Valuable versatile reactivity of thiaisatoic anhydrides: Expedient solid-phase synthesis of thieno[1,4]diazepine-2,5-diones

Article abstract of DOI:10.1055/s-2008-1078210

An expedient route for the generation of substituted thieno[3,2-e][1,4] diazepine-2,5-dione analogues is described herein. It was demonstrated in solution that thiaisatoic anhydride and its N-alkylated equivalents react in opposite ways with amino acids in basic conditions. This versatile reactivity was used to develop an efficient strategy on solid support. Wang resin-bound thiaisatoic anhydride was coupled with N-alkylated α-amino acids, cyclo-condensed and effectively cleaved from the polymer to provide a preliminary collection of thieno[3,2-e][1,4]diazepine-2,5-diones in 83-99% purity and 71-95% yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078210

2360
LETTER
Valuable Versatile Reactivity of Thiaisatoic Anhydrides: Expedient Solid-
Phase Synthesis of Thieno[1,4]diazepine-2,5-diones
T
hienodiazepinedi
a
ones
S
PS nn Brouillette, Pascal Verdié, Jean Martinez, Vincent Lisowski*
Institut des Biomolécules Max-Mousseron, UMR 5247, CNRS, Universités Montpellier I et II, UFR de Sciences Pharmaceutiques et Bio-
logiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France
Fax +33(4)67548654; E-mail: vincent.lisowski@univ-montp1.fr
Received 3 June 2008
O
H
basic
conditions
Abstract: An expedient route for the generation of substituted
thieno[3,2-e][1,4]diazepine-2,5-dione analogues is described here-
in. It was demonstrated in solution that thiaisatoic anhydride and its
N-alkylated equivalents react in opposite ways with amino acids in
basic conditions. This versatile reactivity was used to develop an ef-
ficient strategy on solid support. Wang resin-bound thiaisatoic an-
hydride was coupled with N-alkylated a-amino acids, cyclo-
condensed and effectively cleaved from the polymer to provide a
preliminary collection of thieno[3,2-e][1,4]diazepine-2,5-diones in
83–99% purity and 71–95% yield.
N
C
O
N
O
O
S
S
O
O
1
2
route B:
route A:
1) α-amino acids
H2O, Et3N, r.t.
2) H+
α-amino acids
H2O, 40 °C
Key words: 1H-thieno[3,2-d][1,3]oxazine-2,4-dione, thiaisatoic
anhydride, 3,4-dihydro-1H-thieno[3,2-e][1,4]diazepine-2,5-dione,
thienodiazepines, solid-phase synthesis
CO2H
NH2
H
HN
HN
R
N
CO2H
S
O
O
R
CO2H
S
The well-known diazepine-containing cholecystekinin
(CCK) receptor antagonists (L364,718 and L365,260)
were recently reported by our group to also inhibit the p38
mitogen-activated protein kinase (MAPK) activity with a
possible interaction with its ATP binding site as demon-
strated in dynamic docking studies.1 The p38 MAP kinase
has emerged as an attractive target for chemotherapy of
rheumatoid arthritis and other inflammatory disorders,
with several inhibitors currently undergoing clinical tri-
als.2–5 Therefore, part of our efforts is today directed to-
wards the design of selective p38 MAPK heterocyclic-
fused diazepine-based inhibitors. The diazepine scaffold
is one of the classical examples of privileged structures
which has proved its effectiveness in a number of pharma-
ceutical drugs and still continues to attract much interest
today in medicinal chemistry.6–12 In this context, the syn-
thesis of combinatorial focused libraries is a valuable tool
to explore structure–activity relationships and the main
key for the success of such an approach is the use of par-
allel solid-phase organic synthesis. In this paper we report
an expedient solid-supported synthesis of substituted
thienodiazepinediones employing an N-polymer-bound
thiaisatoic anhydride as starting material.
4
3
R = α-amino acid side chains
Scheme 1 Known reactivity of anhydride 1 with a-amino acids
dazolidinediones18 and thienodiazepinediones.19 In our
previous studies, we demonstrated that 1H-thieno[3,2-
d][1,3]oxazine-2,4-dione (1) reacts in an opposite way to
isatoic anhydride when treated by a-amino acids (a-aa) in
basic protic or aprotic conditions to afford ureidodiacid
(3) by oxazine ring opening at the carbamic carbonyl
(route B, Scheme 1).18 Surprisingly, the selectivity of this
nucleophilic attack can be satisfyingly reversed in favor of
the carboxylic carbonyl to restore an isatoic anhydride-
like reactivity in neutral protic conditions (amide 4, route
A, Scheme 1).19 This unexpected result demonstrated that
the basicity of the medium and the nature of the solvent
have a great importance in the course of the reaction. Sup-
ported by a kinetic study of the reactions of amines with
isatoic anhydride,20 we hypothesized the existence of an
isocyanate intermediate 2 for which the formation could
be subordinated to ionization of oxazine 1 in basic condi-
tions, directing the nucleophilic attack toward the forma-
tion of the ureidodiacid (3, Scheme 1).
Since isatoic anhydrides13 are versatile intermediates in
medicinal and organic chemistry,14–17 we recently report-
ed regioselective ring opening of the isatoic anhydride
isoster 1 by nucleophilic attack of a-amino acids to pro-
vide two libraries of optically pure thienylimi-
While many different solid-phase approaches exist for the
benzodiazepine scaffold,21 to the best of our knowledge,
only one example has been described for the thiophene se-
ries in a five-step process from a resin-bound aldehyde.22
The previously discussed postulate of the isocyanate in-
termediate formation in basic conditions led us to imagine
that the alkylation of the thiaisatoic anhydride’s nitrogen
would impede the nucleophilic attack on the carbamic car-
SYNLETT 2008, No. 15, pp 2360–2364
1
5
.0
9
.2
0
0
8
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1078210; Art ID: G18808ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Thienodiazepinediones SPS
2361
R1
bonyl. Consequently, attaching thiaisatoic anhydride 1 on
solid support by its nitrogen would allow its regioselective
ring opening and afford the expected N-substituted
thieno[3,2-e][1,4]diazepine-2,5-diones.
O
O
H
N
R1X, K2CO3
DMF, r.t., 1 h
N
O
O
S
S
O
O
To validate our strategy, we first studied in solution the re-
activity of the previously reported23 N-methyl thiaisatoic
anhydride (5) towards its reaction with cyclic (Pro), acy-
clic (Gly, Ala), bulky (Phe) and N-alkylated (Sar) amino
acids in formerly described conditions (H2O, 40 °C, 10
equiv a-aa).19 As expected, a slow (8–24 h) but complete-
ly selective nucleophilic attack was observed to afford the
amides 7 as detected by LC-MS. Reaction time can be
drastically reduced to five minutes by a preactivation of
the a-aa with Et3N to afford at room temperature the same
amides 7 with the same total selectivity (Scheme 2).
Therefore, thiaisatoic anhydride 1 and its N-methyl coun-
terpart 5, submitted to the same aqueous basic conditions
(route B, Scheme 1 for 1; Scheme 2 for 5), led to a com-
plete opposite reactivity. The corresponding acquired
amides 7 were then cyclized in refluxing AcOH for one to
six hours to afford the thieno[3,2-e][1,4]diazepinedione
analogues 9 (Scheme 2) in 55–79% yield from anhydride
5. This favorable reactivity of N-methyl thiaisatoic anhy-
dride (5), with no labile hydrogen, prompted us to contin-
ue our investigation for the application of this approach on
solid support. Reactivity of the N-p-methoxybenzylthia-
isatoic anhydride (6) was thus studied in solution as a
mimic of the solid-supported Wang resin linker. Anhy-
dride 6 was synthesized by alkylation of thiaisatoic anhy-
dride 1 with p-methoxybenzyl chloride (PMBCl) in 81%
yield, using an inorganic base (K2CO3) in anhydrous
DMF at room temperature for one hour. The akin amides
8 were consequently obtained by ring opening of anhy-
dride 6 with the same natural and synthetic a-amino acids
in the presence of Et3N in water at room temperature for
five minutes. Addition of DMF drops was necessary for
PMB-bearing compounds complete solubility. Accord-
ingly, diazepines 10 were then obtained in 64–98% yield
from anhydride 6 by cyclocondensation of amides 8 in re-
fluxing AcOH for 4–6 h (Scheme 2). Interestingly, it was
observed that in the case of N-alkylated amino acids such
as Sar and Pro, heating in the previous step was sufficient
to convert the precursors 7c,d and 8c,d into N-substituted
diazepines 9c,d and 10c,d, respectively. As previously de-
scribed for proline-containing peptides,24 the N-alkylated
amide bond of the pseudo-dipeptides 7c,d and 8c,d must
have a cis/trans geometry which facilitates this cyclocon-
densation.
5, R1 = Me, 83%
6, R1 = PMB, 81%
1
R2
R3
N
CO2H
H
Et3N
H2O, r.t., 5 min
R1
R1
O
NH
N
R2
R3
R3
N
AcOH
N
CO2H
reflux, 1–6 h
S
S
O
O
R2
9, R1 = Me, 55–79%
10, R1 = PMB, 64–98%
a, R2 = H, R3 = H
7, R1 = Me
8, R1 = PMB
b, R2 = Me, R3 = H
c, R2 = H, R3 = Me
d, R2, R3 = –(CH2)3–
e, R2 = Bn, R3 = H
Scheme 2 Reactivity of N-substituted thiaisatoic anhydride
and 1721 cm–1; moreover, the C–Br band at 592 cm–1 dis-
appeared. Quantitatively, the loading of the resin was as-
certained by treating a measured amount of the resin-
bound anhydride 11 twice with 50% TFA in CH2Cl2 at
room temperature for 30 minutes and evaluating its recov-
ery. Resin-bound amides 12 were produced by treatment
of anhydride 11 with a variety of amino acids (500 mol%)
in the presence of Et3N (1000 mol%), in a mixture of
H2O–DMF (1:4). The combination of DMF and water was
necessary to allow decent swelling of the polystyrene res-
in and complete solubility of the amino acids. Glycine,
alanine, and proline analogues as well as phenylalanine
were chosen to attack the resin-bound anhydride 11. Aze-
tidine-2-carboxylic and pipecolic acids were also used to
study the ring constraint of the following cyclocondensa-
tion. It was observed that heating at 50 °C was necessary
for the total conversion of anhydride 11 into the corre-
sponding resin-bound amide 12.
Treatment of resin-bound anhydride 11 with natural a-aa
(where R3 = H), such as Ala (R2 = Me) and Phe (R2 = Bn),
allowed the formation of the supported amides 12. How-
ever, the solid-phase cyclocondensation to the diazepines
using acidic conditions (AcOH, r.t. to 80 °C) or coupling
reagents (such as DIC–HOBt, BOP–HOBt, HBTU–
DIEA, and EDC) proved to be unsuccessful. Cleavage
from the resin using TFA–CH2Cl2 (1:1) at room tempera-
ture for 30 minutes only delivered the uncyclized acids. In
spite of this failure, the formation of the corresponding di-
azepines was pursued in solution by heating the acidic res-
in filtrates at reflux for 24 hours. Nonetheless, this
alternative solid-phase approach with a-aa (where
Our solution-phase protocol was adapted to the solid
phase using the commercially affordable, widely used,
and easily cleavable Wang resin.25,26 Resin-bound thiaisa-
toic anhydride 11 was synthesized by attachment of anhy-
dride 1 to 4-(bromomethyl)phenoxymethyl polystyrene
(Wang bromide resin)27–29 using K2CO3 in DMF at room
temperature for one hour (Scheme 3).30,31 Qualitatively,
anchoring of the loaded resin 11 was indicated by IR spec-
troscopy of resin samples. Sharp indicative signals were
observed for C=O stretching bands, respectively, at 1774
Synlett 2008, No. 15, 2360–2364 © Thieme Stuttgart · New York

2362
Y. Brouillette et al.
LETTER
O
Table 1 N-Substituted Thienodiazepinediones 14a–h SPOS
H
N
Entry
Structure
Yield (%)a Purity (%)b
O
PS
Br
O
S
O
O
HN
1
Br
brominated
Wang resin
1
95
90
92
83
:
N
Br
S
O
K2CO3
DMF, r.t., 1 h
O
HN
HN
HN
R2
2
3
R3
NH
N
O
N
N
CO2H
R3
N
S
S
S
H
O
O
O
O
CO2H
Et3N
S
O
S
O
R2
DMF–H2O (4:1)
50 °C, 5 h
O
80
95
99
90
12a–h
11
N
50 °C
O
O
O
HN
R2
R3
N
R2
R3
TFA–CH2Cl2 (1:1)
r.t., 24 h
N
4
N
N
S
S
O
O
14a–h
13a–h
Scheme 3 Solid-phase synthesis of thienodiazepinedione analogues
O
HN
HN
HN
HN
5
6
7
8
86
79
88
71
98
83
95
86
R3 = H) did not give higher yields and purities than our
previously reported solution-phase protocol.19 On the oth-
er hand, in accordance with our previous solution study
with N-alkylated a-aa, simply heating the reaction mix-
tures of the solid-supported amides 12a–h (where
R3 = alkyl) at 50 °C in DMF–H2O (4:1) for five hours di-
rectly afforded the corresponding resin-bound thienodiaz-
epines 13a–h. These observations demonstrated that
partial cis conformation induced by N-alkylation
(R3 π H) is essential for a cyclization in nonacidic condi-
tions, in both solution- and solid-phase approaches.
N
S
S
S
S
O
O
O
O
O
OH
N
O
OH
N
Cleavage of the products from the resin was effected by
treating resins 13a–h twice with TFA–CH2Cl2 (1:1) at
room temperature for 30 minutes. A mixture of NH- and
N-p-hydroxybenzyl thienodiazepines was obtained as in-
ferred by LC-MS analysis. The N-hydroxybenzylated
diazepines were presumed to originate from an anom-
alous cleavage of the benzyl ether bond through which
p-hydroxybenzyl bromide was attached to Merrifield
resin.32–34 Although the use of a 2-(4-bromomethylphen-
oxy)ethyl polystyrene resin or HF cleavage are suggested
to avoid formation of hydroxybenzylated byproduct aris-
ing from breakdown of the linker, these approaches are
expensive or necessitate special equipment. In our case,
the prolonged stirring in TFA–CH2Cl2 (1:1) for an extra
23 hours afforded the diazepines 14 as sole product after
filtration of the resin, evaporation of the filtrate, and tritu-
ration with an Et2O–pentane (1:1) mixture. In this manner,
optically pure thienodiazepinediones 14 of high purity
(83–99%) were obtained in 71–95% yield (Table 1).
O
N
a Based on ascertained loading of resin 11.
b As determined by reversed-phase HPLC with monitoring at 214 nm.
These results prove the effectiveness of this methodology
with cyclic and acyclic N-alkylated a-aa, and allow a con-
sequent diversification (R2, R3) to design potential MAPK
inhibitors.
In conclusion, we demonstrated that thiaisatoic anhydride
1 and its N-alkylated derivatives react in an opposite man-
ner with a-amino acid nucleophiles in basic conditions,
providing evidence of the isocyanate 2 equilibrium. This
Synlett 2008, No. 15, 2360–2364 © Thieme Stuttgart · New York

LETTER
Thienodiazepinediones SPS
2363
J. D. J.; Beher, D.; Tang, Y. S.; Liu, W. S. J. Med. Chem.
2003, 46, 2275.
finding was used to prepare in solution a library composed
of ten N-substituted thieno[3,2-e][1,4]diazepine-2,5-di-
one analogues 9 and 10 in 55–98% yield.35,36 Transposi-
tion of this protocol to the solid-phase allowed the initial
synthesis of a series of eight 1H-thieno[3,2-e][1,4]diaz-
epine-2,5-dione analogues 14 in purities and yields of 83–
99% and 71–95%, respectively, in a three-step process.37
The potential of this protocol is now being explored for
preparing large libraries of structurally diverse thienodi-
azepines that may have beneficial uses in the MAPK inhi-
bition field.
(12) Hunt, J. T.; Ding, C. Z.; Batorsky, R.; Bednarz, M.; Bhide,
R.; Cho, Y.; Chong, S.; Chao, S.; Gullo-Brown, J.; Guo, P.;
Kim, S. H.; Lee, F. Y. F.; Leftheris, K.; Miller, A.; Mitt, T.;
Patel, M.; Penhallow, B. A.; Ricca, C.; Rose, W. C.;
Schmidt, R.; Slusarchyk, W. A.; Vite, G.; Manne, V. J. Med.
Chem. 2000, 43, 3587.
(13) For a review on the chemistry of isatoic anhydride, see:
Coppola, G. M. Synthesis 1980, 505.
(14) Beutner, G. L.; Kuethe, J. T.; Yasuda, N. J. Org. Chem.
2007, 72, 7058.
(15) Kamel, A. A.; Abdou, W. M. Synlett 2007, 1269.
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D. K. H.; Rakhit, S.; Gaudreault, R. C. Bioorg. Med. Chem.
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(17) Snider, B. B.; Wu, X. X. Org. Lett. 2007, 9, 4913.
(18) Brouillette, Y.; Lisowski, V.; Guillon, J.; Massip, S.;
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(19) Brouillette, Y.; Lisowski, V.; Martinez, J. J. Org. Chem.
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(20) Bunnett, J. F.; Naff, M. B. J. Am. Chem. Soc. 1966, 88, 4001;
and cited references therein.
(21) For a review on the recent advances in the solid-phase
combinatorial synthetic strategies of the benzodiazepine-
based privileged structures, see: (a) Kamal, A.; Reddy,
K. L.; Devaiah, V.; Shankaraiah, N.; Reddy, D. R. Mini-Rev.
Med. Chem. 2006, 6, 53. (b) Kamal, A.; Shankaraiah, N.;
Prabhakar, S.; Ratna, R. e. d. d. y. C.; Markandeya, N.;
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by grants from Société de Chimie Théra-
peutique (SCT) and the Laboratoires Servier. The authors thank Mr.
Pierre Sanchez for performing mass spectral analyses as well as
Professors F. Fabis and S. Rault for initial scientific discussion.
Y.B. thanks the Laboratoires Servier for a doctoral scholarship.
References and Notes
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Garcin, G.; Martinez, J. J. Comb. Chem. 2007, 9, 254.
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J. A. J. Org. Chem. 1997, 62, 1240.
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(35) Typical Experimental Procedure for the Ring Opening
of Thiaisatoic Anhydrides 5 and 6
A stirring suspension of N-p-methoxybenzylthieno[3,2-
d][1,3]oxazine-2,4-dione (6, 7.00 g, 24.22 mmol) and the
corresponding a-amino acid (26.64 mmol) in H2O (100 mL)
was treated with Et3N (7.43 mL, 53.29 mmol) at r.t. for 30
min. Drops of DMF can be added to favor complete
solubility. The resulting solution was partitioned with
EtOAc. The aqueous phase was extracted with EtOAc (3 ×
40 mL) and the combined organic layers were washed with
brine, dried over Na2SO4, filtered, and evaporated to afford
the corresponding product 8.
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C.; Hess, P.; Treiber, A.; Thorin, E.; Morrison, K.;
Buchmann, S.; Bur, D.; Ramuz, H.; Clozel, M.; Fischli, W.;
Weller, T. J. Med. Chem. 2004, 47, 2776.
Acid 8e: white solid, mp 68–70 °C; [a]D20 –18.7 (c 0.3,
DMSO). 1H NMR (300 MHz, DMSO-d6): d = 7.57 (m, 2 H),
7.46 (d, 1 H, J = 5.4 Hz), 7.26 (m, 5 H), 7.22 (d, 2 H, J = 7.3
(11) Churcher, I.; Williams, S.; Kerrad, S.; Harrison, T.; Castro,
J. L.; Shearman, M. S.; Lewis, H. D.; Clarke, E. E.; Wrigley,
Synlett 2008, No. 15, 2360–2364 © Thieme Stuttgart · New York

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Y. Brouillette et al.
LETTER
130.8, 129.5, 128.9, 128.4, 128.2, 126.5, 124.9, 122.7,
113.9, 55.0, 55.0, 48.6, 34.3. HRMS: m/z calcd for
C22H21N2O3S [M + H+]: 393.1273; found: 393.1298; Rf = 0.4
(CHCl3–EtOAc, 4:1).
Hz), 6.87 (d, 2 H, J = 7.1 Hz), 6.74 (d, 1 H, J = 5.4 Hz), 4.52
(q, 1 H, J = 8.0), 4.31 (d, 2 H, J = 5.5), 3.71 (s, 3 H), 3.10 (d,
2 H, J = 8.0 HZ). 13C NMR (75 MHz, DMSO-d6): d = 173.4,
164.6, 158.3, 154.5, 138.3, 131.8, 129.1, 129.0, 128.4,
128.1, 126.3, 117.6, 113.9, 100.6, 55.0, 53.6, 47.5, 36.1.
HRMS: m/z calcd for [M + H+] C22H23N2O4S: 411.1379;
found: 411.1360.
(37) General SPS Procedure
Wang bromide resin (5.0 g, 1.6 mmol/g) was swollen in 50
mL of DMF, treated with anhydride 1 (2.03 g, 12.0 mmol)
and K2CO3 (2.21 g, 16.0 mmol) for 1 h at r.t. and
sequentially washed with H2O, DMF, and CH2Cl2 to afford
the beige resin-bound anhydride 11. Thienodiazepine resin
13 was synthesized by treating a suspension of resin 11
(0.400 g, 0.56 mmol) in DMF–H2O (10 mL, 4:1) with the
respective amino acid (500 mol%) and Et3N (1000 mol%)
for 5 h at 50 °C, and then washed with DMF, H2O, and
CH2Cl2. Thienodiazepines 14 were obtained by treating
diazepine resin 13 (0.400 g, 0.52 mmol) with TFA–CH2Cl2
(8 mL, 1:1) for 24 h.
(36) Typical Experimental Procedure for the Synthesis of
Thieno[3,2-e][1,4]diazepinediones 9 and 10
A solution of acid 8 in AcOH was magnetically stirred at
reflux for 1–6 h. The resulting solution was concentrated
under reduce pressure and triturated with Et2O to afford the
corresponding thienodiazepine 10. This procedure can be
directly applied to the crude mixture of acids 7 and 8, after
evaporation of volatile material, to attain a one-flask
protocol directly to thienodiazepines 9 and 10. The workup
remains the same.
(S)-1-(4-Methoxybenzyl)-3-benzyl-3,4-dihydro-1H-
thieno[3,2-e][1,4]diazepine-2,5-dione (10e): orange solid,
mp 66–68 °C; [a]D20 +27.5 (c 0.1, DMSO). 1H NMR (300
MHz, DMSO-d6): d = 8.50 (d, 1 H, J = 3.5 Hz), 7.81 (d, 1 H,
J = 5.3 Hz), 7.37–7.20 (m, 6 H), 7.03 (d, 2 H, J = 8.5 Hz),
6.81 (d, 2 H, J = 8.6 Hz), 5.23 (d, 1 H, J = 15.5 Hz), 4.89 (d,
1 H, J = 15.5 Hz), 4.17 (m, 1 H), 3.68 (s, 3 H), 3.24 (dd, 1 H,
J = 13.8, 5.3 Hz), 2.98 (dd, 1 H, J = 13.5, 9.0 Hz). 13C NMR
(75 MHz, DMSO-d6): d = 168.6, 162.8, 158.4, 140.4, 137.8,
(S)-3,4-Dihydro-3,4-dimethylthieno[3,2-e][1,4]diazepine-
2,5-dione (14b): beige solid, mp 191–194 °C; [a]D20 +51.6 (c
0.1, DMSO). 1H NMR (300 MHz, DMSO-d6): d = 10.91 (s,
1 H), 7.78 (d, 1 H, J = 5.1 Hz), 6.80 (d, 1 H, J = 5.1 Hz), 4.20
(q, 1 H, J = 6.9 Hz), 2.93 (s, 3 H), 1.34 (d, 3 H, J = 7.0). 13
C
NMR (75 MHz, DMSO-d6): d = 169.2, 162.5, 138.1, 131.4,
128.5, 121.3, 54.7, 30.8, 12.6. HRMS: m/z calcd for
C8H11N2O2S [M + H+]: 211.0541; found: 211.0575.
Synlett 2008, No. 15, 2360–2364 © Thieme Stuttgart · New York

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