Efficient and selective deprotection method for N-protected 2(3H)-benzoxazolones and 2(3H)-benzothiazolones

Article abstract of DOI:10.1016/j.tet.2004.08.070

Cyclic carbamate flanked with heterocyclic or aliphatic moieties are frequently used in medicinal chemistry. The synthesis of derivatives bearing a free NH often requires the use of a protection method. A literature search reveals very few protection/deprotection methods for cyclic carbamates. In this paper, we described different methods applicable to 2(3H)-benzoxazolone and 2(3H)-benzothiazolone. Graphical abstract

Full text of DOI:10.1016/j.tet.2004.08.070

Tetrahedron 60 (2004) 10321–10324
Efficient and selective deprotection method for N-protected
2(3H)-benzoxazolones and 2(3H)-benzothiazolones
a
a
b
a
Pascal Carato,a, Saıd Yous, Didier Sellier, Jacques H. Poupaert, Nicolas Lebegue
*
¨
and Pascal Berthelota
a
´
´
Laboratoire de Chimie Therapeutique, Faculte de Pharmacie, EA 1043, 3, rue du Professeur Laguesse, BP 83, 59006 Lille cedex, France
bLaboratory of Medicinal Chemistry, School of Pharmacy, UCL, Avenue Emmanuel Mounier, 73, B-1200 Brussels, Belgium
Received 25 May 2004; accepted 19 August 2004
Available online 22 September 2004
Abstract—Cyclic carbamate flanked with heterocyclic or aliphatic moieties are frequently used in medicinal chemistry. The synthesis of
derivatives bearing a free NH often requires the use of a protection method. A literature search reveals very few protection/deprotection
methods for cyclic carbamates. In this paper, we described different methods applicable to 2(3H)-benzoxazolone and 2(3H)-benzothiazolone.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
formylation, acylation or the cleavage of N-benzyle
derivative with NBS, AIBN could induced secondary
products. Therefore, in an effort to fill this gap, we explored
various protecting groups and examined their ease of
deprotection.
2(3H)-Benzoxazolones and 2(3H)-benzothiazolones deriva-
tives have attracted considerable attention as a result of their
medicinal properties. Several potentially useful drugs and
pharmacological tools based on these pharmacophores have
been developed in recent years.1–6 N-methyl-2(3H)-benz-
oxazolones and 2(3H)-benzothiazolones have been largely
used in medicinal chemistry, but surprisingly their N–H
homologues are less accessible although in many cases, a
free N(3)–H group is an essential structural requirement
for activity and receptor selectivity of these 2(3H)-
benzazolones derivatives. Moreover, the NH heterocycle
can serve as a pivotal structure for the constitution of a
library N-derivatized analogues.
2. Results and discussion
2.1. Protection/deprotection of cyclic carbamate on
phenyl ring (1a,b) via different methods
The compounds 2a,b–10a,b, in Scheme 1, were synthetized
by methods A or B, according the reagent desired, with
2(3H)-benzoxazolone (1a) or 2(3H)-benzothiazolinone
(1b). Various deprotection methods, described in Table 1,
were then tested.
Indeed, in many cases encountered in our own research,
reactions that are successful in the N-methyl series cannot
be applied in the N–H series: C(6)-formylation,7,8 C(6)-
tributyltin derivatization, photohalogenation,9 crotonisa-
tion, etc.10,11 Obviously, the use of N-protected 2(3H)-
benzazolones are in order for the success of these reactions.
However, close inspection of the literature reveals very few
indications concerning protecting groups of cyclic carba-
mates that can be easily introduced and subsequently
smoothly removed. Indeed, benzyl protecting group12 was
found in this series of heterocycle but reaction of
As expected, deprotection of derivatives 2a and 2b did take
place under mild acid (methods C and D), basic (method F)
Scheme 1. Protection and deprotection of 2(3H)-benzazolones derivatives
(2a,b–10a,b) via different methods. (a): method A: ClP (P: COR or SO2R),
Bu4NBr, K2CO3, CH2Cl2; method B: ClP (P: MOM or MEM), K2CO3,
Keywords: 2(3H)-Benzoxazolone; 2(3H)-Benzothiazolone; Protecting
groups.
´
DMF (b) method C: TFA; method D: HCl 12 N (3 equiv), MeOH; method
E: TiCl4 (3 equiv), CH2Cl2; method F: KOH (3 equiv), MeOH; method G:
* Corresponding author. Tel.: C33-3-20964040; fax: C33-3-20-964913;
e-mail: pcarato@pharma.univ-lille2.fr
´
´
´
Bu4NF (1 M in solution in THF, 3 equiv), THF.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.070

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P. Carato et al. / Tetrahedron 60 (2004) 10321–10324
Table 1. results of deprotection attempts of 2(3H)-benzazolones derivatives (2a,b–10a,b)
Entry
X
Protecting groups
TFA (C)
HCl–MeOH (D)
TiCl4–CH2Cl2 (E)
KOH–MeOH (F)
Bu4NF–THF (G)
2a
2b
O
S
1 h rt (85%)
1 h rt (81%)
2 h rt (79%)
N
N
0.5 h rt (89%)
0.5 h rt (68%)
1 h rt (91%)
1 h rt (95%)
1.5 h rt (89%)
3a
3b
O
S
N
N
N
N
N
N
0.5 h rt (30%)
0.5 h rt (91%)
1 h rt (95%)
1 h rt (97%)
4a
4b
O
S
N
N
N
N
N
N
0.5 h rt (78%)
0.5 h rt (94%)
0.25 h rt (98%)
0.25 h rt (95%)
5a
5b
O
S
N
N
N
N
N
N
0.5 h rt (39%)
0.5 h rt (90%)
0.25 h rt (89%)
0.25 h rt (94%)
6a
6b
O
S
N
N
N
N
2 h rt (90%)
2 h rt (86%)
0.5 h rt (20%)
0.5 h rt (95%)
0.5 h rt (96%)
0.5 h rt (98%)
7a
7b
O
S
N
N
N
N
N
N
0.5 h rt (10%)
0.5 h rt (90%)
0.5 h rt (96%)
0.5 h rt (93%)
8a
8b
O
S
N
N
N
N
N
N
Ring opening
N
1 h rt (93%)
1 h rt (97%)
9a
9b
O
S
4 h reflux (92%)
4 h reflux (96%)
N
N
N
N
N
N
N
N
10a
10b
O
S
4 h reflux (95%)
4 h reflux (97%)
N
N
N
N
N
N
N
N
N: unsuccessful test performed 1 day at room temperature and then 1 day at reflux; rt: room temperature.
and neutral (method G) conditions and therefore the
N-acetyl cannot be considered as a good protecting group.
Compounds 3a,b–5a,b and 7a,b, respectively with COPh,
CONHEt, CO2Et and SO2Me, resisted in acid medium
(methods C, D and E). Application of the method F, in basic
media, to the compounds 3b–5b and 7b give the desired
derivative 1b with good yield (90–95%), but in the 2(3H)-
benzoxazolone series (3a–5a and 7a) we observed that
deprotected compounds were accompanied by important
amounts of ring opening products (such as 2-aminophenol)
which reduced the yield (10 to 78%). Deprotection method
G, for compounds 3a,b–5a,b and 7a,b, with Bu4NF in
THF,13,14 however gives excellent yields (89–98%).
phenylsulfonyl) phenol. Compounds 8a,b were successfully
cleaved with Bu4NF (THF, rt, 1 h, 93 and 97%). Deprotec-
tion of compounds 9a,b and 10a,b was realized only in TFA
at reflux for 4 h, nevertheless with very good yields (92 to
97%).
In order to validate the interest of the protecting group for
2(3H)-benzazolone, we applied our results to a benchmark,
i.e. the synthesis of 6-benzoyl-2(3H)-benzothiazolone. In
our laboratory we observed indeed that the introduction of
tributyltin in the 6-position of the 2(3H)-benzothiazolone
could be performed only on N-methyl compounds and not
on the free NH series. In Scheme 2, we introduced the MEM
protecting group on 6-bromo-2(3H)-benzothiazolone (12) to
synthetise the corresponding tributyltin derivative. The
benzoyl moiety was then easily introduced and the resulting
Compound 6a,b (Cbz protected) was not deprotected in acid
media (method C and D) but in mild basic media (XZS:
95% and XZO: 20%) with method F (30 min at rt) and also
by methods E and G with excellent yields (86–98%).
Another attempt of deprotection of 6a,b was performed by
hydrogenolysis in THF using Pd/C (5 h, rt), which gave the
deprotected derivatives 1a,b with excellent yields (XZO:
94% and XZS: 97%). Method G with Bu4NF in THF was
found to be a very good alternative (6a: 96% and 6b: 98%)
specially because we did not observe any ring opening
products.
Surprisingly, with compound 8b we did not observe any
deprotection either in acid or basic medium (methods C, D,
E and F). In the corresponding 2(3H)-benzoxazolone series
(8a) we observed ring opening, which gave 2-amino-(N-
Scheme 2. Protection of 2(3H)-benzothiazolone. (a): MEM-Cl, K2CO3,
DMF (b): (Bu3Sn)2, Pd(PPh3)4, toluene (c): ClCOPh, PdCl2(PPh3)2, toluene
(d): TFA.

P. Carato et al. / Tetrahedron 60 (2004) 10321–10324
10323
compound was then deprotected to afford the free NH
derivative (15).
(cyclohexane). Mp 90–91 8C. IR (KBr) 2870, 1726, 1688,
1
1600 cmK1. H NMR (CDCl3) dZ2.75 (s, 3H), 7.15–7.29
(m, 3H), 8.25 (m, 1H).
More specifically, 6-bromobenzothiazolinone15 (11) was
protected in DMF with MEM group to afford compound 12.
Tributyltin derivative 13 was obtained from the bromo
precursor 12 via Stille’s reaction with (Bu3Sn)2 and
Pd(PPh3)4 in toluene. Compound 13 can then embarked in
coupling reactions with various aryl or cycloalkylcarbonyl
chlorides. In Scheme 2, to exemplify the validity of our
approach, we introduced a benzoyl group in 6-position to
give derivative 14. The MEM protection group was then
cleaved in refluxed TFA for 2 h to furnish the expected
compound 15.16
4.1.2. 3-Acetyl-2(3H)-benzothiazolone (2b). Yield 84%
(cyclohexane). Mp 103–104 8C. IR (KBr) 2930, 1695, 1676,
1
1600 cmK1. H NMR (CDCl3) dZ2.80 (s, 3H), 7.03–7.24
(m, 3H), 8.15 (m, 1H).
4.1.3. 3-Benzoyl-2(3H)-benzoxazolone (3a). Yield 70%
(cyclohexane). Mp 178–179 8C. IR (KBr) 1805, 1697,
1600 cmK1. 1H NMR (CDCl3) dZ7.25–7.38 (m, 3H), 7.48–
7.59 (m, 2H), 7.67 (m, 1H), 7.81–7.92 (m, 3H).
4.1.4. 3-Benzoyl-2(3H)-benzothiazolone (3b). Yield 81%
(cyclohexane). Mp 165–166 8C. IR (KBr) 1702, 1724,
1600 cmK1. 1H NMR (CDCl3) dZ7.32–7.48 (m, 3H), 7.65–
7.78 (m, 2H), 7.84 (m, 1H), 7.95–8.14 (m, 3H).
3. Conclusion
In conclusion, we found different protecting groups which
can be used in acid or basic medium reaction conditions and
subsequently removed without major problems. The COPh,
CONHEt, CO2Et, CO2CH2Ph, SO2CH3 derivatives (3a,b–
7a,b) resisted in acid conditions and were cleaved in basic
medium. MOM and MEM protection (9a,b–10a,b) resisted
in basic media and were cleaved in TFA. The SO2Ph
protection (8b) resisted in acid and basic media and was
cleaved with Bu4NF in THF (method G).
4.1.5. 3-Ethylaminocarbonyl-2(3H)-benzoxazolone (4a).
Yield 80% (cyclohexane). Mp 104–106 8C. IR (KBr) 3350,
1
2970, 1737, 1658, 1600 cmK1. H NMR (CDCl3) dZ1.30
(t, JZ7.30 Hz, 3H), 3.20 (q, JZ7.30 Hz, 2H), 5.00 (m, 1H),
7.23–7.30 (m, 3H), 8.05 (m, 1H).
4.1.6. 3-Ethylaminocarbonyl-2(3H)-benzothiazolone
(4b). Yield 88% (cyclohexane). Mp 112–113 8C. IR (KBr)
3340, 2954, 1701, 1665, 1600 cmK1. 1H NMR (CDCl3) dZ
1.35 (t, JZ7.20 Hz, 3H), 3.20 (q, JZ7.20 Hz, 2H), 5.05 (m,
1H), 7.11–7.23 (m, 3H), 8.10 (m, 1H).
Method G in particular constitutes a mild and selective
method of deprotection for N-protected-2(3H)-benzazo-
lones (derivatives 3a,b–8a,b) with excellent yields
(89–98%) and was compatible both with acid or basic-
sensitive groups. To exemplify the validity of our approach,
we synthesized compounds 15 via N-MEM protection.
These deprotection methods could be extended to other
cyclic carbamates, such as oxazolo[4,5]pyridin-2(3H)-ones,
hydantoins, and barbiturates.
4.1.7. 3-Ethoxycarbonyl-2(3H)-benzoxazolone (5a).
Yield 70% (petroleum ether). Mp 70–71 8C. IR (KBr)
1
2975, 1852, 1747, 1600 cmK1. H NMR (CDCl3) dZ1.51
(t, JZ7.34 Hz, 3H), 4.55 (q, JZ7.34 Hz, 2H), 7.26–7.38
(m, 3H), 7.80 (m, 1H).
4.1.8. 3-Ethoxycarbonyl-2(3H)-benzothiazolone (5b).
Yield 90% (petroleum ether). Mp 65–66 8C. IR (KBr)
1
2971, 1845, 1746, 1600 cmK1. H NMR (CDCl3) dZ1.50
4. Experimental
(t, JZ7.30 Hz, 3H), 4.50 (q, JZ7.30 Hz, 2H), 7.31–7.53
(m, 3H), 8.10 (m, 1H).
4.1. General methods of protection
Method A (2a,b–8a,b). To a solution of 2(3H)-benzazolones
(22 mmol) in CH2Cl2 (30 mL), K2CO3 (66 mmol), Bu4NBr
(1 mmol) and the desired acid chloride reagent (66 mmol)
were added. The reaction was refluxed for 4 h. The solvent
was evaporated under reduce pressure. The solution was
hydrolyzed with water (30 mL) and stirred for 1 h. The
precipitate was filtered and recrystallized from the appro-
priate solvent.
4.1.9. Benzyloxycarbonyl-2(3H)-benzoxazolone (6a).
Yield 70% (cyclohexane). Mp 130–131 8C. IR (KBr)
1809, 1749, 1600 cmK1 1H NMR (CDCl3) dZ5.50 (s,
.
2H), 7.16–7.28 (m, 3H), 7.36–7.46 (m, 3H), 7.50–63–7.24
(m, 2H), 7.75 (m, 1H).
4.1.10. Benzyloxycarbonyl-2(3H)-benzothiazolone (6b).
Yield 88% (cyclohexane). Mp 62–63 8C. IR (KBr) 1739,
1709, 1600 cmK1. 1H NMR (CDCl3) dZ5.55 (s, 2H), 7.26–
7.45 (m, 8H), 7.55 (m, 1H).
Method B (9a,b–10a,b). To a solution of 2(3H)-benzazo-
lones (22 mmol) in DMF (30 mL), K2CO3 (66 mmol) was
added. The reaction was stirred at 80 8C for 1 h and the
desired chlororeagent (66 mmol) added. The solution
was stirred for 3 h at the same temperature. The solvent
was evaporated under reduced pressure. The solution was
hydrolyzed with water (30 mL) and stirred for 1 h. The
precipitate was filtered and recrystallized with the appro-
priate solvent.
4.1.11. 3-Methylsulfonyl-2(3H)-benzoxazolone (7a).
Yield 75% (cyclohexane). Mp 142–143 8C. IR (KBr)
1733, 1600, 1185 cmK1 1H NMR (CDCl3) dZ3.50 (s,
.
3H), 7.18–7.31 (m, 3H), 7.70 (m, 1H).
4.1.12. 3-Methylsulfonyl-2(3H)-benzothiazolone (7b).
Yield 79% (cyclohexane). Mp 148–149 8C. IR (KBr)
1697, 1600, 1185 cmK1 1H NMR (CDCl3) dZ3.60 (s,
.
3H), 7.28–7.43 (m, 3H), 8.10 (m, 1H).4.1.
4.1.1. 3-Acetyl-2(3H)-benzoxazolone (2a). Yield 90%

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P. Carato et al. / Tetrahedron 60 (2004) 10321–10324
4.1.13. 3-Phenylsulfonyl-2(3H)-benzoxazolone (8a).
Yield 96% (cyclohexane). Mp 145–146 8C. IR (KBr)
(s, 2H), 7.30 (d, 1H, JZ7.90 Hz), 7.40 (dd, 1H, JZ7.90 Hz,
JZ1.05 Hz), 7.50 (s, 1H).
1
1733, 1600, 1190 cmK1. H NMR (CDCl3) dZ7.25 (m,
1H), 7.35–7.48 (m, 2H), 7.60 (m, 2H), 7.70 (m, 1H), 8.10
(m, 2H), 8.25 (m, 1H).
4.1.21. 6-Benzoyl-3-methylethoxymethyl-2(3H)-benzo-
thiazolone (14). 6-Tributylstannic-3-methylethoxymethyl-
2(3H)-benzothia-zolone (13) (1.9 mmol) in toluene (10 mL)
was placed under argon, dichlorobis(triphenylphosphine)
palladium (0.18 mmol) and benzoylchloride (2.8 mmol)
were added. The reaction was refluxed for 16 h. The
solution was evaporated under reduced pressure. The
residue was purified by flash column chromatography with
CH2Cl2/EtOAc (9/1) and recrystallized in cyclohexane.
Yield 86%. Mp 101–102 8C; IR 1696, 1649. 1HNMR
(CDCl3): dZ3.35 (s, 3H), 3.50 (m, 2H), 3.75 (m, 2H), 5.50
(s, 2H), 7.40 (d, 1H, JZ8.70 Hz), 7.50 (m, 2H), 7.60 (m,
1H), 7.80 (m, 2H), 7.85 (dd, 1H, JZ8.70 Hz, JZ1.10 Hz),
8.00 (d, 1H, JZ1.10 Hz).
4.1.14. 3-Phenylsulfonyl-2(3H)-benzothiazolone (8b).
Yield 96% (cyclohexane). Mp 136–137 8C. IR (KBr)
1
1717, 1620, 1190 cmK1. H NMR (CDCl3) dZ7.30 (m,
1H), 7.32–7.45 (m, 2H), 7.60 (m, 2H), 7.70 (m, 1H), 8.10
(m, 2H), 8.25 (m, 1H).
4.1.15. 3-Methoxymethyl-2(3H)-benzoxazolone (9a).
Yield 90% (cyclohexane). Mp 90–91 8C. IR (KBr) 1762,
1600 cmK1. 1H NMR (CDCl3) dZ3.40 (s, 3H), 5.20 (s, 2H),
7.12–7.29 (m, 4H).
4.1.16. 3-Methoxymethyl-2(3H)-benzothiazolone (9b).
Yield 95% (cyclohexane). Mp 114–115 8C. IR (KBr)
1695, 1600 cmK1 1H NMR (CDCl3) dZ3.35 (s, 3H),
.
5.10 (s, 2H), 7.02–7.24 (m, 4H).
References and notes
4.1.17. 3-Methoxyethoxymethyl-2(3H)-benzoxazolone
(10a). Yield 90% (cyclohexane). Mp 28–29 8C. IR (KBr)
2882, 1782, 1600 cmK1. 1H NMR (CDCl3) dZ3.30 (s, 3H),
3.50 (t, JZ7.00 Hz, 2H), 3.75 (t, JZ7.00 Hz, 2H), 5.40 (s,
2H), 7.15–7.36 (m, 4H).
1. Diouf, O.; Carato, P.; Depreux, P.; Bonte, J. P.; Caignard,
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2. Diouf, O.; Carato, P.; Lesieur, I.; Rettori, M. C.; Caignard,
D. H. Eur. J. Med. Chem. 1999, 34, 69–73.
3. Carato, P.; Bonte, J. P.; Lesieur, D.; Depreux, P.; Caignard, D.
H.; Millan, M.; Newman-Tancredi, A.; Renard, P.; Rettori, M.
C. Eur. Patent Chem. Abstr., 1998, P4662x.
4.1.18. 3-Methoxyethoxymethyl-2(3H)-benzothiazolone
(10b). Yield 93% (cyclohexane). Mp 75–76 8C. IR (KBr)
2898, 1709, 1600 cmK1. 1H NMR (CDCl3) dZ3.30 (s, 3H),
3.50 (t, JZ7.05 Hz, 2H), 3.70 (t, JZ7.05 Hz, 2H), 5.35 (s,
2H), 7.06–7.28 (m, 4H).
4. Carato, P.; Depreux, P.; Lesieur, D.; Millan, M.; Newman-
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5. Lesieur, D.; Delmas, E.; Yous, S.; Depreux, P.; Guillaumet,
G.; Dacquet, C.; Levens, N.; Boutin, J.; Bennejean, C.; Renard,
P. French Patent 00-01289, 2000.
4.1.19. 6-Bromo-3-methylethoxymethyl-2(3H)-benzo-
thiazolone (12). To a mixture of 6-bromo-2(3H)-benzo-
thiazolone (11) (5 g, 21.7 mmol) in DMF (50 mL),
potassium carbonate (9 g, 65.2 mmol) and MEM-Cl
(9.9 mL, 86.8 mmol) were added. The reaction was stirred
at 90 8C for 2 h. The solution was evaporated under reduced
pressure and 50 mL of water added. The solution was
extracted with CH2Cl2, then the organic layer evaporated
under reduced pressure. The residue was recrystallized in
cyclohexane. Yield 92%. Mp 97–98 8C. IR 1692, 1600. 1H
NMR (CDCl3) dZ3.30 (s, 3H), 3.50 (m, 2H), 3.70 (m, 2H),
5.50 (s, 2H), 7.15 (d, 1H, JZ8.30 Hz), 7.45 (dd, 1H, JZ
8.30 Hz, JZ1.50 Hz), 7.55 (d, 1H, JZ1.50 Hz).
6. Lesieur, D.; Blanc-Delmas, E.; Bennejean, C.; Chavatte, P.;
Guillaumet, G.; Dacquet, C.; Levens, N.; Boutin, J.; Renard, P.
French Patent 01-12205, 2001.
7. Bonte, J. P.; Lesieur, D.; Lespagnol, Ch.; Plat, M.; Cazin,
J. C.; Cazin, M. Eur. J. Med. Chem. 1974, 9, 491–496.
8. Kanyonyo, M. R.; Ucar, H.; Isa, M.; Carato, P.; Lesieur, D.;
Renard, P.; Poupaert, J. H. Bull. Soc. Chim. Belg. 1996, 105,
17–22.
9. Liacha, M.; Yous, S.; Depreux, P.; Poupaert, J. H.; Lesieur, D.
Heterocycles 1999, 51, 1929–1944.
10. Moussavi, Z.; Depreux, P.; Lesieur, I.; Sauzieres, J. Hetero-
cycles 1991, 32, 2119–2125.
4.1.20. 6-Tributyltin-3-methylethoxymethyl-2(3H)-
benzothiazolinone (13). To a mixture of 6-bromo-3-
methylethoxymethyl-2(3H)-benzothiazolone (12) (5 mmol)
in toluene (20 mL) under argon, tetrakis(triphenyl phos-
phine) palladium (0.5 mmol) and bis(tributyltin) (10 mmol)
were added. The reaction was refluxed for 16 h. The
solution was evaporated under reduced pressure. The oily
residue was purified by flash column chromatography with
petroleum ether/EtOAc (9.5/0.5) to give an oily product.
11. Depreux, P.; Moussavi, Z.; Lesieur, D. Synth. Commun. 1992,
22, 1541–1545.
12. Baker, S. R.; Parsons, A. F.; Wilson, M. Tetrahedron Lett.
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´ ´
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Chem. 1988, 25, 1503–1509.
1
Yield 63%. IR 1692, 1605. HNMR (CDCl3): dZ0.90 (t,
9H, JZ5.90 Hz), 1.10 (t, 6H, JZ6.10 Hz), 1.35 (m, 6H),
1.55 (m, 6H), 3.35 (s, 3H), 3.55 (m, 2H), 3.75 (m, 2H), 5.45
16. Yous, S.; Poupaert, J. H.; Lesieur, I.; Depreux, P.; Lesieur, D.
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