A novel construction of 2-benzazepine scaffold based on TiCl 4-mediated tandem Mannich reaction - Aromatic electrophilic substitution

Article abstract of DOI:10.1002/hlca.200900107

A novel construction of 2-benzazepine derivatives based on TiCl ₄-mediated tandem Mannich reaction of electron-rich benzyl iminium ions with alkenyl ethers and Friedel - Crafts-type alkylation is described. The protocol is amenable to provide the tricyclic furo[3,2-d][2]benzazepine and pyrano[3,2-d][2]benzazepine derivatives, respectively, with 2,3-dihydrofuran or 3,4-dihydro-2H-pyran as the substrates.

Full text of DOI:10.1002/hlca.200900107

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Helvetica Chimica Acta – Vol. 92 (2009)
A Novel Construction of 2-Benzazepine Scaffold Based on TiCl4-Mediated
Tandem Mannich Reaction – Aromatic Electrophilic Substitution
by Liangxi Li, Zhiming Li, and Quanrui Wang*
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai, 200433, P. R. China
(phone: þ 862165643978; fax: þ 862165641740; e-mail: qrwang@fudan.edu.cn)
A novel construction of 2-benzazepine derivatives based on TiCl4-mediated tandem Mannich
reaction of electron-rich benzyl iminium ions with alkenyl ethers and Friedel – Crafts-type alkylation is
described. The protocol is amenable to provide the tricyclic furo[3,2-d][2]benzazepine and pyrano[3,2-
d][2]benzazepine derivatives, respectively, with 2,3-dihydrofuran or 3,4-dihydro-2H-pyran as the
substrates.
Introduction. – The 2-benzazepine motif is a core structure in a number of
pharmacologically important compounds [1]. Several members of this class have been
found to exhibit hypotensive, anticonvulsant, analgesic, and antiarrhythimic activities,
and also have been proved to be useful as antagonists of muscarinic (M3) receptors and
for the treatment of mental disorders and hypoxia [2][3]. Many naturally occurring
molecules also contain a 2-benzazepine skeleton. For example, the alkaloids of the
Amaryllidaceae group including galanthamine, lycoramine, and narwedine are tetrahydro-
2-benzazepine derivatives [1][4][5]. In addition, many simpler synthetic analogues
have been disclosed to possess a broad spectrum of biological activities [6]. Accordingly,
considerable attention has been devoted to the development of convenient and
efficient synthesis of families of this privileged heterocyclic ring system [1].
The most widely used methodologies involve Pictet – Spengler cyclization [7], the
Schmidt reaction on tetralones [8], cyclization of benzyl amine and cinnamyl chloride
[9], a ring-closing metathesis strategy [10], and transformation of the Baylis – Hillman
adducts via tandem Ritter and Houben – Hoesch reactions [11]. A recent article by
Nagumo et al. reported a novel construction of 2-benzazepines based on TMSOTf-
promoted 7-endo Friedel – Crafts-type reaction of vinyloxiranes [12]. However, these
approaches require multistep sequences or expensive reagents.
Our strategy for developing a novel synthesis of 2-benzazepines is outlined in
Scheme 1. We envisioned that the initial reaction of benzylic iminium ions A with vinyl
ethers B may give rise to oxonium ions C with formation of a CꢀC bond. The
intermediates C will be capable of concurrent Friedel – Crafts-type alkylation to give
the 7-endo-trig cyclization products, i.e., 2-benzazepines, by formation of a new CꢀC
bond. Remarkably, there is no precedent of this tandem synthesis of 2-benzazepines.
Results and Discussions. – To test our hypothesis, we firstly synthesized from 1a via
2a the aminoacetal 3a as the precursor of the required benzyl iminium ion 4a. Thus,
ꢀ 2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 92 (2009)
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Scheme 1
benzaldehyde 1a was subjected to reductive amination with MeNH2 to afford N-
benzylmethylamine 2a, which was readily converted to 3a by reaction with parafor-
maldehyde and anhydrous EtOH under basic conditions [13] (Scheme 2).
Scheme 2
a) MeNH2, C6H6, reflux, 2 h; b) NaBH4, EtOH, 3 h (80 – 85%); c) (CH2O)n, EtOH, K2CO3, 1 – 2 d
(95%).
The aminoacetal 3a and 2,3-dihydrofuran 5a were selected as the substrates to
screen the appropriate Lewis acid used for the generation of the benzyl iminium ion 4a
(Scheme 3 and Table 1). If 4a can be formed in situ, it should undergo an electrophilic
addition with the pre-added 5a to give the oxonium ion 6a. Electrophilic aromatic
substitution on the ortho-position of the Ph ring would afford the tricyclic
furobenzazepine 7aa. Examples of 2-benzazepines fused with an additional furan ring
are rare (for a recent synthesis, see [14]). Otherwise, 6a could lose a H-atom to furnish
a trivial Mannich product 8aa. As shown in Table 1, the use of AlCl3 or SbCl5 as the
Lewis acid was proved to be unsuccessful for triggering the expected reaction (Table 1,
Entries 1 and 2). Interestingly, switching the Lewis acid to both Me2SiCl2 and a mixture
with AlCl3 only led to 8aa in comparable yields (Table 1, Entries 3 and 4). Finally, to our
delight, by utilizing TiCl4 as the Lewis acid, the reaction occurred smoothly to afford
the desired product 7aa as the only product in good yield (Table 1, Entry 5).
Having found the optimal Lewis acid for this reaction, it was necessary to optimize
the reaction temperature. In our case, all reactions carried out from ꢀ 788 to the
ambient temperature led to the formation of 7aa (Table 2), but cooling with ice bath
(ꢀ 5 to þ 58) was adopted in terms of easy operation and high yield of the product.

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Helvetica Chimica Acta – Vol. 92 (2009)
Scheme 3
Table 1. Screening for the Appropriate Lewis Acid for the Synthesis of 7aa and 8aaa)
Entry
Lewis acid
Yield of 7aab) [%]
Yield of 8aab) [%]
1
2
3
4
5
AlCl3
SbCl5
0
0
0
0
81
0
0
65
71
0
Me2SiCl2
Me2SiCl2/ AlCl3 (1 : 1)
TiCl4
a) Reaction conditions: 3a (3 mmol), 2,3-dihydrofuran (5a; 3.9 mmol), Lewis acid (3 mmol), dry CH2Cl2
(7 ml), ꢀ 5 to þ 58, 3 h. b) Yields of products isolated by silica gel column chromatography.
Table 2. Screening for the Optimal Reaction Temperature for the Synthesis of 7aaa)
Entry
T [8]
Yieldb) [%]
1
2
3
4
ꢀ 78
ꢀ 40
ꢀ 10
20
40
81
82
71
a) Reagents and reaction conditions were the same as provided in the footnote of Table 1. b) Yields
obtained after chromatography.
Having established the optimum conditions, a number of different combinations of
substrates were used to probe the scope and feasibility of this methodology for
preparation of 2-benzazepine derivatives (Table 3).
Depending on the electronic nature of the starting aminoacetal 3 (Scheme 2), the
reaction sequence afforded either the tricylic 2-benzazepines 7 or a trivial uncyclized
product 8, or a mixture of 4-(hydroxyalkyl)-substituted 2,3-dihydro-2-benzazepines 9.
The formation of 9 may be accounted for by the acid-promoted ring opening of the

Helvetica Chimica Acta – Vol. 92 (2009)
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Table 3. Preparation of 2-Benzoazepine Derivatives by TiCl4-promoted Tandem Mannich Reaction and
Electrophilic Aromatic Substitution
Entry
3
R
5
n
Product
Yielda) [%]
1
2
3
3a
3a
3b
3,4-(MeO)2
3,4-(MeO)2
3-MeO
5a
5b
5a
1
2
1
7aa
7ab
7ba
9ba
8bb
9bb
9ca
9cb
9ba
9bb
9ca
9cb
8da
8ea
82
68
25
31
34
35
4
3b
3-MeO
5b
2
b
5
6
3c
3c
3b
3b
3c
3c
3d
3e
2,3-(MeO)2
2,3-(MeO)2
3-MeO
5a
5b
5a
5b
5a
5b
5a
5a
1
2
1
2
1
2
1
1
)
)
b
7c)
8c)
9c)
10c)
11
68
72
56
3-MeO
2,3-(MeO)2
2,3-(MeO)2
H
b
)
67
70
12
3-Me
a) Yields of products isolated by silica gel column chromatography. b) Undetermined due to difficulty in
purification. c) 2.0 Equiv. of TiCl4 were employed.
initially formed tricyclic products 7. This illuminated that the attached additional furan
or pyran ring of 7 did not tolerate acidic conditions. It was also shown that the amount
of the employed TiCl4 affected the product distribution. As shown by the representa-
tive results in Table 3, the substrate 3a bearing two electron-donating groups reacted
with both 2,3-dihydrofuran (5a) and 3,4-dihydro-2H-pyran (5b) using 1 equiv. of TiCl4
as the Lewis acid to afford cleanly the tricyclic compounds 7aa and 7ab in 82 and 68%
yield, respectively (Table 3, Entries 1 and 2). However, the use of 3b, which holds only
one MeO group, afforded a mixture of the tricyclic product 7ba and the bicyclic product
9ba in the case of 5a, and 8bb and 9bb in the case of 5b in essentially the same amount
(Table 3, Entries 3 and 4). When using 3c as substrate, the reaction gave intricate
inseparable products (Table 3, Entries 5 and 6). Nevertheless, increasing the amount of
the employed TiCl4 to two equivalents, the reaction using 3b afforded the bicyclic fused
heterocycles 9ba and 9bb in good yields without the detection of the uncyclized
products 8 (Table 3, Entries 7 and 8). This suggested that excessive Lewis acid is
beneficial to the concurrent aromatic electrophilic substitution. This was further
verified by the reaction of 3c bearing two electron-donating MeO groups at the C(2)
and C(3) positions, which delivered again the bicyclic compounds 9ca and 9cb,
respectively, though not in quite as good yields (Table 3, Entries 9 and 10). At this

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point, it may be concluded that the presence of electron-donating groups on the
benzene ring is helpful to the electrophilic aromatic substitution thus leading to the
formation of the 2-benzazepine core. Accordingly, the reaction of 3d as well as 3e
lacking a strong electron-donating MeO group gave only the trivial uncyclized products
9da and 9ea, respectively, in good yields (Table 3, Entries 11 and 12), and increasing the
amount of TiCl4 to 2 equiv. did not give any cyclized products 7 or 9 (data not shown in
Table 3).
The trans ring fusion between the attached furan or pyran ring, respectively, and the
seven-membered ring in the tricyclic products 7aa, 7ab, and 7ba has been tentatively
1
assigned by inspection of the relatively large H,1H-coupling constant (> 9 Hz) of
HꢀC(3a)/C(4a) with HꢀC(10b)/C(11b). Further proof to this stereochemical assign-
ment came from the fact that no NOE for 7ab could be observed between the angular
H-atoms HꢀC(11b) (apparent d at d(H) 4.28, J ¼ 9.6 Hz) and HꢀC(4a) (m centered at
d(C) 1.75).
Finally, we applied the developed novel method with the open-chain enol ether 5c
as a substrate (Table 4). The reaction with aminoacetals 3a – 3c proceeded smoothly
under similar conditions. Notably, the isolated products were 2,3-dihydro-1H-benz-
azepines 10a – 10c. The formation of 10 may be explained by invoking the 4-ethoxy-
2,3,4,5-tetrahydro-1H-2-benzazepines 11 (Figure) as intermediates via subsequent
elimination of a molecule of EtOH.
Figure. The proposed structure of intermediate 11
Table 4. Preparation of 2,3-Dihydro-1H-2-benzazepines 10 Using 5ca)
Entry
3
R
Product
Yielda) [%]
1
2
3
3a
3b
3c
3,4-(MeO)2
3-MeO
2,3-(MeO)2
10a
10b
10c
71
67
55
a) 2.0 Equiv. of TiCl4 were employed. b) Yields of products isolated by silica gel column chromatography.
In conclusion, an efficient tandem synthesis of pharmaceutically important 2-
benzazepines was developed. The protocol relies on TiCl4 mediated Mannich-type
reaction of electron-rich benzyl iminium ions generated in situ from aminoacetals with
alkenyl ethers such as 2,3-dihydrofuran, 3,4-dihydro-2H-pyran, or ethyl vinyl ether and
concurrent Friedel – Crafts-type electrophilic substitution.

Helvetica Chimica Acta – Vol. 92 (2009)
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Experimental Part
General. CH2Cl2 was dried by refluxing over CaH2, and other reagents were commercially available
and used without further purification. Flash column chromatography (FC): silica gel 60 (SiO2; 230 – 400
mesh) with CH2Cl2/MeOH mixture for elution. IR Spectra: in CH2Cl2 or as KBr disc with a Nicolet-360
1
spectrophotometer; absorptions given in cmꢀ1. H-NMR Spectra: JEOL ECA 400; chemical shifts (d)
reported in ppm relative to TMS as internal standard; coupling constants (J) in Hz. GC/MS: 30 m HP-
5MS cap. column on a Hewlett-Packard 6890GC/5973MS system. HR-ESI-MS: SHIMADZU LCMS-IT-
TOF.
General Procedure for the Preparation of N-Benzyl-N-methylamines 2. Gaseous MeNH2 was
bubbled into a soln. of benzaldehyde 1 (0.05 mol) in benzene (70 ml) for 1 h under stirring, then the
resulting mixture was heated to reflux, and the produced H2O was removed by azeotropic distillation.
Upon completion of the reaction (2 h), the mixture was evaporated in vacuo. The residue was dissolved
in 70 ml of EtOH, and NaBH4 (2.27 g, 0.06 mol) was added in portions under stirring. After stirring at r.t.
for 4 h, the solvent was removed in vacuo, the residue was dissolved in 200 ml of CH2Cl2, washed
successively with H2O and brine, dried (Na2SO4), and filtered. The filtrate was concentrated in vacuo to
give a yellow oil, which was subjected to vacuum distillation to afford the pure product 2.
General Procedure for Preparation of Amino Acetals 3. Anh. N-benzyl-N-methylamine 2 (10 mmol),
dry EtOH (2.3 ml, 4.0 mol-equiv.), and anh. K2CO3 (1.51 g, 11 mmol, 1.1 mol-equiv.) were stirred at 08
for 15 min. Paraformaldehyde (0.33 g, 11 mmol, 1.1 mol-equiv.) was added in one portion, and the
mixture was stirred at r.t. for 1 d. The reaction was monitored by TLC (CH2Cl2/MeOH 15 :1). In case the
reaction did not reach completion, an additional amount of paraformaldehyde (60 mg, 2 mmol) and 2 ml
of anh. Et2O were fed into the mixture, which then was stirred further overnight. The mixture was
filtered, and the cake was washed several times with anh. Et2O. The combined filtrate was concentrated
in vacuo to give the product 3, which could be used for the next step without purification. (Note: The
products 3 are prone to decompose on exposure to moisture.)
General Experimental Procedure for the Tandem Mannich and Aromatic Electrophilic Substitution
Reactions. To a soln. of 3 (3.0 mmol) in dry CH2Cl2 (7 ml) was added the alkenyl ether 5 (3.9 mmol,
1.3 equiv.). After cooling to ꢀ 58, anh. TiCl4 (as specified in Tables 3 and 4) was added dropwise over
10 min. After stirring for 3 h, the temp. was allowed gradually to warm to r.t., then the mixture was
poured into a sat. aq. NaHCO3 soln. The org. phase was separated, the aq. phase was extracted with
CH2Cl2 or AcOEt (3 ꢁ 60 ml). The org. phases were combined, dried (Na2SO4), and concentrated under
reduced pressure. The residue was purified by CC (CH2Cl2/MeOH 1:1) to give the products 7, 8, 9, or 10.
3,3a,4,5,6,10b-Hexahydro-8,9-dimethoxy-5-methyl-2H-furo[3,2-d][2]benzazepine (7aa). Eluent
CH2Cl2/MeOH 60 :1. Colorless oil. Yield: 82%. IR (KBr): 3400, 2926, 1607, 1514, 1463, 1276, 1114,
1029. 1H-NMR (400 MHz, CDCl3): 7.03 (s, 1 H); 6.57 (s, 1 H); 5.13 (d, J ¼ 9.2, 1 H); 3.99 – 3.95 (m, 1 H);
3.81 (s, 3 H); 3.79 (s, 3 H); 3.73 (d, J ¼ 13.3, 1 H); 3.70 – 3.63 (m, 1 H); 3.37 (d, J ¼ 13.3, 1 H); 2.70 – 2.62
(m, 1 H); 2.54 (dd, J ¼ 2.5, 12.6, 1 H); 2.22 (s, 3 H); 2.02 – 1.96 (m, 1 H); 1.90 (t, J ¼ 12.1, 1 H); 1.33 – 1.24
(m, 1 H). 13C-NMR (100 MHz, CDCl3): 148.4; 147.3; 131.9; 121.2; 113.1; 108.5; 79.5; 67.0; 56.1; 55.9; 55.8;
55.6; 43.2; 39.0; 31.9. GC/MS: 263 (Mþ). HR-ESI-MS: 264.1662 ([M þ H]þ, C15H22NOþ3 ; calc. 264.1600).
2,3,4,4a,5,6,7,11b-Octahydro-9,10-dimethoxy-6-methylpyrano[3,2-d][2]benzazepine (7ab). Eluent:
CH2Cl2/MeOH 60 :1. Colorless solid. Yield: 68%. IR (KBr): 3431, 2928, 2837, 1604, 1514, 1444, 1270,
1
1213, 1114, 1027, 821. H-NMR (400 MHz, CDCl3): 7.31 (s, 1 H); 6.62 (s, 1 H); 4.28 (d, J ¼ 9.6, 1 H);
4.20 – 4.14 (m, 1 H); 3.96 (s, 3 H); 3.85 (s, 3 H); 3.82 – 3.80 (m, 1 H); 3.53 (d, J ¼ 14.2, 1 H); 3.45 – 3.39
(m, 1 H); 2.85 (d, J ¼ 14.2, 1 H); 2.72 – 2.66 (m, 1 H); 2.22 (s, 3 H); 1.78 – 1.67 (m, 3 H); 1.62 – 1.59 (m,
1 H); 1.21 – 1.17 (m, 1 H). 13C-NMR (100 MHz, CDCl3): 147.8; 146.7; 135.2; 127.5; 113.3; 109.0; 79.8; 67.5;
65.9; 61.4; 56.0 (2 MeO); 42.8; 36.2; 29.2; 25.5. HR-ESI-MS: 278.1744 ([M þ H]þ, C16H24NO3þ ; calc.
278.1756).
2,3,3a,4,5,6-Hexahydro-8-methoxy-5-methyl-2H-furo[3,2-d][2]benzazepine (7ba). Eluent: CH2Cl2/
MeOH 50 :1. Colorless oil. Yield: 25%. IR (KBr): 3455, 2943, 2617, 1613, 1505, 1481, 1254, 1069.
1H-NMR (400 MHz, CDCl3): 7.33 (d, J ¼ 8.7, 1 H); 6.77 (dd, J ¼ 2.3, 8.7, 1 H); 6.60 (d, J ¼ 2.3, 1 H); 5.10
(d, J ¼ 9.2, 1 H); 3.96 – 3.92 (m, 1 H); 3.83 (d, J ¼ 13.5, 1 H); 3.70 (s, 3 H); 3.67 – 3.61 (m, 1 H); 3.46 (d,
J ¼ 13.5, 1 H); 2.74 – 2.69 (m, 1 H); 2.60 (dd, J ¼ 2.3, 12.4, 1 H); 2.26 (s, 3 H); 2.03 – 1.96 (m, 1 H); 1.91 (t,

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Helvetica Chimica Acta – Vol. 92 (2009)
J ¼ 12.4, 1 H); 1.35 – 1.29 (m, 1 H). 13C-NMR (100 MHz, CDCl3): 158.7; 131.5; 129.5; 116.0; 115.9; 112.5;
79.5; 67.0; 56.2; 55.5; 55.3; 43.0; 39.2; 31.8. HR-ESI-MS: 234.1487 ([M þ H]þ, C14H20NO2þ ; calc.
234.1494).
1-(4,5-Dihydrofuran-3-yl)-N-(3,4-dimethoxybenzyl)-N-methylmethanamine (8aa). Eluent: CH2Cl2/
MeOH 80 :1. Colorless oil. Yield: 71%. 1H-NMR (400 MHz, CDCl3): 6.89 (s, 1 H); 6.80 (s, 2 H); 6.24 (s,
1 H); 4.35 (t, J ¼ 9.6, 2 H); 3.88 (s, 3 H); 3.84 (s, 3 H); 3.41 (s, 2 H); 3.00 (s, 2 H); 2.64 (t, J ¼ 9.6, 2 H); 2.17
(s, 3 H).
1-(3,4-Dihydro-2H-pyran-5-yl)-N-(3-methoxybenzyl)-N-methylmethanamine (8bb). Eluent:
CH2Cl2/MeOH 80 :1. Colorless oil. Yield: 34%. IR (KBr): 2940, 2782, 1667, 1601, 1488, 1264, 1155,
1051, 877. 1H-NMR (400 MHz, CDCl3): 6.99 (d, J ¼ 8.2, 1 H); 6.67 (dd, J ¼ 8.2, 2.3, 1 H); 6.59 (d, J ¼ 2.3,
1 H); 6.24 (s, 1 H); 3.73 (s, 3 H); 3.68 (s, 2 H); 3.56 (t, J ¼ 6.4, 2 H); 3.28 (s, 2 H); 2.31 (s, 3 H); 2.13 (t, J ¼
7.6, 2 H); 1.71 – 1.67 (m, 2 H). 13C-NMR (100 MHz, CDCl3): 158.1; 139.1; 138.3; 131.3; 129.6; 126.2;
114.8; 112.2; 61.9; 61.3; 60.5; 55.3; 42.6; 34.6; 32.0.
2-(2,3-Dihydro-8-methoxy-2-methyl-1H-2-benzazepin-4-yl)ethanol (9ba). Eluent: CH2Cl2/MeOH
1
20 :1. Yellow oil. Yield: 68%. IR (KBr): 3394, 2939, 1609, 1504, 1466, 1254, 1043. H-NMR (400 MHz,
CDCl3): 7.09 (d, J ¼ 8.7, 1 H); 6.78 (dd, J ¼ 2.7, 8.7, 1 H); 6.68 (d, J ¼ 2.7, 1 H); 6.41 (s, 1 H); 3.79 (s, 3 H);
3.76 (t, J ¼ 6.0, 2 H); 3.70 (s, 2 H); 3.16 (s, 2 H); 2.41 (t, J ¼ 6.0, 2 H); 2.40 (s, 3 H). 13C-NMR (100 MHz,
CDCl3): 158.4; 137.9; 137.1; 130.9; 130.0; 128.8; 115.2; 112.4; 62.5; 60.1; 60.0; 55.4; 43.1; 41.3. HR-ESI-
MS: 234.1490 ([M þ H]þ, C14H20NO2þ ; calc. 234.1494).
3-(2,3-Dihydro-8-methoxy-2-methyl-1H-2-benzazepin-4-yl)propan-1-ol (9bb). Eluent: CH2Cl2/
MeOH 25 :1. Yellow oil. Yield: 72%. IR (KBr): 3411, 2934, 1608, 1501, 1278, 1248, 1034. 1H-NMR
(400 MHz, CDCl3): 7.05 (d, J ¼ 8.7, 1 H); 6.74 (dd, J ¼ 1.8, 8.7, 1 H); 6.65 (d, J ¼ 1.8, 1 H); 6.30 (s, 1 H);
3.78 (s, 3 H); 3.75 (s, 2 H); 3.64 (t, J ¼ 6.4, 2 H); 3.34 (s, 2 H); 2.37 (s, 3 H); 2.20 (t, J ¼ 7.8, 2 H); 1.79 –
1.73 (m, 2 H). 13C-NMR (100 MHz, CDCl3): 158.1; 139.1; 138.3; 131.3; 129.6; 126.2; 114.8; 112.2; 61.9;
60.5; 55.3; 42.6; 34.6; 32.0.
2-(2,3-Dihydro-8,9-dimethoxy-2-methyl-1H-2-benzazepin-4-yl)ethanol (9ca). Eluent: CH2Cl2/
1
MeOH 20 :1. Yellow oil. Yield: 56%. H-NMR (400 MHz, CDCl3): 6.89 (d, J ¼ 8.7, 1 H); 6.85 (d, J ¼
8.7, 1 H); 6.56 (s, 1 H); 3.93 (s, 2 H); 3.84 (s, 3 H); 3.80 (t, J ¼ 7.9, 2 H); 3.78 (s, 3 H); 3.14 (s, 2 H);
2.55 (s, 3 H); 2.46 (t, J ¼ 7.9, 2 H). 13C-NMR (100 MHz, CDCl3): 151.6; 147.5; 136.3; 131.5; 131.4; 126.3;
124.8; 112.2; 61.4; 57.3; 55.9; 50.2; 46.0; 42.6; 40.8.
N-Benzyl-1-(4,5-dihydrofuran-3-yl)-N-methylmethanamine (8da). Eluent: CH2Cl2/MeOH 80 :1.
1
Colorless oil. Yield: 67%. H-NMR (400 MHz, CDCl3): 7.29 – 7.21 (m, 5 H); 6.22 (s, 1 H); 4.32 (t, J ¼
9.4, 2 H); 3.44 (s, 2 H); 3.00 (s, 2 H); 2.63 (t, J ¼ 9.4, 2 H); 2.14 (s, 3 H). 13C-NMR (100 MHz, CDCl3):
143.1; 139.5; 129.0; 128.3; 127.0; 112.7; 70.4; 61.4; 53.7; 42.4; 31.6. GC/EI-MS: 203.1 (Mþ).
1-(4,5-Dihydrofuran-3-yl)-N-methyl-N-(3-methylbenzyl)methanamine (8ea). Eluent: CH2Cl2/
MeOH 80 :1. Colorless oil. Yield: 70%. 1H-NMR (400 MHz, CDCl3): 7.20 – 7.05 (m, 4 H); 6.25 (s,
1 H); 4.36 (t, J ¼ 9.6, 2 H); 3.43 (s, 2 H); 3.03 (s, 2 H); 2.69 – 2.64 (m, 2 H); 2.35 (s, 3 H); 2.17 (s, 3 H).
13C-NMR (100 MHz, CDCl3): 143.2; 139.3; 137.9; 129.7; 128.2; 127.7; 126.0; 112.7; 70.5; 61.4; 53.8; 42.4;
31.6; 21.5. GC/EI-MS: 217.2 (Mþ).
2,3-Dihydro-7,8-dimethoxy-2-methyl-1H-2-benzazepine (10a). Eluent: CH2Cl2/MeOH 60 :1. Yellow
oil. Yield: 71%. IR (KBr): 3393, 2968, 1604, 1520, 1466, 1353, 1274, 1116. 1H-NMR (400 MHz, CDCl3):
6.70 (s, 1 H); 6.64 (s, 1 H); 6.37 (d, J ¼ 12.4, 1 H); 5.70 (dt, J ¼ 3.7, 12.4, 1 H); 3.88 (s, 3 H); 3.86 (s, 3 H);
3.78 (s, 2 H); 3.51 (s, 2 H); 2.41 (s, 3 H). 13C-NMR (100 MHz, CDCl3): 147.7; 147.6; 131.1; 129.4; 129.1;
129.0; 113.8; 112.5; 61.1; 59.8; 56.1 (2 MeO); 43.3. HR-ESI-MS: 220.1312 ([M þ H]þ, C13H18NO2þ ; calc.
220.1337).
2,3-Dihydro-8-methoxy-2-methyl-1H-2-benzazepine (10b). Eluent: CH2Cl2/MeOH 70 :1. Yellow oil.
Yield: 67%. IR (KBr): 3402, 2958, 2524, 1608, 1504, 1466, 1258, 1031, 874. 1H-NMR (400 MHz, CDCl3):
7.09 (d, J ¼ 8.2, 1 H); 6.72 (dd, J ¼ 2.3, 8.2, 1 H); 6.65 (d, J ¼ 2.3, 1 H); 6.36 (d, J ¼ 10.5, 1 H); 5.64 – 5.59
(m, 1 H); 3.82 (s, 2 H); 3.79 (s, 3 H); 3.52 (s, 2 H); 2.39 (s, 3 H). 13C-NMR (100 MHz, CDCl3): 158.6;
140.0; 132.0; 129.2; 129.1; 128.2; 114.8; 111.8; 61.7; 60.2; 55.3; 43.3. HR-ESI-MS: 190.1242 ([M þ H]þ,
C12H16NOþ; calc. 190.1232).
2,3-Dihydro-8,9-dimethoxy-2-methyl-1H-2-benzazepine (10c). Eluent: CH2Cl2/MeOH 70 :1. Yellow
oil. Yield: 55%. 1H-NMR (400 MHz, CDCl3): 6.90 (d, J ¼ 8.2, 1 H); 6.75 (d, J ¼ 8.2, 1 H); 6.39 (d,

Helvetica Chimica Acta – Vol. 92 (2009)
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J ¼ 11.9, 1 H); 5.68 – 5.63 (m, 1 H); 3.90 (s, 2 H); 3.85 (s, 3 H); 3.78 (s, 3 H); 2.19 (s, 2 H); 2.48 (s, 3 H).
GC/EI-MS: 219.2 (Mþ).
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Received March 23, 2009