Synthesis of benzo-, pyrido-, thieno- and imidazo-fused N-hydroxy-4-oxopyrimidine-2-carboxylic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.12.033

N-Hydroxy-4-oxoquinazoline-2-carboxamide derivatives (cyclic hydroxamic acids) and related pyrido- and thieno-substituted analogues, as well as a N-hydroxyhypoxanthine-2-carboxamide were synthesised for the first time, by means of a four-step sequence tha

Full text of DOI:10.1016/j.tetlet.2010.12.033

Tetrahedron Letters 52 (2011) 753–756
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Tetrahedron Letters
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Synthesis of benzo-, pyrido-, thieno- and imidazo-fused
N-hydroxy-4-oxopyrimidine-2-carboxylic acid derivatives
Lluís Bosch a, Jean-François Mouscadet b, Xio-Ju Ni b, Jaume Vilarrasa a,
⇑
a Departament de Química Orgànica, Facultat de Química, Universitat de Barcelona, Diagonal 647, 08028 Barcelona, Catalonia, Spain
b LBPA, CNRS, École Normale Supérieure de Cachan, 94235 Cachan, France
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Hydroxy-4-oxoquinazoline-2-carboxamide derivatives (cyclic hydroxamic acids) and related pyrido-
and thieno-substituted analogues, as well as a N-hydroxyhypoxanthine-2-carboxamide were synthesised
for the first time, by means of a four-step sequence that involves a smooth reaction of aminohydroxa-
mates with methyl trimethoxyacetate. Other strategies were unsuccessful.
Received 11 November 2010
Revised 2 December 2010
Accepted 7 December 2010
Available online 13 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Fused N-hydroxypyrimidin-4-ones
Methyl trimethoxyacetate
Amidation of esters
Raltegravir (Isentress, MK-0518), developed by Merck, is the
first HIV-1 integrase inhibitor (INI) approved by the FDA.1 Raltegra-
vir and its congeners (Fig. 1),1b,c elvitegravir (Gilead) and S/GSK
candidates have similar pharmacophoric elements and mechanism
of action.1d,e
position 2 hampered the N-oxidation. Although we achieved the
conversion of X = CN into X = COOMe with NaOMe in MeOH at
50 °C, the methoxy group could not be replaced by the 4-fluoro-
benzylamino group (a substitution that was very easy when the
N-oxide substituent was absent). Moreover, whereas deamination
of adenine derivatives (to obtain hypoxanthine derivatives) was
quite efficient in our hands, either with adenosine deaminase or
via nitrosation, the N-oxide derivatives did not react. In short,
the route via formation of N-oxides is not feasible.
Approach b involved a ring opening–ring closing process by
using hydroxylamine (or a protected derivative of it, such as
NH2OBn or NH2OTr) to attack the oxazinones of Scheme 1. We pre-
pared the corresponding imidazo-oxazinone6 by the treatment of
the o-amino carboxylic acid with a large excess of ClCOCOOMe
The interest of some of us in hydroxamates2a and the well-
known chelating power of hydroxamic acids2b prompted us to pro-
pose alternative candidates based on the replacement of the C–OH
group of raltegravir by a N–OH group, which would enhance the
acidity of the OH proton and would improve the coordination with
magnesium ions. Thus, we designed N-hydroxypyrimidinone
derivatives as shown in Figure 1 (bottom). The challenge was to de-
velop a general approach, as simple as possible, to these unknown
molecules.
The strategies analysed by us at the beginning of our project are
summarised in Scheme 1. In the first approach (a), we envisaged
the N-oxidation of N3 of 4-amino-pyrimidines and of N1 of ade-
O
O–K+
nine,3 where the
p-electron donating ability of the amino group
N
N
N
F
O
N
F
is crucial for the formation of the N-oxide. The subsequent deam-
ination, either enzymatically or via diazotization,4 should afford
the desired N-hydroxy pyrimidones (cyclic hydroxamic acids).
While 2-cyano derivatives of adenine and adenosine (Scheme 1,
top, X = CN)5 gave the N-oxide in acceptable conversions (with a
large excess of m-CPBA in CH2Cl2, as the reagent of choice among
eight reagents examined), the corresponding methyl ester
(X = COOMe) and amide (X = CONHCH2C6H4F = CONH-4-FBn) did
not. In other words, a slight increase in the steric hindrance at
O
N
HN
Raltegravir
O
O
N
O
N
OH
OH
N
O
O
N
O
S
F
F
O
O
N
HN
N
N
HN
N
O
O
4
OH
R'
3
N
2
1
N
O
R
HN
⇑
Corresponding author. Tel.: +34 93 4021258, fax: +34 93 3397878.
E-mail address: jvilarrasa@ub.edu (J. Vilarrasa).
Figure 1. Raltegravir and two examples of congeners. N-Hydroxypyrimidin-4-one
derivatives proposed as alternative candidates.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.033

754
L. Bosch et al. / Tetrahedron Letters 52 (2011) 753–756
NH2
NH2
N
and 2f were readily separated by column chromatography). On the
O–
X
+
other hand, owing to the decomposition of amino esters 1i and 1j
in strong basic media, we prepared 2i and 2j by the standard
coupling of the corresponding amino acids with O-(4-methoxyben-
zyl)hydroxylamine (NH2OPMB) and 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide (EDC).12
We then subjected 2a and (MeO)3CCOOMe excess to a screening
of solvents, acid catalysts, temperatures and reaction times. Most
relevant results are shown in Table 1.
Acid catalysis was required, as expected for an orthoester, to
achieve the complete conversion of 2a into 3a. Not only TsOH
and Lewis acids were active, in several solvents (see entries 2–10
of Table 1) but also weaker acids such as AcOH could be used
(entry 11). With 2 mol % of TsOH in refluxing CH3CN (entry 12),
the cyclisation occurred in 4 h.
N
N
N
X
X = I, CN, COOMe,
CONH-4-FBn
X = CN, COOMe
a
O
O
O
N
OH
N
O-PG
OMe
b
d
N
O
H
O
O
F
NH2
N
O
HN
OMe
MeO
OMe
OMe
c
O
O
O
O-PG
OH
NH2
OMe
NH2
N
H
NH2
X
O
O
OMe
This cyclisation or condensation is general, as it could be ap-
plied to 2-aminohydroxamates 2b–f, to aminopyridines 2g and
2h and to thiophene derivatives 2i and 2j, as indicated in Table
2, with some adaptations. Afterwards, the ester groups of 3a–j
were transformed into carboxamides 4a–j,13 which were subjected
to the cleavage of the O–PMB bond with TFA, to give the desired
cyclic hydroxamic acids, 5a–j.
X = OMe, 4-FBn, Cl
Scheme 1. Retrosynthetic analysis of N-hydroxypyrimidin-4-ones.
and DIPEA in CH3CN. Opening with hydroxylamine derivatives
gave mixtures coming from the attack of the hydroxylamines at
the diverse electrophilic positions. Moreover, heating the open
compounds in Ac2O gave rise to degradation compounds.
Finally, we obtained N-hydroxyhypoxanthine 5k14 in three
high-yielding steps from 2k as detailed in Scheme 3.
According to disconnection c, the hydroxamates (PG = Bn or PG
= 4-methoxybenzyl = PMB), prepared from the amino ester, ben-
zylamine or 4-methoxybenzylamine and LiN(SiMe3)2 (LiHMDS)
were heated with dimethyl oxalate and NaOEt,7 in search of direct
cyclisation. Only starting material was recovered. Heating with
MeOCO-CONH-4-FBn was also unsuccessful. With ClCOCOOMe
and DIPEA or in pyridine, mainly the O-acylation occurred. On
the other hand, with K2CO3 or with DMAP, NHCOCOOMe deriva-
tives were obtained, but their cyclisation to N-hydroxypyrimidi-
nones under several dehydrating conditions did not take place.
Among all the approaches that we attempted only that one indi-
cated as d in Scheme 1 turned out to be productive. Although the
reaction of vicinal amino carboxamides with alkyl orthoformates
such as CH(OR)3 is classical8 and orthoesters such as methyl
2,2,2-trimethoxyacetate9 have been used with vicinal diamines
or aminophenols,9d,e there are no reported precedents, according
to a SciFinder search, of the reaction of amino hydroxamates with
this oxalic acid orthoester. We first examined the conversion of
amino ester 1a (methyl anthranilate) into benzohydroxamate 2a
(Scheme 2). An excess of a strong base such as LiHMDS was re-
quired.10 With a stronger base such as LDA the reaction was even
faster.10 Without the strong base the reaction did not progress,
even in refluxing 1,4-dioxane. The more general conditions starting
from amino esters 1a–e, the analogous pyridines 1g and 1h and
the methyl 5-aminoimidazole-4-carboxylate 1k11 are shown in
Scheme 2, which gave rise to good-to-excellent yields of hydroxa-
mates of type 2 (in the case of 1e, a mixture was obtained, but 2e
Samples of the molecules thus prepared (5a, 5e, 5f and 5k) were
tested as inhibitors of the 3’-processing and strand transfer activi-
ties of HIV-1 integrase at a single 10
lM concentration, with regard
to raltegravir;15a unfortunately, no activity was observed. They also
appeared to be inactive for concentrations up to 10
antiviral, single-round-of-infection assay.15b
lM in an HIV-1
In summary, we have synthesised new benzo-, pyrido-, thieno-
and imidazo-fused N-hydroxypyrimidinones (quinazolinone,
pyridopyrimidinone, thienopyrimidinone and hypoxanthine ring
systems) with carboxyl derivatives at position 2. The optimized se-
quence involves the reaction of ester groups with NH2OPMB and a
strong base (LDA or LiHMDS) as well as a crucial acid-catalysed
condensation of these amino hydroxamates with methyl trim-
ethoxyacetate, which has been carefully investigated to provide
Table 1
Survey of cyclisation conditionsa
O
O
N
OPMB
NHOPMB
catalyst
N
+
3 MeOH
+ (MeO)3CCOOMe
(n equiv)
solvent
NH2
COOMe
temp., time
2a
3a
Entry
n
Catalyst (mol %) Solvent
Temp. (°C) Time (h) Yield (%)
1
2
3
4
5
6
7
8
2.5
—
DMF
90
20
20
80
20
80
80
90
15
4
4
0.5
4
0.5
0.5
0.5
0.5
3
61
95
97
96
96
95d
98
98
97
97
98
98
2.0 TsOH (10)b
2.5 BF3ÁEt2O (10)
2.5 BF3ÁEt2O (10)
2.5 Sc(OTf)3 (10)c
2.5 Sc(OTf)3 (10)
2.5 TsOH (10)
2.5 TsOH (10)
2.5 TsOH (10)
2.5 TsOH (10)
2.5 AcOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
Dioxane 90
Toluene 90
90
O
O
O
R'
R
R'
R
NH2OPMB
NHOPMB
OMe
NHOPMB
LiHMDS
THF, 0 ºC, 2 h
or
NH2
2g, 92—95%
N
NH2
NH2
9
2a, 90—92%
2b, 85—90%
2c, 84—86%
2d, 91—95%
2e, 50—55%
1a, R = R' = H
1b, R = H, R' = Br
1c, R = R' = OMe
1d, R,R' = benzo
LDA, —78 ºC/
—10 ºC, 0.5 h
THF
10
11
12
O
0.5
4
NHOPMB
2.0 TsOH (2)
CH3CN
80
1e, R = COOMe, R' = H
N
NH2
2h, 90—92%
+ 2f, R =CONHOPMB, 35%
a
b
c
From 1 mmol of 2a in 10 mL of solvent.
TsOH means commercially available 4-toluenesulfonic acid-hydrate.
Scandium trifluoromethanesulfonate of 99% purity. In trials with 1 mol % of
O
O
O
NHOPMB
NHOPMB
N
NHOPMB
NH2
2k, 86—90%
TfOH, under the conditions of entry 5, only a conversion of 10% was noted after
72 h. Thus, the activity of Sc(OTf)3 is not due to the possible content of TfOH as
impurity.
N
4-FBn
NH2
S
NH2
S
2i
2j
d
The O–PMB bond was cleaved under these conditions: the yield refers to PMB-
deprotected 3a.
Scheme 2. Amino hydroxamates 2a–k.

L. Bosch et al. / Tetrahedron Letters 52 (2011) 753–756
755
Table 2
Acknowledgements
From amino esters 2a–j to quinazolinones 5a–f, pyridopyrimidinones 5g and 5h and
thienopyrimidinones 5i and 5ja
This study was started with funds from the FP6 of the European
Union Commission, within the TRIoH project (LSHB-CT-2003-
503480, 2004–2007), which included a studentship to L.B. during
this period and from a Spanish Government grant SAF2005-
24643-E (2006 and 2007). During 2008 and part of 2009, L.B.
enjoyed a fellowship from the Fundació Bosch Gimpera. X.J.N. is
a fellow of East China Normal University (ECNU, Shangai). Related
preliminary experiments on the formation of N-oxides by I. Cialicu
and M. Rosa, as DEA students (Universitat de Barcelona), are also
acknowledged.
O
N
O
N
(MeO)3CCOOMe
(2.5 equiv)
OPMB
COY
OH
N
N
2a—j
TsOH (10 mol%)
CH3CN, 80 ºC, 0.5 h
CONH-4-FBn
3a—j, Y = OMe
5a—j
4-FC6H4CH2NH2 (1.2 equiv)
CH3CN, 80 ºC, 6 h
TFA—CH2Cl2 (1:4)
PhOMe, rt, 0.5 h
4a—j, Y = NH-4-FBn
a—c, e, f = benzo seriesa g, h = pyrido series
d = naphtho series
i, j = thieno series
Entry Step 1
Yield (%) Step 2
Yieldb (%) Step 3
Yield (%)
1
2
3
4
5
6
7
8
9
10
2a to 3a
2b to 3b
2c to 3c
95–98
98
92
3a to 4a
3b to 4b 86
3c to 4c 87
3d to 4d 85
91
4a to 5a
4b to 5b
4c to 5c
95
92
90
References and notes
1. Raltegravir is commercialised as its potassium salt due to its better
pharmacokinetic profile. See: (a) Summa, V.; Petrocchi, A.; Bonelli, F.;
Crescenzi, B.; Donghi, M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Gonzalez Paz, O.;
Hazuda, D. J.; Jones, P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi,
E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.; Witmer, M. V.;
Rowley, M. J. Med. Chem. 2008, 51, 5843–5855 (discovery of raltegravir); (b)
Nizi, E.; Orsale, M. V.; Crescenzi, B.; Pescatore, G.; Muraglia, E.; Alfieri, A.;
Gardelli, C.; Spieser, S. A. H.; Summa, V. Bioorg. Med. Chem. Lett. 2009, 19, 4617–
4621. and references cited therein; (c) Ferrara, M.; Fiore, F.; Summa, V.;
Gardelli, C. Bioorg. Med. Chem. Lett. 2010, 20, 5031–5034; for very recent,
representative reviews, see: (d) Vandekerckhove, L. P. R.; Christ, F.; Debyser, Z.;
Owen, A.; Back, D.; Voet, A.; Schapiro, J.; Vogelaers, D. Antiviral Res. 2009, 71–
79; (e) Metifiot, M.; Marchand, C.; Maddali, K.; Pommier, Y. Viruses 2010, 2,
1336–1347.
2. In connection with total syntheses of natural products: (a) Olivella, A.;
Rodríguez-Escrich, C.; Urpí, F.; Vilarrasa, J. J. Org. Chem. 2008, 73, 1578–1581.
and references therein; For a review, see: (b) Codd, R. Coord. Chem. Rev. 2008,
252, 1387–1408.
3. For N-oxidations with mCPBA, see: (a) Nowak, I.; Cannon, J.; Robins, M. Org.
Lett. 2006, 8, 4565–4568; (b) Saladino, R.; Carlucci, P.; Danti, M.; Crestini, C.;
Mincione, E. Tetrahedron 2000, 56, 10031–10037; with other oxidizing agents:
(c) Rong, D.; Philips, V.; Rubio, R.; Castro, M.; Wheelhouse, R. Tetrahedron Lett.
2008, 49, 6933–6935; (d) Zhu, X.; Kreutter, K.; Hu, H.; Player, M.; Gaul, M.
Tetrahedron Lett. 2008, 49, 832–834.
2d to 3d 85
4d to 5d 90
2e to 3e
2f to 3f
2g to 3g
89
3e to 4e
3f to 4f
3f to 4g
89
93
85
4e to 5e
4f to 5fc
4g to 5g
4h to 5h 92
4i to 5i
4j to 5j
95
97
87
91
90d
2h to 3h 85e
3h to 4h 85
2i to 3i
2j to 3j
92f
90f
3i to 4i
3j to 4j
70g
75g
90
92
a
b
c
See Scheme 2 for the substituents (groups/rings).
Similar results in refluxing THF.
The CONHOPMB group at position 4 of the aromatic ring was also cleaved to
CONHOH.
d
120 mol % of TsOHÁH2O was required in this case, owing to the basicity of the 2-
aminopyridine moiety. Refluxing AcOH was not sufficient whereas heating at
140 °C (MW) gave rise to degradation. On the other hand, heating overnight with
10 mol % of BF3, at 80 °C in a closed vial caused an almost complete disappearance
of 2g (to give in 80% isolated yield the desired 3g).
e
This cyclisation was performed in refluxing AcOH.
For 2 h in refluxing CH3CN.
With 220 mol % of 4-FBnNH2 and dropwise addition of 200 mol % of LDA, in THF
f
g
at À78 °C, stirring for 4 h. Heating with 4-FBnNH2 (as in entries 1–8) gave rise to
decarboxylation.
4. For deamination studies, see: (a) Charafeddine, A.; Chapuis, H.; Strazewski, P.
Org. Lett. 2007, 9, 2787–2790; (b) Porcari, A.; Ptak, R.; Borysko, K.; Breitenbach,
J.; Drach, J.; Townsend, L. Nucleosides, Nucleotides Nucleic Acids 2003, 22, 2171–
2193. and references cited therein.
OMe
OMe 3.73
163.3
3.83
55.3
5. We prepared them as follows: conversion of protected guanosines to 2-amino-
6-chloropurine derivatives, diazotization to yield 6-chloro-2-iodo analogues,
replacement of iodide with cyanide (with CuCN, in the presence of Pd(0)/
Xantphos), and amino-dechlorination. We introduced the amino group on C6
with NH3/1,4-dioxane (without concomitant deacetylation of tri-O-
acetyladenosines). See: (a) Grunewald, C.; Kwon, T.; Piton, N.; Forster, U.;
Wachtveitl, J.; Engels, J. W. Bioorg. Med. Chem. 2008, 16, 19–26; (b) Ohno, M.;
Gao, Z.-G.; Van Rompaey, P.; Tchilibon, S.; Kim, S.-K.; Harris, B. A.; Gross, A. S.;
Duong, H. T.; Van Calenbergh, S.; Jacobson, K. A. Bioorg. Med. Chem. 2004, 12,
2995–3007; (c) Sakamoto, T.; Ohsawa, K. J. Chem. Soc., Perkin Trans. 1 1999,
2323–2326 (this method, reported for aromatic rings, was the most efficient in
our hands).
6. (a) Nouira, I.; Kostakis, I. K.; Dubouilh, C.; Chosson, E.; Iannelli, M.; Besson, T.
Tetrahedron Lett. 2008, 49, 7033–7036; (b) Kalusa, A.; Chessum, N.; Jones, K.
Tetrahedron Lett. 2008, 49, 5840–5842. and references cited therein; (c)
Brunton, S. A.; Stibbard, J. H. A.; Rubin, L. L.; Kruse, L. I.; Guicherit, O. M.;
Boyd, E. A.; Price, S. J. Med. Chem. 2008, 51, 1108–1110; (d) Vostrov, E. S.;
Novikov, A. A.; Maslivets, A. N.; Aliev, Z. G. Russ. J. Org. Chem. 2007, 43, 224–227.
7. For the condensation of 2-aminobenzamides with diethyl oxalate or
MeOCOCOCl, see: (a) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. J. Org. Chem. 2007, 72,
6270–6272; (b) Mason, J. J.; Bergman, J. Org. Biomol. Chem. 2007, 5, 2486–2490;
(c) Shemchuk, L. A.; Chernykh, V. P.; Arzumanov, P. S.; Starchikova, I. L. Russ. J.
Org. Chem. 2007, 43, 1830–1835. and references therein; (d) Chavan, S. P.;
Sivappa, R. Tetrahedron Lett. 2004, 45, 997–999.
55.0
O
5.38
79.9
153.0
160.2
159.0
O
O
N
N
H
4.74
76.7
7.19
O
N
(MeO)3CCOOMe
143.5
N
7.79
NH210.56
146.4
140.9
N
160.6
TsOH (cat.)
CH3CN
80 ºC, 1 h
N
5.05
44.8
5.90
N
3.98
COOMe 53.7
5.30
46.9
2k
3k
DMSO-d6
162.7
CDCl3
F
161.5
95%
F
(J = 244 Hz)
F
H2N 3.84
161.7
CH3CN, 80 ºC, 6 h
90%
45.7
OMe
3.87
153.4 O
N
5.24
80.4
55.6
153.8
160.2
O
12.05
TFA–CH2Cl2
OH
N160.2
O
N
N
N
8.28
141.7
1:4
8.06
149.1
161.O0
HN
F
149.8
F
141.1
O
N
N
PhOMe
rt, 0.5 h
N
161.6
5.36
45.7
5.11
47.4
HN
162.1
9.36
4.46
41.3
8.07
4.63
43.2
92%
F
F
5k
4k
162.8
161.2
DMSO-d6
CDCl3
Scheme 3. From 2k to 5k. Chemical shifts (dH in regular type, dC in italics).
8. (a) Heravi, M. M.; Sadjadi, S.; Haj, N. M.; Oskooie, H. A.; Shoar, R. H.;
Bamoharram, F. F. Tetrahedron Lett. 2009, 50, 943–945; (b) Dabiri, M.; Salehi, P.;
Mohammadi, A. A.; Baghbanzadeh, M. Synth. Commun. 2005, 35, 279–283. and
references cited therein.
9. Prepared according to: (a) Barrett, A. G. M.; Carr, R. A. E.; Attwood, S. V.;
Richardson, G.; Walshe, N. D. A. J. Org. Chem. 1986, 51, 4840–4856; we have
found (SciFinder search) a study dealing with a related cyclisation, with 2-
aminobenzamide and (EtO)3CCOOEt, in 24% yield: (b) Musser, J. H.; Hudec, T.
T.; Bailey, K. Synth. Commun. 1984, 14, 947–953. this outcome may have
discouraged the use of such orthoesters; cf. (c) Aliabiev, S. B.; Bykova, R. V.;
Kravchenko, D. V.; Ivachtchenko, A. V. Lett. Org. Chem. 2007, 4, 273–280
(isoxazole derivatives and (EtO)3CCOOEt at 120 °C); (d) Boyle, K. E.; MacMillan,
K. S.; Ellis, D. A.; Lajiness, D. A.; Robertson, W. M.; Boger, D. L. Bioorg. Med. Chem.
Assignments confirmed by 2D NMR (HSQC).
excellent yields of the cyclic compounds under very mild condi-
tions. Overall, the protocol reported herein for the first time for
the synthesis of N-hydroxypyrimidinones 5a–k (four-steps, most
of them in 85–98% yields, up to 76% overall yield) appears to be
of wide scope. In short, in the unsuccessful search for new antiviral
drugs we have developed the best procedure to date for reaching
hitherto unknown pyrimidinone-2-carboxylic acid derivatives,
which may enjoy other applications.16

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L. Bosch et al. / Tetrahedron Letters 52 (2011) 753–756
Lett. 2010, 20, 1854–1857; (e) Venable, J. D.; Kindrachuk, D. E.; Peterson, M. L.;
Edwards, J. P. Tetrahedron Lett. 2010, 51, 337–339 and references therein.
14. Compound 5k: mp 262.5–264.0 °C (dec); 1H NMR (400 MHz, DMSO-d6) d 4.46
(d, J = 6.1 Hz, 2H), 5.36 (s, 2H), 7.19 (m, 4H), 7.39 (m, 4H), 8.28 (s, 1H), 9.36 (t,
J = 6.1 Hz, 1H), 12.05 (s, 1H); 13C NMR (100.6 MHz, DMSO-d6) d 41.3, 45.7,
115.0 (d, J = 21.4 Hz), 115.5 (d, J = 21.5 Hz), 123.5, 129.1 (d, J = 8.2 Hz), 129.7 (d,
J = 8.4 Hz), 132.6 (d, J = 3.0 Hz), 134.3 (d, J = 3.0 Hz), 141.7, 144.9, 149.1, 153.4,
10. Optimized conditions: 1.5 equiv of PMBONH3+ClÀ plus 4.5 equiv of LiHMDS (at
0 °C for 2 h) or 4.1 equiv of LDA (from À78 °C to À10 °C, 0.5 h); yields were
similar. We could also prepare 2-aminobenzohydroxamic acid (deprotected
2a) by treatment of 1a with a very large excess of NH2OH/MeOH in a sealed
tube, but this procedure failed with the less reactive esters of our series. For
direct substitutions of NHOH for OMe, see: (a) Griffith, D.; Krot, K.; Comiskey,
J.; Nolan, K. B.; Marmion, C. J. Dalton Trans. 2008, 137–147. and references cited
therein; (b) Riva, E.; Gagliardi, S.; Mazzoni, C.; Passarella, D.; Rencurosi, A.;
Vigo, D.; Martinelli, M. J. Org. Chem. 2009, 74, 3540–3543; for the direct
substitution of NHOBn for OMe, see: (c) Gissot, A.; Volonterio, A.; Zanda, M. J.
Org. Chem. 2005, 70, 6925–6928; (d) Guzzo, P. R.; Miller, M. J. J. Org. Chem.
1994, 59, 4862–4867.
160.2, 161.2 (d, J = 242.4 Hz), 161.6 (d, J = 244.0 Hz); HMRS (ESI, m/z), calcd for
+
C
20H16F2N5O3 (M+H+) 412.1216, found 412.1204.
15. Under the following conditions: 100 nM of HIV-1 IN (B strain), 10 mM MgCl2,
pH 7.0, 37 °C, see: (a) Deprez, E.; Barbe, S.; Kolaski, M.; Leh, H.; Zouhiri, F.;
Auclair, C.; Brochon, J. C.; Le Bret, M.; Mouscadet, J. F. Mol. Pharmacol. 2004, 65,
85–98. raltegravir afforded an IC50 value of 40 nM; (b) Delelis, O.; Malet, I.; Na,
L.; Tchertanov, L.; Calvez, V.; Marcelin, A. G.; Subra, F.; Deprez, E.; Mouscadet, J.
F. Nucleic Acids Res. 2009, 37, 1193–1201. Stock solutions were prepared in
DMSO at concentrations of 10 mg/mL. HeLa-CD4+-b-gal reporter cells were
infected in triplicate with an amount of 3 ng of p24 antigen in the presence of
increasing concentrations of the drugs. The EC50 values were determined 48 h
post infection as the concentration of drug inhibiting b-galactosidase
production by 50% in comparison to results for the untreated infected cells;
11. Preparation of 1k according to procedures reported for related benzyl
derivatives: (a) Lin, X.; Robins, M. Collect. Czech. Chem. Commun. 2006, 71,
1029–1041. also see:; (b) Suwinski, J.; Szczepankiewicz, W.; Swierczek, K.;
Walczak, K. Eur. J. Org. Chem. 2003, 1080–1084. and references cited therein.
12. For standard 2-aminothiophene-3-carboxamides, see: Aurelio, L.; Valant, C.;
Figler, H.; Flynn, B. L.; Linden, J.; Sexton, P. M.; Christopoulos, A.; Scammells, P.
J. Bioorg. Med. Chem. 2009, 17, 7353–7361. and references cited therein.
13. For related amidations, see: Shemchuk, L. A.; Chernykh, V. P.; Kryskiv, O. S. Zh.
Org. Farm. Khim. 2005, 3, 9–12 (Chem. Abstr. 2005, 145, 314927).
raltegravir was used as
a control (EC50 = 10 nM). Cytotoxicities were
determined in parallel on uninfected cells.
16. Regarding 2-carboxyl or 2-carbonyl derivatives of pyrimidin-4-ones, 75
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