Synthesis of benzomorphan analogues by intramolecular Buchwald-Hartwig cyclization

Article abstract of DOI:10.1002/ejoc.200600688

A new strategy toward the important class of benzomorphans is described. The key bond formation is based on an intramolecular Buchwald-Hartwig enolate arylation reaction. Thus, alkylation of piperidones with ortho-bromobenzyl bromides provides the necessary substrates. In the presence of a palladium catalyst, a sterically hindered phosphane ligand, and a base, carbon-carbon bond formation to tricyclic benzomorphan derivatives takes place. After removal of the N-protecting group, derivatization reactions are possible. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200600688

FULL PAPER
DOI: 10.1002/ejoc.200600688
Synthesis of Benzomorphan Analogues by Intramolecular Buchwald–Hartwig
Cyclization
Anton S. Khartulyari[a] and Martin E. Maier*[a]
Keywords: Cyclization / Benzomorphan / Pd catalysis / Scaffold / Arylation
A new strategy toward the important class of benzomorphans
is described. The key bond formation is based on an intramo-
lecular Buchwald–Hartwig enolate arylation reaction. Thus,
alkylation of piperidones with ortho-bromobenzyl bromides
provides the necessary substrates. In the presence of a palla-
dium catalyst, a sterically hindered phosphane ligand, and a
base, carbon–carbon bond formation to tricyclic benzomor-
phan derivatives takes place. After removal of the N-protect-
ing group, derivatization reactions are possible.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Many active drugs contain a cyclic core structure, fre-
quently incorporating heteroatoms. In addition, other posi-
tions are decorated with groups that directly interact with
matching partners on the receptor. Besides the type, the rel-
ative orientation of these groups is a key factor in determin-
ing biological activity. Prototypical cases are the opioid an-
algetics.[1] Morphine (1),[2] the natural lead structure con-
fers its activity through an agonistic modulation at the µ-
receptor (Figure 1). In the course of structure/activity stud-
ies,[3] other opiod receptors, such as the κ-, the δ-, and the
ORL-1 receptor were discovered.[4] The desired analgetic
properties result mainly by binding of a ligand to the µ- and
the κ-receptor. Of clinical relevance are µ-agonist,[5] partial
agonist (compound that shows agonistic as well as antago-
nistic effects at the µ-receptor) and mixed agonist/antago-
nists.[6] The latter type of drugs include compounds that are
κ-agonists/µ-agonists or κ-agonists/µ-antagonists, respec-
tively. For example, pentazocine is classified as κ-agonist/
partial µ-agonist. The stronger the µ-agonistic part, the
more a problem of dependence can occur.
As the essential structural features of morphine the phe-
nol and the piperidine ring were identified. In order to find
analgetics with improved properties and reduced side effects
a range of morphine analogs were prepared. These varia-
tions include the synthesis of truncated systems. Thus,
opening of the cyclohexene ring (ring C) yields the benzo-
morphans, such as 2 and 3.[7–9] Also the nitrogen atoms can
be repositioned, as illustrated with structures 4 and 5.[10] In
addition, variations in the ring size have been performed in
the benzomorphan series.[11] Another important core struc-
Figure 1. Structures of morphine (1), and prominent analogs de-
rived from it.
ture is represented by the 5-arylmorphan skeleton 6.[12] Fi-
nally, a range of µ-selective opioids without morphinan
structure were discovered over the years.[5] Among the sim-
pler morphine analogs, the benzomorphan and benzazocine
tricyclic ring system are the most important ones.[8] Classi-
cal routes to such compounds include SN2 reactions with
a nucleophilic amine, formation of amides, intramolecular
Friedel–Crafts alkylation, or iminium ion cyclizations.[3]
However, due to the reactions employed, the type of substit-
uents is restricted at certain positions.
With the advent of new powerful organometallic trans-
formations, such as cross-coupling or C–H insertions, the
chemistry of classical drugs might be substantially broad-
ened. Thus, structures that previously seemed difficult to
prepare might now be more easily accessible. A case in
point is the Buchwald–Hartwig arylation of enolates in the
presence of a palladium catalyst [Equation (1)].[13–15]
[a] Universität Tübingen, Institut für Organische Chemie,
Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax: +49-7071-295137
martin.e.maier@uni-tuebingen.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 317–324
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. S. Khartulyari, M. E. Maier
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(1)
Our goal was to apply this reaction in an intramolecular
setting towards the synthesis of new benzomorphan scaf-
folds.[16] After adding suitable functional groups, compound
7 appeared as an initial target (Figure 2). Further discon-
nection leads to the piperidones 9 and the ortho-bromoben-
zyl bromides 10. Alkylation between the two carbonyl
groups (cf. 8) or at the terminus (cf. 12) by Weiler alky-
lation[17] should provide the substrates for the intramolecu-
lar ketone arylation. A related strategy has been described
for the bridging of some carbocyclic ketones.[16h]
Scheme 1. Alkylation of ethyl 1-benzyl-4-oxopiperidine-3-carboxyl-
ate (14) and palladium-catalyzed intramolecular ketone arylation
of 15a to yield the benzomorphan derivative 16a.
Figure 2. Synthetic strategy towards benzomorphans based on an
intramolecular Buchwald–Hartwig arylation.
Figure 3. X-ray structure of benzomorphan 16a. The crystal sample
was obtained by crystallization from hot heptane.
It seemed appropriate to remove the N-benzyl protecting
group by palladium-catalyzed hydrogenation to obtain the
Results
The commercially available 1-benzyl-4-oxopiperidine (13) strategic benzomorphan derivative. However, under various
was first converted into the keto ester 14 using diethyl car- conditions (H2, Pd/C, EtOH, 23 °C, 12 h; EtOH/AcOH,
bonate in the presence of NaH (Scheme 1). The alkylation 60 °C, 72 h) formation of the desired product was not ob-
of the keto ester 14 was performed in THF with potassium served. Most likely, steric hindrance interferes with the hy-
carbonate as the base.[18] Under these conditions a reason- drogenation step. Therefore, we tried to convert the benzyl
able yield for the alkylation product 15a could be obtained. group into an urethane protecting group.[19] In the event,
Other bases like KOtBu in THF or NaH in toluene were stirring of the tricyclic compound 16a with ethoxycarbonyl
tried, but the K2CO3/THF system gave the best results. The chloride at elevated temperature for 3 d provided the
intramolecular ketone α-arylation was performed using ethoxycarbonyl compound 17a in good yield. Again,
K3PO4 (3 equiv.), tBu3P (4 mol-%) and Pd(dba)2 (2 mol-%) attempts to cleave the ethyl carbamate under acidic condi-
in refluxing toluene (Scheme 1).[13–15] This way, the tricyclic tions (concd. HCl, reflux) or with trimethylsilyl iodide
compound 16a was obtained in 65% yield. The reaction (TMSI) were not successful in our hands – the starting ma-
was also run on a multigram scale. In this case the product terial remained unchanged. A solution could be found by
was isolated by precipitation from the reaction mixture af- using Cbz chloride instead. Thus, heating of the tricyclic
ter filtration of inorganic material. The structure of the tri- compound 16a with Cbz chloride for several days led to the
cyclic ring system 16a was additionally proven by an X-ray Cbz-protected tricyclic piperidone 17b in 70% yield
analysis (Figure 3).
(Scheme 2). Deprotection was achieved by stirring of the
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Benzomorphan Analogues by Intramolecular Buchwald–Hartwig Cyclization
FULL PAPER
Cbz compound 17b with trimethylsilyl iodide in acetonitrile
for 1 h.[20] The deprotected compound 18 was isolated as
the hydrate and the corresponding ammonium salt. The
presence of the hydrate is evident from a characteristic peak
in the 13C NMR spectrum at δ = 91.5 ppm. With the amine
18 in hand, two representative N-derivatization reactions
were performed in order to show the potential of 18 as a
useful scaffold. Thus, reaction of the amine 18 with phenyl
isocyanate in the presence of triethylamine gave a high yield
of the urea 19. Reaction of 18 was also possible with tosyl
chloride under comparable conditions yielding the sulfon-
amide 20.
Scheme 3. Alkylation of ethyl 1-benzyl-4-oxopiperidine-3-carboxyl-
ate (14) with benzyl bromides 10b and 10c.
Scheme 4. Palladium-catalyzed intramolecular ketone arylation to
yield the benzomorphan derivatives 16b and 16c.
Scheme 2. Conversion of the N-benzyl compound 16a to the ure-
thanes 17a and 17b. Cleavage of the Cbz group to yield the ammo-
nium iodide 18 followed by derivatization reactions on the tricyclic
amino ketone.
Using the two benzyl bromides 10b and 10c, substrate
15b which features a sterically demanding methyl group
next to the bromo substituent, and substrate 15c with an
electron-donating methoxy substituent (Scheme 3) were
prepared. The benzyl bromides 10a–c were obtained from
commercial sources or prepared according to the litera-
ture.[21–23] These derivatives were then subjected to the pal-
ladium-catalyzed cyclization under the same conditions as
for 15a resulting successfully in benzomorphans 16b and
16c (Scheme 4).
Scheme 5. Synthesis of ethyl 1-benzyl-3-oxopiperidine-4-carboxyl-
ate (23) and its Pd-catalyzed cyclization to 24.
In another venture, by changing the position of the nitro-
gen atom in the piperidone ring, the isomeric benzomor-
Because the N-methyl group is rather common in natural
phan derivative 24 was synthesized as shown in Scheme 5. products as well as synthetic drugs, it was of interest to see
The piperidone 22 was prepared from ethyl 2-bromoacetate whether compounds of type 7 could be accessed with an
and benzylamine, followed by alkylation of the resulting N-methyl instead of an N-benzyl group. These compounds
compound with ethyl γ-bromobutyrate to give the diester might be prepared from the N–H derivative (cf. 18) or di-
21. Treatment of the latter with NaH in dioxane furnished rectly from N-methyl-4-oxopiperidine3-carboxylate. In the
the piperidone 22 by Dieckmann condensation, according latter route (Scheme 6), it was required to use the ammo-
to a known procedure.[24] Alkylation of the keto ester 22 nium salt[25] 25a for the alkylation of 26,[26] because with
with the benzyl bromide 10a provided the substrate 23. Pal- the benzyl bromide 10a the nitrogen atom in the piperidone
ladium-catalyzed cyclization of 23 was performed under ring reacts first.[27] The crucial cyclization was run under
similar conditions as for 15a.
the same conditions that had proven useful with the N-ben-
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319

A. S. Khartulyari, M. E. Maier
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run under nitrogen. All commercially available compounds (Acros,
Aldrich, Fluka, Merck) were used without purification. 1H
(400 MHz) and 13C NMR (100 MHz): spectra were recorded at
295 K either in CDCl3 or [D6]DMSO; chemical shifts are calibrated
to the residual proton and carbon resonance of the solvent: CDCl3
(δH = 7.25 ppm, δC = 77.0 ppm), [D6]DMSO (δH = 2.49 ppm, δC
= 39.5 ppm). HRMS (FT-ICR): Electron spray ionization (ESI)
combined with a fourier transform ion cyclotron resonance mass
detector. Analytical LC-MS: HP 1100 Series connected with an ESI
MS detector Agilent G1946C; positive mode with fragmentor volt-
age of 40 eV; column: Nucleosil 100-5, C-18 HD, 5 µm, 70ϫ3 mm,
Macherey–Nagel; eluent: NaCl solution (5 m)/acetonitrile; gradi-
ent: 0–10–15–17–20 min with 20–80–80–99–99% acetonitrile; flow:
0.5 mLmin–1. Flash chromatography: silica gel 43–60 µm. Thin-
layer chromatography: silica gel plates Sil G/UV254.
zyl derivatives (15a Ǟ 16a), but required longer reaction
times. While the yield for the tricyclic compound 28a was
not very high, this reaction provides the desired compound
in a very efficient way (Scheme 6). Compound 27b was pre-
pared in an analogous fashion. Under identical conditions
as for the cyclization of substrate 15a, the cyclization of 27a
and 27b proceeds slower and requires longer reaction times.
The use of other bases, such as KOtBu or NaOtBu did not
lead to an improvement.
Ethyl
(15a): To a suspension of anhydrous K2CO3 (8.01 g, 58 mmol) and
ethyl 1-benzyl-4-oxopiperidine-3-carboxylate (14) (3.93 g,
N-Benzyl-3-(2-bromobenzyl)-4-oxopiperidine-3-carboxylate
15 mmol) in anhydrous THF (25 mL) was added under nitrogen
a solution of 2-bromobenzyl bromide (10a) (4.5 g, 18.0 mmol) in
anhydrous THF (25 mL). The mixture was refluxed for 6 h. Then
the inorganic materials were filtered and washed with THF. The
combined filtrates were concentrated to give an oily residue. The
product was isolated by flash chromatography (petroleum ether/
ethyl acetate, 20:1; Rf = 0.05), yield 4.73 g (73%), slightly yellow
oil. 1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 8.0 Hz, 1 H,
ar.), 7.28–7.02 (m, 7 H, ar.), 7.05–7.00 (m, 1 H, ar.), 4.15–4.00 (m,
2 H, CO2CH2CH3), 3.62 (d, J = 13.1 Hz, 1 H, PhCH2NR2), 3.56
(dd, J = 11.6, 2.8 Hz, 1 H, 2-H), 3.47 (d, J = 13.1 Hz, 1 H,
PhCH2NR2), 3.45 (d, J = 14.4 Hz, 1 H, o-BrC6H4CH2), 3.15 (d, J
= 14.4 Hz, 1 H, o-BrC6H4CH2), 3.01–2.95 (m, 1 H, 5-H), 2.91–2.81
(m, 1 H, 5-H), 2.80 (ddd, J = 14.4, 3.3, 2.0 Hz, 1 H, 6-H), 2.32 (d,
J = 11.5 Hz, 1 H, 2-H), 2.30–2.23 (m, 1 H, 6-H), 1.09 (t, J = 7.0 Hz,
CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 205.3
(C=O), 170.7 (CO2Et), 137.7, 136.3, 132.8, 132.1, 128.9, 128.2,
128.1, 127.2, 127.0, 125.9 (ar.), 62.2 (C-3, quat.), 61.8, 61.4, 61.0,
52.6, 40.5, 35.8 (6 C, sec.), 13.8 (CO2CH2CH3) ppm. HRMS (ESI):
calcd. for C22H24BrNO3 [M + H]+ 430.1012, found 430.1013.
Scheme 6. Alkylation of the N-methyl piperidone 26 with the am-
monium salts 25a and 25b followed by cyclization to the N-methyl-
substituted benzomorphan derivatives 28a and 28b.
Ethyl N-Benzyl-3-(2-bromo-3-methylbenzyl)-4-oxopiperidine-3-car-
boxylate (15b): The reaction was performed with piperidone 14
(1.31 g, 5.0 mmol) and the benzyl bromide 10b (1.32 g, 5.0 mmol)
as described above. Purification of the crude product by flash
chromatography (petroleum ether/ethyl acetate, 20:1; Rf = 0.05)
Conclusion
We could show that the tactical sequence of alkylation
of a cyclic keto ester with an ortho-bromobenzyl bromide,
followed by an intramolecular ketone arylation reaction
gave the alkylated product 15b (1.2 g, 54%) as colorless crystals,
1
(Buchwald–Hartwig palladium-catalyzed cyclization) pro- m.p. 60–61 °C. H NMR (400 MHz, CDCl3): δ = 7.26–7.25 (m, 5
H, ar.), 7.05–6.93 (m, 3 H, ar.), 4.12–3.97 (m, 2 H, CO2CH2CH3),
3.60 (d, J = 13.1 Hz, 1 H, PhCH2NR2), 3.52 (dd, J = 11.4, 3.0 Hz,
1 H, 2-H), 3.49 (d, J = 14.4 Hz, 1 H, ArCH2), 3.43 (d, J = 13.1 Hz,
1 H, PhCH2NR2), 3.16 (d, J = 14.4 Hz, 1 H, ArCH2), 2.98–2.91
(m, 1 H, 5-H), 2.87–2.78 (m, 1 H, 5-H), 2.38–2.32 (m, 4 H, CH3Ar
and 6-H), 2.30 (d, J = 11.4 Hz, 1 H, 2-H), 2.27–2.20 (m, 1 H, 6-H),
1.05 (t, J = 7.0 Hz, 3 H, CO2CH2CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 205.3 (C=O), 170.8 (CO2Et), 138.4, 137.8, 136.7 (3 C,
quat. ar.), 129.4, 129.2, 128.9 (4 C, tert. ar.), 128.7 (quat. ar.), 128.2,
127.2, 126.3 (4 C, tert. ar.), 62.2 (C-3, quat.), 61.8, 61.4, 61.1, 52.5,
40.5, 36.5 (6 C, sec.), 24.5 (CH3Ar), 13.8 (CO2CH2CH3) ppm.
HRMS (ESI): calcd. for C23H27BrNO3 [M + H]+ 444.1169, found
444.1174.
vides an efficient access to novel bicyclic benzomorphan
scaffolds. From the N-benzyl compound 16a the amine 18
(hydroiodide) could be obtained, which was subjected to
some derivatization reactions. Other targets that contain an
aryl or hetaryl ring in a complex structure should be access-
ible as well.
Experimental Section
General: Unless otherwise noted, all reactions were performed in
oven-dried glassware. All solvents used in the reactions were puri-
fied before use. Dry diethyl ether, tetrahydrofuran, and toluene
were distilled from sodium and benzophenone, whereas dry dichlo-
romethane, dimethylformamide, methanol, ethyl acetate, benzene,
and triethylamine were distilled from CaH2. Petroleum ether with
a boiling range of 40–60 °C was used. Reactions were generally
Ethyl
N-Benzyl-3-(2-bromo-5-methoxybenzyl)-4-oxopiperidine-3-
carboxylate (15c): The reaction was performed with piperidone 14
(2.61 g, 10.0 mmol) and benzyl bromide 10c (2.95 g, 11.0 mmol) as
described above. Purification of the crude product by flash
320
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Benzomorphan Analogues by Intramolecular Buchwald–Hartwig Cyclization
FULL PAPER
chromatography (petroleum ether/diethyl ether, 9:1; Rf = 0.1) gave
the alkylated product 15c (2.4 g, 52%), yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.37 (d, J = 8.8 Hz, 1 H, 3Ј-H, ar.), 7.31–
3.41 (d, J = 17.3 Hz, 1 H, 6-H), 3.16 (dd, J = 11.2, 2.8 Hz, 1 H, 4-
H), 3.10 (d, J = 11.2 Hz, 1 H, 4-H), 3.02 (ddd, J = 10.6, 2.8 Hz, 1
H, 2-H), 2.71 (dd, J = 10.6, 2.5 Hz, 1 H, 2-H), 2.16 (s, 3 H, CH3Ar),
7.21 (m, 5 H, N-benzyl, ar.), 6.78 (d, J = 3.0 Hz, 1 H, 6Ј-H, ar.), 1.29 (t, J = 7.1 Hz, 3 H, CO2CH2CH3) ppm. 13C NMR (100 MHz,
6.62 (dd, J = 8.8, 3.0 Hz, 1 H, 4Ј-H, ar.), 4.16–4.03 (m, 2 H, CDCl3): δ = 208.0 (C=O), 170.3 (CO2Et), 138.2, 136.2, 134.6 (4 C,
CO2CH2CH3), 3.72 (s, 3 H, CH3OAr), 3.66–3.58 (m, 2 H, quat. ar.), 128.2, 128.0, 127.8, 127.0, 126.7, 124.3 (4 C, tert. ar.),
PhCH2NR2 and 2-H), 3.50 (d, J = 13.3 Hz, 1 H, PhCH2NR2), 3.41
63.2, 61.5, 60.2, 59.4 (4 C, sec.), 58.9 (C-5, quat.), 49.0 (C-1, tert.),
(d, J = 14.4 Hz, 1 H, ArCH2), 3.13 (d, J = 14.4 Hz, 1 H, ArCH2), 41.1 (C-6, sec.), 18.4 (CH3Ar), 14.1 (CO2CH2CH3) ppm. IR (film):
3.03–2.97 (m, 1 H, 5-H), 2.93–2.83 (m, 1 H, 5-H), 2.40 (ddd, J = ν = 2951, 2812, 1728, 1458, 1261, 1107, 744 cm–1. HRMS (ESI):
˜
14.4, 3.3, 2.0 Hz, 1 H, 6-H), 2.33–2.24 (m, 2 H, 2-H and 6-H),
1.12 (t, J = 7.1 Hz, 3 H, CO2CH2CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 205.3 (C=O), 170.8 (CO2Et), 158.4 (MeOC, quat. ar.),
137.7, 137.2 (2 C, quat. ar.), 133.1, 128.9, 128.2, 127.2, 117.5 (7 C,
tert. ar.), 116.4 (quat. ar.), 114.3 (tert. ar.), 62.3 (C-3, quat.), 61.8,
61.4, 60.9 (3 C, sec.), 55.4 (CH3OAr), 52.6 (PhCH2NR2), 40.5 (C-
5), 36.0 (ArCH2) 13.8 (CO2CH2CH3) ppm. HRMS (ESI): calcd.
for C23H27BrNO4 [M + H]+ 460.1118, found 460.1125.
calcd. for C23H26NO3 [M + H]+ 364.1907, found 364.1917.
Ethyl N-Benzyl-8-methoxy-11-oxo-1,3,4,6-tetrahydro-1,5-methano-
3-benzazocine-5(2H)-carboxylate (16c): This compound was pre-
pared as described above using the alkylated compound 15c
(577 mg, 1.25 mmol). The crude product was purified by flash
chromatography (petroleum ether/ethyl acetate, 20:1; Rf = 0.1),
yield 144 mg (40%), yellow oil which crystallizes within several
1
days, m.p. 84–85 °C. H NMR (400 MHz, CDCl3): δ = 7.19–7.15
Ethyl N-Benzyl-11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-benzazoc-
ine-5(2H)-carboxylate (16a): An oven-dried Schlenk tube fitted
with a rubber septum was purged with nitrogen and charged with
(m, 3 H, ar.), 6.97–6.93 (m, 2 H, ar.), 6.86–6.82 (m, 1 H, ar.), 6.75–
6.72 (m, 2 H, ar.), 4.27–4.20 (m, 2 H, CO2CH2CH3), 3.97 (d, J =
17.4 Hz, 1 H, 6-H), 3.84 (s, 3 H, CH3OAr), 3.57 (s, 2 H,
PhCH2NR2), 3.39 (dd, J = 2.5 Hz, 1 H, 1-H), 3.38 (d, J = 17.4 Hz,
1 H, 6-H), 3.15 (dd, J = 11.2, 2.8 Hz, 1 H, 4-H), 3.08 (d, J =
11.2 Hz, 1 H, 4-H), 2.97 (ddd, J = 10.6, 2.8 Hz, 1 H, 2-H), 2.71
(dd, J = 10.5, 2.5 Hz, 1 H, 2-H), 1.29 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 207.5
(C=O), 170.3 (CO2Et), 158.8 (MeOC, quat. ar.), 138.2, 137.4, 129.6
(3 C, quat. ar.), 128.5, 128.2, 128.1, 127.1, 112.3, 111.4 (8 C, tert.
ar.), 63.4, 62.0, 61.5, 60.3 (4 C, sec.), 58.8 (C-5, quat.), 55.3
(CH3OAr), 52.0 (C-1, tert.), 41.1 (C-6), 14.1 (CO2CH2CH3) ppm.
ethyl
1-benzyl-3-(2-bromobenzyl)-4-oxopiperidine-3-carboxylate
(15a) (4.30 g, 10 mmol), anhydrous toluene (50 mL), K3PO4
(4.25 g, 20 mmol), and Pd(dba)2 (115 mg, 2 mol%). Then the tube
was purged with nitrogen, and tBu3P (10 mL of 0.04  in toluene,
4 mol%) was added. The mixture was vigorously stirred in an oil
bath at 110 °C for 12 h. The reaction mixture was then cooled to
room temperature, diluted with diethyl ether (100 mL), filtered
through Celite and concentrated in vacuo. The crude material was
dissolved in diethyl ether and then the solvent was evaporated. This
procedure was repeated three times which results in the precipi-
tation of the crude product. The solids were washed with a mixture
of pentane/diethyl ether (5:1), filtered and dried in vacuo. Alterna-
tively, the crude material may be purified by flash chromatography
on silica gel (petroleum ether/diethyl ether, 9:1; Rf = 0.2). The pre-
cipitation method provided the tricyclic compound 16a (2.3 g,
65%) as a yellow solid, m.p. 117–119 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.31–7.25 (m, 1 H, ar.), 7.22–7.12 (m, 5 H, ar.), 6.95–
6.87 (m, 3 H, ar.), 4.25 (dd, J = 14.1, 7.1 Hz, CO2CH2CH3), 4.01
(d, J = 17.1 Hz, 1 H, 6-H), 3.57 (dd, J = 14.5 Hz, 2 H, PhCH2NR2),
3.42 (dd, J = 2.5 Hz, 1 H, 1-H), 3.41 (d, J = 17.2 Hz, 1 H, 6-H),
3.19 (dd, J = 11.2, 2.8 Hz, 1 H, 4-H), 3.11 (d, J = 11.2 Hz, 1 H, 4-
H), 3.00 (ddd, J = 10.6, 2.8 Hz, 1 H, 2-H), 2.75 (dd, J = 10.6,
2.5 Hz, 1 H, 2-H), 1.30 (t, J = 7.1 Hz, CO2CH2CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 207.4 (C=O), 170.2 (CO2Et), 138.2,
137.3, 136.3 (3 C, quat. ar.), 128.2, 128.1, 127.5, 127.1, 127.0, 126.2,
126.2 (CH, ar.), 63.5, 61.8, 61.5, 60.2 (4 C, sec.), 59.1 (C-5, quat.),
IR (KBr): ν = 2943, 2816, 1724, 1608, 1454, 1265, 1088, 741 cm–1.
˜
HRMS (ESI): calcd. for C23H26NO4 [M + H]+ 380.18563, found
380.18573; methanol adduct (hemiacetal) calcd. for C24H30NO5 [M
+ CH3OH + H]+ 412.2119, found 412.2111.
Diethyl 11-Oxo-1,6-dihydro-1,5-methano-3-benzazocine-3,5(2H)-di-
carboxylate (17a): The N-benzyl-protected substrate 16a (225 mg,
0.64 mmol) was mixed with ethoxycarbonyl chloride (5 mL) and
the mixture was heated at 60 °C for 3 d. Then, the excess of ethyl
chloroformate was removed by distillation in vacuo. Flash
chromatography (petroleum ether/ethyl acetate, 5:1; Rf = 0.1–0.2)
of the residue gave the product 17a (135 mg, 64%) as an oil. Con-
version of starting material was around 75%. 1H NMR (400 MHz,
CDCl3): δ = 7.23–7.14 (m, 2 H), 7.13–7.00 (m, 2 H), 4.79 (dd, J =
13.6, 3.3 Hz, 0.6 H), 4.60–4.37 (m, 0.5 H), 4.32–4.22 (m, 2.6 H),
4.05–3.87 (m, 1.6 H), 3.77–3.51 (m, 4 H), 3.47–3.30 (m, 1.3 H),
1.31 (t, J = 7.1 Hz, 3 H), 1.13 (t, J = 7.1 Hz, 1 H), 0.77 (t, J =
7.1 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 205.3, 169.3,
155.8, 134.8, 134.4, 128.2, 127.7, 127.3, 126.8, 61.8, 61.6, 59.7, 53.9,
53.2, 52.5, 39.0, 14.1 ppm. According to the NMR spectroscopic
data, 17a is a mixture of rotamers. HRMS (ESI): calcd. for
C18H22NO5 [M + H]+ 332.1493, found 332.1491.
52.7 (C-1, tert.), 41.0 (C-6), 14.1 (CO CH CH ) ppm. IR (KBr): ν
˜
2
2
3
= 2985, 2816, 1724, 1450, 1256, 744 cm–1. HRMS (ESI): calcd. for
C22H23NO3 [M + H]+ 350.1751, found 350.1752; methanol adduct
(hemiacetal): calcd. for C23H28NO4 [M + CH3OH + H]+ 382.2013,
found 382.2008. CCDC-624497 contains the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
3-Benzyl 5-Ethyl 11-Oxo-1,6-dihydro-1,5-methano-3-benzazocine-
3,5(2H)-dicarboxylate (17b): The N-benzyl compound 16a (1.0 g,
2.8 mmol) was mixed with benzyloxycarbonyl chloride (5 mL). The
resulting mixture was then heated at 80 °C until the reaction was
finished (up to 7 d). During this time, every day, additional Cbz
chloride (1 mL) was added. The progress of this reaction was moni-
tored by LC-MS. After completion, the liquid part was removed
by distillation in vacuo at 80 °C. The crude product was purified
by flash chromatography (petroleum ether/ethyl acetate, 5:1; Rf =
0.1–0.2), yield 0.78 g (70%) of 17b as a colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 7.36–7.03 (m, 7 H), 7.02–6.85 (m, 2 H),
Ethyl N-Benzyl-10-methyl-11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-
benzazocine-5(2H)-carboxylate (16b): This compound was prepared
as described above using 455 mg (1.02 mmol) of the alkylated com-
pound 15b. The crude product was purified by flash chromatog-
raphy (petroleum ether/ethyl acetate, 20:1; Rf = 0.1), yield 95 mg
(30%), colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.20–7.14
(m, 4 H, ar.), 7.07–7.01 (m, 2 H, ar.), 6.96–6.88 (m, 2 H, ar.), 4.24
(dd, J = 14.4, 7.1 Hz, 2 H, CO2CH2CH3), 3.99 (d, J = 17.3 Hz, 1
H, 6-H), 3.65 (dd, J = 2.5 Hz, 1 H, 1-H), 3.57 (s, 2 H, PhCH2NR2), 4.98–4.72 (m, 2 H), 4.62–4.39 (m, 1.5 H), 4.32–4.22 (m, 2.5 H),
Eur. J. Org. Chem. 2007, 317–324
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321

A. S. Khartulyari, M. E. Maier
4.03–3.90 (m, 1 H), 3.77–3.63 (m, 1 H), 3.59–3.52 (m, 1.5 H), 3.46– equilibrium with adduct of water addition to the ketone), providing
FULL PAPER
3.28 (m, 1.5 H), 1.35–1.27 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 205.2, 169.3, 169.2, 155.6, 154.9, 136.0, 135.8, 134.8,
134.6, 134.3, 133.5, 128.5, 128.4, 128.4, 128.3, 128.2, 127.9, 127.8,
127.6, 127.4, 127.2, 126.9, 126.8, 67.6, 67.5, 61.9, 59.6, 59.1, 54.1,
53.9, 53.2, 52.4, 52.4, 39.2, 39.0, 14.1 ppm. According to the NMR
the tosylate 20 as a light yellow oil, yield 42 mg (80%). This com-
pound contains some hydrate. 1H NMR (400 MHz, CDCl3): δ =
7.46 (d, J = 8.3 Hz, 2 H, ar.), 7.26–7.10 (m, 4 H, ar.), 7.11 (d, J =
7.6 Hz, 1 H, ar.), 6.95 (d, J = 7.6 Hz, 1 H, ar.), 4.26 (dd, J = 14.2,
7.1 Hz, 2 H, CO2CH2CH3), 4.13 (dd, J = 12.1, 3.3 Hz, 1 H, 4-H),
4.03 (d, J = 17.6 Hz, 1 H, 6-H), 3.93 (ddd, J = 11.6, 2.8 Hz, 1 H,
4-H), 3.51 (dd, J = 2.5 Hz, 1 H, 1-H), 3.46 (d, J = 17.6 Hz, 1 H,
6-H), 3.40 (d, J = 12.1 Hz, 1 H, 4-H), 3.12 (dd, J = 11.6, 2.5 Hz,
1 H, 4-H), 2.40 (s, 3 H, p-CH3C6H4SO2N), 1.29 (m, 3 H,
CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 205.2
(C=O), 169.0 (CO2Et), 143.9, 134.8, 134.7, 134.2 (4 C, quat. ar.),
129.8, 128.0, 127.9, 127.2, 127.2, 127.1 (8 C, tert. ar.), 62.1 (sec.),
58.1 (quat.), 55.9, 54.9, 51.3 (3 C, aliph.), 34.0 (C-6, sec.), 21.5 (p-
CH3C6H4SO2N), 14.1 (CO2CH2CH3) ppm. HRMS (ESI): calcd.
for C22H24NO5S [M + H]+ 414.1370, found 414.1366; calcd. for
C22H23NNaO5S [M + Na]+ 436.1174, found 436.1174.
spectroscopic data, 17b is a mixture of rotamers. IR (film): ν =
˜
3440, 2931, 1713, 1443, 1227, 748 cm–1. HRMS (ESI): calcd. for
C23H24NO5 [M + H]+ 394.1649, found 394.1651.
Ethyl 11-Oxo-1,3,4,6-tetrahydro-1,5-methano-3-benzazocine-5(2H)-
carboxylate Hydroiodide Hydrate (18): A solution of the Cbz-pro-
tected compound 17b (350 mg, 0.9 mmol) in CH3CN (35 mL) was
placed in a water bath at room temperature and treated with Me3-
SiI (1 mL, 7.3 mmol) in a dropwise fashion. The mixture was
stirred for 1 h, before the CH3CN was evaporated in vacuo [longer
reaction time (up to 24 h) causes complete decomposition of the
product]. The residue was treated with water (35 mL) and this solu-
tion was washed with CH2Cl2. The aqueous phase was then con-
centrated to dryness resulting in yellow crystals of pure product 18,
yield 290 mg (80%), m.p. 170–172 °C. 1H NMR (400 MHz, [D6]-
DMSO): δ = 9.19 (br. s, 1 H), 7.50–7.30 (m, 1 H), 7.30–7.17 (m, 4
H, ar.), 4.25–4.13 (m, 2 H, CO2CH2CH3), 3.64 (d, J = 17.7 Hz, 1
H, 6-H), 3.53–3.30 (m, 3 H), 3.15–3.08 (m, 3 H), 3.04 (d, J =
17.7 Hz, 1 H, 6-H), 1.25 (t, J = 7.1 Hz, 3 H, CO2CH2CH3) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 171.0, 134.7, 134.3 (2 C,
quat. ar.), 129.1, 127.9, 127.0, 126.3 (4 C, tert. ar.), 91.5 [C(OH)2],
61.4 (CO2CH2CH3), 48.5, 48.3, 47.0, 44.2, 35.6 (5 C, aliph.), 13.9
Ethyl
1-Benzyl-4-(2-bromobenzyl)-3-oxopiperidine-4-carboxylate
(23): A mixture of potassium tert-butoxide (7.5 g, 65.0 mmol) and
absolute tetrahydrofuran (150 mL) was stirred at room temperature
for 0.5 h. The resulting milky solution was cooled to 0 °C, and then
ethyl N-benzyl-3-oxo-4-piperidinecarboxylate hydrochloride[24] (22)
(10.0 g, 33.6 mmol) was added through a powder dropping funnel
whereby the temperature was kept below 5 °C. The mixture was
then warmed to room temperature and further stirred for 1 h, re-
sulting in a yellow solution. After cooling to 0 °C, a solution of 2-
bromobenzyl bromide (8.8 g, 35.2 mmol) in absolute THF
(40.0 mL) was added dropwise within 0.5 h. A maximum tempera-
ture of 2 °C was observed. The reaction mixture was warmed to
room temperature and stirred for 4 h. The reaction solution was
cooled to 0 °C, before saturated NH4Cl solution (100 mL) was
added. After separation of the layers, the aqueous phase was ex-
tracted with ethyl acetate (2ϫ100 mL). The combined organic lay-
ers were washed twice with saturated NaCl solution, dried with
Na2SO4, and filtered. The solvent was evaporated under reduced
pressure and the residue purified by flash chromatography (petro-
leum ether/ethyl acetate, 10:1; Rf = 0.2) to yield 7.4 g (50%) of the
product 23 as a slightly yellow oil. This compound should be used
immediately after isolation, or can be kept under an inert gas at
–20 °C for a longer time. 1H NMR (400 MHz, CDCl3): δ = 7.57
(d, J = 8.1 Hz, 1 H, ar.), 7.37–7.22 (m, 7 H, ar.), 7.15–7.08 (m, 1
(CO CH CH ) ppm. IR (KBr): ν = 3903, 3325, 2924, 2816, 1724,
˜
2
2
3
1458, 1238, 1053, 771 cm–1. HRMS (ESI): calcd. for C15H18NO3
[M]+ 260.1281, found 260.1286; methanol adduct (hemiacetal):
calcd. for C16H22NO4 [M + CH3OH]+ 292.1543, found 292.1543.
Ethyl N-(Anilinocarbonyl)-11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-
benzazocine-5(2H)-carboxylate (19): Et3N (25 µL, 0.18 mmol) was
added to a solution of the salt 18 (45 mg, 0.11 mmol) in acetonitrile
(15 mL) and the mixture was stirred for 1 h. Then, phenyl isocya-
nate (20 µL, 0.18 mmol) was added and stirring was continued at
room temperature for 24 h. The solvent was evaporated and the
residue treated with hot CCl4. Non-soluble material, which mainly
consists of triethylammonium salt, was removed by filtration and
the filtrate concentrated in vacuo. The urea derivative 19 was ob-
tained as a light yellow powder, yield 35 mg (84%), m.p. 199–
H, ar.), 4.25–4.15 (m,
2 H, CO2CH2CH3), 3.57 (s, 2 H,
1
203 °C. H NMR (400 MHz, CDCl3): δ = 7.30–7.22 (m, 2 H, ar.),
PhCH2NR2), 3.51 (d, J = 14.1 Hz, 1 H, 2-H), 3.31 (d, J = 14.1 Hz,
1 H, 2-H), 3.24 (d, J = 15.9 Hz, 1 H, ArCH2), 3.12 (d, J = 15.9 Hz,
1 H, ArCH2), 2.80–2.70 (m, 1 H, CH2CH2), 2.65–2.55 (m, 2 H,
CH2CH2), 1.87–1.77 (m, 1 H, CH2CH2), 1.22 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 203.9
(C=O), 169.8 (CO2Et), 137.1 (quat. ar.), 136.2 (quat. ar.), 132.9,
132.3, 128.8, 128.3, 128.2, 127.3, 127.0 (9 C, tert. ar.), 125.9 (quat.
ar.), 62.2 (C-4, quat.), 61.5, 61.4, 58.7, 48.7, 37.4, 30.0 (6 C, sec.),
13.9 (CO2CH2CH3) ppm.
7.17–7.08 (m, 4 H, ar.), 6.97–6.91 (m, 1 H, ar.), 6.75 (d, J = 7.8 Hz,
2 H, ar.), 5.47 (br. s, 1 H, NHPh), 4.88 (dd, J = 13.6, 3.0 Hz, 1 H,
4-H), 4.33–4.23 (m, 2 H, CO2CH2CH3), 4.03–3.93 (m, 2 H, 6-H
and 4-H), 3.69–3.62 (m, 3 H), 3.52 (d, J = 17.8 Hz, 1 H, 6-H),
1.30 (t, J = 7.1 Hz, 3 H, CO2CH2CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 204.6 (C=O), 169.2 (CO2Et), 155.1 [R2NC(=O)-
NHPh], 138.1, 135.1, 134.9 (3 C, quat. ar.), 128.7, 128.5, 128.1,
127.4, 127.3, 123.4, 120.5 (9 C, tert. ar.), 62.0, 59.8, 54.6, 53.5, 52.4
(5 C, aliph.), 39.0 (C-6, sec.), 14.0 (CO CH CH ) ppm. IR (KBr): ν
˜
2
2
3
Ethyl 2-Benzyl-11-oxo-1,3,4,6-tetrahydro-1,5-methano-2-benzazoc-
ine-5(2H)-carboxylate (24): An oven-dried Schlenk tube fitted with
a rubber septum was purged with nitrogen and charged with 23
(430 mg, 1 mmol) in 5 mL of anhydrous toluene, K3PO4 (425 mg,
= 3348, 2920, 1743, 1635, 1535, 1446, 1234, 1026, 752 cm–1. HRMS
(ESI): calcd. for C22H23N2O4 [M + H]+ 379.1652, found 379.1656;
calcd. for C22H22N2NaO4 [M + Na]+ 401.1472, found 401.1475.
Ethyl 11-Oxo-N-tosyl-1,3,4,6-tetrahydro-1,5-methano-3-benzazoc- 2 mmol), and Pd(dba)2 (34.5 mg, 6 mol%). Then the tube was
ine-5(2H)-carboxylate (20): Et3N (25 µL, 0.18) was added to a solu-
tion of the salt 18 (48 mg, 0.12 mmol) in acetonitrile (15 mL) and
the mixture stirred for 1 h. Then, tosyl chloride (35 mg, 0.18 mmol)
was added and stirring was continued at room temperature for ad-
ditional 24 h. Then, the solvent was evaporated and the residue
purified by flash chromatography (petroleum ether/ethyl acetate,
3:1; Rf = 0.1 and 0.3, both spots are the product, compound is in
purged with nitrogen, and tBu3P (3 mL of 0.04  in toluene,
12 mol%) was added. The mixture was vigorously stirred in an oil
bath at 110 °C for 48 h [if starting material is still present in the
reaction mixture, additional Pd(dba)2 (34.5 mg) and tBu3P (3 mL
of 0.04  in toluene) should be added and heating continued until
completion]. The reaction mixture was then cooled to room tem-
perature and filtered through Celite. Then, the solvent was evapo-
322
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 317–324

Benzomorphan Analogues by Intramolecular Buchwald–Hartwig Cyclization
FULL PAPER
1
rated and the residue purified by flash chromatography (petroleum
ether/ethyl acetate, 5:1; Rf = 0.5), providing the compound 24 as a
light yellow oil, yield 125 mg (35%). 1H NMR (400 MHz, CDCl3):
δ = 7.38–7.30 (m, 5 H, ar.), 7.28–7.21 (m, 3 H, ar.), 6.98 (d, J =
7.6 Hz, 1 H, ar.), 4.29 (dd, J = 14.4, 7.1 Hz, 2 H, CO2CH2CH3),
4.08 (s, 1 H, 1-H), 4.07 (d, J = 17.6 Hz, 1 H, 6-H), 3.69 (d, J =
0.73 g (35%) as a slightly yellow oil. H NMR (400 MHz, CDCl3):
δ = 7.10–7.05 (m, 2 H, ar.), 7.00–6.96 (m, 1 H, ar.), 4.19–4.06 (m,
2 H, CO2CH2CH3), 3.53 (d, J = 14.4 Hz, 1 H, ArCH2), 3.43 (dd,
J = 11.6, 2.8 Hz, 1 H, 2-H), 3.22 (d, J = 14.4 Hz, 1 H, ArCH2),
3.04–2.96 (m, 1 H, 5-H), 2.94–2.84 (m, 1 H, 5-H), 2.45–2.37 (m, 4
H, CH3Ar and 6-H), 2.32–2.25 (m, 4 H, NCH3 and 6-H), 2.2 (d,
13.4 Hz, 1 H, PhCH2NR2), 3.42 (d, J = 13.4 Hz, 1 H, PhCH2NR2), J = 11.6 Hz, 1 H, 2-H), 1.15 (t, J = 7.1 Hz, 3 H, CO2CH2CH3)
3.27 (d, J = 17.6 Hz, 1 H, 6-H), 2.87 (dddd, J = 13.2, 5.5, 1.8 Hz,
1 H, 3-H), 2.61 (ddd, J = 12.5, 5.5, 1.8 Hz, 1 H, 4-H), 2.49 (ddd,
J = 12.8, 3.1 Hz, 1 H, 4-H), 1.98 (ddd, J = 13.4, 3.0, 1.8 Hz, 1
ppm. 13C NMR (100 MHz, CDCl3): δ = 204.9 (C=O), 170.4
(CO2Et), 138.6, 136.5 (2 C, quat. ar.), 129.5, 129.3 (2 C, tert. ar.),
128.6 (quat. ar.), 126.4 (tert. ar.), 62.9 (sec.), 61.6 (C-3, quat.), 61.5,
H, 3-H), 1.33 (t, J = 7.1 Hz, 3 H, CO2CH2CH3) ppm. 13C NMR 55.8 (2 C, sec.), 45.6 (NCH3), 40.6, 36.7 (2 C, sec.), 24.6 (CH3Ar),
(100 MHz, CDCl3): δ = 205.0 (C=O), 171.2 (CO2Et), 137.8 (quat.
ar.), 136.4 (quat. ar.), 130.4 (tert. ar.), 129.9 (quat. ar.), 128.7, 128.6,
128.5, 127.3, 127.1, 126.2 (8 C, tert. ar.), 67.9 (C-1, tert.), 61.7
(CO2CH2CH3), 57.7 (PhCH2NR2), 57.1 (C-5, quat.), 42.8 (C-4,
sec.), 40.2 (C-6, sec.), 37.3 (C-2, sec.), 14.2 (CO2CH2CH3) ppm. IR
13.8 (CO2CH2CH3) ppm. HRMS (ESI): calcd. for C17H23BrNO3
[M + H]+ 368.0856, found 368.0857.
Ethyl N-Methyl-11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-benzazoc-
ine-5(2H)-carboxylate Hydrochloride (28a): An oven-dried Schlenk
tube fitted with a rubber septum was purged with argon and
charged with ethyl 3-(2-bromobenzyl)-N-methyl-4-oxopiperidine-3-
carboxylate (27a) (745 mg, 2.16 mmol) in 10 mL of anhydrous tolu-
ene, K3PO4 (1.3 g, 6.1 mmol), and Pd(dba)2 (50 mg, 4 mol-%).
Then the tube was purged with nitrogen, and tBu3P (4 mL of a
0.04  solution in toluene, 8 mol-%) was added. The mixture was
vigorously stirred in an oil bath at 120 °C for 72 h. The reaction
mixture was then cooled to room temperature, diluted with diethyl
ether (10 mL), and filtered through Celite. The filtrate was concen-
trated under reduced pressure. The crude material was then treated
with a concentrated ethanol solution of HCl (1 mL), and sub-
sequently the solvent was evaporated. The residue was dissolved in
water (5 mL), and the solution washed with diethyl ether (10 mL)
and CH2Cl2 (10 mL). The aqueous solution was concentrated, and
the residue dried in vacuo to give 206 mg (35%) of the salt 28a as
a yellow oily solid. 1H NMR (400 MHz, CDCl3); free base: δ =
7.25–7.12 (m, 3 H, ar.), 6.97 (d, J = 7.6 Hz, 1 H, ar.), 4.27 (dd, J
= 14.4, 7.1 Hz, CO2CH2CH3), 4.02 (d, J = 17.4 Hz, 1 H, 6-H), 3.52
(d, J = 17.45 Hz, 1 H, 6-H), 3.39 (dd, J = 2.5 Hz, 1 H, 1-H), 3.15
(dd, J = 11.2, 2.8 Hz, 1 H, 4-H), 3.02 (d, J = 11.2 Hz, 1 H, 4-H),
2.99 (ddd, J = 10.6, 2.5 Hz, 1 H, 2-H), 2.67 (dd, J = 10.6, 2.8 Hz,
1 H, 2-H), 2.25 (s, 3 H, NCH3), 1.31 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 207.5
(C=O), 170.3 (CO2Et), 137.3, 135.8 (2 C, quat. ar.), 127.5, 127.2,
126.6, 126.3 (4 C, tert. ar.), 66.6, 64.7, 61.6 (3 C, sec.), 58.6 (C-5,
quat.), 52.5 (sec.), 45.0 (NCH3), 41.0 (sec.), 14.1 (CO2CH2CH3)
(film): ν = 2974, 2831, 1732, 1450, 1227, 737 cm–1. HRMS (ESI):
˜
calcd. for C22H24NO3 [M + H]+ 350.1751, found 350.1749.
(ortho-Bromobenzyl)dimethylanilinium Bromide (25a): This com-
pound was prepared by a modified literature procedure.[25] N,N-
Dimethylaniline (12.2 g, 0.1 mol) and ortho-bromobenzyl bromide
(10a) (25.0 g, 0.1 mol) were mixed and diluted with benzene
(100 mL). The resulting solution was stirred at room temperature
for 48 h, and then concentrated to dryness. The solids were treated
with a 1:1 mixture of petroleum ether/diethyl ether and the slurry
was heated before it was filtered. The yield was quantitive. The salt
1
25a should be kept under nitrogen. H NMR (400 MHz, CDCl3):
δ = 7.86 (d, J = 7.7 Hz, 2 H), 7.54–7.40 (m, 5 H), 7.24–7.14 (m, 2
H), 5.52 (s, 2 H), 3.93 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 144.6, 135.4, 133.6, 132.4, 130.7, 130.4, 127.9, 127.7, 127.3,
121.5, 71.7, 53.7 ppm.
Ethyl 3-(2-Bromobenzyl)-N-methyl-4-oxopiperidine-3-carboxylate
(27a): To a suspension of NaH (235 mg, 5.85 mmol, 60% in min-
eral oil) was added ethyl 1-methyl-4-oxopiperidine-3-carboxylate[27]
(26) (1.07 g, 5.8 mmol) in toluene (20 mL). The mixture was then
kept at 80 °C for 1 h. Then, powdered (ortho-bromobenzyl)dimeth-
ylanilinium bromide (25a) (2.06 g, 5.55 mmol) was added in one
portion to the suspension of the sodium salt at room temperature.
This mixture was refluxed for 6 h. After cooling, the mixture was
poured carefully into water (30 mL). The organic layer was sepa-
rated, washed with saturated aqueous NaCl solution (2ϫ20 mL),
dried with Na2SO4, filtered, and concentrated to give an oily resi-
due. The crude product was purified by flash chromatography (pe-
troleum ether/ethyl acetate, 1:1; Rf = 0.25) to give 0.74 g (38%) of
27a as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.51 (d,
J = 7.9 Hz, 1 H, ar.), 7.20–7.17 (m, 2 H, ar.), 7.09–7.03 (m, 1 H,
ar.), 4.17–4.08 (m, 2 H, CO2CH2CH3), 3.47 (d, J = 14.4 Hz, 1 H,
o-BrC6H4CH2), 3.43 (dd, J = 11.6, 3.0 Hz, 1 H, 2-H), 3.17 (d, J =
14.4 Hz, 1 H, o-BrC6H4CH2), 3.04–2.97 (m, 1 H, 5-H), 2.94–2.84
(m, 1 H, 5-H), 2.42 (ddd, J = 14.4, 3.0, 2.0 Hz, 1 H, 6-H), 2.32–
2.25 (m, 4 H, NCH3 and 6-H), 2.20 (d, J = 11.6 Hz, 1 H, 2-H),
1.15 (t, J = 7.1 Hz, 3 H, CO2CH2CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 204.9 (C=O), 170.3 (CO2Et), 136.1 (quat. ar.), 132.9,
132.2, 128.4, 127.1 (4 C, tert. ar.), 125.9 (quat. ar.), 62.9 (C-3,
quat.), 61.6, 55.8 (2 C, sec.), 45.6 (NCH3), 40.5, 36.0 (2 C, sec.),
14.0 (CO2CH2CH3) ppm. HRMS (ESI): calcd. for C16H21BrNO3
[M + H]+ 354.0699, found 354.0701.
ppm. IR (film): ν = 3378 cm–1 (br), 2819, 2673, 1720, 14589, 1281,
˜
1084, 768 cm–1. HRMS (ESI): calcd. for C16H20NO3 [M + H]+
274.1438, found 274.1432; methanol adduct (hemiacetal): calcd. for
C17H24NO4 [M + CH3OH + H]+ 306.1700, found 306.1699.
Ethyl
N,10-Dimethyl-11-oxo-1,3,4,6-tetrahydro-1,5-methano-3-
benzazocine-5(2H)-carboxylate (28b): The cyclization was per-
formed as described for 28a using 147 mg (0.4 mmol) of 27b. The
cyclized product 28b was isolated by flash chromatography (petro-
leum ether/ethyl acetate, 20:1; Rf = 0.15), yield 41 mg (36%). 1H
NMR (400 MHz, CDCl3): δ = 7.13–7.09 (m, 1 H, ar.), 7.03–6.98
(m, 2 H, ar.), 4.30–4.23 (m, 2 H, CO2CH2CH3), 4.01 (d, J =
17.3 Hz, 1 H, 6-H), 3.60 (dd, J = 2.5 Hz, 1 H, 1-H), 3.49 (d, J =
17.3 Hz, 1 H. 6-H), 3.14 (dd, J = 11.2, 2.8 Hz, 1 H, 4-H), 3.02 (d,
J = 11.2 Hz, 1 H, 4-H), 2.99 (ddd, J = 10.6, 2.5 Hz, 1 H, 2-H),
2.63 (dd, J = 10.6, 2.8 Hz, 1 H, 2-H), 2.27 (s, 3 H, CH3), 2.23 (s, 3
H, CH3), 1.31 (t, J = 7.1 Hz, 3 H, CO2CH2CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 208.1 (C=O), 170.4 (CO2Et), 135.7, 135.3,
134.7, 128.0, 126.8, 124.6 (6 C, ar.), 66.3, 62.4, 61.5 (3 C, sec.), 58.5
(C-5, quat.), 48.7 (C-1, tert.), 45.1 (NCH3), 41.0 (sec.), 18.5
(CH3Ar), 14.1 (CO2CH2CH3) ppm.
Ethyl 3-(2-Bromo-3-methylbenzyl)-N-methyl-4-oxopiperidine-3-car-
boxylate (27b): The alkylation was performed as described for 27a.
For this reaction 1.07 g (5.8 mmol) of 26 and 2.22 g (5.7 mmol) of
the anilinium salt 25b were used. The product was isolated by flash
chromatography (petroleum ether/diethyl ether, 1:1; Rf = 0.2), yield
Supporting Information (See footnote on the first page of this arti-
1
cle): H- and 13C NMR spectra for important intermediates.
Eur. J. Org. Chem. 2007, 317–324
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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323

A. S. Khartulyari, M. E. Maier
FULL PAPER
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Received: August 7, 2006
Published Online: November 3, 2006
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Eur. J. Org. Chem. 2007, 317–324