Synthesis of 5-substituted 7,8-benzomorphans by intramolecular cyclization of N-protected 4,4-disubstituted 1,4-dihydropyridines

PAPER

2147

Synthesis of 5-Substituted 7,8-Benzomorphans by Intramolecular Cyclization

of N-Protected 4,4-Disubstituted 1,4-Dihydropyridines

S

ynthesis of 5-Su

o

bstituted 7, 8

r

-Benzom

n

orphans elia E. Schmaunz, Jörg Pabel, Klaus T. Wanner*

Department of Pharmacy – Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstrasse 7,

Haus C, 81377 München, Germany

Fax +49(89)218077247; E-mail: klaus.wanner@cup.uni-muenchen.de

Received 15 April 2010

Dedicated to Professor Rolf Huisgen with best wishes on the occasion of his 90^thbirthday

of the piperidine ring of the 7,8-benzomorphan skeleton

as the decisive step of the synthetic sequence as exempli-

Abstract: An efficient and high yielding method for the synthesis

of 7,8-benzomorphans with varying substituents at C5 has been de-

veloped. It is based on an acid-catalyzed intramolecular cyclization

reaction of N-protected 4,4-disubstituted 1,4-dihydropyridines,

fied by the synthesis of 3 from 4-amino-1,2,3,4-tetrahy-

dronaphthalene-2-acetic acid (7).¹⁰In

a different

which are easily accessible by the addition of diorganomagnesium approach, the key step is represented by the formation of

compounds to N-silylpyridinium ions. The cyclization reaction pro-

the central ring of 3, typically accomplished by intramo-

ceeds via N-acyliminium ions generated from the 1,4-dihydropyri-

lecular a-amidoalkylation reactions via N-acyliminium

dine moiety that undergo electrophilic aromatic substitution

ions utilizing starting compounds like 4-benzyl-substitut-

reaction at the benzyl substituent present at C4 of the 1,4-dihydro-

ed piperidine derivative 8 (Scheme 1).⁹

pyridine ring system.

Key words: alkaloids, benzomorphans, electrophilic aromatic sub-

stitution, N-acyliminium ion, intramolecular cyclization

2'

HO

1'

7

3'

4'

6

5

8

1

O

9

The structural motif of a bridged piperidine ring system is

found in a large number of natural products and biologi-

cally active compounds.¹Morphine (1) represents the

most prominent example of this class of compounds. It is

an extremely potent analgesic of great importance, but its

use is limited due to various side effects, such as addiction

caused by its psychotropic activity. Extensive research

has been performed to develop analogues of morphine

with a simplified structure and improved pharmacological

profile.²This has resulted in a wide variety of morphine-

like compounds. Particularly, interesting pharmacological

activities were found (Figure 1)^1,3–5for compounds exhib-

iting the morphan (4) or the 6,7-benzomorphan ring sys-

tem (2), especially when an additional substituent at C5

was present; GPA 1657 (5), a well-known analgesic, is an

example of this type of compound (Figure 1).⁶

Me

N

NH

3

NH

4

2

HO

morphine (1)

6,7-benzomorphan (2)

7,8-benzomorphan (3)

R

Me

NH

N

morphan (4)

GPA 1657 (5)

5-substituted 7,8-benzo-

morphan 6

Figure 1 Structures of morphine, morphan, and benzomorphan de-

rivatives

In contrast to 5-substituted 6,7-benzomorphan deriva-

tives, the isomeric 5-substituted 7,8-benzomorphans are

rarely reported in literature.⁷In addition, for the com-

pounds published, to the best of our knowledge, no phar-

macological data regarding their analgesic activity and

side effect profile have been provided. Accordingly, we

considered it worthwhile to develop an efficient synthetic

access to 5-substituted 7,8-benzomorphan derivatives 6

(Figure 1).

NH₂

CO₂Et

R

NH

N

O

7

3

8

Scheme 1 Common strategies for the construction of 7,8-benzo-

morphans

In this study, we present a highly flexible and efficient

method for the preparation of 5-substituted 7,8-benzo-

morphans 9 that is based on the use of 4,4-disubstituted

1,4-dihydropyridines 10 as key compounds. Compounds

10 are easily accessible from 4-substituted pyridines 11,

using a reaction that we have previously reported, by trap-

ping their N-silylpyridinium ions with diorganomagne-

sium reagents.¹¹It was reasoned that the 1,4-

dihydropyridines 10 are of high synthetic utility for the

preparation of N-protected 7,8-benzomorphans 9. Thus,

For the synthesis of 5-unsubstituted 7,8-benzomorphan

derivatives several procedures have been published in the

literature.^8,9A common strategy is based on the formation

SYNTHESIS 2010, No. 13, pp 2147–2160

x

x.

x

.

2

0

1

0

Advanced online publication: 28.05.2010

DOI: 10.1055/s-0029-1218808; Art ID: C01910SS

2148

C. E. Schmaunz et al.

PAPER

we set out to determine the feasibility of this transforma- ed in Table 1 including the yields for the synthesis of

tion reaction, which should proceed via intramolecular compounds required in this study that were available to us

substitution of the benzyl substituent in position 4 of 10 by from previous work already published in literature.

an iminium or N-acyliminium ion generated from the 1,4-

dihydropyridine moiety (Scheme 2).

The cyclization was first attempted with the N-silyl-1,4-

dihydropyridine 13f, in order to establish a direct access

to N-unprotected 7,8-benzomorphans 9 with a double

bond remaining in the piperidine ring system. However,

instead of the desired cyclization product 16 only a de-

composition product, 4-benzylpyridine (12c), was isolat-

ed when a solution of 13f in dichloromethane was treated

with hydrogen chloride gas at –78 °C and the temperature

was raised to 40 °C (Table 2, entry 1).

R²

N

R⁴

NH

N

H

6

9

Therefore, for the next cyclization reaction the N-acetyl-

protected 4,4-dibenzyl-1,4-dihydropyridine 14f was used.

Under reaction conditions similar to those applied for the

unsuccessful cyclization of the N-silyl-protected dihydro-

pyridine 13f, now, 12% of the desired N-acetylated 7,8-

benzomorphan 15f (Table 2, entry 2) was found in the

crude reaction product (¹H NMR analysis) and also the

majority of the starting material 14f had remained un-

changed [ratio (15f + 16 + 12c)/14f = 12:88; Table 2, en-

try 2].

R¹

R²

N

R³

10

N

11

Scheme 2 Proposed synthetic strategy

The starting materials required for this study, the 4,4-di-

substituted N-silyl-protected 1,4-dihydropyridines 13a–g

and their N-acetyl derivatives 14a–g, were prepared ac-

cording to a synthetic procedure that we had previously

published.¹¹Thus, the respective 4-substituted pyridine

derivatives 12a–e were treated with triisopropylsilyl tri-

flate and subsequently with dialkylmagnesium derivatives

which gave the addition products 13a–g in reasonable to

good yields. The N-acetyl derivatives 14a–g were ob-

tained by treating the N-silyl-1,4-dihydropyridines 13a–g

with acetyl chloride. The results of both reactions are list-

As electrophilic substitution reactions are known to pro-

ceed best in polar solvents,¹²dichloromethane was re-

placed by ethanol in further experiments. Accordingly,

14f was treated with ethanolic hydrochloric acid (1.25 M)

at room temperature. After four hours, only minute

amounts of the cyclization product 15f could be detected

1

by H NMR analysis (ratio 15f/16/12c = 5:0:95). The

crude product consisted mainly of 4-benzylpyridine (12c)

(Table 2, entry 3), and, in addition, some starting material

14f was still present [(15f + 16 + 12c)/14f = 87:13].

Table 1 Synthesis and Acetylation of N-Silyl-Protected 4,4-Disubstituted Dihydropyridines

R¹

R³

R²

R¹

R³

R¹

R²

O

R²

1. TIPSOTf, r.t.

2. R³₂Mg, –78 °C

Cl

CH₂Cl₂

N

Si

N

O

14a–g

12a–e

13a–g

Entry

Starting material

R³Mg

Products

2

12

R¹

R²

R³

13

Yield (%)

14

Yield (%)

1

2

3

4

5

6

7

a^a

b^a

c

PMB

H

PMB

Bn

a

b

c

d

e

f

56

75

a

b

c

d

e

f

81

90

CH₂CH₂Ph

Bn

Ph

Bn

Et

(73)^b

(78)^b

(92)^b

(85)^b

52

89

c

i-Pr

Bn

91

d

c

92

Bn

(96)^b

88

e

CO₂Et

Bn

g

^aPreparation described in the experimental section.

^bData from the literature.¹¹

Synthesis 2010, No. 13, 2147–2160 © Thieme Stuttgart · New York

PAPER

Synthesis of 5-Substituted 7,8-Benzomorphans

2149

Table 2 Optimization of the Intramolecular Cyclization

phosphate buffer

(pH 7.0, c = 1.0 M)

HCl

+

N

R

N

H

N

R

N

R

+

–

Cl

13f R = TIPS

14f R = Ac

12c

15f

16

Entry

Starting

Acid

Solvent

c (M)

Time (h) Temp (°C)

Compound ratio^a

material

13f

15f/16/12c

(15f + 16 + 12c)/14f or 13f

1

2

3

4

5

6

HCl_gas

HCl

CH₂Cl₂

1

4

3

–78 → 40

0:0:100

100:0:0

5:0:95

100:0

12:88

87:13

6:94

14f

CH₂Cl₂

–78 → 40

14f

EtOH

1.25

4.0

r.t.

14f

HCl

1,4-dioxane

100:0:0

0:0:100

100:0:0

13f

HCl

100:0

14f

HCl

4.0

^aAccording to ¹H NMR of the crude reaction product.

To prevent the removal of the N-acetyl group by the sol- chloric acid in 1,4-dioxane by 4.0 M hydrochloric acid in

vent, which was considered to trigger the formation of the 1,4-dioxane resulted, again, in a completely clean trans-

decomposition product 12c, in a further experiment etha- formation of 14f into the desired cyclization product 15f,

nol was replaced by 1,4-dioxane. In this case, when 14f however, the starting material was also fully consumed

was treated with 1.25 M hydrochloric acid in 1,4-dioxane, (r.t., 3 h; ¹H NMR analysis) and 15f was isolated in 97%

no decomposition reaction occurred and the sole product yield (Table 3, entry 6). Interestingly, when these reaction

was the desired compound 15f, but in low amounts as conditions (4.0 M HCl in 1,4-dioxane) were applied to the

most of the starting material 14f had remained unchanged N-silyl-protected 1,4-dihydropyridine 13f, again only a

(¹H NMR; Table 2, entry 4). Replacing the 1.25 M hydro- complete destruction of the starting material 13f and

Table 3 Formation of N-Acetyl-7,8-benzomorphans

R²

R¹

HCl_dioxane

R²

(c = 4.0 M)

NaBH₄

R²

N

TFA

CH₂Cl₂

r.t., 3 h

r.t.

N

O

15a–f

O

14a–f

17a–f

Entry

Starting material

Time (h)

Products

14

a

b

c

R¹

R²

15

Yield (%)

17

a

b

c

Yield (%)

1

2

3

4

5

6

PMB

OMe

H

2

23

7

a

b

c

d

e

f

94

95

94

97

95

84

89

91

84

80

CH₂CH₂Ph

Et

H

d

e

i-Pr

Ph

Bn

H

5

d

e

H

20

3

f

H

f

Synthesis 2010, No. 13, 2147–2160 © Thieme Stuttgart · New York

2150

C. E. Schmaunz et al.

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quantitative formation of 12c occurred, highlighting the avoid uncontrolled loss of HCl. Then the conversion is

necessity of the N-acetyl group present in the 1,4-dihydro- complete within one hour with the yield for 15g amount-

pyridine derivative 14f for a successful cyclization reac- ing to 88% (Scheme 3).

tion (Table 2, entry 5).

The optimized reaction conditions (Table 2, entry 6) were

then applied to a series of 4,4-disubstituted N-acetyl-1,4-

dihydropyridines 14a–e exhibiting different 4-substitu-

ents in addition to a 4-benzyl or a 4-(4-methoxybenzyl)

moiety. After adjusting the reaction time, the reaction

conditions worked well in each case effecting a clean and

complete cyclization reaction and providing the desired

benzomorphans 15a–e in high yields (94–97%, Table 3).

EtO₂C

HCl_dioxane(c = 4.0 M)

80 °C, MW, 1 h

N

O

14g

15g (88%)

The 3,4-unsaturated N-acetyl-7,8-benzomorphans 15a–f,

can, of course, also be further transformed into the saturat-

ed compounds 17a–f. This transformation is easily ac-

complished by treating the unsaturated compounds 15a–f

with sodium borohydride in trifluoroacetic acid providing

the saturated benzomorphans 17a–f in high yields, i.e. 80–

95% (Table 3).

Scheme 3 Cyclization of 14g under microwave irradiation

Additional experiments revealed that heating the 1,4-di-

hydropyridines 14a–f in acidic solutions in the presence

of water results in concomitant cyclization and N-depro-

tection reactions giving rise to benzomorphans 18a–f.

This was considered to provide an efficient access to the

corresponding amino derivatives by subjecting the thus

formed imines 18a–f to a subsequent reduction. This was

indeed the case. Hence, complete cyclization and depro-

tection of the 1,4-dihydropyridines 14a–f occurred when

solutions of the starting compounds in 4.0 M hydrochloric

acid in 1,4-dioxane, to which 10 equivalents of water had

been added, were heated by microwave to 100 °C for one

hour.¹H NMR spectra were taken from the crude products

resulting from these reactions and they were in clear sup-

port of the proposed structures 18. Furthermore, when the

crude reaction products were treated with sodium cy-

anoborohydride and hydrochloric acid in diethyl ether so-

lution in methanol, the saturated amines were formed

(Table 4). These were subsequently transformed into the

In addition, the cyclization reaction of the 1,4-dihydropy-

ridine 14g exhibiting an ester function in the 3-position of

the piperidine ring was attempted under the cyclization

conditions successfully used for the transformation of

14a–f into the 7,8-benzomorphans 15a–f. In this case, as

a result of the presence of the electron-withdrawing ester

function, the cyclization reaction proceeded very slowly

at room temperature. After 20 hours, only 20% of the

starting compound 14g had been converted into the de-

sired product 15g (¹H NMR) and when the reaction was fi-

nally completed after four days, also small amounts of

unidentified side products were found. These drawbacks

were easily overcome when the reaction was performed at

80 °C under microwave irradiation, in a closed system to

Table 4 Formation of 7,8-Benzomorphan Hydrochlorides

R²

R¹

1. TFA, CH₂Cl₂

r.t., 12 h

HCl_dioxane

H₂O (10 equiv)

1. NaBH₃CN, HCl_Et₂

MeOH, r.t., 1 h

O

R²

100 °C, MW, 1 h

2. Boc₂O, NaHCO₃

1,4-dioxane, r.t., 12 h

2. K₂CO₃

N

N⁺

N

Cl^–

3. HCl_Et2

O

H

Boc

18a–f

O

19a–f

20a–f

14a–f

Entry

Starting material

Products

14

R¹

R²

OMe

H

19

Yield (%)

20

a

b

c

Yield (%)

1

2

3

4

5

6

a

b

c

d

e

f

PMB

a

b

c

d

e

f

71

61

57

64

57

60

91

95

92

93

97

CH₂CH₂Ph

Et

H

i-Pr

Ph

Bn

H

d

e

H

f

Synthesis 2010, No. 13, 2147–2160 © Thieme Stuttgart · New York

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Synthesis of 5-Substituted 7,8-Benzomorphans

2151

dialkylmagnesium reagent was added dropwise. The resulting yel-

low-to-red-colored mixture was slowly warmed to –50 °C and

stirred overnight. Workup was performed by addition of 1.0 M

phosphate buffer (pH 7) and extraction of the aqueous layer with

CH₂Cl₂. The combined organic layers were dried (MgSO₄) and con-

centrated in vacuo. For oxidation the residue was stirred at ambient

air for 24 h without solvent. The crude product was taken up in Et₂O

(10 mL) and extracted with aq 2.0 M HCl (4 × 10 mL). The com-

bined aqueous layers were washed with Et₂O (2 × 20 mL). The acid-

ic soln was then treated with K₂CO₃until a pH of 9 was reached.

The aqueous layer was extracted with CH₂Cl₂(4 × 40 mL). The

combined organic layers were dried (MgSO₄) and concentrated in

vacuo. The crude product was purified by flash chromatography on

silica gel.

N-Boc derivatives 19a–f using di-tert-butyl dicarbonate

as the isolation of the carbamates 19a–f was far more con-

venient. In every case the yields for the reaction sequence

leading to the N-Boc-protected 7,8-benzomorphans 19a–f

were quite pleasing (57–71%, Table 4). The N-Boc-pro-

tected 7,8-benzomorphans 19a–f represent a convenient

source for the preparation of the N-unprotected com-

pounds 20a–f. Thus, treatment of N-Boc-protected com-

pounds 19a–f with trifluoroacetic acid and finally with

hydrochloric acid in diethyl ether solution subsequent to a

basic workup gave hydrochlorides 20a–f in high yields

(Table 4).

The failure of the cyclization reactions of N-silyl-1,4-di-

hydropyridine 13f under acidic conditions (Table 2) sug-

gests that the cyclization step precedes the N-deprotection

in the transformation of the N-acetyl-1,4-dihydropy-

ridines 14a–f into 18a–f. This seems quite reasonable as

N-acyliminium ions are known to be distinctly more reac-

tive than their iminium ion counterparts. To further sup-

port the above assumption, in an additional experiment

the N-silyl-protected dihydropyridine 13f was also sub-

jected to the more forcing reaction conditions used for the

formation of 18a–f. Again, no cyclization reaction oc-

curred, instead the starting material completely decom-

posed to benzylpyridine 12c.

Unsaturated 5-Substituted N-Acetyl-Protected 7,8-Benzomor-

phans 15; General Procedure (GP2)

A soln of 4,4-disubstituted N-acetyl-1,4-dihydropyridine 14 in 4.0

M HCl in 1,4-dioxane was stirred at r.t. for the time given in

Table 3. The reaction was quenched by addition of 1.0 M phosphate

buffer (pH 7) until a pH of 7 was reached. The aqueous layer was

extracted with CH₂Cl₂. The combined organic layers were dried

(MgSO₄) and concentrated in vacuo. The raw material was purified

by flash chromatography (alumina) to yield the desired product.

5-Substituted N-Acetyl-Protected 7,8-Benzomorphans 17; Gen-

eral Procedure (GP3)

A soln of the corresponding unsaturated N-acetyl-protected 7,8-

benzomorphan 15 in CH₂Cl₂was added to a soln of NaBH₄in TFA

and the mixture was stirred at r.t. for 3 h. 2 M NaOH (4 mL) and

K₂CO₃were added to the soln to adjust the pH value in the range of

10–12 and the aqueous layer was then extracted with CH₂Cl₂(4 × 7

mL). The combined organic layers were dried (MgSO₄) and con-

centrated in vacuo. The raw material was purified by flash chroma-

tography (alumina) to yield the desired product.

In conclusion, we have developed an easy and straightfor-

ward method for the preparation of 5-substituted 7,8-ben-

zomorphans. It is based on acid-catalyzed intramolecular

cyclizations of 4,4-disubstituted N-acetyl-1,4-dihydropy-

ridines 14a–g, resulting in the formation of unsaturated 5-

substituted N-acetyl-7,8-benzomorphans 15a–g, which

can be easily transformed into the saturated compounds as

demonstrated by the preparation of 17a–f. Furthermore, a

method was developed for the concomitant cyclization

and N-deprotection of N-acetyl-1,4-dihydropyridines

5-Substituted N-Boc-Protected 7,8-Benzomorphans 19; Gener-

al Procedure (GP4)

A soln of 4,4-disubstituted N-acetyl-1,4-dihydropyridine 14 and

H₂O (10 equiv) in 4.0 M HCl in 1,4-dioxane was heated to 100 °C

under microwave conditions. After 1 h, the soln was quenched by

14a–f that was used for the preparation of the saturated N- the addition of 1.0 M phosphate buffer (pH 7). The aqueous layer

was extracted with CH₂Cl₂. The combined organic layers were dried

(MgSO₄) and concentrated in vacuo. The crude product was dis-

Boc-protected 7,8-benzomorphans 19a–f, which are con-

venient precursors for the synthesis of the 7,8-benzomor-

solved in MeOH and treated with NaBH₃CN (2.5 equiv) at r.t. After

phan hydrochlorides 20a–f.

addition of 2.0 M HCl in Et₂O (5.0 equiv), the mixture was stirred

at r.t. for 1 h and subsequently quenched with 1.0 M phosphate buff-

er (pH 7). The aqueous layer was extracted with CH₂Cl₂. The com-

bined organic layers were dried (MgSO₄), and concentrated in

vacuo. The raw material was dissolved in 1,4-dioxane–0.5 M

NaHCO₃soln (1:1) and treated with Boc₂O and stirred overnight.

The mixture was extracted with CH₂Cl₂and the combined organic

layers were dried (MgSO₄) and concentrated in vacuo. The crude

material was purified by flash chromatography (alumina).

All solvents and chemicals were obtained from commercial sources

and were utilized without further purification unless otherwise stat-

ed. All reactions were performed using flame-dried glassware under

an argon atmosphere. All solvents were freshly dried using standard

procedures.¹³Microwave experiments were performed in sealed

glass vials using a Biotage Initiator Microwave Synthesizer. ¹H and

¹³C spectra were recorded on a JNMR-GX 400 (Joel, 400 MHz) or

a JNMR-GX 500 (Joel, 500 MHz) spectrometer, respectively. The

1

5-Substituted 7,8-Benzomorphan Hydrochlorides 20; General

Procedure (GP5)

assignment of H NMR resonances refers to the numbering of the

7,8-benzomorphan skeleton 3 (Figure 1). Infrared spectra were ob-

tained on a Perkin-Elmer model 1600 FT-IR spectrophotometer.

Microanalytical data for C, H, and N were determined on a Heraeus

Rapid Analyser and on an Elementar Vario EL Analyser. Flash

chromatography was performed with 40–63 mesh silica gel or 50–

150 mesh alumina (neutral Brockmann activity III).

The corresponding N-Boc-protected 7,8-benzomorphan 19 was dis-

solved in CH₂Cl₂and TFA was added and the mixture was stirred at

r.t. for 12 h. K₂CO₃was added to the soln to adjust the pH value in

the range of 10–12. The aqueous layer was extracted with CH₂Cl₂.

The combined organic layers were washed with 0.5 M NaHCO₃

soln, dried (MgSO₄), and concentrated in vacuo. The product was

dissolved in Et₂O, acidified with 2.0 M ethereal HCl and concentrat-

ed in vacuo.

4-Substituted Pyridines 12; General Procedure (GP1)

The pyridine was dissolved in CH₂Cl₂and treated with TIPSOTf at

r.t. After 15 min the clear soln was cooled to –78 °C, and then the

Synthesis 2010, No. 13, 2147–2160 © Thieme Stuttgart · New York

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C. E. Schmaunz et al.

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4-(4-Methoxybenzyl)pyridine (12a)¹⁴

¹H NMR (400 MHz, CDCl₃): d = 0.98 [d, J = 7.3 Hz, 18 H,

CH(CH₃)₂], 1.08–1.25 [m, 3 H, CH(CH₃)₂], 1.48–1.55 (m, 2 H,

CH₂CH₂Ph), 2.56 (s, 2 H, CCH₂Ph), 2.58–2.67 (m, 2 H,

CH₂CH₂Ph), 4.17 (d, J = 8.3 Hz, 2 H, NCHCH), 5.99 (d, J = 8.3 Hz,

2 H, NCH), 7.02–7.36 (m, 10 H, CH_Ar).

¹³C NMR (100 MHz, CDCl₃): d = 11.28 (d), 17.72 (q), 33.49 (t),

39.88 (s), 46.23 (t), 52.12 (t), 105.66 (d), 125.25 (d), 125.43 (d),

127.30 (d), 128.16 (d), 128.51 (d), 129.30 (d), 130.92 (d), 138.89

(s), 144.07 (s).

According to GP1 from pyridine (196 mg, 200 mL, 2.47 mmol),

TIPSOTf (833 mg, 731 mL, 2.72 mmol) in CH₂Cl₂(3 mL) and 0.13

M (PMB)₂Mg in THF (39.5 mL) [(PMB)₂Mg was prepared accord-

ing to the literature¹⁵from Mg (875 mg, 36.0 mmol) in THF (20

mL), 1-(iodomethyl)-4-methoxybenzene (3.76 g, 3.25 mL, 24.0

mmol) in THF (60 mL), and 1,4-dioxane (2.33 g, 2.25 mL, 26.4

mmol)]. Purification by flash chromatography (silica gel, EtOAc–

MeOH, 97:3); light yellow oil; yield: 386 mg (78%).

MS (CI, CH₅): m/z (%) = 340 (100), 432 (53) [M + H]⁺.

+

4-(2-Phenylethyl)pyridine (12b)

HRMS (EI⁺): m/z [M]⁺calcd for C₂₉H₄₁NSi: 431.3008; found:

According to GP1 from pyridine (196 mg, 200 mL, 2.47 mmol),

TIPSOTf (833 mg, 731 mL, 2.72 mmol) in CH₂Cl₂(5 mL), and 0.32

M (PhCH₂CH₂)₂Mg in Et₂O (15.5 mL) [(PhCH₂CH₂)₂Mg was pre-

pared according to the literature¹⁵from Mg (6.94 g, 0.285 mol) in

Et₂O (40 mL), PhCH₂CH₂Br (40.7 g, 30.0 mL, 0.220 mol) in Et₂O

(120 mL), and 1,4-dioxane (21.3 mg, 20.6 mL, 0.242 mol)]. Purifi-

cation by flash chromatography (silica gel, CH₂Cl₂–MeOH, 97:3);

colorless crystals; yield: 354 mg (78%); mp 69 °C (Lit.¹⁶mp 69–70

°C).

431.3036.

Ethyl 4,4-Dibenzyl-1-(triisopropylsilyl)-1,4-dihydropyridine-3-

carboxylate (13g)

According to the literature^17afrom 12e^17b(685 mg, 2.84 mmol),

TIPSOTf (957 mg, 839 mL, 3.13 mmol) in CH₂Cl₂(20 mL), and 0.5

M Bn₂Mg in THF (6.25 mL) [Bn₂Mg was prepared according to the

literature¹⁵from 1.0 M BnMgCl soln in THF (25 mL) and 1,4-diox-

ane (2.42 g, 2.34 mL, 27.5 mmol)]. Workup was performed with 1.0

M phosphate buffer (20 mL, pH 7) and extraction with CH₂Cl₂(4 ×

40 mL). Purification by flash chromatography (silica gel, n-pen-

tane–EtOAc, 95:5); colorless crystals; yield: 725 mg (52%); mp 62–

63 °C; R_f= 0.17 (silica gel, n-pentane–EtOAc, 95:5).

4,4-Bis(4-methoxybenzyl)-1-(triisopropylsilyl)-1,4-dihydropy-

ridine (13a)

According to the literature¹¹from 12a (104.6 mg, 0.525 mmol),

TIPSOTf (177 mg, 155 mL, 0.577 mmol) in CH₂Cl₂(5 mL), and

0.032 M (PMB)₂Mg in Et₂O (32.8 mL), at –50 °C for 12 h

[(PMB)₂Mg was prepared according to the literature¹⁵from Mg

(875 mg, 36.0 mmol) in Et₂O (20 mL), 1-iodomethyl-4-methoxy-

benzene (3.76 g, 3.25 mL, 24.0 mmol) in Et₂O (60 mL), and 1,4-di-

oxane (2.33 g, 2.25 mL, 26.4 mmol)]. Workup of the crude product

was performed with 1.0 M phosphate buffer (10 mL, pH 7) and ex-

traction with CH₂Cl₂(4 × 20 mL). Purification by flash chromatog-

raphy (alumina, gradient n-pentane–EtOAc, 90:10, then 80:20) and

fractional crystallization (n-pentane); colorless crystals; yield: 141

mg (56%); mp 55–56 °C; R_f= 0.94 (alumina, n-pentane–EtOAc,

9:1).

IR (KBr): 3083, 3028, 2865, 1695, 1665, 1567, 1453, 1234 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 0.75 [d, J = 7.5 Hz, 18 H,

CH(CH₃)₂], 0.98 [sept, J = 7.5 Hz, 3 H, CH(CH₃)₂], 1.35 (t, J = 7.1

Hz, 3 H, CH₂CH₃), 2.51 (d, J = 13.0 Hz, 2 H, CH₂Ph), 3.68 (d,

J = 13.0 Hz, 2 H, CH₂Ph), 4.27 (q, J = 7.1 Hz, 2 H, CH₂CH₃), 4.39

(d, J = 8.1 Hz, 1 H, NCHCH), 5.63 (dd, J = 8.1, 1.3 Hz, 1 H,

NCHCH), 6.89 (d, J = 1.3 Hz, 1 H, NCHC), 7.01–7.21 (m, 10 H,

CH_Ar).

¹³C NMR (100 MHz, CDCl₃): d = 11.03 (d), 14.84 (q), 17.43 (q),

44.73 (s), 48.15 (t), 59.32 (t), 103.44 (s), 113.23 (d), 125.63 (d),

126.76 (d), 127.56 (d), 130.93 (d), 140.42 (s), 143.69 (d), 169.01

(s).

IR (KBr): 3031, 2944, 2863, 2831, 1674, 1609, 1511, 1463, 1442,

1286, 1243 cm^–1.

+

MS (CI, CH₅): m/z (%) = 165 (100), 398 (80), 490 (56) [M + H]⁺.

¹H NMR (400 MHz, CDCl₃): d = 0.84 [d, J = 7.3 Hz, 18 H,

CH(CH₃)₂], 0.96–1.08 [m, 3 H, CH(CH₃)₂], 2.57 (s, 4 H, CH₂), 3.76

(s, 6 H, CH₃), 4.12 (d, J = 8.3 Hz, 2 H, NCHCH), 5.73 (d, J = 8.3

Hz, 2 H, NCH), 6.73–6.78 (m, 4 H, CH_Ar,m), 7.03–7.08 (m, 4 H,

CH_Ar,o).

¹³C NMR (100 MHz, CDCl₃): d = 11.12 (d), 17.52 (q), 41.47 (s),

50.35 (t), 55.17 (q), 105.79 (d), 112.75 (d), 128.74 (d), 131.70 (s),

131.81 (d), 157.59 (s).

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₃₁H₄₄NO₂Si: 490.3141;

found: 490.3120.

Anal. Calcd for C₃₁H₄₃NO₂Si: C, 76.02; H, 8.85; N, 2.86. Found: C,

75.88; H, 8.71; N, 2.83.

1-[4,4-Bis(4-methoxybenzyl)pyridin-1(4H)-yl]ethanone (14a)

According to the literature^11bfrom 13a (22.4 mg, 0.0500 mmol) and

AcCl (7.9 mg, 7.1 mL, 0.10 mmol) in CH₂Cl₂(3 mL). Workup was

performed with 1.0 M phosphate buffer (3 mL, pH 7) and extraction

with CH₂Cl₂(4 × 4 mL). Purification by flash chromatography (alu-

mina, n-pentane–EtOAc, 8:2); colorless oil; yield: 14.7 mg (81%);

R_f= 0.09 (alumina, n-pentane–EtOAc, 9:1).

+

MS (CI, CH₅): m/z (%) = 200 (52), 356 (39), 478 (100) [M + H]⁺.

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₃₀H₄₄NO₂Si: 478.3141;

found: 478.3133.

Anal. Calcd for C₃₀H₄₃NO₂Si: C, 75.42; H, 9.07; N, 2.93. Found:

C, 75.36; H, 9.08; N, 3.00.

IR (film): 3002, 2909, 2834, 1671, 1625, 1611, 1511, 1374 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 2.00 (s, 3 H, C=OCH₃), 2.68 (s, 4

H, CH₂Ph), 3.78 (s, 6 H, OCH₃), 4.70 (dd, J = 8.4, 2.6 Hz, 1 H,

NCHCH), 4.84 (dd, J = 8.5, 2.6 Hz, 1 H, NCHCH), 6.35 (dd,

J = 8.4, 1.7 Hz, 1 H, NCH), 6.74–6.81 (m, 4 H, CH_Ar,m), 6.97–7.05

(m, 5 H, NCH, CH_Ar,o).

¹³C NMR (100 MHz, CDCl₃): d = 21.27 (q), 41.80 (s), 48.30 (t),

55.16 (q), 113.07 (d), 113.97 (d), 114.60 (d), 121.36 (d), 123.21 (d),

129.62 (s), 131.57 (d), 131.59 (d), 157.98 (s), 165.92 (s).

4-Benzyl-4-(2-phenylethyl)-1-(triisopropylsilyl)-1,4-dihydropy-

ridine (13b)

According to the literature¹¹from 12b (303 mg, 1.65 mmol),

TIPSOTf (557 mg, 488 mL, 1.82 mmol) in CH₂Cl₂(10 mL), and 0.4

M Bn₂Mg in THF (8.25 mL) [Bn₂Mg was prepared according to the

literature¹⁵from 1.0 M BnMgCl soln in THF (25 mL) and 1,4-diox-

ane (2.42 g, 2.34 mL, 27.5 mmol)]. Workup was performed with 1.0

M phosphate buffer (10 mL, pH 7) and extraction with CH₂Cl₂(4 ×

20 mL). Purification by flash chromatography (alumina, n-pen-

tane); colorless crystals; yield: 354 mg (75%); mp 63–65 °C;

R_f= 0.5 (alumina, n-pentane).

MS (CI, CH₅): m/z (%) = 200 (27), 242 (32), 364 (100) [M + H]⁺.

+

HRMS (EI⁺): m/z [M]⁺calcd for C₂₃H₂₅NO₃: 363.1834; found:

363.1823.

IR (KBr): 3078, 3026, 2938, 2863, 2830, 1669, 1602, 1493, 1452

cm^–1.

Synthesis 2010, No. 13, 2147–2160 © Thieme Stuttgart · New York

PAPER

Synthesis of 5-Substituted 7,8-Benzomorphans

2153

1-[4-Benzyl-4-(2-phenylethyl)pyridin-1(4H)-yl]ethanone (14b)

According to the literature^11bfrom 13b (200 mg, 0.464 mmol) and

AcCl (40.1 mg, 36.4 mL, 0.510 mmol) in CH₂Cl₂(10 mL). Workup

was performed with 1.0 M phosphate buffer (10 mL, pH 7) and ex-

traction with CH₂Cl₂(4 × 10 mL). Purification by flash chromatog-

raphy (alumina, n-pentane–EtOAc, 9:1); colorless oil; yield: 132

mg (90%); R_f= 0.36 (alumina, n-pentane–EtOAc, 9:1).

NCHCH), 4.81 (dd, J = 8.6, 2.7 Hz, 1 H, NCHCH), 6.46 (dd,

J = 8.5, 1.7 Hz, 1 H, NCH), 7.04–7.10 (m, 2 H, CH_Ar,o), 7.10–7.14

(dd, J = 8.6, 1.7 Hz, 1 H, NCH), 7.12–7.18 (m, 1 H, CH_Ar,p), 7.18–

7.24 (m, 2 H, CH_Ar,m).

¹³C NMR (100 MHz, CDCl₃): d = 17.84 (q), 18.03 (q), 21.33 (q),

36.79 (d), 43.76 (s), 46.55 (t), 112.63 (d), 113.00 (d), 121.77 (d),

123.6 (d), 125.97 (d), 127.52 (d), 130.67 (d), 138.18 (s), 165.99 (s).

IR (film): 3084, 3060, 3026, 2926, 2848, 1693, 1673, 1624, 1454,

1418, 1375 cm^–1.

+

MS (CI, CH₅): m/z (%) = 164 (61), 256 (100) [M + H]⁺.

HRMS–ESI⁺: m/z [M + H]⁺calcd for C₁₇H₂₂NO: 256.1701; found:

¹H NMR (500 MHz, CDCl₃): d = 1.60–1.74 (m, 2 H, CH₂CH₂Ph),

2.15 (s, 3 H, COCH₃), 2.43–2.59 (m, 2 H, CH₂CH₂Ph), 2.70 (s, 2 H,

CH₂Ph), 4.71 (dd, J = 8.4, 2.7 Hz, 1 H, NCHCH), 4.84 (dd, J = 8.5,

2.7 Hz, 1 H, NCHCH), 6.57 (dd, J = 8.4, 1.7 Hz, 1 H, NCH), 7.07–

7.12 (m, 2 H, CH_Bn,o), 7.12–7.16 (m, 2 H, CH_Ph,o), 7.16–7.21 (m, 2

H, CH_Bn,p, CH_Ph,p), 7.21–7.30 (m, 5 H, NCH, CH_Bn,m, CH_Ph,m).

¹³C NMR (100 MHz, CDCl₃): d = 21.40 (q), 32.55 (t), 40.49 (s),

43.64 (t), 50.36 (t), 113.73 (d), 114.34 (d), 121.77 (d), 123.64 (d),

125.68 (d), 126.20 (d), 127.70 (d), 128.32 (d), 128.34 (d), 130.74

(d), 136.94 (s), 142.61 (s), 166.12 (s).

256.1688.

Anal. Calcd for C₁₇H₂₁NO: C, 79.96; H, 8.29; N, 5.49. Found: C,

79.72; H, 8.29; N, 5.41.

1-[4-Benzyl-4-phenylpyridin-1(4H)-yl]ethanone (14e)

According to the literature^11bfrom 13e (301 mg, 0.743 mmol) and

AcCl (64.3 mg, 58.5 mL, 0.819 mmol) in CH₂Cl₂(10 mL). Workup

was performed with 1.0 M phosphate buffer (10 mL, pH 7) and ex-

traction with CH₂Cl₂(4 × 10 mL). Purification by flash chromatog-

raphy (alumina, n-pentane–EtOAc, 9:1); colorless oil; yield: 199

mg (92%); R_f= 0.30 (alumina, n-pentane–EtOAc, 9:1).

+

MS (CI, CH₅): m/z (%) = 184 (29), 226 (56), 318 (100) [M + H]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₂₂H₂₃NO: 317.1780; found:

317.1767.

IR (film): 3084, 3058, 3027, 2920, 2851, 1694, 1673, 1526, 1444,

1417, 1375 cm^–1.

Anal. Calcd for C₂₂H₂₃NO: C, 83.24; H, 7.30; N, 4.41. Found: C,

82.86; H, 7.27; N, 4.43.

¹H NMR (500 MHz, CDCl₃): d = 2.10 (s, 3 H, COCH₃), 3.14 (s, 2

H, CH₂Ph), 5.04 (dd, J = 8.4, 2.7 Hz, 1 H, NCHCH), 5.15 (dd,

J = 8.5, 2.7 Hz, 1 H, NCHCH), 6.52 (dd, J = 8.4, 1.7 Hz, 1 H,

NCH), 6.94–7.06 (m, 2 H, CH_Bn,o), 7.13–7.21 (m, 4 H, NCH,

CH_Bn,m, CH_Bn,p), 7.21–7.25 (m, 1 H, CH_Ph,p), 7.31–7.42 (m, 4 H,

CH_Ph,o, CH_Ph,m).

¹³C NMR (125 MHz, CDCl₃): d = 21.24 (q), 43.80 (s), 48.92 (t),

113.57 (d), 113.96 (d), 120.52 (d), 122.32 (d), 126.26 (d), 126.33

(d), 126.42 (d), 127.57 (d), 128.52 (d), 130.73 (d), 137.23 (s),

147.85 (s), 166.04 (s).

1-[4-Benzyl-4-ethylpyridin-1(4H)-yl]ethanone (14c)

According to the literature^11bfrom 13c (222 mg, 0.624 mmol) and

AcCl (58.8 mg, 53.4 mL, 0.748 mmol) in CH₂Cl₂(10 mL). Workup

was performed with 1.0 M phosphate buffer (10 mL, pH 7) and ex-

traction with CH₂Cl₂(4 × 10 mL). Purification by flash chromatog-

raphy (alumina, n-pentane–EtOAc, 9:1); colorless crystals; yield:

134 mg (89%); mp 49–50 °C; R_f= 0.42 (alumina, n-pentane–

EtOAc, 9:1).

+

MS (CI, CH₅): m/z (%) = 156 (48), 198 (67), 290 (100) [M + H]⁺.

IR (KBr): 3085, 3027, 2962, 2929, 2848, 1673, 1624, 1453, 1375

cm^–1.

HRMS–ESI⁺: m/z [M + H]⁺calcd for C₂₀H₂₀NO: 290.1545; found:

290.1532.

¹H NMR (500 MHz, CDCl₃): d = 0.81 (t, J = 7.5 Hz, 3 H, CH₂CH₃),

1.38 (q, J = 7.5 Hz, 2 H, CH₂CH₃), 2.12 (s, 3 H, COCH₃), 2.65 (s, 2

H, CH₂Ph), 4.61 (dd, J = 8.4, 2.7 Hz, 1 H, NCHCH), 4.73 (dd,

J = 8.5, 2.7 Hz, 1 H, NCHCH), 6.53 (dd, J = 8.4, 1.7 Hz, 1 H,

NCH), 7.07–7.12 (m, 2 H, CH_Ar,o), 7.15–7.20 (m, 2 H, NCH,

CH_Ar,p), 7.21–7.26 (m, 2 H, CH_Ar,m).

¹³C NMR (125 MHz, CDCl₃): d = 9.80 (q), 21.36 (q), 34.17 (t),

40.83 (s), 50.02 (t), 113.83 (d), 114.43 (d), 121.64 (d), 123.53 (d),

126.10 (d), 127.62 (d), 130.71 (d), 137.37 (s), 166.05 (s).

Ethyl 1-Acetyl-4,4-dibenzyl-1,4-dihydropyridine-3-carboxylate

(14g)

According to the literature^17aa soln of 13g (252 mg, 515 mmol) and

AcCl (121 mg, 110 mL, 1.55 mmol) in CH₂Cl₂(10 mL) was heated

to 65 °C under microwave conditions. After 9 h, the soln was

quenched by addition of 1.0 M phosphate buffer (10 mL, pH 7). The

aqueous layer was extracted with CH₂Cl₂(4 × 10 mL). The com-

bined organic layers were dried (MgSO₄) and concentrated in vac-

uo. The crude product was purified by flash chromatography (silica

gel, n-pentane–EtOAc, 9:1); colorless oil; yield: 170 mg (88%);

R_f= 0.18 (silica gel, n-pentane–EtOAc, 9:1).

MS (CI, CH₅): m/z (%) = 150 (87), 242 (100) [M + H]⁺.

+

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₁₆H₂₀NO: 242.1545; found:

242.1533.

IR (film): 3061, 3028, 2958, 2920, 2850, 1695, 1673, 1604, 1454,

1372 cm^–1.

Anal. Calcd for C₁₆H₁₉NO: C, 79.63; H, 7.94; N, 5.80. Found: C,

79.68; H, 7.80; N, 5.85.

¹H NMR (400 MHz, C₂D₂Cl₄, 100 °C): d = 1.35 (t, J = 7.1 Hz, 3 H,

CH₂CH₃), 1.91 (s, 3 H, COCH₃), 2.75 (d, J = 13.3 Hz, 2 H, CH₂Ph),

3.56 (d, J = 13.3 Hz, 2 H, CH₂Ph), 4.29 (q, J = 7.1 Hz, 2 H,

CH₂CH₃), 4.83 (d, J = 8.4 Hz, 1 H, NCHCH), 6.50–6.74 (m, 1 H,

NCHCH), 7.00–7.22 (m, 10 H, CH_Ar), 7.56 (s, 1 H, NCHC).

¹³C NMR (100 MHz, C₂D₂Cl₄, 100 °C): d = 14.38 (q), 20.70 (q),

44.53 (s), 47.03 (t), 60.32 (t), 113.12 (s), 117.27 (d), 120.99 (d),

126.13 (d), 127.69 (d), 130.56 (d), 133.75 (d), 138.36 (s), 165.96

(s), 166.73 (s).

1-[4-Benzyl-4-isopropylpyridin-1(4H)-yl]ethanone (14d)

According to the literature^11bfrom 13d (256 mg, 0.693 mmol) and

AcCl (59.8 mg, 54.4 mL, 0.762 mmol) in CH₂Cl₂(10 mL). Workup

was performed with 1.0 M phosphate buffer (10 mL, pH 7) and ex-

traction with CH₂Cl₂(4 × 10 mL). Purification by flash chromatog-

raphy (alumina, n-pentane–EtOAc, 9:1); colorless crystals; yield:

160 mg (91%); mp 61–62 °C; R_f= 0.43 (alumina, n-pentane–

EtOAc, 9:1).

IR (KBr): 3055, 3029, 2966, 2936, 2874, 1671, 1625, 1374 cm^–1.

MS (CI, CH₅): m/z (%) = 284 (68), 376 (100) [M + H]⁺.

+

¹H NMR (400 MHz, CDCl₃): d = 0.94 [d, J = 6.8 Hz, 6 H,

CH(CH₃)₂], 1.53–1.64 [sept, J = 6.8 Hz, 1 H, CH(CH₃)₂], 2.06 (s, 3

H, COCH₃), 2.69 (s, 2 H, CH₂Ph), 4.67 (dd, J = 8.5, 2.7 Hz, 1 H,

HRMS–ESI⁺: m/z [M + H]⁺calcd for C₂₄H₂₆NO₃: 376.1913; found:

376.1907.

Synthesis 2010, No. 13, 2147–2160 © Thieme Stuttgart · New York

2154

C. E. Schmaunz et al.

PAPER

1-[7⁴-Methoxy-5-(4-methoxybenzyl)-2-aza-7(1,2)-benzenabicy-

clo[3.2.1]octaphan-3-en-2-yl]ethanone (15a)

1-[5-Ethyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octaphan-3-en-2-

yl]ethanone (15c)

According to GP2 from 14a (19.0 mg, 0.0523 mmol) in 4.0 M HCl

in 1,4-dioxane (1 mL). Workup was performed after 2 h with phos-

phate buffer (7 mL) and extraction with CH₂Cl₂(4 × 7 mL). Purifi-

cation by flash chromatography (alumina, gradient n-pentane–

EtOAc, 90:10, then 80:20); colorless crystals; yield: 17.9 mg

(94%); mp 124–126 °C; R_f= 0.15 (alumina, n-pentane–EtOAc,

9:1).

According to GP2 from 14c (44.6 mg, 0.185 mmol) in 4.0 M HCl in

1,4-dioxane (2 mL). Workup was performed after 7 h with phos-

phate buffer (10 mL) and extraction with CH₂Cl₂(4 × 10 mL). Pu-

rification by flash chromatography (alumina, gradient n-pentane–

EtOAc, 95:5, then 90:10); colorless oil; yield: 41.8 mg (94%);

R_f= 0.33 (alumina, n-pentane–EtOAc, 9:1).

IR (film): 3060, 2963, 2920, 2850, 1666, 1632, 1447, 1416, 1376

cm^–1.

IR (KBr): 3059, 2997, 2910, 2833, 1665, 1632, 1611, 1512, 1450,

1415, 1376, 1424 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 0.97 (t, J = 7.5 Hz, 3 H, CH₂CH₃),

1.47–1.67 (m, 2 H, CH₂CH₃), 1.79 (ddd, J = 12.7, 3.4, 2.0 Hz,

0.95 × 1 H, H9), 1.85 (ddd, J = 12.7, 2.7, 1.9 Hz, 0.95 × 1 H, H9),

1.75–1.88 (m, 0.05 × 1 H, H9), 1.96–2.01 (dt, J = 12.5, 2.1 Hz, 0.05

× 1 H, H9), 2.12 (s, 0.95 × 3 H, COCH₃), 2.50 (s, 0.05 × 3 H,

COCH₃), 2.72 (d, J = 16.7 Hz, 1 H, H6), 2.80 (d, J = 16.7 Hz, 1 H,

H6), 4.79 (dd, J = 8.3, 1.9 Hz, 0.95 × 1 H, H4), 4.89 (dd, J = 8.4, 2.1

Hz, 0.05 × 1 H, H4), 5.19 (t_br, J = 3.0 Hz, 0.05 × 1 H, H1), 6.01 (t_br,

J = 3.0 Hz, 0.95 × 1 H, H1), 6.42 (dd, J = 8.3, 1.0 Hz, 0.95 × 1 H,

H3), 7.03 (dd, J = 8.4, 1.1 Hz, 0.05 × 1 H, H3), 7.01–7.23 (m, 3 H,

CH_Ar), 7.30 (dd, J = 7.4, 1.3 Hz, 0.05 × 1 H, H4¢), 7.53 (dd, J = 7.4,

1.5 Hz, 0.95 × 1 H, H4¢).

¹H NMR (500 MHz, CDCl₃): d = 1.80 (ddd, J = 12.7, 2.7, 2.0 Hz, 1

H, H9), 1.84 (ddd, J = 12.7, 3.4, 2.0 Hz, 0.96 × 1 H, H9), 1.89–1.93

(m, 0.04 × 1 H, H9), 2.09 (s, 0.96 × 3 H, C=OCH₃), 2.45 (s, 0.04 ×

1 H, C=OCH₃), 2.64 (dd, J = 16.1, 1.3 Hz, 1 H, H6), 2.70 (d,

J = 13.4 Hz, 1 H, CH₂Ph), 2.81 (d, J = 16.1 Hz, 1 H, H6), 2.83 (d,

J = 13.4 Hz, 1 H, CH₂Ph), 3.74 (s, 0.96 × 3 H, OCH₃), 3.76 (s, 0.04

× 3 H, OCH₃), 3.80 (s, 0.04 × 3 H, OCH₃), 3.80 (s, 0.96 × 3 H,

OCH₃), 4.85 (dd, J = 8.2, 2.0 Hz, 0.96 × 1 H, H4), 4.97 (dd, J = 8.4,

2.1 Hz, 0.04 × 1 H, H4), 5.09 (t_br, J = 3.1 Hz, 0.04 × 1 H, H1), 5.93

(t_br, J = 3.0 Hz, 0.96 × 1 H, H1), 6.39 (dd, J = 8.2, 1.0 Hz, 0.96 × 1

H, H3), 6.74 (dd, J = 8.4, 2.8 Hz, 0.96 × 1 H, H2¢), 6.77–6.80 (m,

0.04 × 3 H, H2¢, CH_Bn,m), 6.81–6.88 (m, 0.96 × 2 H, CH_Bn,m), 6.95

(d, J = 8.5 Hz, 0.96 × 1 H, H1¢), 6.98–7.02 (m, 0.04 × 3 H, H3, H1¢,

H4¢), 7.04 (d, J = 2.7 Hz, 0.96 × 1 H, H4¢), 7.09–7.15 (m, 2 H,

CH_Bn,o). Ratio of rotational isomers 96:4.

¹³C NMR (100 MHz, CDCl₃):¹⁸d = 8.01 (q), 21.54 (q), 32.75 (t),

33.06 (t), 33.27 (s), 41.83 (t), 47.10 (d), 115.66 (d), 123.94 (d),

126.29 (d), 127.51 (d), 128.69 (d), 129.77 (d), 135.81 (s), 136.17

(s), 167.29 (s).

¹³C NMR (125 MHz, CDCl₃):¹⁸d = 21.57 (q), 33.70 (t), 34.48 (s),

40.93 (t), 46.29 (t), 47.39 (d), 55.24 (q), 55.31 (q), 113.32 (d),

113.43 (d), 114.86 (d), 115.24 (d), 123.97 (d), 127.59 (s), 129.29

(s), 129.61 (d), 131.45 (d), 136.86 (s), 158.01 (s), 158.26 (s), 167.32

(s).

+

MS (CI, CH₅): m/z (%) = 242 (100) [M + H]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₁₆H₁₉NO: 241.1467; found:

241.1439.

1-[5-Isopropyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octaphan-3-

en-2-yl]ethanone (15d)

+

MS (CI, CH₅): m/z (%) = 364 (100) [M + H]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₂₃H₂₅NO₃: 363.1834; found:

363.1823.

According to GP2 from 14d (18.7 mg, 0.0732 mmol) in 4.0 M HCl

in 1,4-dioxane (1 mL). Workup was performed after 5 h with phos-

phate buffer (7 mL) and extraction with CH₂Cl₂(4 × 7 mL). Purifi-

cation by flash chromatography (alumina, gradient n-pentane–

EtOAc, 95:5, then 90:10); colorless oil; yield: 17.6 mg (94%);

R_f= 0.42 (alumina, n-pentane–EtOAc, 9:1).

1-[5-(2-Phenylethyl)-2-aza-7(1,2)-benzenabicyclo[3.2.1]octa-

phan-3-en-2-yl]ethanone (15b)

According to GP2 from 14b (18.9 mg, 0.0595 mmol) in 4.0 M HCl

in 1,4-dioxane (1 mL). Workup was performed after 23 h with phos-

phate buffer (7 mL) and extraction with CH₂Cl₂(4 × 7 mL). Purifi-

cation by flash chromatography (alumina, gradient n-pentane–

EtOAc, 95:5, then 90:10); colorless oil; yield: 18.0 mg (95%);

R_f= 0.34 (alumina, n-pentane–EtOAc, 9:1).

IR (film): 3059, 2960, 2924, 2873, 1664, 1636, 1448, 1417, 1376

cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 0.97 [d, J = 6.9 Hz, 3 H,

CH(CH₃)₂], 1.01 [d, J = 6.9 Hz, 3 H, CH(CH₃)₂], 1.74 [sept, J = 6.9

Hz, 1 H, CH(CH₃)₂], 1.78 (ddd, J = 12.8, 3.5, 2.1 Hz, 1 H, H9), 1.90

(dt_br, J = 12.8, 2.5 Hz, 0.95 × 1 H, H9), 1.99–2.06 (m, 0.05 × 1 H,

H9), 2.12 (s, 0.95 × 3 H, COCH₃), 2.50 (s, 0.05 × 3 H, COCH₃), 2.72

(dd, J = 16.6, 1.5 Hz, 1 H, H6), 2.88 (d, J = 16.6 Hz, 1 H, H6), 4.85

(dd, J = 8.3, 2.1 Hz, 0.95 × 1 H, H4), 4.96 (dd, J = 8.4, 2.1 Hz, 0.05

× 1 H, H4), 5.18 (t_br, J = 3.1 Hz, 0.05 × 1 H, H1), 6.00 (t_br, J = 3.0

Hz, 0.95 × 1 H, H1), 6.43 (dd, J = 8.3, 0.9 Hz, 0.95 × 1 H, H3), 7.03

(dd, J = 8.4, 1.0 Hz, 0.05 × 1 H, H3), 7.09 (d_br, J = 7.4 Hz, 1 H, H1¢),

7.11–7.24 (m, 2 H, H2¢, H3¢), 7.30 (dd, J = 7.4, 1.3 Hz, 0.05 × 1 H,

H4¢), 7.53 (dd, J = 7.5, 1.4 Hz, 0.95 × 1 H, H4¢). Ratio of rotational

isomers 95:5.

IR (film): 3060, 3024, 2921, 2853, 1666, 1633, 1452, 1416, 1376

cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.78–1.93 (m, 2 H, CH₂CH₂Ph),

1.90 (ddd, J = 12.6, 3.3, 2.0 Hz, 1 H, H9), 1.93–2.01 (dt_br, J = 12.6,

2.3 Hz, 1 H, H9), 2.14 (s, 0.96 × 3 H, COCH₃), 2.51 (s, 0.04 × 3 H,

COCH₃), 2.61–2.77 (m, 2 H, CH₂CH₂Ph), 2.80 (d, J = 16.5 Hz, 1 H,

H6), 2.90 (d, J = 16.5 Hz, 1 H, H6), 4.87 (dd, J = 8.2, 2.0 Hz, 0.96

× 1 H, H4), 4.98 (dd, J = 8.5, 2.0 Hz, 0.04 × 1 H, H4), 5.22 (t_br,

J = 3.1 Hz, 0.04 × 1 H, H1), 6.05 (t_br, J = 3.0 Hz, 0.96 × 1 H, H1),

6.47 (d, J = 8.2 Hz, 0.96 × 1 H, H3), 7.09 (d_br, J = 7.4 Hz, 0.04 × 1

H, 1 H, H3, H1¢), 7.12–7.25 (m, 5 H, H2¢, H3¢, CH_Ph,o, CH_Ph,p),

7.27–7.37 (m, 2 H, CH_Ph,m), 7.54 (d, J = 7.5 Hz, 1 H, H4¢). Ratio of

rotational isomers 96:4.

¹³C NMR (125 MHz, CDCl₃):¹⁸d = 17.08 (q), 17.30 (q), 21.57 (q),

30.72 (t), 35.16 (d), 35.88 (s), 39.52 (t), 47.09 (d), 114.40 (d),

124.13 (d), 126.26 (d), 127.52 (d), 128.87 (d), 129.71 (d), 136.00

(s), 136.13 (s), 167.30 (s).

¹³C NMR (100 MHz, CDCl₃):¹⁸d = 21.62 (q), 30.30 (t), 33.13 (t),

33.42 (s), 42.38 (t), 42.81 (t), 47.10 (d), 115.35 (d), 124.32 (d),

125.89 (d), 126.48 (d), 127.65 (d), 128.30 (d), 128.48 (d), 128.74

(d), 129.85 (d), 135.59 (s), 136.10 (s), 142.44 (s), 167.38 (s).

+

MS (CI, CH₅): m/z (%) = 242 (25), 256 (100) [M + H]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₁₇H₂₁NO: 255.1623; found:

255.1622.

+

MS (CI, CH₅): m/z (%) = 318 (100) [M + H]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₂₂H₂₃NO: 317.1780; found:

317.1773.

Synthesis 2010, No. 13, 2147–2160 © Thieme Stuttgart · New York

PAPER

Synthesis of 5-Substituted 7,8-Benzomorphans

2155

1-[5-Phenyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octaphan-3-en-

2-yl]ethanone (15e)

phosphate buffer (25 mL, pH 7) and the aqueous layer was extracted

with CH₂Cl₂(4 × 25 mL). The combined organic layers were dried

(MgSO₄) and concentrated in vacuo. The crude material was puri-

fied by flash chromatography (alumina, gradient n-pentane–EtOAc,

95:5, then 90:10); colorless crystals; yield: 43.3 mg (88%); mp 65–

68 °C; R_f= 0.31 (alumina, n-pentane–EtOAc, 9:1).

According to GP2 from 14e (54.9 mg, 0.190 mmol) in 4.0 M HCl in

1,4-dioxane (2 mL). Workup was performed after 20 h with phos-

phate buffer (10 mL) and extraction with CH₂Cl₂(4 × 10 mL). Pu-

rification by flash chromatography (alumina, gradient n-pentane–

EtOAc, 95:5, then 90:10); colorless oil; yield: 53.4 mg (97%);

R_f= 0.25 (alumina, n-pentane–EtOAc, 9:1).

IR (KBr): 3060, 3026, 2978, 1927, 2870, 1699, 1683, 1610, 1453,

1376, 1227, 1213 cm^–1.

IR (film): 3059, 3023, 2925, 1667, 1631, 1445, 1414, 1376 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.33 (t, J = 7.1 Hz, 3 H, CH₂CH₃),

1.81 (dd, J = 13.0, 3.6 Hz, 1 H, H9), 1.91 (dt, J = 13.0, 2.5 Hz, 1 H,

H9), 2.18 (s, 3 H, COCH₃), 2.89 (d, J = 16.8 Hz, 1 H, H6), 3.04 (d,

J = 13.4 Hz, 1 H, CH₂Ph), 3.51 (m, 2 H, H6, CH₂Ph), 4.20 (dq,

J = 10.8, 7.1 Hz, 1 H, CH₂CH₃), 4.29 (dq, J = 10.8, 7.1 Hz, 1 H,

CH₂CH₃), 5.89 (t_br, J = 2.9 Hz, 1 H, H1), 7.09–7.16 (m, 4 H, H1¢,

H3¢, CH_Ph,o), 7.16–7.23 (m, 2 H, H2¢, CH_Ph,p), 7.23–7.30 (m, 2 H,

CH_Ph,m), 7.44 (d_br, J = 7.8 Hz, 1 H, H4¢), 7.61 (d, J = 0.9 Hz, 1 H,

H3).

¹³C NMR (100 MHz, CDCl₃): d = 14.41 (q), 21.53 (q), 33.79 (t),

35.85 (s), 40.99 (t), 43.26 (t), 46.85 (d), 60.07 (t), 114.14 (s), 126.32

(d), 126.44 (d), 127.86 (d), 127.97 (d), 129.01 (d), 129.56 (d),

130.60 (d), 134.80 (s), 135.85 (s, d), 137.74 (s), 166.42 (s), 168.31

(s).

¹H NMR (400 MHz, CDCl₃): d = 2.15 (s, 0.95 × 3 H, COCH₃),

2.22–2.32 (m, 0.05 × 1 H, 0.95 × 2 H, H9), 2.32–2.38 (dt, J = 12.7,

2.3 Hz, 0.05 × 1 H, H9), 2.53 (s, 0.05 × 3 H, COCH₃), 3.14 (dd,

J = 16.4, 1.9 Hz, 0.05 × 1 H, H6), 3.16 (d, J = 16.5 Hz, 0.95 × 1 H,

H6), 3.35 (d, J = 16.5 Hz, 0.95 × 1 H, H6), 3.39 (d, J = 16.4 Hz, 0.05

× 1 H, H6), 5.11 (dd, J = 8.3, 1.2 Hz, 0.95 × 1 H, H4), 5.19 (dd,

J = 8.5, 2.3 Hz, 0.05 × 1 H, H4), 5.28 (t_br, J = 3.0 Hz, 0.05 × 1 H,

H1), 6.12 (t_br, J = 3.0 Hz, 0.95 × 1 H, H1), 6.52 (dd, J = 8.3, 0.9 Hz,

0.95 × 1 H, H3), 7.11–7.33 (m, 0.05 × 1 H, 4 H, H3, H1¢, H2¢, H3¢,

CH_Ph,p), 7.33–7.45 (m, 2 H, CH_Ph,m), 7.45–7.54 (m, 2 H, CH_Ph,o),

7.57 (d, J = 7.5, 1.5 Hz, 1 H, H4¢). Ratio of rotational isomers 95:5.

¹³C NMR (125 MHz, CDCl₃):¹⁸d = 21.52 (q), 35.48 (t), 37.53 (s),

42.58 (t), 47.39 (d), 115.76 (d), 124.07 (d), 125.62 (d), 126.63 (d),

126.68 (d), 127.78 (d), 128.64 (d), 128.78 (d), 129.76 (d), 135.48

(s), 135.51 (s), 146.66 (s), 167.33 (s).

+

MS (CI, CH₅): m/z (%) = 376 (100) [M + H]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₂₄H₂₅NO₃: 375.1834; found:

375.1849.

MS (CI, CH₅): m/z (%) = 290 (100) [M + H]⁺.

+

HRMS (EI⁺): m/z [M]⁺calcd for C₂₀H₁₉NO: 289.1467; found:

289.1469.

1-[7⁴-Methoxy-5-(4-methoxybenzyl)-2-aza-7(1,2)-benzenabicy-

clo[3.2.1]octaphan-2-yl]ethanone (17a)

1-[5-Benzyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octaphan-3-en-

2-yl]ethanone (15f)

According to GP3 from 15a (28.4 mg, 0.0781 mmol) in CH₂Cl₂(1

mL) and NaBH₄(5.9 mg, 0.16 mmol) in TFA (2 mL). Purification

by flash chromatography (alumina, gradient n-pentane–EtOAc 8:2,

then 7:3); colorless crystals; yield: 27.1 mg (95%); mp 51–53 °C;

R_f= 0.08 (alumina, n-pentane–EtOAc, 8:2).

According to GP2 from 14f^11b(44.3 mg, 0.146 mmol) in 4.0 M HCl

in 1,4-dioxane (2 mL). Workup was performed after 3 h with phos-

phate buffer (10 mL) and extraction with CH₂Cl₂(4 × 10 mL). Pu-

rification by flash chromatography (alumina, gradient n-pentane–

EtOAc, 95:5, then 90:10); colorless crystals; yield: 42.9 mg (97%);

mp 116–117 °C; R_f= 0.30 (alumina, n-pentane–EtOAc, 9:1).

IR (KBr): 3066, 2996, 2909, 2834, 1637, 1611, 1512, 1502, 1420,

1245 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.54 (m, 2 H, H4), 1.75 (s_br, 0.77

× 2 H, H9), 1.77 (s_br, 0.23 × 2 H, H9), 2.02 (s, 0.77 × 3 H, C=OCH₃),

2.33 (s, 0.23 × 3 H, C=OCH₃), 2.28–2.45 (m, 0.23 × 1 H, H3), 2.52–

2.65 (m, 3 H, H6, CH₂Ph), 2.82–2.97 (m, 0.77 × 1 H, 1 H, H3, H6),

3.44 (d_br, J = 13.0 Hz, 0.77 × 1 H, H3), 3.74 (s, 0.77 × 3 H, C3¢-

OCH₃), 3.76 (s, 0.23 × 3 H, C3¢-OCH₃), 3.80 (s, 3 H, C_Bn,p-OCH₃),

4.34 (d_br, J = 12.6 Hz, 0.23 × 1 H, H3), 4.94 (s_br, 0.23 × 1 H, H1),

5.92 (s_br, 0.77 × 1 H, H1), 6.59 (s_br, 0.23 × 1 H, H4¢), 6.72–6.81 (m,

0.77 × 1 H, 1 H, H4¢, H2¢), 6.84 (d, J = 8.3 Hz, 2 H, CH_Bn,m), 6.98

(d, J = 9.0 Hz, 0.77 × 1 H, H1¢), 7.01 (d, J = 8.7 Hz, 0.23 × 1 H,

H1¢), 7.07 (d, J = 8.3 Hz, 2 H, CH_Bn,o). Ratio of rotational isomers

77:23.

¹³C NMR (100 MHz, CDCl₃): d = 21.93 (q, minor + major), 32.85

(s, minor + major), 34.93 (t, minor), 36.09 (t, major), 36.96 (t, mi-

nor), 37.48 (t, minor), 38.18 (t, minor + major), 38.26 (t, major),

40.06 (t, major), 47.94 (d, major), 49.75 (t, minor + major), 54.09

(d, minor), 55.25 (q, minor + major), 55.36 (q, minor + major),

112.56 (d, major), 113.01 (d, minor), 113.39 (d, minor + major),

114.09 (d, minor), 114.97 (d, major), 128.73 (d, major), 129.09 (s,

minor + major), 129.18 (d, minor), 129.66 (s, major), 129.86 (s, mi-

nor), 131.51 (d, minor + major), 134.92 (s, minor), 135.82 (s, ma-

jor), 157.92 (s, minor + major), 158.23 (s, minor + major), 167.79

(s, minor), 168.44 (s, major).

IR (KBr): 3060, 3025, 2919, 2848, 1665, 1632, 1451, 1417, 1376

cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.80–1.98 (m, 2 H, H9), 2.08 (s,

0.95 × 3 H, COCH₃), 2.46 (s, 0.05 × 1 H, COCH₃), 2.72 (d_br,

J = 16.6 Hz, 1 H, H6), 2.77 (d, J = 13.2 Hz, 1 H, CH₂Ph), 2.89 (d,

J = 13.2 Hz, 1 H, CH₂Ph), 2.90(d, J = 16.6 Hz, 1 H, H6), 4.88 (dd,

J = 8.3, 1.6 Hz, 0.95 × 1 H, H4), 5.00 (dd, J = 8.4, 2.1 Hz, 0.05 × 1

H, H4), 5.15 (t_br, J = 3.1 Hz, 0.05 × 1 H, H1), 5.99 (t_br, J = 3.0 Hz,

0.95 × 1 H, H1), 6.39 (dd, J = 8.3, 0.9 Hz, 0.95 × 1 H, H3), 7.01 (dd,

J = 8.4, 1.1 Hz, 0.05 × 1 H, H3), 7.04 (d_br, J = 7.2 Hz, 1 H, H1¢),

7.07–7.19 (m, 2 H, H2¢, H3¢), 7.19–7.28 (m, 3 H, CH_Ph,o, CH_Ph,p),

7.28–7.36 (m, 2 H, CH_Ph,m), 7.49 (dd, J = 7.4, 1.6 Hz, 1 H, H4¢). Ra-

tio of rotational isomers 95:5.

¹³C NMR (100 MHz, CDCl₃):¹⁸d = 21.50 (q), 33.59 (t), 34.22 (s),

41.62 (t), 47.07 (d), 47.14 (t), 115.14 (d), 123.97 (d), 126.37 (d),

126.43 (d), 127.54 (d), 128.01 (d), 128.68 (d), 129.72 (d), 130.52

(d), 135.52 (s), 135.83 (s), 137.14 (s), 167.30 (s).

+

MS (CI, CH₅): m/z (%) = 304 (100) [M + H]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₂₁H₂₁NO: 303.1623; found:

303.1649.

Ethyl 2-Acetyl-5-benzyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]oc-

taphan-3-ene-4-carboxylate (15g)

A soln of 14g (49.1 mg, 0.131 mmol) in 4.0 M HCl in 1,4-dioxane

(4 mL) was heated to 80 °C under microwave conditions in a closed

system for 1 h. The reaction was quenched by addition of 1.0 M

+

MS (CI, CH₅): m/z (%) = 366 (100) [M + H]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₂₃H₂₇NO₃: 365.1991; found:

365.1990.

Synthesis 2010, No. 13, 2147–2160 © Thieme Stuttgart · New York

2156

C. E. Schmaunz et al.

PAPER

1-[5-(2-Phenylethyl)-2-aza-7(1,2)-benzenabicyclo[3.2.1]octa-

phan-2-yl]ethanone (17b)

HRMS (EI⁺): m/z [M]⁺calcd for C₁₆H₂₁NO: 243.1623; found:

243.1624.

According to GP3 from 15b (60.2 mg, 0.190 mmol) in CH₂Cl₂(1

mL) and NaBH₄(14.3 mg, 0.379 mmol) in TFA (2 mL). Purifica-

tion by flash chromatography (alumina, gradient n-pentane–EtOAc,

9:1, then 8:2); colorless oil; yield: 50.9 mg (84%); R_f= 0.35 (alumi-

na, n-pentane–EtOAc, 8:2).

1-[5-Isopropyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octaphan-2-

yl]ethanone (17d)

According to GP3 from 15d (41.2 mg, 0.161 mmol) in CH₂Cl₂(1

mL) and NaBH₄(12.2 mg, 0.322 mmol) in TFA (2 mL). Purifica-

tion by flash chromatography (alumina, gradient n-pentane–EtOAc,

9:1, then 8:2); colorless crystals; yield: 37.6 mg (91%); mp 59–62

°C; R_f= 0.34 (alumina, n-pentane–EtOAc, 8:2).

IR (film): 3023, 2918, 2849, 1638, 1492, 1453, 1421 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.53–1.90 (m, 6 H, H4, H9,

CH₂CH₂Ph), 2.04 (s, 0.70 × 3 H, COCH₃), 2.35 (s, 0.30 × 3 H,

COCH₃), 2.41 (td, J = 13.6, 3.7 Hz, 0.30 × 1 H, H3), 2.63–2.71 (m,

2 H, CH₂CH₂Ph), 2.80–3.02 (m, 0.70 × 1 H, 2 H, H3, H6), 3.50

(dd_br, J = 13.6, 5.1 Hz, 0.70 × 1 H, H3), 4.40 (dd_br, J = 13.6, 5.5 Hz,

0.30 × 1 H, H3), 5.03 (t_br, J = 2.9 Hz, 0.30 × 1 H, H1), 6.00 (t_br,

J = 2.9 Hz, 0.70 × 1 H, H1), 7.09–7.37 (m, 9 H, CH_Ar). Ratio of ro-

tational isomers 70:30.

¹³C NMR (100 MHz, CDCl₃): d = 21.98 (q, minor), 22.01 (q, ma-

jor), 29.44 (t, minor), 29.49 (t, major), 31.74 (s, major), 31.76 (s, mi-

nor), 34.70 (t, minor), 36.50 (t, major), 37.28 (t, minor), 37.57 (t,

minor), 38.15 (t, major), 39.00 (t, major), 39.08 (t, minor), 39.93 (t,

major), 46.93 (t, major), 46.98 (t, minor), 47.50 (d, major), 53.77 (d,

minor), 125.87 (d, minor + major), 126.22 (d, minor), 126.32 (d,

major), 127.66 (d, major), 127.84 (d, major), 128.09 (d, minor),

128.28 (d, minor + major), 128.33 (d, minor), 128.48 (d, minor +

major), 129.28 (d, major), 134.39 (s, minor), 135.36 (s, major),

137.60 (s, major), 137.78 (s, minor), 142.47 (s, minor), 142.48 (s,

major), 167.80 (s, minor), 168.44 (s, major).

IR (KBr): 3019, 2971, 2958, 2940, 2875, 1627, 1427 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 0.92 [m, 6 H, CH(CH₃)₂], 1.41–

1.55 [m, 2 H, CH(CH₃)₂, H4], 1.62–1.72 (m, 0.70 × 1 H, 1 H, H9,

H4), 1.75 (m, 1 H, H9), 1.81 (dt, J = 12.6, 2.7 Hz, 0.30 × 1 H, H9),

2.02 (s, 0.70 × 3 H, COCH₃), 2.34 (s, 0.30 × 3 H, COCH₃), 2.35–

2.43 (td, J = 13.7, 3.7 Hz, 0.30 × 1 H, H3), 2.68 (d, J = 17.9 Hz, 0.70

× 1 H, H6), 2.71 (d, J = 17.9 Hz, 0.30 × 1 H, H6), 2.83 (d, J = 17.9

Hz, 0.30 × 1 H, H6), 2.84 (d, J = 17.9 Hz, 0.70 × 1 H, H6), 2.92 (td,

J = 13.6, 3.6 Hz, 0.70 × 1 H, H3), 3.48 (dd_br, J = 13.6, 5.3 Hz, 0.70

× 1 H, H3), 4.38 (dd_br, J = 13.7, 5.8 Hz, 0.30 × 1 H, H3), 5.01 (t_br,

J = 3.0 Hz, 0.30 × 1 H, H1), 5.97 (t_br, J = 3.0 Hz, 0.70 × 1 H, H1),

7.10–7.17 (m, 0.30 × 1 H, 2 H, H4¢, H1¢, H3¢), 7.18–7.25 (m, 1 H,

H2¢), 7.27–7.31 (m, 0.70 × 1 H, H4¢). Ratio of rotational isomers

70:30.

¹³C NMR (125 MHz, CDCl₃): d = 16.45 (q, minor + major), 16.56

(q, minor), 16.61 (q, major), 21.94 (q, minor), 21.97 (q, major),

33.74 (s, major), 33.78 (s, minor), 34.48 (t, major), 34.54 (t, minor),

34.70 (t, minor), 35.32 (t, major), 35.56 (t, minor), 35.83 (t, minor

+ major), 38.57 (d, minor + major), 39.97 (t, major), 47.56 (d, ma-

jor), 53.85 (d, minor), 126.02 (d, minor), 126.12 (d, major), 127.54

(d, major), 127.97 (d, minor), 128.05 (d, major), 128.15 (d, minor),

128.53 (d, minor), 129.19 (d, major), 134.58 (s, minor), 135.58 (s,

major), 138.05 (s, major), 138.27 (s, minor), 167.73 (s, minor),

168.41 (s, major).

MS (EI, 70 eV): m/z (%) = 319.2 (36) [M]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₂₂H₂₅NO: 319.1936; found:

319.1968.

1-[5-Ethyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octaphan-2-

yl]ethanone (17c)

According to GP3 from 15c (59.7 mg, 0.247 mmol) in CH₂Cl₂(1

mL) and NaBH₄(18.7 mg, 0.495 mmol) in TFA (2 mL). Purifica-

tion by flash chromatography (alumina, gradient n-pentane–EtOAc,

9:1, then 8:2); colorless oil; yield: 53.6 mg (89%); R_f= 0.34 (alumi-

na, n-pentane–EtOAc, 8:2).

MS (EI, 70 eV): m/z (%) = 214.1 (100), 257.1 (45) [M]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₁₇H₂₃NO: 257.1780; found:

257.1786.

1-[5-Phenyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octaphan-2-

yl]ethanone (17e)

According to GP3 from 15e (68.4 mg, 0.236 mmol) in CH₂Cl₂(1

mL) and NaBH₄(17.9 mg, 0.473 mmol) in TFA (2 mL). Purifica-

tion by flash chromatography (alumina, gradient n-pentane–EtOAc,

9:1, then 8:2); colorless crystals; yield: 57.9 mg (84%); mp 129–130

°C; R_f= 0.22 (alumina, n-pentane–EtOAc, 8:2).

IR (film): 3060, 2962, 2924, 2849, 1638, 1421 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 0.92 (t, J = 7.5 Hz, 3 H, CH₂CH₃),

1.32–1.43 (m, 2 H, CH₂CH₃), 1.43–1.52 (m, 0.30 × 1 H, H4), 1.43–

1.55 (m, 1 H, H4), 1.56–1.63 (m, 1 H, H4), 1.65 (ddd, J = 12.9, 3.2,

1.7 Hz, 0.70 × 1 H, H9), 1.69–1.74 (m, 1 H, H9), 1.77 (dt, J = 12.5,

2.6 Hz, 0.30 × 1 H, H9), 2.02 (s, 0.70 × 3 H, COCH₃), 2.34 (s, 0.30

× 3 H, COCH₃), 2.34–2.42 (td, J = 13.7, 3.7 Hz, 0.30 × 1 H, H3),

2.71 (d, J = 17.7 Hz, 0.70 × 1 H, H6), 2.74 (d, J = 17.7 Hz, 0.30 × 1

H, H6), 2.81 (d, J = 17.7 Hz, 0.30 × 1 H, H6), 2.82 (d, J = 17.7 Hz,

0.70 × 1 H, H6), 2.92 (td, J = 13.5, 3.7 Hz, 0.70 × 1 H, H3), 3.46

(dd_br, J = 13.6, 5.6 Hz, 0.70 × 1 H, H3), 4.37 (dd, J = 13.7, 5.7 Hz,

0.30 × 1 H, H3), 5.00 (t_br, J = 3.0 Hz, 0.30 × 1 H, H1), 5.98 (t_br,

J = 2.9 Hz, 0.70 × 1 H, H1), 7.08–7.16 (m, 0.30 × 1 H, 2 H, H4¢, H1¢,

H3¢), 7.17–7.25 (m, 1 H, H2¢), 7.28 (dd, J = 7.5, 1.0 Hz, 0.70 × 1 H,

H4¢). Ratio of rotational isomers 70:30.

¹³C NMR (125 MHz, CDCl₃): d = 7.27 (q, minor), 7.31 (q, major),

21.97 (q, minor), 22.00 (q, major), 31.49 (s, major), 31.52 (s, mi-

nor), 34.75 (t, minor), 36.12 (t, major), 36.88 (t, minor), 36.94 (t,

minor + major), 37.16 (t, minor), 37.69 (t, major), 38.59 (t, major),

38.64 (t, minor), 39.99 (t, major), 47.59 (d, major), 53.87 (d, minor),

126.07 (d, minor), 126.17 (d, major), 127.55 (d, major), 127.84 (d,

major), 127.98 (d, minor), 128.23 (d, minor), 128.32 (d, minor),

129.22 (d, major), 134.52 (s, minor), 135.49 (s, major), 137.92 (s,

major), 138.12 (s, minor), 167.75 (s, minor), 168.40 (s, major).

IR (KBr): 3061, 3021, 2914, 2872, 1624, 1438, 1425 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 1.76–1.88 (m, 1 H, H4), 2.04 (s,

0.73 × 3 H, COCH₃), 2.02–2.11 (m, 1 H, H4), 2.23–2.31 (m, 0.73 ×

2 H, H9), 2.29–2.37 (m, 0.27 × 2 H, H9), 2.40 (s, 0.27 × 3 H,

COCH₃), 2.56 (td, J = 13.8, 3.7 Hz, 0.27 H × 1 H, H3), 3.11 (td,

J = 13.7, 3.5 Hz, 0.73 × 1 H, H3), 3.13 (d_br, J = 17.9 Hz, 1 H, H6),

3.26 (d, J = 17.9 Hz, 0.73 × 1 H, H6), 3.28 (d, J = 17.9 Hz, 0.27 × 1

H, H6), 3.56 (dd_br, J = 13.7, 5.4 Hz, 0.73 × 1 H, H3), 4.46 (dd_br,

J = 13.8, 5.6 Hz, 0.27 × 1 H, H3), 5.19 (t_br, J = 3.0 Hz, 0.27 × 1 H,

H1), 6.17 (t_br, J = 2.9 Hz, 0.73 × 1 H, H1), 7.10–7.29 (m, 0.23 × 1

H, 4 H, H4¢, H1¢, H2¢, H3¢, CH_Ph,p), 7.33–7.42 (m, 0.73 × 1 H, 4 H,

H4¢, CH_Ph,o, CH_Ph,m). Ratio of rotational isomers 77:23.

¹³C NMR (125 MHz, CDCl₃): d = 21.93 (q, minor + major), 34.73

(t, major), 34.87 (t, minor), 35.57 (s, major), 35.60 (s, minor), 35.89

(t, minor), 39.26 (t, minor), 40.09 (t, major), 41.62 (t, major), 41.64

(t, minor), 47.41 (d, major), 53.72 (d, minor), 124.47 (d, minor),

124.50 (d, major), 126.38 (d, minor + major), 126.39, (d, minor),

126.49 (d, major), 127.68 (d, major), 127.76 (d, major), 128.17 (d,

minor), 128.19 (d, minor), 128.63 (d, minor + major), 129.22 (d,

MS (APCI⁺): m/z (%) = 244 (64) [M + H]⁺, 266 (67) [M + Na]⁺, 509

(100) [2 M + Na]⁺.

PAPER

Synthesis of 5-Substituted 7,8-Benzomorphans

2157

major), 133.87 (s, minor), 134.81 (s, major), 137.55 (s, major),

137.71 (s, minor), 149.71 (s, minor), 149.79 (s, major), 167.74 (s,

minor), 168.46 (s, major).

6.63 (d_br, J = 2.2 Hz, 0.54 × 1 H, H4¢), 6.66 (d, J = 2.7 Hz, 0.46 × 1

H, H2¢), 6.68 (d, J = 2.7 Hz, 0.54 × 1 H, H2¢), 6.72 (d_br, J = 2.2 Hz,

0.46 × 1 H, H4¢), 6.76 (d, J = 8.5 Hz, 2 H, CH_Bn,m), 6.86–6.93 (m, 1

H, H1¢), 6.99 (d, J = 8.5 Hz, 2 H, CH_Bn,o). Ratio of rotational iso-

mers 46:54.

MS (EI, 70 eV): m/z (%) = 206.1 (74), 217.1 (34), 232.2 (66), 291.2

(100) [M]⁺.

¹³C NMR (100 MHz, C₂D₂Cl₄): d = 28.72 (q, minor), 29.02 (q, ma-

jor), 32.68 (s, major), 32.84 (s, minor), 36.29 (t, minor or major),

36.35 (t, minor or major), 36.94 (t, major), 37.73 (t, minor or major),

38.09 (t, minor or major), 49.99 (t, minor or major), 50.06 (t, minor

or major), 50.13 (d, minor), 51.26 (d, major), 55.51 (q, major),

55.63 (q, minor + major), 55.72 (q, minor), 79.63 (s, minor), 79.80

(s, major), 112.67 (d, major), 112.77 (d, minor), 113.66 (d, minor +

major), 114.43 (d, major), 114.81 (d, minor), 129.07 (d, minor),

129.22 (d, major), 129.68 (s, minor or major), 129.70 (s, minor or

major), 129.83 (s, minor or major), 129.97 (s, minor or major),

131.91 (d, minor + major), 136.24 (s, major), 136.67 (s, minor),

154.60 (s, major), 154.90 (s, minor), 157.74 (s, major), 157.86 (s,

minor), 158.23 (s, minor + major).

HRMS (EI⁺): m/z [M]⁺calcd for C₂₀H₂₁NO: 291.1623; found:

291.1628.

1-[5-Benzyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octaphan-2-

yl]ethanone (17f)

According to GP3 from 15f (30.0 mg, 0.0989 mmol) in CH₂Cl₂(1

mL) and NaBH₄(7.5 mg, 0.20 mmol) in TFA (2 mL). Purification

by flash chromatography (alumina, gradient n-pentane–EtOAc, 9:1,

then 8:2); colorless oil; yield: 24.3 mg (80%); R_f= 0.27 (alumina,

n-pentane–EtOAc, 8:2).

IR (film): 3059, 3025, 2915, 1637, 1452, 1420 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 1.51–1.67 (m, 2 H, H4), 1.79 (d_br,

J = 3.0 Hz, 0.70 × 2 H, H9), 1.83 (d_br, J = 2.9 Hz, 0.30 × 2 H, H9),

1.99 (s, 0.70 × 3 H, COCH₃), 2.32 (s, 0.30 × 3 H, COCH₃), 2.36 (td,

J = 13.2, 4.8 Hz, 0.30 × 1 H, H3), 2.58–2.72 (m, 3 H, H6, CH₂Ph),

2.88 (td, J = 13.4, 4.1 Hz, 0.70 × 1 H, H3), 2.97 (d, J = 17.7 Hz, 0.3

× 1 H, H6), 2.98 (d, J = 17.7 Hz, 0.70 × 1 H, H6), 3.44 (dd_br,

J = 13.4, 4.8 Hz, 0.70 × 1 H, H3), 4.34 (dd_br, J = 13.2, 4.8 Hz, 0.30

× 1 H, H3), 5.00 (t_br, J = 2.9 Hz, 0.30 × 1 H, H1), 5.98 (t_br, J = 3.0

Hz, 0.70 × 1 H, H1), 7.04–7.22 (m, 0.3 × 1 H, 2 H, H4¢, H1¢, H3¢),

7.14–7.22 (m, 3 H, H2¢, CH_Bn,o), 7.22–7.28 (m, 0.70 × 1 H, 1 H, H4¢,

CH_Bn,p), 7.28–7.34 (m, 2 H, CH_Bn,m). Ratio of rotational isomers

70:30.

¹³C NMR (100 MHz, CDCl₃): d = 21.94 (q, minor + major), 32.81

(s, major), 32.84 (s, minor), 34.67 (t, minor), 36.10 (t, major), 37.01

(t, minor), 37.63 (t, minor), 38.30 (t, major), 38.92 (t, minor), 38.99

(t, major), 39.87 (t, major), 47.52 (d, major), 50.59 (t, minor), 50.67

(t, major), 53.80 (d, minor), 126.17 (d, minor), 126.28 (d, major),

126.43 (d, minor + major), 126.46 (d, minor), 127.60 (d, major),

127.74 (d, major), 128.01 (d, minor + major), 128.17 (d, minor),

128.24 (d, minor), 129.16 (d, major), 130.63 (d, minor + major),

134.08 (s, minor), 135.05 (s, major), 136.95 (s, minor), 137.04 (s,

major), 137.66 (s, major), 137.86 (s, minor), 167.70 (s, minor),

168.36 (s, major).

+

MS (CI, CH₅): m/z (%) = 246 (26), 368 (100), 424 (7) [M + H]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₂₆H₃₃NO₄: 423.2410; found:

423.2404.

tert-Butyl 5-(2-Phenylethyl)-2-aza-7(1,2)-benzenabicy-

clo[3.2.1]octaphane-1-carboxylate (19b)

According to GP4 from 14b (76.9 mg, 0.242 mmol) and H₂O (43.6

mg, 43.6 mL, 2.42 mmol) in 4.0 M HCl in 1,4-dioxane (3 mL),

NaBH₃CN (38.1 mg, 0.606 mmol) and 2.0 M HCl in Et₂O (606 mL)

in MeOH (4 mL), and Boc₂O (79.3 mg, 0.363 mmol) in 1,4-diox-

ane–NaHCO₃soln (5 mL). Purification by flash chromatography

(alumina, gradient n-pentane, then n-pentane–EtOAc, 97:3); color-

less oil; yield: 55.8 mg (61%); R_f= 0.27 (silica gel, n-pentane–

EtOAc, 95:5).

IR (film): 3024, 2972, 2919, 2849, 1688, 1454, 1408, 1364, 1168

cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.44 [s, 0.45 × 9 H, C(CH₃)₃],

1.50–1.74 (m, 4 H, H4, CH₂CH₂Ph), 1.55 [s, 0.55 × 9 H, C(CH₃)₃],

1.74–1.84 (m, 2 H, H9), 2.55 (td, J = 13.3, 3.7 Hz, 0.55 × 1 H, H3),

2.56–2.74 (m, 0.45 × 1 H, 2 H, H3, CH₂CH₂Ph), 2.80 (d, J = 17.8

Hz, 0.45 × 1 H, H6), 2.82 (d, J = 17.8 Hz, 0.55 × 1 H, H6), 2.89 (d,

J = 17.8 Hz, 0.55 × 1 H, H6), 2.91 (d, J = 17.8 Hz, 0.45 × 1 H, H6),

3.74 (m, 0.45 × 1 H, H3), 3.87 (dd_br, J = 13.3, 4.9 Hz, 0.55 × 1 H,

H3), 5.31 (s_br, 0.55 × 1 H, H1), 5.48 (s_br, 0.45 × 1 H, H1), 7.09–7.24

(m, 0.55 × 1 H, 6 H, H4¢, H1¢, H2¢, H3¢, CH_{phenylethyl,o}, CH_{phenylethyl,p}),

7.25–7.36 (m, 0.45 × 1 H, 2 H, H4¢, CH_{phenylethyl,m}). Ratio of rotation-

al isomers 45:55.

¹³C NMR (125 MHz, CDCl₃): d = 28.46 (q, minor), 28.67 (q, ma-

jor), 29.51 (t, minor + major), 31.40 (s, major), 31.56 (s, minor),

36.48 (t, major), 36.67 (t, minor), 36.90 (t, major), 37.29 (t, major),

37.67 (t, minor), 37.71 (t, minor), 38.89 (t, major), 39.00 (t, minor),

47.17 (t, minor + major), 49.67 (d, minor), 50.80 (d, major), 79.40

(s, minor), 79.65 (s, major), 125.80 (d, minor + major), 126.02 (d,

major), 126.15 (d, minor), 127.48 (d, minor), 127.59 (d, major),

127.77 (d, minor), 128.01 (d, major), 128.31 (d, minor + major),

128.34 (d, major), 128.45 (d, minor + major), 129.06 (d, minor),

135.34 (s, major), 135.74 (s, minor), 137.45 (s, major), 137.53 (s,

minor), 142.71 (s, minor + major), 154.50 (s, major), 154.71 (s, mi-

nor).

MS (EI, 70 eV): m/z (%) = 143.1 (100), 214.1 (59), 305.2 (36) [M]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₂₁H₂₃NO: 305.1780; found:

305.1778.

tert-Butyl 7⁴-Methoxy-5-(4-methoxybenzyl)-2-aza-7(1,2)-ben-

zenabicyclo[3.2.1]octaphane-1-carboxylate (19a)

According to GP4 from 14a (23.5 mg, 0.0647 mmol) and H₂O (11.6

mg, 11.6 mL, 0.647 mmol) in 4.0 M HCl in 1,4-dioxane (2 mL),

NaBH₃CN (10.2 mg, 0.162 mmol) and 2.0 M HCl in Et₂O (323 mL)

in MeOH (4 mL), and Boc₂O (21.2 mg, 0.0970 mmol) in 1,4-diox-

ane–NaHCO₃soln (5 mL). Purification by flash chromatography

(alumina, gradient n-pentane–EtOAc, 95:5, then 90:10); colorless

crystals; yield: 19.4 mg (71%); mp 58–62 °C; R_f= 0.44 (alumina, n-

pentane–EtOAc, 9:1).

IR (KBr): 2973, 2932, 2834, 1687, 1612, 1512, 1405, 1364, 1247,

1170 cm^–1.

¹H NMR (400 MHz, C₂D₂Cl₄): d = 1.32 [s, 0.46 × 9 H, C(CH₃)₃],

1.26–1.52 (m, 2 H, H4), 1.43 [s, 0.54 × 9 H, C(CH₃)₃], 1.56–1.72

(m, 2 H, H9), 2.36 (td, J = 13.3, 3.6 Hz, 0.54 × 1 H, H3), 2.36–2.53

(m, 0.46 × 1 H, 1 H, H3, H6), 2.44 (d, J = 13.9 Hz, 1 H, CH₂Ph),

2.49 (d, J = 13.9 Hz, 1 H, CH₂Ph), 2.72 (d_br, J = 17.3 Hz, 1 H, H6),

3.53–3.61 (m, 0.46 × 1 H, H3), 3.65 (s, 0.46 × 3 H, C3¢-OCH₃), 3.65

(s, 0.54 × 3 H, C3¢-OCH₃), 3.70 (s, 3 H, C_Bn,p-OCH₃), 3.61–3.72 (m,

0.54 × 1 H, H3), 5.12 (s_br, 0.54 × 1 H, H1), 5.28 (s_br, 0.46 × 1 H, H1),

MS (ESI⁺): m/z (%) = 322.1 (100), 378.3 (65) [M + H]⁺, 400.2 (66)

[M + Na]⁺, 423.3 (87), 755.4 (11) [2 M + H]⁺, 777.5 (63) [2 M +

Na]⁺, 1155.8 (11) [3 M + Na]⁺.

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₂₅H₃₂NO₂: 378.2433; found:

378.2428.

2158

C. E. Schmaunz et al.

PAPER

tert-Butyl 5-Ethyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octa-

phane-1-carboxylate (19c)

¹³C NMR (125 MHz, CDCl₃): d = 16.46 (q, major), 16.60 (q, mi-

nor), 28.46 (q, minor), 28.67 (q, major), 33.39 (s, major), 33.53 (s,

minor), 34.42 (t, major), 34.60 (t, minor), 34.81 (t, minor + major),

35.70 (t, major), 35.80 (t, minor), 36.48 (t, major), 37.67 (t, minor),

38.63 (d, minor + major), 49.71 (d, minor), 50.82 (d, major), 79.27

(s, minor), 79.53 (s, major), 125.81 (d, major), 125.93 (d, minor),

127.35 (d, minor), 127.46 (d, major), 127.97 (d, minor), 128.21 (d,

major), 128.95 (d, minor), 135.53 (s, major), 135.94 (s, minor),

137.90 (s, major), 137.94 (s, minor), 154.53 (s, major), 154.73 (s,

minor).

According to GP4 from 14c (54.0 mg, 0.224 mmol) and H₂O (40.3

mg, 40.3 mL, 2.24 mmol) in 4.0 M HCl in 1,4-dioxane (2 mL),

NaBH₃CN (35.2 mg, 0.559 mmol) and 2.0 M HCl in Et₂O (559 mL)

in MeOH (4 mL), and Boc₂O (73.3 mg, 0.336 mmol) in 1,4-diox-

ane–NaHCO₃soln (5 mL). Purification by flash chromatography

(alumina, gradient n-pentane, then n-pentane–EtOAc, 97:3); color-

less oil; yield: 38.2 mg (57%); R_f= 0.32 (alumina, n-pentane–

EtOAc, 95:5).

IR (film): 3062, 2969, 2927, 2850, 1691, 1454, 1408, 1364, 1169

cm^–1.

MS (ESI⁺): m/z (%) = 260.3 (68), 316.4 (43) [M + H]⁺, 338.1 (37)

[M + Na]⁺, 631.5 (22) [2 M + H]⁺, 653.4 (100) [2 M + Na]⁺, 968.6

(23) [3 M + Na]⁺.

HRMS (EI⁺): m/z [M]⁺calcd for C₂₀H₂₉NO₂: 315.2198; found:

315.2210.

¹H NMR (500 MHz, CDCl₃): d = 0.91 [t, J = 7.5 Hz, 3 H, CH₂CH₃],

1.34–1.40 (m, 2 H, CH₂CH₃), 1.43 [s, 0.44 × 9 H, C(CH₃)₃], 1.40–

1.60 (m, 2 H, H4), 1.54 [s, 0.56 × 9 H, C(CH₃)₃], 1.65–1.73 (m, 2 H,

H9), 2.51 (td, J = 13.5, 3.8 Hz, 0.56 × 1 H, H3), 2.59 (td, J = 12.9,

4.7 Hz, 0.44 × 1 H, H3), 2.67 (d, J = 17.8 Hz, 0.44 × 1 H, H6), 2.69

(d, J = 18.0 Hz, 0.56 × 1 H, H6), 2.75 (d, J = 18.0 Hz, 0.56 × 1 H,

H6), 2.77 (d, J = 17.8 Hz, 0.44 × 1 H, H6), 3.67–3.74 (m, 0.44 × 1

H, H3), 3.83 (dd_br, J = 13.5, 5.0 Hz, 0.56 × 1 H, H3), 5.28 (s_br, 0.56

× 1 H, H1), 5.45 (s_br, 0.44 × 1 H, H1), 7.06–7.15 (m, 2 H, H1¢, H3¢),

7.15–7.23 (m, 0.56 × 1 H, 1 H, H4¢, H2¢), 7.32 (d_br, J = 7.2 Hz, 0.44

× 1 H, H4¢). Ratio of rotational isomers 44:56.

¹³C NMR (100 MHz, CDCl₃): d = 7.30 (q, minor + major), 28.45 (q,

minor), 28.66 (q, major), 31.12 (s, major), 31.27 (s, minor), 36.27

(t, minor), 36.48 (t, major), 36.51 (t, major), 36.85 (t, major), 37.08

(t, minor + major), 37.25 (t, minor), 37.70 (t, minor), 38.42 (t, ma-

jor), 38.54 (t, minor), 49.73 (d, minor), 50.84 (d, major), 79.29 (s,

minor), 79.54 (s, major), 125.86 (d, major), 125.99 (d, minor),

127.37 (d, minor), 127.48 (d, major), 127.77 (d, minor), 128.01 (d,

major), 128.29 (d, major), 129.00 (d, minor), 135.45 (s, major),

135.86 (s, minor), 137.78 (s, major), 137.85 (s, minor), 154.54 (s,

major), 154.73 (s, minor).

tert-Butyl 5-Phenyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octa-

phane-1-carboxylate (19e)

According to GP4 from 14e (20.3 mg, 0.0697 mmol) and H₂O (12.5

mg, 12.5 mL, 0.697 mmol) in 4.0 M HCl in 1,4-dioxane (2 mL),

NaBH₃CN (10.9 mg, 0.174 mmol) and 2.0 M HCl in Et₂O (174 mL)

in MeOH (4 mL), and Boc₂O (22.8 mg, 0.104 mmol) in 1,4-diox-

ane–NaHCO₃soln (5 mL). Purification by flash chromatography

(alumina, gradient n-pentane, then n-pentane–EtOAc, 97:3); color-

less crystals; yield: 13.9 mg (57%); mp 103–104 °C; R_f= 0.25 (sil-

ica gel, n-pentane–EtOAc, 95:5).

IR (KBr): 3060, 2974, 2930, 2868, 1689, 1453, 1409, 1364, 1167

cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.44 [s, 0.46 × 9 H, C(CH₃)₃], 1.57

[s, 0.54 × 9 H, C(CH₃)₃], 1.74–1.89 (m, 1 H, H4), 1.97 (d_br, J = 13.4

Hz, 0.46 × 1 H, H4), 2.04 (d_br, J = 13.4 Hz, 0.54 × 1 H, H4), 2.17–

2.37 (m, 2 H, H9), 2.69 (td, J = 13.4, 3.3 Hz, 0.54 × 1 H, H3), 2.77

(td, J = 13.4, 3.3 Hz, 0.46 × 1 H, H3), 3.08 (d_br, J = 17.9 Hz, 1 H,

H6), 3.22 (d, J = 17.9 Hz, 0.46 × 1 H, H6), 3.24 (d, J = 17.9 Hz, 0.54

× 1 H, H6), 3.79 (dd_br, J = 13.4, 5.3 Hz, 0.46 × 1 H, H3), 3.92 (dd_br,

J = 13.4, 5.4 Hz, 0.54 × 1 H, H3), 5.48 (s_br, 0.54 × 1 H, H1), 5.65

(s_br, 0.46 × 1 H, H1), 7.10 (d_br, J = 7.4 Hz, 1 H, H1¢), 7.13–7.32 (m,

0.54 × 1 H, 3 H, H4¢, H2¢, H3¢, CH_Ph,p), 7.32–7.45 (m, 0.46 × 1 H, 4

H, H4¢, CH_Ph,o, CH_Ph,m). Ratio of rotational isomers 46:54.

¹³C NMR (100 MHz, CDCl₃): d = 28.43 (q, minor), 28.67 (q, ma-

jor), 34.86 (t, minor), 35.10 (t, major), 35.29 (s, major), 35.45 (s, mi-

nor), 36.62 (t, major), 37.84 (t, minor), 39.35 (t, major), 39.69 (t,

minor), 41.42 (t, major), 41.57 (t, minor), 49.60 (d, minor), 50.72 (d,

major), 79.54 (s, minor), 79.80 (s, major), 124.56 (d, minor + ma-

jor), 126.21 (d, minor or major), 126.30 (d, minor or major), 127.60

(d, minor or major), 127.68 (d, minor or major), 127.84 (d, minor or

major), 128.26 (d, minor or major), 128.54 (d, minor + major),

129.00 (d, minor or major), 134.73 (s, minor or major), 135.12 (s,

minor or major), 137.36 (s, minor or major), 137.46 (s, minor or ma-

jor), 150.31 (s, minor + major), 154.43 (s, minor or major), 154.67

(s, minor or major).

MS (ESI⁺): m/z (%) = 302.2 (60) [M + H]⁺, 324.3 (66) [M + Na]⁺,

603.5 (14) [2 M + H]⁺, 625.3 (100) [2 M + Na]⁺.

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₁₉H₂₈NO₂: 302.2120; found:

302.2115.

Anal. Calcd for C₁₉H₂₇NO₂: C, 75.71; H, 9.03; N, 4.65. Found: C,

75.43; H, 8.96; N, 4.71.

tert-Butyl 5-Isopropyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octa-

phane-1-carboxylate (19d)

According to GP4 from 14d (48.3 mg, 0.189 mmol) and H₂O (34.0

mg, 34.0 mL, 1.89 mmol) in 4.0 M HCl in 1,4-dioxane (2 mL),

NaBH₃CN (29.7 mg, 0.473 mmol) and 2.0 M HCl in Et₂O (473 mL)

in MeOH (4 mL), and Boc₂O (61.9 mg, 0.284 mmol) in 1,4-diox-

ane–NaHCO₃soln (5 mL). Purification by flash chromatography

(alumina, gradient n-pentane, then n-pentane–EtOAc, 97:3); color-

less oil; yield: 38.2 mg (64%); R_f= 0.37 (silica gel, n-pentane–

EtOAc, 95:5).

IR (film): 2971, 2938, 2877, 1691, 1453, 1408, 1365, 1168 cm^–1.

MS (ESI⁺): m/z (%) = 294.1 (100), 350.2 (46) [M + H]⁺, 372.3 (59)

[M + Na]⁺, 699.4 (25) [2 M + H]⁺, 721.4 (96) [2 M + Na]⁺, 1070.6

(12) [3 M + Na]⁺.

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₂₃H₂₈NO₂: 350.2120; found:

350.2115.

¹H NMR (500 MHz, CDCl₃): d = 0.90 [d, J = 6.9 Hz, 3 H,

CH(CH₃)₂], 0.92 [d, J = 6.9 Hz, 3 H CH(CH₃)₂], 1.43 [s, 0.44 × 9 H,

C(CH₃)₃], 1.54 [s, 0.56 × 9 H, C(CH₃)₃], 1.36–1.74 [m, 3 H, H4,

CH(CH₃)₂], 1.69–1.77 (m, 2 H, H9), 2.51 (td, J = 13.6, 3.2 Hz, 0.56

× 1 H, H3), 2.58 (td, J = 13.4, 3.0 Hz, 0.44 × 1 H, H3), 2.63 (d,

J = 17.7 Hz, 0.44 × 1 H, H6), 2.65 (d, J = 17.7 Hz, 0.56 × 1 H, H6),

2.77 (d, J = 17.7 Hz, 0.56 × 1 H, H6), 2.78 (d, J = 17.7 Hz, 0.44 × 1

H, H6), 3.71 (dd_br, J = 13.4, 4.9 Hz, 0.44 × 1 H, H3), 3.84 (dd_br,

J = 13.6, 5.0 Hz, 0.56 × 1 H, H3), 5.28 (s_br, 0.56 × 1 H, H1), 5.45

(s_br, 0.44 × 1 H, H1), 7.07–7.15 (m, 2 H, H1¢, H3¢), 7.15–7.24 (m,

0.56 × 1 H, 1 H, H4¢, H2¢), 7.32 (d_br, J = 7.3 Hz, 0.44 × 1 H, H4¢).

Ratio of rotational isomers 44:56.

tert-Butyl 5-Benzyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octa-

phane-1-carboxylate (19f)

According to GP4 from 14f (15.4 mg, 0.0508 mmol) and H₂O (9.1

mg, 9.1 mL, 0.51 mmol) in 4.0 M HCl in 1,4-dioxane (2 mL),

NaBH₃CN (8.0 mg, 0.13 mmol) and 2.0 M HCl in Et₂O (127 mL) in

MeOH (4 mL), and Boc₂O (16.6 mg, 0.0761 mmol) in 1,4-dioxane–

NaHCO₃soln (5 mL). Purification by flash chromatography (alumi-

na, gradient n-pentane, then n-pentane–EtOAc, 97:3); colorless

PAPER

Synthesis of 5-Substituted 7,8-Benzomorphans

2159

crystals; yield: 11.1 mg (60%); mp 99–101 °C; R_f= 0.27 (silica gel,

n-pentane–EtOAc, 95:5).

5-(2-Phenylethyl)-2-aza-7(1,2)-benzenabicyclo[3.2.1]octa-

phane Hydrochloride (20b)

According to GP5 from 19b (22.8 mg, 0.0604 mmol) in CH₂Cl₂(2

mL) and TFA (2 mL); colorless crystals; yield: 18.0 mg (95%); mp

200–208 °C (dec.).

IR (KBr): 3063, 3025, 2979, 2928, 2870, 1687, 1452, 1404, 1168

cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 1.41 [s, 0.45 × 9 H, C(CH₃)₃],

1.35–1.67 (m, 2 H, H4), 1.53 [s, 0.55 × 9 H, C(CH₃)₃], 1.69–1.86

(m, 2 H, H9), 2.48 (td, J = 13.5, 3.7 Hz, 0.55 × 1 H, H3), 2.55 (td,

J = 13.5, 3.5 Hz, 0.45 × 1 H, H3), 2.56–2.66 (m, 1 H, H6), 2.62 (d,

J = 13.1 Hz, 1 H, CH₂Ph), 2.66 (d, J = 13.1 Hz, 1 H, CH₂Ph), 2.92

(d, J = 17.7 Hz, 0.55 × 1 H, H6), 2.93 (d, J = 17.7 Hz, 0.45 × 1 H,

H6), 3.68 (dd_br, J = 13.5, 5.2 Hz, 0.45 × 1 H, H3), 3.80 (dd_br,

J = 13.5, 5.6 Hz, 0.55 × 1 H, H3), 5.29 (s_br, 0.55 × 1 H, H1), 5.46

(s_br, 0.45 × 1 H, H1), 7.05 (d_br, J = 7.6 Hz, 1 H, H1¢), 7.07–7.13 (m,

1 H, H3¢), 7.13–7.20 (m, 0.55 × 1 H, 3 H, H4¢, H2¢, CH_Bn,o), 7.21–

7.25 (m, 1 H, CH_Bn,p), 7.27–7.33 (m, 0.45 × 1 H, 2 H, H4¢, CH_Bn,m).

Ratio of rotational isomers 45:55.

¹³C NMR (125 MHz, CDCl₃): d = 28.43 (q, minor), 28.65 (q, ma-

jor), 32.52 (s, major), 32.66 (s, minor), 36.30 (t, minor), 36.37 (t,

major), 36.42 (t, major), 37.61 (t, minor + major), 37.94 (t, minor),

38.73 (t, major), 38.87 (t, minor), 49.68 (d, minor), 50.78 (t, major),

50.81 (d, major), 50.86 (t, minor), 79.36 (s, minor), 79.61 (s, major),

125.97 (d, major), 126.10 (d, minor), 126.31 (d, minor + major),

127.41 (d, minor), 127.52 (d, major), 127.67 (d, minor), 127.93 (d,

major + minor), 128.20 (d, major), 128.91 (d, minor), 130.68 (d, mi-

nor + major), 134.98 (s, major), 135.40 (s, minor), 137.27 (s, ma-

jor), 137.30 (s, minor), 137.50 (s, major), 137.56 (s, minor), 154.42

(s, major), 154.64 (s, minor).

IR (KBr): 3025, 2927, 2715, 2646, 2486, 2361, 2342, 1587, 1493,

1455, 1455 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.67–1.93 (m, 3 H, CH₂CH₂Ph,

H4), 1.89 (d_br, J = 13.2 Hz, 1 H, H9), 2.16 (t_br, J = 12.4 Hz, 1 H,

H4), 2.47 (d_br, J = 13.2 Hz, 1 H, H9), 2.62–2.73 (m, 2 H,

CH₂CH₂Ph), 2.62–2.91 (m, 1 H, H3), 2.87 (d, J = 18.0 Hz, 1 H, H6),

3.02 (d, J = 18.0 Hz, 1 H, H6), 3.23 (d_br, J = 9.3 Hz, 1 H, H3), 4.82

(s_br, 1 H, H1), 7.17–7.24 (m, 4 H, H1¢, CH_{phenylethyl,p}, CH_{phenylethyl,o}),

7.27–7.37 (m, 4 H, H2¢, H3¢, CH_{phenylethyl,m}), 7.64 (d, J = 6.4 Hz, 1 H,

+

H4¢), 9.40 (s_br, 1 H, NH₂), 9.98 (s_br, 1 H, NH₂).

¹³C NMR (100 MHz, CDCl₃): d = 29.33 (t), 30.96 (s), 33.87 (t),

34.63 (t), 36.67 (t), 39.01 (t), 46.23 (t), 51.87 (d), 125.99 (d), 127.08

(d), 128.31 (d), 128.41 (d), 128.54 (d), 128.91 (s), 129.72 (d),

130.73 (d), 138.63 (s), 141.88 (s).

MS (FAB, NBA): m/z (%) = 278 (100) [M – Cl]⁺.

HRMS (ESI⁺): m/z [M – Cl]⁺calcd for C₂₀H₂₄N: 278.1909; found:

278.1902.

Anal. Calcd for C₂₀H₂₃N·HCl·0.25 H₂O: C, 75.45; H, 7.76; N, 4.40.

Found: C, 75.25; H, 7.82; N, 4.16.

5-Ethyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octaphane Hydro-

chloride (20c)

According to GP5 from 19c (18.8 mg, 0.0624 mmol) in CH₂Cl₂(2

mL) and TFA (2 mL); colorless crystals; yield: 14.0 mg (95%); mp

203–211 °C (dec.).

MS (ESI⁺): m/z (%) = 308.2 (94), 364.4 (44) [M + H]⁺, 386.1 (100)

[M + Na]⁺, 727.5 (21) [2 M + H]⁺, 749.4 (92) [2 M + Na]⁺, 1112.5

(20) [3 M + Na]⁺.

HRMS (ESI⁺): m/z [M + H]⁺calcd for C₂₄H₃₀NO₂: 364.2277; found:

364.2271.

IR (KBr): 3028, 2930, 2849, 2730, 2653, 2485, 1636, 1588, 1455,

1432 cm^–1.

Anal. Calcd for C₂₄H₂₉NO₂: C, 79.30; H, 8.04; N, 3.85. Found: C,

79.07; H, 7.77; N, 3.91.

¹H NMR (400 MHz, CDCl₃): d = 0.94 (t, J = 7.5 Hz, 3 H, CH₂CH₃),

1.39–1.56 (m, 2 H, CH₂CH₃), 1.72 (d_br, J = 14.1 Hz, 1 H, H4), 1.81

(d_br, J = 13.8 Hz, 1 H, H9), 2.03 (td_br, J = 14.1, 4.7 Hz, 1 H, H4),

2.37 (d_br, J = 13.8 Hz, 1 H, H9), 2.67–2.81 (m, 1 H, H3), 2.74 (d,

J = 18.0 Hz, 1 H, H6), 2.88 (d, J = 18.0 Hz, 1 H, H6), 3.19 (dd_br,

J = 12.7, 4.7 Hz, 1 H, H3), 4.79 (s_br, 1 H, H1), 7.17 (d, J = 7.5 Hz,

1 H, H1¢), 7.21–7.37 (m, 2 H, H2¢, H3¢), 7.63 (d, J = 7.5 Hz, 1 H,

7⁴-Methoxy-5-(4-methoxybenzyl)-2-aza-7(1,2)-benzenabicyc-

lo[3.2.1]octaphane Hydrochloride (20a)

According to GP5 from 19a (14.7 mg, 0.0347 mmol) in CH₂Cl₂(1.5

mL) and TFA (1.5 mL); colorless crystals; yield: 11.4 mg (91%);

mp 217–222 °C (dec.).

+

H4¢), 9.39 (s_br, 1 H, NH₂), 9.93 (s_br, 1 H, NH₂).

IR (KBr): 2928, 2834, 2731, 2646, 2483, 1612, 1586, 1511, 1453,

1242 cm^–1.

¹³C NMR (100 MHz, CDCl₃): d = 7.13 (q), 30.76 (s), 33.56 (t),

34.27 (t), 36.39 (t), 36.66 (t), 38.53 (t), 51.92 (d), 126.93 (d), 128.38

(d), 129.04 (s), 129.60 (d), 130.69 (d), 138.94 (s).

MS (ESI⁺): m/z (%) = 202 (100) [M – Cl]⁺, 439 (34) [2 M – Cl]⁺.

HRMS (FAB): m/z [M – Cl]⁺calcd for C₁₄H₂₀N: 202.1596; found:

¹H NMR (500 MHz, CDCl₃): d = 1.69 (d_br, J = 13.6 Hz, 1 H, H4),

1.87 (d_br, J = 13.1 Hz, 1 H, H9), 2.12 (t_br, J = 13.6 Hz, 1 H, H4), 2.43

(d_br, J = 13.1 Hz, 1 H, H9), 2.51 (d, J = 17.4 Hz, 1 H, H6), 2.65 (s,

2 H, CH₂Ph), 2.61–2.77 (m, 1 H, H3), 2.95 (d, J = 17.4 Hz, 1 H,

H6), 3.17 (d_br, J = 9.7 Hz, 1 H, H3), 3.79 (s, 3 H, OCH₃), 3.83 (s, 3

H, OCH₃), 4.76 (s_br, 1 H, H1), 6.84 (d, J = 8.5 Hz, 3 H, H2¢, CH_Bn,m),

7.01 (d, J = 8.5 Hz, 1 H, H1¢), 7.10 (d, J = 8.5 Hz, 2 H, CH_Bn,o), 7.18

202.1624.

5-Isopropyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octaphane Hy-

drochloride (20d)

+

(s_br, 1 H, H4¢), 9.26 (s_br, 1 H, NH₂), 9.94 (s_br, 1 H, NH₂).

¹³C NMR (100 MHz, CDCl₃): d = 32.15 (s), 34.08 (t), 35.37 (t),

37.01 (t), 37.34 (t), 49.18 (t), 52.47 (d), 55.35 (q), 55.82 (q), 113.65

(d), 113.88 (d), 117.66 (d), 128.30 (s), 129.32 (s), 129.44 (d),

130.41 (s), 131.61 (d), 158.32 (s), 158.51 (s).

MS (FAB, NBA): m/z (%) = 154 (100), 324 (23) [M – Cl]⁺.

HRMS (FAB): m/z [M – Cl]⁺calcd for C₂₁H₂₆NO₂: 324.1964;

According to GP5 from 19d (36.4 mg, 0.115 mmol) in CH₂Cl₂(2

mL) and TFA (2 mL); colorless crystals; yield: 26.6 mg (92%); mp

239–241 °C (dec.).

IR (KBr): 2961, 2930, 2877, 2732, 2670, 2496, 1588, 1455 cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 0.92 [d, J = 6.8 Hz, 3 H,

CH(CH₃)₂], 0.97 [d, J = 6.8 Hz, 3 H, CH(CH₃)₂], 1.54–1.68 [sept,

J = 6.8 Hz, 1 H, CH(CH₃)₂], 1.79 (d_br, J = 13.4 Hz, 1 H, H4), 1.84

(d_br, J = 13.7 Hz, 1 H, H9), 2.02 (td_br, J = 13.4, 3.5 Hz, 1 H, H4),

2.40 (d_br, J = 13.7 Hz, 1 H, H9), 2.69 (d, J = 18.1 Hz, 1 H, H6),

2.64–2.81 (m, 1 H, H3), 2.90 (d, J = 18.1 Hz, 1 H, H6), 3.21 (d_br,

J = 13.4 Hz, 1 H, H3), 4.79 (s_br, 1 H, H1), 7.19 (d, J = 7.4 Hz, 1 H,

H1¢), 7.22–7.37 (m, 2 H, H2¢, H3¢), 7.62 (d, J = 7.3 Hz, 1 H, H4¢),

found: 324.1980.

Anal. Calcd for C₂₁H₂₅NO₂·HCl·0.25 H₂O: C, 69.22; H, 7.33; N,

3.84. Found: C, 69.11; H, 7.09; N, 3.79.

+

9.35 (s_br, 1 H, NH₂), 9.91 (s_br, 1 H, NH₂).

2160

C. E. Schmaunz et al.

PAPER

¹³C NMR (100 MHz, CDCl₃): d = 16.29 (q), 16.42 (q), 32.00 (t),

32.08 (t), 33.02 (s), 35.63 (t), 36.69 (t), 38.13 (d), 51.89 (d), 126.87

(d), 128.59 (d), 129.09 (s), 129.57 (d), 130.60 (d), 139.11 (s).

MS (ESI⁺): m/z (%) = 264 (100) [M – Cl]⁺, 527 (18) [2 (M – HCl)

+ H]⁺, 563 (62) [2 M – Cl]⁺.

HRMS (ESI⁺): m/z [M – Cl]⁺calcd for C₁₉H₂₂N: 264.1752; found:

264.1746.

MS (DEI⁺): m/z (%) = 155 (100), 172 (76), 215 (37) [M – Cl]⁺.

HRMS (DEI⁺): m/z [M – Cl]⁺calcd for C₁₅H₂₂N: 215.1674; found:

215.1654.

Anal. Calcd for C₁₉H₂₁N·HCl·0.20 H₂O: C, 75.21; H, 7.44; N, 4.62.

Found: C, 75.04; H, 7.51; N, 4.62.

Anal. Calcd for C₁₅H₂₁N·HCl·0.33 H₂O: C, 69.88; H, 8.86; N, 5.43.

Found: C, 69.71; H, 8.64; N, 5.38.

References

5-Phenyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octaphane Hydro-

chloride (20e)

According to GP5 from 19e (20.0 mg, 0.0572 mmol) in CH₂Cl₂(2

mL) and TFA (2 mL); colorless crystals; yield: 15.2 mg (93%); mp

>252 °C (dec.).

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IR (KBr): 3025, 2932, 2793, 2745, 2638, 2566, 2477, 1585, 1496,

1452, 1429 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 2.14 (d_br, J = 13.8 Hz, 1 H, H4),

2.32 (d_br, J = 13.3 Hz, 1 H, H9), 2.39 (t_br, J = 13.8 Hz, 1 H, H4), 2.92

(m, 1 H, H3), 3.03 (d_br, J = 13.3 Hz, 1 H, H9), 3.24 (d, J = 18.0 Hz,

1 H, H6), 3.29 (d, J = 18.0 Hz, 1 H, H6), 3.21–3.33 (m, 1 H, H3),

5.00 (s_br, 1 H, H1), 7.20 (d, J = 7.3 Hz, 1 H, H1¢), 7.24–7.46 (m, 7

H, H2¢, H3¢, CH_Ph), 7.71 (d, J = 7.0 Hz, 1 H, H4¢), 9.54 (s_br, 1 H,

+

NH₂), 10.17 (s_br, 1 H, NH₂).

¹³C NMR (125 MHz, CDCl₃): d = 32.47 (t), 34.68 (s), 36.73 (t),

36.82 (t), 41.41 (t), 51.92 (d), 124.51 (d), 126.84 (d), 127.26 (d),

128.29 (d), 128.42 (s), 128.80 (d), 129.84 (d), 130.70 (d), 138.62

(s), 147.96 (s).

MS (ESI⁺): m/z (%) = 250 (100) [M – Cl]⁺, 535 (18) [2 M – Cl]⁺.

HRMS (ESI⁺): m/z [M – Cl]⁺calcd for C₁₈H₂₀N: 250.1596; found:

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(15) Wakefield, B. J. Organomagnesium Methods in Organic

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Mendeleev Commun. 2007, 17, 343.

(17) (a) Sperger, C. A.; Wanner, K. T. Tetrahedron 2009, 65,

5824. (b) Wallace, D. J.; Gibb, A. D.; Cottrell, I. F.;

Kennedy, D. J.; Brands, K. M. J.; Dolling, U. H. Synthesis

2001, 1784.

(18) Due to the small percentage of the minor rotamer, only the

signals of the major rotamer are listed.

250.1589.

5-Benzyl-2-aza-7(1,2)-benzenabicyclo[3.2.1]octaphane Hydro-

chloride (20f)

According to GP5 from 19f (26.5 mg, 0.0729 mmol) in CH₂Cl₂(2

mL) and TFA (2 mL); colorless crystals; yield: 21.3 mg (97%); mp

112–116 °C (dec.).

IR (KBr): 3024, 2928, 2813, 2735, 2666, 2484, 1587, 1494, 1453

cm^–1.

¹H NMR (400 MHz, CDCl₃): d = 1.73 (d_br, J = 14.0 Hz, 1 H, H4),

1.89 (d_br, J = 13.6 Hz, 1 H, H9), 2.17 (td_br, J = 14.0, 4.7 Hz, 1 H,

H4), 2.50 (d_br, J = 13.6 Hz, 1 H, H9), 2.61 (d, J = 17.9 Hz, 1 H, H6),

2.62–2.78 (m, 1 H, H3), 2.73 (s, 2 H, CH₂Ph), 3.05 (d, J = 17.9 Hz,

1 H, H6), 3.19 (dd_br, J = 12.9, 4.7 Hz, 1 H, H3), 4.80 (s_br, 1 H, H1),

7.13 (d, J = 7.3 Hz, 1 H, H1¢), 7.16–7.37 (m, 7 H, H2¢, H3¢, CH_Bn),

+

7.59 (dd, J = 7.4, 1.0 Hz, 1 H, H4¢), 9.39 (s_br, 1 H, NH₂), 9.96 (s_br,

+

1 H, NH₂).

¹³C NMR (100 MHz, CDCl₃): d = 31.92 (s), 33.92 (t), 35.38 (t),

36.61 (t), 38.00 (t), 49.94 (t), 51.92 (d), 126.73 (d), 126.99 (d),

128.20 (d), 128.38 (d), 128.52 (s), 129.64 (d), 130.58 (d), 130.61

(d), 136.14 (s), 138.68 (s).

Article Doi

Synthesis of 5-substituted 7,8-benzomorphans by intramolecular cyclization of N-protected 4,4-disubstituted 1,4-dihydropyridines

DOI: 10.1055/s-0029-1218808

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Article abstract of DOI:10.1055/s-0029-1218808

Full text of DOI:10.1055/s-0029-1218808

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