A Practical synthesis of 5,5′-methylene-bis(benzotriazole)

Full text of DOI:10.1080/00304940902802172

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Organic Preparations and Procedures
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A Practical Synthesis of 5,5′-Methylene-
bis(benzotriazole)
Haining Gu b , Biao Yu a , Peng-Fei Zhang a & Wei-Ming Xu b
a College of Material, Chemistry and Chemical Engineering ,
Hangzhou Normal University , Hangzhou, PR, China
b Analytical Center , Zhejiang University , Hangzhou, PR, China
Published online: 22 Apr 2009.
To cite this article: Haining Gu , Biao Yu , Peng-Fei Zhang & Wei-Ming Xu (2009) A Practical Synthesis
of 5,5′-Methylene-bis(benzotriazole), Organic Preparations and Procedures International: The New
Journal for Organic Synthesis, 41:2, 162-164, DOI: 10.1080/00304940902802172
To link to this article: http://dx.doi.org/10.1080/00304940902802172
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Gu et al.
Organic Preparations and Procedures International, 41:162–164, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940902802172
A Practical Synthesis
of 5,5ꢀ-Methylene-bis(benzotriazole)
Haining Gu,2 Biao Yu,1 Peng-Fei Zhang,1 and Wei-Ming Xu2
1College of Material, Chemistry and Chemical Engineering, Hangzhou Normal
University, Hangzhou, P. R. China
2Analytical Center, Zhejiang University, Hangzhou, P. R. China
5,5ꢀ-Methylene-bis(benzotriazole) (2) is a versatile intermediate in the preparation of several
metal passivators1 and light-sensitive materials.2 Though it is a useful molecule, a review of
the literature, including patents, indicated the absence of an easily performed synthesis. As
part of our research program on the study of green chemistry,3 we have developed a practical
pilot-scale method for the preparation of 5,5ꢀ-methylene- bis(benzotriazole) from methyl
nitrite and tetraaminodiphenylmethane (Scheme 1). The latter compound was prepared
by reduction of 3,3ꢀ-dinitro-4,4ꢀ-diaminodiphenylmethane obtained by acid-catalyzed rear-
rangement of bis(2-nitroanilino)methane according to literature procedures.4,5 This process
is efficient, environmentally benign, and easy to work up.
Scheme 1
We initially followed the conditions used by Viswanathan et al.6 for the preparation of
benzotriazole, but only obtained very poor yield of 5,5ꢀ-methylene-bis(benzotriazole) (2)
and at least three recrystallizations were required to purify the product. Further investigation
indicated that the choice of the diazotizing agent is the key factor in the above reaction and
the yield of 5,5ꢀ-methylene-bis(benzotriazole) (2) increased to 92% when methyl nitrite
was used instead of sodium nitrite. An outstanding feature of this process is that the purity
of the crude product is greater than 98.5%.
Submitted September 26, 2008.
Address correspondence to Wei-Ming Xu, Zhejiang University, Analytical Center, Hangzhou
310028, P. R. China. E-mail: wmxu@zju.edu.cn

Synthesis of 5,5ꢀ-Methylene-bis(Benzotriazole)
Experimental Section
163
Mps and bps are uncorrected. The purity of products was established on an Agilent 1100
HPLC. 1H NMR spectra were recorded in CDCl3 on a Bruker 400 (400 MHz) instrument
with TMS as an internal standard. Infrared spectra were obtained on a Shimadzu IR-408
instrument. All chemicals were reagent grade and available commercially. The elemental
analysis was performed on a Flash EA1112 instrument.
Methyl Nitrite (prepared just prior to use)
In a 1-L round-bottomed flask, fitted with a pressure equalizing addition funnel filled with
250 mL 12 M hydrochloric acid, and a gas tube in a well ventilated hood, was placed 172.5
g (2.5 mol) of sodium nitrite, 135 mL methanol, and 250 mL water. The temperature was
raised to 35◦C and hydrochloric acid was added dropwise over 2 hours. The methyl nitrite
evolved was passed through a water trap to remove acid and then bubbled through the
reaction mixture below via the gas tube.
5,5ꢀ-Methylene-bis(benzotriazole)
In a 5-L round-bottomed flask, fitted with a mechanical stirrer, and a gas tube in a well
ventilated hood, was placed 270.0 g (1.18 mol) of tetraaminodiphenylmethane, 4040 mL
methanol, and 440 mL of water under a nitrogen atmosphere. The temperature was raised
to 40◦C and methyl nitrite (152.5g, 2.5 mol, prepared above) was added through the tube
for about 2 hours while the temperature was kept at about 40◦C via water bath. When the
reaction was complete, the temperature was raised to 50◦C and the mixture was stirred for
another 20 min. to expel excess methyl nitrite. The mixture was then poured into 7 L water,
and the precipitated crystals were collected and dried in vacuo to afford 272.0 g (92%) of
the crude product as a pale red solid (HPLC > 98.5%), mp. 238–240◦C. 1H NMR (DMSO-
d6): δ 4.32 (2 H, s), 7.37 (2 H, d, J = 8.8 Hz), 7.80–7.86 (4 H, m), 15.6 (2 H, b).
An analytical sample was prepared by recrystallization from methanol, mp. 239–240◦C.7
Anal. Calcd. for C13H10N6: C, 62.39; H, 4.03; N, 33.58. Found: C, 62.58; H, 3.97;
N, 33.42.
Acknowledgments
We thank the National Natural Science Foundation of China (Grant No. 20602029) and
the Science and Technology Foundation of Zhejiang Province (Grant No. 2007C11014) for
financial support.
References
1. D. R. Clack and W. D. Philips, GB1514359 1978; Chem. Abstr., 89, 215412 (1978).
2. S. Bauer, EP268553 1988; Chem. Abstr., 110, 163601 (1988).
3. X. C. Yu, H. Gu and W. M. Xu, Org. Prep. Proced. Int., 38, 467 (2006).

164
Tang and Cen
4. N. Viswanathan, B. S. Joshi, D. H. Gawad, U. B. Gokhale, A. R. Sidhaye and G. R. Rajasekariah,
Indian J. Chem., Section B, 24B, 730 (1985); Chem. Abstr., 105, 172352 (1985).
5. V. V. Korshak, A. A. Izyneev, D. M. Mognonov, V. P. Mazurevskii, Zh. P. Mazurevskaya, I. S.
Novak, G. F. Slezko, A. I. Prokosova and A. D. Markov, Akad. Nauk SSSR, 143 (1971); Chem.
Abstr., 78, 110732 (1971).
6. A. A. Joshi and C. L. Viswanathan, Bioorg. Med. Chem. Lett., 16, 2613 (2006).
7. None of the previous references has reported a melting point for this compound.
Organic Preparations and Procedures International, 41:164–168, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940902802347
A Practical Synthesis
of (7-Methoxynaphth-1-yl)acetic Acid
Jia-Deng Tang and Jun-Da Cen
Department of Chemistry, Shanghai Institute of Pharmaceutical Industry,
Shanghai, P. R. China
The neurohormone melatonin (5-methoxy-N-acetyltryptamine, 1), which is mainly secreted
from the pineal gland or chemically synthesized, is putatively involved in several physio-
logical processes including circadian rhythms, retinal physiology, seasonal breeding, and
cardiovascular regulation.1–3 Since the therapeutic efficacy of melatonin is limited by its
short biological half-life, analogs of melatonin were designed and synthesized. It is known
that naphthalenic ligands have a high affinity for the melatonin receptor.4 Among these
ligands, agomelatine (N-[2-(7-methoxynaphth-1-yl) ethyl]acetamide, 2), which contains
the naphthalene moiety instead of indole nucleus, is currently in clinical trial.5
(7-Methoxynaphth-1-yl)acetic acid (6), a key intermediate to 2, has been prepared in
three steps using substituted tetralone 3 as starting material6 (Scheme). Treatment of 3 with
BrCH2CO2Et through a Reformatsky reaction afforded 4b whose extranuclear double bond
Submitted July 14, 2008.
Address correspondence to Jia-Deng Tang, Department of Chemistry, Shanghai Institute of
Pharmaceutical Industry, Shanghai 200437, P. R. China. E-mail: blueskytang2003@yahoo.com.cn