From thienodiazepinediones to thienopyridinones: Flexible synthesis of substituted thieno[3,2-e][1,4]diazepinones and 6-aminothieno[3,2-b]pyridinones

Article abstract of DOI:10.1021/jo900627a

(Chemical Equation Presented) N-Substituted thienodiazepinedione opening with a series of organomagnesium bromides allowed the subsequent cyclization to the seven-membered ring thieno[3,2-e][1,4]diazepinone in 52-99% yields or to the six-membered ring thi

Full text of DOI:10.1021/jo900627a

From Thienodiazepinediones to Thienopyridinones: Flexible
Synthesis of Substituted Thieno[3,2-e][1,4]diazepinones and
6-Aminothieno[3,2-b]pyridinones
Yann Brouillette, Jean Martinez, and Vincent Lisowski*
Institut des Biomole´cules Max-Mousseron, UMR 5247, CNRS, UniVersite´s Montpellier I et II, UFR des
Sciences Pharmaceutiques et Biologiques, 15 AVenue Charles Flahault,
34093 Montpellier Cedex 5, France
Vincent.lisowski@uniV-montp1.fr
ReceiVed March 30, 2009
N-Substituted thienodiazepinedione opening with a series of organomagnesium bromides allowed the
subsequent cyclization to the seven-membered ring thieno[3,2-e][1,4]diazepinone in 52-99% yields or
to the six-membered ring thieno[3,2-b]pyridinones in 45-55% yields. Effective syntheses introducing
considerable diversity onto these valuable scaffolds are described.
Introduction
Benzo[1,4]diazepin-2-ones and benzo[b]pyridin-2-ones (also
referred to as quinolin-2(1H)-ones) are two privileged structures1,2
which have attracted considerable attention in the design of
biologically active molecules.3-9 The chemistry developed
around these two important scaffolds has contributed to the
* To whom correspondence should be addressed. Phone: 33-(0)4 67 54 86
53. Fax: 33-(0)4 67 54 86 54.
(1) Priviliged structures defined by: Evans, B. E.; Rittle, K. E.; Bock, M. G.;
Dipardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling,
P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31,
2235–2246.
FIGURE 1. Structures of biologically important thieno[2,3-e]diazepine
and thieno[2,3-c] or [2,3-b]pyridine compounds.
emergence of the useful thiophene isosters, namely the
thieno[1,4]diazepin-2-ones and the thieno[b]pyridin-2-ones se-
ries. Clotiazepam (brand name Trecalmo) is a thienodiazepine
marketed drug with anxiolytic, anticonvulsant, sedative, and
muscle relaxant properties (Figure 1).10,11 Ticlopidine (trade
name Ticlid) and Clopidogrel (trade names Plavix and Clopilet)
are two antiplatelet drugs derived from the thieno[c]pyridine
skeleton, often used in the treatment of coronary artery disease,
peripheral vascular disease, and cerebrovascular disease.12
Moreover, thieno[b]pyridin-2-one derivatives have found various
biological applications as new AMP-activated protein Kinase
(2) Priviliged structures defined by: Patchett, A. A.; Nargund, R. P. Annu.
Rep. Med. Chem. 2000, 35, 289–298.
(3) Grasberger, B. L.; Lu, T. B.; Schubert, C.; Parks, D. J.; Carver, T. E.;
Koblish, H. K.; Cummings, M. D.; LaFrance, L. V.; Milkiewicz, K. L.; Calvo,
R. R.; Maguire, D.; Lattanze, J.; Franks, C. F.; Zhao, S. Y.; Ramachandren, K.;
Bylebyl, G. R.; Zhang, M.; Manthey, C. L.; Petrella, E. C.; Pantoliano, M. W.;
Deckman, I. C.; Spurlino, J. C.; Maroney, A. C.; Tomczuk, B. E.; Molloy, C. J.;
Bone, R. F. J. Med. Chem. 2005, 48, 909–912.
(4) Karp, G. M.; Manfredi, M. C.; Guaciaro, M. A.; Ortlip, C. L.; Marc, P.;
Szamosi, I. T. J. Agric. Food Chem. 1997, 45, 493–500.
(5) Bouhlal, D.; Gode, P.; Goethals, G.; Massoui, M.; Villa, P.; Martin, P.
Heterocycles 2001, 55, 303–312.
(6) Webb, R. R.; Barker, P. L.; Baier, M.; Reynolds, M. E.; Robarge, K. D.;
Blackburn, B. K.; Tischler, M. H.; Weese, K. J. Tetrahedron Lett. 1994, 35,
2113–2116.
(7) Ribeiro, N.; Tabaka, H.; Peluso, J.; Fetzer, L.; Nebigil, C.; Dumont, S.;
Muller, C. D.; Desaubry, L. Bioorg. Med. Chem. Lett. 2007, 17, 5523–5524.
(8) Wang, Z.; Wang, B.; Wu, H. J. Comb. Chem. 2007, 9, 811–817.
(9) Hewawasam, P.; Fan, W. H.; Knipe, J.; Moon, S. L.; Boissard, C. G.;
Gribkoff, V. K.; Starrett, J. E. Bioorg. Med. Chem. Lett. 2002, 12, 1779–1783.
(10) Nakamoto, Y.; Ishizuka, Y.; Fujii, M. JPO 61172884 A 1986.
(11) Nakanishi, M.; Tahara, T.; Araki, K.; Shiroki, M.; Tsumagari, T.;
Takigawa, Y. J. Med. Chem. 1973, 16, 214–219.
(12) Pereillo, J. M.; Maftouh, M.; Andrieu, A.; Uzabiaga, M. F.; Fedeli, O.;
Savi, P.; Pascal, M.; Herbert, J. M.; Maffrand, J. P.; Picard, C. Drug Metab.
Dispos. 2002, 30, 1288–1295.
10.1021/jo900627a CCC: $40.75  2009 American Chemical Society
Published on Web 05/29/2009
J. Org. Chem. 2009, 74, 4975–4981 4975

Brouillette et al.
SCHEME 1. N4-Substitution of thienodiazepinediones
regulators (compound 1) for the treatment of diabetes, metabolic
syndrome, and obesity (Figure 1),13 as inhibitors of macrophage
migration inhibitory factor (MIF) in the field of immune related
disorders or tumor associated angiogenesis,14 as potent and
selective p38 MAP Kinase inhibitors,15 as cytoprotectants and
inhibitors of [3H]glycine binding to the N-methyl-D-aspartate
(NMDA) receptor,16 and as cholesterol acyl transferase inhibi-
tors for the treatment of hypercholesterolemia or atherosclero-
sis.17
Since most synthetic routes described in the literature refer
to the [2,3] type fusion between the thiophene and these seven-
or six-membered heterocycles, access to the isomeric [3,2] type
fusion is a more intricate task. In this context, we have recently
described a general synthetic protocol to generate new thieno[3,2-
e]diazepine-2,5-diones by regioselective ring-opening of thieno-
[3,2-d][1,3]oxazine-2,4-dione (or 2-thiaisatoic anhydride)18 by
R-amino acids, followed by intramolecular cyclocondensation.19
This methodology was further extended to the solid phase with
N-alkylated R-amino acids leading to C3,N4-disubstituted
thieno[3,2-e]diazepinediones.20 In our ongoing interest for the
development of focused heterocyclic libraries, we present herein
further diversification of our privileged scaffold, by the access
to new C5-arylated thieno[3,2-e]diazepin-2-ones 16 and 17.
In this vein, the commonly employed synthetic route to C5-
arylated benzo[1,4]diazepines starts from benzophenone deriva-
tives. The major limitation of this methodology is the estab-
lishment of a C-5 substituent at an early stage in the synthesis,
which is not ideal for the preparation of analogues containing
diversity at this position. So far, two pathways have appeared
to introduce C-5 diversity onto the benzo[1,4]diazepine-2,5-
dione motif. The first selectively converts the benzodiazepinedi-
one to the monoimidoyl chloride by treatment with phosphorus
oxychloride (POCl3) and N,N-dimethylaniline at reflux for 5 h.21
Subsequent Suzuki cross-coupling allowed the introduction of
a wide variety of aromatic and heteroaromatic substituents.22
However, the imidoyl chloride isolation is fastidious and the
product was found to be unstable if not allowed to react within
a few hours. The second method was reported in 1980 for a
new synthesis of diazepam, where the action of phenylmagne-
sium chloride on a 4-acetyl-benzodiazepinedione gave the
corresponding benzophenone, which was treated with an excess
of hydroxylamine hydrochloride in pyridine to provide the
deacetylated oxime, which was then cyclized back to the
7-chloro-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-
one (or diazepam) by action of aqueous alcoholic NaHSO3.23
To our knowledge, only a few accounts of C-5 diversification
of the thieno[3,2-e]diazepine scaffold were reported, all from
(3-aminothiophen-2-yl)phenylmethanone intermediates.24,25
Results and Discussion
In respect to literature precedents and in the context of our
latest methodology to access thieno[3,2-e][1,4]diazepines, our
efforts were converged toward the modification of the N-4, C-5
lactam of the thienodiazepine. Our first attempts to diversify
the C-5 carbonyl of the thienodiazepine were carried out with
POCl3. Unfortunately, in our hands, these assays were unsuc-
cessful in forming the corresponding imidoyl chloride. There-
fore, our efforts were directed toward the use of Grignard
reagents on N4-acylated thienodiazepinediones. To react ad-
equately, the N4-substitution of thieno[3,2-e][1,4]diaze-
pinediones 2 was first studied. Further diversification of the
thieno[3,2-e][1,4]diazepinedione 2 can be introduced at the N-4
position of the diazepine ring by a different means than direct
cyclization of the appropriate N-alkylated R-amino acid (R-aa).20
Successful alkylation of 5 was rendered possible with the
nucleophilic substitution of alkyl halides (MeI, allylCl, BnBr)
in the presence of an inorganic base (like NaH or LiHMDS), in
THF, at 0 °C to room temperature, for 18 h leading to diazepines
6-8 in 55% to 60% yields (Scheme 1). Acylation of 5 with
acetyl chloride also furnished the disubstituted thienodiaz-
epinedione 9, but in a low yield of 20%. These results provided
evidence of feasible N4-substitution of N1-alkylated thienodi-
azepinediones. Recently, the use of the tert-butyloxycarbonyl
(Boc) group was described for the acylation of a benzodiaz-
epine.26 Since N4-Boc protection would provide a profitable
electro-withdrawing effect for subsequent Grignard reactions,
carbamate protection of the N4-thienodiazepines derived from
glycine 2-3, phenylalanine 4, and alanine 5 were prepared by
using di-tert-butyl dicarbonate (Boc2O) and sodium hydride in
THF at room temperature (Scheme 1). In sum, the acylation
was more effective when the C-3 position of the diazepine was
unsubstituted (10 (83%), 11 (94%)) rather than comprised of
an amino acid side chain ((12 (48%), 13 (45%)). A similar
observation was reported with the case of a C3-methyl benzo-
(13) Zhao, G.; Iyengar, R. R.; Judd, A. S.; Cool, B.; Chiou, W.; Kifle, L.;
Frevert, E.; Sham, H.; Kym, P. R. Bioorg. Med. Chem. Lett. 2007, 17, 3254–
3257.
(14) Sircar, J.; Kumar, K. C. S.; Davis, T. J.; Ying, W. WO 2006 102191
A1.
(15) Brookings, D. C.; Davis, J. M.; Langham, B. J. WO 2004 113347
A1.
(16) Buchstaller, H.-P.; Siebert, C. D.; Steinmetz, R.; Frank, I.; Berger, M. L.;
Gottschlich, R.; Leibrock, J.; Krug, M.; Steinhilber, D.; Noe, C. R. J. Med. Chem.
2006, 49, 864–871.
(17) Meguro, K.; Nishinomiya, H.; Takatsuki, O. EP 0472116A1 1991.
(18) Brouillette, Y.; Martinez, J.; Lisowski, V. Eur. J. Org. Chem. 2009. In
press. DOI: 10.1002/ejoc.200801007.
(19) Brouillette, Y.; Lisowski, V.; Fulcrand, P.; Martinez, J. J. Org. Chem.
2007, 72, 2662–2665.
(20) Brouillette, Y.; Verdie´, P.; Martinez, J.; Lisowski, V. Synlett 2008, 15,
2360–2364.
(21) Wade, P. C.; Vogt, B. R.; Toeplitz, B.; Puar, M. S.; Gougoutas, J. Z. J.
Org. Chem. 1979, 44, 88–99.
(24) Hirai, K.; Sugimoto, H.; Ishiba, T. J. Org. Chem. 1980, 45, 253–260.
(25) Hromatka, O.; Binder, D.; Pixner, G. Monatsh. Chem. 1975, 106, 1103–
1109.
(22) Nadin, A.; Lopez, J. M. S.; Owens, A. P.; Howells, D. M.; Talbot, A. C.;
Harrison, T. J. Org. Chem. 2003, 68, 2844–2852.
(23) Gates, M. J. Org. Chem. 1980, 45, 1675–1681.
(26) Churcher, I.; Ashton, K.; Butcher, J. W.; Clarke, E. E.; Harrison, T.;
Lewis, H. D.; Owens, A. P.; Teall, M. R.; Williams, S.; Wrigley, J. D. J. Bioorg.
Med. Chem. Lett. 2003, 13, 179–183.
4976 J. Org. Chem. Vol. 74, No. 14, 2009

From Thienodiazepinediones to Thienopyridinones
TABLE 1. 5-Arylthieno[3,2-e][1,4]diazepinones 16 and 17
SCHEME 2. Synthesis of
5-Arylthieno[3,2-e][1,4]diazepinones 16 and 17
entry
R1
R2
yield (%)
16a
16b
16c
16d
16e
16f
16g
16h
17a
17b
17c
17d
17e
17f
H
H
H
Bn
Bn
Bn
Me
Me
H
H
OMe
Cl
H
OMe
Cl
H
OMe
H
OMe
Cl
H
58a
62a
66a
99a
99a
99a
86a
71a
54
60
52
79
85
H
H
Bn
Bn
Bn
Me
Me
OMe
Cl
H
89
75
80
17g
17h
OMe
a Yields over 3 steps from diazepine 11, 12, or 13.
acid side chains. The resulting ketones 14 were no longer
isolated but rather directly reacted in the next two steps to form
the corresponding 1-(4-methoxybenzyl)-5-aryl-thieno[3,2-e][1,4]-
diazepin-2-ones 16 isolated in medium to good yields of
58-99% over three steps (Table 1).
Removal of the PMB group from the thienodiazepine was
effectively performed by using an excess of ammonium ceri-
um(IV) nitrate (Ce(NH4)2(NO3)6), referred to as CAN, in a
mixture of CH3CN-H2O for 2 h at room temperature (Scheme
2).28,29 Therefore, thieno[1,4]diazepines 17a-h were recovered
in pure form in 52-89% yields (Table 1).
diazepine.23 Most of these C3,N4-disubstituted thienodiazepines
are sterically hindered and gave a mixture of two conformers
1
on the H and 13C NMR spectra at room temperature, which
were simplified by gradual heating (20 to 70 °C) of the
deuterated solution during NMR acquisitions.
With the Boc protected thienodiazepines 10-13 in hand, it
was now possible to diversify the C-5 carbonyl by treatment
with a Grignard reagent. Our first attempt was initiated with
diazepine 11 to afford the ketone 14a by a rapid exothermic
carbon-carbon bond formation using phenylmagnesium bro-
mide in THF at room temperature, in 66% yield (Scheme 2).
The alkoxymagnesium bromide intermediate was converted to
the ketone 14a after opening of the diazepine ring by rupture
of the N-4, C-5 bond. The Grignard reagent’s attack proceeds
with good selectivity onto the C-5 vs. Boc carbonyls of the
thienodiazepine 11, resulting mainly in the formation of the
corresponding ketone 14a as well as some deprotected diazepine
3, which was recuperated at the purification step. This observa-
tion was previously reported with benzodiazepines bearing
different acyl groups (such as trifluoroacetyl, propionyl, n-
butyroyl, and isobutyroyl),23 but was not formerly cited with
the Boc group.26 In the next step, the amine 15a was obtained
after Boc removal, using 50% TFA in DCM at room temperature
for 15 min, without affecting the stability of the orthogonal
p-methoxybenzyl (PMB) group. Intramolecular cyclization of
15a was then performed by addition of a non-nucleophilic base
like triethylamine to form the seven-membered ring 16a, which
was purified by flash column chromatography27 and isolated in
88% yield.
Access to thienodiazepines 16 from ketones 14 by cyclocon-
densation led us to envisage an alternative synthetic pathway
to produce six-membered heterocycles. Indeed, with the N-Boc-
ketones 14 derived from glycine in hand, we were in a position
to deprotonate the vicinal methylene instead of deprotecting the
Boc group. Deprotonation of ketones 14a-c and 18 was carried
out with potassium tert-butoxide (KOtBu) in THF for 30 min
at room temperature and permitted condensation to the hydroxy
six-membered ring 19 (Scheme 3). In a different way than with
the diazepine formation, the six-membered rings were formed
without spontaneous dehydration. Therefore, compound 19 was
completely converted to the aromatic pyridinones 20, in the
N-PMB and the N-Me series, by using an excess amount of
p-TsOH. After this one-pot three-step process, tert-butyl-4,5-
dihydro-5-oxo-7-arylthieno[3,2-b]pyridin-6-ylcarbamate 20 was
purified by flash column chromatography and isolated in yields
of 45-55% (Table 2). The deficient Grignard selectivity of
attack at the C-5 carbonyl of the thienodiazepines 10-11 (vs.
the Boc group) as well as the partial hydrolysis of pyridinone
20 back to pyridinone 19 during the purification step contributed
to lower the yield of this six-membered heterocycle series.
Access to this valuable scaffold pushed us to study its
reactivity. Thus, a preliminary experiment to illustrate the use
of this new strategy was initiated with an isocyanate. The Boc
group was readily cleaved from 20b with a 50% TFA solution
in DCM, and after evaporation of the volatile material, acylation
of amine 21 with a representative p-chlorophenylisocyanate in
DCM proceeded smoothly to give urea 22 in 62% yields
(Scheme 4).
To validate this methodology, thienodiazepines 11-13 were
submitted to Grignard reactions in the presence of p-chloro-,
p-methoxy-, and phenyl magnesium bromides. Restitution of
thienodiazepines 4 and 5 from the attack at the Boc carbonyl
was not observed by LC-MS at 214 nm with the diazepines
derived from phenylalanine 12 or alanine 13, probably due to
the steric hindrance or the electrodonating effect of these amino
(28) Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.;
Smith, A. D. Chem. Commun. 2000, 337–338.
(29) Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.;
Smith, A. D. J. Chem. Soc. Perkin Trans. 1 2000, 3765–3774.
(27) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.
J. Org. Chem. Vol. 74, No. 14, 2009 4977

Brouillette et al.
SCHEME 3. Synthesis of
6-Amino-7-arylthieno[3,2-b]pyridinone Analogues 20
ieno[3,2-b]pyridin-5-ones 20 was described in 45-55% yields.
Considering the utility of thienodiazepines and thienopyridino-
nes, the scope of these reactions is now under further investiga-
tion in our laboratories.
Experimental Section
Typical Procedure for Alkylation of N(4)-Diazepinediones
5.20 A stirring solution of thienodiazepinedione 5 (0.100 g, 0.32
mmol) in THF (10 mL) was treated with NaH 60% in oil (0.025 g,
0.64 mmol) at 0 °C for 5 min. MeI (0.04 mL, 0.64 mmol) is added
to the stirring suspension and agitated to rt for 18 h. The volatile
material is evaporated and the residue is partitioned between H2O
and EtOAc. The aqueous phase was extracted with EtOAc and the
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and evaporated. The residue is further purified
by flash chromatography. Note: Conformers impede the formation
1
of sharp signals on the H NMR spectra at rt. Method A for the
retention time refers to an HPLC method that is summarized in
the Supporting Information.
(S)-1-(4-Methoxybenzyl)-3,4-dihydro-3,4-dimethylthieno[3,2-
e][1,4]diazepine-2,5-dione (6): yield 55%; beige solid, mp 112-114
1
°C; [R]20 29.4 (c 0.1, DMSO); H NMR (CDCl3) δ 7.42 (d, 1H,
D
J ) 5.4 Hz), 7.09 (d, 2H, J ) 8.5 Hz), 6.86 (d, 1H, J ) 5.3 Hz),
6.82 (d, 2H, J ) 8.6 Hz), 5.13 (d, 1H, J ) 15.3 Hz), 4.87 (d, 1H,
J ) 15.3 Hz), 4.37 (quad, 1H, J ) 7.0 Hz), 3.77 (s, 3H), 3.08 (s,
3H), 1.25 (s, 3H); 13C NMR (CDCl3) δ 168.3, 163.6, 159.2, 140.9,
130.3, 128.7, 128.3, 125.9, 121.2, 114.4, 55.4, 52.6, 50.4, 29.8,
13.4; HRMS calcd for [M + H+] C17H19N2O3S 331.1116, found
331.1097; Rt 2.31 (method A); Rf 0.6, CHCl3-AcOEt (1:1).
(S)-1-(4-Methoxybenzyl)-4-allyl-3,4-dihydro-3-methylthieno[3,2-
TABLE 2. 6-Amino-7-arylthieno[3,2-b]pyridinone Analogues 20
entry
R1
R2
yields (%)
20a
20b
20c
20d
20e
20f
PMB
PMB
PMB
Me
Me
Me
H
OMe
Cl
H
OMe
Cl
52
47
45
51
49
55
e][1,4]diazepine-2,5-dione (7): yield 57%; beige solid, mp 98-100
1
°C; [R]20 9.6 (c 0.2, DMSO); H NMR (DMSO-d6) δ 7.82 (d,
D
1H, J ) 5.4 Hz), 7.25 (br s, 1H), 7.06 (d, 2H, J ) 8.1 Hz), 6.82 (d,
2H, J ) 7.6 Hz), 5.75 (m, 1H), 5.3-5.06 (m, 4H), 4.47-4.32 (m,
2H), 3.92 (m, 1H), 3.69 (s, 3H), 1.47-1.17 (m, 3H); 13C NMR
(DMSO-d6) δ 168.9, 163.6, 158.9, 140.9, 134.4, 131.1, 129.2, 128.7,
122.5, 116.9, 114.3, 55.4, 52.5, 48.5, 43.8, 13.5; HRMS calcd for
[M + H+] C19H21N2O3S 357.1273, found 357.1271; Rt 2.59 (method
A); Rf 0.6, CHCl3-AcOEt (9:1).
SCHEME 4. Amino Substitution of
6-Amino-7-arylthieno[3,2-b]pyridinone 20b
(S)-1-(4-Methoxybenzyl)-4-benzyl-3,4-dihydro-3-methylth-
ieno[3,2-e][1,4]diazepine-2,5-dione (8): yield 60%; beige solid,
1
mp 66-68 °C; [R]20 73.6 (c 0.1, DMSO); H NMR (DMSO-d6)
D
δ 7.85 (d, 1H, J ) 5.4 Hz), 7.35-7.17 (m, 6H), 6.97 (d, 2H, J )
8.4 Hz), 6.79 (d, 2H, J ) 8.4 Hz), 5.26 (m, 1H), 4.88 (m, 2H),
4.51 (m, 2H), 3.69 (s, 3H), 1.43 (m, 3H); 13C NMR (DMSO-d6) δ
168.2, 163.6, 158.4, 140.2, 138.1, 130.9, 128.6, 128.2, 127.8, 127.1,
126.9, 124.7, 122.1, 113.9, 55.0, 52.3, 47.9, 44.5, 13.5; HRMS calcd
for [M + H+] C23H23N2O3S 407.1429, found 407.1405; MS (ESI,
m/z) 407.2 [M + H]+; Rt 2.90 (method A); Rf 0.6, CHCl3-AcOEt
(9:1).
(S)-1-(4-Methoxybenzyl)-4-acetyl-3,4-dihydro-3-methylth-
ieno[3,2-e][1,4]diazepine-2,5-dione (9): yield 20%; beige solid,
mp 67-70 °C; [R]20D -46.7 (c 0.2, DMSO); 1H NMR (DMSO-d6)
δ 8.03 (d, 1H, J ) 5.4 Hz), 7.13 (d, 1H, J ) 5.4 Hz), 7.09 (d, 2H,
J ) 8.8 Hz), 6.88 (d, 2H, J ) 8.5 Hz), 5.88 (quad, 1H, J ) 7.6
Hz), 5.15 (d, 1H, J ) 15.9 Hz), 5.03 (d, 1H, J ) 15.9 Hz), 3.71 (s,
3H), 1.27 (s, 3H); 13C NMR (DMSO-d6) δ 171.3, 168.6, 163.6,
158.4, 141.0, 135.4, 128.4, 127.7, 123.1, 114.1, 113.9, 55.0, 51.0,
49.1, 26.1, 13.9; HRMS calcd for [M + H+] C18H19N2O4S 359.1066,
found 359.1045; Rt 2.66 (method A); Rf 0.6, CHCl3-AcOEt (9:1).
Typical Procedure for the N(4)-Boc Protection of Diaz-
epinediones 2-5. A solution of thienodiazepinedione 3 (4.00 g,
13.2 mmol) in THF (100 mL) was treated with NaH (60% dispersed
in oil, 1.33 g, 33.1 mmol) at 0 °C and stirred for 5 min. Then Boc2O
(5.75 g, 26.4 mmol) was added and the reaction mixture was left
to stir to rt for 1 h. The volatile material was evaporated and the
residue was partitioned between H2O and EtOAc. The aqueous
Conclusions
In conclusion, it was demonstrated that thienodiazepinediones
can also be substituted at their N-4 position by alkylation (with
alkyl halides) or acylation (with acetyl chloride or Boc2O).
Subsequently, diversification of their C-5 position can be
achieved rapidly in three steps to furnish 5-arylthieno[3,2-
e][1,4]diazepin-2-one 16 in 58-99% yields. Furthermore, from
the same ketone intermediates 14, access to 6-amino-7-arylth-
4978 J. Org. Chem. Vol. 74, No. 14, 2009

From Thienodiazepinediones to Thienopyridinones
phase was extracted with EtOAc and the combined organic layers
were washed with brine, dried over Na2SO4, filtered, and evaporated.
The residue was further purified by flash chromatography.
tert-Butyl 2,3-dihydro-1-methyl-2,5-dioxo-1H-thieno[3,2-e]-
[1,4]diazepine-4(5H)-carboxylate (10): yield 83%; off-white solid,
1) solution (15 mL) and stirred for 15 min at rt. To the stirring
solution of amine 15a is added triethylamine dropwise until pH 8
then the solution is stirred for 5 min. The volatile material was
evaporated and the residue was partitioned between H2O and
EtOAc. The aqueous phase was extracted with EtOAc and the
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and evaporated. The residual thienodiazepine 16
was further purified by flash column chromatography.
1-(4-Methoxybenzyl)-5-phenyl-1H-thieno[3,2-e][1,4]diazepin-
2(3H)-one (16a): yield 58%; beige solid, mp 45-48 °C; 1H NMR
(DMSO-d6) δ 7.87 (d, 1H, J ) 5.4 Hz), 7.51-7.41 (m, 5H), 7.36
(d, 1H, J ) 5.4 Hz), 6.99 (d, 2H, J ) 8.5 Hz), 6.78 (d, 2H, J ) 8.5
Hz), 5.09 (s, 2H), 4.37 (s, 2H), 3.67 (s, 3H); 13C NMR (DMSO-d6)
δ 165.5, 164.4, 158.4, 144.6, 138.6, 130.7, 130.3, 128.9, 128.8,
128.2, 128.0, 125.1, 122.1, 113.8, 58.0, 55.0, 48.2; HRMS calcd
for [M + H+] C21H19N2O2S 363.1167, found 363.1177; Rt 2.11
(method A).
1-(4-Methoxybenzyl)-5-(4-methoxyphenyl)-1H-thieno[3,2-
e][1,4]diazepin-2(3H)-one (16b): yield 62%; light-beige solid, mp
58-61 °C; 1H NMR (DMSO-d6) δ 7.91 (d, 1H, J ) 5.4 Hz), 7.50
(d, 2H, J ) 8.8 Hz), 7.36 (d, 1H, J ) 5.4 Hz), 7.01 (d, 2H, J ) 8.8
Hz), 6.99 (d, 2H, J ) 8.6 Hz), 6.78 (d, 2H, J ) 8.7 Hz), 5.08 (s,
2H), 4.34 (br s, 2H), 3.81 (s, 3H), 3.68 (s, 3H); 13C NMR (DMSO-
d6) δ 165.6, 164.0, 161.7, 158.3, 145.1, 131.3, 131.0, 130.2, 128.7,
128.0, 124.8, 122.3, 113.8, 113.7, 57.0, 55.4, 55.0, 48.4; HRMS
calcd for [M + H+] C22H21N2O3S 393.1273, found 393.1263; Rt
2.19 (method A); Rf 0.4, CHCl3-AcOEt (7:3).
1
mp 148-149 °C; H NMR (DMSO-d6) δ 8.06 (d, 1H, J ) 5.5
Hz), 7.26 (d, 1H, J ) 5.5 Hz), 4.43 (br s, 2H), 3.34 (s, 3H), 1.45
(s, 9H); 13C NMR (DMSO-d6) δ 167.3, 160.9, 150.6, 143.0, 134.2,
122.8, 109.1, 83.2, 47.8, 33.9, 27.5; HRMS calcd for [M + H+]
C13H17N2O4S 297.0909, found 297.0910; Rt 1.99 (method A); Rf
0.5, CHCl3-AcOEt (4:1).
tert-Butyl 1-(4-methoxybenzyl)-2,3-dihydro-2,5-dioxo-1H-
thieno[3,2-e][1,4]diazepine-4(5H)-carboxylate (11): yield 94%;
1
light beige solid, mp 140-142 °C; H NMR (DMSO-d6) δ 7.98
(d, 1H, J ) 5.4 Hz), 7.20 (d, 1H, J ) 5.4 Hz), 7.09 (d, 2H, J ) 7.2
Hz), 6.85 (d, 2H, J ) 7.0 Hz), 5.09 (s, 2H), 4.54 (s, 2H), 3.70 (s,
3H), 3.30 (s, 3H), 1.47 (s, 9H); 13C NMR (DMSO-d6) δ 167.1,
160.8, 158.4, 150.5, 141.8, 134.2, 128.5, 127.9, 123.9, 123.0, 114.0,
83.3, 55.0, 48.1, 48.0, 27.5; HRMS calcd for [M + H+]
C20H23N2O5S 403.1328, found 403.1301; Rt 2.74 (method A); Rf
0.5, CHCl3-AcOEt (9:1).
(S)-tert-Butyl 1-(4-methoxybenzyl)-3-benzyl-2,3-dihydro-2,5-
dioxo-1H-thieno[3,2-e][1,4]diazepine-4(5H)-carboxylate (12):
yield 48%; yellow beige solid, mp 66-68 °C dec; [R]20D -13.3 (c
1
0.2, DMSO); H NMR (DMSO-d6 at 65 °C) δ 8.02 (br s, 1H),
7.27 (m, 5H), 7.06 (d, 3H, J ) 8.5 Hz), 6.83 (d, 2H, J ) 7.8 Hz),
5.55 (br s, 1H), 5.09 (br s, 2H), 3.72 (s, 3H), 3.33 (br s, 0.5H),
2.86 (m, 1.5H), 1.42 (s, 9H); 1H NMR (DMSO-d6 at 20 °C) δ 8.09
(d, 0.7H, J ) 5.4 Hz), 7.98 (d, 0.3H, J ) 5.4 Hz), 7.27 (m, 4.6H),
7.04 (m, 3.3H), 6.85 (d, 1.3H, J ) 8.6 Hz), 6.78 (d, 0.7H, J ) 8.5
Hz), 5.55 (t, 0.7H, J ) 8.7 Hz), 5.45 (d, 0.3H, J ) 15.7 Hz), 5.09
(t, 1.3H, J ) 17.1 Hz), 4.93 (d, 0.3H, J ) 15.6 Hz), 4.78 (t, 0.3H,
J ) 7.5 Hz), 3.71 (s, 2H), 3.68 (s, 1H), 3.55 (dd, 0.3H, J ) 13.7,
8.2 Hz), 3.40 (dd, 0.3H, J ) 13.9, 7.0 Hz), 3.00 (dd, 0.7H, J )
13.8, 7.9 Hz), 2.82 (dd, 0.7H, J ) 13.8, 9.7 Hz), 1.44 (s, 3H), 1.37
(s, 6H); HRMS calcd for [M + H+] C27H29N2O5S 493.1797, found
493.1772; Rt 3.32 (method A); Rf 0.9, CHCl3-AcOEt (9:1).
(S)-tert-Butyl 1-(4-methoxybenzyl)-2,3-dihydro-3-methyl-2,5-
dioxothieno[3,2-e][1,4]diazepine-4(5H)-carboxylate (13): yield
45%; orange solid, mp 147-150 °C; 1H NMR (DMSO-d6) δ 7.99
(d, 1H, J ) 5.3 Hz), 7.25 (br s, 1H), 7.07 (d, 2H, J ) 8.3 Hz), 6.84
(d, 2H, J ) 8.0 Hz), 5.20 (br s, 2H), 3.71 (m, 1H), 3.70 (s, 3H),
3.30 (s, 3H), 1.45 (s, 9H); 13C NMR (DMSO-d6) δ 169.1, 158.9,
159.0, 142.1, 135.0, 129.0, 128.3, 124.2, 123.6, 114.4, 113.8, 83.8,
55.4, 49.0, 49.0, 27.9, 14.5; HRMS calcd for [M + H+]
C21H25N2O5S 417.1484, found 417.1470; Rt 2.90 (method A); Rf
0.7, CHCl3-AcOEt (9:1).
1-(4-Methoxybenzyl)-5-(4-chlorophenyl)-1H-thieno[3,2-
e][1,4]diazepin-2(3H)-one (16c): yield 66%; light-beige solid, mp
56-59 °C; 1H NMR (DMSO-d6) δ 7.91 (d, 1H, J ) 5.4 Hz), 7.53
(s, 4H), 7.36 (d, 1H, J ) 5.4 Hz), 6.99 (d, 2H, J ) 8.6 Hz), 6.79
(d, 2H, J ) 8.7 Hz), 5.09 (s, 2H), 4.37 (br s, 2H), 3.68 (s, 3H); 13
C
NMR (DMSO-d6) δ 165.3, 163.5, 158.4, 145.2, 136.9, 135.8, 131.2,
130.8, 128.7, 128.4, 128.0, 124.3, 122.3, 113.9, 57.7, 55.0, 48.4;
HRMS calcd for [M + H+] C21H18N2O2SCl 397.0778, found
397.0760; Rt 2.33 (method A); Rf 0.6, CHCl3-AcOEt (7:3).
(S)-1-(4-Methoxybenzyl)-3-benzyl-5-phenyl-1H-thieno[3,2-
e][1,4]diazepin-2(3H)-one (16d): yield 99%; light yellow solid,
mp 68-70 °C; [R]20D 2.0 (c 0.1, DMSO); 1H NMR (DMSO-d6) δ
7.85 (d, 1H, J ) 5.4 Hz), 7.51-7.20 (m, 11H), 6.93 (d, 2H, J )
8.5 Hz), 6.74 (d, 2H, J ) 8.5 Hz), 5.34 (d, 1H, J ) 15.3 Hz), 4.87
(d, 1H, J ) 15.3 Hz), 3.92 (t, 1H, J ) 6.8 Hz), 3.67 (s, 3H), 3.57-
3.40 (m, 2H); 13C NMR (DMSO-d6) δ 165.9, 162.4, 158.4, 144.3,
139.1, 138.3, 130.7, 130.5, 129.7, 128.9, 128.8, 128.2, 128.1, 128.0,
126.0, 125.3, 122.2, 113.8, 66.0, 55.0, 48.6, 37.8; HRMS calcd for
[M + H+] C28H25N2O2S 453.1637, found 453.1637; Rt 2.76 (method
A); Rf 0.7, CHCl3-AcOEt (9:1).
(S)-1-(4-Methoxybenzyl)-3-benzyl-5-(4-methoxyphenyl)-1H-
thieno[3,2-e][1,4]diazepin-2(3H)-one (16e): yield 99%; yellow
solid, mp 70-72 °C; [R]20D -7.9 (c 0.1, DMSO); 1H NMR (DMSO-
d6) δ 7.83 (d, 1H, J ) 5.4 Hz), 7.39-7.16 (m, 8H), 6.97 (d, 2H, J
) 8.7 Hz), 6.92 (d, 2H, J ) 8.5 Hz), 6.74 (d, 2H, J ) 8.4 Hz),
5.32 (d, 1H, J ) 15.4 Hz), 4.87 (d, 1H, J ) 15.3 Hz), 3.87 (t, 1H,
J ) 6.6 Hz), 3.79 (s, 3H), 3.67 (s, 3H), 3.51-3.40 (m, 2H); 13C
NMR (DMSO-d6) δ 166.2, 161.5, 161.3, 158.3, 144.1, 139.2, 139.2,
130.6, 130.2, 129.7, 128.8, 128.0, 128.0, 126.0, 125.5, 122.2, 113.8,
113.6, 66.0, 55.3, 55.0, 48.6, 37.8; HRMS calcd for [M + H+]
C29H27N2O3S 483.1742, found 483.1761; Rt 2.73 (method A); Rf
0.6, CHCl3-AcOEt (9:1).
Typical Procedure for the Synthesis of Ketones 14 or 18. A
solution of N-Boc thienodiazepinedione 11 (0.200 g, 0.5 mmol) in
dry THF (15 mL) was treated with a commercially available 1.0
M solution of PhMgBr (0.6 mL, 0.6 mmol) in THF then the solution
was stirred for 5 min at rt. The volatile material was evaporated
and the residue was purified by flash chromatography.
1
Ketone 14a: yield 66%; beige solid, mp 46-50 °C; H NMR
(DMSO-d6) δ 7.98 (d, 1H, J ) 4.7 Hz), 7.63 (m, 5H), 7.04 (d, 1H,
J ) 4.7 Hz), 6.98 (d, 2H, J ) 7.7 Hz), 6.86 (t, 1H, J ) 5.4 Hz),
6.69 (d, 2H, J ) 7.8 Hz), 4.68-.53 (m, 2H), 3.69 (m, 2H), 3.67 (s,
3H), 1.40 (s, 9H); 13C NMR (DMSO-d6) δ 186.8, 168.7, 158.5,
155.6, 142.55, 138.2, 133.8, 132.7, 132.1, 129.8, 129.2, 128.8,
128.6, 128.3, 113.5, 77.9, 54.8, 51.2, 42.6, 28.2; HRMS calcd for
[M + H+] C26H29N2O5S 481.1797, found 481.1782; Rt 3.16 (method
A); Rf 0.7, CHCl3-AcOEt (7:1).
(S)-1-(4-Methoxybenzyl)-3-benzyl-5-(4-chlorophenyl)-1H-
thieno[3,2-e][1,4]diazepin-2(3H)-one (16f): yield 99%; light yel-
1
Typical Direct Procedure for the Synthesis of 1-(4-methoxy-
benzyl)-5-aryl-1H-thieno[3,2-e][1,4]diazepin-2(3H)-one (16). A
solution of Boc-protected thienodiazepinedione 11 (0.200 g, 0.5
mmol) in dry THF (15 mL) was treated with a commercially
available 1.0 M solution of PhMgBr (0.6 mL, 0.6 mmol) in THF
then the mixture was stirred for 5 min at rt. Volatile material were
evaporated and the ketone 14a was dissolved in a TFA-DCM (1:
low solid, mp 61-64 °C; [R]20 -3.4 (c 0.2, DMSO); H NMR
D
(CDCl3) δ 7.47-7.31 (m, 10H), 7.00 (d, 1H, J ) 5.4 Hz), 6.97 (d,
2H, J ) 8.7 Hz), 6.72 (d, 2H, J ) 8.7 Hz), 5.30 (d, 1H, J ) 15.2
Hz), 4.85 (d, 1H, J ) 15.2 Hz), 3.96 (t, 1H, J ) 6.7 Hz), 3.74 (s,
3H), 3.80-3.62 (m, 2H); 13C NMR (CDCl3) δ 166.5, 162.8, 159.1,
145.3, 139.2, 137.7, 136.5, 131.3, 130.4, 130.1, 129.4, 128.7, 128.5,
128.5, 128.4, 126.4, 121.7, 114.2, 66.6, 55.4, 50.4, 38.1; HRMS
J. Org. Chem. Vol. 74, No. 14, 2009 4979

Brouillette et al.
calcd for [M + H+] C28H24N2O2SCl 487.1247, found 487.1245; Rt
3.19 (method A); Rf 0.6, CHCl3-AcOEt (95:5).
1H), 8.21 (br s, 1H), 7.53 (d, 2H, J ) 8.8 Hz), 7.40 (d, 2H, J )
7.2 Hz), 7.32 (t, 2H, J ) 7.4 Hz), 7.23 (t, 1H, J ) 7.1 Hz), 7.08
(d, 2H, J ) 9.0 Hz), 7.07 (d, 1H, J ) 4.9 Hz), 4.03 (m, 1H), 3.85
(s, 3H), 3.52-3.34 (m, 2H); 13C NMR (DMSO-d6) δ 166.5, 163.9,
162.9, 145.3, 138.0, 137.0, 132.6, 131.3, 129.6, 128.2, 126.4, 122.1,
120.0, 114.0, 63.6, 55.6, 35.1; HRMS calcd for [M + H+]
C21H19N2O2S 363.1167, found 363.1141; Rt 2.17 (method A).
(S)-3-Benzyl-5-(4-chlorophenyl)-1H-thieno[3,2-e][1,4]diazepin-
(S)-1-(4-Methoxybenzyl)-3-methyl-5-phenyl-1H-thieno[3,2-
e][1,4]diazepin-2(3H)-one (16g): yield 86%; white solid, mp
1
58-60 °C; [R]20 56.2 (c 0.1, DMSO); H NMR (DMSO-d6) δ
D
7.86 (d, 1H, J ) 5.4 Hz), 7.51-7.47 (m, 5H), 7.38 (d, 1H, J ) 5.4
Hz), 6.95 (d, 2H, J ) 8.3 Hz), 6.76 (d, 2H, J ) 8.4 Hz), 5.35 (d,
1H, J ) 15.3 Hz), 4.86 (d, 1H, J ) 15.2 Hz), 3.87 (quad, 1H, J )
6.3 Hz), 3.67 (s, 3H), 1.64 (d, 3H, J ) 6.3 Hz); 13C NMR (DMSO-
d6) δ 167.1, 162.1, 158.3, 144.2, 138.4, 130.6, 130.2, 128.9, 128.2,
128.1, 125.5, 122.1, 113.8, 109.1, 59.7, 55.0, 48.5, 18.1; HRMS
calcd for [M + H+] C22H21N2O2S 377.1324, found 377.1308; Rt
2.14 (method A); Rf 0.4, CHCl3-AcOEt (9:1).
2(3H)-one (17f): yield 89%; off-white solid, mp 88-90 °C dec;
1
[R]20 -10.3 (c 0.2, DMSO); H NMR (DMSO-d6) δ 11.41 (s,
D
1H), 8.05 (d, 1H, J ) 5.1 Hz), 7.56 (s, 4H), 7.38 (d, 2H, J ) 7.0
Hz), 7.30 (t, 2H, J ) 7.3 Hz), 7.22 (t, 1H, J ) 7.2 Hz), 6.99 (d,
1H, J ) 5.3 Hz), 3.89 (m, 1H), 3.48 (dd, 1H, J ) 13.7, 5.5 Hz),
3.38 (dd, 1H, J ) 13.7, 8.6 Hz); 13C NMR (DMSO-d6) δ 166.4,
162.3, 144.0, 138.7, 136.4, 136.0, 134.1, 131.5, 129.6, 128.5, 128.1,
126.1, 121.7, 120.3, 65.2, 36.4; HRMS calcd for [M + H+]
C20H16N2OSCl 367.0672, found 367.0663; Rt 2.33 (method A).
(S)-3-Methyl-5-phenyl-1H-thieno[3,2-e][1,4]diazepin-2(3H)-
(S)-1-(4-Methoxybenzyl)-5-(4-methoxyphenyl)-3-methyl-1H-
thieno[3,2-e][1,4]diazepin-2(3H)-one (16h): yield 71%; white
solid, mp 46-50 °C; [R]20D 21.3 (c 0.1, DMSO); 1H NMR (DMSO-
d6) δ 7.83 (d, 1H, J ) 5.4 Hz), 7.45 (d, 2H, J ) 8.5 Hz), 7.35 (d,
1H, J ) 5.3 Hz), 6.98 (d, 2H, J ) 8.8 Hz), 6.94 (d, 2H, J ) 8.9
Hz), 6.75 (d, 2H, J ) 8.2 Hz), 5.32 (d, 1H, J ) 15.4 Hz), 4.86 (d,
1H, J ) 15.4 Hz), 3.83 (quad, 1H, J ) 6.3 Hz), 3.80 (s, 3H), 3.67
(s, 3H), 1.62 (d, 3H, J ) 6.3 Hz); 13C NMR (DMSO-d6) δ 167.4,
161.3, 161.2, 158.3, 144.1, 130.8, 130.5, 130.0, 128.9, 128.0, 125.7,
122.1, 113.8, 113.5, 59.4, 55.3, 55.0, 48.5, 18.1; HRMS calcd for
[M + H+] C23H23N2O3S 407.1429, found 407.1404; Rt 2.23 (method
A); Rf 0.5, CHCl3-AcOEt (9:1).
Typical PMB Removal Procedure for the Synthesis of
5-Aryl-1H-thieno[3,2-e][1,4]diazepin-2(3H)-one (17). A solution
of 1-(4-methoxybenzyl)-5-phenyl-thienodiazepinone 16a (0.100 g,
0.28 mmol) in 6 mL of CH3CN-H2O (3:1) was treated with CAN
(0.757 g, 1.38 mmol) and the mixture was stirred for 2 h at rt.
Volatile material was lyophilized and the residue was partitioned
between H2O and EtOAc. The aqueous phase was extracted with
EtOAc and the combined organic layers were washed with brine,
dried over Na2SO4, filtered, and evaporated. Trituration with a
solution of Et2O-pentane (1:1) afforded pure products 17.
5-Phenyl-1H-thieno[3,2-e][1,4]diazepin-2(3H)-one (17a): yield
54%; white solid, mp 56-58 °C; 1H NMR (DMSO-d6) δ 11.0 (br
s, 1H), 7.88 (d, 1H, J ) 5.3 Hz), 7.63-7.43 (m, 5H), 6.95 (d, 1H,
J ) 5.3 Hz), 4.23 (s, 2H); 13C NMR (DMSO-d6) δ 167.0, 164.2,
142.7, 139.2, 130.9, 130.5, 129.2, 128.1, 121.5, 109.0, 58.4; HRMS
calcd for [M + H+] C13H11N2O1S 243.0592, found 243.0609; Rt
1.27 (method A).
5-(4-Methoxyphenyl)-1H-thieno[3,2-e][1,4]diazepin-2(3H)-
one (17b): yield 60%; light-yellow solid, mp 71 °C dec; 1H NMR
(DMSO-d6) δ 11.50 (br s, 1H), 8.15 (d, 1H, J ) 5.3 Hz), 7.69 (d,
2H, J ) 8.7 Hz), 7.08 (d, 2H, J ) 8.7 Hz), 7.05 (d, 1H, J ) 5.3
Hz), 4.26 (s, 2H), 3.85 (s, 3H); 13C NMR (DMSO-d6) δ 166.5,
165.2, 162.6, 145.0, 136.0, 132.4, 128.1, 122.2, 119.8, 114.0, 55.6,
55.2; HRMS calcd for [M + H+] C14H13N2O2S 273.0698, found
273.0676; Rt 1.48 (method A).
5-(4-Chlorophenyl)-1H-thieno[3,2-e][1,4]diazepin-2(3H)-
one (17c): yield 52%; white solid, mp 201-204 °C dec; 1H NMR
(DMSO-d6) δ 11.69 (s, 1H), 8.24 (d, 1H, J ) 5.1 Hz) 7.76 (d, 2H,
J ) 8.2 Hz), 7.64 (d, 2H, J ) 8.2 Hz), 7.08 (d, 1H, J ) 5.2 Hz),
4.33 (s, 2H); 13C NMR (DMSO-d6) δ 167.8, 165.5, 146.0, 137.7,
137.6, 134.1, 132.3, 128.7, 122.2, 119.0, 55.0; HRMS calcd for
[M + H+] C13H10N2OSCl 277.0202, found 277.0210; Rt 1.55
(method A).
1
one (17g): yield 75%; white solid, H NMR (DMSO-d6) δ 11.52
(br s, 1H), 8.15 (s, 1H), 7.73-7.38 (m, 5H), 7.04 (d, 1H, J ) 5.4
Hz), 3.87 (quad, 1H, J ) 6.3 Hz), 1.64 (d, 3H, J ) 6.3 Hz); HRMS:
calcd for [M + H+] C14H13N2OS 257.0749, found 257.0757; Rt
1.30 (method A).
(S)-5-(4-Methoxyphenyl)-3-methyl-1H-thieno[3,2-e][1,4]dia-
zepin-2(3H)-one (17h): yield 80%; white solid, mp 189-191 °C;
1
[R]20 -135.6 (c 0.1, DMSO); H NMR (DMSO-d6) δ 11.90 (s,
D
1H), 8.37 (d, 1H, J ) 5.4 Hz), 7.77 (d, 2H, J ) 8.6 Hz), 7.17 (d,
2H, J ) 8.9 Hz), 7.15 (d, 1H, J ) 5.4 Hz), 4.07 (quad, 1H, J )
5.7 Hz), 3.89 (s, 3H), 1.63 (d, 3H, J ) 6.0 Hz); 13C NMR (DMSO-
d6) δ 167.2, 165.3, 163.7, 146.8, 133.8, 125.5, 122.3, 118.9, 114.2,
114.2, 56.9, 55.8, 14.3; HRMS calcd for [M + H+] C15H15N2O2S
287.0854, found 287.0825; Rt 1.52 (method A).
Typical Direct Procedure for the Synthesis of 6-Ami-
nothieno[3,2-b]pyridinones (20). A solution of Boc-protected
N-methylthienodiazepinedione 14a (1.200 g, 3.0 mmol) in dry THF
(100 mL) was treated with a commercially available 1.0 M solution
of p-methoxyphenylmagnesium bromide (3.3 mL, 3.3 mmol) in
THF then the mixture was stirred for 5 min at rt. Complete
conversion of starting material was ascertained by LCMS or TLC.
The yellow solution was then treated with a commercially available
1.0 M solution of KOtBu (6.6 mL, 6.6 mmol) in THF and stirred
for 30 min at rt. p-Toluenesulphonic acid (2.500 g, 13.2 mmol)
was added to the cloudy solution and then the solution was stirred
at rt for 10 min. Volatile material was evaporated and the residue
was partitioned between H2O and EtOAc. The aqueous phase was
extracted with EtOAc and the combined organic layers were washed
with brine, dried over Na2SO4, filtered, and evaporated. The residual
20b was further purified by flash column chromatography.
tert-Butyl 4-(4-methoxybenzyl)-7-(4-chlorophenyl)-4,5,6,7-tet-
rahydro-7-hydroxy-5-oxothieno[3,2-b]pyridin-6-ylcarbamate (19c):
light yellow solid, mp 55 °C; 1H NMR (DMSO-d6) δ 8.01 (d, 1H,
J ) 5.1 Hz), 7.61 (d, 2H, J ) 8.5 Hz), 7.56 (d, 2H, J ) 8.5 Hz),
7.08 (d, 1H, J ) 5.1 Hz), 6.95 (s, 1H), 6. 94 (d, 2H, J ) 8.1 Hz),
6.65 (d, 2H, J ) 8.4 Hz), 4.57 (d, 2H, J ) 6.2 Hz), 3.60 (m, 5H),
1.38 (s, 9H); 13C NMR (DMSO-d6) δ 185.7, 168.8, 158.5, 155.7,
142.5, 137.7, 136.7, 133.6, 132.4, 130.8, 129.9, 129.3, 128.5, 128.1,
113.5, 78.0, 54.8, 51.3, 42.7, 28.2; HRMS calcd for [M + H+]
C26H28N2O5SCl 515.1407, found 515.1379; Rt 3.29 (method A); Rf
0.4, DCM-AcOEt (9:1).
(S)-3-Benzyl-5-phenyl-1H-thieno[3,2-e][1,4]diazepin-2(3H)-
one (17d): yield 79%; off-white solid, mp 94-96 °C dec; [R]20
tert-Butyl 4-(4-methoxybenzyl)-4,5-dihydro-5-oxo-7-phenylth-
ieno[3,2-b]pyridin-6-ylcarbamate (20a): yield 52%; beige solid,
D
-14.8 (c 0.1, DMSO); 1H NMR (DMSO-d6) δ 11.46 (s, 1H), 8.08
(s, 1H), 7.54 (m, 5H), 7.31 (m, 5H), 6.79 (s, 1H), 3.96 (s, 1H),
3.42 (m, 2H); 13C NMR (DMSO-d6) δ 166.4, 163.9, 144.4, 138.5,
136.7, 135.0, 131.8, 130.0, 129.6, 128.4, 128.1, 126.2, 121.8, 120.5,
64.8, 36.0; HRMS calcd for [M + H+] C20H17N2OS 333.1062,
found 333.1041; Rt 2.02 (method A); Rf 0.4, CHCl3-AcOEt (4:1).
(S)-3-Benzyl-5-(4-methoxyphenyl)-1H-thieno[3,2-e][1,4]diazepin-
1
mp 198-200 °C; H NMR (DMSO-d6) δ 8.05 (s, 1H), 7.91 (d,
1H, J ) 5.5 Hz), 7.50 (m, 5H), 7.43 (d, 1H, J ) 5.5 Hz), 7.32 (d,
2H, J ) 8.6 Hz), 6.90 (d, 2H, J ) 8.7 Hz), 5.43 (s, 2H), 3.73 (s,
3H), 1.26 (s, 9H); 13C NMR (DMSO-d6) δ 159.8, 158.6, 154.1,
140.8, 135.6, 131.0, 129.4, 128.9, 128.4, 128.0, 121.8, 118.5, 118.0,
114.0, 78.3, 55.1, 47.3, 27.9; HRMS calcd for [M + H+]
C26H27N2O4S 463.1692, found 463.1692; Rt 3.03 (method A); Rf
0.5, DCM-AcOEt (4:1).
2(3H)-one (17e): yield 85%; off-white solid, mp 89-91 °C dec;
1
[R]20 -35.3 (c 0.1, DMSO); H NMR (DMSO-d6) δ 11.65 (s,
D
4980 J. Org. Chem. Vol. 74, No. 14, 2009

From Thienodiazepinediones to Thienopyridinones
tert-Butyl 4-(4-methoxybenzyl)-4,5-dihydro-7-(4-methoxyphe-
nyl)-5-oxothieno[3,2-b]pyridin-6-ylcarbamate (20b): yield 47%;
beige solid, mp 154-157 °C; H NMR (DMSO-d6) δ 7.96 (br s,
C19H20N2O3SCl 391.0883, found 391.0869; Rt 2.93 (method A); Rf
0.4, CHCl3-AcOEt (1:1).
1
Procedure for the Synthesis of 6-(Oxothieno[3,2-b]pyridinyl)-
ureas (22). A solution of thienopyridinone 20b (0.100 g, 0.2 mmol)
in TFA-DCM (1:1) was stirred for 30 min at rt. Complete
conversion of starting material was ascertained by LCMS or TLC.
The reddish solution was then evaporated as best as possible (and
re-evaporated after addition of Et2O). The residue was dissolved
in DCM, treated with the corresponding isocyanate (0.2 mmol),
and stirred for 10 min at rt. Volatile material was evaporated and
the residue was filtered over a frit, washed with H2O and CH3CN,
and dried under vacuum overnight to afford pure 1-(4-(4-meth-
oxybenzyl)-4,5-dihydro-7-(4-methoxyphenyl)-5-oxothieno[3,2-b]py-
ridin-6-yl)-3-(4-chlorophenyl)urea (22): yield 62%; gray solid, mp
1H), 7.88 (d, 1H, J ) 5.5 Hz), 7.44 (d, 2H, J ) 8.4 Hz), 7.39 (d,
1H, J ) 5.6 Hz), 7.31 (d, 2H, J ) 8.4 Hz), 7.06 (d, 2H, J ) 8.5
Hz), 6.89 (d, 2H, J ) 8.5 Hz), 5.41 (s, 2H), 3.81 (s, 3H), 3.71 (s,
3H), 1.28 (s, 9H); 13C NMR (DMSO-d6) δ 159.8, 159.6, 158.6,
154.2, 140.7, 131.5, 130.8, 129.8, 129.4, 128.8, 127.7, 121.6, 118.8,
117.9, 113.9, 113.8, 113.7, 78.2, 55.2, 55.0, 47.3, 28.0; HRMS calcd
for [M + H+] C27H29N2O5S 493.1797, found 493.1779; Rt 3.07
(method A); Rf 0.7, DCM-AcOEt (7:3).
tert-Butyl 4,5-dihydro-4-methyl-5-oxo-7-phenylthieno[3,2-
b]pyridin-6-ylcarbamate (20d): yield 51%; off-white solid, mp
77-79 °C; 1H NMR (CDCl3) δ 7.57 (m, 3H), 7.51 (d, 1H, J ) 5.5
Hz), 7.43 (m, 2H), 7.10 (d, 1H, J ) 5.5 Hz), 6.64 (br s, 1H), 3.80
(s, 3H), 1.23 (s, 9H); 13C NMR (CDCl3) δ 160.1, 152.7, 140.0,
138.5, 136.7, 130.0, 129.0, 128.7, 128.7, 128.0, 121.8, 116.5, 80.3,
32.9, 28.0; HRMS calcd for [M + H+] C19H21N2O3S 357.1273,
found 357.1259; Rt 2.66 (method A); Rf 0.4, CHCl3-AcOEt (1:1).
tert-Butyl 4,5-dihydro-7-(4-methoxyphenyl)-4-methyl-5-oxo-
thieno[3,2-b]pyridin-6-ylcarbamate (20e): yield 49%; beige solid,
mp 81-82 °C; 1H NMR (CDCl3) δ 7.53 (d, 2H, J ) 8.8 Hz), 7.51
(d, 1H, J ) 5.4 Hz), 7.09 (d, 1H, J ) 5.4 Hz), 6.99 (d, 2H, J ) 8.7
Hz), 6.61 (br s, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 1.26 (s, 9H); 13C
NMR (CDCl3) δ 160.1, 160.0, 152.9, 140.0, 138.8, 132.2, 129.4,
129.1, 128.9, 121.7, 116.5, 114.2, 80.2, 55.5, 32.9, 28.1; HRMS
calcd for [M + H+] C20H23N2O4S 387.1379, found 387.1378; Rt
2.63 (method A); Rf 0.3, CHCl3-AcOEt (1:1).
1
186-188 °C; H NMR (DMSO-d6) δ 8.95 (s, 1H), 7.90 (d, 1H, J
) 5.5 Hz), 7.65 (s, 1H), 7.49 (d, 2H, J ) 8.6 Hz), 7.44 (d, 1H, J
) 5.6 Hz), 7.37 (d, 2H, J ) 8.6 Hz), 7.34 (d, 2H, J ) 8.6 Hz),
7.26 (d, 2H, J ) 8.8 Hz), 7.05 (d, 2H, J ) 8.6 Hz), 6.90 (d, 2H,
J ) 8.5 Hz), 5.44 (s, 2H), 3.79 (s, 3H), 3.72 (s, 3H); 13C NMR
(DMSO-d6) δ 159.8, 159.4, 158.6, 153.3, 141.0, 140.0, 139.0, 130.3,
129.3, 128.9, 128.8, 128.4, 128.1, 124.9, 121.6, 119.5, 119.3, 117.9,
113.9, 113.8, 55.1, 55.0, 47.4; HRMS calcd for [M + H+]
C29H25N3O4SCl 546.1254, found 546.1225; Rt 2.99 (method A).
Acknowledgment. This work was supported by grants from
the Socie´te´ de Chimie The´rapeutique (SCT) and the Laboratoires
Servier. The authors thank Mr. Pierre Sanchez and Dr. Pascal
Verdie´ for performing mass spectral analyses. Y.B. thanks the
Laboratoires Servier for a doctoral scholarship.
tert-Butyl 7-(4-chlorophenyl)-4,5-dihydro-4-methyl-5-oxo-
thieno[3,2-b]pyridin-6-ylcarbamate (20f): yield 55%; beige solid,
mp 120-121 °C; 1H NMR (DMSO-d6) δ 8.07 (br s, 1H), 7.97 (d,
1H, J ) 5.5 Hz), 7.59 (d, 2H, J ) 5.4 Hz), 7.48 (d, 2H, J ) 8.5
Hz), 7.44 (d, 1H, J ) 5.6 Hz), 3.70 (s, 3H), 1.25 (s, 9H); 13C NMR
(DMSO-d6) δ 159.5, 153.8, 141.5, 134.5, 133.5, 130.8, 129.8, 128.5,
121.6, 117.8, 117.6, 78.4, 32.4, 27.8; HRMS calcd for [M + H+]
Supporting Information Available: Experimental details and
1H and 13C NMR spectral data for compounds 6-13, 14a, 16,
17, 19c, 20, and 22. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO900627A
J. Org. Chem. Vol. 74, No. 14, 2009 4981