Synthesis of alkaloids by stevens rearrangement of nitrile-stabilized ammonium ylides: (±)-laudanosine, (±)-laudanidine, (±)-armepavine, (±)-7-methoxycryptopleurine, and (±)-xylopinine

Article abstract of DOI:10.1021/jo400659n

The Stevens rearrangement of nitrile-stabilized ammonium ylides in conjunction with the reductive removal of the nitrile function permits the facile construction of α-branched amines from α-aminonitriles. We employed this reaction sequence for the preparation of (±)-laudanosine, (±)-laudanidine and (±)-armepavine, (±)-7- methoxycryptopleurine, and (±)-xylopinine from two closely related and readily accessible bicyclic α-aminonitriles. The final products were obtained in high to almost quantitative yields (71-98%) from the quaternary ammonium salts obtained by N-alkylation of these starting materials.

Full text of DOI:10.1021/jo400659n

Subscriber access provided by Criss Library, UNO
Article
Synthesis of Alkaloids by Stevens Rearrangement of Nitrile-Stabilized
Ammonium Ylides: (+/-)-Laudanosine, (+/-)-Laudanidine, (+/-)-
Armepavine, (+/-)-7-Methoxycryptopleurine, and (+/-)-Xylopinine
Julio Cesar Orejarena Pacheco, Günther Lahm, and Till Opatz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400659n • Publication Date (Web): 01 May 2013
Downloaded from http://pubs.acs.org on May 8, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of Alkaloids by Stevens Rearrangement of Nitrile-
Stabilized Ammonium Ylides: (±)-Laudanosine, (±)-
Laudanidine, (±)-Armepavine, (±)-7-Methoxycryptopleurine,
and (±)-Xylopinine
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Julio Cesar Orejarena Pacheco, Günther Lahm, and Till Opatz*
Address: Institute of Organic Chemistry, University of Mainz, Duesbergweg 10–14, Dꢀ55128
Mainz, Germany
Email: opatz@uniꢀmainz.de
Table of Contents/ Abstract Graphic
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 34
1
2
3
4
5
6
7
8
9
Abstract
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The Stevens rearrangement of nitrileꢀstabilized ammonium ylides in conjunction with the
reductive removal of the nitrile function permits the facile construction of αꢀbranched amines
from αꢀaminonitriles. We employed this reaction sequence for the preparation of (±)ꢀ
laudanosine, (±)ꢀlaudanidine and (±)ꢀarmepavine, (±)ꢀ7-methoxycryptopleurine, and (±)ꢀ
xylopinine from two closely related and readily accessible bicyclic α ꢀaminonitriles. The final
products were obtained in high to almost quantitative yields (71–98%) from the quaternary
ammonium salts obtained by Nꢀalkylation of these starting materials.
Introduction
Due to its strong anion stabilizing capacity, the nitrile group can for instance be used for the
preparation of stable αꢀaminocarbanions1ꢀ3 carrying free NHꢀprotons without the necessity of
using a protecting group. We have employed this methodology for the preparation of various Nꢀ
heterocycles and alkaloids but an additional conjugative stabilization of the anion is required to
suppress the competing retroꢀStrecker reaction in the deprotonation step.4ꢀ6 The same effect
permits the facile generation of stabilized ammonium ylides by Nꢀalkylation of αꢀaminonitriles
and their subsequent deprotonation. Ylides of this type7ꢀ10 have e.g. been used in [2,3]ꢀ
sigmatropic rearrangements involving allylic substituents11ꢀ15 or in substitution and addition
reactions16ꢀ20. In contrast, Stevens rearrangements of nitrileꢀstabilized ammonium ylides have
only rarely been reported.21ꢀ23 An interesting exception is the ring enlargement of Liu and Liang
who combined the [1,2]ꢀmigration with a reductive decyanation.24 The lability of the C–CN bond
ACS Paragon Plus Environment

Page 3 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
in the product of this rearrangement in a polar environment leads to the formation of small
concentrations of the cyanideꢀiminium ion pair, the cation of which can easily be trapped by a
hydride ion from a mild reductant such as NaCNBH3 or NaBH4.25ꢀ29 The net result of this
reaction sequence is the substitution of the nitrile group in the parent aminonitrile by the Nꢀalkyl
group with the higher migratory aptitude. Although the Stevens rearrangement of nonstabilized
ylides prepared from 1,2,3,4ꢀtetrahydrosoquinolinium salts was achieved by Grethe et al., harsh
reaction conditions30 were required and resulted in low yields.31 In contrast, the nitrile group in
the αꢀposition of the isoquinolinium salt allows the use of milder reaction conditions and
significantly improves purity and yield of the products (Scheme 1).32ꢀ34 The method also
compares favourably with the use of αꢀstannylated ammonium salts as recently exemplified by a
fiveꢀstep synthesis of the phenanthridolizidine alkaloid (±)ꢀtylophorine.35,36
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 34
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Stevens rearrangement/reduction sequence
Results and Discussion
In continuation of our studies, we herein report on the application of the traceless N→Cꢀshift of
benzylic substituents for the preparation of benzylisoquinolineꢀ, tetrahydroprotoberberineꢀ and
phenanthroquinolizidineꢀtype alkaloids from readily available precursors.
Polycyclic alkaloids belonging to the aboveꢀmentioned structural classes play an important
role in the world of biologically active alkaloids and have been demonstrated to possess antiꢀ
inflammatory,37,38 antiꢀallergic,39,40 antiꢀasthmatic,39,40 antibacterial,41 antifungal,42 antitumor43
and antiviral44 effects (Figure 1). In the phenanthroꢀalkaloids, the quinolizidineꢀbased compounds
ACS Paragon Plus Environment

Page 5 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
regularly show a much higher potency in antiproliferative assays than their indolizidine
counterparts.45,46
7
8
9
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeO
MeO
MeO
MeO
N
Me
N
MeO
OMe
OH
(±)-Laudanidine (2)
(±)-7-Methoxycryptopleurine (1)
MeO
MeO
N
N
MeO
Me
MeO
Me
MeO
OMe
HO
(±)-Armepavine (3)
(±)-Laudanosine (4a)
MeO
N
MeO
OMe
OMe
(±)-Xylopinine (5)
Figure 1. Alkaloid targets.
The synthesis of the 1ꢀbenzyl tetrahydroisoquinolines 4a–d was achieved by condensation of
homoveratrylamine (6) followed by BischlerꢀNapieralski cyclization, providing 6,7ꢀdimethoxy
3,4ꢀdihydroisoquinoline (7) in 87% yield, followed by Nꢀmethylation with methyl iodide to
obtain iminium salt 8 in quantitative yield. Treatment of this compound with aqueous KCN
affords αꢀaminonitrile 9 as a universal building block. NꢀBenzylation of 9 with different benzyl
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 34
1
2
3
4
5
6
7
8
9
bromides 10a–d leads to the corresponding tetrahydroisoquinolinium salts 11a–d in moderate to
very high yield. These materials were treated with KHMDS in THF at 0 °C to generate the
nitrileꢀstabilized ammonium ylides 12a–d, which readily undergo a Stevensꢀrearrangement at that
temperature to lead to the Cꢀalkylated αꢀaminonitriles 13a–d.47
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
These compounds are prone to the spontaneous liberation of cyanide. However, the attempted
isolation of the related enamines resulted in side reactions. In contrast, in situꢀreduction of the
crude rearrangement products 13a–d with NaCNBH3 gave compounds 4a–d in 82–87% yield
(scheme 3) and high purity. Desilylation of 4b and hydrogenolytic debenzylation of 4c afforded
(±)ꢀlaudanidine (2) in 85% and 98% yield, respectively, while debenzylation of 4d produced (±)ꢀ
armepavine (3) in 97% yield (Scheme 2).
ACS Paragon Plus Environment

Page 7 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Synthesis of 1ꢀbenzyl tetrahydroisoquinolines 4a–d
For the preparation of 7ꢀmethoxycryptopleurine (1), spiro ammonium salt 17 was prepared in
quantitative yield by reaction of 2ꢀcyanopiperidine 16, prepared from piperidine (14) by Nꢀ
chlorination and basic dehydrochlorination followed by HCN addition,48,49 with dibromide 15.36
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 34
1
2
3
4
5
6
7
8
9
It could be converted to 1 in 82% yield over two steps without isolation of the intermediate
aminonitrile 19. The isolation of 17 can be circumvented if a oneꢀpot procedure is applied to 15,
generating 1 in 53% yield (Scheme 3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Synthesis of (±)ꢀ7ꢀmethoxycryptopleurine
ACS Paragon Plus Environment

Page 9 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Reaction of 6,7ꢀdimethoxyꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ1ꢀcarbonitrile (21)50,51 with
dibromide 23 obtained by double bromomethylation of vertatrole (22) according to Tayama et. al.
gave the spirocyclic ammonium salt 24 (94%).52 Xylopinine (5) was obtained after Stevens
rearrangement followed by reduction of the crude αꢀaminonitrile with NaCNBH3 in 98 % yield
over two steps. By combining the Nꢀalkylation with the rearrangement/reduction sequence in a
oneꢀpot procedure, the overall yield of 5 could be increased to 97% (Scheme 4).53
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1) HCO2H, ,
MeO
MeO
MeO
then POCl3
NH
CN
NH2
MeO
(ref. 44)
MeO
2) KCN, HCl
21
23
6
r.t.
59%
MeO
(CH2O)n, HBr
Br
Br
THF,
DIPEA,
reflux
79%
MeO
MeO
(ref. 46)
22
MeO
94%
Br
MeO
MeO
N
MeO
OMe
N
CN
24
OMe
5
KHMDS, THF, 0 °C,
then NaCNBH3, THF, r.t.
98%
OMe
OMe
Scheme 4. Synthesis of (±)ꢀxylopinine
In summary, the Stevens rearrangement of nitrileꢀstabilized ammonium ylides in combination
with the reductive removal of the nitrile group provides an efficient method for the construction
of polycyclic alkaloids from simple precursors. In the case of (±)ꢀ7ꢀmethoxycryptopleurine (1),
this represents shortest synthesis of this compound reported so far. The nitrile group allows the
unambiguous selection of the endpoint of the 1,2ꢀmigration, being an advantage over the direct
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 34
1
2
3
4
5
6
7
8
9
deprotonation of ammonium salts which may result in the formation of product mixtures if more
than one site for a thermodynamically feasible proton abstraction exists. No products resulting
from a competing SommeletꢀHauser rearrangement,23,54 a [1,4]ꢀmigration55 or Hofmann
elimination47 were detected in our reactions. In contrast to the use of αꢀstannylated or αꢀsilylated
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ammonium salts,34,56,57 αꢀaminonitriles are more easy and economical to prepare. Currently, we
are investigating asymmetric reductions for the enantioselective synthesis of αꢀbranched amines.
Experimental Section
General Methods. All reactions requiring anhydrous conditions were performed in dried
glassware under argon atmosphere. Reactions requiring a temperature of 0 °C were performed
using a water/ice bath. All reagents and solvents were obtained from commercial suppliers
without further purification. Anhydrous THF was distilled from potassium / benzophenone under
argon. Melting points were determined in open capillary tubes and are uncorrected. NMR spectra
1
were recorded with a 300 MHz spectrometer (300 MHz H and 75.5 MHz 13C), a 400 MHz (400
1
MHz 1H and 100.6 MHz 13C) or with a 600 MHz spectrometer (600 MHz H and 151 MHz 13C).
Deuterated solvents were used as internal standard.. The spectra were measured in CDCl3 and
[D6]DMSO, the chemical shifts were referenced to the residual solvent signal (CDCl3 : δH = 7.26
ppm, δC = 77.16 ppm; [D6]DMSO: δH = 2.50 ppm,δC = 39.52 ppm).58 IR spectra were recorded
using a diamond ATR unit or NaCl plates and are reported in terms of frequency of absorption (ν,
cmꢀ1). ESIꢀHRMS spectra were recorded on a QꢀTOF instrument with a dual source and a
suitable external calibrant. Thinꢀlayer chromatography was carried out on 0.2ꢀmm silica gel
plates with fluorescence indicator. Substance bands were detected by illumination with UV light
(254 and 360 nm).
ACS Paragon Plus Environment

Page 11 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
6,7-Dimethoxy-3,4-dihydroisoquinoline (7).
7
8
9
Under ice cooling, formic acid (3.48 g, 75.6 mmol) was added to 3,4ꢀ
dimethoxyphenylethylamine 6 (10.0 g, 55.2 mmol). The reaction mixture was heated to reflux
over 2 hours or until TLC indicated complete conversion.59 After cooling down, and following
the methodology of Rohloff and coꢀworkers,60 the yellow reaction mixture was diluted with
dichloromethane (10 mL) and PCl5 (12.9 g, 61.8 mmol) was added in small portions over 90
minutes while maintaining the temperature between 35–40 °C. The HCl generated was collected
in a gas scrubber with a 1 N NaOH solution. After the addition, the reaction mixture was stirred
for additional 30 minutes at the same temperature. After cooling, a mixture of ice (30 g) and
hexane (10 mL) was added, and the aqueous layer was separated. The organic residue was
washed with water (2 × 50 mL) and the combinated aqueous layers were adjusted to pH > 12 by
careful addition of NaOH (cooling). The mixture was extracted with diethyl ether (4 × 50 mL),
the extracts were dried over Na2SO4, and the solvent was removed in vacuo to give 7 (10.5 g,
87%) as a yellow oil.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1HꢀNMR (300 MHz, CDCl3):
δ = 8.21 (s, 1H, Hꢀ1), 6.79 (s, 1H, Hꢀ8), 6.66 (s, 1H, Hꢀ5), 3.90,
3.88 (2s, 2 × 3H, C6ꢀOCH3, C7ꢀOCH3 ), 3.71 (t, J = 7.8 Hz, 2H, Hꢀ4), 2.66 (t, J = 7.8 Hz, 2H, Hꢀ
3) ppm.
3,4-Dihydro-3,4-dimethoxy-2-methylisoquinolinium iodide (8).
Methyl iodide (1.14 mL, 18.3 mmol) was added dropwise to a solution of compound 7 (2.01 g,
9.21 mmol) in dry diethyl ether. The reaction mixture was stirred over night at room temperature.
The precipitate was filtered off and washed several times with diethyl ether. After drying in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 34
1
2
3
4
vacuo, compound 8 (3.05 g, quantitative yield) was obtained as a yellow solid. Mp: 198–200 °C
5
6
(dec), (lit.61 Mp: 200–201 °C).
7
8
9
1H NMR (300 MHz, CDCl3)
δ = 9.67 (s, 1H, Hꢀ1), 7.55 (s, 1H, Hꢀ8), 6.86 (s, 1H, Hꢀ5), 4.01(t, J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
= 8.4 Hz, 2H, Hꢀ3), 3.98 (s, 3H, C6ꢀOCH3), 3.87 (s, 3H, NꢀCH3), 3.85 (s, 3H, C7ꢀOCH3), 3.28 (t,
J= 8.4 Hz, 2H, Hꢀ4) ppm.
1-Cyano-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (9).
A solution of KCN (1.76 g, 27.0 mmol) in water (5 mL) was added to a solution of the
isoquinolinium salt 8 (2.09 g, 8.99 mmol) in water (20 mL). The reaction mixture was stirred
over night at room temperature and was extracted with dichloromethane (3 × 20 mL). The
combined organic layers were washed with water, dried over Na2SO4, and the solvent was
evaporated in vacuo to afford the compound 9 (2.06 g, 99%) as a yellow solid. Mp: 126–128 °C
(dec), (lit.62 Mp: 127–128 °C).
Rf = 0.61 (cyclohexane/EtOAc/HNEt2 = 5/3/1).
IR (NaCl): 2940 (m), 2805 (m), 2217 (w), 1612 (m), 1518 (s), 1464 (m), 1256 (s), 1227 (s), 1140
(s), 1103 (s), 1012 (s) cm–1.
1H NMR, COSY (400 MHz, CDCl3)
δ = 6.64 (s, 1H, Hꢀ8), 6.59 (s, 1H, Hꢀ5), 4.63 (s, 1H, Hꢀ1),
3.83, 3.84 (2s, 2 × 3H, C6ꢀOCH3, C7ꢀOCH3), 3.0–2.90 (m, Hbꢀ4), 2.89–2.82 (m, Haꢀ3), 2.74 (dd, J
= 11.0, 4.0 Hz, 1H, Hbꢀ3), 2.71–2.64 (m, 1H, Hbꢀ4), 2.57 (s, 1H, NꢀCH3) ppm.
13C NMR, HMBC, HSQC (100,6 MHz, CDCl3)
δ = 149.2 (C7), 147.8 (C6), 126.2 (C8a), 121.3
(C4a), 116.8 (CN), 111.5 (C5), 109.4 (C8), 56.6 (C1), 56.0 (C6ꢀOMe), 55.9 (C7ꢀOMe), 48.4 (C3)
43.7 (NꢀCH3), 28.1 (C4) ppm.
Synthesis of Benzyl Bromides 10a-d.
ACS Paragon Plus Environment

Page 13 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3,4ꢀDimethoxybenzyl bromide (10a), 4ꢀmethoxyꢀ3ꢀ(triisopropylsilanyloxy)benzyl bromide
(10b), 4ꢀmethoxyꢀ3ꢀ(benzyloxy)benzyl bromide (10c) and 4ꢀ(benzyloxy)benzyl bromide (10d)
were prepared according to known procedures.63ꢀ66
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for the Preparation of cis/trans-2-Aryl-1-cyano-6,7-dimethoxy-2-methyl-
1,2,3,4-tetrahydroisoquinolinium Salts (11a-d): The benzylic bromide (1.72 mmol) was added
to a stirred solution of (9) (0.860 mmol) in dry THF (6 mL). The mixture was heated to 40 °C for
1–3 days. The precipitate formed was filtered and washed several times with THF to afford the
title compounds.
cis/trans-1-Cyano-2-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-
tetrahydroisoquinolinium bromide (11a).
The reaction was carried out during 24 h, using isoquinoline 9 (200 mg, 0.861 mmol) and
bromide 10a (397 mg, 1.72 mmol). The isoquinolinium salt 11a was obtained as a diastereomeric
mixture in a 12:88 cis/transꢀratio (1H NMR) in the form of a pale yellow solid (378 mg, 95%)
which was used in the next step without further purification.
IR (ATR): 2959 (w, br), 2836 (w), 2566 (w), 1728 (w), 1606 (m), 1518 (s), 1465 (m), 1262 (s),
1119 (m), 817 (m) cm–1.
1H NMR, COSY, NOESY (600 MHz, DMSOꢀd6) transꢀ11a:
δ = 7.12 (s, 2H, Hꢀ5’, Hꢀ2’), 7.06 (s,
1H, Hꢀ6’), 7.04 (s, 1H, Hꢀ5), 7.03 (s, 1H, Hꢀ8), 6.37 (s, 1H, Hꢀ1), 4.87 (d, J = 12.9 Hz, 1H, N–
CHa–Ar), 4.75 (d, J = 12.9 Hz, 1H, N–CHb–Ar), 3.98–3.91 (m, 1H, Haꢀ3), 3.90ꢀ3.84 (m, 1H, Hbꢀ
3), 3.82–3.80 (3s, 3 × 3H, C4’ꢀOCH3, C6ꢀOCH3, C7ꢀOCH3), 3.79 (s, 3H, C3’ꢀOCH3), 3.26 (s, 3H,
NꢀCH3), 3.26–3.19 (m, 2H, Hꢀ4) ppm. Characteristic signals for cisꢀ11a:
δ = 6.20 (s, 1H, Hꢀ1),
4.94 (d, J = 12.9 Hz, 1H, NꢀCHaꢀAr), 4.90 (d, J = 12.9 Hz, 1H, NꢀCHbꢀAr) ppm.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 34
1
2
13C NMR, HMBC, HSQC (150.6 MHz, DMSOꢀd6)
δ
= 150.8 (C6), 150.3 (C4’), 148.7 (C3’),
3
4
5
6
7
8
148.4 (C7), 126.4 (C2’), 122.6 (C4a), 118.1 (C1’) 116.0 (C6’), 114.1 (C8a), 113.7 (CN), 112.1
(C5), 111.8 (C5’), 109.5 (C8), 65.8 (N–CH2–Ar), 59.3 (C1), 56.8 (C3), 55.8 (C6ꢀOMe), 55.7 (C7ꢀ
OMe), 55.6 (C4’ꢀOMe), 55.5 (C3’ꢀOMe), 46.2 (N–CH3), 22.5 (C4) ppm.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ESIꢀMS (m/z): 206.0 (100) [M – C10H11NO2]+, 383.1 (65) [M]+, 356.2 (14.8) [M – HCN]+.
ESIꢀHRMS: calcd for [C22H27N2O4]+ 383.1971, found 383.1958.
cis/trans-1-Cyano-6,7-dimethoxy-2-(4-methoxy-3-(triisopropylsilyloxy)benzyl)-2-methyl-
1,2,3,4-tetrahydroisoquinolinium bromide (11b).
The reaction was carried out during 48 h, using isoquinoline 9 (200 mg, 0.861 mmol) and
bromide 10b (642 mg, 1.72 mmol). The isoquinolinium salt 11b was obtained as a diastereomeric
mixture in a cis/transꢀratio of 13:87 (1H NMR), in the form of a pale yellow solid (442 mg, 85%)
which was used in the next step without further purification.
IR (ATR): 2941 (w, br), 2865 (w), 2562 (w), 1658 (w), 1602 (m), 1513 (s), 1442 (m), 1268 (s),
1166 (m), 810 (m) cm–1.
1H NMR, COSY, NOESY (400 MHz, DMSOꢀd6) transꢀ11b:
δ = 7.14 (s, 2H, Hꢀ5’, Hꢀ2’), 7.02 (s,
1H, Hꢀ5), 7.00 (s, 1H, Hꢀ6’), 6.99 (s, 1H, Hꢀ8), 6.37 (s, 1H, Hꢀ1), 4.86 (d, J = 12.8 Hz, 1H, N–
CHa–Ar), 4.75 (d, J = 12.8 Hz, 1H, N–CHb–Ar), 3.99ꢀ3.89 (m, 1H, Haꢀ3), 3.88ꢀ3.81 (m, 1H, Hbꢀ
3), 3.81, 3.80 (2s, 2 × 3H, C4’ꢀOCH3, C6ꢀOCH3), 3.79 (s, 3H, C7ꢀOCH3), 3.24 (s, 3H, N–CH3),
3.24ꢀ3.13 (m, 2H, Hꢀ4), 1.29–1.16 (m, 3H, SiꢀCH), 1.04 (d, J = 7.5 Hz, 3 × 6H, Si–CH–(CH3)3)
ppm. Characteristic signal of cisꢀ11b:
δ = 7.19 (s, 2H, Hꢀ5’, Hꢀ2’), 6.18 (s, 1H, Hꢀ1), 4.95 (d, J =
12.8 Hz, 1H, N–CHa–Ar) ppm.
13C NMR, HMBC, HSQC (100.6 MHz, DMSOꢀd6)
δ = 152.6 (C4’), 150.1 (C6), 148.5 (C7),
144.5 (C3’), 127.3 (C2’), 124.4 (C6’), 122.6 (C4a), 118.1 (C1’), 114.5 (C8a), 113.4 (CN), 112.6
ACS Paragon Plus Environment

Page 15 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(C5’), 112.1 (C5), 109.4 (C8), 65.5 (N–CH2–Ar), 59.2 (C1), 56.7 (C3), 55.8 (C6ꢀOMe), 55.7 (C4’ꢀ
OMe), 55.2 (C7ꢀOMe), 46.8 (N–CH3), 22.6 (C4), 17.8 (6 × CH3), 12.3 (3 × CH) ppm.
ESIꢀMS (m/z): 498.3 (100) [M – HCN]+, 206.0 (82) [M – C18H29NO2Si]+, 525.20 (39) [M]+.
ESIꢀHRMS: calcd for [C30H45N2O4Si]+ 525.3149, found 525.3156.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
cis/trans-2-(3-(Benzyloxy)-4-methoxybenzyl)-1-cyano-6,7-dimethoxy-2-methyl-1,2,3,4-
tetrahydroisoquinolinium bromide (11c).
The reaction was carried out during 48 h using isoquinoline 9 (200 mg, 0.861 mmol) and bromide
10c (528 mg, 1.72 mmol). The isoquinolinium salt 11c was obtained as a diastereomeric mixture
in a cis/transꢀratio of 6:94 (1H NMR) in the form of a beige solid (339 mg, 73%) which was used
in the next step without further purification. The NMR spectra showed the presence of some
remaining THF, the attempted removal of which led to beginning decomposition.
IR (ATR): 2943 (w, br), 2838 (w), 2564 (w), 1663 (w), 1606 (m), 1521 (s), 1443 (m), 1263 (s),
1121 (m), 815 (m) cm–1.
1H NMR, COSY, NOESY (600 MHz, DMSOꢀd6) transꢀ11c:
δ = 7.45 (d, J = 7.5 Hz, 2H, Hꢀ2’’,
Hꢀ6’’), 7.41 (t, J = 7.5 Hz, 2H, Hꢀ3’’, Hꢀ5’’), 7.35 (t, J = 7.5 Hz, 1H, Hꢀ4’’), 7.17–7.11 (m, 3H,
Hꢀ6’, Hꢀ5’, Hꢀ2’), 7.05 (s, 1H, Hꢀ5), 7.03 (s, 1H, Hꢀ8), 6.30 (s, 1H, Hꢀ1), 5.16 (d, J = 11.7 Hz,
1H, O–CHa–Ph), 5.11 (d, J = 11.7 Hz, 1H, O–CHb–Ph), 4.80 (d, J = 12.9 Hz, 1H, N–CHa–Ar),
4.72 (d, J = 12.9 Hz, 1H, N–CHb–Ar), 3.97ꢀ3.91 (m, 1H, Haꢀ3), 3.90–3.83 (m, 1H, Hbꢀ3), 3.83 (s,
3H, C4’ꢀOCH3), 3.82 (s, 3H, C6ꢀOCH3, 3.78 (s, 3H, C7ꢀOCH3), 3.21 (s, 3H, N–CH3), 3.27ꢀ3.17
(m, 2H, Hꢀ4) ppm. Characteristic signal for cisꢀ11c:
δ = 7.07 (s, 1H, Hꢀ5), 7.01 (s, 1H, Hꢀ8), 6.15
(s, 1H, Hꢀ1) ppm.
13C NMR, HMBC, HSQC (150.6 MHz, DMSOꢀd6)
δ = 151.1 (C4’), 150.3 (C6), 148.5 (C7),
147.7 (C3’), 136.6 (C1’’), 128.5 (C3’’, C5’’), 128.0 (C4’’), 127.9 (C2’’, C6’’), 126.7 (C2’),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 34
1
2
3
4
5
6
7
8
9
122.6 (C4a), 117.9 (C1’), 117.7 (C6’), 114.1 (C8a), 113.7 (CN), 112.1 (C5), 111.8 (C5’), 109.5
(C8), 69.8 (O–CH2–Ar), 66.0 (N–CH2–Ar), 59.3 (C1), 56.8 (C3), 55.8 (C6ꢀOMe, C7ꢀOMe), 55.7
(C4’ꢀOMe), 46.1 (N–CH3), 22.5 (C4) ppm.
ESIꢀMS (m/z): 206.0 (100) [M – C16H15NO2]+, 432.2 (94) [M – HCN]+, 559.1 (91) [M]+.
ESIꢀHRMS: calcd for [C28H31N2O4]+ 459.2284, found 459.2283.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
cis/trans-2-(4-(Benzyloxy)benzyl)-1-cyano-6,7-dimethoxy-2-methyl-1,2,3,4-
tetrahydroisoquinolinium bromide (11d).
The reaction was carried out during 72 h using isoquinoline 9 (200 mg, 0.861 mmol) and bromide
10d (528 mg, 1.72 mmol) of. The isoquinolinium salt 11d was obtained as a diastereomeric
mixture in a cis/transꢀratio of 3:97 (1HꢀNMR) in the form of a beige solid (267 mg, 61%) which
was used in the next step without further purification. The NMR spectra showed the presence of
some remaining THF, the attempted removal of which led to beginning decomposition.
IR (ATR): 2972 (w), 2838 (w), 2564 (w), 1662 (w), 1610 (m), 1516 (s), 1454 (m), 1237 (s), 1119
(s), 811 (m) cm–1.
1H NMR, COSY, NOESY (600 MHz, DMSOꢀd6) trans-11d:
δ = 7.50 (d, J = 8.4 Hz, 2H, Hꢀ2’,
Hꢀ6’), 7.47 (d, J = 7.5 Hz, 2H, Hꢀ2’’, Hꢀ6’’), 7.41 (t, J = 7.5 Hz, 2H, Hꢀ3’’, Hꢀ5’’), 7.35 (t, J =
7.5 Hz, 1H, Hꢀ4’’), 7.18 (d, J = 8.4 Hz, 2H, Hꢀ3’, Hꢀ5’), 7.02 (s, 1H, Hꢀ5), 6.99 (s, 1H, Hꢀ8),
6.36 (s, 1H, Hꢀ1), 5.17 (s, 2H, O–CH2–Ph), 4.85 (d, J = 12.9 Hz, 1H, N–CHa–Ar), 4.78 (d, J =
12.9 Hz, 1H, N–CHb–Ar), 3.97ꢀ3.91 (m, 1H, Haꢀ3), 3.90ꢀ3.81 (m, 1H, Hbꢀ3), 3.80 (2s, 2 × 3H,
C6ꢀOCH3, C7ꢀOCH3), 3.23 (s, 3H, N–CH3), 3.27ꢀ3.17 (m, 2H, Hꢀ4) ppm. Characteristic signals
for cisꢀ11d:
δ = 7.18 (d, J = 8.6 Hz, 2H, Hꢀ3’, Hꢀ5’), 6.91 (s, 1H, Hꢀ5), 6.90 (s, 1H, Hꢀ8), 6.14 (s,
1H, Hꢀ1), 4.94 (d, J = 13.1 Hz, 1H, N–CHa–Ar), 4.90 (d, J = 13.1 Hz, 1H, N–CHb–Ar) ppm.
ACS Paragon Plus Environment

Page 17 of 34
The Journal of Organic Chemistry
1
2
13C NMR, HMBC, HSQC (150.6 MHz, DMSOꢀd6)
δ
= 160.8 (C4’), 150.6 (C6), 148.9 (C7),
3
4
5
6
7
8
137.1 (C1’’), 135.3 (C2’, C6’) 129.0 (C3’’, C5’’), 128.6 (C4’’), 128.3 (C2’’, C6’’), 123.0 (C4a),
118.6 (C1’), 115.9 (C3’, C5’), 114.5 (C8a), 114.1 (CN), 112.4 (C5), 110.0 (C8), 69.9 (O–CH2–
Ph), 66.4 (N–CH2–Ar), 60.0 (C1), 56.9 (C3), 56.3 (C6ꢀOMe), 56.2 (C7ꢀOMe), 46.2 (N–CH3), 23.0
(C4) ppm.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ESIꢀMS (m/z): 206.0 (100) [M – C15H13NO]+, 402.2 (82) [M – HCN]+, 429.1 (31) [M]+.
ESIꢀHRMS: calcd for [C27H29N2O3]+ 429.2178, found 429.2191.
General Procedure for the Stevens Rearrangement and Reductive Decyanation.36
A solution of KHMDS (56 mg, 0.28 mmol) in dry THF (1 mL) was added to a stirred suspension
of the corresponding salt (0.26 mmol) in dry THF (7 mL) at 0 °C. After stirring for 1.5–3 h at this
temperature, EtOH (1 mL) and NaCNBH3 (57 mg, 0.91 mmol) were added and the mixture was
allowed to reach room temperature. Acetic acid (85 ꢁL, 1.5 mmol) was added dropwise and the
mixture was stirred for 12 h. Saturated aq NaHCO3 (15 mL) was added, and the product was
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine, dried
over Na2SO4 and concentrated in vacuo. The products 4a–d were purified by recrystallization or
column chromatography.
(±)-Laudanosine (4a).
According to the general procedure and after 14 h of reaction time, compound 4a (77 mg, 83%)
was obtained from the isoquinolinium salt 11a (120 mg, 0.259 mmol) as a white solid after
recrystallization from ethanol. Mp: 114–116 °C dec. (lit.67 Mp: 114–115 °C).
Rf = 0.4 (CHCl3/MeOH = 10/1).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 34
1
2
3
4
5
6
IR (ATR): 2932 (m, br), 2832 (m), 1608 (w), 1511 (s), 1463 (m), 1226 (s), 1138 (s), 1101 (m),
1027 (s), 861 (m) cm−1.
7
8
9
1H NMR, COSY (400 MHz, CDCl3)
δ = 6.74 (d, J = 8.1 Hz, 1H, Hꢀ5’), 6.61 (dd, J = 8.1, 1.9 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H, Hꢀ6’), 6.58 (d, J = 1.9 Hz, 1H, Hꢀ2’), 6.54 (s, 1H, Hꢀ5), 6.03 (s, 1H, Hꢀ8), 3.82, 3.81 (2s, 2 ×
3H, C6ꢀOCH3, C4’ꢀOCH3), 3.76 (s, 3H, C3’ꢀOCH3), 3.68 (dd, J = 7.7, 4.9 Hz, 1H, Hꢀ1), 3.55 (s,
3H, C7ꢀOCH3), 3.19 – 3.13 (m, 1H, Haꢀ3), 3.13 (dd, J = 13.7, 4.9 Hz, 1H, Ar–CHa), 2.87– 2.69
(m, 2H, Haꢀ4, Hbꢀ3), 2.75 (dd, J = 13.7, 7.7 Hz, 1H, Ar–CHb), 2.57 (dt, J = 14.9, 4.0 Hz, 1H, Hbꢀ
4), 2.52 (s, 3H, N–CH3) ppm.
13C NMR, HMBC, HSQC (100.6 MHz, CDCl3)
δ = 148.5 (C4’), 147.3, 147.2 (C6, C3’), 146.3
(C7), 132.4 (C1’), 129.1 (C8a), 125.9 (C4a), 121.8 (C6’), 112.9 (C2’), 111.1 (C5), 111.0 (C8),
110.9 (C5’), 64.8 (C1), 55.9, 55.8 (C6ꢀOCH3, C4’ꢀOCH3), 55.7 (C3’ꢀOCH3), 55.5 (C7ꢀOCH3), 46.9
(C3), 42.6 (NꢀCH3), 40.8 (Ar–CH2), 25.5 (C4) ppm.
ESIꢀMS (m/z): 358.1 (100) [M+H]+.
ESIꢀHRMS: calcd for [C21H27NO4+H]+ 358.2018, found 358.2010.
The spectroscopic data are in accordance with those reported in the literature.68
(±)-O-(Triisopropylsilyl)laudanidine (4b).
According to the general procedure and after 15 h of reaction time, compound 4b (109 mg, 84%)
was obtained from the isoquinolinium salt 11b (157 mg, 0.259 mmol) as a pale yellow oil after
purification by column chromatography (cyclohexane/EtOAc/HNEt2 = 10/3/1).
Rf = 0.60 (cyclohexane/EtOAc/HNEt2 = 5/3/1).
IR (ATR): 2940 (m, br), 2864 (m), 1608 (w), 1510 (s), 1463 (m), 1227 (s), 1136 (s), 1102 (m),
1032 (m), 882 (m) cm−1.
ACS Paragon Plus Environment

Page 19 of 34
The Journal of Organic Chemistry
1
2
1H NMR, COSY (600 MHz, CDCl3)
δ = 6.71 (d, J = 2.1 Hz, 1H, Hꢀ2’), 6.70 (d, J = 8.2 Hz, 1H,
3
4
5
6
7
8
Hꢀ5’), 6.55 (dd, J = 8.2, 2.1 Hz, 1H, Hꢀ6’), 6.54 (s, 1H, Hꢀ5), 6.13 (s, 1H, Hꢀ8), 3.83 (s, 3H, C6ꢀ
OCH3), 3.76 (s, 3H, C4’ꢀOCH3), 3.62 (dd, J = 7.5, 4.7 Hz, 1H, Hꢀ1), 3.60 (s, 3H, C7ꢀOCH3), 3.14
(ddd, J = 12.4, 8.7, 5.1 Hz, 1H, Haꢀ3), 3.07 (dd, J = 13.7, 4.7 Hz, 1H, Ar–CHa), 2.80 (ddd, J =
15.9, 8.7, 5.6 Hz, 1H, Haꢀ4), 2.76–2.69 (m, 1H, Hbꢀ3), 2.73 (dd, J = 13.7, 7.5 Hz, 1H, ArꢀCHb),
2.58 (dt, J = 15.9, 4.8 Hz, 1H, Hbꢀ4), 2.51 (s, 3H, NꢀCH3), 1.26–1.17 (m, 3H, CH), 1.07 (d, J =
7.4 Hz, 18H, CH3) ppm.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13C NMR, HMBC, HSQC (150.6 MHz, CDCl3)
δ = 149.3 (C4’), 147.3 (C6), 146.5 (C7), 145.3
(C3’), 132.6 (C1’), 129.6 (C8a), 126.1 (C4a), 122.8 (C2’), 121.9 (C5’), 111.9 (C6’), 111.1 (C5),
110.9 (C8), 65.1 (C1), 55.8, 55.7 (C6ꢀOCH3, C4’ꢀOCH3), 55.6 (C7ꢀOCH3), 47.3 (C3), 42.9 (N–
CH3), 40.6 (ArꢀCH2), 25.8 (C4), 18.0 (6 × CH3), 13.0 (3 × CH) ppm.
ESIꢀMS (m/z): 500.2 (100) [M]+.
ESIꢀHRMS: calcd for [C29H45NO4Si+H]+ 500.3196, found 500.3179.
(±)-O-Benzyllaudanidine (4c).
According to the general procedure and after 15 h of reaction time, compound 4c (112 mg, 82%)
was obtained from the isoquinolinium salt 11c (140 mg, 0.260 mmol) as a white solid after
recrystallization from ethanol. Mp: 90–92 °C (dec), (lit.69 Mp: 90.5–91.5 °C).
Rf = 0.69 (cyclohexane/EtOAc/HNEt2 = 5/3/1).
IR (ATR): 2937 (m, br), 2860 (m), 1610 (w), 1510 (s), 1463 (m), 1275 (s), 1131 (s), 1101 (m),
1015 (m), 863 (m) cm−1.
1H NMR, COSY (400 MHz, CDCl3)
δ = 7.41 (d, J = 7.0 Hz, 2H, Hꢀ6’’, Hꢀ2’’), 7.34 (t, J = 7.3
Hz, 2H, Hꢀ5’’, Hꢀ3’’ ), 7.28 (m, 1H, Hꢀ4’’), 6.77 (d, J = 8.1 Hz, 1H, Hꢀ5’), 6.66 (d, J = 2.0 Hz,
1H, Hꢀ2’), 6.60 (dd, J = 8.1, 2.0 Hz, 1H, Hꢀ6’), 6.54 (s, 1H, Hꢀ5), 5.99 (s, 1H, Hꢀ8), 5.07 (s, 2H,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 34
1
2
3
4
5
6
7
8
9
PhꢀCH2), 3.84, 3.83 (2s, 2 × 3H, C6ꢀOCH3, C4’ꢀOCH3), 3.59 (dd, J = 7.7, 5.1 Hz, 1H, Hꢀ1), 3.16 –
3.07 (m, 1H, Haꢀ3), 3.06 (dd, J = 13.7, 5.1 Hz, 1H, Ar–CHa), 2.84 – 2.77 (m, 1H, Haꢀ4), 2.76ꢀ2.69
(m, 1H, Hbꢀ3), 2.72 (dd, J = 13.7, 7.7 Hz, 1H, Ar–CHb), 2.54 (dt, J = 15.6, 4.6 Hz, 1H, Hbꢀ4),
2.48 (s, 3H, N–CH3) ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13C NMR, HMBC, HSQC (100.6 MHz, CDCl3)
δ = 148.1 (C4’), 147.8 (C3’), 147.3 (C6), 146.4
(C7), 137.4 (C1’’), 132.5 (C1’), 129.4 (C4a), 128.6 (C3’’, C5’’), 127.9 (C4’’), 127.4 (C2’’, C6’’),
126.1 (C8a), 122.7 (C6’), 115.9 (C2’), 111.7 (C5’), 111.2 (C5), 111.0 (C8), 71.1 (PhꢀCH2), 64.9
(C1), 56.2, 55.9 (C6ꢀOCH3, C4’ꢀOCH3), 55.6 (C7ꢀOCH3), 47.1 (C3), 42.8 (N–CH3), 40.8 (Ar–
CH2), 25.7 (C4) ppm.
ESIꢀMS (m/z): 434.2 (100) [M+H]+.
ESIꢀHRMS: calcd for [C27H31NO4+H]+ 434.2331, found 434.2329.
The spectroscopic data are in accordance with those reported in the literature.69
(±)-O-Benzylarmepavine (4d).
According to the general procedure and after 13 h of reaction time, compound 4d (91 mg, 87%)
was obtained from the isoquinolinium salt 11d (132 mg, 0.259 mmol) as a viscous yellow oil
after purification by column chromatography (cyclohexane/EtOAc/HNEt2 = 10/3/1).
Rf = 0.58 (cyclohexane/EtOAc/HNEt2 = 5/3/1).
IR (ATR): 2926 (m, br), 2858 (m), 1612 (w), 1511 (s), 1463 (m), 1250 (s), 1101 (m), 1066 (m),
1015 (m), 862 (m) cm−1.
1H NMR, COSY (400 MHz, CDCl3)
δ = 7.44–7.35 (m, 4H, Hꢀ6’’, Hꢀ5’’, Hꢀ3’’, Hꢀ2’’), 7.34 –
7.29 (m, 1H, Hꢀ4’’), 7.01 (d, J = 8.5 Hz, 2H, Hꢀ6’, Hꢀ2’), 6.88 (d, J = 8.5 Hz, 2H, Hꢀ5’, Hꢀ3’),
6.55 (s, 1H, Hꢀ5), 6.00 (s, 1H, Hꢀ8), 5.04 (s, 2H, PhꢀCH2), 3.83 (s, 3H, C6ꢀOCH3), 3.67 (dd, J =
7.9, 5.0 Hz, 1H, Hꢀ1), 3.52 (s, 3H, C7ꢀOCH3), 3.24–3.13 (m, 1H, Haꢀ3), 3.14 (dd, J = 13.7, 5.0
ACS Paragon Plus Environment

Page 21 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
Hz, 1H, ArꢀCHa), 2.88–2.81 (m, 1H, Haꢀ4), 2.80–2.71 (m, 1H, Hbꢀ3), 2.75 (dd, J = 13.7, 7.9 Hz,
1H, ArꢀCHb), 2.59 (dt, J = 15.5, 4.5 Hz, 1H, Hbꢀ4), 2.53 (s, 3H, NꢀCH3) ppm.
7
8
9
13C NMR, HMBC, HSQC (100.6 MHz, CDCl3)
δ = 157.2 (C4’), 147.3 (C6), 146.3 (C7), 137.3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(C1’’), 132.3 (C1’), 130.8 (C6’ꢀC2’), 129.4 (C8a), 128.7 (C5’’, C3’’), 128.0 (C4’’), 127.5 (C6’’,
C2’’), 126.0 (C4a), 114.7 (C5’, C3’), 111.2 (C5), 111.1 (C8), 70.1 (Ph–CH2), 65.0 (C1), 56.0 (C6ꢀ
OCH3), 55.6 (C7ꢀOCH3), 46.9 (C3), 42.3 (N–CH3), 40.5 (Ar–CH2), 25.6 (C4) ppm.
ESIꢀMS (m/z): 404.2 (100) [M+H]+.
ESIꢀHRMS: calcd for [C26H29NO3+H]+ 404.2226, found 404.2212.
(±)-Laudanidine (2).
Method A.
To a solution of silyl ether 4b (90 mg, 0.18 mmol) in DMF (1 mL) was added a solution of KF
(21 mg, 0.36 mmol) in water (0.1 mL). After stirring the reaction mixture over night at room
temperature, sat. aq NH4Cl (8 mL) was added and the mixture was extracted with EtOAc (4 × 5
mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated under
reduced pressure. To remove the remaining silicon compounds, the crude material was dissolved
in MeCN (3 mL) and extracted with nꢀhexane (6 mL). The MeCNꢀlayer was concentrated in
vacuo to afford the title compound (53 mg, 85%) as a white solid. Mp: 165–166 °C (dec), (lit.70
Mp: 164–165 °C).
Rf = 0.26 (cyclohexane/EtOAc/HNEt2 = 5/3/1).
IR (ATR): 3437 (w, br), 2937 (m, br), 2835 (w), 1610 (w), 1510 (s), 1463 (m), 1253 (s), 1131
(m), 1015 (m), 863 (m) cm−1.
1H NMR, COSY (400 MHz, CDCl3)
δ = 6.78 (d, J = 2.1 Hz, 1H, Hꢀ2’), 6.72 (d, J = 8.2 Hz, 1H,
Hꢀ5’), 6.55 (s, 1H, Hꢀ5), 6.53 (dd, J = 8.2, 2.1 Hz, 1H, Hꢀ6’), 6.06 (s, 1H, Hꢀ8), 3.85, 3.83 (2s, 2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 34
1
2
3
4
5
6
7
8
9
× 3H, C6ꢀOCH3, C4’ꢀOCH3 ), 3.68 (dd, J = 7.7, 5.2 Hz, 1H, Hꢀ1), 3.57 (s, 3H, C7ꢀOCH3), 3.19
(ddd, J = 12.5, 8.8, 5.1 Hz, 1H, Haꢀ3), 3.11 (dd, J = 13.7, 5.2 Hz, 1H, Ar–CHa), 2.89–2.74 (m,
2H, Haꢀ4, Hbꢀ3), 2.71 (dd, J = 13.7, 7.7 Hz, 1H, Ar–CHb), 2.61 (dt, J = 15.4, 3.9 Hz, 1H, Hbꢀ4),
2.51 (s, 3H, N–CH3) ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13C NMR, HMBC, HSQC (100.6 MHz, CDCl3)
δ = 147.4 (C6), 146.4 (C7), 145.6 (C3’), 145.1
(C4’), 133.5 (C1’), 129.5 (C8a), 125.8 (C4a), 121.4 (C6’), 115.9 (C2’), 111.2 (C5), 111.1 (C8),
110.6 (C5), 64.9 (C1), 56.1 (C4’ꢀOCH3), 55.9 (C6ꢀOCH3), 55.6 (C7ꢀOCH3), 46.8 (C3), 42.7 (N–
CH3), 40.9 (Ar–CH2), 25.4 (C4) ppm.
ESIꢀMS (m/z): 344.2 (100) [M+H]+.
ESIꢀHRMS: calcd for [C20H25NO4+H]+ 344.1862, found 344.1856.
The spectroscopic data are in accordance with those reported in the literature.71
Method B.
A mixture of benzyl ether 4c (90 mg, 0.21 mmol) and 10% Pd/C (11 mg) in MeOH (8 mL) was
stirred under a H2ꢀatmosphere at room temperature over 3 h. The reaction mixture was filtered
through a pad of celite and the solvent was evaporated in vacuo to afford the title compound (71
mg, 98%) as a white solid. Mp: 164–166 °C (dec). The spectroscopic data of the product are
identical to those of the material obtained by method A.
(±)-Armepavine (3).
A mixture of benzyl ether 4d (100 mg, 0.248 mmol) and 10% Pd/C (13 mg) in MeOH (10 mL)
was stirred under a H2 atmosphere at room temperature over 2 hours. The reaction mixture was
filtered through a pad of celite and the solvent was evaporated in vacuo to afford the title
compound (76 mg, 97%) as a white solid. Mp: 165–167 °C (dec), (lit.72 Mp: 166 °C).
ACS Paragon Plus Environment

Page 23 of 34
The Journal of Organic Chemistry
1
2
3
4
Rf = 0.20 (cyclohexane/EtOAc/HNEt2 = 5/3/1).
5
6
7
8
IR (ATR): 3438 (w, br), 2924 (m), 2835 (w), 1611 (w), 1513 (s), 1463 (m), 1252 (s), 1115 (m),
1014 (m), 829 (m) cm−1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR, COSY (600 MHz, CDCl3)
δ = 6.90 (d, J = 8.3 Hz, 2H, Hꢀ6’, Hꢀ2’), 6.63 (d, J = 8.3 Hz,
1H, Hꢀ5’, Hꢀ3’), 6.56 (s, 1H, Hꢀ5), 6.00 (s, 1H, Hꢀ8), 3.83 (s, 3H, C6ꢀOCH3), 3.71 (dd, J = 8.1,
5.2 Hz, 1H, Hꢀ1), 3.55 (s, 3H, C7ꢀOCH3), 3.25 (ddd, J = 12.6, 9.4, 5.3 Hz, 1H, Haꢀ3), 3.13 (dd, J
= 13.7, 5.2 Hz, 1H, Ar–CHa), 2.92–2.79 (m, 2H, Haꢀ4, Hbꢀ3), 2.74 (dd, J = 13.7, 8.1 Hz, 1H, Ar–
CHb), 2.62 (dt, J = 15.9, 5.3 Hz, 1H, Hbꢀ4), 2.53 (s, 3H, N–CH3) ppm.
13C NMR, HMBC, HSQC (150.6 MHz, CDCl3)
δ = 154.8 (C4’), 147.4 (C6), 146.4 (C7), 131.0
(C1’), 130.9 (C6’, C2’), 128.8 (C8a), 125.3 (C4a), 115.5 (C5’, C3’), 111.2 (C8, C5), 65.0 (C1),
55.9 (C6ꢀOCH3), 55.6 (C7ꢀOCH3), 46.2 (C3), 42.2 (N–CH3), 40.6 (Ar–CH2), 24.7 (C4) ppm.
ESIꢀMS (m/z): 314.2 (100) [M+H]+.
ESIꢀHRMS: calcd for [C19H23NO3+H]+ 314.1756, found: 314.1749.
Piperidine-2-carbonitrile (16).
The title compound was prepared in 55% yield from piperidine 14 by combining the protocol of
Gravel et al 48
HCN addition.
Colorless oil, bp 91
.
for the preparation of 1ꢀpiperideine with the protocol of De Kimpe et al.49 for the
–
93 °C (16 mbar), lit. bp 91–
95 °C (16 mbar).49
1H NMR (400 MHz, CDCl3): δ = 3.97 (t, J = 4.2 Hz, CHN), 3.01
–2.81 (m, 2H, NCH2), 1.82–
1.41 (m, 6H, CH2CH2CH2).
2'-Cyano-5,6,9,10-tetramethoxy-1,3-dihydrospiro[dibenzo[e,g]isoindole-2,1'-piperidin]-1'-
ium bromide (17).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 34
1
2
3
4
A
mixture of 9,10ꢀbis(bromomethyl)ꢀ2,3,6,7ꢀtetramethoxyphenanthrene36 (15, 4.40 g,
5
6
7
8
9.09 mmol) and DIPEA (1.55 mL, 9.11 mmol, 1.0 eq) in dry THF (100 mL) was heated under
reflux with stirring while piperidineꢀ2ꢀcarbonitrile (16, 1.00 g, 9.07 mmol, 1.0 eq) was added
dropwise. The mixture was heated to reflux for 20 h. It was cooled to room temperature, filtered
and washed with ice cold water to afford the title compound (4.7 g, quant.) as a white solid, mp
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
261–263 °C (dec.).
IR (ATR): 2980 (w), 2866 (w), 1614 (w), 1522 (m), 1483 (s), 1422 (s), 1255 (s), 1160 (s), 857
(s), 770 (m), 624 (m) cm–1.
1H NMR, COSY, NOESY (400 MHz, DMSOꢀd6): δ = 8.12 (s, 2H, 2 x ArꢀH), 7.34 (s, 1H, ArꢀH),
7.26 (s, 1H, ArꢀH), 5.86–5.41 (m, 5H, Haꢀ1, Hbꢀ1, Haꢀ3, Hbꢀ3, Hꢀ2'), 4.06 (s, 6H, 2 x OCH3), 3.98
(s, 3H, OCH3), 3.97 (s, 3H, OCH3), 3.95–3.93 (m, 1H), 3.89–3.83 (m, 2H), 2.24–2.10 (m, 1H),
2.09–1.97 (m, 1H), 1.90–1.79 (m, 2H) 1.31–1.20 (m, 1H) ppm.
13C NMR, HMBC, HSQC (100.6 MHz DMSOꢀd6): δ = 149.6 (C5, C10), 149.1 (C6, C9) 124.8
(PhꢀC), 124.8 (PhꢀC), 124.2 (PhꢀC), 124.2 (PhꢀC), 119.9 (PhꢀC), 119.9 (PhꢀC) 114,4 (CN), 105.5
(PhꢀC), 105.3 (PhꢀC), 104.7 (PhꢀC) , 104.7 (PhꢀC), 69.0 (C1, C3) 61.9 (C6'), 60,9 (C2'), 56.1 (2 x
OCH3), 55.8 (2 x OCH3) 25.3 (C3'), 20.2, 18.5 ppm.
ESIꢀMS (m/z): 433.2 (100) [M]+.
ESIꢀHRMS: calcd for [C26H29N2O4]+ 433.2127, found 433.2131.
(±)-7-Methoxycryptopleurine (1).
To a stirred solution of 2'ꢀCyanoꢀ5,6,9,10ꢀtetramethoxyꢀ1,3ꢀdihydrospiro[dibenzo[e,g]isoindoleꢀ
2,1'ꢀpiperidin]ꢀ1'ꢀium bromide (17, 500 mg, 0.974 mmol) in dry THF (50 mL) was added
KHMDS (214 mg, 1.07 mmol, 1.1 eq) dissolved in dry THF (4 mL) at 0 °C. The reaction mixture
was stirred at this temperature for 2.5 h before ethanol (20 mL) and NaBH4 (120 mg, 3.17 mmol,
ACS Paragon Plus Environment

Page 25 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3.0 eq) were added. The mixture was stirred at room temperature for 10 h, quenched with
saturated aq. NaHCO3 (40 mL) and extracted with CHCl3 (3 x 100 mL). The combined organic
layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was
purified by flash column chromatography (SiO2, CHCl3 + 0.5% MeOH) to afford the title
compound (326 mg, 82%) as a white solid.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rf = 0.27 (CH2Cl2/MeOH = 20 :1)
mp 243–246 °C (dec.), lit. mp 246–
247 °C.73
IR (ATR): 2928 (m), 2829 (w, sh), 1614 (w), 1511 (m), 1466 (m), 1423 (s), 1244 (s), 1209 (m),
1
1149 (m), 1041 (m), 837 (m), 769 (m) 725 (s) cm– .
1HꢀNMR, COSY (400 MHz, CDCl3): δ = 7.76 (s, 1H, ArꢀH), 7.75 (s, 1H, ArꢀH), 7.17 (s, 1H, Arꢀ
2
H), 7.05 (s, 1H, ArꢀH), 4.30 (d, J = 15.4 Hz, 1H, Hꢀ9), 4.08 (s, 6H, 2 x OCH3), 4.02 (s, 3H,
2
OCH3), 4.01 (s, 3H, OCH3), 3.52 (d, J =15.4 Hz, 1H, Hꢀ9), 3.26 (d, J = 11.5 Hz, 1H, Hꢀ11),
3.06–2.95 (m, 1H), 2.90–277 (m, 1H), 2.37–2.22 (m, 2H, Hꢀ14a, Hꢀ11), 2.05–1.70 (m, 4H),
1.58–1.33 (m, 2H) ppm.
13C NMR, HMBC, HSQC (100.6 MHz, CDCl3): δ = 148.7 (2 x Cq–OMe), 148.5 (Cq–OMe),
148.3 (Cq–OMe), 125.2, 125.1, 124.8, 123.9, 123.5, 123.4 (6 x Cq), 103.9, 103.5, 103.3, 103.0 (4
x CH), 57.5 (C14a), 56.4 (C11), 56.2 (C9), 56.1 (2 x OCH3), 56.0 (2 x OCH3), 34.7, 33.7, 26.0,
24.4 ppm.
ESIꢀMS (m/z): 408.3 (100) [M+H]+.
ESIꢀHRMS: calcd for [C25H30NO4]+ 408.2175, found 408.2166.
Oneꢀpot procedure: A mixture of 9,10ꢀbis(bromomethyl)ꢀ2,3,6,7ꢀtetramethoxyphenanthrene36
(15, 500 mg, 1.03 mmol) and DIPEA (178 ꢁL, 1.05 mmol, 1.0 eq) in dry THF (30 mL) was
heated under reflux with stirring while piperidineꢀ2ꢀcarbonitrile (16, 121 mg, 1.10 mmol, 1.1 eq)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 34
1
2
3
4
5
6
7
8
9
was added dropwise. The mixture was heated under reflux for 20 h. After cooling to 0 °C, a
solution of KHMDS (658 mg, 3.30 mmol, 3.3 eq) in dry THF (5 mL) was added. The reaction
mixture was stirred at this temperature for 2 h before ethanol (20 mL) and NaBH4 (240 mg,
6.34 mmol, 6.2 eq) were added. The mixture was stirred at room temperature for 20 h, quenched
with saturated aq. NaHCO3 (50 mL) and extracted with CHCl3 (3 x 100 mL). The combined
organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash column chromatography (SiO2, CHCl3 + 0.5% MeOH) to afford the
title compound (210 mg, 53%) as a white solid. The spectroscopic data of the product were
identical to those of the sample prepared by the stepwise method.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1'-Cyano-5,6,6',7'-tetramethoxy-3',4'-dihydro-1'H-spiro[isoindoline-2,2'-isoquinolin]-2-ium
bromide (24).
A mixture of 1,2ꢀbis(bromomethyl)ꢀ4,5ꢀdimethoxybenzene52 (23, 1.48 g, 4.57 mmol) and DIPEA
(0.80 mL, 4.7 mmol, 1.0 eq) in dry THF (50 mL) was heated under reflux with stirring while 6,7ꢀ
dimethoxyꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ1ꢀcarbonitrile59 (21, 1.00 g, 4.58 mmol, 1.0 eq)
dissolved in dry THF (10 mL) was added dropwise. The mixture was heated to reflux for 20 h. It
was cooled to room temperature, filtered and washed with ice cooled chloroform (50 mL) to
afford the title compound (1.98 g, 94%) as a beige solid, mp 205–208°C (dec.).
IR (ATR): 2995 (w), 2912 (w), 2835 (w), 1510 (s), 1465 (m), 1338 (m), 1260 (s), 1229 (s), 1123
(s), 1105 (m), 989 (m), 852 (m) cm–1.
1H NMR, COSY (400 MHz, DMSOꢀd6): δ = 7.15 (s, 1H, ArꢀH), 7.07 (s, 2H, 2 x ArꢀH), 7.00 (s,
1H, ArꢀH), 6.98 (s, 1H, Hꢀ1'), 5.32–5.16 (m, 2H, CH2), 5.16 (d, J =14.8 Hz , 1H, CH2), 4.94 (d, J
ACS Paragon Plus Environment

Page 27 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
=14.8 Hz, 1H, CH2), 4.28–4.17 (m, 1H, Hꢀ3') 4.17–4.04 (m, 1H, Hꢀ3') 3.82 (s, 3H, OCH3), 3.78
(s, 3H, OCH3), 3.76 (s, 6H, 2x OCH3) 3.38–3.29 (m, 2H, Hꢀ4') ppm.
13C NMR, HMBC, HSQC (100.6 MHz DMSOꢀd6): δ = 150.5 (Cq–OMe), 149.8 (2 x Cq–OMe),
148.3(Cq–OMe), 123.8 (Cq), 123.5 (Cq), 122.6 (Cq), 114.6 (Cq), 113.9 (Cq) , 112.1 (CH), 110.1
(CH), 106.8 (CH), 106.7 (CH), 68.2, 65.8, 59.6 (C1'), 56.3 (C3'), 55.9 (2 x OCH3) 55.8 (OCH3),
55.7 (OCH3), 23.6 (C4') ppm.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ESIꢀMS (m/z): 381.2 (100) [M]+.
ESIꢀHRMS: calcd for [C22H25N2O4]+ 381.1814, found 381.1815.
(±)-Xylopinine (5).
To a stirred solution 1'ꢀcyanoꢀ5,6,6',7'ꢀtetramethoxyꢀ3',4'ꢀdihydroꢀ1'Hꢀspiro[isoindolineꢀ2,2'ꢀ
isoquinolin]ꢀ2ꢀium bromide (24, 500 mg, 1.08 mmol) in dry THF (50 mL) was added sa solution
of KHMDS (239 mg, 1.20 mmol, 1.1 eq) in dry THF (5 mL) at 0 °C. The reaction mixture was
stirred at this temperature for 3.5 h. Ethanol (8 mL) and NaCNBH3 (230 mg, 3.66 mmol, 3.4 eq)
were added and the miyture was allowed to warm to room temperature before AcOH (1.6 mL)
was added dropwise. The mixture was stirred at room temperature for 6 h, quenched with
saturated aq. NaHCO3 (60 mL) and extracted with CHCl3 (3 x 100 mL). The combined organic
layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was
purified by flash column chromatography (SiO2, CHCl3 + 2% MeOH) to afford the title
compound (376 mg, 98%) as an pale orange solid, mp 150–153 °C (dec.), lit. mp 150–
151°.74
Rf = 0.40 (CH2Cl2/MeOH) = 19 : 1
IR (ATR): 2934 (w), 2833 (w), 1609 (w), 1513 (s), 1462 (m), 1257 (s), 1141 (m), 1099 (m), 855
(m), 768 (m) cm–1.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 34
1
2
1HꢀNMR (400 MHz, CDCl3): δ = 6.73 (s, 1H, ArꢀH), 6.66 (s, 1H, ArꢀH), 6.60 (s, 1H, ArꢀH), 6.57
(s, 1H, ArꢀH), 3.93 (d, J = 14.6 Hz, 1H), 3.88 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.85 (s, 3H,
OCH3), 3.84 (s, 3H, OCH3), 3.67 (d, J = 14.7 Hz, 1H), 3.58 (dd, J = 11.3, 3.9 Hz, 1H), 3.24 (dd, J
= 15.8 Hz, 3.9 Hz, 1H), 3.19–3.08 (m, 2H), 2.83 (dd, J = 15.8 Hz, 11.3 Hz, 1H), 2.71–2.56 (m,
2H) ppm.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13C NMR (100.6 MHz, CDCl3): δ = 147.6 (Cq–OMe), 147.5 (Cq–OMe), 147.4 (Cq–OMe), 147.3
(Cq–OMe), 129.8, 126.7, 126.3, 126.2 (4 x Cq), 111.4 (2C), 109.0, 108.5 (4 x CH), 59.7, 58.4,
56.1 (4C) 51.5, 36.4, 29.2 ppm.
ESIꢀMS (m/z): 356.2 (100) [M+H]+.
ESIꢀHRMS: calcd for [C21H26NO4]+ 356.1862, found 356.1852.
Oneꢀpot procedure: A mixture of 1,2ꢀbis(bromomethyl)ꢀ4,5ꢀdimethoxybenzene52 (23, 500 mg,
1.54 mmol) and DIPEA (270 ꢁL, 1.59 mmol, 1.0 eq) in dry THF (50 mL) was heated under
reflux with stirring while 6,7ꢀdimethoxyꢀ1,2,3,4ꢀtetrahydroisoquinolineꢀ1ꢀcarbonitrile (21,
337 mg, 1.54 mmol, 1.0 eq) dissolved in dry THF (5 mL) was added dropwise. The mixture was
heated under reflux for 15 h. After cooling to 0 °C, a solution of KHMDS (922 mg, 4.62 mmol,
3.3 eq) in dry THF (8 mL) was added. The reaction mixture was stirred at this temperature for
2 h. Ethanol (15 mL) and NaCNBH3 (774 mg, 12.3 mmol, 8.0 eq) were added and the solution
was allowed to warm to room temperature before AcOH (5 mL) was added dropwise. The
mixture was stirred at room temperature for 14 h, quenched with saturated aq. NaHCO3 (70 mL)
and extracted with CHCl3 (3 x 100 mL). The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column
chromatography (SiO2, CHCl3 + 2% MeOH) to afford the title compound (531 mg, 97%) as an
ACS Paragon Plus Environment

Page 29 of 34
The Journal of Organic Chemistry
1
2
3
4
pale orange solid, mp 149
–
152 °C (dec.). The spectroscopic data of the product were identical to
5
6
those of the sample prepared by the stepwise procedure.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment