PAPER
Solid-Phase Synthesis of Functionalized Azacycles
143
cis-15b: Rf 0.35 (tBuOMe/NEt3 99:1).
HRMS (C14H19NO, M+): calcd 217.1466, found 217.1478.
1H NMR (CDCl3): δ = 2.06Ð2.25 (m, 2H, H-3), 2.38Ð2.59 (m, 2H,
H-6), 2.84 (dddd, 1H, J = 10/9/4/2.5 Hz, H-2), 3.33 (dd, 1H, J = 10/
10 Hz, CH2O), 3.61 (dd, 1H, J = 10/4 Hz, CH2O), 3.71 (dd, 1H, J =
10/2.5 Hz, H-7), 5.81Ð5.91 (m, 2H, H-4, H-5), 7.20Ð7.48 (m, 5H,
Ar-H).
IR (film): ν = 3351 cmÐ1 (br, OÐH, NÐH).
(1-Benzoyl-7-phenyl-2,3,6,7-tetrahydro-1H-azepine-2-yl)meth-
anol (15d)
The crude cleavage product was purified by flash chromatography
(CH2Cl2/tBuOMe 9:1) to obtain 15d (28 mg, 88%) as a separable
mixture of two diastereomeric products. To assign the stereochem-
istry of the diastereomers, about 0.5 mg each were dissolved in
MeOH (0.1 mL), KOH (10 mg) was added, the mixture was heated
to 50¡C for 15 min, diluted with water and extracted with tBuOMe.
The TLC of the two extracts were compared with authentic samples
of 15b.
NOE (400 MHz, CDCl3): δ = 2.84 (H-2) ↔ 3.71 (H-7) (4%).
13C NMR (CDCl3): δ = 34.1 (CH2, C-6), 39.8 (CH2, C-3), 59.5 (CH,
C-2 or C-7), 62.8 (CH, C-2 or C-7), 66.2 (CH2, CH2O), 126.4 (CH),
127.1 (CH), 128.5 (CH), 129.7 (CH), 130.3 (CH), 145.8 (Cq, Ar-C).
HRMS (C13H17NO, M+): calcd 203.1310, found 203.1313.
IR (film): ν = 3400, 3281 cmÐ1 (OÐH, NÐH).
trans-15b: Rf 0.17 (tBuOMe/NEt3 99:1).
1H NMR (CDCl3): δ = 2.19Ð2.27 (m, 1H, H-3), 2.29Ð2.39 (m, 1H, H-
3), 2.43Ð2.51 (m, 1H, H-6), 2.76Ð2.85 (m, 1H, H-6), 3.36Ð3.45 (m, 2H,
CH2O, H-2), 3.52 (dd, 1H, J = 15/9 Hz, CH2O), 4.33 (dd, 1H, J = 11/3
Hz, H-7), 5.70Ð5.79 (m, 2H, H-4, H-5), 7.20Ð7.48 (m, 5H, Ar-H).
cis-15d: Rf 0.42 (CH2Cl2/tBuOMe 3:1).
trans-15d: Rf 0.48 (CH2Cl2/tBuOMe 3:1).
1H NMR (CDCl3, 55¡C): δ = 2.06Ð2.16 (m, 1Hcis, H-3a), 2.26 (ddd,
1Hcis, J = 16/7/6 Hz, H-3b), 2.34Ð2.45 (m, 1Htrans, H-3a), 2.54 (ddd,
1Htrans, J =15/8/6 Hz, H-6a), 2.72Ð2.81 (m, 1Hcis, H-6a; m, 1Htrans
,
H-6b), 2.92 (ddd, 1Hcis, J = 17/6/6 Hz, H-6b), 3.18Ð3.27 (m, 1Hcis,
CH2O; 1Htrans, H-3b), 3.43 (dd, 1Hcis, J = 11/8 Hz, CH2O), 3.99 (dd,
1Htrans, J = 12.5/6 Hz, CH2O), 4.06Ð4.16 (m, 1Htrans, H-2), 4.21 (d,
1Htrans, J = 12.5 Hz, CH2O), 4.45Ð4.60 (m, 2Hcis, H-7, H-2), 5.04
(dd, 1Htrans, J = 11/6 Hz, H-7), 5.64Ð5.74 (m, 1Htrans, =CH), 5.76Ð
5.83 (m, 1Htrans, =CH), 5.79Ð5.86 (m, 1Hcis, =CH), 5.95Ð6.03 (m,
1Hcis, =CH), 7.21Ð7.53 (m, 10H, Ar-H)
13C NMR (CDCl3): δ = 31.9 (CH2, Ph-CHCH2), 37.3 (CH2,
CH2CHCH2O), 55.5 (CH), 56.4 (CH), 65.4 (CH2, CH2O), 126.5
(CH), 126.9 (CH), 128.4 (CH), 128.5 (CH), 129.2 (CH), 145.4 (Cq,
Ar-C).
HRMS (C13H17NO, M+): calcd 203.1310, found 203.1322.
IR (film): ν = 3400, 3276 cmÐ1 (OÐH, NÐH).
13C NMR (CDCl3, not coalesced, mixture of stereoisomers): δ =
28.9 (CH2), 32.3 (CH2), 56.7 (CH), 59.1 (CH), 63.8 (CH), 64.6
(CH2), 123.7Ð130.8 (8 CH), 136.9 (Cq), 137.5 (Cq), 141.4 (Cq),
174.9 (Cq).
HRMS (C20H21NO2, M+): calcd 307.15723, found 307.1577.
IR (film): ν = 3402 (OÐH), 1615 cmÐ1 (C=O).
(8-Phenyl-1,2,3,4,7,8-hexahydroazocin-2-yl)methanol (15c)
The crude cleavage product was dissolved in MeOH (0.3 mL), some
KOH was added, after 2 min the mixture was dissolved in water
(2 mL) and extracted with EtOAc (3 × 2 mL). The combined organ-
ic layers were dried (MgSO4) and concentrated. This crude product
was purified by flash chromatography (EtOAc/tBuOMe 1:1) to ob-
tain 15c (20 mg, 87%) (mixture of 2 diastereomers, cis/trans 1:2).
Epoxidation
cis-15c: Rf 0.45 (tBuOMe/NEt3 99:1).
14d (200 mg) was suspended in CH2Cl2 (4 mL) and Cl3CCN (1.7 g,
12 mmol). A solution of K2HPO4 (0.5 g) in 30% aq H2O2 (1 mL)
was added and the resulting mixture was shaken under reflux for
3 h. The polymer was filtered, washed with water, MeOH, CH2Cl2,
and Et2O (2 mL each) and dried in vacuo.
1H NMR (CDCl3): δ = 1.32 (dddd, 1H, J = 14.5/10.5/9/4 Hz, H-3a),
1.69 (dddd, 1H, J = 14.5/6/6/3 Hz, H-3b), 2.19Ð2.29 (m, 1H, H-4a),
2.35Ð2.44 (m, 1H, H-4b), 2.48 (ddd, 1H, J = 13.5/10/5 Hz, H-7a),
2.68 (ddd, 1H, J = 13.5/9.5/5 Hz, H-7b), 2.86 (dddd, 1H, J = 10.5/
10/5/3 Hz, H-2), 3.03 (dd, 1H, J = 10/10 Hz, CH2O), 3.48 (dd, 1H,
J = 10/5 Hz, CH2O), 3.85 (dd, 1H, J = 5/5 Hz, H-8), 5.66 (ddd, 1H,
J = 10/9.5/8 Hz, H-6), 5.94 (ddd, 1H, J = 10/8/8 Hz, H-5), 7.21Ð7.39
(m, 5H, Ar-H).
2-Benzoyl-5-hydroxy-3-phenyl-7-oxa-2-azabicyc-
lo[4.2.1]nonane (17)
Isolation from the solid phase: resin 16 (100 mg) was treated ac-
cording to the general cleavage procedure. The crude product was
purified by flash chromatography (tBuOMe/MeOH 100:0Ð98:2) to
yield 17 (12 mg, 70%) as mixture of two diastereomeric products.
NOE (400 MHz, CDCl3): δ = 2.86 (H-2) ↔ 3.85 (H-8) (3%).
13C NMR (CDCl3): δ = 24.4 (CH2, C-3), 33.8 (CH2, C-4 or C-7),
34.9 (CH2, C-4 or C-7), 59.0 (CH, C-2 or C-8), 62.6 (CH, C-2 or C-
8), 66.3 (CH2, CH2O), 126.2 (CH), 126.8 (CH), 127.0 (CH), 128.4
(CH), 132.9 (CH), 144.7 (Cq, Ar-C).
HRMS (C14H19NO, M+): calcd 217.1466, found 217.1460.
IR (film): ν = 3400, 3330 cmÐ1 (OÐH, NÐH).
trans-15c, Rf 0.35 (tBuOMe/NEt3 99:1).
1H NMR (CDCl3): δ = 1.13 (dddd, 1H, J = 14/12.5/11/2.5 Hz, H-
3a), 1.68 (dddd, 1H, J = 14/6/2.5/2 Hz, H-3b), 2.17Ð2.27 (m, 1H, H-
4a), 2.29Ð2.38 (m, 2H, H-4b, H-7), 2.61Ð2.69 (m, 1H, H-2), 2.86
(dd, 1H, J = 10/9 Hz, CH2O), 2.87 (dddd, 1H, J = 13/12/10/1 Hz, H-
7), 3.14 (dd, 1H, J = 10/5 Hz, CH2O), 3.89 (dd, 1H, J = 12.5/3.5 Hz,
H-8), 5.76 (dddd, 1H, J = 11/7/7/2 Hz, H-6), 6.05 (dddd, 1H, J = 11/
7.5/7.5/1 Hz, H-5), 7.23Ð7.29 (m, 1H, Ar-H), 7.33Ð7.39 (m, 2H, Ar-
H), 7.42Ð7.47 (m, 2H, Ar-H).
13C NMR (CDCl3): δ = 25.4 (CH2, C-3), 29.9 (CH2, C-4 or C-7),
33.8 (CH2, C-4 or C-7), 54.0 (CH, C-2 or C-8), 58.1 (CH, C-2 or C-
8), 66.3 (CH2, CH2O), 127.3 (CH), 127.9 (CH), 128.5 (CH), 128.8
(CH), 133.0 (CH), 143.3 (Cq, Ar-C).
Diastereomer A: Rf 0.42 (tBuOMe).
1H NMR (CDCl3): δ = 2.01 (ddd, 1H, J = 15/8/7 Hz, H-9a), 2.27Ð
2.31 (m, 1H, H-4a), 2.45 (d, 1H, J = 15 Hz, H-9b), 2.81 (br d, 1H, J
= 16 Hz, H-4b), 4.07 (dd, 1H, J = 7/5 Hz, H-5), 4.14 (d, 1H, J =
10 Hz, H-8a), 4.19Ð4.24 (m, 1H, H-8b), 4.28 (dd, 1H, J = 8/5 Hz,
H-6), 5.07Ð5.22 (m, 1H, H-1), 5.36Ð5.60 (m, 1H, H-3), 7.19Ð7.42
(m, 10H, Ar-H).
13C NMR (CDCl3): δ = 28.0 (CH2, C-4 or C-9), 34.0 (CH2, C-4 or
C-9), 56.2 (CH, C-1), 71.2 (CH, C-5), 77.2 (CH2, C-8), 80.7 (CH,
C-6), 125.6 (CH), 125.8 (CH), 127.1 (CH), 128.5 (CH), 128.8 (CH),
129.5. (CH), 136.8 (Cq, Ar-C), 141.2 (Cq, Ar-C).
MS (EI): m/z (%) = 323 (M+, 24), 252 (16, M+ Ð C4H7O), 105 (100),
77 (44).
HRMS (C20H21NO3, M+): calcd 323.15215, found 323.15214.
IR (film): ν = 3423 (OÐH), 1614 cmÐ1 (C=O).
Synthesis 1999, No. 1, 138–144 ISSN 0039-7881 © Thieme Stuttgart · New York