Intramolecular Diels - Alder reaction of 4-(N-furfuryl)aminobut-1-enes. New approach to the synthesis of 6,8a-epoxyoctahydroisoquinoline (3-aza-11-oxatricyclo[6.2.1.01,6]undec-9-ene) derivatives

Article abstract of DOI:10.1023/B:RUCB.0000037856.61928.c4

The intramolecular Diels - Alder reaction of readily accessible 4-substituted 4-(N-furfuryl)aminobut-1-enes was studied and a new one-step method was developed for the synthesis of 6,8a-epoxy-1,2,3,4,4a,5,6,8a- octahydroisoquinoline (3-aza-11-oxatricyclo[

Full text of DOI:10.1023/B:RUCB.0000037856.61928.c4

860
Russian Chemical Bulletin, International Edition, Vol. 53, No. 4, pp. 860—872, April, 2004
Intramolecular Diels—Alder reaction of 4ꢀ(Nꢀfurfuryl)aminobutꢀ1ꢀenes.
New approach to the synthesis of 6,8aꢀepoxyoctahydroisoquinoline
(3ꢀazaꢀ11ꢀoxatricyclo[6.2.1.01,6]undecꢀ9ꢀene) derivatives
a
b
a
a
a
F. I. Zubkov,a E. V. Nikitina, K. F. Turchin, A. A. Safronova, R. S. Borisov, and A. V. Varlamov
ꢀ
aPeoples' Friendship University of Russia,
6 ul. MiklukhoꢀMaklaya, 117198 Moscow, Russian Federation.
Fax: +7 (095) 952 0745. Eꢀmail: fzubkov@sci.pfu.edu.ru
bCenter for Drug Chemistry, AllꢀRussian Chemical and Pharmaceutical Research Institute,
7 Zubovskaya ul., 119815 Moscow, Russian Federation.
Eꢀmail: turchin@drug.org.ru
The intramolecular Diels—Alder reaction of readily accessible 4ꢀsubstituted 4ꢀ(Nꢀfurꢀ
furyl)aminobutꢀ1ꢀenes was studied and a new oneꢀstep method was developed for the synthesis
of 6,8aꢀepoxyꢀ1,2,3,4,4a,5,6,8aꢀoctahydroisoquinoline (3ꢀazaꢀ11ꢀoxatricyclo[6.2.1.01,6]undecꢀ
9ꢀene) derivatives. The [4+2]ꢀcycloaddition proceeds stereoselectively to form exoꢀadducts.
The influence of substituents at the nitrogen atom in 4ꢀ(Nꢀfurfuryl)aminobutꢀ1ꢀenes on the
cycloaddition pathway was examined.
Key words: homoallylamines, intramolecular [4+2]ꢀcycloaddition, furans, intramolecular
Diels—Alder reaction, 6,8aꢀepoxyoctahydroisoquinolines, 3ꢀazaꢀ11ꢀoxatricyclo[6.2.1.01,6]unꢀ
decꢀ9ꢀenes.
Decahydroisoquinoline represents a major structural
We are carrying out systematic investigation into the
reactivity of secondary homoallylamines, viz., 4ꢀsubstiꢀ
tuted 4ꢀNꢀaryl(aralkyl)aminobutꢀ1ꢀenes. Based on this
class of compounds, preparative methods have been deꢀ
veloped for the synthesis of tetrahydroquinolines,21
benzꢀ2ꢀazepines,22 6ꢀsubstituted and allꢀcis spiroꢀfused
2ꢀphenylpiperidinꢀ4ꢀols,23 azetidines, and 1,2,3ꢀoxaꢀ
thiazines.24
Recently, we have proposed an original approach to
the synthesis of a new heterocyclic system, viz., 3ꢀspiroꢀ
fused 6,8aꢀepoxyoctahydroisoquinoline (3ꢀazaꢀ11ꢀoxaꢀ
tricyclo[6.2.1.01,6]undecꢀ9ꢀene), based on the exoꢀstereoꢀ
selective intramolecular [4+2]ꢀcyclization of 1ꢀallylꢀ1ꢀ
(Nꢀfurfuryl)aminocycloalkanes.25
The aim of the present study was to investigate the
stereochemical features of this process and the electronic
and steric effects of substituents in the allylic fragꢀ
ment and cyclizing agents (acid anhydrides and halides)
(Scheme 1).
The starting azomethines, which were prepared by conꢀ
densation of furfurylamine with cyclic ketones23,26 (see
Scheme 1), were not isolated in the individual state and
were introduced into the reactions with the Grignard reꢀ
agents directly after distillation of benzene from the reacꢀ
tion mixture.
fragment of more than 500 various alkaloids.1 However,
the reactivity of hydrogenated 6,8aꢀepoxyisoquinolines,
which are synthetic precursors of polyhydroxyperhydroꢀ
isoquinolines, has not been adequately investigated. This
is associated primarily with the lack of general and reliꢀ
able procedures for the preparation of these compounds.
One of the most efficient approaches to the synthesis of
epoxyoctahydroisoquinolines involves the intramolecular
[4+2]ꢀcycloaddition of alkenylfurans. This reaction,
which has been described for the first time in the study
of photooxidation of furylcyclophane,2 is efficient for
the construction of hydrogenated derivatives of the
isoindole,3—7 indole, and quinoline series.8—13 A versaꢀ
tile preparative method for the synthesis of hydrogeꢀ
nated indoles and quinolines14 is based on the intramoꢀ
lecular [4+2]ꢀcycloaddition of Nꢀallyl(butenyl)ꢀNꢀ
(αꢀfuryl)urethanes.8—13
Examples of the use of the Diels—Alder reaction for
the construction of octa(hexa)hydroꢀ6,8aꢀepoxyisoquinoꢀ
line systems are scarce.15—19 This is associated with the
ambiguity (compared to the synthesis of 5,7aꢀepoxyisoꢀ
indoles) of the [4+2]ꢀcycloaddition of tertiary furfurylꢀ
butenylamines as well as with the fact that some of these
compounds are not easily accessible. The stereoselective
synthesis of enantiomeric 6,8aꢀepoxyꢀ1,2,3,4,4a,5,6,8aꢀ
octahydroisoquinolines has recently been described.20
Homoallylamines 1a—e underwent partial cyclization
into exoꢀepoxyoctahydroisoquinoline derivatives 2a—e at
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 824—836, April, 2004.
1066ꢀ5285/04/5304ꢀ0860 © 2004 Plenum Publishing Corporation

Cyclization of 4ꢀ(Nꢀfurfuryl)aminobutꢀ1ꢀenes
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
861
Scheme 1
1—3: X = bond (a), CH2 (b), (CH2)2 (c), NMe (d), NEt (e)
160—200 °C. As a result, amines 1a—c,e isolated by
vacuum distillation were contaminated (according to the
1H NMR spectroscopic data) with 5—9% of the correꢀ
sponding tricyclic compounds 2a—c,e. The exception is
compound 1d (X = NMe), which is contaminated with
25% of epoxyoctahydroisoquinoline 2d. Adduct 2d was
isolated from the mixture in the individual state in 5% yield
by crystallization. In other cases, we did not undertake
attempts to isolate compounds 2 in the individual state.
Apparently, thermal intramolecular cyclization of amines
1a—e is an equilibrium reaction. However, attempts to
increase the yield of tricyclic systems 2a—e by refluxing
furfurylamines 1a—e in highꢀboiling solvents (oꢀxylene,
pseudocumene, or durene) failed.
To the contrary, intramolecular cyclization of homoꢀ
allylamines 1a—e in boiling acetic anhydride, which inꢀ
volved Nꢀacylation as the first step, proceeded readily and
stereoselectively to give exoꢀDielsꢀAlder adducts 3a—e in
48—71% yields (see Scheme 1).
Refluxing of methallyl derivatives 4a,b in acetic anꢀ
hydride led only to acetylation of the N atom giving rise
to amides 5a,b. The fact that intramolecular cyclization
does not occur is apparently attributable to destabilizaꢀ
tion of the transition state due to steric hindrance caused
by the Me group of the methallyl fragment.
mixture of the major (1fmaj) and minor (1fmin) isomers due
to the presence of the tertꢀbutyl fragment, which hinders
inversion of the cyclohexane ring (Scheme 2). According
to the 13C NMR spectroscopic data, isomer 1fmaj with the
equatorial orientation of the allyl substituent slightly preꢀ
dominated in the reaction mixture. The 1fmin : 1fmaj ratio
in the reaction mixture was ~45 : 55, i.e., the addition of
the Grignard reagent proceeded nonstereospecifically.
Vacuum distillation of isomers of 1f was also accompaꢀ
nied by partial intramolecular cyclization into epoxyꢀ
octahydroisoquinoline derivatives 2f (after distillation, the
1f : 2f ratio was ~4 : 1, the total yield of compounds 1f and
2f was 65%). Unlike amines 1a—e, refluxing of a mixture
of 1f and 2f in oꢀxylene led to further cyclization. After
heating for 5 h, the 1f : 2f ratio decreased to ~1 : 1 (more
prolonged heating led to a decrease in the total yield of
amines 1f and 2f and had virtually no effect on their
ratio).
Cyclization of a mixture of isomeric allylamines 1f
and tricyclic compounds 2f in boiling acetic anhydride
proceeds readily and stereoselectively to give a mixture of
isomers of 3f in virtually quantitative yield; the ratio of
these isomers corresponds to the ratio of isomers of 1f in
the starting mixture (3fmin : 3fmaj ≈ 45 : 55).
All isomers of compounds 1f, 2f, and 3f were isolated
in the individual state by column chromatography. Their
spatial structures were established by 13C NMR spectroꢀ
Unlike homoallylamines 1a—e, 1ꢀallylꢀ4ꢀtertꢀbutylꢀ
1ꢀ(Nꢀfurfuryl)aminocyclohexane (1f) was prepared as a

862
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Zubkov et al.
Scheme 2
The stereochemistry of the epoxyoctahydroisoquinoꢀ
line moiety is identical for the isomer pairs of 2f and 3f
1
and was established by H NMR spectroscopy (Tables 2
and 3). In the spectra of all compounds, the spinꢀspin
coupling constants for analogous protons have similar valꢀ
3
ues (3JH(7A),H(8) < 1 Hz, JH(7B),H(8) = 4.4—4.6 Hz,
3
3JH(6),H(7A) = 7.7—7.3 Hz, JH(6),H(7B) = 2.7—3.6 Hz).
According to the published data,29 these constants are
indicative of the endo orientation of the H(6) and H(7A)
protons and the exo orientation of the H(7B) proton. The
H(6) atom is in the axial orientation with respect to the
piperidine ring, as evidenced by the large value of the
vicinal spinꢀspin coupling constant between one of
protons at the C(5) atom and the H(6) proton (3J =
11.8—13.2 Hz).
We believe that the ease of intramolecular [4+2]ꢀcycloꢀ
addition of amines 1 in acetic anhydride is attributable
not to the Thorpe—Ingold effect associated with the "conꢀ
traction" of the endocyclic angles30 but to flattening of
the amide fragment in the initially formed Nꢀacyl derivaꢀ
tive. This flattening increases ordering of the dieneꢀ
dienophilic fragment of the molecule resulting in a deꢀ
crease in the entropy of formation of the transition
state.31,32
In recent studies33—38 of intramolecular cyclization
of NꢀRꢀNꢀallylfurfurylamines, the influence of the volꢀ
ume and electronic effects of the substituents R at the
N atom on this process was examined. The yield of
intramolecular cycloaddition adducts was found to inꢀ
crease substantially with increase in the volume of the
substituent.
To estimate the influence of the substituent at the
N atom on the formation of 6,8aꢀepoxyoctahydroisoꢀ
quinolines 6a—e and 7a—e, we carried out the intramoꢀ
lecular cycloaddition of allylamines 1b,c in propionic anꢀ
hydride, a mixture of acetic anhydride and formic acid,
chloroacetyl chloride, benzoyl chloride, and boiling xyꢀ
lene in the presence of an excess of trifluoroacetic anꢀ
hydride (see the Experimental section). NꢀAcylꢀsubstiꢀ
tuted tricyclic compounds 6a—e and 7a—e were prepared
in yields from 40 to 60% (Scheme 3).
scopy on the assumption that the chair conformation of
the cyclohexane ring with the equatorial orientation of
the bulky tertꢀbutyl substituent (a "conformational anꢀ
chor") is retained in all the compounds under study. In
this case, the orientation of the C(5)—C(4) bond in the
major isomer differs from that in the minor isomer.
It is known27,28 that in the 13C NMR spectra of symꢀ
metrical isomeric dimethylcyclohexanes, the higherꢀfield
signal for the C atoms of the Me groups belongs to the
isomer in which the diequatorial arrangement of the Me
groups cannot occur. The upfield shift of the signal for the
axial methyl carbon atom compared to the signal for the
equatorial carbon atom, which was estimated based on the
published data for isomeric 1,4ꢀdimethylcyclohexanes,28
is ~5 ppm.
A comparison of the 13C chemical shifts for the analoꢀ
gous C atoms in the isomer pairs of 1f—3f shows that the
signal for the C(5) atom in the minor isomers is noticeꢀ
ably (by 5.4—8.3 ppm) shifted upfield (the numbering of
atoms in the isomers of 1f presented in Scheme 2 was
changed for the ease of viewing, see Table 1), the differꢀ
ences in the chemical shifts of all other C atoms being
substantially smaller. Taking into account the aforesaid,
this fact is indicative of the axial orientation of the
C(5)—C(4) bond in the minor isomers, which corresponds
to the cis arrangement of the C(5) atom and the tertꢀbutyl
substituent.
Scheme 3
6, 7: R = H (a), Et (b), CH2Cl (c), Ph (d), CF3 (e)
n = 1 (1b, 6a—e), 2 (1c, 7a—e)

Table 1. 13C NMR spectra of compounds 1f, 2f, and 3f (CDCl3)a
Comꢀ
δ (1JC,H/Hz)
pound
b
C(1)
C(2)
C(4)
54.0
C(5)
∆
C(6)
C(7)
C(8)
C(9)
C(10)
106.0
C(2´)
C(6´)
36.0
C(3´)
C(5´)
23.1
C(4´)
1fmin
1fmaj
2fmin
154.6
38.9
(134.5)
35.9
(∼125)
8.3 133.9
117.8
141.4
110.0
47.7
(~125)
(151.5) (154.0, (201.5) (174.0) (174.0)
157.0)
(125.5)
(~125)
155.1
83.9
38.3
(134.0)
53.1
51.0
44.2
(125.0)
134.4
117.2
141.2
110.0
105.7
35.1
21.8
47.9
(122.5)
(151.5) (154.0, (201.5) (174.5) (174.0)
157.0)
(125.5)
(126.0)
42.6
(132.5,
136.5)
37.5
(126.0)
8.1
5.4
30.1
35.0
78.4
137.3
135.7
41.3
30.9
22.9
22.6
48.0
(135.0) (135.0) (162.7) (173.0) (171.0) (124.0) (125.0) (126.0) (124.0) (123.5)
2fmaj
3fmin
3fmaj
83.9
86.5
85.1
42.4
(134.0)
50.2
61.5
59.4
45.6
(126.0)
30.4
35.0
78.5
137.3
135.9
41.0
29.6
22.0
21.7
48.6
(135.0) (134.0) (162.5) (173.0) (172.0) (124.5) (124.0) (125.0) (126.0) (123.0)
45.3
(138.0)
34.7
(128.0)
32.6
31.2
77.9
136.1
136.1
33.0
28.4
23.9
23.1
46.5
(134.5) (135.0) (162.5) (~174) (~174) (128.5) (128.5) (126.0) (126.0) (126.0)
45.4
40.1
31.4
33.8
78.5
137.9
134.7
37.3
34.0
22.9
21.7
47.4
(137.0)
(129.0)
(135.0) (135.0) (163.5) (174.0) (172.0) (125.0, (125.5) (127.0) (127.0) (124.5)
135.0)
a The chemical shifts of the C atoms of the 4´ꢀtertꢀbutyl and acetyl groups (δ, J/Hz): 1fmin, 27.5 (C3H9, J = 124.5), 32.2 (Cquat); 1fmaj, 27.5 (C3H9,
J = 124.5), 32.3 (Cquat); 2fmin, 27.4 (C3H9, J = 124.5), 32.1 (Cquat); 2fmaj, 27.5 (C3H9, J = 124.5), 32.3 (Cquat); 3fmin, 25.8 (CH3, J = 128.0), 27.3
(C3H9, J = 124.5), 32.0 (Cquat), 171.0 (CO); 3fmaj, 25.4 (CH3, J = 128.0), 27.2 (C3H9, J = 124.5), 32.2 (Cquat), 173.2 (CO).
b The difference in the chemical shifts of the axial and equatorial C(5) atoms in the pairs of the corresponding isomers.

Table 2. Chemical shifts (δ) of the protons in the 1H NMR spectra of Nꢀsubstituted epoxyoctahydroisoquinolines 3a—j, 6a—e, and 7a—e (CDCl3)
Comꢀ
pound
δ
H(2А) H(2В) H(5ax
)
H(5eq
)
H(6) H(7ax
)
H(7eq
)
H(8)
H(9) H(10)
X
R, R´
3а
3b
3c
3d
4.03
(d)
3.94
(d)
1.42—1.79, 1.95—2.22 (both m)
4.91
(dd)
6.36
(dd)
6.09
(d)
2.10
(s, Ме)
1.79—1.42, 2.22—1.95 (both m, 8 Н, cycloꢀC5H8)
3.92
(d)
3.75
(d)
1.46
(dd)
1.86
(dd)
1.72
(m)
1.47
(dd)
1.38
(m)
4.86
(dd)
6.30
(dd)
6.12
(d)
2.11
(s, Ме)
1.25, 2.64 (both m, 2 Н, H(2)´); 1.35—1.50 (m, 6 Н,
Н(3´), Н(4´), Н(5´)); 1.40, 2.84 (both m, 2 Н, Н(6´))
4.04
(d)
3.47
(d)
*
1.96
(dd)
*
*
1.41
(dt)
4.90
(d)
6.32 (s)
2.14
(s, Ме)
1.20—2.00, 2.57 (both m, 15 Н, cycloꢀC7H12,
Н(5ax), Н(6), Н(7ax))
4.02
(d)
3.90
(d)
*
1.71
*
*
*
4.94
(dd)
6.39
(dd)
6.10
(d)
2.17
(s, Ме)
1.83—1.90, 2.30—2.60 (both m, 4 H and 7 H each,
Н(5ax), Н(6), 2 Н(7), piperidine);
(br.d)
2.26 (s, 3 Н, NMe); 3.17 (m, 1 Н, Н(3´))
3e
4.04
(d)
3.89
(d)
*
*
3.21
(m)
*
1.43
(dt)
4.93
(br.d) (dd)
6.38
6.08
(d)
2.16
(s, Ме)
1.08 (t, 3 Н, СН3СН2); 1.35—1.90,
2.20—2.65 (m, 11 Н, piperidine, 2 Н(5),
Н(7ax); 2.38 (q, 2 Н, СН2СН3)
3fmaj
4.05
(d)
3.78
(d)
1.72
(q)
1.45
(q)
1.84
(m)
1.36
(m)
1.42
(dd)
4.86
(dd)
6.32
(dd)
5.99
(d)
2.09
(s, Ме)
0.77 (s, 9 Н, But); 0.96, 2.35 (both m, 1 H each,
C(6´)Н2); 1.01, 1.56 (both m, 1 H each, C(3´)Н2);
1.03 (m, 1 Н, H(4´)); 1.03, 3.38 (both m, 1 H each,
C(2´)Н2); 1.09, 1.54 (both m, 1 H each, C(5´)Н2)
3fmin
4.04
(d)
3.46
(d)
1.19
(m)
2.16
(q)
1.58
(m)
1.37
(m)
1.50
(dd)
4.85
(dd)
6.26
(dd)
6.28
(d)
2.11
(s, Ме)
0.79 (s, 9 Н, But); 1.12 (m, 1 Н, H(4´)); 1.02,
1.61 (both m, 1 H each, C(3´)Н2); 1.11, 1.60 (both m,
1 H each, C(5´)Н2); 1.79, 2.34 (both m, 1 H each,
C(6´)Н2); 1.60, 2.92 (both m, 1 H each, C(2´)Н2)
3g
5.01
(br.s) (br.d)
3.35
1.35—1.80, 2.20—2.40 (both m)
4.87
(dd) (br.d)
6.28
6.41
(d)
2.04
(s, 3 Н)
~5.03 (br.s, 1 Н, H(4)); 7.15—7.35 (m, Ph)

3h
3i
4.39
(br.d) (br.d)
3.67
1.25—1.50, 1.60—1.80,
1.90—2.05 (all m)
4.88
(br.d) (dd)
6.29
6.24
(d)
2.04
(br.s, Me)
1.86 (s, Me); 7.15—7.35 (m, Ph)
4.41
(br.s)
3.88
(d)
1.40, 1.58, 1.95—1.85 (all m)
4.91 6.36 (s, 2 H)
(d)
1.96
(s, Me)
2.15 (br.s, Ме); 7.14 (t, Нo);
7.29—7.33, 7.50—7.60 (both m, Ar)
3j
4.39
(br.d) (br.d)
4.11
2.37
(dd)
2.64
(dd)
1.40—1.50,
1.50—1.70 (both m)
4.93
(br.s)
6.32
(dd)
6.00
(d)
2.15
(br.s, Me)
7.05—7.50 (m, Ph)
6а
6b
5.00
(d)
3.43
(d)
1.32
(dd)
2.11
(dd)
*
1.53
(dd)
1.41
(ddd)
4.93
(dd)
6.39
(dd)
6.07
(d)
8.44
(s, Н)
1.86—1.98 (m, 11 Н, cycloꢀC6H10, Н(6))
3.98
(d)
3.81
(d)
*
1.93
(dd)
1.20—1.95 (m)
4.91
(dd)
6.34
(dd)
6.20
(d)
1.12
(t, СН3СН2);
2.73, 2.92 (both m, 1 H each, cycloꢀC6H10);
1.30, 1.40—1.54, 1.76 (all m, 12 H each,
2.44 (m, СН2СН3) cycloꢀC6H10, Н(5ax), Н(6), 2 Н(7))
6c
6d
6e
7a
7b
4.01
(d)
3.89
(d)
1.20—1.95 (m)
4.92
(dd)
6.37
(dd)
6.20
(d)
4.02, 4.31
(d, СН2Сl)
1.20—1.95 (both m, 8 Н, cycloꢀC6H10);
2.97, 2.56 (both m, 1 H each, cycloꢀC6H10
)
3.94
(d)
3.85
(d)
1.25—1.75, 1.75—1.95 (both m)
4.89
(dd)
6.29
(dd)
5.99
(d)
7.40—7.52
(m, Ph)
1.75—1.95, 1.25—1.75 (both m, 8 Н, cycloꢀC6H10);
2.54, 3.19 (both m, 1 H each, cycloꢀC7H12
)
4.15
(d)
3.68
(d)
*
2.15
(dd)
*
*
*
4.93
(dd)
6.35
(dd)
6.27
(d)
—
1.35—1.80 (m, 11 Н, cycloꢀC6H10, Н(5ax),
Н(6), 2 Н(7)); 2.70 (m, 2 Н, cycloꢀC6H10
)
4.74
(d)
3.54
(d)
1.30—2.30 (m)
4.92
(dd)
7.38
(dd)
6.09
(d)
8.47 (s, Н)
1.30—2.30 (m, 12 Н, cycloꢀC7H12)
4.06
(d)
3.46
(d)
1.90—2.00, 2.50—2.70 (both m)
4.88
(d)
6.30
(s)
1.14 (t, СН3СН2) 1.25—1.90, 2.50—2.70 (both m, 12 Н,
2.30—2.50
cycloꢀC7H12)
(m, СН2СН3)
7c
7d
7e
4.07
(d)
3.57
(d)
*
*
*
1.98
(dd)
*
*
*
*
*
1.42
(ddd)
4.91
(dd)
6.32
(dd)
6.41
(d)
4.03, 4.19
(d, СН2Сl)
2.49, 2.63 (both m, 1 H each, cycloꢀC7H12);
1.20—1.95 (m, 13 Н, cycloꢀC7H12, Н(5ax),
Н(6), Н(7eq))
3.91
(d)
3.62
(d)
1.99
(dd)
*
*
4.88
(dd)
6.29
(dd)
6.20
(d)
7.36—7.44
(m, Ph)
1.43—1.93 (m, 13 Н, cycloꢀC7H12, Н(5ax),
Н(6), 2 Н(7)); 2.60, 2.83 (both m, 1 H each,
cycloꢀC7H12
)
4.25
(dq)
3.42
(d)
*
2.06
(dd)
4.91
(dd)
6.30
(dd)
6.37
(d)
—
1.20—2.00, 2.40—2.60 (both m, 16 Н,
cycloꢀC7H12, 2 Н(5), 2 Н(7))
* The signals for the protons overlap with a complex multiplet of the H atoms of the cycloalkane ring.

866
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Zubkov et al.
Table 3. Spin coupling constants (J ) of the protons in the 1H NMR spectra of Nꢀsubstituted epoxyoctahydroisoquinolines 3a—j,
6a—e, and 7a—e (CDCl3)
Comꢀ
pound
J/Hz
2A, 2B
5
ax, 5eq 5eq, 6
5ax, 6
6, 7ax
6, 7eq 7ax, 7eq 7eq, 8
8, 9
9, 10
X, R, and R´
3a
3b
3c
3d
15.4
15.4
15.0
15.6
15.0
15.8
15.1
14.3
14.7
14.6
15.0
15.3
15.3
*
13.5
13.1
*
*
5.1
3.1
*
*
12.5
*
*
*
11.8
13.0
*
*
*
*
7.6
*
*
*
7.3
7.7
*
*
*
*
3.4
4.3
*
3.7
3.2
3.6
*
*
*
*
2.9
*
*
11.3
11.3
*
11.3
11.3
11.0
*
*
*
*
11.3
*
4.0
4.5
4.3
4.3
3.7
4.4
4.4
4.3
4.3
3.7
—
1.3
1.7
—
1.8
1.5
1.7
1.5
1.8
1.5
—
6.0
5.8
—
5.8
5.8
5.8
5.8
5.8
5.8
—
—
—
—
—
3e
*
*
3J(CH3CH2) = 7.3
3fmaj
3fmin
3g
3h
3i
3j
6a
6b
13.2
13.8
*
*
*
14.3
13.5
13.4
6.4
3.4
*
*
*
4.6
5.7
4.9
—
—
—
—
3Jo,m = 3Jm,p = 7.5
12.2
12.2
*
*
7.5
*
1.5
1.7
1.2
5.8
5.7
5.5
—
4.6
4.5
—
3J(CH3CH2) = 7.3,
2J(CН(A)Н(B)) = 15.3
2J(СН2Cl) = 12.8
—
6c
6d
6e
7a
7b
15.6
15.0
15.6
15.3
15.3
*
*
*
*
4.0
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
4.3
4.3
4.3
4.3
4.3
1.5
1.5
1.2
1.5
—
5.8
5.8
5.8
5.5
—
13.4
*
*
—
—
*
3J(CH3CH2) = 7.3,
2J(CН(A)Н(B)) = 16.5
2J(СН2Cl) = 12.2
—
7c
7d
7e
15.2
15.1
15.3
13.1
13.3
13.1
3.4
4.0
*
4.0
*
2.4
11.3
*
*
4.3
4.4
4.3
1.5
1.6
1.2
5.5
5.8
6.1
*
*
*
*
5J(Н(2A)CF3) = 1.2
* Spin coupling constants were not measured due to overlap of the signals for the corresponding protons with the signals for the
protons of the cycloalkane substituent.
Scheme 4
The results of our study did not allow us to make an
unambiguous conclusion about the influence of the subꢀ
stituents R on the cyclization process. The size of the
annelated ring also has no substantial effect. It should
only be noted that the yields of the corresponding Nꢀacyl
derivatives 3b and 3c were somewhat higher (~70%) than
those of analogs containing other substituents R. The presꢀ
ence of electronꢀwithdrawing groups at the N atom (R =
CH2Cl or CF3) allows the cyclization temperature to be
lowered.
1, 3
g
h
i
j
R1
Ph
H
Ph
Me
pꢀPhC6H4
Ph
Ph
Homoallylamines 1g—j, which were prepared from
acyclic aldehydes and ketones according to an analogous
procedure, also undergo stereoselective cyclization in
boiling acetic anhydride to form exoꢀadducts 3g—j
(J7ꢀexo,6ꢀendo = 3.4—4.0 Hz). Compounds 3g—j were preꢀ
pared in 34—70% yields (Scheme 4).
R2
Me
substantial broadening of the signals for the H(2) and
H(4) protons due to hindered rotation of the acetyl group
about the amide bond (CO—N). The nature of the solꢀ
vent (CDCl3, DMSOꢀd6, CD3OH, and C6D6) and heatꢀ
ing of a sample in an NMR tube to 65 °C had no effect on
the resolution of these signals. Therefore, we failed to
measure the spin coupling constant J4,5 and determine
the orientation of the H(4) proton in the piperidine ring
of amide 3g (see Tables 2 and 3).
1
According to the H NMR spectroscopic data, tricyꢀ
clic compounds 3h and 3i bearing different substituents
R1 and R2 were prepared as the only geometrical isomer
as regards the arrangement of the substituents relative to
the epoxide bridge. Unfortunately, the 1H NMR NOE
experiments for octahydroisoquinolines 3h,i did not allow
us to unambiguously determine the orientations of the
substituents at the C(4) atom. The interpretation of the
1H NMR spectra of compound 3g is complicated by a
In conclusion, it should be noted that the reaction
mixtures prepared by cyclization of all homoallylamines 1
in acetic anhydride contained impurities of acyclic

Cyclization of 4ꢀ(Nꢀfurfuryl)aminobutꢀ1ꢀenes
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
867
saturated solution of ammonium chloride. The products were
extracted with diethyl ether (3×100 mL), the extract was dried
with MgSO4, the solvent was distilled off, and the residue was
fractionated in vacuo. Homoallylamines 1a—j (in a mixture with
epoxy derivatives 2a—j) and 4a,b were obtained as labile paleꢀ
yellow oils. The chromatographic mobilities of amines 1a—j and
4a,b were measured in a 1 : 3 ethyl acetate—hexane system.
After vacuum distillation of allylamine 1d, the distillate parꢀ
tially crystallized. The crystals were filtered off, washed with
cold hexane, and twice recrystallized from hexane. 1´ꢀMethylꢀ
6,8aꢀepoxyspiro[1,2,3,4,4a,5,6,8aꢀoctahydroisoquinolineꢀ3,4´ꢀ
piperidine] (2d) was obtained in 5% yield, m.p. 110—111 °C,
Rf 0.16. Found (%): C, 71.58; H, 9.42; N, 11.90. C14H22N2O.
Calculated (%): C, 71.76; H, 9.46; N, 11.95. IR, ν/cm–1: 1638
(C=C). 1H NMR, δ: 1.05—2.05 (m, 10 H); 2.29 (s, 3 H,
N(1´)Me); 2.35—2.50 (m, 4 H, H(3´) and H(5´)); 3.37 (s, 2 H,
H(2)); 4.92 (dd, 1 H, H(8), J = 4.6 Hz, J = 1.7 Hz); 5.96 (d,
1 H, H(10), J = 5.5 Hz); 6.38 (dd, 1 H, H(9), J = 5.5 Hz, J =
1.7 Hz). MS, m/z (Irel (%)): 234 [M]+ (23), 205 (3), 176 (20),
163 (13), 138 (37), 122 (11), 111 (22), 110 (16), 109 (26), 96
(100), 81 (89), 70 (38), 53 (32).
Nꢀacetylꢀsubstituted derivatives (results of TLC and
1H NMR spectroscopy of crude reaction mixtures), which
indicates that cycloaddition is reversible.
To summarize, we developed a new oneꢀstep preparaꢀ
tive procedure for the synthesis of hydrogenated
6,8aꢀepoxyisoquinolines based on the intramolecular
Diels—Alder reaction of readily accessible 4ꢀ(Nꢀfurꢀ
furyl)aminobutꢀ1ꢀenes. We made an attempt to estimate
the influence of substituents in the starting furfurylalkenes
on the rate of [4+2]ꢀcycloaddition and demonstrated that
the cyclizing agent has no effect on the yields of the target
products.
Experimental
The reagents were purchased from Acros Organics. The IR
spectra were recorded on URꢀ20 and Specord IRꢀ75 spectromꢀ
eters in KBr pellets (for crystalline compounds) or in a film (for
oils). The mass spectra were obtained on Finnigan MAT95XL
and Hewlett—Packard MSꢀ5988 mass spectrometers with direct
inlet of the sample into the ion source; the ionizing energy
was 70 eV. The 1H and 13C NMR spectra were measured on
Bruker WPꢀ200 (200 MHz) and Varian Unity+400 (400 MHz
for 1H and 100.6 MHz for 13C) instruments in CDCl3, C6H6, or
DMSOꢀd6 at 23 °C. The 1H NMR spectroscopic data for
homoallylamines 1a—j and 4a,b are given in Tables 4 and 5. The
chemical shifts were measured in the δ scale with Me4Si as the
internal standard. The AB systems in the 1H NMR spectra are
marked with asterisks. Thinꢀlayer chromatography was carried
out with the use of Silufol plates (visualization with iodine vaꢀ
por). The yields, physicochemical characteristics, results of elꢀ
emental analysis, and selected spectroscopic data for homoꢀ
allylamines 1a—j and 4a,b and epoxyoctahydroisoquinolines
3a—j, 6a—e, and 7a—e are given in Tables 6 and 7.
1ꢀAllylꢀ1ꢀNꢀfurfurylaminocyclopentane (1a), ꢀcyclohexane
(1b), ꢀcycloheptane (1c), 1ꢀallylꢀ4ꢀtertꢀbutylꢀ1ꢀNꢀfurfurylꢀ
aminocyclohexane (1f), 4ꢀallylꢀ4ꢀNꢀfurfurylaminoꢀ1ꢀmethylꢀ
piperidine (1d), 4ꢀallylꢀ1ꢀethylꢀ4ꢀNꢀfurfurylaminopiperidine (1e),
4ꢀNꢀfurfurylaminoꢀ4ꢀphenylbutꢀ1ꢀene (1g), 4ꢀNꢀfurfurylaminoꢀ
4,4ꢀdiphenylbutꢀ1ꢀene (1j), 4ꢀNꢀfurfurylaminoꢀ4ꢀphenylpentꢀ1ꢀ
ene (1h), 4ꢀNꢀfurfurylaminoꢀ4ꢀ(biphenylꢀ4ꢀyl)pentꢀ1ꢀene (1i),
1ꢀNꢀfurfurylaminoꢀ1ꢀmethallylcyclohexane (4a), and 1ꢀNꢀfurꢀ
furylaminoꢀ1ꢀmethallylcycloheptane (4b) (general procedure).
A solution of freshly distilled furfurylamine (0.2 mol) and the
corresponding aldehyde or ketone (0.2 mol) in benzene (70 mL)
was refluxed using a Dean—Stark trap for 1—4 h until the theoꢀ
retical amount of water (~3.6 mL) was collected. If the separaꢀ
tion of water proceeded slowly, several drops of glacial acetic
acid were added. The solvent was removed under reduced presꢀ
sure. Azomethines were used in the subsequent step without
additional workup.
Vacuum distillation of 1f afforded a mixture of isomers of
allylamine 1f and isoquinoline 2f. According to the 1H NMR
spectroscopic data, the ratio of isomers 1fmaj and 1fmin was
~55 : 45, the 1f : 2f ratio being 4 : 1. The total yield was 65%,
b.p. 154—160 °C (1 Torr). The resulting mixture was chromaꢀ
tographed on Al2O3 (15×1.5 cm) using a 1 : 100 ethyl acꢀ
etate—hexane mixture as the eluent. Allylamines 1fmaj and 1fmin
were isolated as paleꢀyellow oils.
4´ꢀtertꢀButylꢀ6,8ꢀepoxyspiro[(1,2,3,4,4a,5,6,8aꢀoctaꢀ
hydro)isoquinolineꢀ1,3´ꢀcyclohexanes] 2fmaj and 2fmin were preꢀ
pared as colorless crystals.
Isoquinoline 2fmaj, the yield was 7%, m.p. 99—102.5 °C,
Rf 0.29. Found (%): C, 78.72; H, 10.70; N, 5.21. C18H29NO.
Calculated (%): C, 78.49; H, 10.61; N, 5.09. IR, ν/cm–1: 1598
(C=C); 3295 (NH). 1H NMR, δ: 0.82 (s, 9 H, But); 0.90 (m,
1 H, H(4´)); 0.90 and 2.20 (both m, 1 H each, 2 H(2´)); 1.16 (q,
1 H, H(5B), J = 13.2 Hz, J = 12.2 Hz); 1.20 and 1.48 (both m,
1 H each, 2 H(5´)); 1.26 and 1.36 (both m, 1 H each, 2 H(6´));
1.35 (ddd, 1 H, H(7B), J = 11.2 Hz, J = 4.7 Hz, J = 2.7 Hz);
1.35 and 1.44 (both m, 1 H each, 2 H(3´)); 1.47 (q, 1 H, H(7A),
J = 11.2 Hz, J = 7.5 Hz, J ≈ 0 Hz); 1.53 (q, 1 H, H(5A), J =
13.2 Hz, J = 6.1 Hz); 1.74 (dddd, 1 H, H(6), J = 12.2 Hz, J =
7.5 Hz, J = 6.1 Hz, J = 2.7 Hz); 3.29* (1 H, H(2B), J =
15.2 Hz); 3.31* (1 H, H(2A), J = 15.2 Hz); 4.88 (q, 1 H, H(8),
J = 4.6 Hz, J = 1.8 Hz); 5.93 (d, 1 H, H(10), J = 5.8 Hz); 6.32
(q, 1 H, H(9), J = 5.8 Hz, J = 1.8 Hz). MS, m/z (Irel (%)): 275
[M]+ (6), 266 (2), 234 (6), 176 (45), 163 (6), 154 (15), 122 (8),
91 (9), 80 (12), 81 (100), 79 (10), 77 (9), 67 (7), 57 (47), 53 (22),
43 (10), 41 (53), 39 (12).
Isoquinoline 2fmin, the yield was 3%, m.p. 127—129 °C,
Rf 0.10. Found (%): C, 78.56; H, 10.60; N, 5.11. C18H29NO.
Calculated (%): C, 78.49; H, 10.61; N, 5.09. IR, ν/cm–1: 1610
1
Freshly prepared azomethine was added under gentle reflux
to a solution of allylmagnesium bromide (methallylmagnesium
chloride for compounds 4a,b), which was prepared from alꢀ
lyl bromide (methallyl chloride) (0.3 mol) and magnesium
(0.6 mol), in anhydrous diethyl ether (a 1 : 1 THF—diethyl ether
mixture for compounds 4a,b) (200 mL). The reaction mixture
was stirred at 25 °C for 1 h, cooled to 0 °C, and poured onto ice
(100 mL). The resulting emulsion was destroyed by adding a
(C=C); 3320 (NH). H NMR, δ: 0.78 (s, 9 H, But); 0.82 (ddd,
1 H, H(5B), J = 13.5 Hz, J = 12.3 Hz, J = 1.5 Hz); 0.92 and 1.56
(both m, 1 H each, 2 H(3´)); 0.93 (m, 1 H, H(4´)); 1.00 and 2.15
(both m, 1 H each, 2 H(2´)); 1.06 and 1.50 (both m, 1 H each,
2 H(5´)); 1.28 and 1.32 (both m, 1 H each, 2 H(6´)); 1.35 (ddd,
1 H, H(7B), J = 11.2 Hz, J = 4.6 Hz, J = 2.7 Hz); 1.46 (q, 1 H,
H(7A), J = 11.2 Hz, J = 7.6 Hz, J ≈ 0 Hz); 1.62 (m, 1 H, H(6));
2.16 (q, 1 H, H(5A), J = 13.5 Hz, J = 5.8 Hz); 3.25 (d, 1 H,

868
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Zubkov et al.
1
Table 4. Chemical shifts (δ) of the protons in the H NMR spectra of solutions of homoallylamines 1a—j and 4a,b (CDCl3)
Comꢀ
pound
δ
H(1)cis H(1)trans H(2)
H(3)
NCH2
Furan H
NH
R and R´
α
β
β´
1a
1b
1c
1d
5.09
(dd)
5.10
(dd)
5.09
(m)
5.05
(dd)
5.08
(dd)
5.07
(m)
5.82
(m)
5.86
(m)
5.85
(m)
5.85
(m)
2.26
(d)
2.21
(d)
2.20
(dt)
2.22
(d)
3.66
(s)
3.68
(s)
3.68
(s)
3.68
(s)
7.29
(dd)
7.33
(dd)
7.32
(dd)
7.34
(dd)
6.24
(dd)
6.29
(dd)
6.28
(dd)
6.30
(dd)
6.10
(d)
1.73
(br.s)
—
1.25—1.75 (m, 8 Н, cycloꢀC5H8)
1.25—1.70 (m, 10 Н, cycloꢀC6H10
1.25—1.95 (m, 12 Н, cycloꢀC7H12
1.56—1.67 (m, 4 Н, С(3´)H2);
6.15
(dd)
6.14
(dd)
6.17
(m)
)
)
—
5.13
(m)
5.09
(m)
1.19
(br.s) 2.28 (m, 4 Н, С(2´)H2);
2.35—2.48 (s, 3 Н, NMe)
1e
5.11
(m)
5.09
(m)
5.85
(m)
2.22
(d)
3.68
(s)
7.34
(dd)
6.29
(dd)
6.15
(dd)
—
—
1.08 (t, 3 Н, NCH2CH3); 1.61 (m,
4 Н, С(3´)H2); 2.30—2.60 (m, 4 Н,
С(2´)H2); 2.41 (q, 2 Н, NCH2CH3)
0.84 (s, 9 Н, But); 0.90 (m, 1 Н,
H(4´)); 1.23, 1.50 (both m, 2 H each,
С(3´)H2, С(5´)H2);
1fmaj
5.07
(m)
5.04
(m)
5.86
(m)
2.12
(d)
3.63
(s)
7.32
(d)
6.28
(dd)
6.15
(d)
1.23, 1.75 (both m, 2 H each,
С(2´)H2, С(6´)H2)
1fmin
5.11
(m)
5.10
(m)
5.81
(m)
2.28
(d)
3.73
(s)
7.31
(d)
6.26
(dd)
6.12
(d)
—
0.84 (s, 9 Н, But); 0.98 (m, 1 Н,
H(4´)); 1.12, 1.62 (both m, 2 H each,
С(3´)H2, С(5´)H2);
1.30, 1.73 (both m, 2 H each,
С(2´)H2, С(6´)H2)
1g
1h
1i
5.04
(m)
5.04
(dd)
5.08
(dd)
5.02
(m)
4.90
(m)
4.90
(m)
5.06
(m)
5.68
(m)
5.65
(m)
5.68
(ddt)
5.53
(m)
2.40 3.67, 3.51 7.33
(m) (both d) (d)
2.50 3.58, 3.45 7.32
(d) (both d) (d)
2.54 3.60, 3.49 7.33
6.28
(dd)
6.27
(dd)
6.28
(dd)
6.26
(dd)
6.29
(dd)
6.29
(dd)
6.06
(d)
6.11
(d)
6.13
(d)
6.11
(d)
6.15
(dd)
6.15
(dd)
1.85
(s)
1.70
7.35—7.20 (m, 5 Н, Ph);
3.66 (t, H)
1.50 (s, Me);
5.06
(dd)
5.10
(br.d)
5.00
(m)
(br.s) 7.40—7.60 (m, 5 Н, Ph)
1.81
(s)
1.85
(br.s)
—
1.53 (s, Me); 7.42 (t, 1 Н, Нo);
7.52—7.61 (m, 8 Н, pꢀPhС6Н4)
7.05—7.45 (m, 10 Н, 2 Ph)
(m)
3.09
(d)
(both d)
3.44
(s)
(d)
7.29
(d)
1j
4a
4b
4.70
1.84
2.17
3.69
(s)
3.72
(s)
7.33
(dd)
7.32
(dd)
1.20—1.70 (m, 10 Н, cycloꢀC6H10
1.35—1.70 (m, 12 Н, cycloꢀC7H12
)
)
(m) (br.s, Me) (br.s)
4.71 1.84 2.18
(m) (br.s, Me) (br.s)
—
H(2B), J = 15.2 Hz); 3.43 (d, 1 H, H(2A), J = 15.2 Hz); 4.84 (q,
1 H, H(8), J = 4.6 Hz, J = 1.7 Hz); 5.90 (d, 1 H, H(10), J =
5.8 Hz); 6.30 (q, 1 H, H(9), J = 5.8 Hz, J = 1.7 Hz). MS,
m/z (Irel (%)): 275 [M]+ (8), 266 (4), 176 (18), 154 (19), 122 (8),
91 (11), 80 (12), 81 (100), 79 (8), 77 (9), 67 (7), 57 (39), 53 (17),
43 (10), 41 (60), 39 (13).
3ꢀAcetylspiro[3ꢀazaꢀ11ꢀoxatricyclo[6.2.1.01,6]undecꢀ9ꢀeneꢀ
4,1´ꢀcyclopentane] (3a), ꢀcyclohexane] (3b), ꢀcycloheptane] (3c),
ꢀ4´ꢀmethylpiperidine] (3d), ꢀ4´ꢀethylpiperidine] (3e),
ꢀ4´ꢀtertꢀbutylcyclohexane] (3f); 3ꢀacetylꢀ3ꢀazaꢀ11ꢀoxatriꢀ
cyclo[6.2.1.01,6]undecꢀ9ꢀeneꢀ[4ꢀphenyl] (3g), ꢀ4,4ꢀdiphenyl]
(3j), ꢀ4ꢀmethylꢀ4ꢀphenyl] (3h), ꢀ4ꢀ(biphenylꢀ4ꢀyl)ꢀ4ꢀmethylꢀ4]
(3i) (general procedure). Homoallylamine 1a—j or 4a,b (0.1 mol)
was refluxed in a 20ꢀfold molar excess of acetic anhydride for
3—6 h (TLC control). An excess of the anhydride was distilled
off under reduced pressure, the residue was poured into water
(200 mL), and NaHCO3 was added to pH 9—10. The reaction
mixture was extracted with ethyl acetate (3×70 mL) and the
extract was dried with MgSO4. After removal of the solvent, the
residue was recrystallized from a hexane—ethyl acetate mixture.
Tricyclic compounds 3a—j were prepared as colorless crystals.
NꢀAcyl derivatives 5a,b, which were obtained as paleꢀyellow
oils, were purified by chromatography on Al2O3 (hexane as the
eluent).

Cyclization of 4ꢀ(Nꢀfurfuryl)aminobutꢀ1ꢀenes
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
869
Table 5. Spinꢀspin coupling constants (J ) of protons in the 1H NMR spectra of solutions of homoallylamines 1a—j and 4a,b (CDCl3)
Comꢀ
pound
J/Hz
J1,1
J1cis,2
J1trans,2
J2,3
J3A,4 JNCH(A)H(B)
J of furan H atoms
Other J
α,β
α,β´
β,β´
1a
1b
1c
1d
1.3
2.4
≈2.4
1.3
2.4
2.4
2.3
2.1
2.1
1.8
2.1
1.7
1.7
10.4
11.0
≈11.0
10.2
10.7
10.3
10.5
9.8
17.1
16.5
≈16.2
16.9
16.5
17.0
16.8
16.8
16.8
17.4
≈17.4
7.4
7.3
7.3
7.4
7.3
7.4
7.4
6.4
7.6
7.4
7.0
—
—
—
—
—
—
—
—
7.0
—
—
—
—
—
—
—
—
—
—
—
—
14.7
13.7
13.6
*
2.1
1.8
1.8
1.8
1.8
1.9
1.9
1.8
1.8
1.8
1.5
1.8
1.8
0.5
0.6
0.9
0.8
0.9
0.9
0.9
—
—
—
—
0.9
0.9
3.4
3.1
3.4
3.2
3.1
3.2
3.2
3.1
3.1
3.0
3.1
3.4
3.1
—
—
J1´,3´cis = J1´,3´trans = 1.0
—
1e
3J(CH3CH2) = 7.0
1fmaj
1fmin
1g
1h
1i
1j
4a
4b
—
—
—
—
10.4
10.2
≈10.1
Jo,m = Jm,p = 7.6
—
—
—
3.3
3.1
—
—
—
* Spin coupling constants were not measured.
Table 6. Yields and physicochemical characteristics of homoallylamines 1a—j and 4a,b
Comꢀ
pound (%)
Yield
M.p.
/°C
(p/Torr)
Rf
Molecular weight
Found
Calculated
Molecular
formula
IR,
(%)
ν/cm–1
Found, Calculated
[M]+
C
H
N
С=С NH
1614 3327
1a
62
71
67
45
61
25
17
72
55
46
28
63
62
133—138
(8.0)
127—129
(2.0)
154—157
(7.0)
130—134
(2.0)
127—136
(3.0)
154—160
(1.0)
0.50a
0.63b
0.65b
0.23c
0.32d
0.54a
0.43a
0.47a
0.48a
0.60b
0.62a
0.67a
0.55a
205
219
233
234
248
275
275
205
219
233
234
248
275
275
227
241
317
303
233
247
76.09
76.06
76.70
76.67
77.23
77.21
71.81
71.76
72.60
72.54
9.30
9.33
9.58
9.65
9.90
9.93
9.37
9.46
9.69
9.74
6.83
6.82
6.35
6.39
6.00
6.00
11.96
11.95
11.30
11.28
5.00
5.09
5.11
5.09
6.17
6.16
5.75
5.80
4.37
4.41
4.59
4.62
6.03
6.00
5.72
5.66
С13H19NO
С14H21NO
С15H23NO
С14H22N2O
С15H24N2O
С18H29NO
С18H29NO
С15H17NO
С16H19NO
С22H23NO
С21H21NO
С15H23NO
С16H25NO
1b
1632 3335
1640 3340
1630 3325
1638 3332
1633 3340
1635 3330
1645 3342
1642 3320
1636 3338
1653 3320
1645 3347
1627 3367
1c
1d
1e
1fmaj
1fmin
1g
78.67 10.61
78.49 10.61
78.49 10.52
78.49 10.61
42
118—120
(2.0)
157—159
(3.0)
176—180
(4.0)
167—171
(2.0)
116—117.5
(1.0)
136—138
(1.5)
186
[M – 41]+
241
79.30
79.26
79.39
79.63
83.12
83.24
83.08
83.13
77.00
77.21
7.45
7.54
7.89
7.94
7.25
7.30
6.94
6.98
9.85
9.93
1h
1i
317
303
1j
4a
218
[M – 15]+
232
4b
77.56 10.00
77.68 10.19
[M – 15]+
a Ethyl acetate—hexane (1 : 3).
b Ethyl acetate—hexane (1 : 2).
c PriOH—NH4OH (25%) (1 : 1).
d Ethyl acetate.

870
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Zubkov et al.
Table 7. Yields and physicochemical characteristics of epoxyoctahydroisoquinolines 3a—j, 6a—e, and 7a—e
Comꢀ
pound (%)
Yield
M.p.a
/°C
Rf
Molecular
weight
Found
Calculated
Molecular
formula
IR,
ν/cm–1
(%)
C
H
N
С=С
NCO
3a
3b
3c
3d
3e
3fmaj
3fmin
3g
3h
3i
48
71
68
50
48
27
19
34
37
38
42
22
52
40
61
40
23
56
38
56
40
88—89
134—135
135—136
98.5—101
113—114
175.5—177
189.5—191
117—118
152—153
151—152
150.5—152
Oil
0.28b
0.62c
0.26b
0.11d
0.21c
0.39e
0.28e
0.47c
0.13b
0.31f
0.14b
0.21g
0.26b
0.50f
0.37b
0.53b
0.24c
0.48e
0.44e
0.42b
0.50b
247
261
275
276
290
317
317
269
283
359
345
247
275
295
323
315
261
289
309
337
329
72.62
72.84
73.36
73.53
74.27
74.14
69.40
69.53
70.52
70.31
75.71
75.67
75.64
75.67
75.58
75.81
76.48
76.29
80.07
80.19
80.11
79.97
73.00
72.84
74.11
74.14
64.97
64.97
78.07
77.98
60.77
60.94
73.48
73.53
74.83
74.70
66.03
65.90
78.55
78.30
62.11
61.99
8.34
8.56
8.79
8.87
9.15
9.15
8.81
8.75
8.98
9.02
9.90
9.84
9.81
9.84
7.20
7.11
7.59
7.47
6.90
7.01
6.49
6.71
8.63
8.56
9.20
9.15
7.48
7. 50
7.69
7.79
6.08
6.39
8.88
8.87
9.35
9.40
7.68
7.81
8.27
8.06
6.80
6.73
5.81
5.66
5.24
5.36
5.26
5.09
10.10
10.14
9.55
9.65
4.40
4.41
4.48
4.41
5.25
5.20
4.75
4.94
3.94
3.90
4.00
4.05
5.37
5.66
5.04
5.09
4.57
4.74
4.28
4.33
4.49
4.44
5.27
5.36
4.90
4.84
4.57
4.52
4.32
4.15
4.01
4.25
С15H21NO2
С16H23NO2
С17H25NO2
С16H24N2O2
С17H26N2O2
С20H31NO2
С20H31NO2
С17H19NO2
С18H21NO2
С24H25NO2
С23H23NO2
С15H21NO2
С17H25NO2
С16H22NO2Cl
С21H25NO2
С16H20NO2F3
С16H23NO2
С18H27NO2
С17H24NO2Cl
С22H27NO2
С17H22NO2F3
1630
1630
1623
1650
1674
1729
1640
1620
1639
1646
1633
1640
1647
1637
1647
1633
1685
1626
1648
1653
1633
3j
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
58—60
89.5—90.5
157.5—159
46—47
107—109
85.5—87
121—122.5
173.5—175
93.5—97.5
1697
1651
a From an ethyl acetate—hexane mixture.
b Ethyl acetate—hexane (1 : 3).
c Ethyl acetate.
d EtOH—NH4OH (25%) (5 : 1).
e Ethyl acetate—hexane (1 : 1).
f Ethyl acetate—hexane (1 : 2).
g Ethyl acetate—hexane (2 : 1).
Compound 3a. MS, m/z (Irel (%)): 247 [M]+ (18), 206 (10),
204 (6), 164 (6), 126 (15), 122 (9), 82 (7), 81 (100), 53 (6), 43
(11), 41 (5).
Compound 3b. MS, m/z (Irel (%)): 261 [M]+ (63), 246 (2),
220 (19), 218 (13), 204 (34), 176 (12), 140 (40), 122 (14), 121
(29), 98 (10), 81 (100), 80 (9), 43 (25), 40 (26).

Cyclization of 4ꢀ(Nꢀfurfuryl)aminobutꢀ1ꢀenes
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
871
Compound 3c. MS, m/z (Irel (%)): 276 (5), 275 [M]+ (45),
260 (4), 234 (12), 204 (24), 176 (11), 154 (41), 135 (18), 122
(11), 112 (9), 82 (9), 81 (100), 53 (10), 43 (18), 41 (11).
Compound 3d. MS, m/z (Irel (%)): 276 [M]+ (10), 247(3),
233 (58), 138 (40), 136 (20), 122 (13), 110 (20), 109 (25), 97
(13), 96 (100), 94 (18), 81 (62), 72 (17), 70 (30), 53 (27), 44
(22), 43 (83), 42 (46).
Compound 3e. MS, m/z (Irel (%)): 290 [M]+ (27), 275 (10),
261 (8), 248 (14), 247 (100), 152 (42) 150 (18), 124 (14), 123
(13), 122 (21), 110 (64), 108 (14), 85 (14), 84 (25), 58 (12), 43
(17), 42 (15).
0.145 mol). The reaction mixture was refluxed for 5 h, poured
into water (100 mL), alkalified with sodium hydrogencarbonate
to pH 9—10, and extracted with diethyl ether (3×50 mL). The
organic phases were combined and dried with MgSO4. After
removal of the solvent, the residue was chromatographed on
Al2O3 (20×4 cm) using a 1 : 5 ethyl acetate—hexane mixture as
the eluent. Tricyclic compounds 6a and 7a were prepared as a
brown oil and colorless crystals, respectively.
Compound 6a. MS, m/z (Irel (%)): 247 [M]+ (12), 206 (18),
166 (8), 151 (6), 125 (28), 122 (8), 96 (8), 81 (100), 79 (10), 53
(10), 44 (64), 41 (12), 28 (20).
Epoxyisoquinoline 3f was prepared as a mixture of isomers
3fmaj and 3fmin in a total yield of 65%. The mixture was resolved
by column chromatography on Al2O3 (30×2 cm) using a 1 : 20
ethyl acetate—hexane system as the eluent.
Compound 7a. MS, m/z (Irel (%)): 261 [M]+ (4), 242 (2),
220 (5), 204 (2), 167 (3), 140 (10), 135 (5), 125 (15), 122 (7),
113 (4), 95 (10), 91 (5), 82 (7), 81 (100), 79 (6), 67 (8), 55 (9),
53 (13), 41 (18).
Compound 3fmaj. MS, m/z (Irel (%)): 317 [M]+ (13), 260
(29), 218 (16), 196 (15), 177 (16), 176 (26), 140 (10), 81 (100),
57 (19), 43 (16), 41 (15).
3ꢀPropionylspiro[3ꢀazaꢀ11ꢀoxatricyclo[6.2.1.01,6]undecꢀ9ꢀ
eneꢀ4,1´ꢀcyclohexane] (6b), ꢀcycloheptane] (7b) (general proceꢀ
dure). Homoallylamine 1b,c (0.1 mol) was refluxed in a 20ꢀfold
molar excess of propionic anhydride for 4 h. An excess of the
anhydride was removed under reduced pressure, the residue was
poured into water (200 mL), and the mixture was neutralized
with sodium hydrogencarbonate; pH was brought to 9—10. The
mixture was extracted with ethyl acetate (3×70 mL). The orꢀ
ganic extracts were combined and dried with MgSO4. After reꢀ
moval of the solvent, the residue was recrystallized from hexane.
Tricyclic compounds 6b and 7b were prepared as colorless
crystals.
Compound 3fmin. MS, m/z (Irel (%)): 317 [M]+ (18), 276
(14), 260 (19), 218 (11), 196 (26), 177 (17), 176 (15), 140 (10),
81 (100), 57 (18), 43 (14), 41 (13).
Compound 3g. MS, m/z (Irel (%)): 269 [M]+ (16), 228 (8),
227 (26), 210 (12), 208 (15), 188 (9), 186 (8), 146 (7), 138 (33),
104 (13), 96 (46), 91 (19), 81 (100), 53 (12), 43 (21).
Compound 3h. MS, m/z (Irel (%)): 283 [M]+ (2), 268 (1),
161 (4), 162 (6), 129 (6), 117 (7), 103 (10), 91 (20), 81 (60), 77
(22), 65 (10), 53 (17), 43 (100), 41 (13), 39 (8).
Compound 3i. MS, m/z (Irel (%)): 359 [M]+ (16), 302 (10),
276 (5), 238 (20), 220 (14), 205 (12), 196 (22), 194 (11), 180
(15), 179 (19), 178 (18), 167 (8), 165 (18), 163 (10), 152 (16), 96
(8), 81 (100), 43 (15).
Compound 3j. MS, m/z (Irel (%)): 345 [M]+ (25), 302 (2),
283 (3), 252 (29), 251 (20), 224 (20), 182 (34), 180 (12), 178
(16), 165 (34), 129 (16), 128 (15), 115 (12), 91 (35), 81 (100), 77
(28), 53 (23), 43 (73), 41 (10).
Compound 6b. MS, m/z (Irel (%)): 276 (12), 275 [M]+ (78),
234 (14), 219 (12), 218 (44), 178 (16), 176 (18), 154 (43), 122
(11), 121 (21), 98 (8), 81 (100), 79 (7), 57 (6), 41 (6).
Compound 7b. MS, m/z (Irel (%)): 290 (2), 289 [M]+ (8),
260 (6), 232 (4), 218 (12), 196 (18), 183 (14), 182 (100), 181
(36), 176 (8), 168 (19), 154 (10), 112 (7), 91 (17), 81 (52), 28 (15).
3ꢀChloroacetylspiro[3ꢀazaꢀ11ꢀoxatricyclo[6.2.1.01,6]undecꢀ
9ꢀeneꢀ4,1´ꢀcyclohexane] (6c), ꢀcycloheptane] (7c) (general proꢀ
cedure). Triethylamine (4 mL, 0.03 mol) was added to a solution
of homoallylamine 1b,c (0.018 mol) in acetonitrile (25 mL).
Chloroacetyl chloride (2.1 mL, 0.027 mol) was added to the
reaction mixture at 5 °C. The reaction mixture was stirred at
~20 °C for 4 h (TLC control), poured into water (100 mL), and
extracted with diethyl ether (3×50 mL). The organic phases were
combined and dried with MgSO4. After removal of the solvent,
the residue was chromatographed on Al2O3 (30×3 cm) using a
1 : 100 ethyl acetate—hexane mixture as the eluent. Tricyclic
compounds 6c and 7c were obtained as colorless crystals.
Compound 6c. MS, m/z (Irel (%)): 297 (0.34), 295 [M]+ (1),
261 (2), 260 (9), 256 (3), 254 (8), 174 (4), 138 (3), 122 (5), 121
(4), 91 (2), 82 (6), 81 (100), 79 (4), 67 (3), 53 (6), 41 (4).
Compound 7c. MS, m/z (Irel (%)): 309 [M]+ (2), 274 (29),
188 (8), 135 (9), 122 (8), 95 (8), 81 (100), 77 (5), 67 (8), 55 (6),
53 (9), 41 (9).
Compound 5a, the yield was 69%, Rf 0.49 (ethyl acꢀ
etate—hexane, 1 : 1). Found (%): C, 74.23; H, 9.11; N, 5.02.
C
17H25NO2. Calculated (%): C, 74.14; H, 9.15; N, 5.09. IR,
ν/cm–1: 1633 (C=C and C=O). 1H NMR, δ: 1.15—1.35 and
1.40—1.60 (both m, 10 H, (CH2)5); 1.74 (br.s, 3 H, C(2)Me);
2.18 (s, 3 H, C(O)Me); 2.74 (s, 2 H, H(3)); 4.44 (br.s, 2 H,
NCH2); 4.66 and 4.86 (both m, 1 H each, H(1)); 6.19 (dd, 1 H,
H(γ), J = 0.9 Hz, J = 3.1 Hz); 6.33 (dd, 1 H, H(β), J = 1.8 Hz,
J = 3.1 Hz); 7.35 (br.d, 1 H, H(α), J = 1.8 Hz). MS,
m/z (Irel (%)): 275 [M]+ (1), 221 (5), 220 (36), 178 (14), 140 (4),
121 (5), 96 (3), 82 (7), 81 (100), 69 (3), 53 (7), 43 (6), 41 (3).
Compound 5b, the yield was 67%, Rf 0.36 (ethyl acꢀ
etate—hexane, 1 : 1). Found (%): C, 74.58; H, 9.41; N, 4.80.
C18H27NO2. Calculated (%): C, 74.70; H, 9.40; N, 4.84. IR,
ν/cm–1: 1627 (C=C and C=O). 1H NMR, δ: 1.37—1.48 (m,
12 H, (CH2)6); 1.71 (br.s, 3 H, C(2)Me); 2.23 (s, 3 H, C(O)Me);
2.64 (s, 2 H, H(3)); 4.44 (br.s, 2 H, NCH2); 4.62 and 4.83
(both m, 1 H each, 2 H(1)); 6.20 (dd, 1 H, H(γ), J = 0.8 Hz, J =
3.2 Hz); 6.34 (dd, 1 H, H(β), J = 1.7 Hz, J = 3.2 Hz); 7.35 (dd,
1 H, H(α), J = 1.7 Hz, J = 0.8 Hz). MS, m/z (Irel (%)): 234
[M – 55]+ (25), 192 (12), 140 (3), 135 (3), 96 (6), 95 (3), 82 (6),
81 (100), 67 (3), 55 (3), 53 (7), 43 (6), 41 (4).
3ꢀBenzoylspiro[3ꢀazaꢀ11ꢀoxatricyclo[6.2.1.01,6]undecꢀ9ꢀ
eneꢀ4,1´ꢀcyclohexane] (6d), ꢀcycloheptane] (7d) (general proceꢀ
dure). Benzoyl chloride (2.62 g, 2.2 mL, 0.019 mol) was added
dropwise to a solution of amines 1b,c (0.0125 mol) and triethylꢀ
amine (9.10 g, 0.09 mol) in toluene (50 mL). The reaction
mixture was refluxed for 2—3 h, poured into water (200 mL),
alkalified with sodium hydrogencarbonate, and extracted with
ethyl acetate. The organic phase was dried with MgSO4, the
solvent was distilled off, and the residue (brown oil) was trituꢀ
rated in a hexane—diethyl ether mixture (1 : 1, v/v). The crystals
3ꢀFormylspiro[3ꢀazaꢀ11ꢀoxatricyclo[6.2.1.01,6]undecꢀ9ꢀeneꢀ
4,1´ꢀcyclohexane] (6a), ꢀcycloheptane] (7a) (general procedure).
Acetic anhydride (4.2 mL, 0.045 mol) was added to a solution
of homoallylamines 1b,c (0.015 mol) in HCOOH (6 mL,

872
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Zubkov et al.
that formed were filtered off and recrystallized from a hexꢀ
ane—ethyl acetate mixture. Adducts 6d and 7d were obtained as
colorless crystals.
Compound 6d. MS, m/z (Irel (%)): 323 [M]+ (2), 282 (2),
266 (2), 158 (5), 144 (3), 122 (6), 106 (12), 105 (100), 91 (10),
81 (86), 79 (17), 78 (10), 77 (92), 67 (10), 53 (24), 51 (15), 41
(20), 39 (9).
Compound 7d. MS, m/z (Irel (%)): 338 (10.7), 337 [M]+
(44), 296 (10), 266 (23), 232 (11), 216 (44), 158 (5), 135 (8), 122
(6), 106 (8), 105 (100), 95 (5), 81 (85), 79 (6), 77 (44), 67 (7), 53
(8), 51 (5), 41 (7).
13. A. Padwa, M. A. Brodney, M. Dimitroff, B. Liu, and T. Wu,
J. Org. Chem., 2001, 66, 3119.
14. A. Padwa, M. Dimitroff, A. G. Waterson, and T. Wu, J. Org.
Chem., 1997, 62, 4088.
15. K. A. Parker and M. R. Adamchuk, Tetrahedron Lett., 1978,
19, 1689.
16. M. S. Bailey, B. J. Brisdon, D. W. Brown, and K. M. Stark,
Tetrahedron Lett., 1983, 24, 3037.
17. T. Hudlicky, G. Butora, S. P. Fearnley, A. G. Gum, P. J.
Persichini III, M. R. Stabile, and J. S. Merola, J. Chem.
Soc., Perkin Trans. 1, 1995, 2393.
3ꢀTrifluoroacetylspiro[3ꢀazaꢀ11ꢀoxatricyclo[6.2.1.01,6]unꢀ
decꢀ9ꢀeneꢀ4,1´ꢀcyclohexane] (6e), ꢀcycloheptane] (7e) (general
procedure). Trifluoroacetic anhydride (9.8 mL, 0.07 mol)
was added dropwise to a solution of homoallylamines 1b,c
(0.019 mol) in oꢀxylene (20 mL). The reaction mixture was
boiled for 5 h and poured into water (100 mL); pH was brought
to 9—10 by adding a 25% aqueous solution of ammonia. The
mixture was extracted with diethyl ether (3×70 mL). The orꢀ
ganic extracts were combined and dried with MgSO4. After reꢀ
moval of the solvents, the residue was chromatographed on Al2O3
(25×3 cm) using hexane as the eluent. Tricyclic compounds 6e
and 7e were obtained as colorless crystals.
Compound 6e. MS, m/z (Irel (%)): 315 [M]+ (3), 275 (2),
274 (13), 272 (3), 234 (2), 193 (2), 122 (5), 107 (2), 94 (3), 91
(3), 82 (5), 81 (100), 79 (5), 77 (4), 69 (3), 53 (7), 41 (4).
Compound 7e. MS, m/z (Irel (%)): 329 [M]+ (2), 288 (8),
272 (3), 258 (2), 248 (2), 136 (3), 122 (3), 107 (2), 95 (6), 91 (3),
82 (5), 81 (100), 79 (3), 77 (3), 67 (4), 55 (3), 53 (4), 41 (4).
18. P. Metz, D. Seng, R. Fröhlich, and B. Wibbeling, Synlett,
1996, 741.
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22. C. O. Puentes and V. V. Kouznetsov, J. Heterocycl. Chem.,
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23. A. Varlamov, V. Kouznetsov, F. Zubkov, A. Chernyshev,
O. Shurupova, L. Y. Vargas Méndez, A. P. Rodríguez, J. R.
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This study was financially supported by the Russian
Foundation for Basic Research (Project No. 01ꢀ03ꢀ
32844).
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Received December 2, 2003;
in revised form February 16, 2004