Synthesis of 1,5-methano-3-benzazocines by intramolecular Buchwald-Hartwig arylation of 2-piperidinones

Article abstract of DOI:10.1016/j.tet.2007.10.088

A conceptually novel route to 1,5-methano-3-benzazocines based on an intramolecular Buchwald-Hartwig arylation was developed. The reaction required the use of the zinc enolate of the piperidinone substrates. These substrates, piperidin-2-ones with a 2-bro

Full text of DOI:10.1016/j.tet.2007.10.088

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Tetrahedron 64 (2008) 356e363
www.elsevier.com/locate/tet
Synthesis of 1,5-methano-3-benzazocines by intramolecular
BuchwaldeHartwig arylation of 2-piperidinones
*
Gedu Satyanarayana, Martin E. Maier
Institut fu¨r Organische Chemie, Universita¨t Tu¨bingen, Auf der Morgenstelle 18, 72076 Tu¨bingen, Germany
Received 9 September 2007; received in revised form 12 October 2007; accepted 25 October 2007
Abstract
A conceptually novel route to 1,5-methano-3-benzazocines based on an intramolecular BuchwaldeHartwig arylation was developed. The
reaction required the use of the zinc enolate of the piperidinone substrates. These substrates, piperidin-2-ones with a 2-bromobenzyl substituent
in the 5-position were prepared by reductive amination of 4-formyl esters. The latter could be obtained via Michael addition of enamines,
derived from 3-arylpropanals, to ethyl acrylate.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Cyclization; Pd catalysis; Arylation; Benzazocines; Scaffolds
HO
O
1. Introduction
N
8
O
H
1
10a
10
11
Many polycyclic alkaloids are useful drugs or serve as
interesting lead compounds. In this regard morphine (1) and
cytisine (2) are prominent examples (Fig. 1). Whereas the
analgetic morphine is an agonist for the m-receptor,1 cytisine
acts as a potent agonist at nicotinic acetylcholine recep-
tors.2e4 Disregarding the nitrogen atoms, these two natural
products have in common a 5,6,7,8,9,10-hexahydro-5,9-meth-
anobenzo[8]annulene substructure 3. Using this tricyclic ring
system a number of nitrogen-containing analogs were de-
signed and synthesized over the years. For example, a range
of benzomorphans [1,2,3,4,5,6-hexahydro-2,6-methano-3-
benzazocines (4)], such as pentazocine (6) were developed
as useful analgetics.5 Quite recently the isomeric 1,5-meth-
ano-3-benzazocines 5 served as a lead structure in the develop-
ment of varenicline (7) as a drug for smoking cessation.6,7 One
should also mention that 1,5-methano-3-benzazocines deriva-
tives have been used as constrained tyrosine analogs in the
search for SH2 (Src homology 2) ligands.8 Typically, tricyclic
structures such as 4 or 5 are produced by using classical
NMe
N
H
HO
4
morphine (1)
(–)-cytisine (2)
8
10a
6a
10
10a
1
6
5
6a
6
4a
5
11
4
2
9
1
11
N
2
H
N
H
7
3
4
5
HO
N
N
N
N
pentazocine (6)
varencline (7)
H
Figure 1. Structure of morphine (1) and cytisine (2), their common core 3, the
nitrogen-containing core structures 4 and 5, as well as derived pharmaceuticals.
key reactions like Grewe cyclization, Mannich reaction, or
Michael addition.5 Furthermore, lactam intermediates are fre-
quently used.9
* Corresponding author. Tel.: þ49 7071 2975247; fax: þ49 7071 295137.
E-mail address: martin.e.maier@uni-tuebingen.de (M.E. Maier).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.088

G. Satyanarayana, M.E. Maier / Tetrahedron 64 (2008) 356e363
357
Heck coupling with allylalcohol (Scheme 1, Table 1).19,22 The
resulting aldehydes 9aec were then converted to the enamines
10aec using pyrrolidine in CHCl3 together with molecular
sieves.23 Treatment of the crude enamines with ethyl acry-
late24 provided the 4-formyl esters 11aec. It was then planned
to perform a reductive amination with benzylamine followed
by lactam formation. If the reduction was performed with so-
dium cyanoborohydride,25 the desired piperidinones 12aec
were the only product. Under otherwise typical conditions,26,27
that is, stirring the aldehyde ester 11a with benzylamine, ace-
tic acid, and sodium triacetoxyborohydride a mixture of the
enamide 13 and the lactam 12a was formed. The yields for
the individual steps of the sequence shown in Scheme 1 are
given in Table 1. Compound 9b was prepared as described
in the literature from 3-bromo-4-iodotoluene.28,29 As a further
advanced starting material we targeted 3-(2-bromo-5-meth-
oxyphenyl)propanal (9c) (Scheme 1, Table 1). This aldehyde
is available from 3-methoxybenzaldehyde30 or from 3-iodo-
phenyl methyl ether.31 The latter route involves bromination
to give 4-bromo-3-iodophenyl methyl ether31 8c, which was
then subjected to the JefferyeHeck reaction22 with
allylalcohol.
R
R
O
Br
Pd(dba)2, tBu3P
O
(1)
(2)
CO2Et
CO2Et
R
K3PO4, toluene
110 °C, 12 h (65%)
N
Bn
N
Bn
1. LiN(SiMe3)2, ZnCl2
2. ArBr, Pd(dba)2, L
THF, 65 °C
N
O
N
Bn
O
Bn
PCy2
L
Me2N
Figure 2. Intramolecular BuchwaldeHartwig arylation of ketones yielding
3-benzazocines (Eq. 1) and intermolecular lactam arylation (Eq. 2).
In order to broaden the range of accessible polycyclic
amines, we initiated a program aimed at the use of metal cata-
lyzed transformations as key steps. For example, we recently
disclosed the synthesis of various 1,5-methano-3-benzazocines
based on a BuchwaldeHartwig cyclization.10 In this approach,
piperidinone derivates containing a 2-bromobenzyl group were
converted under palladium catalysis to tricyclic products
(Fig. 2, Eq. 1). As can be seen, a ketone was arylated during
this process, positioning the keto function in the methano
bridge. We reasoned that it might be possible to employ a lac-
tam for the intramolecular arylation to reach 3-benzazocines
as well. The literature contains a number of arylation reactions
for activated methylene and methine groups. Thus, intermole-
cular arylation reactions of ketones,11 esters,12 nitriles,13 and
amides14,15 have been described.16 Furthermore, examples of
intramolecular processes for the arylation of amides17 and
other compounds18,19 are known. In general, sterically hin-
dered, electron-rich phosphine or N-heterocyclic carbene
ligands are required. Moreover, the counterion for the enolate
can be crucial. Thus, zinc enolates seem to provide a broader
scope in the arylation of esters, imides, and piperidinones. In
this regard, the group of Cossy reported on the arylation of
N-protected 2-piperidinones using the corresponding zinc eno-
lates and the Buchwald ligand L (Fig. 2, Eq. 2).15 These ary-
lations were performed with 2 equiv of piperidinone. In this
paper we illustrate a concise route of the corresponding cycli-
zations substrates as well as the realization of the intramole-
cular BuchwaldeHartwig arylation.
R1
R2
CHO
I
R1
R2
Pd(OAc)2,
OH
Et3BnNCl, NaHCO3
DMF, 40 °C, 24 h
Br
Br
8a-c
9a-c
23 to 80 °C
N
R1
(a) EtO2C
H
, 4 Å MS
N
CHCl3, 5 to 23 °C
(b) AcOH/H2O
23 to 80 °C
R2
Br
10a-c
BnNH2, AcOH
Na(CN)BH3
R1
R1
R2
CHO
Bn
O
N
CO2Et
MeOH, 65 °C
12 h
R2
Br
11a-c
Br
12a-c
BnNH2, AcOH
Na(OAc)3BH
Bn
O
N
11a
+
12a (29%)
(CH2Cl)2, 12 h, 82 °C
Br
13 (35%)
Scheme 1. Synthesis of the cyclization substrates 12aec via reductive amina-
tion of the formyl esters 11aec.
In order to prepare the piperidinone 12d, which features
a 2-bromo-4,5-dimethoxybenzyl substituent at the 5-position
a late stage bromination was chosen (Scheme 2). Thus, vera-
trole was converted to 1,2-dimethoxy-4-iodobenzene (14) by
iodination in presence of HgO.32 A subsequent Jefferye
Heck reaction of 14 with allylalcohol led to the propanal33
2. Results
In order to produce 1,5-methano-3-benzazocines by intra-
molecular arylation of piperidinones, a 2-bromobenzyl group
would have to be installed in the 5-position of a 2-piperidi-
none. There are a few reports in the literature for such
structures.20,21 We sought a more flexible route and considered
5-(2-bromophenyl)-4-formyl-pentanoic acid esters as precur-
sors for the desired piperidinones. The synthesis started from
bromoiodobenzenes 8aec, which were subjected to a Jefferye
Table 1
Yields for the individual steps in the synthesis of the piperidinones 12aec
R1
R2
Coupling step
compound (%)
Michael addition
compound (%)
Reductive amination
compound (%)
H
H
9a (80)
9b (70)
9c (70)
11a (50)
11b (40)
11c (46)
12a (82)
12b (72)
12c (71)
H
OMe
Me
H

358
G. Satyanarayana, M.E. Maier / Tetrahedron 64 (2008) 356e363
15 in 72% yield along with the isomeric aldehyde 16 (16%).
After separation of the two isomers by chromatography,
enamine formation on aldehyde 15 was followed by Michael
addition of the intermediate enamine to ethyl acrylate. This
allowed the isolation of the 4-formyl ester 18 in reasonable
yield. Reaction with benzylamine under reductive conditions
provided the substituted piperidinone 19. Due to the elec-
tron-rich aromatic ring bromination to give 12d was rather
facile, taking place within 30 min at 0 ꢀC.
a stronger base [NaN(SiMe3)2], the same ligand t-Bu3P but
Pd(dba)2 as palladium source and with added ZnF2 in THF
as solvent there was also no cyclized product (entry 2). Not
even the debrominated 2-piperidinone 21 could be identified
by LCeMS. If, however, the additive was changed to ZnCl2
(4 equiv) the tricyclic lactam 20 was formed, even though
the yield was not too high (entry 3). Also higher temperatures
(entry 4) did not result in a better yield. Since the Cossy group
had successfully employed the biphenyl ligand L (Fig. 2, Eq.
2) in bimolecular lactam arylations, we tried this ligand as
well. While the product 20 was formed the yield was still in
the 30% range (entry 5). The highest yield could be realized
using lithium tetramethylpiperidide (LiTMP) as base, which
led to the product 20 in 40% isolated yield. Since the condi-
tions explained in Table 2 (entry 3) were simple and reliable
we used those for larger scale runs and for other substrates.
As can be seen from Table 3, the crucial palladium-medi-
ated cyclizations on substrates 12bed did take place with
comparable yields. For substrate 12d featuring a rather elec-
tron-rich aromatic ring (entry 4), the chemical yield (30%)
of the tricylic compound 20d was somewhat lower than that
in the other cases. The IR spectra of the tricyclic compounds
show a prominent band between 1640 and 1651 cmꢁ1 due to
the amide C]O stretching. These values are typical for
N,N-disubstituted amides. In the 1H NMR spectra each of
the three methylene groups of the polycyclic ring system ap-
pears as doublet of doublet (AB system). The 4-H pair is de-
shielded most, followed by the 6-H pair. The hydrogen atoms
of the methano bridge (H-11) resonate at higher field at around
2.1 and 1.9 ppm, respectively. The methine signals 1-H and
5-H appear at around 3.5 and 2.5 ppm, respectively. According
to Chem3D force field calculations (see Supplementary data),
the piperidinone ring adopts an envelope-like conformation to
allow for planarity around the amide bond.
MeO
MeO
I
Pd(OAc)2,
OH
Et3BnNCl, NaHCO3
DMF, 40 °C, 24 h
14
MeO
MeO
CHO
+
MeO
MeO
CHO
16 (16%)
15 (72%)
N
H
MeO
MeO
MeO
, 4 Å MS
N
15
CHCl3, 5 to 23 °C
17
BnNH2, AcOH
Na(CN)BH3
23 to 80 °C
CHO
(a) EtO2C
CO2Et
(b) AcOH/H2O
MeOH, 65 °C
12 h (71%)
MeO
Bn
23 to 80 °C (40%)
18
MeO
MeO
MeO
MeO
Bn
Br2, CH2Cl2
N
N
0 °C, 30 min
(100%)
O
Br
12d
O
19
Scheme 2. Synthesis of piperidinone 12d from iodobenzene 14.
With the substrates in hand we screened a range of condi-
tions using 12a for achieving the BuchwaldeHartwig cycliza-
tion (Table 2). Using the rather weak t-BuONa as base, t-Bu3P
as ligand, and Pd(OAc)2 as palladium source18 the only prod-
uct formed was the debrominated lactam 21 (entry 1) in 50%
yield. We then turned to the use of zinc enolates.15 With
3. Conclusion
In summary we could illustrate a novel strategy to 3-benz-
azocines. The key step in this strategy is the intramolecular
BuchwaldeHartwig arylation of piperidinones that carry a 2-
bromobenzyl substituent in the 5-position. It turned out that
this lactam arylation requires formation of the intermediate
zinc enolates. While the yields are moderate this concept
Table 2
Reaction of the piperidinone with base, palladium source, and a phosphine
ligand under various conditionsa
Bn
Bn
N
N
+
N
O
Br
O
Bn
12a
20a
21
O
Table 3
BuchwaldeHartwig arylation of piperidinones to give 3-benzazocines 20aed
Entry Base
Ligand Additive Solvent Temp Yield
[ꢀC]
Yield
20a (%) 21 (%)
6
7
6
R1
R1
R2
Bn
O
5
Pd(dba)2, NaN(SiMe3)2
N
5
4
1b
2
t-BuONa t-Bu3P
d
Toluene 110
d
d
36
35
33
40
50
d
d
d
d
d
11
ZnCl2, tBu3P, THF
65 °C, 12 h
R2
N
Br
12a-d
10a
3
1
NaHMDS t-Bu3P ZnF2
NaHMDS t-Bu3P ZnCl2
NaHMDS t-Bu3P ZnCl2
THF
THF
65
65
Bn
3
20a-d
O
4
Dioxane 100
5
NaHMDS
LiTMP
L ZnCl2
t-Bu3P ZnCl2
THF
THF
65
65
Entry
R1
R2
Substrate
Product
Yield (%)
6
1
2
3
4
H
H
12a
12b
12c
20a
20b
20c
20d
36
33
34
30
Palladium source¼Pd(dba)2 (7e10 mol %), except for entry 1.
H
Me
H
a
Typical amounts of reagents: NaHMDS (4 equiv), ZnCl2 (4 equiv), t-Bu3P
(15 mol %), Pd(dba)2 (10 mol %).
OMe
OMe
OMe
12d
b
Palladium source¼Pd(OAc)2.

G. Satyanarayana, M.E. Maier / Tetrahedron 64 (2008) 356e363
359
allows for the formation of pharmaceutically interesting tricy-
clic compounds that might be difficult to access by standard
methods. We also note that the 5-substituted piperidinones,
which are of interest itself are easily accessible from alde-
hydes by a sequence of Michael addition followed by reduc-
tive amination and lactam formation.
d [ppm]¼203.0 (CH, CH]O), 172.7 (C, OC]O), 137.8 (C,
C-10), 133.0 (CH), 131.3 (CH), 128.3 (CH), 127.5 (CH),
124.5 (C, C-20), 60.5 (CH2, OCH2CH3), 50.8 (CH, C-4),
35.2 (CH2, C-5), 31.4 (CH2, C-2), 23.6 (CH2, C-3), 14.1
(CH3, OCH2CH3).
4.3. Ethyl 5-(2-bromo-4-methylphenyl)-4-
formylpentanoate (11b)
4. Experimental
4.1. General
The reaction was performed with aldehyde29 9b (1.4 g,
4.9 mmol), pyrrolidine (0.8 mL, 9.8 mmol), and ethyl acrylate
(0.75 mL, 6.85 mmol) as described above. Purification of the
crude product by flash chromatography (ethyl actate/hexane,
1:8) furnished the aldehyde ester 11b (800 mg, 40% for two
steps) as colorless oil. 1H NMR (400 MHz, CDCl3):
d [ppm]¼9.67 (1H, s, CH]O), 7.36 (1H, s, 30-H), 7.08 (1H,
d, J¼7.9 Hz, 50-H), 7.02 (1H, d, J¼7.9 Hz, 60-H), 4.10 (2H,
q, J¼7.1 Hz, OCH2CH3), 3.15e3.00 (1H, m, 4-H), 2.88e
2.70 (2H, m, 5-H), 2.48e2.20 (2H, m, 2-H), 2.28 (3H, s,
ArCH3), 2.10e1.98 (1H, m) and 1.88e1.70 (1H, m) [3-H],
1.22 (3H, t, J¼7.1 Hz, OCH2CH3); 13C NMR (100 MHz,
CDCl3): d [ppm]¼203.2 (CH, CH]O), 172.8 (C, OC]O),
138.5 (C), 134.6 (C), 133.5 (CH, C-30), 131.1 (CH, C-50),
128.3 (CH, C-60), 124.2 (C, C-20), 60.5 (CH2, OCH2CH3),
51.0 (CH, C-4), 34.9 (CH2, C-5), 31.5 (CH2, C-2), 23.7
(CH2, C-3), 20.6 (CH3, ArCH3), 14.2 (CH3, OCH2CH3).
1H and 13C NMR: Bruker Avance 400, spectra were re-
corded at 295 K in CDCl3. Chemical shifts are calibrated to
the residual proton and carbon resonance of the solvent:
CDCl3 (dH 7.25, dC 77.0 ppm). HRMS (FT-ICR): Bruker Dal-
tonic APEX 2 with electron spray ionization (ESI). Analytical
LCeMS: HP 1100 Series connected with an ESI MS detector
Agilent G1946C, positive mode with fragmentor voltage of
40 eV, column: Nucleosil 100-5, C-18 HD, 5 mm, 70ꢂ3 mm
Machery-Nagel, eluent: NaCl solution (5 mM)/acetonitrile,
gradient: 0e10e15e17e20 min with 20e80e80e99e99%
acetonitrile, flow: 0.5 mL minꢁ1. Flash chromatography: J.T.
Baker silica gel 43e60 mm. Thin-layer chromatography
Machery-Nagel Polygram Sil G/UV254. Solvents were distilled
prior to use; petroleum ether with a boiling range of 40e60 ꢀC
was used. Reactions were generally run under a nitrogen
atmosphere.
4.4. Ethyl 5-[2-bromo-5-(methyloxy)phenyl]-4-
formylpentanoate (11c)
4.2. Ethyl 5-(2-bromophenyl)-4-formylpentanoate (11a)
To a cooled (0 ꢀC), stirred solution of the aldehyde 9a
(770 mg, 3.6 mmol) in CHCl3 (5 mL) were added molecular
˚
sieves (4 A, 4.2 g) followed by pyrrolidine (0.59 mL,
The reaction was performed with aldehyde31 9c (1.7 g,
7.0 mmol), pyrrolidine (1.16 mL, 14.1 mmol), and ethyl acry-
late (1.07 mL, 9.87 mmol) as described above. Purification of
the crude product by flash chromatography (ethyl acetate/hex-
ane, 1:6) furnished the aldehyde ester 11c (1.2 g, 46% for
two steps) as colorless oil. 1H NMR (400 MHz, CDCl3):
d [ppm]¼9.68 (1H, s, CH]O), 7.41 (1H, d, J¼8.9 Hz, 30-H),
6.77 (1H, d, J¼3.1 Hz, 60-H), 6.65 (1H, dd, J¼8.9 and 3.1 Hz,
40-H), 4.10 (2H, q, J¼7.1 Hz, OCH2CH3), 3.76 (3H, s, OCH3),
3.08 (1H, dd, J¼12.7, 6.9 Hz, 4-H), 2.90e2.65 (2H, m, 5-H),
2.50e2.25 (2H, m, 2-H), 2.20e1.90 (1H, m) and 1.90e1.73
(1H, m) [3-H], 1.22 (3H, t, J¼7.1 Hz, OCH2CH3); 13C NMR
(100 MHz, CDCl3): d [ppm]¼203.0 (CH, CH]O), 172.8 (C,
OC]O), 158.9 (C, C-50), 138.8 (C, C-10), 133.6 (CH, C-30),
117.1 (CH, C-60), 114.8 (C, C-20), 114.0 (CH, C-40), 60.5
(CH2, OCH2CH3), 55.4 (CH3, OCH3), 50.8 (CH, C-4), 35.4
(CH2, C-5), 31.5 (CH2, C-2), 23.7 (CH2, C-3), 14.2 (CH3,
OCH2CH3).
7.2 mmol). The reaction mixture was stirred for 4 h at room
temperature. Then the mixture was filtered, with washing of
the molecular sieves using diethyl ether (3ꢂ10 mL). The com-
bined filtrates were washed with aqueous NaHCO3 solution,
dried (Na2SO4), filtered, and concentrated in vacuo to provide
the crude enamine 10. To the crude enamine in CH3CN (8 mL)
at 5 ꢀC was added ethyl acrylate (0.59 mL, 5.4 mmol). The re-
sultant mixture was stirred for 2 h at room temperature, and
then refluxed for 2 h. After cooling the mixture to room tem-
perature, AcOH (1 mL) in H2O (4 mL) was added followed
by refluxing the mixture for 2 h. After cooling to ambient tem-
perature, the mixture was treated with 3 N HCl, and extracted
with ethyl acetate (3ꢂ10 mL). The combined organic extracts
were washed with saturated NaCl solution, dried (Na2SO4),
and filtered. Concentration of the filtrate and purification of
the residue by flash chromatography (ethyl acetate/hexane,
1:9) furnished the aldehyde ester 11a (566 mg, 50% for two
steps) as a colorless oil. 1H NMR (400 MHz, CDCl3):
d [ppm]¼9.67 (1H, s, CH]O), 7.52 (1H, d, J¼8.1 Hz, Are
H), 7.25e7.16 (2H, m, AreH), 7.10e7.03 (1H, m, AreH),
4.09 (2H, q, J¼7.1 Hz, OCH2CH3), 3.17e3.06 (1H, m, 4-H),
2.90e2.70 (2H, m, 5-H), 2.48e2.20 (2H, m, 2-H), 2.10e
1.90 (1H, m, 3-H), 1.90e1.70 (1H, m, 3-H), 1.21 (3H, t,
J¼7.1 Hz, OCH2CH3); 13C NMR (100 MHz, CDCl3):
4.5. 1-Benzyl-5-(2-bromobenzyl)-2-piperidinone (12a)
and 1-benzyl-5-(2-bromobenzyl)-3,4-dihydro-2(1H )-
pyridinone (13)
To a stirred solution of the aldehyde ester 11a (300 mg,
0.96 mmol) in CH2ClCH2Cl (5 mL) at room temperature,
were added sequentially benzylamine (0.2 mL, 1.9 mmol),
AcOH (0.1 mL), and Na(OAc)3BH (609 mg, 2.87 mmol),

360
G. Satyanarayana, M.E. Maier / Tetrahedron 64 (2008) 356e363
followed by refluxing the mixture for 12 h. After cooling to
ambient temperature, saturated NaHCO3 solution was added,
and the mixture extracted with ethyl acetate (3ꢂ5 mL). The
combined organic layers were washed with saturated NaCl so-
lution, dried with Na2SO4, and filtered. Evaporation of the fil-
trate and purification of the residue by flash chromatography
(ethyl acetate/hexane, 1:2) furnished the cyclic enamide 13
(120 mg, 35%) (first fraction) as brown viscous oil. Further
elution of the column with ethyl acetate/hexane (1:1) provided
the required cyclic amide 12a (100 mg, 29%) as light brown-
ish viscous oil.
4.7. 1-Benzyl-5-(2-bromo-4-methylbenzyl)-2-
piperidinone (12b)
As described for compound 12a, the formyl ester 11b
(1.0 g, 3.06 mmol) in MeOH (8 mL) was reacted with benzyl-
amine (0.67 mL, 6.1 mmol), AcOH (0.3 mL), and Na(CN)BH3
(192 mg, 3.06 mmol). Purification of the crude product by
flash chromatography (ethyl acetate/hexane, 1:1) furnished
the cyclic amide 12b (818 mg, 72%) as light brownish viscous
oil. IR (neat): nmax/cmꢁ1¼2922, 1643, 1492, 1453, 1259, 701;
1H NMR (400 MHz, CDCl3): d [ppm]¼7.25e7.05 (6H, m,
AreH), 6.83 (1H, d, J¼7.9 Hz, 50-H), 6.70 (1H, d,
J¼7.9 Hz, 60-H), 4.59 and 4.28 (2H, 2d, J¼14.8 Hz, NCH2Ph),
3.05 (1H, ddd, J¼12.0, 4.8, 1.3 Hz) and 2.84 (1H, dd, J¼12.0
and 9.7 Hz) [6-H], 2.57e2.34 (3H, m), 2.33e2.15 (1H, m),
2.13 (3H, s, ArCH3), 2.12e1.94 (1H, m), 1.71 (1H, br s),
1.50e1.30 (1H, m); 13C NMR (100 MHz, CDCl3):
d [ppm]¼169.5 (C, NC]O), 138.0 (C), 137.1 (C), 135.3
(C), 133.3 (CH), 130.6 (CH), 128.5 (2C, CH), 128.1 (3C,
CH), 127.2 (CH), 124.3 (C, C-20), 52.0 (CH2, NCH2Ph),
50.7 (CH2, C-6), 38.7 (CH2, CH2Ar), 34.1 (CH, C-5), 31.2
(CH2, C-3), 26.6 (CH2, C-4), 20.5 (CH3, ArCH3); HRMS
(ESI): calcd for C20H23NBrO [MþH]þ 372.0957, found
372.0957.
4.5.1. Data for enamide 12
IR (neat): nmax/cmꢁ1¼2925, 1668, 1407, 1211, 752; 1H
NMR (400 MHz, CDCl3): d [ppm]¼7.44 (1H, d, J¼8.1 Hz,
AreH), 7.30e7.09 (6H, m, AreH), 7.06 (1H, d, J¼8.1 Hz,
AreH), 7.05e6.95 (1H, m, AreH), 5.72 (1H, s, CH]C),
4.57 (2H, s, NCH2Ph), 3.35 (2H, s, CH2Ar), 2.48 (2H, t,
J¼8.4 Hz, 4-H), 2.16 (2H, t, J¼8.4 Hz, 3-H); 13C NMR
(100 MHz, CDCl3): d [ppm]¼168.6 (C, NC]O), 138.0 (C),
137.1 (C), 132.9 (CH), 130.5 (CH), 128.5 (2C, CH), 128.0
(CH), 127.5 (2C, CH), 127.3 (2C, CH), 126.3 (CH), 124.9
(C, C-20), 117.4 (C), 48.9 (CH2, NCH2Ph), 39.8 (CH2,
CH2Ar), 31.1 (CH2, C-3), 24.0 (CH2, C-4); HRMS (ESI):
calcd for C19H19NBrO [MþH]þ 356.0644, found 356.0644.
4.8. 1-Benzyl-5-(2-bromo-5-methoxybenzyl)-2-
piperidinone (12c)
4.6. 1-Benzyl-5-(2-bromobenzyl)-2-piperidinone (12a) by
reductive amination with Na(CN)BH3
As described for compound 12a, the formyl ester 11c
(1.0 g, 3.06 mmol) in MeOH (8 mL) was reacted with benzyl-
amine (0.48 mL, 4.4 mmol), AcOH (0.3 mL), and Na(CN)BH3
(180 mg, 2.9 mmol). Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:1) as eluent fur-
nished the cyclic amide 12c (800 mg, 71%) as light brownish
viscous oil. IR (neat): nmax/cmꢁ1¼2932, 1643, 1493, 1474,
To a stirred solution of the aldehyde ester 11a (350 mg,
1.12 mmol) in MeOH (3 mL) were added sequentially
benzylamine (0.24 mL, 2.23 mmol), AcOH (0.1 mL), and
Na(CN)BH3 (140 mg, 2.2 mmol) at room temperature. Then
the mixture was refluxed for 12 h. After cooling to room tem-
perature, saturated NaHCO3 solution was added, and the mix-
ture extracted with ethyl acetate (3ꢂ5 mL). The combined
organic layers were washed with saturated NaCl solution,
dried with Na2SO4, and filtered. Concentration of the filtrate
and purification of the residue by flash column chromatogra-
phy (ethyl acetate/hexane, 1:1) furnished the cyclic amide
12a (330 mg, 82%) as a light brownish viscous oil. IR
(neat): nmax/cmꢁ1¼2925, 1641, 1492, 1261, 1022, 754, 701;
1H NMR (400 MHz, CDCl3): d [ppm]¼7.44 (1H, dd, J¼8.1
and 1.0 Hz, AreH), 7.34e7.12 (5H, m, AreH), 7.12e7.05
(1H, m, AreH), 7.02e6.93 (1H, m, AreH), 6.88 (1H, dd,
J¼7.6, 1.5 Hz, AreH), 4.65 and 4.34 (2H, 2d, J¼14.5 Hz,
NCH2Ph), 3.12 (1H, ddd, J¼12.0, 4.8, 1.3 Hz) and 2.91 (1H,
dd, J¼12.0, 9.6 Hz) [6-H], 2.70e2.40 (3H, m), 2.38e2.23
(1H, m), 2.20e2.03 (1H, m), 1.85e1.70 (1H, m) and 1.57e
1.40 (1H, m) [4-H]; 13C NMR (100 MHz, CDCl3):
d [ppm]¼169.5 (C, NC]O), 138.5 (C), 137.0 (C), 133.0
(CH), 131.0 (CH), 128.5 (2C, CH), 128.1 (3C, CH), 127.3
(2C, CH), 124.6 (C, C-20), 52.0 (CH2, NCH2Ph), 50.2 (CH2,
C-6), 39.2 (CH2, CH2Ar), 34.0 (CH, C-5), 31.2 (CH2, C-3),
26.7 (CH2, C-4); HRMS (ESI): calcd for C19H21NBrO
[MþH]þ 358.0801, found 358.0800.
1
1242, 701; H NMR (400 MHz, CDCl3): d [ppm]¼7.23 (1H,
d, J¼8.7 Hz, 30-H), 7.20e7.00 (5H, m, AreH), 6.52e6.33
(2H, m, AreH), 4.51 and 4.30 (2H, 2d, J¼14.5 Hz, NCH2Ph),
3.55 (3H, s, OCH3), 3.01 (1H, dd, J¼12.0, 4.8 Hz), 2.81 (1H,
dd, J¼12.0, 9.6 Hz) [6-H], 2.50 (1H, dd, J¼13.5, 6.4 Hz),
2.46e2.30 (2H, m), 2.30e2.13 (1H, m), 2.02 (1H, br s),
1.69 (1H, br s), 1.48e1.30 (1H, m); 13C NMR (100 MHz,
CDCl3): d [ppm]¼169.5 (C, NC]O), 158.7 (C), 139.4 (C),
137.0 (C), 133.4 (CH, C-30), 128.5 (2C, CH), 127.9 (2C,
CH), 127.2 (CH), 116.7 (CH, C-60), 114.9 (C, C-20), 113.4
(CH, C-40), 55.3 (CH3, OCH3), 52.2 (CH2, NCH2Ph), 50.2
(CH2, C-6), 39.4 (CH2, CH2Ar), 34.1 (CH, C-5), 31.3 (CH2,
C-3), 26.6 (CH2, C-4); HRMS (ESI): calcd for C20H23NBrO
[MþH]þ 388.0907, found 388.0909.
4.9. 1-Benzyl-5-(2-bromo-4,5-dimethoxybenzyl)-2-
piperidinone (12d)
To a cooled (0 ꢀC), stirred solution of the lactam 19 (1.1 g,
3.2 mmol) in CH2Cl2 (30 mL) was slowly added molecular
bromine (0.17 ml, 3.4 mmol) followed by stirring the mixture
at the same temperature for 30 min. Then, the reaction mixture

G. Satyanarayana, M.E. Maier / Tetrahedron 64 (2008) 356e363
361
was washed with aqueous NaHCO3 solution. The organic
4.11. Ethyl 5-[2-bromo-4,5-bis(methyloxy)phenyl]-4-
formylpentanoate (18)
layer was dried with Na2SO4, filtered, and concentrated in va-
cuo. Purification of the residue by flash chromatography (ethyl
acetate/hexane, 7:3) furnished the aryl bromide 12d (1.36 g,
100%) as brown viscous oil. IR (neat): nmax/cmꢁ1¼2930,
The reaction was performed with aldehyde 15 (1.9 g,
9.8 mmol), pyrrolidine (1.2 mL, 14.7 mmol), and ethyl acry-
late (1.49 mL, 13.7 mmol) as described above. Purification
of the crude product by flash column chromatography (ethyl
actate/hexane, 1:3) furnished the aldehyde ester 18 (1.13 g,
40% for two steps) as colorless oil. 1H NMR (400 MHz,
CDCl3): d [ppm]¼9.65 (1H, s, CH]O), 6.77 (1H, d,
J¼8.1 Hz, 50-H), 6.69 (1H, d, J¼2.0 Hz, 20-H), 6.66 (1H, dd,
J¼8.1, 2.0 Hz, 60-H), 4.09 (2H, q, J¼7.1 Hz, OCH2CH3),
3.84 (3H, s) and 3.83 (3H, s) [2OCH3], 3.00e2.87 (1H, m,
4-H), 2.75e2.60 (2H, m, 5-H), 2.45e2.20 (2H, m, 2-H),
2.03e1.88 (1H, m) and 1.85e1.70 (1H, m) [3-H], 1.21 (3H,
t, J¼7.1 Hz, OCH2CH3); 13C NMR (100 MHz, CDCl3):
d [ppm]¼203.8 (CH, CH]O), 172.8 (C, OC]O), 149.0 (C,
C-30), 147.7 (C, C-40), 130.6 (C, C-10), 120.9 (CH), 112.0
(CH), 111.3 (CH), 60.5 (CH2, OCH2CH3), 55.8 (2C,
2OCH3), 52.6 (CH, C-4), 34.8 (CH2, C-5), 31.5 (CH2, C-2),
23.5 (CH2, C-3), 14.1 (CH3, OCH2CH3).
1
1640, 1507, 1440, 1257, 1217, 1164, 1029, 703; H NMR
(400 MHz, CDCl3): d [ppm]¼7.45e7.18 (5H, m, AreH),
7.00 (1H, s, 30-H), 6.55 (1H, s, 60-H), 4.67 and 4.50 (2H, 2d,
J¼14.8 Hz, NCH2Ph), 3.85 (3H, s) and 3.79 (3H, s)
[2OCH3], 3.20 (1H, ddd, J¼12.0, 4.8, 1.3 Hz) and 2.99 (1H,
dd, J¼12.0, 9.6 Hz) [6-H], 2.78e2.50 (3H, m), 2.48e2.28
(1H, m), 2.28e2.09 (1H, m), 1.96e1.80 (1H, m), 1.67e1.44
(1H, m); 13C NMR (100 MHz, CDCl3): d [ppm]¼169.7 (C,
NC]O), 148.3 (C, C-40), 148.2 (C, C-50), 137.1 (C), 130.5
(C), 128.6 (2C, CH), 128.1 (2C, CH), 127.3 (CH), 115.6 (CH,
C-30), 114.4 (C, C-20), 113.4 (CH, C-60), 56.1 (2C, 2OCH3),
52.3 (CH2, NCH2Ph), 50.3 (CH2, C-6), 39.0 (CH2, CH2Ar), 34.6
(CH, C-5), 31.4 (CH2, C-3), 26.8 (CH2, C-4); HRMS (ESI):
calcd for C21H25NBrO3 [MþH]þ 418.1012, found 418.1014.
4.10. 3-(3,4-Dimethoxyphenyl)-propan-1-al (15) and
2-(3,4-dimethoxyphenyl)-propan-1-al (16)
4.12. 1-Benzyl-5-(3,4-dimethoxybenzyl)-2-piperidinone
(19)
To a stirred solution of Pd(OAc)2 (127.5 mg, 0.57 mmol),
allylalcohol (2.58 mL, 37.9 mmol), triethylbenzylammonium
chloride (3.88 g, 17.0 mmol), and NaHCO3 (3.18 g,
37.9 mmol) in DMF (40 mL) was added iodoveratrol 14
(5.0 g, 18.9 mmol) and the resulting blackish brown solution
was heated at 40 ꢀC for 24 h. The reaction was quenched
with aqueous NH4Cl and the mixture extracted with ethyl
acetate (3ꢂ15 mL). The combined organic layers were washed
with saturated NaCl solution, dried (Na2SO4), and filtered.
Evaporation of the solvent and purification of the crude mate-
rial by flash chromatography (ethyl acetate/hexane, 1:4) fur-
nished the 2-methylacetaldehyde 16 (600 mg, 16%) as the
first fraction (colorless oil). Further elution of the column
with ethyl acetate/hexane, 1:3, provided the required alde-
hyde33 15 (2.6 g, 72%) as colorless oil.
As described for compound 12a, the formyl ester 18
(1.08 g, 3.7 mmol) in MeOH (8 mL) was reacted with benzyl-
amine (0.8 mL, 7.3 mmol), AcOH (0.3 mL), and Na(CN)BH3
(231 mg, 3.7 mmol). Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 7:3) furnished the cy-
clic amide 19 (880 mg, 71%) as light brownish viscous oil. IR
(neat): nmax/cmꢁ1¼2925, 1638, 1515, 1461, 1258, 700; H
1
NMR (400 MHz, CDCl3): d [ppm]¼7.60e7.34 (5H, m, Are
H), 6.94 (1H, d, J¼8.6 Hz, 60-H), 6.77 (1H, s, 20-H), 6.76
(1H, d, J¼8.6 Hz, 50-H), 4.79 and 4.69 (2H, 2d, J¼14.5 Hz,
NCH2Ph), 4.03 (3H, s) and 4.01 (3H, s) [2OCH3], 3.35 (1H,
ddd, J¼12.0, 4.8, 1.3 Hz) and 3.11 (1H, dd, J¼12.0, 9.7 Hz)
[6-H], 2.83e2.50 (4H, m), 2.32e2.15 (1H, m), 2.12e2.00
(1H, m), 1.77e1.58 (1H, m); 13C NMR (100 MHz, CDCl3):
d [ppm]¼169.8 (C, NC]O), 148.9 (C, C-30), 147.5 (C, C-
40), 137.1 (C), 131.6 (C), 128.6 (2C, CH), 128.1 (2C, CH),
127.3 (CH), 120.8 (CH, C-60), 112.0 (CH, C-50), 111.2 (CH,
C-20), 55.9, 55.8 (2C, 2OCH3), 52.3 (CH2, NCH2Ph), 50.3
(CH2, C-6), 39.1 (CH2, CH2Ar), 35.8 (CH, C-5), 31.3 (CH2,
C-3), 26.9 (CH2, C-4); HRMS (ESI): calcd for C21H26NO3
[MþH]þ 340.1907, found 340.1907.
4.10.1. Data for 15
1H NMR (400 MHz, CDCl3): d [ppm]¼9.80 (1H, s,
CH]O), 6.78 (1H, d, J¼8.4 Hz, 50-H), 6.74e6.67 (2H, m,
AreH), 3.85 (3H, s) and 3.84 (3H, s) [2OMe], 2.90 (2H, t, 3-H)
and 2.75 (2H, t, 2-H) [2ꢂJ¼7.4 Hz]; 13C NMR (100 MHz,
CDCl3): d [ppm]¼201.6 (CH, CH]O), 148.9 (C), 147.5 (C),
132.9 (C, C-10), 120.0 (CH, C-60), 111.6 (CH), 111.3 (CH),
55.9, 55.8 (2OMe), 45.5 (CH2, C-2), 27.7 (CH2, C-3).
4.13. 3-Benzyl-3,4,5,6-tetrahydro-1,5-methano-3-
benzazocin-2(1H )-one (20a)
4.10.2. Data for 16
1H NMR (400 MHz, CDCl3): d [ppm]¼9.64 (1H, s,
CH]O), 6.86 (1H, d, J¼8.1 Hz, 50-H), 6.75 (1H, dd, J¼8.1,
2.0 Hz, 60-H), 6.67 (1H, d, J¼2.0 Hz, 20-H), 3.86 (6H, s,
2OMe), 3.56 (1H, q, J¼7.1 Hz, 2-H), 1.41 (3H, d, J¼7.1 Hz,
sec-CH3); 13C NMR (100 MHz, CDCl3): d [ppm]¼201.0
(CH, CH]O), 149.4 (C), 148.5 (C), 130.0 (C, C-10), 120.4
(CH), 111.6 (CH), 111.3 (CH), 55.9 (2C, OCH3), 52.5 (CH,
C-2), 14.6 (CH3).
In an oven dried Schlenk tube fitted with a rubber septum,
a solution of the amide 12a (160 mg, 0.45 mmol) in anhydrous
THF (5 mL) was treated with NaHMDS solution (0.89 mL,
2 M in THF, 1.78 mmol) at 0 ꢀC followed by stirring the mix-
ture for 10 min at 0 ꢀC. To the resulting solution of the amide
enolate were added sequentially anhydrous ZnCl2 (243 mg,
1.78 mmol), t-Bu3P (0.56 mL, 0.12 M in toluene, 15 mol %),

362
G. Satyanarayana, M.E. Maier / Tetrahedron 64 (2008) 356e363
and Pd(dba)2 (25.7 mg, 10 mol %) at 0 ꢀC. The reaction mix-
ture was heated in an oil bath at 65 ꢀC for 12 h before it was
cooled to room temperature and washed with aqueous NH4Cl
solution. After separation of the layers, the aqueous layer was
extracted with ethyl acetate (3ꢂ3 mL). The combined organic
layers were washed with saturated NaCl solution, dried
(Na2SO4), and filtered. Evaporation of the filtrate and purifica-
tion of the crude material by flash chromatography (ethyl ac-
etate/hexane, 2:3) furnished the benzazocine 20a (45 mg,
36%) as brown viscous oil. IR (neat): nmax/cmꢁ1¼2925,
(18.7 mg, 7 mol %) were added as described for compound
20a. Purification of the crude product by flash chromatography
(ethyl acetate/hexane, 2:3) furnished the benzazocine 20c
(47 mg, 34%) as brown viscous oil. IR (neat): nmax/cmꢁ1
¼
2930, 1640, 1492, 1453, 1258, 701;1H NMR(400 MHz, CDCl3):
d [ppm]¼7.35e7.08 (4H, m, AreH), 6.95e6.85 (2H, m, Are
H), 6.67 (1H, dd, J¼8.4, 2.5 Hz, 9-H), 6.56 (1H, d, J¼2.5 Hz,
7-H), 4.42 and 4.37 (2H, 2d, J¼15.0 Hz, NCH2Ph), 3.72 (3H,
s, OCH3), 3.57 (1H, s, 1-H), 3.47 (1H, dd, J¼12.7, 6.4 Hz)
and 2.98 (1H, d, J¼12.7 Hz) [4-H], 3.12 (1H, dd, J¼17.6,
6.3 Hz) and 2.61 (1H, d, J¼17.6 Hz) [6-H], 2.48 (1H, br s, 5-
H), 2.16 (1H, d) and 1.97 (1H, d) [J¼12.2 Hz, 11-H]; 13C
NMR (100 MHz, CDCl3): d [ppm]¼171.5 (C, NC]O), 158.7
(C, C-8), 137.2 (C), 135.6 (C), 129.8 (CH), 128.6 (C), 128.5
(2C, CH), 127.6 (2C, CH), 127.1 (CH), 113.8 (CH, C-7),
112.0 (CH, C-9), 55.3 (CH3, OCH3), 53.9 (CH2, NCH2Ph),
49.4 (CH2, C-4), 42.5 (CH, C-1), 36.1 (CH2, C-6), 26.9 (CH2,
C-11), 25.7 (CH, C-5); HRMS (ESI): calcd for C20H22NO2
[MþH]þ 308.1645, found 308.1645.
1
1648, 1489, 1452, 1258, 700; H NMR (400 MHz, CDCl3):
d [ppm]¼7.40e6.80 (9H, m, AreH), 4.43 and 4.36 (2H, 2d,
J¼14.8 Hz, NCH2Ph), 3.63 (1H, s, 1-H), 3.49 (1H, dd,
J¼12.5, 6.4 Hz) and 2.99 (1H, d, J¼12.5 Hz) [4-H], 3.15 (1H,
dd, J¼17.6, 6.6 Hz) and 2.64 (1H, d, J¼17.6 Hz) [6-H], 2.50
(1H, s, 5-H), 2.18 (1H, d) and 2.00 (1H, d) [J¼12.5 Hz, 11-H];
13C NMR (100 MHz, CDCl3): d [ppm]¼171.2 (C, NC]O),
137.1 (C), 136.1 (C), 134.4 (C), 128.9 (CH), 128.7 (CH), 128.4
(2C, CH), 127.6 (2C, CH), 127.1 (2C,CH), 126.2 (CH), 54.0
(CH2, NCH2Ph), 49.4 (CH2, C-4), 43.4 (CH, C-1), 35.8
(CH2, C-6), 26.7 (CH2, C-11), 25.8 (CH, C-5); HRMS (ESI):
calcd for C19H20NO [MþH]þ 278.1539, found 278.1539.
4.16. 3-Benzyl-8,9-dimethoxy-3,4,5,6-tetrahydro-1,5-
methano-3-benzazocin-2(1H )-one (20d)
4.14. 3-Benzyl-9-methyl-3,4,5,6-tetrahydro-1,5-methano-
3-benzazocin-2(1H )-one (20b)
The reaction was performed with the enolate of the amide
12d (200 mg, 0.48 mmol) [prepared from NaHMDS (2 M in
THF, 0.96 mL, 1.9 mmol)] in anhydrous THF (5 mL). Then,
sequentially anhydrous ZnCl2 (261 mg, 1.9 mmol), t-Bu3P
(0.6 mL, 0.12 M in toluene, 15 mol %), and Pd(dba)2
(27.7 mg, 10 mol %) were added as described for compound
20a. Purification of the crude product by flash chromatography
(ethyl acetate/hexane, 6:4) furnished the benzazocine 20d
The reaction was performed with the enolate of the amide
12b (180 mg, 0.48 mmol) [prepared from NaHMDS (0.96 mL
of 2 M in THF, 1.9 mmol)] in anhydrous THF (5 mL). Then,
sequentially anhydrous ZnCl2 (263 mg, 1.9 mmol), t-Bu3P
(0.6 mL of 0.12 M in toluene, 15 mol %), and Pd(dba)2
(27.8 mg, 10 mol %) were added as described for compound
20a. Purification of the crude product by flash chromatography
(ethyl acetate/hexane, 2:3) furnished the benzazocine 20b
(48 mg, 30%) as brown viscous oil. IR (neat): nmax/cmꢁ1
¼
2930, 1641, 1494, 1452, 1259, 699; 1H NMR (400 MHz,
CDCl3): d [ppm]¼7.25e7.05 (3H, m, AreH), 6.93e6.82
(2H, m, AreH), 6.80 (1H, s, 10-H), 6.46 (1H, s, 7-H), 4.38
and 4.34 (2H, 2d, J¼14.8 Hz, NCH2Ph), 3.78 (3H, s) and
3.74 (3H, s) [2OCH3], 3.48 (1H, s, 1-H), 3.43 (1H, dd,
J¼12.5, 6.6 Hz) and 2.93 (1H, d, J¼12.5 Hz) [4-H],
3.02 (1H, dd, J¼17.6, 6.6 Hz) and 2.50 (1H, d, J¼17.6 Hz)
[6-H], 2.44 (1H, s, 5-H), 2.12 and 1.92 (2H, 2d, J¼12.7 Hz,
11-H); 13C NMR (100 MHz, CDCl3): d [ppm]¼171.5 (C,
NC]O), 148.2 (C), 147.3 (C), 137.2 (C), 128.5 (2C, CH),
128.2 (C), 127.6 (2C, CH), 127.1 (CH), 126.2 (C), 111.4
(2C, CH, C-7, C-10), 55.9 (2C, 2OCH3), 53.9 (CH2, NCH2Ph),
49.4 (CH2, C-4), 42.9 (CH, C-1), 35.7 (CH2, C-6), 26.9 (CH2,
C-11), 25.8 (CH, C-5); HRMS (ESI): calcd for C21H24NO3
[MþH]þ 338.1751, found 338.1750.
(46 mg, 33%) as brown viscous oil. IR (neat): nmax/cmꢁ1
¼
2924, 1650, 1494, 1453, 1259, 706; 1H NMR (400 MHz,
CDCl3): d [ppm]¼7.50e6.60 (8H, m, AreH), 4.42 and 4.38
(2H, 2d, J¼14.8 Hz, NCH2Ph), 3.58 (1H, s, 1-H), 3.48 (1H,
dd, J¼12.5, 6.6 Hz) and 2.98 (1H, d, J¼12.5 Hz) [4-H], 3.10
(1H, dd, J¼17.6, 7.1 Hz) and 2.60 (1H, d, J¼17.6 Hz) [6-
H], 2.48 (1H, br s, 5-H), 2.25 (3H, s, ArCH3), 2.15 and 1.97
(2H, 2d, J¼12.0 Hz, 11-H); 13C NMR (100 MHz, CDCl3):
d [ppm]¼171.3 (C, NC]O), 137.2 (C), 135.9 (C), 135.7
(C), 131.2 (C), 129.3 (CH), 128.6 (CH), 128.5 (2C, CH), 128.0
(CH), 127.6 (2C, CH), 127.1 (CH), 54.0 (CH2, NCH2Ph), 49.4
(CH2, C-4), 43.4 (CH, C-1), 35.5 (CH2, C-6), 26.8 (CH2, C-
11), 25.9 (CH, C-5), 20.9 (CH3, ArCH3); HRMS (ESI): calcd
for C20H22NO [MþH]þ 292.1696, found 292.1696.
4.17. 1,5-Dibenzyl-2-piperidinone (21)
4.15. 3-Benzyl-8-methoxy-3,4,5,6-tetrahydro-1,5-
methano-3-benzazocin-2(1H )-one (20c)
An oven dried Schlenk tube fitted with a rubber septum was
purged with nitrogen and charged with the cyclic amide 12a
(100 mg, 0.28 mmol), anhydrous toluene (5 mL), t-BuONa
(134 mg, 1.4 mmol), and t-Bu3P (0.35 mL, 0.12 M in toluene,
15 mol %). Then the tube was purged with nitrogen, and
Pd(OAc)2 (6.4 mg, 10 mol %) was added. The reaction mix-
ture was heated in an oil bath at 110 ꢀC for 12 h. The reaction
The reaction was performed with the enolate of the amide
12c (180 mg, 0.46 mmol) [prepared from NaHMDS (0.69 mL
of 2 M in THF, 1.39 mmol)] in anhydrous THF (5 mL). Then,
sequentially anhydrous ZnCl2 (190 mg, 1.39 mmol), t-Bu3P
(0.38 mL, 0.12 M in toluene, 10 mol %), and Pd(dba)2

G. Satyanarayana, M.E. Maier / Tetrahedron 64 (2008) 356e363
363
9. See for example: Mitsuhashi, K.; Shiotani, S.; Oh-uchi, R.; Shiraki, K.
Chem. Pharm. Bull. 1969, 17, 434e453.
mixture was then cooled to room temperature and filtered
through Celite. The filter cake was washed with ethyl acetate.
Concentration of the filtrate under reduced pressure and puri-
fication of the crude material by flash chromatography (ethyl
acetate/hexane, 1:1) furnished the debrominated cyclic amide
10. Khartulyari, A. S.; Maier, M. E. Eur. J. Org. Chem. 2007, 317e324.
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10186e10189.
21 (39 mg, 50%) as light yellow viscous oil. IR (neat): nmax
/
cmꢁ1¼2924, 1642, 1494, 1454, 1260, 701; 1H NMR
(400 MHz, CDCl3): d [ppm]¼7.35e7.05 (8H, m, AreH),
6.97 (2H, d, J¼6.9 Hz, AreH), 4.56 and 4.42 (2H, 2d,
J¼14.8 Hz, NCH2Ph), 3.11 (1H, ddd, J¼12.2, 5.1, 1.5 Hz)
and 2.87 (1H, dd, J¼12.2, 9.9 Hz) [6-H], 2.58e2.38 (3H,
m), 2.38e2.23 (1H, m), 2.10e1.90 (1H, m), 1.88e1.70 (1H,
m) and 1.52e1.33 (1H, m) [4-H]; 13C NMR (100 MHz,
CDCl3): d [ppm]¼169.7 (C, NC]O), 139.1 (C), 137.1 (C),
128.8 (2C, CH), 128.5 (2C, CH), 128.4 (2C, CH), 128.1
(2C, CH), 127.3 (CH), 126.3 (CH), 52.3 (CH2, NCH2Ph),
50.2 (CH2, C-6), 39.4 (CH2, CH2Ar), 35.7 (CH, C-5), 31.3
(CH2, C-3), 26.8 (CH2, C-4); HRMS (ESI): calcd for
C19H22NO [MþH]þ 280.1696, found 280.1695.
14. (a) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc.
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Cossy, J.; de Filippis, A.; Pardo, D. G. Synlett 2003, 2171e2174; (c) de
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16. For a review, see: Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36,
234e245.
17. (a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998,
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Acknowledgements
18. For some other recent examples of intramolecular BuchwaldeHartwig
´
´
´
reactions, see: (a) Sole, D.; Vallverdu, L.; Solans, X.; Bardıa, M. F.;
Bonjoch, J. J. Am. Chem. Soc. 2003, 125, 1587e1594; (b) Muratake,
H.; Natsume, M.; Nakai, H. Tetrahedron 2004, 60, 11783e11803; (c)
MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7,
Financial support by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie is gratefully acknow-
ledged. We thank Graeme Nicholson (Institute of Organic
Chemistry) for measuring the HRMS spectra. G.S. thanks
the Alexander von Humboldt foundation for a postdoctoral
fellowship.
´
3421e3424; (d) Sole, D.; Urbaneja, X.; Bonjoch, J. Org. Lett. 2005, 7,
5461e5464; (e) Zhou, H.; Liao, X.; Yin, W.; Ma, J.; Cook, J. M.
J. Org. Chem. 2006, 71, 251e259 and references therein.
19. For an example with a double bond between aryl bromide and enolate,
`
see: Bruyere, D.; Bouyssi, D.; Balme, G. Tetrahedron 2004, 60, 4007e
4017.
20. Hartmann, R. W.; Reichert, M. Arch. Pharm. Pharm. Med. Chem. 2000,
333, 145e153.
Supplementary data
21. Takahashi, K.; Yamamoto, S.; Naka, M. PCT Int. Appl., (Ono Pharmaceu-
tical Co., Ltd., Japan), WO 2003043988, 2003, 362 pp; CAN 139: 6888.
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S. J.; Hursthouse, M. B.; Sheldrake, P. W.; Whittall, N.; Hii, K. K. Tetra-
hedron Lett. 2003, 44, 3675e3678.
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2007.10.088.
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