Asymmetric synthesis of 1-substituted tetrahydro-3-benzazepines as NMDA receptor antagonists

FULL PAPER

DOI: 10.1002/ejoc.200600746

Asymmetric Synthesis of 1-Substituted Tetrahydro-3-benzazepines as NMDA

Receptor Antagonists

Ursula Wirt,^[a]Dirk Schepmann,^[a]and Bernhard Wünsch*^[a]

Keywords: Asymmetric synthesis / Chiral auxiliary / Medicinal chemistry / 3-Benzazepines / NMDA Receptor antagonists /

σ Receptor ligands / Structure affinity relationships

A novel asymmetric synthesis of 1-substituted tetrahydro-3-

benzazepines (R)-15 and (S)-15 has been performed. Starting

with o-phenylenediacetic acid (1) and (R)-phenylglycinol as

chiral auxiliary the tricyclic oxazololactam (3R)-10 was syn-

thesized as key intermediate. Deprotonation of (3R)-10 with

LDA led to an enolate, which was trapped with different aryl-

alkyl and alkyl halides to yield 6-substituted oxazololactams

(6R)-12 with high diastereoselectivity. The best dia-

stereomeric ratio (about 95:5) was achieved with benzyl bro-

mide and 2-methylbenzyl bromide. The diastereomers were

separated using preparative HPLC to obtain dia-

cedures (LiAlH₄/AlCl₃, then NH₄HCO₂, Pd/C) led to enantio-

merically pure 1-substituted tetrahydro-3-benzazepines (R)-

15. Starting the synthesis with (R)- and (S)-phenylglycinol

provided both enantiomers (R)-15 and (S)-15, which were in-

vestigated for their affinity to the PCP binding site of the

NMDA receptor. The NMDA receptor affinities of the enan-

tiomeric pairs are very similar. With a K_ivalue of 1.66 µ

M the

2-methylbenzyl-substituted derivative (R)-15c displays the

highest NMDA receptor affinity in this series.

stereomerically pure (6R)-12. Two successive reduction pro- Germany, 2007)

on the stereochemistry. For example (S)-I displays high

1. Introduction

NMDA receptor affinity (K_i= 35.4 nM) whereas its enantio-

mer (R)-I is less active (K_i= 3756 nM).^[5]Recently, we

found that the homologous tetrahydro-3-benzazepines II

(K_i= 8.74 µ) and III (K_i= 1.05 µ) also interact with the

PCP binding site of the NMDA receptor.^[6](see Figure 1)

However, only racemates have been considered in this study.

The NMDA receptor represents an excitatory ionotropic

glutamate receptor, which plays a crucial role in several neu-

rological processes like learning and memory.^[1,2]However,

overstimulation of the NMDA receptor with the endogenic

ligand (S)-glutamate leads to a massive influx of Ca²⁺-ions

through the ion channel into the neuron. The increase of

the intracellular Ca²⁺-concentration causes acute damage

of neurons, which is observed after stroke or brain injury.

The NMDA receptor is also involved in the development of

chronic neurodegenerative disorders including Alzheimer’s

disease, Parkinson’s disease, epilepsy and amyotrophic lat-

eral sclerosis. Therefore, the NMDA receptor represents an

interesting target for the therapy of these neurological dis-

orders.^[3,4]

In the focus of our interest are ligands, which interact

with the PCP binding site located inside of the ion channel.

Ligands interacting with the PCP binding site act as un-

competitive NMDA receptor antagonists because they

block the channel and therefore stop the Ca²⁺influx.

1-Substituted tetrahydroisoquinolines have been de-

scribed as highly active antagonists of the NMDA receptor.

The interaction with the PCP binding site depends strongly

Figure 1. Lead compounds with NMDA receptor affinity.

In this communication we describe the first general

asymmetric synthesis of 1-substituted tetrahydro-3-benz-

azepines VI (see Figure 2). The concept of using bicyclic lac-

tam IV derived from phenylglycinol should be applied. Dia-

stereoselective alkylation of IV should yield the substituted

lactam V, which after reduction and hydrogenolysis should

give the desired 1-substituted tetrahydro-3-benzazepines VI

in enantiomerically pure form. In order to investigate the

relationship between the stereochemistry and the NMDA

receptor affinity both enantiomers were to be prepared.

[a] Institut für Pharmazeutische und Medizinische Chemie der

Westfälischen Wilhelms-Universität Münster,

Hittorfstraße 58–62, 48149 Münster, Germany

Fax: +49-251-8332144

E-mail: wuensch@uni-muenster.de

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Tetrahydro-3-benzazepines as NMDA Receptor Antagonists

FULL PAPER

Figure 2. Concept of the asymmetric synthesis of 1-substituted

tetrahydro-3-benzazepines.

The asymmetric synthesis of enantiomerically pure piper-

idine derivatives using chiral bicyclic lactams derived from

(R)- or (S)-phenylglycinol as chiral auxiliary has been de-

scribed in literature.^[7–10]The concept of using phenylglyci-

nol as chiral auxiliary was also applied to the synthesis of

enantiomerically pure substituted piperazines^[11]and tetra-

hydroisoquinolines.^[12,13]

Scheme 1. Reagents and conditions: (a) SOCl₂, toluene, reflux. (b)

(R)-phenylglycinol, NEt₃, CH₂Cl₂, room temp. (c) Me₃SiCl,

CH₃OH, 0 °C.

azepinone (3R)-10 was isolated by flash chromatography in

54% yield. Furthermore a small amount (7%) of the side

2. Chemistry

According to our plan (see Figure 2) the oxazolo[3]- product (R)-11 was isolated. The highest yield of the prod-

benzazepinone 10 represents the key intermediate of the uct (3R)-10 (54%) was obtained by performing the cycliza-

synthesis. The synthesis of 10 (Scheme 1 and Scheme 2) tion of (R)-9 at 0 °C. Raising of reaction temperature led to

started from the commercially available o-phenylenediacetic increasing amounts of the side product (R)-11.

acid 1 which was transformed with SOCl₂into anhydride 2.

The oxazolo[3]benzazepinone (3R)-10 was formed as a

The chiral information was introduced by reaction of the single diastereomer. Careful thin layer chromatography and

anhydride 2 with (R)-phenylglycinol to afford the amido HPLC analysis of the crude product mixture did not indi-

acid (R)-3. In order to obtain the oxazolo[3]benzazepinone cate the presence of the second diastereomer. These obser-

(3R)-10 it was necessary to reduce the carboxylic acid of vations point out that the cyclization of (R)-9 to (3R)-10 is

(R)-3 to the oxidation level of an aldehyde. First, the direct a highly diastereoselective reaction. The relative configura-

reduction of the methyl ester (R)-4 was investigated using tion of (3R)-10 was determined by nuclear Overhauser ef-

diisobutylaluminium hydride as selective reducing fect (NOE). Irradiation with the resonance frequency of the

agent.^[14,15]However, all attempts failed to obtain the alde- proton in position 11a (δ = 5.1 ppm) resulted in increasing

hyde (R)-5 since overreduction to the corresponding alcohol of the signals of the phenyl protons. An increase of the sig-

took place (Scheme 1).

nal at 5.4 ppm (3-H) was not observed. Therefore, the pro-

Therefore it was planned to reduce the ester (R)-4 to the ton in position 11a and the phenyl residue in position 3 are

corresponding alcohol and subsequently oxidize the pri- cis configured. Thus, the novel chiral center C-11a is (S)-

mary alcohol to an aldehyde. For this purpose protection configured.

of the alcohol group of the phenylglycinol moiety was nec-

Next the diastereoselective alkylation in position 6 of the

essary, which was performed with triisopropylsilyl chloride oxazolo[3]benzazepinone (3R)-10 was investigated. The

and imidazole to afford the silyl ether (R)-6.^[16]Reduction amide (3R)-10 was deprotonated with LDA to provide an

of the ester (R)-6 with LiBH₄provided quantitatively the enolate, which was trapped with various arylalkyl and alkyl

primary alcohol (R)-7. Selective oxidization of the alcohol halides. After careful optimization of the reaction condi-

(R)-7 with Dess–Martin periodinan^[17,18]led to the aldehyde tions the alkylation was performed successfully and repro-

(R)-8 in 83% yield. Deprotection of the silyl ether and ace- ducibly. In order to obtain the enantiomeric 3-benzazepines

talization of the aldehyde (R)-8 proceeded upon treatment the oxazolo[3]benzazepine (3S)-10 was synthesized analo-

with CH₃OH and HCl to give the amido acetal (R)-9. Fi- gously using (S)-phenylglycinol as chiral auxiliary. The cor-

nally, the amido acetal (R)-9 was cyclized with catalytic responding deprotonation and alkylation is also shown in

amounts of HCl in CHCl₃. The desired oxazolo[3]benz- Scheme 3.

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463

U. Wirt, D. Schepmann, B. Wünsch

FULL PAPER

Scheme 2. Reagents and conditions: (a) triisopropylsilyl chloride, imidazole, DMF, room temp. (b) LiBH₄, THF, room temp. (c) Dess–

Martin periodinane, CH₂Cl₂, room temp. (d) HCl, 1% in CH₃OH, room temp. (e) CHCl₃, HCl, room temp.

The ratio of the diastereomeric alkylation products 12/

On the left side in Figure 4 a model of the enolate of

13 was determined by HPLC analysis. All products with (3R)-10 is depicted. The model shows axial orientation of

arylalkyl substituents 12a–d were obtained with high dia- the phenyl moiety of the oxazolidine substructure favoring

stereoselectivity. Only 4.9 to 7.8% of the minor dia- Re-face attack at the enolate double bond by the corre-

stereomer 13a–d was detected. The alkylation of (3R)-10 sponding alkyl halides.

and (3S)-10 with CH₃I provided the diastereomeric prod-

ucts 12e and 13e in the ratio of about 80:20, respectively graphic and spectroscopic properties, (R)-configuration was

(see Table 1 and Figure 3). assigned to the novel chiral center in position 6 of the major

According to comparable diastereoselectivity, chromato-

In order to identify the minor diastereomer HPLC analy- diastereomers 12b–e and (S)-configuration to the minor

sis was combined with MS and DAD detection. At last the diastereomers 13b–e.

mixture of diastereomers (6R)-12/(6S)-13 and (6S)-12/(6R)-

In order to get to the enantiomerically pure 1-substituted

13 was separated by preparative RP18-HPLC respectively, tetrahydro-3-benzazepines 15 the diastereomerically pure

to obtain diastereomerically pure products. The recorded tricyclic compounds 12 were reduced in two steps. First re-

[10,20]

¹H NMR spectra of the purified products unequivocally action with LiAlH₄/AlCl₃

led to reduction of the

prove the structures of the minor diastereomers 13a–e.

amide and reductive opening of the oxazolidine ring to af-

The relative configuration of the new stereogenic center ford the N-benzyl derivatives 14a–e with excellent yields.

was determined by X-ray crystal structure analysis of the Careful HPLC and LC/MS-analysis of 14 showed that the

benzylated derivative (6R)-12a. The X-ray crystal structure reduction proceeded without any epimerization in position

analysis revealed (R)-configuration in position 6 and con- 1. Finally hydrogenolysis of the diastereomerically pure de-

firmed the (S)-configuration of C-11a^[19](Figure 4 right).

rivatives 14a–e with ammonium formate and Pd/C^[21]re-

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Tetrahydro-3-benzazepines as NMDA Receptor Antagonists

FULL PAPER

Figure 3. Mean values of the product ratios 12/13 in the (R)- and

(S)-series depending on different substituents.

Scheme 3. Reagents and conditions: (a) LDA, RX, THF, 0 °C. a:

RX = C₆H₅CH₂Br; b: RX = C₆H₅CH₂CH₂I; c: RX = 2-

CH₃C₆H₄CH₂Br; d: RX = 4-H₃COC₆H₄CH₂Br; e: RX = CH₃I.

Table 1. Ratio of the diastereomeric alkylation products 12/13

formed by alkylation of (3R)-10 and (3S)-10 (HPLC analysis).

Figure 4. Model of the enolate of (3R)-10 (left) and X-ray crystal

structure of the benzylated oxazolobenzazepine (6R)-12a (right).

tor as well as to the σ₁and σ₂receptor was determined

in competition experiments with radioligands. The affinity

towards σ receptors was included into this study, because

some potent NMDA antagonists also interact with σ recep-

tors and vice versa. In the assay systems the radioligands

[³H]-(+)-MK-801 (NMDA), [³H]-(+)-pentazocine (σ₁) and

[³H]-ditolylguanidine (σ₂) were employed. The receptor af-

finities are summarized in Table 2. When the screening with

high test compound concentrations indicated low affinity

only the inhibition of the radioligand binding (in%) at a

test compound concentration of 10 µ is listed. Only one

experiment was performed for medium affinity compounds,

whereas three experiments were carried out for high affinity

compounds. In these cases the standard error of the mean

was calculated and is given in Table 2.

sulted in the desired enantiomerically pure 1-substituted

tetrahydro-3-benzazepines 15a–e (Scheme 4).

The 1,3-disubstituted 3-benzazepines 14a–e reveal very

low affinities toward the PCP-binding site of the NMDA

receptor. However the arylalkyl-substituted tetrahydro-3-

benzazepines 15a–d are binding in the low micromolar

3. Receptor Binding Studies

The affinity of the 1,3-disubstituted 3-benzazepines (1R)- range. The enantioselective NMDA receptor interaction of

and (1S)-14a–e and the 1-substituted 3-benzazepines (R)- 15a–d is shown graphically in Figure 5. Since both enantio-

and (S)-15a–e to the PCP binding site of the NMDA recep- mers of the methyl-substituted 3-benzazepines (R)-and (S)-

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465

U. Wirt, D. Schepmann, B. Wünsch

FULL PAPER

Figure 5. NMDA receptor affinities of enantiomerically pure 1-

substituted 3-benzazepines 15a–15d.

Scheme 4. Reagents and conditions: (a) LiAlH₄, AlCl₃, THF, 0 °C,

(b) NH₄HCOO, Pd/C, CH₃OH, reflux. a: R = PhCH₂; b: R =

PhCH₂CH₂; c: R = 2-CH₃C₆H₄CH₂; d: R = 4-H₃COC₆H₄CH₂; e:

R = CH₃.

Within this series of ligands the 3-benzazepines with a

benzyl (15a) and a 2-methylbenzyl (15c) residue possess the

highest NMDA receptor affinities, the K_ivalues are in the

15e led to very low inhibition of the radioligand binding at range between 1.7 to 4.3 µ. Extension of the aryl–nitrogen

a test concentration of 10 µ the K_ivalues were not deter- distance of the substituent 15b and introduction of an elec-

mined.

tron donating methoxy group 15d lead to reduced NMDA

Table 2. Affinities of the 3-benzazepines towards NMDA, σ₁and σ₂receptors.

Compd.

R

NMDA

σ₁

σ₂

K_i[µM]ϮSEM^[a]

(1R)-14a

(1S)-14a

(R)-15a

benzyl

phenethyl

2-methylbenzyl

4-methoxybenzyl

methyl

23

(0%)

4.3Ϯ2.5

3.5Ϯ0.4

(0%)

3.8

(5%)

3.4

26

2.7

(10%)

5.3

0%

(0%)

5.0

14

5.7

13

(0%)

2.3

8.3

0.69Ϯ0.4

2.1

10

9.0

–

2.2Ϯ1.2 nM

1.9Ϯ0.4 nM

–

9.7

13.0

4.04

5.8

3.6

35

1.1

4.2

(10%)

29

5.2

2.8

15

2.5

7.9

7.0

5.9

(0%)

10

20

–

(S)-15a

(1R)-14b

(1S)-14b

(R)-15b

(0%)

11Ϯ2

26Ϯ4

(0%)

(S)-15b

(1R)-14c

(1S)-14c

(R)-15c

(0%)

1.7Ϯ0.5

3.8Ϯ1.5

(0%)

(S)-15c

(1R)-14d

(1S)-14d

(R)-15d

(0%)

33Ϯ4

36Ϯ2

(0%)

22

(0%)

(S)-15d

(1R)-14e

(1S)-14e

(R)-15e

methyl

(S)-15e

(5%)

(+)-MK-801

Dexoxadrol

(+)-Pentazocine

Haloperidol

Ditolylguanidine

2.89Ϯ1.14 nM

38.9Ϯ9.9 nM

–

20.2Ϯ2.3 nM

[a] Values in % give the inhibition of the radioligand binding at a test compound concentration of 10 µ.

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Tetrahydro-3-benzazepines as NMDA Receptor Antagonists

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60, 40–63 µm (Merck), parentheses include: Diameter of the col-

umn [cm], eluent, fraction size [mL], R_f. Melting points: Melting

Point Apparatus SMP3 (Stuart Scientific). Elemental analyses: Va-

rioEL (Elementar). MS: GCQ Finnigan MAT (thermo-Finnigan),

EI = electron impact. IR: ATR-FT-IR-480 Plus Fourier Transform

Spektrometer (Jasco). ¹H NMR (400 MHz), ¹³C NMR (100 MHz):

Mercury-400BB spectrometer (Varian), δ in ppm related to tet-

receptor affinity. Surprisingly, significant differences be-

tween the NMDA receptor affinities of the enantiomeric

pairs are not observed. According to Figure 5 the (R)-

enantiomers (except 15a) seem to have slightly higher affin-

ities than their (S)-enantiomers. However, with the excep-

tion of the low affinity phenethyl derivative 15b the prefer-

ence of the NMDA receptor for the (R)-enantiomers is not

significant.

1

ramethylsilane; the assignments of H and ¹³C NMR signals were

supported by 2D NMR techniques. HPLC: Hitachi LaChrom L-

The methylated 3-benzazepines 14e and 15e display very

7150 (Merck). Optical rotation: Polarimeter 341 (Perkin–Elmer), λ

low NMDA receptor affinity. Obviously small substituents = 589 nm, unit, c (g/100 mL), solvent, 1 dm, 20 °C.

in position 1 of the 3-benzazepine ring system are unfavor-

able for high NMDA receptor affinity.

The σ receptor affinities of the 3-benzazepines 14a–d and

15a–d with arylalkyl substituents are very similar. These re-

sults indicate that the nature of the C-1 substituent, an ad-

ditional substituent in position 3 and the C-1 configuration

do not significantly influence the σ₁and σ₂receptor affin-

ity.

However, the σ receptor affinities of the methylated 3-

benzazepines 14e and 15e are very interesting. The (R)-con-

figured 3-benzazepine (1R)-14e (K_i= 0.69 µ) represents

the most active σ₁ligand in this series. The σ₁affinity of

(1R)-14e is about eightfold higher than its σ₂receptor affin-

5.2. General Procedures

5.2.1. General Procedure A: Synthesis of the 6-Substituted Oxazolo-

benzazepinones 12a–e, 13a–e: A solution of oxazolo-benzazepinone

10 in THF was cooled to 0 °C under nitrogen atmosphere. A solu-

tion of LDA (2  in THF) was added and the mixture was stirred

for 1 h at 0 °C. Then, the respective alkyl- or arylalkyl halide was

added and the mixture was stirred for another 2–2.5 h at 0 °C. The

mixture was quenched with a saturated NH₄Cl solution and ex-

tracted three times with Et₂O. The organic layer was washed with

a saturated NH₄Cl solution and with H₂O. The combined aqueous

layers were reextracted with Et₂O. The combined organic layers

were dried (Na₂SO₄) and concentrated in vacuo.

5.2.2. General Procedure B. Reduction of the 6-Substituted Oxazolo-

ity. The enantiomer (1S)-14e reveals also σ₁receptor selec- benzazepinones 14a–e: Under N₂AlCl₃was dissolved in THF at

0 °C. After 5 min a LiAlH₄solution (1  in THF) was added. The

mixture was stirred for 20 min at room temp. Then the mixture was

cooled to 0 °C and a solution of the respective 6-substituted ox-

azolo-benzazepinone 12 in THF was added. After 1–2 h the reac-

tion was quenched with H₂O. After addition of Et₂O (10 mL) the

mixture was washed three times with H₂O. The combined aqueous

layers were reextracted with Et₂O. The combined organic layers

were dried (Na₂SO₄) and concentrated in vacuo.

tivity. The similar σ₁receptor affinities of the enantiomers

(1R)-14e and (1S)-14e leads to the conclusion that the con-

figuration in position 1 has only little influence on the σ₁

receptor interaction.

The enantiomeric 1-methyl-3-benzazepines (R)- and (S)-

15e reveal very similar σ₁and σ₂receptor affinity. Further-

more a significant difference in receptor interaction be-

tween the (R)- and (S)-configured 3-benzazepines was not

determined.

5.2.3. General Procedure C. Synthesis of the 1-Substituted 3-Benz-

azepines 15a–e: The respective 1-substituted 3-benzazepine 14 was

dissolved in MeOH. Then dry ammonium formate and Pd/C were

added and the mixture was heated under reflux for 2–4.5 h. The

catalyst was removed by filtration and the solution was concen-

trated in vacuo.

4. Conclusion

Herein, we have presented the first general asymmetric

synthesis of enantiomerically pure 1-substituted tetrahydro-

3-benzazepines 14 and 15. Exemplarily, five different sub-

stituents have been introduced in position 1 and the corre-

sponding 3-benzazepines have been pharmacologically

evaluated in receptor binding studies. 3-Benzazepines with

a benzyl (15a) and a 2-methylbenzyl (15c) substituent show

the highest NMDA receptor affinity (K_i= 1.7–4.3 µ).

However, an enantioselective receptor interaction was not

observed. This is probably due to the low affinity of the

ligands. In order to improve the NMDA receptor affinity

and the enantioselective receptor interaction further varia-

tions of the 3-benzazepine ring system will be performed

following the method described in this communication.

5.3. 1,5-Dihydro-3-benzoxepine-2,4-dione (2): To a solution of o-

phenylenediacetic acid (1, 4.85 g, 25.0 mmol) in toluene (50 mL)

thionyl chloride (1.8 mL, 25.0 mmol) was added dropwise. The

mixture was heated under reflux for 24 h and then concentrated in

vacuo. The product was directly used without further purification.

The yield of 2 (88%) was determined by integration of characteris-

tic NMR signals. C₁₀H₈O₃(176.2). IR: ν = 1745. ¹H NMR

˜

(CDCl₃): δ = 4.05 (s, 4 H, CH₂COOR), 7.20–7.30 (m, 4 H, arom.)

ppm.

5.4. (R)-2-{[N-(2-Hydroxy-1-phenylethyl)carbamoylmethyl]phenyl}-

acetic Acid [(R)-3]: To a solution of anhydride 2 (264 mg, 1.5 mmol)

in CH₂Cl₂(5 mL) triethylamine (0.21 mL, 1.5 mmol) and a solu-

tion of (R)-phenylglycinol (206 mg, 1.5 mmol) in CH₂Cl₂(5 mL)

were added. The mixture was stirred for 3 h at room temp. Then

the mixture was extracted four times with 0.15  NaOH. The com-

bined aqueous layers were acidified with 1  HCl (pH 3) and ex-

tracted three times with CH₂Cl₂. The combined organic extracts

were dried (Na₂SO₄) and concentrated in vacuo to one third of the

original volume. Overnight colorless crystals were formed, which

5. Experimental Section

5.1. General: Unless otherwise noted, moisture-sensitive reactions

were conducted under dry nitrogen. Petroleum ether used refers to

the fraction boiling at 40–60 °C. Thin layer chromatography: Silica

gel 60 F₂₅₄plates (Merck). Flash chromatography (fc):^[22]Silica gel

were isolated by filtration. Colorless solid, m.p. 150.7–151.8 °C,

20

yield 0.37 g (79%). [α] = –61.3 (c = 0.925, MeOH). C₁₈H₁₉NO₄

589

(313.4). MS (EI): m/z = 295 [M – H₂O], 282 [M – CH₂OH], 106

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467

U. Wirt, D. Schepmann, B. Wünsch

[C H N]. IR: ν = 3447 (O–H), 3315 (N–H), 3021 (C–H), 1706 CO₂CH₃), 54.9 (1 C, NHCHPh), 66.9 (1 C, CH₂OSi), 126.9, 127.4,

FULL PAPER

˜

7

8

1

(CO₂H), 1649 (CONH), 1535 (N–H). H NMR ([D₆]DMSO): δ =

3.32–3.70 (m, 6 H, CH₂COOH, CH₂CON, CH₂OH), 4.78–4.83 (m,

1 H, NHCHPh), 7.13–7.28 (m, 9 H, arom.), 8.48 (d, J = 8.2 Hz, 1

H, NH) ppm. ¹³C NMR ([D₆]DMSO): δ [ppm] = 55.8 (1 C,

NHCHPh), 65.4 (1 C, CH₂OH), 127.1, 127.4, 127.4, 127.5, 128.7,

130.6, 131.0, 134.9, 136.2, 141.9 (12 C, arom.), 170.4 (1 C, CONH),

173.4 (1 C, COOH). The signals for the ArCH₂carbon atoms are

superimposed by the DMSO signal at δ = 40 ppm.

128.2, 128.4, 128.5, 131.1, 131.4, 133.5, 134.3, 140.4 (12 C, arom.),

170.2 (1 C, CONH), 172.0 (1 C, COOCH₃).

5.9. Methyl (S)-2-͗2-{N-[1-Phenyl-2-(triisopropylsilyloxy)ethyl]-

carbamoylmethyl}phenyl͘-acetate [(S)-6]: The synthesis of (S)-6 was

performed as described for (R)-6 using amido ester (S)-4 (1.1 g,

3.4 mmol), imidazole (0.58 g, 8.48 mmol) and triisopropylsilyl chlo-

20

ride (0.88 mL, 4.1 mmol). Colorless oil, yield 1.40 g (85%). [α]

589

= –20.2 (c = 0.5, CH₂Cl₂).

5.5. (S)-2-{[N-(2-Hydroxy-1-phenylethyl)carbamoylmethyl]phenyl}-

acetic Acid [(S)-3]: The synthesis of (S)-3 was performed as de-

scribed for (R)-3 using anhydride 2 (3.9 g, 22.1 mmol) in CH₂Cl₂

(115 mL), triethylamine (3.1 mL, 22.1 mmol) and (S)-phenylglyci-

5.10. (R)-2-[2-(2-Hydroxyethyl)phenyl]-N-[1-phenyl-2-(triisopropyl-

silyloxy)ethyl]acetamide [(R)-7]: To a solution of (R)-6 (2.69 g,

5.57 mmol) in THF (40 mL) a LiBH₄solution (2  in THF;

11.1 mL, 22.3 mmol) was added. The mixture was stirred for 18 h

at room temp. The mixture was quenched with a saturated solution

of NH₄Cl. The mixture was extracted with Et₂O, the organic layer

was dried (Na₂SO₄) and concentrated in vacuo. The residue was

nol (3.0 g, 22.1 mmol) in CH₂Cl₂(30 mL). Colorless solid, m.p.

20

151.9 °C, yield 3.73 g (54%). [α] = +60.5 (c = 1.035, MeOH).

589

5.6.

Methyl

(R)-2-{2-[N-(2-Hydroxy-1-phenylethyl)carbamoyl-

methyl]phenyl}acetate [(R)-4]: Amido acid (R)-3 (1.02 g, 3.25 mmol)

was dissolved in MeOH (80 mL), the solution was cooled to 0 °C

and trimethylsilyl chloride (1.23 mL, 9.75 mmol) was added. The

reaction mixture was stirred for 19 h at room temp. Then the mix-

ture was concentrated in vacuo. The residue was dissolved in Et₂O

and concentrated again in vacuo. The residue was purified by fc (Ø

purified by fc (Ø 5 cm, petroleum ether/ethyl acetate = 2:5, 30 mL,

20

R_f= 0.47) to get a colorless oil, yield 2.37 g (93%). [α] = +18.3

589

(c = 1.34, CH₂Cl₂). C₂₇H₄₁NO₃Si (455.7). Calcd. C 71.16, H 9.07,

N 3.07, found C 70.76, H 9.29, N 3.08. MS (EI): m/z = 456 [M],

412 [M – C H O], 106 [C H N]. IR: ν = 3402 (O–H), 3284 (N–H),

˜

2

4

7

8

2940, 2863 (C–H), 1646 (CONH), 1507 (N–H). ¹H NMR (CDCl₃):

δ [ppm] = 0.81–0.92 [m, 21 H, Si{CH(CH₃)₂}₃], 2.12 (s, 1 H, OH),

2.87 (t, J = 6.6 Hz, 2 H, CH₂CH₂OH), 3.70 (s, 2 H, CH₂CONH),

3.76 (dd, J = 10.2/3.9 Hz, 1 H, CH₂OSi), 3.80 (t, J = 6.6 Hz, 2 H,

CH₂CH₂OH), 3.88 (dd, J = 10.2/3.9 Hz, 1 H, CH₂OSi), 5.00 (dt, J

= 7.0/3.9 Hz, 1 H, NHCHPh), 6.53 (d, J = 7.0 Hz, 1 H, NH), 7.14–

7.28 (m, 9 H, arom.). ¹³C NMR (CDCl₃): δ [ppm] = 11.9 (6C,

SiCHCH₃), 18.0 (3 C, SiCHCH₃), 36.2 (1 C, ArCH₂), 41.5 (1 C,

ArCH₂), 54.9 (1 C, NHCHPh), 63.3 (1 C,CH₂OH), 66.8 (1 C,

CH₂OSi), 126.9, 127.5, 127.5, 128.3, 128.5, 130.9, 131.0, 133.8,

138.0, 140.3 (12 C, arom.), 170.9 (1 C, CONH).

4 cm, petroleum ether/ethyl acetate = 2:5, 30 mL, R_f= 0.25). Color-

20

less solid, m.p. 117.4–118.1 °C, yield 886 mg (83%). [α] = –4.35

589

(c = 2.2, CH₂Cl₂). C₁₉H₂₁NO₄(327.4). Calcd C 69.71, H 6.47, N

4.28, found C 69.65, H 6.47, N 4.25. MS (EI): m/z = 296 [M –

OCH ], 106 [C H N]. IR: ν = 3512 (O–H), 3287 (N–H), 2950 (C–

˜

3

7

8

H), 1718 (CO₂CH₃), 1648 (CONH), 1539 (N–H). ¹H NMR

(CDCl₃): δ [ppm] = 2.32 (s, 1 H, OH), 3.67–3.82 (m, 9 H,

CH₂COOCH₃, CH₂CON, CH₂OH), 5.04–5.08 (m,

1

H,

NHCHPh), 6.55 (d, J = 6.3 Hz, 1 H, NH), 7.15–7.33 (m, 9 H,

arom.). ¹³C NMR (CDCl₃): δ [ppm] = 38.9 (1 C, ArCH₂), 41.2 (1

C, ArCH₂), 52.7 (1 C, CH₃), 56.2 (1 C, NHCHPh), 66.5 (1 C,

CH₂OH), 126.8, 127.9, 128.2, 128.5, 128.9, 131.0, 131.5, 133.1,

134.2, 139.2 (12 C, arom.), 171.4 (1 C, CONH), 173.1 (1 C, CO-

OCH₃).

5.11. (S)-2-[2-(2-Hydroxyethyl)phenyl]-N-[1-phenyl-2-(triisopropyl-

silyloxy)ethyl]acetamide [(S)-7]: The synthesis of (S)-7 was performed

as described for (R)-7 using (S)-6 (1.03 g, 2.13 mmol) in THF

(50 mL), LiBH₄solution (2  in THF, 4.26 mL, 8.52 mmol). Color-

5.7.

Methyl

(S)-2-{2-[N-(2-Hydroxy-1-phenylethyl)carbamoyl-

20

less oil, yield 759 mg (78%). [α] = –18.6 (c = 1.01, CH₂Cl₂).

589

methyl]phenyl}acetate [(S)-4]: The synthesis of (S)-4 was performed

as described for (R)-4 using amido acid (S)-3 (2.1 g, 6.70 mmol)

5.12.

(R)-2-[2-(Formylmethyl)phenyl]-N-[1-phenyl-2-(triisopropyl-

silyloxy)ethyl]acetamide [(R)-8]: Dess–Martin periodinane (893 mg,

2.12 mmol) was dissolved in CH₂Cl₂(20 mL). Then a solution of

alcohol (R)-7 (800 mg, 1.76 mmol) in CH₂Cl₂(25 mL) was added

dropwise. The mixture was stirred for 1 h at room temp. Then Et₂O

(20 mL) and 1  NaOH (10 mL) were added and the mixture was

stirred for 15 min. The organic layer was washed with 1  NaOH

(20 mL) and H₂O (15 mL). The aqueous layer was extracted three

times with Et₂O. The combined organic layers were dried (Na₂SO₄)

and concentrated in vacuo. The residue was purified by fc (Ø 4 cm,

in MeOH (100 mL), trimethylsilyl chloride (2.5 mL, 20.1 mmol).

20

Colorless solid, m.p. 118.2 °C, yield 1.28 g (58%). [α] = +3.86 (c

589

= 2.5, CH₂Cl₂).

5.8. Methyl (R)-2-͗2-{N-[1-Phenyl-2-(triisopropylsilyloxy)ethyl]-

carbamoylmethyl}phenyl͘acetate [(R)-6]: Amido ester (R)-4 (1.27 g,

3.88 mmol) and imidazole (660.4 mg, 9.7 mmol) were dissolved in

DMF (4 mL). triisopropylsilyl chloride (1.00 mL, 4.66 mmol) was

added dropwise and the mixture was stirred for 16 h at room temp.

The mixture was quenched with H₂O. The aqueous layer was ex-

tracted with Et₂O, the combined organic extracts were dried

(Na₂SO₄) and concentrated in vacuo. The residue was purified by

petroleum ether/ethyl acetate = 2:5, 20 mL, R_f= 0.73). Colorless

20

oil, yield 657 mg (83%). [α]

= +9.44 (c = 4.48, CH₂Cl₂).

589

C₂₇H₃₉NO₃Si (453.7). MS (EI): m/z = 454 [M], 410 [M – C₂H₄O],

106 [C H N]. IR: ν = 2941, 2863 (C–H), 1724 (CHO), 1645

fc (Ø 4 cm, petroleum ether/ethyl acetate = 5:2, 30 mL, R_f= 0.25).

˜

7

8

20

Colorless oil, yield 1.72 g (91%). [α] = +21.7 (c = 0.5, CH₂Cl₂).

589

(CONH), 1533 (N–H). ¹H NMR (CDCl₃): δ [ppm] = 0.75–0.88 [m,

21 H, Si{CH(CH₃)₂}₃], 3.53 (s, 2 H, CH₂CONH), 3.68 (d, J =

1.6 Hz, 2 H, CH₂CHO), 3.69 (dd, J = 9.8/3.9 Hz, 1 H, CH₂OSi),

3.82 (dd, J = 9.8/3.9 Hz, 1 H, CH₂OSi), 4.91 (dt, J = 7.8/3.9 Hz, 1

H, NHCHPh), 6.30 (d, J = 7.8 Hz, 1 H, NH), 7.09–7.24 (m, 9 H,

arom.), 9.62 (t, J = 1.5 Hz, 1 H, CH₂CHO).

C₂₈H₄₁NO₄Si (483.7). Calcd. C 69.52, H 8.54, N 2.90, found C

69.16, H 8.50, N 2.91. MS (EI): m/z = 484 [M], 106 [C₇H₈N]. IR:

ν = 3316 (N–H), 2941, 2864 (C–H), 1734 (CO CH ), 1647

˜

2

3

(CONH), 1522 (N–H). ¹H NMR (CDCl₃): δ [ppm] = 0.81–0.91 [m,

21 H, Si{CH(CH₃)₂}₃], 3.65 (s, 3 H, OCH₃), 3.66 (s, 2 H, CH₂),

3.69 (s, 2 H, CH₂), 3.76 (dd, J = 9.8/3.9 Hz, 1 H, CH₂OSi), 3.87

(dd, J = 9.4/3.9 Hz, 1 H, CH₂OSi), 5.01 (dt, J = 7.8/3.9 Hz, 1 H,

NHCHPh), 6.47 (d, J = 7.8 Hz, 1 H, NH), 7.15–7.30 (m, 9 H,

5.13.

(S)-2-[2-(Formylmethyl)phenyl]-N-[1-phenyl-2-(triisopropyl-

silyloxy)ethyl]acetamide [(S)-8]: The synthesis of (S)-8 was per-

arom.). ¹³C NMR (CDCl₃): δ [ppm] = 11.9 (6C, SiCHCH₃), 18.0 formed as described for (R)-8 using alcohol (S)-7 (647 mg,

(3 C, SiCHCH₃), 38.8 (1 C, ArCH₂), 41.7 (1 C, ArCH₂), 52.4 (1 C, 1.42 mmol) and Dess–Martin periodinane (691 mg, 1.63 mmol) in

468

www.eurjoc.org

Eur. J. Org. Chem. 2007, 462–475

Tetrahydro-3-benzazepines as NMDA Receptor Antagonists

FULL PAPER

performed as described for (3R)-10 using amido acetal (S)-9

20

CH₂Cl₂(40 mL). Colorless oil, yield 550.3 mg (85%). [α] = –8.43

589

(c = 2.53, CH₂Cl₂).

(1.29 g, 3.76 mmol) in CHCl₃(800 mL) and 12 drops of conc. HCl.

20

Colorless solid, m.p. 152.2 °C, yield 527.4 mg (50%). [α] = –31.2

589

5.14. (R)-2-[2-(2,2-Dimethoxyethyl)phenyl]-N-(2-hydroxy-1-phenyl-

ethyl)acetamide [(R)-9]: Amido aldehyde (R)-8 (552 mg, 1.22 mmol)

was dissolved in a 1% methanolic HCl (40 mL). The mixture was

stirred for 5 h at room temp. Then a saturated solution of NaHCO₃

was added. The aqueous layer was extracted three times with Et₂O.

The combined organic layers were washed with a saturated solution

of NaHCO₃and with H₂O. The combined aqueous layers were

reectracted with Et₂O. The Et₂O solution was dried (Na₂SO₄) and

concentrated in vacuo. The residue was purified by fc (Ø 2 cm,

petroleum ether/ethyl acetate = 1:6, 10 mL, R_f= 0.24). Pale yellow

(c = 0.51, CH₂Cl₂). The side product (S)-11 was not isolated.

5.18. (3R,6R,11aS)-6-Benzyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]-

oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6R)-12a] and (3R,6S,11aS)-

6-Benzyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benz-

azepin-5(6H)-one [(6S)-13a]: According to the General Procedure

A oxazolo-benzazepinone (3R)-10 (200 mg, 0.716 mmol) in THF

(50 mL) was treated with LDA solution (394 µL, 0.788 mmol) and

benzyl bromide (85.0 µL, 0.716 mmol). The residue was purified by

fc [Ø 3 cm, cyclohexane/ethyl acetate = 8:2, 10 mL, R_f[(6R)-12a] =

0.33, R_f[(6S)-13a] = 0.31] to obtain a mixture of diastereomers,

yield 249.0 mg (94%), diastereomeric ratio (HPLC): 95.1:4.9 [(6R)-

12a:(6S)-13a]. The diastereomers were separated by another fc {Ø

3 cm, cyclohexane/ethyl acetate = 30:2, 5 mL, tlc: cyclohexane/ethyl

acetate = 5:2, R_f[(6R)-12a] = 0.43, R_f[(6S)-13a] = 0.38}.

oil, which solidified in the refrigerator to give a pale yellow solid,

20

m.p. 84.1–85.6 °C, yield 368 mg (88%). [α]

= +5.90 (c = 0.67,

589

CH₂Cl₂). C₂₀H₂₅NO₄(343.4) Calcd. C 69.95, H 7.43, N 4.08, found

C 69.86, H 7.55, N 3.89. MS (EI): m/z = 312 [M – OCH₃], 106

[C H N]. IR: ν = 3584 (O–H), 3285 (N–H), 3062, 2943 (C–H),

˜

7

8

1

1644 (CONH), 1539 (N–H), 1071 (C–O–C). H NMR (CDCl₃): δ

[ppm] = 1.67 (s, 1 H, OH), 2.94 [dd, J = 5.5/14.1 Hz, 1 H,

CH₂CH(OCH₃)₂], 2.99 [dd, J = 5.5/14.1 Hz, 1 H, CH₂CH-

(OCH₃)₂], 3.28 (s, 3 H, OCH₃), 3.29 (s, 3 H, OCH₃), 3.72–3.80 (m,

(6R)-12a: Colorless solid, m.p. 128.0–128.9 °C, yield 148.7 mg

20

(56%), de 99.85% (HPLC). [α]

= –114.9 (c = 0.432, CH₂Cl₂).

589

C₂₅H₂₃NO₂(369.5) Calcd. C 81.27, H 6.27, N 3.79, found C 81.16,

H 6.25, N 3.66. MS (EI): m/z = 369 [M], 278 [M-Benzyl], 120

4

H, CH₂CONH, CHCH₂OH), 4.55 [t, J = 5.6 Hz, 1 H,

[PHCHCH O], 91[C H ]. IR: ν = 3025, 2939, 2871 (C–H), 1651

˜

2

7

1

CH₂CH(OCH₃)₂], 5.07–5.08 (m, 1 H, NHCHPh), 6.17 (d, J =

7.2 Hz, 1 H, NH), 7.12–7.32 (m, 9 H, arom.).

(C=O). H NMR (CDCl₃): δ [ppm] = 3.11 (dd, J = 14.1/7.0 Hz, 1

H, CH₂CHC=O), 3.21 (dd, J = 15.3/5.1 Hz, 1 H, CH₂CHNO), 3.43

(dd, J = 15.6/3.9 Hz, 1 H, CH₂CHNO), 3.60 (dd, J = 8.6/7.8 Hz,

1 H, OCH₂CH), 3.59 (dd, J = 13.4/7.0 Hz, 1 H, CH₂CHC=O), 4.04

(t, J = 7.0 Hz, 1 H, CH₂CHC=O), 4.29 (t, J = 8.2 Hz, 1 H,

OCH₂CH), 5.14 (t, J = 4.3 Hz, 1 H, CH₂CHNO), 5.22 (t, J =

8.3 Hz, 1 H, OCH₂CH), 6.95–7.23 (m, 14 H, arom.). ¹³C NMR

(CDCl₃): δ [ppm] = 36.5 (1 C, CH₂CHC=O), 37.3 (1 C,

CH₂CHON), 51.9 (1 C, CH₂CHC=O), 60.6 (1 C, CHCH₂O), 71.6

(1 C, CHCH₂O), 88.7 (1 C, CH₂CHON), 126.3, 126.4, 127.7, 128.0,

128.5, 128.5, 128.9, 129.4, 130.4, 133.1, 140.0, 140.1 (18 C, arom.),

169.0 (1 C, CONR₂).

5.15. (S)-2-[2-(2,2-Dimethoxyethyl)phenyl]-N-(2-hydroxy-1-phenyl-

ethyl)acetamide [(S)-9]: The synthesis of (S)-9 was performed as

described for (R)-9 using amido aldehyde (S)-8 (471 mg,

1.04 mmol) 1% methanolic HCl (40 mL). Pale yellow solid, m.p.

20

88.0 °C, yield 252.3 g (70%). [α] = –6.93 (c = 1.00, CH₂Cl₂).

589

5.16.

(3R,11aS)-3-Phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-

b][3]benzazepin-5(6H)-one [(3R)-10] and (R)-3-(2-Hydroxy-1-phenyl-

ethyl)-1,3-dihydro-3-benzazepin-2-one [(R)-11]: To a solution of

amido acetal (R)-9 (101 mg, 0.29 mmol) in CHCl₃(50 mL) 2–

3 drops of conc. HCl were added. The mixture was stirred for 3 h

at 0 °C and then concentrated in vacuo. The residue was purified

by fc [Ø 2 cm, petroleum ether/ethyl acetate = 5:2, 10 mL, R_f[(3R)-

10] = 0.22, R_f[(R)-11] = 0.51]. Two products were isolated:

1

(6S)-13a: Colorless solid, yield: 6.4 mg (2.4%). H NMR (CDCl₃):

δ [ppm] = 3.18 (dd, J = 14.6/7.6 Hz, 1 H, CH₂CHC=O), 3.25 (dd,

J = 14.7/3.3 Hz, 1 H, CH₂CHNO), 3.49 (dd, J = 14.6/10.7 Hz, 1

H, CH₂CHNO), 3.61 (dd, J = 14.6/7.2 Hz, 1 H, CH₂CHC=O), 3.75

(dd, J = 8.8/5.7 Hz, 1 H, OCH₂CH), 4.29 (t, J = 7.4 Hz, 1 H,

CH₂CHC=O), 4.38 (dd, J = 8.7/7.9 Hz, 1 H, OCH₂CH), 5.14 (dd,

J = 10.7/3.3 Hz, 1 H, CH₂CHNO), 5.31 (dd, J = 7.8/5.7 Hz, 1 H,

OCH₂CH), 7.01–7.21 (m, 14 H, arom.).

(3R)-10: Colorless solid, m.p. 151.8–152.5 °C, yield 44.4 mg (54%).

20

[α]

= +31.9 (c = 0.54, CH₂Cl₂). C₁₈H₁₇NO₂(279.3) Calcd. C

589

77.40, H 6.13, N 5.01, found C 77.20, H 6.03, N 5.07. MS (EI): m/z

= 279 [M], 120 [PhCHCH O]. IR: ν = 2926 (C–H), 1640 (C=O). ¹H

˜

2

NMR (CDCl₃): δ [ppm] = 3.33–3.41 (m, 2 H, CH₂CHON), 3.74

(dd, J = 8.8/7.2 Hz, 1 H, OCH₂CH), 3.85 (d, J = 16.5 Hz, 1 H,

CH₂C=O), 3.96 (d, J = 16.4 Hz, 1 H, CH₂C=O), 4.46 (t, J =

5.19. (3S,6S,11aR)-6-Benzyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]-

oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6S)-12a] and (3S,6R,11aR)-

6-Benzyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benz-

azepin-5(6H)-one [(6R)-13a]: The synthesis of (6S)-12a was per-

formed as described for (6R)-12a according to the General Pro-

cedure A using oxazolo-benzazepinone (3S)-10 (200 mg,

0.716 mmol) in THF_abs.(50 mL), LDA solution (394 µL,

0.788 mmol) and benzyl bromide (85.0 µL, 0.716 mmol). (6S)-12a:

8.4 Hz,

1 H, OCH₂CH), 5.06 (dd, J = 7.1/5.1 Hz, 1 H,

CH₂CHNO), 5.40 (t, J = 7.6 Hz, 1 H, OCH₂CH), 7.17–7.31 (m, 9

H, arom.). ¹³C NMR (CDCl₃): δ [ppm] = 37.1 (1 C, CH₂CHON),

43.3 (1 C, CH₂C=O), 60.2 (1 C, CHCH₂O), 71.8 (1 C, CHCH₂O),

89.2 (1 C, CH₂CHON), 126.3, 127.8, 128.1, 129.0, 129.5, 129.6,

133.8, 134.2, 140.1 (12 C, arom.), 167.0 (1 C, CONR₂).

colorless solid, yield 148 mg (56%), de 100% (HPLC) after fc puri-

20

(R)-11: Colorless solid, yield 4.5 mg (5.4%). [α]

= –62.1 (c =

fication. [α]

= +113.5 (c = 0.14, CH₂Cl₂). (6R)-13a: Colorless

589

1.01, CH₂Cl₂). C₁₈H₁₇NO₂(279.3). MS (EI): m/z = 261 [M – H₂O].

solid, yield 5.3 mg (2.0%).

IR: ν = 3316 (OH), 3030, 2957 (C–H), 1660 (C=O). ¹H NMR

˜

5.20. (3R,6R,11aS)-6-Phenethyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]-

oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6R)-12b] and (3R,6S,11aS)-

6-Phenethyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo-[2,3-b][3]-

benzazepin-5(6H)-one [(6S)-13b]: According to the General Pro-

cedure A oxazolo-benzazepinone (3R)-10 (136.2 mg, 0.488 mmol)

in THF (35 mL) was treated with LDA solution (317 µL,

0.634 mmol) and 2-phenylethyl iodide (84.9 µL 0.585 mmol). The

residue was purified by fc [Ø 3 cm, cyclohexane/ethyl acetate =

15:2, 10 mL, R_f[(6R)-12b] = 0.48, R_f[(6S)-13b] = 0.44 in cyclohex-

(CDCl₃): δ [ppm] = 3.44 (d, J = 12.1 Hz, 1 H, ArCH₂C=O), 3.65

(d, J = 12.5 Hz, 1 H, ArCH₂C=O), 3.83 (dd, J = 11.5/8.4 Hz, 1 H,

PhCHCH₂OH), 3.88 (dd, J = 11.7/6.7 Hz, 1 H, PhCHCH₂OH),

6.00 (t, J = 8.2/6.7 Hz, 1 H, PhCHCH₂OH), 6.08 (d, J = 9.4 Hz, 1

H, CH=CH), 6.39 (d, J = 9.4 Hz, 1 H, CH=CH), 7.17–7.31 (m, 9

H, arom.).

5.17.

(3S,11aR)-3-Phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-

b][3]benzazepin-5(6H)-one [(3S)-10]: The synthesis of (3S)-10 was

Eur. J. Org. Chem. 2007, 462–475

www.eurjoc.org

469

U. Wirt, D. Schepmann, B. Wünsch

2869 (C–H), 1653 (C=O). H NMR (CDCl₃): δ [ppm] = 2.20 (s, 3

FULL PAPER

ane/ethyl acetate = 5:2]. to obtain a mixture of diastereomers

1

95.6 mg (51%), diastereomeric ratio (HPLC): 92.7:7.3 (6R)-12b/ H, ArCH₃), 3.17 (dd, J = 14.1/8.7 Hz, 1 H, CH₂CHC=O), 3.41

(6S)-13b. The diastereomers were separated by preparative HPLC

[Phenomenex Gemini C18 5 µ, 250ϫ21.2 mm, MeOH/H₂O =

(dd, J = 14.9/6.7 Hz, 1 H, CH₂CHNO), 3.49 (dd, J = 14.9/3.2 Hz,

1 H, CH₂CHNO), 3.61 (dd, J = 14.1/5.5 Hz, 1 H, CH₂CHC=O),

75:25, flow 13 mL/min, λ = 254 nm, 30 mg, t_R[(6R)-12b] = 3.70 (t, J = 8.6 Hz, 1 H, OCH₂CH), 4.05 (dd, J = 8.6/5.5 Hz, 1 H,

41.0 min, t_R[(6S)-13b] = 46.3 min].

CH₂CHC=O), 4.42 (t, J = 8.6 Hz, 1 H, OCH₂CH), 5.19 (dd, J =

6.3/3.6 Hz, 1 H, CH₂CHNO), 5.35 (t, J = 8.2 Hz, 1 H, OCH₂CH),

6.76–7.30 (m, 13 H, arom.). ¹³C NMR (CDCl₃): δ [ppm] = 19.5 (1

C, ArCH₃); 35.1 (1 C, CH₂CHC=O), 37.6 (1 C, CH₂CHON), 52.2

(1 C, CH₂CHC=O), 61.0 (1 C, CHCH₂O), 71.8 (1 C, CHCH₂O),

89.3 (1 C, CH₂CHON), 125.8, 126.4, 126.5, 127.8, 128.9, 129.8,

130.3, 130.3, 133.0, 136.8, 137.4, 137.8, 140.0 (18 C, arom.), 169.4

(1 C, CONR₂).

(6R)-12b: Colorless solid, m.p. 142.7–143.5 °C, yield 79.6 mg

20

(43%), de 100% (HPLC). [α]

= –98.8 (c = 0.52, CH₂Cl₂).

589

C₂₆H₂₅NO₂(383.5). Calcd. C 81.43, H 6.57, N 3.65, found 80.91,

H 6.71, N 3.39. MS (EI): m/z = 383 [M], 279 [M – CH₂CHPhenyl],

91 [C H ]. IR: ν = 3025, 2918, 2865 (C–H), 1658 (C=O). ¹H NMR

˜

7

(CDCl₃): δ [ppm] = 2.08–2.16 (m, 1 H, CH₂CH₂CH), 2.52–2.69 (m,

3 H, CH₂CH₂CH), 3.28 (dd, J = 15.5/4.1 Hz, 1 H, CH₂CHNO),

3.40 (dd, J = 15.6/4.4 Hz, 1 H, CH₂CHNO), 3.63 (t, J = 8.2 Hz, 1

H, OCH₂CH), 3.72 (t, J = 6.8 Hz, 1 H, CH₂CHC=O), 4.25 (t, J =

1

(6S)-13c: Colorless solid, yield: 6.1 mg (4.4%). H NMR (CDCl₃):

δ [ppm] = 2.17 (s, 3 H, ArCH₃), 3.19 (dd, J = 15.0/8.2 Hz, 1 H,

CH₂CHC=O), 3.29 (dd, J = 14.9/3.1 Hz, 1 H, CH₂CHNO), 3.45–

3.53 (m, 2 H, CH₂CHNO, CH₂CHC=O), 3.79 (dd, J = 8.8/5.4 Hz,

1 H, OCH₂CH), 4.22 (dd, J = 7.9/6.6 Hz, 1 H, CH₂CHC=O), 4.39

(dd, J = 8.7/7.8 Hz, 1 H, OCH₂CH), 5.29–5.33 (m, 2 H,

CH₂CHNO, OCH₂CH), 6.85–7.23 (m, 13 H, arom.).

8.5 Hz,

1 H, OCH₂CH), 5.13–5.18 (m, 2 H, CH₂CHNO,

OCH₂CH), 7.06–7.28 (m, 14 H, arom.). ¹³C NMR (CDCl₃): δ

[ppm] = 30.8 (1 C, CH₂CH₂Ph), 33.9 (1 C, CH₂CH₂Ph), 36.9 (1 C,

CH₂CHON), 47.6 (1 C, CH₂CHC=O), 60.4 (1 C, CHCH₂O), 71.6

(1 C, CHCH₂O), 88.4 (1 C, CH₂CHON), 126.2, 126.4, 126.5, 127.6,

127.7, 128.1, 128.6, 128.8, 129.0, 130.5, 133.3, 138.3, 140.5, 141.8

(18 C, arom.), 169.1 (1 C, CONR₂).

5.23. (3S,6S,11aR)-6-(2-Methylbenzyl)-3-phenyl-2,3,11,11a-tetra-

hydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6S-12c)] and

(3S,6R,11aR)-6-(2-Methylbenzyl)-3-phenyl-2,3,11,11a-tetrahydro-

[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6S-13c)]: The synthesis

of (6S)-12c was performed as described for (6R)-12c using (3S)-

10 (176 mg, 0.629 mmol) in THF (45 mL), LDA solution (377 µL,

0.754 mmol) and 2-methylbenzyl bromide (92.3 µL, 0.691 mmol).

(6S)-13b: Colorless solid, yield 7.4 mg (3.9%). C₂₆H₂₅NO₂(383.5).

¹H NMR (CDCl₃): δ [ppm] = 2.20–2.25 (m, 1 H, CH₂CH₂CH),

2.58–2.72 (m, 3 H, CH₂CH₂CH), 3.28 (dd, J = 14.7/3.4 Hz, 1 H,

CH₂CHNO), 3.45 (dd, J = 14.7/10.4 Hz, 1 H, CH₂CHNO), 3.82

(dd, J = 8.6/5.8 Hz, 1 H, OCH₂CH), 3.93 (t, J = 7.3 Hz, 1 H,

CH₂CHC=O), 4.46 (t, J = 8.2 Hz, 1 H, OCH₂CH), 5.19 (dd, J

= 10.6/3.2 Hz, 1 H, CH₂CHNO), 5.40 (dd, J = 7.5/5.9 Hz, 1 H,

OCH₂CH), 7.11–7.31 (m, 14 H, arom.).

(6S)-12c: Colorless solid, yield 89.6 mg (37%), de 98.7% (HPLC).

20

[α]

= +73.2 (c = 0.87, CH₂Cl₂). HPLC purity: a) Phenomenex

589

Gemini C18, 80% MeOH/20% H₂O, flow 0.8 mL/min, λ = 254 nm,

t_R= 14.9 min, purity 94.8%; b) Phenomenex Gemini C18, 80%

MeOH/20% H₂O, flow 0.8 mL/min, λ = 220 nm, t_R= 14.8 min,

purity 95.5 %. mp: 69.5–71.2 °C. (6R)-13c: Colorless solid, yield

3.1 mg (1.3%).

5.21. (3S,6S,11aR)-6-Phenethyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]-

oxazolo[2,3-b][3]benzazepin-5(6H)-one [(S)-12b] and (3S,6R,11aR)-

6-Phenethyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benz-

azepin-5(6H)-one [(R)-13b]: The synthesis of (6S)-12b was per-

formed as described for (6R)-12b. (3S)-10 (230 mg, 0.823 mmol) in

THF (57 mL) was treated with LDA solution (535 µL, 1.07 mmol)

and 2-phenylethy iodide (143 µL, 0.99 mmol). (6S)-12b: Colorless

5.24. (3R,6R,11aS)-6-(4-Methoxybenzyl)-3-phenyl-2,3,11,11a-tetra-

hydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6R)-12d] and

(3R,6S,11aS)-6-(4-Methoxybenzyl)-3-phenyl-2,3,11,11a-tetrahydro-

[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6S)-13d]: According to

the General Procedure A oxazolo-benzazepinone (3R)-10 (173 mg,

0.618 mmol) in THF (45 mL) was treated with LDA solution

(371 µL, 0.741 mmol) and 4-methoxybenzyl bromide (97.9 µL

0.680 mmol). The residue was purified by fc (Ø 3 cm, cyclohexane/

ethyl acetate = 15:2, 10 mL), R_f[(6R)-12d] = 0.27, R_f[(6S)-13d]

= 0.22 in cyclohexane/ethyl acetate = 5:2 to obtain a mixture of

diastereomers, yield 193.0 mg (78%), diastereomeric ratio (HPLC):

92.8:7.2 [(6R)-12d:(6S)-13d]. The diastereomers were separated by

p r e p a r at i v e H P LC [ P h e n o m e n e x G e m i n i C 1 8 5 µ m ,

250ϫ21.2 mm, MeOH/H₂O = 75:25, flow 14 mL/min, λ = 254 nm,

50 mg, t_R[(6R)-12d] = 26.3 min, t_R[(6S)-13d] = 28.3 min].

solid, m.p. 141.9–142.7 °C, yield 126 mg (40%), de 100% (HPLC).

20

[α] = +102.7 (c = 0.81, CH₂Cl₂). (6R)-13b: Colorless solid, yield

589

13.5 mg (4.3%).

5.22. (3R,6R,11aS)-6-(2-Methylbenzyl)-3-phenyl-2,3,11,11a-tetra-

hydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6R)-12c] and

(3R,6S,11aS)-6-(2-Methylbenzyl)-3-phenyl-2,3,11,11a-tetrahydro-

[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6S)-13c]: According to

the General Procedure A oxazolo-benzazepinone (3R)-10 (100 mg,

0.358 mmol) in THF (25 mL) was treated with LDA solution

(215 µL, 0.430 mmol) and 2-methylbenzyl bromide (52.6 µL

0.394 mmol). The residue was purified by fc [Ø 2 cm, cyclohexane/

ethyl acetate = 15:2, 5 mL, R_f[(6R)-12c] = 0.37, R_f[(6S)-13c] =

0.32 in cyclohexane/ethyl acetate = 5:2]. to obtain a mixture of

diastereomers: 114.2 mg (83 %), diastereomeric ratio (HPLC):

93.3:6.7 [(6R)-12c:(6S)-13c]. The diastereomers were separated by

p r e p a r at i v e H P LC [ P h e n o m e n e x G e m i n i C 1 8 5 µ m ,

250ϫ21.2 mm, MeOH/H₂O = 75:25, flow 14 mL/min, λ = 254 nm,

23 mg, t_R[(6R)-12c] = 38.2 min, t_R[(6S)-13c] = 40.2 min].

(6R)-12d: Colorless solid, m.p. 65.2–66.1 °C, yield 98.9 mg (40%),

20

de 98.6% (HPLC). [α] = –106.9 (c = 0.98, CH₂Cl₂). C₂₆H₂₅NO₃

589

(399.5). HPLC purity: a) Phenomenex Gemini C18 5 µm, 75%

MeOH/25% H₂O, flow 0.8 mL/min, λ = 254 nm, t_R= 21.5 min,

purity 97.6 %; b) RP Select B LiChrospher, 80 % CH₃CN/20%

H₂O, flow 0.8 mL/min, λ = 254 nm, t_R= 5.7 min, purity 96.7%.

(6R)-12c: Colorless solid, m.p. 69.2–71.4 °C, yield 77.0 mg (56%),

MS (EI): m/z = 399 [M], 121 [CH C H OCH ]. IR: ν = 2931, 2834

˜

2 6 4 3

20

1

de 99.3% (HPLC). [α] = –74.7 (c = 0.56, CH₂Cl₂). C₂₆H₂₅NO₂

(C–H), 1651 (C=O), 1245 (O–CH₃). H NMR (CDCl₃): δ [ppm] =

3.11 (dd, J = 13.6/7.3 Hz, 1 H, CH₂CHC=O), 3.26 (dd, J = 15.1/

5.3 Hz, 1 H, CH₂CHNO), 3.48 (dd, J = 15.3/3.5 Hz, 1 H,

CH₂CHNO), 3.58 (dd, J = 13.7/7.0 Hz, 1 H, CH₂CHC=O), 3.67

(t, J = 8.5 Hz, 1 H, OCH₂CH), 3.75 (s, 3 H, OCH₃), 4.04 (t, J =

7.1 Hz, 1 H, CH₂CHC=O), 4.35 (t, J = 8.4 Hz, 1 H, OCH₂CH),

589

(383.5). HPLC purity: a) Phenomenex Gemini C18, 80 % Meth-

anol/20% H₂O, flow 0.8 mL/min, λ = 254 nm, t_R= 19.0 min, purity

98.5%; b) RP Select B LiChrospher, 60% CH₃CN/40% H₂O, flow

0.6 mL/min, λ = 254 nm, t_R= 9.9 min, purity 97.8%. MS (EI): m/z

= 383 [M], 278 [M – CH CH Phenyl], 77 [C H ]. IR: ν = 3026,

˜

2

3

6

5

470

www.eurjoc.org

Eur. J. Org. Chem. 2007, 462–475

Tetrahydro-3-benzazepines as NMDA Receptor Antagonists

FULL PAPER

5.18 (t, J = 4.5 Hz, 1 H, CH₂CHNO), 5.28 (t, J = 8.0 Hz, 1 H, 5.27. (3S,6S,11aR)-6-Methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]-

OCH₂CH), 6.96–7.29 (m, 13 H, arom.). ¹³C NMR (CDCl₃): δ oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6S)-12e] and (3S,6R,11aR)-

[ppm] = 35.9 (1 C, CH₂CHC=O), 37.4 (1 C, CH₂CHON), 52.3 (1 6-Methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benz-

C, CH₂CHC=O), 55.4 (1 C, OCH₃), 60.6 (1 C, CHCH₂O), 71.6 (1 azepin-5(6H)-one [(6R)-13e]: The synthesis of (6S)-12e was per-

C, CHCH₂O), 88.8 (1 C, CH₂CHON), 126.3, 127.7, 128.0, 128.9, formed as described for (6R)-12e using (3S)-10 (214 mg,

130.3, 130.4, 132.1, 133.1, 137.9, 140.1 (18 C, arom.), 169.1 (1 C,

CONR₂).

0.766 mmol) in THF (45 mL), LDA solution (460 µL, 0.920 mmol)

and methyl iodide (52.5 µL, 0.843 mmol). (6S)-12e: Colorless solid,

m.p. 167.2–168.8 °C, yield 83.4 mg (37 %), de 100 % (HPLC).

1

(6S)-13d: Colorless solid, yield 4.2 mg (1.7%). H NMR (CDCl₃):

20

[α] = +187.7 (c = 0.33, CH₂Cl₂). HPLC-purity: a) Phenomenex

589

δ [ppm] = 3.11 (dd, J = 14.3/7.3 Hz, 1 H, CH₂CHC=O), 3.25 (dd,

J = 14.9/3.2 Hz, 1 H, CH₂CHNO), 3.43–3.54 (m, 2 H, CH₂CHNO,

CH₂CHC=O), 3.77 (dd, J = 9.0/5.5 Hz, 1 H, OCH₂CH), 3.68 (s, 3

H, OCH₃), 4.22 (t, J = 7.3 Hz, 1 H, CH₂CHC=O), 4.37 (t, J =

8.4 Hz, 1 H, OCH₂CH), 5.19 (dd, J = 10.6/3.1 Hz, 1 H,

CH₂CHNO), 5.30 (t, J = 6.5 Hz, 1 H, OCH₂CH), 6.59–7.24 (m,

13 H, arom.).

Gemini C18 5 µm, 75% MeOH/25% H₂O flow 0.6 mL/min, λ =

254 nm, t_R= 10.8 min, purity 99.4%; b) RP Select B LiChrospher,

80 % CH₃CN/20 % H₂O, flow 0.6 mL/min, λ = 254 nm, t_R

=

7.1 min, purity 99.8 %. (6R)-13e: Colorless solid, yield 20.6 mg

(9.2%).

5.28. (2R)-2-[(1R)-1-Benzyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-

yl]-2-phenylethan-1-ol [(1R)-14a]: According to the General Pro-

cedure B AlCl₃(49.3 mg, 0.37 mmol) in THF (3 mL) and LiAlH₄

solution (1.12 mL, 1.12 mmol) were treated with (6R)-12a (148 mg,

0.40 mmol) in THF (3 mL). The residue was purified by fc (Ø 2 cm,

5.254. (3S,6S,11aR)-6-(4-Methoxybenzyl)-3-phenyl-2,3,11,11a-

tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6S)-12d] and

(3S,6R,11aR)-6-(4-Methoxybenzyl)-3-phenyl-2,3,11,11a-tetrahydro-

[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6R)-13d]: The synthe-

sis of (6S)-12d was performed as described for (6R)-12d using (3S)-

10 (173 mg, 0.62 mmol) in THF (45 mL), LDA solution (372 µL,

0.744 mmol) and 4-methoxybenzyl bromide (98.3 µL, 0.682 mmol).

cyclohexane/ethyl acetate = 8:2, 5 mL, R_f= 0.23). Colorless solid,

20

m.p. 99.7–100.2 °C, yield 115 mg (80%). [α] = –41.6 (c = 1.45,

589

CH₂Cl₂). C₂₅H₂₇NO (357.5). Calcd. C 83.99, H 7.61, N 3.92, found

C 83.25, H 7.58, N 3.80. HPLC purity: a) RP 18 Superspher^®100,

80 % MeOH/20 % H₂O +0.1 % Et₂NH, flow 0.8 mL/min, λ =

254 nm, t_R= 26.0 min, purity 98.2%, b) RP 8e LiChrospher^®100,

60 % CH₃CN/40 % H₂O + 0.1 % Et₂NH, flow 0.8 mL/min, λ =

254 nm, t_R= 29.0 min, purity 96.8%. MS (EI): m/z = 326 [M –

(6S)-12d: Colorless solid, m.p. 64.8–65.9 °C, yield 91.2 mg (37%),

de 100% (HPLC). [α] = +105.3 (c = 0.85, CH₂Cl₂). C₂₆H₂₅NO₂

20

589

(399.5). HPLC-purity: a) Phenomenex Gemini C18 5 µm, 80%

MeOH/20% H₂O flow 0.8 mL/min, λ = 254 nm, t_R= 13.0 min,

purity 99.8 %; b) RP Select B LiChrospher, 60 % CH₃CN/40 %

H₂O, flow 0.8 mL/min, λ = 254 nm, t_R= 14.6 min, purity 99.8%.

(6R)-13d: Colorless solid, yield 6.6 mg (2.7%).

CH OH], 91 [C H ]. IR: ν = 3448 (O–H), 3025, 2923, 2848 (C–H).

˜

2

7

¹H NMR ([D₆]DMSO): δ [ppm] = 2.12–2.17 (m, 1 H, CH₂CH₂N),

2.38–2.41 (m, 1 H, CHCH₂N), 2.59–2.61 (m, 1 H, CHCH₂N), 2.78

(dd, J = 14.9/7.0 Hz, 1 H, PhCH₂CH), 2.85–2.94 (m, 2 H,

CH₂CH₂N, CH₂CH₂N), 3.06–3.15 (m, 3 H, CH₂CH₂N,

PhCH₂CH, PhCH₂CH), 3.55–3.64 (m, 2 H, CHCH₂OH,

CHCH₂OH), 3.77–3.81 (m, 1 H, CHCH₂OH), 4.37–4.40 (m, 1 H,

OH), 6.90–7.25 (m, 14 H, arom.). ¹³C NMR ([D₆]DMSO): δ [ppm]

= 37.2 (1 C, PhCH₂CH), 37.9 (1 C, CH₂CH₂N), 49.5 (1 C,

PhCH₂CH), 52.5 (1 C, CH₂CH₂N), 56.9 (1 C, CHCH₂N), 61.9 (1

C, CHCH₂OH), 72.1 (1 C, CHCH₂OH), 126.4, 126.5, 126.6, 127.5,

128.4, 128.7, 129.0, 129.2, 129.8, 130.2, 139.0, 141.5, 141.7, 144.8

(18 C, arom.).

5.26. (3R,6R,11aS)-6-Methyl-3-phenyl-2,3,11,11a-tetrahydro-

[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one [(6R)-12e] and

(3R,6S,11aS)-6-Methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo-

[2,3-b][3]benzazepin-5(6H)-one [(6S)-13e]: According to the General

Procedure A oxazolo-benzazepinone (3R)-10 (194 mg, 0.700 mmol)

in THF (20 mL) was treated with LDA solution (417 µL,

0.835 mmol) and methyl iodide (47.6 µL 0.765 mmol). The residue

was purified by fc [Ø 3 cm, cyclohexane/ethyl acetate = 8:2, 5 mL,

R_f[(6R)-12e] = 0.33, R_f[(6S)-13e] = 0.26 in cyclohexane/ethyl ace-

tate = 5:2] to obtain a mixture of diastereomers, yield 168.1 mg

(82%), diastereomeric ratio (HPLC): 80.3:19.7 [(6R)-12e:(6S)-13e].

The diastereomers were separated by preparative HPLC [Phe-

nomenex Gemini C18 5 µ, 250ϫ21.2 mm, MeOH/H₂O = 75/25,

flow 12 mL/min, λ = 254 nm, 23 mg, t_R[(6R)-12e] = 13.4 min,

t_R[(6S)-13e] = 17.2 min].

5.29. (2S)-2-[(1S)-1-Benzyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-

yl]-2-phenylethan-1-ol [(1S)-14a]: The synthesis of (1S)-14a was per-

formed as described for (1R)-14a according to the General Pro-

cedure B using AlCl₃(38.9 mg, 0.292 mmol) in THF (3 mL), Li-

AlH₄solution (881 µL, 0.881 mmol) and (6S)-12a (117 mg,

(6R)-12e: Colorless solid, m.p. 166.3 °C, yield 113.6 mg (55%), de

= –184.8 (c = 0.63, CH₂Cl₂). C₁₉H₁₉NO₂

(293.4) Calcd. C 77.79, H 6.53, N 4.77, found C 77.63, H 6.73, N

20

0.317 mmol) in THF (4 mL). Colorless solid, m.p. 100.1–100.7 °C,

100% (HPLC). [α]

589

20

yield 97.7 mg (86%). [α] = +44.2 (c = 0.49, CH₂Cl₂). C₂₅H₂₇NO

589

(357.5). HPLC-purity: a) RP 18 Superspher^®100, 80% MeOH/20%

H₂O + 0.1% Et₂NH, flow 0.8 mL/min, λ = 220 nm, t_R= 19.2 min,

purity 98.2%; b) RP 8e LiChrospher^®100, 60% CH₃CN/40% H₂O

+ 0.1% Et₂NH, flow 0.8 mL/min, λ = 220 nm, t_R= 22.5 min, pu-

rity 96.4%.

4.54. MS (EI): m/z = 293 [M], 120 [PhCHCH₂O], 91 [C₇H₇], 77

[C H ]. IR: ν = 3030, 2872 (C–H), 1653 (C=O). ¹H NMR (CDCl ):

˜

6

5

3

δ [ppm] = 1.57 (d, J = 7.1 Hz, 3 H, CH₃CH), 3.37 (dd, J = 15.4/

3.9 Hz, 1 H, CH₂CHNO), 3.59 (dd, J = 15.4/4.2 Hz, 1 H,

CH₂CHNO), 3.72 (dd, J = 8.9/7.5 Hz, 1 H, OCH₂CH), 4.02 (q, J

= 7.0 Hz, 1 H, CH₃CH), 4.31 (dd, J = 8.8/8.2 Hz, 1 H, OCH₂CH),

5.20 (t, J = 7.8 Hz, 1 H, OCH₂CH), 5.31 (t, J = 4.0 Hz, 1 H,

CH₂CHNO), 7.24–7.34 (m, 9 H, arom.).

(6S)-13e: Colorless solid, yield 27.8 mg (13.5 %). ¹H NMR

(CDCl₃): δ [ppm] = 1.64 (d, J = 7.1 Hz, 3 H, CH₃CH), 3.27 (dd, J

= 13.9/3.2 Hz, 1 H, CH₂CHNO), 3.54 (dd, J = 13.8/11.2 Hz, 1 H,

CH₂CHNO), 3.74 (dd, J = 8.8/7.2 Hz, 1 H, OCH₂CH), 4.13 (q, J

5.30. (2R)-2-[(1R)-1-Phenethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-

3-yl]-2-phenylethan-1-ol [(1R)-14b]: According to the General Pro-

cedure B AlCl₃(28.7 mg, 0.215 mmol) in THF_abs.(3 mL) and Li-

AlH₄solution (0.65 mL, 0.65 mmol) were treated with (6R)-12b

(89.6 mg, 0.23 mmol) in THF (3 mL). The residue was purified by

fc (Ø 1 cm, cyclohexane/ethyl acetate = 8:2, 5 mL, R_f= 0.30). Col-

20

orless oil, yield 78.9 mg (91%). [α] = –20.0 (c = 1.19, CH₂Cl₂).

589

= 7.0 Hz, 1 H, CH₃CH), 4.48 (t, J = 8.5 Hz, 1 H, OCH₂CH), 4.93 C₂₆H₂₉NO (371.5). HPLC purity: a) Phenomenex Gemini C18

(dd, J = 11.2/3.1 Hz, 1 H, CH₂CHNO), 5.43 (t, J = 7.7 Hz, 1 H,

OCH₂CH), 7.08–7.33 (m, 9 H, arom.).

5 µm, 60% CH₃CN/40% H₂O + 0.1% Et₂NH, flow 0.8 mL/min, λ

= 220 nm, t_R= 68.3 min, purity 96.1%; b) RP 18 Superspher^®100,

Eur. J. Org. Chem. 2007, 462–475

www.eurjoc.org

471

U. Wirt, D. Schepmann, B. Wünsch

FULL PAPER

80 % MeOH/20 % H₂O + 0.1 % Et₂NH, flow 0.8 mL/min, λ =

254 nm, t_R= 37.0 min, purity 99.6%. MS (EI): m/z = 372 [M], 91

5.34. (2R)-2-[(1R)-1-(4-Methoxybenzyl)-2,3,4,5-tetrahydro-1H-3-

benzazepin-3-yl]-2-phenylethan-1-ol [(1R)-14d]: According to the

General Procedure B AlCl₃(30.7 mg, 0.230 mmol) in THF_abs.

[C H ]. IR: ν = 3426 (O–H), 3059, 3024, 2932 (C–H). ¹H NMR

˜

7

([D₆]DMSO): δ [ppm] = 1.82–1.91 (m, 1 H, CH₂CH₂CH), 2.00– (3 mL) and LiAlH₄solution (0.70 mL, 0.70 mmol) were treated

2.10 (m, 1 H, CH₂CH₂CH), 2.15–2.21 (m, 1 H, CHCH₂N), 2.31– with (6R)-12d (99.9 mg, 0.250 mmol) in THF (4 mL). The residue

2.38 (m, 1 H, ArCH₂CH₂N), 2.45–2.55 (m, 3 H, ArCH₂CH₂N),

2.68–2.76 (m, 2 H, CH₂CH₂CH, CH₂CH₂CH), 2.82–2.91 (m, 1 H, R_f= 0.28). Colorless oil, yield 86.0 mg (89%). [α] = –60.9 (c =

was purified by fc (Ø 2 cm, cyclohexane/ethyl acetate = 8:2, 5 mL,

20

589

CHCH₂N), 2.98–3.03 (m, 1 H, CH₂CH₂CH), 3.71–3.77 (m, 2 H, 1.46, CH₂Cl₂). C₂₆H₂₉NO₂(387.5). HPLC purity: a) Phenomenex

CHCH₂OH, CHCH₂OH), 3.88–3.95 (m, 1 H, CHCH₂OH), 4.40– Gemini C18 5 µm, 80% MeOH/20% H₂O + 0.1% Et₂NH, flow

4.43 (m, 1 H, OH) 6.96–7.30 (m, 14 H, arom.). ¹³C NMR ([D₆]- 1.0 mL/min, λ = 254 nm, t_R= 15.0 min, purity 96.6%; b) RP Select

DMSO): δ [ppm] = 33.6 (1 C, CH₂CH₂CH), 34.1 (1 C, CH₂CH₂N), B LiChrospher, 60 % CH₃CN/40 % H₂O + 0.1 % Et₂NH, flow

37.3 (1 C, CH₂CH₂CH), 47.9 (1 C, CH₂CH₂CH), 53.0 (1 C, 0.8 mL/min, λ = 220 nm, t_R= 17.3 min, purity 98.3%. MS (EI):

CH₂CH₂N), 56.9 (1 C, CHCH₂N), 61.6 (1 C, CH₂CHOH), 72.0 (1 m/z = 357 [M – OCH ], 121 [CH C H OCH ]. IR: ν = 3419 (O–

˜

3

2

6

4

3

C, CH₂CHOH) 126.3, 126.5, 126.6, 127.5, 128.4, 128.9, 129.1, H), 2932, 2831 (C–H), 1243 (O–CH₃). ¹H NMR ([D₆]DMSO): δ

129.3, 130.4, 139.6, 141.3, 143.0, 145.3 (18 C, arom.).

[ppm] = 2.09–2.18 (m, 1 H, CH₂CH₂N), 2.38–2.41 (m, 1 H,

CHCH₂N), 2.56–2.65 (m, 1 H, CHCH₂N), 2.75–2.87 (m, 3 H,

CH₂CH₂N, CH₂CH₂N), 2.98–3.12 (m, 3 H, PhCH₂CH,

PhCH₂CH), 3.55–3.64 (m, 2 H, CHCH₂OH, CHCH₂OH), 3.70 (s,

3 H, OCH₃), 3.78–3.83 (m, 1 H, CHCH₂OH), 4.38–4.41 (m, 1 H,

OH), 6.77–7.24 (m, 13 H, arom.). ¹³C NMR ([D₆]DMSO): δ [ppm]

= 37.0 (1 C, PhCH₂CH), 37.2 (1 C, CH₂CH₂N), 49.8 (1 C,

PhCH₂CH), 52.4 (1 C, CH₂CH₂N), 55.6 (1 C, OCH₃), 56.9 (1 C,

CHCH₂N), 61.9 (1 C, CHCH₂OH), 72.1 (1 C, CHCH₂OH), 126.5,

127.4, 128.4, 129.2, 130.2, 130.7, 133.5, 139.0, 141.5, 144.9, 160.0

(18 C, arom.).

5.31. (2S)-2-[(1S)-1-Phenethyl-2,3,4,5-tetrahydro-1H-3-benzazepin-

3-yl]-2-phenylethan-1-ol [(1S)-14b]: The synthesis of (1S)-14b was

performed as described for (1R)-14b using AlCl₃(38.8 mg,

0.291 mmol), LiAlH₄solution (879 µL, 0.879 mmol) and (6S)-12b

(121 mg, 0.316 mmol) in THF (4 mL). Colorless oil, yield 107 mg

20

(91%). [α]

= +20.2 (c = 1.05, CH₂Cl₂). HPLC purity: a) Phe-

589

nomenex Gemini C18 5 µm, 80 % MeOH/20 % H₂O + 0.1 %

Et₂NH, flow 1.2 mL/min, λ = 254 nm, t_R= 26.2 min, purity 99.6%;

b) RP Select B LiChrospher, 60 % CH₃CN/40 % H₂O + 0.1 %

Et₂NH, flow 1.2 mL/min, λ = 254 nm, t_R= 33.4 min, purity 97.9%.

5.35. (2S)-2-[(1S)-1-(4-Methoxybenzyl)-2,3,4,5-tetrahydro-1H-3-

benzazepin-3-yl]-2-phenylethan-1-ol [(1S)-14d]: The synthesis of

(1S)-14d was performed as described for (1R)-14d using AlCl₃

(27.6 mg, 0.207 mmol) in THF (3 mL), LiAlH₄solution (626 µL,

5.32. (2R)-2-[(1R)-1-(2-Methylbenzyl)-2,3,4,5-tetrahydro-1H-3-

benzazepin-3-yl]-2-phenylethan-1-ol [(1R)-14c]: According to the

General Procedure B AlCl₃(44.4 mg, 0.33 mmol) in THF (3 mL)

and LiAlH₄solution (1.00 mL, 1.00 mmol) were treated with (6R)-

12c (139 mg, 0.36 mmol) in THF (4 mL). The residue was purified

0.626 mmol) and (6S)-12d (90.0 mg, 0.225 mmol) in THF (4 mL).

20

Colorless oil, yield 76.0 mg (87%). [α]

= +63.2 (c = 1.32,

589

by fc (Ø 2 cm, cyclohexane/ethyl acetate = 8:2, 5 mL, R_f= 0.31).

CH₂Cl₂). HPLC purity: a) Phenomenex Gemini C18 5 µm, 80%

MeOH/20% H₂O + 0.1% Et₂NH, flow 1.0 mL/min, λ = 254 nm,

t_R= 11.1 min, purity 95.7%, b) RP Select B LiChrospher, 60%

CH₃CN/40% H₂O + 0.1% Et₂NH, flow 1.0 mL/min, λ = 220 nm,

t_R= 11.8 min, purity 96.4%.

20

Colorless solid, m.p. 116.6–117.8 °C, yield 115 mg (85%). [α]

=

589

–49.3 (c = 0.68, CH₂Cl₂). C₂₆H₂₉NO (371.5). HPLC purity: a) Phe-

nomenex Gemini C18 5 µm, 80 % MeOH/20 % H₂O + 0.1 %

Et₂NH, flow 1.0 mL/min, λ = 254 nm, t_R= 19.4 min, purity 97.3%;

b) RP Select B LiChrospher, 80 % CH₃CN/20 % H₂O + 0.1 %

Et₂NH, flow 1.0 mL/min, λ = 220 nm, t_R= 7.4 min, purity 96.3%.

5.36. (2R)-2-[(1R)-1-Methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-

MS (EI): m/z = 340 [M – CH OH]. IR: ν = 3482 (O–H), 3019, yl]-2-phenylethan-1-ol [(1R)-14e]: According to the General Pro-

˜

2

2931, 2832, (C–H). ¹H NMR ([D₆]DMSO): δ [ppm] = 2.10–2.17 cedure B AlCl₃(47.5 mg, 0.36 mmol) in THF (3 mL) and LiAlH₄

(m, 1 H, CH₂CH₂N), 2.14 (s, 3 H, CH₃), 2.35–2.38 (m, 1 H,

CHCH₂N), 2.67–2.73 (m, 1 H, CHCH₂N), 2.75–2.91 (m, 1 H, (113.6 mg, 0.39 mmol) in THF (3 mL). The residue was purified by

PhCH₂CH), 2.84–2.88 (m, 1 H, PhCH₂CH), 2.92–2.97 (m, 2 H, fc (Ø 2 cm, cyclohexane/ethyl acetate = 8:2, 5 mL, R_f= 0.20). Col-

solution (1.08 mL, 1.08 mmol) were treated with (6R)-12e

20

CH₂CH₂N, CH₂CH₂N), 3.10–3.18 (m, 2 H, CH₂CH₂N, orless oil, yield 98.7 mg (91%). [α] = –10.5 (c = 1.29, CH₂Cl₂).

589

PhCH₂CH), 3.61–3.70 (m, 2 H, CHCH₂OH, CHCH₂OH), 3.82– C₁₉H₂₃NO (281.4). HPLC purity: a) RP 18 LiChrospher^®100, 80%

3.87 (m, 1 H, CHCH₂OH), 4.42–4.44 (m, 1 H, OH), 6.79–7.26 (m,

MeOH/20% H₂O + 0.1% Et₂NH, flow 0.6 mL/min, λ = 254 nm,

13 H, arom.). ¹³C NMR ([D₆]DMSO): δ [ppm] = 19.7 (1 C, CH₃),

t_R= 14.8 min, purity 97.0%; b) RP 8e LiChrospher^®100, 60%

35.0 (1 C, PhCH₂CH), 37.4 (1 C, CH₂CH₂N), 48.6 (1 C, CH₃CN/40% H₂O + 0.1% Et₂NH, flow 0.6 mL/min, λ = 254 nm,

PhCH₂CH), 52.5 (1 C, CH₂CH₂N), 57.1 (1 C, CHCH₂N), 61.8 (1 t_R= 15.5 min, purity 99.1%. MS (EI): m/z = 250 [M – CH₂OH],

1

C, CHCH₂OH), 72.2 (1 C, CHCH₂OH), 126.2, 126.5, 126.6, 127.5, 91 [C H ], 77 [C H ]. IR: ν = 3409 (O–H), 2958, 2928 (C–H). H

˜

7

6

5

128.4, 129.3, 130.3, 130.5, 136.5, 139.0, 139.6, 141.5, 144.8 (18 C, NMR ([D₆]DMSO): δ [ppm] = 2.13 (d, J = 7.2 Hz, 3 H, CH₃),

arom.).

2.29–2.33 (m, 1 H, CHCH₂N), 2.50–2.60 (m, 2 H, CH₂CH₂N),

2.65–2.68 (m, 1 H, CHCH₂N), 2.83–2.85 (m, 2 H, CH₂CH₂N),

2.98–3.05 (m, 1 H, CH₃CH), 3.67–3.73 (m, 2 H, CHCH₂OH,

CHCH₂OH), 3.83–3.90 (m, 1 H, CHCH₂OH), 4.38–4.41 (m, 1 H,

OH), 7.00–7.27 (m, 9 H, arom.). ¹³C NMR ([D₆]DMSO): δ [ppm]

= 18.9 (1 C, CH₃), 37.0 (1 C, CH₂CH₂N), 53.1 (1 C, CH₂CH₂N),

59.0 (1 C, CHCH₂N), 61.8 (1 C, CHCH₂OH), 71.3 (1 C,

CHCH₂OH), 126.4, 126.7, 127.4, 128.4, 129.2, 129.8, 139.7, 141.7,

146.1 (12 C, arom.), the CH₃–CH signal is superimposed by the

DMSO signal.

5.33. (2S)-2-[(1S)-1-(2-Methylbenzyl)-2,3,4,5-tetrahydro-1H-3-

benzazepin-3-yl]-2-phenylethan-1-ol [(1S)-14c]: The synthesis of

(1S)-14c was performed as described for (1R)-14c using AlCl₃

(28.0 mg, 0.210 mmol) in THF_abs.(3 mL), LiAlH₄solution

(635 µL, 0.635 mmol) and (6S)-12c (87.6 mg, 0.228 mmol) in THF

(4 mL). Colorless solid, m.p. 116.6–117.5 °C, yield 72.3 mg (85%).

20

[α] = +47.9 (c = 1.38, CH₂Cl₂). C₂₆H₂₉NO (371.5). HPLC purity:

589

a) Phenomenex Gemini C18 5 µm, 80 % MeOH/20 % H₂O flow

1.0 mL/min, λ = 220 nm, t_R= 33.9 min, purity 97.9%; b) RP Select

B LiChrospher, 60 % CH₃CN/40 % H₂O + 0.1 % Et₂NH, flow

1.0 mL/min, λ = 220 nm, t_R= 29.7 min, purity 96.4%.

5.37. (2S)-2-[(1S)-1-Methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-3-

yl]-2-phenylethan-1-ol [(1S)-14e]: The synthesis of (1S)-14e was per-

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Tetrahydro-3-benzazepines as NMDA Receptor Antagonists

FULL PAPER

yellow oil, yield 44.3 mg (66%). [α] = –16.1 (c = 2.00, CH₂Cl₂).

C₁₈H₂₁N (251.4). HPLC purity: a) Phenomenex Gemini C18, 80%

Methanol/20% H₂O + 0.1% Et₂NH, flow 0.8 mL/min, λ = 220 nm,

t_R= 15.7 min, purity 98.2%; b) RP Select B LiChrospher, 60%

CH₃CN/40% H₂O + 0.1% Et₂NH, flow 1.0 mL/min, λ = 220 nm,

t_R= 26.1 min, purity 97.1%.

20

formed as described for (1R)-14e using AlCl₃(35.0 mg,

0.262 mmol) in THF (3 mL), LiAlH₄solution (793 µL,

589

0.793 mmol) and (6S)-12e (83.7 mg, 0.285 mmol) in THF (4 mL).

20

Colorless oil, yield 58.0 mg (72%). [α]

= +15.6 (c = 2.86,

589

CH₂Cl₂). HPLC purity: a) Phenomenex Gemini C18 5 µm, 80%

MeOH/20% H₂O + 0.1% Et₂NH, flow 0.6 mL/min, λ = 254 nm,

t_R= 20.2 min, purity 95.8%, b) RP Select B LiChrospher, 80%

CH₃CN/20% H₂O + 0.1% Et₂NH, flow 1.0 mL/min, λ = 254 nm,

t_R= 5.3 min, purity 97.0%.

5.42. (R)-1-(2-Methylbenzyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

[(R)-15c]: According to the General Procedure C (1R)-14c

(99.5 mg, 0.268 mmol) in MeOH (20 mL) was treated with ammo-

nium formate (169 mg, 2.68 mmol) and Pd/C (10.0 mg). The resi-

due was purified by fc (Ø 2 cm, CH₂Cl₂/methanol = 8:1, 5 mL, R_f

= 0.29). The combined fractions were dried (K₂CO₃) and concen-

trated in vacuo. Pale yellow oil, yield 36.4 mg (54%). [α]²₅₈⁰₉= –48.1

(c = 1.66, CH₂Cl₂). C₁₈H₂₁N (251.4). HPLC purity: a) Phenomenex

Gemini C18 5 µm, 80% MeOH/20% H₂O + 0.1% Et₂NH, flow

0.8 mL/min, λ = 254 nm, t_R= 9.6 min, purity 99.2%; b) RP Select

B LiChrospher, 80 % CH₃CN/20 % H₂O + 0.1 % Et₂NH, flow

1.0 mL/min, λ = 254 nm, t_R= 9.4 min, purity 98.3%. MS (EI): m/z

5.38. (R)-1-Benzyl-2,3,4,5-tetrahydro-1H-3-benzazepine [(R)-15a]:

According to the General Procedure C a solution of (1R)-14a

(72.4 mg, 0.203 mmol) in MeOH (20 mL) was treated with ammo-

nium formate (128 mg, 2.0 mmol) and Pd/C (7.2 mg). The residue

was purified by fc (Ø 1 cm, CH₂Cl₂/acetone = 1:8, 5 mL, R_f= 0.10).

20

Pale yellow oil, yield 35.7 mg (74%). [α]

= –35.0 (c = 0.67,

589

CH₂Cl₂). C₁₇H₁₉N (237.4). HPLC purity: a) RP 18 Superspher^®

100, 80% MeOH/20% H₂O + 0.1% Et₂NH, flow 0.6 mL/min, λ =

254 nm, t_R= 20.7 min, purity 95.2%; b) RP 8e LiChrospher^®100,

60 % CH₃CN/40 % H₂O + 0.1 % Et₂NH, flow 0.6 mL/min, λ = = 252 [M], 236 [M – NH], 146 [M – CH C H CH ]. IR: ν = 3344

˜

2

6

4

3

254 nm, t_R= 15.6 min. purity 96.6%. MS (EI): m/z = 237 [M], 222

(N–H), 3013, 2927, 2815 (C–H), 1490, 1448 (C–H). ¹H NMR

[M – NH], 146 [M – benzyl], 91 [C H ]. IR: ν = 3343 (N–H), 3060, (CDCl₃): δ [ppm] = 2.25 (s, 3 H, CH₃), 2.81–2.93 (m, 2 H, ArCH₂,

˜

7

3023, 2925, 2816 [υ(C–H)], 1491, 1452 [δ(C–H)]. ¹H NMR CH₂NH), 3.00–3.14 (m, 5 H, ArCH₂, CH₂NH, CH), 3.17–3.27 (m,

(CDCl₃): δ [ppm] = 2.06 (m, 1 H, NH), 2.75–2.93 (m, 4 H, 2 H, ArCH₂, CH₂NH), 6.89–7.26 (m, 8 H, arom.). ¹³C NMR

CH₂NHCH₂), 2.99–3.15 (m, 5 H, ArCH₂, ArCH, PhCH₂), 6.91– (CDCl₃): δ [ppm] = 19.7 (3 C, CH₃), 34.9 (1 C, ArCH₂), 40.0 (1 C,

7.20 (m, 9 H, arom.).

ArCH₂), 49.0 (1 C, CH₂NH), 49.9 (1 C, CH), 52.0 (1 C, CH₂NH),

125.9, 129.4, 130.2, 130.5, 136.5, 139.3, 141.2, 144.3 (12 C, arom.).

5.39. (S)-1-Benzyl-2,3,4,5-tetrahydro-1H-3-benzazepine [(S)-15a]:

The synthesis of (S)-15a was performed as described for (R)-15a.

5.43. (S)-1-(2-Methylbenzyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

(1S)-14a (83 mg, 0.232 mmol) in CH₃OH (15 mL) was treated with [(S)-15c]: The synthesis of (S)-15c was performed as described for

ammonium formate (146.4 mg, 2.32 mmol) and Pd/C (8.3 mg). Pale

(R)-15c using (1S)-14c (65.5 mg, 0.176 mmol) in MeOH (15 mL),

20

yellow oil, yield 49.3 mg (90%). [α] = +34.7 (c = 0.27, CH₂Cl₂).

ammonium formate (111.2 mg, 1.76 mmol) and Pd/C (6.5 mg). Pale

589

HPLC purity: a) RP 18 Superspher^®100, 60% CH₃CN/40% H₂O

+ 0.1% Et₂NH, flow 0.6 mL/min, λ = 254 nm, t_R= 28.5 min, pu-

rity 96.2%; b) Phenomenex Gemini C18, 80% MeOH/20% H₂O +

0.1% Et₂NH, flow 0.6 mL/min, λ = 254 nm, t_R= 12.9 min, purity

96.4%.

yellow oil, yield 24.0 mg (54%). [α] = +48.4 (c = 0.21, CH₂Cl₂).

20

589

C₁₈H₂₁N (251.4). HPLC purity: a) Phenomenex Gemini C18, 80%

MeOH/20% H₂O + 0.1% Et₂NH, flow 0.8 mL/min, λ = 254 nm,

t_R= 11.2 min, purity 97.2%; b) RP Select B LiChrospher, 80%

CH₃CN/20% H₂O + 0.1% Et₂NH, flow 1.0 mL/min, λ = 254 nm,

t_R= 8.5 min, purity 96.5%.

5.40. (R)-1-Phenethyl-2,3,4,5-tetrahydro-1H-3-benzazepin [(R)-15b]:

According to the General Procedure C (1R)-14b (54.1 mg,

0.146 mmol) in MeOH (15 mL) was treated with ammonium for-

mate (91.8 mg, 1.46 mmol) and Pd/C (5.4 mg). The residue was

purified by fc (Ø 2 cm, CH₂Cl₂/methanol = 8:1, 5 mL, R_f= 0.40).

5.44. (R)-1-(4-Methoxybenzyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

[(R)-15d]: According to the General Procedure C (1R)-14d

(76.5 mg, 0.197 mmol) in MeOH (18 mL) was treated with ammo-

nium formate (125 mg, 1.97 mmol) and Pd/C (7.7 mg). The residue

was purified by fc (Ø 2 cm, CH₂Cl₂/methanol = 8:1, 5 mL, R_f=

0.25). The combined fractions were dried (K₂CO₃) and concen-

trated in vacuo. Pale yellow oil, yield 27.4 mg (52%). [α]²₅₈⁰₉= –60.9

(c = 1.01, CH₂Cl₂). C₁₈H₂₁NO (267.4). HPLC purity: a) Phe-

nomenex Gemini C18 5 µm, 80 % MeOH/20 % H₂O + 0.1 %

Et₂NH, flow 0.8 mL/min, λ = 254 nm, t_R= 7.9 min, purity 96.6%,

b) RP Select B LiChrospher, 60 % CH₃CN/40 % H₂O + 0.1 %

Et₂NH, flow 1.0 mL/min, λ = 254 nm, t_R= 12.8 min, purity 98.3%.

MS (EI): m/z = 267 [M], 146 [M – CH₂C₆H₄OCH₃], 121

The combined fractions were dried (K₂CO₃) and concentrated in

20

vacuo. Pale yellow oil, yield 21.4 mg (58%). [α]

= +17.0 (c =

589

0.38, CH₂Cl₂). C₁₈H₂₁N (251.4). HPLC purity: a) Phenomenex

Gemini C18, 80 % Methanol/20 % H₂O + 0.1 % Et₂NH, flow

0.8 mL/min, λ = 254 nm, t_R= 11.9 min, purity 97.8%; b) RP Select

B LiChrospher, 60 % CH₃CN/40 % H₂O + 0.1 % Et₂NH, flow

1.0 mL/min, λ = 254 nm, t_R= 24.1 min, purity 98.3%. MS (EI):

m/z = 251 [M], 236 [M – NH], 147 [PhCH₂CH₂CHCH₂NH], 91

[C H ]. IR: ν = 3343 (N–H), 3022, 2924, 2852 (C–H), 1491, 1452

˜

7

(C–H). ¹H NMR (Pyridin-D₅): δ [ppm] = 0.95–0.99 (m, 2 H,

CH₂CH₂CH), 1.31–1.38 (m, 1 H, CH₂CH₂CH), 1.44–1.54 (m, 3 1490, 1448 (C–H). H NMR (CDCl₃): δ [ppm] = 2.83–2.91 (m, 2

H, CH₂CH₂NH, CH₂CH₂NH, CH₂CH₂CH), 1.57–1.62 (m, 1 H, H, CH₂NH, ArCH₂), 2.93–2.97 (m, 2 H, CH₂NH), 3.02–3.04 (m,

[CH C H OCH ]. IR: ν = 3344 (N–H), 3013, 2927, 2815 (C–H),

˜

2 6 4 3

1

CHCH₂NH), 1.72–1.76 (m, 1 H, CHCH₂NH), 1.89–1.98 (m, 3 H, 2 H, ArCH₂), 3.07–3.21 (m, 3 H, CH, CH₂NH, ArCH₂), 3.77 (s, 3

CH₂CH₂NH, CH₂CH₂NH, CHCH₂NH), 5.93–6.15 (m, 9 H, H, OCH₃), 6.71–7.26 (m, 8 H, arom.). ¹³C NMR (CDCl₃): δ [ppm]

arom.). ¹³C NMR (Pyridin-D₅): δ [ppm] = 32.1 (1 C, CH₂CH₂CH), = 36.9 (1 C, ArCH₂), 39.5 (1 C, ArCH₂), 48.7 (1 C, CH₂NH), 50.5

33.2 (1 C, CH₂CH₂CH), 38.9 (1 C, CH₂CH₂NH), 48.0 (1 C, (1 C, CH), 51.4 (1 C, CH₂NH), 55.5 (1 C, OCH₃), 126.5, 129.1,

CHCH₂), 48.3 (1 C, CH₂CH₂NH), 51.6 (1 C, CHCH₂), 124.9,

130.3, 130.4, 132.9, 141.0, 144.2, 158.1 (12 C, arom.).

125.2, 125.3, 127.6, 127.7, 129.7, 140.6, 142.0, 144.2 (12 C, arom.).

5.45. (S)-1-(4-Methoxybenzyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

[(S)-15d]: The synthesis of (S)-15d was performed as described for

(R)-15d using (1S)-14d (67.4 mg, 0.174 mmol) in MeOH (15 mL),

5.41. (S)-1-Phenethyl-2,3,4,5-tetrahydro-1H-3-benzazepine [(S)-

15b]: The synthesis of (S)-15b was performed as described for (R)-

15b using (1S)-14b (100 mg, 0.269 mmol) in methanol (15 mL), am-

ammonium formate (109.7 mg, 1.74 mmol) and Pd/C (6.7 mg). Pale

20

monium formate (170 mg, 2.69 mmol) and Pd/C (10.0 mg). Pale yellow oil, yield 19.5 mg (42%). [α] = +63.8 (c = 0.87, CH₂Cl₂).

589

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U. Wirt, D. Schepmann, B. Wünsch

FULL PAPER

HPLC purity: a) Phenomenex Gemini C18, 80% MeOH/20% H₂O

+ 0.1% Et₂NH, flow 0.8 mL/min, λ = 254 nm, t_R= 11.1 min, pu-

rity 98.9%, b) RP Select B LiChrospher, 60% CH₃CN/40% H₂O

+ 0.1% Et₂NH, flow 1.0 mL/min, λ = 220 nm, t_R= 16.9 min, pu-

rity 99.2%.

rated and centrifuged at 23500 g for 20 min at 4 °C. The pellet was

resuspended in buffer (5 m Tris-acetate with 1 m EDTA, pH 7.5)

and centrifuged again at 31000ϫ g (20 min, 4 °C). This procedure

was repeated twice. The final pellet was resuspended in buffer, the

protein concentration was determined according to the method of

Bradford^[24]using bovine serum albumin as standard, and sub-

sequently the preparation was frozen (–83 °C) in 1.5 mL portions

containing about 0.8 mg protein/mL.

5.46. (R)-1-Methyl-2,3,4,5-tetrahydro-1H-3-benzazepine [(R)-15e]:

According to the General Procedure C (1R)-14e (86.9 mg,

0.309 mmol) in MeOH (20 mL) was treated with ammonium for-

mate (195 mg, 3.09 mmol) and Pd/C (8.7 mg). The residue was 6.2.2. Performance of the Assay: The test was performed with the

purified by fc (Ø 1 cm, CH₂Cl₂/methanol = 8:1, 5 mL, R_f= 0.10).

radioligand [³H]-(+)-MK-801 (22.0 Ci/mmol; Perkin–Elmer). The

thawed membrane preparation (about 100 µg of the protein) was

incubated with various concentrations of test compounds, 2 nM

[³H]-(+)-MK-801, and TRIS/EDTA-buffer (5 m/1 m, pH 7.5) in

a total volume of 200 µL for 180 min at room temp. The incubation

was terminated by rapid filtration through the presoaked filtermats

using the cell harvester. After washing each well five times with

300 µL of water, the filtermats were dried at 95 °C. Subsequently,

the solid scintillator was placed on the filtermat and melted at

The combined fractions were dried (K₂CO₃) and concentrated in

20

vacuo. Pale yellow oil, yield 22.7 mg (46%). [α]

= +3.54 (c =

589

0.87, CH₂Cl₂). C₁₁H₁₅N (161.3). HPLC purity: a) Phenomenex

Gemini C18 5 µm, 80% MeOH/20% H₂O + 0.1% Et₂NH, flow

0.6 mL/min, λ = 254 nm, t_R= 8.3 min, purity 97.8%, b) RP Select

B LiChrospher, 80 % CH₃CN/20 % H₂O + 0.1 % Et₂NH, flow

1.2 mL/min, λ = 254 nm, t_R= 12.0 min, purity 97.4%. MS (EI):

m/z = 161 [M], 146 [M – NH], 119 [M – CH CHCH ]. IR: ν = 3358

˜

3

2

(N–H), 3016, 2924 (C–H), 1489, 1450 (C–H). ¹H NMR (CDCl₃): δ 95 °C. After 5 min, the solid scintillator was allowed to solidify at

[ppm] = 1.41 (d, J = 7.4 Hz, 3 H, CH₃), 2.80–2.83 (m, 1 H, room temperature. The bound radioactivity trapped on the filters

CHCH₂NH), 2.97–3.02 (m, 2 H, CH₂CH₂NH, ArCH₂), 3.18–3.21 was counted in the scintillation analyzer. The non-specific binding

(m, 3 H, CH₂CH₂NH, ArCH₂, CHCH₂NH), 3.30–3.34 (m, 1 H,

CH), 7.10–7.26 (m, 4 H, arom.). ¹³C NMR (CDCl₃): δ [ppm] =

18.1 (1 C, CH₃), 36.3 (1 C, ArCH₂), 38.6 (1 C, ArCH), 46.7 (1 C,

CH₂NH), 53.2 (1 C, CH₂NH), 126.9, 127.2, 130.0, 140.1, 144.2 (6

C, arom.).

was determined with 10 µ (+)-MK-801. The K_dvalue of the ra-

dioligand [³H]-(+)-MK-801 is 2.26 nM.

6.3. Determination of the σ₁Receptor Affinity (modified according

to ref.^[25]

)

6.3.1. Preparation of the Receptor Material: Five guinea pig brains

were homogenized with the potter (500–800 rpm, 10 up-and-down

strokes) in 6 volumes of cold 0.32  sucrose. The suspension was

centrifuged at 1200ϫ g for 10 min at 4 °C. The supernatant was

separated and centrifuged at 23500ϫ g for 20 min at 4 °C. The

pellet was resuspended in buffer (50 m TRIS, pH 7.4) and incu-

bated at room temp. for 30 min. After the incubation, the suspen-

sion was centrifuged again at 23500 g for 20 min at 4 °C. The final

pellet was resuspended in buffer, the protein concentration was de-

termined according to the method of Bradford^[24]using bovine se-

rumalbuminasstandard,andsubsequentlythepreparationwasfrozen

(–80 °C) in 1.5 mL portions containing about 1.5 mg protein/mL.

5.47. (S)-1-Methyl-2,3,4,5-tetrahydro-1H-3-benzazepine [(S)-15e]:

The synthesis of (S)-15e was performed as described for (R)-15e

using (1S)-14e (54.4 mg, 0.193 mmol) in MeOH (15 mL), ammo-

nium formate (122 mg, 1.93 mmol) and Pd/C (5.4 mg). Pale yellow

20

oil, yield 9.5 mg (31%). [α] = –2.85 (c = 0.43, CH₂Cl₂). HPLC

589

purity: a) Phenomenex Gemini C18, 80% MeOH/20% H₂O + 0.1%

Et₂NH, flow 0.6 mL/min, λ = 254 nm, t_R= 9.2 min, purity 98.5%,

b) RP Select B LiChrospher, 80 % CH₃CN/20 % H₂O + 0.1 %

Et₂NH, flow 1.2 mL/min, λ = 254 nm, t_R= 12.0 min, purity 97.9%.

6. Receptor Binding Studies

6.1. Materials and General Procedures: Homogenizer: Elvehjem

Potter (B. Braun Biotech International). Centrifuge: High-speed

cooling centrifuge model Sorvall RC-5C plus (Thermo Finnigan).

Filter: Printed Filtermat Typ B (Perkin–Elmer), presoaked in 0.5%

aqueous polyethylenimine for 2 h at room temp. before use. The

filtration was carried out with a MicroBeta FilterMate-96 Harves-

ter (Perkin–Elmer). The scintillation analysis was performed using

Meltilex (Typ A) solid scintillator (Perkin–Elmer). The solid scintil-

lator was melted on the filtermat at a temperature of 95 °C for

5 min. After solidification of the scintillator at room temp., the

scintillation was measured using a MicroBeta Trilux scintillation

analyzer (Perkin–Elmer). The counting efficiency was 40%. All ex-

periments were carried out in triplicates using standard 96-well-

multiplates (Diagonal). The IC₅₀values were determined in compe-

tition experiments with six concentrations of the test compounds

6.3.2. Performance of the σ₁Assay: The test was performed with

the radioligand [³H]-(+)-pentazocine (42.5 Ci/mmol; Perkin–El-

mer). The thawed membrane preparation (about 75 µg of the pro-

tein) was incubated with various concentrations of test compounds,

2 nM [³H]-(+)-pentazocine, and buffer (50 m TRIS, pH 7.4) in a

total volume of 200 µL for 180 min at 37 °C. The incubation was

terminated by rapid filtration through the presoaked filtermats

using the cell harvester. After washing each well five times with

300 µL of water, the filtermats were dried at 95 °C. Subsequently,

the solid scintillator was placed on the filtermat and melted at

95 °C. After 5 min, the solid scintillator was allowed to solidify at

room temp. The bound radioactivity trapped on the filters was

counted in the scintillation analyzer. The non-specific binding was

determined with 10 µ (+)-pentazocine. The K_dvalue of the ra-

and were calculated with the program GraphPad Prism^®3.0 dioligand [³H]-(+)-pentazocine is 2.9 nM.^[26

]

(GraphPad Software) by non-linear regression analysis. The K_ival-

6.4. Determination of the σ₂Receptor Affinity (modified according

to ref.^[25]

ues were calculated according to Cheng and Prusoff^[23]and are

given as mean value + SEM from three independent experiments.

)

6.4.1 Preparation of the Receptor Material: 2 rat livers were cut into

small pieces and homogenized with the potter (500–800 rpm, 10

up-and-down strokes) in 6 volumes of cold 0.32  sucrose. The sus-

pension was centrifuged at 1200ϫ g for 10 min at 4 °C. The super-

natant was separated and centrifuged at 31000 g for 20 min at 4 °C.

The pellet was resuspended in buffer (50 m TRIS, pH 8.0) and

incubated at room temp. for 30 min. After the incubation, the sus-

6.2. Determination of the Affinity to the Phencyclidine Binding Site

of the NMDA Receptor:

6.2.1. Preparation of the Receptor Material: Fresh pig brain cortex

was homogenized with the potter (500–800 rpm, 10 up-and-down

strokes) in 6 volumes of cold 0.32  sucrose. The suspension was

centrifuged at 1200 g for 10 min at 4 °C. The supernatant was sepa-

474

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Eur. J. Org. Chem. 2007, 462–475

Tetrahydro-3-benzazepines as NMDA Receptor Antagonists

FULL PAPER

[7] M. Amat, C. Escolano, N. Llor, Tetrahedron: Asymmetry 2003,

14, 1679–1683.

pension was centrifuged again at 31000 g for 20 min at 4 °C. The

final pellet was resuspended in buffer, the protein concentration

was determined according to the method of Bradford^[24]using bo-

vine serum albumin as standard, and subsequently the preparation

was frozen (–80 °C) in 1.5 mL portions containing about 2 mg pro-

tein/mL.

[8] M. Amat, N. Llor, J. Bosch, Tetrahedron Lett. 1994, 35, 2223–

2226.

[9] M. Amat, J. Bosch, J. Hidalgo, J. Org. Chem. 2000, 65, 3074–

3084.

[10] M. Amat, N. Llor, J. Hidalgo, A. Hernández, J. Bosch, Tetrahe-

dron: Asymmetry 1996, 7, 977–980.

6.4.2. Performance of the σ₂Assay: The test was performed with the

radioligand [³H]-ditolylguanidine (50 Ci/mmol; ARC). The thawed

membrane preparation (about 100 µg of the protein) was incubated

with various concentrations of test compounds, 3 nM [³H]-ditol-

ylguanidine, 500 nM (+)-pentazocine and buffer (50 m TRIS, pH

8.0) in a total volume of 200 µL for 180 min at 25 °C. The incu-

bation was terminated by rapid filtration through the presoaked

filtermats using the cell harvester. After washing each well five

times with 300 µL of water, the filtermats were dried at 95 °C. Sub-

sequently, the solid scintillator was placed on the filtermat and

melted at 95 °C. After 5 min, the solid scintillator was allowed to

solidify at room temp. The bound radioactivity trapped on the fil-

ters was counted in the scintillation analyzer. The non-specific

binding was determined with 10 µ ditolylguanidine. The K_dvalue

of the radioligand [³H]-ditolylguanidine is 17.9 nM.^[27]

[11] V. Schanen, C. Riche, H.-P. Husson, A. Chiaroni, J.-C. Quirion,

Tetrahedron Lett. 1994, 35, 2533–2536.

[12] N. Philippe, V. Levacher, G. Dupas, G. Quéguiner, J. Bourguig-

non, Org. Lett. 2000, 2, 2185–2187.

[13] M. Yamato, K. Hashigaki, S. Ishikawa, N. Qais, Tetrahedron

Lett. 1988, 29, 6949–6950.

[14] E. Winterfeldt, Synthesis 1975, 617–630.

[15] N. M. Yoon, Y. S. Gyoung, J. Org. Chem. 1985, 50, 2443–2450.

[16] T. D. Nelson, R. D. Crouch, Synthesis 1996, 1031.

[17] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4156–4158.

[18] A. Speicher, V. Bomm, T. Eicher, J. Prakt. Chem. 1996, 338,

588–590.

[19] U. Wirt, R. Fröhlich, B. Wünsch, Tetrahedron: Asymmetry

2005, 16, 2199–2202.

[20] M. Amat, M. Cantó, N. Llor, J. Org. Chem. 2002, 67, 5343–

5351.

[21] S. Ram, L. D. Spicer, Tetrahedron Lett. 1987, 28, 515–516.

[22] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923–

2925.

[1] W. Danysz, C. G. Parsons, I. Bresink, G. Quack, Drugs News

Persp. 1995, 8, 261–277.

[2] Z. L. Kruk, C. J. Pycock, Neurotransmitter and Drugs, 3rd ed.

1991, 159–168.

[3] E. H. F. Wong, A. J. Kemp, Annu. Rev. Pharmacol. Toxicol.

1991, 31, 401–425.

[23] Y. Cheng, H. W. Prusoff, Biochem. Pharmacol. 1973, 22, 3099–

3108.

[24] M. M. Bradford, Anal. Biochem. 1976, 72, 248–254.

[25] C. A. Maier, B. Wünsch, J. Med. Chem. 2002, 45, 438–448.

[26] D. L. De-Haven-Hudkins, L. C. Fleissner, F. Y. Ford-Rice, Eur.

J. Pharmacol. Mol. Pharmacol. Sect. 1992, 227, 371–378.

[27] R. H. Mach, C. R. Smith, S. R. Childers, Life Sci. 1995, 57,

57–62.

[4] H. Bräuner-Osborne, J. Egebjerg, E. O. Nielsen, U. Madsen,

P. J. Krogsgaard-Larsen, J. Med. Chem. 2000, 43, 2609–2645.

[5] K. T. Wanner, H. Beer, G. Höfner, M. Ludwig, Eur. J. Org.

Chem. 1998, 2019–2029.

Received: August 23, 2006

Published Online: November 21, 2006

[6] O. Krull, B. Wünsch, Bioorg. Med. Chem. 2004, 12, 1439–1451.

Eur. J. Org. Chem. 2007, 462–475

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475

Article Doi

Asymmetric synthesis of 1-substituted tetrahydro-3-benzazepines as NMDA receptor antagonists

DOI: 10.1002/ejoc.200600746

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Article abstract of DOI:10.1002/ejoc.200600746

Full text of DOI:10.1002/ejoc.200600746

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