Inter- and intramolecular [4+2]-cycloaddition reactions with 4,4-disubstituted N -silyl-1,4-dihydropyridines as precursors for N-protonated 2-azabutadiene intermediates

Article abstract of DOI:10.1055/s-0033-1341044

An efficient and straightforward method for the synthesis of polycyclic ring systems with a central 2-azabicyclo[2.2.2]octane unit is developed. The process is based on [4+2]-cycloaddition reactions that are performed with N-protonated 2-azabutadiene intermediates as heterodienes, generated from 4,4-disubstituted N-silyl 1,4-dihydropyridines. As dienophiles, cyclopentadiene for the intermolecular cycloaddition and an allyl moiety already attached to the 4,4-disubstituted 1,4-dihydropyridines for the intramolecular variant, are used.

Full text of DOI:10.1055/s-0033-1341044

1630▌
PAPER
paper
Inter- and Intramolecular [4+2]-Cycloaddition Reactions with 4,4-Disubstituted
N-Silyl-1,4-dihydropyridines as Precursors for N-Protonated 2-Azabutadiene
Intermediates
Cycloadditions of 1,4-Dihydropyridines as Heterodiene Precursors
Cornelia E. Schmaunz,a Peter Mayer,b Klaus T. Wanner*a
a
Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Haus C, 81377
München, Germany
Fax +49(89)218077247; E-mail: klaus.wanner@cup.uni-muenchen.de
b
Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Haus D, 81377 München, Germany
Received: 24.01.2014; Accepted after revision: 27.02.2014
dienophiles have been reported by Hartman et al.7 The re-
Abstract: An efficient and straightforward method for the synthe-
actions were performed in the presence of an acid as the
sis of polycyclic ring systems with a central 2-azabicyclo[2.2.2]oc-
catalyst to generate N-protonated 2-azabutadienes as in-
termediates, which underwent intermolecular [4+2] cycli-
tane unit is developed. The process is based on [4+2]-cycloaddition
reactions that are performed with N-protonated 2-azabutadiene in-
termediates as heterodienes, generated from 4,4-disubstituted N-si- zations
with
different
alkenes
(styrene,
lyl 1,4-dihydropyridines. As dienophiles, cyclopentadiene for the
allyltrimethylsilane, cyclopentadiene, furan, thiophene).
Similarly, intramolecular [4+2]-cyclization reactions
were also carried out with 4-phenyl-substituted 1,4-dihy-
dropyridines in which the dienophile, an alkene moiety,
required for the cyclization with the generated intermedi-
ate N-protonated 2-azabutadiene, was already present in
the molecule as an ortho-substituent attached to a phenyl
residue at the 4-position.7
intermolecular cycloaddition and an allyl moiety already attached to
the 4,4-disubstituted 1,4-dihydropyridines for the intramolecular
variant, are used.
Key words: hetero-Diels–Alder reaction, 1,4-dihydropyridines,
heterocycles, polycycles, imines
The 2-azabicyclo[2.2.2]octane ring system (1) is found in
various biologically active compounds. Well-known ex-
amples include ibogaine (2), a psychoactive indole alka-
loid, and dioscorine (3), which is a modulator of the
nicotinic acetylcholine receptor and leads to disorders in
the central nervous system (Figure 1).1
We previously demonstrated the high synthetic utility of
4,4-disubstituted N-silyl-1,4-dihydropyridines,8 that are
easily accessible by trapping reactions of N-silylpyridini-
um ions, for the synthesis of 5-substituted 7,8-benzomor-
phans, as well as for 4,4-disubstituted 2-cyanopiperidines
and 2,6-dicyanopiperidines.9
Herein, we report on the highly efficient synthesis of
10,10-disubstituted 8-azatricyclo[5.2.2.02,6]undeca-3,8-
dienes by acid-catalyzed cycloaddition reactions employ-
ing 4,4-disubstituted 1,4-dihydropyridines and cyclopen-
tadiene as starting materials. The Diels–Alder addition
products derived from 4,4-disubstituted 1,4-dihydropyri-
dines could be successfully used in subsequent intramo-
lecular Friedel–Crafts-type cyclization reactions resulting
in polycyclic nitrogen heterocycles possessing both a 2-
azabicyclo[2.2.2]octane and a 7,8-benzomorphane sub-
structure. In addition, Diels–Alder reactions were per-
formed with 4-allyl-substituted 1,4-dihydropyridines,
which proceeded intramolecularly leading to 1-substitut-
ed 4-azatricyclo[3.3.1.02,7]non-3-enes with a unique poly-
cyclic skeleton.
MeO
Me
N
O
O
N
N
H
HN
2-azabicyclo-
[2.2.2]octane (1)
ibogaine (2)
dioscorine (3)
Figure 1 Structures of 2-azabicyclo[2.2.2]octane (1), ibogaine (2)
and dioscorine (3)
The synthesis of 2-azabicyclo[2.2.2]octane derivatives is
often carried out via Diels–Alder reactions using pyri-
dines,2 pyridones,3 1,2-dihydropyridines,4 3,4-dihydro-
pyridines,5 or activated 1,4-dihydropyridines,6,7 as dienes
for the cyclizations. In the case of 1,4-dihydropyridines,
Craig et al. published, for example, the [4+2] cyclization
The 4,4-disubstituted N-silyl-1,4-dihydropyridines 5a–e
that were required as starting materials for the intramolec-
ular cycloaddition reactions were prepared following a
published procedure; treatment of the respective pyridine
derivatives 4a–e with triisopropylsilyl triflate gave the
corresponding pyridinium salts, which were subsequently
trapped with diorganomagnesium compounds.8 The
yields for the obtained addition products, 1,4-dihydropyr-
idines 5a–e, are given in Table 1, where, for the sake of
of
N-phenyl-3,5-diethyl-2-propyl-1,4-dihydropyridine
with maleic anhydride.6 Further examples of inter- and
intramolecular Diels–Alder reactions of 1,4-dihydropyri-
dines, more precisely 4-aryl-substituted dimethyl 2,6-di-
methyl-1,4-dihydropyridine-3,5-dicarboxylates,
with
SYNTHESIS 2014, 46, 1630–1638
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DOI: 10.1055/s-0033-1341044; Art ID: SS-2014-T0056-OP
© Georg Thieme Verlag Stuttgart · New York

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Cycloadditions of 1,4-Dihydropyridines as Heterodiene Precursors
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Table 1 Synthesis of 10,10-Disubstituted 8-Azatricyclo[5.2.2.02,6]undeca-3,8-dienes 6a–e
R
R
R
1. TIPSOTf
r.t.
R
R
R
R
HN+
2. R2Mg
–78 °C
HCl–EtOH
(c = 1.25 M)
70 °C, 2 h
N
N
4a–e
N
Cl–
Si
6a–ea
5a–e
Entry
Starting material
Products
4
R
5
Yield (%)
6
Yield (%)
1
2
3
4
5
a
Et
a
b
c
81b
85b
56b
61
a
b
c
80
84
87
77
85
b
Bn
cb
dc
eb
PMB
4-FC6H4CH2
CH2CH2Ph
d
e
d
e
62b
a Structures of only one of the two enantiomers of the racemic compounds are shown.
b Data obtained from the literature.8,9
c The preparation of 4d is described in the experimental section.
completeness, the data for the preparation of compounds Accordingly, the pyridine derivatives 4a and 4e were
published earlier are also listed.8,9
treated with triisopropylsilyl triflate to give the respective
N-silylpyridinium ions, which were subsequently trapped
with diallylmagnesium (allyl2Mg) to afford the 1,4-dihy-
dropyridines 5f and 5i. The yields for these compounds, 5f
and 5i, were quite low, but still in the range common for
trapping reactions performed with diallylmagnesium as
can be seen from the yields obtained for the preparation of
5g,h reported earlier,8 that are also listed in Table 3, as
these compounds have been used here as well. Upon heat-
ing at reflux temperature in ethanolic hydrogen chloride
solution (1.25 M) the 1,4-dihydropyridines 5f–i under-
went the desired cyclization into the 1-substituted 4-aza-
The intermolecular [4+2] cyclizations of the 1,4-dihydro-
pyridines 5a–e with cyclopentadiene could be realized ef-
ficiently by heating the components in ethanolic hydrogen
chloride solution (1.25 M) at 70 °C, leading to the desired
products 6a–e in good to high yields (77–87%, Table 1).
In the next step, the obtained 5,5-diarylsubstituted 2-aza-
bicyclo[2.2.2]octane derivatives 6b–d were used as start-
ing materials for the intramolecular Friedel–Crafts-type
cyclization reactions. Treatment of imines 6b–d with ace-
tyl chloride in dichloromethane to generate the corre-
sponding N-acetyliminium ions resulted in smooth
intramolecular electrophilic aromatic substitution reac-
tions of the aryl substituents opposite to the cylcopentene
bridge in 6b–d, providing the polycyclic nitrogen hetero-
cycles 7a–c in high yields (86–94%, Table 2). In addition
to the 2-azabicyclo[2.2.2]octane substructure present in
the starting materials 6b–d, the generated polycyclic pi-
peridine derivatives 7a–c contain a 7,8-benzomorphane
subunit.
Table 2 Synthesis of Polycyclic Nitrogen Heterocycles 7a–c
R
R
AcCl
AcN
N
CH2Cl2
r.t., 2 h
R
7a–ca
The structures of the polycyclic piperidine derivatives 7a–
c were deduced from comprehensive 2D NMR studies,
and exemplified for 7a by an X-ray crystal structure anal-
ysis, the result of which is given in Figure 2.
R
6b–da
Entry
Starting material
Product
Having successfully performed acid-catalyzed intermo-
lecular Diels–Alder reactions between the 1,4-dihydro-
pyridines 5a–e and cyclopentadiene, we next turned our
attention to the intramolecular variant of these cycloaddi-
tion reactions. The required 4,4-disubstituted N-silyl-1,4-
dihydropyridines 5f–i, possessing an allyl group at the 4-
position, were again synthesized via N-silylpyridinium
ion intermediates following the above described method.
6
R
7
Yield (%)
1
2
3
b
c
H
a
b
c
92
94
86
OMe
F
d
a Structures of only one of the two enantiomers of the racemic com-
pounds are shown.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1630–1638

1632
C. E. Schmaunz et al.
PAPER
Figure 3 X-ray crystal structure of 8c10
in the presence of ethereal hydrogen chloride in methanol.
This afforded the desired 4-azatricyclo[3.3.1.02,7]non-
anes, which were isolated as hydrochlorides 9a–d in good
to high yields (80–92%, Table 3).
Figure 2 X-ray crystal structure of 7a10
tricyclo[3.3.1.02,7]non-3-ene derivatives 8a–d (63–95%,
In summary, we have described an easy and straightfor-
ward method for the synthesis of polycyclic ring systems
that starts from N-silyl-1,4-dihydropyridine derivatives as
key compounds. Upon reaction under acidic conditions,
these compounds served as precursors for the generation
of N-protonated 2-azabutadienes as heterodienes in
[4+2]-cycloaddition reactions. These underwent smooth
intermolecular cycloaddition reactions with cyclopentadi-
ene as a dienophile, and with allyl moieties attached to the
1,4-dihydropyridine precursors in intramolecular hetero-
Diels–Alder reactions, leading to polycyclic tetrahydro-
pyridine and piperidine derivatives with a 2-azabicyclo-
[2.2.2]octane ring system as the core unit.
Table 3).
The structures of compounds 8a–d were established by
NMR studies. The respective assignments were corrobo-
rated unambiguously by X-ray crystallography of 8c (Fig-
ure 3), which neatly highlights the unique skeleton of this
class of compounds.
According to the structures of the products, the vinyl
group of the allyl moiety has added via the terminal car-
bon at position 2 and with the inner carbon at position 5 of
the piperidine ring. This regioselectivity (leading to 8a–d)
is likely to be a result of the improved charge-stabilizing
effects that can operate when the cycloaddition takes
place with this orientation. In fact, the regioselectivity ob-
served for the intermolecular cycloaddition reactions
leading to the products 6a–e can be explained in the same
way (Table 1).
All solvents and chemicals were obtained from commercial sources
and were utilized without further purification unless otherwise stat-
ed. All reactions were performed using flame-dried glassware under
an argon atmosphere. Absolute solvents were freshly dried using
standard procedures.11 Flash chromatography was performed with
Merck 40–63 mesh silica gel or Fluka 50–150 mesh alumina (neu-
The fully saturated analogues of imines 8a–d were finally
obtained upon reduction with sodium cyanoborohydride
Table 3 Synthesis of 1-Substituted 4-Azatricyclo[3.3.1.02,7]nonane Hydrochlorides 9a–d
R
R
HCl–EtOH
(c = 1.25 M)
NaBH3CN, MeOH
HCl–Et2O
1.TIPSOTf
r.t.
H
R
N+
H
R
reflux, 1 h
r.t., 1 h
R
HN+
Cl–
N
2. (allyl)2Mg
–78 °C
N
N
4a,b,e,f
Cl–
8a–da
Si
9a–da
5f–i
Entry
Starting material
Products
4
R
5
Yield (%)
8
Yield (%)
9
Yield (%)
1
2
3
4
a
f
Et
f
25
a
b
c
95
63
92
83
a
b
c
80
84
89
92
Ph
Bn
g
h
i
20b
12b
19
b
e
CH2CH2Ph
d
d
a Structures of only one of the two enantiomers of the racemic compounds are shown.
b Data obtained from the literature.8
Synthesis 2014, 46, 1630–1638
© Georg Thieme Verlag Stuttgart · New York

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Cycloadditions of 1,4-Dihydropyridines as Heterodiene Precursors
1633
tral Brockmann activity III). Melting points were determined on a
Büchi melting point apparatus (no. 510 Dr. Tottoli). IR spectra were
obtained using a Perkin-Elmer model 1600 FT-IR spectrophotome-
ter. 1H and 13C NMR spectra were recorded on a JNMR-GX 400 (Je-
ol, 400 MHz) or a JNMR-GX 500 (Jeol, 500 MHz) spectrometer.
Multiplicities given for 13C NMR spectra were deduced from DEPT
experiments. Low-resolution MS (CI) were recorded on a Hewlett
Packard 5989 mass spectrometer. HRMS were obtained on a JEOL
MStation 700. Microanalytical data for C, H, and N were deter-
mined using a Heraeus Rapid Analyser and an Elementar Vario EL
Analyser.
4,4-Bis(4-fluorobenzyl)-1-triisopropylsilyl-1,4-dihydropyri-
dine (5d)
The title product was prepared in analogy to the literature8 starting
from 4d (101 mg, 0.540 mmol) and TIPSOTf (182 mg, 160 μL,
0.594 mmol) in CH2Cl2 (5 mL) and 0.05 M (4-FC6H4CH2)2Mg in
Et2O (21.6 mL), at –50 °C for 12 h; (4-FC6H4CH2)2Mg was pre-
pared according to the literature13 from Mg (875 mg, 36.0 mmol) in
Et2O (20 mL), 1-chloromethyl-4-fluorobenzene (3.47 mg, 2.87 mL,
24.0 mmol) in Et2O (60 mL), and 1,4-dioxane (2.33 g, 2.25 mL,
26.4 mmol). Work-up of the crude product was performed with 1.0
M phosphate buffer (10 mL, pH 7) and extraction with CH2Cl2 (4 ×
20 mL). Purification by flash chromatography (alumina, n-pentane)
and fractional crystallization (n-pentane) gave the desired product.
10,10-Disubstituted 8-Azatricyclo[5.2.2.02,6]undeca-3,8-dienes
6; General Procedure (GP1)
Yield: 149 mg (61%); colorless crystals; mp 64–67 °C; Rf = 0.67
(alumina, n-pentane).
A solution of 4,4-disubstituted N-silyl-1,4-dihydropyridine 5 and
cyclopentadiene (cyclopentadiene was prepared by heating dicyclo-
pentadiene at 190 °C and collecting the distilled cyclopentadiene
which was used immediately) in 1.25 M ethanolic HCl was heated
to 70 °C. After 2 h, the solution was quenched by the addition of 1.0
M phosphate buffer (pH 7) until a pH of 7 was reached. The aq layer
was extracted with CH2Cl2. The combined organic layers were dried
(MgSO4) and concentrated in vacuo. The residue was purified by
flash chromatography to yield the desired product.
IR (KBr): 3043, 2953, 2892, 2866, 1669, 1600, 1508, 1473, 1460,
1441, 1280, 1216 cm–1.
1H NMR (400 MHz, CD2Cl2): δ = 0.82 [d, J = 7.4 Hz, 18 H,
CH(CH3)2], 0.94–1.09 [m, 3 H, CH(CH3)2], 2.59 (s, 4 H, CH2), 4.10
(d, J = 8.3 Hz, 2 H, NCHCH), 5.74 (d, J = 8.3 Hz, 2 H, NCH), 6.83–
6.97 (m, 4 H, CHAr,m), 7.03–7.17 (m, 4 H, CHAr,o).
13C NMR (100 MHz, CDCl3): δ = 11.5 [d, 3 C, CH(CH3)2], 17.6 [q,
6 C, CH(CH3)2], 42.3 (s, 1 C, NCHCHC), 50.8 (t, 2 C, CH2), 105.4
(d, 2 C, NCHCH), 114.2 (d, JCF = 21.1 Hz, 4 C, CHAr,m), 129.7 (d, 2
C, NCH), 132.7 (d, JCF = 7.0 Hz, 4 C, CHAr,o), 135.9 (d, JCF = 3.0
Hz, 2 C, CAr), 161.8 (d, JCF = 242.3 Hz, 2 C, CF).
8-Substituted N-Acetyl-12-aza-10(1,2)-benzenatetracy-
clo[6.4.1.02,6.07,11]tridecaphan-4-enes 7; General Procedure
(GP2)
The corresponding 8-azatricyclo[5.2.2.02,6]undeca-3,8-diene 6 and
AcCl were dissolved in CH2Cl2 and the mixture was stirred at r.t.
After 2 h, the solution was quenched by the addition of 1.0 M phos-
phate buffer (pH 7). The aq layer was extracted with CH2Cl2, and
the combined organic layers dried (MgSO4) and concentrated in
vacuo. The residue was purified by flash chromatography (alumina)
to yield the desired product.
+
MS (CI, CH5 ): m/z (%) = 344 (66), 454 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C28H38F2NSi: 454.2742;
found: 454.2733.
Anal. Calcd for C28H37F2NSi: C, 74.13; H, 8.22; N, 3.09. Found: C,
74.02; H, 7.96; N, 3.04.
1-Substituted 4-Azatricyclo[3.3.1.02,7]non-3-enes 8; General
Procedure (GP3)
4-Allyl-4-ethyl-1-triisopropylsilyl-1,4-dihydropyridine (5f)
The title product was prepared in analogy to the literature8 starting
from 4-ethylpyridine (1.00 g, 1.06 mL, 9.33 mmol) and TIPSOTf
(3.14 g, 2.76 mL, 10.3 mmol) in CH2Cl2 (8 mL) and 0.5 M allyl2Mg
in THF (37.3 mL); allyl2Mg was prepared according to the
literature13 from 1.0 M allylMgCl solution in THF (50.0 mL), and
1,4-dioxane (4.84 g, 55.0 mmol, 4.69 mL). Work-up of the crude
product was performed with 1.0 M phosphate buffer (20 mL, pH 7)
and extraction with CH2Cl2 (4 × 20 mL). Purification by flash chro-
matography (alumina, n-pentane) gave the desired product.
A solution of 4,4-disubstituted N-silyl-1,4-dihydropyridine 5 in
1.25 M ethanolic HCl was heated at 100 °C for 1 h. The solvent was
evaporated under reduced pressure. The residue was washed care-
fully with cold n-pentane and CH2Cl2, and then 1.0 M phosphate
buffer (pH 7) was added. The aq layer was extracted with CH2Cl2.
The combined organic layers were dried (MgSO4) and concentrated
in vacuo. The residue was purified by flash chromatography (alumi-
na) to yield the desired product.
1-Substituted 4-Azatricyclo[3.3.1.02,7]nonane Hydrochlorides
9; General Procedure (GP4)
Yield: 704 mg (25%); colorless oil; Rf = 0.97 (alumina, n-pentane).
The corresponding 4-azatricyclo[3.3.1.02,7]non-3-ene
8
and
IR (film): 3074, 3042, 2959, 2894, 2868, 1668, 1639, 1600, 1463,
1384, 1370, 1287cm–1.
NaBH3CN were dissolved in MeOH. After addition of ethereal HCl,
the mixture was stirred at r.t. for 1 h and subsequently quenched
with H2O and then K2CO3 was added to the solution until a pH of
11 was reached. The aq layer was extracted with CH2Cl2 (× 10). The
combined organic layers were dried (MgSO4) and concentrated in
vacuo. The product was dissolved in Et2O, acidified with 2.0 M
ethereal HCl, and concentrated in vacuo.
1H NMR (500 MHz, CDCl3): δ = 0.85 (t, J = 7.5 Hz, 3 H, CH2CH3),
1.07 [d, J = 7.3 Hz, 18 H, CH(CH3)2], 1.17 (q, J = 7.5 Hz, 2 H,
CH2CH3), 1.23 [m, 3 H, CH(CH3)2], 1.97 (dt, J = 7.2, 1.2 Hz, 2 H,
CH2CHCH2), 4.05 (d, J = 8.3 Hz, 2 H, NCHCH), 4.88–5.03 (m, 2
H, CH2CHCH2), 5.87 (ddt, J = 17.4, 10.3, 7.2 Hz, 1 H, CH2CHCH2),
6.06 (d, J = 8.3 Hz, 2 H, NCH).
13C NMR (125 MHz, CDCl3): δ = 10.0 (q, 1 C, CH2CH3), 11.7 [d, 3
C, CH(CH3)2], 18.1 [q, 6 C, CH(CH3)2], 36.4 (t, 1 C, CH2CH3), 38.5
(s, 1 C, NCHCHC), 50.1 (t, 1 C, CH2CHCH2), 106.0 (d, 2 C,
NCHCH), 115.7 (t, 1 C, CH2CHCH2), 129.4 (d, 2 C, NCH), 137.0
(d, 1 C, CH2CHCH2).
4-(4-Fluorobenzyl)pyridine (4d)12
The title product was prepared in analogy to the literature9a starting
from py (196 mg, 200 μL, 2.47 mmol) and TIPSOTf (833 mg, 731
μL, 2.72 mmol) in CH2Cl2 (3 mL), and 0.11 M (4-FC6H4CH2)2Mg
in THF (46.6 mL); (4-FC6H4CH2)2Mg was prepared according to
the literature12 from Mg (875 mg, 36.0 mmol) in THF (20 mL), 1-
chloromethyl-4-fluorobenzene (3.47 mg, 2.87 mL, 24.0 mmol) in
THF (60 mL), and 1,4-dioxane (2.33 g, 2.25 mL, 26.4 mmol). Puri-
fication was accomplished by flash chromatography (silica gel,
EtOAc–MeOH, 97:3). Analytical data were in accordance with lit-
erature data.13
+
MS (CI, CH5 ): m/z (%) = 264 (100), 306 (37) [M + H]+.
HRMS (EI+): m/z [M]+ calcd for C19H35NSi: 305.2539; found:
305.2535.
4-Allyl-4-(2-phenylethyl)-1-triisopropylsilyl-1,4-dihydropyri-
dine (5i)
The title product was prepared in analogy to the literature8 starting
from 4-(2-phenylethyl)pyridine (840 mg, 4.58 mmol) and TIPSOTf
(1.54 g, 1.35 mL, 5.04 mmol) in CH2Cl2 (5 mL) and 0.5 M allyl2Mg
Yield: 390 mg (84%); light yellow oil.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1630–1638

1634
C. E. Schmaunz et al.
PAPER
in THF (18.3 mL); allyl2Mg was prepared according to the
literature13 from 1.0 M allylMgCl solution in THF (50.0 mL), and
1,4-dioxane (4.84 g, 55.0 mmol, 4.69 mL). Work-up of the crude
product was performed with 1.0 M phosphate buffer (10 mL, pH 7)
and extraction with CH2Cl2 (4 × 10 mL). Purification by flash chro-
matography (alumina, n-pentane) gave the desired product.
Yield: 262 mg (84%); light yellow oil; Rf = 0.26 (silica gel, CH2Cl2–
MeOH, 97:3).
IR (film): 3085, 3057, 3027, 3001, 2927, 2848, 1617, 1602, 1494,
1453 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.65–1.74 (m, 2 H, NCHCH2),
2.23–2.31 (m, 1 H, CH=CHCH2), 2.44 (d, J = 14.2 Hz, 1 H, CH2Ph),
2.47–2.60 (m, 2 H, CH=CHCH2, CH=CHCH2CH), 2.63 (dd, J =
4.1, 2.5 Hz, 1 H, N=CHCH), 2.70 (d, J = 14.2 Hz, 1 H, CH2Ph), 2.81
(d, J = 14.8 Hz, 1 H, CH2Ph), 3.00 (d, J = 14.8 Hz, 1 H, CH2Ph),
3.42–3.50 (m, 1 H, CH=CHCH), 4.30 (dd, J = 4.6, 2.3 Hz, 1 H,
NCHCH2), 5.35–5.45 (m, 1 H, CH=CHCH2), 5.55–5.65 (m, 1 H,
CH=CHCH2), 7.03–7.10 (m, 2 H, CHAr,o), 7.18–7.22 (m, 1 H,
CHAr,p), 7.22–7.37 (m, 7 H, CHAr), 8.10 (d, J = 4.1 Hz, 1 H, N=CH).
13C NMR (100 MHz, CDCl3): δ = 37.97 (t, 1 C, NCHCH2), 38.04 (t,
1 C, CH=CHCH2), 39.0 (d, 1 C, CH=CHCH2CH), 41.7 (s, 1 C,
N=CHCHC), 43.3 (t, 1 C, CH2Ph), 44.5 (d, 1 C, N=CHCH), 45.2 (t,
1 C, CH2Ph), 45.8 (d, 1 C, CH=CHCH), 59.8 (d, 1 C, NCHCH2),
126.27 (d, 1 C, CHAr,p), 126.30 (d, 1 C, CHAr,p), 128.1 (d, 2 C, CHAr,m),
128.3 (d, 2 C, CHAr,m), 130.3 (d, 2 C, CHAr,o), 130.6 (d, 2 C, CHAr,o),
131.3 (d, 1 C, CH=CHCH2), 133.0 (d, 1 C, CH=CHCH2), 138.5 (s,
1 C, CAr), 138.8 (s, 1 C, CAr), 175.1 (d, 1 C, N=CH).
Yield: 329 mg (19%); colorless crystals; mp 34–35 °C; Rf = 0.70
(alumina, n-pentane).
IR (KBr): 3072, 3027, 2946, 2867, 1668, 1604, 1496, 1463, 1454,
1287 cm–1.
1H NMR (500 MHz, CD2Cl2): δ = 1.09 [d, J = 7.4 Hz, 18 H,
CH(CH3)2], 1.22–1.33 [m, 3 H, CH(CH3)2], 1.41–1.47 (m, 2 H,
CH2CH2Ph), 2.02 (d, J = 7.2 Hz, 2 H, CH2CHCH2), 2.52–2.67 (m,
2 H, CH2CH2Ph), 4.19 (d, J = 8.3 Hz, 2 H, NCHCH), 4.88–5.05 (m,
2 H, CH2CHCH2), 5.89 (ddt, J = 17.4, 10.3, 7.2 Hz, 1 H,
CH2CHCH2), 6.13 (d, J = 8.3 Hz, 2 H, NCH), 7.10–7.15 (m, 1 H,
CHAr,p), 7.15–7.19 (m, 2 H, CHAr,o), 7.21–7.26 (m, 2 H, CHAr,m).
13C NMR (125 MHz, CDCl3): δ = 11.8 [d, 3 C, CH(CH3)2], 18.0 [q,
6 C, CH(CH3)2], 33.4 (t, 1 C, CH2CH2Ph), 38.5 (s, 1 C, NCHCHC),
46.7 (t, 1 C, CH2CH2Ph), 50.6 (t, 1 C, CH2CHCH2), 106.1 (d, 2 C,
NCHCH), 115.9 (t, 1 C, CH2CHCH2), 125.6 (d, 1 C, CHAr,p), 128.5
(d, 2 C, CHAr,m), 128.8 (d, 2 C, CHAr,o), 129.8 (d, 2 C, NCH), 136.9
(d, 1 C, CH2CHCH2), 144.6 (s, 1 C, CAr).
+
MS (CI, CH5 ): m/z (%) = 236 (24), 328 (100) [M + H]+.
HRMS (EI+): m/z [M]+ calcd for C24H25N: 327.1987; found:
327.1944.
+
MS (CI, CH5 ): m/z (%) = 340 (51), 382 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C25H40NSi: 382.2930; found
382.2921.
10,10-Bis(4-methoxybenzyl)-8-azatricyclo[5.2.2.02,6]undeca-
3,8-diene (6c)
The title product was prepared according to GP1 starting from 5c
(53.1 mg, 0.111 mmol) and cyclopentadiene (36.7 mg, 41.7 μL,
0.555 mmol) in 1.25 M ethanolic HCl (2 mL). Work-up was per-
formed with phosphate buffer and extraction with CH2Cl2 (4 × 4
mL). Purification by flash chromatography (alumina, n-pentane–
CH2Cl2–MeOH, 70:30:3) gave the desired product.
10,10-Diethyl-8-azatricyclo[5.2.2.02,6]undeca-3,8-diene (6a)
The title product was prepared according to GP1 from 5a (393 mg,
1.34 mmol) and cyclopentadiene (442 mg, 501 μL, 6.69 mmol) in
1.25 M ethanolic HCl (10 mL). Work-up was performed with phos-
phate buffer and extraction with CH2Cl2 (4 × 10 mL). Purification
by flash chromatography (silica gel, CH2Cl2–MeOH, 97:3) gave the
desired product.
Yield: 37.4 mg (87%); light yellow oil; Rf = 0.48 (alumina, n-pen-
tane–MeOH, 97:3).
Yield: 216 mg (80%); light yellow oil; Rf = 0.24 (silica gel, CH2Cl2–
IR (film): 3046, 2999, 2930, 2836, 1612, 1581, 1512, 1463, 1455,
1442 cm–1.
MeOH, 97:3).
IR (film): 3047, 2962, 2925, 2877, 1617, 1458, 1441, 1379, 1344
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.57–1.76 (m, 2 H, NCHCH2),
2.21–2.31 (m, 1 H, CH=CHCH2), 2.37 (d, J = 14.2 Hz, 1 H, CH2Ph),
2.44–2.65 (m, 3 H, N=CHCH, CH=CHCH2, CH=CHCH2CH), 2.60
(d, J = 14.2 Hz, 1 H, CH2Ph), 2.74 (d, J = 14.7 Hz, 1 H, CH2Ph),
2.91 (d, J = 14.7 Hz, 1 H, CH2Ph), 3.41–3.51 (m, 1 H, CH=CHCH),
3.78 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 4.24–4.36 (m, 1 H,
NCHCH2), 5.37–5.44 (m, 1 H, CH=CHCH2), 5.57–5.63 (m, 1 H,
CH=CHCH2), 6.76–6.83 (m, 2 H, CHAr,m), 6.84–6.92 (m, 2 H,
CHAr,m), 6.94–7.02 (m, 2 H, CHAr,o), 7.16–7.23 (m, 2 H, CHAr,o),
8.05 (d, J = 4.1 Hz, 1 H, N=CH).
13C NMR (100 MHz, CDCl3): δ = 37.7 (t, 1 C, NCHCH2), 38.0 (t, 1
C, CH=CHCH2), 38.9 (d, 1 C, CH=CHCH2CH), 41.9 (s, 1 C,
NCHCH2C), 42.6 (t, 1 C, CH2Ph), 44.2 (t, 1 C, CH2Ph), 44.4 (d, 1
C, N=CHCH), 45.8 (d, 1 C, CH=CHCH), 55.1 (q, 1 C, OCH3), 55.2
(q, 1 C, OCH3), 59.8 (d, 1 C, NCHCH2), 113.5 (d, 2 C, CHAr,m),
113.6 (d, 2 C, CHAr,m), 130.5 (s, 1 C, CAr), 130.6 (s, 1 C, CAr), 131.2
(d, 2 C, CHAr,o), 131.3 (d, 1 C, CH=CHCH2), 131.5 (d, 2 C, CHAr,o),
133.0 (d, 1 C, CH=CHCH2), 158.0 (s, 1 C, CAr,p), 158.1 (s, 1 C,
1H NMR (400 MHz, CDCl3): δ = 0.73 (t, J = 7.4 Hz, 3 H, CH2CH3),
0.82 (t, J = 7.4 Hz, 3 H, CH2CH3), 1.10 (dq, J = 14.7, 7.4 Hz, 1 H,
CH2CH3), 1.15 (dd, J = 13.2, 1.9 Hz, 1 H, NCHCH2), 1.22–1.33 (m,
2 H, CH2CH3, NCHCH2), 1.40 (dq, J = 14.7, 7.4 Hz, 1 H, CH2CH3),
1.52 (dq, J = 14.7, 7.4 Hz, 1 H, CH2CH3), 2.20–2.27 (m, 1 H,
CH=CHCH2), 2.43–2.53 (m, 2 H, CH=CHCH2, CH=CHCH2CH),
2.57 (dd, J = 4.2, 2.6 Hz, 1 H, N=CHCH), 3.10–3.24 (m, 1 H,
CH=CHCH), 4.16–4.28 (m, 1 H, NCHCH2), 5.36–5.48 (m, 1 H,
CH=CHCH2), 5.53–5.64 (m, 1 H, CH=CHCH2), 8.22 (d, J = 4.3 Hz,
1 H, N=CH).
13C NMR (125 MHz, CDCl3): δ = 7.9 (q, 1 C, CH2CH3), 8.3 (q, 1 C,
CH2CH3), 28.6 (t, 1 C, CH2CH3), 31.0 (t, 1 C, CH2CH3), 38.4 (t, 2
C, CH=CHCH2, NCHCH2), 38.7 (d, 1 C, CH=CHCH2CH), 39.5 (s,
1 C, N=CHCHC), 44.5 (d, 1 C, N=CHCH), 45.6 (d, 1 C,
CH=CHCH), 60.4 (d, 1 C, NCHCH2), 131.9 (d, 1 C, CH=CHCH2),
132.9 (d, 1 C, CH=CHCH2), 176.1 (d, 1 C, N=CH).
+
MS (CI, CH5 ): m/z (%) = 138 (35), 204 (100) [M + H]+.
CAr,p), 175.2 (d, 1 C, N=CH).
HRMS (EI+): m/z [M]+ calcd for C14H21N: 203.1674; found:
203.1662.
MS (FAB, NBA): m/z (%) = 200.2 (28), 266.2 (23), 322.2 (5), 388.1
(100) [M + H]+.
HRMS (FAB, NBA): m/z [M + H]+ calcd for C26H30NO2: 388.2277;
found: 388.2280.
10,10-Dibenzyl-8-azatricyclo[5.2.2.02,6]undeca-3,8-diene (6b)
The title product was prepared according to GP1 starting from 5b
(400 mg, 0.960 mmol) and cyclopentadiene (317 mg, 360 μL, 4.80
mmol) in 1.25 M ethanolic HCl (10 mL). Work-up was performed
with phosphate buffer and extraction with CH2Cl2 (4 × 10 mL). Pu-
rification by flash chromatography (silica gel, CH2Cl2–MeOH,
97:3) gave the desired product.
10,10-Bis(4-fluorobenzyl)-8-azatricyclo[5.2.2.02,6]undeca-3,8-
diene (6d)
The title product was prepared according to GP1 starting from 5d
(30.7 mg, 0.0677 mmol) and cyclopentadiene (22.4 mg, 25.4 μL,
Synthesis 2014, 46, 1630–1638
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cycloadditions of 1,4-Dihydropyridines as Heterodiene Precursors
1635
0.339 mmol) in 1.25 M ethanolic HCl (2 mL). Work-up was per-
formed with phosphate buffer and extraction with CH2Cl2 (4 × 4
mL). Purification by flash chromatography (alumina, n-pentane–
CH2Cl2–MeOH, 70:30:3) gave the desired product.
1-[8-Benzyl-12-aza-10(1,2)-benzenatetracyclo[6.4.1.02,6.07,11]tri-
decaphan-4-en-12-yl]ethanone (7a)
The title product was prepared according to GP2 starting from 6b
(90.9 mg, 0.278 mmol) and AcCl (33.0 mg, 30.0 μL, 0.420 mmol)
in CH2Cl2 (4 mL). Work-up was performed with phosphate buffer
(5 mL) and extraction with CH2Cl2 (4 × 5 mL). Purification by flash
chromatography (alumina, n-pentane–EtOAc, 50:50) gave the de-
sired product.
Yield: 18.9 mg (77%); light yellow oil; Rf = 0.60 (alumina, n-pen-
tane–MeOH, 97:3).
IR (film): 3048, 3000, 2926, 2853, 1621, 1604, 1509, 1445, 1223
cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.63–1.72 (m, 2 H, NCHCH2),
2.23–2.31 (m, 1 H, CH=CHCH2), 2.39 (d, J = 14.4 Hz, 1 H, CH2Ph),
Yield: 94.3 mg (92%); colorless crystals; mp 96–98 °C; Rf = 0.44
(silica gel, n-pentane–EtOAc, 50:50).
IR (KBr): 3039, 2981, 2964, 2926, 2914, 2850, 1637, 1489, 1446,
1402 cm–1.
2.48–2.65 (m,
4
H, CH2Ph, CH=CHCH2, N=CHCH,
CH=CHCH2CH), 2.76 (d, J = 14.9 Hz, 1 H, CH2Ph), 2.95 (d, J =
14.9 Hz, 1 H, CH2Ph), 3.41–3.48 (m, 1 H, CH=CHCH), 4.30–4.33
(m, 1 H, NCHCH2), 5.39–5.43 (m, 1 H, CH=CHCH2), 5.59–5.64
(m, 1 H, CH=CHCH2), 6.90–7.06 (m, 6 H, CHAr,o, CHAr,m), 7.17–
7.23 (m, 2 H, CHAr,o), 8.07 (d, J = 4.1 Hz, 1 H, N=CH).
13C NMR (125 MHz, CDCl3): δ = 37.9 (t, 1 C, NCHCH2), 38.0 (t, 1
C, CH=CHCH2), 38.9 (d, 1 C, CH=CHCH2CH), 41.7 (s, 1 C,
NCHCH2C), 42.7 (t, 1 C, CH2Ph), 44.3 (t, 1 C, CH2Ph), 44.4 (d, 1
C, N=CHCH), 45.8 (d, 1 C, CH=CHCH), 59.7 (d, 1 C, NCHCH2),
115.0 (d, JCF = 21.0 Hz, 2 C, CHAr,m), 115.2 (d, JCF = 21.0 Hz, 2 C,
CHAr,m), 131.0 (d, 1 C, CH=CHCH2), 131.5 (d, JCF = 7.7 Hz, 2 C,
CHAr,o), 131.8 (d, JCF = 7.7 Hz, 2 C, CHAr,o), 133.2 (d, 1 C,
CH=CHCH2), 133.9 (d, JCF = 3.4 Hz, 1 C, CAr), 134.1 (d, JCF = 3.4
1H NMR (500 MHz, CDCl3): δ = 1.72 (dd, J = 14.0, 2.8 Hz, 1 H,
NCHCH2), 1.95 (dd, J = 14.0, 3.1 Hz, 1 H, NCHCH2), 2.02 (s, 3 H,
COCH3), 2.05 (t, J = 3.8 Hz, 1 H, NCHCHC), 2.28–2.34 (m, 1 H,
CH=CHCH2), 2.51 (d, J = 17.0 Hz, 1 H, NCHCHCCH2), 2.62–2.67
(m, 1 H, CH=CHCH2CH), 2.72–2.79 (m, 1 H, CH=CHCH2), 2.81
(d, J = 17.0 Hz, 1 H, NCHCHCCH2), 2.92 (d, J = 13.4 Hz, 1 H,
CH2Ph), 2.98 (d, J = 13.4 Hz, 1 H, CH2Ph), 3.61–3.75 (m, 2 H,
CH=CHCH, NCHCH2), 5.13 (d, J = 3.8 Hz, 1 H, NCHCHC), 5.67–
5.73 (m, 1 H, CH=CHCH2), 5.82–5.88 (m, 1 H, CH=CHCH2), 6.99
(br d, J = 7.3 Hz, 1 H, NCHCCCH), 7.06–7.14 (m, 2 H, NCHC-
CHCH, NCHCCCHCH), 7.22–7.37 (m, 5 H, CHBn), 7.93 (dd, J =
7.6, 1.4 Hz, 1 H, NCHCCH).
13C NMR (125 MHz, CDCl3): δ = 22.5 (q, 1 C, COCH3), 34.0 (s, 1
C, NCHCHC), 37.1 (d, 1 C, NCHCHC), 37.4 (t, 1 C, CH=CHCH2),
38.1 (d, 1 C, CH=CHCH2CH), 39.2 (t, 1 C, NCHCH2), 41.9 (t, 1 C,
NCHCHCCH2), 44.2 (d, 1 C, CH=CHCH), 47.2 (t, 1 C, CH2Ph),
50.7 (d, 1 C, NCHCHC), 53.4 (d, 1 C, NCHCH2), 125.6 (d, 1 C,
Hz, 1 C, CAr), 161.5 (d, JCF = 245.2 Hz, 1 C, CAr,p), 161.6 (d, JCF
=
245.2 Hz, 1 C, CAr,p), 174.8 (d, 1 C, N=CH).
MS (FAB, NBA): m/z (%) = 188.1 (32), 254.2 (20), 298.3 (11),
364.2 (100) [M + H]+.
HRMS (FAB, NBA): m/z [M + H]+ calcd for C24H24F2N: 364.1877;
NCHCCHCH), 126.7 (d,
1
C, CHAr,p), 127.7 (d,
1
C,
found: 364.1875.
NCHCCCHCH), 128.4 (d,
2 C, CHAr,m), 129.1 (d,
1
C,
NCHCCCH), 130.8 (d, 2 C, CHAr,o), 131.2 (d, 1 C, CH=CHCH2),
131.6 (d, 1 C, CH=CHCH2), 132.2 (d, 1 C, NCHCCH), 134.6 (s, 1
C, CAr), 136.9 (s, 1 C, CAr), 138.1 (s, 1 C, CBn), 169.0 (s, 1 C, C=O).
10,10-Bis(2-phenylethyl)-8-azatricyclo[5.2.2.02,6]undeca-3,8-di-
ene (6e)
The title product was prepared according to GP1 starting from 5e
(95.5 mg, 0.214 mmol) and cyclopentadiene (70.7 mg, 80.3 μL,
1.07 mmol) in 1.25 M ethanolic HCl (2.5 mL). Work-up was per-
formed with phosphate buffer and extraction with CH2Cl2 (4 × 5
mL). Purification by flash chromatography (alumina, n-pentane–
CH2Cl2–MeOH, 70:30:3) gave the desired product.
+
MS (CI, CH5 ): m/z (%) = 219 (25), 370 (100) [M + H]+.
HRMS (EI+): m/z [M]+ calcd for C26H27NO: 369.2093; found:
369.2085.
1-[8-(4-Methoxybenzyl)-12-aza-10(1,2)-benzenatetracy-
clo[6.4.1.02,6.07,11]tridecaphan-4-en-12-yl]ethanone (7b)
The title product was prepared according to GP2 starting from 6c
(13.6 mg, 0.0351 mmol) and AcCl (8.3 mg, 7.5 μL, 0.11 mmol) in
CH2Cl2 (2 mL). Work-up was performed with phosphate buffer (2
mL) and extraction with CH2Cl2 (4 × 2 mL). Purification by flash
chromatography (alumina, n-pentane–EtOAc, 60:40) gave the de-
sired product.
Yield: 64.6 mg (85%); light yellow oil; Rf = 0.35 (silica gel, CHCl3–
MeOH, 97:3).
IR (film): 3057, 3024, 2999, 2927, 2860, 1616, 1602, 1495, 1453
cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.30 (dd, J = 13.4, 1.7 Hz, 1 H,
NCHCH2), 1.44 (ddd, J = 13.9, 12.3, 4.3 Hz, 1 H, CH2CH2Ph), 1.47
(dd, J = 13.4, 3.8 Hz, 1 H, NCHCH2), 1.71 (ddd, J = 13.9, 12.7, 5.5
Hz, 1 H, CH2CH2Ph), 1.76–1.91 (m, 2 H, CH2CH2Ph), 2.21–2.32
Yield: 14.1 mg (94%); colorless crystals; mp 196–198 °C; Rf = 0.49
(alumina, n-pentane–EtOAc, 50:50).
(m,
1 H, CH=CHCH2), 2.46–2.67 (m, 6 H, CH2CH2Ph,
IR (KBr): 3055, 3027, 2982, 2954, 2936, 2902, 2882, 2833, 1631,
1608, 1508, 1462, 1440, 1409, 1240 cm–1.
CH=CHCH2, CH=CHCH2CH), 2.71 (dd, J = 4.2, 2.6 Hz, 1 H,
N=CHCH), 3.25–3.33 (m, 1 H, CH=CHCH), 4.27–4.31 (m, 1 H,
NCHCH2), 5.40–5.48 (m, 1 H, CH=CHCH2), 5.59–5.65 (m, 1 H,
CH=CHCH2), 7.11–7.38 (m, 10 H, CHAr), 8.25 (d, J = 4.2 Hz, 1 H,
N=CH).
13C NMR (125 MHz, CDCl3): δ = 30.1 (t, 1 C, CH2CH2Ph), 30.5 (t,
1 C, CH2CH2Ph), 38.2 (t, 1 C, CH=CHCH2), 38.4 (d, 1 C,
CH=CHCH2CH), 38.7 (t, 1 C, NCHCH2), 39.2 (t, 1 C, CH2CH2Ph),
39.4 (s, 1 C, NCHCH2C), 41.6 (t, 1 C, CH2CH2Ph), 44.7 (d, 1 C,
N=CHCH), 45.5 (d, 1 C, CH=CHCH), 60.1 (d, 1 C, NCHCH2),
125.9 (d, 1 C, CHAr,p), 126.0 (d, 1 C, CHAr,p), 128.2 (d, 2 C, CHAr,o),
128.3 (d, 2 C, CHAr,o), 128.5 (d, 2 C, CHAr,m), 128.6 (d, 2 C, CHAr,m),
131.3 (d, 1 C, CH=CHCH2), 133.0 (d, 1 C, CH=CHCH2), 142.27 (s,
1 C, CAr), 142.32 (s, 1 C, CAr), 175.6 (d, 1 C, N=CH).
1H NMR (500 MHz, CDCl3): δ = 1.68 (dd, J = 14.0, 2.8 Hz, 1 H,
NCHCH2), 1.91 (dd, J = 14.0, 3.2 Hz, 1 H, NCHCH2), 2.01 (br t,
J = 3.8 Hz, 1 H, NCHCHC), 2.04 (s, 3 H, C=OCH3), 2.27–2.35 (m,
1 H, CH=CHCH2), 2.42 (d, J = 16.7 Hz, 1 H, NCHCHCCH2), 2.60–
2.66 (m, 1 H, CH=CHCH2CH), 2.73 (d, J = 16.7 Hz, 1 H,
NCHCHCCH2), 2.72–2.80 (m, 1 H, CH=CHCH2), 2.86 (d, J = 13.6
Hz, 1 H, CH2Ph), 2.90 (d, J = 13.6 Hz, 1 H, CH2Ph), 3.62–3.68 (m,
1 H, CH=CHCH), 3.68–3.72 (m, 1 H, NCHCH2), 3.75 (s, 3 H,
OCH3), 3.81 (s, 3 H, OCH3), 5.09 (d, J = 3.8 Hz, 1 H, NCHCHC),
5.67–5.73 (m, 1 H, CH=CHCH2), 5.81–5.87 (m, 1 H, CH=CHCH2),
6.73 (dd, J = 8.4, 2.8 Hz, 1 H, NCHCCCHCH), 6.85–6.92 (m, 3 H,
NCHCCCH, CHBn,m), 7.16–7.22 (m, 2 H, CHAr,o), 7.56 (d, J = 2.8
Hz, 1 H, NCHCCH).
+
MS (CI, CH5 ): m/z (%) = 250 (18), 290 (19), 356 (100) [M + H]+.
HRMS (EI+): m/z [M]+ calcd for C26H29N: 355.2300; found:
13C NMR (125 MHz, CDCl3): δ = 22.3 (q, 1 C, C=OCH3), 33.9 (s,
1 C, NCHCHC), 36.9 (d, 1 C, NCHCHC), 37.2 (t, 1 C,
CH=CHCH2), 37.9 (d, 1 C, CH=CHCH2CH), 38.6 (t, 1 C,
355.2310.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1630–1638

1636
C. E. Schmaunz et al.
PAPER
NCHCH2), 40.9 (t, 1 C, NCHCHCCH2), 44.0 (d, 1 C, CH=CHCH),
46.1 (t, 1 C, CH2Ph), 50.7 (d, 1 C, NCHCHC), 53.3 (d, 1 C,
NCHCH2), 55.25 (q, 1 C, OCH3), 55.29 (q, 1 C, OCH3), 113.6 (d, 2
C, CHBn,m), 115.2 (d, 1 C, NCHCCCHCH), 115.5 (d, 1 C,
NCHCCH), 126.4 (s, 1 C, NCHCC), 129.8 (d, 1 C, NCHCCCH),
129.9 (s, 1 C, CBn), 130.9 (d, 1 C, CH=CHCH2), 131.5 (d, 3 C,
CHAr,o, CH=CHCH2), 137.7 (s, 1 C, NCHC), 157.2 (s, 1 C, NCHC-
CHC), 158.3 (s, 1 C, CBn,p), 168.8 (s, 1 C, C=O).
H, NCHCH2CH), 1.13–1.23 (m, 2 H, CH2CH3, NCHCH2CHCH2),
1.30 (dq, J = 14.9, 7.5 Hz, 1 H, CH2CH3), 1.60–1.68 (m, 2 H,
NCHCH2C, NCHCH2CH), 1.99 (ddt, J = 8.9, 6.6, 2.1 Hz, 1 H,
NCHCH2CHCH2), 2.06–2.13 (m, 1 H, NCHCH2CH), 2.84–2.90
(m, 1 H, NCHCH), 4.52–4.57 (m, 1 H, NCHCH2), 8.10 (d, J = 3.4
Hz, 1 H, NCHCH).
13C NMR (125 MHz, CDCl3): δ = 8.5 (q, 1 C, CH2CH3), 27.3 (d, 1
C, NCHCH2CH), 31.1 (t, 1 C, NCHCH2CH), 32.7 (t, 1 C, CH2CH3),
36.1 (t, 1 C, NCHCH2C), 41.2 (t, 1 C, NCHCH2CHCH2), 42.4 (d, 1
C, NCHCH), 43.1 (s, 1 C, NCHCHC), 55.7 (d, 1 C, NCHCH2),
167.2 (d, 1 C, NCHCH).
MS (FAB, NBA): m/z (%) = 430.3 (100) [M + H]+.
HRMS (FAB, NBA): m/z [M + H]+ calcd for C28H32NO3: 430.2382;
found: 430.2376.
MS (ESI+): m/z (%) = 150.1 (100) [M + H]+.
HRMS (EI+): m/z [M]+ calcd for C10H15N: 149.1204; found:
1-[8-(4-Fluorobenzyl)-12-aza-10(1,2)-benzenatetracy-
clo[6.4.1.02,6.07,11]tridecaphan-4-en-12-yl]ethanone (7c)
149.1203.
The title product was prepared according to GP2 starting from 6d
(13.0 mg, 0.0358 mmol) and AcCl (8.4 mg, 7.7 μL, 0.11 mmol) in
CH2Cl2 (2 mL). After a reaction time of 4 h, the work-up was per-
formed with phosphate buffer (2 mL) and extraction with CH2Cl2 (4
× 2 mL). Purification by flash chromatography (alumina, gradient
n-pentane–CH2Cl2, 60:40, then 50:50) gave the desired product.
1-Phenyl-4-azatricyclo[3.3.1.02,7]non-3-ene (8b)
The title product was prepared according to GP3 starting from 5g
(136 mg, 0.383 mmol) in 1.25 M ethanolic HCl (4 mL). Work-up
was performed with phosphate buffer and extraction with CH2Cl2 (4
× 5 mL). Purification by flash chromatography (alumina, n-pen-
tane–CH2Cl2–MeOH, 90:10:2) gave the desired product.
Yield: 12.5 mg (86%); colorless crystals; mp 171–173 °C; Rf = 0.09
(alumina, n-pentane–CH2Cl2, 60:40).
Yield: 47.5 mg (63%); colorless oil; Rf = 0.40 (alumina, n-pentane–
IR (KBr): 3050, 2987, 2929, 2854, 1635, 1622, 1508, 1498, 1407
cm–1.
CH2Cl2–MeOH, 90:10:2).
IR (film): 3082, 3059, 3026, 2994, 2936, 2863, 1608, 1494, 1446,
1343, 1333 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.67 (dd, J = 14.0, 2.8 Hz, 1 H,
NCHCH2), 1.92 (dd, J = 14.0, 3.2 Hz, 1 H, NCHCH2), 2.01 (t, J =
3.8 Hz, 1 H, NCHCHC), 2.04 (s, 3 H, COCH3), 2.27–2.35 (m, 1 H,
CH=CHCH2), 2.44 (d, J = 16.6 Hz, 1 H, NCHCHCCH2), 2.63 (tt,
J = 9.6, 1.8 Hz, 1 H, CH=CHCH2CH), 2.71 (d, J = 16.6 Hz, 1 H,
NCHCHCCH2), 2.73–2.81 (m, 1 H, CH=CHCH2), 2.90 (d, J = 13.6
Hz, 1 H, CH2Ph), 2.94 (d, J = 13.6 Hz, 1 H, CH2Ph), 3.61–3.67 (m,
1 H, CH=CHCH), 3.68–3.72 (m, 1 H, NCHCH2), 5.09 (d, J = 3.8
Hz, 1 H, NCHCHC), 5.63–5.72 (m, 1 H, CH=CHCH2), 5.83–5.89
(m, 1 H, CH=CHCH2), 6.84 (td, J = 8.4, 2.8 Hz, 1 H,
NCHCCCHCH), 6.93 (dd, J = 8.4, 5.8 Hz, 1 H, NCHCCCH), 7.00–
7.06 (m, 2 H, CHBn,m), 7.20–7.26 (m, 2 H, CHBn,o), 7.69 (dd, J =
10.3, 2.8 Hz, 1 H, NCHCCH).
1H NMR (500 MHz, CDCl3): δ = 1.14–1.21 (m, 1 H, NCHCH2CH),
1.24 (ddd, J = 12.7, 4.4, 2.1 Hz, 1 H, NCHCH2C), 1.61 (d, J = 9.1
Hz, 1 H, NCHCH2CHCH2), 1.79 (dd, J = 12.7, 3.1 Hz, 1 H,
NCHCH2CH), 2.02 (dd, J = 12.7, 2.9 Hz, 1 H, NCHCH2C), 2.20–
2.26 (m, 1 H, NCHCH2CH), 2.54 (ddt, J = 9.1, 6.9, 2.1 Hz, 1 H,
NCHCH2CHCH2), 3.27–3.32 (m, 1 H, NCHCH), 4.62–4.68 (m, 1
H, NCHCH2), 6.94–7.01 (m, 2 H, CHAr,o), 7.14–7.19 (m, 1 H,
CHAr,p), 7.24–7.31 (m, 2 H, CHAr,m), 8.35 (d, J = 2.9 Hz, 1 H,
NCHCH).
13C NMR (125 MHz, CDCl3): δ = 27.5 (d, 1 C, NCHCH2CH), 30.8
(t, 1 C, NCHCH2CH), 40.9 (t, 1 C, NCHCH2C), 41.2 (t, 1 C,
NCHCH2CHCH2), 43.3 (d, 1 C, NCHCH), 45.8 (s, 1 C, NCHCHC),
55.9 (d, 1 C, NCHCH2), 124.8 (d, 2 C, CHAr,o), 126.0 (d, 1 C,
CHAr,p), 128.4 (d, 2 C, CHAr,m), 147.7 (s, 1 C, CAr), 166.9 (d, 1 C,
NCHCH).
13C NMR (125 MHz, CDCl3): δ = 22.2 (q, 1 C, COCH3), 33.8 (s, 1
C, NCHCHC), 36.7 (d, 1 C, NCHCHC), 37.2 (t, 1 C, CH=CHCH2),
37.8 (d, 1 C, CH=CHCH2CH), 38.7 (t, 1 C, NCHCH2), 40.9 (t, 1 C,
NCHCHCCH2), 43.9 (d, 1 C, CH=CHCH), 46.1 (t, 1 C, CH2Ph),
+
MS (CI, CH5 ): m/z (%) = 198 (100) [M + H]+.
50.2 (d, 1 C, NCHCHC), 53.1 (d, 1 C, NCHCH2), 114.8 (d, JCF
=
HRMS (EI+): m/z [M]+ calcd for C14H15N: 197.1204; found:
197.1198.
21.8 Hz, 1 C, NCHCCCHCH), 115.1 (d, JCF = 21.1 Hz, 2 C, CH-
Bn,m), 118.3 (d, JCF = 21.8 Hz, 1 C, NCHCCH), 129.7 (d, JCF = 2.9
Hz, 1 C, NCHCC), 130.1 (d, JCF = 7.6 Hz, 1 C, NCHCCCH), 131.1
1-Benzyl-4-azatricyclo[3.3.1.02,7]non-3-ene (8c)
(d, 1 C, CH=CHCH2), 131.2 (d, 1 C, CH=CHCH2), 131.9 (d, JCF
7.8 Hz, 2 C, CHBn,o), 133.4 (d, JCF = 3.1 Hz, 1 C, CBn), 138.3 (d, JCF
=
=
The title product was prepared according to GP3 starting from 5h
(71.7 mg, 0.195 mmol) in 1.25 M ethanolic HCl (3 mL). Work-up
was performed with phosphate buffer and extraction with CH2Cl2 (4
× 5 mL). Purification by flash chromatography (alumina, n-pen-
tane–CH2Cl2–MeOH, 90:10:2) gave the desired product.
7.6 Hz, 1 C, NCHC), 160.6 (d, JCF = 243.5 Hz, 1 C, NCHCCHC),
161.7 (d, JCF = 245.3 Hz, 1 C, CBn,p), 168.8 (s, 1 C, CO).
+
MS (CI, CH5 ): m/z (%) = 406 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C26H26F2NO: 406.1982;
found: 406.1977.
Yield: 37.8 mg (92%); colorless crystals; mp 94 °C; Rf = 0.66 (alu-
mina, n-pentane–CH2Cl2–MeOH, 90:10:3).
1-Ethyl-4-azatricyclo[3.3.1.02,7]non-3-ene (8a)
IR (KBr): 3079, 3060, 3023, 2993, 2972, 2948, 2922, 2856, 1605,
1494, 1453, 1435, 1348, 1343, 1329 cm–1.
The title product was prepared according to GP3 starting from 5f
(108 mg, 0.355 mmol) in 1.25 M ethanolic HCl (3 mL). Work-up
was performed with phosphate buffer and extraction with CH2Cl2 (4
× 5 mL). Purification by flash chromatography (alumina, n-pen-
tane–CH2Cl2–MeOH, 90:10:2) gave the desired product.
1H NMR (400 MHz, CDCl3): δ = 0.95–1.08 (m, 2 H, NCHCH2C,
NCHCH2CH), 1.16 (d, J = 9.0 Hz, 1 H, NCHCH2CHCH2), 1.59 (dd,
J = 12.6, 3.1 Hz, 1 H, NCHCH2C), 1.62 (dd, J = 12.5, 2.9 Hz, 1 H,
NCHCH2CH), 2.04–2.10 (m, 1 H, NCHCH2CH), 2.13 (ddt, J = 9.0,
6.6, 2.1 Hz, 1 H, NCHCH2CHCH2), 2.47 (d, J = 13.3 Hz, 1 H,
CH2Ph), 2.55 (d, J = 13.3 Hz, 1 H, CH2Ph), 2.96–3.05 (m, 1 H,
NCHCH), 4.47–4.54 (m, 1 H, NCHCH2), 7.00–7.09 (m, 2 H,
CHAr,o), 7.16–7.23 (m, 1 H, CHAr,p), 7.23–7.31 (m, 2 H, CHAr,m),
8.05 (d, J = 3.7 Hz, 1 H, NCHCH).
Yield: 50.6 mg (95%); colorless oil; Rf = 0.69 (alumina, n-pentane–
CH2Cl2–MeOH, 90:10:3).
IR (film): 2958, 2935, 2876, 2854, 1613, 1462, 1442, 1378, 1346,
1334, 1269 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.70 (t, J = 7.5 Hz, 3 H, CH2CH3),
0.92 (ddd, J = 12.4, 4.5, 2.1 Hz, 1 H, NCHCH2C), 1.01–1.08 (m, 1
Synthesis 2014, 46, 1630–1638
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cycloadditions of 1,4-Dihydropyridines as Heterodiene Precursors
1637
13C NMR (100 MHz, CDCl3): δ = 27.7 (d, 1 C, NCHCH2CH), 31.1
(t, 1 C, NCHCH2CH), 36.8 (t, 1 C, NCHCH2C), 41.1 (t, 1 C,
NCHCH2CHCH2), 42.2 (d, 1 C, NCHCH), 43.0 (s, 1 C, NCHCHC),
46.3 (t, 1 C, CH2Ph), 55.7 (d, 1 C, NCHCH2), 126.1 (d, 1 C, CHAr,p),
128.2 (d, 2 C, CHAr,m), 129.5 (d, 2 C, CHAr,o), 138.0 (s, 1 C, CAr),
166.8 (d, 1 C, NCHCH).
1-Phenyl-4-azatricyclo[3.3.1.02,7]nonane Hydrochloride (9b)
The title product was prepared according to GP4 starting from 8b
(29.7 mg, 0.151 mmol) and NaBH3CN (10.4 mg, 0.166 mmol) in
MeOH (2 mL) and 1.0 M ethereal HCl solution (0.753 mL). Work-
up was performed with H2O and K2CO3 followed by extraction with
CH2Cl2 (10 × 3 mL) to give the desired product.
+
MS (CI, CH5 ): m/z (%) = 212 (100) [M + H]+.
Yield: 29.7 mg (84%); colorless crystals; mp 241–246 °C (dec.).
HRMS (EI+): m/z [M]+ calcd for C15H17N: 211.1361; found:
211.1366.
IR (KBr): 3024, 2941, 2858, 2752, 2653, 2471, 1604, 1495, 1442
cm–1.
1H NMR (400 MHz, CD3OD): δ = 1.80 (d, J = 9.4 Hz, 1 H,
NCHCH2CHCH2), 2.11 (dd, J = 14.6, 3.3 Hz, 1 H, NCHCH2CH),
2.20–2.30 (m, 2 H, NCHCH2C, NCHCH2CH), 2.36–2.46 (m, 2 H,
NCHCH2C, NCHCH2CHCH2), 2.54–2.61 (m, 1 H, NCHCH2CH),
2.67–2.74 (m, 1 H, NCH2CH), 3.42 (br d, J = 13.5 Hz, 1 H,
NCH2CH), 3.54 (br d, J = 13.5 Hz, 1 H, NCH2CH), 3.80–3.86 (m,
1 H, NCHCH2), 7.18–7.27 (m, 3 H, CHAr,o, CHAr,p), 7.30–7.38 (m,
2 H, CHAr,m).
1-(2-Phenylethyl)-4-azatricyclo[3.3.1.02,7]non-3-ene (8d)
The title product was prepared according to GP3 starting from 5i
(114 mg, 0.297 mmol) in 1.25 M ethanolic HCl (3 mL). Work-up
was performed with phosphate buffer and extraction with CH2Cl2 (4
× 5 mL). Purification by flash chromatography (alumina, n-pen-
tane–CH2Cl2–MeOH, 90:10:2) gave the desired product.
Yield: 55.6 mg (83%); colorless crystals; mp 61–63 °C; Rf = 0.49
(alumina, n-pentane–CH2Cl2–MeOH, 90:10:2).
13C NMR (125 MHz, CD3OD): δ = 30.4 (d, 1 C, NCHCH2CH), 30.9
(t, 1 C, NCHCH2CH), 36.2 (d, 1 C, NCH2CH), 39.5 (t, 1 C,
IR (KBr): 3047, 3025, 3000, 2960, 2930, 2850, 1608, 1495, 1453,
1346 cm–1.
NCHCH2C), 39.8 (t, 1 C, NCH2CH). 43.0 (t,
1
C,
1H NMR (500 MHz, CDCl3): δ = 0.99–1.10 (m, 2 H, NCHCH2C,
NCHCH2CH), 1.21 (d, J = 9.0 Hz, 1 H, NCHCH2CHCH2), 1.50
(ddd, J = 13.4, 11.1, 5.9 Hz, 1 H, CH2CH2Ph), 1.59–1.69 (m, 2 H,
NCHCH2CH, CH2CH2Ph), 1.75 (dd, J = 12.6, 3.0 Hz, 1 H,
NCHCH2C), 2.04 (ddt, J = 9.0, 6.6, 1.9 Hz, 1 H, NCHCH2CHCH2),
2.10–2.15 (m, 1 H, NCHCH2CH), 2.35–2.49 (m, 2 H, CH2CH2Ph),
2.90–2.94 (m, 1 H, NCHCH), 4.55–4.60 (m, 1 H, NCHCH2), 7.11–
7.19 (m, 3 H, CHAr,o, CHAr,p), 7.23–7.29 (m, 2 H, CHAr,m), 8.08 (d,
J = 3.6 Hz, 1 H, NCHCH).
13C NMR (125 MHz, CDCl3): δ = 27.7 (d, 1 C, NCHCH2CH), 30.9
(t, 1 C, CH2CH2Ph), 31.0 (t, 1 C, NCHCH2CH), 36.5 (t, 1 C,
NCHCH2C), 41.8 (t, 1 C, NCHCH2CHCH2), 42.31 (t, 1 C,
CH2CH2Ph), 42.33 (s, 1 C, NCHCHC), 43.0 (d, 1 C, NCHCH), 55.8
(t, 1 C, NCHCH2), 125.8 (d, 1 C, CHAr,p), 128.2 (d, 2 C, CHAr,o),
128.3 (d, 2 C, CHAr,m), 142.2 (s, 1 C, CAr), 167.1 (d, 1 C, NCHCH).
NCHCH2CHCH2), 45.6 (s, 1 C, NCH2CHC), 48.1 (d, 1 C,
NCHCH2), 125.7 (d, 2 C, CHAr,o), 127.6 (d, 1 C, CHAr,p), 129.8 (d,
2 C, CHAr,m), 147.9 (s, 1 C, CAr).
+
MS (CI, CH5 ): m/z (%) = 122 (50), 200 (100) [M – Cl]+.
HRMS (EI+): m/z [M – HCl]+ calcd for C14H17N: 199.1361; found:
199.1332.
1-Benzyl-4-azatricyclo[3.3.1.02,7]nonane Hydrochloride (9c)
The title product was prepared according to GP4 starting from 8c
(20.6 mg, 0.0975 mmol) and NaBH3CN (15.3 mg, 0.244 mmol) in
MeOH (2 mL) and 1.0 M ethereal HCl solution (0.487 mL). Work-
up was performed with H2O and K2CO3 followed by extraction with
CH2Cl2 (10 × 3 mL) to give the desired product.
Yield: 21.4 mg (89%); colorless crystals; mp 170–172 °C (dec.).
IR (KBr): 3061, 2956, 2930, 2837, 2810, 2783, 2753, 2726, 2669,
2537, 2509, 2475, 1598, 1495, 1451, 1432 cm–1.
+
MS (CI, CH5 ): m/z (%) = 226 (100) [M + H]+.
HRMS (EI+): m/z [M]+ calcd for C16H19N: 225.1517; found:
225.1517.
1H NMR (500 MHz, CD3OD): δ = 1.35 (d, J = 9.5 Hz, 1 H,
NCHCH2CHCH2), 1.90 (dd, J = 14.5, 3.8 Hz, 1 H, NCHCH2C),
1.94 (dd, J = 14.6, 3.9 Hz, 1 H, NCHCH2CH), 1.95–2.01 (m, 1 H,
NCHCH2C), 2.06–2.14 (m, 2 H, NCHCH2CH, NCHCH2CHCH2),
2.26–2.31 (m, 1 H, NCH2CH), 2.40–2.46 (m, 1 H, NCHCH2CH),
2.70 (s, 2 H, CH2Ph), 3.10 (dd, J = 13.4, 1.7 Hz, 1 H, NCH2CH),
3.19 (dd, J = 13.4, 2.2 Hz, 1 H, NCH2CH), 3.63–3.68 (m, 1 H,
NCHCH2), 7.12–7.18 (m, 2 H, CHAr,o), 7.19–7.24 (m, 1 H, CHAr,p),
7.26–7.33 (m, 2 H, CHAr,m).
1-Ethyl-4-azatricyclo[3.3.1.02,7]nonane Hydrochloride (9a)
The title product was prepared according to GP4 starting from 8a
(22.7 mg, 0.152 mmol) and NaBH3CN (23.9 mg, 0.380 mmol) in
MeOH (2 mL) and 1.0 M ethereal HCl solution (0.760 mL). Work-
up was performed with H2O and K2CO3 followed by extraction with
CH2Cl2 (10 × 3 mL) to give the desired product.
Yield: 22.8 mg (80%); colorless oil.
13C NMR (125 MHz, CD3OD): δ = 30.8 (d, 1 C, NCHCH2CH), 31.6
(t, 1 C, NCHCH2CH), 35.0 (d, 1 C, NCH2CH), 36.7 (t, 1 C,
IR (film): 2958, 2934, 2875, 2794, 2657, 2519, 2474, 1745, 1626,
1601, 1460, 1440 cm–1.
NCHCH2C), 38.9 (t,
1
C, NCH2CH), 42.2 (t,
1
C,
1H NMR (500 MHz, CD3OD): δ = 0.86 (t, J = 7.5 Hz, 3 H,
CH2CH3), 1.33–1.52 (m, 3 H, CH2CH3, NCHCH2CHCH2), 1.86–
1.93 (m, 1 H, NCHCH2C), 1.93–2.02 (m, 2 H, NCHCH2CHCH2,
NCHCH2CH), 2.05 (dd, J = 14.2, 3.5 Hz, 1 H, NCHCH2C), 2.09–
2.22 (m, 2 H, NCHCH2CH, NCH2CH), 2.41–2.48 (m, 1 H,
NCHCH2CH), 3.21–3.25 (m, 2 H, NCH2CH), 3.69–3.74 (m, 1 H,
NCHCH2).
NCHCH2CHCH2), 43.2 (s, 1 C, NCH2CHC), 45.6 (t, 1 C, CH2Ph),
48.0 (d, 1 C, NCHCH2), 127.5 (d, 1 C, CHAr,p), 129.5 (d, 2 C,
CHAr,m), 130.8 (d, 2 C, CHAr,o), 138.6 (s, 1 C, CAr).
+
MS (CI, CH5 ): m/z (%) = 214 (100) [M – Cl]+.
HRMS (EI+): m/z [M – HCl]+ calcd for C15H19N: 213.1517; found:
213.1496.
13C NMR (125 MHz, CD3OD): δ = 8.2 (q, 1 C, CH2CH3), 30.4 (d, 1
C, NCHCH2CH), 31.4 (t, 1 C, NCHCH2CH), 32.3 (t, 1 C, CH2CH3),
35.3 (d, 1 C, NCH2CH), 36.5 (t, 1 C, NCHCH2C), 39.0 (t, 1 C,
NCH2CH), 41.5 (t, 1 C, NCHCH2CHCH2), 43.2 (s, 1 C,
NCH2CHC), 48.0 (d, 1 C, NCHCH2).
1-(2-Phenylethyl)-4-azatricyclo[3.3.1.02,7]nonane Hydrochlo-
ride (9d)
The title product was prepared according to GP4 starting from 8d
(20.0 mg, 0.0888 mmol) and NaBH3CN (13.9 mg, 0.222 mmol) in
MeOH (2 mL) and 2.0 M ethereal HCl solution (0.222 mL). Work-
up was performed with H2O and K2CO3 followed by extraction with
CH2Cl2 (10 × 3 mL) to give the desired product.
+
MS (CI, CH5 ): m/z (%) = 152 (100) [M – Cl]+.
HRMS (EI+): m/z [M – HCl]+ calcd for C10H17N: 151.1361; found:
151.1356.
Yield: 21.5 mg (92%); colorless crystals; mp 170–172 °C (dec.).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1630–1638

1638
C. E. Schmaunz et al.
PAPER
IR (KBr): 3024, 2945, 2932, 2859, 2829, 2800, 2757, 2716, 2652,
2521, 2469, 1600, 1495, 1454, 1435 cm–1.
(4) (a) Maia, A. A.; Freitas-Gil, R. P.; Gil, L. F.; Marazano, C.
Lett. Org.Chem. 2004, 1, 168. (b) Reding, M. T.; Fukuyama,
T. Org. Lett. 1999, 1, 973. (c) Takenaka, N.; Huang, Y.;
Rawal, V. H. Tetrahedron 2002, 58, 8299. (d) Matsumura,
Y.; Nakamura, Y.; Maki, T.; Onomura, O. Tetrahedron Lett.
2000, 41, 7685.
(5) (a) Evans, D. A.; Scheidt, K. A.; Downey, C. W. Org. Lett.
2001, 3, 3009. (b) Lamy-Schelkens, H.; Giomi, D.; Ghosez,
L. Tetrahedron Lett. 1989, 30, 5887.
1H NMR (500 MHz, CD3OD): δ = 1.38 (d, J = 9.5 Hz, 1 H,
NCHCH2CHCH2), 1.68 (ddd, J = 13.6, 9.8, 7.1 Hz, 1 H,
CH2CH2Ph), 1.78 (ddd, J = 13.6, 9.8, 7.1 Hz, 1 H, CH2CH2Ph),
1.94–2.01 (m, 2 H, NCHCH2C, NCHCH2CH), 2.02–2.08 (m, 1 H,
NCH2CHCH2), 2.09–2.18 (m, 2 H, NCHCH2C, NCHCH2CH),
2.20–2.25 (m, 1 H, NCH2CH), 2.43–2.50 (m, 1 H, NCHCH2CH),
2.52–2.64 (m, 2 H, CH2CH2Ph), 3.21–3.25 (m, 2 H, NCH2CH),
3.69–3.75 (m, 1 H, NCHCH2), 7.11–7.17 (m, 1 H, CHAr,p), 7.17–
7.22 (m, 2 H, CHAr,o), 7.22–7.28 (m, 2 H, CHAr,m).
(6) (a) Craig, D.; Schaefgen, L.; Tyler, W. P. J. Am. Chem. Soc.
1948, 70, 1624. (b) Craig, D.; Kuder, A. K.; Efroymson, J.
J. Am. Chem. Soc. 1950, 72, 5236.
13C NMR (125 MHz, CD3OD): δ = 30.6 (d, 1 C, NCHCH2CH), 31.2
(t, 1 C, CH2CH2Ph or NCHCH2CH), 31.3 (t, 1 C, CH2CH2Ph or
NCHCH2CH), 35.9 (d, 1 C, NCH2CH), 36.7 (t, 1 C, NCHCH2C),
(7) (a) Hartman, G. D.; Halczenko, W.; Phillips, B. T. J. Org.
Chem. 1985, 50, 2427. (b) Hartman, G. D.; Phillips, B. T.;
Halczenko, W. J. Org. Chem. 1985, 50, 2423. (c) Hartman,
G. D.; Halczenko, W.; Phillips, B. T. J. Org. Chem. 1986,
51, 142. (d) Hartman, G. D.; Phillips, B. T.; Halczenko, W.
J. Org. Chem. 1987, 52, 1136. (e) Hartman, G. D.; Phillips,
B. T.; Halczenko, W.; Pitzenberger, S. M. J. Org. Chem.
1989, 54, 4134.
38.9 (t,
1 C, NCH2CH), 42.0 (t, 1 C, CH2CH2Ph or
NCHCH2CHCH2), 42.1 (t, 1 C, CH2CH2Ph or NCHCH2CHCH2),
42.7 (s, 1 C, NCH2CHC), 47.9 (d, 1 C, NCHCH2), 126.9 (d, 1 C,
CHAr,p), 129.3 (d, 2 C, CHAr), 129.4 (d, 2 C, CHAr), 143.5 (s, 1 C,
CAr).
+
MS (CI, CH5 ): m/z (%) = 228 (100) [M – Cl]+.
(8) (a) Bräckow, J.; Wanner, K. T. Tetrahedron 2006, 62, 2395.
(b) Bräckow, J. PhD Thesis; Ludwig-Maximilians-
Universität München: Germany, 2006.
HRMS (EI+): m/z [M – HCl]+ calcd for C16H21N: 227.1674; found:
227.1648.
(9) (a) Schmaunz, C. E.; Pabel, J.; Wanner, K. T. Synthesis
2010, 2147. (b) Schmaunz, C. E.; Wanner, K. T. Synthesis
2011, 3332. (c) Schmaunz, C. E. PhD Thesis; Ludwig-
Maximilians-Universität München: Germany, 2012.
(10) The crystallographic data for compounds 7a and 8c have
been deposited at the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
918295 and CCDC 918294, respectively. Copies of the
data can be obtained free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].
ORTEP (Burnett, M. N.; Johnson, C. K. ORTEP-III: Oak
Ridge Thermal Ellipsoid Plot Program for Crystal Structure
Illustrations, Oak Ridge National Laboratory Report
ORNL-6895, 1996); Windows version (Farrugia, L. J.,
Univ. Glasgow) used.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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