Tosylation/mesylation of 4-hydroxy-3-nitro-2-pyridinones as an activation step in the construction of dihydropyrido[3,4-b] benzo[f][1,4]thiazepin-1-one based anti-HIV agents

Article abstract of DOI:10.1016/j.tetlet.2005.02.128

Reaction of 4-hydroxy-3-nitropyridinone 8 with TsCl and MsCl, respectively, resulted in rapid and quantitative formation of ditosylate 13 and dimesylate 16. Through chemoselective reaction of 16 with thiophenol 17 the key 4-thioaryl substituted intermedia

Full text of DOI:10.1016/j.tetlet.2005.02.128

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2919–2922
Tosylation/mesylation of 4-hydroxy-3-nitro-2-pyridinones as an
activation step in the construction of dihydropyrido[3,4-b]
benzo[f ][1,4]thiazepin-1-one based anti-HIV agents
Pierre Storck,a Anne-Marie Aubertinb and David S. Griersona,c,
*
aInstitut de Chimie des Substances Naturelles CNRS, Ave de la Terrasse, 91198 Gif-sur-Yvette, France
b
´
´
´
U74 INSERM, Institut de Virologie, Faculte de Medicine 3 rue, Koeberle, 67000 Strasbourg, France
cUMR 176 CNRS-Institut Curie, Laboratoire de Pharmacochimie, Section de Recherche, Batiment 110,
Centre Universitaire, 91405 Orsay, France
Received 2 June 2004; revised 18February 2005; accepted 18February 2005
Abstract—Reaction of 4-hydroxy-3-nitropyridinone 8 with TsCl and MsCl, respectively, resulted in rapid and quantitative form-
ation of ditosylate 13 and dimesylate 16. Through chemoselective reaction of 16 with thiophenol 17 the key 4-thioaryl substituted
intermediate 18 was obtained in 78% yield. This compound was efficiently converted to the target tricyclic products 4a and b. Com-
pound 4a, in particular, is a potent inhibitor in vitro (IC50 = 2 nM) of wild type HIV-1 replication.
Ó 2005 Elsevier Ltd. All rights reserved.
Arylthiopyridinones 1a and b are key members of a fam-
ily of potent non-nucleoside type inhibitors of HIV-1
reverse transcriptase (Scheme 1).1 In a program to look
at SAR in this series, and in particular for compounds,
which maintain activity against the Tyr181/188 mutants
conferring resistance to the related NNRTIꢀs HEPT 2
and pyridinone 3,2,3 one objective was to construct the
conformationally restrained analogues 4a and b. Such
dihydropyrido[3,4-b] benzo[f][1,4]thiazepin-1-ones bear
a structural resemblance to nevirapine 5.4 However,
analysis of the structures of HEPT and nevirapine com-
plexed with RT suggests that in order for thiazepinones
4a and 4b to conserve a crucial hydrogen bond to the
Lys101 residue in the hydrophobic pocket of rt they
must adopt an orientation different to that for nevira-
pine.5 It was thus of considerable interest to determine
whether molecules 4 display anti-HIV activity.6,7
O
O
H
N
X
NH2
S
HN
HN
A
S
4a X = H, CN
4b X = O
R
R
1a (R = Me; IC50 = 0.014 µM)
1b (R = H; IC50 = 0.32 µM)
Cl
O
O
H
N
O
H
H
N
O
N
N
Cl
O
N
S
HO
HEPT 2
L697,661 3
N
N
N
A
Central to our synthesis of these molecules was the need
to develop effective means to activate the C-4 center in
4-hydroxy-3-nitropyridinone 8 with respect to nucleo-
philic (SNAr) substitution by an appropriate o-substi-
N
H
O
Nevirapine 5
Scheme 1.
Keywords: Mesylation; Pyridinones; Dihydropyridobenzothiazepin-1-
ones; Anti-HIV; Reverse transcriptase.
*
tuted thiophenol. In earlier work it was found that,
whereas the approach involving conversion of the less
Corresponding author. Tel.: +33 1 6986 3086; fax: +33 1 6907
5381; e-mail: david.grierson@curie.u-psud.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.128

2920
P. Storck et al. / Tetrahedron Letters 46 (2005) 2919–2922
hindered 5-methyl substituted pyridinone 6 to the chloro
derivative 7 using POCl3 is efficient (80%), the yields for
the corresponding conversion of 5,6-dialkyl substituted
pyridinone 8–9 are low (12–34%), and in fact, poorly
reproducible.1a,8 A study was thus made of the prepara-
tion and synthetic utility of the corresponding 4-tosyl-
ates/mesylates of these two pyridinones and their
subsequent conversion to the target thiazepinones.
OTs
O
TsCl (2 eq), TEA
CH2Cl2, 20˚C
NO2
X
NO2
X
N
HN
98%
PhSH
36%
15 = SPh
13 = OTs
8 X = OH
9 X = Cl
POCl3
n-Bu4NOH,
EtOH, 20˚C
15 min, 91%
It was found (Scheme 2) that the reaction of the 5-
methyl substituted pyridinone 6 with excess TsCl
(4 equiv) in pyridine at either room temperature, or at
ꢀ20 °C, led to immediate formation of pyridinium salt
11 (>80% pure by NMR; remaining impurities pyri-
dineÆHCl).9 This result indicated that selective mono-
tosylation of the C-4 hydroxyl group had occurred,
and further, that the derived tosylate 10 was highly reac-
tive. This secondary reaction was easily suppressed using
2,6-lutidine as the amine solvent. However, when
1 equiv only of TsCl was employed in the presence of
this hindered base the bistosylated compound 12, and
not the expected product 10, was obtained in an equal
mixture with the starting pyridinone 6.10 In the corre-
sponding reaction of the more hindered pyridinone 8
with 2 equiv of TsCl and Et3N in CH2Cl2 at room tem-
perature the bistosylate 13 was obtained in 98% yield
(Scheme 3).
O
NO2
OTs
LiCl, THF
reflux
HN
+
13
8
14
Scheme 3.
and 8. As already shown, these molecules react with
each other to give 13. In contrast, in the reaction of bis-
tosylate 13 with thiophenol (CH2Cl2, Et3N, 20 °C, 12 h)
clean displacement of the 4-OTs group occurred leading
to selective formation of compound 15, albeit in only
moderate yield.
A plausible explanation for this result is that rate of for-
mation of 12 and 13 from the initially formed monotosy-
lates is much faster than the formation of these
montosylates themselves.11 Another possibility is that
the monotosylate, which is formed reacts also as a tosyl
transfer reagent, in which instance the bistosylated
product would accumulate as the concentration of TsCl
in the medium diminishes. The later scenario was re-
jected following the observed formation of monotosyl-
ate 14 as a stable compound when bistosylate 13 was
treated under mild hydrolysis conditions (aqueous Bu4-
NOH in EtOH, RT, 15 min; 91%). Interestingly, when
compound 14 was reacted with LiCl in refluxing THF
a 1:1 mixture of bistosylate 13 and pyridinone 8 was ob-
tained. In this reaction chloride ion reacts preferentially
at the sulfur atom of the C-4 OTs group generating TsCl
To obtain a more reactive partner in the reaction with
thiophenyl derivatives, pyridinone 8 was converted to
the dimesylate intermediate 16 (Scheme 4). Under opti-
mum conditions [MsCl (3 equiv), DIPEA (3 equiv) in
CH2Cl2 at 20 °C for 2 min] quantitative conversion to
16 [mp 134 °C (EtOH)] was achieved. The reaction of
this bismesylate with thiophenol derivative 1712 provi-
ded the desired condensation product 18 in 78% overall
yield from 8. This sequence is thus both more rapid and
more efficient than the traditional POCl3 activation
approach.
At this point the option was open to hydrolyze 18 to the
corresponding pyridinone 19 (NaOMe/MeOH); 95%.
However, as the solubility characteristics of intermedi-
ates retaining the 2-OMs facilitated isolation/purifica-
tion, conditions were developed to carry this
functionality through to the last steps in the synthesis
of the thiazepinone ring. In this context, reduction of
the nitro group in 18 to give 20 under catalytic hydro-
genation conditions proved advantageous relative to
the use of SnCl2Æ2H2O. Note that under hydrogenation
conditions partial loss of OTBS group occurred. Com-
plete transformation of 20 to 21 was achieved by treat-
ment of the mixture with TBAF in THF–HOAc, the
acid being added to neutralize any hydroxide ion present
in the TBAF solution. Using the Dess–Martin reagent
the primary OH group in 21 was oxidized giving alde-
hyde 22 (91%). This intermediate spontaneously cyclized
to the water sensitive imine 23, which was converted to
its more stable aminonitrile derivative through reaction
with TMSCN (ZnBr2 cat, EtOAc, reflux). Treatment of
this compound under aqueous base conditions led to
loss of HCN and imine ring opening giving back 22.
In contrast, hydrolysis of the OMs-imidate motif with
O
O
NO2
X
TsCl (4 eq), Pyr
20˚C, >80%
NO2
OTs
HN
HN
POCl3
6 X = OH
7 X = Cl
10
TsCl (1 eq),
2,6-lutidine
(via 10)
O
OTs
NO2
NO2
OTs
Cl-
HN
N
+
N
+ 6
11
12 (50%)
Scheme 2.

P. Storck et al. / Tetrahedron Letters 46 (2005) 2919–2922
2921
O
OMs
OMs
1. TBAF,
NO2
OH
NO2
S
NO2
MsCl, CH2Cl2
HN
N
N
THF-HOAc
18
DIPEA, 20˚C, 2min
2. Dess-Martin
Oxidation
OMs
100%
CHO
8
16
24
TBSO
HS
K2CO3,
CH2Cl2,
20˚C, 12 h
78%
H2, Pd/C, THF
(81%yield from 18))
17
O
OMs
H
O
1. MnO2, 7 d,
30%
OMs
H
N
OR
N
NH2
S
HN
N
NO2
H2, Pd/C
EtOH
N
N
2. NaOMe,
MeOH,81%
S
S
S
OTBS
25
OR
4b
Scheme 5.
20 R = TBS
21 R = H
18
TBAF, 20˚C
THF - HOAc (9 : 1)
91% from 18
proved to be 100 times more active than compound
1b, which similarly lacks the 30,50-dimethyl substitution
on the phenyl ring. In contrast, relative to 1b no real
gain in activity was observed for the amide analog 4b
[IC50 = 0.084 lM]. None of these compounds displayed
any appreciable cytotoxicity (IC50 > 10ꢀ5 M). From
these results it can be deduced that the tricyclic structure
of compounds 4 reflect the active conformation of the
more flexible arylthiopyridinones 1 bound in the hydro-
phobic pocket of RT.
OH-
95%
Dess-Martin Oxid.
10 min, 91%
O
NO2
S
HN
OMs
NH2
S
OTBS
N
CHO
19
22
Acknowledgments
We thank the ANRS (Agence Nationale pour la Recher-
che contre le SIDA) for a scholarship for P.S.
OMs
O
H
CN
1. TMSCN,
ZnBr2, 94%
N
Supplementary data
N
N
HN
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.
2005.02.128.
S
2. p-TsOH ,
THF-H2O
70%
S
23
4a
Scheme 4.
References and notes
acid [p-TsOH, H2O–THF (1:1)] gave the target tricyclic
pyridinone 4a.
´
1. (a) Dolle, V.; Fan, E.; Nguyen, C. H.; Aubertin, A.-M.;
Kirn, A.; Andreola, M. L.; Jamieson, G.; Tarrago-Litvak,
L.; Bisagni, E. J. Med. Chem. 1995, 38, 4679–4686; see
´
Aubertin, A.-M.; Kirn, A.; Andreola, M. L.; Ventura, M.;
Tarrago-Litvak, L.; Bisagni, E. J. Med. Chem. 2000, 43,
3949–3962.
In an alternate series of reactions, the O-TBS group in
intermediate 18 was removed, the liberated primary
alcohol was oxidized, and the derived nitro aldehyde
24 was reductively cyclized under catalytic hydrogen
conditions to give the amine 25 in 81% overall yield
(Scheme 5). Interestingly, oxidation of amine 25 using
MnO2 proceeded beyond the formation of imine 23,
providing, after hydrolysis, direct access to amide 4b.13
also: (b) Dolle, V.; Nguyen, C. H.; Legraverend, M.;
2. (a) Miyasaka, T.; Tanaki, H.; Baba, M.; Hayakawa, H.;
Walker, R. T.; Balzarini, J.; De Clercq, E. J. Med. Chem.
1989, 32, 2507–2509; (b) Buckheit, R. W., Jr.; Fliakas-
Boltz, V.; Yeagy-Bargo, S.; Weislow, O.; Mayers, D. L.;
Boyer, P. L.; Hughes, S. H.; Pan, B.-C.; Chu, S.-H.; Bader,
J. P. Virology 1995, 210, 186–193; (c) Balzarini, J.; Baba,
M.; De Clercq, E. Antimicrob. Agents Chemother. 1995,
39, 998–1002; (d) Baba, M.; Shigeta, S.; Yuasa, S.;
Takashima, H.; Sekiya, K.; Ubasawa, M.; Tanaka, H.;
Miyasaka, T.; Walker, R. T.; De Clercq Antimicrob.
Tested in the LAI CEM-SS cell system assay14 com-
pound 4a [IC50 = 0.002 lM] proved to be essentially
equipotent with the reference molecule 1a. Most inter-
estingly, this rigidified arylthiopyridinone analogue

2922
P. Storck et al. / Tetrahedron Letters 46 (2005) 2919–2922
Agents Chemother. 1994, 38, 688–692; (e) Hopkins, A. L.;
Grozinger, K. G.; Cullen, E.; Kapadia, S. R.; Patel, U. R.;
Fuchs, V. U.; Mauldin, S. C.; Vitous, J.; Behnke, M. L.;
Klunder, J. M.; Pal, K.; Skiles, J. W.; McNeil, D. W.;
Rose, J. M.; Chow, G. C.; Skoog, M. T.; Wu, J. C.;
Schmidt, G.; Engel, W. W.; Eberlein, W. G.; Saboe, T. D.;
Campbell, S. J.; Rosenthal, A. S.; Adams, J. J. Med.
Chem. 1991, 34, 2231–2241; (c) Wu, J. C.; Warren, T. C.;
Adams, J.; Proudfoot, J.; Skiles, J.; Raghaven, P.; Perry,
C.; Potocki, I.; Farina, P. R.; Grob, P. M. Biochemistry
1991, 30, 2026–2202; (d) Murphy, R. L.; Montaner, J.
Exp. Opin. Investig. Drugs 1996, 5, 1183–1199.
Ren, J.; Esnouf, R. M.; Willcox, B. E.; Jones, E. Y.; Ross,
C.; Miyasaka, T.; Walker, R. T.; Tanaka, H.; Stammers,
D. K.; Stuart, D. I. J. Med. Chem. 1996, 39, 1589–1600; (f)
Hopkins, A. L.; Ren, J.; Tanaka, H.; Baba, M.; Okamato,
M.; Stuart, D. I.; Stammers, D. K. J. Med. Chem. 1999,
42, 4500–4505; (g) Buckheit, R. W., Jr.; Watson, K.;
Fliakas-Boltz, V.; Russell, J.; Loftus, T. L.; Osterling, M.
C.; Turpin, J. A.; Pallansch, L. A.; White, E. L.; Lee,
J.-W.; Lee, S.-H.; Oh, J.-W.; Kwon, H.-S.; Chung, S.-G.;
Cho, E.-H. Antimicrob. Agents Chemother. 2001, 45, 393–
400; (h) El-Brollosy, N. R.; Jorgensen, P. T.; Dahan, B.;
Boel, A. M.; Pedersen, E. B.; Nielsen, C. J. Med. Chem.
2002, 45, 5721–5726.
5. Ren, J.; Esnouf, R.; Garman, E.; Somers, D.; Ross, C.;
Kirby, I.; Keeling, J.; Darby, G.; Jones, Y.; Stuart, D.;
Stammers, D. Nat. Struct. Biol. 1995, 2, 293–302.
6. For the synthesis of cyclic analogues of HEPT; see:
Maruenda, H.; Johnson, F. J. Med. Chem. 1995, 38, 2145–
2151.
7. For ꢁsimilarꢀ tricyclic compounds and their anti-HIV
activity; see: (a) Artico, M.; Stefancich, G.; Silvestri, R.;
Massa, S.; Pagnozzi, E.; Loi, A. G.; Musu, D.; Doa, M.;
Scano, P.; La Colla, P. Med. Chem. Res. 1994, 4, 283–290;
(b) Campiani, G.; Nacci, V.; Fiorini, I.; De Filippis, M. P.;
Garofalo, A.; Greco, G.; Novellino, E.; Altamura, S.; Di
Renzo, L. J. Med. Chem. 1996, 39, 2672–2680.
8. For a recent study of the chloration of 4-hydroxy-2-
pyridinones; see: Azuma, Y.; Morone, M.; Nagayama, K.;
Kawamata, Y.; Sato, A. Heterocycles 2003, 60, 1461–
1468, and references therein.
9. In an analogous fashion 6-chloropyrimidines react with
pyridine derivatives to give the corresponding pyridinium
salts; see: Schmidt, A.; Hetzheim, A.; Albrecht, D.
Heterocycles 1996, 43, 2153–2167.
10. N-Tosyl-2-pyridinones were not formed under these con-
ditions see: Posner, G. J. Org. Chem. 1992, 57, 4088–4097.
11. The reaction of in situ generated monotosylate 10 with a
second equivalent of TsCl is rapid, but still slower than the
reaction of this intermediate with pyridine to give 11. In
both instances the products precipitated from the reaction
medium.
12. (a) Arnoldi, A.; Carughi, M. Synthesis 1988, 155–157; (b)
Kasmai, H. S.; Mischke, S. G. Synthesis 1989, 763–765.
13. San Martin, R.; de Marigorta, E. M.; Moreno, I.;
Dominguez, E. Heterocycles 1997, 45, 757–763.
3. (a) Saari, W. S.; Hoffman, J. M.; Wai, J. S.; Fisher, T. E.;
Rooney, C. S.; Smith, A. M.; Thomas, C. M.; Goldman,
M. E.; OꢀBrien, J. A.; Nunberg, J. H.; Quintero, J. C.;
Schleif, W. A.; Emini, E. A.; Stern, A. M.; Anderson, P. S.
J. Med. Chem. 1991, 34, 2922–2925; (b) Hoffman, J. M.;
Wai, J. S.; Thomas, C. M.; Levin, R. B.; OꢀBrien, J. A.;
Goldman, M. E. J. Med. Chem. 1992, 35, 3784–3791; (c)
Saari, W.; Wai, J. S.; Fisher, T. E.; Thomas, C. M.;
Hoffman, J. M.; Rooney, C. S.; Smith, A. M.; Jones, J. H.;
Bamberger, D. L.; Goldman, M. E.; OꢀBrien, J. A.;
Nunberg, J. H.; Qintero, J. C.; Schleif, W. A.; Emini, E.
A.; Anderson, P. S. J. Med. Chem. 1992, 35, 3792–3802;
(d) Sari, J. S.; Williams, T. M.; Bamberger, D. L.; Fisher,
T. E.; Hoffman, J. M.; Hudcosky, R. J.; MacTough, S. C.;
Rooney, C. S.; Saari, W. S.; Thomas, C. M.; Goldman, M.
E.; OꢀBrien, J. A.; Emini, E. A.; Nunberg, J. H.; Quintero,
J. C.; Schleif, W. A.; Anderson, P. S. J. Med. Chem. 1993,
36, 249–255; (e) Hoffman, J. M.; Smith, A. M.; Rooney, C.
S.; Fisher, T. E.; Wai, J. S.; Thomas, C. M.; Bamberger,
D. L.; Barnes, J. L.; Williams, T. M.; Jones, J. H.; Olson,
B. D.; OꢀBrien, J. A.; Goldman, M. E.; Nunberg, J. H.;
Quintero, J. C.; Schleif, W. A.; Emini, E. A.; Anderson, P.
S. J. Med. Chem. 1993, 36, 953–966; (f) Nunberg, J. H.;
Schleif, W. A.; Boots, E. J.; OꢀBrien, J. A.; Quintero, J. C.;
Hoffman, J. M.; Emini, E. A.; Goldman, M. E. J. Virol.
1991, 65, 4887–4892.
4. (a) Merluzzi, V. J.; Hargrave, K. D.; Labadia, M.;
Grozinger, K.; Skoog, M.; Wu, J. C.; Shin, C.-K.; Eckner,
K.; Hattox, S.; Adams, J.; Rosethal, A. S.; Faanes, R.;
Ecknert, R. J.; Koup, R. A.; Sullivan, J. L. Science 1990,
250, 1411–1413; (b) Hargrave, K. D.; Proudfoot, J. R.;
14. Moog, C.; Wick, A.; Le Ber, P.; Kim, A.; Aubertin, A. M.
Antiviral Res. 1994, 24, 275–288.