A one-pot selective synthesis of N-Boc protected secondary amines: Tandem direct reductive amination/N-Boc protection

Article abstract of DOI:10.1016/j.tet.2012.06.055

A one-pot tandem direct reductive amination of aldehydes with primary amines resulting in N-Boc secondary amines using a (Boc)₂O/sodium triacetoxyborohydride (STAB) system is reported. The tandem procedure is efficient, selective, and versatile, giving excellent yields of N-Boc protected secondary amines even in those cases where the products are prone to intramolecular lactamization.

Full text of DOI:10.1016/j.tet.2012.06.055

Supporting Information
A One-Pot Selective Synthesis of N-Boc Protected Secondary Amines: Tandem
Direct Reductive Amination/N-Boc Protection
Raghupathi Neelarapu, and Pavel A. Petukhov*
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy,
University of Illinois at Chicago, 833, S. Wood Street, Chicago, IL-60612, USA
pap4@uic.edu
Table of Contents
NMR Spectroscopic Data……………………………………………………...S2 S22
S1

NMR Spectroscopic Data
O
N
OMe
Boc
5.02
1.98
4.5
2.96
2.00
2.00
13.03 4.18
1.5
7.5
7.0
6.5
6.0
5.5
5.0
4.0
3.5
3.0
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 6a in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 6a in CDCl3
S2

O
MeO
N
OMe
Boc
1.01
2.99
2.00
4.5
3.05 2.99
2.00
2.02
2.18 11.014.19
1.5
7.5
7.0
6.5
6.0
5.5
5.0
4.0
3.5
3.0
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 6b in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 6b in CDCl3
S3

O
O
O
N
Boc
OMe
2.90
2.00
6.0
1.89
3.19
2.08
3.0
2.18
13.98 4.68
1.5
7.0
6.5
5.5
5.0
4.5
4.0
3.5
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 6c in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 6c in CDCl3
S4

O
N
OMe
Boc
F
2.01 2.02
7.0
2.01
3.05
2.02
3.0
2.06
13.73 4.37
1.5
7.5
6.5
6.0
5.5
5.0
4.5
4.0
3.5
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 6d in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 6d in CDCl3
S5

O
N
OMe
Boc
O2N
1.96
8.0
1.98
7.5
2.00
4.5
3.06
3.5
2.06
2.06
17.86
1.5
8.5
7.0
6.5
6.0
5.5
5.0
4.0
3.0
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 6e in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 6e in CDCl3
S6

O
N
N
OMe
Boc
1.99
8.5
0.99 1.09
7.5
2.00
3.09
3.5
2.13
3.0
2.06
18.20
1.5
8.0
7.0
6.5
6.0
5.5
5.0
4.5
4.0
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 6f in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 6f in CDCl3
S7

O
N
OMe
N
Boc
0.99
8.5
2.05 2.06
8.0
2.07 1.02
2.00
4.5
3.03
3.5
2.01
3.0
2.02
13.38 4.40
1.5
7.5
7.0
6.5
6.0
5.5
5.0
4.0
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 6g in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 6g in CDCl3
S8

O
O
O2N
N
OMe
Boc
1.93
1.95
0.97
0.94
6.5
2.00
4.5
3.15
3.5
1.95
2.11
13.63 4.64
1.5
8.5
8.0
7.5
7.0
6.0
5.5
5.0
4.0
3.0
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 6h in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 6h in CDCl3
S9

O
S
N
OMe
Boc
2.03 3.141.01 0.96
2.00
4.5
3.08
1.99
2.12
14.11 4.53
1.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.0
3.5
3.0
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 6i in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 6i in CDCl3
S10

O
N
OMe
Boc
3.091.02 3.03
7.5
2.00
3.03
2.03
2.03
13.65 4.32
1.5
8.0
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 6j in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 6j in CDCl3
S11

OMe
N
Boc
O
5.00
2.00
4.5
2.98
2.00
2.01
2.02
9.09
1.5
7.5
7.0
6.5
6.0
5.5
5.0
4.0
3.5
3.0
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 9 in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
1H NMR Spectrum of 9 in CDCl3
S12

O
N
OMe
Boc
5.15
2.00
4.5
3.01
2.00
2.01
13.32
1.5
7.5
7.0
6.5
6.0
5.5
5.0
4.0
3.5
3.0
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 10 in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 10 in CDCl3
S13

NHBoc
N
Boc
5.06
0.81
2.00
4.5
3.99
3.0
22.27
1.5
7.5
7.0
6.5
6.0
5.5
5.0
4.0
3.5
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 18 in CDCl3
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 18 in CDCl3
S14

MeO
N
Boc
6.03
2.97
2.00
4.5
3.01
2.00
2.01
2.5
13.23
1.5
7.5
7.0
6.5
6.0
5.5
5.0
4.0
3.5
3.0
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 20 in CDCl3
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 20 in CDCl3
S15

N
Boc
2.06
3.0
1.00
2.5
6.44 9.33 3.37 2.14 2.052.00
1.5 1.0 0.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
2.0
0
Chemical Shift (ppm)
1H NMR Spectrum of 23 in CDCl3
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 23 in CDCl3
S16

N
Boc
5.13
2.00
4.5
1.99
3.0
6.08 12.97 3.39 2.09
1.5 1.0
7.5
7.0
6.5
6.0
5.5
5.0
4.0
3.5
2.5
2.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 25 in CDCl3
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 25 in CDCl3
S17

N
Boc
O
OEt
5.35
2.00
4.5
2.05
1.92
3.0
11.75 3.21 0.94
1.5 1.0
0.99
7.5
7.0
6.5
6.0
5.5
5.0
4.0
3.5
2.5
2.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 27 in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 27 in CDCl3
S18

O
N
O2N
Boc
2.04
2.07
5.66
7.5
1.00
0.96
6.5
4.29
4.5
9.01
1.5
8.5
8.0
7.0
6.0
5.5
5.0
4.0
3.5
3.0
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 28 in CDCl3
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)
13C NMR Spectrum of 28 in CDCl3
S19

Boc
N
OEt
O
BnO
6.03 2.222.43
7.5 7.0
2.42
5.0
2.24
4.0
2.00
3.5
1.73 10.71 3.75 1.67 1.05
1.5 1.0
8.0
6.5
6.0
5.5
4.5
3.0
2.5
2.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 30 in CDCl3
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 30 in CDCl3
S20

OMe
N
Boc
1.94 2.01
7.0
3.03
2.00
6.18 9.76 3.24 2.15
1.5 1.0
7.5
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 32 in CDCl3
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 32 in CDCl3
S21

OMe
O
O
N
Boc
1.89 3.052.05
7.0
2.00
6.0
2.01
3.16
9.00
1.5
6.5
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.0
0.5
0
Chemical Shift (ppm)
1H NMR Spectrum of 33 in CDCl3
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
13C NMR Spectrum of 33 in CDCl3
S22