Aromatic chlorination with thionyl chloride. Applications in the synthesis of chlorinated isoflavones

Article abstract of DOI:10.1080/10426500701509485

Genistein (1) undergoes selective chlorination on treatment with thionyl chloride to give first 8-chlorogenistein (10) and then 6,8-dichlorogenistein (8). Biochanin A (18) gives the 6,8-dichloro derivative 19. A mechanism is suggested for the unexpected a

Full text of DOI:10.1080/10426500701509485

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Aromatic Chlorination with
Thionyl Chloride. Applications
in the Synthesis of Chlorinated
Isoflavones
Otto Soidinsalo a & Kristiina Wähälä a
a Laboratory of Organic Chemistry, Department of
Chemistry, University of Helsinki, Finland
Version of record first published: 03 Dec 2007.
To cite this article: Otto Soidinsalo & Kristiina Wähälä (2007): Aromatic Chlorination
with Thionyl Chloride. Applications in the Synthesis of Chlorinated Isoflavones,
Phosphorus, Sulfur, and Silicon and the Related Elements, 182:12, 2761-2767
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Phosphorus, Sulfur, and Silicon, 182:2761–2767, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701509485
Aromatic Chlorination with Thionyl Chloride.
Applications in the Synthesis of Chlorinated Isoflavones
Otto Soidinsalo
¨
¨ ¨
Kristiina Wahala
Laboratory of Organic Chemistry, Department of Chemistry,
University of Helsinki, Finland
Genistein (1) undergoes selective chlorination on treatment with thionyl chloride to
give first 8-chlorogenistein (10) and then 6,8-dichlorogenistein (8). Biochanin A (18)
gives the 6,8-dichloro derivative 19. A mechanism is suggested for the unexpected
aromatic chlorinations.
Keywords Biochanin A; chlorination; daidzein; genistein; thionyl chloride; isoflavone
INTRODUCTION
In connection with our recent work on isoflavonoid derivatives, a rou-
tine chlorination by thionyl chloride of a genistein (1) derivative carry-
ing an O-(ω-carboxyalkyl) group in 7-position unexpectedly resulted in
concomitant chlorination at C-8, as was clear from the EI mass spec-
1
1
trum and from the H and 13C NMR spectra augmented with H-13C
HMQC and HMBC 2D measurements. Apart from an isolated example
in the literature1 of thionyl chloride apparently acting as a source of
Cl+ towards hydroxy- and aminophenothiazines, chlorination of phenol
derivatives by neat SOCl2 is unknown. Phenol itself is reported2 to give
phenyl chlorosulfinate or diphenyl sulfite in high yield under reflux con-
ditions. At lower temperatures p-chlorophenol was isolated at a level of
a few percent in addition to much tarry residue. There is also a report3
of a 3-hydroxypyrrole derivative undergoing chlorination by SOCl2 at
C-2. According to the mechanism suggested the reaction proceeds via
the sulfinate ester, which delivers a chloride to C-2 and also produces
sulfur monoxide.3
Received March 26, 2007; accepted June 12, 2007.
Otto Soidinsalo wishes to thank Dr. Jorma Matikainen for guidance in HRMS.
Address correspondence to Kristiina Wa¨ha¨la¨, Laboratory of Organic Chemistry, De-
partment of Chemistry, P.O. Box 55, University of Helsinki, 00014 Helsinki, Finland.
E-mail: kristiina.wahala@helsinki.fi
2761

2762
O. Soidinsalo and K. Wa¨ha¨la¨
As for isoflavones, a 1980 report4 states that the parent isoflavone
(2) does not react at all with thionyl chloride, while 7-hydroxyisoflavone
(3) gives 7-chloroisoflavone (4), and 7-methoxyisoflavone (5) gives 6-
chloro-7-methoxyisoflavone (6), both in moderate yields (Scheme 1).
Although reaction mechanisms were not discussed in the paper, it
seems likely that in some of the above reactions SOCl2 functions as
a Cl− donor while in others it is a Cl+ donor. Incidentally, chlorination
of 3 using sulfuryl chloride gave4 6,8-dichloro-7-hydroxyisoflavone (7)
and a chlorinated isoflavanone, while 5 gave chloroisoflavanones only.
These isoflavanones result from the chlorination of the double bond
in 2,3-position. In 2003, unidentified mono- and/or dichloroisoflavones
were observed to result from the action of hypochlorous acid on
isoflavones.5] Very recently a Japanese group reported6 the formation
R1
H
H
H
H
H
H
Cl
Cl
H
Cl
H
H
H
Cl
R2
OH
H
OH
Cl
OMe
R3
H
H
H
H
H
R4
OH
H
H
H
H
H
H
OH
H
OH
OH
OH
OH
OH
R5
OH
H
H
H
H
H
H
OH
OH
OH
OH
OH
OH
OH
R6
H
H
H
H
H
H
H
H
H
H
Cl
H
Cl
OH
1
2
3
4
5
6
7
8
9
genistein
isoflavone
7-hydroxyisoflavone
7-chloroisoflavone
7-methoxyisoflavone
6-chloro-7-methoxyisoflavone
6,8-dichloro-7-hydroxyisoflavone
6,8-dichlorogenistein
daidzein
OMe Cl
OH
OH
OH
OH
OH
OH
OH
OH
Cl
Cl
H
H
H
Cl
Cl
H
10 8-chlorogenistein
11 3ꢀ-chlorogenistein
12
6-chlorogenistein
13 3ꢀ,6-dichlorogenistein
14
8-chloro-3ꢀ,4ꢀ,5,7-
tetrahydroxyisoflavone
3ꢀ-chlorodaidzein
8-chlorodaidzein
15
16
H
OH
OH
OH
OH
OH
OH
OMe
H
H
H
H
Cl
OMe
H
H
H
H
OH
OH
H
OH
OH
OH
OMe
OMe
OH
Cl
H
Cl
H
H
H
H
Cl
Cl
H
Cl
H
17 3ꢀ,8-dichlorodaidzein
18
biochanin A
19 6,8-dichlorobiochanin A
20 glycitein
21 trimethoxygenistein
H
OMe OMe
SCHEME 1

Aromatic Clorination with Thionyl Chloride
2763
of 6,8-dichlorogenistein (8) in 10% yield from the HOCl chlorination
of genistein (1), and of 3ꢀ,5ꢀ,8-trichlorodaidzein (65%) from a similar
reaction of daidzein (9). Two flavones were reported7 to give the 3-
monochloro derivatives in low yield on treatment with SOCl2, irrespec-
tive of the nature of substituents (6-methyl or 7-methoxy). The authors
suggest a mechanism involving a flavylium chlorosulfite intermediate
and elimination of sulfur monoxide.
Interestingly, a number of chlorinated hydroxyisoflavones are nat-
ural products in their own right, as metabolites of the parent hy-
droxyisoflavones, and possess antioxidant and other biological ac-
tivity. Known examples include 8-chloro- and 6,8-dichlorogenistein8
(10 and 8, respectively), 3ꢀ-chlorogenistein5 (11), 6-chloro- and 3ꢀ,6-
dichlorogenistein9 (12 and 13, respectively), and 8-chloro-3ꢀ,4ꢀ,5,7-
tetrahydroxyisoflavone10,11 (14). Total synthesis from appropriate
chloro-substituted monocyclic starting materials has been published12
for 14 and, without any experimental or spectroscopic data, for 11
and the daidzeins 15, 16, and 17, which however have not been iden-
tified as natural products.5 As shown below, our examination of the
genistein/SOCl2 reaction provides an expedient laboratory synthesis of
the bacterially produced8 chlorinated genisteins 8 and 10.
RESULTS AND DISCUSSION
We find that the reaction of genistein (1) in neat SOCl2 proceeds highly
selectively and gives 70% yield of 8-chlorogenistein (10), which is read-
1
ily identified by its EI mass spectrum and H and 13C NMR spectra.
Its identity is further confirmed by HMQC and HMBC experiments
(Scheme 2). The spectra were also in agreement with those reported
1
8
genistein R1 = OH
6,8-dichlorogenistein R1 = OH, R2 = R3 = Cl
biochanin A R1 = OMe
18
10 8-chlorogenistein R3 = H, R1 = OH, R2 = Cl
19
6,8-dichlorobiochanin A R1 = OMe, R2 = R3 = Cl
SCHEME 2

2764
O. Soidinsalo and K. Wa¨ha¨la¨
in the literature8 for the fermentation broth product. The reason for
the high selectivity at the position 8 may be explained by the para ad-
dition with respect to the OH group. Continued reaction with added
fresh SOCl2 gives 6,8-dichlorogenistein (8) in 60% yield, with the spec-
tral data again in conformity with the (13C incomplete) earlier data.8
We found that the addition of fresh SOCl2 was necessary in order to
achieve the dichlorinated compound. Attempts to speed up the reaction
by employing a higher temperature or microwave irradiation did not
prove beneficial. Also chlorination with thionyl chloride in the presence
of dimethyl sulfoxide13 only resulted in complex mixtures of various
chlorinated products.
With biochanin A (18), only the dichlorinated product 19 was ob-
tained whereas daidzein (9) and glycitein (20) just gave intractable
mixtures with SOCl2. Experiments with simple model compounds such
as resorcinol, phloroglucinol, and trihydroxyacetophenone yielded com-
plex mixtures of various chlorinated products according to GC-MS,
whereas no reaction was observed with 4-hydroxyacetophenone. Ad-
ditionally, genistein (1) was also reacted with sulfuryl chloride, but no
1
selectively chlorinated products could be detected by H NMR. Fur-
ther experiments were conducted with genistein trimethyl ether (21)
and SOCl2 to discount the possibility that the chlorinations observed
require the presence of a free hydroxy group at the phenolic ring A.
Monochlorination of 21 was detected by LC-MS after stirring the reac-
tion mixture at room temperature for 30 min. According to 1H NMR and
LC-MS, chlorination occurs at ring A, but without positional selectivity,
giving an inseparable mixture of chlorinated compounds.
As regards the reaction mechanism in the SOCl2-mediated aromatic
chlorination, obviously the intermediacy of Cl+ is implied. This in it-
self is unusual, as normally SOCl2 is a source of Cl−. This means that
the oxidation state of sulfur must be reduced in the process. We tenta-
tively suggest the reaction route depicted in Scheme 3, which produces
sulfur monoxide, and which is reminiscent but different from the mech-
anism of the flavone chlorinations mentioned above.7 Sulfur monoxide
has been suggested as a product in certain other redox reactions of
thionyl chloride14−16 but detection of SO has not been possible owing
to its ready disproportionation17 to SO2 and elemental sulfur. In our
reactions, we have not isolated elemental sulfur but a slight turbidity
of the solvent SOCl2 was observed, possibly indicating the presence of
S8. An alternative is that initial attack of the phenolic ring might occur
directly on chlorine instead on sulfur. Also in this case the eliminated
S(O)Cl would easily form SO and Cl−. Finally, mechanisms involving
the initial formation of a phenolic sulfinate ester3 are excluded as al-
ready mentioned.

Aromatic Clorination with Thionyl Chloride
2765
SCHEME 3
CONCLUSION
Genistein (1) and biochanin A (18) were selectively chlorinated with
thionyl chloride yielding the monochlorinated compound 10, as well
as the dichlorinated analogues (8 and 19). Other factors possibly con-
tributing to the reaction were also investigated, such as activation with
DMSO, the use of higher reaction temperature and microwave irra-
diation. However, these methods did not yield satisfactory results as
the selectivity of the chlorination reaction was lost. A plausible mecha-
nism for the selective chlorination of 5-hydroxyisoflavones by SOCl2 is
suggested.
EXPERIMENTAL
NMR spectra were measured with a Varian Gemini 2000 or with a
Bruker Avance 500 spectrometer using TMS as internal standard.

2766
O. Soidinsalo and K. Wa¨ha¨la¨
Chemical shifts are given as δ values and coupling constants in Hz.
Mass spectra were obtained with a JEOL JMS SX102 mass spectrom-
eter at 70 eV. LC-MS(ESI+) was performed on a HP 1100 instrument
equipped with Mariner ESI-TOF. Melting points were determined in
open capillary tubes with a GWB melting point apparatus and are un-
corrected. TLC was performed on Merck RP-18 F254s plates. MPLC was
performed with a Buchi sepacore instrument using 40 × 150 mm RP-
18 packed columns, mobile phase MeCN : H2O (70 : 30), 0.1% HCOOH,
and a flow rate of 50 mL/min.
General Synthetic Procedure
The isoflavone (ca. 0.36 mmol) was dissolved in freshly distilled thionyl
chloride (15 mL). The solution was stirred in a flask equipped with a
CaCl2 tube at room temperature for 7 d. The orange solution was slowly
added into ice-water (200 mL) CAUTION. The precipitate formed was
filtered off, washed with water (20 mL), dried in vacuo and purified
by MPLC. For 6,8-dichlorogenistein, the 7-day treatment was repeated
twice before quench. For 6,8-dichlorobiochanin A, a single 7-day repe-
tition was sufficient.
8-Chlorogenistein (10)
1
White solid; 78 mg (70%); m.p. 243–245◦C from EtOH/H2O. H NMR
(200 MHz, DMSO-d6): δ = 6.44 (s, 1H, 6-H), 6.83 (d, J = 8.4 Hz, 2H,
3ꢀ-H, 5ꢀ-H), 7.39 (d, J = 8.4 Hz, 2H, 2ꢀ-H, 6ꢀ-H), 8.49 (s, 1H, 2-H), 9.61
(s, 1H, 4ꢀ-H), 11.68 (s, 1H, 7-OH), 12.93 (s, 1H, 5-OH); 13C NMR (50
MHz, DMSO-d6): δ = 97.2 (C-8), 99.1 (C-6), 105.2 (C-4a), 115.2 (C-3ꢀ,
C-5ꢀ), 120.9 (C-1ꢀ), 122.7 (C-3), 130.4 (C-2ꢀ, C-6ꢀ), 153.0 (C-8a), 154.3 (C-
2), 157.8, (C-4ꢀ), 160.0 (C-5), 160.2 (C-7), 180.4 (C-4). MS: m/z 304, 186,
118. HRMS: calcd. for C15H9ClO5: 304.0139; found: 304.0130.
6,8-Dichlorogenistein (8)
1
White solid; 75 mg, 60%; m.p. 280–282◦C from MeCN/H2O. H NMR
(200 MHz, DMSO-d6): δ = 6.84 (d, J = 7.8 Hz, 2H, 3ꢀ-H, 5ꢀ-H), 7.41
(d,J = 7.8 Hz, 2H, 2ꢀ-H, 6ꢀ-H), 8.56 (s, 1H, 2-H), 9.41 (s, 1H, 4ꢀ-H), 11.64
(s, 1H, 7-OH), 13.69 (s, 1H, 5-OH); 13C NMR (50 MHz, DMSO-d6): δ =
98.8 (C-8), 104.2 (C-6), 105.1 (C-4a), 115.1 (C-3ꢀ, C-5ꢀ), 120.4 (C-1ꢀ), 122.6
(C-3), 130.2 (C-2ꢀ, C-6ꢀ), 150.9 (C-8a), 154.5 (C-2), 155.6 (C-5), 155.7 (C-
7), 157.7 (C-4ꢀ) 180.0 (C-4). MS: m/z 338, 220, 118. HRMS: calcd. for
C15H8Cl2O5: 337.9749; found: 337.9743.

Aromatic Clorination with Thionyl Chloride
2767
6,8-Dichlorobiochanin A (19)
1
White solid; 80 mg, 65%; m.p. 201–203oC from MeCN/H2O. H NMR
(300 MHz, acetone-d6): δ = 3.84 (s, 3H, 4ꢀ-OMe), 7.00 (d,J = 8.4 Hz, 2H,
3ꢀ-H, 5ꢀ-H), 7.57 (d,J = 8.4 Hz, 2H, 2ꢀ-H, 6ꢀ-H), 8.39 (s, 1H, 2-H), 10.12
(s, 1H, 7-OH), 13.72 (s, 1H, 5-OH); 13C NMR (75 MHz, acetone-d6): δ =
55.2 (4ꢀ-OMe), 98.8 (C-8), 104.2 (C-6), 105.1 (C-4a), 113.8 (C-3ꢀ, C-5ꢀ),
122.1 (C-1ꢀ), 122.3 (C-3), 130.2 (C-2ꢀ, C-6ꢀ), 150.8 (C-8a), 154.8 (C-2),
155.6 (C-5), 155.7 (C-7), 159.4 (C-4ꢀ) 179.9 (C-4). MS: m/z 352, 220, 132.
HRMS: calcd. for C16H10Cl2O5: 351.9905; found: 351.9881.
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