A two-stage synthesis of 8,10a-epoxypyrido[2,1-a]isoindoles: Stereochemistry of the [4+2] cycloaddition of maleic anhydride with 2,6-difurylpiperidin-4-ones

Article abstract of DOI:10.1055/s-0029-1217033

A new straightforward synthesis of 8,10a-epoxypyrido[2,1-a]isoindoles and their 7-carboxylic acids from 2,6-difurylsubstituted piperidin-4-ones and maleic anhydride or acryloyl chloride via the intramolecular Diels-Alder reaction has been demonstrated. It

Full text of DOI:10.1055/s-0029-1217033

PAPER
4235
A Two-Stage Synthesis of 8,10a-Epoxypyrido[2,1-a]isoindoles:
Stereochemistry of the [4+2] Cycloaddition of Maleic Anhydride with
2,6-Difurylpiperidin-4-ones
I
MD
A
F
of
M
a
e
leic
A
nhyd
d
ride
w
ith 2,6
o
-Difurylpipe
r
ridin-4-ones I. Zubkov,*a Inga K. Airiyan,a Konstantin F. Turchin,b Vladimir P. Zaytsev,a Atash V. Gurbanov,c
Abel M. Maharramov,c Victor N. Khrustalev,d Alexandr S. Peregudov,d Eugeniya V. Nikitina,a Alexey V. Varlamova
a
Organic Chemistry Department, Russian Peoples Friendship University,
Miklukho-Maklaya St. 6, Moscow 117198, Russian Federation
Fax +7(95)9550779; E-mail: fzubkov@sci.pfu.edu.ru
Center of Drugs Chemistry, All-Russian Institute for Chemical and Pharmaceutical Research,
b
Zubovskaya St. 7, Moscow 119815, Russian Federation
Baku State University, Z. Khalilov St. 23, Baku 1148, Azerbaijan
Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
c
d
Vavilov St. 28, Moscow 119991, Russian Federation
Received 23 June 2009; revised 28 July 2009
[4+2] cycloaddition of the olefinic fragment with the fu-
Abstract: A new straightforward synthesis of 8,10a-epoxypyri-
ran ring (in amide II), resulting in substituted and/or con-
densed 2,3,7,7a-tetrahydro-3a,6-epoxyisoindolones III.
do[2,1-a]isoindoles and their 7-carboxylic acids from 2,6-difuryl-
substituted piperidin-4-ones and maleic anhydride or acryloyl chlo-
ride via the intramolecular Diels–Alder reaction has been demon-
strated. It has been shown that a one-stage synthesis of the title
compounds can be performed under mild conditions and with high
levels of regio- and stereoselectivity from easily accessible 2-fu-
rylpiperidines.
Therefore, we recently developed an efficient approach
for the synthesis of hydrogenated hydroxyisoquinolines,6
isoindolo[2,1-a]quinoline,7
isoindolo[2,1-b]benzaze-
pine,8 and isoindolo[1,2-a]isoquinoline9 carboxylic acids.
Here we report a study of the cycloaddition of a,b-unsat-
urated acid derivatives with compounds containing the
furfurylaminic fragment; 2-furyl-substituted piperidines.
Key words: intramolecular Diels–Alder furan reaction, IMDAF,
stereoselective synthesis, furans, 2,6-difurylpiperidin-4-ones, pyri-
do[2,1-a]isoindoles
The starting materials, 2,6-difurylpiperidin-4-ones 2a–l,
were easily prepared from commercially available ke-
tones 1a–g,i,j and furfural or 5-methylfurfural in one step
(Scheme 2). The commercially unavailable ketone, dieth-
yl 4-oxoheptanedioate (1h), was obtained as previously
described.10 The reaction to form 2 was performed accord-
ing to the literature procedure,11 but without heating the
reaction mixture; a solution of ketone, furfural or 5-meth-
ylfurfural (2 equiv), and ammonium acetate (2 equiv) in
ethanol was allowed to react at room temperature for three
days. After standard workup, the target products, piperid-
inones 2a–l, were isolated in moderate yields. The best re-
sults were obtained for the symmetric and phenyl-
substituted compounds 2f,g,i,l that crystallize well
(Table 1).
The chemistry and methods for the synthesis of hydro-
genized pyrido[2,1-a]isoindoles are well known in organ-
ic chemistry,1 but there are very few references to their
8,10a-epoxy-substituted analogues.2 Nevertheless, these
derivatives of 3a,6-epoxyisoindolones3 are essential inter-
mediates for the synthesis of polyfunctional-substituted
isoindoles,4 many of which can be widely used in practice.
The reactions of furfurylamines and unsaturated 2-furyl-
substituted azaheterocycles I (Scheme 1) with maleic an-
hydride and a,b-unsaturated acid chlorides were system-
atically investigated by our research group.5 It was
established that the reactions proceed via N-acylation of
furfurylamine I followed by a spontaneous intramolecular
O
O
[4+2]
N
N
O
O
O
N
H
O
cycloaddition
O
acylation
O
HO2C
HO2C
III
I
II
Scheme 1
SYNTHESIS 2009, No. 24, pp 4235–4255
x
x.
x
x
.
2
0
0
9
Advanced online publication: 12.10.2009
DOI: 10.1055/s-0029-1217033; Art ID: Z13609SS
© Georg Thieme Verlag Stuttgart · New York

4236
F. I. Zubkov et al.
PAPER
O
O
R1
R2
R1
O
R2
1a– j
EtOH
O
H
H
R3
N
H
R3
R3
r.t., 3 d
O
O
O
O
R3
2a–l
NH4OAc
Scheme 2
Table 1 Yields of 2,6-Di-2-furylpiperidin-4-ones 2a–l
According to LC-MS data 2,6-difuryl-3-phenylpiperidi-
none is not generated under the aforementioned condi-
tions. Likewise, we established that condensation of
acetone and cyclohexanone with furfural and ammonium
acetate does not proceed under the described conditions.12
It was found that, in the case of acetone, high-molecular
products of condensation (m/z = 271 [M+], 309 and above)
were obtained. The reaction with cyclohexanone leads to
2,6-bis(2-furylmethylene)cyclohexanone only. All at-
tempts to carry out the synthesis in alternative solvents,
such as N,N-dimethylformamide and acetic acid, via iso-
lation of the a,a¢-bis(2-furylmethylene)cyclohexanone
were unsuccessful.
Product
2a
R1
R2
R3
H
Yielda (%)
H
Me
34
33
28
31
28
62
66
30
56
31
27
41
2b
2c
H
Et
H
H
Pr
H
2d
2e
H
i-Pr
H
H
CH2CH=CH2
H
2f
Ph
Ph
H
2g
Me
Me
H
Based on the high values of the coupling constants of the
pairs of the axial protons H2(a), H3(a), and H5(a), H6(a)
(10.5–13 Hz), it was determined that all piperidinones
2a–l obtained were isolated as individual all-equatorial
isomers. The minor isomers of the compounds 2a–c,e,g,k
with the 3(a)-substituent detected in the crude reaction
mixture (LC-MS) could not be isolated.
2h
2i
CH2CO2Et
CH2CO2Et
H
Me
Et
Ph
H
2j
Ph
H
2k
2l
H
Me
Me
Me
Me
Me
Modification of the easily accessible 2,6-difuryl-3,5-di-
methylpiperidin-3-one 2g was performed by the follow-
a The averaged yields for 3 optimal syntheses.
Me
O
Me
O
Me
Me
O
Me
3 76%
7 40%
O
O
N
H
N
Ac
p-TsOH
HO2CCO2H
160 °C, 0.5 h
Ac2O, PhMe
Δ, 2 h
for 6a
O
HO
R
4
Me
O
Me
5
6
3
2
Me
Me
Me
O
Me
MeMgI
1. NH2NH2
2. KOH
1
N
O
O
O
or PhLi
Et2O
N
H
N
H
H
O
4 50%
2g
6a R = Me 72%
6b R = Ph 29%
NaBH4, MeOH
Δ, 1 h
for 6a
Me
S8, DMF
Me
OH
Me
Me
Me
5 54%
8 74%
O
O
N
N
H
O
O
Scheme 3
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

PAPER
IMDAF of Maleic Anhydride with 2,6-Difurylpiperidin-4-ones
4237
ing chemical transformations. The N-acetyl-substituted 3 The dehydration and oxidation of the piperidinol 6a af-
and deoxo derivative 4, piperidinols 5, 6 were obtained forded the 1,2,5,6-tetrahydropyridine 7 and the 2,6-difu-
according to standard procedures (Scheme 3).
rylpyridine 8, respectively (Scheme 3).
It should be noted that, under the conditions of the The next step of our study describes the reaction between
Kishner–Wolff reduction (Huang–Minlon modification) piperidines 2 and 4 and derivatives of a,b-unsaturated ac-
of all-equatorial piperidinone 2g, we isolated 2(e),6(e)-di- ids. Both reactions went smoothly and under mild reaction
furyl-3(e),5(a)-dimethylpiperidine 4 only (3J5,6 = 2.7 Hz conditions (Scheme 4).
3
and J2,3 = 10.5 Hz). This surprising fact was observed
We suppose that the acylation of the symmetric pipe-
ridines 2f–h,l with acryloyl chloride and maleic anhydride
proceeds via acylation of the nitrogen atom and leads to
previously,13 but requires careful consideration and will
be the subject of a later publication.
It is interesting also that toluene was used as the solvent in the intermediate amides IV and V. The formation of the
the synthesis of the N-acetylpiperidinone 3. Thus, boiling N-acryloyl derivative IV was monitored by TLC and LC-
(140 °C, 1 h) the amine 2g in excess of acetic anhydride MS of the crude reaction mixture. The intermediate male-
yielded amide 3 in 30% yield, which, probably, can be ex- ic acid monoamides V were not detected. When boiled in
plained by the ring opening of the piperidine ring at the C– benzene or toluene, the intermediate acetyl derivatives IV
N bond under these conditions.14 The alcohols 5 and 6 and V undergo spontaneous intramolecular Diels–Alder
were isolated as individual 4(a)-OH diastereomers. The reaction with a furan (IMDAF). Thus, the [4+2] cycload-
preferred formation of the 4(a)-OH piperidinols of the dition proceeds between the furan ring and the double
type 5 and 6a after reduction by sodium borohydride or bond of the N-acetyl fragment and yields corresponding
the reaction of methyl- or phenylmagnesium iodide with adducts 9f–h,l and 11f–h,l. It was found that the reaction
the 2,6-diarylpiperidinones are wellknown in the litera- time is significantly shorter in the case of maleic anhy-
ture.15 The reaction of the compound 2g with phenylmag- dride (from 2–8 h for acryloyl chloride to 1–2 h for maleic
nesium bromide does not afford the target piperidinone anhydride). This fact may be explained by the electron-
6b. Using phenyllithium instead of the Grignard reagent, withdrawing effect of the carboxylic group in the dieno-
the corresponding alcohol 6b was obtained in low yield. philic fragment of the intermediate V.
The axial orientation of the protons H2 and H6 and of 4-
It should be noted, that in all cases the IMDAF process
was carried out under thermodynamic control (heating un-
til no changes occurs by TLC or in LC-MS spectrum of
the reaction mixture).
OH in the amino alcohols 5 and 6a was confirmed by
comparison15 and additionally by the absence of cross
peaks between protons H2(H6)/H4 (in 5) and H2(H6)/
4-Me (in 6a) in the NOESY spectra.
The reaction of acryloyl chloride and maleic anhydride
with 3(e),5(a)-dimethylpiperidine 4 is regioselective and
O
O
N
Cl
R1
O
R2
H
2
R1
O
R2
1
3
[4+2]
exo-
O
9f 45%
9g 82%
9h 86%
9l 87%
10
8
4
N
PhH, Et3N
Δ, 2–6 h
5
9
O
4
O
O
6
O
O
R1
O
R2
O
R3
R3
R3
7
5
3
R3
IV
6
2
N1
H
O
N
O
N
R1
O
R2
R1
O
R2
H
2
1
R3
R3
3
O
11f 55%
11g 86%
11h 80%
11l 84%
O
[4+2]
exo-
O
10
2f R1 = R2 = Ph, R3 = H
4
2g R1 = R2 = Me, R3 = H
2h R1 = R2 = CH2CO2Et, R3 = H
2l R1 = R2 = R3 = Me
PhMe
Δ, 0.5–2 h
5
9
O
O
O
6
O
R3
R3
R3
8
7
R3
HO2C
CO2H
V
Me
O
Me
H
Me
O
Me
H
1
2
Me
Me
5
4
3
3
Cl
10
6
2
4
N
N
O
O
O
O
5
N1
9
O
7
O
6
PhH, Et3N
O
H
O
PhMe, Δ, 2 h
O
O
8
Δ, 4 h
4
10 70%
12 58%
HO2C
Scheme 4
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

4238
F. I. Zubkov et al.
PAPER
O
N
R2
H
2
1
Cl
3
O
10
8
4
B
5
9
O
PhH, Et3N
Δ, 2–8 h
O
6
O
O
R3
9a–e,k
7
R3
R2
O
N
O
N
O
N
B
A
O
H
2
R2
H
2
R2 = Me
MeOH or
EtOH
Me
H
1
1
3
3
R3
R3
2a–e,k
O
O
O
10
10
8
4
4
5
5
B
9
9
O
H+
PhMe
Δ, 2–4 h
O
O
7
O
6
6
O
O
R3
8
7
R3
YO2C
HO2C
11a–e,k
13a Y = Me 70%
13b Y = Et 75%
Scheme 5
affects the 2-furyl substituent only. Solely one regioiso-
mer of compounds 10 and 12 was isolated from the reac-
tion mixture in moderate yield. The configuration of the
adducts 10 and 12 shown in Scheme 4 follows from con-
sideration of the vicinal spin-spin coupling constants
Table 2 Yields of Hexahydro-2H-8,10a-epoxypyrido[2,1-a]isoin-
doles 9a–e,k and 11a–e,k
Substrate R2
R3
Yield (%)
9
11
84
82
67
40
70
87
3
3J1,10b = 11.8 Hz and J3,4 = 4.4 Hz as compared with the
2a
2b
2c
2d
2e
2k
Me
H
67
63
45
55
45
57
same constants of the adducts 9g,h,l and 11g,h,l
(3J1,10b = 10.8–12.4 Hz, 3J3,4 = 0–2.8 Hz). As the coupling
constants (3J3,4) of compounds 10 and 12 and 9 and 11
have the same values, the spatial positions of 1-methyl
group in these compounds are equal.
Et
H
Pr
H
i-Pr
H
It is notable that the cycloaddition proceeds with only one
furan ring of the 2,6-difurylpiperidines 2 and 4 even when
a threefold excess of acylating agent (acryloyl chloride or
maleic anhydride) was used. The cycloaddition proceeds
neither for the N-acetyl derivative 3 nor for the pyridine 8
even in boiling xylene.
CH2CH=CH2
Me
H
Me
Thus, the adducts of cycloaddition 9a–e,k obtained after
crystallization have no impurities. However, the corre-
sponding adducts 11a–e have 4–8% impurity of the minor
In all instances the cycloaddition proceeds in a stereose-
lective manner, where exo addition of the furan core to the
dienophile prevails and leads to a single diastereomer of
the hexahydro-2H-8,10a-epoxypyrido[2,1-a]isoindoles
9f–h,l and 10 or their 7-carboxylic acids 11f–h,l and 12.
1
isomer 11¢ (Scheme 6) in accordance with the H NMR
data.
Using the reaction of 3-isopropyl-2,6-difurylpiperidinone
2d and maleic anhydride as an example, it was shown that
The reaction of acryloyl chloride or maleic anhydride with
the asymmetric 3-R2-2,6-difurylpiperidin-4-ones 2a–e,k
has the same mechanism and yields adducts 9a–e,k and
11a–e,k (Scheme 5, Table 2).
O
R2
2
1
rapidly
3
H
[4+2]
exo-
10
4
N
B
5
9
O
N
In this case, the reaction proceeds not only stereospecifi-
cally, but also regioselectively. It means that the IMDAF
proceeds with the furan ring in position 2 only (labeled A
in Scheme 5). The reaction is believed to depend on the
steric interaction between the alkyl groups R2 in position
3 and the 2-furyl fragment (Scheme 6) in the transition
state. It causes a preferred conformation of furyl ring A in
the position favoring the [4+2] cycloaddition (in com-
pounds 2a–e,k, the plane of furan fragment A and the
plane of the piperidine cycle are orthogonal16), while the
furan ring in position 6 B experiences free rotation about
the C6–2-furyl-B bond.
O
O
7
free
6
R2
O
rotation
8
11
HO2C
B
O
O
O
R2
O
O
H
HO2C
[4+2]
N
A
transition state
exo-
O
of Diels–Alder reaction
slowly
O
11′
CO2H
Scheme 6
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

PAPER
IMDAF of Maleic Anhydride with 2,6-Difurylpiperidin-4-ones
4239
the regioselectivity of the process greatly depends on the
temperature of the synthesis. Piperidinone 2d (as well as
the other corresponding compounds) reacts with an
equimolar amount of maleic anhydride in benzene at 22
1
°C slowly. According to H NMR data, the residue ob-
tained after 72 hours in the course of the reaction (44%
yield) contains an approximately 1:2 mixture of isomers
11d¢/11d. The ratio of the isomers decreases to ~1:4 in
boiling benzene (2 h, 40% yield). Using toluene as the sol-
vent, we isolated the adduct in 39% yield, which con-
tained a small amount of the minor isomer (11d¢/11d
~1:9). Boiling the reaction mixture at 140 °C (o-xylene, 2
h), we obtained solely regioisomer 11d in 32% yield.
The carboxylic acids 11a–e,k are fine-grained powders
poorly soluble in most organic solvents including dimeth-
yl sulfoxide. Consequently it has been difficult to deter-
mine their spatial structure by NMR spectroscopy alone.
In particular, the orientation of the 8,10a-epoxy bridge in
Diels–Alder adducts 9 and 11 was ambiguous. It was nec-
essary to obtain the corresponding methyl or ethyl esters
13 in order to determine their structures. The esters 13 are
well soluble and crystallized readily. Their conformation
Figure 1 Molecular structure of ester 13a; thermal ellipsoids are
shown at 50% probability level
1
was studied by H and 13C NMR spectroscopy in detail.
well-identifiable signals of C8 (d = 78.5–81.5) and C10a
(d = 90.0–90.5) of the oxabicyclo[2.2.1]heptene frag-
ment. The chemical shifts of these carbon atoms depend
neither on the solvents used (CDCl3 and DMSO-d6), nor
on the substituents on the ring.
Moreover, in the case of methyl ester 13a, a single crystal
suitable for the X-ray analysis was obtained by slow crys-
tallization from ethanol–chloroform (Figure 1).
Based on the X-ray crystal structure data, it was possible
to assign the signals in the NMR spectra of the adducts
9a–h,k,l, 11a–h,k,l, and 12. The signals of the proton
H10b with d = 4.2–4.9 (J10b,1 = 11.7–12.3 Hz) and of the
low-field proton H4 (d = 5.0–5.9) with J4,3a = 0–2.5 Hz are
the most characteristic. The values of these coupling con-
stants give a good fit with the dihedral angles H10b–
C10b–C1H1 = 169.7° and H4–C4–C3–H3A = 67.8° as-
certained using X-ray diffraction analysis. The exo-orien-
tation of the substituent in the oxabicyclo[2.2.1]heptene
fragment is confirmed by the value of the spin-spin cou-
pling constant J6a,7endo = 8.9–9.3 Hz and the absence of a
coupling constant J8,7endo (~ 0 Hz). It is interesting to men-
tion some special characteristics of the 13C NMR spectra:
It was also interesting to investigate the cycloaddition of
unsaturated acid anhydrides with the asymmetric disubsti-
tuted 5-alkyl-3-phenylpiperidinones 2i,j (Scheme 7).
Similarly to the synthesis of 9 and 11 described above
(Scheme 5), the reaction proceeds stereospecifically as an
exo-[4+2] cycloaddition, but, in this case, it is difficult to
make a conclusion about regioselectivity.
Adducts 9i,j/9i¢,j¢ were isolated from the reaction mix-
tures in ratios 9i/9i¢ 1:4 (77% total yield) and 9j/9j¢ 1:1.3
(78%). The ratio of isomers can be explained by the simi-
lar size of the 3-phenyl and the 5-methyl or 5-ethyl groups
in the starting piperidinones 2i,j. Obviously, the effective
volume of the ethyl group in the compound 2j is greater
O
O
R1
H
Ph
O
R1
O
Ph
H
2
2
1
Cl
1
3
3
O
10
8
10
4
4
N
N
5
5
PhH, Et3N
9
9
O
O
7
6
Δ, 2–6 h
6
O
O
O
8
7
R1
O
Ph
O
9i,j (minor)
9i′,j′ (major)
N
H
O
N
O
2
R1
3
Ph
H
R1
H
Ph
2
1
1
3
2i R1 = Me
2j R1 = Et
O
O
O
10
8
10
4
N5
4
9
PhMe
Δ, 4 h
O
9
O
O
O
7
6
6
O
O
7
8
HO2C
CO2H
11i′,j′ (major)
11i,j (minor)
Scheme 7
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

4240
F. I. Zubkov et al.
PAPER
than that of the methyl group in piperidinone 2i, which in- ethanol–N,N-dimethylformamide mixtures, we isolated
fluences the isomeric composition of the adducts 9i,j. the predominant isomers 11i¢,j¢ only.
When R = Me, isomer 9i¢ prevails, in the case of the ad-
It was not possible to determine the structure of regioiso-
duct from 2j (R = Et) the isomeric ratio between 9j and 9j¢
mers 9 obtained from 2i,j using NMR data. The single
is essentially 1:1. All adducts 9i,j and 9i¢,j¢ were isolated
crystals of adducts 9i and 9i¢ were obtained by slow crys-
after fractional crystallization or column chromatography.
tallization from a mixture of heptane–ethyl acetate. The
Acids 11i,j and 11i¢,j¢ were obtained as mixtures of iso- molecular structures of 9i and 9i¢ were established by X-
mers, whose ratio were determined as 11i/11i¢ 1:4 and 11j/ ray diffraction analysis (Figures 2 and 3).
11j¢ 1:6 by 1H NMR spectroscopy. Unfortunately, it was
The unit cell of 9i¢ contains four crystallographically inde-
not possible to run the chromatographic separation of
pendent molecules differing by only the rotation angle of
these isomers due to their poor solubility. After fractional
crystallization of the tetracycles 11i,j and 11i¢,j¢ from
the furyl substituent about the exo-C4–C(furyl) bond.
Therefore, only the average geometrical parameters of the
9i¢ molecules are discussed below.
Compounds 9i, 9i¢, and 13a comprise fused tetracyclic
systems containing three five-membered rings (pyrrolidi-
none and tetrahydro- and dihydrofurans) and one six-
membered (piperidinone) ring and are distinguished by
substituents at C1, C3, and C7 (Figures 1– 3). Five-mem-
bered rings have the usual envelope conformations. The
central six-membered ring adopts a twist-boat conforma-
tion (the C3 and C10B carbon atoms are out of the mean
plane defined by the other atoms of the ring by 0.511 and
0.503; 0.587 and 0.529; and 0.578 and 0.521 Å for 9i, 9i¢,
and 13a, respectively). The N5 nitrogen atom has a trigo-
nal-planar geometry (the sums of the bond angles about
N5 are 359.4°, 359.9°, and 360.0° for 9i, 9i¢ and 13a, re-
spectively). The dihedral angles between the planes of the
pyrrolidinone and piperidinone rings are 16.3°, 16.0°, and
17.6° for 9i, 9i¢, and 13a, respectively. In all compounds,
the substituent at C1 is in an equatorial position, whereas
the substituents at the C3 (for 9i and 9i¢) and C4 are in ax-
ial positions.
Figure 2 Molecular structure of the minor regioisomer 9i
As stated above, according to the X-ray data (Figures 1–
3), the substituents in positions 3 and 4 occupy unfavor-
able axial positions in the piperidine ring of the adducts 9
and 11. We suppose that the steric hindrance is responsi-
ble for the relatively low yield (~50%) of the adducts from
the cycloaddition of maleic anhydride and acryloyl chlo-
ride with 2,6-difuryl-3,5-diphenylpiperidinone 2f. The
adducts 9f and 11f seem to require bulky substituents in
the N-acyl intermediates IV and V (Scheme 4) to occupy
axial positions in transition states.
The reaction between piperidinols 6a,b and maleic anhy-
dride proceeds via the acylation of the nitrogen atom only,
the axial 4-hydroxy group does not participate in the reac-
tion (Scheme 8). Similarly to the preceding cases, the acy-
lations of nitrogen result in spontaneous exo-[4+2]
cycloaddition to give hydroxy acids 15a,b in high yield
and stereoselectivity. The reaction of the amino alcohol
6a with acryloyl chloride yields adduct 14 in moderate
yield. Methyl ester 16 was obtained after boiling the
8,10a-epoxypyrido[2,1-a]isoindole carboxylic acid 15a in
methanol.
The configuration of the adducts 14–16 were determined
by 1H and 13C NMR spectroscopy based on analogy to the
adducts 9 and 11.
Figure 3 Molecular structure of major regioisomer 9i¢
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

PAPER
IMDAF of Maleic Anhydride with 2,6-Difurylpiperidin-4-ones
4241
HO
Me
1
Me
Me
H
Cl
2
3
4
10
O
N
5
9
PhH, Et3N
Δ, 2–8 h
for 6a
O
O
7
6
O
8
HO
R
14 40%
Me
O
Me
O
N
H
HO
Me
HO
R
1
Me
O
Me
H
Me
O
Me
H
2
3
6a R = Me
6b R = Ph
O
O
MeOH
10
O
N
N
4
H+
for 15a
9
O
PhMe
Δ, 2–4 h
O
7
6
O
O
8
MeO2C
HO2C
16 90%
15a 96%
15b 88%
Scheme 8
HO
O
NH
N
NH2OH⋅HCl
NaOH
Me
Me
Me
HC≡CH
KOH
O
O
O
N
H
EtOH, Δ, 2 h
DMSO
105 °C, 6 h
N
N
H
O
O
O
2a
17 81%
18 12%
O
N
NH
Me
Me
[O]
17
O
O
N
H
N
O
O
H
VI
Scheme 9
To our astonishment, the reaction of piperidinol 5 with Herein we reported an efficient two-stage method for the
maleic anhydride under the same conditions gave a mix- synthesis of octahydro-2H-8,10a-epoxypyrido[2,1-a]iso-
ture of at least four exo-adducts from the cycloaddition in indoles and their 7-carboxylic acids based on the IMDAF
~80% total yield. All attempts to isolate individual iso- reaction between 2-furylpiperidines and anhydrides of
mers from this mixture were unsuccessful. The same situ- a,b-unsaturated carboxylic acids. The reaction proceeds
ation was observed for the reaction of piperidinol 5 and as an exo-[4+2] cycloaddition with high regio- and stereo-
acryloyl chloride. Two major products were detected in selectivity giving the target compounds in good yields.
the reaction mixture, the structures of which were not es-
tablished. The behavior of amino alcohol 5 under the con-
ditions of the cycloaddition reaction is unclear.
All reagents were purchased from Acros Chemical Co. All solvents
were used without further purification. Melting points were deter-
mined using a SMP10 and are uncorrected. IR spectra were ob-
tained in KBr pellets for solids or in thin film for oils using an IR-
Fourier spectrophotometer Infralum FT-801. NMR spectra 1H (400
or 600 MHz) and 13C (100.6 or 150.9 MHz) were recorded for solns
in CDCl3 or DMSO-d6 at 30 °C and traces of CHCl3 (1H NMR d =
7.26 and 13C NMR d = 76.90) or DMSO-d5 (1H NMR d = 2.49 and
In the last part of our investigation we attempted to obtain
previously unknown furylpyrrolo[3,2-c]pyridines based
on piperidinone 2a by the Trofimov reaction.17 However,
treatment of the oxime 17 with gaseous acetylene in pres-
ence of super base (KOH/DMSO) unexpectedly afforded
the aromatic pyrrolopyridine 18 in low yield (Scheme 9). 13C NMR d =39.43) were used as the internal standard. Mass spectra
were measured either on Thermo Focus DSQ II (EI, 70 eV, ion
Obviously, the reaction mechanism is similar to the
source temperature was 200 °C, gas chromatographic inlet with
Trofimov mechanism, but the initial diaryl-substituted
Varian FactorFour VF-5ms column) or on Thermo Trace DSQ (EI,
70 eV, ion source temperature was 200 °C, direct inlet probe). The
purity of the obtained substances and composition of the reaction
mixtures were controlled by TLC Sorbfile plates. The separation of
the final products was carried out by column chromatography on
4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine VI is unsta-
ble under the reaction conditions and gives pyrrolo[3,2-
c]pyridine 18 after the dehydrogenation in presence of
dimethyl sulfoxide and atmospheric oxygen.
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

4242
F. I. Zubkov et al.
PAPER
alumina (activated, neutral, 50–200 mm) or by the fractional crys-
tallization.
used. After evaporation of Et2O, the residue (viscous brown oil) was
transformed into its oxalate by the following method: to the residue,
dissolved in anhyd Et2O (250–350 mL), sat. anhyd oxalic acid in
Et2O (70–150 mL) was added until pale-brown residue formation
was complete. The residue was filtered off, washed with acetone
(100 mL), and then boiled in acetone (200 mL). The remaining res-
idue was filtered off and dried in air to give piperidinone oxalates of
2c,d,e. For further transformations the oxalates were dissolved in
H2O and 10% NH4OH soln was added until pH 9–10. The thus ob-
tained free base was extracted with Et2O. The organic layers were
separated, dried (MgSO4), filtered, and evaporated to give pale-yel-
low viscous oils that occasionally crystallized when left to stand.
X-ray Crystal Structure Determination of the Cycloadducts 9i,
9i¢, and 13a (Figures 1–3)
Compound 9i: (C22H21NO4, M = 375.41), monoclinic, space group
P21/c, at T = 100 K: a = 13.9081(6), b = 10.9800(5), c = 13.6640(6)
Å, b = 118.0570(10)°, V = 1841.42(14) Å3, Z = 4, dcalcd = 1.354 g/
cm3, F(000) = 792, m = 0.093 mm–1. 27584 total reflections (6675
unique reflections, Rint = 0.032) were measured on a Bruker
SMART APEX II CCD diffractometer [l(MoKa) radiation, graph-
ite monochromator, w and j scan mode, 2qmax = 65°]. The structure
was determined by direct methods and refined by full-matrix least
squares technique with anisotropic displacement parameters for
non-hydrogen atoms. The hydrogen atoms were placed in calculat-
ed positions and refined within riding model with fixed isotropic
displacement parameters [Uiso(H) = 1.5Ueq(C) for the CH3 groups
and Uiso(H) = 1.2Ueq(C) for the other groups]. The final divergence
factors were R1 = 0.042 for 5612 independent reflections with
I > 2s(I) and wR2 = 0.116 for all independent reflections, S = 1.006.
All calculations were carried out using the SHELXTL program.18,19
(2S*,3R*,6R*)-2,6-Di-2-furyl-3-methylpiperidin-4-one (2a)
Yield: 34%; mp 63–64 °C (Lit.11b 40 °C).
IR: 3317 (NH), 1706 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 0.92 (d, J3,Me = 6.5 Hz, 3 H, 3-
CH3), 2.35 (br s, 1 H, NH), 2.71 (dd, J5B,6 = 3.0 Hz, 2J5,5 = 13.6 Hz,
1 H, H5B), 2.84 (dq, J3,2 = 10.7 Hz, J3,Me = 6.5 Hz, 1 H, H3), 2.85
(dd, J5A,6 = 12.1 Hz, 2J5,5 = 13.6 Hz, 1 H, H5A), 3.80 (d, J2,3 = 10.7
Hz, 1 H, H2), 4.17 (dd, J6,5A = 12.1 Hz, J6,5B = 3.0 Hz, 1 H, H6),
6.21 (br d, Jb¢,b = 3.2 Hz, 1 H, Hb*), 6.29 (dd, Ja,b = 1.8 Hz,
Jb¢,b = 3.2 Hz, 1 H, Hb), 6.32 (m, 2 H, Hb¢, Hb¢*), 7.36 (dd,
Jb¢,a = 0.8 Hz, Ja,b = 1.8 Hz, 1 H, Ha), 7.39 (dd, Jb¢,a = 0.6 Hz,
Ja,b = 1.8 Hz, 1 H, Ha*).
Compound 9i¢: (C22H21NO4, M = 375.41), monoclinic, space group
Pc, at T = 120 K: a = 15.807(3), b = 9.8372(18), c = 23.727(4) Å,
b = 90.299(3)°, V = 3689.5(12) Å3, Z = 8, dcalcd = 1.352 g/cm3,
F(000) = 1584, m = 0.093 mm–1. 27376 total reflections (6337
unique reflections, Rint = 0.036) were measured on a Bruker
SMART 1000 CCD diffractometer [l(MoKa) radiation, graphite
monochromator, w and j scan mode, 2qmax = 50°]. The structure
was determined by direct methods and refined by full-matrix least
squares technique with anisotropic displacement parameters for
non-hydrogen atoms. The hydrogen atoms were placed in calculat-
ed positions and refined within riding model with fixed isotropic
displacement parameters [Uiso(H) = 1.5Ueq(C) for the CH3 groups
and Uiso(H) = 1.2Ueq(C) for the other groups]. The final divergence
factors were R1 = 0.104 for 5744 independent reflections with
I > 2s(I) and wR2 = 0.229 for all independent reflections,
S = 1.007. All calculations were carried out using the SHELXTL
program.18,19
MS (EI, 70 eV): m/z (%) = 245 (28) [M]+, 175 (3), 174 (10), 150 (2),
146 (2), 136 (5), 123 (14), 122 (31), 108 (10), 95 (30), 94 (100), 93
(97), 79 (31), 66 (40), 65 (35), 56 (23), 40 (12).
Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C,
68.48; H, 6.20; N, 5.89.
(2S*,3R*,6R*)-3-Ethyl-2,6-di-2-furylpiperidin-4-one (2b)
Yield: 33%; mp 45–47 °C (Lit.11b 47 °C).
IR: 3316 (NH), 1707 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 0.81 (t, JCH2,Me = 7.0 Hz, 3 H,
CH3), 1.28 (m, 1 H, CHAHBCH3), 1.60 (m, 1 H, CHAHBCH3), 2.31
(br s, 1 H, NH), 2.70 (dd, J5B,6 = 2.5 Hz, 2J5,5 = 13.0 Hz, 1 H, H5B),
2.73 (m, 1 H, H3), 2.84 (dd, 2J5,5 = J5A,6 = 13.0 Hz, 1 H, H5A), 3.91
(d, J2,3 = 10.9 Hz, 1 H, H2), 4.15 (dd, J6,5B = 2.5 Hz, J6,5A = 13.0 Hz,
1 H, H6), 6.21 (br d, Jb¢,b = 3.1 Hz, 1 H, Hb¢), 6.31 (m, 3 H, Hb, Hb*,
Hb¢*), 7.35 (br d, Ja,b = 1.6 Hz, 1 H, Ha), 7.39 (br d, Ja,b = 1.6 Hz,
1 H, Ha*).
Compound 13a: (C19H19NO6, M = 357.35), monoclinic, space
group Cc, at T = 293 K: a = 9.839(2), b = 18.078(4), c = 10.664(2)
Å, b = 113.86(3)°, V = 1734.7(6) Å3, Z = 4, dcalcd = 1.368 g/cm3,
F(000) = 752, m = 0.103 mm–1. 2229 total reflections (2202 unique
reflections, Rint = 0.021) were measured on an Enraf-Nonius CAD-
4 four-circle automated diffractometer [l(MoKa) radiation, graph-
ite monochromator, w scan mode, 2qmax = 56°]. The structure was
determined by direct methods and refined by full-matrix least
squares technique with anisotropic displacement parameters for
non-hydrogen atoms. The hydrogen atoms were placed in calculat-
ed positions and refined within riding model with fixed isotropic
displacement parameters [Uiso(H) = 1.5Ueq(C) for the CH3 groups
and Uiso(H) = 1.2Ueq(C) for the other groups]. The final divergence
factors were R1 = 0.043 for 1748 independent reflections with
I > 2s(I) and wR2 = 0.123 for all independent reflections,
S = 1.000. All calculations were carried out using the SHELXTL
program.18,19
MS (EI, 70 eV): m/z (%) = 259 (15) [M]+, 174 (10), 149 (3), 137 (9),
122 (21), 107 (6), 96 (14), 94 (100), 77 (8), 65 (10), 55 (14), 39 (27).
Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C,
69.39; H, 6.55; N, 5.45.
(2S*,3R*,6R*)-2,6-Di-2-furyl-3-propylpiperidin-4-one (2c)
Yield: 28%; mp (oxalate) 154 °C.
IR: 3316 (NH), 1713 cm–1 (C=O).
1H NMR (600 MHz, CDCl3): d = 0.75 (t, J = 7.2 Hz, 3 H, CH2CH3),
1.02 (m, 2 H, CH2CH3), 1.27 (m, 1 H, CHAHBCH2CH3), 1.63 (m, 1
H, CHAHBCH2CH3), 2.27 (br s, 1 H, NH), 2.67 (dd, J5B,6 = 3.0 Hz,
2J5,5 = 13.4 Hz, 1 H, H5B), 2.72 (ddd, J3,2 = 10.5 Hz, J3,CH2A = 7.6
Hz, J3,CH2B = 2.0 Hz, 1 H, H3), 2.80 (dd, J5A,6 = 12.1 Hz, 2J5,5 = 13.4
Hz, 1 H, H5A), 3.85 (d, J3,2 = 10.5 Hz, 1 H, H2), 4.12 (dd, J5B,6 = 3.0
Hz, J5A,6 = 12.1 Hz, 1 H, H6), 6.17 (br d, Jb,b¢ = 3.2 Hz, 1 H, Hb¢),
6.24 (br d, Jb,b¢ = 3.2 Hz, 1 H, Hb¢), 6.27 (dd, Ja,b = 1.8 Hz, Jb,b¢ = 3.2
Hz, 1 H, Hb), 6.29 (dd, Ja,b = 1.8 Hz, Jb,b¢ = 3.2 Hz, 1 H, Hb), 7.31
(dd, Ja,b = 1.8 Hz, Ja,b¢ = 0.6 Hz, 1 H, Ha), 7.35 (dd, Ja,b = 1.8 Hz,
Ja,b¢ = 0.6 Hz, 1 H, Ha).
Piperidinones 2a–l; Typical Procedure
A soln of furfural or 5-methylfurfural (~25 mL, 0.3 mol) and
NH4OAc (23 g, 0.3 mol) in EtOH (150 mL) was added to a soln of
1a–j (0.15 mol) in EtOH (50 mL). The resulting clear mixture was
allowed to react at r.t. for 3 d. The brown mixture obtained was then
diluted with Et2O (400 mL) and washed with H2O (3 × 200 mL).
The organic layer was separated, dried (MgSO4), filtered, evaporat-
ed, and purified by column chromatography (alumina, hexane) to
give 2a,b,f–j,l as white prisms in good to moderate yields. Piperid-
inone 2k was isolated as bright-yellow needles. In case of poor crys-
tallizing piperidinones 2c,d,e, column chromatography was not
MS (EI, 70 eV): m/z (%) = 273 (14) [M]+, 244 (3), 188 (2), 174 (5),
151 (4), 122 (11), 96 (19), 94 (100), 77 (13), 66 (18), 55 (51).
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

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IMDAF of Maleic Anhydride with 2,6-Difurylpiperidin-4-ones
4243
Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.29; H, 7.33; N, 5.19.
JMe,3(Me,5) = 6.6 Hz, 2 H, H3, H5), 3.76 (d, J2,3(5,6) = 10.8 Hz, 2 H,
H2, H6), 6.27 (dd, Ja,b¢ = 0.8 Hz, Jb¢,b = 3.2 Hz, 2 H, Hb¢), 6.31 (dd,
Ja,b = 1.8 Hz, Jb¢,b = 3.2 Hz, 2 H, Hb), 7.38 (dd, Jb¢,a = 0.8 Hz,
Ja,b = 1.8 Hz, 2 H, Ha).
MS (EI, 70 eV): m/z (%) = 259 (13) [M]+, 174 (14), 146 (3), 136
(29), 123 (23), 108 (100), 96 (16), 80 (16), 79 (54), 77 (27), 55 (14),
53 (15), 39 (42).
(2S*,3R*,6R*)-2,6-Di-2-furyl-3-isopropylpiperidin-4-one (2d)
Yield: 31%; mp 54–55 °C.
IR: 3288 (NH), 1703 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 0.74 [d, JCH,Me = 7.3 Hz, 3 H,
CH(CH3)A(CH3)B], 1.02 [d, JCH,Me = 6.7 Hz,
3
H,
Anal. Calcd for C17H15NO3: C, 69.48; H, 6.61; N, 5.40. Found: C,
69.30; H, 6.51; N, 5.61.
CH(CH3)A(CH3)B], 1.93 [m, 1 H, CH(CH3)2], 2.25 (br s, 1 H, NH),
2
2.67 (dd, J5B,6 = 2.7 Hz, J5,5 = 14.1 Hz, 1 H, H5B), 2.77 (dd,
J3,2 = 11.4 Hz, J3,CH(Me)2 = 6.5 Hz, 1 H, H3), 2.79 (dd, J5A,6 = 11.2
Hz, 2J5,5 = 14.1 Hz, 1 H, H5A), 4.14 (d, J2,3 = 11.4 Hz, 1 H, H2), 4.17
(dd, J6,5A = 11.2 Hz, J6,5B = 2.7 Hz, 1 H, H6), 6.32–6.19 (m, 4 H,
Hb, Hb¢, Hb*, Hb¢*), 7.34 (dd, Ja,b = 1.8 Hz, Ja,b¢ = 0.8 Hz, 1 H,
Ha), 7.38 (dd, Ja,b = 1.8 Hz, Ja,b¢ = 0.8 Hz, 1 H, Ha*).
MS (EI, 70 eV): m/z (%) = 273 (21) [M]+, 258 (8), 188 (8), 174 (11),
151 (7), 122 (11), 121 (11), 96 (18), 95 (11), 94 (100), 88 (5), 69
(22), 65 (5).
Diethyl 2,2¢-[(2R*,3S*,5R*,6S*)-2,6-Di-2-furyl-4-oxopiperi-
dine-3,5-diyl]diacetate (2h)
Yield: 30%; mp 62 °C.
IR: 3313 (NH), 1715 (C=O), 1726 cm–1 (CO2Et).
1H NMR (400 MHz, CDCl3): d = 1.19 (t, JCH2,Me = 7.0 Hz, 6 H,
CH2CH3), 2.20 (dd, 2J = 17.2 Hz, JCH2A,3(5) = 3.8 Hz, 2 H,
CHAHBCO2Et), 2.56 (dd, 2J = 17.2 Hz, JCH2B,3 = 7.6 Hz, 2 H,
CHAHBCO2Et), 3.39 (ddd, J2,3(5,6) = 11.0 Hz, JCH2A,3 = 3.8 Hz,
JCH2B,3 = 7.6 Hz, 2 H, H3, H5), 4.01 (q, JCH2,Me = 7.0 Hz, 4 H,
CH2CH3), 4.03 (d, J2,3(5,6) = 11.0 Hz, 2 H, H2, H6), 6.28 (m, 4 H,
Hb, Hb¢), 7.37 (dd, Jb¢,a = 0.6 Hz, Ja,b = 1.6 Hz, 2 H, Ha).
MS (EI, 70 eV): m/z (%) = 403 (39) [M]+, 386 (4), 358 (44), 316
(27), 298 (6), 274 (10), 270 (12), 228 (17), 208 (50), 195 (47), 175
(26), 174 (27), 146 (9), 122 (60), 107 (41), 96 (15), 79 (11), 55 (21),
44 (100).
Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.17; H, 7.24; N, 5.09.
(2S*,3R*,6R*)-3-Allyl-2,6-di-2-furylpiperidin-4-one (2e)
Yield: 28%; mp (oxalate) 138 °C.
IR: 3294 (NH), 1712 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 2.14–2.27 (m, 2 H, CH2CH=CH2),
2
2.72 (dd, J5B,6 = 2.4 Hz, J5,5 = 13.7 Hz, 1 H, H5B), 2.84 (dd,
Anal. Calcd for C21H25NO7: C, 62.52; H, 6.25; N, 3.47. Found: C,
62.45, H, 6.25; N, 3.49.
J5A,6 = 12.0 Hz, 2J5,5 = 13.7 Hz, 1 H, H5A), 2.89 (m, 1 H, H3), 3.96
(d, J2,3 = 10.9 Hz, 1 H, H2), 4.16 (dd, J6,5B = 2.4 Hz, J6,5A = 12.0 Hz,
1 H, H6), 4.85 (br d, J2¢,3¢trans = 17.2 Hz, 1 H, CH2CH=CHtransHcis),
4.91 (br d, J2¢,3¢cis = 10.5 Hz, 1 H, CH2CH=CHtransHcis), 5.67 (ddt,
(2R*,3S*,5R*,6S*)-2,6-Di-2-furyl-5-methyl-3-phenylpiperidin-
4-one (2i)
J2¢,1¢ = 7.2 Hz, J2¢,3¢cis = 10.5 Hz, J2¢,3¢trans = 17.2 Hz, 1 H, CH=CH2),
Yield: 56%; mp 129 °C.
6.20 (br d, Jb¢,b = 3.0 Hz, 1 H, Hb¢), 6.28–6.32 (m, 3 H, Hb, Hb*,
Hb¢*), 7.34 (br d, Ja,b = 1.6 Hz, 1 H, Ha), 7.38 (br d, Ja,b = 1.6 Hz,
1 H, Ha*).
MS (EI, 70 eV): m/z (%) = 271 (7) [M]+, 228 (1), 105 (5), 94 (100),
IR: 3326 (NH), 1726 cm–1 (C=O).
1H NMR (600 MHz, CDCl3): d = 1.00 (d, J5,Me = 6.5 Hz, 3 H, 5-
CH3), 2.49 (br s, 1 H, NH), 3.10 (ddq, J5,b¢ = 0.9 Hz, J5,Me = 6.5 Hz,
J5,6 = 10.9 Hz, 1 H, H5), 4.00 (d, J5,6 = 10.9 Hz, 1 H, H6), 4.16 (d,
J2,3 = 11.1 Hz, 1 H, H3), 4.40 (d, J2,3 = 11.1 Hz, 1 H, H2), 5.93 (dd,
Ja,b¢ = 0.7 Hz, Jb¢,b = 3.2 Hz, 1 H, Hb¢), 6.11 (dd, Ja,b = 1.8 Hz,
Jb¢,b = 3.2 Hz, 1 H, Hb), 6.36 (dd, Ja,b¢ = 0.7 Hz, Jb¢,b = 3.2 Hz, 1 H,
Hb¢*), 6.38 (dd, Ja,b = 1.9 Hz, Jb¢,b = 3.2 Hz, 1 H, Hb*), 7.05 (dd,
Jmeta,ortho = 7.2 Hz, Jpara,ortho = 0.8 Hz, 2 H, Hortho), 7.21 (m, 1 H,
65 (25), 53 (14), 39 (44).
Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C,
70.65; H, 6.40; N, 5.11.
(2R*,3S*,5R*,6S*)-2,6-Di-2-furyl-3,5-diphenylpiperidin-4-one
(2f)
Hpara), 7.26 (m, 2 H, Hmeta), 7.26 (dd, Jb¢,a = 0.7 Hz, Ja,b = 1.8 Hz, 1
H, Ha), 7.44 (dd, Jb¢,a = 0.7 Hz, Ja,b = 1.9 Hz, 1 H, Ha*).
Yield: 62%; mp 149–151 °C.
IR: 3283 (NH), 1693 cm–1 (C=O).
MS (EI, 70 eV): m/z (%) = 321 (13) [M]+, 240 (3), 226 (2), 202 (6),
198 (3), 185 (38), 174 (41), 170 (14), 161 (5), 141 (6), 136 (5), 122
(6), 118 (24), 108 (100), 96 (10), 79 (9).
1H NMR (600 MHz, CDCl3): d = 2.63 (br s, 1 H, NH), 4.23 (d,
J2,3(5,6) = 11.0 Hz, 2 H, H3, H5), 4.54 (d, J2,3(5,6) = 11.0 Hz, 2 H, H2,
H6), 5.93 (br d, Ja,b = 3.3 Hz, 2 H, Hb¢), 6.09 (dd, Ja,b = 3.3 Hz,
Ja,b = 1.6 Hz, 2 H, Hb), 7.03 (dd, Jortho,para = 1.0 Hz, Jmeta,ortho = 7.7
Hz, 4 H, Hortho Ph), 7.13 (dt, Jmeta,para = 7.7 Hz, Jortho,para = 1.0 Hz, 2
H, Hpara Ph), 7.19 (br t, Jmeta,para = Jmeta,ortho = 7.7 Hz, 4 H, Hmeta),
7.25 (dd, Jb¢,a = 0.7 Hz, Ja,b = 1.8 Hz, 2 H, Ha).
MS (EI, 70 eV): m/z (%) = 383 (7) [M]+, 366 (8), 335 (3), 207 (9),
185 (28), 174 (88), 179 (100), 141 (93), 118 (26), 115 (79), 91 (47),
90 (76), 77 (20), 65 (18).
Anal. Calcd for C20H19NO3: C, 74.75; H, 5.96; N, 4.36. Found: C,
74.61; H, 5.51; N, 4.35.
(2R*,3S*,5R*,6S*)-3-Ethyl-2,6-di-2-furyl-5-phenylpiperidin-4-
one (2j)
Yield: 31%; mp 116–117 °C.
IR: 3329 (NH), 1713 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 0.80 (t, JCH2,Me = 7.5 Hz, 3 H,
CH2CH3), 1.25 (ddq, JCH2,Me = 7.5 Hz, JCH2A,3 = 3.2 Hz, 2JCH2 = 15.1
Hz, 1 H, CHAHBCH3), 1.68 (m, 1 H, CHAHBCH3), 2.42 (br s, 1 H,
NH), 2.92 (ddd, JCH2A,3 = 3.2 Hz, J2,3 = 10.9 Hz, JCH2B,3 = 7.5 Hz, 1
H, H3), 4.05 (d, J2,3 = 10.9 Hz, 1 H, H2), 4.11 (br d, J6,5 = 10.8 Hz,
1 H, H6), 4.33 (d, J6,5 = 10.8 Hz, 1 H, H5), 5.87 (dd, Ja,b¢ = 0.8 Hz,
Jb¢,b = 3.3 Hz, 1 H, Hb¢), 6.06 (dd, Ja,b = 1.8 Hz, Jb¢,b = 3.3 Hz, 1 H,
Hb), 6.31 (dd, Ja,b¢ = 0.8 Hz, Jb¢,b = 3.2 Hz, 1 H, Hb¢*), 6.34 (dd,
Ja,b = 1.6 Hz, Jb¢,b = 3.2 Hz, 1 H, Hb*), 7.02 (dd, Jmeta,ortho = 7.3 Hz,
Jpara,ortho = 1.0 Hz, 2 H, Hortho), 7.24–7.15 (m, 3 H, Hpara, Hmeta), 7.23
Anal. Calcd for C25H21NO3: C, 78.31; H, 5.52; N, 3.65. Found: C,
78.21; H, 5.78; N, 3.75.
(2R*,3S*,5R*,6S*)-2,6-Di-2-furyl-3,5-dimethylpiperidin-4-one
(2g)
Yield: 66%; mp 73.5–74.5 °C (Lit.11b 57 °C).
IR: 3315 (NH), 1705 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 0.91 (d, JMe,3(Me,5) = 6.6 Hz, 6 H,
3-CH3, 5-CH3), 2.27 (br s, 1 H, NH), 2.95 (dq, J2,3(5,6) = 10.8 Hz,
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

4244
F. I. Zubkov et al.
PAPER
(2R*,3R*,5R*,6S*)-2,6-Di-2-furyl-3,5-dimethylpiperidine (4)
(dd, Jb¢,a = 0.8 Hz, Ja,b = 1.8 Hz, 1 H, Ha), 7.40 (dd, Jb¢,a = 0.8 Hz,
Ja,b = 1.8 Hz, 1 H, Ha*).
MS (EI, 70 eV): m/z (%) = 335 (12) [M]+, 240 (3), 216 (4), 198 (2),
185 (40), 174 (44), 170 (20), 150 (7), 141 (12), 123 (6), 122 (100),
118 (16), 107 (15), 96 (9), 91 (7), 81 (6), 79 (6).
A mixture of 2g (8.0 g, 30.9 mmol), ethylene glycol (90 mL), and
hydrazine hydrate (7.8 mL, 0.15 mol) was boiled for 3 h (TLC mon-
itoring). The mixture was cooled and powdered KOH (10.4 g, 0.18
mmol) was added. Then the mixture was refluxed for ~3 h. When
the evolution of gas had ceased, the mixture was cooled, poured into
H2O (350 mL), and extracted with EtOAc (5 × 70 mL). The com-
bined organic extracts were washed with H2O (2 × 80 mL), dried
(MgSO4), and concentrated. The residue, viscous brown oil, was
purified by column chromatography (alumina, hexane–EtOAc,
15:1). The first fraction crystallized on standing to give crude 4 as a
yellow solid. Further crystallization (hexane with charcoal) gave 4
as big transparent crystals; yield: 3.9 g (50%); mp 72–73 °C.
Anal. Calcd for C21H21NO3: C, 75.20; H, 6.31; N, 4.18. Found: C,
75.35; H, 6.37; N, 3.99.
(2S*,3R*,6R*)-3-Methyl-2,6-bis(5-methyl-2-furyl)piperidin-4-
one (2k)
Yield: 27%; mp 70–72 °C.
IR: 3306 (NH), 1712 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 0.92 (d, J3,Me = 6.5 Hz, 3 H, 3-
CH3), 2.25 (br s, 3 H, furyl-CH3), 2.27 (br s, 3 H, furyl-CH3*), 2.28
(br s, 1 H, NH), 2.69 (dd, J5B,6 = 2.6 Hz, J5B,5A = 13.7 Hz, 1 H, H5B),
2.83 (dq, J3,2 = 10.7 Hz, J3,Me = 6.5 Hz, 1 H, H3), 2.82 (dd,
J5A,6 = 12.1 Hz, J5A,5B = 13.7 Hz, 1 H, H5A), 3.70 (d, J2,3 = 10.7 Hz,
1 H, H2), 4.08 (dd, J6,5B = 2.6 Hz, J6,5A = 12.1 Hz, 1 H, H6), 5.89
(m, 2 H, Hb, Hb*), 6.07 (br d, Jb¢,b = 2.9 Hz, 1 H, Hb¢), 6.14 (br d,
Jb¢,b = 2.9 Hz, 1 H, Hb¢*).
IR: 3307 cm–1 (NH).
1H NMR (CDCl3, 400 MHz): d = 0.75 (d, J5,Me = 6.8 Hz, 3 H, 5-
CH3), 0.94 (d, J3,Me = 6.8 Hz, 3 H, 3-CH3), 1.53 [br dt, J5(e),4(a) = 4.6
Hz, 2J4,4 = J3(a),4(a) = 13.1, Hz, 1 H, H4(a)], 1.79 [ddd, J3(a),4(e) = 2.6
2
Hz, J5(e),4(e) = 3.8 Hz, J4,4 = 13.1 Hz, 1 H, H4(e)], 1.82 (br s, 1 H,
NH), 2.05 [dddq, J3(a),4(e) = 2.6 Hz, J3,Me = 6.8 Hz, J3(a),2(a) = 10.5 Hz,
J3(a),4(a) = 13.1 Hz, 1 H, H3(a)], 2.20 (dddq, J5(e),6(a) = 2.7 Hz,
J5(e),4(e) = 3.8 Hz, J5(e),4(a) = 4.6 Hz, J5,Me = 6.8 Hz, 1 H, H5(e)], 3.44
[d, J2(a),3(a) = 10.5 Hz, 1 H, H2(a)], 4.07 [d, J6(a),5(e) = 2.7 Hz, 1 H,
H6(a)], 6.12 (br dd, Ja,b¢ = 0.7 Hz, Jb¢,b = 3.2 Hz, 1 H, Hb¢*), 6.23
(dd, Ja,b¢ = 0.6 Hz, Jb¢,b = 3.2 Hz, 1 H, Hb¢), 6.29 (dd, Ja,b = 1.8 Hz,
Jb¢,b = 3.2 Hz, 1 H, Hb), 6.31 (dd, Ja,b = 1.8 Hz, Jb¢,b = 3.2 Hz, 1 H,
Hb*), 7.30 (br dd, Jb¢,a = 0.7 Hz, Ja,b = 1.8 Hz, 1 H, Ha*), 7.35 (dd,
Jb¢,a = 0.6 Hz, Ja,b = 1.8 Hz, 1 H, Ha).
13C NMR (100.6 MHz, CDCl3): d = 13.1 and 18.9 (3-CH3, 5-CH3),
32.2 and 29.7 (C3, C5), 40.8 (C4), 59.0 and 62.8 (C2, C6), 104.8 and
106.5 (Cb¢, Cb¢*), 110.0 (2C, Cb, Cb*), 141.5 and 140.9 (Ca, Ca*),
156.7 and 156.4 (furyl-Cq, furyl-Cq*).
MS (EI, 70 eV): m/z (%) = 256 (14), [M]+, 214 (10), 213 (5), 171
(8), 107 (9), 91 (25), 77 (47), 53 (22, 43 (100).
Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.19; H, 6.87; N, 5.09.
(2R*,3S*,5R*,6S*)-3,5-Dimethyl-2,6-bis(5-methyl-2-furyl)pipe-
ridin-4-one (2l)
Yield: 41%; mp 85–86 °C.
IR: 3282 (NH), 1704 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 0.92 (d, JMe,3(Me,5) = 6.5 Hz, 6 H,
3-CH3, 5-CH3), 2.27 (d, JMe,b¢ = 0.6 Hz, 6 H, furyl-CH3, furyl-
CH3*), 2.75 (br s, 1 H, NH), 2.90 (dq, J3,2(5,6) = 10.8 Hz,
JMe,3(Me,5) = 6.5 Hz, 2 H, H3, H5), 3.66 (d, J3,2(5,6) = 10.8 Hz, 2 H,
H2, H6), 5.88 (dq, JMe,b¢ = 0.6 Hz, Jb¢,b = 3.0 Hz, 2 H, Hb¢, Hb¢*),
6.12 (br d, Jb¢,b = 3.0 Hz, 2 H, Hb, Hb*).
MS (EI, 70 eV): m/z (%) = 245 (39) [M]+, 230 (2), 216 (9), 202 (3),
175 (11), 146 (10), 137 (21), 136 (21), 124 (39), 122 (13), 108 (54),
96 (21), 95 (43), 94 (63), 81 (55), 79 (57), 77 (32), 68 (19), 55 (100).
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C,
73.16; N, 5.92; H, 7.39.
MS (EI, 70 eV): m/z (%) = 287 (35) [M]+, 244 (5), 202 (20), 150
(40), 137 (13), 122 (100), 110 (20), 101 (8), 79 (7), 77 (6), 43 (7).
(2R*,3S*,4S*,5R*,6S*)-2,6-Di-2-furyl-3,5-dimethylpiperidin-4-
ol (5)
Anal. Calcd for C17H21NO3: C, 71.06; H, 7.37; N, 4.87. Found: C,
70.98; H, 7.50; N, 4.75.
NaBH4 (0.76 g, 0.019 mmol) was added to a soln of 2g (5.0 g, 0.019
mmol) in MeOH (70 mL). The mixture was refluxed with vigorous-
ly stirring for 1 h. Then the resultant mixture was cooled, poured
into H2O (250 mL), and extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were dried (Na2SO4) and concentrated.
Further crystallization of the solid residue (hexane–EtOAc) gave
the 5 as white crystals; yield: 54%; mp 113–114 °C.
(2R*,3S*,5R*,6S*)-1-Acetyl-2,6-di-2-furyl-3,5-dimethylpiperi-
din-4-one (3)
A mixture of 2g (3.8 g, 1.5 mmol) in toluene (20 mL) and Ac2O (7.5
mL, 7.5 mmol) was refluxed at 110 °C for 2 h. Then the mixture was
cooled, poured into H2O (150 mL), and aq 25% NH3 soln was added
until pH 9–10. The organic products were extracted with EtOAc (3
× 70 mL). The combined organic extracts were dried (MgSO4), fil-
tered, and evaporated to give crude 3. Further crystallization (hex-
ane–EtOAc) gave 3 as large white crystals; yield: 76%; mp 70–76
°C.
IR: 3317 (br, OH), 3310 cm–1 (NH).
1H NMR (600 MHz, CDCl3): d = 0.86 (d, JMe,3(Me,5) = 6.9 Hz, 6 H,
3-CH3, 5-CH3), 1.59 and 1.83 (br s, 1 H + 1 H, OH, NH), 2.14 (ddq,
J3,4(4,5) = 2.5 Hz, JMe,3(Me,5) = 6.9 Hz, J2,3(5,6) = 10.7 Hz, 2 H, H3, H5),
3.87 (br t, J3,4(4,5) = 2.5 Hz, 1 H, H4), 4.02 (d, J2,3(5,6) = 10.7 Hz, 2 H,
H2, H6), 6.23 (dd, Ja,b¢ = 0.8 Hz, Jb¢,b = 3.2 Hz, 2 H, Hb¢), 6.30 (dd,
Ja,b = 1.8 Hz, Jb¢,b = 3.2 Hz, 2 H, Hb), 7.35 (dd, Jb¢,a = 0.8 Hz,
Ja,b = 1.8 Hz, 2 H, Ha).
MS (EI, 70 eV): m/z (%) = 261 (21) [M]+, 232 (3), 214 (1), 202 (2),
175 (8), 174 (12), 160 (10), 152 (12), 146 (6), 136 (11), 124 (10),
108 (36), 96 (100), 94 (27), 81 (35), 79 (45), 77 (24), 57 (23), 41
(55).
IR: (KBr): 1646 (NAc), 1711 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.26 (d, JMe,3(Me,5) = 7.0 Hz, 6 H,
3-CH3, 5-CH3), 2.19 (br s, 3 H, NAc), 3.26 (dq, JMe,3(Me,5) = 7.0 Hz,
J2,3(6,5) = 6.5 Hz, 2 H, H3, H5), ~5.3 (very br s, 2 H, H2, H6), 6.09
(br s, 2 H, Hb¢, Hb¢*), 6.29 (dd, Ja,b = 1.8 Hz, Jb¢,b = 3.2 Hz, 2 H, Hb,
Hb*), 7.26 (dd, Jb¢,a = 0.8 Hz, Ja,b = 1.8 Hz, 2 H, Ha, Ha*).
MS (EI, 70 eV): m/z (%) = 301 (8) [M]+, 258 (1), 242 (100), 220 (3),
165 (52), 150 (24), 123 (42), 108 (38), 79 (18), 77 (10), 43 (12).
Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C,
69.13; H, 7.51; N, 5.47.
Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C,
67.78; H, 6.25; N, 4.56.
Piperidinols 6a,b; General Procedure
A soln of 2g (6.0 g, 23 mmol) in anhyd Et2O (70 mL) was added
dropwise at reflux to a stirred soln of MeMgI [prepared from MeI
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

PAPER
IMDAF of Maleic Anhydride with 2,6-Difurylpiperidin-4-ones
4245
(4.7 mL, 75 mmol) and Mg turnings (2.3 g, 94 mmol) in anhyd Et2O
(100 mL)] (for 6a) or to a soln of PhLi [prepared from PhBr (12 mL,
0.115 mol) and Li wire (1.6 g, 0.23 mol) in anhyd Et2O (150 mL)]
(for 6b). After the addition of 2g, the mixture was stirred at reflux
for 1–2 h. Then the cooled mixture was poured into sat. aq NH4Cl
soln (100 mL) under ice cooling. The mixture was extracted with
Et2O (3 × 100 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated. Further crystallization of the
solid products (hexane–EtOAc) gave 6a,b as white needles.
Jb¢,b = 3.2 Hz, 1 H, Hb¢), 6.25 (dd, Ja,b = 1.8 Hz, Jb¢,b = 3.2 Hz, 1 H,
Hb), 6.27 (dd, Ja,b = 1.8 Hz, Jb¢,b = 3.2 Hz, 1 H, Hb*), 7.29 (dd,
Jb¢,a = 0.7 Hz, Ja,b = 1.8 Hz, 1 H, Ha*), 7.31 (dd, Jb¢,a = 0.8 Hz,
Ja,b = 1.8 Hz, 1 H, Ha).
MS (EI, 70 eV): m/z (%) = 257 (6) [M]+, 242 (7), 176 (5), 162 (100),
147 (64), 133 (11), 119 (26), 91 (10).
Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C,
74.99; H, 7.61; N, 5.40.
2,6-Di-2-furyl-3,4,5-trimethylpyridine (8)
(2R*,3S*,4S*,5R*,6S*)-2,6-Di-2-furyl-3,4,5-trimethylpiperidin-
Sulfur powder (1.2 g, 36.3 mmol) was added to a soln of 6a (1.0 g,
3.70 mmol) in DMF (25 mL). The resultant mixture was refluxed
for 8 h (TLC monitoring). Then the mixture was cooled, poured into
H2O (250 mL), and extracted with EtOAc (4 × 80 mL). The com-
bined organic layers were dried (MgSO4), concentrated, and puri-
fied by column chromatography (alumina, EtOAc–hexane, 1:10) to
give 8 as yellow needles; yield: 0.68 g (74%); mp 120 °C.
1H NMR (400 MHz, CDCl3): d = 2.33 (s, 3 H, 4-CH3), 2.47 (s, 6 H,
3-CH3, 5-CH3), 6.51 (dd, Ja,b = 1.7 Hz, Jb¢,b = 3.3 Hz, 2 H, Hb), 6.83
(dd, Ja,b¢ = 0.8 Hz, Jb¢,b = 3.3 Hz, 2 H, Hb¢), 7.55 (dd, Jb¢,a = 0.8 Hz,
Ja,b = 1.7 Hz, 2 H, Ha).
4-ol (6a)
Yield: 72%; mp 88–90 °C.
IR: 3310–3956 (br, OH), 2983 cm–1 (NH).
1H NMR (600 MHz, CDCl3): d = 0.80 (d, JMe,3(Me,5) = 6.8 Hz, 6 H,
3-CH3, 5-CH3), 1.31 (s, 3 H, 4-CH3), 1.96 (br s, 2 H, NH, OH), 1.98
(dq, JMe,3(Me,5) = 6.8 Hz, J2,3(5,6) = 10.7 Hz, 2 H, H3, H5), 3.96 (d,
J2,3(5,6) = 10.7 Hz, 2 H, H2, H6), 6.23 (dd, Ja,b¢ = 0.8 Hz, Jb¢,b = 3.1
Hz, 2 H, Hb¢), 6.29 (dd, Ja,b = 1.8 Hz, Jb¢,b = 3.1 Hz, 2 H, Hb), 7.34
(dd, Jb¢,a = 0.8 Hz, Ja,b = 1.8 Hz, 2 H, Ha).
13C NMR (150.9 MHz, CDCl3): d = 11.1 (3-CH3, 5-CH3), 25.4 (4-
CH3), 44.2 (C3, C5), 56.6 (C2, C6), 72.8 (C4), 107.1 and 109.9 (Cb,
Cb¢), 141.5 (Ca), 156.0 (furyl-Cq).
MS (EI, 70 eV): m/z (%) = 253 (100) [M]+, 224 (40), 198 (25), 181
(20), 167 (3), 127 (4), 115 (9), 91 (5), 77 (7).
MS (EI, 70 eV): m/z (%) = 275 (20) [M]+, 258 (1), 176 (5), 175 (5),
174 (13), 166 (7), 160 (40), 146 (4), 136 (11), 108 (30), 96 (100), 79
(27), 43 (66), 39 (31).
Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C,
75.80; H, 6.08; N, 5.69.
Anal. Calcd for C16H21NO3: C, 69.79; H, 7.44; N, 7.69. Found: C,
69.61; H, 7.48; N, 7.72.
Adducts 9a–h,k,l, 9i,j, 9i¢,j¢, and 10; Typical Procedure
A mixture of 2a–l or 4 (10 mmol) in benzene (25 mL), acryloyl
chloride (1.3 mL, 15 mmol), and Et3N (2.5 mL, 20 mmol) was re-
fluxed for 6 h (TLC monitoring). The mixture was then poured into
H2O (100 mL) and aq 5% HCl soln was added until pH ~6 and it was
extracted with EtOAc (3 × 80 mL). The combined organic layers
were dried (MgSO4) and concentrated to give crude products. Fur-
ther crystallization (hexane–EtOAc) gave 9a–h,k,l and mixtures of
regioisomers 9i/9i¢ and 9j/9j¢ as white needles. The mixtures of re-
gioisomers 9i/9i¢ and 9j/9j¢ were separated using column chroma-
tography (alumina, hexane–EtOAc, 5:1) or fractional crystallization
(hexane–EtOAc). For adducts 9i and 9i¢ monocrystals were ob-
tained by the slow crystallization (Et2O–heptane–EtOAc).
(2R*,3S*,4S*,5R*,6S*)-2,6-Di-2-furyl-3,5-dimethyl-4-phenyl-
piperidin-4-ol (6b)
Yield: 29%; mp 80–83 °C.
IR: 3599 (OH), 2973 cm–1 (NH).
1H NMR (400 MHz, CDCl3): d = 0.44 (d, JMe,3(Me,5) = 6.8 Hz, 6 H,
3-CH3, 5-CH3), 1.92 (br s, 1 H, NH or OH), 2.46 (dq, JMe,3(Me,5) = 6.8
Hz, J2,3(5,6) = 10.6 Hz, 2 H, H3, H5), 4.15 (d, J2,3(5,6) = 10.6 Hz, 2 H,
H2, H6), 6.24 (dd, Ja,b¢ = 0.6 Hz, Jb¢,b = 3.1 Hz, 2 H, Hb¢), 6.28 (dd,
Ja,b = 1.8 Hz, Jb¢,b = 3.1 Hz, 2 H, Hb), 7.24 (br t, Jortho,para = 7.3 Hz,
1 H, Hpara Ph), 7.34 (dd, Jb¢,a = 0.6 Hz, Ja,b = 1.8 Hz, 2 H, Ha), 7.38–
7.36 (m, 4 H, Hortho, Hmeta Ph).
MS (EI, 70 eV): m/z (%) = 337 (10) [M]+, 319 (1), 304 (2), 228 (5),
202 (3), 177 (5), 160 (100), 136 (18), 108 (21), 105 (40), 96 (98), 77
(18), 44 (7).
(1R*,4R*,6aR*,8S*,10aS*,10bS*)-4-(2-Furyl)-1-methyl-
1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-a]isoin-
dole-2,6(8H)-dione (9a)
Yield: 67%; mp 146 °C.
IR: 1729 (C=O), 1696 cm–1 (N–C=O).
Anal. Calcd for C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C,
74.52; H, 6.97; N, 4.19.
1H NMR (400 MHz, CDCl3): d = 1.14 (d, J1,1-CH3 = 7.0 Hz, 3 H, 1-
CH3), 1.62 (dd, J7endo,6a = 8.8 Hz, J7endo,7exo = 11.9 Hz, 1 H, H7endo),
2.21 (ddd, J7exo,6a = 3.5 Hz, J7exo,8 = 4.5 Hz, J7exo,7endo = 11.9 Hz, 1 H,
H7exo), 2.54 (dd, J6a,7exo = 3.5 Hz, J6a,7endo = 8.8 Hz, 1 H, H6a), 2.90
(dd, J3A,4 = 5.7 Hz, 2J3,3 = 17.0 Hz, 1 H, H3A), 2.93 (dd, J3B,4 = 2.6
(2R*,3R*,6S*)-2,6-Di-2-furyl-3,4,5-trimethyl-1,2,5,6-tetrahy-
dropyridine (7)
A mixture of 6a (2.5 g, 9.73 mmol), anhyd p-TsOH (1.0 g, 5.8
mmol) and anhyd oxalic acid (8.76 g, 0.10 mol) was heated at 160–
165 °C for 30 min. Then the mixture was cooled, dissolved in H2O
(150 mL), neutralized with aq 25% NH3 soln, and extracted with
Et2O (3 × 100 mL). The combined organic extracts were washed
with 10% aq NH3 soln (2 × 70 mL), dried (MgSO4), and concentrat-
ed. The residue, a deep-brown oil, was purified by column chroma-
tography (alumina, hexane, then Et2O) to give 7 as pale-yellow
viscous oil; yield: 40%; Rf = 0.72 (hexane–EtOAc, 1:2).
Hz, 2J3,3 = 17.0 Hz, 1 H, H3B), 2.97 (dq, J1,10b = 12.0 Hz, J1,1-CH3
=
7.0 Hz, 1 H, H1), 4.34 (d, J10b,1 = 12.0 Hz, 1 H, H10b), 5.11 (dd,
J8,9 = 0.8 Hz, J8,7exo = 4.5 Hz, 1 H, H8), 5.34 (dd, J4,3B = 2.6 Hz,
J4,3A = 5.7 Hz, 1 H, H4), 6.22 (dd, J4¢,5¢ = 1.8 Hz, J4¢,3¢ = 3.2 Hz, 1 H,
H4¢), 6.24 (dd, J3¢,5¢ = 0.7 Hz, J3¢,4¢ = 3.2 Hz, 1 H, H3¢), 6.38 (br s, 2
H, H10, H9), 7.25 (dd, J5¢,3¢ = 0.7 Hz, J5¢,4¢ = 1.8 Hz, 1 H, H5¢).
13C NMR (100.6 MHz, CDCl3): d = 208.1 (C2), 173.6 (C6), 152.4
(d, C2¢), 142.2 (C5¢), 136.8 and 132.9 (C9, C10), 110.4 and 107.5 (C3¢,
C4¢), 90.6 (C10a), 78.8 (C8), 59.3 (C6a), 47.9, 46.2, 44.5 (C1, C4, C10b),
41.8 (C3), 28.4 (C7), 10.2 (1-CH3).
IR: 3546 (NH), 1633 cm–1 (C=C).
1H NMR (400 MHz, CDCl3): d = 0.97 (d, JMe,5 = 6.8 Hz, 3 H, 5-
CH3), 1.41 (d, 4J5,Me = 1.0 Hz, 3 H, 4-CH3), 1.70 (d, 4J2,Me = 1.0 Hz,
3 H, 3-CH3), 1.95 (dq, JMe,5 = 6.8 Hz, J5,6 = 9.5 Hz, 1 H, H5), 2.58
(br t, 1 H, NH), 3.65 (d, J5,6 = 9.5 Hz, 1 H, H6), 4.56 (br s, 1 H, H2),
6.16 (dd, Ja,b¢ = 0.7 Hz, Jb¢,b = 3.2 Hz, 1 H, Hb¢*), 6.20 (br d,
MS (EI, 70 eV): m/z (%) = 299 (10) [M]+, 271 (3), 228 (11), 200 (2),
190 (8), 177 (8), 162 (23), 148 (11), 135 (23), 121 (12), 108 (43), 94
(74), 79 (36), 66 (54), 65 (50), 55 (100), 39 (78).
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

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F. I. Zubkov et al.
PAPER
Anal. Calcd for C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C,
68.32; H, 5.62; N, 4.58.
1H NMR (400 MHz, CDCl3): d = 0.98 [d, JCH,Me(A) = 7.0 Hz, 3 H,
CH(CH3)A(CH3)B], 1.19 [d, JCH,Me(B) = 7.0 Hz,
3
H,
CH(CH3)A(CH3)B], 1.61 (dd, J7endo,6a = 9.0 Hz, J7endo,7exo = 11.6 Hz,
1 H, H7endo), 2.05 [m, 1 H, CH(CH3)2], 2.20 (dt, J7exo,6a = J7exo,8 = 3.5
Hz, J7exo,7endo = 11.6 Hz, 1 H, H7exo), 2.53 (dd, J6a,7exo = 3.5 Hz,
J6a,7endo = 9.0 Hz, 1 H, H6a), 2.81 (dd, J1,1¢ = 1.9 Hz, J1,10b = 11.9 Hz,
1 H, H1), 2.86 (dd, J3A,4 = 2.4 Hz, 2J3,3 = 16.0 Hz, 1 H, H3A), 2.92
(dd, J3B,4 = 5.7 Hz, 2J3,3 = 16.0 Hz, 1 H, H3B), 4.64 (d, J10b,1 = 11.9
Hz, 1 H, H10b), 5.11 (dd, J8,7exo = 3.5 Hz, J8,9 = 1.3 Hz, 1 H, H8),
5.29 (dd, J4,3A = 2.4 Hz, J4,3B = 5.7 Hz, 1 H, H4), 6.20–6.22 (m, 2 H,
H3¢, H4¢), 6.36 (dd, J9,8 = 1.3 Hz, J9,10 = 5.7 Hz, 1 H, H9), 6.40 (d,
J9,10 = 5.7 Hz, 1 H, H10), 7.26 (br s, 1 H, H5¢).
13C NMR (100.6 MHz, CDCl3): d = 207.9 (C2), 173.8 (C6), 152.9
(C2¢), 142.5 (C5¢), 136.7 (C9), 133.3 (C10), 110.6 (C4¢), 107.5 (C3¢),
90.7 (C10a), 79.0 (C8), 57.1 (C10b), 54.1 (C1), 48.4 (C6a), 46.8 (C4),
44.4 (C3), 28.7 (C7), 27.3 [CH(CH3)2], 22.4 and 17.3 [CH(CH3)2].
(1R*,4R*,6aR*,8S*,10aS*,10bS*)-1-Ethyl-4-(2-furyl)-
1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-a]isoin-
dole-2,6(8H)-dione (9b)
Yield: 63%; mp 169 °C.
IR: 1725 (C=O), 1691 cm–1 (N–C=O).
1H NMR (400 MHz, CDCl3): d = 0.94 (t, JCH2,Me = 7.5 Hz, 3 H,
2
CH2CH3), 1.58 (m, JCH2,Me = 7.5 Hz, JCH2 = 14.4 Hz, J1,CH2A = 5.6
Hz, J1,CH2B = 3.9 Hz, 2 H, CH2CH3), 1.62 (dd, J7endo,6a = 8.9 Hz,
J7endo,7exo = 11.8 Hz, 1 H, H7endo), 2.21 (ddd, J7exo,6a = 3.8 Hz,
J7exo,8 = 4.5 Hz, J7exo,7endo = 11.8 Hz, 1 H, H7exo), 2.55 (dd,
J6a,7exo = 3.8 Hz, J6a,7endo = 8.9 Hz, 1 H, H6a), 2.90 (dd, J3B,4 = 2.1
Hz, 2J3,3 = 16.9 Hz, 1 H, H3B), 2.98 (dd, J3A,4 = 6.1 Hz, 2J3,3 = 16.9
Hz, 1 H, H3A), 2.89 (ddd, J1,10b = 12.1 Hz, J1,CH2A = 5.6 Hz,
J1,CH2B = 3.9 Hz, 1 H, H1), 4.60 (d, J10b,1 = 12.1 Hz, 1 H, H10b),
5.12 (br d, J8,7exo = 4.5 Hz, 1 H, H8), 5.33 (dd, J4,3B = 2.1 Hz,
J4,3A = 6.1 Hz, 1 H, H4), 6.23 (s, 2 H, H3¢, H4¢), 6.41 (br s, 2 H, H9,
H10), 7.26 (s, 1 H, H5¢).
13C NMR (100.6 MHz, CDCl3): d = 207.9 (C2), 173.6 (C6), 152.5
(C2¢), 142.2 (C5¢), 136.9 and 132.6 (C9, C10), 110.3 and 107.4 (C3¢,
C4¢), 90.5 (C10a), 78.7 (C8), 56.4 (C6a), 49.7, 48.0, 46.3 (C10b, C1, C4),
43.0 (C3), 28.4 (C7), 18.3 (CH2CH3), 10.3 (CH2CH3).
MS (EI, 70 eV): m/z (%) = 327 (63) [M]+, 284 (32), 272 (4), 256
(69), 207 (10), 190 (48), 174 (7), 163 (38), 162 (40), 148 (11), 136
(100), 121 (79), 94 (80), 69 (10), 55 (37).
Anal. Calcd for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C,
69.66; H, 6.78; N, 4.23.
(1R*,4R*,6aR*,8S*,10aS*,10bS*)-1-Allyl-4-(2-furyl)-
1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-a]isoin-
dole-2,6(8H)-dione (9e)
Yield: 45%; mp 106 °C.
IR: 1693 (N–C=O), 1719 cm–1 (C=O).
MS (EI, 70 eV): m/z (%) = 313 (7) [M]+, 284 (2), 242 (11), 190 (3),
174 (5), 163 (10), 162 (16), 148 (7), 135 (10), 122 (32), 107 (18), 94
(63), 77 (20), 66 (40), 65 (34), 55 (100), 39 (55).
Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C,
68.89; H, 6.23; N, 4.56.
1H NMR (400 MHz, CDCl3): d = 1.61 (dd, J7endo,6a = 9.0 Hz,
J7endo,7exo = 11.4 Hz, 1 H, H7endo), 2.18 (ddd, J7exo,6a = 3.0 Hz,
J7exo,8 = 4.5 Hz, J7exo,7endo = 11.4 Hz, 1 H, H7exo), 2.24 (m, 1 H,
CHAHBCH=CH2), 2.53 (dd, J6a,7exo = 3.0 Hz, J6a,7endo = 9.0 Hz, 1 H,
H6a), 2.84 (dd, J3A,4 = 6.2 Hz, 2J3,3 = 16.3 Hz, 1 H, H3A), 2.87 (m,
1 H, H1), 2.97 (dd, J3B,4 = 1.5 Hz, 2J3,3 = 16.3 Hz, 1 H, H3B), 3.99
(m, 1 H, CHAHBCH=CH2), 4.59 (d, J10b,1 = 12.0 Hz, 1 H, H10b),
5.09–5.13 (m, 2 H, CH=CH2), 5.13 (br d, J8,7exo = 4.5 Hz, 1 H, H8),
5.32 (br d, J4,3B = 1.5 Hz, J4,3A = 6.2 Hz, 1 H, H4), 5.69 (ddt,
(1R*,4R*,6aR*,8S*,10aS*,10bS*)-4-(2-Furyl)-1-propyl-
1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-a]isoin-
dole-2,6(8H)-dione (9c)
Yield: 45%; mp 183 °C.
IR: 1718 (C=O), 1692 cm–1 (N–C=O).
1H NMR (600 MHz, CDCl3): d = 0.86 (t, JCH2,Me = 7.3 Hz, 3 H,
CH2CH3), 1.26 (m, 1 H, CHAHBCH3), 1.42 (m, 1 H, CHAHBCH3),
1.53 (m, 1 H, CHAHBCH2CH3), 1.59 (dd, J7endo,6a = 8.7 Hz,
J7endo,7exo = 11.8 Hz, 1 H, H7endo), 1.73 (m, 1 H, CHAHBCH2CH3),
2.19 (ddd, J7exo,6a = 3.2 Hz, J7exo,8 = 4.4 Hz, J7exo,7endo = 11.8 Hz, 1 H,
H7exo), 2.53 (dd, J6a,7exo = 3.2 Hz, J6a,7endo = 8.7 Hz, 1 H, H6a), 2.87
J2¢,1¢ = 5.4 Hz, J2¢,3¢cis = 9.4 Hz, J2¢,3¢trans = 16.8 Hz, 1 H, CH=CH2),
6.22 (br s, 2 H, H3¢, H4¢), 6.39 (dd, J10,9 = 6.0 Hz, J8,9 = 1.3 Hz, 1 H,
H9), 6.40 (d, J9,10 = 6.0 Hz, 1 H, H10), 7.25 (br s, 1 H, H5¢).
13C NMR (100.6 MHz, CDCl3): d = 207.1 (C2), 173.5 (C6), 152.4
(C2¢), 142.2 (C5¢), 136.6, 133.9, 132.8 (C9, C10, CH2CH=CH2), 118.5
(CH2CH=CH2), 110.3 and 107.4 (C3¢, C4¢), 90.5 (C10a), 78.6 (C8),
56.2 (C6a), 48.6, 47.9, 46.3 (C1, C4, C10b), 43.0 (C3), 29.7
(CH2CH=CH2), 28.3 (C7).
MS (EI, 70 eV): m/z (%) = 325 (3) [M]+, 283 (3), 270 (1), 254 (5),
213 (1), 190 (3), 174 (3), 162 (7), 148 (3), 134 (13), 121 (24), 107
(7), 94 (58), 81 (15), 77 (17), 66 (44), 55 (100), 39 (55).
2
(m, 1 H, H1), 2.89 (dd, J3B,4 = 6.0 Hz, J3,3 = 16.7 Hz, 1 H, H3B),
2
2.96 (dd, J3A,4 = 2.0 Hz, J3,3 = 16.7 Hz, 1 H, H3A), 4.54 (d,
J10b,1 = 12.1 Hz, 1 H, H10b), 5.10 (d, J8,7exo = 4.4 Hz, 1 H, H8), 5.31
(dd, J4,3A = 2.0 Hz, J4,3B = 6.0 Hz, 1 H, H4), 6.21 (s, 2 H, H3¢, H4¢),
6.38 (br s, 2 H, H9, H10), 7.24 (s, 1 H, H5¢).
13C NMR (100.6 MHz, CDCl3): d = 207.9 (C2), 173.6 (C6), 152.5
(C2¢), 142.2 (C5¢), 136.9 and 132.6 (C9, C10), 110.3 and 107.4 (C3¢,
C4¢), 90.5 (C10a), 78.7 (C8), 57.1 (C6a), 49.0, 48.0, 46.3 (C10b, C1, C4),
42.7 (C3), 28.4 and 27.6 (C7, CH2CH2CH3), 19.5 (CH2CH2CH3),
14.4 (CH2CH2CH3).
Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C,
70.24; H, 5.98; N, 4.32.
(1R*,3S*,4R*,6aR*,8S*,10aS*,10bS*)-4-(2-Furyl)-1,3-diphe-
nyl-1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-
a]isoindole-2,6(8H)-dione (9f)
Yield: 45%; mp 116 °C.
IR: 1699 cm–1 (br, N–C=O, C=O).
1H NMR (600 MHz, CDCl3): d = 1.54 (dd, J7,6a = 8.8 Hz,
J7endo,7exo = 11.8 Hz, 1 H, H7endo), 2.21 (ddd, J7exo,6a = 3.4 Hz,
J8,7exo = 4.5 Hz, J7endo,7exo = 11.8 Hz, 1 H, H7exo), 2.45 (dd,
J7endo,6a = 8.8 Hz, J6a,7exo = 3.4 Hz, 1 H, H6a), 4.18 (d, J10b,1 = 12.2
Hz, 1 H, H10b), 4.40 (br s, 1 H, H3), 4.45 (d, J10b,1 = 12.2 Hz, 1 H,
H1), 5.05 (dd, J8,9 = 1.6 Hz, J8,7 = 4.5 Hz, 1 H, H8), 5.35 (d,
J9,10 = 5.8 Hz, 1 H, H10), 5.93 (br s, 1 H, H4), 6.00 (dd, J8,9 = 1.6
Hz, J9,10 = 5.8 Hz, 1 H, H9), 6.29 (dd, J3¢,4¢ = 3.2 Hz, J5¢,4¢ = 1.8 Hz,
MS (EI, 70 eV): m/z (%) = 327 (10) [M]+, 299 (1), 256 (11), 190 (2),
176 (3), 163 (13), 148 (7), 136 (16), 107 (19), 94 (61), 77 (18), 66
(36), 55 (100).
Anal. Calcd for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C,
69.81; H, 6.67; N, 4.38.
(1R*,4R*,6aR*,8S*,10aS*,10bS*)-4-(2-Furyl)-1-isopropyl-
1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-a]isoin-
dole-2,6(8H)-dione (9d)
Yield: 55%; mp 226 °C.
IR: 1720 (C=O), 1689 cm–1 (N–C=O).
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

PAPER
IMDAF of Maleic Anhydride with 2,6-Difurylpiperidin-4-ones
4247
1 H, H4¢), 6.45 (br dd, J3¢,4¢ = 3.2 Hz, J5¢,3¢ = 0.7 Hz, 1 H, H3¢), 6.75
(dd, Jortho,para = 0.9 Hz, Jortho,meta = 7.5 Hz, 2 H, Hortho Ph), 7.13–7.18
(m, 3 H, HPh), 7.33 (dd, J4¢,5¢ = 1.8 Hz, J3¢,5¢ = 0.7 Hz, 1 H, H5¢), 7.41
(br t, Jpara,meta = 7.5 Hz, 1 H, Hpara Ph), 7.48 (br t, J = 7.5 Hz, 2 H,
HPh), 7.53 (br d, J = 7.5 Hz, 2 H, HPh).
13C NMR (100.6 MHz, CDCl3): d = 205.2 (C2), 174.1 (C6), 151.9
(C2¢), 142.6 (C5¢), 135.3 and 132.1 (C9, C10), 129. 6 and 129.5 (4 C,
H10), 6.41 (dd, J9,8 = 1.7 Hz, J10,9 = 6.0 Hz, 1 H, H9), 7.31 (br d,
5¢,4¢ = 1.9 Hz, 1 H, H5¢).
J
13C NMR (100.6 MHz, CDCl3): d = 207.3 (C2), 174.0 (C6), 171.4
and 170.5 (CO2Et), 151.5 (C2¢), 142.4 (C5¢), 137.7 and 132.3 (C9,
C10), 110.3 and 108.3 (C3¢, C4¢), 90.3 (C10a), 78.9 (C8), 61.2 and 60.9
(CO2CH2CH3), 56.4 (C4), 51.0, 48.4, 48.0, 45.8 (C1, C3, C6a, C10b),
34.7 and 29.5 (CH2CO2Et), 28.4 (C7), 14.19 and 14.18
(CO2CH2CH3).
MS (EI, 70 eV): m/z (%) = 457 (15) [M]+, 412 (11), 386 (23), 371
(25), 370 (100), 356 (12), 352 (17), 344 (20), 340 (11), 324 (20),
316 (15), 312 (37), 296 (10), 282 (11), 270 (40), 266 (15), 228 (17),
194 (60), 190 (34), 180 (23), 179 (15), 174 (13), 162 (18), 149 (25),
148 (17), 122 (31), 107 (61), 96 (20), 95 (15), 81 (12), 79 (14), 65
(11), 55 (66), 43 (38).
C
C
ortho-Ph), 128.4 and 127.1 (4 C, Cmeta-Ph), 128.2 and 127.6 (2 C,
para-Ph), 110.4 and 107.8 (C3¢, C4¢), 90.5 (C10a), 78.6 (C8), 56.4, 49.7,
48.0, 46.3, 43.0 (C10b, C1, C3, C4, C6a), 28.4 (C7).
MS (EI, 70 eV): m/z (%) = 437 (44) [M]+, 409 (7), 366 (16), 240
(11), 239 (29), 238 (7), 224 (14), 198 (10), 197 (19), 184 (10), 174
(12), 171 (28), 170 (100), 169 (49), 157 (13), 147 (19), 142 (61),
128 (10), 115 (23), 91 (11), 90 (12), 81 (12), 59 (16), 58 (11), 55
(39).
Anal. Calcd for C24H27NO8: C, 63.01; H, 5.95; N, 3.06. Found: C,
62.73; H, 5.72; N, 3.15.
Anal. Calcd for C28H23NO4: C, 76.87; N, 3.20; H, 5.30. Found: C,
76.96; N, 3.23; H, 5.31.
(1R*,3S*,4R*,6aR*,8S*,10aS*,10bS*)-4-(2-Furyl)-3-methyl-1-
phenyl-1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-
a]isoindole-2,6(8H)-dione (9i) and
(1R*,3S*,4R*,6aR*,8S*,10aS*,10bS*)-4-(2-Furyl)-1,3-dimeth-
yl-1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-a]isoin-
dole-2,6(8H)-dione (9g)
Yield: 82%; mp 116 °C.
IR: 1692 cm–1 (br, C=O, N–C=O).
1H NMR (400 MHz, CDCl3): d = 1.13 (d, J3,3-CH3 = 6.7 Hz, 3 H, 3-
CH3), 1.36 (d, J1,1-CH3 = 7.6 Hz, 3 H, 1-CH3), 1.63 (dd, J7endo,6a = 8.9
Hz, J7endo,7exo = 11.7 Hz, 1 H, H7endo), 2.24 (ddd, J7exo,6a = 3.8 Hz,
J7exo,8 = 4.3 Hz, J7exo,7endo = 11.7 Hz, 1 H, H7exo), 2.55 (dd,
J6a,7exo = 3.8 Hz, J6a,7endo = 8.9 Hz, 1 H, H6a), 2.93–3.09 (m, 2 H, H3,
H1), 4.28 (d, J10b,1 = 12.2 Hz, 1 H, H10b), 5.03 (br s, 1 H, H4), 5.14
(d, J8,7exo = 4.3 Hz, 1 H, H8), 6.22 (br d, J4¢,3¢ = 3.2 Hz, 1 H, H4¢),
6.26 (br d, J3¢,4¢ = 3.2 Hz, 1 H, H3¢), 6.39 (br s, 2 H, H10, H9), 7.25
(dd, J5¢,3¢ = 0.6 Hz, J5¢,4¢ = 1.6 Hz, 1 H, H5¢).
(1S*,3R*,4S*,6aS*,8R*,10aR*,10bR*)-4-(2-Furyl)-1-methyl-3-
phenyl-1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-
a]isoindole-2,6(8H)-dione (9i¢)
Total yield of isomers mixture: 77%; ratio 9i/9i¢ (isolated mixture)
1:4 (1H NMR).
Compound 9i
Yield: 11%; mp 161–163 °C (hexane–EtOAc).
IR: 1703 cm–1 (br, N–C=O, C=O).
1H NMR (600 MHz, CDCl3): d = 1.59 (dd, J7endo,6a = 8.8 Hz,
J7endo,7exo = 11.9 Hz, 1 H, H7endo), 1.61 (d, J3,3-CH3 = 7.7 Hz, 3 H, 3-
CH3), 2.24 (ddd, J7exo,6a = 3.4 Hz, J7exo,8 = 4.6 Hz, J7exo,7endo = 11.9
Hz, 1 H, H7exo), 2.52 (dd, J6a,7exo = 3.4 Hz, J6a,7endo = 8.8 Hz, 1 H,
H6a), 3.26 (dq, J3,4 = 2.0 Hz, J3,3-CH3 = 7.7 Hz, 1 H, H3), 4.17 (d,
J10b,1 = 12.3 Hz, 1 H, H10b), 4.82 (d, J10b,1 = 12.3 Hz, 1 H, H1), 5.11
(dd, J8,9 = 1.7 Hz, J8,7exo = 4.6 Hz, 1 H, H8), 5.19 (d, J4,3 = 2.0 Hz, 1
H, H4), 5.52 (d, J9,10 = 5.8 Hz, 1 H, H10), 6.08 (dd, J9,10 = 5.8 Hz,
J9,8 = 1.7 Hz, 1 H, H9), 6.31 (dd, J4¢,5¢ = 1.8 Hz, J4¢,3¢ = 3.3 Hz, 1 H,
H4¢), 6.42 (dd, J3¢,5¢ = 0.9 Hz, J3¢,4¢ = 3.3 Hz, 1 H, H3¢), 7.12–7.14
(m, 2 H, Hortho Ph), 7.30–7.35 (m, 3 H, Hpara, Hmeta Ph), 7.34 (dd,
13C NMR (100.6 MHz, CDCl3): d = 210.3 (C2), 174.3 (C6), 152.4
(C2¢), 141.9 (C5¢), 136.6 and 132.8 (C9, C10), 110.2 and 107.3 (C3¢,
C4¢), 90.9 (C10a), 78.7 (C8), 59.0 (C6a), 52.6, 47.8, 46.3, 43.8 (C10b
,
C1, C3, C4), 28.4 (C7), 17.3 and 10.1 (1-CH3, 3-CH3).
MS (EI, 70 eV): m/z (%) = 313 (9) [M]+, 298 (3), 285 (1), 242 (11),
214 (2), 177 (8), 162 (46), 148 (9), 135 (8), 122 (10), 108 (65), 94
(16), 79 (67), 66 (31), 55 (100), 39 (37).
J
5¢,3¢ = 0.9 Hz, J5¢,4¢ = 1.8 Hz, 1 H, H5¢).
Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C,
69.34; H, 6.25; N, 4.51.
13C NMR (100.6 MHz, CDCl3): d = 209.0 (C2), 174.7 (C6), 152.4
(d, C2¢), 142.3 (C5¢), 135.4 and 132.2 (C9, C10), 134.2 (Cipso-Ph), 130.0
(2 C, Cmeta-Ph), 128.6 (2 C, Cortho-Ph), 127.8 (Cpara-Ph), 110.4 and 107.5
(C3¢, C4¢), 90.9 (C10a), 78.8 (C8), 59.5, 55.7, 52.7, 47.9, 47.4 (C1, C3,
C4, C6a, C10b), 28.6 (C7), 17.2 (3-CH3).
MS (EI, 70 eV): m/z (%) = 375 (88) [M]+, 360 (2), 347 (6), 320 (4),
304 (38), 239 (29), 238 (11), 177 (12), 174 (25), 171 (13), 170 (84),
169 (12), 162 (21), 148 (29), 141 (24), 135 (11), 118 (31), 115 (12),
109 (10), 108 (100), 79 (12), 55 (37).
Diethyl 2,2¢-(1R*,3S*,4R*,6aR*,8S*,10aS*,10bS*)-2,2¢-[4-(2-
Furyl)-2,6-dioxo-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-epoxy-
pyrido[2,1-a]isoindole-1,3-diyl]diacetate (9h)
Yield: 86%; mp 132–133 °C.
IR: 1694 (N–C=O), 1730 cm–1 (C=O, CO2Et).
1H NMR (400 MHz, CDCl3): d = 1.25 (t, JCH2,Me = 7.4 Hz, 3 H, A-
CH2CH3), 1.27 (t, JCH2,Me = 7.4 Hz, 3 H, B-CH2CH3), 1.61 (dd,
J7endo,6a = 8.9 Hz, J7endo,7exo = 12.0 Hz, 1 H, H7endo), 2.23 (ddd,
J7exo,6a = 3.5 Hz, J7exo,8 = 4.6 Hz, J7exo,7endo = 12.0 Hz, 1 H, H7exo),
2.47 (dd, 2JCH2 = 17.7 Hz, J1,CH2A = 5.4 Hz, 1 H, 1-CHAHBCO2Et),
2.53 (dd, J6a,7exo = 3.5 Hz, J6a,7endo = 8.9 Hz, 1 H, H6a), 2.70 (dd,
2JCH2 = 16.8 Hz, J3,CH2A = 8.7 Hz, 1 H, 3-CHAHBCO2Et), 2.77 (dd,
2JCH2 = 16.8 Hz, J3,CH2B = 4.7 Hz, 1 H, 3-CHAHBCO2Et), 2.95 (dd,
2JCH2 = 17.7 Hz, J1,CH2B = 4.0 Hz, 1 H, 1-CHAHBCO2Et), 3.23 (ddd,
J1,CH2B = 4.0 Hz, J1,CH2A = 5.4 Hz, J10b,1 = 12.0 Hz, 1 H, H1), 3.51
(ddd, J3,CH2B = 4.7 Hz, J3,CH2A = 8.7 Hz, J3,4 = 2.8 Hz, 1 H, H3), 4.12
(q, JCH2,Me = 7.4 Hz, 2 H, CO2CH2CH3), 4.21–4.12 (m, 2 H,
CO2CH2CH3), 4.90 (d, J10b,1 = 12.0 Hz, 1 H, H10b), 5.12 (dd,
J8,9 = 1.3 Hz, J8,7exo = 4.7 Hz, 1 H, H8), 5.14 (br d, J4,3 = 2.8 Hz, 1
H, H4), 6.24 (dd, J4¢,5¢ = 1.9 Hz, J4¢,3¢ = 3.3 Hz, 1 H, H4¢), 6.29 (dd,
Anal. Calcd for C23H21NO4: C, 73.58; H, 5.64; N, 3.73. Found: C,
73.30; H, 5.53; N, 3.77.
Compound 9i¢
Yield: 27%; mp 187–188 °C.
IR: 1702 cm–1 (N–C=O, C=O).
1H NMR (600 MHz, CDCl3): d = 1.11 (dd, J4,1-CH3 = 0.3 Hz,
J1,1-CH3 = 7.0 Hz, 3 H, 1-CH3), 1.64 (dd, J7endo,6a = 8.7 Hz,
J7endo,7exo = 11.8 Hz, 1 H, H7endo), 2.27 (ddd, J7exo,6a = 3.7 Hz,
J7exo,8 = 4.6 Hz, J7exo,7endo = 11.8 Hz, 1 H, H7exo), 2.54 (dd,
J6a,7exo = 3.7 Hz, J6a,7endo = 8.7 Hz, 1 H, H6a), 3.04 (dq, J1,10b = 12.1
Hz, J1,1-CH3 = 7.0 Hz, 1 H, H1), 4.07 (J10b,1 = 12.1 Hz, 1 H, H10b),
4.28 (d, J4,3 = 0.8 Hz, 1 H, H3), 5.14 (dd, J8,9 = 1.4 Hz, J8,7exo = 4.5
4
J3¢,5¢ = 0.8 Hz, J3¢,4¢ = 3.3 Hz, 1 H, H3¢), 6.30 (d, J10,9 = 6.0 Hz, 1 H,
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

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F. I. Zubkov et al.
PAPER
Hz, 1 H, H8), 5.84 (d, J3,4 = 0.8 Hz, 1 H, H4), 6.27 (dd, J4¢,5¢ = 1.8
Hz, J4¢,3¢ = 3.2 Hz, 1 H, H4¢), 6.28 (dd, J9,10 = 6.0 Hz, 1 H, H10),
6.33 (br d, J3¢,4¢ = 3.2 Hz, 1 H, H3¢), 6.38 (dd, J8,9 = 1.4 Hz,
J9,10 = 6.0 Hz, 1 H, H9), 7.31 (dd, J5¢,3¢ = 0.8 Hz, J5¢,4¢ = 1.8 Hz, 1 H,
H5¢), 7.35 (m, 1 H, Hpara Ph), 7.39–7.43 (m, 4 H, Hortho, Hmeta Ph).
13C NMR (100.6 MHz, CDCl3): d = 207.4 (C2), 174.0 (C6), 152.0
(d, C2¢), 142.5 (C5¢), 136.9 and 132.7 (C9, C10), 134.4 (Cipso-Ph), 129.4
(2 C, Cmeta-Ph), 126.8 (2 C, Cortho-Ph), 127.9 (Cpara-Ph), 110.4 and 107.8
(C3¢, C4¢), 90.7 (C10a), 78.8 (C8), 58.3 and 55.9 (C1, C4), 49.4, 47.9,
44.3 (C3, C6a, C10b), 28.5 (C7), 11.5 (1-CH3).
MS (EI, 70 eV): m/z (%) = 375 (19) [M]+, 347 (5), 304 (4), 294 (2),
239 (6), 177 (5), 174 (16), 170 (62), 169 (30), 148 (24), 141 (83),
135 (19), 118 (38), 115 (57), 108 (100), 90 (53), 79 (76), 77 (51), 66
(62).
(dd, J4¢,5¢ = 1.5 Hz, J4¢,3¢ = 3.2 Hz, 1 H, H4¢), 7.27 (d, J9,10 = 5.8 Hz,
1 H, H10), 6.32 (br d, J3¢,4¢ = 3.2 Hz, 1 H, H3¢), 6.37 (dd, J9,10 = 5.8
Hz, J9,8 = 1.1 Hz, 1 H, H9), 7.42 (br d, J5¢,4¢ = 1.5 Hz, 1 H, H5¢),
7.30–7.44 (m, 5 H, HPh).
13C NMR (100.6 MHz, CDCl3): d = 206.6 (C2), 174.0 (C6), 154.0
(d, C2¢), 142.5 (C5¢), 136.9 and 132.5 (C9, C10), 133.3 (Cipso-Ph), 129.3
(2 C, Cmeta-Ph), 126.9 (2 C, Cortho-Ph), 127.9 (Cpara-Ph), 110.4 and 107.8
(C3¢, C4¢), 90.6 (C10a), 78.7 (C8), 56.2, 55.2, 49.7, 48.9, 48.0 (C1, C3,
C4, C6a, C10b), 28.5 (C7), 18.4 (1-CH2CH3), 9.9 (1-CH2CH3).
MS (EI, 70 eV): m/z (%) = 389 (86) [M]+, 360 (9), 318 (30), 298
(16), 266 (4), 244 (25), 239 (59), 238 (29), 224 (7), 211 (19), 191
(3), 174 (31), 170 (75), 169 (30), 149 (18), 148 (66), 141 (59), 122
(100), 118 (24), 115 (30), 107 (32), 91 (21), 77 (14), 55 (50).
Anal. Calcd for C24H23NO4: C, 74.02; H, 5.95; N, 3.60. Found: C,
73.83; H, 6.17; N, 3.51.
Anal. Calcd for C23H21NO4: C, 73.58; H, 5.64; N, 3.73. Found: C,
73.51; H, 5.58; N, 3.70.
(1R*,4R*,6aR*,8S*,10aS*,10bS*)-1,8-Dimethyl-4-(5-methyl-2-
furyl)-1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-
a]isoindole-2,6(8H)-dione (9k)
(1R*,3S*,4R*,6aR*,8S*,10aS*,10bS*)-3-Ethyl-4-(2-furyl)-1-
phenyl-1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-
a]isoindole-2,6(8H)-dione (9j) and
Yield: 57%; mp 206–207 °C.
(1S*,3R*,4S*,6aS*,8R*,10aR*,10bR*)-1-Ethyl-4-(2-furyl)-3-
phenyl-1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-
a]isoindole-2,6(8H)-dione (9j¢)
IR: 1701 cm–1 (br, C=O, N–C=O).
1H NMR (600 MHz, CDCl3): d = 1.16 (d, J1,1-CH3 = 6.8 Hz, 3 H, 1-
CH3), 1.69 (s,
3 H, 8-CH3), 1.73 (dd, J7endo,6a = 8.7 Hz,
Total yield of isomers mixture: 78%; ratio 9j/9j¢ (isolated mixture)
1:1.3 (1H NMR).
J7endo,7exo = 11.8 Hz, 1 H, H7endo), 1.99 (dd, J7exo,6a = 3.5 Hz,
J7exo,7endo = 11.8 Hz, 1 H, H7exo), 2.21 (br s, 3 H, 5-CH3¢), 2.67 (dd,
J6a,7exo = 3.5 Hz, J6a,7endo = 8.7 Hz, 1 H, H6a), 2.93 (dd, J3,3 = 17.1
Hz, J3B,4 = 6.2 Hz, 1 H, H3B), 2.95 (dq, J1,1-CH3 = 6.8 Hz,
J10b,1 = 12.0 Hz, 1 H, H1), 3.02 (dd, 2J3,3 = 17.1 Hz, J3A,4 = 2.0 Hz,
1 H, H3A), 4.28 (d, J10b,1 = 12.0 Hz, 1 H, H10b), 5.32 (br dd,
J3B,4 = 6.2 Hz, J3A,4 = 2.0 Hz, 1 H, H4), 5.83 (dq, 4J5¢-CH3,4¢ = 0.7 Hz,
2
Compound 9j
Yield: 35%; mp 161–163 °C.
IR: 1693 cm–1 (br, C=O, N–C=O).
1H NMR (400 MHz, CDCl3): d = 1.21 (d, J3,3-CH3 = 7.4 Hz, 3 H, 3-
CH2CH3), 1.57 (dd, J7endo,6a = 8.8 Hz, J7endo,7exo = 11.8 Hz, 1 H,
H7endo), 1.90–2.10 (m, 2 H, 3-CH2CH3), 2.22 (ddd, J7exo,6a = 3.3 Hz,
J7exo,8 = 4.4 Hz, J7exo,7endo = 11.8 Hz, 1 H, H7exo), 2.50 (dd,
J6a,7exo = 3.3 Hz, J6a,7endo = 8.8 Hz, 1 H, H6a), 2.97 (m, 1 H, H3),
4.12 (d, J10b,1 = 12.4 Hz, 1 H, H10b), 4.82 (d, J10b,1 = 12.4 Hz, 1 H,
H1), 5.09 (dd, J8,9 = 1.3 Hz, J8,7exo = 4.4 Hz, 1 H, H8), 5.19 (br d,
J4,3 = 1.0 Hz, 1 H, H4), 5.50 (d, J9,10 = 5.8 Hz, 1 H, H10), 6.07 (dd,
J9,10 = 5.8 Hz, J9,8 = 1.3 Hz, 1 H, H9), 6.28 (dd, J4¢,5¢ = 1.8 Hz,
J
3¢,4¢ = 3.0 Hz, 1 H, H4¢), 6.12 (br d, J4¢,3¢ = 3.0 Hz, 1 H, H3¢), 6.24
(d, J10,9 = 5.7 Hz, 1 H, H10), 6.39 (br d, J10,9 = 5.7 Hz, 1 H, H9).
13C NMR (100.6 MHz, CDCl3): d = 208.4 (C2), 173.8 (C6), 151.8
and 150.6 (C2¢, C5¢), 140.1 and 133.4 (C9, C10), 107.9 and 106.3 (C3¢,
C4¢), 90.4 (C10a), 87.1 (C8), 59.6 (C6a), 51.2 (C4), 46.3 and 44.5 (C1,
C
CH3).
10b), 42.1 (C3), 34.6 (C7), 18.9 (5-CH3¢), 13.5 and 10.2 (1-CH3, 8-
MS (EI, 70 eV): m/z (%) = 327 (80) [M]+, 310 (2), 284 (30), 256
(66), 232 (6), 190 (9), 177 (26), 176 (52), 149 (38), 122 (100), 108
(58), 79 (18), 77 (15), 55 (32).
J
4¢,3¢ = 3.2 Hz, 1 H, H4¢), 6.40 (br d, J3¢,4¢ = 3.2 Hz, 1 H, H3¢), 7.08–
7.11 (m, 2 H, Hortho Ph), 7.27–7.32 (m, 4 H, Hpara, Hmeta Ph, H5¢).
13C NMR (100.6 MHz, CDCl3): d = 208.4 (C2), 174.7 (C6), 152.6
(d, C2¢), 142.3 (C5¢), 135.4 and 132.2 (C9, C10), 134.5 (Cipso-Ph), 130.0
(2 C, Cmeta-Ph), 128.6 (2 C, Cortho-Ph), 127.8 (Cpara-Ph), 110.4 and 107.4
(C3¢, C4¢), 91.0 (C10a), 78.8 (C8), 59.2 (C4), 55.5, 54.8, 50.2, 47.9 (C1,
C3, C6a, C10b), 28.6 (C7), 24.7 (3-CH2CH3), 12.3 (3-CH2CH3).
MS (EI, 70 eV): m/z (%) = 389 (74) [M]+, 360 (9), 318 (15), 298 (3),
266 (4), 244 (6), 239 (18), 224 (9), 191 (6), 174 (14), 170 (100), 169
(23), 148 (23), 141 (31), 122 (64), 107 (16), 91 (15), 77 (11), 55
(43).
Anal. Calcd for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C,
69.61; H, 6.57; N, 4.38.
(1R*,3S*,4R*,6aR*,8S*,10aS*,10bS*)-1,3,8-Trimethyl-4-(5-
methyl-2-furyl)-1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyri-
do[2,1-a]isoindole-2,6(8H)-dione (9l)
Yield: 87%; mp 195 °C.
IR: 1714 (C=O), 1685 cm–1 (N–C=O).
1H NMR (400 MHz, CDCl3): d = 1.11 (d, J1,1-CH3 = 6.7 Hz, 3 H, 1-
CH3), 1.36 (d, J3,3-CH3 = 7.8 Hz, 3 H, 3-CH3), 1.67 (s, 3 H, 8-CH3),
1.71 (dd, J7endo,6a = 8.7, J7endo,7exo = 11.9 Hz, 1 H, H7endo), 1.97 (dd,
J7exo,6a = 3.5, J7exo,7endo = 11.9 Hz, 1 H, H7exo), 2.17 (br s, 3 H, 5-
CH3¢), 2.65 (dd, J6a,7exo = 3.5, J6a,7endo = 8.7 Hz, 1 H, H6a), 2.94 (dq,
J1,1-CH3 = 6.7 Hz, J1,10b = 12.2 Hz, 1 H, H1), 3.05 (dq, J3,3-CH3 = 7.8
Hz, J3,4 = 12.2 Hz, 1 H, H3), 4.21 (d, J10b,1 = 12.2 Hz, 1 H, H10b),
4.98 (br d, J4,3 = 2.1 Hz, 1 H, H4), 5.78 (dq, J4¢,3¢ = 3.0 Hz,
J4¢,Me = 1.0 Hz, 1 H, H4¢), 6.11 (br d, J3¢,4¢ = 3.0 Hz, 1 H, H3¢), 6.22
(d, J9,10 = 5.6 Hz, 1 H, H10), 6.37 (d, J9,10 = 5.6 Hz, 1 H, H9).
13C NMR (100.6 MHz, CDCl3): d = 210.9 (C2), 174.6 (C6), 151.8
and 150.7 (C2¢, C5¢), 140.0 and 133.4 (C9, C10), 107.8 and 106.2 (C3¢,
C4¢), 90.8 (C10a), 87.1 (C8), 59.2 (C4), 52.7, 51.2, 46.7, 43.9 (C1, C3,
C6a, C10b), 34.74 (C7), 18.9 and 17.7 (8-CH3, 5-CH3¢), 13.5 and 10.3
(1-CH3, 3-CH3).
Anal. Calcd for C24H23NO4: C, 74.02; H, 5.95; N, 3.60. Found: C,
73.93; H, 6.15; N, 3.71.
Compound 9j¢
Yield: 31%.
IR: 1693 (N–C=O), 1718 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 0.63 (d, J1,1-CH3 = 7.5 Hz, 3 H, 1-
CH2CH3), 1.46 (m, 1 H, 1-CHAHBCH3), 1.62 (dd, J7endo,6a = 8.9 Hz,
J7endo,7exo = 11.8 Hz, 1 H, H7endo), 1.90 (m, 1 H, 1-CHAHBCH3), 2.23
(dt, J7exo,6a = J7exo,8 = 4.0 Hz, J7exo,7endo = 11.8 Hz, 1 H, H7exo), 2.53
(dd, J6a,7exo = 4.0 Hz, J6a,7endo = 8.9 Hz, 1 H, H6a), 3.01 (br dt, J1,CH2
~ 3.8 Hz, J1,10b = 11.4 Hz, 1 H, H1), 4.25 (d, J3,4 = 0.5 Hz, 1 H, H3),
4.27 (d, J10b,1 = 11.4 Hz, 1 H, H10b), 5.12 (dd, J8,9 = 1.1 Hz,
J8,7exo = 4.0 Hz, 1 H, H8), 5.81 (br d, J4,3 = 0.5 Hz, 1 H, H4), 6.26
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

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IMDAF of Maleic Anhydride with 2,6-Difurylpiperidin-4-ones
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MS (EI, 70 eV): m/z (%) = 341 (76) [M]+, 326 (4), 298 (6), 270 (62),
246 (8), 191 (24), 176 (100), 149 (25), 122 (77), 77 (13), 55 (22).
H4¢), 6.34 (br d, J3¢,4¢ = 3.0 Hz, 1 H, H3¢), 6.46 (dd, J8,9 = 1.4 Hz,
J9,10 = 5.7 Hz, 1 H, H9), 6.60 (d, J9,10 = 5.7 Hz, 1 H, H10), 7.51 (dd,
5¢,3¢ = 0.7 Hz, J5¢,4¢ = 1.8 Hz, 1 H, H5¢), 12.32 (br s, 1 H, CO2H).
13C NMR (100.6 MHz, DMSO-d6): d = 208.9 (C2), 173.6 (C6),
170.4 (CO2H), 153.5 (C2¢), 142.9 (C5¢), 136.9 (C9), 135.8 (C10),
110.8 (C4¢), 107.6 (C3¢), 90.3 (C10a), 81.4 (C8), 57.4 (C10b), 51.2 (C7),
46.4, 45.1, 44.5 (C1, C4, C6a), 42.4 (C3), 10.4 (1-CH3).
MS (EI, 70 eV): m/z (%) = 343 (21) [M]+, 325 (2), 298 (1), 262 (2),
244 (30), 229 (11), 228 (88), 202 (12), 189 (19), 176 (38), 162
(100), 161 (23), 135 (33), 122 (34), 108 (56), 94 (66), 77 (14), 66
(21), 65 (24), 55 (9).
J
Anal. Calcd for C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C,
70.58; H, 6.88; N, 4.19.
(1S*,3S*,4R*,6aR*,8S*,10aS*,10bS*)-4-(2-Furyl)-1,3-dimeth-
yl-1,3,4,6a,7,10b-hexahydro-2H-8,10a-epoxypyrido[2,1-a]isoin-
dol-6(8H)-one (10)
Maize yellow rhombuses; yield: 0.6 g (70%); mp 131–132 °C.
IR: 1680 cm–1 (C=C, N–C=O).
1H NMR (400 MHz, CDCl3): d = 0.97 (d, J = 6.9 Hz, 3 H, CH3),
1.01 (d, J = 6.7 Hz, 3 H, CH3), 1.32 [m, 1 H, H2(e)], 1.53 (dd,
J7endo,6a = 8.9 Hz, J7,7 = 11.8 Hz, 1 H, H7endo), 1.56 [ddd, 2J2,2 = 13.8,
3J = 9.6 Hz, 3J = 12.0 Hz, 1 H, H2(a)], 2.13 (ddd, J6a,7exo = 3.6 Hz,
J7,7 = 11.8 Hz, J8,7exo = 4.6 Hz, 1 H, H7exo), 2.32 (m, 1 H, H3), 2.43
(dd, J6aendo,7endo = 8.9 Hz, J6aendo,7exo = 3.6 Hz, 1 H, H6aendo), 2.46 (m,
1 H, H1), 3.94 (d, J10b,1 = 11.8 Hz, 1 H, H10b), 4.86 (br d, J3,4 = 4.4
Hz, 1 H, H4), 5.06 (d, J8,9 = 1.7 Hz, J8,7exo = 4.6 Hz, 1 H, H8), 6.24
(dd, J3¢,5¢ = 0.8 Hz, J4¢,3¢ = 3.3 Hz, 1 H, H3¢), 6.27 (dd, J5¢,4¢ = 1.8 Hz,
Anal. Calcd for C18H17NO6: C, 62.97; H, 4.99; N, 4.08. Found: C,
63.05; H, 5.13; N, 3.90.
(1R*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-1-Ethyl-4-(2-furyl)-2,6-
dioxo-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-epoxypyrido[2,1-
a]isoindole-7-carboxylic Acid (11b)
Yield: 82%; mp 226 °C.
IR: 3407 (OH), 1737 (CO2H), 1717 (C=O), 1654 cm–1 (N–C=O).
J
3¢,4¢ = 3.3 Hz, 1 H, H4¢), 6.34 (dd, J8,9 = 1.7 Hz, J9,10 = 5.8 Hz, 1 H,
H9), 6.40 (d, J9,10 = 5.8 Hz, 1 H, H10), 7.31 (dd, J5¢,3¢ = 0.8 Hz,
5¢,4¢ = 1.8 Hz, 1 H, H5¢).
1H NMR (400 MHz, DMSO-d6): d = 0.84 (t, JCH2,Me = 7.3 Hz, 3 H,
CH2CH3), 1.44 (m, 1 H, CHAHBCH3), 1.69 (m, 1 H, CHAHBCH3),
2.48 (m, 1 H, H1), 2.56 (d, J7endo,6a = 9.3 Hz, 1 H, H6a), 2.75 (dd,
J3B,4 = 1.0 Hz, 2J3,3 = 16.1 Hz, 1 H, H3B), 2.95 (d, J6a,7endo = 9.3 Hz,
J
13C NMR (100.6 MHz, CDCl3): d = 173.1 (C6), 152.6 (C2¢), 141.4
(C5¢), 135.9 and 133.8 (C9, C10), 109.9 and 107.9 (C3¢, C4¢), 90.9
(C10a), 78.4 (C8), 59.4, 52.6 and 47.6 (C4, C6a, C10b), 34.5 (C2), 31.2
and 27.4 (C3, C1), 27.8 (C7), 18.4 and 17.6 (1-CH3, 3-CH3).
MS (EI, 70 eV): m/z (%) = 299 (36) [M]+, 271 (1), 231 (2), 229 (4),
228 (21), 213 (7), 177 (9), 162 (12), 147 (2), 136 (3), 122 (8), 121
(9), 108 (8), 91 (7), 81 (13), 79 (15), 77 (12), 65 (10), 55 (100).
2
1 H, H7endo), 3.27 (dd, J3A,4 = 6.1 Hz, J3,3 = 16.1 Hz, 1 H, H3A),
4.83 (d, J10b,1 = 11.9 Hz, 1 H, H10b), 5.12 (d, J8,9 = 1.0 Hz, 1 H, H8),
5.17 (dd, J4,3B = 1.0 Hz, J4,3A = 6.1 Hz, 1 H, H4), 6.27 (dd, J4¢,5¢ = 1.8
Hz, J4¢,3¢ = 3.2 Hz, 1 H, H4¢), 6.32 (br d, J3¢,4¢ = 3.2 Hz, 1 H, H3¢),
6.46 (dd, J8,9 = 1.0 Hz, J9,10 = 5.6 Hz, 1 H, H9), 6.65 (d, J9,10 = 5.6
Hz, 1 H, H10), 7.51 (br d, J5¢,4¢ = 1.8 Hz, 1 H, H5¢), 12.33 (br s, 1 H,
CO2H).
13C NMR (100.6 MHz, DMSO-d6): d = 209.0 (C2), 173.5 (C6),
170.4 (CO2H), 153.5 (C2¢), 142.9 (C5¢), 137.0 (C9), 135.6 (C10),
110.8 (C4¢), 107.5 (C3¢), 90.2 (C10a), 81.4 (C8), 55.0 (C10b), 51.3 (C7),
49.9, 46.5, 45.1 (C1, C4, C6a), 43.4 (C3), 18.6 (CH2CH3), 10.9
(CH2CH3).
Anal. Calcd for C18H21NO3: C, 77.22; H, 7.07; N, 4.68. Found: C,
76.94; H, 4.50; N, 4.75.
8,10a-Epoxypyrido[2,1-a]isoindole-7-carboxylic Acids
11a–h,k,l, 11i,j, and 11i¢,j¢; Typical Procedure
A soln of 2a–l (21.0 mmol) and maleic anhydride (2.06 g, 21.0
mmol) in toluene (30 mL) was refluxed for 6–8 h. The mixture was
then cooled and formation of white, yellow, or brown solids was ob-
served. The crystals were filtered off and washed first with toluene
(2 × 30 mL), then with acetone (2 × 20 mL) to give 11a–h,k,l and
regioisomeric mixtures 11i/11i¢ and 11j/11j¢ as white or pale-brown
powders. In some cases (for example, in case of acids 11c–e), ad-
ducts were isolated as viscous oils on the flask walls. In such cases,
after cooling, toluene was poured off, and the remained oil was trit-
urated with Et2O. The obtained crystals were filtered off, washed
with acetone, and dried in air. The mixture of regioisomers 11i/11i¢
and 11j/11j¢ was not separated additionally because of the poor sol-
ubility of the obtained compounds in common organic solvents. Af-
ter the fraction crystallization (EtOH–DMF) the major isomers 11i¢
and 11j¢ only were isolated. Mp, IR, EI-MS, 1H and 13C NMR, and
element analysis data are described for the major regioisomers 11i¢
and 11j¢.
MS (EI, 70 eV): m/z (%) = 357 (20) [M]+, 339 (2), 276 (3), 258 (26),
242 (98), 235 (9), 207 (10), 190 (24), 189 (24), 176 (17), 162 (100),
161 (22), 136 (19), 122 (94), 121 (31), 107 (28), 99 (15), 79 (19), 66
(20), 65 (26), 55 (12).
Anal. Calcd for C19H19NO6: C, 63.86; H, 5.36; N, 3.92. Found: C,
63.91; H, 5.14; N, 3.84.
(1R*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-4-(2-Furyl)-2,6-dioxo-1-
propyl-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-epoxypyri-
do[2,1-a]isoindole-7-carboxylic Acid (11c)
Yield: 67%; mp 203–204 °C.
IR: 3497 (OH), 1721 (CO2H), 1736 (C=O), 1655 cm–1 (N–C=O).
1H NMR (400 MHz, DMSO-d6): d = 0.75 (t, JCH2,Me = 6.7 Hz, 3 H,
CH2CH3), 1.15 (m, 1 H, CHAHBCH2CH3), 1.42 (m, 2 H,
CH2CH2CH3), 1.55 (m, 1 H, CHAHBCH2CH3), 2.48 (m, 1 H, H1),
2.54 (d, J7endo,6a = 9.2 Hz, 1 H, H6a), 2.72 (dd, J3B,4 = 1.0 Hz,
2J3,3 = 16.3 Hz, 1 H, H3B), 2.92 (d, J6a,7endo = 9.2 Hz, 1 H, H7endo),
(1R*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-1-Methyl-2,6-dioxo-
1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-epoxypyrido[2,1-
a]isoindole-7-carboxylic Acid (11a)
Yield: 84%; mp 219–220.5 °C.
IR: 3505 (br, OH), 1726 (CO2H, C=O), 1667 cm–1 (N–C=O).
2
3.24 (dd, J3A,4 = 5.0 Hz, J3,3 = 16.3 Hz, 1 H, H3A), 4.77 (d,
J10b,1 = 11.9 Hz, 1 H, H10b), 5.10 (d, J8,9 = 1.5 Hz, 1 H, H8), 5.15
(dd, J4,3B = 1.0 Hz, J4,3A = 5.0 Hz, 1 H, H4), 6.25 (dd, J4¢,5¢ = 1.8 Hz,
J4¢,3¢ = 3.2 Hz, 1 H, H4¢), 6.30 (br d, J3¢,4¢ = 3.2 Hz, 1 H, H3¢), 6.44
1H NMR (400 MHz, DMSO-d6): d = 0.99 (d, J1,1-CH3 = 6.9 Hz, 3 H,
1-CH3), 2.49 (dq, J1,10b = 11.7 Hz, J1,1-CH3 = 6.9 Hz, 1 H, H1), 2.56
(d, J7endo,6a = 9.3 Hz, 1 H, H6a), 2.75 (dd, J3B,4 = 1.7 Hz, 2J3,3 = 16.6
Hz, 1 H, H3B), 2.97 (d, J6a,7endo = 9.3 Hz, 1 H, H7endo), 3.29 (dd,
J3A,4 = 6.2 Hz, 2J3,3 = 16.6 Hz, 1 H, H3A), 4.62 (d, J10b,1 = 11.7 Hz,
1 H, H10b), 5.11 (d, J8,9 = 1.4 Hz, 1 H, H8), 5.19 (dd, J4,3B = 1.7 Hz,
J4,3A = 6.2 Hz, 1 H, H4), 6.27 (dd, J4¢,5¢ = 1.8 Hz, J4¢,3¢ = 3.0 Hz, 1 H,
(dd, J8,9 = 1.5 Hz, J9,10 = 5.5 Hz, 1 H, H9), 6.61 (d, J9,10 = 5.5 Hz, 1
H, H10), 7.48 (br d, J5¢,4¢ = 1.8 Hz, 1 H, H5¢), 12.23 (br s, 1 H,
CO2H).
13C NMR (100.6 MHz, DMSO-d6): d = 209.1 (C2), 173.5 (C6),
170.3 (CO2H), 153.5 (C2¢), 142.9 (C5¢), 136.9 (C9), 135.6 (C10),
110.8 (C4¢), 107.5 (C3¢), 90.2 (C10a), 81.4 (C8), 55.5 (C10b), 51.3 (C7),
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

4250
F. I. Zubkov et al.
PAPER
49.0, 46.5, 45.1 (C1, C4, C6a), 43.2 (C3), 27.9 (CH2CH2CH3), 19.6
(CH2CH2CH3), 14.8 (CH2CH2CH3).
Anal. Calcd for C20H19NO6: C, 65.03; H, 5.18; N, 3.79. Found: C,
64.72; H, 5.37; N, 3.89.
MS (EI, 70 eV): m/z (%) = 371 (19) [M]+, 353 (2), 329 (2), 290 (3),
272 (24), 256 (92), 235 (7), 228 (5), 207 (23), 204 (18), 189 (28),
174 (11), 163 (29), 162 (100), 161 (33), 150 (12), 136 (60), 122
(42), 121 (33), 107 (33), 94 (82), 79 (16), 65 (23), 55 (18).
(1R*,3S*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-4-(2-Furyl)-2,6-di-
oxo-1,3-diphenyl-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-epoxy-
pyrido[2,1-a]isoindole-7-carboxylic Acid (11f)
Yield: 55%; mp >220 °C (dec).
Anal. Calcd for C20H21NO6: C, 64.68; H, 5.70; N, 3.77. Found: C,
64.41; H, 5.78; N, 3.93.
IR: 3389 (br, OH), 1724 (CO2H, C=O), 1700 cm–1 (N–C=O).
1H NMR (600 MHz, DMSO-d6): d = 2.50 (d, J7endo,6a = 9.2 Hz, 1 H,
H6a), 2.79 (d, J7endo,6a = 9.2 Hz, 1 H, H7endo), 4.40 (d, J1,10b = 10.8
Hz, 1 H, H10b), 4.47 (d, J3,4 = 6.6 Hz, 1 H, H3), 5.02 (d, J1,10b = 10.8
Hz, 1 H, H1), 5.10 (d, J8,9 = 1.7 Hz, 1 H, H8), 5.58 (d, J4,3 = 6.6 Hz,
1 H, H4), 5.70 (d, J9,10 = 5.7 Hz, 1 H, H10), 6.11 (dd, J5¢,3¢ = 0.6 Hz,
(1R*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-4-(2-Furyl)-1-isopropyl-
2,6-dioxo-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-epoxypyri-
do[2,1-a]isoindole-7-carboxylic Acid (11d)
Yield: 40%; mp 204–206 °C.
J
4¢,3¢ = 3.2 Hz, 1 H, H3¢), 6.17 (dd, J8,9 = 1.7 Hz, J9,10 = 5.7 Hz, 1 H,
IR: 3510 (br, OH), 1741 (CO2H), 1701 (C=O), 1671 cm–1 (N–C=O).
H9), 6.40 (dd, J5¢,4¢ = 1.8 Hz, J4¢,3¢ = 3.2 Hz, 1 H, H4¢), 6.77 (dd,
J = 1.6 Hz, J = 7.8 Hz, 2 H, HPh), 7.12–7.18, 7.37–7.29 (m, 7 H,
HPh), 7.23 (t, J = 7.7 Hz, 1 H, HPh), 7.86 (br d, J5¢,4¢ = 1.8 Hz, 1 H,
H5¢), 12.24 (br s, 1 H, CO2H).
1H NMR (400 MHz, DMSO-d6): d = 0.90 [d, JCH,Me(A) = 6.0 Hz, 3
H, CH(CH3)A(CH3)B], 1.04 [d, JCH,Me(B) = 6.7 Hz,
3
H,
CH(CH3)A(CH3)B], 1.91 [m,
1 H, CH(CH3)2], 2.47 (dd,
JCH,CHMe2 = 6.5 Hz, J1,10b = 12.0 Hz, 1 H, H1), 2.57 (d, J7endo,6a = 9.4
Hz, 1 H, H6a), 2.67 (dd, J3B,4 = 1.8 Hz, 2J3,3 = 15.4 Hz, 1 H, H3B),
2.92 (d, J7endo,6a = 9.4 Hz, 1 H, H7endo), 3.28 (dd, J3A,4 = 5.7 Hz,
2J3,3 = 15.4 Hz, 1 H, H3A), 4.91 (d, J10b,1 = 12.0 Hz, 1 H, H10b), 5.13
(d, J8,9 = 1.5 Hz, 1 H, H8), 5.13 (dd, J4,3B = 1.8 Hz, J4,3A = 5.7 Hz, 1
H, H4), 6.28 (br s, 2 H, H3¢, H4¢), 6.44 (dd, J8,9 = 1.5 Hz, J9,10 = 5.3
Hz, 1 H, H9), 6.66 (d, J9,10 = 5.3 Hz, 1 H, H10), 7.51 (br d, J5¢,4¢ = 1.8
Hz, 1 H, H5¢), 12.32 (br s, 1 H, CO2H).
13C NMR (100.6 MHz, DMSO-d6): d = 209.1 (C2), 173.5 (C6),
170.4 (CO2H), 153.4 (C2¢), 142.9 (C5¢), 136.9 and 135.6 (C9, C10),
110.8 (C4¢), 107.3 (C3¢), 90.0 (C10a), 81.4 (C8), 55.3 (C10b), 51.3 (C7),
54.1, 46.8, 45.0 (C1, C4, C6a), 44.5 (C3), 27.0 [CH(CH3)2], 22.7 and
17.2 [CH(CH3)2].
13C NMR (100.6 MHz, DMSO-d6): d = 203.1 (C2), 172.6 (CO2H),
168.6 (C6), 150.5 (C2¢), 143.3 (C5¢), 135.3 and 134.9 (C9, C10), 134.5
and 134.1 (Cipso-Ph), 130.15, 130.04, 128.0, 127.4 (Cmeta-Ph, Cortho-Ph),
127.22 and 127.10 (Cpara-Ph), 110.7 and 109.8 (C3¢, C4¢), 89.6 (C10a),
80.8 (C8), 59.8, 56.8, 55.2, 51.9 (C1, C3, C4, C6a), 49.7 (C7), 44.9
(C10b).
MS (EI, 70 eV): m/z (%) = 481 (24) [M]+, 437 (21), 382 (12), 367
(21), 366 (57), 301 (5), 289 (7), 288 (8), 283 (32), 265 (13), 239
(10), 238 (27), 198 (22), 197 (45), 174 (24), 171 (35), 170 (100),
169 (67), 142 (13), 141 (45), 118 (10), 115 (32), 96 (13), 95 (14), 81
(20), 55 (22), 43 (28).
Anal. Calcd for C29H23NO6: C, 72.34; H, 4.81; N, 2.91. Found: C,
72.24; H, 4.91; N, 2.81.
MS (EI, 70 eV): m/z (%) = 371 (22) [M]+, 343 (1), 329 (1), 328 (4),
290 (2), 272 (24), 257 (11), 256 (90), 249 (10), 234 (10), 216 (12),
207 (11), 189 (20), 174 (8), 163 (24), 162 (100), 150 (21), 136 (98),
121 (90), 107 (9), 99 (17), 94 (78), 65 (34), 55 (12).
(1R*,3S*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-4-(2-Furyl)-1,3-
dimethyl-2,6-dioxo-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-ep-
oxypyrido[2,1-a]isoindole-7-carboxylic Acid (11g)
Yield: 86%; mp 236–237.5 °C.
Anal. Calcd for C20H21NO6: C, 64.68; H, 5.70; N, 3.77. Found: C,
64.50; H, 5.78; N, 3.92.
IR: 3232 (br, OH), 1731 (CO2H), 1713 (C=O), 1678 cm–1 (N–C=O).
(1R*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-1-Allyl-4-(2-furyl)-2,6-
dioxo-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-epoxypyrido[2,1-
a]isoindole-7-carboxylic Acid (11e)
Yield: 70%; mp 202 °C.
IR: 3129 (OH), 1731 (CO2H), 1654 cm–1 (N–C=O).
1H NMR (400 MHz, DMSO-d6): d = 0.98 (d, J1,1-CH3 = 6.7 Hz, 3 H,
1-CH3), 1.31 (d, J3,3-CH3 = 8.1 Hz, 3 H, 3-CH3), 2.57 (d,
J7endo,6a = 9.4 Hz, 1 H, H6a), 2.63 (dq, J1,10b = 12.1 Hz, J1,1-CH3 = 6.7
Hz, 1 H, H1), 2.95 (dq, J3,4 = 2.0 Hz, J3,3-CH3 = 8.1 Hz, 1 H, H3),
3.00 (d, J6a,7endo = 9.4 Hz, 1 H, H7endo), 4.58 (d, J10b,1 = 12.1 Hz, 1 H,
H10b), 4.94 (d, J3,4 = 2.0 Hz, 1 H, H4), 5.13 (d, J8,9 = 1.3 Hz, 1 H,
H8), 6.28 (dd, J4¢,5¢ = 2.0 Hz, J4¢,3¢ = 3.4 Hz, 1 H, H4¢), 6.44 (br d,
1H NMR (400 MHz, DMSO-d6): d = 2.13 (m, 1 H, H1), 2.56 (d,
J7endo,6a = 9.2 Hz, 1 H, H6a), 2.49–2.61 (m, 2 H, CH2CH=CH2), 2.77
(dd, J3B,4 = 1.0 Hz, 2J3,3 = 16.0 Hz, 1 H, H3B), 2.97 (d, J7endo,6a = 9.2
Hz, 1 H, H7endo), 3.25 (dd, J3A,4 = 6.1 Hz, 2J3,3 = 16.3 Hz, 1 H, H3A),
4.77 (d, J10b,1 = 11.8 Hz, 1 H, H10b), 4.99–5.03 (m, 2 H,
CH2CH=CH2), 5.13 (d, J8,9 = 1.0 Hz, 1 H, H8), 5.16 (dd, J4,3B = 1.0
Hz, J4,3A = 6.1 Hz, 1 H, H4), 5.73 (m, 1 H, CH2CH=CH2), 6.27 (br
d, J4¢,3¢ = 3.2 Hz, 1 H, H3¢), 6.32 (br d, J4¢,3¢ = 3.2 Hz, 1 H, H4¢), 6.47
(dd, J8,9 = 1.0 Hz, J9,10 = 5.5 Hz, 1 H, H9), 6.66 (d, J9,10 = 5.5 Hz, 1
H, H10), 7.51 (br d, J5¢,4¢ = 1.8 Hz, 1 H, H5¢), 12.34 (br s, 1 H,
CO2H).
13C NMR (100.6 MHz, DMSO-d6): d = 208.2 (C2), 173.5 (C6),
170.4 (CO2H), 153.4 (C2¢), 142.9 (C5¢), 136.9 and 135.6 (C9, C10),
134.8 (CH2CH=CH2), 118.4 (CH2CH=CH2), 110.8 (C4¢), 107.5
(C3¢), 90.1 (C10a), 81.4 (C8), 55.1 (C10b), 51.3 (C7), 59.0, 46.5, 45.0
(C1, C4, C6a), 43.4 (C3), 29.9 (CH2CH=CH2).
J
3¢,4¢ = 3.4 Hz, 1 H, H3¢), 6.46 (dd, J8,9 = 2.0 Hz, J9,10 = 6.0 Hz, 1 H,
H9), 6.59 (d, J9,10 = 6.0 Hz, 1 H, H10), 7.51 (dd, J5¢,3¢ = 0.7 Hz,
5¢,4¢ = 2.0 Hz, 1 H, H5¢), 12.31 (br s, 1 H, CO2H).
J
13C NMR (100.6 MHz, DMSO-d6): d = 210.9 (C2), 173.6 (C6),
171.2 (CO2H), 153.2 (C2¢), 142.8 (C5¢), 136.8 and 135.7 (C9, C10),
110.8 (C4¢), 108.0 (C3¢), 90.7 (C10a), 81.5 (C8), 57.0 (C10b), 52.4,
51.1, 46.9, 45.3, 43.9 (C1, C3, C4, C6a, C7), 17.1 (3-CH3), 10.4 (1-
CH3).
MS (EI, 70 eV): m/z (%) = 357 (14) [M]+, 339 (1), 313 (1), 276 (8),
258 (18), 242 (60), 221 (10), 203 (22), 176 (100), 162 (13), 148
(10), 135 (17), 122 (26), 108 (42), 79 (29), 77 (18), 65 (9), 55 (6).
Anal. Calcd for C19H19NO6: C, 63.86; H, 5.36; N, 3.92. Found: C,
63.48; H, 5.28; N, 3.81.
(1R*,3S*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-1,3-Bis(2-ethoxy-2-
oxoethyl)-4-(2-furyl)-2,6-dioxo-1,3,4,6,6a,7,8,10b-octahydro-
2H-8,10a-epoxypyrido[2,1-a]isoindole-7-carboxylic Acid (11h)
Yield: 80%; mp 218 °C.
MS (EI, 70 eV): m/z (%) = 369 (19) [M]+, 351 (2), 328 (4), 327 (7),
270 (32), 256 (9), 254 (74), 235 (7), 228 (20), 213 (22), 202 (11),
189 (22), 162 (100), 148 (29), 134 (40), 122 (34), 121 (76), 105
(17), 99 (19), 94 (84), 91 (21), 81 (18), 66 (25), 65 (34), 55 (20).
IR: 3406 (br, OH), 1711 cm–1 (CO2, C=O).
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

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IMDAF of Maleic Anhydride with 2,6-Difurylpiperidin-4-ones
4251
1H NMR (400 MHz, DMSO-d6): d = 1.15 (t, JCH2,Me = 7.0 Hz, 3 H,
CH2CH3), 1.20 (t, JCH2,Me = 7.0 Hz, 3 H, CH2CH3), 2.37 (dd,
2JCH2 = 17.0 Hz, J1,CH2A = 6.7 Hz, 1 H, 1-CHAHBCO2Et), 2.57 (d,
J6a,7endo = 9.2 Hz, 1 H, H6a), 2.54–2.68 (m, 2 H, 3-CH2CO2Et), 2.85
(dd, 2JCH2 = 17.0 Hz, J1,CH2B = 8.8 Hz, 1 H, 1-CHAHBCO2Et), 2.99
(d, J7endo,6a = 9.2 Hz, 1 H, H7endo), 3.03 (m, 1 H, H1), 3.30 (m, 1 H,
H3), 4.03 (q, JCH2,Me = 7.0 Hz, 2 H, CO2CH2CH3), 4.11 (q,
JCH2,Me = 7.0 Hz, 2 H, CO2CH2CH3), 4.82 (d, J10b,1 = 12.3 Hz, 1 H,
H10b), 5.00 (br d, J4,3 = 1.5 Hz, 1 H, H4), 5.13 (br s, 1 H, H8), 6.31
(dd, J4¢,5¢ = 1.9 Hz, J4¢,3¢ = 3.3 Hz, 1 H, H4¢), 6.45 (dd, J3¢,5¢ = 0.8 Hz,
(1R*,3S*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-3-Ethyl-4-(2-furyl)-
2,6-dioxo-1-phenyl-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-ep-
oxypyrido[2,1-a]isoindole-7-carboxylic Acid (11j) and
(1S*,3R*,4S*,6aS*,7R*,8S*,10aR*,10bR*)-1-Ethyl-4-(2-furyl)-
2,6-dioxo-3-phenyl-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-ep-
oxypyrido[2,1-a]isoindole-7-carboxylic Acid (11j¢)
Total yield of isomers mixture: 72%; ratio 11j/11j¢ (isolated mix-
ture) 1:6 (1H NMR). After crystallization (EtOH–DMF) individual
isomer 11j¢ was isolated as a white powder.
J
3¢,4¢ = 3.3 Hz, 1 H, H3¢), 6.49 (br s, 2 H, H9, H10), 7.31 (br d,
Compound 11j¢
Yield: 52%; mp 208–209 °C.
J5¢,4¢ = 1.8 Hz, 1 H, H5¢), 12.33 (br s, 1 H, CO2H).
13C NMR (100.6 MHz, DMSO-d6): d = 207.8 (C2), 173.5 (C6),
171.04, 170.99, 170.97 (CO2Et, CO2H), 152.2 (C2¢), 143.2 (C5¢),
137.1 and 135.1 (C9, C10), 110.9 and 108.7 (C3¢, C4¢), 90.1 (C10a),
81.6 (C8), 61.1 and 60.8 (CO2CH2CH3), 54.9 (C4), 51.2, 50.8, 48.5,
45.9, 45.1 (C1, C3, C6a, C7, C10b), 34.6 and 29.9 (CH2CO2Et), 14.50
and 14.46 (CO2CH2CH3).
MS (EI, 70 eV): m/z (%) = 501 (11) [M]+, 456 (8), 414 (12), 402 (7),
388 (13), 386 (56), 356 (11), 340 (44), 313 (16), 312 (100), 270
(26), 266 (31), 247 (47), 238 (40), 228 (40), 202 (20), 194 (74), 174
(59), 148 (29), 122 (64), 107 (88), 91 (35), 79 (50), 77 (43), 65 (19),
55 (37).
IR: 3224 (OH), 1745 (CO2H), 1710 (C=O), 1689 cm–1 (N–C=O).
1H NMR (600 MHz, DMSO-d6): d = 0.97 (t, JCH2,Me = 7.3 Hz, 3 H,
CH2CH3), 1.57 (ddq, JCH2A,Me = 7.3 Hz, J1,CH2A = 2.3 Hz,
2
2JCH2 = 12.7 Hz, 1 H, CHAHBCH3), 1.71 (ddq, JCH2 = 12.7 Hz,
JCH2B,Me = 7.3 Hz, J1,CH2B = 8.2 Hz, 1 H, CHAHBCH3), 2.56 (d,
J7endo,6a = 9.2 Hz, 1 H, H6a), 2.84 (d, J7endo,6a = 9.2 Hz, 1 H, H7endo),
3.02 (ddd, J1,10b = 11.0 Hz, J1,CH2B = 8.2 Hz, J1,CH2A = 2.3 Hz, 1 H,
H1), 4.33 (d, J4,3 = 6.7 Hz, 1 H, H3), 4.64 (J10b,1 = 11.0 Hz, 1 H,
H10b), 5.14 (d, J8,9 = 1.6 Hz, 1 H, H8), 5.50 (d, J3,4 = 6.7 Hz, 1 H,
H4), 6.03 (br d, J4¢,3¢ = 3.2 Hz, 1 H, H3¢), 6.36 (dd, J5¢,4¢ = 1.8 Hz,
J
3¢,4¢ = 3.2 Hz, 1 H, H3¢), 6.47 (dd, J8,9 = 1.6 Hz, J9,10 = 5.5 Hz, 1 H,
H9), 6.66 (d, J9,10 = 5.5 Hz, 1 H, H10), 6.76 (br d, Jortho,meta = 6.9 Hz,
Anal. Calcd for C25H27NO10: C, 59.88; H, 5.43; N, 2.79. Found: C,
59.49; H, 5.48; N, 2.98.
2 H, Hortho Ph), 7.17–7.20 (m, 3 H, Hpara, Hmeta Ph), 7.70 (dd,
J5¢,3¢ = 0.6 Hz, J5¢,4¢ = 1.8 Hz, 1 H, H5¢), 12.23 (br s, 1 H, CO2H).
(1R*,3S*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-4-(2-Furyl)-3-meth-
yl-2,6-dioxo-1-phenyl-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-
epoxypyrido[2,1-a]isoindole-7-carboxylic Acid (11i) and
(1S*,3R*,4S*,6aS*,7R*,8S*,10aR*,10bR*)-4-(2-Furyl)-1-meth-
yl-2,6-dioxo-3-phenyl-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-
epoxypyrido[2,1-a]isoindole-7-carboxylic Acid (11i¢)
13C NMR (100.6 MHz, DMSO-d6): d = 205.4 (C2), 173.1 (CO2H),
169.0 (C6), 151.0 (d, C2¢), 143.5 (C5¢), 136.9 (C9), 136.1 (C10), 134.6
(Cipso-Ph), 130.6 (2 C, Cmeta-Ph), 127.9 (2 C, Cortho-Ph), 127.6 (Cpara-Ph),
111.1 (C3¢), 110.1 (C4¢), 90.1 (C10a), 81.3 (C8), 58.4 (C4), 57.3 (C1),
52.5 (C10b), 50.3 (C6a), 50.0 (C3), 45.3 (C7), 18.1 (CH2CH3), 11.9
(CH2CH3).
Total yield of isomers mixture: 68%; ratio 11i/11i¢ (isolated mix-
ture) 1:4 (1H NMR). After crystallization (EtOH–DMF) individual
isomer 11i¢ was isolated as a white powder.
MS (EI, 70 eV): m/z (%) = 433 (49) [M]+, 415 (4), 404 (4), 389 (19),
372 (9), 352 (22), 334 (36), 318 (100), 283 (41), 265 (25), 263 (27),
235 (54), 232 (55), 184 (15), 170 (57), 169 (20), 148 (10), 141 (29),
122 (63), 118 (34), 107 (31), 96 (20), 80 (25), 78 (21), 55 (19).
Compound 11i¢
Yield: 42%; mp 144–145 °C.
IR: 3540 (br, OH), 1714 (CO2H, C=O), 1652 cm–1 (N–C=O).
Anal. Calcd for C25H23NO6: C, 69.27; H, 5.35; N, 3.23. Found: C,
68.93; H, 5.15; N, 3.40.
1H NMR (400 MHz, CDCl3): d = 1.26 (d, J1,1-CH3 = 6.3 Hz, 3 H, 1-
CH3), 2.82 and 2.85 (2 d, J7endo,6a = 9.1 Hz, 1 H + 1 H, H7endo, H6a),
3.22 (dq, J1,10b = 10.4 Hz, J1,1-CH3 = 6.3 Hz, 1 H, H1), 4.22 (d,
J4,3 = 6.4 Hz, 1 H, H3), 4.50 (J10b,1 = 10.4 Hz, 1 H, H10b), 5.38 (s,
1 H, H8), 5.74 (d, J3,4 = 6.4 Hz, 1 H, H4), 6.00 (dd, J4¢,5¢ = 1.8 Hz,
(1R*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-1,8-Dimethyl-4-(5-meth-
yl-2-furyl)-2,6-dioxo-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-ep-
oxypyrido[2,1-a]isoindole-7-carboxylic Acid (11k)
Yield: 87%; mp 198–200 °C.
IR: 3179 (OH), 1747 (CO2H), 1719 (C=O), 1666 cm–1 (N–C=O).
J
4¢,3¢ = 3.2 Hz, 1 H, H4¢), 6.25 (br d, J3¢,4¢ = 3.2 Hz, 1 H, H3¢), 6.52
1H NMR (400 MHz, DMSO-d6): d = 0.99 (d, J1,1-CH3 = 6.9 Hz, 3 H,
1-CH3), 1.59 (s, 3 H, 8-CH3), 2.17 (s, 3 H, 5-CH3¢), 2.46 (dq,
J1,10b = 11.7 Hz, J1,1-CH3 = 6.9 Hz, 1 H, H1), 2.58 (d, J6a,7endo = 9.1
Hz, 1 H, H6a), 2.72 (dd, 2J3,3 = 16.5 Hz, J3B,4 = 1.8 Hz, 1 H, H3B),
(s, 2 H, H9, H10), 6.80 (m, 2 H, Hortho Ph), 7.17–7.26 (m, 3 H, Hpara
,
Hmeta Ph), 7.43 (br d, J5¢,4¢ = 1.8 Hz, 1 H, H5¢).
13C NMR (100.6 MHz, CDCl3): d = 207.8 (C2), 173.5 (C6), 169.9
(CO2H), 150.0 (d, C2¢), 142.7 (C5¢), 137.1 and 135.3 (C9, C10), 133.2
(Cipso-Ph), 130.2 (2 C, Cmeta-Ph), 127.9 (2 C, Cortho-Ph), 127.6 (Cpara-Ph),
110.76 and 110.73 (C3¢, C4¢), 90.1 (C10a), 81.7 (C8), 61.4 and 57.4
(C1, C4), 52.9, 50.7, 45.7, 43.9 (C3, C6a, C7, C10b), 10.4 (1-CH3).
MS (EI, 70 eV): m/z (%) = 419 (4) [M]+, 387 (1), 376 (3), 338 (3),
320 (10), 318 (9), 305 (13), 304 (35), 283 (10), 265 (10), 238 (53),
221 (21), 203 (14), 197 (25), 184 (19), 176 (49), 170 (97), 141 (94),
118 (87), 108 (100), 96 (57), 90 (45), 80 (63), 78 (73), 65 (25), 55
(57).
2
2.98 (d, J7endo,6a = 9.1 Hz, 1 H, H7endo), 3.26 (dd, J3,3 = 16.5 Hz,
J3A,4 = 6.3 Hz, 1 H, H3A), 4.55 (d, J10b,1 = 11.7 Hz, 1 H, H10b), 5.11
(br dd, J3B,4 = 1.8 Hz, J3A,4 = 6.3 Hz, 1 H, H4), 5.88 (dq, 4J5¢-CH3,3¢
=
0.7 Hz, J3¢,4¢ = 3.0 Hz, 1 H, H4¢), 6.29 (d, J10,9 = 5.4 Hz, 1 H, H9),
6.34 (br d, J4¢,3¢ = 3.0 Hz, 1 H, H3¢), 6.62 (d, J10,9 = 5.4 Hz, 1 H,
H10), 12.30 (br s, 1 H, CO2H).
13C NMR (100.6 MHz, DMSO-d6): d = 209.2 (C2), 172.3 and 170.5
(CO2H, C6), 151.7 and 151.2 (C2¢ and C5¢), 139.9 and 137.0 (C9,
C10), 108.2 and 106.8 (C3¢, C4¢), 89.5 and 88.9 (C8, C10a), 57.8 (C6a),
54.7 (C4), 48.3, 44.7, 46.5 (C1, C7, C10b), 42.5 (C3), 16.3 (5-CH3¢),
13.7 (8-CH3), 10.6 (1-CH3).
Anal. Calcd for C24H21NO6: C, 68.73; H, 5.05; N, 3.34. Found: C,
68.44; H, 4.85; N, 3.17.
MS (EI, 70 eV): m/z (%) = 371 (8) [M]+, 276 (3), 272 (4), 257 (11),
256 (100), 228 (7), 203 (6), 190 (40), 176 (68), 149 (20), 136 (34),
122 (52), 108 (46), 107 (29), 79 (12), 77 (10), 65 (4), 53 (5).
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

4252
F. I. Zubkov et al.
PAPER
Anal. Calcd for C20H21NO6: C, 64.68; H, 5.70; N, 3.77. Found: C,
64.78; H, 5.61; N, 3.93.
Esters 13a,b; Typical Procedure
The acid 11a (3.6 g, 10.5 mmol) was added to MeOH or EtOH (130
mL) and H2SO4 (0.5 mL) was added to the mixture. The resulting
mixture was refluxed for 12 h (TLC monitoring). The mixture was
then cooled, poured into H2O (400 mL), and extracted with CH2Cl2
(5 × 80 mL). The combined organic layers were dried (MgSO4),
concentrated, and purified by column chromatography (alumina,
CH2Cl2) to give a brown oil that crystallized. The crystals of esters
13a,b were washed (Et2O) to give bright brown rhombuses of
13a,b.
(1R*,3S*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-1,3,8-Trimethyl-4-
(5-methyl-2-furyl)-2,6-dioxo-1,3,4,6,6a,7,8,10b-octahydro-2H-
8,10a-epoxypyrido[2,1-a]isoindole-7-carboxylic Acid (11l)
Yield: 84%; mp 220 °C.
IR: 3535, 3196 (br OH), 1751 (CO2H), 1723 (C=O), 1669 cm–1 (N–
C=O).
1H NMR (400 MHz, DMSO-d6): d = 0.96 (d, J1,1-CH3 = 6.7 Hz, 3 H,
1-CH3), 1.27 (d, J3,3-CH3 = 7.5 Hz, 3 H, 3-CH3), 1.58 (s, 3 H, 8-CH3),
2.15 (br d, J4¢,Me = 0.5 Hz, 3 H, 5-CH3¢), 2.56 (d, J7endo,6a = 8.9 Hz, 1
H, H7endo), 2.61 (dq, J1,1-CH3 = 6.7 Hz, J1,10b = 12.4 Hz, 1 H, H1),
2.89 (dq, J3,3-CH3 = 7.5 Hz, J3,4 = 2.0 Hz, 1 H, H3), 2.98 (d,
J6a,7endo = 8.9 Hz, 1 H, H6a), 4.48 (d, J10b,1 = 12.4 Hz, 1 H, H10b),
4.81 (br d, J4,3 = 2.0 Hz, 1 H, H4), 5.86 (dq, J4¢,3¢ = 2.7 Hz,
J4¢,Me = 0.5 Hz, 1 H, H4¢), 6.26 (d, J9,10 = 5.6 Hz, 1 H, H9), 6.39 (d,
Methyl (1R*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-4-(2-Furyl)-1-
methyl-2,6-dioxo-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-ep-
oxypyrido[2,1-a]isoindole-7-carboxylate (13a)
Yield: 70%; mp 205–207 °C.
IR: 1734 (CO2Me), 1716 (C=O), 1680 cm–1 (N–C=O).
1H NMR (400 MHz, CDCl3): d = 1.07 (d, J1,1-CH3 = 6.9 Hz, 3 H, 1-
CH3), 2.73 (d, J7endo,6a = 9.1 Hz, 1 H, H6a), 2.86 (dq, J1,10b = 12.0
Hz, J1,1-CH3 = 6.9 Hz, 1 H, H1), 2.87 (d, J6a,7endo = 9.1 Hz, 1 H,
H7endo), 2.90 (dd, J3B,4 = 6.2 Hz, 2J3,3 = 17.2 Hz, 1 H, H3B), 3.03 (dd,
J
3¢,4¢ = 2.7 Hz, 1 H, H3¢), 6.59 (d, J9,10 = 5.6 Hz, 1 H, H10), 12.24 (br
s, 1 H, CO2H).
13C NMR (100.6 MHz, DMSO-d6): d = 211.1 (C2), 172.2 and 171.1
(C6, CO2H), 151.4 and 151.1 (C2¢, C5¢), 139.9 and 136.8 (C9, C10),
108.6 and 106.8 (C3¢, C4¢), 90.0 and 88.9 (C10a, C8), 57.4, 54.5, 52.6,
48.4, 47.1, 44.1 (C1, C3, C4, C6a, C7, C10b), 17.1 (3-CH3), 16.3 (5-
CH3¢), 13.7 (8-CH3), 10.5 (1-CH3).
MS (EI, 70 eV): m/z (%) = 385 (10) [M]+, 324 (2), 290 (13), 271
(11), 270 (98), 242 (5), 235 (5), 217 (12), 202 (5), 190 (100), 176
(17), 149 (19), 136 (32), 122 (60), 107 (20), 95 (11), 79 (15), 77
(11), 43 (12).
2
J3A,4 = 2.1 Hz, J3,3 = 17.2 Hz, 1 H, H3A), 3.62 (s, 3 H, CO2Me),
4.31 (d, J10b,1 = 12.0 Hz, 1 H, H10b), 5.19 (d, J8,9 = 1.7 Hz, 1 H, H8),
5.28 (br dd, J3A,4 = 2.1 Hz, J4,3B = 6.2 Hz, 1 H, H4), 6.21 (dd,
J
4¢,5¢ = 1.8 Hz, J4¢,3¢ = 3.3 Hz, 1 H, H4¢), 6.46 (d, J9,10 = 5.8 Hz, 1 H,
H10), 6.38 (ddd, J3¢,4¢ = 3.3 Hz, J3¢,5¢ = 0.8, 4J3¢,4 = 1.2 Hz, 1 H, H3¢),
6.41 (dd, J8,9 = 1.7 Hz, J9,10 = 5.8 Hz, 1 H, H9), 7.22 (ddd, J5¢,3¢ = 0.8
Hz, J5¢,4¢ = 1.8, 5J = 0.7 Hz, 1 H, H5¢).
13C NMR (100.6 MHz, CDCl3): d = 207.4 (s, C2), 171.7 (s,
CO2Me), 169.9 (s, C6), 151.6 (s, C2¢), 142.0 (d, J = 203.0 Hz, C5¢),
136.3 (d, J = 177.5 Hz, C9), 134.7 (d, J = 178.0 Hz, C10), 110.3 (d,
J = 175.5 Hz, C4¢), 107.41 (d, J = 178.0 Hz, C3¢), 89.9 (s, C10a), 80.9
(d, J = 168.5 Hz, C8), 58.2 (d, J = 140.0 Hz, C10b), 51.9 (q, J = 147.3
Hz, CO2Me), 51.2 (d, J = 141.5 Hz, C7), 46.1 (d, J = 146.5 Hz, C4),
45.1 (d, J = 141.7 Hz, C6a), 44.2 (d, J = 129.5 Hz, C1), 41.3 (dd,
J = 125.5, 138.0 Hz, C3), 9.7 (q, J = 129.2 Hz, 1-CH3).
Anal. Calcd for C21H23NO6: C, 65.44; H, 6.02; N, 3.63. Found: C,
65.33; H, 6.12; N, 3.74.
(1S*,3S*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-4-(2-Furyl)-1,3-dim-
ethyl-6-oxo-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-epoxypyri-
do[2,1-a]isoindole-7-carboxylic Acid (12)
A mixture of 4 (2.7 g, 11.0 mmol) and maleic anhydride (1.12 g,
11.4 mmol) in toluene (20 mL) was refluxed for 4 h. The mixture
was then cooled and formation of yellow species was observed. The
crystals were filtered off, washed first with toluene (25 mL), then
with acetone (2 × 15 mL) to give 12 as white needles; yield: 2.26 g
(58%); mp 202–204 °C.
MS (EI, 70 eV): m/z (%) = 357 (26) [M]+, 249 (4), 244 (71), 229
(14), 228 (100), 221 (7), 203 (7), 184 (24), 176 (61), 175 (10), 174
(7), 162 (92), 161 (14), 136 (10), 135 (37), 124 (16), 122 (62), 121
(46), 114 (11), 113 (45), 108 (52), 94 (64), 84 (12), 79 (12), 65 (10),
59 (10).
Anal. Calcd for C19H19NO6: C, 63.86; H, 5.36; N, 3.92. Found: C,
63.51; H, 5.39; N, 3.80.
IR: 3472, 3195 (br, OH), 1750 (CO2H), 1665 cm–1 (br, C=O, N–
C=O).
1H NMR (400 MHz, DMSO-d6): d = 0.90 (d, J1,1-CH3 = 6.7 Hz, 3 H,
1-CH3), 0.96 (d, J3,3-CH3 = 6.7 Hz, 3 H, 3-CH3), 1.26 (m, 2 H, H2),
2.22 and 2.33 (two m, 1 H + 1 H, H1, H3), 2.46 (d, J7endo,6a = 9.3 Hz,
1 H, H6a), 2.79 (d, J6a,7endo = 9.3 Hz, 1 H, H7endo), 4.06 (d,
J10b,1 = 11.7 Hz, 1 H, H10b), 4.67 (br d, J3,4 = 4.1 Hz, 1 H, H4), 5.04
(d, J8,9 = 1.2 Hz, 1 H, H8), 6.25 (dd, J3¢,5¢ = 0.8 Hz, J4¢,3¢ = 3.2 Hz, 1
H, H3¢), 6.29 (dd, J5¢,4¢ = 1.8 Hz, J3¢,4¢ = 3.2 Hz, 1 H, H4¢), 6.40 (dd,
J8,9 = 1.2 Hz, J9,10 = 5.7 Hz, 1 H, H9), 6.58 (d, J9,10 = 5.7 Hz, 1 H,
H10), 7.48 (dd, J5¢,3¢ = 0.8 Hz, J5¢,4¢ = 1.8 Hz, 1 H, H5¢), 12.12 (br s,
1 H, CO2H).
13C NMR (100.6 MHz, DMSO-d6): d = 173.4 and 169.9 (CO2H,
C6), 153.7 (C2¢), 142.1 (C5¢), 136.6 and 136.3 (C9, C10), 110.6 (C4¢),
108.2 (C3¢), 90.8 (C10a), 81.1 (C8), 57.9 (C4), 52.8 and 51.2 (C6a, C7),
44.9 (C10b), 34.6 (C2), 31.3 (C3), 27.6 (C1), 18.6 and 18.3 (1-CH3, 3-
CH3).
Ethyl (1R*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-4-(2-Furyl)-1-
methyl-2,6-dioxo-1,3,4,6,6a,7,8,10b-octahydro-2H-8,10a-
epoxypyrido[2,1-a]isoindole-7-carboxylate (13b)
Yield: 75%; mp 251–252 °C.
IR: 1724 (br, C=O, CO2Et), 1678 cm–1 (br, N–C=O).
1H NMR (400 MHz, CDCl3): d = 1.12 (d, J1,1-CH3 = 6.9 Hz, 3 H, 1-
CH3), 1.25 (t, JCH2,CH3 = 7.1 Hz, 3 H, OCH2CH3), 2.78 (d,
J7endo,6a = 9.1 Hz, 1 H, H6a), 2.95 (dq, J1,10b = 12.0 Hz, J1,1-CH3 = 6.9
Hz, 1 H, H1), 2.95 (d, J6a,7endo = 9.1 Hz, 1 H, H7endo), 2.94 (dd,
2
J3B,4 = 5.7 Hz, J3,3 = 17.2 Hz, 1 H, H3B), 3.12 (dd, J3A,4 = 1.8 Hz,
2J3,3 = 17.2 Hz, 1 H, H3A), 4.18 (m, 2 H, OCH2CH3), 4.33 (d,
J10b,1 = 12.0 Hz, 1 H, H10b), 5.26 (d, J8,9 = 1.5 Hz, 1 H, H8), 5.35
(dd, J3A,4 = 1.8 Hz, J4,3B = 5.7 Hz, 1 H, H4), 6.26 (dd, J4¢,5¢ = 1.7 Hz,
J4¢,3¢ = 3.2 Hz, 1 H, H4¢), 6.46 (dd, J3¢,4¢ = 3.2 Hz, J3¢,5¢ = 0.8 Hz, 1 H,
H3¢), 6.47 (dd, J8,9 = 1.5 Hz, J9,10 = 5.7 Hz, 1 H, H9), 6.50 (d,
J9,10 = 5.7 Hz, 1 H, H10), 7.26 (dd, J5¢,3¢ = 0.8 Hz, J5¢,4¢ = 1.8 Hz, 1
H, H5¢).
MS (EI, 70 eV): m/z (%) = 245 (5) [M – 98]+, 244 (40), 228 (30),
213 (10), 202 (7), 188 (3), 176 (19), 162 (22), 147 (11), 136 (35),
122 (56), 121 (100), 108 (65), 99 (26), 91 (36), 81 (70), 79 (65), 77
(61), 65 (37), 55 (41), 39 (70).
13C NMR (100.6 MHz, CDCl3): d = 207.6 (C2), 171.5 (CO2Et),
170.1 (C6), 151.8 (C2¢), 142.2 (C5¢), 136.7 (C9), 134.9 (C10), 110.6
(C4¢), 107.9 (C3¢), 90.1 (C10a), 81.3 (C8), 61.3 (OCH2CH3), 58.6
Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found: C,
66.28; H, 6.35; N, 4.25.
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

PAPER
IMDAF of Maleic Anhydride with 2,6-Difurylpiperidin-4-ones
4253
(C10b), 51.4 (C4), 46.4, 45.5, 44.5 (C1, C6a, C7), 41.6 (C3), 14.1
(OCH2CH3), 10.0 (1-CH3).
MS (EI, 70 eV): m/z (%) = 351 (1) [M]+, 244 (21) [M – 127]+, 228
(23), 189 (9), 176 (13), 162 (100), 135 (42), 122 (42), 121 (40), 108
(67), 99 (56), 94 (72), 79 (26), 65 (47), 55 (17), 39 (48).
(dd, J4¢,5¢ = 1.8 Hz, J3¢,4¢ = 3.2 Hz, 1 H, H4¢), 6.34 (dd, J8,9 = 1.6 Hz,
J9,10 = 5.6 Hz, 1 H, H9), 6.56 (d, J9,10 = 5.6 Hz, 1 H, H10), 7.45 (dd,
5¢,3¢ = 0.6 Hz, J5¢,4¢ = 1.8 Hz, 1 H, H5¢).
13C NMR (100.6 MHz, DMSO-d6): d = 173.5 (CO2H), 169.6 (C6),
153.0 (C2¢), 141.7 (C5¢), 137.5 and 135.4 (C10, C9), 110.3 and 108.6
(C4¢, C3¢), 89.9 (C10a), 81.0 (C8), 70.6 (C2), 58.1 (C4), 53.9, 50.9,
45.1, 44.4, 40.6 (C1, C3, C6a, C7, C10b), 24.4 (2-CH3), 11.3 and 10.3
(1-CH3, 3-CH3).
J
Anal. Calcd for C20H21NO6: C, 64.68; H, 5.70; N, 3.77. Found: C,
65.07; H, 6.01; N, 3.50.
(1R*,2S*,3S*,4R*,6aR*,8S*,10aS*,10bS*)-4-(2-Furyl)-2-hy-
droxy-1,2,3-trimethyl-1,3,4,6a,7,10b-hexahydro-2H-8,10a-ep-
oxypyrido[2,1-a]isoindole-2,6(8H)-one (14)
MS (EI, 70 eV): m/z (%) = 373 (16) [M]+, 275 (30), 274 (19), 258
(15), 222 (17), 206 (4), 176 (14), 174 (13), 166 (36), 160 (46), 151
(5), 136 (11), 124 (52), 108 (45), 96 (100), 81 (37), 79 (30), 72 (9),
55 (18), 43 (76).
A mixture of 6a (1.6 g, 5.1 mmol) in benzene (40 mL), acryloyl
chloride (0.62 mL, 7.6 mmol), and Et3N (1.4 mL, 10.2 mmol) was
refluxed for 6 h (TLC monitoring). The resulting mixture was
poured into H2O (100 mL), washed with aq 5% HCl soln (50 mL),
and extracted with EtOAc (5 × 50 mL). The combined organic lay-
ers were dried (MgSO4) and concentrated to give the crude adduct.
Further crystallization (hexane–EtOAc) gave 14 as white rhom-
buses; yield: 0.68 g (40%); mp 237–238 °C.
Anal. Calcd for C20H23NO6: C, 64.33; H, 6.21; N, 3.75. Found: C,
64.15; H, 6.31; N, 3.70.
(1R*,2S*,3S*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-4-(2-Furyl)-2-
hydroxy-1,3-dimethyl-6-oxo-2-phenyl-1,3,4,6,6a,7,8,10b-oc-
tahydro-2H-8,10a-epoxypyrido[2,1-a]isoindole-7-carboxylic
Acid (15b)
IR: 3414 (OH), 1682 cm–1 (N–C=O).
Yield: 88%; mp 176–180 °C.
1H NMR (400 MHz, CDCl3): d = 0.74 and 1.06 (2 d, JMe,1(3) = 6.7
Hz, 3 H + 3 H, 3-CH3, 1-CH3), 1.26 (s, 3 H, 2-CH3), 1.48 (dd,
J7endo,6a = 8.9 Hz, J7endo,7exo = 11.8 Hz, 1 H, H7endo), 1.92 and 1.99 (2
dq, JMe,1(3) = 6.7 Hz, J1,10b(3,4) = 11.0 Hz, 1 H + 1 H, H1, H3), 2.11
(ddd, J7exo,6a = 3.8 Hz, J7exo,8 = 4.3 Hz, J7exo,7endo = 11.8 Hz, 1 H,
IR: 3179 (br, OH), 1750 (CO2H), 1673 cm–1 (N–C=O).
1H NMR (400 MHz, DMSO-d6): d = 0.18 (d, JMe,3 = 6.7 Hz, 3 H, 3-
CH3), 0.54 (d, JMe,1 = 6.7 Hz, 3 H, 1-CH3), 2.22 (m, 2 H, H1, H3),
5
2.42 (dd, J7endo,6a = 9.2, J6a,4 = 0.8 Hz, 1 H, H6a), 2.70 (d,
J6a,7endo = 9.2 Hz, 1 H, H7endo), 4.19 (d, J10b,1 = 11.0 Hz, 1 H, H10b),
4.33 (dd, J3,4 = 11.0, 5J6a,4 = 0.8 Hz, 1 H, H4), 4.98 (d, J8,9 = 1.5 Hz,
1 H, H8), 5.06 (s, 1 H, OH), 6.19 (dd, J5¢,3¢ = 0.8 Hz, J4¢,3¢ = 3.2 Hz,
1 H, H3¢), 6.27 (dd, J4¢,5¢ = 1.8 Hz, J3¢,4¢ = 3.2 Hz, 1 H, H4¢), 6.35 (dd,
J8,9 = 1.5 Hz, J9,10 = 5.7 Hz, 1 H, H9), 6.53 (d, J9,10 = 5.7 Hz, 1 H,
H10), 7.20 (br t, 1 H, HPh), 7.32–7.41 (m, 4 H, HPh), 7.46 (dd,
5
H7exo), 2.28 (ddd, J6a,7exo = 3.8 Hz, J6a,7endo = 8.9, J6a,4 = 0.9 Hz, 1
H, H6a), 4.02 (d, J10b,1 = 11.0 Hz, 1 H, H10b), 4.26 (dd, J3,4 = 11.0,
5J6a,4 = 0.9 Hz, 1 H, H4), 5.04 (dd, J8,7exo = 4.3 Hz, J8,9 = 1.7 Hz, 1
H, H8), 6.21 (dd, J4¢,3¢ = 3.2 Hz, J3¢,5¢ = 0.8 Hz, 1 H, H3¢), 6.30 (dd,
J8,9 = 1.7 Hz, J9,10 = 5.7 Hz, 1 H, H9), 6.33 (dd, J4¢,5¢ = 1.8 Hz,
J
3¢,4¢ = 3.2 Hz, 1 H, H4¢), 6.40 (d, J9,10 = 5.7 Hz, 1 H, H10), 7.42 (dd,
J5¢,3¢ = 0.8 Hz, J5¢,4¢ = 1.8 Hz, 1 H, H5¢), 11.09 (br s, 1 H, CO2H).
J5¢,3¢ = 0.8 Hz, J5¢,4¢ = 1.8 Hz, 1 H, H5¢).
13C NMR (100.6 MHz, DMSO-d6): d = 173.5 (CO2H), 169.7 (C6),
152.3 (C2¢), 145.8 (Cipso-Ph), 141.9 (C5¢), 137.1 and 135.8 (C10, C9),
128.5 (2 C, CPh), 126.8 (Cpara-Ph), 125.7 (2 C, CPh), 110.3 and 108.7
(C4¢, C3¢), 89.7 (C10a), 81.1 (C8), 77.2 (C2), 58.7 (C4), 54.2, 50.9,
45.2, 45.0, 41.3 (C1, C3, C6a, C7, C10b), 11.5 and 10.8 (1-CH3, 3-
CH3).
MS (EI, 70 eV): m/z (%) = 435 (12) [M]+, 391 (1), 362 (3), 336 (9),
327 (11), 320 (7), 228 (62), 222 (44), 202 (12), 176 (18), 160 (26),
108 (28), 105 (100), 96 (27), 81 (17), 79 (25), 77 (30), 65 (7).
13C NMR (100.6 MHz, CDCl3): d = 172.8 (C6), 151.8 (C2¢), 141.5
(C5¢), 135.2 and 135.0 (C9, C10), 110.1 and 108.9 (C3¢, C4¢), 89.9
(C10a), 78.5 (C8), 72.0 (C2), 59.2 (C4), 54.0 (C10b), 48.0, 43.5, 40.1
(C1, C3, C6a), 28.7 (C7), 24.7 (CH3-2), 10.7 and 10.0 (1-CH3, 3-
CH3).
MS (EI, 70 eV): m/z (%) = 329 (98) [M]+, 311 (19), 296 (26), 258
(17), 242 (30), 207 (14), 178 (70), 166 (44), 162 (17), 124 (100),
108 (50), 96 (16), 81 (22), 79 (24), 55 (28).
Anal. Calcd for C19H23NO4: C, 69.28; H, 7.04; N, 4.25. Found: C,
69.39; H, 6.84; N, 4.29.
Anal. Calcd for C25H25NO6: C, 68.95; H, 5.79; N, 3.22. Found: C,
68.98; H, 5.89; N, 3.46.
Pyrido[2,1-a]isoindole-7-carboxylic Acids 15a,b; Typical Proce-
dure
Methyl (1R*,2S*,3S*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-4-Fu-
ran-2-yl-2-hydroxy-1,2,3-trimethyl-6-oxo-1,3,4,6,6a,7,8,10b-oc-
tahydro-2H-8,10a-epoxypyrido[2,1-a]isoindole-7-carboxylate
(16)
Acid 15a (3.3 g, 8.5 mmol) added to MeOH (120 mL) and several
drops of H2SO4 were added. The resulting mixture was refluxed for
12 h (TLC monitoring). The soln was then cooled, poured into H2O
(250 mL), and extracted with CH2Cl2 (5 × 80 mL). The organic lay-
ers were combined, dried (MgSO4), concentrated, and purified by
column chromatography (alumina, CH2Cl2) to give 16 as bright
brown crystals; yield: 2.97 g (90%); mp 206–208 °C.
A mixture of 6a or 6b (~3 g, 11.0 mmol) and maleic anhydride 1.19
g (12.1 mmol) in toluene (30 mL) was boiled for 4–8 h. At the end
of the reaction formation of bright yellow crystals was observed.
The crystals were filtered, washed first with benzene (2 × 20 mL),
then with acetone (2 × 15 mL), and dried in the open air to give
15a,b as white powders.
(1R*,2S*,3S*,4R*,6aR*,7S*,8R*,10aS*,10bS*)-4-(2-Furyl)-2-
hydroxy-1,2,3-trimethyl-6-oxo-1,3,4,6,6a,7,8,10b-octahydro-
2H-8,10a-epoxypyrido[2,1-a]isoindole-7-carboxylic Acid (15a)
Yield: 96%; mp 220–225 °C.
IR: 3442 (br, OH), 1711 (CO2Me), 1682 cm–1 (N–C=O).
1H NMR (400 MHz, CDCl3): d = 0.74 (d, JMe,3 = 6.7 Hz, 3 H, 3-
CH3), 1.03 (d, JMe,1 = 6.7 Hz, 3 H, 1-CH3), 1.21 (s, 3 H, 2-CH3), 1.97
(dq, JMe,3 = 6.7 Hz, J3,4 = 10.5 Hz, 1 H, H3), 2.05 (dq, JMe,1 = 6.7 Hz,
J1,10b = 11.1 Hz, 1 H, H1), 2.56 (d, J7endo,6a = 9.1 Hz, 1 H, H6a), 2.64
(d, J6a,7endo = 9.1 Hz, 1 H, H7endo), 3.60 (s, 3 H, CO2Me), 4.00 (d,
J10b,1 = 11.1 Hz, 1 H, H10b), 4.21 (d, J3,4 = 10.5 Hz, 1 H, H4), 5.13
(d, J8,9 = 1.7 Hz, 1 H, H8), 6.15 (br d, J3¢,4¢ = 3.6 Hz, 1 H, H3¢), 6.26
(dd, J4¢,5¢ = 1.9 Hz, J4¢,3¢ = 3.6 Hz, 1 H, H4¢), 6.33 (dd, J8,9 = 1.7 Hz,
IR: 3469 (OH), 1747 (CO2H), 1680 cm–1 (br, N–C=O).
1H NMR (400 MHz, DMSO-d6): d = 0.57 (d, JMe,3 = 6.6 Hz, 3 H, 3-
CH3), 0.91 (d, JMe,1 = 6.6 Hz, 3 H, 1-CH3), 1.10 (s, 3 H, 2-CH3), 1.72
(dq, JMe,3 = 6.6 Hz, J3,4 = 10.6 Hz, 1 H, H3), 2.38 (d, J7endo,6a = 9.2
Hz, 1 H, H6a), 2.50 (dq, JMe,1 = 6.6 Hz, J1,10b = 11.1 Hz, 1 H, H1),
2.62 (br d, J6a,7endo = 9.2 Hz, 1 H, H7endo), 3.97 (d, J10b,1 = 11.1 Hz,
1 H, H10b), 4.11 (d, J3,4 = 10.6 Hz, 1 H, H4), 4.49 (s, 1 H, OH), 4.95
(d, J8,9 = 1.6 Hz, 1 H, H8), 6.13 (br d, J4¢,3¢ = 3.2 Hz, 1 H, H3¢), 6.26
Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

4254
F. I. Zubkov et al.
PAPER
J9,10 = 5.7 Hz, 1 H, H9), 6.50 (d, J9,10 = 5.7 Hz, 1 H, H10), 7.30 (br
d, J5¢,4¢ = 1.9 Hz, 1 H, H5¢).
MS (EI, 70 eV): m/z (%) = 264 (100) [M]+, 263 (58), 235 (4), 170
(13), 141 (7), 115 (10), 89 (5), 63 (4).
13C NMR (100.6 MHz, CDCl3): d = 172.1 (CO2CH3), 169.6 (C6),
152.2 (C2¢), 141.1 (C5¢), 136.9 (C9), 135.0 (C10), 110.1 (C4¢), 108.1
(C3¢), 89.8 (C10a), 81.0 (C8), 71.8 (C2), 58.3 (C4), 53.9 (C10b), 52.1
(CO2CH3), 51.3 (C6a), 45.4 (C7), 43.8 (C3), 39.8 (C1), 24.8 (2-CH3),
11.0 (3-CH3), 9.9 (1-CH3).
Anal. Calcd for C16H12N2O2: C, 72.72; H, 4.58; N, 10.60. Found: C,
72.29; N, H, 4.69; 10.97.
Acknowledgment
MS (EI, 70 eV): m/z (%) = 387 (25) [M]+, 369 (3), 356 (1), 274 (45),
258 (14), 256 (13), 236 (20), 202 (7), 176 (17), 166 (35), 124 (60),
113 (47), 108 (36), 96 (21), 81 (32), 79 (37), 65 (18), 59 (21), 43
(100).
The authors are grateful to the Russian Foundation for Basic
Research for the financial support of this work (Grant No.
07-03-00083a).
Anal. Calcd for C21H25NO6: C, 65.10; H, 6.50; N, 3.62. Found: C,
64.82; H, 6.65; N, 3.72.
References
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R. S.; Varlamov, A. V. Tetrahedron 2005, 61, 4099.
(b) Boltukhina, E. V.; Zubkov, F. I.; Nikitina, E. V.;
Varlamov, A. V. Synthesis 2005, 1859. (c) Zubkov, F. I.;
Boltukhina, E. V.; Nikitina, E. V.; Varlamov, A. V. Russ.
Chem. Bull. 2004, 53, 2816.
(8) (a) Zubkov, F. I.; Boltukhina, E. V.; Turchin, K. F.;
Varlamov, A. V. Tetrahedron 2004, 60, 8455. (b) Zubkov,
F. I.; Boltukhina, E. V.; Krapivko, A. P.; Varlamov, A. V.
Chem. Heterocycl. Compd. (Engl. Transl.) 2003, 39, 1534.
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(2S*,3R*,6R*)(4E)-2,6-Di-2-furyl-3-methylpiperidin-4-one
Oxime (17)
A soln of 2a (5.0 g, 0.02 mol), NH2OH·HCl (1.35 g, 0.04 mol), and
NaOH (1.6 g, 0.04 mol) in EtOH (70 mL) was refluxed for 2 h. The
resulting mixture was poured into H2O (250 mL) and extracted with
EtOAc (3 × 70 mL). The combined organic extracts were dried
(MgSO4), concentrated, and purified by the crystallization (hexane–
EtOAc) to give 18 as white crystals; yield: 4.2 g (81%); mp 182–
183 °C (Lit.11b 112 °C).
IR: 3260 (br), 3155, 2978 (NH, OH), 1667 cm–1 (C=N).
1H NMR (400 MHz, CDCl3): d = 0.95 (d, J3,Me = 6.5 Hz, 3 H, 3-
2
CH3), 2.15 [dd, J5(a),6 = 12.4 Hz, J5,5 = 13.8 Hz, 1 H, H5(a)], 2.20
(br s, 1 H, NH), 2.69 (dq, J3,2 = 10.5 Hz, J3,Me = 6.5 Hz, 1 H, H3),
3.98 (d, J2,3 = 10.5 Hz, 1 H, H2), 3.74 [dd, J5(e),6 = 3.0 Hz,
2J5,5 = 13.8 Hz, 1 H, H5(e)], 3.95 (dd, J6,5(e) = 3.0 Hz, J6,5(a) = 12.4
Hz, 1 H, H6), 6.22 (br d, Jb¢,b = 3.2 Hz, 1 H, Hb*), 6.28 (dd,
Ja,b = 1.8 Hz, Jb¢,b = 3.2 Hz, 1 H, Hb), 6.32–6.29 (m, 2 H, Hb¢,
Hb¢*), 7.33 (dd, Jb¢,a = 0.8 Hz, Ja,b = 1.8 Hz, 1 H, Ha), 7.36 (dd,
Jb¢,a = 0.6 Hz, Ja,b = 1.8 Hz, 1 H, Ha*), 7.67 (s, 1 H, OH).
13C NMR (100.6 MHz, CDCl3): d = 159.0 (C4), 155.2 and 154.4 (Ca,
Ca*), 142.0 and 141.9 (Cipso, Cipso*), 110.2 (2 C, Cb¢, Cb¢*), 107.5 and
105.6 (Cb, Cb*), 61.5 (C2), 53.6 (C6), 41.5 (C3), 29.6 (C5), 12.0 (3-
CH3).
MS (EI, 70 eV): m/z (%) = 260 (60) [M]+, 243 (33), 231 (3), 175
(17), 174 (27), 148 (12), 120 (7), 97 (22), 96 (100), 94 (40), 68 (28),
65 (11).
Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C,
64.51; H, 6.31; N, 10.86.
4,6-Di-2-furyl-7-methyl-1H-pyrrolo[3,2-c]pyridine (18)
Powdered KOH (0.89 g, 0.016 mol) was added to a soln of 17 (4.2
g, 0.016 mol) in DMSO (100 mL). The resulting mixture was heated
up to 95 °C and treated with acetylene gas for 5 h. The mixture was
the poured into H2O (350 mL) and extracted with Et2O (6 × 80 mL).
The combined organic layers were dried (Na2SO4), concentrated,
and purified by column chromatography (alumina, hexane) to give
18 as brown needles; yield: 0.52 g (12%); mp 94–96 °C.
IR: 3494 cm–1 (NH).
1H NMR (400 MHz, CDCl3): d = 2.39 (s, 3 H, 7-CH3), 6.50 (dd,
Ja,b = 1.6 Hz, Jb,b¢ = 3.3 Hz, 1 H, Hb), 6.64 (dd, Ja,b = 1.6 Hz,
Jb,b¢ = 3.3 Hz, 1 H, Hb), 6.77 (br d, Jb,b¢ = 3.3 Hz, 1 H, Hb¢), 6.91 (br
d, Jb,b¢ = 3.3 Hz, 1 H, Hb¢), 7.44 (br d, J2,3 = 3.1 Hz, 1 H, H2), 7.46
(br d, Jb,a = 1.6 Hz, 1 H, Ha), 7.52 (s, 1 H, NH), 7.69 (br d, Jb,a = 1.6
Hz, 1 H, Ha), 7.46 (br d, J2,3 = 3.1 Hz, 1 H, H3).
13C NMR (100.6 MHz, CDCl3): d = 153.9 and 148.8 (Cipso, Cipso*),
144.2 and 142.1 (Ca, Ca*), 131.4 and 131.2 (C4, C6), 118.5 (C2),
114.7 (C3), 112.2, 112.1, 111.9 (C7, Cb¢, Cb¢*), 111.4 and 110.7 (C3a,
C7a), 106.6 and 103.8 (Cb, Cb*), 10.4 (7-CH3).
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Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York

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IMDAF of Maleic Anhydride with 2,6-Difurylpiperidin-4-ones
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Synthesis 2009, No. 24, 4235–4255 © Thieme Stuttgart · New York