Dioxopyrrolines. LXII. Diels-alder reaction of 1-aryl-4- and 5-methoxycarbonyl-1H-pyrrole-2,3-diones with various 1,3-dienes

Article abstract of DOI:10.1248/cpb.51.502

Two new dioxopyrrolines (1-aryl-4-methoxycarbonyl-1H-pyrrole-2,3-dione 6 and the 5-methoxycarbonyl isomer 8) behaved as good dienophiles to some kind of 1,3-dienes examined. In most cases, the products were explained by the reaction where the largest lobe

Full text of DOI:10.1248/cpb.51.502

502
Chem. Pharm. Bull. 51(5) 502—507 (2003)
Vol. 51, No. 5
Dioxopyrrolines. LXII.1) Diels–Alder Reaction of 1-Aryl-4- and
5-methoxycarbonyl-1H-pyrrole-2,3-diones with Various 1,3-Dienes
Kunihiko MOHRI, ,a Katsumi YOKOYAMA,a Hiroaki KOMIYA,a Yuhya WATANABE,a Yuki YOSHIDA,a
*
b
Kimiaki ISOBE,a and Yoshisuke TSUDA
b
a Showa Pharmaceutical University; 3–3165 Higashi-tamagawagakuen, Machida, Tokyo 194–8543, Japan: and H. E. J.
Research Institute of Chemistry, University of Karachi; Karachi-75270, Pakistan.
Received November 26, 2002; accepted February 19, 2003
Two new dioxopyrrolines (1-aryl-4-methoxycarbonyl-1H-pyrrole-2,3-dione 6 and the 5-methoxycarbonyl iso-
mer 8) behaved as good dienophiles to some kind of 1,3-dienes examined. In most cases, the products were ex-
plained by the reaction where the largest lobe of HOMO of dienes reacted to the larger LUMO of dienophiles in
an expected cis-endo manner. However, in the reactions of 8 with alkylbutadienes, piperylene and isoprene, ab-
normality in the reaction was observed, which was well explained by taking account of steric factors.
Key words dioxopyrroline; Diels–Alder reaction; steric factor; regioselectivity; 1-aryl-4-methoxycarbonyl-1H-pyrrole-2,3-
dione; 1-aryl-5-methoxycarbonyl-1H-pyrrole-2,3-dione
1H-Pyrrole-2,3-diones (dioxopyrrolines) are useful syn- action.
thon in the organic synthesis.2,3) Particularly, the 4,5-di-
alkoxycarbonyl derivative (1) behaves as a strong dienophile Results and Discussion
to give hydroindoles.4) The cycloaddition of 1 to 1-substi-
Preparation of the Dioxopyrrolines 4-Methoxycar-
tuted butadiene such as 1-methoxy- or 1-sulfenyl-butadiene bonyl and 5-methoxycarbonyl-dioxopyrrolines, 6 and 8, were
smoothly occurred in regio- and stereo-selective manners to synthesized from p-anisidine 4 based on the known method,
give 4-substituted hydroindoles in good yields. Although two respectively. Oxalylation of the enamine 55) prepared from
alkoxycarbonyl groups in 1 are obviously enhancing the methyl propiolate and 4 with oxalyl chloride gave 6 as red-
dienophile activity of the dioxopyrroline, it is hard to predict dish purple prisms in a quantitative yield. While oxalylation
the respective contribution of each group to regioselectivity of the condensation product (an equilibrium mixture of
of this cycloaddition reaction. Therefore, we have newly pre- imine-enamine tautomers)6) of methyl pyruvate and 4 gave 5-
pared two differently substituted dioxopyrrolines, 4- and 5- methoxycarbonyl derivative 8 as red prisms. The spectro-
methoxycarbonyl derivatives 6 and 8, and examined their cy- scopic data [IR, 1H-, 13C-NMR, and high resolution MS (HR-
cloaddition reaction to various butadienes hoping to evaluate MS)] were compatible to the expected structures, respec-
the contribution of each methoxycarbonyl group in the tively.
dienophile on the regioselectivity of treated cycloaddition re-
Diels–Alder Reaction of Dioxopyrrolines, 6 and 8
Chart 1
* To whom correspondence should be addressed. e-mail: mohri@ac.shoyaku.ac.jp
© 2003 Pharmaceutical Society of Japan

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503
Chart 2
Table 1. Diels–Alder Reaction of the Dioxopyrroline (6) with Various Bu- Table 2. Diels–Alder Reaction of the Dioxopyrroline (8) with Butadienes
tadienesa)
Conditions
Yield of
Yield of products
Entry
Butadiene
Entry
Butadienes
Butadiene (A)
2,3-Dimethylbutadiene (B)
Piperylene (C)
1-Methoxybutadiene (D)
Isoprene (E)
2-Trimethylsilyloxybutadiene (F)
1-Acetoxy-3-methylbutadiene (G)
3-Methyl-1-trimethylsilyloxybutadiene (H)
1-Methoxy-3-trimethylsilyloxybutadiene (I)
products
(%)
(%)b)
Temp. Time
Solvent
(°C)
(h)
1
2
3
4
5
6
7
8
9
9 (83)
10 (92)
11 (73)
1
2
3
Piperylene (C)
1-Methoxybutadiene (D)
Isoprene (E)
Benzene
Toluene
Benzene
90
100
90
15 20 (40)a)ϩ21 (40)a)
11
16
24 (23)a)
23 (75)b)
12 (79)
13 (47)ϩ14 (16)
18 (72)
a) Yield was calculated from p-anisidine. b) Yield was calculated from dioxopyr-
roline 8.
16 (67)
17 (69)
19 (29)
33% yield after isolation with silica gel chromatography,
which is produced from the expected adduct 22 by loss of
MeOH followed by aromatization with concomitant cleavage
of C–N bond. By the chromatographic isolation of the prod-
a) Reaction condition: In toluene, 80 °C, 15 h. b) Yield was calculated from
enamine 5.
Diels–Alder reaction of 6 with nine kind of butadienes (A to uct using CC-7 (Mallinckrodt, Inc.) column, the adduct 24
I) were carried out on heating two substrates in toluene at was obtained in 23% yield. Treatment of 24 with SiO2 gave
80 °C for 15 h. In all cases, single product was produced usu- 25 in 70% yield.
ally in good yield except in the case of isoprene (E) where
Structure Determination of the Product The spectro-
two regio isomers were produced as discussed below (see scopic data (MS, IR, 1H- and 13C-NMR) of the above isolated
Table 1). When the dienes beared an OTMS group (F, I), the compounds from the reaction of 6 and dienes were compati-
products were the expected adducts and/or its desilylated ke- ble to the assigned structures, respectively. The regio-chem-
tones. For them the structure determinations and yield calcu- istry in this cycloaddition and stereochemistry of C-4 sub-
lations were made after converting the product into single ke- stituent were determined with the help of H–H two dimen-
tones by treatment with acetic acid.
Butadiene (A) and 2,3-dimethylbutadiene (B) gave 9 and Overhauser enhancement spectroscopy (NOESY).
10 in 83% and 92% yield, respectively. 1-Substituted (by Adducts (9—19) gave correlation peaks between ester
sional (2D) correlated spectroscopy (COSY) and nuclear
alkyl or electron donating group) butadienes (C, D, G, H, I) methyl group and angular H-7a establishing their ring junc-
gave expected endo-adducts (4a-substituted hydroindoles), tures to be cis. For other structure determinations, we will
11, 12, 16, 17, and 19, respectively.
show the procedure by taking 11 as an example. Compound
2-Trimethylsilyloxybutadiene (F) also gave a single adduct 11 showed clear COSY correlation between H-7a (d 4.85—
15 (thereof 18) in 72% yield. However, isoprene (E) gave 4.83, m) and methylene group at d 2.47 (ddd) and 2.19—
two regio-isomers 13 and 14 in a ratio of 3 : 1.
2.14 (m) indicating that C-7 position is CH2. The NOESY
5-Methoxycarbonyldioxopyrroline 8 also gave adducts, spectrum showed a correlation between H-4 (geminal to the
which were isolated as tautomeric enols. There was a notable methyl) and H-7a. Therefore the 4-methyl group must be
difference between 6 and 8 in the reaction of piperylene (C) trans to the ring juncture. Compounds 12, 16, 17, were ana-
and isoprene (E). The addition product of 8 to C was a 1 : 1 lyzed in a similar way by the H–H COSY and NOE correla-
mixture of two regio-isomers, 20 and 21, which were sepa- tion.
rated by chromatography, while isoprene (E) gave a single
The desilylated ketones 18 and 19 were determined as fol-
adduct 23. 1-Methoxybutadiene (D) gave compound 25 in lows. In addition to the other spectral data (which are com-

504
Vol. 51, No. 5
Chart 3
patible to the expected structures), H-7a of 18 (d 5.15, t) 3 was determined as a.
showed COSY correlation peak with methylene group at d Similarly, reduction of 21 gave the alcohol 27. The NMR
2.80 (dd). This indicated that C-7 is CH2. The structure of 19 analysis gave the sequence of H-3 to H-3a to H2-4 to H-5 to
was determined in a similar way where H-7a also exhibited a H-6 to H-7 and to Me, thus the position of methyl group and
NOESY correlation with H-4 showing that the stereochem- the stereochemistry of 3a-OH group being established. The
istry of 4-OMe group is a.
The product from the reaction of 6 and isoprene (E) was cut evidence for the stereochemistry of methyl group at C-7.
an oily mixture of two compounds in a ratio of 3 : 1 as shown On the other hand, reduction of the addition product 23 of
difference NOE spectrum of 27, however, did not give clear-
by the ratio of two methyl signals at d 1.60 and 1.70 in the isoprene to 8 with potassium borohydride in EtOH under
1H-NMR spectrum. Since it was difficult to separate them by CO2 gave a-alcohol 28 (66%) and b-alcohol 29 (21%).
column chromatography, the structure of each component Treatment of 28 with conc. H2SO4 gave the ether 30 in 69%
was determined without separation. Similar procedures as yield. This compound had the same molecular formula (m/z
described above lead to the conclusion that the major product 331) with that before treatment but showed neither OH nor
was 6-methyl 13 and the minor product was 5-methyl adduct olefinic proton signal in the IR and 1H-NMR spectra, indicat-
14. The H-7a signal (d 5.05 t, Jϭ3.8 Hz) of 13 had a COSY ing the ether formation. The structure was supported by the
correlation with a broad doublet (Jϭ3.8 Hz) of H2 at d 2.25 13C-NMR and COSY spectra. Thus, the stereochemistry of
which did not show the correlation with the olefinic H at d 3a-OH group and the position of Me group (at C-5) in 28
5.61 (m). On the other hand, two H at C-4 in 14 appeared at d were determined.
2.78 and 2.55 as an ABq (Jϭ15.5 Hz) which did not show
the correlation with the olefinic H at d 5.38 (m).
Discussion The LUMO coefficient (LCO) of dioxopyr-
rolines 6 and 8 calculated by Gaussian 98 Rev. A7,8) and the
The enol structure of the products from the cycloaddition HOMO coefficient (HCO) of piperylene and isoprene in the
of 8 to dienes were indicated by their positive FeCl3 test, ap- literature9,10) are shown in Fig. 1. The LCO’s indicate that C-
pearance of OH absorption in the IR, and appearance of two 5 is more reactive than C-4. But the differences between
new –Cϭ signals (instead of CO, C-3 and C-3a) in the 13C- those positions are smaller in 8 (0.141) than in 6 (0.304).
NMR spectrum.
The addition reactions of 6 to dienes are expected by at-
The regiochemistries of two isomers 20 and 21 from the tack of the largest HCO’s of dienes to the largest LCO (C-5)
addition reaction of 8 to piperylene were determined as fol- of the dioxopyrroline 6 to give the products in such manner
lows. The compound 20 was reduced with tetra-n-butylam- yielding 4a-substituted cis-endo adducts, except in the case
monium borohydride7) to the alcohol 26, which showed, in of isoprene (E). Although the addition of piperylene (C)
the COSY spectrum, the sequence of H-3 (d 4.32, dd) to H- gave a single product, it also requires some comments.
3a (d 2.16, dd) to H-4 (d 2.60—2.46, m) and to Me (d 1.19,
Isoprene gave the normal product 13, but accompanying
d), thus confirming the position of the Me group at C-4. The with the formation of the regio-isomer 14. Disturbance of the
stereochemistry of 4-Me group was revealed to be b (cis to rule can be explained by taking account of the steric factor.
the ring juncture) by the presence of NOE enhancements of The differences of HCO’s of C-1 and C-4 in these alkyl-buta-
H-3a (18.3%) on irradiation of the Me group. Irradiation of dienes are very small (0.001 for C and 0.044 for E). This im-
H-3 also produced enhancement of H-3a signal (12.9%). The plies that the difference of the reactivity at C-1 and C-4 in
fact implies that the reaction of 8 with piperylene proceeded these dienes is smaller than that in the other dienes bearing
unexpectedly through exo-stereochemistry. At the same time, O-functional groups. The disturbance of the rule may be
the stereochemistry of the newly created hydroxy-group at C- arisen from the steric reasons: obviously addition of isoprene

May 2003
505
Chart 4
give the reverse oriented product 23. In piperylene, its reac-
tive position (C-4) is less hindered than that of isoprene (C-
1). Thus, the addition reaction to 8 takes two paths: one is the
attack of C-4 (of C) to C-5 of 8 (electronically more favored)
and the other is the attack of C-4 (of C) to C-4 of 8 (steri-
cally more favored). Equal formation of 20 and 21 implies
that these two factors play equal role in the reaction of C to
8. Although the reason of the formation of exo-adduct in this
case is not clear, it is not exceptional that thermodynamically
more stable exo-adduct (b-Me isomer is 0.4 kcal/mol more
stable than the a-Me isomer in the dioxo form) is sometimes
favored in the Diels–Alder reaction of dioxopyrrolines.11,12)
Conclusion
In conclusion, new dioxopyrrolines 6 and 8 were shown to
be good dienophiles in 4ϩ2 cycloaddition reaction. Their
LUMO coefficients showed that C-5 had larger values than
those of C-4, but the difference is so small in 8 that the steric
factor sometimes overcomes the electronic factor. Thus the
reaction of 1-O-substituted dienes with 6 gave 4-substituted
hydroindoles with expected endo-stereochemistry and 2-O-
substituted dienes gave 6-substituted hydroindoles. They are
the products where the largest lobe of HOMO of dienes re-
acted with the largest LUMO (C-5) of dioxopyrrolines.
Violations of the rule were observed particularly for the
reactions of 1- and 2-methylbutadiene (piperylene and iso-
Fig. 1
to 6 is sterically less favorable for C-1 than that for C-4. prene) in 8, where the steric factors have to be taken into ac-
Thus, the reverse product 14, which was initiated by attack of count.
less hindered C-4 (of isoprene) to C-5 (of 6), is accompanied
Experimental
in the reaction of isoprene. In the reaction of piperylene (C)
to 6, both the electronic and steric factors play in the same
direction to give the single product 11.
Similarly, the steric factor plays an important role in addi-
tions of 8 to piperylene and isoprene, where piperylene gave
a 1 : 1 mixture of regio-isomers (20, 21) and isoprene gave a
single product (23) with reverse orientation. In compound 8
the difference of LCO between C-4 and C-5 is small (0.141)
and the attack to C-5 is obviously more hindered than that to
C-4. Thus in the reaction of isoprene, attack of C-1 in the
Unless otherwise stated, the following procedure was adopted. Melting
points were determined on a Yanaco melting point apparatus and uncor-
rected. IR spectra were recorded on a JASCO IR-810 spectrophotometer,
1
and data are given in cmϪ1. H- and 13C-NMR spectra were taken with a
1
JEOL JNM-EX90 (90 MHz for H and 22.5 MHz for 13C) or JEOL JNM-
1
AL300 (300 MHz for H and 75 MHz for 13C) or JNM-a500 (500 MHz for
1H) spectrometer, in CDCl3 solutions with tetramethylsilane as an internal
standard and the chemical shifts are given in d values. MS and HR-MS were
taken with a JEOL JMS D-300 and JEOL JMS-HX110A spectrometer and
Mϩ is given in m/z. Elemental analyses were performed with a Yanaco MT-
3. TLC was performed on pre-coated Kieselgel 60 F254 plates and spots were
monitored by UV (254 nm), then developed by spraying 0.5% Ce(SO4)2–
diene to the less hindered C-4 of 8 occurred exclusively to 0.5% (NH4)6Mo7O24 in 5% H2SO4 and heating the plates until coloration

506
Vol. 51, No. 5
took place. Column chromatography was performed on Wakogel C-200 (sil-
ica gel). For medium-pressure liquid chromatography, a Kusano CPS-HS-
221-1 column (silica gel, 22 mm i.d.ϫ100 mm) was used. All organic ex-
tracts were washed with brine, dried over anhydrous MgSO4, and concen-
trated to yield the products.
4-Methoxycarbonyl-1-(4-methoxyphenyl)-1H-pyrrole-2,3-dione (6)
Methyl propiolate (16.8 g, 0.2 mol) was added to a solution of p-anisidine 4
(24.6 g, 0.2 mol) in MeOH (200 ml), and the mixture was stirred overnight at
room temperature. The resultant precipitate was collected by filtration. The
filtrate was purified by chromatography using AcOEt–hexane (1 : 1) as an
eluent to afford further crops of crystals. The crystals were combined and re-
crystallized from AcOEt–MeOH to yield 5 (29.0 g, 72%).
m, H-5), 6.05—6.01 (1H, m, H-6), 4.87 (1H, t, Jϭ7.0 Hz, H-7a), 4.72 (1H,
d, Jϭ4.9 Hz, H-4), 3.84, 3.80, 3.25 (each 3H, s, OMe), 2.53—2.47 (1H, m,
H-7), 2.40—2.34 (1H, m, H-7). 13C-NMR: 194.1, 167.8, 158.8, 157.1,
129.8ϫ2, 125.0ϫ2, 114.5ϫ2, 128.5, 76.2, 59.5, 57.2, 55.2, 53.5, 56.2, 26.9.
HR-MS: Calcd for C18H19NO6: 345.1210. Found: 345.1208. Anal. Calcd for
C18H19NO6: C, 62.60; H, 5.55; N, 4.06. Found: C, 62.58; H, 5.61; N, 3.98.
(3aR*,7aR*)-3a-Methoxycarbonyl-1-(4-methoxyphenyl)-6-methyl-2,3-
dioxo-2,3,3a,4,7,7a-hexahydroindole (13): 1H-NMR: 7.61, 7.42 (each 2H, d,
Jϭ9.2 Hz, Ar-H), 5.62—5.60 (1H, m, H-5), 5.05 (1H, t, Jϭ3.8 Hz, H-7a),
3.85, 3.79 (each 3H, s, OMe), 2.88 (1H, dd, Jϭ15.0, 6.7 Hz) and 2.50 (1H,
br d, Jϭ15.0 Hz, H-4), 2.25 (2H, d, Jϭ3.8 Hz, H-7), 1.60 (3H, s, Me). 13C-
NMR: 196.1, 168.6, 158.9, 157.2, 135.1, 128.5, 124.8ϫ2, 114.8ϫ2, 59.0,
55.5, 53.5, 54.8, 31.3, 28.8, 22.9.
(3aR*,7aR*)-3a-Methoxycarbonyl-1-(4-methoxyphenyl)-5-methyl-2,3-
dioxo-2,3,3a,4,7,7a-hexahydroindole (14): 1H-NMR: 7.44, 7.00 (each 2H, d,
Jϭ9.2 Hz, Ar-H), 5.38 (1H, m, H-6), 4.98 (1H, ddd, Jϭ5.5, 2.8, 0.9 Hz, H-
7a), 3.85, 3.79 (each 3H, s, OMe), 2.78 (1H, d, Jϭ15.5 Hz) and 2.55 (1H,
br d, Jϭ15.5 Hz, H-4), 2.34—2.29 (1H, m) and 2.22—2.15 (1H, m) (H-7),
1.76 (3H, s, Me). 13C-NMR: 196.0, 168.6, 156.0, 157.2, 137.4, 128.8,
124.8ϫ2, 114.8ϫ2, 118.6, 59.1, 55.6, 53.6, 55.3, 33.1, 26.8, 23.1.
To a solution of 5 (29.0 g, 0.14 mol) in THF (10 ml)–ether (400 ml) was
added oxalyl chloride (12.2 ml, 0.14 mol) and the mixture was stirred at
room temperature for 1 h. Dioxane (150 ml) and octane (150 ml) were added
to the mixture, then evaporated in vacuo. The residue was purified by crys-
tallization to give 6 (36.0 g, 98%), as reddish purple needles, mp 154—
1
155 °C (from Et2O). IR (KBr): 1730, 1695. H-NMR: 8.94 (1H, s, ϭCH),
7.42, 6.99 (each 2H, d, Jϭ8.9 Hz, Ar-H) 3.86, 3.85 (each 3H, s, OMe). HR-
MS: Calcd for C13H11NO5: 261.0635. Found: 261.0620.
5-Methoxycarbonyl-1-(4-methoxyphenyl)-1H-pyrrole-2,3-dione (8)
A mixture of methyl pyruvate (5.1 g, 50 mmol) and p-anisidine 4 (616 mg,
5 mmol) was stirred for 1 h at room temperature, then distilled at 5 mmHg to
remove excess methyl pyruvate. The residue was dissolved in ether (5 ml)
and oxalyl chloride (0.87 ml, 10 mmol) in anhydrous ether (50 ml) was
added dropwise to this solution. The resulting mixture was stirred at room
temperature for 10 min. After addition of heptane (5 ml) and benzene (5 ml)
the mixture was concentrated in vacuo and the residue was crystallized from
Et2O–hexane to give 8 (930 mg, 71%) as red prisms. mp 128—129 °C. IR:
(3aR*,4S*,7aR*)-4-Acetoxy-3a-methoxycarbonyl-1-(4methoxyphenyl)-6-
methyl-2,3-dioxo-2,3,3a,4,7,7a-hexahydroindole (16): Red oil. IR (CHCl3):
1760, 1710, 1600, 1500. 1H-NMR: 7.43 (2H, d, Jϭ9.0 Hz, Ar-H), 7.02 (2H,
d, Jϭ9.0 Hz, Ar-H), 5.95 (1H, d, Jϭ5.2 Hz, H-4), 5.91—5.89 (1H, m, H-5),
4.99 (1H, t, Jϭ6.9 Hz, H-7a), 3.86, 3.82 (each 3H, s, OMe), 2.42 (1H, dd,
Jϭ15.6, 6.7 Hz, H-7), 2.33 (1H, dd, Jϭ15.6, 6.7 Hz, H-7), 2.01 (3H, s,
COMe), 1.71 (3H, s, Me). 13C-NMR: 191.8, 169.2, 166.9, 158.9, 156.7,
138.9, 128.1, 124.9ϫ2, 114.6ϫ2, 121.7 (C-5), 69.5, 57.5, 56.4, 55.3, 53.6,
31.6 (C-7), 20.8, 14.0. HR-MS: Calcd for C20H21NO7: 387.1318. Found:
387.1323.
(3aR*,4S*,7aR*)-3a-Methoxycarbonyl-1-(4-methoxyphenyl)-6-methyl-
2,3-dioxo-4-trimethylsilyloxy-2,3,3a,4,7,7a-hexahydroindole (17): Red oil.
IR (CHCl3): 1820, 1770, 1660, 1560. 1H-NMR: 7.41, 7.00 (each 2H, d,
Jϭ9.2 Hz, Ar-H), 5.88—5.85 (1H, m, H-5), 5.08 (1H, d, Jϭ5.5 Hz, H-4),
4.99 (1H, t, Jϭ7.3 Hz, H-7a), 3.85, 3.79 (each 3H, s, OMe), 2.45—2.40 (1H,
m) and 2.34 (1H, dd, Jϭ15.3, 7.3 Hz, H-7), 1.71 (3H, s, Me), 0.06 (9H, s,
OTMS). 13C-NMR: 193.3, 167.8, 158.7, 157.2, 138.2, 128.8, 125.1ϫ2,
114.6ϫ2, 124.8, 69.4, 60.1, 55.9, 55.5, 53.3, 31.9, 23.1. HR-MS: Calcd for
C21H27NO6Si: 417.1606. Found: 417.1601.
(3aR*,7aR*)-3a-Methoxycarbonyl-1-(4-methoxyphenyl)-2,3,6-trioxo-
2,3,3a,4,5,6,7,7a-octahydroindole (18): Light yellow prisms. mp 174—
176 °C (from AcOEt–hexane). IR (KBr): 1770, 1740, 1720, 1700, 1610,
1590, 1520. 1H-NMR: 7.31, 7.00 (each 2H, d, Jϭ9.0 Hz, Ar-H), 5.15 (1H, t,
Jϭ4.9 Hz, H-7a), 3.85, 3.84 (each 3H, s, OMe), 2.80 (1H, dd, Jϭ16.2,
4.9 Hz, H-7), 2.70—2.46 (4H, m, –CH2–ϫ2), 2.25—2.18 (1H, m). 13C-
NMR: 205.7, 194.9, 167.8, 159.7, 156.8, 127.5, 125.4ϫ2, 115.1ϫ2, 57.3,
55.6, 54.1, 53.3, 41.0, 34.9, 26.3. HR-MS: Calcd for C17H17NO6: 331.1057.
Found: 331.1095. Anal. Calcd for C17H17NO6: C, 61.63; H, 5.17; N, 4.23.
Found: C, 61.34; H, 5.24; N, 4.30.
(3aR*,4S*,7aR*)-4-Methoxy-3a-methoxycarbonyl-1-(4-methoxyphenyl)-
2,3,6-trioxo-2,3,3a,4,5,6,7,7a-octahydroindole (19): Yellow prisms. mp
160—163 °C (from AcOEt–hexane). IR (KBr): 1770, 1740, 1710, 1610,
1520. 1H-NMR: 7.42, 7.00 (each 2H, d, Jϭ8.9 Hz, Ar-H), 5.12 (1H, dd,
Jϭ9.8, 7.3 Hz, H-7a), 4.67 (1H, t, Jϭ2.8 Hz, H-4), 3.84, 3.83, 3.33 (each
3H, s, OMe), 2.87 and 2.48 (each 1H, dd, Jϭ19.2, 2.7 Hz, H-5), 2.82—2.80
(2H, m, H-7). 13C-NMR: 204.4, 192.0, 166.4, 159.2, 152.0, 128.2, 124.8ϫ2,
114.9ϫ2, 78.2, 58.2, 55.6, 54.1, 56.9, 55.4, 42.9, 39.6. HR-MS: Calcd for
C18H19NO7: 361.1159. Found: 361.1144.
3-Hydroxy-7a-methoxycarbonyl-1-(4-methoxyphenyl)-4-methyl-2-oxo-
2,4,7,7a-tetrahydroindole (20): Pale yellow needles. mp 204—206 °C (from
AcOEt–hexane). IR (KBr): 3250, 1745, 1690. 1H-NMR: 7.12, 6.88 (each
2H, d, Jϭ9.2 Hz, Ar-H), 5.74—5.68 (1H, m, ϭCH), 5.60—5.54 (1H, m,
ϭCH), 3.79, 3.65 (each 3H, s, OMe), 3.17—3.10 (1H, m, H-7), 3.08 (1H, d,
Jϭ5.8 Hz) and 2.22—2.15 (1H, m, H-4), 1.52 (3H, d, Jϭ7.3 Hz, Me). 13C-
NMR: 170.2, 168.2, 158.8, 140.9, 128.0, 123.2, 131.8 (C-6), 127.4ϫ2,
114.6ϫ2, 121.9, 68.3, 55.4, 52.9, 33.1, 30.9, 17.7. HR-MS: Calcd for
C18H19NO5: 329.1261. Found: 329.1256.
3-Hydroxy-7a-methoxycarbonyl-1-(4-methoxyphenyl)-7-methyl-2-oxo-
2,4,7,7a-tetrahydroindole (21): Pale yellow prisms. mp 205—207 °C (from
CHCl3–hexane). IR (KBr): 3250, 1750, 1680. 1H-NMR: 7.27, 6.90 (each
2H, d, Jϭ9.0 Hz, Ar-H), 5.88—5.83 (1H, m, ϭCH), 5.65—5.60 (1H, m,
ϭCH), 3.80, 3.63 (each 3H, s, OMe), 3.42—3.33 (1H, m, H-7), 3.33—3.27
(1H, m, H-4), 2.83 (1H, dt, Jϭ21.4, 2.9 Hz, H-7), 0.79 (3H, d, Jϭ7.0 Hz,
Me). 13C-NMR: 170.6, 168.4, 157.7, 141.5, 129.4, 118.4, 130.9, 124.3ϫ2,
1
1760, 1720. H-NMR: 7.18—6.89 (4H, m, Ar-H), 5.97 (1H, s, ϭCH), 3.83,
3.81 (each 3H, s, OMe). 13C-NMR: 184.6, 160.0, 159.7, 158.1, 156.6, 126.5,
127.7ϫ2, 114.6ϫ2, 104.0, 55.5, 53.5. HR-MS: Calcd for C13H11NO5:
261.0634. Found: 261.0604.
Diels–Alder Reaction of Dioxopyrroline (6, 8) with Butadienes (Gen-
eral Procedure) A mixture of dioxopyrroline and a diene (4 eq mol, see
Tables 1 and 2) in dry toluene or benzene was heated at appropriate tempera-
ture in a sealed tube with stirring. The reaction mixture was concentrated to
dryness in vacuo. The residue was passed through a short column of SiO2
with AcOEt–hexane. Concentration of the eluate gave a crude product.
(3aR*,7aR*)-3a-Methoxycarbonyl-1-(4-methoxyphenyl)-2,3-dioxo-
2,3,3a,4,7,7a-hexahydroindole (9): Brown prisms. mp 134 °C (from AcOEt–
hexane). IR (KBr): 1770, 1740, 1700, 1610, 1520. 1H-NMR: 7.26, 7.01
(each 2H, d, Jϭ9.1 Hz, Ar-H), 6.03—5.97 (1H, m, H-5), 5.79—5.75 (1H, m,
H-6), 5.03—5.01 (1H, m, H-7a), 3.85, 3.80 (each 3H, s, OMe), 2.93 (1H, dd,
Jϭ15.4, 6.6 Hz) and 2.58 (1H, d, Jϭ15.4 Hz, –CH2–), 2.43—2.35 (1H, m)
and 2.25 (1H, s, –CH2–). 13C-NMR: 195.8, 168.5, 159.0, 157.2, 128.6,
127.9, 126.1, 124.9ϫ2, 114.8ϫ2, 58.8, 55.3, 53.5, 55.0, 28.3, 26.3. HR-MS:
Calcd for C17H17NO5: 315.1107. Found: 315.1108. Anal. Calcd for
C17H17NO5: C, 64.75; H, 5.43; N, 4.44. Found: C, 64.58; H, 5.54; N, 4.57.
(3aR*,7aR*)-3a-Methoxycarbonyl-1-(4-methoxyphenyl)-5,6-dimethyl-
2,3-dioxo-2,3,3a,4,7,7a-hexahydroindole (10): Yellow prisms. mp 149—
152 °C (from AcOEt–hexane). IR (KBr): 1770, 1740, 1710, 1620, 1520. 1H-
NMR: 7.43, 7.01 (each 2H, d, Jϭ8.9 Hz, Ar-H), 5.00 (1H, t, Jϭ3.6 Hz, H-
7a), 3.85, 3.78 (each 3H, s, OMe), 2.64, 2.52 (each 1H, d, Jϭ14.6 Hz,
–CH2–), 2.24 (2H, s, –CH2–), 1.69, 1.54 (each 3H, s, Me). 13C-NMR: 195.8,
168.5, 158.9, 157.2, 128.8, 127.4, 125.6, 124.7ϫ2, 114.8ϫ2, 59.5, 55.5,
53.4, 55.1, 34.8, 33.1, 19.0ϫ2. HR-MS: Calcd for C19H21NO5: 343.1417.
Found: 343.1396. Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08.
Found: C, 66.50; H, 6.24; N, 4.04.
(3aR*,4S*,7aR*)-3a-Methoxycarbonyl-1-(4-methoxyphenyl)-4-methyl-
2,3-dioxo-2,3,3a,4,7,7a-hexahydroindole (11): Light yellow prisms. mp
136—140 °C (from AcOEt–hexane). IR: 1765, 1720, 1690, 1610, 1520. 1H-
NMR: 7.37, 6.99 (each 2H, d, Jϭ9.2 Hz, Ar-H), 5.78 (1H, dt, Jϭ8.9, 3.4 Hz,
H-5), 5.73—5.69 (1H, m, H-6), 4.85—4.83 (1H, m, H-7a), 3.84, 3.81 (each
3H, s, OMe), 2.99—2.93 (1H, m, H-4), 2.47 (1H, ddd, Jϭ15.6, 6.7, 1.8 Hz,
H-7), 2.19—2.14 (1H, m, H-7), 1.41 (3H, d, Jϭ7.3 Hz, Me). 13C-NMR:
195.1, 169.7, 158.9, 157.7, 128.5, 135.0, 125.1, 124.9ϫ2, 114.7ϫ2, 60.4,
57.7, 55.5, 53.3, 34.8, 26.1, 14.8. HR-MS: Calcd for C18H19NO5: 329.1267.
Found: 329.1287. Anal. Calcd for C18H19NO5: C, 65.64; H, 5.82; N, 4.25.
Found: C, 65.72; H, 5.90; N, 4.26.
(3aR*,4S*,7aR*)-4-Methoxy-3a-methoxycarbonyl-1-(4-methoxyphenyl)-
2,3-dioxo-2,3,3a,4,7,7a-hexahydroindole (12): Light yellow prisms. mp
132—134 °C (from AcOEt–hexane). IR (KBr): 1780, 1740, 1710, 1610,
1
1510. H-NMR: 7.43, 6.99 (each 2H, d, Jϭ9.0 Hz, Ar-H), 6.29—6.26 (1H,

May 2003
507
oily product, which was purified by ODS column chromatography using
MeOH–H2O (3 : 1) as an eluent to separate into 28 (65 mg, 66%) and 29
(48 mg, 21%). 28: Colorless prisms. mp 148—150 °C (from AcOEt–
hexane). IR (KBr): 3340, 1740, 1680. 1H-NMR: 7.10, 6.89 (each 2H, d,
Jϭ9.0 Hz, Ar-H), 5.33—5.26 (1H, m, H-6), 4.64 (1H, d, Jϭ7.2 Hz, H-3),
4.30 (1H, br s, OH), 3.80 (6H, s, COOMe, OMe), 2.99 (1H, dd, Jϭ14.5,
7.2 Hz, H-3a), 2.62—2.50 (1H, m, H-7), 2.30—2.01 (3H, m, H-4, H-7), 1.77
(3H, s, Me). 13C-NMR: 176.2, 174.4, 159.0, 134.9, 129.1ϫ2, 127.7, 116.2,
114.3ϫ2, 70.7, 68.0, 55.3, 52.9, 41.7, 28.4, 25.4, 23.0. Anal. Calcd for
C18H21NO5: C, 65.24; H, 6.39; N, 4.23. Found: C, 64.99; H, 6.41; N, 4.24.
29: Light yellow prisms. mp 169—171 °C (from AcOEt–hexane). IR (KBr):
3350, 1740, 1680. 1H-NMR: 7.23—6.82 (4H, m, Ar-H), 5.46 (1H, br s,
ϭCH), 4.19 (1H, d, Jϭ9.0 Hz, H-3), 3.79, 3.64 (each 3H, s, OMe), 3.31—
2.32 (5H, m, –CH2–ϫ2, H-3a), 1.74 (3H, s, Me). 13C-NMR: 175.1, 172.0,
158.9, 132.7, 128.8, 127.8ϫ2, 114.5ϫ2, 117.7, 73.3, 67.0, 55.4, 52.8, 44.7,
30.9, 29.2, 23.3. Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 4.23.
Found: C, 65.01; H, 6.41; N, 4.27.
Reaction of 28 with c-H2SO4 Compound 28 (45 mg, 0.14 mmol) was
treated with c-H2SO4 (120 ml) at room temperature for 10 min. The reaction
mixture was adjusted to pH 5 by adding 10% aqueous NaOH solution and
extracted with CH2Cl2. The product was purified by column chromatography
followed by crystallization from AcOEt–hexane to give the ether 30 (31 mg,
69%) as colorless prisms, mp 124—126 °C. IR (KBr): 1740, 1690. 1H-
NMR: 7.08, 6.90 (each 2H, d, Jϭ9.0 Hz, Ar-H), 4.43 (1H, d, Jϭ5.9 Hz, H-
3), 3.79 (3H, s, OMe), 3.73 (3H, s, COOMe), 3.31 (1H, t, Jϭ4.9 Hz, H-3a),
2.04 (1H, d, Jϭ12.3 Hz, H-4), 1.98—1.76 (4H, m, H-6, H-7), 1.66 (1H, dd,
Jϭ12.3, 4.2 Hz, H-4), 1.44 (3H, s, Me). 13C-NMR: 173.7, 172.5, 159.3,
129.3ϫ2, 128.1, 114.6ϫ2, 81.9, 78.4, 71.4, 55.4, 52.7, 44.1, 35.3. 33.6,
25.4, 23.3. HR-MS: Calcd for C18H21NO5: 331.1417. Found: 331.1392.
114.5ϫ2, 121.9, 70.9, 55.4, 52.9, 34.5, 22.9, 14.9. HR-MS: Calcd for
C18H19NO5: 329.1260. Found: 329.1233.
3-Hydroxy-7a-methoxycarbonyl-1-(4-methoxyphenyl)-5-methyl-2-oxo-
2,4,7,7a-tetrahydroindole (23): Light yellow prisms. mp 206—208 °C (from
Et2O–hexane). IR (KBr): 1740, 1680, 1600, 1500. 1H-NMR: 7.19—6.84
(4H, m, Ar-H), 5.43 (1H, s, ϭCH), 3.81, 3.65 (each 3H, s, OMe), 3.48—
2.09 (4H, m, –CH2–ϫ2), 1.77 (3H, s, Me). 13C-NMR: 170.4, 167.8, 158.6,
140.9, 131.8, 128.7, 121.0, 127.4ϫ2, 114.5ϫ2, 117.7, 66.9, 55.4, 52.8, 33.6,
27.4, 22.7. HR-MS: Calcd for C18H19NO5: 329.1289. Found: 329.1276.
Diels–Alder Reaction of Dioxopyrroline (8) with 1-Methoxybutadiene
A solution of 8 (261 mg, 1 mmol) and 1-methoxybutadiene (252 mg,
3 mmol) in dry toluene (10 ml) was heated at 100 °C for 11 h in a sealed
tube. The reaction mixture was concentrated to dryness in vacuo and the
residue was passed through a column of CC-7 with AcOEt–hexane. Concen-
tration of the eluate gave a crystalline product which was recrystallized from
AcOEt–hexane to give 7a-methoxycarbonyl-1-(4-methoxyphenyl)-2,3-
dioxo-2,3,7,7a-tetrahydroindole (24, 72 mg, 23%) as yellow prisms, mp
155—157 °C. IR (KBr): 1740 (sh), 1720. 1H-NMR: 7.15 (1H, d, Jϭ5.0 Hz),
7.10 (2H, d, Jϭ9.0 Hz), 6.96 (2H, d, Jϭ9.0 Hz), 6.48—6.30 (2H, m), 3.83
(3H, s), 3.74 (3H, s), 3.34 (1H, dd, Jϭ17.4, 6.0 Hz), 2.70—2.51 (1H, m).
13C-NMR: 183.1, 169.7, 161.9, 159.7, 136.8, 130.8, 127.3, 127.2, 126.9ϫ2,
124.1, 115.0ϫ2, 63.2, 55.5, 53.6, 30.7. MS: m/z 313 (Mϩ), 163 (base peak).
HR-MS: Calcd for C17H15NO5: 313.0950. Found: 313.0985.
Work-up the reaction product by silica gel chromatography as in general
procedure gave 2-(2-(4-methoxy)phenylamino-1,2-dioxoethyl)benzoic acid
methyl ester (25, 103 mg, 33%) as light yellow prisms, mp 132—135 °C
(from AcOEt–hexane). IR (KBr): 3350, 1715, 1680. 1H-NMR: 8.84 (1H, s),
8.01 (1H, dd, Jϭ7.6, 1.4 Hz), 7.67 (1H, dt, Jϭ7.6, 1.3 Hz), 7.61 (1H, dt,
Jϭ7.6, 1.4 Hz), 7.59 (2H, d, Jϭ9.1 Hz), 7.52 (1H, dd, Jϭ7.6, 1.3 Hz), 6.89
(2H, d, Jϭ9.1), 3.83, 3.80 (each 3H, s). 13C-NMR: 192.5, 166.7, 157.9,
156.8, 137.4, 132.6, 131.1, 130.8, 129.9, 129.1, 128.3, 121.1ϫ2, 114.2ϫ2,
55.4, 52.6. HR-MS: Calcd for C17H15NO5: 313.0950. Found: 313.0966.
Anal. Calcd for C17H15NO5: C, 65.17; H, 4.82; N, 4.47. Found: C, 65.14; H,
4.94; N, 4.36.
References and Notes
1) Part LXI: Horiguchi Y., Sano T., Kiuchi Y., Tsuda Y., Chem. Pharm.
Bull., 44, 681—689 (1996).
2) Tsuda Y., Yakugaku Zasshi, 101, 295—321 (1981).
3) Tsuda Y., Sano T., “The Alkaloids,” Vol. 48, ed. by Cordell G. A.,
Academic Press, London, 1996, pp. 249—337.
4) Isobe K., Mohri C., Sano S., Mohri K., Enomoto H., Sano T., Tsuda
Y., Chem. Pharm. Bull., 37, 3236—3238 (1989).
5) Huisgen R., Herbig K., Siegel A., Huber H., Chem. Ber., 99, 2526—
2545 (1966).
6) Zaima T., Matsuno C., Mitsuhashi K., Nippon Kagaku Kaishi, 1983,
152—156 (1983).
7) Tsuda Y., Sakai Y., Akiyama K., Isobe K., Chem. Pharm. Bull., 39,
2120—2123 (1991).
8) The conformational structure of 6 and 8 were optimized at the
Hartree–Fock level of theory with the 3-21g* basis set. We used
GAUSSIAN98 program package for molecular orbital calculations.
All the calculations were performed with IBM RS6000/44P-270 com-
puter. Frisch M. J., Trucks G. W., Schlegel H. B., Scuseria G. E., Robb
M. A., Cheeseman J. R., Zakrzewski V. G., Montgomery J. A., Jr.,
Stratmann R. E., Burant J. C., Dapprich S., Millam J. M., Kudin K. N.,
Strain M. C., Farkas O., Tomasi J., Barone V., Cossi M., Cammi R.,
Mennucci B., Pomelli C., Adamo C., Clifford S., Ochterski J., Peters-
son G. A., Ayala P. Y., Cui Q., Morokuma K., Malick D. K., Rabuck
A. D., Raghavachari K., Foresman J. B., Cioslowski J., Ortiz J. V.,
Baboul A. G., Stefanov B. B., Liu G., Liashenko A., Piskorz P., Ko-
maromi I., Gomperts R., Martin R. L., Fox D. J., Keith T., Al-Laham
M. A., Peng C. Y., Nanayakkara A., Gonzalez C., Challacombe M.,
Gill P. M. W., Johnson B., Chen W., Wong M. W., Andres J. L., Gonza-
lez C., Head-Gordon M., Replogle E. S., Pople J. A., Gaussian, Inc.,
Pittsburgh PA, 1998.
9) Smith M. B., “Organic Synthesis,” International Editions, McGraw-
Hill, Inc., New York, 1994, pp. 1113—1129.
10) Kahn S. D., Pau C. F., Overman L. E., Hehre W. J., J. Am. Chem. Soc.,
108, 7381—7396 (1986).
11) Tsuda Y., Ohshima T., Sano T., Toda J., Heterocycles, 19, 2027—2032
(1982).
12) Sano T., Toda J., Kashiwaba N., Ohshima T., Tsuda Y., Chem. Pharm.
Bull., 35, 479—500 (1987).
Treatment of 24 with Silica Gel A mixture of 24 (30 mg) and silica gel
(300 mg) in AcOEt (20 ml) was stirred at room temperature for 1 h. The sil-
ica gel was filtered off and the filtrate was concentrated under pressure.
Crystallization of the product from AcOEt–hexane gave 25 (21 mg, 70%).
Reduction of 20 A solution of 20 (121 mg, 0.37 mmol) in MeOH (7 ml)
was stirred with tetra-n-butylammonium borohydride (378 mg, 1.47 mmol)
for 68 h at room temperature. The reaction mixture was acidified with 5%
HCl and extracted with CHCl3. The product was purified by column chro-
matography [AcOEt–hexane (1 : 1)] to give the starting material 20 (37 mg,
31%) and the reduction product 26 (47 mg, 39%) as colorless flakes, mp
1
103—106 °C (from AcOEt–hexane). IR (KBr): 3450, 1720. H-NMR: 6.99,
6.91 (each 2H, d, Jϭ9.1 Hz, Ar-H), 5.64 (2H, d, Jϭ2.8 Hz, H-5, H-6), 4.75
(1H, d, Jϭ12.1 Hz, OH), 4.32 (1H, dd, Jϭ12.1, 7.0 Hz, H-3), 3.80 (3H, s,
OMe), 3.67 (3H, s, COOMe), 2.75—2.65 (1H, m, H-7), 2.60—2.46 (1H, m,
H-4), 2.34—2.24 (1H, m, H-7), 2.16 (1H, dd, Jϭ11.6, 7.2 Hz, H-3a), 1.19
(3H, d, Jϭ7.0 Hz, Me). 13C-NMR: 175.7, 175.4, 159.2, 134.7, 128.2ϫ2,
128.1, 123.4, 114.7ϫ2, 70.5, 68.8, 55.4, 53.3, 52.1, 33.8, 28.7, 18.5. HR-
MS: Calcd for C18H21NO5: 331.1417. Found: 331.1409.
Reduction of 21 A solution of 21 (100 mg, 0.30 mmol) in MeOH
(10 ml) was stirred with tetra-n-butylammonium borohydride (312 mg,
1.21 mmol) for 117 h at room temperature. The reaction mixture was worked
up as described above. Chromatography of the product gave the starting ma-
terial 21 (32 mg, 32%) and the reduction product 27 (29 mg, 29%), as color-
less prisms, mp 164—166 °C (from AcOEt–hexane). IR (KBr): 3350, 1740,
1
1680. H-NMR: 7.25, 6.86 (each 2H, d, Jϭ9.0 Hz, Ar-H), 5.98—5.88 (1H,
m, H-5), 5.47 (1H, dt, Jϭ9.6, 2.6 Hz, H-6), 4.49 (1H, d, Jϭ7.2 Hz, H-3),
4.17 (1H, br s, OH), 3.85 (3H, s, OMe), 3.80 (3H, s, COOMe), 3.08 (1H,
ddd, Jϭ9.4, 7.2, 4.6 Hz, H-3a), 3.03—2.92 (1H, m, H-7), 2.57 (1H, dt,
Jϭ18.4, 4.6 Hz, H-4), 2.21—2.05 (1H, m, H-4), 0.53 (3H, d, Jϭ7.5 Hz, Me).
13C-NMR: 176.8, 174.3, 159.3, 130.3ϫ2, 129.9, 129.7, 127.2, 114.2ϫ2,
73.2, 70.2, 55.3, 52.9, 43.6, 34.4, 20.3, 15.9. HR-MS: Calcd for C18H21NO5:
331.1418. Found: 331.1398.
Reduction of 23 Potassium borohydride (11 mg, 0.18 mmol) was added
to a solution of 23 (116 mg, 0.35 mmol) in EtOH (5 ml) under CO2 atmos-
phere and the mixture was stirred at room temperature for 12 h. The reaction
mixture was acidified with 5% HCl and extracted with CH2Cl2 to give an