A practical synthesis of 2'-fluoro-4'-hydroxyacetophenone

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Organic Preparations and Procedures
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A Practical Synthesis of 2′-Fluoro- 4′-
hydroxyacetophenone
Xiao-Bo Zhang b , Qun Lu a & Wei-Ming Xu a
a College of Material Chemistry and Chemical Engineering ,
Hangzhou Normal University (Xiasha Campus) , Hangzhou, P. R.
China
b Department of Chemistry , Zhejiang University (Xixi Campus) ,
Hangzhou, P. R. China
Published online: 08 Sep 2009.
To cite this article: Xiao-Bo Zhang , Qun Lu & Wei-Ming Xu (2009) A Practical Synthesis of 2′-Fluoro-
4′-hydroxyacetophenone, Organic Preparations and Procedures International: The New Journal for
Organic Synthesis, 41:5, 419-421, DOI: 10.1080/00304940903163723
To link to this article: http://dx.doi.org/10.1080/00304940903163723
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Organic Preparations and Procedures International, 41:419–421, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903163723
OPPI BRIEFS
A Practical Synthesis of 2ꢀ-Fluoro-
4ꢀ-hydroxyacetophenone
Xiao-Bo Zhang,2 Qun Lu,1 and Wei-Ming Xu1
1College of Material Chemistry and Chemical Engineering, Hangzhou Normal
University (Xiasha Campus) Hangzhou, P. R. China
2Department of Chemistry, Zhejiang University (Xixi Campus) Hangzhou,
P. R. China
2ꢀ-Fluoro-4ꢀ-hydroxyacetophenone (2) is an important building block for many pharma-
ceutically active agents,1 used to treat bacterial and parasitic infections.2 A review of the
literature indicated that its synthesis has rarely been reported.3
Kees and Musser et al. developed the only method to obtain 2ꢀ-fluoro-4ꢀ-
hydroxyacetophenone (2) from 3-fluorophenol (1) through Friedel-Crafts reaction (Scheme
1), but the yield was not reported.3 Numerous repetitions of the procedure showed that
the yield never exceeded 40% and at least 18% of 4ꢀ-fluoro-2ꢀ-hydroxyacetophenone ac-
companied the desired product. Furthermore, the starting compound, 3-fluorophenol (1) is
expensive to purchase and tedious to prepare.4,5
Scheme 1
Based on the report of Gryko et al.6 and as a continuation of our interest in the
study of medicinal compounds,7 we have developed a practical pilot-scale method for the
preparation of 2ꢀ-fluoro-4ꢀ-hydroxyacetophenone (2) from 2ꢀ,4ꢀ-difluoroacetophenone (3)
(Scheme 2); the latter was easily prepared by acetylation of 1,3-difluorobenzene.8
Submitted April 17, 2009.
Address correspondence to Wei-Ming Xu, College of Material Chemistry and Chemical Engi-
neering, Hangzhou Normal University (Xiasha Campus), Hangzhou 310036, P. R. China. E-mail:
wmxu@zju.edu.cn
419

420
Zhang, Lu, and Xu
Scheme 2
It is noteworthy that the use of a mixture of sodium hydroxide and calcium hydroxide
is necessary in this reaction in order to ensure an adequate reaction rate and an acceptable
yield of the product.
Experimental Section
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 internal standard. All chemicals were reagent grade and available commer-
cially. The elemental analysis was performed on a Flash EA1112 instrument.
2ꢀ-Fluoro-4ꢀ-hydroxyacetophenone
In a 1 L round-bottomed flask fitted with a mechanical stirrer was placed 60.0 g (0.38 mol)
of 2ꢀ,4ꢀ-difluoroacetophenone (3), 14.1 g calcium hydroxide, 16.0 g sodium hydroxide
and 500 mL water. The mixture was stirred under reflux for 18 h. Then the mixture was
cooled to room temperature and filtered. The filtrate was extracted with 150 mL CH2Cl2
to recover 11.2 g 2ꢀ,4ꢀ-difluoroacetophenone (HPLC > 96%), and acidified with 100 mL
of 4M hydrochloric acid followed by steam distillation to remove a small quantity of 4ꢀ-
fluoro-2ꢀ-hydroxyacetophenone (about 1.1 g). The water phase was cooled to 5◦C, and
the precipitated crystals collected and dried in vacuo to afford 38.1 g (79%) of the crude
product (2) as a white solid (HPLC > 98.5%). 1H NMR (DMSO- d6): δ 2.46 (3 H, d, J =
4.8 Hz), 6.65 (1 H, d, J = 8.8 Hz), 6.74 (1 H, d, J = 8.8 Hz), 7.75 (1 H, t, J = 8.8 Hz), 10.85
(1 H, b). 13C NMR (DMSO-d6): δ 193.7, 164.1 (J = 12.1 Hz), 163.6 (J = 252.5 Hz), 132.4
(J = 4.7 Hz), 117.1 (J = 12.0 Hz), 112.5 (J = 7.8 Hz), 103.3 (J = 25.4 Hz), 31.0 (J =
7.0 Hz). An analytical sample was prepared by recrystallization from methanol and water
(v/v = 30/70), mp.120–121◦C.9
Anal. Calcd. for C8H7FO2: C, 62.34; H, 4.58. Found: C, 62.44; H, 4.66.
Acknowledgment
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. J. M. Salvino, G. C. Morton, H. J. Mason and R. F. Labaudiniere, WO9967192 1999; Chem. Abstr.,
132, 63782 (1999).

Synthesis of 2ꢀ-Fluoro- 4ꢀ-hydroxyacetophenone
421
2. S. F. Nielsen, K. Schonning, H. Kromann, T. Boesen and M. Larsen, WO2003097576 2003; Chem.
Abstr., 140, 4852 (2003).
3. K. F. Kees, J. H. Musser, J. Chang, M. Skowronek and A. J. Lewis, J. Med. Chem., 29, 2329
(1986).
4. K. Momota, T. Yonezawa and Y. Inoue, JP03232829 1991; Chem. Abstr., 116, 105801 (1991).
5. N. Takechi, Y. Fukai and W. Oka, JP08188545 1996; Chem. Abstr., 125, 247382 (1996).
6. D. T. Gryko, D. Wyrostek, A. Nowak-Krol, K. Abramczyk and M. K. Rogacki, Synthesis, 4028
(2008).
7. H. Gu and W. M. Xu, Org. Prep. Proced. Int., 40, 465 (2008).
8. Y. Liu, S. Wang, C. Zheng, S. Song and L. Kou, Huaxue Shijie, 43, 432 (2002); Chem. Abstr., 139,
133284 (2002).
9. None of the previous references has reported a melting point for this compound.