A stereoselective route to 6-substituted pyrrolo-1,5-benzoxazepinones and their analogues

Article abstract of DOI:10.1016/j.tetlet.2013.07.115

We developed a novel and convenient stereoselective path for the preparation of pyrrolo-1,5-benzoxazepinones (PBOs). This innovative route envisaged the employment of (-)-menthol as convenient chiral auxiliary and a key S_NAr for the stereoselective preparation of a tertiary aryl-alkyl ether. As a further advancement, we exploited this newly conceived synthetic route for the preparation of 2-substituted PBO analogues to either undergo biological evaluation themselves or give access to a variety of further functionalization options.

Full text of DOI:10.1016/j.tetlet.2013.07.115

Tetrahedron Letters 54 (2013) 5387–5390
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A stereoselective route to 6-substituted
pyrrolo-1,5-benzoxazepinones and their analogues
Margherita Brindisi a, Sandra Gemma a, Gloria Alfano a, Giridhar Kshirsagar a, Ettore Novellino b,
Giuseppe Campiani a, , Stefania Butini a
⇑
a European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy
b Dipartimento di Farmacia, University of Naples Federico II, via D. Montesano 49, 80131 Naples, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
We developed a novel and convenient stereoselective path for the preparation of pyrrolo-1,5-benzoxaz-
epinones (PBOs). This innovative route envisaged the employment of (ꢀ)-menthol as convenient chiral
auxiliary and a key SNAr for the stereoselective preparation of a tertiary aryl–alkyl ether. As a further
advancement, we exploited this newly conceived synthetic route for the preparation of 2-substituted
PBO analogues to either undergo biological evaluation themselves or give access to a variety of further
functionalization options.
Received 24 June 2013
Revised 17 July 2013
Accepted 22 July 2013
Available online 27 July 2013
Keywords:
Pyrrolo-1,5-benzoxazepinones
Aryl–alkyl ether
Ó 2013 Elsevier Ltd. All rights reserved.
Menthol
Stereoselective synthesis
Me
Pyrrolo-1,5-benzoxazepinones (PBOs) and pyrrolo-1,5-ben-
zoxazepines (PBOXs) are pharmaceutically relevant heterocycles.
In a variety of medicinal chemistry papers we highlighted the
strong potential of these compounds as biologically active mole-
cules, particularly as antitumor and antiviral agents.1–7 As a part
of our research activity, a major focus was directed toward the
development of novel PBO compounds as nonnucleoside inhibi-
tors of human immunodeficiency virus reverse transcriptase
(HIV-1 RT)1,2,4,6,7 and adenosine kinase (AK).8 A number of extre-
mely potent PBO antivirals were designed and synthesized and, in
more recent papers, the stereoselective interaction with RT has
been ascertained.7 We recently discovered a new allosteric site
for PBO on AK, making the survey of a stereoselective, versatile
route to enantiomerically pure PBO compounds our priority in or-
der to investigate the mode of interaction.8 The traditional retro-
synthetic approach for obtaining racemic PBOs envisaged the C6–
O5 ether bond and the carbonyl group on the pyrrole ring as the
key disconnection points, as shown for the representative com-
pound 1 Eq. (1).4 Alkylation of 2-(1H-pyrrol-1-yl)phenol 2 with
Me
Me
O
OH
N
6
O
OEt
Br
N
2
3
1
(1)
O
Although the enantiomers of PBO compounds proved to be separa-
ble by analytical HPLC,7,8 the poor solubility of our racemates in
typical mobile phases severely limits the scalability of this method.
In addition, the oily nature of these compounds impeded their crys-
tallization for X-ray analysis and for determining their absolute
configuration. Therefore, we desired to develop an efficient, robust,
and reproducible stereoselective strategy to generate PBO com-
pounds. As illustrated in Figure 1 we reasoned that PBO scaffold
(R)-1 could be assembled from a chiral tertiary
a-hydroxy acid
(Synthon I) and an activated aryl fluoride (Synthon II).
The two synthons may be coupled together by means of a SNAr
reaction. The optically pure aryl–alkyl ether obtained would then
undergo classical cyclization route. Furthermore, this newly con-
ceived method could provide an easy access to 2-substituted PBO
analogues (Fig. 1).
the suitable
a-bromophenylacetic esters 3, followed by classical
intramolecular Friedel–Crafts reaction and alkylation at C6, typi-
cally provided racemic PBOs in moderate to good overall yields.4
Chiral tertiary
a
-hydroxy acids are important building blocks9–
⇑
Corresponding author. Tel.: +39 0577 234172; fax: +39 0577 23234254.
E-mail address: campiani@unisi.it (G. Campiani).
12 and synthetic intermediates13–16 for the preparation of complex
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.115

5388
M. Brindisi et al. / Tetrahedron Letters 54 (2013) 5387–5390
condensed with (ꢀ)-menthol in the presence of p-toluenesulfonic
acid,22 while ester 6 underwent a modification of the titanium
(IV) alkoxyde-catalyzed transesterification developed by See-
bach.24 Accordingly, treatment of 6 with (ꢀ)-menthol in the pres-
ence of a catalytic amount of titanium isopropoxide (20 mol %) in
toluene at 100 °C provided the corresponding (ꢀ)-menthyl ester
7 in high yield (Scheme 1).
A number of literature examples show that ketones are suitable
electrophiles to Grignard reagents. Furthermore, these experi-
ments demonstrate how electrophilic addition of organometallics
Synthon I
Chiral tertiary
α-hydroxy acid
2-substituted
analogues
access
to a-menthyl keto esters provide better results in terms of selectiv-
Synthon II
Activated
aryl fluoride
ity when the Grignard reagent is used in the presence of zinc chlo-
ride.17 In these systems in situ Mg/Zn transmetallation at the level
of the Grignard reagent is accompanied by the parallel zinc chela-
tion by the ketoester, thus favoring a syn-coplanar conformation
for the two keto groups. Furthermore, an increased level of diaste-
reoselectivity is reported if para position of an arylglyoxylate is
occupied by an electrondonating group.24 Accordingly, reaction of
keto ester 7 with ethyl magnesium bromide in the presence of
Figure 1. Proposed retrosynthetic approach for the stereoselective synthesis of PBO
compounds and their 2-substituted analogues.
biologically active substances. The diastereoselective addition of
organometallics to a-keto esters bearing cyclohexane-based chiral
2 equiv of zinc chloride afforded chiral
a-hydroxy ester 8
(Scheme 1) in good yield and with a 92:8 dr by NMR determination
(the two diastereoisomers being easily separated by flash chroma-
tography). The ensuing conversion of menthyl ester to its corre-
sponding methyl derivative was performed in order to overcome
subsequent issues with the cleavage of menthyl ester on more hin-
dered substrates which required harsh conditions and provided ex-
tremely poor yields. Saponification22 provided the corresponding
acid (analyzed by chiral HPLC to assess its optical purity)25 in turn
converted into the corresponding methyl ester (R)-9 by a mild pro-
cedure employing methyl iodide in the presence of potassium car-
bonate (Scheme 1).26
auxiliaries represents an efficient method for their stereoselective
synthesis.17–22 To this end, the use of menthol provides many
advantages such as low cost, availability, and good selectivity.16,23
Starting from toluene (4, Scheme 1), a standard Friedel–Crafts acyl-
ation protocol led to ethyl p-tolyl-oxo-acetate 6 and its corre-
sponding free acid 5, both employed for the preparation of the
(ꢀ)-menthyl ester derivative 7. Indeed,
a-ketoacid 5 was
HOOC
O
As the next step we investigated nucleophilic aromatic substi-
tution (SNAr) by an alkoxide as a mild method to synthesize chiral
tertiary aryl–alkyl ethers. Tertiary alkoxides are infrequently used
as nucleophiles. Nevertheless, it has been observed that hindered
tertiary alkoxides are effective nucleophiles in SNAr reactions with
activated aryl fluoride electrophiles.27
On these bases, we originally envisaged 1-fluoro-2-nitroben-
zene as the suitable substrate for the SNAr. The reaction, performed
on both the (ꢀ)-menthyl ester 8 and the methyl ester (R)-9 in the
presence of sodium hydride as the base,28 provided the desired
ethers (R)-10a,b in good yields. No side-product indicative of rad-
ical nucleophilic substitution (SRN1), such as hydro-de-halogena-
tion products or biaryl products was observed. Furthermore, we
b
Me
Me
Me
O
5
Me
Me
O
a
EtOOC
O
Me
O
4
7
c
d
6
Me
Me
O
O
OH
Me
OH
MeO
e,f
O
Et
(R)-9
Et
Me
Me
8
Me
a
O
NO2
O
NH2
g
g
b
c
d
O
O
RO
RO
O
NO2
Et
Et
O
RO
Et
a
,
b
,
c
Me
)-10a,b
Me
( )-11a,b
R
o
r
d
(
R
Me
(
)-10a,
R
R = (-)-menthyl
R = Me
O
(R)-10b,
Me
N
H
O
Scheme 1. Synthesis of aryl–alkyl ethers (R)-10a,b. Reagents and conditions: (a)
AlCl3, ClCOCOOEt, 1,2-DCE, 0 °C for 1 h then 30 °C for 4h, 35% (for 5) and 54% (for 6);
(b) (ꢀ)-menthol, p-TsOH, dry toluene, reflux, 20 h, 55%; (c) (ꢀ)-menthol,
Ti[OCH(CH3)2]4, dry toluene, 100 °C, 12 h, 67%; (d) EtMgBr (1 M solution in dry
diethyl ether), ZnCl2, dry diethyl ether, 0 °C for 2 h, ꢀ78 °C for 3 h, then 25 °C for 1 h,
85%; (e) KOH, MeOH/H2O 1:1, reflux, 92%; (f) MeI, K2CO3, dry DMF, 25 °C, 4 h, 89%;
(g) 1-fluoro-2-nitrobenzene, NaH, 15-crown-5, dry THF, 0 °C to rt, 17 h, 56% for (R)-
10a and 62% for (R)-10b.
(R)-12
Scheme 2. Attempts to the synthesis of intermediates (R)-11a,b. Reagents and
conditions: (a) H2, Pd/C, EtOAc, rt, 30 min, 83%; (b) HCOONH4, Pd/C, dry MeOH, rt,
12 h, 76%; (c) SnCl2ꢁ2H2O, EtOAc, reflux, 2 h, 77%; (d) NH2NH2ꢁH2O, Pd/C, EtOH,
reflux, 3 h, 55%.

M. Brindisi et al. / Tetrahedron Letters 54 (2013) 5387–5390
5389
had no evidence of cine-substitution product, suggestive of
I
NH2
O
benzyne-like intermediate formation. Regrettably, all the at-
tempted reduction protocols on the nitro group of ethers (R)-
10a,b (also employing aniline protecting agents, data not shown)
for the following pyrrole ring construction led to the formation
of the corresponding cyclic amide (R)-12 (Scheme 2).
O
N
O
N
O
a
MeO
MeO
Et
Et
Although the benzoxazine nucleus was not useful for our pur-
poses, the method described in Scheme 2 represents a straightfor-
ward and mild approach to optically pure benzoxazines
substituted at C2, being the hydrogenolysis of the nitro group the
most convenient method. Recently C2 substituted benzoxazines
have been described as potent renin inhibitors.28
Taking a backward step, we reasoned that a SNAr protocol could
have also been applied on a different activated aryl fluoride,
namely 4-nitro-2-pyrrolylfluorobenzene 13 (Scheme 3), deriving
from its 2-amino derivative after a classical Clauson–Kaas pyrrole
ring construction.29 This substrate (13) would still represent a
strongly activated fluoride, with the undeniable benefits of bearing
at the same time the pyrrole ring already installed and the nitro
group as useful entry for further functionalization. Notably, this
approach allows avoiding the use of the Clauson–Kaas conditions
on our aryl–alkyl ether. We also envisaged that the ‘extra’ nitro
group could be suitably detached by a reductive deamination
protocol.
Gratifyingly, SNAr performed on derivative 13 provided the
aryl–alkyl ether (R)-14 in good yield, although lower than that ob-
tained for compound (R)-10b, possibly due to the greater steric
hindrance of the aryl fluoride 13. Subsequent reduction performed
with tin(II) chloride in refluxing ethanol led to aniline derivative
(R)-15. The subsequent step was represented by a one-pot, diazo-
tization–dediazotization to give the deaminated product (R)-16 in
moderate yield.
Me
Me
(R)-15
(R)-17
c,d
b
Br
O
Me
Me
O
O
N
c,d
MeO
O
Et
R
N
(R)-19a
, R = I
Me
(R)-18
(R)-19b, R = Br
Scheme 4. Synthesis of 2-bromo and 2-iodo derivatives (R)-19a,b. Reagents and
conditions: (a) NaNO2, KI, p-TsOH, H2O, MeCN, 0 °C to rt, 2 h, 85%; (b) TMSBr,
NaNO2, TEBAC, CCl4, 0 °C to rt, 36 h, 42%; (c) 15% NaOH, THF/EtOH 1:1, reflux, 5 h,
99%; (d) PCl5, dry CH2Cl2, 35 °C, 15 h, 20–25%.
(R)-16, the synthetic route for the achievement of the PBO scaffold
fully traced out the racemic synthesis, with alkaline hydrolysis of
the methyl ester and subsequent intramolecular Friedel–Crafts
reaction4 leading to the desired (R)-1 (Scheme 3).31
The reaction encompassed the use of sodium nitrite in the pres-
ence of acetic acid as a mild diazotization procedure and sodium
bisulfite as the reducing agent.30 Finally, starting from compound
As a further advancement we intended to exploit this newly
conceived synthetic route for the preparation of 2-substituted
PBO derivatives to either undergo biological evaluation themselves
or give access to a variety of functionalizations. Accordingly, ani-
line (R)-15 was identified as a key versatile intermediate for this
purpose. However, preliminary attempts of employing traditional
Sandmeyer conditions led to complete decomposition of our start-
ing material. As a consequence, we focused our attention on milder
procedures providing halo-substituted analogues ((R)-17 and (R)-
18, Scheme 4). Iodination was indeed performed by using p-tolu-
enesulfonic acid and sodium nitrite as mild diazotization agents
in the presence of potassium iodide.32 This protocol led to the
iodo-derivative (R)-17 in moderate yield. Aniline (R)-15 was also
converted into the corresponding bromo-derivative (R)-18 in a
one-pot reaction using sodium nitrite and bromotrimethylsilane
in the presence of benzyltriethylammonium chloride (TEBAC) in
carbon tetrachloride as the solvent. Bromotrimethylsilane was
used for both the generation of the nitrosonium donor from so-
dium nitrite, and the substitution of the diazonium group.33 Ester
functionalities of (R)-17 and (R)-18 were hydrolyzed and the cor-
responding acids were submitted to intramolecular Friedel–Crafts
cyclization providing the 2-substituted cyclic ketones (R)-19a,b.4,34
In conclusion, we herein developed a novel and convenient ster-
eoselective path for the preparation of PBO compounds character-
ized by a quaternary chiral carbon atom at C6. This innovative
route envisaged the employment of the naturally occurring men-
thol isomer as a convenient chiral auxiliary for the stereoselective
NO2
a
N
F
NH2
O
NO2
O
13
O
N
O
N
b
MeO
MeO
Et
Et
(
R
)-14
Me
(
R
)-15 Me
c
Me
O
N
Me
O
O
d,e
MeO
Et
O
N
preparation of the (R)-tertiary a-hydroxy acid and a key SNAr reac-
(R)-1
(R)-16
tion for the accomplishment of a stereochemically defined tertiary
aryl–alkyl ether. As a further advancement we exploited this newly
conceived synthetic route for the preparation of 2-substituted PBO
analogues by the use of mild diazotization procedures which led to
2-bromo and 2-iodo PBO derivatives to either undergo biological
Me
Scheme 3. Stereoselective synthetic route of (R)-1. Reagents and conditions: (a)
(R)-9, NaH, 15-crown-5, dry THF, 0 °C to rt, 17 h, 32%; (b) SnCl2ꢁ2H2O, EtOH, reflux,
5 h, 90%; (c) NaNO2, NaHSO3, AcOH, EtOH, rt, 3 h, 31%; (d) 15% NaOH, THF/EtOH 1:1,
reflux, 5 h, 99%; (e) PCl5, dry CH2Cl2, 35 °C, 15 h, 20%.

5390
M. Brindisi et al. / Tetrahedron Letters 54 (2013) 5387–5390
16. Rozema, M. J.; Kruger, A. W.; Rohde, B. D.; Shelat, B.; Bhagavatula, L.; Tien, J. J.;
Zhang, W. J.; Henry, R. F. Tetrahedron 2005, 61, 4419–4425.
evaluation themselves or give access to a variety of further func-
tionalizations (e.g., transition metal catalyzed reactions, alkoxyla-
tion). This method may be applied to the synthesis of
enantiomerically pure pyrrolo-1,5-benzothiazepines calcium chan-
nel blockers, analogues of Diltiazem35, and renin inhibitors based
on a benzoxazine nucleus.28
17. Boireau, G.; Deberly, A.; Abenhaim, D. Tetrahedron 1989, 45, 5837–5844.
18. Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908–6909.
19. Akiyama, T.; Nishimoto, H.; Ishikawa, K.; Ozaki, S. Chem. Lett. 1992, 447–450.
20. Basavaiah, D.; Bharathi, T. K. Tetrahedron Lett. 1991, 32, 3417–3420.
21. Basavaiah, D.; Pandiaraju, S.; Bakthadoss, M.; Muthukumaran, K. Tetrahedron:
Asymmetry 1996, 7, 997–1000.
22. Basavaiah, D.; Krishna, P. R. Tetrahedron 1995, 51, 12169–12178.
23. Oertling, H.; Reckziegel, A.; Surburg, H.; Bertram, H. J. Chem. Rev. 2007, 107,
2136–2164.
Acknowledgment
24. Xiang, J. M.; Li, B. L. Helv. Chim. Acta 2010, 93, 2015–2022.
25. HPLC conditions. Column: ChiralPack AS (0.46 ꢂ 25 cm); solvent system: n-
hexane/isopropanol 95:5; UV detector LaPrep 311, 254 nM; sample
concentration: 1 mg/mL; flow: 1 mL/min; peak A (retention time 10.6 min,
area 3.3%), peak B (retention time 14.2 min, area 95.2%).
Authors thank NatSynDrugs for financial support.
References and notes
26. Ji, F.; Wu, W.; Dai, X.; Mori, N.; Wu, J.; Buchwald, P.; Bodor, N. J. Pharm.
Pharmacol. 2005, 57, 1427–1435.
1. Campiani, G.; Nacci, V.; Fiorini, I.; De Filippis, M. P.; Garofalo, A.; Greco, G.;
Novellino, E.; Altamura, S.; Di Renzo, L. J. Med. Chem. 1996, 39, 2672–2680.
2. Campiani, G.; Morelli, E.; Fabbrini, M.; Nacci, V.; Greco, G.; Novellino, E.;
Ramunno, A.; Maga, G.; Spadari, S.; Caliendo, G.; Bergamini, A.; Faggioli, E.;
Uccella, I.; Bolacchi, F.; Marini, S.; Coletta, M.; Nacca, A.; Caccia, S. J. Med. Chem.
1999, 42, 4462–4470.
27. Woiwode, T. F.; Rose, C.; Wandless, T. J. J. Org. Chem. 1998, 63, 9594–9596.
28. Powell, N. A.; Ciske, F. L.; Cai, C.; Holsworth, D. D.; Mennen, K.; Van Huis, C. A.;
Jalaie, M.; Day, J.; Mastronardi, M.; McConnell, P.; Mochalkin, I.; Zhang, E.;
Ryan, M. J.; Bryant, J.; Collard, W.; Ferreira, S.; Gu, C.; Collins, R.; Edmunds, J. J.
Bioorg. Med. Chem. 2007, 15, 5912–5949.
3. Campiani, G.; Ramunno, A.; Fiorini, I.; Nacci, V.; Morelli, E.; Novellino, E.;
Goegan, M.; Mennini, T.; Sullivan, S.; Zisterer, D. M.; Williams, C. D. J. Med.
Chem. 2002, 45, 4276–4281.
4. Fattorusso, C.; Gemma, S.; Butini, S.; Huleatt, P.; Catalanotti, B.; Persico, M.; De
Angelis, M.; Fiorini, I.; Nacci, V.; Ramunno, A.; Rodriquez, M.; Greco, G.;
Novellino, E.; Bergamini, A.; Marini, S.; Coletta, M.; Maga, G.; Spadari, S.;
Campiani, G. J. Med. Chem. 2005, 48, 7153–7165.
5. Mc Gee, M. M.; Gemma, S.; Butini, S.; Ramunno, A.; Zisterer, D. M.; Fattorusso,
C.; Catalanotti, B.; Kukreja, G.; Fiorini, I.; Pisano, C.; Cucco, C.; Novellino, E.;
Nacci, V.; Williams, D. C.; Campiani, G. J. Med. Chem. 2005, 48, 4367–4377.
6. Butini, S.; Brindisi, M.; Cosconati, S.; Marinelli, L.; Borrelli, G.; Coccone, S. S.;
Ramunno, A.; Campiani, G.; Novellino, E.; Zanoli, S.; Samuele, A.; Giorgi, G.;
Bergamini, A.; Di Mattia, M.; Lalli, S.; Galletti, B.; Gemma, S.; Maga, G. J. Med.
Chem. 2009, 52, 1224–1228.
7. Butini, S.; Gemma, S.; Brindisi, M.; Borrelli, G.; Fiorini, I.; Samuele, A.; Karytinos,
A.; Facchini, M.; Lossani, A.; Zanoli, S.; Campiani, G.; Novellino, E.; Focher, F.;
Maga, G. Bioorg. Med. Chem. Lett. 2011, 21, 3935–3938.
29. Butini, S.; Brindisi, M.; Gemma, S.; Minetti, P.; Cabri, W.; Gallo, G.; Vincenti, S.;
Talamonti, E.; Borsini, F.; Caprioli, A.; Stasi, M. A.; Di Serio, S.; Ros, S.; Borrelli,
G.; Maramai, S.; Fezza, F.; Campiani, G.; Maccarrone, M. J. Med. Chem. 2012, 55,
6898–6915.
30. Geoffroy, O. J.; Morinelli, T. A.; Meier, G. P. Tetrahedron Lett. 2001, 42, 5367–
5369.
31. (R)-6-Ethyl-6-(p-tolyl)benzo[b]pyrrolo[1,2-d][1,4]oxazepin-7(6H)-one ((R)-1): 1H
NMR (400 MHz, CDCl3) d 0.98 (t, 3H, J = 7.2 Hz), 2.19 (s, 3H), 2.27–2.30 (m, 1H),
2.37–2.46 (m, 1H), 6.39 (t, 1H, J = 3.2 Hz), 6.90 (dd, 1H, J1 = 2.0 Hz, J2 = 7.6 Hz),
6.95–7.05 (m, 4H), 7.14–7.22 (m, 5H); 13C NMR (75 MHz, CDCl3) d 8.6, 29.9,
32.6, 96.1, 105.0, 111.9, 120.6, 121.7, 125.3, 125.7, 126.3, 127.1, 127.6 (2),
20
436
129.0 (2), 132.8, 138.1, 139.1, 152.6, 196.7; ½
a
ꢃ
ꢀ55.3 (c 0.12, CHCl3); MS
(ESI) m/z 318 [M+H]+, 340 [M+Na]+.
32. Krasnokutskaya, E. A.; Semenischeva, N. I.; Filimonov, V. D.; Knochel, P.
Synthesis 2007, 81–84.
33. Lee, J. G.; Cha, H. T. Tetrahedron Lett. 1992, 33, 3167–3168.
34. (R)-6-Ethyl-2-iodo-6-(p-tolyl)benzo[b]pyrrolo[1,2-d][1,4]oxazepin-7(6H)-one
(19a): 1H NMR (400 MHz, CDCl3) d 0.97 (t, 3H, J = 7.2 Hz), 2.20 (s, 3H), 2.24–
2.31 (m, 1H), 2.35–2.44 (m, 1H), 6.40 (t, 1H, J = 3.6 Hz), 6.61 (d, 1H, J = 8.4 Hz),
6.97 (d, 2H, J = 8.0 Hz), 7.11 (d, 2H, J = 2.0 Hz), 7.12 (s, 1H), 7.23–7.27 (m, 2H),
7.50 (d, 1H, J = 1.6 Hz); 13C NMR (75 MHz, CDCl3) d 1.2, 15.5, 29.9, 66.1, 96.4,
8. Butini, S.; Gemma, S.; Brindisi, M.; Borrelli, G.; Lossani, A.; Ponte, A. M.; Torti,
A.; Maga, G.; Marinelli, L.; La Pietra, V.; Fiorini, I.; Lamponi, S.; Campiani, G.;
Zisterer, D. M.; Nathwani, S. M.; Sartini, S.; La Motta, C.; Da Settimo, F.;
Novellino, E.; Focher, F. J. Med. Chem. 2011, 54, 1401–1420.
9. Subrahmanyam, D.; Sarma, V. M.; Venkateswarlu, A.; Sastry, T. V.; Srinivas, A.
S.; Krishna, C. V.; Deevi, D. S.; Kumar, S. A.; Babu, M. J.; Damodaran, N. K. Bioorg.
Med. Chem. Lett. 2000, 10, 369–371.
10. Visser, T. J.; Van Waarde, A.; Doze, P.; Wegman, T.; Vaalburg, W. Synapse 2000,
35, 62–67.
11. Mayer, P.; Brunel, P.; Imbert, T. Bioorg. Med. Chem. Lett. 1999, 9, 3021–3022.
12. Loupy, A.; Monteux, D. A. Tetrahedron 2002, 58, 1541–1549.
13. Hauser, F. M.; Ganguly, D. J. Org. Chem. 2000, 65, 1842–1849.
14. Vladu, B.; Woynarowski, J. M.; Manikumar, G.; Wani, M. C.; Wall, M. E.; Von
Hoff, D. D.; Wadkins, R. M. Mol. Pharmacol. 2000, 57, 243–251.
15. Roy, S.; Sharma, A.; Chattopadhyay, N.; Chattopadhyay, S. Tetrahedron Lett.
2006, 47, 7067–7069.
112.4, 117.2, 121.2, 125.7, 127.6 (2), 128.4, 129.2 (2), 129.3, 129.9, 130.4, 135.9,
20
138.4, 153.7, 192.3; ½
a
ꢃ
ꢀ29.4 (c 0.09, CHCl3); MS (ESI) m/z 443 [M+H]+, 465
436
[M+Na]+.
(R)-2-Bromo-6-ethyl-6-(p-tolyl)benzo[b]pyrrolo[1,2-d][1,4]oxazepin-
7(6H)-one (19b): 1H NMR (400 MHz, CDCl3) d 0.98 (t, 3H, J = 7.2 Hz), 2.16–
2.27 (m, 1H), 2.28 (s, 3H), 2.34–2.43 (m, 1H), 6.41 (t, 1H, J = 3.2 Hz), 6.78–6.81
(m, 1H), 6.95–6.98 (m, 2H), 7.10–7.15 (m, 4H), 7.22–7.25 (m, 2H); 13C NMR
(75 MHz, CDCl3) d 1.3, 15.6, 30.0, 66.1, 112.4, 115.3, 117.2, 120.5, 125.7, 127.6
20
436
(2), 128.4, 129.2 (2), 129.3, 129.9, 130.4, 135.9, 138.4, 153.7, 192.3; ½
aꢃ
ꢀ17.7
(c 0.06, CHCl3); MS (ESI) m/z 397 [M+H]+.
35. Campiani, G.; Fiorini, I.; De Filippis, M. P.; Ciani, S. M.; Garofalo, A.; Nacci, V.;
Giorgi, G.; Sega, A.; Botta, M.; Chiarini, A.; Budriesi, R.; Bruni, G.; Romeo, M. R.;
Manzoni, C.; Mennini, T. J. Med. Chem. 1996, 39, 2922–2938.