PAPER
Synthesis of 2,3,4,5-Tetrahydro-1,5-methano-1H-3-benzazepine
MS (APCI): m/z = 250.3 [M + 1]+.
1757
prox. 25 ºC and a solution of 1 (18.1 g, 127 mmol) in i-PrOH (227
mL) was added dropwise over 20 min. The reaction is exothermic
and the final temperature reached 32 ºC. The reaction mixture was
stirred for an additional 30 min and sodium sulfite was added in 3
portions (64.0 g, 508 mmol). The mixture was stirred for 1 h and the
i-PrOH was distilled under reduced pressure followed by addition
of H2O (200 mL). The mixture was stirred for 15 min and the solids
were filtered to yield ca. 25 g of a brown solid which triturated with
2:1 hexanes–MTBE (60 mL/30 mL) overnight to yield 6 (16.21 g,
72%).
Anal. Calcd for C18H19N·HCl: C, 75.64; H, 7.05; N, 4.90. Found: C,
75.36; H, 7.06; N, 4.78.
2,3,4,5-Tetrahydro-1,5-methano-1H-3-benzazepine (5)
Rf = 0.2 [TLC, 10% MeOH–CH2Cl2 (NH3)].
1H NMR (400 MHz, CDCl3): d = 7.18 (m, 4 H), 2.97 (m, 4 H), 2.68
(d, J = 12.5 Hz, 2 H), 2.41 (m, 1 H), 1.95 (d, J = 11.0 Hz, 1 H).
MS (APCI): m/z = 160.2 [M + 1]+.
Preparation of 3-Benzyl-2,3,4,5-tetrahydro-1,5-methano-1H-3-
benzazepine (8); Typical Procedure
Preparation of 5 from 1 via Ozonolysis; Typical Procedure
A stream of ozone was bubbled through a solution of benzonorbor-
nadiene, (1, 4.00 g, 28.1 mmol, 1.0 equiv) in MeOH (80 mL) at –78
°C. Once the solution developed a blue color (approx. 20 min),
ozone generation was stopped then oxygen was bubbled through for
5 min to purge the blue color. The solution was further purged with
N2 for 20–40 min to deoxygenate the solution. This solution was
transferred to a Parr bottle. To the cold solution was added of 5%
Pt/C ( 55% wet, 0.20 g, 0.001 equiv, supplied by Johnson Matthey).
The system was passivated with H2, pressurized to 40 PSI of H2, and
gradually warmed to r.t. (ideally the reactor was maintained at 0 °C
or colder). Once the methoxyhydroperoxide glycal 9 was reduced to
10 completely (no reaction to KI–starch was observed, H2 uptake
had ceased and HPLC showed consumption of 9 within 45–60 min),
an additional amount of 5% Pt/C (0.798 g, 0.004 equiv) was added
to the reaction mixture at 0 °C, followed by benzylamine (3.07 mL,
1.0 equiv) and 96% HCOOH (0.56 mL, 0.50 equiv). The system
was repressurized to 50 PSI of H2 and allowed to warm to r.t. Once
compound 10 was consumed (within 4 h, monitored by HPLC), the
reaction mixture was removed from the reactor and filtered through
a pad of celite, washing with MeOH (20 mL). A pressure reactor
was charged with the crude reaction mixture in MeOH (100 mL)
and p-toluene sulfonic acid monohydrate (3.74 g) and 20%
Pd(OH)2/C (0.986 g, 50% wet by weight). The reactor was pressur-
ized to 50 PSI of H2 after passivation and heated to 40 °C. After
heating for 15 h the reactor was cooled to r.t. and the reaction mix-
ture was filtered through celite (washing with MeOH). The filtrate
was concentrated in vacuo and stripped from i-PrOH (20 mL). The
residue was redissolved in i-PrOH (32 mL) and heated to 70 °C. To
the hot solution was added hexane (16 mL) and the resulting solu-
tion was allowed to slowly cool with stirring. Crystals formed and
were stirred at r.t. for 12 h. The white crystals were filtered and
dried to give the tosylate salt of 5 (2.65 g, 28%); mp: 207–208 °C.
Diol 6 (40 g, 227.3 mmol) was stirred in H2O (1050 mL) and 1,2-
dichloroethane (DCE) (420 mL) in a 2 L round-bottomed flask un-
der N2 with cool water bath (ca 10 °C). To this NaIO4 (51 g, 239
mmol) and Et3BnNCl (50 mg) were added. The resulting mixture
was stirred for 1 h (slight initial exotherm), then the layers were sep-
arated and the aqueous layer was extracted with dichloroethane
(200 mL). The organic layer was washed with H2O (4 × 200 mL, or
until no reaction to KI–starch was observed in the aqueous wash)
then dried through a cotton plug. To this solution of 7 was added
benzylamine (25.5 g, 238.6 mmol) and the mixture was stirred for 2
min then immediately transferred over 10 min into a magnetically
stirred dispersion of NaBH(OAc)3 (154 g, 0.727 mmol) in dichloro-
ethane (800 mL) at 0 °C under N2 in a separate 2 L round-bottomed
flask. The resulting orange mixture was allowed to warm to r.t. and
stirred for 30–120 min. The reaction was quenched by addition of
sat. aq Na2CO3 solution (ca 300 mL), carefully at first, and the mix-
ture was stirred for 1 h (pH 9). The layers were separated and the
aqueous layer was extracted with CH2Cl2 (2 × 300 mL). The organic
layer was washed with sat. aq NaCl solution (200 mL), dried
through a cotton plug and evaporated to a red oil. This oil was dis-
solved in a minimum of Et2O and filtered through a silica pad (3 ×
4 inch) eluting with 15% EtOAc–hexanes (+1% of 37% aq NH4OH
solution) to remove baseline red color. Concentration affords 8
(48.5 g, 195 mmol, 85.7%) as a light yellow oil; Rf = 0.75 (TLC,
10% EtOAc–hexanes).
1H NMR (400 MHz, CDCl3): d = 7.16 (m, 7 H), 6.89 (m, 2 H), 3.48
(m, 2 H), 3.08 (m, 2 H), 2.80 (d, J = 9.5 Hz, 2 H), 2.42 (d, J = 9.5
Hz, 2 H), 2.27 (m, 1 H), 1.67 (d, J = 10.0 Hz, 1 H).
MS (APCI): m/z = 250.3 [M + 1]+.
Preparation of 2,3,4,5-Tetrahydro-1,5-methano-1H-3-benz-
azepine (5); Typical Procedure
IR (KBr): 3438, 3021, 2958, 2822, 2758, 2719, 2683, 2611, 2424,
1925, 1606, 1497, 1473, 1428, 1339, 1302, 1259, 1228, 1219, 1176,
1160, 1137, 1122, 1087, 1078, 945, 914, 876, 847, 829, 818, 801,
710, 492 cm–1.
1H NMR (400 MHz, CD3OD): d = 7.69 (d, J = 7.9 Hz, 2 H), 7.43–
7.32 (m, 4 H), 7.23 (d, J = 7.9 Hz, 2 H), 3.37 (d, J = 11.2 Hz, 4 H),
3.30 (br s, 2 H), 3.15 (d, J = 12.4 Hz, 2 H), 2.36 (s, 3 H), 2.40–2.35
(m, 1 H), 2.08 (d, J = 11.2 Hz, 1 H).
Benzylamine 8 (70.65 g, 284 mmol) was stirred in EtOAc (250 mL)
and treated with 3 N HCl·ethyl acetate (1.03 equiv) slowly with
cooling (ice bath). The resulting precipitate was filtered, rinsed with
EtOAc and dried to give the HCl salt of 8 (80.6 g, 100%) as an off
white solid. These solids were dissolved in MeOH (250 mL) in a
Parr bottle. To this was added Pd(OH)2 (7 g of 20% wt/C) and the
mixture was shaken under 50–40 psi of H2 for 24 h or until done by
TLC. The reaction was filtered through a Celite pad and concentrat-
ed to an oily solid. This was azeotropically dried with MeOH (3 ×)
then triturated with acetone and Et2O to precipitate product. Filtra-
tion, concentration of the mother liquors and a second treatment
provided 5 (48.95 g, 88%) as an off white solid. A sample was con-
verted to the free base using CH2Cl2–aq Na2CO3 solution.
13C NMR (100 MHz, CD3OD): d = 140.8, 140.5, 139.1, 127.2,
127.2, 124.3, 122.3, 45.1, 39.7, 37.3, 18.7.
Anal. Calcd for C18H21NO3S: C, 65.23; H, 6.39; N, 4.23; Found: C,
65.05; H, 6.48; N, 4.26.
Acknowledgment
HCl Salt of 8
Rf = 0.75 (TLC, 10% EtOAc–hexanes).
The authors thank Brian T. O’Neill, Tamim Braish and Robert W.
Dugger for helpful suggestions.
1H NMR (400 MHz, CD3OD): d = 7.46–7.40 (m, 5 H), 7.34–7.27
(m, 4 H), 4.27 (s, 2 H), 3.45 (br d, J = 12.1 Hz, 2 H), 3.38 (br s, 2
H), 3.28 (m, 2 H), 2.30 (m, 1 H), 2.05 (d, J = 10.8 Hz, 1 H).
13C NMR (100 MHz, CD3OD): d = 142.0, 131.7, 130.1, 129.0,
128.8, 128.7, 123.9, 60.6, 55.2, 41.5, 39.5.
References
(1) Wittig, G.; Knauss, E. Chem. Ber. 1958, 91, 895.
Synthesis 2004, No. 11, 1755–1758 © Thieme Stuttgart · New York