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Supporting Information
Indium(III)-catalyzed Tandem Synthesis of 2-Alkynyl-3,3-dichloropyrrolidines and
their Conversion to 3-Chloropyrroles
Khushbu Kushwaha,a Chandi C. Malakar,a Sara Stas,a Filip Lemièreb and Kourosch
Abbaspour Tehrania*
a Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan
171, B-2020 Antwerp, Belgium. Fax: (+32)32653233; phone: (+32)32653226.b Biomolecular & Analytical Mass Spectrometry and Center for Proteomics, Department of
Chemistry, University of Antwerp, B-2020 Antwerp, Belgium.
E-mail: [email protected]
Table of Contents
1. Optimization of the reaction conditions
2. Copies of 1H and 13C spectra of starting imines 1a-f
3. Formation of side products 5c' and 5f'
4. Copies of 1H and 13C spectra of 2-alkynylpyrrolidines 5a-q
5. Copies of 1H and 13C spectra of 2-alkenylpyrroles 6a-f and 7
6. Mechanistic study for the borontrifluoride catalyzed synthesis of 5a
7. Mechanistic study for the indium triflate catalyzed synthesis of 5a
8. Copies of 1H and 13C spectra of 3,3-dichloro-1-ethyl-2-
(2-phenylvinyl)pyrrolidine (12a)
9. Copies of 1H and 13C spectra of 13a and 14a
10. References
2-3
4-12
13-15
15-45
45-60
61-62
62-64
65-66
66-69
69
Electronic Supplementary Material (ESI) for RSC Advances.This journal is © The Royal Society of Chemistry 2015
2
1. Optimization of the Reaction Conditions for the Synthesis of 5b using In(OTf)3a
Cl
N
H
1b
2b
5b
N
ClClClCl
In(OTf)3
reaction conditions
Entry Catalyst/[mol%] 2b [equiv] Solvent t [°C] Yield 5b [%]
1 In(OTf)3/25 1.0 DCM 50 60b
2 In(OTf)3/25 1.0 DCE 70 5c
3 In(OTf)3/25 1.0 DCM/HFIP rt 0
4 In(OTf)3/25 1.0 THF 70 SM
5 In(OTf)3/40 1.0 DCM 50 64b
6 In(OTf)3/10 1.0 DCM 50 34b
7 In(OTf)3/25 1.5 DCM 50 74d
8 In(OTf)3/25 2.0 DCM 50 80d
9 In(OTf)3/25 2.5 DCM 50 81d
aAll reactions were performed using 0.5 mmol 1b in DCM (4 mL) in a sealed vial under air
for 18h, unless otherwise stated. bYield after chromatography using a short column of silica
gel.cYield calculated from 1H NMR. d Isolated yield after basic workup.
First of all, we tried to isolate the product 5b, obtained under the optimized reaction conditions, by means of column chromatography on silica gel, which resulted in a reasonably good yield of 60% (entry 1). The more convenient acid base workup yielded a more complex mixture and required still further column chromatography which reduced the yield even more. Replacing dichloromethane with 1,2-dichloroethane as solvent and heating the reaction mixture at 70 °C resulted in a complex mixture and yielded 5b only in 5% yield (entry 2). Since there have been precedents1 that the use of fluorinated solvents can result in extraordinary effects on the efficiency, regioselectivity and stereoselectivity of several chemical reactions, we also used hexafluoroisopropanol (HFIP) as co-solvent. This reaction gave a complex mixture with multiple unidentifiable side products. More polar solvents such as THF did not result in any reaction and only starting materials were recovered (entries 3 and 4). An increase in the amount of In(OTf)3 from 25 mol% to 40 mol%, did not show a relevant improvement and product 5b was isolated in 64% yield. Decreasing the amount of In(OTf)3 to 10 mol% decreased the yield to 34% (entries 5 and 6). When the reaction was conducted with an excess of phenylacetylene (2b) (1.5 equiv) a 74% yield was obtained
3
(entry 7). Further improvement in the reaction was made by using 2 equivalents of phenylacetylene which delivered the product 5b in 80% yield (entry 8). Under this condition the crude reaction mixture was purer and the formation of hemiaminal side product 5b' could be completely avoided as it was not observed in the 1H NMR. With 2.5 equivalents of phenylacetylene 81% yield was obtained, which is not a substantial improvement compared to that from the previous reaction (entry 9).
4
1. Copies of 1H and 13C spectra of starting imines
N-(2,2,4-Trichloro-1-butylidene)ethylamine (1a)
ClH
N
ClCl
1a
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)
2.59
4.26
0.89
1.51
2.95
1.30
2.80
2.81
1.00
1.05
01.
079
1.10
31.
108
1.13
11.
160
1.20
61.
235
1.26
42.
343
2.36
42.
371
2.39
22.
400
2.40
62.
420
2.43
62.
442
2.47
22.
607
2.63
72.
650
2.66
32.
678
2.69
32.
698
2.70
72.
713
2.72
72.
733
2.74
22.
755
2.76
32.
772
2.78
42.
801
2.83
02.
896
2.90
62.
922
2.92
62.
928
2.93
52.
951
2.96
02.
988
3.00
23.
016
3.03
23.
045
3.05
03.
062
3.07
33.
080
3.09
13.
106
3.11
03.
121
3.12
93.
135
3.14
13.
158
3.17
13.
498
3.50
33.
527
3.53
23.
556
3.56
13.
585
3.59
03.
605
3.80
43.
813
3.82
83.
835
3.83
73.
842
3.85
73.
867
7.26
37.
723
7.72
87.
733
5
0102030405060708090100110120130140150160170180f1 (ppm)
15.3
83
39.3
40
46.0
04
53.7
10
76.4
9277
.000
77.5
08
85.7
48
89.7
93
158.
304
Figure 1. 1H (250 MHz) and 13C (62.90 MHz) NMR spectra of 1a in CDCl3.
N-(2,2,4-Trichlorobutylidene)propan-1-amine (1b)
ClH
N
ClCl
1b
6
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)
3.19
2.10
2.09
2.07
2.11
1.00
0.89
50.
914
0.93
2
7.27
62.93.03.13.23.33.43.53.63.73.83.9
f1 (ppm)
2.91
22.
928
2.93
12.
932
2.93
72.
952
3.44
03.
443
3.45
73.
460
3.47
43.
477
3.80
33.
809
3.81
93.
824
3.82
73.
837
3.84
3
1.601.651.70f1 (ppm)
1.60
91.
627
1.64
51.
663
1.68
11.
699
7.717.727.73f1 (ppm)
7.71
57.
718
7.72
1
0102030405060708090100110120130140150160170180f1 (ppm)
11.5
15
23.2
67
39.2
70
45.9
99
60.9
81
76.6
8277
.000
77.3
18
85.6
78
158.
684
Figure 2. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 1b in CDCl3.
7
N-(2,2,4-Trichlorobutylidene)propan-2-amine (1c)
ClH
N
ClCl
1c
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)
6.43
2.12
1.04
2.10
1.00
1.17
31.
189
7.71
4
3.453.503.55f1 (ppm)
3.43
93.
455
3.47
13.
487
3.50
23.
518
3.53
4
1.171.19f1 (ppm)
1.17
3
1.18
9
2.902.922.942.96f1 (ppm)
2.91
22.
918
2.92
82.
933
2.93
72.
946
2.95
23.803.823.843.86
f1 (ppm)
3.81
03.
815
3.82
53.
830
3.83
33.
843
3.84
9
8
0102030405060708090100110120130140150160170180f1 (ppm)
23.2
30
39.2
33
45.8
14
59.4
61
76.4
9277
.000
77.5
09
85.7
49
156.
124
Figure 3. 1H (400 MHz) and 13C (62.90 MHz) NMR spectra of 1c in CDCl3.
N-(2,2,4-Trichlorobutylidene)prop-2-en-1-amine (1d)
ClH
N
ClCl
1d
9
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)
2.31
2.37
2.30
2.58
1.34
1.00
5.88
55.
908
5.92
55.
930
5.94
75.
955
5.96
15.
970
5.97
85.
995
6.00
06.
018
6.04
0
7.26
2
7.74
77.
753
7.75
8
5.135.155.175.195.215.23f1 (ppm)
5.14
35.
149
5.15
65.
161
5.16
65.
172
5.17
8
5.20
65.
212
5.21
95.
226
5.23
2
4.124.144.164.18f1 (ppm)
4.13
04.
136
4.14
24.
148
4.15
24.
158
4.16
44.
170
2.82.93.03.13.23.33.43.53.63.73.83.9f1 (ppm)
2.91
72.
927
2.94
32.
947
2.95
62.
971
2.98
0
3.81
33.
822
3.83
73.
844
3.85
13.
867
3.87
6
Figure 4. 1H (250 MHz) and 13C (62.90 MHz) NMR spectra of 1d in CDCl3.
10
N-(2,2,4-Trichlorobutylidene)butan-1-amine (1e)
ClH
N
ClCl
1e
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)
3.88
2.50
2.22
2.28
2.16
2.17
1.00
7.71
47.
717
3.453.503.553.603.653.703.753.803.85f1 (ppm)
3.47
63.
479
3.49
33.
496
3.51
13.
514
3.80
43.
809
3.81
93.
823
3.82
73.
837
3.84
3
2.922.96f1 (ppm)
2.90
72.
913
2.92
32.
927
2.93
22.
941
2.94
7
1.31.41.51.6f1 (ppm)
1.29
41.
312
1.31
71.
330
1.34
91.
368
1.38
7
1.57
11.
588
1.60
81.
619
1.62
61.
643
0.920.96f1 (ppm)
0.91
5
0.93
4
0.95
2
11
0102030405060708090100110120130140150160170180190f1 (ppm)
13.6
05
20.0
76
32.0
41
39.2
22
45.9
28
58.9
55
76.6
8277
.000
77.3
18
85.6
38
158.
520
Figure 5. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 1e in CDCl3.
N-tert-Butyl-(2,2,4-trichloro-1-butylidene)amine (1f)
ClH
N
ClCl
1f
12
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)
9.70
2.19
2.16
1.00
1.21
0
2.90
92.
919
2.93
52.
939
2.94
12.
948
2.96
42.
973
3.79
23.
800
3.81
63.
823
3.82
53.
830
3.84
63.
855
7.27
3
7.61
1
2.82.93.03.13.23.33.43.53.63.73.83.9f1 (ppm)
2.90
92.
919
2.93
52.
939
2.94
12.
948
2.96
42.
973
3.79
23.
800
3.81
63.
823
3.82
53.
830
3.84
63.
855
0102030405060708090100110120130140150160170180f1 (ppm)
28.9
68
39.5
33
45.8
55
57.2
42
76.4
9277
.000
77.5
09
86.7
24
153.
515
Figure 6. 1H (250 MHz) and 13C (62.90 MHz) NMR spectra of 1f in CDCl3.
13
2. Formation of side products
3,3-Dichloro-1-isopropylpyrrolidin-2-ol (5c')
N
5c'
OH
ClCl
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)
6.00
0.96
2.10
1.10
2.02
1.00
1.53
2
2.14
1
4.70
5
1.101.15f1 (ppm)
1.10
61.
122
1.13
91.
156
2.52.62.72.82.93.03.13.23.3f1 (ppm)
2.53
62.
553
2.56
52.
571
2.58
82.
608
2.62
92.
662
2.88
82.
910
2.92
62.
948
3.06
03.
064
3.08
23.
094
3.11
03.
127
3.14
33.
159
3.17
5
14
05101520253035404550556065707580859095100105110115120125130135140f1 (ppm)
20.0
2821
.113
42.3
7144
.462
50.0
45
76.6
8277
.000
77.3
18
91.5
1092
.037
Figure 7. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5c' in CDCl3.
1-tert-Butyl-3,3-dichloro-2-hydroxypyrrolidine (5f')
N
5f'
OH
ClCl
15
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)
9.60
2.20
2.24
1.00
1.16
8
2.12
12.
485
2.53
12.
543
2.56
32.
608
2.63
22.
660
2.90
42.
937
2.96
43.
001
3.07
33.
104
3.13
1
4.76
6
7.26
4
2.52.62.72.82.93.03.13.2f1 (ppm)
2.48
52.
531
2.54
32.
563
2.60
82.
632
2.66
0
2.90
42.
937
2.96
43.
001
3.07
33.
104
3.13
1
Figure 8. 1H (400 MHz) NMR spectrum of 5f' in CDCl3.
3. Copies of 1H and 13C spectra of 2-alkynylpyrrolidines 5a-q
3,3-Dichloro-1-ethyl-2-(phenylethynyl)pyrrolidine (5a)
N
5a
ClCl
16
Figure 9. 1H (250 MHz) and 13C (63 MHz) NMR spectra of 5a in CDCl3.
3,3-Dichloro-1-propyl-2-(phenylethynyl)pyrrolidine (5b)
N
5b
ClCl
17
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)
3.17
2.13
1.04
4.25
1.04
1.00
3.04
2.04
4.11
2
7.30
07.
304
7.31
27.
317
7.47
57.
477
7.48
17.
483
7.48
57.
494
7.49
9
2.452.502.552.602.652.702.752.802.852.902.953.003.053.103.15f1 (ppm)
2.48
32.
501
2.51
32.
520
2.53
02.
532
2.54
92.
730
2.73
92.
750
2.76
32.
768
2.77
32.
783
2.79
42.
810
2.81
72.
821
2.82
32.
836
2.83
82.
847
2.84
92.
857
2.86
72.
886
2.89
3
3.03
43.
043
3.06
03.
065
3.07
03.
081
3.09
23.
097
3.12
0
0.910.98f1 (ppm)
0.93
30.
952
0.97
0
1.501.551.601.65f1 (ppm)
1.52
11.
540
1.55
91.
578
1.59
61.
614
0102030405060708090100110120130140150160170f1 (ppm)
11.8
01
21.0
60
45.6
2549
.653
55.3
11
71.2
77
82.9
1188
.442
89.0
72
122.
470
128.
229
128.
542
131.
930
Figure 10. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5b in CDCl3.
18
3,3-Dichloro-1-isopropyl-2-(phenylethynyl)pyrrolidine (5c)
N
5c
ClCl
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)
6.71
2.67
1.20
2.26
1.00
3.18
2.23
4.35
6
7.25
77.
302
7.30
67.
314
7.31
97.
461
7.47
17.
480
7.48
5
2.652.702.752.802.852.902.953.003.053.103.15f1 (ppm)
2.68
82.
700
2.70
92.
722
2.73
52.
744
2.75
62.
776
2.79
12.
799
2.81
42.
826
2.83
42.
849
2.90
72.
920
2.93
02.
942
2.95
22.
965
3.02
73.
042
3.04
93.
054
3.06
43.
071
3.08
63.
103
3.11
9
1.101.151.20f1 (ppm)
1.11
61.
132
1.16
41.
181
19
101520253035404550556065707580859095100105110115120125130135140145f1 (ppm)
-400
-200
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
3000
18.9
1421
.343
26.8
92
45.4
3245
.728
50.8
93
68.5
95
76.4
9277
.000
77.5
07
83.2
03
88.4
8289
.136
122.
492
128.
234
128.
513
131.
882
Cyclohexane
Figure 11. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5c in CDCl3.
1-Allyl-3,3-dichloro-2-(phenylethynyl)pyrrolidine (5d)
N
5d
ClCl
20
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)
3.27
1.10
1.09
1.08
1.00
1.06
1.07
1.04
3.03
1.98
2.74
32.
755
2.76
92.
783
2.78
62.
790
2.79
52.
804
2.81
72.
832
2.83
62.
840
2.86
12.
866
2.86
92.
879
2.88
82.
896
3.05
63.
070
3.07
43.
081
3.08
53.
096
3.10
2
4.13
1
7.25
07.
308
7.31
37.
321
7.32
67.
485
7.49
27.
496
7.50
47.
509
5.155.205.255.305.35f1 (ppm)
5.17
65.
177
5.20
15.
203
5.26
55.
269
5.27
35.
277
5.30
85.
312
5.31
65.
320
3.563.583.603.623.64f1 (ppm)
3.56
63.
569
3.57
33.
579
3.58
33.
587
3.59
93.
603
3.60
73.
613
3.61
73.
620
5.805.855.905.956.006.05f1 (ppm)
5.88
35.
897
5.90
25.
908
5.91
55.
922
5.92
65.
940
5.94
45.
951
5.95
85.
965
5.97
05.
984
3.183.203.223.243.26f1 (ppm)
3.19
3
3.21
2
3.22
7
3.24
5
3.023.043.063.083.103.12f1 (ppm)
3.03
13.
049
3.05
63.
070
3.07
43.
081
3.08
53.
096
3.10
2
3.12
3
101520253035404550556065707580859095100105110115120125130135140145150f1 (ppm)
45.8
99
49.2
20
55.8
60
70.7
29
76.6
8277
.000
77.3
1882
.487
88.8
1888
.937
118.
466
122.
302
128.
240
128.
639
131.
934
133.
915
Figure 12. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5d in CDCl3.
21
22
23
24
25
Figure 13. COSY, HMQC and HMBC spectra of 5d in CDCl3.
1-Butyl-3,3-dichloro-2-(phenylethynyl)pyrrolidine (5e)
N
5e
ClCl
26
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)
3.26
2.17
2.13
1.06
4.39
1.08
1.00
3.00
2.06
0.91
80.
936
0.95
5
4.11
7
7.24
77.
302
7.30
67.
314
7.31
97.
474
7.48
47.
493
7.49
8
1.301.351.401.451.501.551.601.65f1 (ppm)
1.34
31.
355
1.36
21.
373
1.37
91.
397
1.41
51.
431
1.49
31.
501
1.50
91.
517
1.52
41.
532
1.53
91.
547
1.55
71.
560
1.57
7
2.452.502.552.602.652.702.752.802.852.902.953.003.053.103.153.20f1 (ppm)
2.51
22.
532
2.54
22.
548
2.55
72.
563
2.57
82.
742
2.75
32.
766
2.77
72.
787
2.79
92.
814
2.82
42.
851
2.87
02.
887
2.89
32.
900
2.91
02.
918
2.93
9
3.03
53.
047
3.06
13.
072
3.08
33.
094
3.09
83.
120
0102030405060708090100110120130140150160170f1 (ppm)
13.9
24
20.5
04
29.8
70
45.8
0449
.639
53.0
87
71.3
0776
.685
77.0
0377
.320
82.9
1288
.432
89.0
65
122.
476
128.
222
128.
523
131.
909
Figure 14. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5e in CDCl3.
27
3,3-Dichloro-1-propyl-2-(ortho-tolylethynyl)pyrrolidine (5f)
N
5f
ClCl
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)
3.31
2.44
3.22
1.13
4.40
1.09
1.00
1.08
2.07
1.06
0.93
80.
956
0.97
5
2.46
6
4.18
1
1.551.601.65f1 (ppm)
1.53
31.
551
1.57
01.
589
1.60
71.
626
2.502.552.602.652.702.752.802.852.902.953.003.053.103.15f1 (ppm)
2.51
62.
534
2.54
52.
552
2.56
32.
581
2.73
92.
759
2.76
52.
777
2.78
52.
804
2.81
22.
826
2.83
02.
836
2.84
52.
857
2.86
12.
866
2.87
52.
883
2.89
5
3.01
73.
045
3.06
33.
071
3.07
53.
084
3.10
5
7.057.107.157.207.257.307.357.407.457.50f1 (ppm)
7.11
77.
121
7.13
57.
138
7.13
97.
153
7.15
7
7.19
37.
208
7.21
37.
217
7.23
17.
234
7.25
07.
256
7.44
7
7.46
6
28
0102030405060708090100110120130140150160170f1 (ppm)
11.8
17
20.8
3021
.105
45.7
30
49.6
34
55.1
59
71.2
31
76.6
8277
.000
77.3
17
86.6
6787
.364
89.1
39
122.
322
125.
456
128.
517
129.
405
132.
250
140.
519
Figure 15. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5f in CDCl3.
3,3-Dichloro-1-propyl-2-(para-tolylethynyl)pyrrolidine (5g)
N
5g
ClCl
29
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)
3.25
2.20
3.55
1.11
4.40
1.12
1.00
2.30
2.16
0.93
00.
949
0.96
7
2.34
5
4.10
3
2.452.502.552.602.652.702.752.802.852.902.953.003.053.103.15f1 (ppm)
2.47
82.
497
2.51
52.
527
2.54
4
2.72
52.
740
2.75
12.
765
2.77
52.
786
2.79
62.
812
2.81
62.
823
2.83
42.
837
2.84
72.
850
2.85
52.
865
2.86
92.
885
2.89
53.
034
3.04
33.
060
3.07
03.
082
3.09
23.
097
1.501.551.601.65f1 (ppm)
1.52
11.
540
1.55
91.
577
1.59
61.
614
7.17.27.37.47.5f1 (ppm)
7.10
67.
126
7.25
1
7.36
97.
390
0102030405060708090100110120130140150160170f1 (ppm)
11.8
25
21.0
7921
.463
45.8
0749
.607
55.3
23
71.3
2776
.682
77.0
0077
.318
82.1
87
88.5
7389
.171
119.
419
128.
978
131.
828
138.
679
Figure 16. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5g in CDCl3.
30
3,3-Dichloro-2-((4-ethylphenyl)ethynyl)-1-propylpyrrolidine (5h)
N
5h
ClCl
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)
3.16
3.41
4.39
1.10
2.43
4.41
1.13
1.00
2.24
2.01
0.93
00.
949
0.96
71.
204
1.22
31.
242
4.10
8
2.452.502.552.602.652.702.752.802.852.902.953.003.053.103.15f1 (ppm)
2.48
22.
500
2.51
12.
518
2.53
02.
548
2.61
52.
634
2.65
32.
672
2.73
62.
745
2.75
62.
768
2.77
72.
781
2.79
12.
803
2.81
72.
827
2.83
42.
836
2.84
52.
851
2.85
42.
865
2.87
32.
884
3.05
93.
071
3.08
33.
093
3.09
7
7.17.27.37.47.5f1 (ppm)
7.13
57.
136
7.15
6
7.39
97.
403
7.41
57.
419
1.501.551.601.65f1 (ppm)
1.52
31.
546
1.56
01.
579
1.59
81.
616
31
0102030405060708090100110120130140150160170180f1 (ppm)
11.7
8615
.371
21.0
55
28.8
13
45.7
6149
.650
55.3
16
71.2
8476
.683
77.0
0077
.318
82.0
96
88.5
8589
.143
119.
602
127.
806
131.
934
145.
035
Figure 17. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5h in CDCl3.
3,3-Dichloro-2-((3-methoxyphenyl)ethynyl)-1-propylpyrrolidine (5i)
5i
N
ClCl
OMe
32
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)
3.27
2.47
1.08
4.27
1.05
3.11
1.00
1.03
1.02
1.03
1.35
0.93
50.
953
0.97
2
3.80
5
4.10
56.856.906.957.007.057.107.157.207.25
f1 (ppm)
6.87
66.
878
6.88
26.
884
6.89
66.
899
6.90
36.
905
7.01
37.
016
7.01
97.
022
7.08
17.
083
7.08
67.
100
7.10
27.
105
7.20
67.
226
7.24
67.
259
2.52.62.72.82.93.03.1f1 (ppm)
2.47
62.
494
2.50
52.
512
2.52
42.
542
2.73
62.
743
2.75
42.
764
2.77
82.
786
2.80
02.
804
2.81
82.
830
2.83
52.
839
2.84
82.
851
2.85
92.
863
2.86
92.
879
2.89
92.
906
3.05
63.
086
3.09
23.
104
3.11
43.
121
1.551.60f1 (ppm)
1.52
81.
547
1.56
61.
585
1.60
31.
622
0102030405060708090100110120130140150160170f1 (ppm)
11.8
38
21.0
85
45.8
05
49.6
56
55.3
0055
.377
71.3
18
76.6
8377
.000
77.3
18
82.7
57
88.2
8289
.063
115.
168
116.
772
123.
422
124.
513
129.
320
159.
252
Figure 18. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5i in CDCl3.
33
3,3-Dichloro-2-((4-chlorophenyl)ethynyl)-1-propylpyrrolidine (5j)
5j
N
ClCl
Cl
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
3.00
2.05
1.00
3.98
1.00
0.94
2.10
2.11
0.93
0.95
0.97
4.09
7.257.307.357.407.45f1 (ppm)
7.28
7.30
7.40
7.42
2.472.492.512.532.55f1 (ppm)
2.47
2.49
2.50
2.50
2.51
2.52
2.53
1.501.551.60f1 (ppm)
1.52
1.54
1.56
1.58
1.59
1.61
2.702.752.802.852.902.953.003.053.103.15f1 (ppm)
34
0102030405060708090100110120130140150160170f1 (ppm)
11.7
90
21.0
22
45.8
08
49.7
39
55.4
63
71.3
39
76.6
8277
.000
77.3
17
88.9
35
120.
922
128.
622
133.
187
134.
699
Figure 19. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5j in CDCl3.
3,3-Dichloro-2-((4-fluoro-3-methylphenyl)ethynyl)-1-propylpyrrolidine (5k)
5k
N
ClCl
F
35
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)
3.32
2.16
3.26
1.05
4.36
1.15
1.00
1.13
2.21
0.93
50.
954
0.97
2
2.24
72.
252
4.08
7
6.906.957.007.057.107.157.207.257.307.357.40f1 (ppm)
6.91
96.
941
6.96
3
7.26
87.
273
7.28
17.
286
7.29
47.
302
7.30
77.
318
7.32
17.
336
7.33
9
2.52.62.72.82.93.03.13.2f1 (ppm)
2.45
82.
507
2.52
1
2.72
82.
737
2.74
62.
757
2.77
92.
817
2.82
62.
837
2.85
22.
866
2.87
12.
886
3.08
53.
097
3.10
8
1.501.551.60f1 (ppm)
1.52
71.
546
1.56
41.
583
1.60
11.
619
0102030405060708090100110120130140150160170f1 (ppm)
11.8
014
.26
14.2
9
21.0
3
45.7
8
49.6
9
55.3
9
71.3
0
76.6
8
82.2
1
87.6
589
.07
160.
1416
2.61
116118120122124126128130132134136f1 (ppm)
115.
022
115.
253
118.
107
125.
060
125.
240
131.
149
131.
232
135.
120
135.
175
14.114.4f1 (ppm)
1433
.188
1436
.687
Figure 20. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5k in CDCl3.
36
3,3-Dichloro-2-((4-bromophenyl)ethynyl)-1-propylpyrrolidine (5l)
5l
N
ClCl
Br
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
3.09
2.04
1.15
4.34
1.05
1.00
2.11
2.17
0.93
30.
951
0.97
0
4.08
8
7.327.347.367.387.407.427.447.467.48f1 (ppm)
7.32
97.
335
7.34
07.
352
7.35
77.
362
7.43
67.
441
7.44
67.
458
7.46
37.
468
1.501.551.60f1 (ppm)
1.52
11.
540
1.55
91.
577
1.59
61.
614
2.52.62.72.82.93.03.1f1 (ppm)
2.47
02.
488
2.50
02.
507
2.51
92.
536
37
0102030405060708090100110120130140150f1 (ppm)
1.00
1
11.7
73
21.0
26
29.6
88
45.7
90
49.7
92
55.4
93
71.3
6376
.682
77.0
0077
.317
88.9
23
121.
341
122.
924
131.
574
133.
403
Figure 21. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5l in CDCl3.
3,3-Dichloro-2-(cyclohexylethynyl)-1-propylpyrrolidine (5m)
5m
N
ClCl
38
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
3.19
3.31
5.66
4.31
1.07
1.05
4.30
1.06
1.00
0.91
00.
928
0.94
7
1.251.301.351.401.451.501.551.601.651.701.751.801.851.90f1 (ppm)
1.28
81.
304
1.31
21.
321
1.34
11.
355
1.36
01.
384
1.39
21.
407
1.41
5
1.47
71.
497
1.51
51.
521
1.53
41.
548
1.55
31.
570
1.68
11.
689
1.69
81.
706
1.71
31.
721
1.73
01.
737
1.74
41.
753
1.76
31.
770
1.78
01.
788
1.80
31.
812
1.82
0
2.352.402.452.502.552.602.652.702.752.802.852.902.953.003.05f1 (ppm)
2.37
82.
396
2.40
72.
414
2.42
42.
427
2.44
42.
480
2.48
42.
496
2.50
12.
505
2.51
42.
522
2.52
62.
664
2.67
22.
675
2.68
32.
693
2.69
72.
698
2.70
52.
713
2.71
92.
737
2.74
42.
762
2.76
52.
769
2.77
32.
785
2.78
92.
793
2.80
42.
808
2.81
32.
831
2.95
82.
985
2.98
82.
997
3.00
83.
018
3.02
5
3.843.86f1 (ppm)
3.85
03.
854
05101520253035404550556065707580859095100105110115120125f1 (ppm)
11.8
38
20.9
53
24.5
2225
.933
28.9
44
32.4
91
45.6
68
49.5
32
55.1
87
70.8
22
73.5
47
89.4
31
93.3
18
Figure 22. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5m in CDCl3.
39
3,3-Dichloro-2-(cyclopentylethynyl)-1-propylpyrrolidine (5n)
5n
N
ClCl
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)
3.26
8.69
2.35
1.08
5.40
1.00
1.00
0.00
00.
070
0.90
90.
928
0.94
6
7.27
0
2.352.402.452.502.552.602.652.702.752.802.85f1 (ppm)
2.35
92.
377
2.38
82.
395
2.40
42.
408
2.42
5
2.65
62.
678
2.68
32.
693
2.70
02.
707
2.71
42.
720
2.72
82.
736
2.74
12.
750
2.75
82.
763
2.77
02.
781
2.79
02.
803
2.81
02.
828
1.451.501.551.601.651.701.751.801.851.901.952.00f1 (ppm)
1.49
51.
514
1.53
31.
551
1.56
81.
574
1.58
11.
584
1.64
41.
654
1.66
01.
672
1.67
61.
685
1.68
91.
703
1.71
21.
721
1.72
41.
728
1.73
71.
742
1.74
91.
763
1.89
11.
903
1.91
01.
921
1.93
5
2.983.003.023.04f1 (ppm)
2.98
62.
993
3.00
23.
007
3.01
43.
024
3.03
1
3.82f1 (ppm)
3.82
23.
826
40
05101520253035404550556065707580859095100105110115120125130f1 (ppm)
11.8
23
20.9
41
24.8
63
30.2
23
33.8
51
45.6
92
49.5
13
55.2
50
70.9
3473
.072
76.6
8277
.000
77.3
18
89.4
51
93.6
69
Figure 23. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5n in CDCl3.
3,3-Dichloro-2-(pent-1-ynyl)-1-propylpyrrolidine (5o)
5o
N
ClCl
41
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.0f1 (ppm)
3.44
3.17
4.53
2.11
1.12
4.59
1.03
1.00
-0.0
0
0.91
0.93
0.95
0.99
1.01
1.03kh-132
3.803.823.843.86f1 (ppm)
3.82
kh-132
2.202.252.302.352.402.45f1 (ppm)
2.24
2.24
2.26
2.26
2.27
2.28
2.36
2.38
2.40
2.43
kh-132
1.481.501.521.541.561.581.601.62f1 (ppm)
1.48
1.50
1.52
1.54
1.55
1.57
1.58
1.60
1.62
kh-132
2.652.702.752.802.852.902.953.003.053.10f1 (ppm)
2.65
2.65
2.68
2.69
2.70
2.75
2.77
2.79
2.81
2.84
2.84
3.01
3.01
3.02
3.02
3.03
3.03
3.04
3.04
3.05
kh-132
0102030405060708090100110120130140150f1 (ppm)
11.7
7913
.372
20.7
6520
.948
22.0
40
45.6
56
49.4
70
55.2
42
70.9
6273
.765
76.6
8277
.000
77.3
18
89.0
2989
.374
Figure 24. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5o in CDCl3.
42
3,3-Dichloro-2-(hex-1-ynyl)-1-propylpyrrolidine (5p)
5p
N
ClCl
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
6.87
6.36
1.91
1.05
1.02
1.00
3.81
3.81
3.82
3.803.813.823.83f1 (ppm)
1523
.027
1524
.992
1526
.960
0.900.95f1 (ppm)
0.90
0.91
0.92
0.93
0.94
0.95
2.252.302.352.40f1 (ppm)
2.26
2.27
2.28
2.30
2.30
2.35
2.37
2.38
2.39
2.40
2.42
2.602.652.702.752.802.852.902.953.003.053.10f1 (ppm)
1.401.451.501.551.60f1 (ppm)
43
05101520253035404550556065707580859095100105110115120125f1 (ppm)
11.7
6913
.494
18.4
4420
.922
21.8
17
30.6
28
45.6
42
49.5
08
55.2
54
70.9
32
73.5
2576
.682
77.0
0077
.318
89.3
31
Figure 25. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5p in CDCl3.
3,3-Dichloro-2-(3,3-dimethylbut-1-ynyl)-1-propylpyrrolidine (5q)
5q
N
ClCl
44
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
3.29
9.21
2.23
1.00
4.31
1.22
1.00
1.25
7
3.86
9
7.28
7
2.402.452.502.552.602.652.702.752.802.852.902.953.003.053.10f1 (ppm)
2.40
62.
424
2.43
52.
443
2.45
42.
472
2.66
22.
683
2.68
82.
700
2.70
82.
726
2.73
52.
744
2.74
72.
751
2.75
62.
765
2.77
62.
781
2.78
62.
795
2.80
32.
811
2.94
42.
954
2.97
12.
988
2.99
83.
001
3.01
03.
031
0.900.95f1 (ppm)
0.91
50.
933
0.95
2
1.501.55f1 (ppm)
1.49
21.
511
1.53
01.
549
1.56
81.
586
05101520253035404550556065707580859095100105110115120125f1 (ppm)
11.7
64
20.7
74
27.5
29
30.8
34
45.6
07
49.5
77
55.1
52
70.6
0871
.616
76.6
8277
.000
77.3
18
89.2
13
97.8
50
Figure 26. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 5q in CDCl3.
45
4. Copies of 1H and 13C spectra of 2-alkenylpyrroles 6a-f and 7
(E/Z)-3-Chloro-1-propyl-2-styryl-1H-pyrrole (6a)/(6b)
6a/6b
N
Cl
0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)
-10000
0
10000
20000
30000
40000
50000
60000
70000
80000
90000
1E+05
1E+05
1E+05
1E+05
1E+05
3.04
2.63
2.11
1.68
2.00
1.66
1.77
0.98
1.74
0.98
0.80
1.87
4.75
1.98
1.61
0.80
70.
826
0.84
40.
943
0.96
10.
980
1.59
11.
609
1.62
81.
646
1.66
41.
683
1.80
4
3.55
23.
570
3.58
8
3.92
03.
939
3.95
6
6.12
66.
133
6.15
76.
164
6.31
06.
340
6.60
8
6.91
1
7.17
07.
213
7.22
97.
240
7.27
07.
280
7.28
87.
300
7.35
97.
379
7.39
77.
489
7.50
8
Figure 27. 1H (400 MHz) NMR spectra of 6a/6b (mixture of E and Z) in CDCl3.
46
(E)-3-Chloro-1-propyl-2-styryl-1H-pyrrole (6a)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0f1 (ppm)
0.18
3.02
2.06
0.11
2.00
0.92
0.96
1.00
2.98
1.96
1.95
0.91
10.
929
0.94
81.
519
1.73
61.
754
1.77
31.
791
1.80
91.
828
3.89
03.
908
3.92
6
6.16.26.36.46.56.66.76.86.97.07.17.27.37.47.5f1 (ppm)
6.12
26.
129
6.57
66.
584
6.87
56.
916
7.22
17.
236
7.25
47.
263
7.32
57.
345
7.36
47.
454
7.47
37.
475
3.803.853.903.954.00f1 (ppm)
3.89
03.
908
3.92
6
47
0102030405060708090100110120130140150160f1 (ppm)
11.1
94
24.3
75
50.0
01
76.6
8277
.000
77.3
17
108.
887
111.
460
115.
477
121.
468
126.
042
127.
282
128.
487
128.
649
134.
165
137.
964
Figure 28. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 6a in CDCl3.
(Z)-3-Chloro-1-propyl-2-styryl-1H-pyrrole (6b)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)
3.02
0.44
2.02
0.28
2.00
0.27
1.05
0.98
0.97
0.99
1.92
3.00
0.33
0.25
0.77
00.
788
0.80
7
1.55
41.
572
1.59
01.
608
1.62
71.
645
3.503.553.603.653.703.753.803.853.903.95f1 (ppm)
3.51
43.
533
3.55
0
3.92
53.
943
3.96
0
6.16.26.36.46.56.66.76.86.97.07.17.27.37.47.5f1 (ppm)
6.08
96.
096
6.27
36.
303
6.57
86.
585
6.66
86.
698
7.10
97.
112
7.12
87.
133
7.17
57.
188
7.19
27.
196
7.20
37.
206
7.21
67.
217
7.22
17.
243
48
0102030405060708090100110120130140150160170180f1 (ppm)
11.0
4911
.128
24.2
3824
.286
49.8
9550
.641
76.6
8277
.000
77.3
18
108.
119
110.
556
116.
938
120.
487
121.
922
125.
509
127.
597
128.
272
128.
336
131.
190
134.
208
137.
058
Figure 29. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 6b in CDCl3.
(E/Z)-1-Butyl-3-chloro-2-styryl-1H-pyrrole (6c)
6c
N
Cl
49
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)
4.96
3.57
3.70
3.12
3.50
2.27
2.83
1.97
2.37
1.37
2.32
1.40
1.00
2.72
6.12
2.34
2.01
0.00
00.
074
0.80
80.
826
0.84
40.
917
0.93
60.
954
3.53.63.73.83.94.0f1 (ppm)
3.53
43.
552
3.57
0
3.91
23.
931
3.94
9
1.11.21.31.4f1 (ppm)
1.15
61.
174
1.19
31.
212
1.23
11.
288
1.30
61.
325
1.34
41.
3631.51.61.71.8
f1 (ppm)
1.50
31.
522
1.53
51.
540
1.54
41.
558
1.70
51.
718
1.72
41.
728
1.74
2
6.06.16.26.36.46.56.66.76.86.97.07.17.27.37.47.57.6f1 (ppm)
6.08
66.
093
6.11
56.
122
6.27
36.
303
6.56
16.
569
6.57
66.
667
6.69
76.
878
6.91
97.
103
7.10
67.
123
7.12
77.
172
7.18
57.
189
7.19
37.
199
7.20
37.
214
7.21
77.
224
7.22
97.
233
7.26
57.
319
7.33
97.
358
7.44
97.
451
7.45
27.
469
7.47
27.
473
50
05101520253035404550556065707580859095100105110115120125130135140145f1 (ppm)
13.5
3213
.625
19.6
9019
.852
33.0
3733
.149
47.9
3648
.092
76.6
8277
.000
77.3
17
108.
122
108.
943
110.
531
111.
487
115.
498
120.
415
125.
487
127.
582
128.
487
134.
178
137.
066
138.
005
106107108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138139f1 (ppm)
108.
122
108.
943
110.
531
111.
487
115.
498
116.
971
120.
415
121.
381
125.
487
126.
041
127.
276
127.
582
128.
267
128.
323
128.
655
131.
159
134.
178
137.
066
138.
005
125.48125.52125.56f1 (ppm)
125.
487
125.
502
Figure 30. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 6c
(mixture of E and Z) in CDCl3.
51
52
53
Figure 31. 2D-NMR spectra of 6c in CDCl3.
(E/Z)-3-Chloro-2-(4-methylstyryl)-1-propyl-1H-pyrrole (6d)
6d
N
Cl
54
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
3.95
3.22
3.19
2.00
7.29
2.00
1.64
1.70
0.92
0.65
0.95
0.92
0.78
3.64
2.20
1.08
1.86
0.77
20.
790
0.80
90.
903
0.92
10.
940
1.57
71.
595
1.61
31.
631
1.76
32.
292
2.35
2
3.52
33.
541
3.55
9
3.87
63.
895
3.91
2
6.16.26.36.46.56.66.76.86.97.07.17.27.37.4f1 (ppm)
6.09
1
6.21
06.
240
6.56
06.
567
6.57
96.
586
6.63
96.
668
6.82
16.
862
7.01
8
7.14
27.
162
7.18
97.
230
7.35
07.
370
3.53.63.73.83.94.0f1 (ppm)
05101520253035404550556065707580859095100105110115120125130135140145150f1 (ppm)
49.850.4f1 (ppm)
49.9
250
.00
24.324.4f1 (ppm)
24.3
424
.37
21.3f1 (ppm)
21.2
121
.25
11.011.5f1 (ppm)
11.0
711
.19
55
105106107108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138139140f1 (ppm)
108.
04
108.
85
110.
37
111.
20
114.
62
115.
96
120.
35
121.
26
125.
7112
5.73
125.
99
126.
81
128.
3012
8.66
129.
0112
9.38
131.
1513
1.70
134.
1813
4.35
135.
22
137.
2113
7.51
Figure 32. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 6d in CDCl3.
(E/Z)-3-Chloro-2-(3-methoxystyryl)-1-propyl-1H-pyrrole (6e)
6e
N
Cl
OMe
56
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)
2.98
2.84
1.99
1.60
2.00
2.88
2.23
1.49
0.77
10.
790
0.80
80.
903
0.92
10.
940
3.52
03.
538
3.55
63.
641
3.82
03.
839
3.87
93.
897
3.91
56.16.26.36.46.56.66.76.86.97.07.17.27.3
f1 (ppm)1.
000.
72
0.94
1.70
1.87
1.84
0.77
0.88
0.77
3.76
2436
.502
2439
.449
2446
.450
2449
.388
2510
.187
2522
.063
2627
.806
2630
.621
2633
.432
2659
.827
2667
.065
2669
.097
2671
.343
2691
.833
2694
.347
2700
.199
2702
.688
2745
.245
2761
.664
2794
.451
2796
.262
2829
.407
2847
.055
2854
.959
2862
.911
2875
.587
2892
.037
2895
.161
2897
.107
2903
.056
1.451.501.551.601.651.701.751.801.85f1 (ppm)
621.
429
628.
769
636.
039
643.
263
650.
599
658.
007
689.
917
697.
269
704.
545
711.
763
719.
097
723.
105
726.
510
0102030405060708090100110120130140150160f1 (ppm)
11.0
811
.20
24.3
324
.38
49.9
150
.01
55.0
055
.28
10.811.211.6f1 (ppm)
11.0
811
.20
24.324.5f1 (ppm)
24.3
324
.38
49.550.0f1 (ppm)
49.9
150
.01
54.855.2f1 (ppm)
55.0
0
55.2
8
57
110115120125130135140145150155160f1 (ppm)
108.
1010
8.94
110.
6011
1.61
114.
21
115.
79
118.
73
120.
5412
1.33
121.
58
125.
40
128.
2912
9.19
129.
51
134.
30
138.
19
139.
50
159.
4215
9.91
111.50111.55111.60111.65111.70f1 (ppm)
111.
61
111.
64
Figure 33. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 6e in CDCl3.
E/Z-(3-Chloro-2-(4-fluoro-3-methylstyryl)-1-propyl-1H-pyrrole (6f)
6f
N
ClF
58
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
3.08
2.89
2.08
1.81
2.95
3.00
2.02
1.75
1.00
0.76
0.95
2.80
0.83
3.18
0.73
0.86
2.33
6.16.26.56.66.76.86.97.07.17.27.3f1 (ppm)
6.09
6.10
6.12
6.22
6.25
6.57
6.57
6.59
6.59
6.62
6.75
6.80
6.83
6.85
6.97
6.99
7.14
7.18
2.152.202.252.30f1 (ppm)
2.16
92.
172
2.29
02.
294
1.551.601.651.701.751.801.85f1 (ppm)
1.56
1.58
1.60
1.62
1.63
1.65
1.73
1.75
1.76
1.78
1.80
1.82
3.53.63.83.94.0f1 (ppm)
3.52
3.54
3.56
3.88
3.90
3.91
0102030405060708090100110120130140150160170f1 (ppm)
14.514.7f1 (ppm)
14.4
914
.52
14.5
614
.60
49.950.1f1 (ppm)
49.8
80
49.9
68
24.324.424.5f1 (ppm)
24.3
0424
.355
10.411.2f1 (ppm)
11.0
4211
.179
59
108110112114116118120122124126128130132134136138140142144146148150152154156158160162164166f1 (ppm)
108.
138
108.
896
110.
501
111.
323
120.
481
121.
365
159160161162f1 (ppm)
159.
449
159.
603
161.
902
162.
048
133.0133.5f1 (ppm)
132.
7313
2.80
132.
84
133.
8113
3.85
129130131132f1 (ppm)
129.
0812
9.13
130.
76
131.
8013
1.85
124.4124.6124.8125.0125.2125.4125.6f1 (ppm)
124.
374
124.
548
124.
735
124.
814
124.
895
125.
071
125.
348
125.
494
114.7114.9115.1115.3115.5116.3116.5f1 (ppm)
114.
737
114.
961
114.
981
115.
004
115.
105
115.
331
116.
317
116.
336
Figure 34. 1H (400 MHz) and 13C (100 MHz) NMR spectra of 6f in CDCl3.
3-Chloro-2-(hex-1-ynyl)-1-propyl-1H-pyrrole (7)
7
N
Cl
60
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
4.59
4.43
8.54
3.60
3.18
2.29
2.22
1.01
1.00
6.06.16.26.36.46.56.6f1 (ppm)
6.01
6.02
6.49
6.50
2.42.52.62.73.53.63.73.83.9f1 (ppm)
2.48
2.49
2.51
3.83
3.85
3.87
1.21.31.41.51.61.71.81.9f1 (ppm)
1.72
1.74
1.76
1.78
1.79
1.81
0.850.900.951.00f1 (ppm)
0.88
0.90
0.91
0.93
0.95
0.97
Figure 35. 1H (400 MHz) NMR spectrum of 7 in CDCl3.
61
5. Mechanistic study for the borontrifluoride mediated reaction of imine with potassium
alkynyltrifluoroborate
Cl
N
H
Ph BF3K
1 equiv BF3.OEt2
DCM, rt, 18 hCl
N
Ph
F2B
Cl
HN
Ph
NF2B
Ph
N
Ph
A
aqueousworkup
aqueousworkup
1a
2a (1 equiv)
5a
X
3a
B
ClCl ClCl ClCl
ClClClCl
+ KBF4
Scheme 1. Reaction mechanism of the Lewis acid promoted Petasis type reaction of α,α,ω-
trichloroaldimines with organotrifluoroborates.
In a previous paper from our lab1 it was established that the reaction of α,α-dichloroaldimines
with potassiumtrifluoroborates results in an aminodifluoroborane intermediate which upon
aqueous workup gives the β,β-dichloroamine. Because a ring closure takes place in the
Petasis reaction of α,α,ω-trichloroaldimines with trifluoroborates, it would be valuable to
establish if the ring closure either occurs during the reaction itself or during the aqueous
workup. Since the aminodifluoroborane nitrogen atom is less nucleophilic it is expected that
ring closure cannot take place after the addition of the alkyne moiety to the imino carbon. As
a consequence the ring closure must occur during the aqueous workup. In order to prove the
existence of an intermediate aminodifluoroborane, the reaction mixture obtained after Petasis
reaction of N-(2,2,4-trichloro-1-butylidene)ethylamine (1a), potassium phenylethynyl-
trifluoroborate (2a) and BF3·OEt2, was filtered, evaporated and analysed by 1H, 19F and 11B
NMR. The solid, which was filtered off prior to evaporation was shown to be KBF4 by
comparison with a commercially available reference sample. The signals in the 1H NMR
(CDCl3) of the filtrate after evaporation were shifted downfield compared to the signals of
3,3-dichloro-2-phenylethynylpyrrolidine (5a), pointing to the existence of an
aminodifluoroborane intermediate A. Especially, the signal at 3.78 ppm is characteristic for a
ClCH2 and not a NCH2, indicating the presence of non-ring closed Mannich product. These
results confirm the earlier stated assumption that first aminodifluoroborane A is formed and
that ring closure takes only place during aqueous workup. A second experiment was executed
to confirm the obtained results. The NMR sample of the filtrate was treated with a few drops
62
of water and the 1H NMR was recorded again to check if trichlorinated Mannich product 3a
was present. In this case the formation of pyrrolidine 5a (18%) and 3a (82%) was observed.
The presence of the latter was interpreted by an upfield shift of all the NMR-signals
compared to the signals of aminodifluoroborane A (striking shift for CCl2CHN from 5.00
ppm (A) to 4.80 ppm (3a)). Scheme 1 depicts the reaction mechanism of the Lewis acid
mediated borono Mannich type reaction of α,α,ω-trichloroaldimines 1 with
organotrifluoroborates 2. First, aminodifluorborane A is formed which after aqueous workup
is turned into the trichlorinated propargylic amine 3a. Subsequently, an intramolecular
nucleophilic substitution of the ω-chloro atom by the amine nitrogen atom of 3a leads to
pyrrolidine 5a.
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)
3.00
0.58
2.16
3.15
1.47
1.07
5.88
0.18
CH2Cl2
1
2
3
4
H5
O6
Cl7
Cl8
Cl9
2,2,4-trichlorobutanal (A')
A' A + A'
1
2
3
4
5
N6
Cl7
Cl8
Cl9
10
CH311
B12
13
14
15
16
17
18
19
F20
F21
A
A A'
B
CH1
2 3
4 5
6
78
A''
A''
A + A''
A
A
Figure 36. 1H (400 MHz) NMR spectra of intermediate A in CDCl3.
6. Mechanistic study for the In(OTf)3 catalyzed reaction of imine with phenylacetylene
To prove that ring closure takes place during the alkynylation, a reaction was carried out
between imine (1b) and phenylacetylene (2 equiv) in the presence of In(OTf)3 (0.25 equiv) in
CH2Cl2 at 50 °C for 18 h. This reaction mixture was evaporated in vacuo and its 1H NMR
was measured. The mass spectrum of the reaction mixture showed a [M+H+] peak at 282
indicating the formation of the pyrrolidine ring during the reaction, while the absence of a
63
peak at 318 excludes the trichlorinated open chain intermediate (Figure 37). The 1H NMR
spectrum (Figure 38) also suggests the formation of a pyrrolidine ring, either complexed with
the Lewis acid or in the form of a hydrochloride salt (X = H or In(OTf)3; Figure 39, triplet at
1.03, multiplet at 1.94-1.83, multiplets at 2.96-3.13 & 3.45 ppm). A very broad peak around 5
ppm accounts for the NCHCCl2 proton and this downfield shift, compared to the NCHCCl2
proton (4.11 ppm) of 5b (Figure 10) is indicative for a positively charged nitrogen atom. A
comparison was made of this spectrum with the 1H NMR of an independently prepared
sample of the hydrochloride of pyrrolidine 5b (Figure 39). Since both spectra are not the
same, it can be concluded that most probably pyrrolidine 5b formed a complex with In(OTf)3
during the reaction.
Figure 37. Mass spectrum of reaction mixture.
64
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.0f1 (ppm)
0.87
3.00
0.59
2.06
0.27
0.86
0.69
0.84
2.24
0.42
1.04
0.66
4.32
2.09
0.13
0.94
00.
959
0.97
71.
012
1.03
11.
049
1.69
81.
717
1.86
51.
883
1.89
21.
907
1.92
52.
800
2.82
03.
043
3.05
03.
059
3.07
13.
110
3.44
9
3.75
73.
777
3.79
6
5.01
05.
128
5.29
2
7.26
17.
298
7.31
37.
321
7.33
27.
337
7.34
87.
350
7.36
07.
378
7.39
77.
427
7.44
67.
464
7.47
77.
481
7.49
77.
500
7.52
17.
557
7.56
07.
578
9.24
0
1
2N+3
4
5
X 7
Cl8
Cl9
10 11 12
13 14
15
1617
18
CH319
Cl-20 B
A'
B + A''
A' A'
B
B
1
2
3
4
H5
O6
Cl7
Cl8
Cl9
A'
CH31
2
3NH24
A'''
12
3
4 5
6 7 CH8
A''
A'''
A'''
A''+ B
Figure 38. 1H (400 MHz) NMR spectra of reaction mixture in CDCl3.
0123456789101112131415f1 (ppm)
3.00
1.78
1.12
1.29
0.14
3.38
1.22
1.28
1.23
0.90
3.50
2.04
0.91
1.02
41.
042
1.06
11.
225
1.23
41.
242
1.25
71.
285
2.99
03.
006
3.01
73.
035
3.05
23.
070
3.30
13.
514
3.64
13.
695
3.71
33.
730
3.74
84.
096
4.11
34.
131
4.14
9
5.38
9
7.37
67.
394
7.41
37.
438
7.45
77.
475
7.55
57.
573
13.6
15
EtOH
1
2N+3
4
5
H6
7
Cl8
Cl9
10 11 12
13 14
15
1617
18
CH319
Cl-20
1.01.11.21.3f1 (ppm)
1.02
41.
042
1.06
1
1.22
51.
234
1.24
21.
257
1.28
5
2.53.03.54.04.5f1 (ppm)
2.99
03.
006
3.01
73.
035
3.05
23.
070
3.30
13.
514
4.09
64.
113
4.13
14.
149
Figure 39. 1H (400 MHz) NMR spectra of hydrochloride salt of pyrrolidine 5b in CDCl3.
65
7. Copies of 1H and 13C spectra of 3,3-dichloro-1-ethyl-2-(2-phenylvinyl)pyrrolidine
(12a)
12a
N
ClCl
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)
3.13
0.59
1.11
1.06
3.16
2.04
1.00
1.00
3.23
1.96
1.07
01.
099
1.12
81.
257
2.16
7
7.25
57.
265
7.28
67.
293
7.29
97.
312
7.31
87.
336
7.34
27.
369
7.37
67.
445
7.45
07.
469
7.47
77.
484
2.302.402.502.602.702.802.903.00f1 (ppm)
2.28
52.
313
2.34
12.
362
2.39
02.
418
2.51
42.
542
2.55
12.
578
2.58
72.
614
2.68
62.
705
2.72
22.
742
2.76
22.
778
2.79
82.
805
2.82
72.
835
2.85
42.
858
2.86
42.
884
2.89
42.
914
2.94
2
3.33.4f1 (ppm)
3.30
33.
336
3.34
03.
355
3.36
03.
392
3.40
13.
4346.16.26.36.46.56.66.76.8
f1 (ppm)
6.15
36.
186
6.21
76.
249
6.67
1
6.73
4
66
102030405060708090100110120130140150160170180f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
140012.5
54
46.5
1847
.902
49.3
84
76.4
9277
.000
77.5
0880
.670
91.5
86
125.
586
126.
796
128.
048
128.
595
136.
044
136.
372
Figure 40. 1H (250 MHz) and 13C (63 MHz) NMR spectra of 12a in CDCl3.
8. Copies of 1H and 13C Spectra of 13a and 14a
3-Chloro-1-ethyl-2-(2-phenylvinyl)-1H-pyrrole (13a)
13aN
Cl
67
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)
2.93
2.00
0.90
0.93
1.01
2.27
1.99
1.93
0.00
0
1.351.44f1 (ppm)
1.35
61.
385
1.41
4
3.903.954.004.05f1 (ppm)
3.94
53.
974
4.00
34.
032
6.16.26.36.46.56.66.7f1 (ppm)
6.12
86.
140
6.58
46.
596
6.86.97.07.17.27.37.47.57.6f1 (ppm)
6.87
2
6.93
8
7.20
17.
213
7.22
67.
230
7.23
97.
254
7.25
97.
264
7.27
97.
311
7.33
57.
342
7.36
37.
370
7.45
57.
484
7.49
0
102030405060708090100110120130140150160f1 (ppm)
-200
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000
2100
2200
2300
2400
16.4
15
42.9
98
76.4
9277
.000
77.5
08
109.
085
111.
497
115.
336
120.
461
125.
318
126.
036
127.
294
128.
638
137.
911
Figure 41. 1H (250 MHz) and 13C (63 MHz) NMR spectra of 13a in CDCl3.
68
3-Chloro-1-ethyl-2-(2-phenylethyl)-1H-pyrrole (14a)
14aN
Cl
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
3.25
3.96
2.00
0.91
0.95
5.02
0.00
0
2.82
52.
837
2.85
12.
862
2.87
3
6.06.16.26.36.46.5f1 (ppm)
6.05
56.
067
6.45
96.
471
7.107.157.207.257.30f1 (ppm)
7.12
57.
142
7.15
17.
158
7.19
27.
202
7.21
77.
219
7.22
67.
246
7.26
87.
275
7.29
57.
302
7.30
9
1.201.251.30f1 (ppm)
1.22
1
1.25
1
1.28
0
3.553.603.65f1 (ppm)
3.57
6
3.60
5
3.63
4
3.66
3
69
0102030405060708090100110120130140150160170f1 (ppm)
16.4
52
26.1
07
35.6
47
41.8
09
76.4
9277
.000
77.5
08
107.
158
109.
020
117.
623
126.
100
128.
392
128.
448
141.
236
Figure 42. 1H (250 MHz) and 13C (63 MHz) NMR spectra of 14a in CDCl3.
9. References
1. (a) K. K. Nanda and B. W. Trotter, Tetrahedron Lett., 2005, 46, 2025; (b) C. Cativiella, J.
I. García, J. A. Mayoral and L. Salvatella, Can. J. Chem., 1994, 72, 308. (c) H. C. Brown,
E. J. Mead and C. J. Shoaf, J. Am. Chem. Soc., 1956, 78, 3613; (d) D. Vuluga, J. Legros,
B. Crousse, A. M. Z. Slawin, C. Laurence, P. Nicolet and D. Bonnet-Delpon, J. Org.
Chem., 2011, 76, 1126-1133; (e) C. C. Malakar, S. Stas, W. Herrebout and K. Abbaspour
Tehrani, Chem. Eur. J., 2013, 19, 14263; (f) G. A. Price, A. K. Brisdon, K. R. Flower, R.
G. Pritchard and P. Quayle, Tetrahedron Lett., 2014, 55, 151.
2. C. C. Malakar, B. U. W. Maes and K. Abbaspour Tehrani, Adv. Synth. Catal., 2012, 354,
3461.
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