Practical synthesis of 3-oxa-6-azabicyclo[31.1]heptane hydrotosylate; A novel morpholine-based building block

Article abstract of DOI:10.1055/s-0032-1316748

Bridged bicyclic morpholines are important building blocks in medicinal chemistry research. The bicyclic morpholine 3-oxa-6-azabicylo[3.1.1]heptane (3a) is of particular interest as a morpholine isostere because it is achiral and shows similar lipophilicity to that of morpholine, based on the cLogP of a derived analogue. The first synthesis of morpholine 3a (tosylate salt) is described; the seven-step sequence begins with inexpensive starting materials and uses straightforward chemistry. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0032-1316748

Journal of Synthetic 0rganic Chemistry
SUPPORTING INFORMATION
SYNTHESIS
Supporting Information
for DOI: 10.1055/s-0032-1316748
© Georg Thieme Verlag KG Stuttgart · New York 2012
Thieme

Practical Synthesis of 3-Oxa-6-azabicyclo[3.1.1]heptane
Hydrotosylate; a Novel Morpholine-Based Building Block
Daniel P. Walker,* Brian M. Eklov, Matthew W. Bedore
Kalexsyn, Inc., 4502 Campus Drive, Kalamazoo, MI 49008
dpwalker@kalexsyn.com
Supporting Information
Table of Contents
1H and 13C NMR Spectral data for Compounds
11, 15, 16, 17 and 3a•TsOH ……………..………………………………….…………..S2-S6
S1

O
O
O
O
N
11
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Chemical Shift (ppm)
208
200
192
184
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
-8
Chemical Shift (ppm)
S2

O
O
O
N
O
O
Ot-Bu
15
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
Chemical Shift (ppm)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
-0.5
208
200
192
184
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
-8
Chemical Shift (ppm)
S3

HO
OH
N
O
Ot-Bu
16
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
-0.5
Chemical Shift (ppm)
208
200
192
184
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
-8
Chemical Shift (ppm)
S4

O
N
Ot-Bu
O
17
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
-0.5
Chemical Shift (ppm)
208
200
192
184
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
-8
Chemical Shift (ppm)
S5

x
NH TsOH
O
3a TsOH
x
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Chemical Shift (ppm)
208
200
192
184
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
-8
Chemical Shift (ppm)
S6