Synthesis and reactivity of pyrrolo[3,2-d][1,3]oxazine-2,4-dione. Access to new pyrrolo[3,2-e][1,4]diazepine-2,5-diones

Article abstract of DOI:10.1016/j.tet.2014.05.046

A convenient synthesis of pyrrolo[3,2-d][1,3]oxazine-2,4-dione 4 is described and its reactivity towards various nucleophiles studied. The regioselective ring opening of anhydride 4 or its N-alkylated analog 25 in the presence of alanine or proline afforded, respectively, imidazolidinedione 22 and N-protected pyrrolo[3,2-e][1,4]diazepines 30 and 31 in a one-pot process. In a last part of this study, an alternative route to produce a library of eight non protected pyrrolo[3,2-e][1,4]diazepine-2,5-diones 35a-h is described to overcome the limited reactivity of anhydride 4.

Full text of DOI:10.1016/j.tet.2014.05.046

Tetrahedron 70 (2014) 4631e4639
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and reactivity of pyrrolo[3,2-d][1,3]oxazine-2,4-dione.
Access to new pyrrolo[3,2-e][1,4]diazepine-2,5-diones
Jean-Daniel Malcor, Yann Brouillette, Julien Graffion, Kim Spielmann, Nicolas Masurier,
*
Ludovic T. Maillard, Jean Martinez, Vincent Lisowski
ꢀ
ꢀ
Institut des Biomolecules Max-Mousseron, UMR 5247, CNRS, Universites Montpellier I & II, ENSCM, UFR de Sciences Pharmaceutiques et Biologiques, 15
Avenue Charles Flahault, 34093 Montpellier, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 April 2014
Received in revised form 7 May 2014
Accepted 8 May 2014
Available online 20 May 2014
A convenient synthesis of pyrrolo[3,2-d][1,3]oxazine-2,4-dione 4 is described and its reactivity towards
various nucleophiles studied. The regioselective ring opening of anhydride 4 or its N-alkylated analog 25
in the presence of alanine or proline afforded, respectively, imidazolidinedione 22 and N-protected
pyrrolo[3,2-e][1,4]diazepines 30 and 31 in a one-pot process. In a last part of this study, an alternative
route to produce a library of eight non protected pyrrolo[3,2-e][1,4]diazepine-2,5-diones 35aeh is de-
scribed to overcome the limited reactivity of anhydride 4.
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Pyrrolo[d]oxazine-2,4-dione
Pyrrolodiazepine-2,5-dione
Diazepines
Imidazolidine-2,4-dione
3-Aminopyrrole derivatives
1. Introduction
Access to 3,4-dihydro[1,4]diazepine-2,5-diones has been ex-
tensively studied due to their remarkable biological applications.
Natural and synthetic benzo-fused derivatives have proved their
effectiveness as antitumor agents,1e4 antiamebics,5 antith-
rombotics,6 and bactericides.7 To investigate new analogous
structures, particular attention has been paid to the replacement of
the fused benzene ring by a heterocyclic ring, such as imidazole,8e13
indole,14 furan,15 pyridine,16 isothiazole,17 isoselenoazole,17 quino-
line,18 benzothiophene,19 pyridothiophene.20 In this context, we
recently developed a synthetic pathway to produce thiophene-
fused analogs.21e23
Among other structures, isatoic anhydride and its heterocyclic
analogs have emerged as powerful building blocks to prepare such
[1,4]diazepine-2,5-dione scaffolds. Chemistry of the isatoic anhy-
dride 1 has been extensively studied but that of its derivatives re-
mains less known. The pyridine-based nitrogen-containing
analogs, pyrido[d][1,3]oxazine-2,4-diones 2 (Fig. 1), are among the
most studied derivatives24e26 but other heteroaromatic derivatives
have drawn much less attention.27 The study of oxazine-2,4-diones
Fig. 1. Well-known cyclo[d]oxazine-2,4-diones structures and target compounds.
incorporating heterocyclic five-membered ring, such as thiophene
analogs 3 arose recently.28e39 However, pyrrolo[d]oxazine-2,4-
diones have received very little attention. In continuation of our
recent work on the reactivity of thiaisatoic anhydrides 3 and our
interest in preparing new diazepine platforms, we hereby report
our preliminary results allowing access to a new pyrrole-fused
oxazine-2,4-dione (pyrrolo[3,2-d][1,3]oxazine, analog 4). Its re-
activity and its ability to afford pyrrolo[3,2-e][1,4]diazepinediones
have been studied.
* Corresponding author. Tel.: þ33 (0)411759599; e-mail address: vincent.li-
sowski@univ-montp1.fr (V. Lisowski).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.046

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J.-D. Malcor et al. / Tetrahedron 70 (2014) 4631e4639
2. Results and discussion
under microwave irradiation resulted in a faster conversion, it did
not increase the yield. Similarly, the use of triphosgene or other
carbonylation agents (ClCO2Et, ClCO2CCl3) did not improve the yield.
2.1. Synthesis of anhydride 4
Up to now, two out of three possible ring-incorporations be-
tween pyrrole and oxazinedione have been described in the liter-
ature. Series of pyrrolo[2,3-d][1,3]oxazines 6 and pyrrolo[3,4-d]
[1,3]oxazine-2,4-dione 8 were prepared by cyclization of amino-
2.2. C-2 carbonyl reactivity of N-unsubstituted pyrrolo[3,2-d]
[1,3]oxazine 4
In order to study the reactivity of oxazinedione 4, various nu-
cleophiles, such as amines, alcohols, thiols and amino acids were
evaluated for their ability to react with the C-2 carbonyl with
a subsequent ring opening. Firstly, the reaction of anhydride 4 with
an aliphatic amine, such as isopropylamine, at room temperature
for 5 min (Scheme 3) provided the expected ureido acid 13, which
quickly decarboxylated into analog 14 as demonstrated by analyt-
ical HPLC at 214 nm. The carboxylic acid moiety of urea 13, unlike
analogs in thiophenic series, was not isolated due to the well-
tert-butoxycarbonylpyrroles
5
and
7
using phosgene or
triphosgene.10,40e44 However, to the best of our knowledge, no
route has been described for anhydride 4 (Scheme 1).
known instability of the carboxylic acid on the
a position of pyr-
roles. Addition of HCl 10% (until pH<7) under stirring led to the
total decarboxylation of acid 13 into pyrrole 14 in a quantitative
yield in few minutes. Amide 15, resulting from the isopropylamine
attack on the C-4 carbonyl, was not detected by HPLC-MS analysis,
in agreement with observations made in the thiophene series.36,46
Scheme 1. Published synthesis of pyrrolo[d][1,3]oxazinediones.
The synthesis of anhydride 4 was performed in five steps starting
from commercially available isoxazole (Scheme 2). The sodium
enolate 9, obtained by prior treatment of isoxazole with sodium
ethylate at 0 ꢀC, was condensed on diethyl aminomalonate in
presence of acetic acid and sodium acetate.45 The enamine 10 was
sufficiently stable to be isolated by flash chromatography on silica
gel with 78% yield. Access to ethyl 3-amino-1H-pyrrole-2-
carboxylate 11 was performed by intramolecular cyclization of en-
amine 10 in refluxing sodium ethylate in ethanol for 18 h. Com-
pound 11 was isolated in 65% yield according to procedure
developed by Furneaux et al.45 Subsequently, compound 12 was
obtained by saponification of ester 11 in a refluxing aqueous solution
of potassium hydroxide for 8 h. Compound 12 was not isolated but
its formation was ascertained by the disappearance of ester 11 and
the appearance of a polar spot on the baseline during TLC elution.
Anhydride 4 was thus obtained in 40% overall yield by reaction of 12
with phosgene. This moderate yield could be explained by degra-
dation of the pyrrole ring during the saponification step. Attempts
using milder conditions with other bases (such as LiOH) in refluxing
THF or DCM did not lead to any improvement. Although heating
Scheme 3. Reactivity of the pyrrole anhydride 4 with various nucleophiles.
To further investigate the C-2 reactivity, anhydride 4 was also
reacted with ethanol as a primary alcohol model. Treatment at
room temperature did not lead to any reaction. In refluxing ethanol
for 2 h, the reaction resulted in 70% conversion of the starting
material leading to a mixture of acid 16 (40%) and carbamate 17
(30%) (Scheme 3). In these conditions, no trace of aminoester 11
corresponding to a C-4 attack was observed. Alternatively, carba-
mate 16 was quantitatively obtained with a total conversion of
starting material using sodium ethylate at room temperature for
10 min. Because acid 16 only led to a partial decarboxylation during
workup, a few drops of hydrochloric acid (until pH<7) were di-
rectly added to complete the decarboxylation process into carba-
mate 17. To carry on this reactivity study, the ring opening of the
oxazine 4 was also examinated using thiols, such as propane-2-
thiol in water at room temperature. No conversion of anhydride 4
was observed after 24 h stirring at room temperature in water.
Quantitative conversion of anhydride 4 into acid 18 in less than
5 min was obtained in basic conditions by adding triethylamine
(Scheme 3). The compound 18 was isolated from the mixture by
semi-preparative HPLC. Once again, no trace of the carbothioate 20
corresponding to an attack on C-4 was detected. Treating acid 18
with hydrochloric acid led to its quantitative conversion into car-
bothioate 19 within 5 min in water.
Based on these results and inspired by our previous work on the
Scheme 2. Pyrrolo[3,2-d][1,3]oxazine-2,4-dione synthesis.
reactivity of thiaisatoic anhydrides,21,46 oxazine 4 was reacted with

J.-D. Malcor et al. / Tetrahedron 70 (2014) 4631e4639
4633
the alanine amino acid (Ala) in presence of triethylamine in water
at room temperature. The reaction resulted in the formation of the
expected ureido acid 21 in less than 15 min (Scheme 4). This
compound 21 was immediately heated in acidic conditions for
30 min allowing decarboxylation and cyclization into imidazolidi-
nedione 22 in 75% yield.
oxazine-2,4-dione 4. Very few methodologies are described in the
literature to access such a scaffold. Funke et al. have developed
a
strategy consisting in the rearrangement of cyclo-
propylketimines.15 More recently, Correa et al., have reported an
efficient phenyliodine bis(trifluoroacetate) (PIFA) mediated ap-
proach.47 We therefore investigated the reaction of the dimethy-
lated anhydride 25 with an N-alkylated amino acid, such as proline
(Pro). After 1 h in water at room temperature in basic conditions,
the expected amide 28 (Scheme 6) was detected by LCeMS. This
compound was submitted to an acidic treatment without heating
to promote the cyclocondensation into dipyrrolo[3,2-e][1,4]dia-
zepine 30 in 65% yield. The same experiment was then performed
with alanine. While the ring opening of dimethylated anhydride 25
took place in the same reaction to afford the amide 29, the intra-
molecular cyclization occurred upon heating at 50 ꢀC for 6 h to
obtain pyrrolo[3,2-e][1,4]diazepine 31 in 61% yield.
Scheme 4. Imidazolidinedione 22 synthesis.
Altogether, these results indicate that the pyrrole based-
anhydride 4 reacts in the same way as the previously studied thiai-
satoic anhydrides for, which the regioselectivity on the C-2 position
could be explained by the formation of an isocyanate intermediate 23
in basic conditions.21 Therefore, the alkylation or acylation of the
nitrogen in position 1 on the oxazine-2,4-dione 4 should prevent
formation of isocyanate 23, giving the opportunity to regio-control
the ring opening by nucleophilic attack on the C-4 carbonyl (Fig. 2).
Scheme 6. Synthesis of pyrrolo[3,2-e][1,4]diazepines 30 and 31.
Fig. 2. Structure of the hypothetical mechanism of formation of isocyanate 23.
2.4. Alternative route for the synthesis of 3-substituted pyr-
rolo[3,2-e][1,4]diazepine-2,5-diones
2.3. Reactivity of N-substituted pyrrole on C-4 carbonyl
In contrast to others [1,3]oxazinediones, like isatoic anhydride 1,
azaisatoic 2 or thiaisatoic 3, the anhydride 4 bears two substitutable
nitrogens. The oxazine’s hydrogen being more acidic than the
pyrrole’s hydrogen, a selective alkylation was intended. Deproto-
nation with an inorganic base, such as potassium carbonate (K2CO3)
in stoichiometric quantities in DMF at room temperature, followed
by subsequent addition of 1 equiv of methyl iodide, led to the
monomethylated anhydride 24 (Scheme 5) in 72% yield. The N,N0-
dimethylated anhydride 25 was obtained in 80% yield from oxazine
4 by treatment with an excess of base and methyl iodide at room
temperature for 5 h in a minimum quantity of DMF (Scheme 5). As
suggested, oxazines 24 and 25 led to a C-4 nucleophilic attack by
isopropylamine to give the adducts 26 and 27 in 71% and 58% yields,
respectively (Scheme 5).
The main drawbacks of this methodology are the moderate
yields to produce anhydride 4 on a gram scale and the necessity to
substitute the oxazine nitrogen to control the nucleophilic attack at
the C4-carbonyl. Therefore, an alternative synthetic route was
intended to efficiently produce a non N-substituted pyrrolo[3,2-e]
[1,4]diazepinone library.
With this perspective, the aminoester 11 was here used as the
starting material and N-(tert-butoxycarbonyl)-
nine were chosen as N-protected amino acid models (Scheme 7).
Boc- (or )-Phe-OH was coupled to the free amine of 11 using N,N-
L and D-phenylala-
L
D
diisopropylethylamine (DIEA) as base and (benzotriazol-1-yloxy)
tris(dimethylamino)phosphonium hexafluorophosphate (BOP) as
coupling reagent in DCM. After extraction and purification on silica
gel, the amide 32a was obtained as a colorless solid in 90% yield.
Hydrolysis of the ester was then carried out in a mixture of NaOH
2 M and ethanol under reflux. After completion of the reaction, the
ethanol was removed under vacuum and the pH was adjusted to 7
with aqueous HCl 2 M. A white precipitate was formed and the
mixture was cooled to 0 ꢀC, providing the carboxylic acid 33a in 92%
yield upon filtration. Conditions for Boc removal without de-
carboxylation at the pyrrole position 2 were then investigated.
Optimal conditions consisted in the use of TFA/DCM (20/80 v/v).
The deprotection was performed at room temperature for 20 min
then the mixture was quenched by dilution with H2O/Et2O 50/50.
The amine 34a was recovered after lyophilization of the aqueous
layer and engaged without any further purification in the cycliza-
tion reaction. Formation of the seven-membered ring occurred by
intramolecular coupling in the presence of DIEA and BOP. The 3-
benzyl-pyrrolo[3,2-e][1,4]diazepine 35a was obtained as a color-
less solid after purification by silica gel chromatography in 57%
yield over the two final steps (Boc deprotection and intramolecular
Scheme 5. Reactivity of N-alkylated anhydride 4.
Those preliminary results triggered our interest in the synthesis
of new pyrrolo[1,4]diazepine derivatives from pyrrolo[3,2-d][1,3]

4634
J.-D. Malcor et al. / Tetrahedron 70 (2014) 4631e4639
Scheme 7. Synthesis of 3-substituted pyrrolo[3,2,e][1,4]diazepine-2,5-diones 35.
coupling) and 47% overall yield. As a major issue of the procedure,
chiral HPLC analysis and optical rotation measurement of pyrrolo-
diazepinone 35a synthesized from either (Boc-L (or D)-Phe-OH)
convenient methodology for the synthesis of new imidazolidine-
dione 22 and N-methylated pyrrolo[3,2-e][1,4]diazepine-2,5-
diones 30 and 31. In the last part of this study we developed an
alternative route to produce a library of eight non-protected pyr-
rolo[3,2-e][1,4]diazepine-2,5-diones 35aeh in good yields from
aminoester 11. In light of the potential biological activities of such
diazepine derivatives,48 these unusual heterocyclic fused [1,4]dia-
zepines are currently under investigation for biological activities
and results will be reported in due course.
showed complete racemization of the C-3 stereocenter. Whereas
a [
a
]
20 of ꢁ26.85 was found for compound 32a, the optical rotation
D
of compounds 33a and 35a were found to be close to 0, demon-
strating that chirality was lost during the saponification step. All
attempts to reduce racemization (reaction at room temperature,
stoichiometric quantity of base or the use of other bases) failed so
far.
We explored the scope of the reaction sequence starting from
seven racemic N-protected Boc-amino acids derived from iso-
leucine (Ile), tryptophan (Trp), norleucine (Nle), proline (Pro), me-
thionine (Met), tyrosine (Tyr) and leucine (Leu). All the N-Boc-
amino acids were coupled to the free amine of 11 in good to ex-
cellent yields (86e98%). After hydrolysis of esters 32bee, the cor-
responding carboxylic acids 33bee were isolated as previously
described with fair to excellent yields (50e96%). For less hydro-
phobic amino acid derivatives, i.e., Met, Tyr and Pro (compounds
33feh), the expected product did not precipitate in satisfying
quantities at 0 ꢀC. Therefore, the aqueous solution was extracted
several times with DCM leading to colorless solids (63e80% yields),
which were used in the next step without any further purification.
After Boc deprotection and intramolecular coupling, the expected
3-substituted pyrrolo[3,2-e][1,4]diazepine-2,5-diones 35beh were
obtained in moderate to good yields (28e78%). This route allowed
4. Experimental
4.1. General
Reagents and solvents were purchased from SigmaeAldrich
(Saint-Quentin Fallavier, France) and Carlo Erba (Peypin, France).
Amino acids derivatives were from IRIS Biotech (Marktredwitz,
Germany). Melting points were measured both on Kofler bench and
in open capillaries. Optical rotations were measured on a Perkin
Elmer 341 polarimeter in a 100 mm long cell with wavelength
l
¼589 nm. ESI HRMS mass spectra were recorded on a Q-Tof I mass
spectrometer (Waters, Manchester, U.K.) fitted with an electrospray
ion (ESI) source. 1H NMR (300 MHz) and 13C NMR (75 MHz) were
recorded in DMSO-d6 at room temperature on a 300 MHz Bruker
Advance III nuclear magnetic resonance (NMR) instrument.
Chemical shifts are reported in parts per million (
field/upfield from residual DMSO ( 2.50 and 39.5). Coupling con-
d units) down-
the synthesis of
a library of eight pyrrolo[3,2-e][1,4]dia-
d
zepinediones starting from aminoester 11 in four steps with overall
yields ranging from 19% to 71%.
stants (J) are reported in hertz (Hz). Analytical HPLC was performed
on a Waters 1525 HPLC system equipped with a Chromolith
SpeedRod RP-18 (4.6 mmꢂ50 mm) column using a 3 min gradient
going from 100% H2O (0.1% TFA) to 100% CH3CN (0.1% TFA) at a flow
Although a significant variation of yields was observed due to
the last critical ring-formation step, this synthetic path proved to be
compatible with a wide range of amino acids, with side chains
bearing bulky alkyls (Nle, Leu, Ile), aromatic ring (Phe), heterocycles
(Trp), sulfur (Met) or alcohol (Tyr). Current efforts are focused on
the production of chiral pyrrolodiazepinones and more specifically
on an alternative saponification procedure to retain the stereo-
chemistry of incorporated amino acid.
rate of 5 mL minꢁ1, or with a Merck Chromolith Flash RP18e (5
mm,
225ꢂ4.6 mm) using a 5 min gradient going from 100% H2O (0.1%
TFA) to 100% CH3CN (0.1% TFA) at a flow rate of 3 mL minꢁ1. Thin
layer chromatography (TLC) was carried out on aluminum plates
covered with 0.2 mm of silica. Flash chromatography was per-
formed on silica gel 230e400 mesh or on automatic flash chro-
matographic system (Isolera One BiotageÒ). Enantiomeric excess
(e.e.) were measured on a Chiracel OD-RH (5
reverse phase column, using a flow rate of 1 mL/min and isocratic
m
m, 150ꢂ4.6 mm)
3. Conclusion
gradient of 80:20 H2O (0.1% TFA):CH3CN (0.1% TFA) over 30 min.
Analyses of cyclic compounds synthesized from L- or D-phenylala-
nine showed complete racemization in both cases (data not
shown).
We have first developed a practical sequence for the synthesis of
the new pyrrole-fused oxazinedione 4 in five steps from isoxazole.
The reactivity of the anhydride 4 was investigated toward various
nucleophiles, such as amine, alcohol, thiol and
a-amino acids.
Contrary to its benzene analog, i.e., isatoic anhydride 1, the nucle-
ophilic attack only proceeded on the carbonyl group of the carba-
mate moiety (C-2) and not on the carboxylic carbonyl (C-4). Relying
on our previous studies on thiaisatoic anhydrides 3, we have
demonstrated that the regioselectivity towards nucleophiles could
be oriented to the carboxylic carbonyl (C-4) when oxazine 4 is N-
methylated. This versatile reactivity prompted us to apply this
4.2. Experimental details
4.2.1. Pyrrolo[3,2-d][1,3]oxazine-2,4(1H,5H)-dione (4). Aminoester
1145 (1.00 g, 6.58 mmol) was heated to reflux in water in the
presence of potassium hydroxide (1.84 g, 32.90 mmol) for 8 h. Sa-
ponification was monitored by TLC (eluent: AcOEt 100%, detector:

J.-D. Malcor et al. / Tetrahedron 70 (2014) 4631e4639
4635
UV lamp). Anhydride 4 was obtained upon addition of 20% phos-
gene solution in toluene (40 mmol) on the intermediate carboxyl-
ate 12 at 0 ꢀC under vigorous stirring during 15 min. The mixture
was brought up to room temperature and the aqueous layer
extracted by several portions of ethyl acetate. The organic layers
were gathered, washed with brine, dried upon Na2SO4, filtered and
evaporated, leading to anhydride 4 as a brown solid. Yield: 40%. Mp
a suspension of anhydride 4 (100 mg, 0.66 mmol) and alanine
(65 mg, 0.72 mmol) in 5 mL of water at room temperature. The
suspension was stirred until a homogenous solution is obtained.
HCl 10% was added until pH<5. The mixture was heated at reflux
for 30 min. A portion of ethyl acetate was added and the aqueous
phase extracted with ethyl acetate (3ꢂ20 mL). Organic layers were
combined, washed with brine, dried upon Na2SO4, filtered and
evaporated to give imidazolidine 22 as colorless oil. Yield: 75%. 1H
>210 ꢀC (decomp.). 1H NMR (DMSO-d6):
d 12.26 (br s, 1H), 11.42 (br
s,1H), 7.34 (d,1H, J¼2.7 Hz), 5.90 (d,1H, J¼2.7 Hz). 13C NMR (DMSO-
NMR (DMSO-d6): d 10.86 (br s, 1H), 8.27 (s, 1H), 7.01 (d, 1H,
d6):
d
152.3, 148.9, 137.2, 130.5, 105.2, 95.5. HRMS: calcd for [MþH]þ
J¼1.6 Hz), 6.70 (dd, 1H, J¼4.8 Hz, 2.3 Hz), 6.32 (d, 1H, J¼1.2 Hz), 4.16
C6H5N2O3 153.0300, found 153.0302.
(q, 1H, J¼6.8 Hz), 1.30 (d, 3H, J¼6.8 Hz). 13C NMR (DMSO-d6):
d
173.5, 155.6, 128.6, 116.2, 111.6, 103.0, 51.5, 17.4. MS (ESI, m/z) for
4.2.2. 1-Isopropyl-3-(1H-pyrrol-3-yl)urea
(14). Isopropylamine
C8H10N3O2 180.2.
(0.112 mL, 1.32 mmol) was added to a suspension of anhydride 4
(100 mg, 0.66 mmol) in 5 mL of water at room temperature. The
suspension was stirred until a homogenous solution was obtained.
Aqueous HCl 10% was added until pH<7. The mixture was parti-
tioned with ethyl acetate and the aqueous phase was extracted
with ethyl acetate (2ꢂ20 mL). Organic layers were combined,
washed with brine, dried upon Na2SO4, filtered and evaporated to
4.2.7. 1-Methylpyrrolo[3,2-d][1,3]oxazine-2,4(1H,5H)-dione (24). A
portion of K2CO3 (10 mg, 0.69 mmol) was added to a solution of
anhydride 4 (100 mg, 0.66 mmol) in a small volume of DMF (5 mL)
at room temperature. Methyl iodide (0.043 mL, 0.69 mmol) was
added to the mixture and stirred for 3e4 h at room temperature.
HCl 10% was added to the solution until pH¼7. The mixture was
partitioned between water and ethyl acetate. The aqueous layer
was extracted with ethyl acetate (3ꢂ20 ml). The organic layers
were combined, washed with brine, dried upon Na2SO4, filtered
and evaporated to give monomethylated oxazine 24 as a gray solid.
give urea 14 in quantitative yield. 1H NMR (DMSO-d6):
d 10.27 (br s,
1H), 7.65 (s, 1H), 6.71 (quad, 1H, J¼3.9 Hz, 2.1 Hz), 6.51 (quad, 1H,
J¼5.0 Hz, 2.7 Hz), 5.80 (quad, 1H, J¼4.2 Hz, 2.6 Hz), 5.60 (d, 1H,
J¼7.6 Hz), 3.70 (sept, 1H, J¼6.5 Hz), 1.06 (d, 6H, J¼6.5 Hz). 13C NMR
(DMSO-d6):
d
156.6, 125.5, 117.0, 107.8, 102.0, 42.5, 2. HRMS: calcd
Yield: 72%. Mp 196e199 ꢀC (decomp.). 1H NMR (DMSO-d6):
(br s, 1H), 7.43 (d, 1H, J¼2.4 Hz), 6.23 (d, 1H, J¼2.7 Hz), 3.35 (s, 3H).
d 12.46
for [MþH]þ C8H14N3O 168.1137, found 168.1150.
13C NMR (DMSO-d6):
d 151.7, 149.2, 139.4, 130.6, 105.2, 96.0, 32.5.
4.2.3. Ethyl 1H-pyrrol-3-ylcarbamate (17). A chunk of sodium
(31 mg, 1.32 mmol) was dissolved in absolute ethanol (5 mL) at
room temperature. Anhydride 4 (100 mg, 0.66 mmol) was added
and the mixture was stirred until a homogenous solution is ob-
tained. HCl 10% was added until pH<7. The ethanol was evaporated,
and the remaining solid was solubilized in a minimum of water and
purified on reverse phase semi-preparative HPLC to give carbamate
HRMS: calcd for [MþH]þ C7H7N2O3 167.0457, found 167.0440.
4.2.8. 1,5-Dimethylpyrrolo[3,2-d][1,3]oxazine-2,4(1H,5H)-dione
(25). A portion of K2CO3 (23 mg, 1.65 mmol) was added to a solu-
tion of anhydride 4 (100 mg, 0.66 mmol) in a small volume of DMF
(10 mL) at room temperature. Methyl iodide (0.103 mL, 1.65 mmol)
was added to the mixture and stirred for 5 h at room temperature.
HCl 10% was added until pH¼7. A precipitate forms and the mixture
was filtrated. A portion of ethyl acetate was added to the filtrate and
the aqueous phase extracted with ethyl acetate (3ꢂ20 mL). The
organic layers were combined, washed with brine, dried upon
Na2SO4, filtered and evaporated to give oxazine 25 as a gray solid.
17 in quantitative yield. 1H NMR (400 MHz, DMSO-d6)
d (ppm)
12.73 (br s, 1H), 11.44 (s, 1H), 8.55 (s, 1H), 6.86 (t, 1H, J¼2.9 Hz), 6.52
(s, 1H), 4.14 (q, 2H, J¼7.1 Hz), 1.23 (t, 3H, J¼7.1 Hz). 13C NMR
(75 MHz, DMSO-d6)
d (ppm) 153.1, 131.9, 123.2, 108.4, 100.9, 61.2,
14.9. HRMS (ESI) m/z: calcd for C7H11N2O2 [MþH]þ 155.0821, found
[MþH]þ¼155.0839.
Yield: 80%. Mp 180e183 ꢀC. 1H NMR (DMSO-d6):
d 7.45 (d, 1H,
J¼2.7 Hz), 6.17 (d, 1H, J¼2.8 Hz), 3.83 (s, 3H), 3.32 (s, 3H). 13C NMR
4.2.4. 3-{[(Isopropylsulfonyl) carbonyl]amine}-1H-pyrrole-2-
carboxylic acid (18). Triethylamine (0.184 mL, 1.32 mmol) was
added to a suspension of anhydride 4 (100 mg, 0.66 mmol) and
propane-2-thiol (0.123 mL, 1.32 mmol) in 5 mL of water at room
temperature. The suspension was stirred until a homogenous so-
lution was obtained. The mixture was directly purified on reverse
phase semi-preparative HPLC to give the acid 18 as a gray solid in
(DMSO-d6): d 151.5,149.0,139.4,134.6,105.5, 94.7, 35.1, 32.2. HRMS:
calcd for [MþH]þ C8H9N2O3 181.0613, found 181.0626.
4.2.9. N-Isopropyl-3-(methylamino)-1H-pyrrole-2-carboxamide
(26). Isopropylamine (0.112 mL, 1.32 mmol) was added to a sus-
pension of N-methylated 24 (100 mg, 0.66 mmol) in 5 mL of water
at room temperature. The suspension was stirred until a homoge-
nous solution was obtained. HCl 10% was added until pH<7. The
mixture was lyophilized to give amide 26 as a gray oil. Yield: 71%.
quantitative yield. Mp 127e128 ꢀC. 1H NMR (DMSO-d6):
d 11.56 (s,
1H), 9.26 (s, 1H), 6.88 (t, 1H, J¼3.0 Hz), 6.57 (s, 1H), 3.56 (sept, 1H,
J¼6.9 Hz), 1.32 (d, 6H, J¼6.9 Hz). 13C NMR (DMSO-d6):
d
163.4,162.6,
1H NMR (DMSO-d6):
d
11.84 (br s, 1H), 7.96 (d, 1H, J¼7.2 Hz), 7.00 (t,
130.4, 122.5, 108.5, 102.0, 35.5, 23.2. HRMS: calcd for [MþH]þ
1H, J¼3.0 Hz), 6.26 (t, 1H, J¼2.4 Hz), 4.05 (sept, 1H, J¼6.6 Hz), 2.87
C9H13N2O3S 229.0647, found 229.0648.
(s, 3H), 1.17 (d, 6H, J¼6.6 Hz). 13C NMR (DMSO-d6):
d 159.4, 128.6,
120.5, 115.2, 102.3, 40.5, 35.4, 22.4. HRMS: calcd for [MþH]þ
4.2.5. S-Isopropyl N-(1H-pyrrol-3-yl) carbamothioate (19). A solu-
tion of HCl 5% was added to acid 18 (0.050 g, 0.272 mmol) in 5 mL of
CH3CNeH2O (1:1) until pH<7. The mixture was stirred 5 min at
room temperature and lyophilized to give pyrrole 19 as a purple
solid in quantitative yield. Mp 131e132 ꢀC. 1H NMR (DMSO-d6):
C9H16N3O 182.1293, found 182.1279.
4.2.10. N-Isopropyl-1-methyl-3-(methylamino)-1H-pyrrole-2-
carboxamide (27). Isopropylamine (0.337 mL, 3.96 mmol) was
added to a suspension of N,N0-dimethylated anhydride 25 (100 mg,
0.66 mmol) in 5 mL of water at room temperature. The suspension
was stirred until a homogenous solution was obtained. HCl 10% was
added until pH<7. A portion of ethyl acetate was added to the fil-
trate and the aqueous phase extracted with ethyl acetate
(3ꢂ10 mL). The organic layers were combined, washed with brine,
dried upon Na2SO4, filtered and evaporated to give amine 27 as
d
10.45 (br s, 1H), 9.83 (br s, 1H), 6.86 (s, 1H), 6.55 (s, 1H), 5.94 (s,
1H), 3.38 (sept, 1H, J¼6.8 Hz), 1.28 (d, 6H, J¼6.8 Hz). 13C NMR
(DMSO-d6): d 162.4,127.4,116.1,107.7,100.5, 35.0, 23.9. HRMS: calcd
for [MþH]þ C8H13N2OS 185.0749, found 185.0736.
4.2.6. (S)-5-Methyl-3-(1H-pyrrol-3-yl)imidazolidine-2,4-dione
(22). Triethylamine (0.20 mL, 1.44 mmol) was added to
a gray oil. Yield: 58%. 1H NMR (DMSO-d6):
d
7.35 (d, 1H, J¼7.2 Hz),

4636
J.-D. Malcor et al. / Tetrahedron 70 (2014) 4631e4639
6.67 (d, 1H, J¼3.0 Hz), 5.70 (d, 1H, J¼2.7 Hz), 4.67 (br d, 1H,
J¼4.8 Hz), 3.99 (sept, 1H, J¼6.6 Hz), 3.7 (s, 3H), 2.61 (d, 3H,
dissolved in DCM:water 1:1. The aqueous layer was extracted once
with DCM. The organic layers were gathered, dried over anhydrous
Na2SO4 and evaporated under vacuum.
J¼5.1 Hz), 1.13 (d, 6H, J¼6.6 Hz). 13C NMR (DMSO-d6):
d 159.8, 139.9,
124.4, 110.9, 95.5, 38.5, 35.2, 32.0, 21.3. HRMS: calcd for [MþH]þ
For others residues (Pro, Met and Tyr), the pyrrole derivative 32
was suspended in NaOH 2 N:EtOH 3:1. The mixture was heated to
reflux and stirred for approximately one hour. The reaction was
monitored by HPLC. The ethanol was then evaporated under vac-
uum, HCl 2 N was added dropwise until pH<7 and DCM added to
the remaining mixture. The aqueous layer was extracted with DCM
(4ꢂ10 mL). The organic layers were gathered, dried over anhydrous
Na2SO4, filtered and evaporated under vacuum.
The saponified pyrrole derivatives 33aeh were dissolved in
5 mL of 20% TFA in DCM. The mixtures were stirred at room tem-
perature for 10e20 min. The reactions were monitored by HPLC and
quenched at completion by a 50 mL of Et2O:water 1:1. The organic
layers were washed with water (2ꢂ20 mL). The aqueous layers
were gathered and lyophilized to yield a gray powder.
Compounds 34aeh, as TFA salts (1 equiv) and DIEA (1.2 equiv)
were dissolved in DCM. When the starting material remained in
suspension, small amounts of DMF were added until the reaction
became homogenous. BOP (1.2 equiv) was added. The mixture was
stirred at room temperature for 5e6 h. The reaction was monitored
by HPLC. The DCM was evaporated under vacuum to give a brown
oil. The oil was dissolved in AcOEt:water 1:1. The organic layers
were washed with 0.1% TFA in water (2ꢂ10 mL), saturated NaHCO3
(2ꢂ10 mL) and brine, dried over anhydrous Na2SO4 and evaporated
under vacuum to give a brown oil. The crude products were puri-
fied by silica gel flash chromatography using methanol and
dichloromethane as eluents to yield a colorless solid.
C10H18N3O 196.1450, found 196.1446.
4.2.11. 1,4-Dimethyl-1,4-5a,6,7,8-hexahydrodipyrrolo[1,2-a:30,20-e]
[1,4]diazepine-5,10-dione (30). Triethylamine (0.20 mL, 1.45 mmol)
was added to a suspension of N,N0-dimethylated anhydride 25
(100 mg, 0.66 mmol) and proline (84 mg, 0.72 mmol) in 5 mL of
water at room temperature. The suspension was stirred until
complete transformation of anhydride 25 (monitored by HPLC at
214 nm). Acetic acid was added to the solution until pH<7 and the
mixture was stirred at room temperature for two hours. A portion
of ethyl acetate was added to the filtrate and the aqueous phase
extracted with ethyl acetate (3ꢂ10 mL). The organic layers were
combined, washed with brine, dried upon Na2SO4, filtered and
evaporated to give diazepine 30 as a white solid. Yield: 65%.
Mp>230 ꢀC. [
a
]
20 þ251.0 (c 0.2, DMSO). 1H NMR (DMSO-d6):
d 6.98
D
(d, 1H, J¼2.9 Hz), 6.09 (d, 1H, J¼2.9 Hz), 4.10 (d, 1H, J¼6.7 Hz), 3.75
(d, 3H, J¼6.7 Hz), 3.38 (m, 2H), 3.20 (s, 3H), 2.46 (m, 1H), 1.80 (m,
3H). 13C NMR (DMSO-d6):
d 167.6, 159.4, 131.5, 127.2, 116.7, 99.5,
57.6, 45.7, 35.8, 34.1, 26.5, 23.4. HRMS: calcd for [MþH]þ
C12H16N3O2 234.1243, found 234.1214.
4.2.12. (S)-3,4-Dihydro-1,3,6-trimethylpyrrolo[3,2-e][1,4]diazepine-
2,5(1H,6H)-dione (31). Triethylamine (0.20 mL, 1.45 mmol) was
added to a suspension of N,N0-dimethylated anhydride 25 (100 mg,
0.66 mmol) and alanine (64 mg, 0.72 mmol) in 5 mL of water at
room temperature. The suspension was stirred until complete
transformation of anhydride 25 (monitored by HPLC at 214 nm).
Acetic acid was added to the solution until pH<7 and the mixture
was stirred at 50 ꢀC during 6 h. The solvent is evaporated and the
residue partitioned between ethyl acetate and water. The aqueous
phase was extracted with ethyl acetate (3ꢂ20 mL). The organic
layers were combined, washed with brine, dried upon Na2SO4, fil-
tered, evaporated and purified by silica gel chromatography (elu-
4.3.1. (R)-Ethyl-3-(2-(4-(tert-butoxy)-3,4-dioxo-1-phenylbutan-2-yl)
hydrazinyl)-1H-pyrrole-2-carboxylate (32a). Colorless solid. Yield:
20
90%. Mp 136.0e138.4 ꢀC. [
a
]
D
ꢁ26.85 (c 0.1, DCM). 1H NMR
(400 MHz, DMSO-d6) d (ppm) 11.64 (s, 1H), 9.76 (s, 1H), 7.53 (d, 1H,
J¼8.1 Hz), 7.29 (s, 2H), 7.28 (s, 2H), 7.21 (m, 1H), 6.94 (t, 1H,
J¼2.9 Hz), 6.85 (t, 1H, J¼2.5 Hz), 4.30 (q, 2H, J¼7.1 Hz), 4.24 (m, 1H),
3.24 (dd, 1H, J¼3.9, 9.9 Hz), 2.84 (dd, 1H, J¼2.9 Hz, 10.1 Hz), 1.31 (t,
ent: 100% ethyl acetate) to give diazepine 31 as a white solid. Yield:
9H), 1.26 (t, 3H, J¼6.3 Hz). 13C NMR (75 MHz, DMSO)
d (ppm) 169.9,
20
61%. Mp>230 ꢀC. [
d
a
]
þ310.0 (c 0.2, DMSO). 1H NMR (DMSO-d6):
161.3, 155.9, 138.8, 131.1, 129.6, 128.6, 126.7, 123.8, 108.5, 102.3, 79.1,
60.1, 57.3, 36.9, 28.5, 15.0. HRMS (ESI) m/z: calcd for C21H28N3O5
[MþH]þ 402.2029, found [MþH]þ¼402.2035.
D
7.80 (d, 1H, J¼4.5 Hz), 7.02 (d, 1H, J¼2.8 Hz), 6.10 (d, 1H, J¼2.9 Hz),
3.88 (quint, 1H, J¼6.0 Hz), 3.77 (s, 3H), 3.22 (s, 3H), 1.21 (d, 3H,
J¼6.8 Hz). 13C NMR (DMSO-d6):
d 169.1, 161.9, 132.0, 127.6, 116.6,
99.3, 48.3, 35.7, 33.8, 15.0. HRMS: calcd for [MþH]þ C10H14N3O2
4.3.2. 3-(2-(4-(tert-Butoxy)-3,4-dioxo-1-phenylbutan-2-yl)hydra-
208.1086, found 208.1064.
zinyl)-1H-pyrrole-2-carboxylic acid (33a). Colorless solid. Yield:
20
92%. Mp 151.9e154.9 ꢀC. [
a]
ꢁ3.01 (c 0.1, DCM). 1H NMR
D
4.3. General procedure for the synthesis of pyrrolo[3,2-e][1,4]
(400 MHz, DMSO-d6) d (ppm) 11.48 (s, 1H), 9.90 (s, 1H), 7.51 (d, 1H,
diazepinediones 35
J¼8.1 Hz), 7.28 (s, 2H), 7.27 (s, 2H), 7.20 (m, 1H), 6.87 (t, 1H,
J¼2.9 Hz), 6.83 (t, 1H, J¼2.5 Hz), 4.19 (m, 1H), 3.23 (dd, 1H, J¼3.7 Hz,
10.2 Hz), 2.82 (dd, 1H, J¼2.7 Hz, 11.1 Hz), 1.31 (s, 9H). 13C NMR
To a solution of pyrrole amino-ester 11 (1 equiv) in DCM, DIEA
(2 equiv), the appropriate Boc-protected amino acid (1.2 equiv) and
BOP (1.2 equiv) are added successively. The mixture was stirred for
3e4 h at room temperature. The reaction was monitored by HPLC.
Once the starting material has completely disappeared, the DCM
was evaporated to give a yellow solid, which was dissolved in
AcOEt:water 1:1. The organic layer was washed with KHSO4 1 M
(2ꢂ10 mL), saturated NaHCO3 (2ꢂ20 mL) and brine, dried over
anhydrous Na2SO4 and evaporated under vacuum to give a yellow
solid. The crude product was purified by silica gel flash chroma-
tography using methanol and dichloromethane as eluents.
Each highly hydrophobic pyrrole derivatives 32 (Phe, Ile, Trp,
Leu and Nle) was suspended in NaOH 2 N:EtOH 3:1. The mixture
was heated and stirred for one hour. The reaction was monitored by
HPLC. The ethanol was evaporated under vacuum and the
remaining mixture cooled down to 0 ꢀC. HCl 2 N was added
dropwise under vigorous stirring until the pH became acidic and
a precipitate appeared. The mixture was filtered and the precipitate
(75 MHz, DMSO-d6)
d (ppm) 169.7, 162.8, 155.9, 138.9, 130.9, 129.4,
128.5, 126.6, 122.8, 109.1, 102.1, 78.9, 57.2, 36.8, 28.5. HRMS (ESI) m/
z: calcd for C14H16N3O3 [MþH]þ 274.1192, found [MþH]þ¼274.1188
(unprotected).
4.3.3. 3-Benzyl-3,4-dihydropyrrolo[3,2-e][1,4]diazepine-2,5(1H,6H)-
dione (35a). Colorless solid. Yield: 57%. Mp 236ꢁ239 ꢀC. [
a
]
20 þ1.41
D
(c 0.1, DCM). 1H NMR (400 MHz, DMSO-d6)
d (ppm) 11.40 (s, 1H),
10.25 (s, 1H), 7.57 (d, 1H, J¼5.1 Hz), 7.29 (m, 4H), 7.20 (m, 1H), 6.91
(t, 1H, J¼2.9 Hz), 5.83 (t, 1H, J¼2.6 Hz), 3.90 (m, 1H), 3.18 (dd, 1H,
J¼5.9 Hz, 8.2 Hz), 2.84 (dd, 1H, J¼5.2 Hz, 9.1 Hz). 13C NMR (75 MHz,
DMSO-d6)
d (ppm) 169.1, 162.9, 138.6, 129.7, 128.6, 127.9, 126.7,
123.1, 115.7, 100.5, 55.9, 34.6. HRMS (ESI) m/z: calcd for C14H14N3O2
[MþH]þ 256.1086, found [MþH]þ¼256.1096.
4 . 3 . 4 . E t h y l 3 - ( 2 - ( ( t e r t - b u t o x y c a r b o n y l ) a m i n o ) - 3 -
methylpentanamido)-1H-pyrrole-2-carboxylate
(32b). Colorless

J.-D. Malcor et al. / Tetrahedron 70 (2014) 4631e4639
4637
solid. Yield: 95%. Mp 64.5e67.5 ꢀC. 1H NMR (400 MHz, DMSO-d6)
111.9, 110.5, 100.6, 55.0, 24.8. HRMS (ESI) m/z: calcd for C16H15N4O2
[MþH]þ 295.1195, found [MþH]þ¼295.1197.
d
(ppm) 11.61 (s, 1H), 9.60 (s, 1H), 7.41 (d, 1H, J¼7.0 Hz), 6.91 (t, 1H,
J¼3.0 Hz), 6.80 (t, 1H, J¼2.5 Hz), 4.30 (q, 2H, J¼6.0 Hz), 3.89 (t, 1H,
J¼6.3 Hz), 1.89 (m, 1H), 1.40 (s, 9H), 1.33 (t, 3H, J¼7.1 Hz), 1.24 (m,
2H), 0.87 (d, 3H, J¼6.8 Hz), 0.82 (t, 3H, J¼7.3 Hz). 13C NMR
4.3.10. Ethyl 3-(2-((tert-butoxycarbonyl)amino)hexanamido)-1H-pyr-
role-2-carboxylate (32d). Colorless oil. Yield: 93%.1H NMR (400 MHz,
(75 MHz, DMSO-d6)
d
(ppm) 169.7, 161.2, 156.4, 131.2, 123.7, 108.3,
DMSO-d6)
d
(ppm) 11.59 (s, 1H), 9.69 (s, 1H), 7.47 (d, 1H, J¼6.8 Hz),
102.3, 78.9, 60.6, 60.1, 36.3, 28.6, 24.9, 16.1, 14.9, 11.9. HRMS (ESI)
6.91 (t,1H, J¼2.9 Hz), 6.80 (t,1H, J¼2.5 Hz), 4.30 (m, 2H), 4.29 (m,1H),
1.79 (m, 1H), 1.58 (m, 1H), 1.41 (t, 9H), 1.33 (t, 3H, J¼7.1 Hz), 1.28 (m,
2H),1.20 (m, 2H), 0.86 (t, 3H, J¼6.8 Hz). 13C NMR (75 MHz, DMSO-d6)
m/z: calcd for
C
18H30N3O5 [MþH]þ 368.2185, found
[MþH]þ¼368.2181.
d
(ppm) 170.6, 161.2, 156.3, 131.3, 123.8, 108.4, 102.2, 79.0, 60.1, 55.9,
4.3.5. 3-(2-((tert-Butoxycarbonyl)amino)-3-methylpentanamido)-
31.0, 28.7, 28.6, 15.0, 14.4, 14.3. HRMS (ESI) m/z: calcd for C18H30N3O5
[MþH]þ 368.2185, found [MþH]þ¼368.2180.
1H-pyrrole-2-carboxylic acid (33b). Colorless solid. Yield: 96%. Mp
144.4e148 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d (ppm) 12.71, 11.51 (s,
1H), 9.72 (s, 1H), 7.39 (d, 1H, J¼7.3 Hz), 6.84 (t, 1H, J¼2.9 Hz), 6.78 (t,
1H, J¼2.5 Hz), 3.86 (t, 1H, J¼6.4 Hz), 1.90 (m, 1H), 1.40 (s, 9H), 1.36
(m, 1H), 1.26 (m, 1H), 0.86 (d, 3H, J¼6.9 Hz), 0.81 (t, 3H, J¼7.2 Hz).
4.3.11. 3-(2-((tert-Butoxycarbonyl)amino)hexanamido)-1H-pyrrole-
2-carboxylic acid (33d). Colorless solid. Yield: 50%. Mp
93.5e91.1 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d (ppm) 11.44 (s, 1H),
13C NMR (75 MHz, DMSO-d6)
d
(ppm) 167.7, 161.0, 154.4, 129.1,
9.82 (s, 1H), 7.46 (d, 1H, J¼7.0 Hz), 6.91 (t, 1H, J¼2.9 Hz), 6.80 (t, 1H,
120.8, 107.0, 100.2, 76.9, 58.5, 34.4, 26.6, 22.9, 14.1, 10.1. HRMS (ESI)
J¼2.4 Hz), 3.89 (m, 1H), 1.79 (m, 1H). 1.576 (m, 1H), 1.41 (t, 9H), 1.29
m/z: calcd for
C
11H18N3O3 [MþH]þ 240.1348, found
(m, 4H), 0.86 (t, 3H, J¼6.8 Hz). 13C NMR (75 MHz, DMSO-d6)
d (ppm)
[MþH]þ¼240.1332 (unprotected).
170.0, 162.6, 155.7, 130.5, 122.3, 108.7, 101.5, 78.4, 55.3, 30.5, 28.1,
27.9, 21.7, 13.8. HRMS (ESI) m/z: calcd for C11H18N3O3 [MþH]þ
240.1348, found [MþH]þ¼240.1348 (unprotected).
4.3.6. 3-(Sec-butyl)-3,4-dihydropyrrolo[3,2-e][1,4]diazepine-
2,5(1H,6H)-dione (35b). Colorless solid. Yield: 78%. Mp
139.8e141.3 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
(ppm) 11.37 (s, 1H),
4.3.12. 3-Butyl-3,4-dihydropyrrolo[3,2-e][1,4]diazepine-2,5(1H,6H)-
dione (35d). Brown oil. The crude product was purified by silica gel
flash chromatography using 0% MeOH to 7% MeOH in CH2Cl2 to
yield a colorless solid. Yield: 59%. Mp 130.1e131.9 ꢀC. 1H NMR
10.18 (s, 1H), 7.71 (d, 1H, J¼6.6 Hz), 6.86 (t, 1H, J¼2.9 Hz), 5.79 (t, 1H,
J¼2.6 Hz), 3.28 (d, 1H, J¼3.6 Hz, 6.7 Hz), 1.82 (m, 1H), 1.54 (m, 1H),
1.17 (m, 1H), 0.86 (d, 3H, J¼6.7 Hz), 0.78 (t, 3H, J¼7.4 Hz). 13C NMR
(75 MHz, DMSO-d6)
d
(ppm) 169.3, 162.6, 127.6, 122.9, 115.6, 100.4,
(400 MHz, DMSO-d6) d (ppm) 11.38 (s, 1H), 10.16 (s, 1H), 7.54 (d, 1H,
61.0, 32.5, 24.9, 16.3, 10.5. HRMS (ESI) m/z: calcd for C11H16N3O2
J¼4.8 Hz), 6.86 (t, 1H, J¼2.9 Hz), 5.81 (t, 1H, J¼2.6 Hz), 3.56 (s, 1H),
[MþH]þ 222.1243, found [MþH]þ¼222.1252.
1.78 (m, 1H), 1.58 (m, 1H), 1.27 (m, 4H), 0.85 (t, 3H, J¼7.2 Hz). 13
C
NMR (75 MHz, DMSO-d6)
d (ppm) 169.2, 162.3, 127.5, 122.6, 115.2,
4.3.7. Ethyl
3-(2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)
100.1, 53.9, 28.2, 27.9, 21.9, 13.9. HRMS (ESI) m/z: calcd for
C
propanamido)-1H-pyrrole-2-carboxylate (32c). Colorless solid.
11H16N3O2 [MþH]þ 222.1243, found [MþH]þ¼222.1246.
Yield: 94%. Mp 103.4e105.8 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
(ppm) 11.64 (s,1H),10.83 (s,1H), 9.78 (s,1H), 7.57 (d,1H, J¼7.8 Hz),
4.3.13. Ethyl 3-(2-(1-(tert-butoxy)-4-methylpentanamido)-1H-pyr-
7.47 (d, 1H, J¼7.5 Hz), 7.34 (d, 1H, J¼8.0 Hz), 7.16 (s, 1H), 7.07 (t, 1H,
J¼7.0 Hz), 6.98 (t, 1H, J¼7.9 Hz), 6.94 (t, 1H, J¼2.9 Hz), 6.86 (t, 1H,
J¼2.5 Hz), 4.28 (q, 2H, J¼6.9 Hz), 4.23 (m, 1H), 3.29 (dd, 1H,
J¼3.6 Hz, 11.2 Hz), 2.99 (dd, 1H, J¼10.4 Hz, 14.6 Hz), 1.32 (s, 1H), 1.06
role-2-carboxylate (32e). Colorless solid. Yield: 98%. Mp
55.7e57.4 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d (ppm) 9.68 (s, 1H),
7.45 (d, 1H, J¼6.6 Hz), 6.87 (t, 1H, J¼2.9 Hz), 6.77 (t, 1H, J¼2.5 Hz),
4.27 (q, 2H, J¼7.1 Hz), 3.94 (m, 1H), 1.55 (m, 3H), 1.41 (d, 9H), 1.29 (t,
3H, J¼7.1 Hz), 0.87 (d, 3H, J¼6.4 Hz), 0.84 (d, 3H, J¼6.3 Hz). 13C NMR
(t, 3H, J¼7.0 Hz). 13C NMR (75 MHz, DMSO-d6)
d (ppm) 170.3, 161.2,
156.0, 136.6, 131.3, 127.6, 123.9, 123.8, 121.4, 118.8, 118.6, 111.8, 111.0,
108.4, 102.3, 79.0, 60.1, 56.9, 28.5, 27.3, 14.9. HRMS (ESI) m/z: calcd
for C23H29N4O5 [MþH]þ 441.2138, found [MþH]þ¼441.2126.
(75 MHz, DMSO-d6) d (ppm) 170.8, 161.1, 156.1, 131.8, 123.7, 108.3,
102.13, 79.0, 60.0, 54.2, 28.5, 24.9, 23.4, 21.6, 14.9. HRMS (ESI) m/z:
calcd for C18H30N3O5 [MþH]þ 368.2185, found [MþH]þ¼368.2189.
4.3.8. 3-(2-((tert-Butoxycarbonyl)amino)-3-(1H-indol-3-yl)prop-
4.3.14. 3-(2-(1-(tert-Butoxy)-4-methylpentanamido)-1H-pyrrole-2-
anamido)-1H-pyrrole-2-carboxylic acid (33c). Colorless solid. Yield:
carboxylic acid (33e). Colorless solid. Yield: 76%. Mp 76.5e78.9 ꢀC.
93%. Mp 116.6e118.5 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
(ppm)
1H NMR (400 MHz, DMSO-d6)
d (ppm) 11.48 (s, 1H), 9.85 (d, 1H,
12.68 (s, 1H), 11.51 (s, 1H), 10.82 (s, 1H), 9.92 (s, 1H), 7.57 (d, 1H,
J¼7.8 Hz), 7.51 (dd, 1H, J¼7.5 Hz, 13.1 Hz), 7.35 (d, 1H, J¼8.0 Hz), 7.17
(s, 1H), 7.07 (t, 1H, J¼6.9 Hz), 6.99 (t, 1H, J¼6.9 Hz), 6.89 (t, 1H,
J¼2.9 Hz), 6.86 (t, 1H, J¼2.5 Hz), 4.19 (m, 1H), 3.14 (dd, 1H, J¼4.6 Hz,
14.5 Hz), 2.97 (dd, 1H, J¼11.1 Hz, 14.5 Hz), 1.328 (s, 1H). 13C NMR
J¼7.4 Hz), 7.52 (d, 1H, J¼8.2 Hz), 7.06 (s, 1H), 6.86 (t, 1H, J¼2.9 Hz),
6.80 (t,1H, J¼2.5 Hz), 3.93 (m, 1H), 1.62 (m, 3H), 1.41 (d, 9H), 0.89 (d,
3H, J¼6.5 Hz), 0.86 (d, 3H, J¼6.4 Hz). 13C NMR (75 MHz, DMSO-d6)
d
(ppm) 170.8, 163.0, 156.1, 131.1, 122.9, 109.0, 102.0, 78.4, 52.3, 28.7,
24.8, 23.4, 21.7. HRMS (ESI) m/z: calcd for C11H18N3O3 [MþH]þ
(75 MHz, DMSO-d6)
d (ppm) 170.2, 162.9, 156.0, 136.6, 131.1, 127.6,
240.1348, found [MþH]þ¼240.1342 (unprotected).
123.9, 122.9, 121.4, 118.8, 118.6, 111.8, 111.2, 109.0, 102.8, 78.9, 56.8,
28.5, 27.2. HRMS (ESI) m/z: calcd for C16H17N4O3 [MþH]þ 313.1301,
found [MþH]þ¼313.1315 (unprotected).
4.3.15. 3-Isobutyl-3,4-dihydropyrrolo[3,2-e][1,4]diazepine-
2,5(1H,6H)-dione (35e). Colorless solid. Yield: 47%. Mp
147.8e150.2 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d (ppm) 11.40 (s, 1H),
4.3.9. 3-((1H-Indol-3-yl)methyl)-3,4-dihydropyrrolo[3,2-e][1,4]dia-
10.20 (d, 1H, J¼7.4 Hz), 7.56 (d, 1H, J¼4.9 Hz), 6.90 (t, 1H, J¼2.9 Hz),
5.82 (t, 1H, J¼2.5 Hz), 3.61 (m, 1H), 1.62 (m, 3H), 0.88 (d, 3H,
J¼6.5 Hz), 0.83 (d, 3H, J¼6.4 Hz). 13C NMR (75 MHz, DMSO-d6)
zepine-2,5(1H,6H)-dione (35c). Colorless solid. Yield: 74%. Mp
187.8e191.2 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d (ppm) 11.37 (s, 1H),
10.86 (s, 1H), 10.25 (s, 1H), 7.45 (d, 1H, J¼7.9 Hz), 7.42 (dd, 1H,
J¼4.8 Hz, 13.1 Hz), 7.34 (d, 1H, J¼8.0 Hz), 7.23 (d, 1H, J¼2.2 Hz), 7.06
(t, 1H, J¼7.9 Hz), 6.93 (t, 1H, J¼7.1 Hz), 6.89 (t, 1H, J¼2.9 Hz), 5.82 (t,
1H, J¼2.6 Hz), 3.88 (m, 1H), 3.29 (dd, 1H, J¼5.8 Hz, 14.9 Hz), 2.99
d (ppm) 169.6, 162.6, 127.6, 123.0, 115.6, 100.5, 52.6, 37.6, 24.5, 23.1,
22.2. HRMS (ESI) m/z: calcd for C11H16N3O2 [MþH]þ 222.1243,
found [MþH]þ¼222.1239.
(dd, 1H, J¼8.9 Hz, 14.8 Hz). 13C NMR (75 MHz, DMSO-d6)
d
(ppm)
4.3.16. Ethyl 3-(2-((tert-butoxycarbonyl)amino)-4-(methylthio)bu-
tanamido)-1H-pyrrole-2-carboxylate (32f). Colorless oil. Yield: 88%.
169.5, 162.5, 136.6, 128.0, 127.5, 124.7, 123.1, 121.4, 118.8, 118.6, 115.6,

4638
J.-D. Malcor et al. / Tetrahedron 70 (2014) 4631e4639
1H NMR (400 MHz, DMSO-d6)
d
(ppm) 11.65 (s,1H), 9.77 (s,1H), 7.62
57.4, 36.4, 29.0, 15.0. HRMS (ESI) m/z: calcd for C25H36N3O6 [MþH]þ
474.2604, found [MþH]þ¼474.2602.
(d, 1H, J¼7.2 Hz), 6.63 (t, 1H, J¼3.0 Hz), 6.81 (t, 1H, J¼2.5 Hz), 4.31
(m, 2H), 4.12 (m, 1H), 2.10 (s, 3H), 2.04 (m, 1H), 1.87 (m, 1H), 1.42 (s,
9H), 1.38 (m, 1H), 1.34 (t, 3H, J¼7.1 Hz), 1.21 (m, 1H). 13C NMR
4.3.23. 3-(3-(4-(tert-Butoxy)phenyl)-2-((tert-butoxycarbonyl)
amino)propanamido)-1H-pyrrole-2-carboxylic acid (33h). Colorless
solid. Yield: 80%. Mp 100.6e101.5 ꢀC. 1H NMR (400 MHz, DMSO-d6)
(75 MHz, DMSO-d6)
d (ppm) 170.2, 161.2, 156.1, 131.3, 123.8, 108.4,
102.2, 79.2, 60.1, 54.7, 31.0, 30.4, 28.6, 15.0, 14.3. HRMS (ESI) m/z:
calcd for C17H28N3O5S [MþH]þ 386.1750, found [MþH]þ¼386.1753.
d
(ppm) 11.49 (s, 1H), 9.87 (s, 1H), 7.51 (d, 1H, J¼8.2 Hz), 7.19 (d, 2H,
J¼8.4 Hz), 6.87 (t, 1H, J¼2.9 Hz), 6.85 (d, 2H, J¼8.4 Hz), 6.86 (t, 1H,
J¼2.5 Hz), 4.19 (m, 1H), 3.19 (dd, 1H, J¼3.8 Hz, 13.9 Hz), 2.76 (dd, 1H,
4.3.17. 3-(2-((tert-Butoxycarbonyl)amino)-4-(methylthio)butana-
mido)-1H-pyrrole-2-carboxylic acid (33f). Yellow solid. Yield: 76%.
J¼2.8, 13.8 Hz), 1.31 (m, 9H). 13C NMR (75 MHz, DMSO-d6)
d (ppm)
Mp 152.4e150.8 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
(ppm) 11.45 (s,
169.8, 163.0, 156.0, 153.8, 133.6, 130.9, 130.0, 124.0, 123.9, 109.2,
102.0, 78.1, 57.3, 36.3, 29.0. HRMS (ESI) m/z: calcd for C18H24N3O4
[MþH]þ 346.1767, found [MþH]þ¼346.1780 (unprotected).
1H), 9.99 (s, 1H), 7.58 (d, 1H, J¼7.4 Hz), 6.83 (t, 1H, J¼2.9 Hz), 6.78 (t,
1H, J¼2.5 Hz), 4.09 (m, 1H), 2.05 (s, 3H), 2.03 (m, 1H), 1.86 (m, 1H),
1.41 (s, 9H), 1.38 (m, 2H). 13C NMR (75 MHz, DMSO-d6)
d (ppm)
170.0, 156.1, 101.9, 79.1, 78.5, 54.6, 31.1, 30.5, 28.6, 15.0. HRMS (ESI)
4.3.24. 3-(4-Hydroxybenzyl)-3,4-dihydropyrrolo[3,2-e][1,4]dia-
m/z: calcd for
C
10H16N3O3S [MþH]þ 258.0912, found
zepine-2,5(1H,6H)-dione (35h). Colorless solid. Yield: 28%. Mp
[MþH]þ¼258.0901 (unprotected).
138.2e142.3 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d (ppm) 11,488 (s,
1H), 10.22 (s, 1H), 9.20 (s, 1H), 7.49 (d, 1H, J¼5.1 Hz), 7.10 (d, 2H,
J¼8.4 Hz), 6.90 (t, 1H, J¼2.9 Hz), 6.66 (d, 2H, J¼8.4 Hz), 5.81 (t, 1H,
J¼2.6 Hz), 3.79 (m,1H), 3.06 (dd,1H, J¼5.9 Hz,14.2 Hz), 2.75 (dd,1H,
4.3.18. 3-(2-(Methylthio)ethyl)-3,4-dihydropyrrolo[3,2-e][1,4]dia-
zepine-2,5(1H,6H)-dione (35f). Colorless oil. Yield: 65%. 1H NMR
(400 MHz, DMSO-d6)
d
(ppm) 11.42 (s, 1H), 10.22 (s, 1H), 7.62 (d, 1H,
J¼5.5 Hz, 14.3 Hz). 13C NMR (75 MHz, DMSO-d6)
d (ppm) 169.3,
J¼4.5 Hz), 6.91 (t, 1H, J¼2.9 Hz), 5.82 (t, 1H, J¼2.6 Hz), 3.78 (m, 1H),
162.51, 156.3, 130.8, 128.6, 128.0, 123.1, 115.8, 115.4, 100.6, 56.3, 33.9.
HRMS (ESI) m/z: calcd for C14H14N3O3 [MþH]þ 272.1035, found
[MþH]þ¼272.1029.
2.09 (m, 1H), 2.02 (s, 3H), 1.88 (m, 1H), 1.49 (m, 2H). 13C NMR
(75 MHz, DMSO-d6)
d (ppm) 168.9, 162.4, 127.5, 122.7, 115.2, 100.1,
52.2, 29.8, 28.1, 14.5. HRMS (ESI) m/z: calcd for C10H14N3O2S
[MþH]þ 240.0807, found [MþH]þ¼240.0767.
Acknowledgements
4.3.19. Ethyl 3-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-
Financial support for this study was provided by the Region
Languedoc-Roussillon (chercheur d’avenir 2011 grant to V.L.). We
thank Mr. Pierre Sanchez for performing mass spectral analyses. J.-
1H-pyrrole-2-carboxylate (32g). Colorless solid. Yield: 91%. Mp
104.1e106.6 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d (ppm) 11.63 (s, 1H),
9.42 (s, 1H), 6.92 (t, 1H, J¼2.9 Hz), 6.79 (t, 1H, J¼2.5 Hz), 4.27 (m,
ꢀ ꢀ
ꢀ
ꢀ
D.M. thanks the Direction Generale de la Competitivite, de l’In-
2H), 3.42 (m, 2H), 1.84 (m, 2H), 1.42 (s, 9H), 1.30 (t, 3H, J¼7.0 Hz),
dustrie et des Services (DGCIS) for a doctoral scholarship.
1.26 (m, 2H). 13C NMR (75 MHz, DMSO-d6)
d (ppm) 170.6, 161.2,
156.7, 131.1, 123.8, 108.4, 102.2, 79.6, 61.7, 60.1, 47.1, 31.4, 28.2, 23.9,
14.9. HRMS (ESI) m/z: calcd for C17H26N3O5 [MþH]þ 352.1872,
found [MþH]þ¼352.1876.
Supplementary data
1H and 13C NMR spectral data for compounds 4, 14, 17e19, 22,
24e27, 30e35. This material is available free of charge via the In-
ternet. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2014.05.046.
4.3.20. 3-(1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxamido)-1H-
pyrrole-2-carboxylic acid (33g). Yellow oil. Yield: 63%. 1H NMR
(400 MHz, DMSO-d6) d (ppm) 12.76 (s, 1H), 11.51 (s, 1H), 9.76 (d, 1H,
J¼47.268 Hz), 6.86 (t, 1H, J¼2.9 Hz), 6.75 (t, 1H, J¼2.5 Hz), 4.17 (m,
References and notes
1H), 3.39 (m, 2H), 1.82 (m, 2H), 1.82 (m, 2H), 1.41 (d, 9H), 1.26 (m,
2H). 13C NMR (75 MHz, DMSO-d6)
d (ppm) 170.4, 163.1, 153.7, 131.1,
1. 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,
909e912.
122.9, 109.0, 101.9, 79.5, 61.7, 46.7, 31.1, 28.3, 23.8. HRMS (ESI) m/z:
calcd for C10H14N3O3 [MþH]þ 224.1035, found [MþH]þ¼224.1038
(unprotected).
2. Koblish, H. K.; Zhao, S. Y.; Franks, C. F.; Donatelli, R.; Tominovich, R.; LaFrance, L.;
Leonard, K.; Gushue, J.; Parks, D.; Calvo, R.; Milkiewicz, K.; Marugan, J. J.;
Raboisson, P.; Cummings, M.; Grasberger, B.; Lu, T. B.; Molloy, C. J.; Maroney, A. C.
Mol. Cancer Ther. 2006, 5, 160e169.
3. Parks, D. J.; LaFrance, L. V.; Calvo, R. R.; Milkiewicz, K. L.; Gupta, V.; Lattanze, J.;
Ramachandren, K.; Carver, T. E.; Petrella, E. C.; Cummings, M. D.; Maguire, D.;
Grasberger, B. L.; Lu, T. B. Bioorg. Med. Chem. Lett. 2005, 15, 765e770.
4. Kariyone, K.; Yazawa, H.; Kohsaka, M. Chem. Pharm. Bull. 1971, 19, 2289e2293.
5. Singh, R.; Jain, P. C.; Anand, N. Indian J. Chem., Sect. B 1981, 20, 129e131.
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, 2113e2116.
7. Bouhlal, D.; Gode, P.; Goethals, G.; Massoui, M.; Villa, P.; Martin, P. Heterocycles
2001, 55, 303e312.
4.3.21. 5a,6,7,8-Tetrahydrodipyrrolo[1,2-a:30,20-e][1,4]diazepine-
5,10(1H,4H)-dione (35g). Brown oil. The crude product was purified
by silica gel flash chromatography using 0% MeOH to 5% MeOH in
CH2Cl2 to yield a colorless solid. Yield: 57%. Mp 207.5e210.6 ꢀC. 1H
NMR (400 MHz, DMSO-d6)
(t, 1H, J¼2.9 Hz), 5.82 (t, 1H, J¼2.5 Hz), 4.06 (m, 1H), 3.55 (m, 2H),
1.92 (m, 4H). 13C NMR (75 MHz, DMSO-d6)
(ppm) 168.6, 160.7,
d (ppm) 11.46 (s, 1H), 10.31 (s, 1H), 6.88
d
127.3, 122.6, 116.2, 100.7, 58.3, 46.5, 26.5, 24.0. HRMS (ESI) m/z:
calcd for C10H12N3O2 [MþH]þ 206.0930, found [MþH]þ¼206.0934.
8. Hosmane, R. S.; Bhan, A.; Karpel, R. L.; Siriwardane, U.; Hosmane, N. S. J. Org.
Chem. 1990, 55, 5882e5890.
9. Daly, J. W.; Hide, I.; Bridson, P. K. J. Med. Chem. 1990, 33, 2818e2821.
10. Hosmane, R. S.; Bhan, A. J. Heterocycl. Chem. 1990, 27, 2189e2196.
11. Bridson, P. K.; Weirich, T. P. J. Heterocycl. Chem. 1988, 25, 1179e1182.
12. Ivanov, E. I. Khim. Geterotsikl. Soedin. 1998, 828e831.
4.3.22. Ethyl 3-(3-(4-(tert-butoxy)phenyl)-2-((tert-butoxycarbonyl)
amino) propanamido)-1H-pyrrole-2-carboxylate (32h). Colorless
solid. Yield: 86%. Mp 63.4e65.4 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
(ppm) 11.63 (s, 1H), 9.70 (s, 1H), 7.50 (d, 1H, J¼8.0 Hz), 7.19 (d, 2H,
J¼8.4 Hz), 6.93 (t, 1H, J¼2.9 Hz), 6.88 (d, 2H, J¼8.4 Hz), 6.84 (t, 1H,
J¼2.5 Hz), 4.30 (q, 2H, J¼7.1 Hz), 4.21 (m, 1H), 3.18 (dd, 1H, J¼3.6 Hz,
13.8 Hz), 2.78 (dd, 1H, J¼4.1 Hz, 14.4 Hz), 1.31 (t, 9H, J¼6.2 Hz), 1.25
13. Ivanov, E. I.; Kalayanov, G. D.; Yaroshchenko, I. M. Khim. Geterotsikl. Soedin. 1990,
997e998.
14. Garcia, C. J. Heterocycl. Chem. 1973, 10, 51e53.
15. Funke, C.; Es-Sayed, M.; de Meijere, A. Org. Lett. 2000, 2, 4249e4251.
16. Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem. 1997,
62, 1240e1256.
(t, 3H, J¼6.2 Hz). 13C NMR (75 MHz, DMSO-d6)
d (ppm) 169.8, 161.1,
156.0, 153.9, 133.4, 131.0, 130.0, 124.0, 123.8, 108.5, 102.3, 78.1, 60.1,

J.-D. Malcor et al. / Tetrahedron 70 (2014) 4631e4639
4639
17. Ueda, T.; Kato, Y.; Sakakibara, J.; Murata, M. Chem. Pharm. Bull. 1988, 36,
2902e2908.
34. Barker, J. M.; Huddleston, P. R.; Holmes, D. J. Chem. Res., Miniprint 1986,
1462e1470.
18. Guendel, W.; Bohnert, S. Z. Naturforsch. B 1988, 43, 769e777.
19. Hamilton, H. W.; Nishiguchi, G.; Hagen, S. E.; Domagala, J. D.; Weber, P. C.;
Gracheck, S.; Boulware, S. L.; Nordby, E. C.; Cho, H.; Nakamura, T.; Ikeda, S.;
Watanabe, W. Bioorg. Med. Chem. Lett. 2002, 12, 2981e2983.
20. Fedorov, A. E.; Shestopalov, A. M.; Belyakov, A. A. Russ. Chem. Bull. 2003, 52,
2197e2202.
35. Barker, J. M.; Huddleston, P. R.; Holmes, D. J. Chem. Res., Synop. 1986, 155.
36. Fabis, F.; Jolivet-Fouchet, S.; Robba, M.; Landelle, H.; Rault, S. Tetrahedron 1998,
54, 10789e10800.
37. Le Foulon, F. X.; Braud, E.; Fabis, F.; Lancelot, J. C.; Rault, S. Tetrahedron 2003, 59,
10051e10057.
38. Le Foulon, F. X.; Braud, E.; Fabis, F.; Lancelot, J. C.; Rault, S. J. Comb. Chem. 2005,
7, 253e257.
39. Ogawva, K.; Yamawaki, I.; Matsusita, Y. I.; Nomura, N.; Kador, P. F.; Kinoshita, J.
21. Brouillette, Y.; Lisowski, V.; Fulcrand, P.; Martinez, J. J. Org. Chem. 2007, 72,
2662e2665.
ꢀ
22. Brouillette, Y.; Verdie, P.; Martinez, J.; Lisowski, V. Synlett 2008, 2360e2364.
H. Eur. J. Med. Chem. 1993, 28, 769e781.
23. Brouillette, Y.; Sujol, G.; Martinez, J.; Lisowski, V. Synthesis 2009, 389e394.
24. Hurd, C. D.; Bethune, V. G. J. Org. Chem. 1970, 35, 1471e1475.
25. Beckwith, A. L.; Hickman, R. J. J. Chem. Soc. C 1968, 2756e2759.
26. Brouillette, Y.; Martinez, J.; Lisowski, V. Eur. J. Org. Chem. 2009,
3487e3503.
40. Ross, J. R.; Laks, J. S.; Wang, D. L. C.; Sowell, J. W. Synthesis 1985, 796e798.
41. Player, M. R.; Sowell, J. W.; Williams, G. R.; Cowley, G. T. J. Heterocycl. Chem.
1994, 31, 209e214.
42. Player, M. R.; Sowell, J. W.; Patil, G. S.; Kam, C. M.; Powers, J. C. Bioorg. Med.
Chem. Lett. 1994, 4, 949e954.
27. Norman, M. H.; Navas, F.; Thompson, J. B.; Rigdon, G. C. J. Med. Chem. 1996, 39,
4692e4703.
28. Baker, B. R.; Joseph, J. P.; Schaub, R. E.; Mcevoy, F. J.; Williams, J. H. J. Org. Chem.
1953, 18, 138e152.
43. Player, M. R.; Sowell, J. W. J. Heterocycl. Chem. 1995, 32, 1537e1540.
44. Bayomi, S. M.; Alrashood, K. A. Monatsh. Chem. 1991, 122, 725e730.
45. Compound 11 was prepared from an experimental procedure adapted from
Furneaux, R. H.; Tyler, P. C. J. Org. Chem. 1999, 64, 8411e8412.
46. Brouillette, Y.; Lisowski, V.; Guillon, J.; Massip, S.; Martinez, J. Tetrahedron 2007,
63, 7538e7544.
€
€
29. Gutschow, M.; Kuerschner, L.; Neumann, U.; Pietsch, M.; Loser, R.; Koglin, N.;
Eger, K. J. Med. Chem. 1999, 42, 5437e5447.
30. Gewald, K.; Schinke, E.; Bottcher, H. Chem. Ber. 1966, 99, 94e100.
31. Gewald, K.; Neumann, G. Chem. Ber. 1968, 101, 1933e1939.
32. Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36,
333e345.
47. Correa, A.; Tellitu, I.; Dominguez, E.; Moreno, I.; San Martin, R. J. Org. Chem.
2005, 70, 2256e2264.
48. Abbas, S. E.; Awadallah, F. M.; Ibrahil, N. A.; Gouda, A. M.; Shehata, B. A. Med.
Chem. Res. 2011, 20, 1015e1023.
33. Huddleston, P. R.; Barker, J. M. Synth. Commun. 1979, 9, 731e734.