-
trostatic interactions of the oxygen of the furan ring with the
positive nitrogen at the dipole and by the interaction of the
carbonyl group with the aromatic ring of the dipole. Both factors
favor the endo approaches (Scheme 7) but are absent in the exo
ones. Finally, the moderate π-facial selectivity, which was lower
in apolar solvents, suggests that steric interactions, clearly favor-
ing the approach of the dipole to the opposite face to that
occupied by the OMe group at C-5 at the furanone ring (anti
approach), must be partially compensated by some kind of
electrostatic interaction favoring the syn approach, which will
reduce its importance in polar solvents, thus increasing the
stereoselectivity (compare entry 1 with entries 2 and 3 of
Table 1). Such interactions could be established between the
hydrogen of the dipole and the oxygen of the OMe group at C-5
of dipolarophile (Scheme 7), as has been postulated in other
cycloadditions.14c
Reactions of isoquinolinium bromide 1-HBr with furanones
7a and 7b led to mixtures of syn and anti isomers as a result of the
endo approach of the dipole to both faces of the double bond, the
anti adducts (anti-endo-21a and anti-endo-21b)27 being the major
ones (Scheme 8). These were separated by flash column
chromatography and then crystallized by precipitation in hex-
aneꢀAcOEt (anti-endo-21a) or Et2O (anti-endo-21b). Only one
of the minor adducts (syn-endo-21a) could be isolated and
properly characterized as a pure diastereoisomer.
The anti/syn and endo/exo character of compounds 20 and
21 was assigned from the values of the J3,3a and J3a,4 coupling
constants, respectively. Values smaller than 2.3 Hz are indicative
of the antiperiplanar arrangement of the involved protons, which
In summary, we have demonstrated that the 1,3-dipolar
reactions of isoquinolinium ylides with acyclic (3ꢀ6) and cyclic
(7a and 7b) sulfinyl ethylenes constitute a direct and efficient
route to highly functionalized and enantiomerically pure
1,2,3,10b-tetrahydro- or 1,2,3,5,6,10b-hexahydropyrrolo[2,1-
a]isoquinoline-3-carboxylates, a skeleton frequently found in
compounds exhibiting valuable pharmacological activity.
’ EXPERIMENTAL SECTION
General Methods. Acetonitrile was dried over activated 4 Å
molecular sieves. Silica gel 60 (230ꢀ400 mesh ASTM) and DC-
Alufolien 60 F254 were used for flash column chromatography and
analytical TLC, respectively. Melting points were determined in open
capillary tubes and are uncorrected. NMR spectra were determined in
CDCl3 solutions, unless otherwise indicated, at 300 and 75 MHz for 1H
and 13C NMR, respectively. Chemical shifts (δ) are reported in ppm and
J values are given in hertz. The IR spectra frequencies are given in cmꢀ1
.
The optical rotations were measured at room temperature in the solvent
and concentration (g/100 mL) indicated in each case. Isoquinolinium 1-
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HBr and 2-HBr were synthesized according to the procedure described
in ref 16a using ethanol as solvent.
Ethyl [1S,2R,3S,10bR,(S)R]-1-tert-Butyl-1-cyano-2-(p-toly-
lsulfinyl)-1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-
3-carboxylate (11-endo). Compound endo-11 was obtained as the
sole compound following the general procedure from (Z)-2-tert-butyl-
3-[(R)-p-tolylsulfinyl]propenonitrile (5) and the isoquinolinium 1-HBr
after 30 min of reaction. It was purified by flash column chromatography
(AcOEtꢀhexane, 1:3).Yield: 43%, white solid. Mp (Et2Oꢀhexane):
116ꢀ117 °C. [R]2D0: þ613.8 (c 0.5, CHCl3). IR (KBr): 2229, 1736,
1630, 1567, 1491, 1081, 1051 cmꢀ1. 1H NMR δ: 7.57 and 7.34 (AA0BB0
system, 4 H), 7.23 (m, 2 H), 7.08 (m, 2 H), 6.25 (d, J = 7.6, 1 H), 5.56 (d,
J = 7.6, 1 H), 5.01 (d, J = 3.1, 1 H), 4.81 (s, 1 H), 3.96 (dq, J = 7.1 and 2.0,
2 H), 3.58 (d, J = 3.1, 1 H), 2.42 (s, 3 H), 1.21 (s, 9 H), 1.02 (t, J = 7.1, 3
H). 13C NMR δ: 170.3 (CO), 142.2 (C), 139.9 (C), 136.1 (CH), 134.1
(C), 130.1 (CH), 129.4 (CH), 125.4 (C), 125.2 (CH), 124.7 (CH),
124.0 (CH), 118.5 (CN), 103.6 (CH), 69.7 (CH), 65.7 (CH), 61.9
(CH2), 60.9 (CH), 59.8 (C), 36.5 (C), 27.7 (CH3), 21.4 (CH3), 13.8
(CH3). Anal. Calcd for C27H30N2O3S: C 70.10, H 6.54, N 6.06, S 6.93.
Found: C 69.96, H 6.41, N 5.98, S 7.06.
Ethyl (1R,10bS)-1-tert-Butyl-1-cyano-1,10b-dihydropyrrolo-
[2,1-a]isoquinoline-3-carboxylate (13). Although this compound
was not detected in the 1H NMR spectrum of the crude reaction mixture,
it was obtained after the flash column chromatography by decomposi-
tion of adduct endo-11 on the silica gel. Yield: 19%. IR (film): 2216,
1701, 1421, 1222, 1088 cmꢀ1. 1H NMR δ: 7.58 (m, 1 H), 7.44 (d, J = 7.7,
1 H), 7.20 (m, 2 H), 7.05 (dd, J = 7.3 and 2.0, 1 H), 5.75 (d, J = 7.7, 1 H),
5.75 (s, 1 H), 4.88 (s, 1 H), 4.30 (dq, J = 6.9 and 3.6, 2 H), 1.35 (t, J = 6.9,
3 H), 1.21 (s, 9 H). 13C NMR δ: 160.1, 136.5, 133.6, 127.95, 127.90,
126.6, 125.2, 125.0, 123.9, 118.8, 110.1, 104.6, 63.5, 61.6, 57.0, 36.9,
27.5, 14.1.
Methyl [1S,2R,3S,10bR,(S)R]-1-Cyano-2-(p-tolylsulfinyl)-
1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline-3-carbo-
xylate (endo-14). Compound endo-14 was obtained as the sole
compound following the general procedure from (Z)-3-[(R)-p-tolylsul-
finyl]propenonitrile (3) and 2-HBr after 5 min of reaction. It was
purified by filtration of the solid formed upon addition of CH3CNꢀ
Et2O (1:1) to the reaction mixture. The filtrate was evaporated and
purified by flash column chromatography (AcOEtꢀhexane, 1:10).
Yield: 78%, white solid. Mp (Et2O): 155ꢀ156 °C. [R]2D0: þ153.6
(c 0.5, CHCl3). IR (KBr): 2243, 1725, 1596, 1494, 1084, 1046 cmꢀ1. 1H
NMR δ:7.73and7.37 (AA0BB0 system, 4H), 7.20(m, 3H), 6.95(m, 1H),
4.54 (d, J = 5.0, 1 H), 4.52 (d, J = 5.2, 1 H), 3.98 (dd, J = 8.1 and 5.2, 1 H),
3.67 (s, 3 H), 3.40 (dd, J = 8.1 and 5.0, 1 H), 3.37 (m, 1 H), 2.99 (m, 3 H),
2.44 (s, 3 H). 13C NMR δ: 171.5 (CO), 142.9 (C), 139.4 (C), 135.0 (C),
131.3 (C), 130.3 (CH), 129.2 (CH), 127.7 (CH), 126.4 (CH), 126.0
(CH), 125.0 (CH), 116.5 (CN), 67.5 (CH), 64.4 (CH), 63.3 (CH), 52.4
(CH3), 45.6 (CH2), 37.0 (CH), 29.3 (CH2), 21.5 (CH3). Anal. Calcd for
C22H22N2O3S: C 66.98, H 5.62, N 7.10, S 8.13. Found: C 66.64, H 5.44, N
7.03, S 8.09.
Methyl [1S,2R,3S,10bS,(S)R]-1-n-Butyl-1-cyano-2-(p-tolyl-
sulfinyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline-
3-carboxylate (endo-15). Compound endo-15 was obtained as the
sole compound following the general procedure from (Z)-2-n-butyl-
3-[(R)-p-tolylsulfinyl]propenonitrile (4) and 2-HBr after 20 min of
reaction. It was purified by flash column chromatography (AcOEtꢀ
hexane, 1:3). Yield: 70%, white solid. Mp: 106ꢀ107 °C. [R]2D0: þ146.0
(c 0.5, CHCl3). IR (KBr): 2233, 1752, 1493, 1427, 1083, 1050 cmꢀ1. 1H
NMR δ: 7.61 and 7.34 (AA0BB0 system, 4 H), 7.21 (m, 3 H), 7.12 (m, 1
H), 4.49 (d, J = 3.9, 1 H), 4.29 (s, 1 H), 3.64 (d, J = 3.9, 1 H), 3.54 (s, 3
H), 3.51 (m, 1 H), 3.00 (m, 3 H), 2.42 (s, 3 H), 2.08 (m, 1 H), 1.86 (m, 1
H), 1.62 (m, 1 H), 1.34 (m, 3 H), 0.92 (t, J = 7.1, 3 H). 13C NMR δ:
172.0 (CO), 142.4 (C), 139.6 (C), 135.4 (C), 130.9 (C), 130.0 (CH),
129.4 (CH), 127.9 (CH), 126.2 (CH), 126.0 (CH) 124.7 (CH), 119.2
(CN), 73.7 (CH), 69.2 (CH), 62.7 (CH), 52.4 (CH3), 51.4 (C), 46.3
(CH2), 37.9 (CH2), 29.1 (CH2), 27.8 (CH2), 22.7 (CH2), 21.4 (CH3),
Reaction of (Z)-3-p-Tolylsulfinylacrylonitriles 3ꢀ5 with
Azomethine Ylides 1 and 2. General Procedure. To a stirred
solution of sulfinylacrylonitrile (0.16 mmol) and the salt (0.22 mmol) in
dry acetonitrile (4 mL), under argon and at room temperature, was
added DBU (0.19 mmol). After the time indicated in each case, the
solvent was evaporated in vacuo and the residue was dissolved in
dichloromethane and it was washed with water. The aqueous layers
were extracted with dichloromethane several times. The organic layers
were dried (Na2SO4), filtered, and concentrated in vacuo. The purifica-
tion method is indicated in each case.
Ethyl [(S)R]-1-Cyano-2-(p-tolylsulfinyl)-1,2,3,10b-tetrahydro-
pyrrolo[2,1-a]isoquinoline-3-carboxylate (9). Compounds 9
were obtained as mixture of diastereoisomers endo- and exo-9 following
the general procedure from (Z)-3-[(R)-p-tolylsulfinyl]propenonitrile
(3) and the isoquinolinium 1-HBr after 5 min of reaction. The major
adduct endo-9 was separated by filtration of the crude mixture. The
filtrate was evaporated and the residue was purified by flash column
chromatography (AcOEtꢀhexane, 1:3). The combined yield is 93%.
[1S,2R,3S,10bR,(S)R]-endo-9. Yield: 81%, white solid. Mp
(CHCl3): 146ꢀ148 °C. [R]D20: þ402.0 (c 0.5, CHCl3). IR (KBr):
2240, 1747, 1625, 1568, 1494, 1458, 1309, 1212, 1041 cmꢀ1. 1H NMR
δ: 7.72 and 7.31 (AA0BB0 system, 4 H), 7.21 (td, J = 7.5 and 1.3, 1 H),
7.08 (td, J = 7.5 and 1.3, 1 H), 7.01 (m, 1 H), 6.87 (m, 1 H), 6.26 (d, J =
7.6, 1 H), 5.39 (d, J = 7.6, 1 H), 5,13 (d, J = 4.9, 1 H), 4.83 (d, J = 5.5, 1
H), 4.14 (q, J = 7.2, 2 H), 3.92 (dd, J = 7.9 and 5.5, 1 H), 3.28 (dd, J = 7.9
and 4.9, 1 H), 2.44 (s, 3 H), 1.23 (t, J = 7.2, 3 H). 13C NMR (DMSO-d6)
δ: 170.2 (CO), 141.6 (C), 139.6 (C), 134.9 (CH), 132.7 (C), 130.0
(CH), 128.8 (CH), 126.7 (CH), 125.9 (C), 125.6 (CH), 124.4 (CH),
124.3 (CH), 117.3 (CN), 98.4 (CH), 64.1 (CH), 62.6 (CH), 61.3
(CH2), 59.5 (CH), 39.9 (CH), 21.1 (CH3), 13.6 (CH3). Anal. Calcd for
C23H22N2O3S: C 67.96, H 5.46, N 6.89, S 7.89. Found: C 67.85, H 5.23,
N 6.94, S 7.60.
1
[1S,2R,3R,10bS,(S)R]-exo-9. Yield: 12%. H NMR δ: 7.69 and
7.36 (AA0BB0 system, 4 H), 7.15 (m, 2 H), 6.98 (m, 2 H), 6.06 (d, J = 7.5,
1 H), 5.31 (d, J = 7.5, 1 H), 5.26 (d, J = 3.8, 1 H), 4.05ꢀ3.73 (m, 5 H),
2.42 (s, 3 H), 1.05 (t, J = 7.2, 3 H).
Ethyl 1-Cyanopyrrolo[2,1-a]isoquinoline-3-carboxylate
(12)18. Compound 12 was obtained by decomposition of adducts 9
upon standing in a refrigerator for 2 months. It was purified by flash
column chromatography (AcOEtꢀhexane, 1:6). Yield: 80%. 1H NMR
δ: 9.32 (d, J = 7.5, 1 H), 8.95 (m, 1 H), 7.76 (s, 1 H), 7.64ꢀ7.80 (m, 3
H), 7.22 (d, J = 7.5, 1 H), 4.41 (q, J = 7.1, 2 H), 1.43 (t, J = 7.1, 3 H).
Ethyl [1S,2R,3S,10bS,(S)R]-1-Butyl-1-cyano-2-(p-tolylsulfinyl)-
1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-3-carboxy-
late (endo-10). Compound endo-10 was obtained as the sole compound
following the general procedure from (Z)-2-n-butyl-3-[(R)-p-tolylsulfi-
nyl]propenonitrile (4) and the isoquinolinium 1-HBr after 20 min of
reaction. It was purified by filtration of the solid formed upon addition
of Et2O to the reaction mixture. Yield: 76%, white solid. Mp
(Et2Oꢀhexane): 122ꢀ123 °C. [R]2D0: þ555.4 (c 0.5, CHCl3). IR
(KBr): 2233, 1742, 1630, 1568, 1493, 1458, 1084, 1044 cmꢀ1 1H
.
NMR δ: 7.57 and 7.32 (AA0BB0 system, 4 H), 7.24 (td, J = 7.4 and 0.9, 1
H), 7.07 (m, 2 H), 6.97 (d, J = 7.4, 1 H), 6.20 (d, J = 7.6, 1 H), 5.45 (d, J =
7.6, 1 H), 4.95 (d, J = 3.8, 1 H), 4.51 (s, 1 H), 3.95 (q, J = 7.1, 2 H), 3.45
(d, J = 3.8, 1 H), 2.39 (s, 3 H), 1.92 (m, 1 H), 1.60 (m, 2 H), 1.32 (m, 3
H), 1.06 (t, J = 7.1, 3 H), 0.89 (t, J = 7.1, 3 H). 13C NMR δ: 170.2 (CO),
142.4 (C), 139.5 (C), 135.2 (CH), 132.8 (C), 130.1 (CH), 129.4 (CH),
126.6 (CH), 125.5 (CH), 125.3 (CH), 124.9 (C), 124.4 (CH), 118.3
(CN), 102.0 (CH), 70.2 (CH), 69.6 (CH), 62.7 (CH), 62.0 (CH2), 52.8
(C), 36.4 (CH2), 27.9 (CH2), 22.6 (CH2), 21.4 (CH3), 13.8 (CH3),
13.7 (CH3). Anal. Calcd for C27H30N2O3S: C 70.10, H 6.54, N 6.06, S
6.93. Found: C 69.94, H 6.55, N 6.00, S 7.06.
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ARTICLE
13.8 (CH3). Anal. Calcd for C26H30N2O3S: C 69.30, H 6.71, N 6.22, S
7.12. Found: C 69.35, H 6.59, N 6.28, S 7.26.
1-tert-Butyl 3-Ethyl 2-(diethoxymethyl)pyrrolo[2,1-a]isoqui-
noline-1,3-dicarboxylate (18). Compound 18 was obtained nearly
pure after several flash column chromatographies of different mixtures of
cycloadducts 17. Yield: indeterminate, pale yellow solid. Mp: 129ꢀ
131 °C. IR (KBr): 1713, 1689, 1413, 1377, 1247, 1213, 1067 cmꢀ1. 1H
NMRδ: 9.24 (d, J= 7.7, 1 H), 8.35 (m, 1 H), 7.65(m, 1 H), 7.49(m, 2 H),
7.00 (d, J = 7.7, 1 H), 6.16 (s, 1 H), 4.44 (q, J = 7.1, 2 H), 3.74 (dq, J = 9.3
and7.1, 1 H), 3.60 (dq, J= 9.3and 7.1, 1 H), 1.69 (s, 9 H), 1.44 (t, J =7.1, 3
H), 1.25 (t, J = 7.1, 6 H). 13C NMR δ: 167.3 (CO), 161.5 (CO), 131.8
(C), 130.6 (C), 128.7 (C), 127.8 (CH), 127.6 (CH), 126.9 (CH), 124.5
(C), 124.4 (CH), 124.0 (CH), 113.6 (CH), 113.3 (C), 112.5 (C), 98.8
(CH), 81.7 (C), 63.4 (CH2), 60.5 (CH2), 28.1 (CH3), 15.2 (CH3), 14.3
(CH3). MS (ESIþ): m/z (%) 464 [M þ Naþ] (42), 396 (12), 340 (30),
294 (100). HRMS-ESI: m/z [M þ Naþ] calcd for C25H31NO6Na
464.2043, found 464.2040.
Methyl (1R,10bS)-1-tert-Butyl-1-cyano-1,5,6,10b-tetrahydro-
pyrrolo[2,1-a]isoquinoline-3-carboxylate (16). Compound 16
was obtained as the sole compound following the general procedure
from (Z)-2-tert-butyl-3-[(R)-p-tolylsulfinyl]propenonitrile (5) and 2-
HBr after 30 min of reaction. It was purified by flash column chroma-
tography (AcOEtꢀhexane, 1:60). Yield: 56%, white solid. Mp
(AcOEtꢀhexane): 122ꢀ123 °C. [R]2D0: þ128.6 (c 0.5, CHCl3). IR
(film): 2222, 1710, 1486, 1455, 1250, 1093 cmꢀ1. 1H NMR δ: 7.25 (m, 3
H), 7.07 (m, 1 H), 5.77 (s, 1 H), 5.06 (s, 1 H), 4.32 (m, 1 H), 3.83 (s, 3
H), 2.98 (m, 1 H), 2.85 (m, 1 H), 2.48 (m, 1 H) 1.21 (s, 9 H). 13C NMR
δ: 161.7 (CO), 142.7 (C), 136.8 (C), 134.0 (C), 128.9 (CH), 128.5
(CH), 127.2 (CH), 126.4 (CH), 118.6 (CN), 113.5 (CH), 66.1 (CH),
62.3 (C), 52.1 (CH3), 43.8 (CH2), 38.6 (C), 27.9 (CH2), 25.4 (CH3).
Anal. Calcd for C19H22N2O2: C 73.52, H 7.14, N 9.03. Found: C 73.35,
H 7.11, N 9.04.
1-tert-Butyl 3-Ethyl 2-formylpyrrolo[2,1-a]isoquinoline-
1,3-dicarboxylate (19). Although this compound was not detected
in the 1H NMR spectrum of the crude reaction mixture, it was obtained
after the flash column chromatography by decomposition of adducts 17
on the silica gel. Yield: 51%, yellow solid. Mp: 175ꢀ176 °C. IR (KBr):
1713, 1693, 1673, 1413, 1377, 1249, 1219, 1160, 1106, 1065 cmꢀ1. 1H
NMR δ: 10.67 (s, 1 H), 9.26 (d, J = 7.6, 1 H), 8.46 (m, 1 H), 7.69 (m, 1
H), 7.58 (m, 2 H), 7.15 (d, J = 7.6, 1 H), 4.49 (q, J = 7.1, 2 H), 1.70 (s, 9
H), 1.45 (t, J = 7.1, 3 H). 13C NMR δ: 188.4 (CHO), 165.8 (CO), 160.6
(CO), 131.0 (C), 130.2 (C), 129.6 (C), 128.7 (CH), 128.3 (CH), 127.6
(C), 127.3 (CH), 124.6 (C), 124.5 (CH), 124.0 (CH), 116.0 (CH),
112.7 (C), 82.7 (C), 61.5 (CH2), 27.9 (CH3), 14.3 (CH3). MS (ESIþ):
m/z (%) 368 [M þ Hþ] (30), 312 (45), 294 (100), 59 (68). HRMS-
ESI: m/z [M þ Hþ] calcd for C21H22NO5 368.1492, found 368.1500.
Ethyl (()-3-Methoxy-1-oxo-3a,4,11b,11c-tetrahydro-1H,3H-
furo[30,40:3,4]pyrrolo[2,1-a]isoquinoline-4-carboxylate (endo-
20). A mixture of diastereoisomers anti-endo-20 and syn-endo-20 in
77:23 ratio was obtained from 5-methoxyfuran-2(5H)-one (8) and the
isoquinolinium 1-HBr after 5 min. They were purified by flash column
chromatography (AcOEtꢀhexane, 2:5). The combined yield is 80%.
(()-(3R,3aS,4S,11bR,11cR)-anti-endo-20. Compound anti-
endo-20 was obtained as the major product. Yield: 63%, red oil. IR
(film): 1782, 1734, 1626, 1567, 1458, 1115 cmꢀ1. 1H NMR δ: 7.15 (m, 3
H), 6.94 (m, 1 H), 6.04 (d, J = 7.6, 1 H), 5.31 (d, J = 1.1, 1 H), 5.31 (d, J =
7.6, 1 H), 5.16 (d, J = 6.8, 1 H), 4.25 (d, J = 2.2, 1 H), 4.24 (q, J = 7.1, 2
H), 3.49 (s, 3 H), 3.41 (dd, J = 8.2 and 6.8, 1 H), 3.24 (ddd, J = 8.2, 2.2
and 1.1, 1 H), 1.32 (t, J = 7.1, 3 H). 13C NMR δ: 173.4 (CO), 170.1
(CO), 133.5 (CH), 131.8 (C), 128.1 (CH) 127.0 (CH), 125.6 (C),
125.4 (CH), 124.3 (CH), 107.1 (CH), 101.2 (CH), 69.4 (CH), 62.9
(CH), 61.8 (CH2), 56.4 (CH3), 48.0 (CH), 47.7 (CH), 14.0 (CH3). MS
(ESIþ): m/z (%) 352 [M þ Naþ] (33), 330 [M þ Hþ] (100). HRMS-
ESI: m/z [M þ Hþ] calcd for C18H20NO5 330.1335, found 330.1339.
(()-(3R,3aR,4R,11bS,11cS)-syn-endo-20. Compound syn-endo-
20 was obtained as the minor product. Yield: 16%, red oil. IR (film): 1778,
1736, 1626, 1568, 1494, 1146 cmꢀ1. 1H NMR δ: 7.19 (m, 1 H), 7.12 (m, 2
H), 6.96 (d, J = 7.3, 1 H), 6.01 (d, J = 7.6, 1 H), 5.49 (d, J = 6.9, 1 H), 5.29
(d, J = 7.6, 1 H), 5.01 (d, J = 7.2, 1 H), 4.92 (d, J = 1.6, 1 H), 4.22 (q, J = 7.1,
2 H), 3.60 (s, 3 H), 3.56 (ddd, J = 9.1, 6.9 and 1.6, 1 H), 3.29 (dd, J = 9.1
and 7.2, 1 H), 1.31 (t, J = 7.1, 3 H). 13C NMR δ: 172.4 (CO), 171.2 (CO),
135.1 (CH), 132.1 (C), 128.2 (CH), 126.9 (CH), 125.9 (C), 125.2 (CH),
124.4 (CH), 102.4 (CH), 100.6 (CH), 65.7 (CH), 63.5 (CH), 61.7
(CH2), 58.2(CH3), 50.8(CH), 44.0 (CH),14.1(CH3). MS (ESIþ): m/z
(%) 352 [M þ Naþ] (28), 330 [M þ Hþ] (100). HRMS-ESI: m/z [M þ
Hþ] calcd for C18H20NO5 330.1335, found 330.1333.
Reaction of Dipolarophiles 6ꢀ8 with Azomethine Ylides
1. General Procedure. To a stirred solution of 1.13 mmol of
dipolarophile and 400 mg (1.35 mmol) of isoquinolinium 1-HBr in
dry acetonitrile (40 mL), under argon atmosphere and at room
temperature, was added DBU (1.35 mmol). After the time indicated
in each case, the solvent was evaporated in vacuo and the residue was
dissolved in dichloromethane and washed with water. The aqueous
layers were extracted with dichloromethane several times. The organic
layers were dried (Na2SO4), filtered, and concentrated in vacuo. The
products were isolated by column chromatography with the eluent
indicated in each case.
1-tert-Butyl 3-Ethyl 2-(diethoxymethyl)-1-p-tolylsulfinyl-
1,2,3,10b-tetrahydropyrrolo[2,1-a]isoquinoline-1,3-dicarbo-
xylate (17). Compound 17 was obtained as a mixture of diaster-
eoisomers from tert-butyl 4,4-diethoxy-2-p-tolylsulfinylbut-2-enoate (6)
and isoquinolinium bromide 1-HBr following the general procedure
1
after 15 min of reaction. The H NMR analyses of the crude reaction
mixture shows the signals corresponding to primary adducts endo- and
exo-17 along with those of compound 18 in a 59:36:5 ratio. The products
were isolated by flash column chromatography (AcOEtꢀhexane, 1:5).
[1R,2R,3R,10bS,(S)S]-endo-17. Compound endo-17 was ob-
tained as the major cycloadduct. Yield: 30%, yellow pale solid. Mp
(AcOEt-hexane): 135ꢀ136 °C (dec). [R]2D0: ꢀ125.7 (c 0.35, CHCl3).
IR (KBr): 1732, 1698, 1626, 1463, 1366, 1254, 1037 cmꢀ1. 1H NMR δ:
7.78 and 7.24 (AA0BB0 system, 4 H), 7.50 (d, J = 7.3 and 1.6, 1 H), 7.11
(m, 2 H), 6.88 (dd, J = 7.3 and 2.5, 1 H), 6.11 (d, J = 7.3, 1 H), 5.81 (s, 1
H), 5.13 (d, J = 7.3, 1 H), 4.68 (d, J = 8.5, 1 H), 4.34ꢀ4.24 (m, 3 H), 3.73
(dq, J = 9.1 and 7.1, 1 H), 3.45 (dd, J = 8.5 and 4.2, 1 H), 3.27ꢀ3.14 (m,
2 H), 2.95 (dq, J = 9.1 and 7.1, 1 H), 2.39 (s, 3 H), 1.35 (t, J = 7.1, 3 H),
1.14 (t, J = 7.1, 3 H), 1.04 (s, 9 H), 0.54 (t, J = 7.1, 3 H).13C NMR δ:
170.9 (CO), 167.5 (CO), 141.4 (C), 138.1 (C), 134.1 (CH), 134.0 (C),
128.9 (CH), 128.5 (CH), 127.9 (CH) 127.7 (CH), 125.4 (C), 125.0
(CH), 124.3 (CH), 99.9 (CH) 96.5 (CH), 83.7 (C), 82.5 (C), 68.1
(CH), 65.8 (CH), 62.4 (CH2), 61.6 (CH2), 56.5 (CH2), 42.8 (CH),
27.4 (CH3), 21.3 (CH3), 15.1 (CH3), 14.3 (CH3), 14.2 (CH3). MS
(ESIþ): m/z (%) 606 [M þ Naþ] (43), 584 [M þ Hþ] (38), 510
(100), 444 (58). HRMS-ESI: m/z [M þ Hþ] calcd for C32H42NO7S
584.2676, found 584.2672.
[1R,2R,3S,10bR,(S)S]-exo-17. Compound exo-17 was obtained as
the minor cycloadduct. It could not be isolated diastereoisomerically
pure. The chemical shifts were measured from the 1H NMR spectrum of
a mixture endo- and exo-17 in a ratio 70:30. It was indicated that only the
signals that are not overlapped are those of other compounds. 1H NMR
δ: 7.73 and 7.32 (AA0BB0 system, 4 H), 6.77 (d, J = 7.5, 2 H), 6.49 (d, J =
7.5, 1 H), 5.99 (d, J = 7.5, 1 H), 5.20 (d, J = 5.4, 1 H), 5.09 (d, J = 7.0,
1 H), 5.07 (s, 1 H), 4.11 (dd, J = 7.0 and 5.4, 1 H), 2.41 (s, 3 H), 1.11
(s, 9 H).
Ethyl [3S,(S)S]-3-Ethoxy-11c-p-tolylsulfinyl-1-oxo-3a,4,11b,-
11c-tetrahydro-1H,3H-furo[30,40:3,4]pyrrolo[2,1-a]isoquino-
line-4-carboxylate (endo-21a). A mixture of diastereoisomers anti-
endo-21a and syn-endo-21a in 83:17 ratio was obtained from [5S,(S)S]-
5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-one (7a) and the isoquinolinium
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The Journal of Organic Chemistry
ARTICLE
1-HBr after 5 min. They were purified by flash column chromatography
(acetoneꢀhexane, 1:4). The combined yield is 95%.
Hþ] (65), 342 (100). HRMS-FAB: m/z [M þ Hþ] calcd for
C26H28NO6S 482.1637, found 482.1644.
[3S,3aR,4R,11bS,11cR,(S)S]-anti-endo-21a. Compound anti-
endo-21a was obtained as the major product. Yield: 79%, white solid. Mp
(hexaneꢀAcOEt): 134ꢀ135 °C (dec). [R]2D0: þ304.0 (c 0.5, CHCl3).
IR (KBr): 1772, 1741, 1630, 1150, 1082, 1051 cmꢀ1. 1H NMR δ: 7.70
and 7.34 (AA0BB0 system, 4 H), 7.41 (m, 1 H), 7.19 (m, 2 H), 6.95 (m, 1
H), 6.01 (d, J = 7.5, 1 H), 5.42 (d, J = 7.5, 1 H), 5.29 (s, 1 H), 5.23 (d, J =
2.6, 1 H), 4.31 (s, 1 H), 4.10 (m, 2 H), 3.64 (m, 1 H), 3.49 (m, 1 H), 3.35
(d, J = 2.6, 1 H), 2.42 (s, 3 H), 1.31 (t, J = 7.1, 3 H), 1.10 (t, J = 7.1, 3 H).
13C NMR δ: 168.4 (CO), 167.6 (CO), 143.0 (C), 136.0 (C), 133.2
(CH), 131.4 (C), 129.8 (CH), 128.8 (CH), 128.7 (CH), 126.8 (CH),
125.9 (CH), 124.6 (CH), 124.0 (C), 105.4 (CH), 103.0 (CH), 78.1 (C),
70.4 (CH), 66.4 (CH), 65.6 (CH2), 62.0 (CH2), 51.2 (CH), 21.4
(CH3), 14.6 (CH3), 14.0 (CH3). Anal. Calcd for C26H27NO6S: C 64.85,
H 5.65, N 2.91, S 6.66. Found: C 64.74, H 5.69, N 2.95, S 6.82.
[3S,3aS,4S,11bR,11cS,(S)S]-syn-endo-21a. Compound syn-
endo-21a was obtained as the minor product. Yield: 16%, white solid.
Mp (hexaneꢀAcOEt): 159ꢀ161 °C (dec). [R]2D0: ꢀ418.8 (c 0.25,
CHCl3). IR (KBr): 1764, 1729, 1631, 1493, 1083, 1057 cmꢀ1. 1H NMR
δ: 7.46 (m, 3 H), 7.45ꢀ7.19 (m, 4 H), 7.01 (m, 1 H), 5.93 (d, J = 7.6, 1
H), 5.37 (d, J = 7.6, 1 H), 5.28 (s, 1 H), 4.94 (d, J = 1.2, 1 H), 4.40 (d, J =
7.3, 1 H), 4.31 (m, 2 H), 3.69 (m, 2 H), 3.44 (m, 1 H), 2.39 (s, 3 H), 1.36
(t, J = 7.2, 3 H), 1.17 (t, J = 7.1, 3 H). 13C NMR δ: 170.1 (CO), 168.0
(CO), 143.0 (C), 135.8 (C), 135.7 (CH), 132.1 (C), 130.2 (CH), 129.1
(CH), 127.4 (CH), 125.8 (CH), 124.8 (CH), 124.7 (CH), 102.0 (CH),
100.9 (CH), 82.7 (C), 66.8 (CH), 66.7 (CH2), 65.5 (CH), 62.1 (CH2),
44.8 (CH), 21.5 (CH3), 14.9 (CH3), 14.3 (CH3). Anal. Calcd for
C26H27NO6S: C 64.85, H 5.65, N 2.91, S 6.66. Found: C 64.68, H 5.55,
N 2.87, S 7.10.
’ ASSOCIATED CONTENT
S
Supporting Information. NMR spectra of all new com-
b
pounds and X-ray ORTEP and crystallographic data for com-
pounds endo-17, anti-endo-21a, syn-endo-21a, and anti-endo-21b
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
joseluis.garcia.ruano@uam.es; rosario.martin@uam.es
’ ACKNOWLEDGMENT
We thank DGICYT (Grant CTQ2009-12168/BQU) and
Comunidad Autꢀonoma de Madrid (AVANCAT S2009/PPQ-
1634) for financial support.
’ REFERENCES
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Ethyl [3R,(S)S]-3-Ethoxy-11c-p-tolylsulfinyl-1-oxo-3a,4,11b,11c-
tetrahydro-1H,3H-furo[30,40:3,4]pyrrolo[2,1-a]isoquinoline-
4-carboxylate (endo-21b). A mixture of diastereoisomers anti-endo-
21b and syn-endo-21b in 89:11 ratio was obtained from [5R,(S)S]-
5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-one (7b) and the isoquinolinium
1-HBr after 5 min. They were purified by flash column chromatography
(AcOEtꢀhexane, 1:2). The combined yield is 85%.
[3R,3aS,4S,11bR,11cS,(S)S]-anti-endo-21b. Compound anti-
endo-21b was obtained as the major product. Yield: 76%, white solid.
Mp: 147ꢀ148 °C (dec). [R]2D0: ꢀ410.4 (c 0.5, CHCl3). IR (KBr): 1751,
1628, 1494, 1080, 1053 cmꢀ1. 1H NMR δ: 7.52 (m, 1H), 7.46 and 7.27
(AA0BB0 system, 4 H), 7.29 (m, 2 H), 7.03 (m, 1 H), 5.99 (d, J = 7.5, 1
H), 5.44 (s, 1 H), 5.43 (d, J = 7.5, 1 H), 5.19 (d, J = 2.1, 1 H), 4.36 (m, 3
H), 3.41 (m, 1 H), 3.28 (q, J= 7.0, 2 H), 2.38 (s, 3 H), 1.41 (t, J =7.1, 3 H),
0.83 (t, J = 7.0, 3 H). 13C NMR δ: 168.6 (CO), 168.3 (CO), 142.4 (C),
135.5 (C), 134.0 (CH), 131.4 (C), 129.7 (CH), 129.1 (CH), 127.7
(CH), 126.2 (CH), 125.5 (CH), 124.9 (CH), 124.4 (C), 106.5 (CH),
103.3 (CH), 82.2 (C), 72.2 (CH), 65.3 (CH), 65.1 (CH2), 62.3 (CH2),
48.9 (CH), 21.3 (CH3), 14.4 (CH3), 14.3 (CH3). Anal. Calcd for
C26H27NO6S: C 64.85, H 5.65, N 2.91, S 6.66. Found: C 64.95,
H 5.53, N 2.90, S 7.15.
(3) (a) Baunbæk, D.; Trinkler, N.; Ferandin, Y.; Lozach, O.;
Ploypradith, P.; Rucirawat, S.; Ishibashi, F.; Iwao, M.; Meijer, L. Mar.
Drugs 2008, 6, 514–527. (b) Shen, L.; Yan, X.; Yang, B.; He, Q.; Hu, Y.
Eur. J. Med. Chem. 2010, 45, 11–18 and references therein.
(4) For hydropyrrolo[2,1-a]isoquinolines, see: (a) Keith, J. M.;
Gomez, L. A.; Barbier, A. J.; Wilson, S. J.; Boggs, J. D.; Lord, B.; Mazur,
C.; Aluisio, L.; Lovenberg, T. W.; Carruthers, N. I. Bioorg. Med. Chem.
Lett. 2007, 17, 4374–4377. (b) Keith, J. M.; Gomez, L. A.; Wolin, R. L.;
Barbier, A. J.; Wilson, S. J.; Boggs, J. D.; Mazurt, C.; Fraser, I. C.; Lord, B.;
Aluisio, L.; Lovenberg, T. W.; Carruthers, N. I. Bioorg. Med. Chem. Lett.
2007, 17, 2603–2607.(c) Apodaca, R.; Barbier, A. J.; Carruthers, N. I.;
Gomez, L. A.; Keith, J. M.; Lovenberg, T. W.; Wolin, R. L. PCT Int.
Appl. 2006 WO 2006138604; Chem. Abstr. 2006, 146, 100661.
(d) Vennemann, M.; Baer, T.; Braunger, J.; Gekeler, V.; Gimmnich,
P.; Ciapetti, P.; Contreras, J.; Wermuth, C. G. PCT Int. Appl. 2006 WO
2006075012; Chem. Abstr. 2006, 145, 167105.
(5) For pyrrolo[2,1-a]isoquinoline-1-carboxylates, see: (a) Niewoehner,
U.; Bauser, M.; Ergueden, J.; Flubacher, D.; Naab, P.; Repp, T.;
Stoltefuss, J.; Burkhardt, N.; Sewing, A.; Schauer, M.; Schlemmer, K.;
Weber, O.; Boyer, S.; Miglarese, M.; Ying, S. PCT Int. Appl. 2003 WO
2003014115; Chem. Abstr. 2003, 138, 187650. (b) Ashton, M. J.; Dron,
[3R,3aR,4R,11bS,11cR,(S)S]-syn-endo-21b. Compound syn-
endo-21b was obtained as the minor product. Yield: 9%, yellow solid.
Mp: 108ꢀ110 °C (dec). [R]2D0: þ90.07 (c 0.675, CHCl3). IR (film):
1770, 1749, 1631, 1596, 1493, 1146, 1082, 1049 cmꢀ1. 1H NMR δ: 7.69
(AA0BB0 system, 2 H), 7.41 (m, 3 H), 7.24 (m, 2 H), 6.99 (m, 1 H), 5.91
(d, J = 7.6, 1 H), 5.37 (d, J = 7.1, 1 H), 5.35 (d, J = 7.6, 1 H), 4.89 (s, 1 H),
4.85 (d, J = 1.3, 1 H), 3.89 (m, 1 H), 3.80 (m, 2 H), 3.67 (m, 1 H), 3.59
(dd, J = 7.1 and 1.3, 1 H), 2.45 (s, 3 H), 1.26 (t, J = 7.1, 3 H), 1.17 (t, J =
7.1, 3 H). 13C NMR δ: 169.7 (CO), 168.5 (CO), 143.5 (C), 135.6 (C),
134.7 (CH), 132.1 (C), 130.1 (CH), 128.9 (CH), 127.7 (CH), 126.3
(CH), 125.4 (CH), 124.8 (CH), 124.2 (C), 101.3 (CH), 100.8 (CH),
81.4 (C), 66.8 (CH2), 66.4 (CH), 65.0 (CH), 61.6 (CH2), 45.8 (CH),
21.4 (CH3), 14.9 (CH3), 13.9 (CH3). MS (FABþ): m/z (%) 482 [M þ
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ARTICLE
D. I.; Fenton, G.; Lythgoe, D. J.; Newton, C. G.; Riddell, D. Eur. Pat.
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(16) For nonasymmetric cycloadditions of these dipoles (less stu-
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(9) (a) Gothelf, K. V.; Jøgensen, K. A. Chem. Rev. 1998, 98, 863–909.
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(10) For some recent examples, see: (a) Bica, K.; Gaertner, P.
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(17) It was available from furfural according to the procedure
previously described: Schenck, G. O. Liebigs Ann. 1953, 584, 156–176.
(18) The endo or exo terms indicate, respectively, the cis or trans
arrangement of the CN (or CO2t-Bu) group with respect to the
dihydropyridine (for 1-HBr) or tetrahydropyridine (for 2-HBr) moi-
eties at the pyrrolidine ring formed in the reactions from azomethine
ylide. They are related to the endo and exo addition modes of dipole,
using as a reference the nitrile group at the dipolarophile.
(19) Tominaga, Y.; Ichihara, Y.; Mori, T.; Kamio, C.; Hosomi, A.
J. Heterocycl. Chem. 1990, 27, 263.
(20) Compound 12 is also obtained from endo-9 upon standing for
several weeks in the refrigerator.
(21) Dipolarophile 6 did not react with stabilized thiazolium N-ylide.
(22) When the ester group is located at C-2, the δ value is 1.39ꢀ1.50
ppm, whereas when it is positioned at C-1 and adopts a trans arrange-
ment with respect to H-10b, the δ value is 1.08ꢀ1.12 ppm.
(23) Tsuge, O.; Kanemasa, S.; Takenaka, S. Bull. Chem. Soc. Jpn.
1986, 59, 3631–3635.
(11) García Ruano, J. L.; Tito, A.; Peromingo, M. T. J. Org. Chem.
2002, 67, 981–987. (b) García Ruano, J. L.; Tito, A.; Peromingo, M. T.
J. Org. Chem. 2003, 68, 10013–10019.
(12) García Ruano, J. L.; Fraile, A.; Martín, M. R.; Gonzꢀalez, G.;
Fajardo, C. J. Org. Chem. 2008, 73, 8484–8490.
(24) Therefore, the adducts with H-3 and H-10b in a trans arrange-
ment were formed predominantly.
(13) The only reported examples on asymmetric [3þ 2] cycloaddition
of azomethine ylides to vinyl sulfoxides are described in refs 11 and 12 as
well as in the following ones dealing with the reactions of vinylsulfoxides
with 3-oxidopyridium betaine to afford tropanes: (a) Takahashi, T.;
Kitano, K.; Hagi, H.; Nihonmatsu, H.; Koizumi, T. Chem. Lett.
1989, 597. (b) Takahashi, T.; Fujii, A.; Sugita, J.; Hagi, T.; Kitano, K.;
Arai, Y.; Koizumi, T. Tetrahedron: Asymmetry 1991, 2, 1379. (c) Araldi,
G. L.; Prakash, K. R. C.; George, C.; Kozikowski, A. P. Chem. Commun.
1997, 1875. (d) Prakash, K. R. C.; Trzcinska, M.; Johson, K. M.;
Kozikowski, A. P. Bioorg. Med. Chem. Lett. 2000, 10, 1443.
(25) CCDC809008 contains the supplementary crystallographic
data for endo-17. These data can be obtained free of charge via www.
ccdc.cam.ac.uk/data_request/cif or by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223.
(26) Attractive interaction between the electron-withdrawing sub-
stituent at the dipolarophile and the heteroaromatic ring of the ylide has
been proposed by other authors; see ref 16a.
(27) The syn or anti character of these adducts is indicative of the cis
or trans relationship between H-3 and H-3a, respectively. It is related to
the face of the dipolarophile where the dipole approaches, taking as a
reference the spatial arrangement of the alkoxy group (for this
nomenclature, see: (a) Keller, E.; de Lange, B.; Rispens, M. T.; Feringa,
B. L. Tetrahedron 1993, 49, 8899. (b) Trost, B. M.; Crawley, M. L.
Chem.—Eur. J. 2004, 10, 2237). Thus, syn-adducts result from the
approach of dipole to the face where the OEt group is positioned,
whereas the anti-adducts are obtained by approach to the opposite face.
The endo or exo terms indicate, respectively, the cis or trans arrange-
ment adopted by furanone and dihydropyridine moieties at the pyrro-
lidine ring formed in the reactions from azomethine ylide. They are
related to the endo and exo addition modes of dipole, using as a
reference the carbonyl group at the furanone ring..
(14) These features had also been reported for reactions of vinyl
sulfoxides with other dipoles such as diazoalkanes: (a) García Ruano,
J. L.; Fraile, A.; Martín, M. R. Tetrahedron: Asymmetry 1996, 7, 1943. (b)
García Ruano, J. L.; Alonso de Diego, S. A.; Blanco, D.; Martín Castro,
A. M.; Martín, M. R.; Rodríguez Ramos, J. H. Org. Lett. 2001, 3, 3173. (c)
García Ruano, J. L.; Fraile, A.; Gonzꢀalez, G.; Martín, M. R.; Clemente,
F. R.; Gordillo, R. J. Org. Chem. 2003, 68, 6522. (d) García Ruano, J. L.;
Alonso, M.; Fraile, A.; Martín, M. R.; Peromingo, M. T.; Tito, A. J. Org.
Chem. 2005, 70, 8942. (e) Cruz, D.; Yuste, F.; Martín, M. R.; Tito, A.;
García Ruano, J. L. J. Org. Chem. 2009, 74, 3820–3826. Nitrile oxides:(f)
García Ruano, J. L.; Fraile, A.; Martín, M. R. Tetrahedron 1999,
55, 14491. (g) García Ruano, J. L.; Bercial, F.; Fraile, A.; Martín, M. R.
Synlett 2002, 73. Nitrones:(h) García Ruano, J. L.; Andrꢀes, I.; Fraile, A.;
Martín Castro, A. M.; Martín, M. R. Tetrahedron Lett. 2004, 45, 4653. (i)
García Ruano, J. L.; Andrꢀes, I.; Fraile, A.; Martín Castro, A. M.; Martín,
M. R. J. Org. Chem. 2005, 70, 8825. Carbonyl ylides:(j) García Ruano,
J. L.; Fraile, A.; Martín, M. R.; Nu~nez, A. J. Org. Chem. 2006,
71, 6536–6541. Allenoates and sulfonyl allenes:(k) García Ruano, J.
L; Nꢀu~nez, A.; Martín, M. R.; Fraile, A. Org. Chem. 2008, 73, 9366–9371.
(l) Nꢀu~nez, A.; Martín, M. R.; Fraile, A.; García Ruano, J. L. Chem.—Eur.
J. 2010, 16, 5443–5453.
(28) It is noteworthy that compound 8 did not react with thiazolium
ylide (see ref 12).
(29) CCDC809009, CCDC809010, and CCDC809011 contain the
supplementary crystallographic data for anti-endo-21a, anti-endo-21b,
and syn-endo-21a, respectively. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_re-
quest@ccdc.cam.ac.uk, or by contacting The Cambridge
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The Journal of Organic Chemistry
ARTICLE
Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: þ44 1223.
(30) The reactions of ylide 1 with sulfinylfuranones 7 were assayed
in different solvents. Unfortunately, the reaction mixtures obtained in
less polar solvent than acetonitrile (toluene or dichloromethane) were
complex and any certain conclusion can be inferred.
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