Thionation of Tryptanthrin, Rutaecarpine, and Related Molecules with a Reagent Prepared from P4S10 and Pyridine

Article abstract of DOI:10.1021/acs.joc.6b01346

Reaction of P₄S₁₀ in hot pyridine produces a crystalline solid which can be collected and used for thionations in other solvents such as acetonitrile and sulfolane. The biologically active natural products tryptanthrine, rutaecarpine, 7,8-dehydrorutaecarpine, and some related compounds have now been converted to thionated versions simply by heating the molecules with this thionating reagent in sulfolane (typically at 135 °C for 20 min) followed by a workup in water. No chromatography was necessary.

Full text of DOI:10.1021/acs.joc.6b01346

Subscriber access provided by Northern Illinois University
Article
Thionation of tryptanthrin, rutaecarpine and related
molecules with a reagent prepared fromP4S10 and pyridine.
Ngarita Kingi, and Jan Bergman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01346 • Publication Date (Web): 15 Aug 2016
Downloaded from http://pubs.acs.org on August 16, 2016
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 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Thionation of tryptanthrin, rutaecarpine and related molecules
with a reagent prepared fromP4S10 and pyridine.
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
Ngarita Kingi and Jan Bergman*
Karolinska Institute, Department of Biosciences at Novum, SE-141 57 Huddinge, Sweden
and Vironova Medical, SE-113 30 Stockholm, Sweden
Email: jan.bergman@ki.se
ABSTRACT: Reaction of P4S10 in hot pyridine produces a crystalline solid which can be collected
and used for thionations in other solvents such as acetonitrile and sulfolane. The biologically
active natural products tryptanthrine, rutaecarpine, 7,8-dehydrorutaecarpine and some related
compounds have now been converted to thionated versions simply by heating the molecules with
this thionating reagent in sulfolane (typically at 135 °C for 20 min) followed by a work-up in water.
No chromatography was necessary.
INTRODUCTION
The reagent, a complex between the element P2S5 and pyridine, 7, is readily prepared by
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 19
1
2
3
4
5
6
7
8
9
heating P4S10 in pyridine for a short period of time (50 min).1 The reagent is isolated as crystals
and can readily be transferred to solvents such as acetonitrile and dimethylsulfone, and used for
thionation of amides in a clean fashion. The work-up (addition to water) is simple, because any
remaining reagent is converted to the water-soluble salt 11. In the present paper these principles
have been applied to the indole alkaloids tryptanthrin, rutaecarpine and 7,8-dehydrorutaecarpine
plus some related molecules.
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
RESULTS AND DISCUSION
The brightly yellow compound 6,12-dihydro-6,12-dioxoindolo[2,1-b]quinazoline, 1 has been
known as a synthetic compound at least since 1892.2 In 1971 the trivial name tryptanthrin was
coined by Zähner3 and Fiedler4,5 when 1 could be isolated from culture solutions of the yeast
Candida lipolytica, which had been doped with large amounts of tryptophan and anthranilic acid.
In 1977 tryptanthrin was identified as a natural product by Bergman when it was isolated from
the fruits of the cannonball tree, Couroupita quianensis, Aubl.6 Subsequently, Honda et al.7-9
identified tryptanthrin as the active principle in the leaves of Strobilanthes cusia o. Kantze, which
has a long tradition in Okinawa as a remedy against dermatophytic infections, notably athlete’s
foot. Tryptanthrin has a manifold of other interesting biological activities. For example, Yang et
al.10 have reported therapeutic activity against Lewis lung cancer tumor in a mouse model. Pitzer
et al.11 have reported activity against malaria, and Grundt has demonstrated interesting inhibition
of Toxoplasma gondii12 and a study by Hwang et al. featured antituberculosis activity.13
Tryptanthrin 1, whose structure was established by X-ray crystallography as early as 1974,14
has also undergone detailed NMR studies.15 An extensive review by Tucker and Grundt is
available16. The basic ring system 2 has been reviewed by Cava and Billimoria.17 Tryptanthrin 1
is best synthesized by condensation of isatin 3 (a co-product from the cannonball tree)6 and
ACS Paragon Plus Environment

Page 3 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
isatoic anhydride 4 with elimination of carbon dioxide.18 (Figure 1) Older less attractive methods
include oxidation of isatin with KMnO4 and other oxydants.12 Several of the more recently
developed approaches to tryptanthrin are also rather unattractive like an electro-synthesis19
starting with isatin and an approach involving ortho-lithiophenyl isocyanide.20
Figure 1. Structures of compounds 1, 2, 3, and 4.
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
There are several examples showing that thionation of biologically active molecules can lead
to products with different and/or improved biological properties. Thus thionation of thalidomide
5a gave a series of mono- di- and trithionated products e.g. 5b.21,22 It was found that 5b
effectively reduces the tumor necrosis factor TNF-α. The di- and trithionated derivatives were
even more efficient in that respect.22 Thionations of nucleosine 6,23 a molecule with interesting
anti-influenza activity, gave an analogue with widened activity, including against H1N1.24 (Figure
2)
Figure 2. Structures of compounds 5 and 6.
We have recently developed a versatile technique for thionations based on the reagent 7 that
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 19
1
2
3
4
5
6
7
8
can be used over a wide range of temperatures (up to 180 °C). Useful solvents are acetonitrile and
sulfolane.1 Sulfolane is a dipolar aprotic industrial solvent commonly used in gas production and
oil refining.25 Sulfolane is also used as a versatile solvent for Friedel-Crafts reactions. The
reagent 7 in sulfolane now has been applied to tryptanthrin and some of its reduced derivatives (8
and 9a), which both have been known for a long period of time.26
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
Figure 3. Structures of compounds 7, 8, 9, 10, 11, and 12.
Tryptanthrin was heated for a short period (135 °C, 20 min) with the reagent 7 in sulfolane
whereupon the cooled (30 °C) mixture was poured into water, which typically precipitates the
product as a solid. Any remaining reagent will quickly decompose to the soluble salt 11.1 In the
experiment just discussed the product is not dithionated tryptanthrin but the coupled product 12b,
which is a blackish compound of low solubility. Compound 12a is known26 and also yielded the
highly insoluble 12b on thionation. This manner of coupling observed is rather characteristic for
this type of molecules.26-30 Thionations of 9a and 8 gave a mixture of the thionated tautomers 9b
ACS Paragon Plus Environment

Page 5 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
and 10b, which could be separated by chromatography.26 (Figure 3) In the 1H NMR spectrum 9b
featured a 1H-singlet at 6.06 ppm, whereas its tautomer 10b exposed a CH2-singlet at 4.08 ppm.
The non-thionated tautomeric pair 9a vs. 10a has previously been discussed in the literature.26 In
the solid state it exists as the imine tautomer 9a but when dissolved in DMSO it exists
exclusively as the amine tautomer 10a but in CDCl3 again as 9a. Xia et al.31 have likewise
reported, without citing previous literature, that the amine tautomer is predominating in CDCl3
(1H-doublet at 79.7 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
The properties of 10b are in strong disagreement with a purported molecule previously
reported to have this structure.32 The literature experiment has now been repeated and the product
has a totally different structure, namely 16 (Scheme 1). The starting material used, 14, was not
attacked by bromine on the methyl group but rather the sulfur atom was oxidized to an
electrophilic species that attacked the phenyl group yielding the fused thiazolium system 15 that
under the basic conditions used underwent a ring-opening, thus eventually yielding the known
benzothiazole derivative 16.33,34 The parent compound, 17, is also known. 33,34
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 19
1
2
3
4
5
Scheme 1.
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
A multitude of biological activities have been reported for the indole alkaloid rutaecarpine 22
which can be isolated from the plant Evodia rutaecarpa. The biological activity of rutaecarpine
includes anticancer effects, antithrombotic activity, anti-inflammatory and analgesic effects and
several reviews are available.35-38 Recently rutaecarpine has been claimed as a remedy against
insomnia caused by caffeine, and is marketed under the name Rutaesomn.39 An efficient and fast
synthesis of rutaecarpine, as previously described by Bergman40, starts from tryptamine, 18, and
isatoic anhydride, 4, and is outlined in Scheme 2. In the 1H NMR spectra rutaecarpine show the
aliphatic protons as two triplets at 3.25 and 5.10 ppm, respectively.
ACS Paragon Plus Environment

Page 7 of 19
The Journal of Organic Chemistry
1
2
3
4
5
Scheme 2
6
7
8
O
NH2
9
O
+
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
N
H
O
N
H
4
18
O
N
H
TFAA
NH2
N
O
HN
N
H
N
H
F3C
20
19
O
O
OH
H
N
N
N
N
H
H
N
HN
F3C
22
21
Rutaecarpine 22 could be readily thionated under standard conditions, i.e. reaction with the
reagent 7 in sulfolane (135 °C, 20 min) followed by work-up in water, which yielded the desired
product 23 as a bright yellow solid. The introduced thiono function featured a signal at 187.4 in
the 13C NMR spectrum. The product 23 was isolated as a 1:1 complex with sulfolane, which was
quite stable but the solvent molecule could be removed by repeated recrystallizations from acetic
acid. The intensity of the color was taken as an indication that 25 is an important resonance
contributor to 24.
When rutaecarpine was heated alone in sulfolane no complex was formed, indicating that the
sulfone group is interacting with the thiono functionality of 24 as illustrated in figure 4.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 19
1
2
3
4
5
Figure 4. 1:1 Complex between thionated rutaecarpine and sulfolane.
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
Figure 5. Resonance of the pair 24, 25 and the structure of 26.
The CF3 group in 21 had a profound influence on the chemical shifts of the four aliphatic protons,
all of them now widely separated between 6.46 and 2.88 ppm.
This CF3-substitueted intermediate 21 was also thionated at 135 °C. It would not have been
unexpected if elimination of trifluoromethane should have taken place. This was not the case and
the thionated version of 21 was obtained, i.e. 26, however when the reaction was performed at
165 °C elimination took place, i.e. 21 gave thionated rutaecarpine 24. (Figure 5) In an additional
experiment it was found that when 21 was heated at 240 °C the element of CF3H was eliminated
and rutaecarpine 22 was formed.
7,8-Dehydrorutaecarpine 27 is known as a congener with rutaecarpine and is synthetically
available by dehydrogenation of rutaecarpine with 2,3-dichloro-4,5-dicyanoquinone (DDQ).40
7,8-Dehydrorutaecarpine has compared with rutaecarpine quite often more potent biological
properties. 41-43, and the compound also has potential for treatment of Alzheimer’s disease.44
Attempted thionation of 7,8-dehydrorutaecarpine 27 (ν C=O, 1671 cm-1) gave a somewhat
ACS Paragon Plus Environment

Page 9 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
perplexing product with an IR absorption at 1732 cm-1, clearly indicating an intact carbonyl
group. This product could by further studies be assigned structure 28 wherein N,N-chelated
phosphorus had been introduced. Mild basic hydrolysis (NaOH, EtOH, and H2O) gave
7,8-dehydrorutaecarpine back.
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
Compared with rutaecarpine (ν C=O, 1652 cm-1) dehydrorutaecarpine (ν C=O, 1671 cm-1) has
a less nucleophilic amide function and a more nucleophilic N heteroatom. Hence an attack of the
two N atoms is preferred over the amide bond. Quite a number of N,N-chelated complexes
including phosphorus have been described in the literature.45,46 Most of them have been obtained
by using Lawesson’s reagent 32. Thus e.g. anthranilamide gave 33. (Figure 6)
Figure 6 Structures of Lawesson’s reagent 32 and the cyclized products 31 and 33.
When 7,8-dehydrorutaecarpine was heated with the reagent 7 in excess at slightly higher
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 19
1
2
3
4
5
6
7
8
temperature the thionated molecule 29 was formed, which after mild hydrolysis gave the desired
thionated compound 30 (Scheme 3).
9
Evodiamine 34 is a biologically interesting congener to rutaecarpine in Evodia rutaecarpa,47
which improves cognitive abilities in transgenic mouse models of Alzheimer’s disease.48 Several
analogues of evodiamine, notably the thio derivative 35, show in vitro and in vivo antitumor
efficacy.49 Racemic evodiamine has resently been resolved.50 In this context is should be noted
that compound 21 is a trifluoro analogue of evodiamine.
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
Against this background thionated evodiamine should be an interesting molecule but
unfortunately the attempted conversion 34→36 failed due to ring-cleavage reactions and also
ready loss of the methyl group. The sensitivity of evodiamine against e.g. acids have been
discussed by Daneili and Palmisani.51
Scheme 4
ACS Paragon Plus Environment

Page 11 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The thionation process could also be extended to substituted rutaecarpine derivatives, thus the
2-chloronated precursor 37 gave the thionated version of 2-chlororutaecarpine 38 in good yields,
as did thionation of euxylophoricine A, 39 (to yield 40 and 41), originally obtained from the
commercially important tree yellowheart, Euxylophora paraensis. (Scheme 4) The nonplanar
hydrate 41 featured, as expected, a complex pattern of the aliphatic protons in the 1HNMR
spectrum. 2-Chlor-orutaecarpine has been described in the literature52 but the preparative method
described there was not used. The route via 37 was preferred.
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
CONCLUSIONS
The reagent formed from P4S10 and pyridine is a useful reagent for thionations, in a wide range of
temperatures of amides and is preferably applied in sulfolane, where the process is quick. Work-
up with water is easy and chromatographic purification is not necessary, as distinct from many
thionations using Lawesson’s reagent, which normally is not used above 110 °C.
EXPERIMENTAL SECTION
General information. NMR Data were recorded on a 300 or 500 MHz instrument, using the
residual solvent signal as reference. Throughout the work DMSO-d6 was use as solvent, unless
stated otherwise, in the NMR experiments. Assignments are based on standard 1H, ATP, 13C high
power decoupling (HPDEC) and 1D NOE-DIFF experiments. IR spectra were acquired on a 330
FT-IR instrument, using ATR technique.
Thionation of tryptanthrin (1), formation of 12b. Tryptanthrin 1 (248 mg, 1 mmol) was
added to sulfolane (8 mL) at 110 °C followed b addition of the thionation reagent 7 (380 mg,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 19
1
2
3
4
5
6
7
8
1mmol) at 110 °C. The reaction was completed by a period (10 min, 130 °C). The bluish-black
reaction mixture was allowed to cool and then poured into water. The blackish product was
purified from hot DMF, 190 mg (78%) of 12b, mp >260 °C. IR 1622, 1600, 1486, 1455, 1347,
1154, 738 cm-1. No NMR data could be obtained for this compound due to solubility reasons.
Anal. Calcd. for C30H16N4S2: C, 72.50; H, 3.25; N, 11.28, Found: C, 72.15; H, 3.08; N, 10.97.
Thionation of the dimeric compound 12a. Compound 12a (116 mg, 0.5 mmol) was added to
sulfolane (6 mL) at 110 °C followed by addition of the thionation reagent 7 (380 mg, 1 mmol) at
110 °C. After a period (10 min, 130 °C) the bluish-black reaction mixture was poured into water.
The blackish solid formed was purified from hot DMF, 108 mg, (78%) of 12b, which was
identical with the product obtained in the previous experiment.
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
6-Hydroxy-5a,6-dihydroindolo[2,1-b]quinazolin-12(5H)-one (8). This molecule was
prepared as described in the literature,26 yield 90 %. The spectroscopic properties were in
agreement with data in the literature26.
Indolo[2,1-b]quinazolin-12(6H)-one (10a). This molecule was prepared as described in the
literature, yield (60 %)26.
Indolo[2,1-b]quinazolin-12(6H)-thione (10b). Compound 8 (234 mg, 1 mmol) was added,
under argon, to sulfolane (10 mL) at 100 °C followed by the reagent 7 (492 mg, 1 mmol). After
10 min the temperature was increased to 135 °C and this temperature kept for 20 min. The
reaction mixture was allowed to cool and added to water. The solid formed was collected and
then separated by column chromatography on silica gel using CH2Cl2 containing a slowly
increasing percentage of MeOH which yielded 10b (125 mg, 50 %, mp 190 °C dec.) and small
amounts of 9b (20 mg, 8 %, mp 190 °C dec.). However, 9b seems to be a more stable form than
10b. Tautomer 9b gave the following data. 1H NMR (DMSO-d6): δ 6.03 (s, 1H), 7.15 (m, 2H),
ACS Paragon Plus Environment

Page 13 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7.25 (m, 2H), 7.54 (dd, 1H), 7.70 (dd, 1H), 8.16 (dd, 1H), 8.58 (d, 1H), 11.7 (s, 1H) ppm. 13C
NMR: δ 80.4, 111.1, 115.0, 115.3, 117.9, 119.5, 120.1, 124.1, 127.5, 129.1, 130.2, 134.8, 137.3,
140.4, 158.5. Anal. Calcd. for C15H10N2S: C, 71.97; H, 4.03; N, 11.19. Found: C, 72.08; H. 3.97;
N, 11.05.
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 major Tautomer 10b gave the following data. 1H NMR (CDCl3): δ 4.08 (s, 2H), 7.34 (m,
1H), 7.45-7.55 (m, 3H), 7.74 (m, 1H), 7.79 (m. 1H), 8.50 (d, 1H), 8.62 (d, 1H). 13C NMR: δ 35.9
(t), 96.2, 100.7, 117.4, 124.5, 126.3, 126.8, 126.9, 127.0, 128.5, 134.4, 140.1, 146.1, 160.1,
185.0.
2-(2-Acetylaminophenyl)benzothiazole (16).Ammonia (aq.,8.0 mL) was added to the
purported bromination product of 2-methyl-3-phenylquinazoline-4(3H)-tione 14 (3.32 g, 0.01
mol)32 in methanol (40 mL) and the reaction mixture was heated at reflux temperature for 1 h.
Concentration and addition of water gave the benzothiazole derivative 16 (2.2 g, 88%), mp 120-
121 °C. The spectroscopic data were in agreement with those in the literature. 33,34
Synthesis of 13b-trifluoromethyl-13b,14-dihydrorutaecarpine (21). This compound was
synthesized as previously described40. 1H NMR δ 2.83 (m, 1H), 2.97 (m, 1H), 3.35 (m, 1H), 5.27
(m, 1H), 6.90 (dd,
7.59 (d, 1H,
70.6 (q,
124.2 (s), 124.9 (s), 125.6 (q,
J
1=8.10 Hz,
J
2=1.90 Hz), 6.94 (d,
J =1.90 Hz), 7.12 (dd, 1H), 7.27 (dd, 1H),
J
=8.10 Hz), 7.81 (d, 1H), 8.10 (s, 1H), 11.0 (s, 1H); 13C NMR: δ 19.8 (t), 37.4 (t),
J
2=30.8 Hz), 112.4 (d), 112.5 (s), 113.6 (s), 113.9 (d), 119.0 (d), 119.5 (d), 123.2 (d),
J
1=301.5 Hz), 129.7 (d), 137.0 (s), 138.3 (s), 145.0 (s), 160.7 (s).
Syntheis of 26 by thionation of 21. Compound 21 (288 mg, 1 mmol) was added to sulfolane
(8mL) at 115 °C followed by addition of the thionation agent 7 (296 mg, 1 mmol). The reaction
was completed at 160 °C (20 min). The pale-yellow reaction mixture was allowed to cool and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 19
1
2
3
4
5
6
7
8
then poured into water. The solid formed was collected and recrystallized from ethanol-water to
give compound 26 as a 1:1 complex with sulfolane, 301 mg (75%), mp 260 °C dec. IR 1611,
1483, 1165, 1142, 934, 758 cm-1. 1H NMR δ 2.88 (m, 1H), 3.05 (m, 1H), 3.69 (m, 1H), 6.44 (m,
1H), 6.89-6.94 (m, 2H), 7.13 (dd, 1H), 7.28 (dd, 1H), 7.41 (dd, 1H), 7.60-7.63 (m, 2H), 8.01 (s,
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), 8.36 (d, 1H), 11.2 (s, 1H); 13C NMR: δ 19.8 (t), 37.4 (t), 70.5 (q,
112.4 (s), 115.3 (d), 119.0 (d), 119.5 (d), 119.6 (d), 121.4 (s), 123.3 (d), 124.4 (s), 124.7 (q,
1=290.5 Hz), 124.8 (s), 133.0 )s), 134.0 (d), 137.1 (s), 139.0 (s), 191.5 (s). ). Anal. Calcd. for
J2=30.5 Hz), 112.4 (d),
J
C19H14F3N3O: C, 63.86; H, 3.95; N, 11.76. Found: C, 63.60; H, 3.79; N, 11.55.
Synthesis of 24 by thionation of rutaecarpine (22). Rutaecarpine (2.88 g, 0.01 mol) was
added to sulfolane (35 mL at 100 °C), followed by addition of the thionation reagent 7 (2.96 g,
0.005 mol) at 100 °C. The reaction was completed by a period (20 min) at 135 °C. The yellow
reaction mixture was allowed to cool whereupon water (150 mL) was added. The crude product
was crystallized from HOAc-DMF, 1:1:1 to give 24 (2.21 g, 70%) mp >260 °C dec. IR 3430,
3030, 1619, 1592, 1561, 1302, 1215, 1146, 1105, 941, 740 cm-1. 1H NMR δ 3.23 (t, 2H), 5.08 (t,
2H), 7.08 (dd, 1H), 7.28 (dd, 1H), 7.50-7.53 (m, 2H), 7.64 (d, 1H), 7.71 (d, 1H), 7.84 (dd, 1H),
8.67 (d, 1H), 11.9 (s, 1H) cm-1. 13C NMR: δ 19.0 (t), 49.1 (t), 112.6 (d), 118.1 (s), 119.8 (d),
120.0 (d), 124.6 (s), 125.0 (d), 127.0 (s), 127.1 (d), 127.3 (d), 128.0 (s), 131.2 (d), 134.8 (d),
139.0 (s), 142.4 (s), 144.3 (s), 187.5 (s). Anal. Calcd. for C18H13N3S: C, 71.26; H, 4.32; N, 13.85.
Found: C, 71.06; H, 4.25;
N, 13.68.
7,8-Dehydrorutaecarpine (27). The method described before was used,40 but on a 10-fold
scale. DDQ (4.54, 0.02 mol) in dioxane (100 mL) was added to a solution of rutaecarpine (5.74 g,
0.02 mol) in dioxane (250 mL). After a period of reflux, 0.5 h, the reaction mixture was
ACS Paragon Plus Environment

Page 15 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
evaporated and the residue extracted with a solution of KOH (15 g) in water (300 mL). The
procedure was repeated until all DDQ-2H had been removed. The residue was recrystallized from
DMF-ethanol, yield 4.95 g (80%), mp 280-281 °C, lit. mp 280-281 °C)40. IR 3232, 1673, 1635,
1570, 1540, 1505, 1463, 1331, 1245, 1158, 1147, 909, 764, 751, 730 cm-1. 1H NMR δ 7.25 (dd,
1H), 7.44-7.48 (m, 2H), 7.68 (d, 1H), 7.75 (d, 1H), 7.80 (d, 1H), 7.88 (dd, 1H), 8.10 (d, 1H), 8.31
(d, 1H), 8.57, (d, 1H), 12.6 (s, 1H). 13C NMR δ 107.9 (d), 112.7 (d), 115.9 (s), 117.6 (d), 119.8
(s), 120.4 (d), 120.7 (d), 121.7 (s), 124.3 (d), 126.1 (d), 126.5 (d), 126.9 (d), 129.3 (s), 134.6 (d),
139.9 (s), 140.0 (s), 147.5 (s), 158.5 (s).
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
Synthesis the complex 28 by thionation of 7,8-Dehydrorutaecarpine (27). 7,8-Dehydro-
rutaecarpine 27 (2.16 g, 0.01 mol) was added to sulfolane (35 mL) at 115 °C. The reaction was
completed by a period (20 min) at 135 °C. The yellow-orange reaction mixture was allowed to
cool, whereupon water (150 mL) was added. The crude product was crystallized from DMF-
ethanol to give 28, yield 2.55 g (75%), mp 260 °, dec. IR 1732, 1663, 1546, 1480, 1299, 1143,
1095, 906, 750 cm-1. 1H NMR (DMSO-d6): δ 7.22 (dd, 1H), 7.39 (dd, 1H), 7.79 (d, 1H), 7.90 (d,
1H), 7.94 (dd, 1H), 8.00 (dd, 1H), 8.11 (dd, 1H), 8.13 (dd, 1H), 8.39 (d, 1H), 8.64 (d, 1H), 12.6
(s, 1H). No satisfactory analytical data could be obtained for this compound, which still
contained some sulfolane.
Hydrolysis of compound 28. Compound 28 (379 mg, 1mmol) was heated at reflux
temperature for 30 min in ethanol (20 mL) and water (10 mL) containing sodium hydroxide (100
mg). The clear solution was concentrated; water containing acetic acid (150 mg) was added. The
solid of 7,8-dehydrorutaecarpine was collected, washed with water and dried, 204 mg (90%).
Synthesis of thionated dehydrorutaecarpine (30). 7,8-Dehydrorutaecarpine 27 (287 mg, 1
mmol) was added to sulfolane (8 mL) at 120 °C followed by the reagent 7 (984 mg, 2 mmol).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 19
1
2
3
4
5
6
7
8
The temperature was increased to 165 °C for 20 min, whereupon the mixture was allowed to
cool. After addition of water and collection by filtration the phosphorus-containing crude product
was heated at reflux temperature for 30 min in ethanol (20 mL) and water (10 mL) containing
sodium hydroxide (200 mg). The clear solution was concentrated; water containing acetic acid
(150 mg) was added. The solid of 30, was collected washed with water and dried, 210 mg (70%),
mp 260 °C. 1H NMR (DMSO-d6): δ 6.98 (dd, 1H), 7.25 (dd, 1H), 7.50-7.55 (m, 2H), 7.66 (d, 1H),
7.74 (d, 1H), 7.99-8.04 (m, 2H), 8.17 (d, 1H), 8.37 (d, 1H). 13C NMR (DMSO-d6): δ 109.3 (d),
112.5 (d), 114.7 (s), 119.0 (d), 119.3 (d), 119.5 (d), 121.3 (d), 121.6 (s), 125.8 (s), 127.5 (d),
128.5 (s), 131.2 (d), 133.5 (d), 135.7 (d), 140.3 (s), 140.8 (s), 144.4 (s), 170.0 (s). ). Anal. Calcd.
for C18H11N3S: C, 71.74; H, 3.68; N, 13.94. Found: C, 71.60; H, 3.58; N, 13.78.
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
Synthesis of 37. This compound was prepared using the method described for 31. Yield: 85%,
mp 210 °C dec. IR 3339, 2937, 1615, 1589, 1543, 1456, 1422, 1327, 1302, 1219, 1077, 940, 813
cm-1. 1H NMR δ 2.80 (m, 1H), 2.94 (m, 1H), 3.27 (m, 1H), 5.15 (dd, 1H), 6.90 (dd, 1H), 6.93 (d,
1H), 7.12 (dd, 1H), 7.26 (dd, 1H), 7.58 (s, 1H), 7.59 (d, 1H), 7.81 (d, 1H), 8.10 (s, 1H).
13C NMR: δ 19.8 (q), 39.0 (q), 70.5 (q,
J2=30.9 Hz), 112.3 (d), 112.5 (s), 113.6 (s), 113.9 (d),
119.0 (d), 119.1 (d), 119.5 (d), 123.2 (s), 124.2 (s), 124.9 (s), 125.2 (q,
J1=301.5 Hz), 129.7 (d),
137.0 (s), 138.3 (s), 145.0 (s), 160.7 (s). Anal. Calcd. for C19H13ClF3N3O: C, 58.25; H, 3.37; N,
10.73. Found: C, 57.95; H, 3.28; N, 10.56.
Synthesis of 38 by thionation of 37. Compound (37) (50 mg, 0.13 mmol) was added to the
mixture and was added to the mixture and the temperature was increased (160 °C). After 0.5h
another portion of reagent 7 was added; this step was repeated two more times. A total of 2.6 eq.
of reagent 7was used. The reaction mixture was allowed to cool and then heated in water for 10
min. The solid (38) formed was collected by filtration as a yellow solid, 63 mg (86%, mp >260
ACS Paragon Plus Environment

Page 17 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
°C. 1H NMR: δ 3.29 (t, 2H), 5.08 (t, 2H), 7.12 (dd, 1H), 7.33 (dd, 1H), 7.51 (d, 1H,
J1=8.5 Hz,
7
8
7.56 (dd, 1H, J1=8.5 Hz, J2=2.0 Hz), 7.66 (d, 1H, J2=2.0 Hz), 7.67 (d, 1H), 8.64 (d, 1H), 11.90
9
(s, 1H). 13C NMR: δ 19.0 (t), 49.1 (t), 112.7 (d), 118.9 (s), 120.0 (d), 120.2 (d), 124.6 (s), 125.3
(d), 126.0 (d), 126.7 (s), 126.8 (s), 127.5 (d), 133.3 (d), 139.2 (s), 139.6 (s), 143.5 (s), 145.5 (s),
186.9 (s). Anal. Calcd. for C18H12ClN3S: C, 64.00, H, 3.58, N, 12.44. Found: C, 63.80, H, 3.47,
N, 12.31.
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
Synthesis of 41 by thionation of euxylophoricine–A, 39. Euxylophoricine–A, (327 mg,
1 mmol) was thionated under standard conditions, with the reagent 7 in sulfolane, (135 °C, 20
min.) after H2O work-up, 41 was obtained as a yellow solid, 280 mg, (82%) mp dec. ~260 °C.
IR 3324, 1621, 1503, 1269, 1173, 1131, 942, 749 cm-1. 1H NMR: δ 2.82 (m, 1H), 3.00 (m, 1H),
3.63 (m, 1H), 3.75 (q, 3H), 3.86 (q, 3H), 6.40 (s, 1H), 6.41 (m, 1H), 7.11 (dd, 1H), 7.26 (dd, 1H),
7.50-7.64 (m, 2H),
7.78 (s, 1H), 7.84 (s, 1H), 11.1 (s, 1H). 13C NMR: δ 19.6 (t), 45.7 (t), 55.7 (q), 55.8 (q), 97.9 (d),
112.3 (d), 112.4 (s), 113.9 (s), 114.8 (d), 117.1 (s), 119.0 (d), 119.5 (d), 123.2 (d), 124.5 (s),
124.7 (s), 134.7 (s), 137.1 (s), 138.8 (s), 154.8 (s), 189.8 (s). Anal. Calcd. for C20H17N3O2S (after
drying): C, 66.10; H, 4.71; N, 11.56. Found: C, 65.94; H, 4.70; N, 11.52.
SUPPORTING INFORMATION. NMR spectra of the majority of the compounds prepared are
featured.
FUNDING SOURCES. This work was funded by the Karolinska Institute and Vironova
Medical.
REFERENCES
(1)Bergman, J.; Pettersson, B.; Hasimbegovic, V.; Svensson, P. H. J. Org. Chem. 2011, 76, 1546.
(2)O'Neill, C. Chem. News 1892, 65, 124.
(3)Schindler, F.; Zähner, H. Arch. Mikrobiol. 1971, 79, 187.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 19
1
2
3
4
5
6
7
8
(4)Fiedler, E.; Fiedler, H. P.; Gerhard, A.; Keller-Schierlein, W.; Koenig, W. A.; Zaehner, H.
Arch. Microbiol. 1976, 107, 249.
(5)Fiedler, H. P. Ph.D. Thesis, Tübingen 1974.
(6)Bergman, J.; Egestad, B.; Lindstroem, J. O. Tetrahedron Lett. 1977, 2625.
(7)Honda, G.; Tabata, M. Planta Med. 1979, 36, 85.
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
(8)Honda, G.; Tabata, M.; Tsuda, M. Planta Med. 1979, 37, 172.
(9)Honda, G.; Tosirisuk, V.; Tabata, M. Planta Med. 1980, 38, 275.
(10)Yang, S.; Li, X.; Hu, F.; Li, Y.; Yang, Y.; Yan, J.; Kuang, C.; Yang, Q. J. Med. Chem. 2013,
56, 8321.
(11)Pitzer, K. K.; Scovill, J. P.; Kyle, D. E.; Gerena, L. WO2000018769A.
(12)Krivogorsky, B.; Nelson, A. C.; Douglas, K. A.; Grundt, P. Bioorg. Med. Chem. Lett. 2013,
23, 1032.
(13)Hwang, J.-M.; Oh, T.; Kaneko, T.; Upton, A. M.; Franzblau, S. G.; Ma, Z.; Cho, S.-N.; Kim,
P. J. Nat. Prod. 2013, 76, 354.
(14)Fedeli, W.; Mazza, F. J. Chem. Soc., Perkin Trans. 2 1974, 1621.
(15)Jarrah, M. Y.; Thaller, V. J. Chem. Res.(M) 1980, 260.
(16)Tucker, A. M.; Grundt, P. ARKIVOC 2012, (i), 546.
(17)Billimoria, A. D.; Cava, M. P. Heterocycles 1996, 42, 453.
(18)Bergman, J.; Lindstroem, J. O.; Tilstam, U. Tetrahedron 1985, 41, 2879.
(19)Batanero, B.; Barba, F. Tetrahedron Lett. 2006, 47, 8201.
(20)Lygin, A. V.; de Meijere, A. Org. Lett. 2009, 11, 389.
(21)Zhu, X.; Giordano, T.; Yu, Q.-S.; Holloway, H. W.; Perry, T. A.; Lahiri, D. K.; Brossi, A.;
Greig, N. H. J. Med. Chem. 2003, 46, 5222.
(22)Yoon, J. S.; Lee, J.-H.; Tweedie, D.; Mughal, M. R.; Chigurupati, S.; Greig, N. H.; Mattson,
M. P. J. Neurosci. Res. 2013, 91, 671.
(23)Gerritz, S. W.; Cianci, C.; Kim, S.; Pearce, B. C.; Deminie, C.; Discotto, L.; McAuliffe, B.;
Minassian, B. F.; Shi, S.; Zhu, S.; Zhai, W.; Pendri, A.; Li, G.; Poss, M. A.; Edavettal, S.;
McDonnell, P. A.; Lewis, H. A.; Maskos, K.; Mortl, M.; Kiefersauer, R.; Steinbacher, S.;
Baldwin, E. T.; Metzler, W.; Bryson, J.; Healy, M. D.; Philip, T.; Zoeckler, M.; Schartman, R.;
Sinz, M.; Leyva-Grado, V. H.; Hoffmann, H.-H.; Langley, D. R.; Meanwell, N. A.; Krystal, M.
PNAS 2011, 108, 15366.
(24)Homman, M.; Kingi, N.; Bergman, J.; Engqvist, R. WO2013171334A1.
(25)Tilstam, U. Org. Process Res. Dev. 2012, 16, 1273.
(26)Bergman, J.; Tilstam, U.; Toernroos, K. W. J. Chem. Soc., Perkin Trans. 1 1987, 519.
(27)Bergman, J.; Eklund, N. Chem. Scr. 1982, 19, 193.
(28)Sandmeyer, T.; Conzetti, A. Zeit. Farb. Text. Chem. 1903, 2, 129.
(29)Sander, L. Ber. Dtsch. Chem. Ges. 1925, 58, 820.
(30)Kollenz, G.; Penn, G.; Theuer, R.; Fabian, W. M. F.; Abd El-Nabi, H. A.; Zhang, X.; Peters,
K.; Peters, E. M.; von Schnering, H. G. Tetrahedron 1996, 52, 5427.
(31)Xia, Z.; Wang, K.; Zheng, J.; Ma, Z.; Jiang, Z.; Wang, X.; Lv, X. Org. Biomol. Chem. 2012,
10, 1602.
(32)Thakur, M. P.; Sinha, S. K. P. Indian J. Chem. 1973, 11, 500.
(33)Lunn, W. H. W.; Harper, R. W. J. Org. Chem. 1972, 37, 607.
(34)Tseng, H.-W.; Liu, J.-Q.; Chen, Y.-A.; Chao, C.-M.; Liu, K.-M.; Chen, C.-L.; Lin, T.-C.;
Hung, C.-H.; Chou, Y.-L.; Lin, T.-C.; Wang, T.-L.; Chou, P.-T. J. Phys. Chem. Lett. 2015, 6,
ACS Paragon Plus Environment

Page 19 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
1477.
(35)Bergman, J. The Alkaloids (N. Y.) 1983, 21, 29.
(36)Lee, S. H.; Son, J.-K.; Jeong, B. S.; Jeong, T.-C.; Chang, H. W.; Lee, E.-S.; Jahng, Y.
Molecules 2008, 13, 272.
(37)Son, J.-K.; Chang, H. W.; Jahng, Y. Molecules 2015, 20, 10800.
(38)Sheu, J.-R. Cardiovasc. Drug Rev. 1999, 17, 237.
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
(39)Xue, L.; Chan, W. K.; Linnet, S. W.; Linnet, T. N.; Linnet Biopharmaceuticals Inc., USA .
2012, p 19pp.; Chemical Indexing Equivalent to 158:77474 (WO).
(40)Bergman, J.; Bergman, S. J. Org. Chem. 1985, 50, 1246.
(41)Gillner, M.; Bergman, J.; Cambillau, C.; Gustafsson, J. A. Carcinogenesis (London) 1989,
10, 651.
(42)Rannug, U.; Agurell, E.; Rannug, A.; Cederberg, H. Environ. Mol. Mutagen. 1992, 20, 289.
(43)Wang, B.; Mai, Y.-C.; Li, Y.; Hou, J.-Q.; Huang, S.-L.; Ou, T.-M.; Tan, J.-H.; An, L.-K.; Li,
D.; Gu, L.-Q.; Huang, Z.-S. Eur. J. Med. Chem. 2010, 45, 1415.
(44)He, Y.; Yao, P.-F.; Chen, S.-b.; Huang, Z.-h.; Huang, S.-L.; Tan, J.-H.; Li, D.; Gu, L.-Q.;
Huang, Z.-S. Eur. J. Med. Chem. 2013, 63, 299.
(45)Shinde, B. R.; Shenoy, S. J.; Pai, N. R. Indian J. Chem., Sect. B 1990, 29B, 711.
(46)Legrand, L.; Lozac'h, N. Bull. Soc. Chim. Fr. 1960, 2088.
(47)Wehle, S.; Espargaro, A.; Sabate, R.; Decker, M. Tetrahedron 2016, 72, 2535.
(48)Yuan, S.-m.; Gao, K.; Wang, D.-m.; Quan, X.-z.; Liu, J.-n.; Ma, C.-m.; Qin, C.; Zhang, L.-f.
Acta Pharmacol. Sin. 2011, 32, 295.
(49)Wang, S.; Fang, K.; Dong, G.; Chen, S.; Liu, N.; Miao, Z.; Yao, J.; Li, J.; Zhang, W.; Sheng,
C. J. Med. Chem. 2015, 58, 6678.
(50)Domonkos, C.; Fitos, I.; Visy, J.; Zsila, F. Phys. Chem. Chem. Phys. 2014, 16, 22632.
(51)Danieli, B.; Palmisano, G. Gazz. Chim. Ital. 1975, 105, 99.
(52)Mohanta, P. K.; Kim, K. Tetrahedron Lett. 2002, 43, 3993.
ACS Paragon Plus Environment