Conversion of azobenzenes into N,N′-diarylhydrazines by sodium dithionite

Article abstract of DOI:10.1055/s-2007-982565

A number of chloro-, methyl- and methoxy-substituted azobenzenes have been reduced to the corresponding hydrazines by using an aqueous solution of Na ₂S₂O₄. The yield is generally excellent, but two compounds, viz. 4,4-dimethoxyazobenzene and 2,2,4,4,6,6- hexamethylazobenzene, gave no hydrazine at all. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-982565

LETTER
1695
Conversion of Azobenzenes into N,N¢-Diarylhydrazines by Sodium Dithionite
D
iarylhydrazine
e
s
by
D
ithio
i
nite Re
v
duction K. Sydnes,*a Shire Elmi,a Per Heggen,a Bjarte Holmelid,a Didrik Malthe-Sørensenb
a
Department of Chemistry, University of Bergen, Allégt. 41, 5007 Bergen, Norway
Fax +4755589490; E-mail: leiv.sydnes@kj.uib.no
b
GE Healthcare, Lindesnes Fabrikker, 4510 Spangereid, Norway
Received 7 March 2007
system. Secondly, when the dithionite–azobenzene molar
ratio was approximately 2.2, which was the value used by
Fieser,5 the consumption of the azobenzene was very
sluggish. The ratio was therefore increased, and when it
was 5.5 or above the conversion appeared to proceed at a
satisfactory rate.
Abstract: A number of chloro-, methyl- and methoxy-substituted
azobenzenes have been reduced to the corresponding hydrazines by
using an aqueous solution of Na2S2O4. The yield is generally excel-
lent, but two compounds, viz. 4,4-dimethoxyazobenzene and
2,2,4,4,6,6-hexamethylazobenzene, gave no hydrazine at all.
Key words: azobenzenes, sodium dithionite, reduction, hydrazines
Selected substituted azobenzenes10 were then reacted
under conditions identical or very similar to those found
to be the best for 1a.11 The results, which are summarized
in Scheme 2 and Table 1, show that most of the azo-
benzenes were converted into the corresponding N,N¢-
diarylhydrazines12,13 in excellent yield and, consequently,
deviate from the course of reaction reported by Fieser and
others, for similar azo compounds.5,6i–q The products were
easy to isolate and purify, but the stability was variable.
Thus, whereas the methylated and methoxylated N,N¢-di-
arylhydrazines (2a–d,i,j) are fairly stable at room temper-
ature even in the presence of air, the chloro-substituted
analogues 2f–h reacted with oxygen8b,13i,14 to furnish the
starting azobenzenes.
Sodium dithionite (Na2S2O4) is a versatile and cheap
reagent, which has been employed to reduce, among a
variety of compounds,1 aldehydes,2 ketones,2,3 unsaturat-
ed ketones,4 and a range of unsaturated nitrogen com-
pounds.5,6 The latter group includes a large number of
azoarenes, which gave the corresponding aminoarenes
when treated with an excess of an aqueous solution of the
sulfur compound at elevated temperature;6i–r a represen-
tative example is shown in Scheme 1.5
N
NH2
NC6H4SO3Na
OH
a
OH
Rn
Rn
a
Orange II
NH2
Scheme 1 Reagents and conditions: (a) Na2S2O4, H2O.
N
N
Rn
On this basis we expected that 2,2¢,3,3¢-tetramethyl-
azobenzene (1a) would be converted into 2,3-dimethyl-
aniline when treated with the reducing reagent under
similar conditions, but to our surprise that appeared not to
be the case; instead, the corresponding hydrazine was
obtained.
Rn
b
NH
NH
Rn
Scheme 2 Reagents and conditions: (a) O2, (CuCl)2, pyridine, r.t.;
In order to explore if this particular reduction with
dithionite is a special case or not, several azobenzenes 1,
prepared by oxidation of aniline derivatives using oxygen,
cuprous chloride, and pyridine as described by Terentiev
and Mogiljanskji,7–9 were investigated. Exploratory ex-
periments with 1a revealed two important features. First,
water, the solvent used by Fieser in his reduction of
Orange II,5 had to be replaced by a mixture of water and
one or several organic solvents to achieve consumption of
the azobenzene at a reasonable rate under reflux. We
settled for a 3:20:20 mixture of dichloromethane,
methanol, and water, which proved to be a useful solvent
(b) Na2S2O4, H2O, MeOH, CH2Cl2, reflux; n = 1 or 2.
Two of the azobenzene investigated failed to give the
corresponding hydrazines. One compound, 1e, reacted as
expected on the basis of Fieser’s report5 and afforded
2,4,6-trimethylaniline in 96% yield (Scheme 3);15 no
N,N¢-bis(2,4,6-trimethylphenyl)hydrazine was isolated.
Another deviation was observed with 4,4¢-dimethoxyazo-
benzene (1k); this compound reacted slowly and gave a
complex product mixture, which contained neither the
hydrazine nor the corresponding aniline derivative. This is
somewhat surprising considering the fact that the 2,2¢- and
3,3¢-analogues gave the corresponding hydrazines in
excellent yields (Table 1).
SYNLETT 2007, No. 11, pp 1695–1698
0
3
.0
7
.2
0
0
7
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-982565; Art ID: D07007ST
© Georg Thieme Verlag Stuttgart · New York

1696
L. K. Sydnes et al.
LETTER
Table 1 Conversion of Substituted Azobenzenes 1 into the Corresponding N,N¢-Diarylhydrazines 2 by Sodium Dithionite Treatment
Substituents of 1
1a: 2,2¢,3,3¢-Me4
1b: 2,2¢,4,4¢-Me4
1c: 2,2¢,6,6¢-Me4
1d: 3,3¢,5,5¢-Me4
1e: 2,2¢,4,4¢,6,6¢-Me6
1f: 2,2¢-Cl2
Molar ratio of Na2S2O4:1
Reaction at reflux (h)
Isolated yield of 2 (%)a
5.5
9.1
2.0
1.6
1.6
1.8
3.0
1.5
1.5
6.0
1.5
1.5
1.5
81
86
80
89
0
9.1
9.1
6.1
10.0
11.3
11.3
11.5
9.3
90
88
80
83
94
0
1g: 3,3¢-Cl2
1h: 4,4¢-Cl2
1i: 2,2¢-(MeO)2
1j: 3,3¢-(MeO)2
1k: 4,4¢-(MeO)2
9–18
a The products were characterized by IR, 1H NMR, and 13C NMR spectroscopy, mass spectrometry, and melting points (when appropriate), and
compared with literature data. All the products are known from the literature, see ref. 1.
Acknowledgment
a
Financial support from the former Nycomed Imaging (now GE
NH2
N
N
Healthcare) is highly appreciated. Thanks are also due to Ann
Margot Whyatt at the University of Bergen, and Dr. Dag Ekeberg at
the Norwegian University of Life Sciences, for skillful technical
assistance.
1e
Scheme 3 Reagents and conditions: (a) Na2S2O4, H2O, MeOH,
CH2Cl2, reflux.
References and Notes
(1) Balasubramanian, M.; Keay, J. G. In Reagents in Organic
Synthesis, Vol. 4; Paquette, L., Ed.; Wiley: New York, 1995,
4554.
(2) de Vries, J. G.; van Bergen, T. J.; Kellogg, R. M. Synthesis
1977, 246.
(3) (a) Camps, F.; Coll, F.; Riba, M. J. Chem. Soc., Chem.
Commun. 1979, 1080. (b) Castaldi, G.; Perdoncin, G.;
Giordano, C.; Minisci, F. Tetrahedron Lett. 1983, 24, 2487.
(4) (a) Camps, F.; Coll, F.; Guitart, J. Tetrahedron 1986, 42,
4603. (b) Louis-Andre, O.; Gelbard, G. Tetrahedron Lett.
1985, 26, 831.
The reduction of azobenzene derivatives to the corre-
sponding N,N¢-diarylhydrazines reported here is a cheap,
simple, and convenient alternative to a number of
methods already available.13d,16 Overreduction to anilines,
which is the main or a significant reaction when other
reducing agents are used,5,6i–r,8h,17 is barely observed. It is
also noteworthy that the reaction conditions are slightly
basic and therefore prevent benzidine rearrangement of
the hydrazobenzenes.13i,j,18
In this context a paper by Park and Han is quite interest-
ing.13c They found that azobenzenes dissolved in aqueous
acetonitrile were reduced by sodium dithionite to the
corresponding hydrazobenzenes when dioctyl viologen,
an electron-transfer catalyst, was present. However, in the
absence of this catalyst no reaction occurred. Thus, the
reducing power of Na2S2O4 is influenced by solvent
effects.
(5) Fieser, L. F. In Organic Syntheses, Coll. Vol. II; Blatt, A. H.,
Ed.; Wiley and Sons: New York, 1943, 35.
(6) (a) Pictet, A.; Gams, A. Chem. Ber. 1909, 42, 2943.
(b) Redemann, C. T.; Redemann, C. E. In Organic
Syntheses, Coll. Vol. III; Horning, E. C., Ed.; Wiley and
Sons: New York, 1955, 69. (c) Schröter, R.; Möller, F.
Stickstoffverbindungen II, Amine In Methoden der
Organischen Chemie (Houben-Weyl), Vol. XI/1; Müller, E.,
Ed.; Georg Thieme Verlag: Stuttgart, 1957, 437.
(d) Overberger, C. G.; Lombardino, J. G.; Hiskey, R. G.
J. Am. Chem. Soc. 1958, 80, 3009. (e) Sherman, W. R.;
Taylor, E. C. Jr. In Organic Syntheses, Coll. Vol. IV;
Rabjohn, N., Ed.; Wiley and Sons: New York, 1963, 247.
(f) Pojer, P. M. Aust. J. Chem. 1979, 32, 201. (g) Park, K.
K.; Oh, C. H.; Joung, W. K. Tetrahedron Lett. 1993, 34,
7445. (h) Novellino, L.; d’Ischia, M.; Prota, G. Synthesis
1999, 793. (i) Shinkai, S.; Honda, N.; Ishikawa, Y.; Manabe,
O. J. Chem. Soc., Perkin Trans. 1 1985, 565. (j) Al-
Sammerrai, D.; Salih, Z. S. Indian J. Chem., Sect. B: Org.
In conclusion, the paper describes a high-yield method for
the preparation of diarylhydrazines from the correspond-
ing azobenzenes. It has been reported previously that the
same reduction can be achieved with Na2S2O4 provided an
electron-transfer catalyst is added. By changing from ho-
mogeneous (aq MeCN) to two-phase (aq MeOH–CH2Cl2)
conditions we have achieved reduction without adding an
electron-transfer catalyst.
Synlett 2007, No. 11, 1695–1698 © Thieme Stuttgart · New York

LETTER
Chem. Incl. Med. Chem. 1987, 26, 180. (k) Morita, Y.;
Diarylhydrazines by Dithionite Reduction
1697
in a ratio of 90:10) gave a solid, which was recrystallized
from EtOH and dried under vacuum. When the azobenzene
precipitated during the hydrolysis, the precipitate was
filtered, washed with H2O on the filter, and dried under
vacuum. The products were characterized by IR, 1H NMR,
and 13C NMR spectroscopy, mass spectrometry, and melting
points (when appropriate), which were compared with
literature data.
Agawa, T.; Kai, Y.; Kanehisa, N.; Kasai, N.; Nomura, E.;
Taniguchi, H. Chem. Lett. 1989, 1349. (l) Noureldin, N. A.;
Bellegarde, J. W. Synthesis 1999, 939. (m) Sander, W.;
Hubert, R.; Kraka, E.; Grafenstein, J.; Cremer, D. Chem.
Eur. J. 2000, 6, 4567. (n) Dinica, R.; Charmantray, F.;
Demeunynck, M.; Dumy, P. Tetrahedron Lett. 2002, 43,
7883. (o) Kornev, K. A.; Zheltov, A. Ya. Russ. J. Gen.
Chem. 2003, 73, 1095. (p) Peng, Y.; Song, G.; Ding, F.
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
2004, 43, 2021. (q) Martin, V. V.; Rothe, A.; Gee, K. R.
Bioorg. Med. Chem. Lett. 2005, 15, 1851. (r) Oniciu, D.;
Bell, R.; McCosar, B.; Bisgaier, C.; Dasseux, J.-L.; Verdijk,
D.; Relou, M.; Smith, D.; Regeling, H.; Leemhuis, F.;
Ebbers, E.; Mueller, R.; Zhang, L.; Pop, E.; Cramer, C.;
Goetz, B.; McKee, A.; Pape, M.; Krause, B. Synth. Commun.
2006, 36, 365.
(10) All the products were known from the literature: 1a [29418-
34-6]: ref. 8k, 8m; 1b [29418-25-5]: ref. 8f, 8g, 8j; 1c
[29418-31-3]: ref. 8f, 8g, 8i, 8k, 8m; 1d [77611-71-3]: ref.
8c, 8r, 8s; 1e [5692-66-0]: ref. 6l, 8d, 8e, 8g, 8h; 1f [7334-
33-0]: ref. 8k, 8m, 8p, 8t, 8u, 8v; 1g [15426-14-9]: ref. 8k,
8m, 8n, 8p, 8q, 8t; 1h [1602-00-2]: ref. 8f, 8g, 8j–m, 8p, 8q,
8s, 8t; 1i [613-55-8]: ref. 8k, 8m, 8n, 8p, 8t, 8u; 1j [6319-23-
9]: ref. 8t, 8u, 8v; 1k [501-58-6]: ref. 8j, 8k–m, 8o, 8p, 8u.
(11) General Procedure for the Reduction of Azobenzenes to
N,N¢-Diarylhydrazines
(7) Terentiev, A. P.; Mogiljanskij, J. D. Dokl. Akad. SSSR, Zh.
Obshch. Khim. 1955, 91, 103.
(8) A number of methods are available for the synthesis of
azobenzenes from various nitrogen-containing benzene
derivatives. See: (a) Schündehütte, K. H.
Azobenzene 1 (0.4–2.1 mmol) was added to a mixture of
H2O (165 mL/mmol of 1), MeOH (165 mL/mmol of 1), and
CH2Cl2 (25 mL/mmol of 1). The resulting mixture was
stirred and heated to reflux, and an excess of sodium
dithionite (see Table 1) was added. After stirring at reflux
(see Table 1), the product mixture was poured into ice and
extracted with Et2O (3 × 100 mL). The combined extracts
were dried (MgSO4) and filtered, and then the solvent was
removed under reduced pressure to give a residue, from
which the product 2 was isolated by flash chromatography
(silica, hexane–EtOAc in a ratio of 90:10). The results are
compiled in Table 1.
Stickstoffverbindungen I In Methoden der Organischen
Chemie (Houben–Weyl), Vol. X/3; Müller, E.; Stroh, R.,
Eds.; Georg Thieme Verlag: Stuttgart, 1965, 371. (b) Lang-
Fugmann, S. Organische Stickstoffverbindungen IV In
Methoden der Organischen Chemie (Houben–Weyl), Vol.
E16d; Klamann, D., Ed.; Georg Thieme Verlag: Stuttgart,
1992, 66. (c) Nölting, E.; Stricker, T. Chem. Ber. 1888, 21,
3138. (d) Chapman, N. B.; Saunders, B. C. J. Chem. Soc.
1941, 496. (e) Horner, L.; Kirmse, W. Justus Liebigs Ann.
Chem. 1955, 597, 66. (f) Edward, J. T. J. Chem. Soc. 1956,
222. (g) Hedayatullah, M.; Dechatre, J. P.; Denivelle, L.
Tetrahedron Lett. 1975, 2039. (h) Bader, H.; Hansen, H.-J.
Helv. Chim. Acta 1979, 62, 2613. (i) Stowell, J. C.; Lau, C.
M. J. Org. Chem. 1986, 51, 1614. (j) Ohe, K.; Uemura, S.;
Sugita, N.; Masuda, H.; Taga, T. J. Org. Chem. 1989, 54,
4169. (k) Wang, X.-Y.; Wang, Y.-L.; Li, J.-P.; Duan, Z.-F.;
Zhang, Z.-Y. Synth. Commun. 1999, 29, 2271. (l) Shaabani,
A.; Lee, D. G. Tetrahedron Lett. 2001, 42, 5833. (m) Li,
X.-C.; Wang, Y.-L.; Wang, J.-Y. J. Chem. Res., Synop.
2002, 540. (n) Prasad, H. S.; Gowda, S.; Gowda, D. C.
Synth. Commun. 2004, 34, 1. (o) Carreno, M. C.; Mudarra,
G. F.; Merino, E.; Ribagorda, M. J. Org. Chem. 2004, 69,
3413. (p) Nanjundaswamy, H. M.; Pasha, M. A. J. Chem.
Res. 2005, 772. (q) Gilbert, A. M.; Failli, A.; Shumsky, J.;
Yang, Y.; Severin, A.; Singh, G.; Hu, W.; Keeney, D.;
Petersen, P. J.; Katz, A. H. J. Med. Chem. 2006, 49, 6027.
(r) Halbritter, G.; Knoch, F.; Wolski, A.; Kisch, H. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1603. (s) Dürr, U.;
Heimemann, F. W.; Kisch, H. J. Organomet. Chem. 1997,
541, 307. (t) Srinivasa, G. R.; Abiraj, K.; Gowda, D. C.
Tetrahedron Lett. 2003, 44, 5835. (u) Mirkhani, V.;
Tangestaninejad, S.; Moghadam, M. J. Chem. Res., Synop.
2003, 792. (v) Pasha, M. A.; Nanjundaswampy, H. M.
J. Chem. Res. 2004, 750.
(12) All the N,N¢-diarylhydrazines except 2,2¢,4,4¢-tetramethyl-
(N,N¢-diphenylhydrazine) (2b) are mentioned several times
in the literature: 2a [107418-14-4]: ref. 8c, 8m, 13f, 13j; 2c
[63615-06-5]: ref. 8m, 13f; 2d [142068-90-4]: ref. 8c; 2e
[5692-66-0]: ref. 8m, 13a; 2f [782-74-1]: ref. 8m, 13g, 13h;
2g [953-01-5]: ref. 8m, 8n, 8q, 13e, 13g; 2h [953-14-0]: ref.
8m, 8p, 8q, 13b–d, 13g, 13h; 2i [787-77-9]: ref. 8m, 8n, 8p,
13e, 13g, 13h, 13j; 2j [1027-32-3]: ref. 13g, 13h, 13j; 2k
[1027-40-3]: ref. 8m, 13b–d. The synthesis and isolation of
2b have been reported by Nölting and Stricker,8c but no data
except the melting point were given.
Data for 2b: mp 119–121 °C (lit.8c mp 120–122 °C). IR
(film): 3364, 3228, 3008, 1627, 1510, 1463, 1444, 1276,
1240, 1153, 1012, 875, 814 cm–1. 1H NMR (200 MHz,
CCl4): d = 2.16 (s, 6 H), 2.19 (s, 6 H), 5.19 (s, 2 H), 6.59–
6.76 (m, 6 H). 13C NMR (50 MHz, CCl4): d = 16.9, 20.3,
111.1, 120.1, 127.4, 127.6, 130.7, 143.7. MS (EI): m/z
(%) = 240 (0.5) [M+], 194 (5), 182 (2), 172 (2), 163 (3), 147
(2), 131 (5), 110 (2), 107 (6), 106 (100), 105 (93), 98 (4), 88
(7), 87 (8), 85 (5), 78 (17), 77 (98), 76 (5), 74 (12). HRMS
(EI): m/z calcd for C16H20N2 [M+]: 240.1626; found:
240.1622.
(13) (a) Helms, A.; Heiler, D.; McLendon, G. J. Org. Chem.
1992, 114, 6227. (b) Karmakar, D.; Prajapati, D.; Sandhu, J.
S. J. Chem. Res., Synop. 1996, 464. (c) Park, K. K.; Han, S.
Y. Tetrahedron Lett. 1996, 37, 6721. (d) Patil, M. L.;
Jnaneshwara, G. K.; Sabde, D. P.; Dongare, M. K.; Sudalai,
A.; Deshpande, V. H. Tetrahedron Lett. 1997, 38, 2137.
(e) Sridhara, M. B.; Srinivasa, G. R.; Gowda, D. C. J. Chem.
Res. 2004, 74. (f) Li, X.; Wang, Y.; Wang, J. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2004, 43, 677.
(g) Kato, T.; Sato, M.; Tabei, K.; Kawashima, E. Chem.
Pharm. Bull. 1975, 23, 456. (h) Lukashevich, V. O. Dokl.
Akad. Nauk SSSR 1964, 159, 1095; Chem. Abstr. 1965, 62,
7607c. (i) Carlin, R. B. J. Am. Chem. Soc. 1945, 67, 928.
(j) Croce, L. J.; Gettler, J. D. J. Am. Chem. Soc. 1953, 75,
874.
(9) General Procedure for the Preparation of Azobenzenes
1a–k from Anilines
Oxygen was bubbled through a mixture of an aniline
derivative (20 mmol), (CuCl)2 (0.20 g, 2.0 mmol), and dry
pyridine (20 mL), which was stirred at r.t. for 1–3 h. The
reaction was quenched by addition of H2O (20 mL), which
in some cases gave a precipitate, in other cases not. When no
precipitate was formed, the hydrolyzate was extracted with
Et2O (3 × 10 mL) and the combined extracts were dried
(MgSO4), filtered, and concentrated on a rotary evaporator.
Purification by flash chromatography (silica, hexane–EtOAc
Synlett 2007, No. 11, 1695–1698 © Thieme Stuttgart · New York

1698
L. K. Sydnes et al.
LETTER
(16) (a) Furst, A.; Moore, R. E. J. Am. Chem. Soc. 1957, 79,
(14) Khurana, J. M.; Ray, A. Bull. Soc. Chem. Soc. Jpn. 1996, 69,
407.
(15) Preparation of 2,4,6-Trimethylaniline
5492. (b) Bavin, P. M. G. Can. J. Chem. 1958, 36, 238.
(c) Olah, G. A. J. Am. Chem. Soc. 1959, 81, 3165.
(d) Cortese, N. A.; Hedck, R. F. J. Org. Chem. 1977, 42,
3491. (e) Kambe, N.; Kondo, K.; Sonoda, N. Angew. Chem.,
Int. Ed. Engl. 1980, 19, 1009. (f) Brown, G. R.; Foubister,
A. J. Synthesis 1982, 1036. (g) Kijuna, M.; Nambu, Y.;
Endo, T.; Okawara, M. J. Org. Chem. 1983, 48, 2407.
(h) Akiba, M.; Cava, M. P. Synth. Commun. 1984, 14, 1119.
(17) (a) Lehmann, J. Reduktion Teil I In Methoden der
Organischen Chemie (Houben–Weyl), Vol. IV/1c; Kropf,
H., Ed.; Georg Thieme Verlag: Stuttgart, 1980, 551.
(b) Hajos, A. Reduktion Teil II In Methoden der
Organischen Chemie (Houben–Weyl), Vol. IV/1d; Kropf,
H., Ed.; Georg Thieme Verlag: Stuttgart, 1981, 365.
(c) Rylander, P. N. Hydrogenation Methods; Academic
Press: London, 1985, 168.
2,2¢,4,4¢,6,6¢-Hexamethylazobenzene (1e, 0.50 g, 1.88
mmol) was added to a mixture of H2O (200 mL), MeOH
(200 mL), and CH2Cl2 (30 mL). The resulting mixture was
stirred and heated to reflux, and Na2S2O4 (2.00 g, 11.5
mmol) was added. After stirring at reflux for 3 h, the product
mixture was poured into ice and extracted with Et2O
(3 × 100 mL). The combined extracts were dried (MgSO4)
and filtered, and the solvent was subsequently removed
under reduced pressure to give a residue, from which 0.42 g
(82%) of 2,4,6-trimethylaniline was isolated by flash
chromatography (silica, hexane–EtOAc in a 90:10 ratio).
The spectroscopic and physical properties of the product
were identical to those of the aniline derivative used to
prepare azobenzene 1e.
(18) Carlin, R. B.; Forshey, W. O. Jr. J. Am. Chem. Soc. 1950, 72,
793.
Synlett 2007, No. 11, 1695–1698 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.