Routes to HIV-integrase inhibitors: efficient synthesis of bicyclic pyrimidones by ring expansion or amination at a benzylic position

Article abstract of DOI:10.1016/j.tetlet.2008.10.119

Ring expansion of [6,6] bicyclic pyrimidones led, through an aziridinium intermediate, to potent HIV-integrase inhibitors with a [7,6] core. A more flexible and diversity-oriented synthesis of functionalized pyrimidohexahydrodiazepines was then developed;

Full text of DOI:10.1016/j.tetlet.2008.10.119

Tetrahedron Letters 50 (2009) 148–151
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Routes to HIV-integrase inhibitors: efficient synthesis of bicyclic
pyrimidones by ring expansion or amination at a benzylic position
*
Maria del Rosario Rico Ferreira , Giuseppe Cecere, Paola Pace, Vincenzo Summa
Department of Medicinal Chemistry, IRBM-MRL, via Pontina Km 30600, 00040 Pomezia (Rome), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Ring expansion of [6,6] bicyclic pyrimidones led, through an aziridinium intermediate, to potent HIV-
integrase inhibitors with a [7,6] core. A more flexible and diversity-oriented synthesis of functionalized
pyrimidohexahydrodiazepines was then developed; the key benzylic substituent was introduced in one
pot by using sequentially DDQ and BnMeNH. Both synthetic routes are described.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 24 July 2008
Revised 20 October 2008
Accepted 22 October 2008
Available online 30 October 2008
Keywords:
Aziridinium
Ring expansion
Pyrimidohexahydrodiazepines
DDQ
Cl
OH
N
In our drug discovery project on HIV-integrase, bicyclic pyrim-
idones (1A in Fig. 1) were identified as potent inhibitors,1 and we
reasoned that an additional heteroatom in the tetrahydropyridine
ring would give us another handle to modulate the physico-chem-
ical properties of this class of compounds. With this idea in mind
we started the synthesis of tetrahydropirazopyrimidones 1B.
The fused bicyclic core was obtained in five steps as depicted in
Schemes 1 and 4 could be isolated in 44% yield from intermediate
OH
N
OH
OBz
N
OBn N
a-d
CO2Me
HN
O
F
HN
N
NHBoc
OBn
2
3
O
N
O
OH
OH
2
2 without the need to purify at intermediate stages using the fol-
N
N
O
HN
e)
O
lowing sequence: reaction with 2 equiv of p-fluorobenzylamine
both formed the carboxamide and cleaved the benzoate-protecting
group. TFA promoted removal of the Boc group then afforded the
free amine. Imine formation by reaction with 1 equiv of chloro-
acetaldehyde and removal of volatiles, followed by reduction in
MeOH then gave crude 3. Base-mediated cyclization, followed by
chromatographic purification, afforded 4. After protection of the
secondary amine as a carbamate and deprotection of the benzyl
group by hydrogenation, the primary alcohol 5 was activated as
Boc
N
HN
f, g
HN
OH
OBn
5
4
F
F
O
O
N
OH
OH
N
N
N
N
N
O
N
O
Boc
h, i
N
O
O
N
HN
O
HN
b, j
OH
OH
N
N
H
n
H
N
N
N
R3
N
6
7
R2
O
Ar
R1
O
Ar
F
F
1B
1A (n=0-2)
Scheme 1. Reagents and conditions: Tetrahydropirazopyrimidones: synthetic
scheme and conditions. (a) 4-Fluorobenzylamine, MeOH, rt; (b) TFA, DCM; (c) aq
ClCH2CHO, CH(OMe)3; (d) NaCNBH3, AcOH, MeOH; (e) t-BuOK, dioxane, reflux; (f)
Boc2O, MeOH; (g) 10% Pd/C, H2, MeOH; (h) MsCl, TEA, CHCl3; (i) 2 M Me2NH, THF, rt;
(j) Ac2O, TEA, DCM.
Figure 1.
* Corresponding author. Tel.: +39 0691093560; fax: +39 0691093654.
E-mail address: ricoferreiram@yahoo.es (M. d. R. R. Ferreira).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.119

M. d. R. R. Ferreira et al. / Tetrahedron Letters 50 (2009) 148–151
149
O
N
O
O
N
O
OH
OH
OH
OH
N
N
N
N
P1
N
N
N
N
O
O
O
O
N
N
a, b
9a
?
HN
HN
HN
N
HN
N
c
a, b
N
O
OH
R
P2
4
Bn
Ar
Versatile intermediate
R
9a: R=Me
9b: R=H
8
R= Me, CONMe2
F
F
F
Scheme 4. Reagents and conditions: Final steps and an alternative intermediate to
this class of compounds. Reagents and conditions: (a) 10% Pd/C, H2, MeOH, aq HCl;
(b) ClCOR, TEA, DCM.
Scheme 2. Pyrimidohexahydrodiazepines by ring expansion of the [6,6] system.
Reagents and conditions: (a) aq HCHO, AcOH, NaCNBH3, MeOH; (b) 10% Pd/C, H2,
MeOH; (c) MsCl, TEA, CH3CN, 0 °C to rt; then MeBnNH (or BnNH2 for 9b), 60 °C.
ble bond (intermediate compatible with mass spectrum) would
lead to the expected [6,6] bicyclic system.
the corresponding mesylate. Displacement with dimethylamine
went cleanly to give 6; Boc cleavage and final acetylation then
led to isolation of 7.3
To finish the synthesis, the benzyl group of 9a was removed by
hydrogenation, and the exocyclic amine was acylated as shown in
Scheme 4 to provide the first analogs in the series. Preliminary SAR
proved sufficiently encouraging to warrant a more extensive
exploration of this novel structural class.
To facilitate a more complete SAR, a better synthesis of a more
versatile intermediate (Scheme 4) with the [7,6] core was needed,
ideally fulfilling the following requirements:
The scaffold 1B is versatile, opening up the possibility for di-
verse functionalization of the endo- and exo-cyclic amines. We
decided to evaluate analogs complementary to 7, bearing the basic
amine on the core and an acyl substituent at the outside of the ring.
To this end, amine 4 was methylated by reductive amination, fol-
lowed by hydrogenation of the benzyl ether, mesylation and reac-
tion with MeBnNH; but to our initial surprise instead of the
anticipated [6,6] system, a hexahydrodiazepine was obtained in
this case (Scheme 2).
(1) Flexibility: potential for the introduction of diversity
(orthogonal P1, P2, and formation of the carboxamide as late
as possible).
(2) Acceptable overall yield.
(3) Trouble-free purification of intermediates (suitable for
multi-gram scale).
Under optimized reaction conditions, bis-amine 9a was isolated
in ca. 25% yield from primary alcohol 8.4 Furthermore, use of differ-
ent amines was disappointing: benzylamine afforded only 15% of
9b, and similar or lower yield resulted when aliphatic primary
amines (e.g., cyclohexyl and benzyl) were used.
A potential rationale for this (not entirely unexpected5) finding,
can be found by invoking the participation of the ring nitrogen to
form an aziridinium ion (path a, Scheme 3) from mesylate 10a.
The corresponding quinoid-like species depicted in Scheme 3 could
also be involved in this reaction.
Based on our previous experience,6 we decided to use N-Boc-4-
piperidone as the starting material. Lactam 11 was prepared by
Beckmann rearrangement according to a published procedure,7
and then converted to amidoxime 12 and reacted with DMDA un-
der conditions previously optimized6,8 to afford 13 in 19% overall
yield on a 25 g scale ( Scheme 5). Conveniently, for large-scale
purposes, no chromatography was needed to obtain pure 13.
For carbamate 10b this mechanism is unlikely, due to the elec-
tron-withdrawing nature of the carbamate; elimination seems to
take place (path b, Scheme 3), and addition of the amine to the dou-
O
N
O
O
O
F
N
OMs
F
H
N
O
N
N
N
H
OH
N
N
R1
N
N
H
N
path a
R2NH2
N
O
O
OMs
O
F
O
NH
N
R2
10a (R1=M e), 10b (R1=Boc)
H
N
N
N
O
F
R2NH2
BocN
path b
O
N
O
OH
F
OH
F
N
N
H
H
BocN
N
N
N
O
NHR2
O
Scheme 3. The two different reaction pathways leading to either [7,6] or [6,6] system depending on the nature of R1.

150
M. d. R. R. Ferreira et al. / Tetrahedron Letters 50 (2009) 148–151
O
NH
a, b
BocN
c, d
O
N
BocN
O
OH
OMe
N
O
OH
OMe
BocN
N
11
BocN
N
O
O
O
Cl
Cl
O
X
OH
OMe
CN
15a X=H
15b X=DDHQ
N
NH
e, f
BocN
BocN
16
OH
N
CN
N
HO
O
12
13
Figure 2. A possible intermediate in the formation of 14 is derivative 16. 15a and
15b were identified as by-products of the reaction.
Scheme 5. Pyrimidohexahydrodiazepine core from commercially available, N-Boc-
4-piperidone. Reagents and conditions: (a) NH2OH (1.2 equiv), MeOH, 55 °C, 2 h; (b)
TsCl, (1.5 equiv), K2CO3 (2.5 equiv), DME/water 1.5:1, 82 °C, 3 h; (c) P4S10
(0.2 equiv), hexamethyldisiloxane (2 equiv), DCM, 1 h; (d) NH2OH (1.2 equiv),
MeOH, 55 °C, 2 h; (e) Dimethyl acetylenedicarboxylate, CH3CN; (f) Xylenes, 145 °C.
diates such as 16, in which there is a covalent bond between DDQH
and the substrate, have been proposed.11b
Even though the use of other nucleophiles was less successful,12
14 itself still represents a versatile intermediate since it bears three
orthogonal-protecting groups (carbamate, benzyl amine and
methyl ester). Thus, R1, R2, and Ar groups could be incorporated
sequentially passing via through either 19 or 21 (Scheme 7) as
appropriate, based on the SAR requirements. Details of these
studies will be reported in due course.13
Despite being precedent with related pyrimidone substrates,9
attempts to functionalize the benzylic position via bromination
failed, resulting only in Boc deprotection under forcing conditions.
We turned our attention to DDQ ( Scheme 6) because of its
known ability to selectively oxidize activated benzylic positions.
We optimized the reaction conditions using different stoichio-
metries of the reagent, and we found that upon treating 13 with
2.1 equiv of DDQ and 6 equiv of benzylmethylamine the desired
amine 14 was obtained in greater than 50% yield.10
Acknowledgements
We thank Silvia Pesci and Edith Monteagudo for the assignment
of several compounds with [7,6] cores. We also thank Ian Stansfield
for revision of this manuscript.
During these trials, we discovered two main side products that
were characterized as 15a and 15b, excess of the nucleophile being
essential to minimize their formation (Fig. 2).
It is generally accepted that quinones (Q) react with C–H bonds
abstracting a hydrogen to give a radical, a second electron is
transferred from the quinol radical (QH.) to form a carbocation or
a donor–acceptor complex.11a However, also electrophilic interme-
References and notes
1. Muraglia, E.; Kinzel, O. D.; Gardelli, C.; Crescenzi, B.; Donghi, M.; Ferrara, M.;
Nizi, E.; Orvieto, F.; Pescatore, G.; Laufer, R.; Gonzalez-Paz, O.; Di Marco, A.;
Fiore, F.; Monteagudo, E.; Fonsi, M.; Felock, P. J.; Rowley, M.; Summa, V. J. Med.
Chem. 2008, 51, 861–874.
2. Gardelli, C.; Nizi, E.; Muraglia, E.; Crescenzi, B.; Ferrara, M.; Orvieto, F.; Pace, P.;
Pescatore, G.; Poma, M.; Rico Ferreira, M. R.; Scarpelli, R.; Homnick, C. F.;
Ikemoto, N.; Alfieri, A.; Verdirame, M.; Bonelli, F.; Gonzalez Paz, O.; Taliani, M.;
Monteagudo, E.; Pesci, S.; Laufer, R.; Felock, P. J.; Stillmock, K. A.; Hazuda, D.;
Rowley, M.; Summa, V. J. Med. Chem. 2007, 50, 4953–4975.
O
O
OH
3. Data for 7: 1H NMR (300 MHz, CD3CN) d 8.59 (1H, br s), 7.44–7.41 (2H, m), 7.13
(2H, t, J = 8.8 Hz), 5.73–5.69 (1H, m) 4.60 (2H, br s), 4.13–4.09 (1H, m), 4.04–
4.00 (1H, m), 3.97–3.90 (1H, m), 3.71–3.52 (3H, m), 2.99 (6H, br s), 2.17 (3H, s)
ppm; MS m/z: 418 (M+H)+.
N
OH
OMe
a
BocN
N
OMe
BocN
N
N
O
N
O
4. Experimental procedure: To a solution of starting 8 (662 mg, 1.7 mmol) in
chloroform (30 mL) and TEA (0.5 mL, 2.2 equiv), MsCl (0.15 mL, 1.2 equiv) was
added, and the mixture was stirred for 1 h at rt. Solvent was removed at 25 °C;
the residue (fully mesylated at primary alcohol and partly mesylated at
phenolic OH) was taken up in dry acetonitrile (30 mL) and treated with
methylbenzylamine (0.7 mL, 4 equiv) overnight at 70 °C. Volatiles were then
Bn
14
13
Scheme 6. Reagents and conditions: (a) DDQ (2–2.5 equiv), dioxane, reflux; then
MeBnNH (6 equiv), dioxane, 65 °C.
O
N
O
O
OH
1) 10% Pd/C, H2
OH
OH
OMe
1) ArCH2NH2
N
N
N
MeOH-aq HCl
H
BocN
BocN
HN
MeOH, r
OMe
N
Ar
2) R1COCl
TEA, DCM
N
N
2) TFA, DCM
O
O
O
N
N
N
R1
Bn
R1
19
18
14
R2CHO, NaCNBH3
MeOH, rt
1) TFA, DCM
2) R2CHO, NaCNBH3
MeOH, rt
O
N
O
O
ArCH2NH2
MeOH, reflux
OH
OH
N
OH
O
N
1) 10% Pd/C, H2
MeOH-aq HCl
2) R1COCl
TEA, DCM
R2
N
N
R2
N
R2
N
H
N
Ar
CO2Me
CO2Me
N
N
N
N
N
R1
R1
Bn
21
22
20
Scheme 7. Further transformations of key intermediate 14 leading to HIV-integrase inhibitors.

M. d. R. R. Ferreira et al. / Tetrahedron Letters 50 (2009) 148–151
151
removed under vacuum, and the residue was purified by RP-HPLC to afford,
after lyophilization, 190 mg (20%) of 9a. Data for 9a: 1H NMR (300 MHz,
CD3CN) d 8.21 (1H, br s), 7.54–7.34 (7H, m), 7.09 (2H, t, J = 8.8 Hz), 5.33 (1H, dd,
J = 17.0, 4.6 Hz) 5.17 (1H, d, J = 9.9 Hz), 4.69–4.48 (4H, m), 4.09 (1H, d,
J = 13.5 Hz), 3.93–3.82 (2H, m), 3.68–3.60 (1H, m), 3.34–3.26 (1H, m), 3.06
(3H,s), 3.04 (3H, s) ppm; MS m/z: 466 (M+H)+.
amine were evaporated, and the residue was taken up in MeOH, acidified with
AcOH and charged on a cationic exchange resin (Varian, Bond Elut SCX).
Impurities were washed off with MeOH, and then elution with 2 M NH3/MeOH
gave, after removing volatiles, a residue that was taken up in EtOAc, washed
with satd NaHCO3, dried, and concentrated to afford 2.3 g (58%) of 14. A sample
of this compound was purified by RP-HPLC for characterization purposes: Data
for 14: 1H NMR (300 MHz, CD3CN) d 7.69 (2H, br s), 7.48 (3H, br s), 5.04 (1H, bd,
J = 14 Hz), 4.75–4.69 (2H, m), 4.37–4.20 (2H, m), 4.01 (3H,s), 3.96–3.84 (2H, m),
3.72 (1H, br s), 3.46 (1H, br s), 2.87 (3H, s), 1.43 (9H, s) ppm;.13C NMR
(300 MHz, CD3CN) d 168.0, 159.9 (br), 157.4, 154.2 (br), 148.4, 145.4, 130.6
(2C), 129.4, 128.7 (2C), 123.2, 81.0, 65.2, 57.2, 52.6, 44.4 (br), 42.6, 41.9 (br),
38.3, 27.1 (3C) ppm; MS m/z: 459 (M+H)+.
5. For the preparation of 2H-1 and 2H-3 benzazepin-2-one derivatives using
related methodology see: Ludivine, J. G.; Pauvert, M.; Collet, S.; Guingant, A.;
Evain, M. Tetrahedron 2007, 63, 11250–11259; For other examples of ring
expansion via aziridinium ions, using azide as nucleophile, see: Chong, H.;
Ganguly, B.; Broker, G. A.; Rogers, R. D.; Brechbiel, M. W. J. Chem. Soc., Perkin
Trans.
1 2002, 18, 2080–2086. on a piperidine; Franz, M. H.; Roper, S.;
Wartchow, R.; Hoffmann, H. M. R. J. Org. Chem. 2004, 69, 2983–2991. on
Cinchona alkaloids. For a general review on the use of aziridium ions see: Cossy,
J.; Gomez Pardo, D. CHEMTRACTS—Org. Chem. 2002, 15, 579–605.
11. (a) Guy, A.; Lemor, A.; Doussot, J.; Lemaire, M. Synthesis 1988, 900–902; (b)
Vanier, C.; Wagner, A.; Mioskowski, C. Synlett 2001, 842–844.
12. When methylamine was added to the activated intermediate, a 1:1 mixture of
desired amine 17a and chloride 17b was obtained.
6. Colarusso, S.; Attenni, B.; Avolio, S.; Malancona, S.; Harper, S.; Altamura, S.;
Koch, U.; Narjes, F. ARKIVOC 2006, vii, 479–495; Ferrara, M.; Crescenzi, B.;
Donghi, M.; Muraglia, E.; Nizi, E.; Pesci, S.; Summa, V.; Gardelli, C. Tetrahedron
Lett. 2007, 48, 8379–8382.
7. Muraoka, O.; Zheng, B. Z.; Okumura, K.; Tanabe, G.; Momose, T.; Eugster, C. H. J.
Chem. Soc., Perkin Trans. 1 1996, 1567–1575.
8. To a suspension of 12 (29.4 g, 0.12 mol) in 500 mL of acetonitrile, DMAD
(15.6 mL, 1.05 equiv) was added in one portion, and the mixture was stirred for
1 h at rt. Solvent was evaporated, and the residue was dissolved in xylenes
(1.2 L) and stirred overnight at 145 °C. Evaporation gave a residue that was
taken up in EtOAc, a black solid was filtered off, and the filtrate was extracted
with sat NaHCO3. CHCl3 was added to the aqueous phase, followed by 6 N HCl
until acid pH; extraction with CHCl3 afforded pure 13 (8 g, 19% from 4-
piperidone). Data for 13: 1H NMR (300 MHz, CDCl3) d 10.55 (1H, br s), 4.42–
4.40 (2H, m), 4.03 (3H, s), 3.72–3.69 (4H, m), 3.12–3.09 (2H, m), 1.48 (9H,
s) ppm; 13C NMR (300 MHz, CD3CN) d 169.8, 158.8, 155.4, 153.1, 148.5, 125.2,
80.7, 53.5, 46.0 (br), 45.0, 43.3 (br), 38.8, 28.3 (3C) ppm; MS m/z: 340 (M+H)+.
9. Kinzel, O. D.; Monteagudo, E.; Muraglia, E.; Orvieto, F.; Pescatore, G.; Rico
Ferreira, M. R.; Rowley, M.; Summa, V. Tetrahedron Lett. 2007, 48, 6552–
6555.
O
O
OH
OH
N
N
H
N
BocN
H
BocN
N
N
N
O
O
Cl
NH
17b
17a
F
F
Reaction was done on the p-fluorobenzylamide to avoid reaction of
methylamine with the methyl ester of 13.
13. Data for 22 (R1 = –COCONMe2, R2 = –SO2Me): 1H NMR (400 MHz, DMSO-d6) d
12.15 (1H, br s, 9.58 (1H, br s), 7.37 (2H, dd, J = 8.6, 5.7 Hz), 7.14 (2H, t,
J = 8.6 Hz), 5.30 (1H, br s), 5.12 (1H, dd, J = 15.7, 3.6 Hz), 4.54–4.44 (2H, m), 4.03
(1H, bd, J = 12.8 Hz), 3.91–3.76 (3H, m), 3.16–3.10 (1H, m), 2.99 (3H, s), 2.96
(3H, s), 2.95 (3H, s), 2.92 (3H, s) ppm; 13C NMR (400 MHz, DMSO-d6) d 167.9,
166.5, 164.8, 161.3 (d, J = 965 Hz), 157.6, 146.8, 146.4, 134.6, 129.5, 129.4,
124.7, 115.2, 114.9, 59.4, 47.9, 46.5, 42.3, 41.5, 36.7, 36.3, 34.6 (br), 32.8 ppm;
MS m/z: 539 (M+H)+.
10. DDQ (4.1 g, 2.1 equiv) was added to a solution of 13 (2.9 g, 8.5 mmol) in dry
1,4-dioxane (150 mL), and the mixture was stirred at 105 °C (oil bath
temperature) overnight. After cooling to rt, benzylmethylamine (6.6 mL,
6 equiv) was added and stirring was continued at 65 °C for 6 h, before
leaving to cool. Dihydro-DDQ was filtered off, dioxane and most of the excess