Synthesis of new azocine derivatives and their functionalization by nucleophilic addition to their iminium salts

Article abstract of DOI:10.1002/ejoc.200400728

A route to the eight-membered nitrogen heterocycles 20a,b is described starting from the 3-alkyl-N-benzylpyridinium salts 14a,b. These azocine derivatives were converted into their respective iminium salts 11 by treatment with methanesulfonic acid. A stud

Full text of DOI:10.1002/ejoc.200400728

FULL PAPER
Synthesis of New Azocine Derivatives and Their Functionalization by
Nucleophilic Addition to Their Iminium Salts
Angela Cristina Leal Badaró Trindade,[a,b] Daniela Cristina dos Santos,[a] Laurent Gil,[c]
Christian Marazano,[d] and Rossimiriam Pereira de Freitas Gil*[a]
Keywords: Azocines / Nitrogen heterocycles / Cycloaddition / Nucleophilic addition / Regioselectivity
A route to the eight-membered nitrogen heterocycles 20a,b is
described starting from the 3-alkyl-N-benzylpyridinium salts
14a,b. These azocine derivatives were converted into their
respective iminium salts 11 by treatment with methanesul-
fonic acid. A study concerning the regioselectivity of nucleo-
philic additions to these salts is presented. Nucleophiles like
hydride or Grignard reagents react selectively in the 2-posi-
tion to give adducts such as 22 and 23, while azide and phen-
ylthiolate attack the 6-position to give 24 and 25, respec-
tively.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Azocine derivatives are an important and diverse class of
compounds that are found in a range of natural and non-
natural products. These eight-membered nitrogen heterocy-
cles are present in complex structures of many natural sub-
stances such apparicine (1),[1] magallanesine (2),[2] and man-
zamine A (3),[3] an important antitumoral marine alkaloid
(Figure 1). Among the nonnatural products, the more com-
monly found azocines are substituted and fully or partly
reduced. These compounds have found application as thera-
peutic agents in view of their various biological properties,
for example as antimalarials, antitussives, nasal deconges-
tants, antihypertensives, and analgesics.[4] Another large
and much-studied class of compounds containing the azoc-
ine ring is synthetic benzofuroazocines (4), which, due their
structure close to that of hypnoanalgesics, possess impor-
tant activity in the central nervous system (CNS).[5] Finally,
these monocyclic medium rings have also found use as syn-
thetic intermediates, for example, in the synthesis of the
pyrrolizidine ring system,[6] and they constitute important
medium-size cycles in conformational studies.
Figure 1. Substances containing the azocine ring.
In spite of its importance, the azocine ring system is gen-
erally difficult to obtain,[4] especially in its highly function-
alized form, and relatively few methods are available for its
preparation. The conventional cyclization methods remain
very specific and usually fail, with few exceptions. Thus,
there are few examples of the preparation of azocines by
cyclization from an alicyclic chain by intramolecular nucle-
ophilic substitution.[7] Other methods used are the fragmen-
tation of a fused 5/5-ring system,[8] and, more commonly,
the [2+2] cycloaddition reaction between an unsaturated
[a] Departamento de Química, ICEx, UFMG
Av. Antônio Carlos, 6627, Belo Horizonte, MG, Brazil
Fax: +55-031-3499-5700
E-mail: rossi@ciclope.lcc.ufmg.br
[b] Departamento de Farmácia, SCS, UFPR,
Av. Pref. Lothário Meissner, 3400, Jd. Botânico, Curitiba, PR,
Brazil
[c] Departamento de Química, ICEB, UFOP, Campus Morro do
Cruzeiro,
Ouro Preto, MG, Brazil
[d] Institut de Chimie des Substances Naturelles,
Avenue de la Terrasse, 91198, Gif-sur-Yvette, France
1052
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400728
Eur. J. Org. Chem. 2005, 1052–1057

New Azocine Derivatives
FULL PAPER
six-membered ring (generally an enamine) and an acetylene
derivative by photochemical or thermal cycloaddition.[9,10]
Considering the high potential of azocine rings, it seems
useful to develop general methodologies to build and func-
tionalize these heterocycles. For example, the synthesis of
an eight-membered iminoalditol was described recently.[11]
We recently reported[12] an access to functionalized azoc-
ine derivatives starting from the pyridinium salts 5 via
1,4,5,6-tetrahydropyridines 6 (Scheme 1; R1 = alkyl or ben-
zyl, R2 = alkyl). These 1,4,5,6-tetrahydropyridines are good
precursors of 1,6-dihydropyridines of type 7, which could
react with common dienophiles to produce isoquinuclidine
derivatives 8.[13] Alternatively, these 1,4,5,6-tetrahydropyri-
dines can also react with acetylene derivatives through a
[2+2] cycloaddition, which affords azocines 10[14] by electro-
cyclic opening of the cyclobutene intermediate 9.
Scheme 2. Nucleophilic additions to azocine iminium rings.
dines 15a,b were initially obtained from 3-alkylpyridinium
salts 14a,b following well-established procedures.[15] These
tetrahydropyridines were obtained with yields of between
61 and 63% and were subsequently oxidized with meta-
chloroperbenzoic acid (1.2 to 1.5 equivalents) at 0 °C to
avoid the possible epoxidation of the double bond. The N-
oxide derivatives 16a,b were characterized and then con-
verted into their respective dihydropyridinium salts 18a,b in
a Polonovsky–Potier reaction[16] with trifluoroacetic anhy-
dride (1.5 to 2 equivalents) to afford the intermediate salts
17a and 17b. These salts are very unstable and cannot be
purified. After removal of solvent and unreacted trifluoro-
acetic anhydride they were immediately treated with sodium
methoxide (5 to 7 equivalents). The methoxide anion bound
to the 4-position of the dihydropyridinium salts to give 18a
(from 16a) and 18b (from 16b). The structures of 18a,b were
Scheme 1. Synthesis of isoquinuclidine and azocine derivatives
from pyridinium salts.
In this paper we describe details of the synthesis of new
azocines derivatives using this strategy. The azocines thus
obtained can be converted into the corresponding iminium
salt (11) by treatment with one equivalent of acid, which
results in loss of methanol. The study of nucleophilic ad-
dition to these new iminium salts to give substituted azoc-
ine derivatives of type 12 or 13 is also reported (Scheme 2).
1
confirmed by H NMR spectroscopy. The spectra display
singlets for the hydrogens of methoxy group at δ =
3.35 ppm, and a multiplet for the allylic hydrogen H-4 at
approximately δ = 3.50 ppm, for both products. The olefinic
proton H-2 appears at δ = 5.93 ppm as a large singlet.
Preparation of 1,6,7,8- and 1,2,7,8-Tetrahydroazocines
Results and Discussion
After isolation, the tetrahydropyridines 18a,b were
warmed under acetonitrile reflux for two hours in the pres-
Preparation of 1,4,5,6-Tetrahydropyridines
The preparation of 1,4,5,6-tetrahydropyridines is out- ence of ethyl propiolate. In this step, the [2+2] cycloaddition
lined in Scheme 3. Thus, the 3-alkyl-1,2,5,6-tetrahydropyri- reaction occurs to produce the cyclobutene intermediates
Eur. J. Org. Chem. 2005, 1052–1057
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1053

R. Pereira de Freitas Gil et al.
FULL PAPER
yields. NMR analysis confirmed the structures of the tetra-
hydroazocines 20a,b.
The azocines 20 form iminium salts 21a,b cleanly and
instantaneouslywhen treated with methanesulfonic acid.
The reaction can be carried out in an NMR tube and the
1
resulting H NMR spectrum shows formation of a single
product with new characteristic olefinic signals correspond-
ing to H-6 (δ = 6.02 ppm), H-4 (δ = 7.55 ppm), and H-2 (δ
= 9.09 ppm). The crude iminium salts 21a,b were immedi-
ately treated with different nucleophiles to produce new
azocine derivatives (Scheme 5).
Scheme 3. Reaction conditions: (i) NaBH4, MeOH/H2O (9:1), re-
flux; (ii) m-CPBA, CH2Cl2, 0 °C; (iii) (CF3CO)2O, CH2Cl2; (iv)
MeONa, MeOH/CH2Cl2 (1:1).
(19a,b). Due to the reaction conditions and to the cyclobut-
ene instability, subsequent electrocyclic ring opening forms
the tetrahydroazocine rings 20a,b (Scheme 4).
Scheme 5. Reaction conditions: (i) MeSO3H, CH2Cl2; (ii) NaBH4,
MeOH/CH2Cl2; (iii) MeMgBr, THF; (iv) NaN3, CH2Cl2, DMF;
(v) PhSNa, CH2Cl2/H2O.
Treatment of iminium salt 21a with sodium borohydride
gave the reduced compound 22, and, as expected for such
a hard nucleophile, the addition occurred in the 2-position.
The structure of 22 was deduced by 1H NMR spectroscopy,
which revealed mainly the signal change of hydrogen H-2
to δ = 3.45 ppm in the reduced product (two hydrogens).
Subsequent reactions were performed with tetrahy-
Scheme 4. Reaction conditions: (i) ethyl propiolate, CH3CN, reflux,
2 h.
The yields of these reactions are good, varying from 57 droazocine 20b, which was initially converted into the corre-
to 94%, despite the instability of the dihydropyridines and sponding iminium salt 21b and subsequently treated with
the cyclobutene intermediates. It is interesting to note that methylmagnesium bromide; 1,2,7,8-tetrahydroazocine (23)
the use of toluene as a solvent gave very low cycloaddition was obtained in 49% yield. Also, the regioisomer resulting
1054
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1052–1057

New Azocine Derivatives
FULL PAPER
128.26, 129.23, (5 C Ph), 132.39 [C(3)], 138.52 (Cquat Ph) ppm. MS
(EI): m/z (%) = 187 (58) [M+], 172 (32), 91 (100). MS (CI) (isobut-
ane): m/z (%) = 188 (100) [MH]+.
from the addition of the methyl group to the 2-position was
obtained preferentially, as confirmed by 1H NMR spec-
troscopy. The products of attack at other positions (4 or 6)
were not observed.
When we used softer nucleophiles like azide and phenyl-
thiolate, the addition occurred in the 6-position of the imin-
ium salt in a conjugated manner. Thus, sodium azide reacts
with the iminium salt 21b to give 1,6,7,8-tetrahydroazocine
(24) in 55% yield. Tetrahydroazocine 25 was the product of
the reaction between iminium salt 21b and sodium phenyl-
thiolate in 68% yield. No other addition products were iso-
lated in these cases.
In the study of the addition of cyanide to iminium salt
21b, the only isolated product was tetrahydropyridine 26.
It is likely that a retro-cycloaddition occurred, even at low
temperature and pH about 4.0 (mild reaction conditions).
Attempts to add iodide (sodium iodide) and sodium ethyl
acetoacetate enolate to iminium salt 21b yielded a complex
mixture of compounds.
1-Benzyl-3-ethyl-1,2,5,6-tetrahydropyridine(15b): Following the pro-
cedure outlined for the preparation of 15a, the salt 1-benzyl-3-eth-
ylpyridinium bromide (9.52 g, 34.24 mmol) was treated with so-
dium borohydride (3.20 g, 85.61 mmol). Pure 15b was obtained as a
pale-orange liquid (4.33 g, 21.53 mmol, 63%). 1H NMR (250 MHz,
3
CDCl3, 25 °C): δ = 0.98 [t, J = 7.5 Hz, 3 H, CH3 (Et)], 1.91 [qd,
3
3J = 1.3, 7.5 Hz, 2 H, CH2 (Et)], 2.11 [m, 2 H, C(5)-H], 2.48 [t, J
= 5.8 Hz, 2 H, C(6)-H], 2.86 [m, 2 H, C(2)-H], 3.56 (s, 2 H, CH2Ph),
5.46 [m, 1 H, C(4)-H], 7.20–7.40 (m, 5 H, Ph) ppm. 13C NMR
(62.9 MHz, CDCl3, 25 °C): δ = 12.05 [CH3 (Et)], 25.90 [C(5)], 27.84
[CH2 (Et)], 49.73 [C(6)], 55.96 [C(2)], 62.91 [CH2Ph], 117.54 [C(4)],
126.92, 128.15, 129.10, (5 C Ph), 137.73 [C(3)], 138.45 (Cquat Ph)
ppm. MS (EI): m/z (%) = 201 (26) [M+], 186 (16), 172 (40), 91
(100).
1-Benzyl-3-methyl-1,2,5,6-tetrahydropyridine N-Oxide(16a): The
tetrahydropyridine 15a (4.80 g, 25.67 mmol) was dissolved in anhy-
drous dichloromethane (30 mL). The solution was cooled to 0 °C,
and meta-chloroperbenzoic acid (6.64 g, 38.50 mmol) was added
slowly. Stirring was continued for 15 min at room temperature. The
mixture was quickly filtered through a short column of alumina
[methanol/dichloromethane (0:100, 2.5:97.5, 5:95), 100 mL of
each], and the N-oxide solution was concentrated under reduced
pressure at room temperature. The N-oxide 16a was obtained as a
brown oil (4.67 g, 22.97 mmol, 92%) that was immediately used for
the next reactions. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.68
(s, 3 H, CH3), 2.32 [m, 1 H, C(5)-H], 2.68 [m, 1 H, C(5)-H], 3.38
Conclusions
Tetrahydroazocines 20 have been synthesized, in good
yields, by an easy five-step method starting from pyridin-
ium salts 5. These tetrahydroazocines were converted into
iminium salts that could be treated with nucleophiles to give
new tetrahydroazocines like 22, 23, 24, and 25 in moderate
yields. It is evident from these studies that the addition to
the iminium salts 21a,b exhibits nucleophile-dependent re-
giospecificity. For example, very soft nucleophiles such as
azide and thiophenolate bind to the softest of the three im-
inium electrophilic centers (position 6), whereas harder nu-
cleophiles such as hydride and Grignard reagent attack the
hardest center (position 2). No attack in position 4 was ob-
served in any case. Attempts to introduce cyano, iodide, and
enolates did not give the expected products. Further studies
to extend this approach to other azocines, including chiral
derivatives,[17] are currently in progress in our laboratories.
3
3
[t, J = 6.2 Hz, 2 H, C(6)-H], 3.55 [dl, J = 16.0 Hz, 1 H, C(2)-H],
3.83 [d, 3J = 16.0 Hz, 1 H, C(2)-H], 4.46 (d, 3J = 12.4 Hz, 1 H,
CH2Ph), 4.52 (d, J = 12.4 Hz, 1 H, CH2Ph), 5.60 [m, 1 H, C(4)-
3
H], 7.38–7.60 (m, 5 H, Ph) ppm. 13C NMR (75.5 MHz, CDCl3,
25 °C): δ = 20.48 (CH3), 23.02 [C(5)], 61.09 [C(6)], 67.24 [C(2)],
72.19 (CH2Ph), 118.60 [C(4)], 128.04 [C(3) or Cquat Ph], 128.40,
129.41, (3 C Ph), 130.13 [C(3) or Cquat Ph], 132.38 (2 C Ph) ppm.
MS (FAB+): m/z (%) = 204 (100) [MH]+, 186 (10). MS (CI) (isobut-
ane): m/z (%) = 204 (4) [MH]+, 202 (5), 188 (100).
1-Benzyl-3-ethyl-1,2,5,6-tetrahydropyridine N-Oxide(16b): Follow-
ing the procedure outlined for the preparation of 16a, the tetrahy-
dropyridine 15b (3.48 g, 17.30 mmol) was treated with meta-chloro-
perbenzoic acid (3.58 g, 20.70 mmol). The N-oxide 16b was ob-
tained as a brown oil (3.68 g, 16.93 mmol, 98%) which was immedi-
ately used for the next reaction. 1H NMR (300 MHz, CDCl3,
3
3
Experimental Section
25 °C): δ = 1.02 [t, J = 7.4 Hz, 3 H, CH3 (Et)], 1.97 [q, J = 7.4
Hz, 2 H, CH2 (Et)], 2.31 [m, 1 H, C(5)–H], 2.70 [m, 1 H, C(5)–H],
1-Benzyl-3-methyl-1,2,5,6-tetrahydropyridine (15a): sodium borohy-
dride (4.00 g, 105.73 mmol) was added slowly to a solution of 1-
benzyl-3-methylpyridinium bromide (14a; 11.07 g, 41.91 mmol) in
methanol/water (9:1; 100 mL). The reaction mixture was stirred for
16 h at room temperature. The solvent was distilled under reduced
pressure, the residue was solubilized with water, and extracted with
ethyl acetate (5×50 mL). The combined organic layers were dried
over anhydrous sodium sulfate, filtered, and concentrated to give
an orange liquid. The crude product was purified by column
chromatography on alumina [ethyl acetate/heptane (0:100 to 2:98),
0.5% to 0.5% by volume of 200 mL]. Pure 15a was obtained as a
yellow liquid (4.80 g, 25.65 mmol, 61%). 1H NMR (250 MHz,
3
3.28 [m, 2 H, C(6)–H], 3.54 [dl, J = 16.0 Hz, 1 H, C(2)–H], 3.72
3
[d, J = 16.0 Hz, 1 H, C(2)–H], 4.36 (s, 2 H, CH2Ph), 5.60 [m, 1
H, C(4)–H], 7.35–7.65 (m, 5 H, Ph) ppm. 13C NMR (75.5 MHz,
CDCl3, 25 °C): δ = 11.60 [CH3 (Et)], 23.29 [C(5)], 27.38 [CH2 (Et)],
61.65 [C(6)], 67.07 [C(2)], 71.78 (CH2Ph), 116.59 [C(4)], 128.48,
129.51, (3 C Ph), 130.35 [C(3) or Cquat Ph], 132.51 (2 C Ph), 133.89
[Cquat Ph or C(3)] ppm. MS (FAB+): m/z (%) = 218 (83) [M+], 200
(13), 91 (100).
1-Benzyl-4-methoxy-3-methyl-1,4,5,6-tetrahydropyridine (18a): The
N-oxide 16a (2.10 g, 10.38 mmol) was dissolved in anhydrous meth-
ylene chloride (20 mL) and the solution was cooled to 0 °C. Tri-
CDCl3, 25 °C): δ = 1.62 (s, 3 H, CH3), 2.11 [m, 2 H, C(5)–H], 2.49 fluoroacetic anhydride (3.00 mL, 20.76 mmol) was added slowly
3
[t, J = 5.7 Hz, 2 H, C(6)-H], 2.84 [m, 2 H, C(2)-H], 3.58 (s, 2 H, and the mixture was stirred at 0 °C for 20 min. After distillation of
CH2Ph), 5.48 [m, 1 H, C(4)-H], 7.20–7.40 (m, 5 H, Ph) ppm. 13C solvent and excess trifluoroacetic anhydride under reduced pres-
NMR (62.9 MHz, CDCl3, 25 °C): δ = 21.09 (CH3), 26.10 [C(5)], sure, the residue was dissolved in anhydrous dichloromethane
49.57 [C(6)], 57.11 [C(2)], 62.94 (CH2Ph), 119.56 [C(4)], 127.04,
(15 mL). This solution was added slowly to a sodium methoxide
Eur. J. Org. Chem. 2005, 1052–1057
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1055

R. Pereira de Freitas Gil et al.
FULL PAPER
solution [prepared by addition of 1.20 g (51.90 mmol) of sodium
to 25 mL of methanol] at 0 °C and the reaction was stirred for
30 min at room temperature. The reaction mixture was poured into
an ethyl acetate/pentane (2:8) mixture with water and the aqueous
layer was extracted with ethyl acetate/pentane (2:8; 5×25 mL). The
combined organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure at room tempera-
ture. The tetrahydropyridine 18a was obtained without purification
as an orange liquid (1.64 g, 7.55 mmol, 73%) which was immedi-
ately used for the next reaction. 1H NMR (250 MHz, CDCl3,
C19H25NO3: calcd. C 72.37, H 8.33, N 4.31; found C 72.35, H 7.99,
N 4.44.
Ethyl 1-Benzyl-5-ethyl-6-methoxy-1,6,7,8-tetrahydroazocine-3-car-
boxylate (20b): Following the procedure outlined for preparation
of 20a, the tetrahydropyridine 18b (395 mg, 1.71 mmol) was treated
with ethyl propiolate (0.92 mL, 9.10 mmol) to give the tetrahy-
droazocine 20b as white crystals (321 mg, 0.97 mmol, 57%, m.p.
116–118 °C). IR (KBr): 1680 (νC=O) cm–1. 1H NMR (200 MHz,
3
CDCl3, 25 °C): δ = 1.05 [m, 1 H, C(7)-H], 1.07 [t, J = 7.4 Hz, 3
3
H, CH3 (Et)], 1.29 [t, J = 7.1 Hz, 3 H, CH3 (EtO)], 1.62 [m, 1 H,
3
25 °C): δ = 1.63 [m, 1 H, C(5)-H], 1.72 (d, J = 0.7 Hz, 3 H, CH3),
C(7)-H], 2.03 [m, 2 H, CH2 (Et)], 2.85 [m, 1 H, C(8)-H], 3.23 (s, 3
H, CH3O), 3.62 [m, 1 H, C(8)-H], 4.06–4.39 [m, 5 H, C(6)-H, CH2
(EtO) and CH2Ph), 6.27 [m, 1 H, C(4)-H], 7.24–7.37 (m, 5 H, Ph),
7.63 [s, 1 H, C(2)-H] ppm. 13C NMR (50.3 MHz, CDCl3, 25 °C):
δ = 12.50 [CH3 (Et)], 14.78 [CH3 (EtO)], 22.21, 22.52 [C(8) and
CH2 (Et)], 45.02 [C(8)], 57.33 (CH3O), 59.87 (CH2Ph), 61.57 (CH2
(EtO)], 79.73 [C(6)], 95.38 [C(3)], 120.73 [C(4)], 127.83, 128.23,
128.99 (5 C Ph), 135.93, 136.74 [C(8) and Cquat Ph], 148.93 [C(2)],
170.03 (COOEt) ppm. C20H24NO3 (329.20): calcd. C 72.98, H 8.32,
N 4.22; found C 72.92, H 8.26, N 4.25.
3
1.99 (dddd, J = 2.7, 2.8, 3.0, 14.0 Hz, 1 H, C(5)-H], 2.72 [m, 2 H,
3
C(6)-H], 3.35 (s, 3 H, OCH3), 3.47 [m, 1 H, C(4)-H], 3.89 [d, J =
3
14.4 Hz, 1 H, CH2Ph), 3.99 (d, J = 14.4 Hz, 1 H, CH2Ph), 5.93
[s, 1 H, C(2)-H], 7.20–7.36 (m, 5 H, Ph) ppm. 13C NMR
(62.9 MHz, CDCl3, 25 °C): δ = 18.73 (CH3), 26.72 [C(5)], 42.38
[C(6)], 55.87 (OCH3), 59.46 (CH2Ph), 74.74 [C(4)], 104.37 [C(3)],
127.06, 128.08, 128.21 (5 C Ph), 135.03 [C(2)], 138.48 (Cquat Ph)
ppm. MS (EI): m/z (%) = 217 (25) [M+], 186 (100), 91 (82). HRMS:
m/z = 217.1461 (calcd. for C14H19NO, m/z = 217.1467).
1-Benzyl-3-ethyl-4-methoxy-1,4,5,6-tetrahydropyridine (18b): Fol-
lowing the procedure outlined for preparation of 18a, the N-oxide
16b (1.02 g, 4.72 mmol) was treated with trifluoroacetic anhydride
(1.00 mL, 7.08 mmol) at 0 °C. The intermediate trifluoroacetate
obtained (17b) was treated with a sodium methoxide solution [0.76
g (33 mmol) of sodium and 20 mL of methanol]. The tetrahy-
dropyridine 18b was obtained as an orange liquid (849 mg,
1-Benzyl-3-ethoxycarbonyl-5-ethyl-7,8-dihydroazocinium Methane-
sulfonate (21b): Methanesulfonic acid (40 µL, 0.60 mmol) was
added to a solution of tetrahydroazocine 20b (50 mg, 0.15 mmol) in
deuterochloroform (0.4 mL) and the mixture was stirred for about
10 min. The formation of iminium salt 21b was confirmed by thin-
layer chromatography and 1H NMR spectroscopy. 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 1.05 [t, 3J = 7.5 Hz, 3 H, CH3 (Et)],
3
3
3.67 mmol, 78%). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.01 [t,
1.37 [t, J = 7.1 Hz, 3 H, CH3 (EtO)], 2.23 [q, J = 7.5 Hz, 2 H,
3
3
3J = 7.4 Hz, 3 H, CH3 (Et)], 1.59 [m, 1 H, C(5)-H], 2.01 [dq, J = CH2 (Et)], 2.83 [m, 2 H, C(7)-H], 4.19 [t, J = 5.7 Hz, 2 H, C(8)-
3
3
2.9, 14.0 Hz, 1 H, C(5)-H], 2.09 (q, J = 7.4 Hz, 2 H, CH2 (Et)],
H], 4.35 [q, J = 7.1 Hz, 2 H, CH2 (EtO)], 5.26 (m, 2 H, CH2Ph),
2.74 [m, 2 H, C(6)-H], 3.34 (s, 3 H, OCH3), 3.56 [m, 1 H, C(4)-H], 6.02 [m,1 H, C(6)–H], 7.49 (m, 5 H, Ph), 7.55 [s, 1 H, C(4)–H],
3
3
3.92 (d, J = 14.4 Hz, 1 H, CH2Ph), 4.02 (d, J = 14.4 Hz, 1 H,
CH2Ph), 5.92 [s, 1 H, C(2)-H], 7.20–7.40 (m, 5 H, Ph) ppm. 13C
NMR (50.3 MHz, CDCl3, 25 °C): δ = 13.47 [CH3 (Et)], 25.44,
26.27 [C(5) and CH2 (Et)], 42.05 [C(6)], 55.38 (OCH3), 59.32
(CH2Ph), 72.74 [C(4)], 110.27 [C(3)], 126.91, 127.91, 128.16 (5 C
Ph), 134.13 [C(2)], 138.32 (Cquat Ph) ppm. MS (EI): m/z (%) = 231
(35) [M+], 200 (100), 91 (100). HRMS: m/z = 231.1619 (calcd. for
C15H21NO, m/z = 231.1623).
9.09 [s, 1 H, C(2)-H] ppm.
Ethyl
1-Benzyl-5-methyl-1,2,7,8-tetrahydroazocine-3-carboxylate
(22): Methanesulfonic acid (176 µL, 2.66 mmol) was added to a
solution of tetrahydroazocine 20a (184 mg, 0.58 mmol) in dichloro-
methane (12 mL) and the mixture was stirred at room temperature
for 15 min. After formation of iminium salt 21a (confirmed by
thin-layer chromatography), a suspension of sodium borohydride
(55 mg, 1.46 mmol) in methanol (20 mL) was added. The mixture
was stirred for 20 h, when thin layer chromatography (ethyl acetate/
hexane 2:8) showed the completion of the reaction. The mixture
was extracted with ethyl acetate/water (5×15 mL of ethyl acetate).
The organic layers were combined and dried with anhydrous so-
dium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
(ethyl acetate/hexane, 5:95). After removal of solvent, the product
22 was obtained as a yellow oil (44 mg, 0.15 mmol, 26%). IR
(KBr): 1720 (νC=O) cm–1. 1H NMR (200 MHz, CDCl3, 25 °C): δ =
Ethyl
1-Benzyl-6-methoxy-5-methyl-1,6,7,8-tetrahydroazocine-3-
carboxylate (20a): Ethyl propiolate (0.56 mL, 5.51 mmol) was
added to a solution of tetrahydropyridine 18a (598 mg, 2.78 mmol)
in acetonitrile (20 mL). This solution was maintained under reflux
for 2 h. After solvent distillation under reduced pressure, the resi-
due was purified by column chromatography on silica gel (ethyl
acetate/hexane, 5:95). The tetrahydroazocine 20a was obtained as
a pale-yellow solid, which was subsequently recrystallized from di-
ethyl ether/heptane to give white crystals (827 mg, 2.62 mmol, 94%,
3
1.28 [t, J = 7.1 Hz, 3 H, CH3 (EtO)], 1.83 (s, 3 H, CH3), 2.22 [m,
m.p. 111–113 °C). IR (KBr): 1680 (νC=O
(250 MHz, CDCl3, 25 °C): δ = 1.03 [m, 1 H, C(7)-H], 1.29 [t, J =
)
cm–1. 1H NMR
2 H, C(7)–H], 2.50 [m, 2 H, C(8)-H], 3.45 [m, 2 H, C(2)-H], 3.73
3
3
(s, 2 H, CH2Ph), 4.20 [q, J = 7.1 Hz, 2 H, CH2 (EtO)], 5.64 [m, 1
3
7.1 Hz, 3 H, CH3 (EtO)], 1.57 [tt, J = 5.0, 12.6 Hz, 1 H, C(7)-H],
H, C(6)–H], 7.12 [s, 1 H, C(4)-H], 7.21–7.32 (m, 5 H, Ph) ppm. 13
C
3
1.64 (d, J = 1.6 Hz, 3 H, CH3), 2.85 [m, 1 H, C(8)-H], 3.24 (s, 3
NMR (50.3 MHz, CDCl3, 25 °C): δ = 14.25 [CH3 (EtO)], 22.46
(CH3), 27.87 [C(7)], 46.54 [C(8)], 49.18 [C(2)], 60.71 [CH2 (EtO)],
61.28 [CH2Ph], 126.89, 128.11, 129.10 (5 C Ph), 130.04 [C(6)],
129.96, 133.33, 139.31 [C(3), C(5) and Cquat Ph), 140.96 [C(4)],
167.74 (COOEt) ppm. HRMS (EI): m/z = 285.1726 (calcd. for
C18H23NO2: 285.1729).
H, CH3O), 3.60 [m, 1 H, C(8)-H], 4.00–4.40 [m, 3 H, C(6)-H and
CH2Ph], 4.20 [q, 3J = 7.1 Hz, 2 H, CH2 (EtO)], 6.28 [m, 1 H, C(4)-
H], 7.23–7.40 (m, 5 H, Ph), 7.61 [s, 1 H, C(2)-H] ppm. 13C NMR
(62.9 MHz, CDCl3, 25 °C): δ = 14.74 [CH3 (EtO)], 16.82 (CH3),
21.12 [C(7)], 44.98 [C(8)], 57.07 (CH3O), 59.82 (CH2Ph), 61.51
[CH2 (EtO)], 79.21 [C(6)], 95.26 [C(3)], 122.39 [C(4)], 127.78,
128.18, 128.93 (5 C Ph), 131.33 [C(5)], 136.61 (Cquat Ph), 148.99
[C(2)], 169.88 (COOEt) ppm. MS (EI): m/z (%) = 315 (100) [M+],
300 (9), 284 (80), 270 (25), 242 (28), 224 (30), 91 (100). HRMS:
Ethyl
1-Benzyl-5-ethyl-2-methyl-1,2,7,8-tetrahydroazocine-3-car-
boxylate (23): The iminium salt 21b was prepared by the procedure
outlined above from the tetrahydroazocine 20b (102 mg,
0.31 mmol) and methanesulfonic acid (82 µL, 1.24 mmol). After
m/z
= 315.1842 (calcd. for C19H25NO3, m/z = 315.1835).
1056
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1052–1057

New Azocine Derivatives
FULL PAPER
formation of the iminium salt the solvent was distilled off under
reduced pressure and the residue was dissolved in anhydrous tetra-
hydrofuran (7 mL). The solution was cooled to –25 °C (nitrogen
atmosphere) and then a methylmagnesium bromide solution (3.0 m
in diethyl ether; 0.72 mL, 2.16 mmol) was added. The reaction mix-
ture was stirred at –20 °C for 30 min and then at room temperature
for the same time. The reaction was stopped by the addition of
ammonium chloride solution 10% (15 mL) and the mixture was
extracted with diethyl ether (5×10 mL). The combined organic lay-
ers were dried with anhydrous sodium sulfate and concentrated to
give an oil that was purified by column chromatography on silica
gel eluting with ethyl acetate/hexane (5:95). The pure product 23
was obtained as a light-yellow oil (47 mg, 0.15 mmol, 49%). 1H
NMR (200 MHz, CDCl3, 25 °C): δ = 1.05 [t, 3J = 7.5 Hz, 3 H,
three additional portions (15 mL) of dichloromethane. The com-
bined organic layers were washed with 1 m sodium hydroxide solu-
tion (15 mL), and then water (20 mL). The organic solution was
dried with anhydrous sodium sulfate and concentrated to give the
crude product 25. This product was purified by column chromatog-
raphy on silica gel (ethyl acetate/hexane, 5:95), and recrystallized
from diethyl ether/pentane to give the tetrahydroazocine 25 as
1
white crystals (71 mg, 0.17 mmol, 68%, m.p. 63–66 °C). H NMR
(200 MHz, CDCl3, 25 °C): δ = 1.04 [t, 3J = 7.4 Hz, 3 H, CH3 (Et)],
3
1.20 [m, 1 H, C(7)-H], 1.30 [t, J = 7.1 Hz, 3 H, CH3 (EtO)], 1.66
[m, 1 H, C(7)-H], 2.15 [m, 2 H, CH2 (Et)], 2.84 [m, 1 H, C(8)-H],
3.87 [m, 1 H, C(8)-H], 4.19 [m, 3 H, CH2 (EtO) and 1×CH2Ph],
4.39 [m, 2 H, C(6)-H and 1×CH2Ph], 6.28 [s, 1 H, C(4)-H], 7.08–
7.32 (m, 10 H, Ph), 7.70 [s, 1 H, C(2)-H] ppm. 13C NMR
(50.3 MHz, CDCl3, 25 °C): δ = 12.72 [CH3 (Et)], 14.91 [CH3
3
3
CH3 (Et)], 1.28 [t, J = 7.2 Hz, 3 H, CH3 (EtO)], 1.34 (d, J = 7.2
3
Hz, 3 H, CH3), 2.04 [m, 2 H, C(7)–H], 2.19 [q, J = 7.5 Hz, 2 H, (EtO)], 22.60 [C(7)], 25.31 [CH2 (Et)], 45.35 [C(8)], 46.78 [C(6)],
CH2 (Et)], 2.52 [m, 1 H, C(8)-H], 2.68 [m, 1 H, C(8)–H], 3.54 (d,
59.89 [CH2 (EtO)], 61.59 (CH2Ar), 95.40 [C(3)], 121.90 [C(4)],
3
3J = 13.6 Hz, 1 H, CH2Ph), 3.81 (m, 1 H, CH2Ph), 4.19 [q, J = 125.38, 127.69, 127.83, 128.28, 128.96, 129.05 (10 C Ph), 134.04,
3
7.2 Hz, C(2)-H and CH2 (EtO)], 5.60 [t, J = 7.9 Hz, 1 H, C(6)-
136.55, 137.50 [C(5) and 2 Cquat Ph], 149.52 [C(2)], 169.98 (COOEt)
H], 7.07 [s, 1 H, C(4)-H], 7.23–7.31 (m, 5 H, Ph) ppm. 13C NMR ppm. C25H29NO2S (407.19): calcd. 73.45, H 6.83, N 3.36; found C
(50.3 MHz, CDCl3, 25 °C): δ = 13.61 [CH3 (Et)], 14.40 [CH3
(EtO)], 16.45 (CH3), 25.03 [C(7)], 29.91 [CH2 (Et)], 44.90 [C(8)],
55.03 [C(2) and CH2Ph], 60.85 [CH2 (EtO)], 126.77, 127.89, 128.26,
128.78 [C(6) and 5 C Ph], 132.95, 139.46, 140.82 [C(3), [C(5) and
Cquat Ph), 138.88 [C(4)], 168.55 (COOEt) ppm. HRMS (EI): m/z =
313.2045 (calcd. for C20H27NO2: 313.2042).
73.67, H 7.17, N 3.44.
Acknowledgments
The authors thank CAPES (Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior) and CNPq (Conselho Nacional de De-
senvolvimento Científico e Tecnológico) for financial support.
Ethyl 6-Azido-1-benzyl-5-ethyl-1,6,7,8-tetrahydroazocine-3-carbox-
ylate (24): The iminium salt 21b was prepared by the procedure
outlined above from the tetrahydroazocine 20b (65 mg, 0.20 mmol)
and methanesulfonic acid (54 µL, 0.83 mmol). After formation of
the iminium salt sodium azide (139 mg, 2.01 mmol) and dimeth-
ylformamide (10 drops) were added at room temperature and the
reaction mixture was stirred for 3 h. After this period, water
(20 mL) was added and the mixture was basified with 10% sodium
carbonate solution and extracted with chloroform (4×10 mL). The
combined organic layers were dried over anhydrous sodium sulfate
and concentrated. After purification by column chromatography
on silica gel (ethyl acetate/hexane, 5:95), the tetrahydroazocine 24
[1] L. Akhter, R. T. Brown, D. Moorcroft, Tetrahedron Lett. 1978,
19, 4137–4140.
[2] E. Valencia, V. Fajardo, A. J. Freyer, M. Shamma, Tetrahedron
Lett. 1985, 26, 993–996.
[3] R. Sakai, T. Higa, C. W. Jefford, G. Bernardinelli, J. Am. Chem.
Soc. 1986, 108, 6404–6405.
[4] P. A. Evans, A. B. Holmes, Tetrahedron 1991, 47, 9131–9166.
[5] D. Tadic, J. T. M. Linders, J. L. Flippen-Anderson, A. E. Ja-
cobson, K. C. Rice, Tetrahedron 2003, 59, 4603–4614.
[6] P. S. Mariano, M. E. Osborn, D. Dunaway-Mariano, B. C.
Gunn, R. C. Pettersen, J. Org. Chem. 1977, 42, 2903–2910.
[7] a) Y. Torisawa, Y. Motohashi, J. Ma, T. Hino, M. Nakagawa,
Tetrahedron Lett. 1995, 36, 5579–5580; b) M. E. Kuehne, S. D.
Cowen, F. Xu, L. S. Borman, J. Org. Chem. 2001, 66, 5303–
5316.
[8] K. Oda, T. Ohnuma, Y. Ban, J. Org. Chem. 1984, 49, 953–959.
See also: a) A. Padwa, T. Hasegawa, B. Liu, Z. Zhang, J. Org.
Chem. 2000, 65, 7124–7133; b) L. G. Voskressensky, T. N. Bo-
risova, L. N. Kulikova, A. V. Varlamov, M. Catto, C. Altomare,
A. Carotti, Eur. J. Org. Chem. 2004, 3128–3135;
[9] D. Donati, S. Fusi, F. Ponticelli, Eur. J. Org. Chem. 2002, 4211–
4216.
[10] M. Acheson, G. Paglietti, P. A. Tasker, J. Chem. Soc., Perkin
Trans. 1 1974, 2496–2500.
[11] G. Godin, E. Garnier, P. Compain, O. R. Martin, K. Ikeda, N.
Asano, Tetrahedron Lett. 2004, 45, 579–581.
[12] L. Gil, R. P. de Freitas Gil, D. C. dos Santos, C. Marazano,
Tetrahedron Lett. 2000, 41, 6067–6069.
[13] A. Maia, R. P. de Freitas Gil, L. Gil, C. Marazano. Lett. Org.
Chem. 2004, 1, 93–98.
1
(37 mg, 0.11 mmol, 55%) was obtained as a yellow oil. H NMR
(200 MHz, CDCl3, 25 °C): δ = 1.07 [t, 3J = 7.4 Hz, 3 H, CH3 (Et)],
3
1.08 [m, 1 H, C(7)-H], 1.29 [t, J = 7.1 Hz, 3 H, CH3 (EtO)], 1.51
[m, 1 H, C(7)-H], 2.05 [m, 2 H, CH2 (Et)], 2.88 [m, 1 H, C(8)–H],
3.68 [m, 1 H, C(8)-H], 4.17 [m, 2 H, CH2 (EtO)], 4.31 (s, 2 H,
CH2Ph), 4.49 [dd, 3J = 5.2, 12.0 Hz, 1 H, C(6)-H], 6.24 [s, 1 H,
C(4)-H], 7.24–7.43 (m, 5 H, Ph), 7.68 [s, 1 H, C(2)-H] ppm. 13C
NMR (50.3 MHz, CDCl3, 25 °C): δ = 12.62 [CH3 (Et)], 14.80 [CH3
(EtO)], 24.21, 29.91 [C(7) and CH2 (Et)], 45.20 [C(8)], 60.11 and
62.09 [CH2 (EtO) and CH2Ph], 62.04 [C(6)], 95.38 [C(3)], 121.05
[C(4)], 127.91, 128.53, 129.18 (5 C Ph), 133.43, 136.47 [C(5) and
Cquat Ph], 149.24 [C(2)], 169.75 (COOEt) ppm. C19H24N4O2
(340.19): calcd. C 67.40, H 7.46, N 16.08; found C 67.04, H 7.11,
N 16.46.
Ethyl 1-Benzyl-5-ethyl-2-methyl-6-phenylthio-1,6,7,8-tetrahydroazo-
cine-3-carboxylate (25): The iminium salt 21b was prepared by the
procedure outlined above from the tetrahydroazocine 20b (84 mg,
0.25 mmol), chloroform (5 mL), and methanesulfonic acid (66 µL,
1.02 mmol). After formation of the iminium salt the mixture was
cooled to 0 °C and a solution of sodium phenylthiolate [prepared
by mixing of 0.16 mL (1.60 mmol) of thiophenol and 1.6 mL of
1 m sodium hydroxide solution] was added quickly. The two-phase
system was stirred vigorously at room temperature for 1 h, after
which a 10% sodium carbonate solution (5 mL) was added. The
organic layer was separated and the aqueous phase washed with
[14] B. Weinstein, L.-C. C. Lin, F. W. Fowler, J. Org. Chem. 1980,
45, 1657–1661.
[15] S. Raucher, R. F. Lawrence, Tetrahedron Lett. 1983, 24, 2927–
2930.
[16] D. S. Grierson, M. Harris, H.-P. Husson, J. Am. Chem. Soc.
1980, 102, 1064–1082.
[17] D. C. dos Santos, R. P. de Freitas Gil, L. Gil, C. Marazano,
Tetrahedron Lett. 2001, 42, 6109–6111.
Received October 13, 2004
Eur. J. Org. Chem. 2005, 1052–1057
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1057