Diels-Alder reactions of three fused nitrogen-containing bicyclic enones: An efficient method toward novel nitrogen-containing angular tricyclic skeletons

Article abstract of DOI:10.1039/b806773m

The syntheses of three fused bicyclic enones, including 1,2,6,6a-tetrahydro-1-tosyl-cyclopenta[b]pyrrol-3(5H)-one, 1,2,3,6,7,7a- hexahydro-4H-1-tosyl-cyclopenta[b]pyridin-4-one and 1,2,5,6,7,7a-hexahydro-3H-1- tosyl-indol-3-one, via anionic cyclization an

Full text of DOI:10.1039/b806773m

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Diels–Alder reactions of three fused nitrogen-containing bicyclic enones: an
efficient method toward novel nitrogen-containing angular tricyclic skeletons†
Chi-Min Chau* and Kuan-Miao Liu*
Received 21st April 2008, Accepted 4th June 2008
First published as an Advance Article on the web 1st July 2008
DOI: 10.1039/b806773m
The syntheses of three fused bicyclic enones, including 1,2,6,6a-tetrahydro-1-tosyl-
cyclopenta[b]pyrrol-3(5H)-one, 1,2,3,6,7,7a-hexahydro-4H-1-tosyl-cyclopenta[b]pyridin-4-one and
1,2,5,6,7,7a-hexahydro-3H-1-tosyl-indol-3-one, via anionic cyclization and Diels–Alder reactions with
various dienes to construct novel nitrogen-containing angular tricyclic skeletons are described.
Introduction
1,2,6,6a-Tetrahydro-1-tosyl-cyclopenta[b]pyrrol-3(5H)-one (7),
1,2,3,6,7,7a-hexahydro-4H-1-tosyl-cyclopenta[b]pyridin-4-one
(8) and 1,2,5,6,7,7a-hexahydro-3H-1-tosyl-indol-3-one (9)
have unique structures, as shown below, and are suggested
synthetically versatile and potential intermediates. They can
be further functionalized via different organic methods and
subsequently used in the construction of core skeletons or total
syntheses of some natural products (Fig. 1). The synthetic utility
of 1,2,5,6,7,7a-hexahydro-3H-indol-3-one had been demonstrated
in the total synthesis of (−)-brunsvigine1 and ( )-lentiginosine,2
wherein SN2 alkylation and oxidative cleavage were used as the key
steps, respectively. Here, we continued to exploit their potential
synthetic applications, and have found that the enone moieties
of these three compounds undergo Diels–Alder cycloadditions
with various dienes to afford novel nitrogen-containing angular
tricyclic skeletons in high yields.
Scheme 1 Synthetic process of enones 7, 8 and 9.
anionic cyclization reaction to furnish the desired enone
compounds. In the preparation of 1,2,6,6a-tetrahydro-1-tosyl-
cyclopenta[b]pyrrol-3(5H)-one 7, the acetal 6 was isolated as a
stable compound, and compound 7 could later be obtained when
treated with an acidic solution.
Fig. 1 The structures and synthetic versatility of enones 7, 8 and 9.
Because of their special fused cyclic enone structures, we
examined their dienophilicity by treating them with various
dienes. The Diels–Alder cycloadducts possess novel nitrogen-
containing angular tricyclic skeletons, which could be important
intermediates toward some natural products, are not easy to obtain
by other methods. Several efforts, including Michael addition
and the subsequent direct alkylation of the resulting enolate or
alkylation of the corresponding silyl enone ether, had been carried
out to introduce an alkyl chain at the bridgehead position of
compound 9; however, all these methods were unsuccessful. Thus
the development of an efficient method or stategy to construct the
desired tricyclic structures or to introduce an alkyl chain at the
bridgehead position is the target of this work.
These three compounds, which have a common and unique
enone moiety across two adjacent rings, were prepared according
to a modified approach, shown in Scheme 1.3 In general, the
vinyl iodides with ester functionalities were treated with n-
BuLi, and the resulting vinyl lithium initiated the intramolecular
School of Applied Chemistry, Chung Shan Medical University, Taichung,
40201, Taiwan, ROC. E-mail: cmchau@csmu.edu.tw, lkm@csmu.edu.tw
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectroscopic and analytical data of all the compounds in Table 1 and
Schemes 1 and 2. CCDC reference numbers 678651–678653. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b806773m
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feature that determined the conformation of the cycloadduct, and
the exo product was obtained due to its lower energy transition
state as compared with that of the endo product.
Results and discussion
To study the Diels–Alder reactions of these three fused cyclic
enones, the treatment of 1,2,5,6,7,7a-hexahydro-3H-1-tosyl-indol-
3-one 9 with 2,3-dimethyl-1,3-butadiene 15 in xylene in a sealed
tube at 180 ◦C was carried out as a model reaction. The
cycloadduct was obtained successfully in 75% yield, but this
method became inconvenient and dangerous when the dienes had
low boiling points. In order to perform the reaction under milder
conditions, we opted for the Lewis acid catalysed method, which
had been used in many other Diels–Alder reactions.4 First, we used
SnCl4 as the catalyst and carried out the Diels–Alder reaction
of compound 9 with 2,3-dimethyl-1,3-butadiene in CH2Cl2 at
In order to illustrate the synthetic utility of this reaction, we
further cleaved the double bond of compound 38 to obtain another
tricyclic skeleton 50, which is similar to the key intermediate in
Yamamura et al.’s skeleton synthesis of manzamine A8 (Scheme 2).
Furthermore, we believed that compounds 36 and 37 could also
be converted into two new structures. In addition to the carbon-
based Diels–Alder reaction, the aza-Diels–Alder reaction, where
nitrogen-containing dienes are used, will be our future subject of
study.
0
◦C. The reaction was completed within 30 min, and the yield
of the adduct was 86%, which is better than that of the thermal
adduct. However, in the cases of 2-methyl-1,3-pentadiene and
1,3-pentadiene, the yields of the products were very poor, and
almost all the starting enone was recovered. The substitution
of SnCl4 with BF3·OEt2 improved the yields dramatically and
also yielded favourable results in the other cases. The results are
summarized in Table 1. In addition, nonsubstituted furan and
N-methyl pyrrole, which were not considered to be good dienes
as compared with cyclopentadiene,5 but were good nucleophiles
towards enone systems,6 were also subjected to the Diels–Alder
reaction in the presence of BF3·OEt2. The reaction results were
consistent with our expectations in that the 1,4-addition products
were predominantly formed. However, the reaction of 7 with furan
furnished the Diels–Alder adduct 39 as the sole compound. In
addition, the stereochemistry of 39, which was identified as endo
by nuclear overhauser effect experiments,7 differed from that of
36, which was the product of the reaction of compound 7 with
cyclopentadiene, and its stereostructure was confirmed as exo by
X-ray analysis, as shown in the ESI.† The exact reason for the
difference in the diastereoselectivity was not entirely clear. We
attempted to illustrate the exo-diastereoselectivity of the reaction
of enone 7 with cyclopentadiene, as shown in Fig. 2. The diene
approached from the less-hindered face, the convex face, of the
fused bicyclic enone; thus, the relative stereochemistry of H1 and
the newly formed bonds in the cycloadduct must be cis.
Scheme 2 One of the synthetic potentials of the Diels–Alder reaction
methodology presented in this study.
Conclusions
In conclusion, we have used the well known Lewis acid-catalysed
Diels–Alder reaction to achieve novel nitrogen-containing angular
tricyclic skeletons, which are not easily obtained by other methods.
It is a synthetically valuable method to establish a third 6-
or 5-membered ring from the structurally unique fused bicyclic
enones. The application of this strategy to construct core skeletons
of natural products, for example, the tricyclic core skeleton of
manzamine A, is currently in progress.
Experimental
General experimental
Reactions were carried out in oven and flame-dried glassware
under a positive pressure of argon. THF was distilled over sodium–
benzophenone. Dichloromethane and xylene were distilled over
calcium hydride. Cyclopentadiene was distilled before use. All
reagents were purchased commercially and used without further
purification. TLC was performed on Merck 5735 DC-plastikfolien
Kieselgel 60 F254 precoated plates. Flash column chromatography
was performed with silica gel Merck 7736 Kieselgel 60H. 1H-
NMR (7.24 ppm for CDCl3 as internal standard) and 13C-NMR
(77.0 ppm for CDCl3 as internal standard) spectra were recorded
on Varian Unity-400 MHz instrument. Coupling constants are
measured in Hertz. IR spectra were recorded from a Bomen
Fig. 2 Proposed transition state illustration of exo-diastereoselectivity of
the Diels–Alder reaction of enone 7 with cyclopentadiene.
Furthermore, the exo preference may be attributed to a sec-
ondary orbital interaction between the carbonyl group of the
fused bicyclic enone and the approached diene, which was not
strong enough because the p orbital alignments were not good for
competing with the repulsive interaction between the methylene of
the diene with the other parts of the enone in the endo transition
state. Consequently, the repulsive steric effect was the dominant
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Table 1 Diels–Alder reactions of enones 7, 8 and 9 with various dienes
Reaction
Reaction
Diene
conditions Producta/yield
Diene conditions Producta/yield
A
C
C
C
B
C
15 R1 = R2 = CH3, R3 = H
16 R1 = CH3, R2 = R3 = H
17 R1 = R3 = CH3, R2 = H
18 R3 = CH3, R1 = R2 H
24 R1 = R2 = CH3, R3 = H (n = 0, m = 1, 89%)
25 (n = 0, m = 2, 86%)
26 (n = 1, m = 1, 90%)
27 R1 = CH3, R2 = R3 = H (n = 0, m = 1, 90%)
28 (n = 0, m = 2, 88%)
29 (n = 1, m = 1, 86%)
30ab + 30bc R1 = R3 = CH3, R2 = H (n = 0, m = 1,
67% + 8%)
31ab + 31bc (n = 0, m = 2, 62% + 8%)
32ab + 32bc (n = 1, m = 1, 70%c)
33ab + 33bc R3 = CH3, R1 = R2 = H (n = 0, m = 1,
66% + 8%)
34ab + 34bc (n = 0, m = 2, 66%d)
35ab + 35bc (n = 1, m = 1, 68%d)
a All the products are racemates. b R3 is trans to the hydrogen at the bridgehead. c R3 is cis to the hydrogen at the bridgehead. d Total yield of the inseparable
mixture.
MB-100FT spectrometer. Melting points were recorded on a Buchi
530 melting point apparatus and are not corrected. HRMS data
were obtained from a FOEL JMS-HX110 spectrometer. Single
crystal X-ray analysis was performed on a Siemens Smart CCD
diffractometer.
Methyl 3-(N-(2-iodocyclopent-2-enyl)-N-tosylamino) propano-
ate (4). To a solution of compound 1 (55.0 mg, 0.26 mmol) in
THF (8 mL) was added triphenyl phosphine (89.4 mg, 0.34 mmol)
and methyl 3-(tosylamino) propanoate (87.6 mg, 0.34 mmol).
After all solid was dissolved completely, DIAD (67 lL, 0.34 mmol)
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was added slowly to the mixture at 0 ◦C. The reaction mixture
was stirred for an additional 1 hour at room temperature (25 ◦C)
followed by removal of the solvent. Purification by flash column
chromatography (ethyl acetate–hexane 1 : 15) afforded compound
4 as a pale yellow solid (96.5 mg, 82%).
1,2,3,6,7,7a-Hexahydro-4H-1-tosyl-cyclopenta[b]pyridin-4-one
(8). To a stirred solution of substrate 4 (801 mg, 1.78 mol) in dry
THF (15 mL) at −100 ◦C was added TMSCl (0.57 mL, 4.46 mmol).
A solution of n-BuLi in n-hexane (2.0 M, 1.80 mL, 3.57 mmol) was
slowly added at −100 ◦C, and the reaction mixture was maintained
at −100 ◦C for 30 min. The cooling bath was removed and the
reaction mixture was quenched at 0 ◦C with a solution of NH4Cl
(saturated, 8 mL) and ether (10 mL) and HCl (2 N, 5 mL). The
mixture was extracted with ether (15 mL × 4). The organic layer
was washed with brine (20 mL) and dried over MgSO4. Removal of
solvent followed by flash column chromatography (ethyl acetate–
hexane 1 : 3) afforded pure compound 8 as a pale yellow solid
(436 mg, 84%).
1H NMR (400 MHz, CDCl3) d 7.70 (d, J = 8.0 Hz, 2H), 7.31 (d,
J = 8.0 Hz, 2H), 6.82 (dd, J = 5.4, 2.4 Hz, 1H), 4.39–4.32 (m, 1H),
3.59–3.53 (m, 2H), 2.69 (dt, J = 13.2, 6.4 Hz, 1H), 2.56–2.44 (m,
1H), 2.40 (s, 3H), 2.39–2.28 (m, 2H), 2.20–2.02 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 194.2 (C), 143.7 (C), 142.7 (CH), 139.0 (C),
134.8 (C), 129.8 (CH), 127.1 (CH), 62.0 (CH), 43.0 (CH2), 38.8
(CH2), 35.9 (CH2), 30.2 (CH2), 21.2 (CH3); IR (neat) 2977, 2880,
1707, 1664 cm−1; MS (EI) m/z 291 (M+, 36), 136 (65), 122 (54),
79 (100); HRMS (EI) m/z calcd for C15H17NO3S 291.0929, found
291.0925; mp 164.3–164.9 ◦C.
1H NMR (400 MHz, CDCl3) d 7.70 (d, J = 8.6 Hz, 2H), 7.27 (d,
J = 8.6 Hz, 2H), 6.30 (brs, 1H), 4.93–4.87 (m, 1H), 3.62 (s, 3H),
3.35–3.25 (m, 1H), 2.99–2.75 (m, 3H), 2.38 (s, 3H), 2.36–2.29 (m,
1H), 2.26–2.16 (m, 1H), 2.09–1.97 (m, 1H), 1.45–1.35 (m, 1H); 13
C
NMR (100 MHz, CDCl3) d 172.0 (C), 145.0 (CH), 143.5 (C), 136.6
(C), 129.6 (CH), 127.5 (CH), 95.4 (C), 71.1 (CH), 51.6 (CH3), 39.5
(CH2), 36.1 (CH2), 33.5 (CH2), 26.1 (CH2), 21.5 (CH3); IR (neat)
2977, 2938, 1755, 1739, 1343 cm−1; MS (EI) m/z 449 (M+, 21),
322 (65), 263 (48), 108 (100), 51 (40); HRMS (EI) m/z calcd for
C16H20INO4S 449.0158, found 449.0157; mp 159.1–160.5 ◦C.
1,2,3,5,6,6a-Hexahydro-3-methoxy-1-tosyl-3-(trimethylsilyloxy)-
cyclopenta[b]pyrrole (6). To a stirred solution of substrate 3
(655 mg, 1.51 mmol) in dry THF (10 mL) at −100 ◦C was added
TMSCl (0.38 mL, 3.01 mmol). A solution of n-BuLi in n◦-hexane
(2.0 M, 1.51 mL, 3.01 mmol) was slowly added at −100 C, and
the reaction mixture was maintained at −100 ◦C for 30 min. The
cooling bath was removed and the reaction mixture was quenched
at 0 ◦C with a solution of NH4Cl (saturated, 5 mL) and ether
(10 mL) and HCl (2 N, 5 mL). The mixture was extracted with
ether (10 mL × 4). The organic layer was washed with brine
(10 mL) and dried over MgSO4. Removal of solvent followed
by flash column chromatography (ethyl acetate–hexane 1 : 25)
afforded pure compound 6 as a pale yellow solid (545 mg, 95%).
1H NMR (400 MHz, CDCl3) d 7.71 (d, J = 8.0 Hz, 2H), 7.27
(d, J = 8.0 Hz, 2H), 5.78 (dd, J = 5.2, 2.0 Hz, 1H), 4.36–4.29 (m,
1H), 3.65 (AB, J = 10.4 Hz, 1H), 3.59 (AB, J = 10.4 Hz, 1H),
3.24 (s, 3H), 2.54–2.42 (m, 3H), 2.38 (s, 3H), 2.06–1.93 (m, 1H),
−0.21 (s, 9H); 13C NMR (100 MHz, CDCl3) d 146.1 (C), 143.2
(C), 134.6 (C), 129.4 (CH), 127.9 (CH), 125.8 (CH), 98.4 (C), 68.3
(CH), 63.1 (CH2), 51.0 (CH3), 35.6 (CH2), 34.9 (CH2), 21.4 (CH3),
0.56 (CH3); IR (neat) 2981, 2936, 1349, 1163 cm−1; MS (EI) m/z
381 (M+, 6), 226 (100), 195 (45), 122 (21); HRMS (EI) m/z calcd
for C18H27NO4SSi 381.1430, found 381.1427; mp 157.5–158.3 ◦C.
3-Tosyl-2,3,3a,4,5,6,6a,7-octahydro-3-aza-cyclopenta[d]napht-
halene-1,8-dione (22). To a solution of compound 9 (65.0 mg,
0.42 mmol) in toluene (8 mL) was added Danishefsky diene
(290 mg, 1.69 mmol). The mixture was refluxed under Ar for
14 hours. After cooling to room temperature, 6 N HCl (1 mL)
was added, and the mixture was stirred for an additional 1 hour.
Addition of water (2 mL) and ether (2 mL) were followed by
extraction with ether (5 mL × 4). The combined organic layer was
washed with saturated NaHCO3 (5 mL) and brine (5 mL) and dried
over MgSO4. After filtration and concentration, purification by
flash column chromatography (ethyl acetate–hexane 1 : 2) afforded
compound 22 as a white solid (106 mg, 70%).
1H NMR (400 MHz, CDCl3) d 7.69 (d, J = 8.0 Hz, 2H), 7.38
(d, J = 8.0 Hz, 2H), 6.12 (d, J = 10.2 Hz, 1H), 6.04 (dd, J = 10.2,
1.6 Hz, 1H), 4.12 (AB, J = 18.2 Hz, 1H), 3.51 (AB, J = 18.2 Hz,
1H), 3.37 (brs, 1H), 2.59 (dd, J = 17.0, 5.6 Hz, 1H), 2.53–2.45 (m,
2H), 2.44 (s, 3H), 2.17 (dd, J = 16.8, 4.4 Hz, 1H), 1.94–1.82 (m,
1H), 1.74–1.50 (m, 3H), 1.44–1.31 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 203.7 (C), 197.4 (C), 144.8 (C), 141.9 (CH), 132.7 (CH),
131.6 (C), 130.1 (CH), 127.9 (CH), 63.4 (CH), 56.3 (C), 54.5 (CH2),
39.6 (CH2), 33.5 (CH), 27.7 (CH2), 25.4 (CH2), 21.6 (CH3), 18.6
(CH2); IR (neat) 1711, 1693, 1672, 1344, 966 cm−1; MS (EI) m/z
359 (M+, 7), 155 (37), 148 (79), 106 (41), 91 (100), 65 (44); HRMS
(EI) m/z calcd for C19H21NO4S 359.1191, found 359.1189.
1,2,6,6a-Tetrahydro-1-tosyl-cyclopenta[b]pyrrol-3(5H)-one (7).
To a solution of compound 6 (292 mg, 0.77 mmol) in THF (10 mL)
was added a solution of acetone (5 mL) and water (5 mL) at 0 ◦C.
pTSA (39.5 mg, 0.23 mmol) was then added and the reaction
mixture was stirred for 1 hour. The reaction mixture was quenched
with water (3 mL) and extracted with ether (10 mL × 4). The
organic layer was washed with brine (10 mL) and dried over
MgSO4. Concentration and silica gel column chromatography
(ethyl acetate–hexane 1 : 5) gave compound 7 as a white solid
(197 mg, 93%).
1H NMR (400 MHz, CDCl3) d 7.70 (d, J = 8.4 Hz, 2H), 7.36 (d,
J = 8.4 Hz, 2H), 6.70 (dd, J = 6.0, 2.8 Hz, 1H), 4.40–4.33 (m, 1H),
4.03 (AB, J = 16.8 Hz, 1H), 3.52 (AB, J = 16.8 Hz, 1H), 2.85–
2.78 (m, 2H), 2.70–2.62 (m, 1H), 2.43 (s, 3H), 2.41–2.25 (m, 1H);
13C NMR (100 MHz, CDCl3) d 191.1 (C), 144.5 (C), 143.1 (C),
139.6 (CH), 131.4 (C), 129.9 (CH), 128.3 (CH), 68.0 (CH), 61.0
(CH2), 37.4 (CH2), 36.7 (CH2), 21.5 (CH3); IR (neat) 2975, 2880,
1705, 1661 cm−1; MS (EI) m/z 277 (M+, 2), 122 (89), 65 (100);
HRMS (EI) m/z calcd for C14H15NO3S 277.0773, found 277.0770;
mp 165.3–166.2 ◦C.
3-Tosyl-8-triethylsilyloxy-3,3a,4,5,6,6a,7,10-octahydro-2H-3-
aza-cyclopenta[d]naphthalen-1-one (23). Compound 9 (61.4 mg,
0.21 mmol) and (buta-1,3-dien-2-yloxy)triethylsilane 14 (117 mg,
0.63 mmol) were dissolved in xylene (2 mL). The mixture was
transferred into a sealed tube and degassed three times under
vacuum. The sealed tube was put into an oven, which was set
◦
at 180 C, for 24 hours. The crude mixture was purified by flash
column chromatography (ethyl acetate–hexane 1 : 10) to afford
compound 23 as a liquid (52.3 mg, 72%).
1H NMR (400 MHz, CDCl3) d 7.66 (d, J = 8.0 Hz, 2H), 7.33
(d, J = 8.0 Hz, 2H), 4.60 (brs, 1H), 3.93 (AB, J = 18.2 Hz, 1H),
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3.37 (AB, J = 18.2 Hz, 1H), 3.10 (t, J = 4.0 Hz, 1H), 2.42 (s,
3H), 2.31–2.22 (m, 1H), 2.20–2.15 (m, 2H), 1.93–1.30 (m, 8H);
13C NMR (100 MHz, CDCl3) d 209.5 (C), 148.4 (C), 144.1 (C),
132.5 (C), 129.8 (CH), 127.6 (CH), 98.3 (CH), 61.8 (CH), 53.3
(CH2), 50.8 (C), 32.2 (CH2), 30.3 (CH), 27.7 (CH2), 25.6 (CH2),
25.3 (CH2), 21.5 (CH3), 19.4 (CH2), 6.6 (CH3), 4.8 (CH2); IR (neat)
1715, 1343, 1216, 841 cm−1; MS (EI) m/z 475 (M+, 1), 321 (75),
292 (34), 263 (96), 155 (49), 91 (100), 86 (62); HRMS (EI) m/z
calcd for C25H37NO4SSi 475.2213, found 475.2217.
(CH3), 19.4 (CH2), 19.1 (CH3), 18.6 (CH3); IR (neat) 1715, 1374,
1371, 1344 cm−1; MS (EI) m/z 373 (M+, 5), 218 (14), 161 (75), 119
(34), 91 (100); HRMS (EI) m/z calcd for C21H27NO3S 373.1712,
found 373.1711.
6-Methyl-1-tosyl-2,3,4,7,7a,8,9,9a-octahydro-1H-indeno[1,7a-
b]pyrrol-3-one (27). The reaction of enone 7 with 2-methyl-1,3-
butadiene 16 gave the cycloadduct 27 in 90% yield.
1H NMR (400 MHz, CDCl3) d 7.70 (d, J = 8.2 Hz, 2H), 7.32 (d,
J = 8.2 Hz, 2H), 5.29 (brs, 1H), 3.93 (dd, J = 7.2, 4.4 Hz, 1H), 3.75
(s, 2H), 2.42 (s, 3H), 2.10–2.00 (m, 2H), 1.88–1.71 (m, 4H), 1.67 (s,
3H), 1.64–1.56 (m, 2H), 1.38–1.28 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 214.0 (C), 144.1 (C), 135.3 (C), 134.5 (C), 129.9 (CH),
127.6 (CH), 117.2 (CH), 69.5 (CH), 59.9 (C), 53.5 (CH2), 39.4
(CH), 31.9 (CH2), 31.7 (CH2), 30.7 (CH2), 28.2 (CH2), 23.8 (CH3),
21.5 (CH3); IR (neat) 1714, 1665, 1376, 1345, 965 cm−1; MS (EI)
m/z 345 (M+, 11), 190 (63), 134 (100), 133 (61), 91 (45); HRMS
(EI) m/z calcd for C19H23NO3S 345.1399, found 345.1396.
General procedure for BF3·OEt2 catalysed Diels–Alder cycload-
ditions. The enone (1 equiv.) was dissolved in dichloromethane
(0.3 M) and cooled to 0 ◦C. BF3·OEt2 (0.3 equiv.) was slowly added
to the solution and it was allowed to stir for 10 min, followed by
the slow addition of diene (2 equiv.). The mixture was stirred for
an additional 30 min. The solution was quenched with water and
ether, and was extracted with diethyl ether (× 4) and then washed
with brine. The combined organic layers were dried over anhydrous
sodium sulfate. After filtration and concentration, purification by
flash column chromatography afforded the desired product.
7-Methyl-1-tosyl-1,2,3,4,5,8,8a,9,10,10a-decahydroindeno[1,7a-
b]pyridin-4-one (28). The reaction of perhydropyridinone 8 with
2-methyl-1,3-butadiene 16 gave the cycloadduct 28 in 88% yield.
1H NMR (400 MHz, CDCl3) d 7.66 (d, J = 8.6 Hz, 2H), 7.27 (d,
J = 8.6 Hz, 2H), 5.29 (brs, 1H), 4.26 (t, J = 8.0 Hz, 1H), 4.08–4.01
(m, 1H), 3.15 (td, J = 12.4, 2.8 Hz, 1H), 2.76–2.62 (m, 2H), 2.39 (s,
3H), 2.33–2.22 (m, 2H), 1.98 (dd, J = 17.2, 7.6 Hz, 1H), 1.80–1.71
(m, 1H), 1.66 (s, 1H), 1.65–1.52 (m, 3H), 1.23–1.07 (m, 2H); 13C
NMR (100 MHz, CDCl3) d 211.0 (C), 143.5 (C), 136.9 (C), 134.1
(C), 129.7 (CH), 127.1 (CH), 117.5 (CH), 61.3 (CH), 56.6 (C), 40.3
(CH2), 38.4 (CH2), 34.5 (CH), 32.5 (CH2), 30.0 (CH2), 28.9 (CH2),
23.7 (CH3), 23.2 (CH2), 21.5 (CH3); IR (neat) 1715, 1666, 1376,
1343, 969 cm−1; MS (EI) m/z 359 (M+, 5), 204 (55), 148 (100), 147
(57), 91 (68); HRMS (EI) m/z calcd for C20H25NO3S 359.1555,
found 359.1558.
5,6-Dimethyl-1-tosyl-2,3,4,7,7a,8,9,9a-octahydro-1H-indeno[1,
7a-b]pyrrol-3-one (24). The reaction of enone 7 with 2,3-
dimethyl-1,3-butadiene 15 gave the cycloadduct 24 in 89% yield.
1H NMR (400 MHz, CDCl3) d 7.70 (d, J = 8.4 Hz, 2H), 7.32
(d, J = 8.4 Hz, 2H), 3.87 (dd, J = 6.0, 5.2 Hz, 1H), 3.80 (AB, J =
18.4 Hz, 1H), 3.73 (AB, J = 18.4 Hz, 1H), 2.41 (s, 3H), 2.39–2.32
(m, 1H), 2.11–1.94 (m, 3H), 1.86–1.63 (m, 4H), 1.62 (s, 3H), 1.54
(s, 3H), 1.32–1.21 (m, 1H); 13C NMR (100 MHz, CDCl3) d 214.2
(C), 144.0 (C), 134.8 (C), 129.9 (CH), 127.5 (CH), 127.0 (C), 123.0
(C), 69.5 (CH), 61.3 (C), 53.4 (CH2), 39.9 (CH), 34.7 (CH2), 33.9
(CH2), 31.7 (CH2), 31.1 (CH2), 21.5 (CH3), 19.6 (CH3), 19.3 (CH3);
IR (neat) 1714, 1374, 1370, 1345 cm−1; MS (EI) m/z 359 (M+, 5),
204 (23), 161 (54), 119 (78), 91 (100); HRMS (EI) m/z calcd for
C20H25NO3S 359.1555, found 359.1553.
6-Methyl-1-tosyl-1,2,3,4,7,7a,8,9,10,10a-decahydrobenzo[d]-
indol-3-one (29). The reaction of enone 9 with 2-methyl-1,3-
butadiene 16 gave the cycloadduct 29 in 86% yield.
6,7-Dimethyl-1-tosyl-1,2,3,4,5,8,8a,9,10,10a-decahydroindeno-
[1,7a-b]pyridin-4-one (25). The reaction of enone 8 with 2,3-
dimethyl-1,3-butadiene 15 gave the cycloadduct 25 in 86% yield.
1H NMR (400 MHz, CDCl3) d 7.66 (d, J = 8.6 Hz, 2H), 7.27 (d,
J = 8.6 Hz, 2H), 4.14 (t, J = 8.4 Hz, 1H), 4.10–4.03 (m, 1H), 3.13
(td, J = 12.8, 2.8 Hz, 1H), 2.79–2.62 (m, 2H), 2.39 (s, 3H), 2.31–
2.21 (m, 2H), 2.05–1.96 (m, 1H), 1.74 (brd, 1H), 1.63 (s, 6H), 1.50–
1.41 (m, 1H), 1.20–0.99 (m, 2H); 13C NMR (100 MHz, CDCl3) d
211.1 (C), 143.5 (C), 137.0 (C), 129.8 (CH), 127.1 (CH), 126.2 (C),
123.4 (C), 61.6 (CH), 58.0 (C), 40.3 (CH2), 38.6 (CH2), 36.4 (CH2),
35.0 (CH), 34.6 (CH2), 28.6 (CH2), 23.6 (CH2), 21.5 (CH3), 19.6
(CH3), 19.2 (CH3); IR (neat) 1715, 1375, 1371, 1343 cm−1; MS (EI)
m/z 373 (M+, 4), 218 (53), 161 (33), 119 (63), 91 (100); HRMS (EI)
m/z calcd for C21H27NO3S 373.1712, found 373.1714.
1H NMR (400 MHz, CDCl3) d 7.65 (d, J = 8.0 Hz, 2H), 7.33 (d,
J = 8.0 Hz, 2H), 5.19 (brs, 1H), 3.95 (AB, J = 17.8 Hz, 1H), 3.35
(AB, J = 17.8 Hz, 1H), 3.04 (brs, 1H), 2.42 (s, 3H), 2.39–2.31 (m,
1H), 2.14–2.00 (m, 2H), 1.91–1.21 (m, 8H), 1.62 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 210.2 (C), 144.1 (C), 132.7 (C), 132.2 (C),
129.9 (CH), 127.7 (CH), 115.8 (CH), 62.3 (CH), 53.5 (CH2), 51.0
(C), 32.7 (CH2), 29.8 (CH), 27.7 (CH2), 26.6 (CH2), 25.3 (CH2),
23.6 (CH3), 21.5 (CH3), 19.5 (CH2); IR (neat) 1715, 1664, 1377,
1345, 966 cm−1; MS (EI) m/z 359 (M+, 11), 204 (17), 148 (100),
147 (68), 91 (45); HRMS (EI) m/z calcd for C20H25NO3S 359.1555,
found 359.1553.
4,6-Dimethyl-1-tosyl-2,3,4,7,7a,8,9,9a-octahydro-1H-indeno[1,
7a-b]pyrrol-3-one (30a, 30b). The reaction of enone 7 with 2-
methyl-1,3-pentadiene 17 gave the cycloadducts 30a and 30b in
67% and 8% yields, respectively.
5,6-Dimethyl-1-tosyl-1,2,3,4,7,7a,8,9,10,10a-decahydrobenzo-
[d]indol-3-one (26). The reaction of enone 9 with 2,3-dimethyl-
1,3-butadiene 15 gave the cycloadduct 26 in 90% yield.
1H NMR (400 MHz, CDCl3) d 7.66 (d, J = 8.4 Hz, 2H), 7.33
(d, J = 8.4 Hz, 2H), 3.93 (AB, J = 18.0 Hz, 1H), 3.38 (AB,
J = 18.0 Hz, 1H), 3.09 (t, J = 8.4 Hz, 1H), 2.42 (s, 3H), 2.31–
2.22 (m, 1H), 2.08–1.98 (m, 3H), 1.82–1.22 (m, 13H); 13C NMR
(100 MHz, CDCl3) d 210.3 (C), 144.1 (C), 133.0 (C), 129.9 (CH),
127.6 (CH), 123.9 (C), 120.4 (C), 62.1 (CH), 53.3 (CH2), 52.3 (C),
34.3 (CH2), 32.8 (CH2), 29.8 (CH), 27.5 (CH2), 25.6 (CH2), 21.5
30a. 1H NMR (600 MHz, CDCl3) d 7.71 (d, J = 8.0 Hz, 2H),
7.34 (d, J = 8.0 Hz, 2H), 5.16 (brs, 1H), 3.90 (dd, J = 6.4, 3.8 Hz,
1H), 3.82 (AB, J = 17.8 Hz, 1H), 3.50 (AB, J = 17.8 Hz, 1H), 2.43
(s, 3H), 2.42–2.35 (m, 1H), 2.15–2.09 (m, 3H), 1.98–1.86 (m, 2H),
1.76–1.71 (m, 1H), 1.66 (s, 3H), 1.52–1.45 (m,1H), 0.67 (d, J =
7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) d 210.9 (C), 144.2 (C),
133.3 (C), 132.9 (C), 129.8 (CH), 127.8 (CH), 123.6 (CH), 69.6
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(CH), 63.2 (C), 56.1 (CH2), 40.3 (CH), 32.5 (CH2), 32.1 (CH),
31.7 (CH2), 31.0 (CH2), 23.4 (CH3), 21.6 (CH3), 16.0 (CH3); IR
(neat) 1715, 1666, 1374, 1373, 1345, 966 cm−1; MS (EI) m/z 359
(M+, 8), 204 (40), 147 (36), 91 (100); HRMS (EI) m/z calcd for
C20H25NO3S 359.1555, found 359.1552.
30b. 1H NMR (600 MHz, CDCl3) d 7.71 (d, J = 8.2 Hz, 2H),
7.31 (d, J = 8.2 Hz, 2H), 5.09 (d, J = 1.5 Hz, 1H), 4.13 (dd, J =
7.0, 3.8 Hz, 1H), 3.72 (s, 2H), 2.52–2.49 (m, 1H), 2.41 (s, 3H),
2.34–2.31 (m, 1H), 2.17–2.12 (m, 1H), 1.84–1.79 (m, 1H), 1.67 (s,
3H), 1.66–1.55 (m, 3H), 1.29–1.20 (m, 1H), 0.65 (d, J = 7.3 Hz,
3H); 13C NMR (150 MHz, CDCl3) d 216.9 (C), 143.9 (C), 136.9
(C), 135.4 (C), 129.8 (CH), 127.4 (CH), 125.2 (CH), 66.2 (C), 64.6
(CH), 54.6 (CH2), 43.1 (CH), 34.7 (CH), 33.8 (CH2), 32.5 (CH2),
32.1 (CH2), 23.4 (CH3), 21.6 (CH3), 16.0 (CH3); IR (neat) 1715,
1665, 1376, 1371, 1343, 966 cm−1; MS (EI) m/z 359 (M+, 5), 204
(55), 147 (28), 91 (100); HRMS (EI) m/z calcd for C20H25NO3S
359.1555, found 359.1554.
133.3 (C), 131.2 (C), 129.9 (CH), 127.7 (CH), 122.8 (CH), 60.8
(CH), 54.9 (C), 54.1 (CH2), 32.6 (CH2), 30.0 (CH), 29.2 (CH),
27.5 (CH2), 25.9 (CH2), 23.4 (CH3), 21.6 (CH3), 19.3 (CH2), 16.1
(CH3); IR (neat) 1716, 1664, 1376, 1372, 1343, 965 cm−1; MS (EI)
m/z 373 (M+, 4), 218 (57), 161 (100), 147 (28), 91 (75); HRMS
(EI) m/z calcd for C21H27NO3S 373.1712, found 373.1712.
4-Methyl-1-tosyl-2,3,4,7,7a,8,9,9a-octahydro-1H-indeno[1,7a-
b]pyrrol-3-one (33a, 33b). The reaction of enone 7 with 1,3-
pentadiene 18 gave the cycloadducts 33a and 33b in 66% and
8% yields, respectively.
33a. 1H NMR (600 MHz, CDCl3) d 7.71 (d, J = 8.0 Hz, 2H),
7.34 (d, J = 8.0 Hz, 2H), 5.73–5.69 (m, 1H), 5.50–5.46 (m, 1H),
3.93 (dd, J = 6.5, 3.8 Hz, 1H), 3.83 (AB, J = 17.8 Hz, 1H), 3.51
(AB, J = 17.8 Hz, 1H), 2.43 (s, 3H), 2.40–0.81 (m, 8H), 0.67
(d, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) d 210.7 (C),
144.2 (C), 133.0 (C), 129.7 (CH), 127.7 (CH), 127.6 (CH), 125.8
(CH), 69.6 (CH), 63.2 (C), 56.1 (CH2), 39.8 (CH), 31.7 (CH2), 31.6
(CH2), 31.0 (CH), 25.9 (CH2), 21.7 (CH3), 15.6 (CH3); IR (neat)
1716, 1645, 1376, 1345, 966 cm−1; MS (EI) m/z 345 (M+, 5), 190
(54), 133 (55), 91 (100); HRMS (EI) m/z calcd for C19H23NO3S
345.1399, found 345.1396.
33b. 1H NMR (600 MHz, CDCl3) d 7.70 (d, J = 8.2 Hz, 2H),
7.30 (d, J = 8.2 Hz, 2H), 5.82–5.78 (m, 1H), 5.42 (brd, J = 9.6 Hz,
1H), 4.16 (dd, J = 7.1, 3.5 Hz, 1H), 3.72 (s, 2H), 2.53–2.48 (m, 1H),
2.42 (s, 3H), 2.38–2.32 (m, 1H), 2.20–2.13 (m, 1H), 1.91–1.83 (m,
1H), 1.80–1.56 (m, 3H), 1.34–1.29 (m, 1H), 0.68 (d, J = 7.3 Hz,
3H); 13C NMR (150 MHz, CDCl3) d 216.6 (C), 143.9 (C), 135.4
(C), 131.6 (CH), 129.8 (CH), 128.6 (CH), 127.3 (CH), 66.2 (C),
64.4 (CH), 54.4 (CH2), 42.2 (CH), 34.1 (CH), 32.5 (CH2), 31.7
(CH2), 28.5 (CH2), 21.6 (CH3), 15.9 (CH3); IR (neat) 1715, 1647,
1376, 1343, 968 cm−1; MS (EI) m/z 345 (M+, 9), 190 (36), 133 (65),
91 (100); HRMS (EI) m/z calcd for C19H23NO3S 345.1399, found
345.1398.
5,7-Dimethyl-1-tosyl-1,2,3,4,5,8,8a,9,10,10a-decahydroindeno-
[1,7a-b]pyridin-4-one (31a, 31b). The reaction of enone 8 with
2-methyl-1,3-pentadiene 17 gave the cycloadducts 31a and 31b in
62% and 8% yields, respectively.
31a. 1H NMR (600 MHz, CDCl3) d 7.66 (d, J = 8.2 Hz, 2H),
7.27 (d, J = 8.2 Hz, 2H), 5.34–5.31 (brs, 1H), 4.39 (t, J = 9.0 Hz,
1H), 4.11–4.06 (m, 1H), 3.10 (td, J = 12.7, 2.9 Hz, 1H), 2.69–2.64
(m, 2H), 2.56–2.53 (m, 1H), 2.27 (d, J = 14.0 Hz, 1H), 2.09 (dd,
J = 18.0, 8.4 Hz, 1H), 1.66–1.52 (m, 2H), 1.63 (s, 1H), 1.47 (dd,
J = 18.0, 8.2 Hz, 1H), 1.19–1.08 (m, 2H), 0.68 (d, J = 7.1 Hz, 3H);
13C NMR (150 MHz, CDCl3) d 210.7 (C), 143.5 (C), 136.8 (C),
130.7 (C), 129.7 (CH), 127.1 (CH), 124.0 (CH), 61.4 (CH), 60.7
(C), 41.0 (CH2), 39.8 (CH2), 32.7 (CH2), 31.9 (CH), 30.6 (CH),
29.2 (CH2), 23.5 (CH3), 21.9 (CH2), 21.5 (CH3), 18.5 (CH3); IR
(neat) 1715, 1665, 1377, 1375, 1345, 966 cm−1; MS (EI) m/z 373
(M+, 6), 218 (50), 161 (100), 147 (36), 91 (77); HRMS (EI) m/z
calcd for C21H27NO3S 373.1712, found 373.1712.
31b. 1H NMR (600 MHz, CDCl3) d 7.67 (d, J = 8.2 Hz, 2H),
7.28 (d, J = 8.2 Hz, 2H), 5.22–5.20 (brs, 1H), 4.34 (td, J = 8.2,
1.4 Hz, 1H), 4.01–3.95 (m, 1H), 3.12 (td, J = 12.3, 4.0 Hz, 1H),
2.75–2.64 (m, 1H), 2.63–2.58 (m, 1H), 2.52 (dd, J = 16.8, 2.4 Hz,
1H), 2.41 (s, 3H), 2.32–2.28 (m, 1H), 2.05 (dd, J = 16.2, 7.3 Hz,
1H), 1.70 (s, 3H), 1.63 (dd, J = 16.2, 5.7 Hz, 1H), 1.48–1.39 (m,
2H), 1.24 (d, J = 7.5 Hz, 3H), 1.12–0.99 (m, 2H); 13C NMR
(150 MHz, CDCl3) d 213.9 (C), 143.6 (C), 136.3 (C), 135.4 (C),
129.7 (CH), 127.3 (CH), 125.9 (CH), 61.4 (C), 57.9 (CH), 41.7
(CH), 41.0 (CH2), 38.8 (CH2), 37.9 (CH), 32.9 (CH2), 29.5 (CH2),
24.4 (CH2), 23.7 (CH3), 21.5 (CH3), 17.5 (CH3); IR (neat) 1715,
1664, 1374, 1372, 1345, 967 cm−1; MS (EI) m/z 373 (M+, 3),
218 (34), 161 (100), 147 (33), 91 (45); HRMS (EI) m/z calcd for
C21H27NO3S 373.1712, found 373.1715.
5-Methyl-1-tosyl-1,2,3,4,5,8,8a,9,10,10a-decahydroindeno[1,7a-
b]pyridin-4-one (34a, 34b). The reaction of enone 8 with
1,3-pentadiene 18 gave an inseparable cycloadduct mixture of 34a
and 34b in a total yield of 66%.
1H NMR (600 MHz, CDCl3) d 7.68–7.65 (m, 4H), 7.32–7.23
(m, 4H), 5.79–5.76 (m, 1H), 5.64–5.53 (m, 1H), 5.54–5.51 (m,
1H), 5.48–5.45 (m, 1H), 4.43–4.41 (m, 1H), 4.13–4.09 (m, 1H),
4.02–3.97 (m, 1H), 3.11 (td, J = 12.0, 4.1 Hz, 1H), 3.05–2.99 (m,
1H), 2.78–2.58 (m, 4H), 2.55–2.45 (m, 2H), 2.44–2.34 (m, 2H), 2.42
(s, 3H), 2.41 (s, 3H), 2.13–2.06 (m, 2H), 2.00–1.94 (m, 1H), 1.89–
1.84 (m, 1H), 1.76–1.64 (m, 2H), 1.54–1.37 (m, 2H), 1.27 (s, 3H),
1.17–1.06 (m, 2H), 1.13 (s, 3H), 1.12 (s, 3H); 13C NMR (150 MHz,
CDCl3) d 143.8 (C), 143.6 (C), 136.3 (C), 134.7 (C), 132.2 (CH),
131.5 (CH), 129.8 (CH), 129.8 (CH), 127.6 (CH), 127.5 (CH),
127.0 (CH), 124.2 (CH), 66.5 (CH), 61.6 (C), 58.5 (C), 57.6 (CH),
48.0 (CH2), 40.9 (CH2), 40.5 (CH), 39.7 (CH2), 38.8 (CH2), 37.0
(CH), 35.0 (CH), 29.9 (CH2), 28.2 (CH), 27.7 (CH2), 27.1 (CH2),
27.0 (CH2), 25.3 (CH2), 24.3 (CH2), 21.5 (CH3), 20.5 (CH3), 17.5
(CH3); IR (neat) 1715, 1649, 1377, 1342, 968 cm−1; MS (EI) m/z
359 (M+, 3), 204 (36), 155 (24), 147 (76), 91 (100); HRMS (EI)
m/z calcd for C20H25NO3S 359.1555, found 359.1552.
4,6-Dimethyl-1-tosyl-1,2,3,4,7,7a,8,9,10,10a-decahydrobenzo-
[d]indol-3-one (32a, 32b). The reaction of enone 9 with 2-methyl-
1,3-pentadiene 17 gave a cycloadduct mixture of 32a and 32b in
a total yield of 70%. After careful purification, a trace amount of
pure 32a was obtained.
32a. 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.0 Hz, 2H),
7.33 (d, J = 8.0 Hz, 2H), 5.09 (brs, 1H), 3.83 (AB, J = 18.0 Hz,
1H), 3.43 (brs, 1H), 3.33 (AB, J = 18.0 Hz, 1H), 2.43 (s, 3H),
2.20–2.04 (m, 4H), 1.70–1.04 (m, 5H), 1.63 (s, 3H), 0.67 (d, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 208.6 (C), 144.1 (C),
4-Methyl-1-tosyl-1,2,3,4,7,7a,8,9,10,10a-decahydrobenzo[d]-
indol-3-one (35a, 35b). The reaction of enone
9 with
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1,3-pentadiene 18 gave an inseparable cycloadduct mixture of 35a
and 35b in a total yield of 68%.
1H), 1.54 (AB, J = 8.6 Hz, 1H), 1.52–1.43 (m, 1H), 1.34–1.25 (m,
1H), 1.23–1.12 (m, 1H), 1.09 (AB, J = 8.6 Hz, 1H), 1.07–0.94 (m,
1H); 13C NMR (100 MHz, CDCl3) d 212.3 (C), 143.9 (C), 139.8
(CH), 136.2 (CH), 136.0 (C), 129.8 (CH), 127.2 (CH), 62.0 (CH),
60.5 (C), 51.4 (CH), 51.1 (CH2), 49.4 (CH), 45.2 (CH2), 42.0 (CH),
29.9 (CH2), 25.4 (CH2), 21.5 (CH3), 19.9 (CH2); IR (neat) 1715,
1666, 1649, 1343, 969 cm−1; MS (EI) m/z 357 (M+, 3), 290 (64),
263 (69), 155 (53), 136 (51), 91 (100), 66 (58), 65 (44); HRMS (EI)
m/z calcd for C20H23NO3S 357.1399, found 357.1398.
1H NMR (400 MHz, CDCl3) d 7.72–7.64 (m, 3.6H), 7.36–7.28
(m, 3.6H), 5.69–5.56 (m, 1.8H), 5.42–5.32 (m, 1.8H), 3.99 (t, J =
4.0 Hz, 1H), 3.87 (AB, J = 17.4 Hz, 0.8H), 3.86 (AB, J = 18.4 Hz,
1H), 3.65 (AB, J = 18.4 Hz, 1H), 3.40 (t, J = 4.4 Hz, 0.8H), 3.32
(AB, J = 17.4 Hz, 0.8H), 2.42 (s, 2.4H), 2.41 (s, 3H), 2.32–1.20
(m, 18H), 0.78 (d, J = 7.6 Hz, 3H), 0.70 (d, J = 7.2 Hz, 2.4H); 13
C
NMR (100 MHz, CDCl3) d 213.9 (C), 208.3 (C), 144.1 (C), 143.8
(C), 135.5 (C), 133.0 (C), 130.6 (CH), 129.9 (CH), 129.8 (CH),
128.6 (CH), 127.7 (CH), 127.3 (CH), 126.1 (CH), 124.0 (CH), 60.7
(CH), 59.3 (CH), 55.0 (C), 54.9 (C), 54.5 (CH2), 54.3 (CH2), 36.5
(CH), 31.6 (CH), 30.3 (CH2), 29.3 (CH), 28.9 (CH), 27.7 (CH2),
27.5 (CH2), 26.6 (CH2), 25.6 (CH2), 25.4 (CH2), 21.5 (CH3), 19.4
(CH2), 16.6 (CH3), 16.5 (CH2), 15.7 (CH3); IR (neat) 1717, 1649,
1375, 1343, 969 cm−1; MS (EI) m/z 359 (M+, 5), 204 (26), 155
(24), 147 (76), 91 (100); HRMS (EI) m/z calcd for C20H25NO3S
359.1555, found 359.1553.
4-(2-Furyl)-1-tosyl-perhydrocyclopenta[b]pyrrol-3-one
(39).
The reaction of enone 7 with furan 20 gave the cycloadduct 39 in
88% yield.
1H NMR (400 MHz, CDCl3) d 7.74 (d, J = 8.2 Hz, 2H), 7.35
(d, J = 8.2 Hz, 2H), 6.49 (dd, J = 5.8, 1.6 Hz, 1H), 6.26 (dd, J =
5.8, 1.6 Hz, 1H), 4.67 (brs, 1H), 4.36 (brs, 1H), 4.14 (t, J = 5.4 Hz,
1H), 3.84 (AB, J = 18.2 Hz, 1H), 3.74 (AB, J = 18.2 Hz, 1H), 2.43
(s, 3H), 2.28–2.18 (m, 2H), 2.10–1.98 (m, 2H), 1.64–1.54 (m, 1H);
13C NMR (150 MHz, CDCl3) d 209.9 (C), 144.4 (C), 137.4 (CH),
133.9 (CH), 133.8 (C), 130.0 (CH), 127.8 (CH), 85.4 (CH), 82.5
(CH), 69.5 (C), 67.9 (CH), 55.5 (CH), 55.5 (CH2), 35.3 (CH2), 28.6
(CH2), 21.6 (CH3); IR (neat) 1715, 1667, 1346, 1172, 968 cm−1; MS
(EI) m/z 345 (M+, 21), 190 (41), 133 (71), 91 (100); HRMS (EI)
m/z calcd for C18H19NO4S 345.1035, found 345.1034.
5-Tosyl-5-azatetracyclo[8.2.1.02,6.02,9]tridec-11-en-3-one
(36).
The reaction of enone 7 with cyclopentadiene 19 gave the
cycloadduct 36 in 93% yield.
1H NMR (400 MHz, CDCl3) d 7.70 (d, J = 8.0 Hz, 2H), 7.33 (d,
J = 8.0 Hz, 2H), 6.30 (dd, J = 5.6, 2.8 Hz, 1H), 6.03 (dd, J = 5.6,
2.8 Hz, 1H), 3.88 (AB, J = 18.2 Hz, 1H), 3.83 (t, J = 6.6 Hz, 1H),
3.79 (AB, J = 18.2 Hz, 1H), 2.80–2.73 (m, 2H), 2.42 (s, 3H), 2.26
(brs, 1H), 2.11–1.96 (m, 2H), 1.83–1.68 (m, 2H), 1.44–1.40 (m,
1H), 1.11–1.01 (m, 1H); 13C NMR (100 MHz, CDCl3) d 214.1 (C),
144.0 (C), 139.8 (CH), 136.0 (CH), 134.5 (C), 129.8 (CH), 127.4
(CH), 69.1 (C), 66.3 (CH), 55.0 (CH), 54.1 (CH2), 50.6 (CH2),
49.3 (CH), 46.0 (CH), 36.8 (CH2), 27.6 (CH2), 21.5 (CH3); IR
(neat) 1716, 1666, 1647, 1345, 970 cm−1; MS (EI) m/z 343 (M+,
3), 188 (42), 131 (69), 91 (100), 66 (58); HRMS (EI) m/z calcd for
C19H21NO3S 343.1242, found 343.1240.
5-(2-Furyl)-1-tosyl-perhydrocyclopenta[b]pyridin-4-one
(40).
The reaction of enone 8 with furan 20 gave the product 40 in 40%
yield.
1H NMR (400 MHz, CDCl3) d 7.72 (d, J = 8.0 Hz, 2H), 7.31
(d, J = 8.0 Hz, 3H), 6.25 (brs, 1H), 6.02 (brd, J = 3.2 Hz, 1H),
4.76–4.64 (m, 1H), 4.08–4.00 (m, 1H), 3.91 (ddd, J = 8.9, 6.4,
2.4 Hz, 1H), 3.31 (ddd, J = 13.5, 10.4, 3.2 Hz, 1H), 2.79 (d,
J = 7.2 Hz, 1H), 2.52–2.32 (m, 2H), 2.41 (s, 3H), 2.11–2.00 (m,
1H), 1.82–1.74 (m, 1H), 1.70–1.58 (m, 1H), 1.40–1.28 (m, 1H);
13C NMR (100 MHz, CDCl3) d 206.6 (C), 156.9 (C), 143.9 (C),
141.3 (CH), 136.1 (C), 129.9 (CH), 127.1 (CH), 110.3 (CH), 105.2
(CH), 59.0 (CH), 57.5 (CH), 41.6 (CH2), 40.2 (CH2), 31.5 (CH),
28.4 (CH2), 27.1 (CH2), 21.5 (CH3); IR (neat) 3018, 2952, 1715,
1344, 1220 cm−1; MS (EI) m/z 359 (M+, 65), 204 (55), 147 (71), 91
(100), 65 (20); HRMS (EI) m/z calcd for C19H21NO4S 359.1191,
found 359.1189.
6-Tosyl-6-azatetracyclo[9.2.1.02,7.02,10]tetradec-12-en-3-one (37).
The reaction of enone 8 with cyclopentadiene 19 gave the
cycloadduct 37 in 91% yield.
1H NMR (400 MHz, CDCl3) d 7.69 (d, J = 8.4 Hz, 2H), 7.30
(d, J = 8.4 Hz, 2H), 6.28 (dd, J = 5.4, 3.0 Hz, 1H), 6.15 (dd, J =
5.4, 3.0 Hz, 1H), 4.07–4.00 (m, 1H), 3.88 (dd, J = 12.4, 5.2 Hz,
1H), 3.33–3.19 (m, 2H), 2.78–2.68 (m, 2H), 2.62 (brs, 1H), 2.41
(s, 3H), 2.40–2.38 (m, 1H), 1.76 (AB, J = 8.0 Hz, 1H), 1.69–1.39
(m, 3H), 1.48 (AB, J = 8.0 Hz, 1H), 0.78–0.68 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 209.3 (C), 143.6 (C), 139.2 (C), 136.9 (C),
136.7 (CH), 129.7 (CH), 127.1 (CH), 66.9 (C), 60.4 (CH), 50.5
(CH2), 49.1 (CH), 47.3 (CH), 45.3 (CH), 41.0 (CH2), 39.9 (CH2),
32.3 (CH2), 25.1 (CH2), 21.5 (CH3); IR (neat) 1715, 1665, 1647,
1344, 969 cm−1; MS (EI) m/z 357 (M+, 6), 290 (53), 263 (71), 155
(42), 136 (51), 91 (100), 66 (49), 65 (42); HRMS (EI) m/z calcd for
C20H23NO3S 357.1399, found 357.1402.
4-(2-Furyl)-1-tosyl-perhydro-3-indolone (41). The reaction of
perhydroindolone 9 with furan 20 gave the product 41 in 85%
yield.
1H NMR (400 MHz, CDCl3) d 7.74 (d, J = 8.0 Hz, 2H), 7.31
(d, J = 8.0 Hz, 3H), 6.30–6.28 (m, 1H), 5.95 (brd, J = 3.2 Hz,
1H), 4.51–4.43 (m, 1H), 3.87 (AB, J = 18.4 Hz, 1H), 3.65 (AB,
J = 18.4 Hz, 1H), 3.56 (brs, 1H), 2.56 (brd, 1H), 2.41 (s, 3H),
2.12–2.02 (m, 1H), 1.85–1.75 (m, 1H), 1.54–1.04 (m, 4H); 13C
NMR (100 MHz, CDCl3) d 208.6 (C), 156.3 (C), 144.2 (C), 141.3
(CH), 135.7 (C), 130.1 (CH), 127.2 (CH), 110.2 (CH), 105.3 (CH),
56.7 (CH), 51.4 (CH2), 51.2 (CH), 31.5 (CH), 29.4 (CH2), 26.3
(CH2), 21.5 (CH3), 18.9 (CH2); IR (neat) 3018, 2952, 1716, 1345,
1218 cm−1; MS (EI) m/z 359 (M+, 12), 204 (41), 147 (78), 91 (100),
65 (38); HRMS (EI) m/z calcd for C19H21NO4S 359.1191, found
359.1190.
5-Tosyl-5-azatetracyclo[9.2.1.02,6.02,10]tetradec-12-en-3-one (38).
The reaction of enone 9 with cyclopentadiene 19 gave the
cycloadduct 38 in 95% yield.
1H NMR (400 MHz, CDCl3) d 7.75 (d, J = 8.0 Hz, 2H), 7.33
(d, J = 8.0 Hz, 2H), 6.34 (dd, J = 6.0, 3.2 Hz, 1H), 5.98 (dd, J =
6.0, 3.2 Hz, 1H), 3.97 (AB, J = 18.2 Hz, 1H), 3.68 (dd, J = 11.0,
6.0 Hz, 1H), 3.67 (AB, J = 18.2 Hz, 1H), 2.79 (brs, 1H), 2.59–2.54
(m, 1H), 2.42 (s, 3H), 2.06 (brs, 1H), 2.02–1.93 (m, 1H), 1.61 (brs,
1-Tosyl-4-(1-methyl-1H-2-pyrrolyl)perhydrocyclopenta[b]pyrrol-
3-one (42). The reaction of perhydropyrrolone 7 with N-methyl
pyrrole 21 gave the product 42 in 88% yield.
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1H NMR (400 MHz, CDCl3) d 7.76 (d, J = 8.0 Hz, 2H), 7.37
(d, J = 8.0 Hz, 2H), 6.54 (brs, 1H), 6.02 (dd, J = 3.6, 2.4 Hz,
1H), 5.79 (brd, J = 3.6 Hz, 1H), 4.59–4.53 (m, 1H), 3.82 (AB, J =
18.0 Hz, 1H), 3.69 (AB, J = 18.0 Hz, 1H), 3.59 (s, 3H), 3.51–3.46
(m, 1H), 2.89 (dd, J = 8.8, 2.8 Hz, 1H), 2.46 (s, 3H), 2.34–2.23
(m, 1H), 2.19–2.08 (m, 1H), 2.07–1.96 (m, 1H), 1.89–1.80 (m, 1H);
13C NMR (100 MHz, CDCl3) d 210.5 (C), 144.3 (C), 134.1 (C),
133.6 (C), 130.0 (CH), 127.7 (CH), 122.1 (CH), 106.6 (CH), 104.7
(CH), 63.3 (CH), 58.7 (CH), 54.7 (CH2), 39.9 (CH), 33.8 (CH3),
33.4 (CH2), 31.4 (CH2), 21.5 (CH3); IR (neat) 3021, 2955, 1714,
1345 cm−1; MS (EI) m/z 358 (M+, 100), 203 (87), 146 (100), 91
(31); HRMS (EI) m/z calcd for C19H22N2O3S 358.1351, found
358.1350.
flash column chromatography (ethyl acetate–hexane 1 : 3) afforded
compound 50 (16 mg, 98%).
1H NMR (400 MHz, CDCl3) d 9.78 (d, J = 1.2 Hz, 1H), 9.62 (d,
J = 2.4 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H),
4.03 (AB, J = 18.4 Hz, 1H), 3.65 (dd, J = 4.2, 4.2 Hz, 1H), 3.45
(AB, J = 18.4 Hz, 1H), 3.02 (dd, J = 18.2, 7.8 Hz, 1H), 2.83–2.65
(m, 2H), 2.44 (s, 3H), 2.38–2.27 (m, 1H), 2.06–1.96 (m, 1H), 1.80–
1.68 (m, 1H), 1.62–1.53 (m, 1H), 1.48–1.32 (m, 2H), 1.30–1.10 (m,
2H); 13C NMR (100 MHz, CDCl3) d 208.2 (C), 201.5 (CH), 200.7
(CH), 144.8 (C), 132.1 (C), 130.1 (CH), 127.8 (CH), 62.5 (C), 57.6
(CH), 53.2 (CH2), 52.5 (CH), 51.8 (CH), 40.9 (CH), 24.8 (CH2),
23.7 (CH2), 23.3 (CH2), 21.6 (CH3), 17.7 (CH2); IR (neat) 1725,
1720, 1715, 1343, 1230, 969 cm−1; MS (EI) m/z 389 (M+, 3), 360
(60), 331 (62), 176 (100); HRMS (EI) m/z calcd for C20H23NO5S
389.4653, found 389.1297.
1-Tosyl-5-(1-methyl-1H-2-pyrrolyl)perhydrocyclopenta[b]pyri-
din-4-one (43). The reaction of enone 8 with N-methyl pyrrole
21 gave the product 43 in 89% yield.
1H NMR (400 MHz, CDCl3) d 7.72 (d, J = 8.0 Hz, 2H), 7.30
(d, J = 8.0 Hz, 2H), 6.50 (brs, 1H), 6.02 (dd, J = 3.4, 2.4 Hz, 1H),
5.85 (brd, J = 3.4 Hz, 1H), 4.75–4.66 (m, 1H), 4.09–4.01 (m, 1H),
3.90 (ddd, J = 8.9, 6.5, 2.2 Hz, 1H), 3.32 (ddd, J = 13.5, 10.5,
3.2 Hz, 1H), 3.50 (s, 3H), 2.66 (d, J = 7.2 Hz, 1H), 2.52–2.34 (m,
2H), 2.41 (s, 3H), 2.11–2.01 (m, 1H), 1.83–1.74 (m, 1H), 1.70–1.59
(m, 1H), 1.40–1.27 (m, 1H); 13C NMR (100 MHz, CDCl3) d 206.6
(C), 143.9 (C), 136.4 (C), 136.1 (C), 129.9 (CH), 127.1 (CH), 121.7
(CH), 106.7 (CH), 104.1 (CH), 59.0 (CH), 57.3 (CH), 41.5 (CH2),
40.3 (CH2), 33.7 (CH3), 31.4 (CH), 28.4 (CH2), 27.0 (CH2), 21.5
(CH3); IR (neat) 3020, 2956, 1715, 1345 cm−1; MS (EI) m/z 372
(M+, 100), 217 (81), 161 (54), 120 (45), 107 (63), 91 (55); HRMS
(EI) m/z calcd for C20H24N2O3S 372.1508, found 372.1511.
Acknowledgements
We thank the National Science Council of the Republic of China
for financial support.
Notes and references
1 C. K. Sha, A. W. Hong and C. M. Huang, Org. Lett., 2001, 3, 2177.
2 C. K. Sha and C. M. Chau, Tetrahedron Lett., 2003, 44, 499.
3 The experimental procedures are in the ESI.
4 For recent reviews, see: (a) E. J. Corey, Angew. Chem., Int. Ed., 2002, 41,
1650; (b) D. A. Evans and J. S. Johnson, in Comprehensive Asymmetric
Catalysis, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer
Press, Berlin, 1999, vol. 3, p. 1177; (c) K. Ishihara and H. Yamamoto,
Eur. J. Org. Chem., 1999, 7, 527.
5 (a) A. P. Kozikowski, W. C. Floyd and M. P. Kuniak, J. Chem. Soc.,
Chem. Commun., 1977, 582–583; (b) H. Takayama, A. Iyobe and T.
Koizumi, J. Chem. Soc., Chem. Commun., 1986, 771–772; (c) B. L.
Feringa, O. J. Gelling and L. Meesters, Tetrahedron Lett., 1990, 31, 7201–
7204.
1-Tosyl-4-(1-methyl-1H-2-pyrrolyl)perhydro-3-indolone
The reaction of enone 9 with N-methyl pyrrole 21 gave the
product 44 in 90% yield.
(44).
1H NMR (400 MHz, CDCl3) d 7.77 (d, J = 8.0 Hz, 2H), 7.31 (d,
J = 8.0 Hz, 2H), 6.52 (brs, 1H), 6.04 (dd, J = 3.6, 2.6 Hz, 1H), 5.85
(brd, J = 3.6 Hz, 1H), 4.67–4.58 (m, 1H), 3.87 (AB, J = 18.2 Hz,
1H), 3.66 (AB, J = 18.2 Hz, 1H), 3.58 (brs, 1H), 3.49 (s, 3H), 2.43
6 (a) H. Suga, T. Kitamura, A. Kakehi and T. Baba, Chem. Commun.,
2004, 12, 1414–1415; (b) L. T. An, J. P. Zou, L. L. Zhang and Y. Zhang,
Tetrahedron Lett., 2007, 48, 4297.
7 The NOE experiments of compound 39 and 36 are shown below:
(brd, 1H), 2.38 (s, 3H), 2.05–2.01 (m, 1H), 1.65–1.04 (m, 5H); 13
C
NMR (100 MHz, d6-DMSO) d 208.9 (C), 143.9 (C), 135.1 (C),
133.3 (C), 130.2 (CH), 127.1 (CH), 121.7 (CH), 106.0 (CH), 106.0
(CH), 56.5 (CH), 51.5 (CH), 51.3 (CH2), 33.1 (CH3), 28.9 (CH),
28.8 (CH2), 26.8 (CH2), 21.0 (CH3), 17.7 (CH2); IR (neat) 3020,
2957, 1715, 1346 cm−1; MS (EI) m/z 372 (M+, 100), 217 (87), 189
(40), 161 (48), 120 (53), 107 (51), 91 (31); HRMS (EI) m/z calcd
for C20H24N2O3S 372.1508, found 372.1505.
Decahydro-1-oxo-3-tosyl-1H-cyclopenta[d]indole-7,9-dicarbal-
dehyde (50). O3 gas was introduced into a solution of compound
38 (15 mg, 0.042 mmol) in CH2Cl2 (3 mL) at 0 ◦C. After
20 min, the ozone was stopped and the excess ozone was removed
by introducing Ar gas into the solution. Finally, Me2S (6 ll,
0.084 mmol) was added into the reaction solution, which was
then stirred for 20 min. The reaction solvent was removed directly
by rotary evaporator to give the crude compound. Purification by
8 (a) S. Li, S. Ohba, S. Kosemura and S. Yamamura, Tetrahedron Lett.,
1996, 37, 7365; (b) S. Li, S. Kosemura and S. Yamamura, Tetrahedron,
1998, 54, 6661
3134 | Org. Biomol. Chem., 2008, 6, 3127–3134
This journal is
The Royal Society of Chemistry 2008
©