Photoreactions of bicyclic aziridines with alkenes and alkynes: A novel synthetic methodology for 8-azabicyclo[3.2.1]octane derivatives

Article abstract of DOI:10.1039/b805801f

The photochemical C-C bond cleavage of bicyclic aziridines 7 and subsequent [3 + 2] cycloaddition with electron-deficient alkenes and alkynes afforded the novel head-to-head adducts selectively and efficiently. The adducts contain the naturally occurring 8-azabicyclo[3.2.1]octane skeleton (e.g. tropane alkaloids). The aziridine 8 fused with a 6-membered ring also afforded the cycloadducts but in poor yields. The methylaziridine 9 reacted with an electron-deficient alkene, affording the head-to-tail adduct 23 in addition to head-to-head adducts 22a and 22b. The photoreactions of bicyclic aziridines with alkenes and alkynes indicate a similar behavior to that of aziridines with a linear chain.

Full text of DOI:10.1039/b805801f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Photoreactions of bicyclic aziridines with alkenes and alkynes: a novel
synthetic methodology for 8-azabicyclo[3.2.1]octane derivatives†
Keitaro Ishii,* Motohiro Kido, Masahiro Noji and Shigeo Sugiyama
Received 7th April 2008, Accepted 6th June 2008
First published as an Advance Article on the web 10th July 2008
DOI: 10.1039/b805801f
The photochemical C–C bond cleavage of bicyclic aziridines 7 and subsequent [3 + 2] cycloaddition
with electron-deficient alkenes and alkynes afforded the novel head-to-head adducts selectively and
efficiently. The adducts contain the naturally occurring 8-azabicyclo[3.2.1]octane skeleton (e.g. tropane
alkaloids). The aziridine 8 fused with a 6-membered ring also afforded the cycloadducts but in poor
yields. The methylaziridine 9 reacted with an electron-deficient alkene, affording the head-to-tail adduct
23 in addition to head-to-head adducts 22a and 22b. The photoreactions of bicyclic aziridines with
alkenes and alkynes indicate a similar behavior to that of aziridines with a linear chain.
Introduction
For the construction of pyrrolidine-containing heterocycles, the
1,3-dipolar cycloaddition of azomethine ylides with alkenes is an
important and useful strategy.1 The aziridine ring is cleaved to
give the corresponding azomethine ylide on irradiation or under
thermal conditions.2 In general, the 1,3-dipolar cycloaddition of
an azomethine ylide possessing one electron-withdrawing group
(EWG) at the ylide carbon and electron-deficient alkenes affords
head-to-tail adducts (2,4-disubstituted pyrrolidines).2b,3
Recently, we reported that b-aziridinylacrylonitrile 1 or acrylate
2 undergo ring opening by irradiation or heating and subsequent
[3 + 2] cycloaddition with electron-deficient alkenes, leading to
head-to-head adducts (2,3-disubstituted pyrrolidines) selectively
and efficiently (Scheme 1).4 One of the resonance forms, the bi-
radical intermediate A, primarily contributes to the cycloaddition
rather than the other resonance form, the azomethine ylide B.
In contrast, the head-to-tail adducts are also formed only in the
thermal reactions of the aziridine 2b because the stabilization of
the azomethine ylide intermediate B (R2 = Ph) is increased by the
phenyl substituent.4c
Scheme 1
We have also reported that the photochemical C–C-bond
cleavage of bicyclic epoxide 3 and consequent [3 + 2] cycloaddition
with ethyl vinyl ether afforded 8-oxobicyclo[3.2.1]octane 4.5 We
have considered that the 8-azabicyclo[3.2.1]octane skeleton could
be also constructed from bicyclic aziridines. This skeleton occurs
naturally in the tropane alkaloids, which possess a wide range of
biological activities. The tropane skeletons 6 are mainly synthe-
sized from 3-oxidopyridinium betaines 5 by dipolar cycloaddition
(Fig. 1).6 A synthesis of 6, involving thermal ring opening of a
bicyclic aziridine and cycloaddition, has been reported by only
one research group.7
Fig. 1
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-
8588, Japan. E-mail: ishiikei@my-pharm.ac.jp; Fax: +81 (0)42 495 8783;
Tel: +81 (0)42 495 8783
† Electronic supplementary information (ESI) available: phase-sensitive
NOESY of compounds (E)-15a, (Z)-15a, (E)-15b, (Z)-17a, (Z)-18a, (Z)-
18b and c, (Z)-23 and 25a. See DOI: 10.1039/b805801f
In this paper, we describe the scope and limitation of the
cycloadditions of bicyclic aziridines 7–10 (Fig. 2) with alkenes
and alkynes for the construction of the 8-azabicyclo[3.2.1]octane
skeleton.
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Fig. 2
Results and discussion
Preparation of aziridines
The c,d-epimino a,b-unsaturated esters 7 and 8 were prepared
by the Horner–Emmons reaction of the ketones 118 and 128
with triethyl phosphonoacetate in 89% (E:Z = 45 : 55) and 68%
(E:Z = 35 : 65) yields, respectively. In a similar manner, the d-
methyl c,d-epimino a,b-unsaturated ester 9 was obtained from
iodoenone 13 by treatment with benzylamine, caesium carbonate
and 1,10-phenanthroline (25% yield) and a subsequent Horner–
Emmons reaction of the obtained aziridine 14 with triethyl
phosphonoacetate in 71% (E:Z = 49 : 51) yield. The (E) and
(Z) configurations of 7–9 were determined by means of the
chemical shifts of their 1H NMR spectra (see Experimental); they
showed signals due to 1-H of the (Z)-isomers at a lower field
(d 3.45–3.69) than those of E-isomers (d 2.06–2.46) because of
the deshielding effect of the carboxyl group.9 The dinitrile 10
was synthesized from the ketone 11 and malononitrile by the
Knoevenagel condensation10 in 69% yield (Scheme 2).
Scheme 2 Reagents and conditions: i, (EtO)2P(O)CH2CO2Et, NaH, DMF
or CH2Cl2, rt; ii, BnNH2, Cs2CO3, xylene, 95 ◦C; iii, CH2(CN)2, NH4OAc,
AcOH, benzene, rt.
of 3-H. Therefore, the stereochemistries of (E)-15a and (E)-15b
were primarily deduced from the phase-sensitive NOESY spectra
(see ESI†).11 The (E) and (Z) configurations of 15 were assigned by
the chemical shifts of 1-H, as mentioned for the case of aziridines
7–9. The photochemical reactions of aziridine 7 with tert-butyl
acrylate (entry 3), N-phenylmaleimide (entries 4 and 5), dimethyl
maleate (entry 6), dimethyl fumarate (entry 7), methyl propiolate
(entry 8), and dimethyl acetylenedicarboxylate (entries 9 and 10)
were performed, and the results are summarized in Table 1 and
Fig. 3.
Reactions of aziridine 7 with various alkenes and alkynes
Direct irradiation of a solution of the aziridine (Z)-7 with 3 equiv.
methyl acrylate in acetonitrile with a low-pressure mercury lamp in
a quartz test tube at room temperature afforded the head-to-head
exo- and endo-adducts (Z)-15a and (Z)-15b in moderate yields,
respectively (Table 1, entry 2). The 1,7-configurations of (Z)-15a
and (Z)-15b were determined by means of the coupling constant of
1-H in the 1H NMR spectra; they showed a singlet for 1,7-cis and
a doublet (J 7.0 Hz) for 1,7-trans. The coupling constant of 1-H
is nearly the same as those of the analogous adducts derived from
carbonyl ylides and alkenes.5b The aziridine (E)-7 also reacted with
methyl acrylate to give the adducts (E)-15a and (E)-15b (Table 1,
entry 1), whose stereochemistries could not be determined by the
coupling constant of 1-H owing to the overlapping with the signal
The exo-products (e.g., 15a, 16a and 17a) were formed pref-
erentially and independently of the (E/Z)-configuration of the
exocyclic double bond. In the transition state C (Fig. 3) the carboxy
group of the alkenes is presumably orientated to be outside the
ring, because of the steric hindrance of the exocyclic double
bond of aziridine ring-cleaved intermediates. (E/Z)-Isomerization
of the exocyclic double bond was not observed during the
irradiation, because the isomerization would occur mainly via the
triplet state of aziridine compounds.4a,b The reaction of aziridine
7 with dimethyl maleate afforded the 6,7-cis (Z)-18a and 6,7-
trans dicarbonyl compounds (Z)-18b and (Z)-18c (entry 6). The
results may indicate that the cycloaddition proceeds stepwise
and/or that the maleate isomerizes to the corresponding fumarate
Table 1 Photochemical reactions of aziridine 7 with various alkenes and alkynesa
Entry
Aziridine
Alkene/alkyne
Reaction time/h
Conversion (%)
Products (yield (%)13)
1
2
3
4
5
6
7
8
9
(E)
(Z)
(E)
(E)
(Z)
(Z)
(Z)
(Z)
(E)
Methyl acrylate
Methyl acrylate
t-Butyl acrylate
N-Phenylmaleimide
N-Phenylmaleimide
Dimethyl maleate
Dimethyl fumarate
Methyl propiolate
Dimethyl
2
3
4
3
2
4
3
4
100
100
94
80
81
99
100
80
(E)-15a (49) and (E)-15b (22)
(Z)-15a (38) and (Z)-15b (21)
(E)-16a (62) and (E)-16b (3)
(E)-17a (59) and (E)-17b (20)
(Z)-17a (60) and (Z)-17b (12)
(Z)-18a (31), (Z)-18b (14) and (Z)-18c (3)
(Z)-18b (52) and (Z)-18c (21)
(Z)-19 (59)
1.5
98
(E)-20 (62)
acetylenedicarboxylate
Dimethyl
acetylenedicarboxylate
10
(Z)
4
100
(Z)-20 (55)
a A 0.060 mol dm−3 solution of aziridine in acetonitrile with 3 equiv. of alkene or alkyne was irradiated at RT.
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Fig. 3
photochemically. The reactions of aziridine 7 and alkynes also
Reactions of aziridines 8, 9 and 10 with an alkene and an alkyne
gave the adducts 19 and 20 in moderate yields (entries 8–
10). In comparison with the cycloaddition of linear aziridine
1 with dimethyl maleate, dimethyl fumarate, and dimethyl
acetylenedicarboxylate,4b bicyclic aziridine 7 reacted smoothly
with those compounds to afford the corresponding adducts.
The structures of adducts 16–20 were also deduced on the basis
of their spectral data. In particular, the stereochemistries of 16–18
were determined by the chemical shift and the multiplicity of the
signals at H-C(1) and H-C(7) for 16 and 18 and at H-C(6) and H-
C(7) for 17 in the 1H NMR spectra (see Table 2) in comparison with
those of the compounds (E/Z)-15a and (E/Z)-15b. Furthermore,
the structures of (Z)-17a and (Z)-18a–c were also confirmed by
phase-sensitive NOESY spectra (see ESI).11
The photochemical reactions of 8–10 with an alkene and an
alkyne were performed, and the results are summarized in
Table 3 and Fig. 4. In order to study the effects of the fused
ring size in the bicyclic aziridine on the [3 + 2] cycloaddition
with an alkyne, the aziridine (Z)-8 was irradiated with dimethyl
acetylenedicarboxylate. The yield of the adduct (Z)-21 from (Z)-
8 drastically decreased (Table 3, entry 1) relative to that of the
adduct (Z)-20 from the aziridine (Z)-7 (Table 1, entry 10). The
same phenomenon has been also observed in the cycloaddition of
7-membered carbonyl ylide and an alkene (4% yield).5b,12
The methyl substituent at the 5-position in aziridine (Z)-9 had
an effect on adduct distribution; the irradiation of (Z)-9 with
Table 2 The chemical shift (ppm) and multiplicity of H-C(1) and H-C(7) in the 1H NMR spectra (in CDCl3) for 15–18, 22 and 25
exo-Adduct
dH-C(1)
dH-C(7)
endo-Adduct
dH-C(1)
dH-C(7)
(E)-15a
(Z)-15a
(E)-16a
(E)-17a
(Z)-17a
(Z)-18ac
(Z)-18cc
(Z)-22a
25a
NAa
5.31 s
NA
2.88 dd
2.88 dd
(E)-15b
(Z)-15b
(E)-16b
(E)-17bc
(Z)-17b
(Z)-18bc
NA
5.34 d
3.55 d
3.39–3.47 br dt
3.46–3.56 br dt
NA
2.78 dd
NA
3.27 or 3.31 db
—
3.53–3.56 br dd
5.72 dd
5.87 d
3.17 ddb
5.43 sd
5.81 s
5.89 s
5.13 s
4.50 s
4.03 ddb
4.28 t
3.70 d
3.65–3.67 br d
2.78 dd
(Z)-22b
25b
5.10 d
4.36 d
3.30–3.39 br dt
3.55–3.64 br dt
2.89 dd
a The signal overlapped with another signal. b Values for H-C(6). c Spectra taken in C6D6. d Values for H-C(7).
Table 3 Photochemical reactions of aziridines 8, 9 and 10 with an alkene and an alkynea
Entry
Aziridine
Alkene/Alkyne
Reaction time/h
Conversion (%)
Products and yields (%)13
1
2
3
4
5
(Z)-8
(Z)-9
(Z)-9
10
Dimethyl acetylenedicarboxylate
Methyl acrylate
Dimethyl acetylenedicarboxylate
Methyl acrylate
3.5
2
2
3
2
96
69
100
100
98
(Z)-21 (17)
(Z)-22a (18), (Z)-22b (5) and (Z)-23 (5)
(Z)-24 (61)
25a (33) and 25b (13)
26 (28)
10
Dimethyl acetylenedicarboxylate
a A 0.060 mol dm−3 solution of aziridine in acetonitrile with 3 equiv. of alkene or alkyne was irradiated at RT.
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Fig. 4
methyl acrylate afforded the head-to-tail adduct (Z)-23 as well
is found in nature (e.g., tropane alkaloids). However, the 7-
azabicyclo[4.1.0]heptane 8 reacted with alkyne to give the adduct
in low yields. The reactions of 5-methylaziridine 9 with electron-
deficient alkenes gave head-to-tail adducts 23 in addition to
head-to-head adducts. The dicyanoaziridine 10 reacted also with
electron-deficient alkenes, but not with non-electron-deficient
alkenes. The photoreactions of bicyclic aziridines and alkenes
showed similar behavior to that of linear aziridines (e.g., 1 and
2). However, the bicyclic aziridines reacted with alkynes better
than linear aziridines.
as head-to-head adducts (Z)-22a and (Z)-22b (Table 3, entry 2).
The formation of the head-to-tail adducts has previously been
observed in the thermal reactions of phenyl-substituted aziridines
2b (Scheme 1).4c The adduct (Z)-23 formed presumably via the
azomethine ylide intermediate stabilized by the methyl substituent.
The sum of yields for all adducts from (Z)-9 were reduced
owing to steric reasons. The reaction of (Z)-9 with dimethyl
acetylenedicarboxylate, however, proceeded smoothly, as did that
of 7 (Table 1, entries 9 and 10).
The electron-withdrawing inductive effects in the side chain of
the bicyclic aziridine on the [3 + 2] cycloaddition with alkenes
were studied. In earlier studies of the 1,3-dipolar cycloaddition
of carbonyl ylide and alkenes, the carbonyl ylides possessing a
stronger electron-withdrawing substituent (e.g., dinitrile) reacted
with electron-rich alkenes better than weaker ones (e.g., diester and
mononitrile).5c Linear dicyanoaziridine reacts with non-electron-
deficient alkenes (vinyl acetate and isoprene) to give the adducts.4c
The reactions of the bicyclic dicyanoaziridine 10 with non-
electron-deficient alkenes (vinyl acetate and isoprene) afforded no
cycloadducts, and the yields of the reactions of 10 and electron-
deficient alkene and alkyne were lower (Table 3, entries 4 and 5)
relative to those of (Z)-7 (Table 1, entries 2 and 10).
Experimental
General
Melting points were measured with a Yanaco MP-3 apparatus
and are uncorrected. IR spectra were recorded on a Hitachi 215
spectrometer. 1H NMR spectra were obtained with a JEOL JNM-
AL300 (300 MHz), a JEOL JNM-AL400 (400 MHz) or a JEOL
JNM-LA500 (500 MHz) spectrometer, and J values are given in
Hz. 13C NMR spectra were recorded on a JEOL JNM-AL300
(75 MHz), a JEOL JNM-AL400 (100 MHz) or a JEOL JNM-
LA500 (125 MHz) spectrometer. Unless otherwise noted, NMR
spectra were measured in CDCl3 using tetramethylsilane as an
internal standard at rt. Mass spectra (MS) and high-resolution
MS (HRMS) were taken on a JEOL JMS-700 spectrometer in the
EI mode at ionization potential of 70 eV. Column chromatography
was performed with Merck silica gel 60 (230–400 mesh) and
preparative TLC with Wakogel B-5F.
The stereo- and regiochemistries of 21–25 were deduced on the
basis of their spectral data. In particular, (E/Z)- and endo/exo-
configurations of 22 and 25 were determined by the chemical shift
and the multiplicity of the 1H NMR signals at H-C(1) and H-C(7)
(see Table 2) in comparison with those of the compounds (E/Z)-
15a and (E/Z)-15b. Furthermore, the structure of 25a was also
confirmed by the phase-sensitive NOESY spectrum (see ESI).11
An Eikosha 60 W low-pressure mercury lamp was used for
irradiation. The photolysis solutions were purged with argon
before and during irradiation.
1
The regiochemistry of (Z)-23 was determined by the H NMR
spectrum; the signals at d 1.83 (dd) and d 2.51–2.61 (br ddd)
due to 2H-C(7) and at d 4.91 due to H-C(1) were observed. The
assignment of the exo-configuration of (Z)-23 was deduced from
the phase-sensitive NOESY spectrum (see ESI).11
Preparations of aziridines
Ethyl
(E)-(6-benzyl-6-azabicyclo[3.1.0]hex-2-ylidene)acetate
[(E)-7] and ethyl (Z)-(6-benzyl-6-azabicyclo[3.1.0]hex-2-ylidene)-
acetate [(Z)-7]. To a suspension of NaH [197 mg, 8.2 mmol;
prepared from a NaH dispersion (60%, 329 mg) by washing it
twice with hexane (5 cm3)] in dry DMF (15 cm3)] was added
dropwise triethyl phosphonoacetate (1.65 cm3, 8.2 mmol) at room
temperature. After the mixture had been stirred for 20 min at room
Conclusions
The reactions of bicyclic aziridine 7 with electron-deficient
alkenes and alkynes selectively and efficiently afforded the novel
head-to-head adducts, whose skeleton, 8-azabicyclo[3.2.1]octane,
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temperature, ketone 118 (1.40 g, 7.48 mmol) was added dropwise,
and the stirring was continued for 1 h at room temperature.
Ice–water was added to the mixture, and the organic phase was
extracted with diethyl ether. The ethereal extract was washed
with brine, dried with MgSO4, and concentrated in vacuo, giving
a residue that was subjected to flash column chromatography
[methylene chloride–ethyl acetate (29 : 1)] to afford (E)-7 (761 mg,
40%) and (Z)-7 (940 mg, 49%).
2.34 (1 H, dddd, J 14.7, 8.1, 3.5 and 1.1, 3-H), 3.27 and 3.12
(2 H, each d, J 14.1, CH2Ph), 3.45 (1 H, d, J 6.1, 1-H), 4.14 and
=
4.15 (2 H, each q, J 7.2, OCH2), 5.84–5.85 (1 H, br s, C CH) and
7.20–7.37 (5 H, m, Ph); dC (100 MHz) 14.5 (q, CH3), 20.9 (t, C-4),
24.2 and 32.2 (2 t, C-3 and -5), 39.3 and 42.0 (2 d, C-1 and C-6),
=
59.7 and 64.1 (2 t, OCH2 and CH2Ph), 117.9 (d, C CH), 126.5,
127.5 and 128.0 (3 d, 5 C in Ph), 139.3 (s, C in Ph), 158.1 (s, C-2)
and 166.4 (s, CO); m/z 271 (M+, 100%), 242 (21), 226 (18), 198
(38), 180 (93), 152 (60), 134 (27), 124 (18), 106 (19) and 91 (90).
(E)-7, an oil (Found: M+ 257.1422. C16H19NO2 requires M,
257.1416); mmax (film)/cm−1 1690 (C O); dH (300 MHz) 1.27 (3 H,
=
t, J 7.2, CH3), 1.73–1.86 (1 H, br dtd, J 13, 9 and 3, 4-H), 2.07–
2.15 (1 H, br dd, J 13 and 8.5, 4-H), 2.24–2.38 (1 H, m, 3-H), 2.46
(1 H, d, J 4.4, 1-H), 2.53–2.56 (1 H, br dd, J 4 and 3, 5-H), 3.19
(1 H, dd, J 18.5 and 9.4, 3-H), 3.51 and 3.58 (2 H, each d, J 14.1,
Ethyl (E)-(6-benzyl-5-methyl-6-azabicyclo[3.1.0]hex-2-ylidene)-
acetate [(E)-9] and ethyl (Z)-(6-benzyl-5-methyl-6-azabicyclo-
[3.1.0]hex-2-ylidene)acetate [(Z)-9]. To a solution of iodoenone
13 (670 mg, 3.02 mmol) in xylene (6 cm3) were added benzylamine
(0.50 cm3, 4.53 mmol), caesium carbonate (1.47 g, 4.52 mmol), and
1,10-phenanthroline (543 mg, 3.02 mmol). The reaction mixture
was stirred 2 h at 50 ◦C. After silica gel filtration, preparative
TLC [hexane–ethyl acetate (2 : 1)] of the filtrate afforded 6-benzyl-
5-methyl-6-azabicyclo[3.1.0]hexan-2-one 14 (150 mg, 25%), an
oil (Found: M+ 201.1146. C13H15NO requires M, 201.1154); mmax
=
CH2Ph), 4.15 (2 H, q, J 7.2, OCH2), 5.96 (1 H, t, J 2.2, C CH)
and 7.23–7.34 (5 H, m, Ph); dC (75 MHz) 14.3 (q, CH3), 27.5
(2 t, C-3 and -4), 47.4 and 50.3 (2 d, C-1 and -5), 59.7 and 61.5
=
(2 t, OCH2 and CH2Ph), 113.5 (d, C CH), 126.9, 127.4 and 128.3
(3 d, 5 C in Ph), 138.8 (s, 1 C in Ph), 164.0 (s, C-2) and 166.4
(s, CO); m/z 257 (M+, 82%), 138 (35), 120 (29) and 91 (100).
(Z)-7, an oil (Found: M+ 257.1417. C16H19NO2 requires M,
(film)/cm−1 1705 (C O); dH (300 MHz) 1.54 (3 H, s, CH3), 1.85
=
257.1416); mmax (film)/cm−1 1695 (C O); dH (300 MHz) 1.25
(1 H, dt, J 12.7 and 9.2, 4-H), 1.96–2.06 (1 H, m, 3-H), 2.04
(1 H, s, 1-H), 2.18–2.27 (1 H, m, 4-H), 2.39–2.51 (1 H, br dt, J
17 and 9, 3-H), 3.74 (2 H, s, CH2Ph) and 7.22–7.35 (5 H, m, Ph);
dC (100 MHz) 13.6 (q, CH3), 31.5 and 34.3 (2 t, C-3 and -4), 50.0
(s, C-5), 52.8 (d, C-1), 55.3 (t, CH2Ph), 126.1, 127.1 and 128.3
(3 d, 5 C in Ph), 138.8 (s, C in Ph) and 212.7 (s, C-2); m/z 201
(M+, 20%), 145 (5), 91 (100), 82 (20) and 65 (7).
=
(3 H, t, J 7.2, CH3), 1.66–1.78 (1 H, m, 4-H), 1.97–2.05 (1 H,
br dd, J 13 and 8, 4-H), 2.19–2.29 (1 H, br dd, J 17 and 9, 3-H),
2.33–2.47 (1 H, m, 3-H), 2.56 (1 H, dd, J 4.2 and 3.3, 5-H), 3.40
and 3.76 (2 H, each d, J 13.9, CH2Ph), 3.69 (1 H, d, J 4.2, 1-H),
=
4.17 (2 H, q, J 7.2, OCH2), 5.84 (1 H, br s, C CH) and 7.21–7.37
(5 H, m, Ph); dC (75 MHz) 14.3 (q, CH3), 26.3 and 30.7 (2 t, C-3
and -4), 45.6 and 48.9 (2 d, C-1 and -5), 59.7 and 61.6 (2 t, OCH2
By analogy with the synthesis of 7, ketone 14 (252 mg,
1.25 mmol) was treated with NaH (60%, 55 mg, 1.38 mmol)
and triethyl phosphonoacetate (0.27 cm3, 1.38 mmol) in dry
methylene chloride (3 cm3) at room temperature, and the resulting
mixture was stirred for 1 h at room temperature. Flash column
chromatography [cyclohexane–ethyl acetate (3 : 1)] of the reaction
mixture afforded (E)-9 (117.8 mg, 35%) and (Z)-9 (121.3 mg, 36%).
(E)-9, an oil (Found: M+ 271.1574. C17H21NO2 requires M,
=
and CH2Ph), 114.4 (d, C CH), 126.9, 127.6 and 128.2 (3 d, 5 C
in Ph), 139.0 (s, C in Ph), 163.5 (s, C-2) and 166.5 (s, CO); m/z 257
(M+, 89%), 138 (38), 120 (29) and 91 (100).
Ethyl
(E)-(7-benzyl-7-azabicyclo[4.1.0]hept-2-ylidene)acetate
[(E)-8] and ethyl (Z)-(7-benzyl-7-azabicyclo[4.1.0]hept-2-ylidene)-
acetate [(Z)-8]. By analogy with the synthesis of 7, ketone
128 (2.60 g, 12.9 mmol) was treated with NaH (60%, 568 mg,
14.2 mmol) and triethyl phosphonoacetate (2.83 cm3, 14.2 mmol)
in dry DMF (26 cm3) at room temperature, and the resulting
mixture was stirred for 1 h at room temperature. Flash column
chromatography [hexane–ethyl acetate (4 : 1)] of the reaction
mixture afforded (E)-8 (848 mg, 24%) and (Z)-8 (1.53 g, 44%).
(E)-8, an oil (Found: M+ 271.1568. C17H21NO2 requires M,
271.1572); mmax (film)/cm−1 1705 (C O); dH (300 MHz) 1.27
=
(3 H, t, J 7.2, CH3), 1.50 (3 H, m, 5-CH3), 1.72 (1 H, dt, J 12.8 and
9.2, 4-H), 2.08 (1 H, dd, J 12.8 and 9.0, 4-H), 2.22 (1 H, s, 1-H),
2.36 (1 H, dtd, J 18.4, 9.2 and 2.8, 3-H), 3.21 (1 H, dd, J 18.4 and
9.0, 3-H), 3.67 and 3.81 (2 H, each d, J 14.8, CH2Ph), 4.15 (2 H,
=
q, J 7.2, OCH2), 5.88 (1 H, br s, C CH) and 7.19–7.34 (5 H, m,
Ph); dC (100 MHz) 13.4 (q, CH3), 14.4 (q, 5-CH3), 28.1 (t, C-4),
271.1572); mmax (film)/cm−1 1710 (C O); dH (300 MHz) 1.27
34.9 (t, C-3), 50.8 (s, C-5), 55.4 (t, CH2Ph), 55.6 (d, C-1), 59.6 (t,
=
=
(3 H, t, J 7.2, CH3), 1.35–1.46 (1 H, m, 4-H), 1.66–1.77 (2 H,
m, 4- and 5-H), 1.93–2.14 (2 H, m, 5- and 6-H), 2.06 (1 H, d, J 6.1,
1-H), 2.60–2.72 (1 H, m, 3-H), 2.79–2.89 (1 H, br d, J 17, 3-H),
3.47 and 3.67 (2 H, each d, J 14.0, CH2Ph), 4.14 (2 H, q, J 7.2,
OCH2), 112.5 (d, C CH), 126.4, 126.9 and 128.1 (3 d, 5 C in Ph),
139.4 (s, C in Ph), 165.6 (s, C-2) and 166.1 (s, CO); m/z 271 (M+,
100%), 226 (20), 180 (58), 152 (75), 134 (73), 106 (21) and 91 (66).
(Z)-9, an oil (Found: M+ 271.1575. C17H21NO2 requires M,
OCH2), 5.85 (1 H, t, J 1.8, C CH) and 7.21–7.33 (5 H, m, Ph);
271.1572); mmax (film)/cm−1 1705 (C O); dH (300 MHz) 1.25
=
=
dC (100 MHz) 14.5 (q, CH3), 19.5 (t, C-4), 23.7 and 25.9 (2 t, C-3
(3 H, t, J 7.2, CH3), 1.49 (3 H, m, 5-CH3), 1.59–1.71 (1 H, m, H-4),
1.94–2.02 (1 H, br dd, J 13 and 8.5, 4-H), 2.18–2.27 (1 H, br dd,
J 17 and 8.5, 3-H), 2.39–2.52 (1 H, m, 3-H), 3.49 (1 H, s, 1-H),
3.74, 3.84 (2 H, each d, J 14.7 Hz, CH2Ph), 4.16 (2 H, q, J 7.2 Hz,
and -5), 42.2 and 45.0 (2 d, C-1 and -6), 59.6 and 63.9 (2 t, OCH2
=
and CH2Ph), 117.3 (d, C CH), 126.7, 127.3 and 128.1 (3 d, 5 C
in Ph), 138.9 (s, C in Ph), 158.3 (s, C-2) and 165.8 (s, CO); m/z 271
(M+, 96%), 226 (25), 198 (43), 180 (100), 152 (66), 134 (30), 124
(18), 106 (24), 91 (90) and 58 (35).
=
OCH2), 5.80 (1 H, br s, C CH) and 7.18–7.38 (5 H, m, Ph); dC
(100 MHz) 13.7 and 14.5 (2 q, 2 CH3), 31.5 and 33.7 (2 t, C-3
and -4), 51.2 (d, C-1), 52.4 (s, C-5), 55.6 and 59.7 (2 t, OCH2 and
(Z)-8, an oil (Found: M+ 271.1577. C17H21NO2 requires M,
271.1572); mmax (film)/cm−1 1710 (C O); dH (300 MHz) 1.27
CH2Ph), 113.4 (d, C CH), 126.4, 127.1 and 128.0 (3 d, 5 C in Ph),
=
=
(3 H, t, J 7.2, CH3), 1.38–1.49 (1 H, m, 4-H), 1.58–1.71 and 1.73–
139.8 (s, C in Ph), 165.2 (s, C-2) and 166.4 (s, CO); m/z 271 (M+,
1.84 (2 H, 2 m, 4- and 5-H), 1.94–2.06 (3 H, m, 3-, 5- and 6-H),
100%), 226 (18), 180 (55), 152 (74), 134 (70), 106 (20) and 91 (62).
3190 | Org. Biomol. Chem., 2008, 6, 3186–3195
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(6-Benzyl-6-azabicyclo[3.1.0]hex-2-ylidene)malononitrile (10).
To a suspension of the ketone 118 (850 mg, 4.55 mmol) in dry
benzene (1.7 cm3) was added malononitrile (0.29 cm3, 4.55 mmol),
ammonium acetate (70 mg, 0.91 mmol) and acetic acid (0.26 cm3,
4.55 mmol). The reaction mixture was stirred for 5 h at room
temperature. The reaction was quenched with water and the
organic phase was extracted with ether. The organic extract was
washed with aqueous sat. NaHCO3 and brine, dried with MgSO4,
and concentrated in vacuo, giving a residue that was subjected to
flash column chromatography [hexane–ether (1 : 1)] to afford 10
(733 mg, 69%) as an oil (Found: M+ 235.1104. C15H13N3 requires
and 128.4 (3 d, 5 C in Ph), 138.5 (s, C in Ph), 156.8 (s, C-2) and
165.8 and 172.4 (2 s, 2 CO); m/z 343 (M+, 59%), 314 (11), 298 (12),
257 (100), 138 (12) and 91 (76).
Ethyl (Z,1RS,5RS,7RS)-(8-benzyl-7-methoxycarbonyl-8-azabi-
cyclo[3.2.1]oct-2-ylidene)acetate [(Z)-15a]. An oil (Found: M+
343.1777. C20H25NO4 requires M, 343.1784); mmax (CHCl3)/cm−1
=
1710 (C O); dH (300 MHz) d 1.12 (3 H, t, J 7.2, CH3), 1.42–1.51
and 2.05–2.13 (2 H, each m, 4-H2), 1.99 (1 H, dd, J 13.2 and 9.7,
6-H), 2.15–2.24 and 2.36–2.49 (2 H, each m, 3-H2), 2.58–2.67 (1 H,
br quintet, J 6.5, 6-H), 2.89 (1 H, dd, J 9.7 and 5.3, 7-H), 3.36–3.41
(1 H, m, 5-H), 3.70 and 3.75 (2 H, each d, J 14, CH2Ph), 3.73 (3 H,
s, OCH3), 3.91 and 4.02 (2 H, each dq, J 10.8 and 7.2, OCH2),
M, 235.1109); mmax (CHCl3)/cm−1 2360 (C N); dH (400 MHz)
≡
1.96 (1 H, dtd, J 13.4, 9.0 and 2.8, 4-H), 2.20 (1 H, ddd, J 13.4, 8.3
and 1.1, 4-H), 2.50–2.63 (1 H, br td, J 19 and 9, 3-H), 2.74–2.84
(1 H, br dd, J 19 and 9, 3-H), 2.93–2.98 (2 H, m, 1- and 5-H),
3.49 and 3.74 (2 H, each d, J 13.4, CH2Ph) and 7.27–7.40 (5 H,
m, Ph); dC (100 MHz) 27.5 and 31.1 (2 t, C-3 and -4), 48.0 and
51.4 (2 d, C-1 and -5), 61.8 (t, CH2Ph), 81.8 [s, C(CN)2], 111.4
and 111.5 (2 s, 2 CN), 127.5, 127.6 and 128.5 (3 d, 5 C in Ph),
137.2 (s, C in Ph) and 186.0 (s, C-2); m/z 235 (M+, 7%), 104 (2),
91 (100), 77 (2) and 65 (8).
=
5.31 (1 H, s, 1-H), 5.66 (1 H, d, J 2.2, C CH) and 7.17–7.33 (5 H,
m, Ph); dC (100 MHz) 14.2 (q, CH3), 28.5, 28.8 and 32.0 (3 t, C-3,
-4 and -6), 46.9 (d, C-7), 52.2 (q, OCH3), 52.3 (t, CH2Ph), 57.0
(d, C-5), 59.9 (t, OCH2), 61.2 (d, C-1), 115.1 (d, C CH), 126.6,
127.9 and 128.1 (3 d, 5 C in Ph), 139.1 (s, C in Ph), 156.3 (s, C-2)
and 165.6 and 174.8 (2 s, 2 CO); m/z 343 (M+, 65%), 314 (15), 298
(13), 257 (100), 138 (11) and 91 (78).
=
Ethyl (Z,1RS,5RS,7SR)-(8-benzyl-7-methoxycarbonyl-8-azabi-
cyclo[3.2.1]oct-2-ylidene)acetate [(Z)-15b]. An oil (Found: M+
343.1793. C20H25NO4 requires M, 343.1784); mmax (CHCl3)/cm−1
Reactions of aziridines 7–10 with alkenes and alkynes
=
1720 and 1710 sh (C O); dH (300 MHz) 1.19 (3 H, t, J 7.2, CH3),
A 0.060 mol dm−3 solution of aziridines 7–10 in dry acetonitrile
with 3 equiv. of with alkenes and alkynes was irradiated with a low-
pressure mercury lamp in a quartz test tube at room temperature.
After removal of the solvent, flash column chromatography
afforded the adducts. The results are summarized in Tables 1 and
3 and Fig. 3 and 4.
1.47–1.57 (1 H, m, 4-H), 2.02–2.23 (3 H, m, 3-, 4- and 6-H), 2.27–
2.39 (1 H, m, 6-H), 2.55–2.68 (1 H, m, 3-H), 3.27–3.33 (1 H, m,
5-H), 3.46–3.56 (1 H, br dt, J 12 and 7, 7-H), 3.59 (3 H, s, OCH3),
3.71 (2 H, s, CH2Ph), 4.02, 4.08 (1 H, each dq, J 10.8 and 7.2,
=
OCH2), 5.34 (1 H, d, J 7.0, 1-H), 5.69 (1 H, d, J 2.2, C CH) and
7.19–7.33 (5 H, m, Ph); dC (100 MHz) 14.4 (q, CH3), 27.9, 29.1
and 29.6 (3 t, C-3, -4 and -6), 46.8 (d, C-7), 51.7 (q, OCH3), 53.4
(t, CH2Ph), 56.7 (d, C-5), 59.7 (t, OCH2), 61.1 (d, C-1), 116.7 (d,
Ethyl (E,1RS,5RS,7RS)-(8-benzyl-7-methoxycarbonyl-8-azabi-
cyclo[3.2.1]oct-2-ylidene)acetate [(E)-15a]. An oil (Found: M+
343.1779. C20H25NO4 requires M, 343.1784); mmax (CHCl3)/cm−1
=
C CH), 126.8, 128.1 and 128.4 (3 d, 5 C in Ph), 138.8 (s, C in Ph),
155.9 (s, C-2) and 165.4 and 173.0 (2 s, 2 CO); m/z 343 (M+, 62%),
=
1720 sh, 1710 (C O); dH (300 MHz) 1.28 (3 H, t, J 7.1, CH3),
314 (11), 298 (12), 257 (100), 138 (11) and 91 (65).
1.42–1.50 and 2.01–2.09 (2 H, each m, 4-H2), 2.05 (1 H, dd, J 12.9
and 9.8 Hz, 6-H), 2.15–2.25 (1 H, m, 3-H), 2.55–2.63 (1 H, br
quintet, J 6, 6-H), 2.88 (1 H, dd, J 9.8 and 5.1, 7-H), 3.38–3.42
(1 H, m, 5-H), 3.65–3.76 (4 H, m, 1-H, 3-H and CH2Ph), 3.71 (3 H,
s, OCH3), 4.15 and 4.16 (2 H, each q, J 7.1, OCH2), 5.54 (1 H, br
Ethyl
(E,1RS,5RS,7RS)-(8-benzyl-7-tert-butoxycarbonyl-8-
azabicyclo[3.2.1]oct-2-ylidene)acetate [(E)-16a]. An oil (Found:
M+ 385.2256. C23H31NO4 requires M, 385.2253); mmax (film)/cm−1
=
1705 (C O); dH (300 MHz) 1.29 (3 H, t, J 7.2, CH3), 1.43 (9 H, s,
OtBu), 1.37–1.50 and 2.01–2.09 (2 H, each m, 4-H2), 1.93 (1 H,
dd, J 13 and 9.7, 6-H), 2.13–2.26 (1 H, m, 3-H), 2.55–2.64 (1 H, br
quintet, J 6, 6-H), 2.78 (1 H, dd, J 9.7 and 5.1, 7-H), 3.39–3.43 (1 H,
m, 5-H), 3.65 and 3.75 (2 H, each d, J 13.9, CH2Ph), 3.62–3.72
(2 H, m, 1- and 3-H), 4.15 and 4.16 (2 H, each q, J 7.2, OCH2),
=
d, J 2.2, C CH) and 7.20–7.33 (5 H, m, Ph); dC (100 MHz) 14.4
(q, CH3), 21.7 (t, C-4), 27.3 (t, C-3), 31.6 (t, C-6), 47.4 (d, C-7),
52.2 (q, OCH3), 52.3 (t, CH2Ph), 57.3 (d, C-5), 59.8 (t, OCH2),
=
68.8 (d, C-1), 114.9 (d, C CH), 126.7, 128.0 and 128.1 (3 d, 5 C
in Ph), 138.7 (s, C in Ph), 157.9 (s, C-2) and 166.1 and 174.5 (2 s,
2 CO); m/z 343 (M+, 54%), 314 (11), 298 (11), 257 (100), 138 (18),
120 (12) and 91 (90).
=
5.50 (1 H, d, J 2.4, C CH) and 7.20–7.33 (5 H, m, Ph); dC
(100 MHz) 14.5 (q, CH3), 21.8 (t, C-4), 27.6 (t, C-3), 28.1 (q,
3 CH3), 31.2 (t, C-6), 48.6 (d, C-7), 52.3 (t, CH2Ph), 57.9 (d, C-5),
Ethyl (E,1RS,5RS,7SR)-(8-benzyl-7-methoxycarbonyl-8-azabi-
cyclo[3.2.1]oct-2-ylidene)acetate [(E)-15b]. An oil (Found: M+
343.1776. C20H25NO4 requires M, 343.1784); mmax (film)/cm−1 1720
=
59.8 (t, OCH2), 68.9 (d, C-1), 80.4 [s, C(CH3)3], 114.7 (d, C CH),
126.6, 128.0 and 128.1 (3 d, 5 C in Ph), 138.8 (s, C in Ph), 158.3
(s, C-2) and 166.1 and 173.2 (2 s, 2 CO); m/z 385 (M+, 41%), 328
(35), 312 (21), 257 (100) and 91 (68).
=
sh and 1710 (C O); dH (300 MHz) 1.28 (1 H, t, J 7.2, CH3), 1.48–
1.56 and 1.98–2.11 (2 H, each m, 4-H2), 2.26 (1 H, dd, J 12.7 and
6.6, 6-H), 2.27–2.42 (2 H, m, 3- and 6-H), 3.33–3.38 (1 H, m, 5-H),
3.39–3.47 (1 H, br dt, J 11 and 7, 7-H), 3.55–3.66 (2 H, m, 1- and
3-H), 3.69 (2 H, s, CH2Ph), 3.60 (3 H, s, OCH3), 4.14 (2 H, q, J
Ethyl
(E,1RS,5RS,7SR)-(8-benzyl-7-tert-butoxycarbonyl-8-
azabicyclo[3.2.1]oct-2-ylidene)acetate [(E)-16b]. An oil (Found:
M+ 385.2258. C23H31NO4 requires M, 385.2253); mmax (CHCl3)/
=
=
7.2, OCH2), 5.47 (1 H, d, J 2.6, C CH) and 7.17–7.37 (5 H, m,
cm−1 1715 (C O); dH (300 MHz) 1.26 (3 H, t, J 7.1, CH3), 1.35
Ph); dC (100 MHz) 14.4 (q, CH3), 21.4 (t, C-4), 27.9 (t, C-3), 29.3
(9 H, s, OtBu), 1.40–1.56 and 1.98–2.11 (2 H, each m, 4-H2),
2.17 (1 H, dd, J 13.0 and 6.2, 6-H), 2.23–2.38 (2 H, m, 3- and
6-H), 3.28–3.39 (2 H, m, 5- and 7-H), 3.55 (1 H, d, J 6.6, 1-H),
(t, C-6), 47.3 (d, C-7), 51.9 (q, OCH3), 53.2 (t, CH2Ph), 57.4 (d,
=
C-5), 59.7 (t, OCH2), 68.7 (d, C-1), 116.8 (d, C CH), 126.9, 128.2
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3.54–3.65 (1 H, m, 3-H), 3.70 (2 H, s, CH2Ph), 4.13 and 4.19 (2 H,
-10), 49.1 and 49.2 (2 d, C-2 and -6), 49.9 (t, CH2Ph), 60.2 and
=
=
each dq, J 11.0 and 7.1 Hz, OCH2), 5.50 (1 H, d, J 2.6, C CH)
60.6 (2 d, C-1 and -7), 60.4 (t, OCH2), 118.0 (d, C CH), 126.3,
and 7.21–7.33 (5 H, m, Ph); dC (100 MHz) 14.5 (q, CH3), 21.6
(t, C-4), 28.0 (t, C-3), 28.0 (q, 3CH3), 29.3 (t, C-6), 47.9 (d, C-7),
53.1 (t, CH2Ph), 57.5 (d, C-5), 59.7 (t, OCH2), 68.6 (d, C-1), 80.7
127.1, 127.7, 128.4, 128.5 and 129.1 (6 d, 10 C in 2 Ph), 132.1 and
138.0 (s, 2 C in 2 Ph), 152.0 (s, C-8), 165.2 (s, CO) and 176.5 and
177.6 (2 s, C-3 and -5); m/z 430 (M+, 84%), 401 (14), 385 (13),
357 (11), 257 (100), 185 (10), 138 (11) and 91 (79).
=
[s, C(CH3)3], 117.1 (d, C CH), 126.8, 128.2 and 128.4 (3 d, 5 C
in Ph), 138.7 (s, C in Ph), 156.9 (s, C-2) and 165.8 and 171.3 (2 s,
Ethyl (Z,1RS,2RS,6SR,7RS)-(11-benzyl-3,5-dioxo-4-phenyl-
2CO); m/z 385 (M+, 49%), 312 (18), 257 (100) and 91 (56).
4,11-diazatricyclo[5.3.1.02,6]undec-8-ylidene)acetate
[(Z)-17b].
White crystals; mp 130–140 ◦C (Found: M+ 430.1897. C26H26N2O4
Ethyl (E,1RS,2SR,6RS,7RS)-(11-benzyl-3,5-dioxo-4-phenyl-
requires M, 430.1893); mmax (CHCl3)/cm−1 1705 (C O); dH
4,11-diazatricyclo[5.3.1.02,6]undec-8-ylidene)acetate
[(E)-17a].
=
An oil (Found: M+ 430.1887. C26H26N2O4 requires M, 430.1893);
(300 MHz) 1.22 (1 H, t, J 7.2, CH3), 1.84–1.96 (1 H, m, 10-H),
2.12–2.37 (2 H, m, 9- and 10-H), 2.37–2.48 (1 H, m, 9-H),
3.67–3.72 (1 H, m, 1-H), 3.74 and 3.80 (2 H, each d, J 13.4,
CH2Ph), 3.88 (1 H, dd, J 10.3 and 7.7, 2-H), 4.05 (1 H, dd, J
10.3 and 7.9, 6-H), 4.05–4.16 (2 H, m, OCH2), 5.72 (1 H, d, J 7.9,
mmax (CHCl3)/cm−1 1710 (C O); dH (300 MHz) 1.31 (3 H, t, J 7.1,
=
CH3), 1.65–1.70 (1 H, br d, J 8, 10-H), 2.13–2.39 (2 H, m, 9- and
10-H), 3.27 and 3.31 (2 H, each d, J 7.6, 2- and 6-H), 3.75–3.93
(5 H, m, 1-H, 7-H, 9-H and CH2Ph), 4.19 and 4.22 (2 H, each
=
7-H), 5.80 (1 H, d, J 1.8, C CH) and 7.21–7.49 (10 H, m, 2 Ph);
=
dq, J 11.0 and 7.1, OCH2), 5.72 (1 H, br s, C CH) and 7.18–7.55
dC (100 MHz) 14.3 (q, CH3), 23.6 and 27.3 (2 t, C-9 and -10),
(10 H, m, 2 Ph); dC (100 MHz) 14.4 (q, CH3), 22.1 (t, C-9), 25.0
48.9 (d, C-2), 49.9 (d, C-6), 53.9 (t, CH2Ph), 58.0 (d, C-1), 60.0 (t,
(t, C-10), 48.8 and 49.5 (2 d, C-2 and -6), 50.1 (t, CH2Ph), 60.1
=
OCH2), 60.2 (d, C-7), 118.6 (d, C CH), 125.7, 127.3, 128.3, 128.4
=
(t, OCH2), 60.7 (d, C-1), 68.0 (d, C-7), 117.3 (d, C CH), 126.3,
and 129.0 (5 d, 10 C in 2 Ph), 131.7 and 137.6 (s, 2 C in 2 Ph),
152.3 (s, C-8), 165.1 (s, CO) and 173.9 and 175.4 (2 s, C-3 and -5);
m/z 430 (M+, 92%), 385 (14), 257 (100), 138 (10) and 91 (61).
127.2, 127.8, 128.4, 128.6 and 129.1 (6 d, 10 C in 2 Ph), 132.0 and
137.6 (2 s, 2 C in 2 Ph), 153.8 (s, C-8), 165.5 (s, CO) and 176.6 and
177.5 (2 s, C-3 and -5); m/z 430 (M+, 92%), 385 (14), 257 (100)
and 91 (66).
Dimethyl (Z,1RS,5RS,6SR,7RS)-8-benzyl-2-ethoxycarbonyl-
methylene-8-azabicyclo[3.2.1]octane-6,7-dicarboxylate [(Z)-18a].
An oil (Found: M+ 401.1837. C22H27NO6 requires M, 401.1838);
Ethyl (E,1RS,2RS,6SR,7RS)-(11-benzyl-3,5-dioxo-4-phenyl-
4,11-diazatricyclo[5.3.1.02,6]undec-8-ylidene)acetate
[(E)-17b].
mmax (film)/cm−1 1740 (C O); dH (C6D6; 300 MHz) 0.78–0.85 (1 H,
=
White crystals; mp 168–170 ◦C (hexane–ethyl acetate) (Found: C,
72.44; H, 6.29; N, 6.34. C26H26N2O4 requires C, 72.54; H, 6.09; N,
m, 4-H), 0.90 (3 H, t, J 7.2, CH3), 1.61–1.80 (3 H, m, 3-H2 and
4-H), 2.91 (1 H, d, J 10.3, 6-H), 3.07 (1 H, d, J 10.3, 7-H), 3.41
and 3.43 (6 H, each s, 2 OCH3), 3.66 (1 H, br s, 5-H), 3.75 and 3.91
(2 H, each d, J 14.1, CH2Ph), 3.83 and 3.91 (2 H, each dq, J 10.8
6.51%); mmax (CHCl3)/cm−1 1715 (C O); dH (300 MHz) 1.28 (1 H,
=
t, J 7.1, CH3), 1.90–1.97 (1 H, br dd, J 14 and 9, 10-H), 2.05–2.16
(1 H, m, 10-H), 2.17–2.28 (1 H, m, 9-H), 3.67 (1 H, dd, J 19.0
and 8.1, 9-H), 3.76 (2 H, s, CH2Ph), 3.74–3.80 (1 H, m, 1-H),
3.85–3.97 (3 H, m, 2-, 6- and 7-H), 4.14 (2 H, q, J 7.1, OCH2),
=
and 7.2, OCH2), 5.62 (1 H, br s, C CH), 5.81 (1 H, s, 1-H), 7.07
(1 H, t, J 7.3, Ph), 7.18–7.23 (2 H, br t, J 7, Ph) and 7.52–7.56 (2 H,
br d, J 7, Ph); dC (C6D6; 100 MHz) 14.0 (q, CH3), 27.6 and 28.1
(2 t, C-3 and -4), 50.7 (2 d, C-6 and -7), 51.3 and 51.4 (2 q, 2 OMe),
51.9 (t, CH2Ph), 59.7 (d, C-5), 59.7 (t, OCH2), 61.3 (d, C-1), 115.9
=
5.67 (1 H, d, J 2.4, C CH) and 7.21–7.52 (10 H, m, 2Ph); dH
(400 MHz; C6D6) 0.91 (3 H, t, J 7.1, CH3), 1.64–1.78 (2 H, m,
10-H2), 2.32–2.43 (1 H, m, 9-H), 3.10 (1 H, dd, J 10.3 and 7.3,
2-H), 3.17 (1 H, dd, J 10.3 and 7.6, 6-H), 3.24–3.29 (1 H, m, 1-H),
3.27 (2 H, s, CH2Ph), 3.53–3.56 (1 H, br d, J 7, 7-H), 3.77–3.84
(1 H, br dd, J 19 and 7, 9-H), 3.88 and 3.96 (2 H, each dq, J
=
(d, C CH), 126.7, 128.0 and 128.4 (3 d, 5 C in Ph), 139.2 (s, C in
Ph), 155.2 (s, C-2) and 164.9, 171.6 and 172.0 (3 s, 3 CO); m/z 401
(M+, 61%), 370 (18), 342 (15), 257 (100) and 91 (79).
=
11.0 and 7.1, OCH2), 5.72 (1 H, d, J 2.7, C CH) and 7.05–7.40
(10 H, m, 2 Ph); dC (100 MHz) 14.4 (q, CH3), 22.1 and 22.2 (2 t,
Dimethyl (Z,1RS,5RS,6SR,7SR)-8-benzyl-2-ethoxycarbonyl-
methylene-8-azabicyclo[3.2.1]octane-6,7-dicarboxylate [(Z)-18b].
An oil contaminated with ca. 30% of (Z)-18c; dH (C6D6; 500 MHz)
0.93 (1 H, t, J 7.0, CH3), 1.19–1.25 (1 H, m, 4-H), 1.72–1.82
(2 H, m, 3- and 4-H), 2.48–2.59 (1 H, m, 3-H), 3.29 and 3.31 (6 H,
each s, 2 OCH3), 3.58 (1 H, d, J 6.7, 6-H), 3.59 and 3.70 (2 H,
each d, J 13.7, CH2Ph), 3.63 (1 H, br s, 5-H), 3.91 and 3.95
(2 H, each dq, J 11.0 and 7.0, OCH2), 4.28 (1 H, t, J 7, 7-H), 5.70
C-9 and -10), 48.6 (d, C-2), 50.3 (d, C-6), 53.5 (t, CH2Ph), 58.8
(d, C-1), 60.0 (t, OCH2), 67.2 (d, C-7), 119.0 (d, C CH), 125.9,
127.4, 128.36, 128.41, 128.6 and 129.1 (6 d, 10 C in 2 Ph), 131.5
and 137.3 (2 s, 2 C in 2 Ph), 152.5 (s, C-8), 165.4 (s, CO) and 174.0
and 175.3 (2 s, C-3 and -5); EI-MS m/z 430 (M+, 97%), 385 (13),
257 (100) and 91 (52).
=
=
(1 H, d, J 2.4, C CH), 5.87 (1 H, d, J 7.0, 1-H), 7.04–7.09 (1 H, m,
Ethyl (Z,1RS,2SR,6RS,7RS)-(11-benzyl-3,5-dioxo-4-phenyl-
Ph), 7.12–7.16 (2 H, m, Ph) and 7.29–7.33 (2 H, m, Ph); dC (C6D6;
125 MHz) 14.2 (q, CH3), 28.1 and 29.0 (2 t, C-3 and -4), 49.1
and 50.6 (2 d, C-6 and -7), 51.6 and 51.7 (2 q, 2 OMe), 53.6
(t, CH2Ph), 59.6 (t, OCH2), 61.4 (d, C-5), 62.3 (d, C-1), 117.6
4,11-diazatricyclo[5.3.1.02,6]undec-8-ylidene)acetate
[(Z)-17a].
White crystals; mp 152–154 ◦C (hexane–ethyl acetate) (Found: C,
72.25; H, 6.01; N, 6.46. C26H26N2O4 requires C, 72.54; H, 6.09; N,
6.51%); mmax (CHCl3)/cm−1 1710 (C O); dH (300 MHz) 1.13 (3 H,
=
=
(d, C CH), 127.3, 128.5 and 128.8 (3 d, 5 C in Ph), 139.0 (s, C in
Ph), 154.8 (s, C-2) and 165.3, 172.0 and 174.3 (3 s, 3CO).
t, J 7.1, CH3), 1.67–1.73 (1 H, m, 10-H), 2.25–2.37 (2 H, m, 9-
and 10-H), 2.42–2.49 (1 H, m, 9-H), 3.29 (2 H, s, 2- and 6-H),
3.74–3.78 (1 H, br s, 1-H), 3.75 and 3.82 (2 H, each d, J 13.7,
CH2Ph), 3.69 and 4.07 (2 H, each dq, J 10.7 and 7.1 Hz, OCH2),
Dimethyl (Z,1RS,5RS,6RS,7RS)-8-benzyl-2-ethoxycarbonyl-
methylene-8-azabicyclo[3.2.1]octane-6,7-dicarboxylate [(Z)-18c].
An oil contaminated with ca. 70% of (Z)-18b; dH (C6D6; 500 MHz)
d 0.93 (3 H, t, J 7.0, CH3), 1.25–1.31 (1 H, m, 4-H), 1.72–1.82
=
5.43 (1 H, s, 7-H), 5.85 (1 H, d, J 2.0, C CH) and 7.16–7.53 (5 H,
m, 2 Ph); dC (100 MHz) 14.1 (q, CH3), 26.4 and 29.0 (2 t, C-9 and
3192 | Org. Biomol. Chem., 2008, 6, 3186–3195
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(2 H, m, 3- and 4-H), 2.48–2.59 (1 H, m, 3-H), 3.24 and 3.33 (6 H,
each s, 2 OCH3), 3.46–3.50 (1 H, m, 5-H), 3.67 and 3.77 (2 H, each
d, J 13.4, CH2Ph), 3.65–3.67 (1 H, br d, J 7, 7-H), 3.84–4.00 (2 H,
399 (M+, 10%), 367 (13), 340 (48), 308 (60), 294 (42), 276 (33), 262
(17) and 91 (100).
Dimethyl (Z,1RS,6SR)-9-benzyl-2-ethoxycarbonylmethylene-9-
azabicyclo[4.2.1]non-7-ene-7,8-dicarboxylate [(Z)-21]. An oil
=
m, OCH2), 4.18 (1 H, t, J 6.7, 6-H), 5.64 (1 H, d, J 2.1, C CH),
5.89 (1 H, s, 1-H), 7.04–7.09 (1 H, m, Ph), 7.12–7.16 (2 H, m, Ph),
and 7.29–7.33 (2 H, m, Ph); dC (C6D6; 125 MHz) 14.2 (q, CH3),
25.7 and 28.2 (2 t, C-3 and -4), 49.8 and 50.0 (2 d, C-6 and -7),
51.5 and 51.9 (2 q, 2 OMe), 53.4 (t, CH2Ph), 59.7 (t, OCH2), 60.1
(Found: M+ 413.1836. C23H27NO6 requires M, 413.1838); mmax
−1
=
(CHCl3)/cm 1720 (C O); dH (300 MHz) 1.22 (3 H, t, J 7.2,
CH3), 1.37–1.54 (1 H, m, 4-H), 1.69–1.85 (1 H, m, 4- and 5-H),
1.88–1.98 (1 H, m, 5-H), 2.30–2.39 (1 H, br dd, J 14 and 7, 3-H),
2.96–3.07 (1 H, br t, J 14, 3-H), 3.71 and 3.77 (6 H, each s, 2 OCH3),
3.75 and 3.83 (2 H, each d, J 13.4, CH2Ph), 4.02 and 4.10 (2 H,
each dq, J 10.8 and 7.2, OCH2), 4.06–4.12 (1 H, m, 6-H), 5.71–
=
(d, C-5), 62.4 (d, C-1), 115.3 (d, C CH), 128.3, 128.5 and 128.7
(3 d, 5 C in Ph), 139.0 (s, C in Ph), 156.5 (s, C-2) and 165.4, 172.4
and 174.0 (3 s, 3 CO).
=
5.74 (1 H, m, C CH), 5.76 (1 H, br s, 1-H) and 7.21–7.38 (5 H,
m, Ph); dC (100 MHz) 14.4 (q, CH3), 23.0 (t, C-4), 34.2 and 38.7
Ethyl (Z,1RS,5SR)-(8-benzyl-7-methoxycarbonyl-8-azabicyclo-
[3.2.1]oct-6-en-2-ylidene)acetate [(Z)-19]. An oil (Found: M+
341.1631. C20H23NO4 requires M, 341.1627); mmax (film)/cm−1 1715
(2 t, C-3 and -5), 52.1 and 52.3 (2 q, 2 OMe), 59.9 (t, OCH2), 61.0
(t, CH2Ph), 70.7 (d, C-6), 73.6 (d, C-1), 115.3 (d, C CH), 126.9,
128.2 and 128.3 (3 d, 5 C in Ph), 132.5, 139.0 and 145.9 (3 s, C-7,
C-8 and C in Ph) and 160.4, 163.0, 165.8 and 166.0 (4 s, C-2 and 3
CO); m/z 413 (M+, 5%), 381 (47), 354 (23), 322 (22), 308 (53), 280
(53) and 91 (100).
=
=
(C O); dH (300 MHz) 1.20 (1 H, t, J 7.2, CH3), 1.49 (1 H, ddd, J
13.2, 7.5 and 2.2, 4-H), 2.03 (1 H, dddd, J 13.2, 10.6, 6.8 and 3.9,
4-H), 2.13–2.21 (1 H, br dd, J 16 and 7, 3-H), 2.47 (1 H, dddd,
J 16.1, 10.6, 8 and 2.5, 3-H), 3.63 and 3.71 (2 H, each d, J 13.4,
CH2Ph), 3.71–3.76 (1 H, m, 5-H), 3.73 (3 H, s, OCH3), 4.05 and
4.13 (2 H, each dq, J 10.8 and 7.2, OCH2), 5.64 (1 H, br d, J 2,
Ethyl
(Z,1RS,5RS,7RS)-(8-benzyl-7-methoxycarbonyl-5-
=
C CH), 5.75 (1 H, s, H-1), 7.05 (1 H, d, J 2.4, 6-H) and 7.19–7.34
methyl-8-azatricyclo[3.2.1]oct-2-ylidene)acetate [(Z)-22a]. An
(5 H, m, Ph); dC (C6D6; 100 MHz) 14.3 (q, CH3), 24.0 and 27.2 (2 t,
oil (Found: M+ 357.1940. C21H27NO4 requires M, 357.1940); mmax
C-3 and -4), 51.7 (q, OMe), 55.5 (t, CH2Ph), 59.8 (t, OCH2), 63.6
(film)/cm−1 1710 (C O); dH (300 MHz) 0.97 (3 H, t, J 7.2, CH3),
=
=
(d, C-5), 64.2 (d, C-1), 115.9 (d, C CH), 126.8, 128.1 and 128.6
1.21 (3 H, s, 5-CH3), 1.51 (1 H, dd, J 13.4 and 7, 4-H), 1.86–1.99
(1 H, m, 4-H), 2.14 (1 H, dd, J 13.0 and 9.7, 6-H), 2.15–2.24 (1 H,
br dd, J 15 and 6, 3-H), 2.34 (1 H, ddd, J 13.0, 5.0 and 1.7, 6-H),
2.42–2.55 (1 H, m, 3-H), 2.78 (1 H, dd, J 9.7 and 5.0, 7-H), 3.42
and 3.76 (2 H, each d, J 14.2, CH2Ph), 3.68 (3 H, s, OCH3), 3.72
and 3.90 (2 H, each dq, J 10.8 and 7.2, OCH2), 5.13 (1 H, s, 1-H),
(3 d, 5 C in Ph), 137.0 and 138.2 (2 s, C-7 and C in Ph), 143.8 (d,
C-6), 152.3 (s, C-2) and 163.9 and 165.4 (2 s, 2 CO); m/z 341 (M+,
15%), 282 (32), 268 (14), 250 (64), 236 (32), 204 (24) and 91 (100).
Dimethyl (E,1RS,5SR)-8-benzyl-2-ethoxycarbonylmethylene-
8-azabicyclo[3.2.1]oct-6-ene-6,7-dicarboxylate [(E)-20]. An oil
(Found: M+ 399.1683. C22H25NO6 requires M, 399.1682); mmax
=
5.73 (1 H, d, J 2.2, C CH) and 7.21–7.29 (5 H, m, Ph); dC (100
MHz) 13.9 (q, CH2CH3), 24.7 (q, 5-CH3), 29.7, 33.9 and 39.9
(3 t, C-3, −4 and -6), 44.7 (d, C-7), 47.3 (t, CH2Ph), 52.1 (q, OMe),
(film)/cm−1 1720 (C O); dH (300 MHz) 1.27 (3 H, t, J 7.2, CH3),
=
1.72–1.81 (1 H, br dd, J 13 and 8, 4-H), 1.89–2.01 (1 H, m,
4-H), 2.30–2.45 and 3.59–3.69 (2 H, each m, 3-H2), 3.66 (2 H, s,
CH2Ph), 3.77 and 3.83 (6 H, each s, 2 OCH3), 3.92–3.95 (1 H, br
t, J 3, 5-H), 4.06 (1 H, s, 1-H), 4.14 (2 H, q, J 7.2, OCH2), 5.62
=
59.9 (s, C-5), 60.0 (t, OCH2), 60.6 (d, C-1), 116.9 (d, C CH),
126.4, 127.8 and 127.9 (3 d, 5 C in Ph), 139.8 (s, C in Ph), 154.3
(s, C-2) and 165.5 and 174.6 (2 s, 2 CO); m/z 357 (M+, 53%), 298
(60), 284 (38), 271 (27), 252 (56), 234 (49), 220 (30), 188 (21) and
91 (100).
=
(1 H, d, J 2.4, C CH) and 7.23–7.35 (5 H, m, Ph); dC (100 MHz)
14.4 (q, CH3), 21.2 and 23.0 (2 t, C-3 and -4), 52.3 and 52.4 (2 q,
2 OMe), 56.2 (t, CH2Ph), 59.9 (t, OCH2), 67.5 (d, C-5), 74.2 (d,
Ethyl
(Z,1RS,5RS,7SR)-(8-benzyl-7-methoxycarbonyl-5-
=
C-1), 116.1 (d, C CH), 127.2, 128.3 and 128.6 (3 d, 5 C in Ph),
methyl-8-azatricyclo[3.2.1]oct-2-ylidene)acetate [(Z)-22b]. An
oil (Found: M+ 357.1944. C21H27NO4 requires M, 357.1940); mmax
137.4, 137.9 and 142.4 (3 s, C-6, C-7 and C in Ph), 151.9 (s, C-2)
and 163.3, 164.7 and 165.9 (3 s, 3 CO); m/z 399 (M+, 10%), 367
(9), 340 (65), 308 (55), 294 (21), 276 (25), 262 (10) and 91 (100).
(CHCl3)/cm−1 1720 (C O); dH (300 MHz) 1.10 (3 H, t, J 7.2,
=
CH3), 1.22 (s, 3H, 5-CH3), 1.49–1.58 (1 H, br dd, J 13 and 8,
4-H), 1.88–1.96 (1 H, br dd, J 13 and 7, 4-H), 2.00 (1 H, ddd, J
13.2, 12 and 1.5, 6-H), 2.11–2.21 (1 H, br dd, J 16 and 7, 3-H),
2.37 (1 H, dd, J 13.2 and 6.4, 6-H), 2.59–2.73 (1 H, m, 3-H),
3.30–3.39 (1 H, br dt, J 12 and 7, 7-H), 3.44 and 3.70 (2 H, each
d, J 13.6, CH2Ph), 3.55 (3 H, s, OCH3), 3.89 and 3.99 (2 H, each
dq, J 10.8 and 7.2, OCH2), 5.10 (1 H, d, J 7.0, 1-H), 5.78 (1 H,
d, J 2.4, C CH) and 7.21–7.27 (5 H, m, Ph); dC (100 MHz) 14.3
(q, CH2CH3), 25.3 (q, 5-CH3), 29.4 (t, C-3), 33.8 (t, C-4), 38.1
(t, C-6), 45.4 (d, C-7), 48.0 (t, CH2Ph), 51.6 (q, OMe), 59.7 (t,
Dimethyl (Z,1RS,5SR)-8-benzyl-2-ethoxycarbonylmethylene-8-
azabicyclo[3.2.1]oct-6-ene-6,7-dicarboxylate [(Z)-20]. An oil
(Found: M+ 399.1683. C22H25NO6 requires M, 399.1682); mmax
(CHCl3)/cm−1 1705 (C O); dH (300 MHz) 1.19 (3 H, t, J 7.1,
=
CH3), 1.72–1.81 (1 H, br dd, J 13 and 9 Hz, 4-H), 1.95–2.07 (1 H,
m, 4-H), 2.29 (1 H, dd, J 16 and 6 Hz, 3-H), 2.55 (1 H, dddd, J
16.3, 10.4, 8.1 and 2.2, 3-H), 3.64 and 3.73 (2 H, each d, J 13.3,
CH2Ph), 3.78 and 3.80 (6 H, each s, 2 OCH3), 3.90–3.93 (1 H, br
t, J 3, 5-H), 4.03 and 4.10 (2 H, each dq, J 10.8 and 7.1, OCH2),
=
=
OCH2), 59.9 (s, C-5), 60.0 (d, C-1), 118.5 (d, C CH), 126.5, 127.9
=
5.65 (1 H, d, J 2.2, C CH), 5.82 (1 H, s, 1-H) and 7.21–7.34 (5 H,
and 128.3 (3 d, 5 C in Ph), 139.8 (s, C in Ph), 154.5 (s, C-2) and
165.2 and 173.0 (2 s, 2 CO); m/z 357 (M+, 77%), 298 (39), 284
(66), 271 (61), 252 (33), 234 (46), 220 (27), 188 (25) and 91 (100).
m, Ph); dC (100 MHz) 14.3 (q, CH3), 25.1 and 27.2 (2 t, C-3 and
-4), 52.28 and 52.31 (2 q, 2 OMe), 56.4 (t, CH2Ph), 59.9 (t, OCH2),
=
66.2 (d, C-5), 67.8 (d, C-1), 116.0 (d, C CH), 127.0, 128.2 and
128.6 (3 d, 5 C in Ph), 137.8 (s, C in Ph), 140.1 and 140.4 (2 s, C-6
Ethyl
(Z,1RS,5RS,6SR)-(8-benzyl-6-methoxycarbonyl-5-
and -7), 150.9 (s, C-2) and 164.0, 164.3 and 165.3 (3 s, 3 CO); m/z
methyl-8-azatricyclo[3.2.1]oct-2-ylidene)acetate [(Z)-23]. An oil
This journal is
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Org. Biomol. Chem., 2008, 6, 3186–3195 | 3193
©

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(Found: M+ 357.1947. C21H27NO4 requires M, 357.1940); mmax
(5 H, m, Ph); dC (100 MHz) 26.3 (t, C-3), 29.5 and 29.8 (2 t, C-4
and -6), 47.1 (d, C-7), 52.4 (q, OMe), 53.4 (t, CH2Ph), 56.4 (d,
C-5), 65.7 (d, C-1), 84.5 [s, C(CN)2], 110.5 and 111.1 (2 s, 2 CN),
127.6, 128.3 and 128.5 (3 d, 5 C in Ph), 136.9 (s, C in Ph), 171.5 (s,
CO) and 179.6 (s, C-2); m/z 321 (M+, 40%), 290 (9), 235 (28) and
91 (100).
(CHCl3)/cm−1 1710 (C O); dH (300 MHz) 1.04 (3 H, t, J 7.2,
=
CH3), 1.12 (3 H, s, 5-CH3), 1.60 (1 H, dd, J 13.2 and 6.8, 4-H),
1.83 (1 H, dd, J 13.2 and 9.4, 7-H), 1.91–2.02 (1 H, br td, J 13
and 6 Hz, 4-H), 2.15–2.23 (1 H, br dd, J 16 and 6, 3-H), 2.45–2.52
(1 H, m, 3-H), 2.51–2.61 (1 H, br ddd, J 13, 7 and 6, 7-H), 2.97
(1 H, dd, J 9.4 and 5.8, 6-H), 3.50 and 3.75 (2 H, each d, J 14.1,
CH2Ph), 3.73 (3 H, s, OCH3), 3.82 and 3.92 (2 H, each dq, J
10.8 and 7.2, OCH2), 4.91 (1 H, d, J 7.0, 1-H), 5.71 (1 H, d, J
Dimethyl
(1RS,5SR)-8-benzyl-2-dicyanomethylene-8-azatri-
cyclo[3.2.1]oct-6-ene-6,7-dicarboxylate (26). Pale yellow crystals;
mp 131–133 ◦C (hexane–ethyl acetate) (Found: C, 66.96; H, 5.24;
N, 10.95. C21H19N3O4 requires C, 66.83; H, 5.07; N, 11.13%);
=
2.0, C CH) and 7.15–7.32 (5 H, m, Ph); dC (100 MHz) 14.1 (q,
CH2CH3), 21.7 (q, 5-CH3), 29.3 (t, C-3), 31.5 (t, C-7), 36.1 (t,
C-4), 47.7 (t, CH2Ph), 51.4 (d, C-6), 51.6 (q, OMe), 57.1 (d, C-1),
mmax (CHCl3)/cm−1 2240 (C N) and 1730 (C O); dH (300 MHz)
1.88–1.95 and 2.14–2.26 (2 H, 2 m, 4-H2), 2.56–2.66 (1 H, br
quintet, J 9, 3-H), 2.94–3.01 (1 H, m, 3-H), 3.72 (2 H, br s,
CH2Ph), 3.83 and 3.87 (6 H, 2 s, 2 OCH3), 4.03 (1 H, br s, 5-H),
4.78 (1 H, s, 1-H) and 7.26–7.38 (5 H, m, Ph); dC (100 MHz) 23.4
and 25.4 (2 t, C-3 and -4), 52.8, (2 q, 2 OMe), 56.4 (t, CH2Ph),
66.9 and 70.0 (2 d, C-1 and -5), 84.4 [s, C(CN)2], 110.2 and 110.8
(2 s, 2 CN), 127.8, 128.5 and 128.6 (3 d, 5 C in Ph), 135.1, 136.0
and 144.6 (3 s, C-6, C-7 and C in Ph), 161.9 and 163.8 (2 s, 2 CO)
and 172.9 (s, C-2); m/z 377 (M+, 18%), 318 (22), 286 (26), 254
(13), 242 (34) and 91 (100).
≡
=
=
59.9 (t, OCH2), 63.3 (s, C-5), 116.1 (d, C CH), 126.4 (d, C in Ph),
127.9 (d, 4 C in Ph), 140.1 (s, C in Ph), 156.5 (s, C-2) and 165.6
and 175.2 (2 s, 2 CO); m/z 357 (M+, 39%), 312 (21), 298 (22), 284
(41), 271 (54), 266 (40), 220 (100), 188 (28) and 91 (89).
Dimethyl (Z,1RS,5RS)-8-benzyl-2-ethoxycarbonylmethylene-
5-methyl-8-azabicyclo[3.2.1]oct-6-ene-6,7-dicarboxylate [(Z)-24].
An oil (Found: M+ 413.1843. C23H27NO6 requires M, 413.1838);
mmax (film)/cm−1 1720 (C O); dH (300 MHz) 1.05 (3 H, t, J 7.2,
=
CH3), 1.32 (3 H, s, 5-CH3), 1.77–1.86 (1 H, br dd, J 13 and 7,
4-H), 1.95 (1 H, ddd, J 13.4, 10.5 and 6.6, 4-H), 2.22–2.30 (1 H,
br dd, J 16 and 6, 3-H), 2.53–2.66 (1 H, m, 3-H), 3.59 and 3.66
(2 H, each d, J 13.6, CH2Ph), 3.70 and 3.86 (6 H, each s, 2 OCH3),
3.81 and 3.97 (2 H, each dq, J 10.8 and 7.2, OCH2), 5.55 (1 H,
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific
Research (C) (No. 13672239) administered by the Japan Society
for the Promotion of Science. The authors wish to thank the
staff of the Analysis Center of Meiji Pharmaceutical University
for performing the elemental analysis and measurements of LA-
NMR (NOESY spectra) (Ms S. Kubota) and mass spectra (Ms
T. Koseki). We are also grateful to Mr T. Ujike and Mr T. Okuda
for their technical assistance.
=
d, J 7.0, 1-H), 5.74 (1 H, d, J 2.4, C CH) and 7.18–7.31 (5 H,
m, Ph); dC (100 MHz) 14.1 (q, CH2CH3), 20.0 (q, 5-CH3), 28.3 (t,
C-3), 29.5 (t, C-4), 49.0 (t, CH2Ph), 52.0 and 52.3 (2 q, 2 OMe),
=
59.8 (t, OCH2), 62.9 (d, C-1), 69.1 (s, C-5), 118.5 (d, C CH),
126.7, 128.0 and 128.4 (3 d, 5 C in Ph), 136.4 and 138.2 (2 s, C-7
and C in Ph), 147.5 and 150.0 (2 s, C-2 and -6) and 162.7, 164.9
and 165.4 (3 s, 3 CO); m/z 413 (M+, 24%), 354 (82), 322 (39), 308
(36), 262 (22) and 91 (100).
References and notes
Methyl (1RS,5RS,7RS)-8-benzyl-2-dicyanomethylene-8-aza-
tricyclo[3.2.1]octane-7-carboxylate (25a). An oil (Found: M+
321.1473. C19H19N3O2 requires M, 321.1477); mmax (CHCl3)/cm−1
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2 (a) R. Huisgen, W. Scheer and H. Huber, J. Am. Chem. Soc., 1967,
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Tetrahedron, 2006, 62, 10865–10878.
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Perkin Trans. 1, 1994, 2353–2354; (b) M. Kotera, K. Ishii, O. Tamura
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6 For recent examples, see: V. K. Aggarwal, R. S. Grainger, G. K. Newton,
P. L. Spargo, A. D. Hobson and H. Adams, Org. Biomol. Chem., 2003, 1,
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≡
=
2240 (C N) and 1730 (C O); dH (300 MHz) 1.68–1.77 (1 H,
br dd, J 13 and 8, 4-H), 2.05 (1 H, dd, J 13.6 and 9.7, 6-H),
2.12–2.25 (1 H, m, 4-H), 2.49 (1 H, ddd, J 16.7, 11.4 and 7.9,
3-H), 2.65–2.74 (1 H, m, 6-H), 2.89 (1 H, dd, J 9.7 and 5.3, 7-H),
2.90–3.00 (1 H, br ddd, J 17, 8 and 1, 3-H), 3.44–3.49 (1 H, m,
5-H), 3.72 (2 H, s, CH2Ph), 3.76 (3 H, s, OCH3), 4.50 (1 H, s, 1-H)
and 7.24–7.37 (5 H, m, Ph); dC (100 MHz) 26.6 (t, C-3), 29.8 (t,
C-4), 31.4 (t, C-6), 47.0 (d, C-7), 52.7 (q, OMe), 53.1 (t, CH2Ph),
56.7 (d, C-5), 65.4 (d, C-1), 82.9 [s, C(CN)2], 111.0 and 111.1 (2 s,
2 CN), 127.5, 128.1 and 128.4 (3 d, 5 C in Ph), 137.0 (s, C in Ph),
172.8 (s, CO) and 180.0 (s, C-2); m/z 321 (M+, 52%), 290 (13), 262
(15), 235 (27) and 91 (100).
Methyl (1RS,5RS,7SR)-8-benzyl-2-dicyanomethylene-8-aza-
tricyclo[3.2.1]octane-7-carboxylate (25b). An oil (Found: M+
321.1479. C19H19N3O2 requires M, 321.1477); mmax (CHCl3)/cm−1
≡
=
2230 (C N) and 1730 (C O); dH (300 MHz) 1.71–1.80 (1 H, br
dd, J 13 and 8, 4-H), 2.14–2.26 (2 H, m, 4- and 6-H), 2.65–2.74
(1 H, br td, J 13 and 7, 6-H), 2.54–2.67 (1 H, br ddd, J 17, 11 and 8,
3-H), 2.86–2.96 (1 H, br dd, J 17 and 7, 3-H), 3.38–3.44 (1 H, m,
5-H), 3.55–3.64 (1 H, br dt, J 12 and 6, 7-H), 3.70 (3 H, s, OCH3),
3.71 (2 H, s, CH2Ph), 4.36 (1 H, d, J 6.4, 1-H) and 7.23–7.38
3194 | Org. Biomol. Chem., 2008, 6, 3186–3195
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View Article Online
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7 J. W. Lown and K. Matsumoto, J. Chem. Soc. D, 1970, 692–693.
8 M. T. Barros, C. D. Maycock and M. R. Ventura, Tetrahedron Lett.,
2002, 43, 4329–4331.
9 The deshielding effect of the carboxyl group was also observed in the
bicyclic epoxide system (see ref. 5c).
10 V. Bardakos and C. Sandris, Org. Magn. Reson., 1981, 15, 339–342.
11 The characteristic cross-peaks between 3-H and 7-H in compounds
(E)-15a, (Z)-15a and 25a and between 6-H and 9-H in (Z)-17a indicate
an exo-configuration. In contrast, in (E)-15b the cross-peak between
1-H and 7-H indicates an endo-configuration. The cross-peaks between
3-H and 7-H and 6-H and 7-H in compound (Z)-18a indicate a 6,7-cis
and exo-configuration. The cross-peaks between 1-H and 7-H and 3-H
and 7-H in (Z)-18b indicate a 6,7-trans and endo-configuration. The
cross-peaks between 3-H and 7-H and 5-H and 6-H in (Z)-18c indicate
a 6,7-trans and exo-configuration. The cross-peak between 3-H and 6-H
in compound (Z)-23 characteristically indicates an exo-configuration.
12 The cycloaddition of the 6-membered carbonyl ylide derived from the
epoxide 3 and ethyl vinyl ether afforded the adduct 4 in 44% yield (see
ref. 5b).
13 Yields for compounds are based on converted starting material.
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