Stereoselective synthesis of novel 2-alkenyl-2,3,4,5-tetrahydro-1,4-epoxy- 1-benzazepines and 2-alkenyl-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ols

PAPER

▌3765

paper

Stereoselective Synthesis of Novel 2-Alkenyl-2,3,4,5-tetrahydro-1,4-epoxy-1-

benzazepines and 2-Alkenyl-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ols

Synthesis of 2-Alkenyltetrahydro-1-benzazepines

Lina María Acosta Quintero,^aAlirio Palma,*^aManuel Nogueras,^bJusto Cobo^b

a

Laboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander, Carrera 27, Calle 9, A.A 678, Bucaramanga,

Colombia

Fax +57(7)6349069; E-mail: apalma@uis.edu.co

b

Inorganic and Organic Department, University of Jaén, Campus Las Lagunillas s/n, 23071, Jaén, Spain

Fax +34(953)211876; E-mail: jcobo@ujaen.es

Received: 13.08.2012; Accepted after revision: 23.10.2012

It is well-documented that substituted o-allylanilines are

Abstract: New series of polyfunctionalized 2,3,4,5-tetrahydro-1,4-

useful precursors for the synthesis of diverse classes of

epoxy-1-benzazepines and 2,3,4,5-tetrahydro-1H-1-benzazepin-4-

nitrogen-containing heterocycles, for example they are

ols substituted at C2 with 2-methylprop-1-enyl, (E)-styryl, and (E)-

pent-1-enyl were synthesized starting from the corresponding N-al-

known to lead to indolines,^1–8indoles,^6–10pyrrolo[1,2-

kenyl-substituted [prenyl, trans-cinnamyl, (E)-hex-2-enyl] 2-allyl- a]indolones,^11,12indolo[1,2-b]isoquinolinones and ben-

zo[5,6][1,2]thiazino[2,3-a]indole 5,5-dioxides,^13–16imid-

anilines by a three-step sequence consisting of selective oxidation

of aromatic secondary amines, intramolecular nitrone–olefin 1,3-di-

azo[1,5-a]indolones and [1,2,5]thiadiazolo[2,3-a]indole

polar cycloaddition, and reductive cleavage. The intramolecular

1,1-dioxides,^17,18quinolines,¹⁹dihydroquinolines,^20–23tet-

1,3-dipolar cycloaddition is stereoselective favoring the exo-cyclo-

rahydroquinolin-2-ones,^24–264,5-dihydro-3H-1-benzaze-

adducts (ratio exo/endo 2–3:1). The stereochemistry was deter-

mined by exhaustive NMR analysis and X-ray diffraction.

pines,¹⁹2,5-dihydro-1H-1-benzazepines,²⁷tetrahydro-1-

benzazepines,^25–29tetrahydro-1-benzazocines,³⁰3,4,5,6-

Key words: 1,3-dipolar cycloaddition, 2,3,4,5-tetrahydro-1,4-ep-

oxy-1-benzazepines, 2,3,4,5-tetrahydro-1H-1-benzazepin-4-ols, re-

ductive cleavage, nitrogen heterocycles

tetrahydro-1-benzazocin-2-ones,^28,293,6-dihydro-1-ben-

zazocin-2-ones,³¹or dihydrodibenzo[b,e]azepines,³²

among other aza-heterocycles (Scheme 1).

R⁴

R³

R²

R³

Me

R¹

N

R¹

R²

N

R²

R¹

R²

N

H

N

R¹

R³

R¹

N

ref. 6–10

O

R²

O

ref. 32

N

ref.

28, 29, 31

R¹

X

ref. 13–16

R²

R¹

N

R²

X = CO, SO₂

R¹

NHR²

ref. 17,18

R³

ref.

25–29

N

R¹

N

X

ref. 19

R²

R¹

R³

N

R²

X = CO, SO₂

ref. 20–23

R³

R²

R³

N

R¹

N

R²

N

R²

N

R²

O

R¹

Scheme 1 o-Allylanilines as versatile precursors for the construction of several classes of nitrogen-containing heterocycles

SYNTHESIS 2012, 44, 3765–3782

Advanced online publication: 08.11.2012

0

3

9

-

7

8

1

4

3

7

-

2

1

0

X

DOI: 10.1055/s-0032-1316808; Art ID: SS-2012-M0665-OP

3766

L. M. Acosta Quintero et al.

PAPER

As part of our search program for bioactive aza-heterocy- 10, 11, we synthesized the corresponding N-prenyl- 3, N-

clic compounds, we have previously reported the use of (trans-cinnamyl)- 4, and N-[(E)-hex-2-enyl]-substituted

nitrones derived from o-allyl-N-(arylmethyl)anilines, 2- o-allylanilines by an efficient two-step sequence from the

allyl-N-(arylmethyl)-1-naphthylamines, and N,2-diallyl- corresponding mono-N-allylanilines 1 (Scheme 3).

anilines as versatile templates to furnish 2,4-disubtituted

tetrahydro-1-benzazepine and tetrahydronaphtho[1,2-

First, N-allylanilines 1a–e were heated with excess boron

trifluoride–diethyl ether complex to give the aza-Claisen

b]azepine nuclei via intramolecular nitrone–olefin 1,3-di-

rearrangement products 2a–e in good yields.³⁵To prepare

polar cycloaddition;^33–35we have established that the in-

the N-prenyl- and N-trans-cinnamyl-substituted anilines

3a–e and 4a–e, nucleophilic substitution of prenyl bro-

mide or trans-cinnamyl chloride with o-allylanilines 2a–e

was used. These intermediates 3, 4 were isolated, after

ternal cycloaddition of this type of nitrone proceeds with

a high level of stereoselectivity towards the formation of

2-exo-1,4-epoxycycloadducts as unique stereoisomers

(Scheme 2). Many of the synthesized tetrahydro-1-ben-

chromatographic purification, in good yields as oily resi-

zazepines and tetrahydronaphtho[1,2-b]azepines have

dues. To introduce the N-[(E)-hex-2-enyl] moiety, nu-

shown remarkable in vitro activity against epimastigote

cleophilic substitution was not efficient and the reductive

and promastigote forms of Trypanosoma cruzi and Leish-

amination methodology was used instead to give o-allyl-

mania chagasi parasites,^36,37most of them bearing an aryl

N-[(E)-hex-2-enyl]anilines 5a,b from the anilines 2b,d.

To perform this reaction, solvent-free condensation of o-

group at C2.

Accordingly, we planned examine the influence of an al- allylaniline 2b or 2d with (E)-hex-2-enal was carried out

kenyl substituent at C2 in the azepine ring on the bioactiv- at room temperature in the presence of molecular sieves (4

ity of benzazepines. We report herein the details of the Å) to yield the corresponding imine intermediate which

synthesis and stereochemistry of six novel series of tetra- was reduced in situ with sodium borohydride in methanol

hydro-1,4-epoxy-1-benzazepines and their reduction to afford 5a or 5b, respectively, in good overall yields.

products, tetrahydro-1-benzazepin-4-ols, bearing at C2 2- The assignment of all signals to individual H and C atoms

methylprop-1-enyl, (E)-styryl, and (E)-pent-1-enyl moi- in compounds 3–5 (see experimental section) were made

eties, with the aim of evaluating their antiparasitic activi- from their chemical shift values and coupling constants,

ty. To the best of our knowledge, these types of and confirmed on the basis of COSY, HSQC, and HMBC

substituted tetrahydro-1-benzazepines have not yet been spectra.

described in the literature.

In the next step of our approach, we focused our attention

To prepare the key intermediates that will afford the target on the transformation of the key intermediates 3–5 into 2-

1,4-epoxy cycloadducts bearing 2-(2-methylprop-1-enyl) alkenyltetrahydro-1,4-epoxy-1-benzazepines by employ-

6, 7, 2-[(E)-styryl] 8, 9, and 2-[(E)-pent-1-enyl] moieties ing the tandem selective oxidation of secondary aromatic

H

O

N

R⁶

H

2-exo-aryltetrahydro-1,4-epoxynaphtho[1,2-b]azepines

ref. 34

R⁴

H

R³

R²

R³

R²

ref. 33

[ O ]

O

+

R⁶

N

H

R⁵

N

R⁵

N

R¹

O^–

H

2-exo-aryltetrahydro-1,4-epoxy-1-benzazepines

ref. 35

R⁴

H

R³

R²

O

R⁷

N

R¹

H

2-exo-vinyltetrahydro-1,4-epoxy-1-benzazepines

Scheme 2 o-Allylanilines as versatile templates for the construction of 2-exo-substituted tetrahydro-1,4-epoxy-1-benzazepine and tetrahydro-

1,4-epoxynaphtho[1,2-b]azepine nuclei

Synthesis 2012, 44, 3765–3782

PAPER

Synthesis of 2-Alkenyltetrahydro-1-benzazepines

3767

R⁴

H_b

H_a

R³

R²

NH Me_(b)

Me_(a)

R¹

3a–e (56–70%)

Me

Br

DMF, Na₂CO₃

Me

R⁴

H_b

R⁴

R³

R²

R³

R²

R³

R²

Ph

Cl

BF₃·OEt₂(1.5 equiv)

120–140 °C, 6–8 h

H_a

Ph

H

NH₂

NH

N

DMF, Na₂CO₃

R¹

2a–e (65–76%)

1a–e

4a–e (63–72%)

H

1.

molecular sieves 4 Å, 25 °C

O

2. NaBH₄, MeOH, 0 to 65 °C

R⁴

H_b

R³

R²

H_a

NH

R¹

5a,b (80–89%)

Scheme 3 Synthesis of N-alkenyl-substituted o-allylanilines 3a–e, 4a–e, and 5a,b

amines (Murahashi methodology)³⁸and thermal intramo- their structures as well as stereochemistry deduced from

lecular 1,3-dipolar cycloaddition (Scheme 4). Thus, the NMR spectroscopic analysis, both 1D and 2D, specially

preparation of the target 1,4-epoxy cycloadducts was car- using the coupling constant values of the tertiary H2 and

ried out by first reacting compounds 3a–e, 4a–e, and 5a,b H4 azepinic protons, together with spatial correlations ob-

in methanol with excess hydrogen peroxide solution in the served in the NOESY spectra. The major products were

presence of catalytic amounts of sodium tungstate at a assigned as 2-exo-1,4-epoxy cycloadducts 6, 8, and 10,

temperature rising from 0 °C to 25 °C. The organic resi- and the minor products as 2-endo-1,4-epoxy cycloadducts

dues (nitrones), obtained after easy work-up and without 7, 9, and 11 in a ratio of 2–3:1.

further purification, were heated in toluene and underwent

intramolecular 1,3-dipolar cycloaddition across the termi-

For endo-cycloadducts 7, 9, and 11 the NOESY shows an

NOE cross-peak between H2 and H4, this shows that the

nal C=C bond of the pendant allylic fragment (dipolaro-

tetrahydro-1,4-epoxy-1-benzazepine ring contains these

phile) in the ortho position to give 1,4-epoxy

two hydrogens in the cis orientation, while for the exo-cy-

cycloadducts in reasonable times and with moderate-to-

cloadducts 6, 8 and 10 this NOE cross-peak does not ap-

pear.

good yields (Table 1). The intramolecular 1,3-dipolar cy-

cloaddition of nitrones from 3 proceeds within six hours,

To confirm the assigned stereochemistry of both exo- and

while that derived from 4 and 5 require more time, up to

endo-1,4-epoxy cycloadducts, single crystal X-ray analy-

sis of derivatives both with pendant 2-prenyl 6c, 6d, 7d,

12 hours; this could be due to steric hindrance.

This thermal 1,3-dipolar cycloaddition accomplished the

formation of both 2-exo- and 2-endo-1,4-epoxy cycload-

ducts along with a considerable amounts of byproduct, in-

dicative of decomposition. The exo- and endo-

and 2-styryl 8b, 8c, 9b, and 9c substituents was also per-

formed.^39–41The molecular structures of isomeric exo-cy-

cloadducts 6d and 8c, and endo-cycloadducts 7d and 9c,

with numbering scheme, are shown in Figure 1 and Figure

cycloadducts were successfully separated by silica gel

2, and agree with the stereochemistry deduced from NMR

column chromatography as high-viscosity maroon oils or

analysis.

as crystalline substances (see experimental section), and

Synthesis 2012, 44, 3765–3782

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L. M. Acosta Quintero et al.

PAPER

R⁴

O

H

R³

N

H

R²

+

H

R¹

8a–e

9a–e

R⁵= H, R⁶= Ph

R⁴

toluene, heat

R⁴

R³

R²

R⁴

O

H

R³

O^–

N

Na₂WO₄

MeOH

toluene, heat

R⁵= R⁶= Me

R²

N

+

N

R²

R¹

H

R¹

R⁵

R⁶

6a–e

7a–e

3a–e, 4a–e, 5a,b

R⁵= H, R⁶= n-Pr

toluene, heat

R⁴

for compds 3, 4, 6–9:

R⁴

O

H

O

a: R¹= R²= R³= R⁴= H

H

R³

b: R¹= R²= R⁴= H, R³= F

c: R¹= R²= R⁴= H, R³= Cl

d: R¹= Me, R²= Cl, R³= R⁴= H

e: R²= R⁴= Me, R¹= R³= H

N

+

H

R²

H

R¹

for compds 5, 10 and 11:

a: R¹= R²= R⁴= H, R³= F

b: R¹= Me, R²= Cl, R³= R⁴= H

10a,b

11a,b

Scheme 4 Synthesis of 2-exo- and 2-endo-1,4-epoxy cycloadducts 6–11

Table 1 Preparation and Yields of exo- and endo-1,4-Epoxy Cycloadducts 6a–e/7a–e, 8a–e/9a–e, and 10a,b/11a,b from o-Allylanilines

3a–e, 4a–e, and 5a,b

Entry

o-Allylaniline

3–5

Temp (°C), time (h)

exo-Cycloadduct

endo-Cycloadduct

Oxidation

1,3-Dipolar cycloaddition

6, 8, 10 Yield^a(%)

7, 9, 11 Yield^a(%)

1

3a

3b

3c

3d

3e

4a

4b

4c

4d

4e

5a

5b

0–25, 12

0–25, 8

100, 6

100, 12

80, 12

70, 12

6a

6b

6c

38

35

40

35

48

52

54

46

45

30

28

7a

7b

7c

16

14

19

15

11

14

20

25

19

18

10

13

2

3

0–25, 8

4

0–25, 72

0–25, 8

6d

6e

7d

7e

5

6

0–25, 36

0–25, 32

0–25, 72

0–25, 24

0–25, 8

8a

8b

8c

9a

9b

9c

7

8

9

8d

8e

9d

9e

10

11

12

10a

10b

11a

11b

0–25, 32

^aYields refer to isolated and pure compounds after column chromatography.

Synthesis 2012, 44, 3765–3782

PAPER

Synthesis of 2-Alkenyltetrahydro-1-benzazepines

3769

Figure 1 ORTEP drawing of molecular structures of the isomeric exo- and endo-cycloadducts 6d and 7d, showing the atom-labeling scheme

Figure 2 ORTEP drawing of molecular structures of the isomeric exo- and endo-cycloadducts 8c and 9c, showing the atom-labeling scheme

The last step of our approach is the reductive cleavage of 2-styryl, and 2-pent-1-enyl moieties and 4-hydroxy group

the N–O bond of the obtained stereoisomeric exo- and are oriented equatorially for the cis isomers 12, 14, and 16

endo-1,4-epoxy cycloadducts.³⁵Thus, exo- and endo-cy- with the tetrahydroazepine ring in the chair conformation,

cloadducts were separately treated with excess zinc pow- and in the case of the trans isomers 13, 15, and 17 the sub-

der in a mixture of glacial acetic acid and concentrated stituents at C2 are oriented equatorially but the 4-hydroxy

hydrochloric acid at 0 °C, for 0.5–2.0 hours (Scheme 5) to group is now in the axial position.

afford the expected cis- and trans-2-alkenyltetrahydro-1-

benzazepin-4-ols, respectively. These novel cyclic γ-ami-

no alcohols were isolated after chromatographic purifica-

tion in excellent yields (Table 2).

We are now developing preliminary biological assays to

evaluate the antiparasitic activity of these compounds. We

have found that both isomeric 1,4-epoxy cycloadducts and

tetrahydro-1-benzazepin-4-ols possess promising activity

The structures and stereochemistry of these novel com- against the epimastigote and amastigote forms of T. cruzi

pounds were determined mainly by 1D and 2D NMR as well as against promastigote form of L. chagasi para-

spectroscopy. As in the case of their precursors the cis or sites, the 7-chloro-substituted 2-endo-(2-methylprop-1-

trans stereochemistry at the stereogenic C2 and C4 of the enyl)tetrahydro-1,4-epoxy-1-benzazepine 7c, and the 7-

tetrahydroazepine ring was established on the basis of chloro-substituted

cis-2-(2-methylprop-1-enyl)tetra-

coupling constant values of the tertiary H2 and H4 protons hydro-1-benzazepin-4-ol 12c are the most active com-

and on the spatial interactions observed in 2D-NOESY pounds, with IC₅₀= 10.4 and 5.8 μM, respectively.

spectra for the cis compounds 12, 14, and 16 but not for Detailed results from this biological study will be reported

the trans derivatives. Both the 2-(2-methylprop-1-enyl), in the near future elsewhere.

Synthesis 2012, 44, 3765–3782

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L. M. Acosta Quintero et al.

PAPER

R⁴

OH

R⁴

O

R³

R²

H

R³

Zn, AcOH, HCl

MeOH, 0 °C

N

for compds 12 and 13:

⁵= R⁶= Me

R²

R⁵

N

R⁵

R¹

H

R

H

R¹

H

R⁶

12a–e, 14a–e, 16a,b

for compds 14 and 15:

⁵= Ph, R⁶= H

6a–e, 8a–e, 10a,b

R

R⁴

for compds 16 and 17:

⁵= n-Pr, R⁶= H

H

R⁴

O

H

R³

R²

R

R³

OH

Zn, AcOH, HCl

MeOH, 0 °C

N

H

R²

R⁶

N

R⁵

R¹

H

R⁵

R⁶

13a–e, 15a–e, 17a,b

7a–e, 9a–e, 11a,b

Scheme 5 Synthesis of cis- and trans-2-alkenyltetrahydro-1H-1-benzazepin-4-ols 12–17

Table 2 Preparation and Yields of 2-Alkenyl-Substituted cis- and trans-Tetrahydro-1H-1-benzazepin-4-ols 12a–e/13a–e, 14a–e/15a–e, and

16a,b/17a,b from exo- and endo-1,4-Epoxy Cycloadducts 6a–e/7a–e, 8a–e/9a–e, and 10a,b/11a,b

Entry

exo/endo-Cycloadducts

Time (min)

cis-Product

Yield^a(%)

trans-Product

Yield^a(%)

1

6a

6b

6c

30

120

60

30

120

60

30

120

60

30

120

60

30

45

30

45

12a

12b

12c

12d

12e

–

96

94

96

94

–

2

–

3

–

4

6d

6e

–

5

–

6

7a

7b

7c

13a

13b

13c

13d

13e

–

90

92

91

90

92

–

7

–

8

–

9

7d

7e

–

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

–

8a

8b

8c

14a

14b

14c

14d

14e

–

92

93

95

85

93

–

8d

8e

–

9a

9b

9c

15a

15b

15c

15d

15e

–

91

92

82

91

–

9d

9e

–

10a

10b

11a

11b

16a

16b

–

95

94

–

17a

17b

90

86

–

^aYields refer to isolated and pure compounds after column chromatography.

Synthesis 2012, 44, 3765–3782

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Synthesis of 2-Alkenyltetrahydro-1-benzazepines

3771

¹H NMR: δ = 6.88 (dd, J = 8.6, 3.0 Hz, 1 H, H3), 6.83 (td, J = 8.6,

3.0 Hz, 1 H, H5), 6.59 (dd, J = 8.6, 4.8 Hz, 1 H, H6), 5.93 (ddt,

J = 17.1, 10.2, 6.2 Hz, 1 H, CH= allyl), 5.38–5.36 (m, 1 H, =CH pre-

nyl), 5.16 (dq, J = 10.1, 1.6 Hz, 1 H, =CH_aH_b), 5.11 (dq, J = 17.1,

1.6 Hz, 1 H, =CH_aH_b), 3.67 (d, J = 6.7 Hz, 2 H, NCH₂), 3.26 (br d,

J = 6.2 Hz, 2 H, CH₂allyl), 1.77 (br s, 3 H, CH_3(a)prenyl), 1.71 (br

s, 3 H, CH_3(b)prenyl).

¹³C NMR: δ = 155.9 (d, J = 233.6 Hz, C4), 142.6 (C1), 136.0 (C=

prenyl), 135.3 (=CH allyl), 125.7 (d, J = 6.7 Hz, C2), 121.6 (CH=

prenyl), 116.9 (=CH₂allyl), 116.5 (d, J = 22.5 Hz, C3), 113.5 (d,

J = 21.4 Hz, C5), 111.7 (d, J = 7.1 Hz, C6), 42.8 (NCH₂), 36.1 (CH₂

allyl), 25.8 (CH_3(a)prenyl), 18.1 (CH_3(b)prenyl).

We have provided a convenient and simple synthetic

methodology to achieve both isomeric 2-exo- and 2-endo-

alkenyltetrahydro-1,4-epoxy-1-benzazepines and cis-

and trans-2-alkenyltetrahydro-1-benzazepin-4-ols, com-

pounds with potential antiparasitic activity that are not

otherwise readily accessible. This work represents an in-

teresting extension of our studies dealing with the synthe-

sis of compounds having in their structure the tetrahydro-

1-benzazepine core in order to develop novel molecules

with potent antiparasitic activity.

GC-MS (EI, 70 eV): m/z (%) = 219 (M^+•, 52), 151 (59), 150 (55),

149 (23), 148 (38), 136 (100), 69 (63).

All reagents and solvents were purchased from Sigma-Aldrich or

Merck and used without further purification. Monitoring of the re-

actions was performed using silica gel TLC plates (silica Merck 60

F254, visualization UV light at 254 and 365 nm). Column chroma-

tography was performed on Merck Kieselgel 60–230 mesh

(ASTM). Melting points were measured with a MEL-TEMP 1201D

capillary apparatus and were not corrected. IR spectra were record-

ed on a Nicolet Avatar 360-FTIR spectrophotometer referenced to

2-Allyl-4-chloro-N-(3-methylbut-2-enyl)aniline (3c)

Time: 3 h; yield: 0.79 g (56%).

IR (liquid film): 3425 (N–H), 1639 (C=C allyl), 919 cm^–1(=C–H

allyl).

¹H NMR: δ = 7.10 (dd, J = 8.6, 2.4 Hz, 1 H, H5), 7.02 (d, J = 2.4

Hz, 1 H, H3), 6.58 (d, J = 8.6 Hz, 1 H, H6), 5.90 (ddt, J = 17.1, 10.2,

6.2 Hz, 1 H, CH= allyl), 5.33–5.29 (m, 1 H, =CH prenyl), 5.15 (dq,

J = 10.2, 1.6 Hz, 1 H, =CH_aH_b), 5.11 (dq, J = 17.1, 1.6 Hz, 1 H,

=CH_aH_b), 3.68 (d, J = 7.3 Hz, 2 H, NCH₂), 3.24 (br d, J = 6.2 Hz, 2

H, CH₂allyl), 1.74 (br s, 3 H, CH_3(a)prenyl), 1.68 (br s, 3 H, CH_3(b)

prenyl).

¹³C NMR: δ = 144.8 (C1), 136.3 (C= prenyl), 135.2 (=CH allyl),

129.5 (C3), 127.4 (C5), 126.7 (C2), 125.6 (C4), 121.3 (CH= pre-

nyl), 117.0 (=CH₂allyl), 112.1 (C6), 42.4 (NCH₂), 36.1 (CH₂allyl),

25.8 (CH_3(a)prenyl), 18.2 (CH_3(b)prenyl).

1

polystyrene standard, using cells equipped with KBr windows. H

and ¹³C NMR spectra were measured at 25 °C on a Bruker Avance

III-400 spectrometer operating at 400 MHz and 100 MHz respec-

tively, using CDCl₃as the solvent. Chemical shifts are relative to

the solvent peaks used as reference [CDCl₃: δ_H= 7.26, and

δ_C= 77.0]. A Hewlett Packard HP 5890 A series II Gas chromato-

graph interfaced to a Hewlett Packard 5972 Mass Selective Detector

with a HP MS ChemStation Data system, and HRMS Waters Mi-

cromass AutoSpect NT (equipped with a direct inlet probe) operat-

ing at 70 eV were used for MS identification.

GC-MS (EI, 70 eV): m/z (%) = 235 (M^+•, ³⁵Cl, 67), 167 (58), 166

(46), 165 (26), 164 (47), 152 (87), 151 (19), 69 (100).

2-Allyl-N-(3-methylbut-2-enyl)anilines 3a–e; General Proce-

dure

1-Bromo-3-methylbut-2-ene (10 mmol) was very slowly added to a

stirred and cooled (ice bath) mixture of 2-allylaniline 2a–e (10

mmol) and Na₂CO₃(10 mmol) in anhyd DMF (25 mL). The mixture

was stirred at 0 °C for 2–6 h (TLC monitoring), it was extracted with

CH₂Cl₂(2 × 100 mL), and the combined organic extracts were

washed with sufficient H₂O to remove the DMF. The soln was dried

(anhyd Na₂SO₄), and the solvent was removed under reduced pres-

sure. The crude product was purified by column chromatography

(silica gel, heptane–EtOAc, 90:1 to 60:1) to give 3a–e as low-vis-

cosity maroon oils.

6-Allyl-3-chloro-2-methyl-N-(3-methylbut-2-enyl)aniline (3d)

Time: 6 h; yield: 0.87 g (70%).

IR (liquid film): 3375 (N–H), 1637 (C=C allyl), 915 cm^–1(=C–H al-

lyl).

¹H NMR: δ = 7.00 (d, J = 8.2 Hz, 1 H, H4), 6.91 (d, J = 8.2 Hz, 1 H,

H5), 5.94 (ddt, J = 17.1, 10.1, 6.1 Hz, 1 H, CH= allyl), 5.37–5.33

(m, 1 H, =CH prenyl), 5.11 (dq, J = 10.1, 1.7 Hz, 1 H, =CH_aH_b),

5.02 (dq, J = 17.1, 1.7 Hz, 1 H, =CH_aH_b), 3.47 (d, J = 7.1 Hz, 2 H,

NCH₂), 3.36 (dt, J = 6.1, 1.7 Hz, 2 H, CH₂allyl), 2.37 (s, 3 H, 2-

CH₃), 1.74 (br s, 3 H, CH_3(a)prenyl), 1.65 (br s, 3 H, CH_3(b)prenyl).

¹³C NMR: δ = 148.0 (C1), 136.7 (=CH allyl), 135.4 (C= prenyl),

133.8 (C3), 130.1 (C6), 129.2 (C2), 128.3 (C5), 123.2 (C4), 122.4

(CH= prenyl), 116.4 (=CH₂allyl), 47.3 (NCH₂), 36.6 (CH₂allyl),

25.9 (CH_3(a)prenyl), 18.0 (CH_3(b)prenyl), 15.9 (2-CH₃).

2-Allyl-N-(3-methylbut-2-enyl)aniline (3a)

Time: 3 h; yield: 0.98 g (65%).

IR (liquid film): 3420 (N–H), 1639 (C=C allyl), 914 cm^–1(=C–H

allyl).

¹H NMR: δ = 7.19 (td, J = 7.4, 1.3 Hz, 1 H, H5), 7.07 (dd, J = 7.4,

1.3 Hz, 1 H, H3), 6.72 (td, J = 7.4, 1.2 Hz, 1 H, H4), 6.67 (dd,

J = 7.4, 1.2 Hz, 1 H, H6), 5.96 (ddt, J = 16.5, 10.2, 6.2 Hz, 1 H, CH=

allyl), 5.39–5.33 (m, 1 H, =CH prenyl), 5.14 (dq, J = 10.2, 1.7 Hz,

1 H, =CH_aH_b), 5.10 (dq, J = 16.5, 1.7 Hz, 1 H, =CH_aH_b), 3.71 (d,

J = 6.7 Hz, 2 H, NCH₂), 3.30 (dt, J = 6.2, 1.7 Hz, 2 H, CH₂allyl),

1.77 (br s, 3 H, CH_3(a)prenyl), 1.72 (br s, 3 H, CH_3(b)prenyl).

¹³C NMR: δ = 146.5 (C1), 136.1 (=CH allyl), 135.7 (C= prenyl),

129.7 (C3), 127.7 (C5), 123.6 (C2), 121.7 (CH= prenyl), 117.1

(C4), 116.2 (=CH₂allyl), 110.6 (C6), 42.0 (NCH₂), 36.4 (CH₂allyl),

25.8 (CH_3(a)prenyl), 18.1 (CH_3(b)prenyl).

GC-MS (EI, 70 eV): m/z (%) = 249 (M^+•, ³⁵Cl, 39), 181 (36), 180

(38), 178 (43), 166 (72), 145 (41), 144 (38), 130 (30), 69 (100).

2-Allyl-3,5-dimethyl-N-(3-methylbut-2-enyl)aniline (3e)

Time: 2 h; yield: 0.85 g (60%).

IR (liquid film): 3419 (N–H), 1634 (C=C allyl), 912 cm^–1(=C–H

allyl).

¹H NMR: δ = 6.47 (s, 1 H, H4), 6.39 (s, 1 H, H6), 5.89 (ddt,

J = 17.0, 10.2, 5.7 Hz, 1 H, CH= allyl), 5.38–5.33 (m, 1 H, =CH pre-

nyl), 5.04 (dq, J = 10.2, 1.7 Hz, 1 H, =CH_aH_b), 5.00 (dq, J = 17.0,

1.7 Hz, 1 H, =CH_aH_b), 3.67 (d, J = 6.7 Hz, 2 H, NCH₂), 3.30 (dt,

J = 5.7, 1.7 Hz, 2 H, CH₂allyl), 2.29 (s, 3 H, 5-CH₃), 2.25 (s, 3 H,

3-CH₃), 1.77 (br s, 3 H, CH_3(a)prenyl), 1.71 (br s, 3 H, CH_3(b)pre-

nyl).

¹³C NMR: δ = 146.7 (C1), 136.6 (C3, C5), 135.5 (C= prenyl), 135.3

(=CH allyl), 121.9 (CH= prenyl), 120.4 (C4), 118.9 (C2), 109.8

(C6), 115.1 (=CH₂allyl), 42.3 (NCH₂), 31.3 (CH₂allyl), 25.7

(CH_3(a)prenyl), 21.5 (5-CH₃), 20.0 (3-CH₃), 18.1 (CH_3(b)prenyl).

GC-MS (EI, 70 eV): m/z (%) = 201 (M^+•, 48), 133 (41), 132 (90),

131 (32), 130 (69), 118 (100), 117 (35), 69 (48).

2-Allyl-4-fluoro-N-(3-methylbut-2-enyl)aniline (3b)

Time: 3 h; yield: 0.90 g (62%).

IR (liquid film): 3417 (N–H), 1637 (C=C allyl), 916 cm^–1(=C–H

allyl).

Synthesis 2012, 44, 3765–3782

3772

L. M. Acosta Quintero et al.

PAPER

GC-MS (EI, 70 eV): m/z (%) = 229 (M^+•, 57), 161 (15), 160 (56),

159 (26), 158 (57), 146 (100), 145 (54), 69 (18).

¹³C NMR: δ = 144.4 (C1), 136.7 (C1′), 135.0 (=CH allyl), 131.8

(=CH cinnamyl), 129.5 (C3), 128.6 (C3′/C5′), 127.6 (C4′), 127.3

(C5), 126.3 (C2′/C6′), 126.3 (CH= cinnamyl), 125.5 (C2), 122.1

(C4), 116.9 (=CH₂allyl), 112.1 (C6), 46.2 (NCH₂), 36.0 (CH₂allyl).

GC-MS (EI, 70 eV): m/z (%) = 283 (M^+•, ³⁵Cl, 22), 166 (7), 117

(100), 115 (46), 91 (27).

2-Allyl-N-(trans-cinnamyl)anilines 4a–e; General Procedure

To a stirred mixture of 2-allylaniline 2a–e (10 mmol), Na₂CO₃(10

mmol), and KI (5 mol%) in anhyd DMF (30 mL), trans-cinnamyl

chloride (10 mmol) was slowly added at r.t. The mixture was stirred

for 22–32 h (TLC control), then extracted with CH₂Cl₂(2 × 100

mL) and washed with H₂O to remove the DMF. The combined or-

ganic layers were dried (anhyd Na₂SO₄), and the solvent removed

under reduced pressure. The crude products were purified by col-

umn chromatography (silica gel, heptane–EtOAc; 80:1 to 50:1) to

give 4a–e as viscous yellow oils.

6-Allyl-3-chloro-N-(trans-cinnamyl)-2-methylaniline (4d)

Time: 32 h; yield: 1.18 g (72%).

IR (liquid film): 3375 (N–H), 1637 (C=C allyl), 967 (C=C trans-

cinnamyl), 916 cm^–1(=C–H allyl).

¹H NMR: δ = 7.41–7.38 (m, 2 H, H2′/H6′), 7.34 (td, J = 7.2, 1.6 Hz,

2 H, H3′/H5′), 7.28–7.24 (m, 1 H, H4′), 7.04 (d, J = 8.2 Hz, 1 H,

H4), 6.95 (d, J = 8.2 Hz, 1 H, H5), 6.62 (d, J = 15.8 Hz, 1 H, =CH

cinnamyl), 6.35 (dt, J = 15.8, 6.3 Hz, 1 H, CH= cinnamyl), 5.97

(ddt, J = 17.1, 10.2, 6.1 Hz, 1 H, CH= allyl), 5.13 (dq, J = 10.2, 1.6

Hz, 1 H, =CH_aH_b), 5.04 (dq, J = 17.2, 1.6 Hz, 1 H, =CH_aH_b), 3.70

(dd, J = 6.3, 1.6 Hz, 2 H, NCH₂), 3.40 (dt, J = 6.1, 1.6 Hz, 2 H, CH₂

allyl), 2.41 (s, 3 H, 2-CH₃).

¹³C NMR: δ = 147.4 (C1), 136.9 (C1′), 136.6 (=CH allyl), 133.8

(C3), 131.5 (=CH cinnamyl), 130.1 (C6), 129.3 (C2), 128.6

(C3′/C5′), 128.3 (C5), 127.6 (CH= cinnamyl), 127.5 (C4′), 126.4

(C2′/C6′), 123.4 (C4), 116.4 (=CH₂allyl), 51.5 (NCH₂), 36.5 (CH₂

allyl), 15.8 (2-CH₃).

2-Allyl-N-(trans-cinnamyl)aniline (4a)

Time: 24 h; yield: 1.37 g (65%).

IR (liquid film): 3432 (N–H), 1638 (C=C allyl), 967 (C=C trans-

cinnamyl), 915 cm^–1(=C–H allyl).

¹H NMR: δ = 7.40 (dd, J = 7.6, 1.6 Hz, 2 H, H2′/H6′), 7.33 (td,

J = 7.6, 1.6 Hz, 2 H, H3′/H5′), 7.27–7.23 (m, 1 H, H4′), 7.18 (td,

J = 7.8, 1.5 Hz, 1 H, H5), 7.09 (dd, J = 7.8, 1.2 Hz, 1 H, H3), 6.74

(td, J = 7.8, 1.5 Hz, 1 H, H4), 6.73 (d, J = 7.8 Hz, 1 H, H6), 6.63 (d,

J = 15.8 Hz, 1 H, =CH cinnamyl), 6.36 (dt, J = 15.8, 5.7 Hz, 1 H,

CH= cinnamyl), 5.99 (ddt, J = 16.5, 10.4, 6.1 Hz, 1 H, CH= allyl),

5.16 (dq, J = 10.4, 1.7 Hz, 1 H, =CH_aH_b), 5.13 (dq, J = 16.5, 1.7 Hz,

1 H, =CH_aH_b), 3.98 (dd, J = 5.7, 1.4 Hz, 2 H, NCH₂), 3.35 (br d,

J = 6.1 Hz, 2 H, CH₂allyl).

¹³C NMR: δ = 146.1 (C1), 136.9 (C1′), 136.1 (=CH allyl), 131.5

(=CH cinnamyl), 129.9 (C3), 128.6 (C3′/C5′), 127.8 (C5), 127.5

(C4′), 127.1 (CH= cinnamyl), 126.4 (C2′/C6′), 123.8 (C2), 117.5

(C4), 116.3 (=CH₂allyl), 110.9 (C6), 46.1 (NCH₂), 36.5 (CH₂allyl).

GC-MS (EI, 70 eV): m/z (%) = 297 (M^+•, ³⁵Cl, 9), 178 (12), 166

(15), 117 (100), 115 (43), 91 (28).

2-Allyl-N-(trans-cinnamyl)-3,5-dimethylaniline (4e)

Time: 22 h; yield: 1.14 g (66%).

IR (liquid film): 3429 (N–H), 1634 (C=C allyl), 967 (C=C trans-

cinnamyl), 913 cm^–1(=C–H allyl).

GC-MS (EI, 70 eV): m/z (%) = 249 (M^+•, 18), 130 (36), 118 (33),

¹H NMR: δ = 7.40 (br d, J = 7.3 Hz, 2 H, H2′/H6′), 7.33 (br t,

J = 7.3 Hz, 2 H, H3′/H5′), 7.27–7.23 (m, 1 H, H4′), 6.63 (d, J = 15.8

Hz, 1 H, =CH cinnamyl), 6.50 (s, 1 H, H4), 6.45 (s, 1 H, H6), 6.37

(dt, J = 15.8, 5.7 Hz, 1 H, CH= cinnamyl), 5.93 (ddt, J = 17.0, 10.3,

5.6 Hz, 1 H, CH= allyl), 5.07 (dq, J = 10.3, 1.8 Hz, 1 H, =CH_aH_b),

5.04 (dq, J = 17.0, 1.8 Hz, 1 H, =CH_aH_b), 3.95 (dd, J = 5.7, 1.4 Hz,

2 H, NCH₂), 3.35 (dt, J = 5.6, 1.8 Hz, 2 H, CH₂allyl), 2.29 (s, 3 H,

5-CH₃), 2.27 (s, 3 H, 3-CH₃).

¹³C NMR: δ = 146.4 (C1), 137.1 (C5), 136.9 (C3), 136.7 (C1′),

135.4 (=CH allyl), 131.4 (=CH cinnamyl), 128.7 (C3′/C5′), 127.6

(C4′), 127.5 (CH= cinnamyl), 126.5 (C2′/C6′), 120.9 (C4), 119.2

(C2), 115.4 (=CH₂allyl), 110.1 (C6), 46.5 (NCH₂), 31.4 (CH₂allyl),

21.7 (5-CH₃), 20.1 (3-CH₃).

117 (100), 115 (61), 91 (39).

2-Allyl-N-(trans-cinnamyl)-4-fluoroaniline (4b)

Time: 24 h; yield: 1.20 g (68%).

IR (liquid film): 3428 (N–H), 1636 (C=C allyl), 966 (C=C trans-

cinnamyl), 917 cm^–1(=C–H allyl).

¹H NMR: δ = 7.41–7.37 (m, 2 H, H2′/H6′), 7.33 (t, J = 7.6 Hz, 2 H,

H3′/H5′), 7.27–7.21 (m, 1 H, H4′), 6.89 (dd, J = 8.4, 3.0 Hz, 1 H,

H3), 6.85 (td, J = 8.8, 3.0 Hz, 1 H, H5), 6.65 (dd, J = 8.8, 4.8 Hz, 1

H, H6), 6.62 (d, J = 16.0 Hz, 1 H, =CH cinnamyl), 6.34 (dt,

J = 16.0, 5.7 Hz, 1 H, CH= cinnamyl), 5.96 (ddt, J = 16.3, 10.2, 6.1,

1 H, CH= allyl), 5.18 (dq, J = 10.2, 1.7 Hz, 1 H, =CH_aH_b), 5.14 (dq,

J = 16.3, 1.7 Hz, 1 H, =CH_aH_b), 3.93 (dd, J = 5.7, 1.4 Hz, 2 H,

NCH₂), 3.31 (br d, J = 6.1 Hz, 2 H, CH₂allyl).

¹³C NMR: δ = 156.0 (d, J = 232.5 Hz, C4), 142.4 (C1), 137.0 (C1′),

135.3 (=CH allyl), 131.8 (=CH cinnamyl), 128.7 (C3′/C5′), 127.7

(C4′), 127.0 (CH= cinnamyl), 126.5 (C2′/C6′), 125.8 (C2), 117.0

(=CH₂allyl), 116.7 (d, J = 22.0 Hz, C3), 113.6 (d, J = 21.8 Hz, C5),

112.0 (d, J = 8.8 Hz, C6), 46.8 (NCH₂), 36.3 (CH₂allyl).

GC-MS (EI, 70 eV): m/z (%) = 277 (M^+•, 58), 160 (44), 159 (32),

158 (61), 146 (68), 145 (44), 117 (100), 115 (73).

2-Allyl-N-[(E)-hex-2-enyl]anilines 5a,b; General Procedure

A mixture of o-allylaniline 2b,d (10 mmol) and (E)-hex-2-enal (10

mmol) was stirred in the presence of molecular sieves (4 Å; 100 mg)

at r.t. Once the imines had formed (TLC monitoring), MeOH (70

mL) was added, and to this soln NaBH₄(40 mmol) was added in

small portions at 0 °C. When the addition was complete, the mixture

was stirred at r.t. for a further 5 h. Finally, H₂O (60 mL) was added

and the mixture was heated to 65 °C for 4 h. The mixture was ex-

tracted with CHCl₃(2 × 100 mL), the combined organic extracts

were dried (anhyd Na₂SO₄), and solvent was removed under re-

duced pressure. The crude product was purified by column chroma-

tography (silica gel, heptane–EtOAc, 80:1 to 50:1) to give products

5a,b as low-viscosity yellow oils.

GC-MS (EI, 70 eV): m/z (%) = 267 (M^+•, 20), 148 (18), 117 (100),

115 (43), 91 (19).

2-Allyl-4-chloro-N-(trans-cinnamyl)aniline (4c)

Time: 21 h; yield: 1.07 g (63%).

IR (liquid film): 3434 (N–H), 1637 (C=C allyl), 967 (C=C trans-

cinnamyl), 920 cm^–1(=C–H allyl).

¹H NMR: δ = 7.39 (dd, J = 7.2, 1.6 Hz, 2 H, H2′/H6′), 7.36 (td,

J = 7.6, 1.6 Hz, 2 H, H3′/H5′), 7.27–7.22 (m, 1 H, H4′), 7.12 (dd,

J = 8.6, 2.4 Hz, 1 H, H5), 7.06 (d, J = 2.4 Hz, 1 H, H3), 6.64 (d,

J = 8.6 Hz, 1 H, H6), 6.61 (d, J = 16.0 Hz, 1 H, =CH cinnamyl),

6.32 (dt, J = 16.0, 5.7 Hz, 1 H, CH= cinnamyl), 5.95 (ddt, J = 16.6,

10.2, 6.1 Hz, 1 H, CH= allyl), 5.18 (dq, J = 10.2, 1.7 Hz, 1 H,

=CH_aH_b), 5.14 (dq, J = 16.6, 1.7 Hz, 1 H, =CH_aH_b), 3.94 (dd,

J = 5.7, 1.4 Hz, 2 H, NCH₂), 3.30 (br d, J = 6.1 Hz, 2 H, CH₂allyl).

2-Allyl-4-fluoro-N-[(E)-hex-2-enyl]aniline (5a)

Time: 10 h; yield: 1.37 g (89%).

IR (liquid film): 3420 (N–H), 1637 (C=C allyl), 917 cm^–1(=C–H

allyl).

Synthesis 2012, 44, 3765–3782

PAPER

Synthesis of 2-Alkenyltetrahydro-1-benzazepines

3773

¹H NMR: δ = 6.84 (td, J = 8.4, 2.8 Hz, 1 H, H5), 6.80 (dd, J = 8.4,

4.8 Hz, 1 H, H6), 6.56 (dd, J = 8.6, 2.8 Hz, 1 H, H3), 5.92 (ddt,

J = 17.2, 10.2, 6.0 Hz, 1 H, CH= allyl), 5.68 (dt, J = 15.2, 6.6 Hz, 1

H, =CH hexenyl), 5.57 (dt, J = 15.2, 5.6 Hz, 1 H, CH= hexenyl),

5.18 (dq, J = 10.2, 1.6 Hz, 1 H, =CH_aH_b), 5.10 (dq, J = 17.2, 1.6 Hz,

1 H, =CH_aH_b), 3.67 (br d, J = 5.6 Hz, 2 H, NCH₂), 3.26 (d, J = 6.0

Hz, 2 H, CH₂allyl), 2.02 (dd, J = 14.7, 6.6 Hz, 2 H, 4′-CH₂hexe-

nyl), 1.40 (dq, J = 14.7, 7.3 Hz, 2 H, 5′-CH₂hexenyl), 0.90 (t,

J = 7.3 Hz, 3 H, 6′-CH₃hexenyl).

¹³C NMR: δ = 155.7 (d, J = 237.0 Hz, C4), 142.5 (C1), 135.2 (=CH

allyl), 133.3 (=CH hexenyl), 126.8 (CH= hexenyl), 125.4 (d, J = 7.0

Hz, C2), 116.8 (=CH₂allyl), 116.4 (d, J = 22.4 Hz, C3), 111.6 (d,

J = 7.7 Hz, C6), 113.3 (d, J = 21.5 Hz, C5), 46.5 (NCH₂), 36.1 (CH₂

allyl), 34.4 (4′-CH₂hexenyl), 22.4 (5′-CH₂hexenyl), 13.6 (6′-CH₃

hexenyl).

2.21 (dddd, J = 12.4, 7.6, 2.4, 1.2 Hz, 1 H, H3_B), 1.74 (d, J = 1.2 Hz,

3 H, CH_3(a)), 1.67 (d, J = 1.2 Hz, 3 H, CH_3(b)).

¹³C NMR: δ = 150.3 (C9a), 132.8 (=C prenyl), 129.8 (C6), 127.9

(CH= prenyl), 126.5 (C8), 125.8 (C7), 125.2 (C5a), 121.8 (C9),

74.7 (C4), 70.8 (C2), 41.3 (C3), 34.8 (C5), 25.6 (CH_3(a)), 18.3

(CH_3(b)).

GC-MS (EI, 70 eV): m/z (%) = 215 (M^+•, 38), 198 (27), 185 (1), 130

(24), 105 (43), 104 (100).

HRMS: m/z [M]⁺calcd for C₁₄H₁₇NO: 215.1310; found: 215.1316.

(2RS,4RS)-2-(2-Methylprop-1-enyl)-2,3,4,5-tetrahydro-1,4-ep-

oxy-1-benzazepine (7a)

White crystals; yield: 0.17 g (16%); mp 41 °C (heptane); R_f= 0.43

(7% EtOAc–heptane).

IR (KBr): 1250 (C–N), 1052 (C–O), 981 cm^–1(N–O).

GC-MS (EI, 70 eV): m/z (%) = 233 (M^+•, 41), 150 (91), 148 (100),

136 (71), 135 (43), 55 (43).

¹H NMR: δ = 7.13–7.06 (m, 3 H, H6, H7, H8), 6.78 (dd, J = 7.8, 1.3

Hz, 1 H, H9), 4.85 (ddd, J = 8.0, 5.2, 2.4 Hz, 1 H, H4), 4.48 (ddt,

J = 9.0, 2.6, 1.2 Hz, 1 H, CH= prenyl), 4.43 (q, J = 8.2 Hz, 1 H, H2),

3.39 (dd, J = 16.6, 5.2 Hz, 1 H, H5_B), 2.67 (dtd, J = 12.2, 8.0, 1.0

Hz, 1 H, H3_B), 2.47 (d, J = 16.6 Hz, 1 H, H5_A), 1.82 (d, J = 1.2 Hz,

3 H, CH_3(a)), 1.65 (d, J = 1.2 Hz, 3 H, CH_3(b)), 1.57 (ddd, J = 12.2,

7.6, 2.4 Hz, 1 H, H3_A).

¹³C NMR: δ = 146.2 (C9a), 138.9 (=C prenyl), 129.7 (C6), 125.7

(C5a), 125.7 (C8), 125.3 (C7), 124.5 (C9), 120.7 (CH= prenyl),

75.7 (C4), 68.8 (C2), 40.6 (C3), 35.8 (C5), 25.8 (CH_3(a)), 18.8

(CH_3(b)).

6-Allyl-3-chloro-N-[(E)-hex-2-enyl]-2-methylaniline (5b)

Time: 12 h; yield: 1.15 g (80%).

IR (liquid film): 3379 (N–H), 1637 (C=C allyl), 915 cm^–1(=C–H

allyl).

¹H NMR: δ = 7.00 (d, J = 8.2 Hz, 1 H, H4), 6.91 (d, J = 8.2 Hz, 1 H,

H5), 5.92 (ddt, J = 17.2, 10.1, 6.0 Hz, 1 H, CH= allyl), 5.62 (dt,

J = 15.6, 6.6 Hz, 1 H, =CH hexenyl), 5.57 (dt, J = 15.6, 6.0 Hz, 1 H,

CH= hexenyl), 5.12 (dq, J = 10.1, 1.6 Hz, 1 H, =CH_aH_b), 5.03 (dq,

J = 17.1, 1.6 Hz, 1 H, =CH_aH_b), 3.46 (br d, J = 6.0 Hz, 2 H, NCH₂),

3.36 (br d, J = 6.0 Hz, 2 H, CH₂allyl), 2.36 (s, 3 H, 2-CH₃), 2.02

(dd, J = 13.9, 6.7 Hz, 2 H, 4′-CH₂hexenyl), 1.40 (dq, J = 14.6, 7.1

Hz, 2 H, 5′-CH₂hexenyl), 0.91 (t, J = 7.1 Hz, 3 H, 6′-CH₃hexenyl).

¹³C NMR: δ = 147.7 (C1), 136.6 (=CH allyl), 133.7 (C3), 133.2

(=CH hexenyl), 129.9 (C6), 129.1 (C2), 128.2 (C5), 127.8 (CH=

hexenyl), 123.1 (C4), 116.3 (=CH₂allyl), 51.5 (NCH₂), 36.6 (CH₂

allyl), 34.4 (4′-CH₂hexenyl), 22.4 (5′-CH₂hexenyl), 15.8 (2-CH₃),

13.7 (6′-CH₃hexenyl).

GC-MS (EI, 70 eV): m/z (%) = 215 (M^+•, 42), 198 (27), 185 (1), 130

(21), 105 (43), 104 (100).

HRMS: m/z [M]⁺calcd for C₁₄H₁₇NO: 215.1310; found: 215.1314.

(2SR,4RS)-7-Fluoro-2-(2-methylprop-1-enyl)-2,3,4,5-tetra-

hydro-1,4-epoxy-1-benzazepine (6b)

White crystals; yield: 0.37 g (35%); mp 72 °C (heptane); R_f= 0.50

(7% EtOAc–heptane).

IR (KBr): 1250 (C–N), 1051 (C–O), 983 cm^–1(N–O).

GC-MS (EI, 70 eV): m/z (%) = 263 (M^+•, ³⁵Cl, 35), 180 (72), 178

¹H NMR: δ = 7.00 (dd, J = 8.6, 5.4 Hz, 1 H, H9), 6.83 (td, J = 8.6,

2.8 Hz, 1 H, H8), 6.79 (dd, J = 8.8, 2.4 Hz, 1 H, H6), 5.40 (br d,

J = 8.8 Hz, 1 H, CH= prenyl), 4.84 (ddd, J = 7.6, 5.2, 2.0 Hz, 1 H,

H4), 4.16 (td, J = 8.6, 2.2 Hz, 1 H, H2), 3.33 (dd, J = 16.8, 5.2 Hz,

1 H, H5_B), 2.44 (d, J = 16.8 Hz, 1 H, H5_A), 2.30 (ddd, J = 12.4, 8.0,

2.0 Hz, 1 H, H3_A), 2.22 (dddd, J = 12.4, 7.6, 2.2, 1.2 Hz, 1 H, H3_B),

1.73 (br s, 3 H, CH_3(a)), 1.66 (br s, 3 H, CH_3(b)).

¹³C NMR: δ = 160.9 (d, J = 243.9 Hz, C7), 146.7 (d, J = 2.6 Hz,

C9a), 133.3 (=C prenyl), 128.2 (CH= prenyl), 127.6 (d, J = 8.2 Hz,

C5a), 123.6 (d, J = 8.5 Hz, C9), 116.5 (d, J = 22.4 Hz, C6), 113.8

(d, J = 22.5 Hz, C8), 74.5 (C4), 71.2 (C2), 41.7 (C3), 35.3 (d,

J = 1.3 Hz, C5), 25.9 (CH_3(a)), 18.6 (CH_3(b)).

(97), 166 (67), 145 (100), 144 (66), 130 (53).

(2SR,4RS)- and (2RS,4RS)-2-Alk-1-enyl-2,3,4,5-tetrahydro-1,4-

epoxy-1-benzazepines 6–11; General Procedure

Na₂WO₄·2 H₂O (10 mol%), and 30% aq H₂O₂soln (30 mmol) were

added to a stirred and cooled (ice bath) soln of the appropriately

substituted N-alk-2-enyl-2-allylaniline 3a–e, 4a–e, and 5a,b (10

mmol) in MeOH (30 mL). The resulting mixture was stirred at 0 °C

for 2 h and then at r.t. for an additional 4–14 h. The solid was re-

moved by filtration and the product was extracted with EtOAc. The

combined organic extracts were dried (anhyd Na₂SO₄) and the sol-

vent was removed under reduced pressure. Toluene (30 mL) was

added to the organic black residue, and the resulting soln was heated

at 70–100 °C for 6–72 h. After cooling the soln to r.t., the solvent

was removed under reduced pressure and the crude product was pu-

rified by column chromatography (silica gel, heptane–EtOAc, 60:1

to 5:1) to give 1,4-epoxycycloadducts 6a–e, 7a–e, 8a–e, 9a–e,

10a,b, and 11a,b as individual diastereomers.

GC-MS (EI, 70 eV): m/z (%) = 233 (M^+•, 27), 216 (15), 203 (1), 148

(19), 123 (46), 122 (100).

HRMS: m/z [M]⁺calcd for C₁₄H₁₆FNO: 233.1216; found: 233.1219.

(2RS,4RS)-7-Fluoro-2-(2-methylprop-1-enyl)-2,3,4,5-tetra-

hydro-1,4-epoxy-1-benzazepine (7b)

White crystals; yield: 0.15 g (14%); mp 66 °C (heptane); R_f= 0.46

(7% EtOAc–heptane).

(2SR,4RS)-2-(2-Methylprop-1-enyl)-2,3,4,5-tetrahydro-1,4-ep-

oxy-1-benzazepine (6a)

White crystals; yield: 0.41 g (38%); mp 78 °C (heptane); R_f= 0.54

(7% EtOAc–heptane).

IR (KBr): 1245 (C–N), 1052 (C–O), 987 cm^–1(N–O).

IR (KBr): 1263 (C–N), 1051 (C–O), 984 cm^–1(N–O).

¹H NMR: δ = 6.78–6.72 (m, 3 H, H6, H8, H9), 4.82 (ddd, J = 8.0,

5.2, 2.2 Hz, 1 H, H4), 4.45 (ddt, J = 8.8, 2.4, 1.2 Hz, 1 H, CH= pre-

nyl), 4.41 (q, J = 8.0 Hz, 1 H, H2), 3.36 (dd, J = 16.6, 5.2 Hz, 1 H,

H5_B), 2.67 (dtd, J = 12.8, 8.0, 0.8 Hz, 1 H, H3_B), 2.46 (d, J = 16.6

Hz, 1 H, H5_A), 1.81 (d, J = 1.2 Hz, 3 H, CH_3(a)), 1.65 (d, J = 0.8 Hz,

3 H, CH_3(b)), 1.55 (ddd, J = 12.8, 7.6, 2.2 Hz, 1 H, H3_A).

¹H NMR: δ = 7.08 (dd, J = 7.6, 1.3 Hz, 1 H, H6), 7.15 (td, J = 7.6,

1.3 Hz, 1 H, H8), 7.11 (td, J = 7.6, 1.3 Hz, 1 H, H7), 7.04 (dd,

J = 7.6, 1.3 Hz, 1 H, H9), 5.43 (ddt, J = 8.8, 2.6, 1.4 Hz, 1 H, CH=

prenyl), 4.87 (ddd, J = 7.6, 5.2, 2.0 Hz, 1 H, H4), 4.22 (td, J = 8.6,

2.4 Hz, 1 H, H2), 3.35 (dd, J = 16.6, 5.2 Hz, 1 H, H5_B), 2.46 (d,

J = 16.6 Hz, 1 H, H5_A), 2.31 (ddd, J = 12.4, 8.1, 2.0 Hz, 1 H, H3_A),

¹³C NMR: δ = 160.6 (d, J = 243.6 Hz, C7), 142.0 (d, J = 2.5 Hz,

C9a), 139.3 (=C prenyl), 127.7 (d, J = 8.1 Hz, C5a), 125.9 (d,

Synthesis 2012, 44, 3765–3782

3774

L. M. Acosta Quintero et al.

PAPER

J = 8.4 Hz, C9), 120.5 (CH= prenyl), 116.0 (d, J = 22.3 Hz, C6),

112.4 (d, J = 22.4 Hz, C8), 75.1 (C4), 68.7 (C2), 40.6 (C3), 35.9 (d,

J = 1.2 Hz, C5), 25.8 (CH_3(a)), 18.8 (CH_3(b)).

GC-MS (EI, 70 eV): m/z (%) = 233 (M^+•, 24), 216 (15), 203 (1), 148

74.8 (C4), 69.7 (C2), 41.8 (C3), 35.0 (C5), 26.0 (CH_3(a)), 18.5

(CH_3(b)), 14.1 (9-CH₃).

GC-MS (EI, 70 eV): m/z (%) = 263 (M^+•, ³⁵Cl, 46), 246 (24), 233

(1), 178 (15), 153 (100), 152 (62).

(21), 123 (45), 122 (100).

HRMS: m/z [M]⁺calcd for C₁₄H₁₆FNO: 233.1216; found: 233.1218.

HRMS: m/z [M]⁺calcd for C₁₅H₁₈ClNO: 263.1077; found:

263.1080.

(2SR,4RS)-7-Chloro-2-(2-methylprop-1-enyl)-2,3,4,5-tetra-

hydro-1,4-epoxy-1-benzazepine (6c)

White crystals; yield: 0.42 g (40%); mp 94 °C (heptane); R_f= 0.57

(7% EtOAc–heptane).

(2RS,4RS)-8-Chloro-9-methyl-2-(2-methylprop-1-enyl)-2,3,4,5-

tetrahydro-1,4-epoxy-1-benzazepine (7d)

White crystals; yield: 0.16 g (15%); mp 107 °C (heptane); R_f= 0.47

(7% EtOAc–heptane).

IR (KBr): 1255 (C–N), 1052 (C–O), 979 cm–¹(N–O).

IR (KBr): 1276 (C–N), 1051 (C–O), 977 cm^–1(N–O).

¹H NMR: δ = 7.11 (dd, J = 8.4, 2.3 Hz, 1 H, H8), 7.07 (d, J = 2.3

Hz, 1 H, H6), 6.98 (d, J = 8.4 Hz, 1 H, H9), 5.40 (ddt, J = 8.8, 2.6,

1.2 Hz, 1 H, CH= prenyl), 4.85 (ddd, J = 7.6, 5.2, 2.2 Hz, 1 H, H4),

4.18 (td, J = 8.4, 2.4 Hz, 1 H, H2), 3.32 (dd, J = 16.7, 5.2 Hz, 1 H,

H5_B), 2.44 (d, J = 16.7 Hz, 1 H, H5_A), 2.29 (ddd, J = 12.4, 8.0, 2.2

Hz, 1 H, H3_A), 2.24 (dddd, J = 12.4, 7.6, 2.4, 1.1 Hz, 1 H, H3_B), 1.73

(d, J = 0.9 Hz, 3 H, CH_3(a)), 1.66 (d, J = 1.1 Hz, 3 H, CH_3(b)).

¹³C NMR: δ = 149.0 (C9a), 133.3 (=C prenyl), 131.1 (C7), 129.7

(C6), 127.6 (C8), 127.2 (C5a), 126.8 (CH= prenyl), 123.2 (C9),

74.3 (C4), 71.0 (C2), 41.4 (C3), 34.8 (C5), 25.7 (CH_3(a)), 18.4

(CH_3(b)).

¹H NMR: δ = 7.12 (d, J = 8.0 Hz, 1 H, H7), 6.87 (d, J = 8.0 Hz, 1 H,

H6), 4.80 (ddd, J = 7.6, 5.2, 2.4 Hz, 1 H, H4), 4.52–4.43 (m, 2 H,

CH= prenyl, H2), 3.32 (dd, J = 16.4, 5.2 Hz, 1 H, H5_B), 2.66 (dt,

J = 12.4, 8.0 Hz, 1 H, H3_B), 2.46 (d, J = 16.4 Hz, 1 H, H5_A), 2.18 (s,

3 H, 9-CH₃), 1.81 (br s, 3 H, CH_3(a)), 1.62 (br s, 3 H, CH_3(b)), 1.58

(ddd, J = 12.4, 7.4, 2.4 Hz, 1 H, H3_A).

¹³C NMR: δ = 146.4 (C9a), 139.6 (=C prenyl), 132.6 (C8), 131.9

(C9), 128.1 (C6), 126.5 (C7), 124.8 (C5a), 120.6 (CH= prenyl),

75.4 (C4), 69.0 (C2), 41.7 (C3), 36.2 (C5), 26.2 (CH_3(a)), 18.9

(CH_3(b)), 15.1 (9-CH₃).

GC-MS (EI, 70 eV): m/z (%) = 263 (M^+•, ³⁵Cl, 47), 246 (30), 233

(1), 178 (18), 153 (100), 152 (61).

GC-MS (EI, 70 eV): m/z (%) = 249 (M^+•, ³⁵Cl, 41), 232 (18), 219

(1), 164 (15), 139 (58), 138 (100).

HRMS: m/z [M]⁺calcd for C₁₄H₁₆ClNO: 249.0920; found:

HRMS: m/z [M]⁺calcd for C₁₅H₁₈ClNO: 263.1077; found:

263.1073.

249.0932.

(2SR,4RS)-6,8-Dimethyl-2-(2-methylprop-1-enyl)-2,3,4,5-tetra-

hydro-1,4-epoxy-1-benzazepine (6e)

White crystals; yield: 0.37 g (35%); mp 87 °C (heptane); R_f= 0.57

(7% EtOAc–heptane).

(2RS,4RS)-7-Chloro-2-(2-methylprop-1-enyl)-2,3,4,5-tetra-

hydro-1,4-epoxy-1-benzazepine (7c)

White crystals; yield: 0.20 g (19%); mp 110 °C (heptane); R_f= 0.50

(7% EtOAc–heptane).

IR (KBr): 1276 (C–N), 1055 (C–O), 971 cm–¹(N–O).

IR (KBr): 1260 (C–N), 1051 (C–O), 983 cm^–1(N–O).

¹H NMR: δ = 6.82 (s, 1 H, H7), 6.73 (s, 1 H, H9), 5.43 (ddt, J = 8.8,

2.8, 1.4 Hz, 1 H, CH= prenyl), 4.91 (ddd, J = 7.6, 5.6, 2.0 Hz, 1 H,

H4), 4.22 (td, J = 8.4, 2.4 Hz, 1 H, H2), 3.12 (dd, J = 16.8, 5.6 Hz,

1 H, H5_B), 2.29 (ddd, J = 12.4, 8.4, 2.0 Hz, 1 H, H3_A), 2.28 (s, 3 H,

8-CH₃), 2.27 (d, J = 16.8 Hz, 1 H, H5_A), 2.21 (dddd, J = 12.4, 7.6,

2.4, 1.2 Hz, 1 H, H3_B), 2.14 (s, 3 H, 6-CH₃), 1.74 (d, J = 1.2 Hz, 3

H, CH_3(a)), 1.67 (d, J = 1.2 Hz, 3 H, CH_3(b)).

¹³C NMR: δ = 150.1 (C9a), 137.5 (C6), 136.0 (C8), 132.6 (=C pre-

nyl), 128.1 (CH= prenyl), 128.0 (C7), 120.3 (C5a), 119.9 (C9), 74.8

(C4), 70.7 (C2), 41.9 (C3), 33.1 (C5), 25.6 (CH_3(a)), 21.1 (8-CH₃),

18.5 (CH_3(b)), 18.3 (6-CH₃).

¹H NMR: δ = 7.09 (br s, 1 H, H6), 7.05 (dd, J = 8.4, 2.1 Hz, 1 H,

H8), 6.73 (d, J = 8.4 Hz, 1 H, H9), 4.84 (ddd, J = 7.6, 5.2, 2.2 Hz, 1

H, H4), 4.46 (ddt, J = 8.8, 2.4, 1.2 Hz, 1 H, CH= prenyl), 4.44 (q,

J = 7.6 Hz, 1 H, H2), 3.36 (dd, J = 16.6, 5.2 Hz, 1 H, H5_B), 2.69

(dtd, J = 12.8, 7.6, 1.0 Hz, 1 H, H3_B), 2.49 (d, J = 16.6 Hz, 1 H,

H5_A), 1.82 (br s, 3 H, CH_3(a)), 1.65 (br s, 3 H, CH_3(b)), 1.57 (ddd,

J = 12.8, 7.6, 2.2 Hz, 1 H, H3_A).

¹³C NMR: δ = 144.6 (C9a), 140.0 (=C prenyl), 131.2 (C7), 129.7

(C6), 127.8 (C5a), 125.9 (C8), 125.7 (C9), 120.3 (CH= prenyl),

75.1 (C4), 68.7 (C2), 40.6 (C3), 35.9 (C5), 25.8 (CH_3(a)), 18.8

(CH_3(b)).

GC-MS (EI, 70 eV): m/z (%) = 243 (M^+•, 56), 226 (27), 213 (1), 158

(12), 133 (100), 132 (50).

GC-MS (EI, 70 eV): m/z (%) = 249 (M^+•, ³⁵Cl, 40), 232 (21), 219

(1), 164 (15), 139 (57), 138 (100).

HRMS: m/z [M]⁺calcd for C₁₄H₁₆ClNO: 249.0920; found:

249.0929.

HRMS: m/z [M]⁺calcd for C₁₆H₂₁NO: 243.1623; found: 243.1618.

(2RS,4RS)-6,8-Dimethyl-2-(2-methylprop-1-enyl)-2,3,4,5-tetra-

hydro-1,4-epoxy-1-benzazepine (7e)

White crystals; yield: 0.12 g (11%); mp 76 °C (heptane); R_f= 0.50

(7% EtOAc–heptane).

(2SR,4RS)-8-Chloro-9-methyl-2-(2-methylprop-1-enyl)-2,3,4,5-

tetrahydro-1,4-epoxy-1-benzazepine (6d)

White crystals; yield: 0.42 g (40%); mp 94 °C (heptane); R_f= 0.61

(7% EtOAc–heptane).

IR (KBr): 1274 (C–N), 1051 (C–O), 976 cm^–1(N–O).

¹H NMR: δ = 7.10 (d, J = 8.0 Hz, 1 H, H7), 6.86 (d, J = 8.0 Hz, 1 H,

H6), 5.45 (br d, J = 8.8 Hz, 1 H, CH= prenyl), 4.86 (ddd, J = 7.6,

5.2, 2.0 Hz, 1 H, H4), 4.11 (td, J = 8.4, 2.4 Hz, 1 H, H2), 3.31 (dd,

J = 16.4, 5.2 Hz, 1 H, H5_B), 2.40 (d, J = 16.4 Hz, 1 H, H5_A), 2.34 (s,

3 H, 9-CH₃), 2.25 (ddd, J = 12.4, 8.0, 2.0 Hz, 1 H, H3_A), 2.19 (dddd,

J = 12.4, 7.6, 2.4, 1.2 Hz, 1 H, H3_B), 1.75 (br s, 3 H, CH_3(a)), 1.64

(br s, 3 H, CH_3(b)).

IR (KBr): 1277 (C–N), 1053 (C–O), 972 cm^–1(N–O).

¹H NMR: δ = 6.81 (s, 1 H, H7), 6.47 (s, 1 H, H9), 4.89 (ddd, J = 8.0,

5.2, 2.2 Hz, 1 H, H4), 4.53 (dt, J = 8.8, 1.2 Hz, 1 H, CH= prenyl),

4.42 (q, J = 8.6 Hz, 1 H, H2), 3.14 (dd, J = 16.8, 5.2 Hz, 1 H, H5_B),

2.66 (dt, J = 12.0, 8.4 Hz, 1 H, H3_B), 2.29 (d, J = 16.8 Hz, 1 H,

H5_A), 2.25 (s, 3 H, 8-CH₃), 2.15 (s, 3 H, 6-CH₃), 1.82 (br s, 3 H,

CH_3(a)), 1.66 (br s, 3 H, CH_3(b)), 1.53 (ddd, J = 12.0, 8.4, 2.4 Hz, 1

H, H3_A).

¹³C NMR: δ = 145.8 (C9a), 138.5 (=C prenyl), 137.2 (C6), 134.7

(C8), 128.0 (C7), 122.7 (C9), 120.9 (C5a), 120.9 (CH= prenyl),

75.7 (C4), 68.6 (C2), 41.1 (C3), 34.1 (C5), 25.7 (CH_3(a)), 21.0 (8-

CH₃), 18.8 (CH_3(b)), 18.5 (6-CH₃).

¹³C NMR: δ = 150.0 (C9a), 132.7 (=C prenyl), 132.3 (C8), 129.2

(C9), 128.2 (C6), 127.9 (CH= prenyl), 126.2 (C7), 123.8 (C5a),

Synthesis 2012, 44, 3765–3782

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Synthesis of 2-Alkenyltetrahydro-1-benzazepines

3775

GC-MS (EI, 70 eV): m/z (%) = 243 (M^+•, 45), 226 (24), 213 (1), 158

(15), 133 (100), 132 (53).

HRMS: m/z [M]⁺calcd for C₁₆H₂₁NO: 243.1623; found: 243.1620.

GC-MS (EI, 70 eV): m/z (%) = 281 (M^+•, 67), 280 (31), 264 (33),

251 (21), 148 (41), 130 (61), 129 (58), 128 (37), 123 (57), 122

(100), 96 (33).

HRMS: m/z [M]⁺calcd for C₁₈H₁₆FNO: 281.1216; found: 281.1225.

(2SR,4RS)-2-[(E)-Styryl]-2,3,4,5-tetrahydro-1,4-epoxy-1-ben-

zazepine (8a)

White crystals; yield: 0.51 g (48%); mp 92 °C (heptane); R_f= 0.44

(7% EtOAc–heptane).

IR (KBr): 1271 (C–N), 1072 (C–O), 976 (N–O), 952 cm^–1(CH=CH

E-styryl).

(2RS,4RS)-7-Fluoro-2-[(E)-styryl]-2,3,4,5-tetrahydro-1,4-ep-

oxy-1-benzazepine (9b)

Pale red crystals; yield: 0.21 g (20%); mp 135 °C (heptane);

R_f= 0.25 (7% EtOAc–heptane).

IR (KBr): 1247 (C–N), 1129 (C–O), 980 (N–O), 964 cm^–1(C=C

E-styryl).

¹H NMR: δ = 7.43–7.40 (m, 2 H, H2′/H6′), 7.34–7.30 (m, 2 H,

H3′/H5′), 7.26–7.21 (m, 1 H, H4′), 7.18 (td, J = 7.4, 2.4 Hz, 1 H,

H8), 7.14 (dd, J = 7.4, 2.4 Hz, 1 H, H6), 7.13 (td, J = 7.4, 1.6 Hz, 1

H, H7), 7.09 (dd, J = 7.4, 1.6 Hz, 1 H, H9), 6.57 (d, J = 16.0 Hz, 1

H, =CH styryl), 6.38 (dd, J = 16.0, 7.2 Hz, 1 H, CH= styryl), 4.95–

4.91 (m, 1 H, H4), 4.20 (td, J = 7.2, 3.0 Hz, 1 H, H2), 3.40 (dd,

J = 16.8, 5.2 Hz, 1 H, H5_B), 2.51 (d, J = 16.8 Hz, 1 H, H5_A), 2.45–

2.35 (m, 2 H, H3_AH_B).

¹H NMR: δ = 7.31–7.24 (m, 5 H, H2′/H6′, H3′/H5′, H4′), 6.90 (dd,

J = 8.4, 5.4 Hz, 1 H, H9), 6.85 (dd, J = 8.8, 2.6 Hz, 1 H, H6), 6.82

(td, J = 8.4, 2.6 Hz, 1 H, H8), 6.67 (d, J = 15.8 Hz, 1 H, =CH styryl),

5.50 (dd, J = 15.8, 8.8 Hz, 1 H, CH= styryl), 4.89 (ddd, J = 7.8, 5.2,

2.2 Hz, 1 H, H4), 4.38 (q, J = 8.4 Hz, 1 H, H2), 3.42 (dd, J = 16.7,

5.2 Hz, 1 H, H5_B), 2.76 (dt, J = 12.4, 8.4, Hz, 1 H, H3_B), 2.54 (d,

J = 16.7 Hz, 1 H, H5_A), 1.79 (ddd, J = 12.4, 8.0, 2.2 Hz, 1 H, H3_A).

¹³C NMR: δ = 150.1 (C9a), 136.8 (C1′), 131.5 (CH= styryl), 129.8

(=CH styryl), 129.8 (C6), 128.5 (C3′/C5′), 127.5 (C8), 126.6 (C4′),

126.5 (C2′/C6′), 126.0 (C7), 125.2 (C5a), 122.0 (C9), 74.9 (C4),

74.5 (C2), 40.8 (C3), 34.7 (C5).

GC-MS (EI, 70 eV): m/z (%) = 263 (M^+•, 45), 246 (48), 233 (12),

130 (74), 129 (53), 128 (30), 105 (61), 104 (100).

¹³C NMR: δ = 160.7 (d, J = 242.8 Hz, C7), 141.6 (C9a), 136.3

(C1′), 135.2 (=CH styryl), 128.6 (C3′/C5′), 128.0 (C4′), 127.7 (d,

J = 8.2 Hz, C5a), 126.5 (C2′/C6′), 125.6 (d, J = 8.4 Hz, C9), 124.8

(CH= styryl), 116.3 (d, J = 22.3 Hz, C6), 112.8 (d, J = 22.3 Hz, C8),

75.4 (C4), 73.3 (C2), 39.9 (C3), 35.8 (C5).

GC-MS (EI, 70 eV): m/z (%) = 281 (M^+•, 64), 280 (41), 264 (33),

251 (12), 148 (29), 130 (62), 129 (58), 128 (33), 123 (56), 122

(100), 96 (30).

HRMS: m/z [M]⁺calcd for C₁₈H₁₇NO: 263.1310; found: 263.1310.

HRMS: m/z [M]⁺calcd for C₁₈H₁₆FNO: 281.1216; found: 281.1214.

(2RS,4RS)-2-[(E)-Styryl]-2,3,4,5-tetrahydro-1,4-epoxy-1-ben-

zazepine (9a)

White crystals; yield: 0.15 g (14%); mp 115 °C (heptane); R_f= 0.29

(7% EtOAc–heptane).

IR (KBr): 1246 (C–N), 1073 (C–O), 1010 (N–O), 968 cm^–1

(2SR,4RS)-7-Chloro-2-[(E)-styryl)-2,3,4,5-tetrahydro-1,4-ep-

oxy-1-benzazepine (8c)

White crystals; yield: 0.57 g (54%); mp 142 °C (heptane); R_f= 0.46

(7% EtOAc–heptane).

IR (KBr): 1247 (C–N), 1177 (C–O), 980 (N–O), 964 cm^–1(C=C

E-styryl).

¹H NMR: δ = 7.41 (d, J = 7.3 Hz, 2 H, H2′/H6′), 7.32 (t, J = 7.3 Hz,

2 H, H3′/H5′), 7.25–7.23 (m, 1 H, H4′), 7.14 (dd, J = 8.4, 2.2 Hz, 1

H, H8), 7.11 (br s, 1 H, H6), 7.03 (d, J = 8.4 Hz, 1 H, H9), 6.56 (d,

J = 16.0 Hz, 1 H, =CH styryl), 6.34 (dd, J = 16.0, 7.4 Hz, 1 H, CH=

styryl), 4.91 (ddd, J = 7.6, 5.3, 2.0 Hz, 1 H, H4), 4.15 (td, J = 7.8,

2.4 Hz, 1 H, H2), 3.35 (dd, J = 16.7, 5.3 Hz, 1 H, H5_B), 2.48 (br d,

J = 16.7 Hz, 1 H, H5_A), 2.42 (dddd, J = 12.6, 7.6, 2.4, 1.0 Hz, 1 H,

H3_B), 2.35 (ddd, J = 12.6, 7.8, 2.0 Hz, 1 H, H3_A).

¹³C NMR: δ = 148.5 (C9a), 136.6 (C1′), 131.1 (C7), 131.0 (CH=

styryl), 129.9 (=CH styryl), 129.6 (C6), 128.5 (C3′/C5′), 127.5

(C4′), 127.1 (C5a), 126.7 (C8), 126.4 (C2′/C6′), 123.3 (C9), 74.4

(C2), 74.3 (C4), 40.6 (C3), 34.5 (C5).

(CH=CH E-styryl).

¹H NMR: δ = 7.32–7.22 (m, 5 H, H2′/H6′, H3′/H5′, H4′), 7.18–7.11

(m, 3 H, H6, H7, H8), 6.92 (dd, J = 7.2, 1.2 Hz, 1 H, H9), 6.69 (d,

J = 16.0 Hz, 1 H, =CH styryl), 5.54 (dd, J = 16.0, 8.8 Hz, 1 H, CH=

styryl), 4.96 (ddd, J = 7.8, 5.2, 2.4 Hz, 1 H, H4), 4.41 (q, J = 8.4 Hz,

1 H, H2), 3.46 (dd, J = 16.6, 5.2, Hz, 1 H, H5_B), 2.77 (ddd, J = 12.4,

8.2, 0.8 Hz, 1 H, H3_B), 2.56 (d, J = 16.6 Hz, 1 H, H5_A), 1.82 (ddd,

J = 12.4, 8.0, 2.4 Hz, 1 H, H3_A).

¹³C NMR: δ = 145.9 (C9a), 136.5 (C1′), 134.8 (=CH styryl), 130.0

(C6), 128.6 (C3′/C5′), 127.9 (C4′), 126.5 (C2′/C6′), 126.2 (C8),

125.8 (C7), 125.8 (C5a), 125.3 (CH= styryl), 124.2 (C9), 76.0 (C4),

73.6 (C2), 40.1 (C3), 35.7 (C5).

GC-MS (EI, 70 eV): m/z (%) = 263 (M^+•, 45), 246 (49), 233 (11),

130 (75), 129 (55), 128 (33), 105 (62), 104 (100).

GC-MS (EI, 70 eV): m/z (%) = 297 (M^+•, ³⁵Cl, 75), 296 (7), 280

(36), 267 (11), 164 (32), 139 (71), 138 (100), 130 (96), 129 (77),

128 (41), 112 (25).

HRMS: m/z [M]⁺calcd for C₁₈H₁₆ClNO: 297.0920; found:

297.0929.

(2SR,4RS)-7-Fluoro-2-[(E)-styryl]-2,3,4,5-tetrahydro-1,4-ep-

oxy-1-benzazepine (8b)

White crystals; yield: 0.55 g (52%); mp 146 °C (heptane); R_f= 0.44

(7% EtOAc–heptane).

IR (KBr): 1244 (C–N), 1132 (C–O), 985 (N–O), 970 cm^–1(C=C

E-styryl).

¹H NMR: δ = 7.43–7.40 (m, 2 H, H2′/H6′), 7.34–7.30 (m, 2 H,

H3′/H5′), 7.25–7.21 (m, 1 H, H4′), 7.06 (dd, J = 8.6, 5.2 Hz, 1 H,

H9), 6.88 (dd, J = 8.5, 2.8 Hz, 1 H, H6), 6.83 (td, J = 8.6, 2.8 Hz, 1

H, H8), 6.56 (d, J = 16.0 Hz, 1 H, =CH styryl), 6.35 (dd, J = 16.0,

7.6 Hz, 1 H, CH= styryl), 4.91 (ddd, J = 7.2, 5.2, 2.2 Hz, 1 H, H4),

4.15 (td, J = 7.6, 3.0 Hz, 1 H, H2), 3.37 (dd, J = 16.8, 5.2 Hz, 1 H,

H5_B), 2.49 (d, J = 16.8 Hz, 1 H, H5_A), 2.42–2.34 (m, 2 H, H3_AH_B).

¹³C NMR: δ = 160.6 (d, J = 242.7 Hz, C7), 145.9 (C9a), 136.7

(C1′), 131.1 (CH= styryl), 129.9 (=CH styryl), 128.5 (C3′/C5′),

127.5 (C4′), 127.2 (d, J = 8.1 Hz, C5a), 126.4 (C2′/C6′), 123.4 (d,

J = 8.4 Hz, C9), 116.2 (d, J = 22.3 Hz, C6), 113.5 (d, J = 22.4 Hz,

C8), 74.5 (C2), 74.2 (C4), 40.7 (C3), 34.8 (d, J = 1.3 Hz, C5).

(2RS,4RS)-7-Chloro-2-[(E)-styryl]-2,3,4,5-tetrahydro-1,4-ep-

oxy-1-benzazepine (9c)

White crystals; yield: 0.26 g (25%); mp 130 °C (heptane); R_f= 0.33

(7% EtOAc–heptane).

IR (KBr): 1253 (C–N), 1179 (C–O), 980 (N–O), 964 cm^–1(C=C

E-styryl).

¹H NMR: δ = 7.32–7.24 (m, 5 H, H2′/H6′, H3′/H5′, H4′), 7.15 (d,

J = 2.2 Hz, 1 H, H6), 7.09 (dd, J = 8.4, 2.2 Hz, 1 H, H8), 6.84 (d,

J = 8.4 Hz, 1 H, H9), 6.68 (d, J = 15.8 Hz, 1 H, =CH styryl), 5.51

(dd, J = 15.8, 8.8 Hz, 1 H, CH= styryl), 4.92 (ddd, J = 7.8, 5.2, 2.2

Hz, 1 H, H4), 4.38 (q, J = 8.4 Hz, 1 H, H2), 3.41 (dd, J = 16.6, 5.2

Hz, 1 H, H5_B), 2.76 (dt, J = 12.3, 8.4 Hz, 1 H, H3_B), 2.53 (br d,

J = 16.6 Hz, 1 H, H5_A), 1.79 (ddd, J = 12.3, 8.1, 2.2 Hz, 1 H, H3_A).

Synthesis 2012, 44, 3765–3782

3776

L. M. Acosta Quintero et al.

PAPER

¹³C NMR: δ = 144.4 (C9a), 136.2 (C1′), 135.3 (=CH styryl), 131.3

(C7), 129.8 (C6), 128.6 (C3′/C5′), 128.0 (C4′), 127.7 (C5a), 126.5

(C2′/C6′), 125.9 (C8), 125.4 (CH= styryl), 124.6 (C9), 75.4 (C4),

73.3 (C2), 39.9 (C3), 35.5 (C5).

GC-MS (EI, 70 eV): m/z (%) = 297 (M^+•, ³⁵Cl, 67), 296 (76), 280

(36), 267 (11), 164 (27), 139 (72), 138 (100), 130 (95), 129 (76),

128 (44), 112 (23).

Hz, 1 H, CH= styryl), 4.97 (ddd, J = 7.2, 5.2, 2.0 Hz, 1 H, H4), 4.19

(td, J = 7.6, 2.8 Hz, 1 H, H2), 3.15 (dd, J = 16.8, 5.2 Hz, 1 H, H5_B),

2.40 (dddd, J = 12.4, 7.2, 2.8, 1.0 Hz, 1 H, H3_B), 2.35 (ddd, J = 12.4,

7.6, 2.0 Hz, 1 H, H3_A), 2.31 (d, J = 16.4 Hz, 1 H, H5_A), 2.30 (s, 3 H,

8-CH₃), 2.17 (s, 3 H, 6-CH₃).

¹³C NMR: δ = 150.0 (C9a), 137.6 (C6), 137.0 (C1′), 136.2 (C8),

131.8 (CH= styryl), 129.8 (=CH styryl), 128.6 (C3′/C5′), 128.3

(C7), 127.6 (C4′), 126.6 (C2′/C6′), 120.4 (C5a), 120.2 (C9), 75.0

(C4), 74.6 (C2), 41.4 (C3), 33.1 (C5), 21.1 (8-CH₃), 18.5 (6-CH₃).

HRMS: m/z [M]⁺calcd for C₁₈H₁₆ClNO: 297.0920; found:

297.0920.

GC-MS (EI, 70 eV): m/z (%) = 291 (M^+·, 39), 172 (80), 158 (100),

145 (38), 91 (41).

HRMS: m/z [M]⁺calcd for C₂₀H₂₁NO: 291.1623; found: 291.1622.

(2SR,4RS)-8-Chloro-9-methyl-2-[(E)-styryl]-2,3,4,5-tetra-

hydro-1,4-epoxy-1-benzazepine (8d)

White crystals; yield: 0.48 g (46%); mp 161 °C (heptane); R_f= 0.47

(7% EtOAc–heptane).

IR (KBr): 1275 (C–N), 1074 (C–O), 983 (N–O), 977 cm^–1(CH=CH

E-styryl).

¹H NMR: δ = 7.44–7.41 (m, 2 H, H2′/H6′), 7.35–7.31 (m, 2 H,

H3′/H5′), 7.27–7.22 (m, 1 H, H4′), 7.13 (d, J = 8.2 Hz, 1 H, H7),

6.88 (d, J = 8.2 Hz, 1 H, H6), 6.60 (d, J = 16.0 Hz, 1 H, =CH styryl),

6.36 (dd, J = 16.0, 7.6 Hz, 1 H, CH= styryl), 4.92 (ddd, J = 7.6, 5.2,

2.0 Hz, 1 H, H4), 4.08 (td, J = 7.8, 2.4 Hz, 1 H, H2), 3.35 (dd,

J = 16.8, 5.2 Hz, 1 H, H5_B), 2.45 (d, J = 16.8 Hz, 1 H, H5_A), 2.41

(dddd, J = 12.6, 7.6, 2.4, 1.0 Hz, 1 H, H3_B), 2.39 (s, 3 H, 9-CH₃),

2.33 (ddd, J = 12.6, 8.0, 2.0 Hz, 1 H, H3_A).

¹³C NMR: δ = 149.5 (C9a), 136.7 (C1′), 132.4 (C8), 130.9 (CH=

styryl), 129.8 (=CH styryl), 129.0 (C9), 128.6 (C3′/C5′), 127.8

(C6), 127.5 (C4′), 126.5 (C2′/C6′), 126.0 (C7), 123.4 (C5a), 74.7

(C4), 72.9 (C2), 40.8 (C3), 34.5 (C5), 13.8 (9-CH₃).

(2RS,4RS)-6,8-Dimethyl-2-[(E)-styryl]-2,3,4,5-tetrahydro-1,4-

epoxy-1-benzazepines (9e)

White crystals; yield: 0.19 g (18%); mp 136 °C (heptane); R_f= 0.29

(7% EtOAc–heptane).

IR (KBr): 1267 (C–N), 1050 (C–O), 978 (N–O), 988 cm^–1(CH=CH

E-styryl).

¹H NMR: δ = 7.31–7.21 (m, 5 H, H2′/H6′, H3′/H5′, H4′), 6.86 (s, 1

H, H9), 6.66 (d, J = 16.0 Hz, 1 H, =CH styryl), 6.60 (s, 1 H, H7),

5.57 (dd, J = 16.0, 8.8 Hz, 1 H, CH= styryl), 4.97 (ddd, J = 7.8, 5.2,

2.2 Hz, 1 H, H4), 4.37 (q, J = 8.4 Hz, 1 H, H2), 3.19 (dd, J = 16.4,

5.2 Hz, 1 H, H5_B), 2.74 (dtd, J = 12.0, 8.2, 0.8 Hz, 1 H, H3_B), 2.36

(d, J = 16.4 Hz, 1 H, H5_A), 2.30 (s, 3 H, 8-CH₃), 2.17 (s, 3 H, 6-

CH₃), 1.76 (ddd, J = 12.0, 8.0, 2.2 Hz, 1 H, H3_A).

¹³C NMR: δ = 145.6 (C9a), 137.5 (C6), 136.7 (C1′), 135.2 (C8),

134.5 (=CH styryl), 128.6 (C3′/C5′), 128.4 (C7), 127.8 (C4′), 126.5

(C2′/C6′), 125.9 (CH= styryl), 122.3 (C9), 121.0 (C5a), 76.0 (C4),

73.3 (C2), 40.6 (C3), 34.1 (C5), 21.0 (8-CH₃), 18.5 (6-CH₃).

GC-MS (EI, 70 eV): m/z (%) = 311 (M^+•, ³⁵Cl, 23), 294 (18), 281

(16), 178 (24), 153 (72), 152 (48), 130 (100), 129 (73), 128 (45).

HRMS: m/z [M]⁺calcd for C₁₉H₁₈ClNO: 311.1077; found:

311.1076.

GC-MS (EI, 70 eV): m/z (%) = 291 (M^+·, 3), 272 (100), 129 (16),

128 (36), 115 (15).

HRMS: m/z [M]⁺calcd for C₂₀H₂₁NO: 291.1623; found: 291.1623.

(2RS,4RS)-8-Chloro-9-methyl-2-[(E)-styryl)-2,3,4,5-tetra-

hydro-1,4-epoxy-1-benzazepine (9d)

White crystals; yield: 0.20 g (19%); mp 142 °C (heptane); R_f= 0.32

(7% EtOAc–heptane).

(2SR,4RS)-7-Fluoro-2-[(E)-pent-1-enyl)-2,3,4,5-tetrahydro-1,4-

epoxy-1-benzazepine (10a)

Viscous maroon oil; yield: 0.32 g (30%); R_f= 0.35 (7% EtOAc–

heptane).

IR (KBr): 1268 (C–N), 1056 (C–O), 990 (N–O), 968 cm^–1(CH=CH

E-styryl).

IR (liquid film): 1271 (C–N), 1035 (C–O), 990 (N–O), 970 cm^–1

¹H NMR: δ = 7.31–7.28 (m, 2 H, H3′/H5′), 7.27–7.23 (m, 1 H, H4′),

7.22–7.19 (m, 2 H, H2′/H6′), 7.18 (d, J = 8.0 Hz, 1 H, H7), 6.93 (d,

J = 8.0 Hz, 1 H, H6), 6.70 (d, J = 15.6 Hz, 1 H, =CH styryl), 5.46

(dd, J = 15.6, 9.2 Hz, 1 H, CH= styryl), 4.87 (ddd, J = 8.0, 5.2, 2.0

Hz, 1 H, H4), 4.41 (q, J = 8.4 Hz, 1 H, H2), 3.38 (dd, J = 16.8, 5.2

Hz, 1 H, H5_B), 2.75 (dtd, J = 12.4, 8.4, 0.8 Hz, 1 H, H3_B), 2.53 (d,

J = 16.8 Hz, 1 H, H5_A), 2.25 (s, 3 H, 9-CH₃), 1.78 (ddd, J = 12.4,

8.0, 2.0 Hz, 1 H, H3_A).

¹³C NMR: δ = 145.7 (C9a), 136.3 (C1′), 135.4 (=CH styryl), 132.5

(C8), 131.0 (C9), 128.7 (C3′/C5′), 128.1 (C6), 128.0 (C7), 126.5

(C4′), 126.4 (C2′/C6′), 124.6 (CH= styryl), 124.4 (C5a), 75.2 (C4),

73.6 (C2), 41.1 (C3), 35.6 (C5), 15.0 (9-CH₃).

(CH=CH E-pentenyl).

¹H NMR: δ = 7.01 (dd, J = 8.6, 5.4 Hz, 1 H, H9), 6.83 (td, J = 8.8,

2.8 Hz, 1 H, H8), 6.78 (dd, J = 9.2, 2.8 Hz, 1 H, H6), 5.63 (dd,

J = 15.2, 6.4 Hz, 1 H, CH= pentenyl), 5.58 (dd, J = 15.2, 5.6 Hz, 1

H, =CH pentenyl), 4.83 (ddd, J = 7.6, 5.4, 2.4 Hz, 1 H, H4), 3.92 (td,

J = 6.4, 2.8 Hz, 1 H, H2), 3.32 (dd, J = 16.8, 5.4 Hz, 1 H, H5_B), 2.44

(d, J = 16.8 Hz, 1 H, H5_A), 2.29 (dddd, J = 12.4, 7.6, 2.8, 1.0 Hz, 1

H, H3_B), 2.24 (ddd, J = 12.4, 7.6, 2.4 Hz, 1 H, H3_A), 2.06–1.99 (m,

2 H, 3′-CH₂), 1.42 (dtd, J = 15.0, 7.2, 1.6 Hz, 2 H, 4′-CH₂), 0.91 (t,

J = 7.2 Hz, 3 H, 5′-CH₃).

¹³C NMR: δ = 160.5 (d, J = 242.4 Hz, C7), 146.2 (d, J = 2.3 Hz,

C9a), 131.8 (CH= pentenyl), 131.3 (=CH pentenyl), 127.2 (d,

J = 8.2 Hz, C5a), 123.4 (d, J = 8.4 Hz, C9), 116.1 (d, J = 22.2 Hz,

C6), 113.4 (d, J = 22.3 Hz, C8), 74.6 (C4), 74.2 (C2), 40.5 (C3),

34.9 (C5), 34.3 (3′-CH₂), 22.2 (4′-CH₂), 13.8 (5′-CH₃).

GC-MS (EI, 70 eV): m/z (%) = 311 (M^+•, ³⁵Cl, 21), 294 (20), 281

(18), 178 (12), 153 (69), 152 (42), 130 (100), 129 (74), 128 (54).

HRMS: m/z [M]⁺calcd for C₁₉H₁₈ClNO: 311.1077; found:

311.1072.

GC-MS (EI, 70 eV): m/z (%) = 247 (M^+•, 15), 230 (9), 217 (1), 148

(24), 123 (49), 122 (100).

HRMS: m/z [M]⁺calcd for C₁₅H₁₈FNO: 247.1372; found: 247.1376.

(2SR,4RS)-6,8-Dimethyl-2-[(E)-styryl]-2,3,4,5-tetrahydro-1,4-

epoxy-1-benzazepine (8e)

White crystals; yield: 0.47 g (45%); mp 123 °C (heptane); R_f= 0.37

(7% EtOAc–heptane).

IR (KBr): 1263 (C–N), 1070 (C–O), 1000 (N–O), 966 cm^–1

(2RS,4RS)-7-Fluoro-2-[(E)-pent-1-enyl)-2,3,4,5-tetrahydro-1,4-

epoxy-1-benzazepine (11a)

Viscous maroon oil; yield: 0.11 g (10%); R_f= 0.26 (7% EtOAc–

heptane).

(CH=CH E-styryl).

¹H NMR: δ = 7.43–7.41 (m, 2 H, H2′/H6′), 7.34–7.30 (m, 2 H,

H3′/H5′), 7.25–7.21 (m, 1 H, H4′), 6.84 (s, 1 H, H7), 6.79 (s, 1 H,

H9), 6.56 (d, J = 16.0 Hz, 1 H, =CH styryl), 6.38 (dd, J = 16.0, 7.6

IR (liquid film): 1250 (C–N), 1049 (C–O), 969 (N–O), 942 cm^–1

(CH=CH E-pentenyl).

Synthesis 2012, 44, 3765–3782

PAPER

Synthesis of 2-Alkenyltetrahydro-1-benzazepines

3777

¹H NMR: δ = 6.85–6.78 (m, 3 H, H6, H8, H9), 5.75 (dtd, J = 15.2,

7.0, 0.6 Hz, 1 H, =CH pentenyl), 4.84 (ddd, J = 8.0, 5.2, 2.0 Hz, 1

H, H4), 4.79 (ddt, J = 15.2, 8.4, 1.2 Hz, 1 H, CH= pentenyl), 4.17

(q, J = 8.4 Hz, 1 H, H2), 3.36 (dd, J = 16.4, 5.2 Hz, 1 H, H5_B), 2.64

(dtd, J = 12.4, 8.4, 0.8 Hz, 1 H, H3_B), 2.46 (br d, J = 16.4 Hz, 1 H,

H5_A), 1.92 (ddd, J = 14.8, 8.2, 1.4 Hz, 2 H, 3′-CH₂), 1.63 (ddd,

J = 12.4, 8.0, 2.0 Hz, 1 H, H3_A), 1.32 (dt, J = 14.8, 7.4 Hz, 2 H, 4′-

CH₂), 0.84 (t, J = 7.4 Hz, 3 H, 5′-CH₃).

¹³C NMR: δ = 160.7 (d, J = 242.4 Hz, C7), 141.7 (d, J = 2.7 Hz,

C9a), 137.0 (=CH pentenyl), 127.7 (d, J = 8.1 Hz, C5a), 125.8 (d,

J = 8.4 Hz, C9), 125.5 (CH= pentenyl), 116.2 (d, J = 22.2 Hz, C6),

112.5 (d, J = 22.3 Hz, C8), 75.2 (C4), 73.2 (C2), 39.7 (C3), 35.9 (d,

J = 1.2 Hz, C5), 34.5 (3′-CH₂), 22.1 (4′-CH₂), 13.6 (5′-CH₃).

mixture was stirred at 0 °C for an additional 0.5–2 h (TLC monitor-

ing). Solid was removed from the mixture by filtration and the fil-

trate was neutralized with 25% aq NH₄OH to pH 8, extracted with

EtOAc (3 × 50 mL), and dried (anhyd Na₂SO₄) and the solvent was

removed under reduced pressure. The crude product was purified by

column chromatography (silica gel, heptane–EtOAc, 10:1 to 1:1) to

give 12, 14, 16 and 13, 15, 17.

cis-2-(2-Methylprop-1-enyl)-2,3,4,5-tetrahydro-1H-1-benzaze-

pin-4-ol (12a)

White crystals; yield: 0.97 g (96%); mp 86 °C (heptane); R_f= 0.31

(33% EtOAc–heptane).

IR (KBr): 3347 cm^–1(N–H, O–H).

¹H NMR: δ = 7.13 (dd, J = 7.6, 1.2 Hz, 1 H, H6), 7.08 (td, J = 7.6,

1.2 Hz, 1 H, H8), 6.88 (td, J = 7.6, 1.2 Hz, 1 H, H7), 6.71 (dd,

J = 7.8, 1.2 Hz, 1 H, H9), 5.31 (ddt, J = 8.4, 2.8, 1.4 Hz, 1 H, CH=

prenyl), 3.80 (tt, J = 9.8, 3.6 Hz, 1 H, H4_ax), 3.61 (ddd, J = 11.2, 8.4,

2.0 Hz, 1 H, H2_ax), 3.31 (br s, 1 H, NH), 3.00 (dd, J = 13.6, 9.8 Hz,

1 H, H5_ax), 2.94 (dt, J = 13.6, 2.0 Hz, 1 H, H5_eq), 2.12 (br s, 1 H,

OH), 2.03 (ddt, J = 12.8, 3.6, 2.0 Hz, 1 H, H3_eq), 1.77 (ddd, J = 12.8,

11.2, 10.0 Hz, 1 H, H3_ax), 1.74 (d, J = 1.3 Hz, 3 H, CH_3(A)), 1.66 (d,

J = 1.3 Hz, 3 H, CH_3(B)).

¹³C NMR: δ = 149.4 (C9a), 134.6 (=C prenyl), 131.7 (C6), 128.3

(C5a), 128.0 (CH= prenyl), 127.5 (C8), 121.7 (C7), 120.1 (C9),

70.0 (C4), 54.5 (C2), 46.8 (C3), 44.6 (C5), 25.7 (CH_3(A)), 18.5

(CH_3(B)).

GC-MS (EI, 70 eV): m/z (%) = 247 (M^+•, 27), 230 (15), 217 (1), 148

(22), 123 (61), 122 (100).

HRMS: m/z [M]⁺calcd for C₁₅H₁₈FNO: 247.1372; found: 247.1375.

(2SR,4RS)-8-Chloro-9-methyl-2-[(E)-pent-1-enyl]-2,3,4,5-tetra-

hydro-1,4-epoxy-1-benzazepine (10b)

Viscous maroon oil; yield: 0.29 g (28%); R_f= 0.38 (7% EtOAc–

heptane).

IR (liquid film): 1255 (C–N), 1053 (C–O), 972 (N–O), 945 cm^–1

(CH=CH E-pentenyl).

¹H NMR: δ = 7.09 (d, J = 8.0 Hz, 1 H, H7), 6.85 (d, J = 8.0 Hz, 1 H,

H6), 5.62 (dd, J = 15.2, 6.4 Hz, 1 H, CH= pentenyl), 5.60 (dd,

J = 15.2, 5.4 Hz, 1 H, =CH pentenyl), 4.85 (ddd, J = 7.6, 5.6, 2.0

Hz, 1 H, H4), 3.85 (td, J = 6.4, 2.8 Hz, 1 H, H2), 3.30 (dd, J = 16.8,

5.6 Hz, 1 H, H5_B), 2.39 (d, J = 16.8 Hz, 1 H, H5_A), 2.35 (s, 3 H, 9-

CH₃), 2.28 (dddd, J = 12.6, 7.6, 2.8, 1.0 Hz, 1 H, H3_B), 2.20 (ddd,

J = 12.6, 7.8, 2.0 Hz, 1 H, H3_A), 2.06–2.00 (m, 2 H, 3′-CH₂), 1.45–

1.40 (m, 2 H, 4′-CH₂), 0.91 (t, J = 7.4 Hz, 3 H, 5′-CH₃).

¹³C NMR: δ = 149.7 (C9a), 132.3 (C8), 131.5 (CH= pentenyl),

131.3 (=CH pentenyl), 128.9 (C9), 127.2 (C6), 125.8 (C7), 123.4

(C5a), 74.6 (C4), 73.2 (C2), 40.5 (C3), 34.4 (C5), 34.2 (3′-CH₂),

22.3 (4′-CH₂), 13.8 (9-CH₃), 13.7 (5′-CH₃).

GC-MS (EI, 70 eV): m/z (%) = 217 (M^+•, 74), 173 (21), 172 (42),

162 (2), 158 (100), 144 (15), 130 (43), 118 (42), 111 (18), 107 (53),

106 (78).

HRMS: m/z [M]⁺calcd for C₁₄H₁₉NO: 217.1467; found: 217.1466.

cis-7-Fluoro-2-(2-methylprop-1-enyl)-2,3,4,5-tetrahydro-1H-1-

benzazepin-4-ol (12b)

White crystals; yield: 0.95 g (94%); mp 71 °C (heptane); R_f= 0.38

(33% EtOAc–heptane).

IR (KBr): 3347 cm^–1(N–H, O–H).

GC-MS (EI, 70 eV): m/z (%) = 277 (M^+•, ³⁵Cl, 33), 260 (21), 247

(1), 178 (9), 153 (100), 152 (50).

¹H NMR: δ = 6.83 (dd, J = 9.2, 2.8 Hz, 1 H, H6), 6.74 (td, J = 8.4,

2.8 Hz, 1 H, H8), 6.63 (dd, J = 8.4, 5.2 Hz, 1 H, H9), 5.27 (ddt,

J = 8.4, 2.8, 1.4 Hz, 1 H, CH= prenyl), 3.74 (tdd, J = 10.0, 3.6, 2.4

Hz, 1 H, H4_ax), 3.52 (ddd, J = 11.2, 8.4, 2.0 Hz, 1 H, H2_ax), 3.20 (br

s, 1 H, NH), 2.98 (dd, J = 13.4, 10.0 Hz, 1 H, H5_ax), 2.85 (dt,

J = 13.4, 1.6 Hz, 1 H, H5_eq), 2.23 (br s, 1 H, OH), 2.00 (ddt,

J = 12.8, 3.6, 2.0 Hz, 1 H, H3_eq), 1.75 (ddd, J = 12.8, 11.2, 10.0 Hz,

1 H, H3_ax), 1.73 (d, J = 1.3 Hz, 3 H, CH_3(A)), 1.65 (d, J = 1.3 Hz, 3

H, CH_3(B)).

¹³C NMR: δ = 157.6 (d, J = 237.9 Hz, C7), 145.5 (d, J = 2.3 Hz,

C9a), 134.7 (=C prenyl), 130.3 (d, J = 7.4 Hz, C5a), 127.8 (CH=

prenyl), 121.0 (d, J = 8.0 Hz, C9), 117.9 (d, J = 21.9 Hz, C6), 113.6

(d, J = 22.0 Hz, C8), 69.8 (C4), 54.8 (C2), 46.8 (C3), 44.3 (d,

J = 0.6 Hz, C5), 25.7 (CH_3(A)), 18.5 (CH_3(B)).

(2RS,4RS)-8-Chloro-9-methyl-2-[(E)-pent-1-enyl]-2,3,4,5-tetra-

hydro-1,4-epoxy-1-benzazepine (11b)

Viscous maroon oil; yield: 0.14 g (13%); R_f= 0.33 (7% EtOAc–

heptane).

IR (liquid film): 1269 (C–N), 1045 (C–O), 979 (N–O), 946 cm^–1

(CH=CH E-pentenyl).

¹H NMR: δ = 7.13 (d, J = 8.0 Hz, 1 H, H7), 6.88 (d, J = 8.0 Hz, 1 H,

H6), 5.79 (dt, J = 15.2, 6.8 Hz, 1 H, =CH pentenyl), 4.80 (ddd,

J = 8.0, 5.2, 2.0 Hz, 1 H, H4), 4.78 (ddt, J = 15.2, 8.6, 1.2 Hz, 1 H,

CH= pentenyl), 4.21 (q, J = 8.4 Hz, 1 H, H2), 3.32 (dd, J = 16.8, 5.2

Hz, 1 H, H5_B), 2.64 (dtd, J = 12.4, 8.2, 1.0 Hz, 1 H, H3_B), 2.46 (d,

J = 16.8 Hz, 1 H, H5_A), 2.26 (s, 3 H, 9-CH₃), 1.98–1.82 (m, 2 H, 3′-

CH₂), 1.65 (ddd, J = 12.4, 8.0, 2.0 Hz, 1 H, H3_A), 1.36–1.26 (m, 2

H, 4′-CH₂), 0.84 (t, J = 7.4 Hz, 3 H, 5′-CH₃).

¹³C NMR: δ = 145.8 (C9a), 137.2 (=CH pentenyl), 132.3 (C8),

131.1 (C9), 127.8 (C6), 126.3 (C7), 125.0 (CH= pentenyl), 124.4

(C5a), 74.9 (C4), 73.6 (C2), 40.9 (C3), 35.6 (C5), 34.4 (3′-CH₂),

22.1 (4′-CH₂), 15.3 (9-CH₃), 13.7 (5′-CH₃).

GC-MS (EI, 70 eV): m/z (%) = 235 (M^+•, 67), 191 (27), 190 (36),

180 (2), 176 (100), 162 (3), 148 (45), 136 (48), 125 (64), 124 (80),

111 (47).

HRMS: m/z [M]⁺calcd for C₁₄H₁₈FNO: 235.1372; found: 235.1372.

cis-7-Chloro-2-(2-methylprop-1-enyl)-2,3,4,5-tetrahydro-1H-1-

benzazepin-4-ol (12c)

White crystals; yield: 0.95 g (94%); mp 95 °C (heptane); R_f= 0.41

(33% EtOAc–heptane).

GC-MS (EI, 70 eV): m/z (%) = 277 (M^+•, ³⁵Cl, 30), 260 (21), 247

(1), 178 (15), 153 (100), 152 (54).

IR (KBr): 3355 cm^–1(N–H, O–H).

cis- and trans-2-Alkenyl-4-hydroxy-2,3,4,5-tetrahydro-1H-1-

benzazepines 12a–e, 13a–e, 14a–e, 15a–e, 16a,b, and 17a,b; Gen-

eral Procedure

Zn powder (6.54 g, 100 mmol), glacial AcOH (4 mL, 70 mmol), and

37% HCl soln (6.81 mL, 70 mmol) were added to a stirred and

cooled (ice bath) soln of 2-exo- and 2-endo-1,4-epoxy cycloadducts

6, 8, 10 and 7, 9, 11 (10 mmol) in MeOH (25 mL). The resulting

¹H NMR: δ = 7.10 (d, J = 2.4 Hz, 1 H, H6), 7.01 (dd, J = 8.2, 2.4

Hz, 1 H, H8), 6.62 (d, J = 8.2 Hz, 1 H, H9), 5.28 (ddt, J = 8.8, 2.6,

1.4 Hz, 1 H, CH= prenyl), 3.77 (tt, J = 9.6, 3.6 Hz, 1 H, H4_ax), 3.57

(ddd, J = 11.2, 8.8, 2.0 Hz, 1 H, H2_ax), 3.29 (br s, 1 H, NH), 2.95

(dd, J = 13.6, 9.6 Hz, 1 H, H5_ax), 2.88 (dt, J = 13.6, 2.0 Hz, 1 H,

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L. M. Acosta Quintero et al.

PAPER

H5_eq), 2.01 (ddt, J = 12.8, 3.6, 2.0 Hz, 1 H, H3_eq), 1.76 (ddd,

J = 12.8, 11.2, 10.0 Hz, 1 H, H3_ax), 1.74 (d, J = 1.4 Hz, 3 H, CH_3(A)),

1.66 (d, J = 1.4 Hz, 3 H, CH_3(B)).

¹³C NMR: δ = 147.9 (C9a), 134.8 (=C prenyl), 131.1 (C6), 129.8

(C5a), 127.6 (CH= prenyl), 127.1 (C8), 126.1 (C7), 121.1 (C9),

69.6 (C4), 54.4 (C2), 46.4 (C3), 44.0 (C5), 25.6 (CH_3(A)), 18.4

(CH_3(B)).

GC-MS (EI, 70 eV): m/z (%) = 251 (M^+•, ³⁵Cl, 72), 207 (27), 206

(36), 196 (3), 192 (97), 178 (6), 164 (42), 152 (39), 141 (84), 140

(98), 111 (100).

¹H NMR: δ = 7.11 (dd, J = 7.6, 1.4 Hz, 1 H, H6), 7.09 (td, J = 7.6,

1.4 Hz, 1 H, H8), 6.88 (td, J = 7.6, 1.0 Hz, 1 H, H7), 6.75 (dd,

J = 7.8, 1.0 Hz, 1 H, H9), 5.27 (ddt, J = 8.4, 2.8, 1.4 Hz, 1 H, CH=

prenyl), 4.23–4.18 (m, 1 H, H4_eq), 3.84 (ddd, J = 10.8, 8.4, 2.4 Hz,

1 H, H2_ax), 3.38 (br s, 1 H, NH), 3.06 (dd, J = 14.0, 2.4 Hz, 1 H,

H5_eq), 3.02 (dd, J = 14.0, 6.0 Hz, 1 H, H5_ax), 1.91 (ddt, J = 14.0, 3.6,

2.4 Hz, 1 H, H3_eq), 1.81 (ddd, J = 14.0, 10.8, 2.8 Hz, 1 H, H3_ax),

1.74 (d, J = 1.0 Hz, 3 H, CH_3(A)), 1.68 (d, J = 1.2 Hz, 3 H, CH_3(B)),

1.52 (br s, 1 H, OH).

¹³C NMR: δ = 149.0 (C9a), 134.3 (=C prenyl), 132.6 (C6), 127.8

(CH= prenyl), 127.8 (C8), 127.0 (C5a), 121.5 (C7), 120.0 (C9),

65.8 (C4), 50.3 (C2), 44.5 (C3), 41.7 (C5), 25.6 (CH_3(A)), 18.4

(CH_3(B)).

HRMS: m/z [M]⁺calcd for C₁₄H₁₈ClNO: 251.1077; found:

251.1075.

GC-MS (EI, 70 eV): m/z (%) = 217 (M^+•, 75), 173 (24), 172 (42),

162 (2), 158 (100), 144 (17), 130 (44), 118 (42), 111 (18), 107 (54),

106 (81).

cis-8-Chloro-9-methyl-2-(2-methylprop-1-enyl)-2,3,4,5-tetra-

hydro-1H-1-benzazepin-4-ol (12d)

White crystals; yield: 0.97 g (96%); mp 105 °C (heptane); R_f= 0.45

(33% EtOAc–heptane).

HRMS: m/z [M]⁺calcd for C₁₄H₁₉NO: 217.1467; found: 217.1495.

IR (KBr): 3405 cm^–1(N–H, O–H).

trans-7-Fluoro-2-(2-methylprop-1-enyl)-2,3,4,5-tetrahydro-1H-

1-benzazepin-4-ol (13b)

White crystals; yield: 0.93 g (92%); mp 75 °C (heptane); R_f= 0.39

(33% EtOAc–heptane).

¹H NMR: δ = 6.92 (d, J = 8.4 Hz, 1 H, H6), 6.89 (d, J = 8.4 Hz, 1 H,

H7), 5.33 (ddt, J = 8.8, 2.8, 1.4 Hz, 1 H, CH= prenyl), 3.81–3.74 (m,

1 H, H4_ax), 3.55 (ddd, J = 11.2, 8.8, 2.2 Hz, 1 H, H2_ax), 3.43 (br s, 1

H, NH), 2.95 (dd, J = 13.6, 7.6 Hz, 1 H, H5_ax), 2.91 (dd, J = 13.6,

1.2 Hz, 1 H, H5_eq), 2.24 (s, 3 H, 9-CH₃), 2.01 (ddt, J = 12.8, 3.6, 2.2

Hz, 1 H, H3_eq), 1.88 (br s, 1 H, OH), 1.77 (d, J = 1.4 Hz, 3 H,

CH_3(A)), 1.74 (ddd, J = 12.8, 11.2, 9.6 Hz, 1 H, H3_ax), 1.67 (d,

J = 1.4 Hz, 3 H, CH_3(B)).

¹³C NMR: δ = 148.8 (C9a), 134.7 (=C prenyl), 132.8 (C8), 129.5

(C6), 127.6 (CH= prenyl), 127.0 (C5a), 124.2 (C9), 121.8 (C7),

69.7 (C4), 54.0 (C2), 46.3 (C3), 44.1 (C5), 25.7 (CH_3(A)), 18.4

(CH_3(B)), 14.3 (9-CH₃).

GC-MS (EI, 70 eV): m/z (%) = 265 (M^+•, ³⁵Cl, 50), 221 (15), 220

(24), 210 (4), 206 (57), 192 (6), 178 (30), 166 (30), 155 (58), 154

(100), 111 (45).

HRMS: m/z [M]⁺calcd for C₁₅H₂₀ClNO: 265.1233; found:

265.1231.

IR (KBr): 3344 cm^–1(N–H, O–H).

¹H NMR: δ = 6.85 (dd, J = 9.2, 2.8 Hz, 1 H, H6), 6.78 (td, J = 8.4,

2.8 Hz, 1 H, H8), 6.68 (dd, J = 8.4, 5.0 Hz, 1 H, H9), 5.24 (ddt,

J = 8.8, 2.8, 1.4 Hz, 1 H, CH= prenyl), 4.23–4.19 (m, 1 H, H4_eq),

3.78 (ddd, J = 10.8, 8.8, 2.4 Hz, 1 H, H2_ax), 3.28 (br s, 1 H, NH),

3.04 (dd, J = 14.0, 1.2 Hz, 1 H, H5_eq), 2.95 (ddd, J = 14.0, 7.0, 0.8

Hz, 1 H, H5_ax), 1.89 (dddd, J = 14.0, 4.0, 2.4, 1.2 Hz, 1 H, H3_eq),

1.79 (ddd, J = 14.0, 10.8, 2.8 Hz, 1 H, H3_ax), 1.73 (d, J = 0.8 Hz, 3

H, CH_3(A)), 1.67 (d, J = 1.2 Hz, 3 H, CH_3(B)), 1.52 (br s, 1 H, OH).

¹³C NMR: δ = 158.0 (d, J = 239.4 Hz, C7), 145.0 (d, J = 2.3 Hz,

C9a), 134.4 (=C prenyl), 129.5 (d, J = 7.3 Hz, C5a), 127.6 (CH=

prenyl), 120.9 (d, J = 7.9 Hz, C9), 118.8 (d, J = 21.9 Hz, C6), 113.9

(d, J = 21.7 Hz, C8), 65.6 (C4), 50.4 (C2), 44.5 (C3), 41.5 (C5),

25.6 (CH_3(A)), 18.5 (CH_3(B)).

GC-MS (EI, 70 eV): m/z (%) = 235 (M^+•, 72), 191 (21), 190 (39),

180 (2), 176 (100), 162 (3), 148 (45), 136 (42), 125 (70), 124 (83),

111 (51).

cis-6,8-Dimethyl-2-(2-methylprop-1-enyl)-2,3,4,5-tetrahydro-

1H-1-benzazepin-4-ol (12e)

White crystals; yield: 0.95 g (94%); mp 116 °C (heptane); R_f= 0.38

(33% EtOAc–heptane).

HRMS: m/z [M]⁺calcd for C₁₄H₁₈FNO: 235.1372; found: 235.1374.

IR (KBr): 3355 cm^–1(N–H, O–H).

trans-7-Chloro-2-(2-methylprop-1-enyl)-2,3,4,5-tetrahydro-

1H-1-benzazepin-4-ol (13c)

Colorless viscous oil; yield: 0.92 g (91%); R_f= 0.46 (33% EtOAc–

heptane).

¹H NMR: δ = 6.64 (s, 1 H, H7), 6.42 (s, 1 H, H9), 5.29 (ddt, J = 8.8,

2.6, 1.4 Hz, 1 H, CH= prenyl), 3.78 (tdd, J = 9.6, 4.2, 2.0 Hz, 1 H,

H4_ax), 3.63 (ddd, J = 11.2, 8.8, 2.4 Hz, 1 H, H2_ax), 3.16 (br s, 1 H,

NH), 3.09 (dt, J = 14.0, 1.6 Hz, 1 H, H5_eq), 2.84 (dd, J = 14.0, 9.6

Hz, 1 H, H5_ax), 2.31 (s, 3 H, 6-CH₃), 2.22 (s, 3 H, 8-CH₃), 2.18 (br

s, 1 H, OH), 2.01 (dddd, J = 12.8, 4.2, 2.4, 1.4 Hz, 1 H, H3_eq), 1.77

(ddd, J = 12.8, 11.2, 9.6 Hz, 1 H, H3_ax), 1.75 (d, J = 1.2 Hz, 3 H,

CH_3(A)), 1.67 (d, J = 1.2 Hz, 3 H, CH_3(B)).

¹³C NMR: δ = 149.5 (C9a), 137.7 (C6), 136.3 (C8), 134.4 (=C pre-

nyl), 128.1 (CH= prenyl), 124.9 (C7), 124.0 (C5a), 118.9 (C9), 69.7

(C4), 54.7 (C2), 46.2 (C3), 37.9 (C5), 25.6 (CH_3(A)), 20.8 (6-CH₃),

20.8 (8-CH₃), 18.5 (CH_3(B)).

IR (liquid film): 3356 cm^–1(N–H, O–H).

¹H NMR: δ = 7.10 (d, J = 2.4 Hz, 1 H, H6), 7.03 (dd, J = 8.4, 2.4

Hz, 1 H, H8), 6.66 (d, J = 8.4 Hz, 1 H, H9), 5.24 (ddt, J = 8.8, 2.4,

1.2 Hz, 1 H, CH= prenyl), 4.23–4.19 (m, 1 H, H4_eq), 3.84 (ddd,

J = 10.4, 8.8, 2.4 Hz, 1 H, H2_ax), 3.37 (br s, 1 H, NH), 3.00 (dd,

J = 14.0, 2.4 Hz, 1 H, H5_eq), 2.96 (dd, J = 14.0, 6.0 Hz, 1 H, H5_ax),

1.89 (ddt, J = 14.0, 4.0, 2.4 Hz, 1 H, H3_eq), 1.82 (ddd, J = 14.0, 10.4,

2.8 Hz, 1 H, H3_ax), 1.73 (d, J = 0.8 Hz, 3 H, CH_3(A)), 1.67 (d, J = 1.0

Hz, 3 H, CH_3(B)), 1.48 (br s, 1 H, OH).

¹³C NMR: δ = 147.5 (C9a), 134.6 (=C prenyl), 132.0 (C6), 129.1

(C5a), 127.5 (CH= prenyl), 127.4 (C8), 126.1 (C7), 121.0 (C9),

65.6 (C4), 50.2 (C2), 44.3 (C3), 41.5 (C5), 25.6 (CH_3(A)), 18.4

(CH_3(B)).

GC-MS (EI, 70 eV): m/z (%) = 245 (M^+•, 65), 201 (24), 200 (40),

190 (2), 186 (58), 172 (9), 158 (30), 146 (32), 135 (33), 134 (100),

111 (3).

HRMS: m/z [M]⁺calcd for C₁₆H₂₃NO: 245.1780; found: 245.1785.

GC-MS (EI, 70 eV): m/z (%) = 251 (M^+•, ³⁵Cl, 72), 207 (24), 206

(36), 196 (3), 192 (89), 178 (6), 164 (39), 152 (39), 141 (84), 140

(90), 111 (100).

HRMS: m/z [M]⁺calcd for C₁₄H₁₈ClNO: 251.1077; found:

251.1076.

trans-2-(2-Methylprop-1-enyl)-2,3,4,5-tetrahydro-1H-1-ben-

zazepin-4-ol (13a)

Colorless viscous oil; yield: 0.91 g (90%); R_f= 0.39 (33% EtOAc–

heptane).

IR (liquid film): 3348 cm^–1(N–H, O–H).

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Synthesis of 2-Alkenyltetrahydro-1-benzazepines

3779

trans-8-Chloro-9-methyl-2-(2-methylprop-1-enyl)-2,3,4,5-tetra-

hydro-1H-1-benzazepin-4-ol (13d)

Colorless viscous oil; yield: 0.91 g (90%); R_f= 0.50 (33% EtOAc–

heptane).

HRMS: m/z [M]⁺calcd for C₁₈H₁₉NO: 265.1467; found: 265.1470.

cis-7-Fluoro-2-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1-benzaze-

pin-4-ol (14b)

White crystals; yield: 0.94 g (93%); mp 137 °C (heptane); R_f= 0.39

(33% EtOAc–heptane).

IR (liquid film): 3402 cm^–1(N–H, O–H).

¹H NMR: δ = 6.91 (d, J = 8.4 Hz, 1 H, H6), 6.89 (d, J = 8.4 Hz, 1 H,

H7), 5.29 (ddt, J = 8.8, 2.8, 1.4 Hz, 1 H, CH= prenyl), 4.20–4.16 (m,

1 H, H4_eq), 3.84 (td, J = 9.2, 4.2 Hz, 1 H, H2_ax), 3.50 (br s, 1 H, NH),

3.00 (d, J = 14.0 Hz, 1 H, H5_eq), 2.97 (dd, J = 14.0, 4.4 Hz, 1 H,

H5_ax), 2.26 (s, 3 H, 9-CH₃), 1.85 (dt, J = 14.0, 4.0 Hz, 1 H, H3_eq),

1.80 (ddd, J = 14.0, 7.6, 4.4 Hz, 1 H, H3_ax), 1.75 (d, J = 1.2 Hz, 3 H,

CH_3(A)), 1.68 (d, J = 1.2 Hz, 3 H, CH_3(B)), 1.59 (br s, 1 H, OH).

¹³C NMR: δ = 148.4 (C9a), 134.4 (=C prenyl), 133.2 (C8), 130.3

(C6), 127.6 (CH= prenyl), 125.9 (C5a), 124.2 (C9), 121.6 (C7),

65.7 (C4), 50.0 (C2), 44.2 (C3), 41.4 (C5), 25.7 (CH_3(A)), 18.3

(CH_3(B)), 14.4 (9-CH₃).

GC-MS (EI, 70 eV): m/z (%) = 265 (M^+•, ³⁵Cl, 49), 221 (15), 220

(33), 210 (4), 206 (56), 192 (6), 178 (33), 166 (28), 155 (60), 154

(100), 111 (45).

HRMS: m/z [M]⁺calcd for C₁₅H₂₀ClNO: 265.1233; found:

265.1223.

IR (KBr): 3319 (N–H), 3288 cm^–1(O–H).

¹H NMR: δ = 7.41–7.38 (m, 2 H, H2′/H6′), 7.37–7.32 (m, 2 H,

H3′/H5′), 7.27–7.25 (m, 1 H, H4′), 6.87 (dd, J = 9.2, 2.8 Hz, 1 H,

H6), 6.78 (td, J = 8.4, 2.8 Hz, 1 H, H8), 6.69 (dd, J = 8.4, 5.0 Hz, 1

H, H9), 6.61 (d, J = 16.0 Hz, 1 H, =CH styryl), 6.33 (dd, J = 16.0,

8.0 Hz, 1 H, CH= styryl), 3.82 (tdd, J = 10.0, 4.0, 2.4 Hz, 1 H, H4_ax),

3.56 (ddd, J = 11.2, 8.0, 1.6 Hz, 1 H, H2_ax), 3.48 (br s, 1 H, NH),

3.03 (dd, J = 13.6, 10.0 Hz, 1 H, H5_ax), 2.92 (dt, J = 13.6, 2.0 Hz, 1

H, H5_eq), 2.18 (ddt, J = 12.8, 4.0, 2.0 Hz, 1 H, H3_eq), 1.88 (ddd,

J = 12.8, 11.2, 10.0 Hz, 1 H, H3_ax), 1.69 (br s, 1 H, OH).

¹³C NMR: δ = 158.1 (d, J = 238.3 Hz, C7), 144.8 (d, J = 2.4 Hz,

C9a), 136.3 (C1′), 131.5 (CH= styryl), 131.1 (=CH styryl), 130.2 (d,

J = 7.4 Hz, C5a), 128.8 (C3′/C5′), 128.0 (C4′), 126.5 (C2′/C6′),

121.2 (d, J = 7.9 Hz, C9), 117.8 (d, J = 21.9 Hz, C6), 113.7 (d,

J = 21.8 Hz, C8), 69.5 (C4), 59.0 (C2), 46.6 (C3), 44.1 (d, J = 0.4

Hz, C5).

GC-MS (EI, 70 eV): m/z (%) = 283 (M^+•, 62), 159 (48), 130 (33),

125 (64), 124 (100), 117 (21), 115 (48), 91 (69), 77 (33).

HRMS: m/z [M]⁺calcd for C₁₈H₁₈FNO: 283.1372; found: 283.1378.

trans-6,8-Dimethyl-2-(2-methylprop-1-enyl)-2,3,4,5-tetra-

hydro-1H-1-benzazepin-4-ol (13e)

Colorless viscous oil; yield: 0.93 g (92%); R_f= 0.44 (33% EtOAc–

heptane).

cis-7-Chloro-2-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1-benzaze-

pin-4-ol (14c)

White crystals; yield: 0.96 g (95%); mp 123 °C (heptane); R_f= 0.43

(33% EtOAc–heptane).

IR (liquid film): 3354 cm^–1(N–H, O–H).

¹H NMR: δ = 6.63 (s, 1 H, H7), 6.44 (s, 1 H, H9), 5.26 (ddt, J = 8.8,

2.8, 1.4 Hz, 1 H, CH= prenyl), 4.23–4.18 (m, 1 H, H4_eq), 3.81 (td,

J = 9.2, 4.0 Hz, 1 H, H2_ax), 3.22 (dd, J = 14.0, 7.6 Hz, 1 H, H5_ax),

2.84 (dd, J = 14.0, 1.2 Hz, 1 H, H5_eq), 2.30 (s, 3 H, 6-CH₃), 2.23 (s,

3 H, 8-CH₃), 1.84 (dt, J = 14.0, 4.0 Hz, 1 H, H3_eq), 1.81 (ddd,

J = 14.0, 7.6, 4.4 Hz, 1 H, H3_ax), 1.74 (d, J = 1.2 Hz, 3 H, CH_3(A)),

1.68 (d, J = 1.2 Hz, 3 H, CH_3(B)), 1.58 (br s, 1 H, OH).

¹³C NMR: δ = 149.3 (C9a), 138.7 (C6), 136.6 (C8), 134.0 (=C pre-

nyl), 128.1 (CH= prenyl), 124.8 (C7), 122.4 (C5a), 118.8 (C9), 65.9

(C4), 50.6 (C2), 44.3 (C3), 35.1 (C5), 25.6 (CH_3(A)), 20.8 (8-CH₃),

20.7 (6-CH₃), 18.4 (CH_3(B)).

IR (KBr): 3400 cm^–1(N–H, O–H).

¹H NMR: δ = 7.41–7.39 (m, 2 H, H2′/H6′), 7.37–7.32 (m, 2 H,

H3′/H5′), 7.30–7.25 (m, 1 H, H4′), 7.13 (d, J = 2.4 Hz, 1 H, H6),

7.04 (dd, J = 8.4, 2.4 Hz, 1 H, H8), 6.67 (d, J = 8.4 Hz, 1 H, H9),

6.62 (d, J = 16.0 Hz, 1 H, =CH styryl), 6.32 (dd, J = 16.0, 8.0 Hz, 1

H, CH= styryl), 3.84 (tt, J = 9.6, 3.6 Hz, 1 H, H4_ax), 3.61 (ddd,

J = 11.2, 8.0, 2.0 Hz, 1 H, H2_ax), 2.99 (dd, J = 14.0, 9.6 Hz, 1 H,

H5_ax), 2.93 (dt, J = 14.0, 2.0, Hz, 1 H, H5_eq), 2.19 (ddt, J = 12.8, 4.0,

2.0 Hz, 1 H, H3_eq), 1.88 (ddd, J = 12.8, 11.2, 9.8 Hz, 1 H, H3_ax),

1.62 (br s, 1 H, OH).

¹³C NMR: δ = 147.3 (C9a), 136.3 (C1′), 131.4 (CH= styryl), 131.2

(=CH styryl), 131.2 (C6), 129.7 (C5a), 128.7 (C3′/C5′), 128.1 (C4′),

127.2 (C8), 126.5 (C2′/C6′), 126.4 (C7), 121.4 (C9), 69.4 (C4), 58.7

(C2), 46.3 (C3), 44.0 (C5).

GC-MS (EI, 70 eV): m/z (%) = 245 (M^+•, 49), 201 (18), 200 (33),

190 (2), 186 (48), 172 (12), 158 (37), 146 (36), 135 (33), 134 (100),

111 (3).

HRMS: m/z [M]⁺calcd for C₁₆H₂₃NO: 245.1780; found: 245.1785.

cis-2-[(E)-Styryl]-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol

GC-MS (EI, 70 eV): m/z (%) = 299 (M^+•, ³⁵Cl, 33), 159 (61), 141

(57), 140 (82), 130 (24), 117 (48), 115 (68), 91 (100), 77 (72).

HRMS: m/z [M]⁺calcd for C₁₈H₁₈ClNO: 299.1077; found:

299.1079.

(14a)

White crystals; yield: 0.93 g (92%); mp 114 °C (heptane); R_f= 0.32

(33% EtOAc–heptane).

IR (KBr): 3318 cm^–1(N–H, O–H).

¹H NMR: δ = 7.42–7.40 (m, 2 H, H2′/H6′), 7.37–7.33 (m, 2 H,

H3′/H5′), 7.30–7.25 (m, 1 H, H4′), 7.15 (dd, J = 7.6, 1.2 Hz, 1 H,

H6), 7.10 (td, J = 7.6, 1.2 Hz, 1 H, H8), 6.91 (td, J = 7.6, 1.2 Hz, 1

H, H7), 6.75 (dd, J = 8.0, 1.2 Hz, 1 H, H9), 6.63 (d, J = 16.0 Hz, 1

H, =CH styryl), 6.36 (dd, J = 16.0, 8.0 Hz, 1 H, CH= styryl), 3.87

(tt, J = 9.6, 3.6 Hz, 1 H, H4_ax), 3.65 (ddd, J = 11.2, 8.0, 2.0 Hz, 1 H,

H2_ax), 3.57 (br s, 1 H, NH), 3.05 (dd, J = 14.0, 9.2 Hz, 1 H, H5_ax),

3.00 (dt, J = 14.0, 2.0 Hz, 1 H, H5_eq), 2.20 (ddt, J = 12.8, 3.6, 2.0

Hz, 1 H, H3_eq), 1.91 (ddd, J = 12.8, 11.2, 9.8 Hz, 1 H, H3_ax), 1.66

(br s, 1 H, OH).

¹³C NMR: δ = 148.7 (C9a), 136.5 (C1′), 131.8 (CH= styryl), 131.6

(C6), 131.0 (=CH styryl), 128.7 (C3′/C5′), 128.0 (C5a), 127.9 (C4′),

127.5 (C8), 126.5 (C2′/C6′), 121.8 (C7), 120.2 (C9), 69.8 (C4), 58.7

(C2), 46.5 (C3), 44.4 (C5).

cis-8-Chloro-9-methyl-2-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1-

benzazepin-4-ol (14d)

White crystals; yield: 0.86 g (85%); mp 138 °C (heptane); R_f= 0.39

(33% EtOAc–heptane).

IR (KBr): 3411 (N–H), 3238 cm^–1(O–H).

¹H NMR: δ = 7.43–7.41 (m, 2 H, H2′/H6′), 7.38–7.34 (m, 2 H,

H3′/H5′), 7.31–7.27 (m, 1 H, H4′), 6.95 (d, J = 8.0 Hz, 1 H, H7),

6.92 (d, J = 8.0 Hz, 1 H, H6), 6.64 (d, J = 16.0 Hz, 1 H, =CH styryl),

6.38 (dd, J = 16.0, 8.0 Hz, 1 H, CH= styryl), 3.85 (tt, J = 8.8, 4.0,

Hz, 1 H, H4_ax), 3.67 (br s, 1 H, NH), 3.59 (ddd, J = 11.2, 8.0, 1.6 Hz,

1 H, H2_ax), 3.00 (dd, J = 13.6, 8.0 Hz, 1 H, H5_ax), 2.97 (dd, J = 13.6,

1.2 Hz, 1 H, H5_eq), 2.29 (s, 3 H, 9-CH₃), 2.18 (ddt, J = 12.8, 3.6, 1.6

Hz, 1 H, H3_eq), 1.88 (ddd, J = 12.8, 11.2, 10.0 Hz, 1 H, H3_ax), 1.69

(br s, 1 H, OH).

GC-MS (EI, 70 eV): m/z (%) = 265 (M^+•, 48), 159 (21), 130 (54),

117 (84), 115 (39), 107 (52), 106 (100), 91 (63), 77 (42).

¹³C NMR: δ = 148.3 (C9a), 136.3 (C1′), 133.0 (C8), 131.5 (CH=

styryl), 131.3 (=CH styryl), 129.4 (C6), 128.7 (C3′/C5′), 128.1

Synthesis 2012, 44, 3765–3782

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L. M. Acosta Quintero et al.

PAPER

(C4′), 127.2 (C5a), 126.5 (C2′/C6′), 124.6 (C9), 122.1 (C7), 69.4

(C4), 58.4 (C2), 45.8 (C3), 43.8 (C5), 14.6 (9-CH₃).

GC-MS (EI, 70 eV): m/z (%) = 313 (M^+•, ³⁵Cl, 36), 159 (39), 155

(41), 154 (100), 130 (38), 117 (21), 115 (44), 91 (75), 77 (36).

HRMS: m/z [M]⁺calcd for C₁₉H₂₀ClNO: 313.1233; found:

313.1234.

¹³C NMR: δ = 158.1 (d, J = 238.3 Hz, C7), 144.3 (d, J = 2.2 Hz,

C9a), 136.6 (C1′), 131.8 (CH= styryl), 130.9 (=CH styryl), 129.5 (d,

J = 7.3 Hz, C5a), 128.7 (C3′/C5′), 127.9 (C4′), 126.4 (C2′/C6′),

121.2 (d, J = 7.9 Hz, C9), 118.7 (d, J = 21.9 Hz, C6), 113.9 (d,

J = 21.7 Hz, C8), 65.4 (C4), 54.8 (C2), 44.3 (C3), 41.6 (C5).

GC-MS (EI, 70 eV): m/z (%) = 283 (M^+•, 60), 159 (45), 130 (15),

125 (64), 124 (100), 117 (21), 115 (48), 91 (71), 77 (36).

HRMS: m/z [M]⁺calcd for C₁₈H₁₈FNO: 283.1372; found: 283.1374.

cis-6,8-Dimethyl-2-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1-ben-

zazepin-4-ol (14e)

White crystals; yield: 0.94 g (93%); mp 124 °C (heptane); R_f= 0.36

(33% EtOAc–heptane).

IR (KBr): 3273 cm^–1(N–H, O–H).

trans-7-Chloro-2-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1-benzaze-

pin-4-ol (15c)

Colorless viscous oil; yield: 0.93 g (92%); R_f= 0.34 (33% EtOAc–

heptane).

IR (liquid film): 3407 cm^–1(N–H, O–H).

¹H NMR: δ = 7.41 (dd, J = 7.2, 1.6 Hz, 2 H, H2′/H6′), 7.35 (td,

J = 7.2, 1.6 Hz, 2 H, H3′/H5′), 7.30–726 (m, 1 H, H4′), 6.67 (s, 1 H,

H7), 6.61 (d, J = 16.0 Hz, 1 H, =CH styryl), 6.47 (s, 1 H, H9), 6.34

(dd, J = 16.0, 8.0 Hz, 1 H, CH= styryl), 3.85 (tdd, J = 9.2, 4.2, 2.2

Hz, 1 H, H4_ax), 3.66 (ddd, J = 11.2, 8.0, 2.0 Hz, 1 H, H2_ax), 3.44 (br

s, 1 H, NH), 3.14 (d, J = 14.0 Hz, 1 H, H5_eq), 2.91 (dd, J = 14.0, 9.2

Hz, 1 H, H5_ax), 2.34 (s, 3 H, 6-CH₃), 2.24 (s, 3 H, 8-CH₃), 2.19 (br

s, 1 H, OH), 2.17 (ddt, J = 12.8, 4.2, 2.0 Hz, 1 H, H3_eq), 1.90 (ddd,

J = 12.8, 11.2, 9.2 Hz, 1 H, H3_ax).

¹³C NMR: δ = 148.8 (C9a), 137.7 (C6), 136.6 (C8), 136.4 (C1′),

131.9 (CH= styryl), 130.8 (=CH styryl), 128.7 (C3′/C5′), 127.9

(C4′), 126.5 (C2′/C6′), 125.1 (C7), 123.9 (C5a), 119.1 (C9), 69.4

(C4), 59.0 (C2), 45.7 (C3), 37.8 (C5), 20.8 (6-CH₃), 20.7 (8-CH₃).

¹H NMR: δ = 7.39–7.37 (m, 2 H, H2′/H6′), 7.36–7.32 (m, 2 H,

H3′/H5′), 7.28–7.24 (m, 1 H, H4′), 7.12 (d, J = 2.4 Hz, 1 H, H6),

7.06 (dd, J = 8.4, 2.4 Hz, 1 H, H8), 6.70 (d, J = 8.4 Hz, 1 H, H9),

6.62 (d, J = 16.0 Hz, 1 H, =CH styryl), 6.29 (dd, J = 16.0, 8.0 Hz, 1

H, CH= styryl), 4.27–4.23 (m, 1 H, H4_eq), 3.88 (ddd, J = 10.4, 8.0,

2.4 Hz, 1 H, H2_ax), 3.63 (br s, 1 H, NH), 3.05 (dd, J = 14.0, 2.4 Hz,

1 H, H5_eq), 2.99 (dd, J = 14.0, 6.4 Hz, 1 H, H5_ax), 2.08–2.02 (m, 1

H, H3_eq), 1.94 (ddd, J = 14.0, 10.4, 3.2 Hz, 1 H, H3_ax), 1.57 (br s, 1

H, OH).

¹³C NMR: δ = 146.8 (C9a), 136.5 (C1′), 131.9 (C6), 131.6 (CH=

styryl), 131.1 (=CH styryl), 129.1 (C5a), 128.7 (C3′/C5′), 127.9

(C4′), 127.5 (C8), 126.4 (C2′/C6′), 126.3 (C7), 121.3 (C9), 65.5

(C4), 54.6 (C2), 44.1 (C3), 41.6 (C5).

GC-MS (EI, 70 eV): m/z (%) = 293 (M^+•, 51), 159 (6), 135 (26), 134

(100), 130 (18), 117 (9), 115 (24), 91 (30), 77 (12).

HRMS: m/z [M]⁺calcd for C₂₀H₂₃NO: 293.1780; found: 293.1779.

GC-MS (EI, 70 eV): m/z (%) = 299 (M^+•, ³⁵Cl, 27), 159 (51), 141

(49), 140 (73), 130 (33), 117 (42), 115 (68), 91 (100), 77 (78).

HRMS: m/z [M]⁺calcd for C₁₈H₁₈ClNO: 299.1077; found:

299.1081.

trans-2-[(E)-Styryl]-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol

(15a)

Colorless viscous oil; yield: 0.92 g (91%); R_f= 0.31 (33% EtOAc–

heptane).

trans-8-Chloro-9-methyl-2-[(E)-styryl]-2,3,4,5-tetrahydro-1H-

1-benzazepin-4-ol (15d)

Colorless viscous oil; yield: 0.83 g (82%); R_f= 0.34 (33% EtOAc–

heptane).

IR (liquid film): 3345 cm^–1(N–H, O–H).

¹H NMR: δ = 7.40–7.37 (m, 2 H, H2′/H6′), 7.35–7.31 (m, 2 H,

H3′/H5′), 7.28–7.24 (m, 1 H, H4′), 7.15 (dd, J = 7.6, 1.6 Hz, 1 H,

H6), 7.12 (td, J = 7.6, 1.6 Hz, 1 H, H8), 6.91 (td, J = 7.6, 1.2 Hz, 1

H, H7), 6.79 (dd, J = 7.6, 1.2 Hz, 1 H, H9), 6.62 (d, J = 16.0 Hz, 1

H, =CH styryl), 6.32 (dd, J = 16.0, 8.0 Hz, 1 H, CH= styryl), 4.29–

4.24 (m, 1 H, H4_eq), 3.86 (ddd, J = 10.4, 8.0, 2.0 Hz, 1 H, H2_ax), 3.65

(br s, 1 H, NH), 3.11 (dd, J = 14.0, 2.0 Hz, 1 H, H5_eq), 3.05 (dd,

J = 14.0, 6.4 Hz, 1 H, H5_ax), 2.10–2.05 (m, 1 H, H3_eq), 1.95 (ddd,

J = 14.0, 10.4, 2.8 Hz, 1 H, H3_ax), 1.53 (br s, 1 H, OH).

¹³C NMR: δ = 148.4 (C9a), 136.6 (C1′), 132.5 (C6), 132.0 (CH=

styryl), 130.8 (=CH styryl), 128.7 (C3′/C5′), 127.9 (C4′), 127.8

(C8), 127.0 (C5a), 126.4 (C2′/C6′), 121.8 (C7), 120.2 (C9), 65.6

(C4), 54.8 (C2), 44.4 (C3), 41.8 (C5).

IR (liquid film): 3395 cm^–1(N–H, O–H).

¹H NMR: δ = 7.41–7.39 (m, 2 H, H2′/H6′), 7.36–7.33 (m, 2 H,

H3′/H5′), 7.29–7.25 (m, 1 H, H4′), 6.93 (s, 2 H, H6, H7), 6.64 (d,

J = 16.0 Hz, 1 H, =CH styryl), 6.33 (dd, J = 16.0, 8.0 Hz, 1 H, CH=

styryl), 4.26–4.22 (m, 1 H, H4_eq), 3.88 (td, J = 9.6, 3.6 Hz, 1 H,

H2_ax), 3.74 (br s, 1 H, NH), 3.07 (dd, J = 14.0, 2.4 Hz, 1 H, H5_eq),

3.00 (dd, J = 14.0, 7.2 Hz, 1 H, H5_ax), 2.30 (s, 3 H, 9-CH₃), 2.04–

1.99 (m, 1 H, H3_eq), 1.97 (ddd, J = 14.0, 9.6, 3.2 Hz, 1 H, H3_ax), 1.60

(br s, 1 H, OH).

¹³C NMR: δ = 147.8 (C9a), 136.5 (C1′), 133.4 (C8), 131.7 (CH=

styryl), 131.1 (=CH styryl), 130.1 (C6), 128.7 (C3′/C5′), 128.0

(C4′), 126.5 (C2′/C6′), 126.1 (C5a), 124.5 (C9), 122.0 (C7), 65.5

(C4), 54.5 (C2), 43.8 (C3), 41.3 (C5), 14.7 (9-CH₃).

GC-MS (EI, 70 eV): m/z (%) = 265 (M^+•, 48), 159 (21), 130 (54),

117 (81), 115 (45), 107 (51), 106 (100), 91 (66), 77 (39).

HRMS: m/z [M]⁺calcd for C₁₈H₁₉NO: 265.1467; found: 265.1457.

GC-MS (EI, 70 eV): m/z (%) = 313 (M^+•, ³⁵Cl, 24), 159 (9), 155

(33), 154 (100), 130 (36), 117 (24), 115 (57), 91 (85), 77 (53).

HRMS: m/z [M]⁺calcd for C₁₉H₂₀ClNO: 313.1233; found:

313.1231.

trans-7-Fluoro-2-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1-benzaze-

pin-4-ol (15b)

Colorless viscous oil; yield: 0.92 g (91%); R_f= 0.27 (33% EtOAc–

heptane).

trans-6,8-Dimethyl-2-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1-ben-

zazepin-4-ol (15e)

White crystals; yield: 0.92 g (91%); mp 105 °C (heptane); R_f= 0.38

(33% EtOAc–heptane).

IR (liquid film): 3348 cm^–1(N–H, O–H).

¹H NMR: δ = 7.39–7.36 (m, 2 H, H2′/H6′), 7.35–7.31 (m, 2 H,

H3′/H5′), 7.28–7.24 (m, 1 H, H4′), 6.88 (dd, J = 9.2, 2.8 Hz, 1 H,

H6), 6.80 (td, J = 8.4, 2.8 Hz, 1 H, H8), 6.72 (dd, J = 8.4, 5.2 Hz, 1

H, H9), 6.61 (d, J = 16.0 Hz, 1 H, =CH styryl), 6.30 (dd, J = 16.0,

8.0 Hz, 1 H, CH= styryl), 4.27–4.24 (m, 1 H, H4_eq), 3.83 (ddd,

J = 10.4, 8.0, 2.4 Hz, 1 H, H2_ax), 3.54 (br s, 1 H, NH), 3.09 (dd,

J = 14.0, 1.6 Hz, 1 H, H5_eq), 2.98 (dd, J = 14.0, 6.8 Hz, 1 H, H5_ax),

2.09–2.03 (m, 1 H, H3_eq), 1.93 (ddd, J = 14.0, 10.4, 2.8 Hz, 1 H,

H3_ax), 1.55 (br s, 1 H, OH).

IR (KBr): 3317 (N–H), 3238 cm^–1(O–H).

¹H NMR: δ = 7.39 (dd, J = 7.2, 1.2 Hz, 2 H, H2′/H6′), 7.34 (dt,

J = 7.2, 1.4 Hz, 2 H, H3′/H5′), 7.29–7.25 (m, 1 H, H4′), 6.66 (s, 1

H, H7), 6.60 (d, J = 15.6 Hz, 1 H, =CH styryl), 6.49 (s, 1 H, H9),

6.30 (dd, J = 15.6, 8.0 Hz, 1 H, CH= styryl), 4.27–4.23 (m, 1 H,

H4_eq), 3.86 (ddd, J = 10.4, 8.0, 3.4 Hz, 1 H, H2_ax), 3.50 (br s, 1 H,

NH), 3.22 (dd, J = 14.0, 7.6 Hz, 1 H, H5_ax), 2.93 (dd, J = 14.0, 2.0

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Synthesis of 2-Alkenyltetrahydro-1-benzazepines

3781

Hz, 1 H, H5_eq), 2.33 (s, 3 H, 6-CH₃), 2.25 (s, 3 H, 8-CH₃), 2.02–1.96

(m, 1 H, H3_eq), 1.94 (ddd, J = 14.0, 10.4, 3.6 Hz, 1 H, H3_ax), 1.65

(br s, 1 H, OH).

¹³C NMR: δ = 148.5 (C9a), 138.5 (C6), 136.7 (C8), 136.7 (C1′),

132.2 (CH= styryl), 130.6 (=CH styryl), 128.7 (C3′/C5′), 127.8

(C4′), 126.4 (C2′/C6′), 124.9 (C7), 122.6 (C5a), 119.1 (C9), 65.7

(C4), 55.2 (C2), 43.8 (C3), 35.2 (C5), 20.9 (6-CH₃), 20.7 (8-CH₃).

GC-MS (EI, 70 eV): m/z (%) = 293 (M^+•, 51), 159 (6), 135 (26), 134

(100), 130 (18), 117 (9), 115 (24), 91 (32), 77 (15).

HRMS: m/z [M]⁺calcd for C₂₀H₂₃NO: 293.1780; found: 293.1778.

¹H NMR: δ = 6.84 (dd, J = 9.2, 2.8 Hz, 1 H, H6), 6.78 (td, J = 8.4,

2.8 Hz, 1 H, H8), 6.69 (dd, J = 8.4, 5.2 Hz, 1 H, H9), 5.66 (dt,

J = 15.2, 6.8 Hz, 1 H, =CH pentenyl), 5.52 (ddt, J = 15.2, 7.6, 1.2

Hz, 1 H, CH= pentenyl), 4.19 (ddt, J = 6.8, 4.8, 2.6 Hz, 1 H, H4_eq),

3.57 (ddd, J = 10.4, 7.6, 2.4 Hz, 1 H, H2_ax), 3.02 (dd, J = 14.0, 1.6

Hz, 1 H, H5_eq), 2.93 (ddd, J = 14.0, 6.8, 0.6 Hz, 1 H, H5_ax), 2.00

(ddd, J = 14.4, 7.6, 0.8 Hz, 2 H, 3′-CH₂), 1.63 (br s, 1 H, OH), 1.93

(dddd, J = 14.0, 4.8, 2.4, 1.0 Hz, 1 H, H3_eq), 1.83 (ddd, J = 14.0,

10.4, 2.8 Hz, 1 H, H3_ax), 1.39 (dq, J = 14.4, 7.2 Hz, 2 H, 4′-CH₂),

0.90 (t, J = 7.2 Hz, 3 H, 5′-CH₃).

¹³C NMR: δ = 158.0 (d, J = 237.9 Hz, C7), 144.6 (d, J = 2.2 Hz,

C9a), 132.6 (CH= pentenyl), 132.1 (=CH pentenyl), 129.3 (d,

J = 7.3 Hz, C5a), 121.0 (d, J = 7.9 Hz, C9), 118.7 (d, J = 21.9 Hz,

C6), 113.9 (d, J = 21.7 Hz, C8), 65.5 (C4), 54.6 (C2), 44.5 (C3),

41.6 (C5), 34.4 (3′-CH₂), 22.3 (4′-CH₂), 13.7 (5′-CH₃).

cis-7-Fluoro-2-[(E)-pent-1-enyl]-2,3,4,5-tetrahydro-1H-1-ben-

zazepin-4-ol (16a)

White crystals; yield: 0.96 g (95%); mp 68 °C (heptane); R_f= 0.30

(33% EtOAc–heptane).

GC-MS (EI, 70 eV): m/z (%) = 249 (M^+•, 44), 205 (12), 204 (12),

180 (3), 162 (100), 148 (27), 136 (34), 125 (36), 124 (50).

HRMS: m/z [M]⁺calcd for C₁₅H₂₀FNO: 249.1529; found: 249.1526.

IR (KBr): 3320 (N–H), 3283 cm^–1(O–H).

¹H NMR: δ = 6.83 (dd, J = 9.2, 2.8 Hz, 1 H, H6), 6.75 (td, J = 8.4,

2.8 Hz, 1 H, H8), 6.65 (dd, J = 8.4, 5.0 Hz, 1 H, H9), 5.68 (dt,

J = 15.4, 6.6 Hz, 1 H, =CH pentenyl), 5.57 (dd, J = 15.4, 7.6 Hz, 1

H, CH= pentenyl), 3.76 (tt, J = 10.0, 3.6 Hz, 1 H, H4_ax), 3.34 (ddd,

J = 11.2, 7.6, 2.0 Hz, 1 H, H2_ax), 3.32 (br s, 1 H, NH), 2.97 (dd,

J = 13.6, 10.0 Hz, 1 H, H5_ax), 2.86 (dt, J = 13.6, 2.0 Hz, 1 H, H5_eq),

2.08 (ddt, J = 12.8, 4.0, 2.0 Hz, 1 H, H3_eq), 2.02 (dd, J = 14.0, 7.2

Hz, 2 H, 3′-CH₂), 1.96 (br s, 1 H, OH), 1.75 (ddd, J = 12.8, 11.2,

10.4 Hz, 1 H, H3_ax), 1.42 (dq, J = 14.0, 7.6 Hz, 2 H, 4′-CH₂), 0.91

(t, J = 7.6 Hz, 3 H, 5′-CH₃).

¹³C NMR: δ = 157.9 (d, J = 237.9 Hz, C7), 145.1 (d, J = 2.3 Hz,

C9a), 132.6 (CH= pentenyl), 132.2 (=CH pentenyl), 130.0 (d,

J = 7.3 Hz, C5a), 121.1 (d, J = 7.9 Hz, C9), 117.7 (d, J = 22.0 Hz,

C6), 113.5 (d, J = 21.7 Hz, C8), 69.6 (C4), 58.7 (C2), 46.8 (C3),

44.2 (C5), 34.3 (3′-CH₂), 22.3 (4′-CH₂), 13.6 (5′-CH₃).

trans-8-Chloro-9-methyl-2-[(E)-pent-1-enyl]-2,3,4,5-tetra-

hydro-1H-1-benzazepin-4-ol (17b)

Colorless viscous oil; yield: 0.87 g (86%); R_f= 0.35 (33% EtOAc–

heptane).

IR (KBr): 3400 cm^–1(N–H, O–H).

¹H NMR: δ = 6.89 (d, J = 7.5 Hz, 2 H, H6, H7), 5.69 (dt, J = 15.2,

6.6 Hz, 1 H, =CH pentenyl), 5.57 (ddt, J = 15.2, 7.6, 1.0 Hz, 1 H,

CH= pentenyl), 4.18 (td, J = 7.2, 3.6 Hz, 1 H, H4_eq), 3.62 (ddd,

J = 10.4, 7.6, 2.8 Hz, 1 H, H2_ax), 3.61 (br s, 1 H, NH), 2.99 (dd,

J = 13.8, 2.4 Hz, 1 H, H5_eq), 2.95 (dd, J = 13.8, 5.6 Hz, 1 H, H5_ax),

2.27 (s, 3 H, 9-CH₃), 2.02 (ddd, J = 14.8, 7.6, 0.8 Hz, 2 H, 3′-CH₂),

1.93–1.88 (m, 1 H, H3_eq), 1.83 (ddd, J = 14.0, 10.4, 3.6 Hz, 1 H,

H3_ax), 1.59 (br s, 1 H, OH), 1.41 (dq, J = 14.8, 7.4 Hz, 2 H, 4′-CH₂),

0.91 (t, J = 7.4 Hz, 3 H, 5′-CH₃).

¹³C NMR: δ = 148.2 (C9a), 133.2 (C8), 132.7 (CH= pentenyl),

132.4 (=CH pentenyl), 130.1 (C6), 126.0 (C5a), 124.3 (C9), 121.7

(C7), 65.6 (C4), 54.3 (C2), 44.0 (C3), 41.3 (C5), 34.3 (3′-CH₂), 22.3

(4′-CH₂), 14.6 (9-CH₃), 13.6 (5′-CH₃).

GC-MS (EI, 70 eV): m/z (%) = 249 (M^+•, 54), 205 (12), 204 (12),

180 (3), 162 (100), 148 (21), 136 (34), 125 (38), 124 (50).

HRMS: m/z [M]⁺calcd for C₁₅H₂₀FNO: 249.1529; found: 249.1528.

cis-8-Chloro-9-methyl-2-[(E)-pent-1-enyl]-2,3,4,5-tetrahydro-

1H-1-benzazepin-4-ol (16b)

Colorless viscous oil; yield: 0.95 g (94%); R_f= 0.27 (33% EtOAc–

heptane).

GC-MS (EI, 70 eV): m/z (%) = 279 (M^+•, ³⁵Cl, 57), 235 (10), 234

(18), 210 (9), 192 (57), 178 (33), 166 (63), 155 (39), 154 (100).

IR (liquid film): 3367 cm^–1(N–H, O–H).

HRMS: m/z [M]⁺calcd for C₁₆H₂₂ClNO: 279.1390; found:

279.1393.

¹H NMR: δ = 6.89 (d, J = 8.0 Hz, 1 H, H7), 6.88 (d, J = 8.0 Hz, 1 H,

H6), 5.70 (dt, J = 15.4, 6.4 Hz, 1 H, =CH pentenyl), 5.62 (dd,

J = 15.4, 7.2 Hz, 1 H, CH= pentenyl), 3.79–3.72 (m, 1 H, H4_ax),

3.54 (br s, 1 H, NH), 3.33 (ddd, J = 11.2, 7.2, 2.0 Hz, 1 H, H2_ax),

2.93 (dd, J = 13.6, 8.0 Hz, 1 H, H5_ax), 2.90 (dd, J = 13.6, 1.6 Hz, 1

H, H5_eq), 2.29 (br s, 1 H, OH), 2.26 (s, 3 H, 9-CH₃), 2.10–2.03 (m,

1 H, H3_eq), 2.04 (dd, J = 14.6, 6.8 Hz, 2 H, 3′-CH₂), 1.74 (ddd,

J = 12.8, 11.2, 10.0 Hz, 1 H, H3_ax), 1.42 (dq, J = 14.6, 7.4 Hz, 2 H,

4′-CH₂), 0.92 (t, J = 7.4 Hz, 3 H, 5′-CH₃).

¹³C NMR: δ = 148.7 (C9a), 132.8 (C8), 132.7 (CH= pentenyl),

132.6 (=CH pentenyl), 129.4 (C6), 127.1 (C5a), 124.3 (C9), 121.9

(C7), 69.5 (C4), 58.2 (C2), 46.0 (C3), 43.9 (C5), 34.3 (3′-CH₂), 22.3

(4′-CH₂), 14.4 (9-CH₃), 13.6 (5′-CH₃).

Acknowledgment

A. Palma and L. M. Acosta would like to thank Colombian Institute

for Science and Research (COLCIENCIAS, Grant No. 1102–521–

28229), for financial support. J. Cobo and M. Nogueras thank Uni-

versidad de Jaén (and its Centro de Instrumentación Científico Téc-

nica) and Consejería de Economía, Innovación, Ciencia y Empleo

(Junta de Andalucía) for financial support.

Supporting Information for this article is available online at

http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi

m

tgioSrantnugIifoop

r

itmnatr

GC-MS (EI, 70 eV): m/z (%) = 279 (M^+•, ³⁵Cl, 76), 235 (12), 234

(18), 210 (2), 192 (93), 178 (36), 166 (39), 155 (43), 154 (100).

HRMS: m/z [M]⁺calcd for C₁₆H₂₂ClNO: 279.1390; found:

279.1393.

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Synthesis 2012, 44, 3765–3782

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Synthesis 2012, 44, 3765–3782

Article Doi

Stereoselective synthesis of novel 2-alkenyl-2,3,4,5-tetrahydro-1,4-epoxy- 1-benzazepines and 2-alkenyl-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ols

DOI: 10.1055/s-0032-1316808

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Article abstract of DOI:10.1055/s-0032-1316808

Full text of DOI:10.1055/s-0032-1316808

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