Pyridine-4-thiol and amphoteric analogs: Novel protection of aryl bromides in strong alkali

Article abstract of DOI:10.1002/hlca.200890219

The use of pyridine-4-thiol (PT) to preserve certain aryl bromides in strong alkali is reported (Scheme 1). The presence of this additive or of some of its amphoteric analogs such as 3-hydroxypyridin-4(1H)-ones suppresses the replacement of the Br-substituent by hydroxide and alkoxide ions. A mechanistic interpretation of the effect is proposed.

Full text of DOI:10.1002/hlca.200890219

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Pyridine-4-thiol and Amphoteric Analogs: Novel Protection of Aryl Bromides
in Strong Alkali
by Wei-Min Chen*, Chao Cheng, Bing-Zhou Li, Tse-Lok Ho1), Zhao-Shuo Cai, Yuqiang Wang, and
Ping-Hua Sun
College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China
(phone: þ 86-20-85224497; fax: þ 86-20-85224766; e-mail: twmchen@jnu.edu.cn)
The use of pyridine-4-thiol (PT) to preserve certain aryl bromides in strong alkali is reported
(Scheme 1). The presence of this additive or of some of its amphoteric analogs such as 3-hydroxypyridin-
4(1H)-ones suppresses the replacement of the Br-substituent by hydroxide and alkoxide ions. A
mechanistic interpretation of the effect is proposed.
Introduction. – Functional-group compatibility is a perennial problem that a
synthetic chemist must face in dealing with the construction of complex molecules. As a
testimonial for the many ways developed to solve such problems, a vast pool of
literature on the use of protecting groups has accumulated [1]. Aryl bromides are often
deemed stable under most reaction conditions, although they are excellent partners for
transition metal-catalyzed processes [2]. But few literature reports deal with the
protection of a halo group. In the present work, we describe a novel protection of aryl
bromides by pyridine-4-thiol and amphoteric analogs such as 3-hydroxypyridin-4(1H)-
ones under nucleophilic aromatic substitution condition.
Results and Discussion. – Previously, we attempted to convert compound 1 to 2 by
hydrolytic cleavage of the exocyclic guanidine moiety (Scheme 1). Rather harsh
reaction conditions such as treatment with KOH in refluxing ethylene glycol were
required [3]. The results were unsatisfactory as the product mixture was complex, and
the desired product was obtained in small yields (Fig. 1). The substituted quinazoli-
nones 3 and 4 were identified as two major by-products by 1H-NMR, MS, and HR-MS.
It appears that the Br-substituent of 1 is susceptible to replacement in strong alkali, a
fact which prompted us to undertake a series of experiments to avert the undesired
reactions.
We were glad to find that the presence of pyridine-4-thiol (PT) has beneficial
effects (Scheme 1). When a few mol-% of PT was added to the reaction mixture,
dramatic changes were observed: the formation of the by-products was almost
suppressed (Fig. 2).
To establish the optimal ratio of 1 and PT for the conversion to 2, we carried out a
series of experiments by varying the amount of PT from 0.1 – 100 mol-%, while
1
)
On leave from National Chiao Tung University, Hsinchu, Taiwan.
ꢀ 2008 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Scheme 1. Reaction of 1 with KOH in the Absence or Presence of PT
Fig. 1. HPLC Plot of the reaction products in the absence of PT
maintaining the concentration of KOH at 0.67 mm in ethylene glycol. Consistent
improvements were achieved when the mol-% of PT was increased from 0.13 – 100
(Fig. 3). The use of a higher concentration of KOH (2.68 mm) did not affect the overall
results (Fig. 4), and an optimal yield of 2 was reached when the reaction was carried
out in the presence of 1 mol-equiv. of PT.
To establish the protective role played by PT, we subjected product 2 to the original
reaction conditions. Within 2 h, about 58% of 2 was converted to give ca. 11% of 3 and

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Fig. 2. HPLC Plot of the reaction products in the presence of 10 mol-% of PT
Fig. 3. Effect of different molar ratios of PT on the production of 2 and 3 (0.67 mm KOH)
Fig. 4. Effect of different molar ratios of PT on the production of 2 and 3 (2.68 mm KOH)

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12% of 4 (Scheme 2). On the contrary, in the presence of 1 equiv. of PT, no noticeable
change of 2 was observed by HPLC analysis after 2 h under reflux. In addition,
treatment of 1 in the presence of PT for up to 4 h did not alter the production of 2
significantly as compared to the reaction time of 2 h.
Scheme 2. Reaction of 2 with KOH in the Absence of PT
The following rationale for our results is proposed. Both the displacement of the Br-
substituent of 1 by hydroxide or alkoxide and its retention in the presence of PT
presumably involve an initial Michael addition (Scheme 3). The intermediate adducts
are reminiscent of the Meisenheimer complexes [4] although the two types of adducts,
i.e., with geminal Br and OH substituents and with geminal Br and SPy substituents,
necessarily have different decomposition rates. Considering the symbiotic effect [5],
the geminal Br,SPy adduct 5 is inherently more stable than the geminal Br,OH
counterpart because of the hard – soft differences [6]. One can also speculate that the
Scheme 3. Mechanism of Protection by PT

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addition rate of PT is much higher (kinetically more favorable) so that OHꢀ ions (and
ethylene glycolate) could hardly compete. On the other hand, once the geminal Br,OH
adduct is formed, extrusion of the Br-substituent would be more rapid.
One might also argue that the elimination should proceed in the strictly reversed
sense to generate the bromo compound from the geminal Br,SPy adduct 5 because the
pyridinethiolate is a better leaving group. This behavior of the geminal Br,SPy adduct
can be changed by adding CuBr and Cu2O to the reaction (Ullmann reaction) [3][7],
and indeed, in this event, the pyridinylsulfanyl-substituted derivative 6 was produced
(Scheme 4).
Scheme 4. Reaction of 1 with KOH in the Presence of PT, CuBr, and Cu2O
Besides PT, hydroxypyridinones are also amphoteric in nature [8]. For this reason,
the presence of 3-hydroxy-2-methylpyridin-4(1H)-one (7) and 2-ethyl-3-hydroxypyr-
idin-4(1H)-one (8) (Fig. 5) in the conversion of 1 to 2 was tested, and indeed,
compounds 7 and 8 had a similar effect as PT (see Fig. 6).
Fig. 5. PT and amphoteric analogs
In conclusion, we found a method for preserving a ꢂlabileꢃ Br-substituent at an
aromatic ring such as that existing in 1 by using pyridine-4-thiol (PT) as an additive. We
are continuing to investigate the applicability of this technique to other chemical
conversions.
This work was partially supported by a grant (No. 30572237) from the National Natural Science
Foundation of China. We also thank Miss Hui-Xin Chen and Yu-Qi Liang who participated in some
preliminary work.
Experimental Part
General. The solvents were available commercially and were purified according to conventional
methods. Starting materials were prepared according to a previous procedure [3]. HPLC: Shimadzu LC-
10-AT chromatograph; Kromasil-C18 column; elution with MeOH/H2O 3 :1, flow rate 0.8 ml/min. NMR
Spectra: Bruker 400-MHz instrument; (D6)DMSO solns.; chemical shifts d in ppm, coupling constants

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Fig. 6. Effect of different molar ratios of 3-hydroxy-2-methylpyridin-4(1H)-one (7) on the production of
2 and 3 (0.67 mm KOH)
J in Hz. MS: ABI-4000-Q-TRAP (ESI) and VG-ZAB-HS spectrometer (FAB); in m/z (rel. %). HR-MS:
MAT-95XP (Thermo) spectrometer at the Zhongshan University Analyses Center, China.
Reaction of Compound 1 with KOH in the Presence or Absence of Pyridine-4-thiol (PT): General
Procedure. A mixture of 1 (0.5g, 1.69 mmol), KOH (0.75g, 13.4 mmol; or 3.0g, 53.6 mmol), and PT (0 –
100 mol-% rel. to 1) in ethylene glycol (20 ml) was refluxed for 2 h. After cooling, the mixture was diluted
with H2O (80 ml), neutralized with conc. HCl soln., and filtered. After washing with H2O, the tan solid
was dried. Products 3 and 4 were isolated by prep. HPLC from the products of the reaction which was
carried out in the absence of PT.
Data of 2-Amino-5-hydroxy-6-methylquinazolin-4(3H)-one (3): 1H-NMR ((D6)DMSO): 2.35 (s,
3 H); 6.37 (s, 2 H); 7.08 (d, J ¼ 8.4, 1 H); 7.46 (d, J ¼ 8.5, 1 H); 11.0 (br., 1 H). MS: 192 (100, [M þ 1]þ).
HR-MS: 192.0768 ([M þ H]þ, C9H10N3O2þ ; calc. 192.0768).
Data of 2-Amino-5-(2-hydroxyethoxy)-6-methylquinazolin-4(3H)-one (4): 1H-NMR ((D6)DMSO):
2.20 (s, 3 H); 3.29 (s, 1 H); 3.68 (q, J ¼ 5.1, 2 H); 3.90 (t, J ¼ 5.0, 2 H); 4.92 (s, 1 H); 6.22 (s, 1 H); 6.87 (d,
J ¼ 8.3, 1 H); 7.36 (d, J ¼ 8.4, 1 H); 10.70 (s, 1 H). MS: 236 (100, [M þ 1]þ). HR-MS: 236.1040
([M þ H]þ, C11H14N3Oþ3 ; calc. 236.1030).
When 3-hydroxy-2-methylpyridin-4(1H)-one (7) or 2-ethyl-3-hydroxypyridin-4(1H)-one (8) was
used as an additive, the procedure was the same as that described above for PT.
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Received April 20, 2008