Synthesis of benzodiazepine β-turn mimetics by an Ugi 4CC/Staudinger/aza-wittig sequence. Solving the conformational behavior of the Ugi 4CC adducts

Article abstract of DOI:10.1021/jo8025862

5-Oxobenzo[e][l,4]diazepine-3-carboxamides were synthesized by sequential Ugi reaction-Staudinger/aza-Wittig cyclization. The pseudopeptidic backbone of the new benzodiazepine derivatives superimposed well with type I, I, II, and II β-turn motifs. The intermediate Ugi adducts were characterized as two conformers of the enol form by the correlation between ¹H NMR spectra and X-ray diffraction structures of model compounds.

Full text of DOI:10.1021/jo8025862

but the pharmacological spectrum of activity for benzodiazepine
site ligands is much wider, being recognized as the first
privileged structures as a result of their capability of acting as
small-molecule inhibitors in protein-protein interactions.3
Protein-protein interactions are ubiquitous, essential to almost
all known biological processes, and offer attractive opportunities
for the development of small molecules that mimic surfaces of
protein-recognition motifs, acting as protein-complex antago-
nists. The interaction between the peptide ligands and their
receptor targets commonly involves ꢀ-turn structures;4 therefore,
the synthesis of peptidomimetics capable of mimicking ꢀ-turn
structures has gained high interest for the discovery of new
therapeutic agents. Benzodiazepines have been proposed several
times as ꢀ-turn mimetics,5 but a landmark discovery in this field
was asperlicin,6 a benzodiazepine derivative from microbial
fermentation that has been modified into a wide variety of
benzodiazepine derivatives which act as selective antagonists
of peptide hormone cholecystokinins CCK1 and CCK2.7 All
these derivatives have in common a voluminous polar group in
the 3-position of the original 1,4-benzodiazepine-5-one moiety,
a feature that could be easily accessed by a Ugi 4CC condensa-
tion, a useful reaction for the benzodiazepine synthesis.3a,8 The
2-azidobenzoic acid9 is a common starting material for the
synthesis of benzodiazepines,10 usually employed in aza-
Wittig6d,10a-c,11 or azide-alkyne cycloaddition8i schemes, which
Synthesis of Benzodiazepine ꢀ-Turn Mimetics by
an Ugi 4CC/Staudinger/Aza-Wittig Sequence.
Solving the Conformational Behavior of the Ugi
4CC Adducts
Mar´ıa San˜udo,† Mar´ıa Garc´ıa-Valverde,*,†
Stefano Marcaccini,§ Jacinto J. Delgado,‡ Josefa Rojo,† and
Toma´s Torroba*,†
Departamento de Qu´ımica, Facultad de Ciencias & Parque
Cient´ıfico Tecnolo´gico, UniVersidad de Burgos,
09001 Burgos, Spain, and Dipartamento di Chimica
Organica “Ugo Schiff”, UniVersita` di Firenze, Via della
Lastruccia 13, I-50121 Sesto Fiorentino (FI), Italy
magaVal@ubu.es; ttorroba@ubu.es
ReceiVed NoVember 26, 2008
(3) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893–930. (b) Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.;
Labaudinie`re, R. F. J. Comb. Chem. 2000, 2, 513–521. (c) Carlier, P. R.; Zhao,
H.; MacQuarrie-Hunter, S. L.; DeGuzman, J. C.; Hsu, D. C. J. Am. Chem. Soc.
2006, 128, 15215–15220. (d) Joseph, C. G.; Wilson, K. R.; Wood, M. S.;
Sorenson, N. B.; Phan, D. V.; Xiang, Z.; Witek, R. M.; Haskell-Luevano, C.
J. Med. Chem. 2008, 51, 1423–1431. (e) Ramajayam, R.; Girdhar, R.; Yadav,
M. R. Mini ReV. Med. Chem. 2007, 7, 793–812.
5-Oxobenzo[e][1,4]diazepine-3-carboxamides were synthe-
sized by sequential Ugi reaction-Staudinger/aza-Wittig
cyclization. The pseudopeptidic backbone of the new ben-
zodiazepine derivatives superimposed well with type I, I′,
II, and II′ ꢀ-turn motifs. The intermediate Ugi adducts were
characterized as two conformers of the enol form by the
(4) (a) Suat, K.; Jois, S. D. S. Curr. Pharm. Des. 2003, 9, 1209–1224. (b)
Robinson, J. A. Acc. Chem. Res. 2008, 41, 1278–1288. (c) Che, Y.; Marshall,
G. R. Expert Opin. Ther. Targets 2008, 12, 101–114.
1
correlation between H NMR spectra and X-ray diffraction
structures of model compounds.
(5) (a) Butini, S.; Gabellieri, E.; Huleatt, P. B.; Campiani, G.; Franceschini,
S.; Brindisi, M.; Ros, S.; Coccone, S. S.; Fiorini, I.; Novellino, E.; Giorgi, G.;
Gemma, S. J. Org. Chem. 2008, 73, 8458–8468.
(6) (a) Liesch, J. M.; Hensens, O. D.; Springer, J. P.; Chang, R. S. L.; Lotti,
V. J. J. Antibiot. 1985, 38, 1638–1641. (b) Evans, B. E.; Bock, M. G.; Rittle,
K. E.; DiPardo, R. M.; Whitter, W. L.; Veber, D. F.; Anderson, P. S.; Freidinger,
R. M Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 4918–4922. (c) Liu, J.-F.; Kaselj,
M.; Isome, Y.; Chapnick, J.; Zhang, B.; Bi, G.; Yohannes, D.; Yu, L.; Baldino,
C. M. J. Org. Chem. 2005, 70, 10488–10493. (d) Al-Said, N. H.; Al-Qaisi, L. S.
Tetrahedron Lett. 2006, 47, 693–694.
The concept of privileged structures constitutes a fruitful
approach to the discovery of novel biologically active molecules.
Privileged structures are molecular scaffolds with versatile
binding properties that are able to provide potent and selective
ligands for different biological targets, also exhibiting good
druglike properties.1 Therefore, privileged structures have been
successfully exploited for the discovery and optimization of
novel bioactive molecules. Benzodiazepines were introduced
into clinical practice for the treatment of anxiety and sleep
disorders due to their specific interaction with the allosteric site
to the benzodiazepine recognition site of the mammalian brain,2
(7) (a) Blakeney, J. S.; Reid, R. C.; Le, G. T.; Fairlie, D. P. Chem. ReV.
2007, 107, 2960–3041. (b) Butler, M. S. Nat. Prod. Rep. 2005, 22, 162–195. (c)
Varnavas, A.; Lassiani, L. Expert Opin. Ther. Pat. 2006, 16, 1193–1213.
(8) Reviews: (a) Marcaccini, S.; Torroba, T. In Multicomponent Reactions;
Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; Chapter
2, pp33-75. (b) Do¨mling, A. Chem. ReV. 2006, 106, 17–89. (c) Do¨mling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210. (d) Dolle, R. E.; Le
Bourdonnec, B.; Morales, G. A.; Moriarty, K. J.; Salvino, J. M J. Comb. Chem.
2006, 8, 597635. Selected examples. (e) Faggi, C.; Marcaccini, S.; Pepino, R.;
Pozo, M. C. Synthesis 2002, 2756–2760. (f) Marcaccini, S.; Miliciani, M.; Pepino,
R. Tetrahedron Lett. 2005, 46, 711–713. (g) Cuny, G.; Bois-Choussy, M.; Zhu,
J. J. Am. Chem. Soc. 2004, 126, 14475–14484. (h) Salcedo, A.; Neuville, L.;
Rondot, C.; Retailleau, P.; Zhu, J. Org. Lett. 2008, 10, 857–860. (i) Akritopoulou-
Zanze, I.; Gracias, V.; Djuric, S. W. Tetrahedron Lett. 2004, 45, 8439–8441. (j)
Kennedy, A. L.; Fryer, A. M.; Josey, J. A. Org. Lett. 2002, 4, 1167–1170. (k)
Ilyn, A. P.; Trifilenkov, A. S.; Kuzovkova, J. A.; Kutepov, S. A.; Nikitin, A. V.;
Ivachtchenko, A. V. J. Org. Chem. 2005, 70, 1478–1481. (l) Banfi, L.; Basso,
A.; Guanti, G.; Kielland, N.; Repetto, C.; Riva, R. J. Org. Chem. 2007, 72,
2151–2160. (m) De Silva, R. A.; Santra, S.; Andreana, P. R. Org. Lett. 2008,
10, 4541–4544.
† Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Burgos. Phone:
34-947-258088. Fax: 34-947-258831.
‡ SCAI, Centro de I+D+i, Universidad de Burgos.
§ University of Florence. Phone: 39-055-4573510. Fax: 39-055-4573302.
(1) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W.; Pippin,
D. A. Comb. Chem. High T. Scr. 2004, 7, 473–493.
(2) (a) Da Settimo, F.; Taliani, S.; Trincavelli, M. L.; Montali, M.; Martini,
C. Curr. Med. Chem. 2007, 14, 2680–2701. (b) Whiting, P. J. Curr. Opin.
Pharmacol. 2006, 6, 24–29. (c) Atack, J. R. Expert Opin. InVest. Drugs 2005,
14, 601–618.
(9) The synthesis is well described in: Budruev, A. V.; Karyakina, L. N.;
Levina, O. P.; Oleinik, A. V. Russian J. Coord. Chem. 2005, 31, 181–184.
10.1021/jo8025862 CCC: $40.75
Published on Web 02/03/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2189–2192 2189

can be also combined with Ugi reactions.8i,12 We have recently
shown that the sequences of classical Ugi or Passerini isocyanide
multicomponent reactions, followed by postcondensation trans-
formations, constitute extremely powerful synthetic tools for
the preparation of structurally diverse complex molecules,
among them heterocyclic compounds with elaborate substitution
patterns, constrained peptides, and peptide mimetics.13 As a new
contribution of this methodology, we want to report in this paper
SCHEME 1
a
new
synthesis
of
ꢀ-turn
mimetic
5-oxo-
benzo[e][1,4]diazepine-3-carboxamides by the Ugi reaction
between arylglyoxals, para-substituted benzylamines, cyclohexyl
isocyanide, and 2-azidobenzoic acid, followed by a Staudinger/
aza-Wittig cyclization of the Ugi products in the presence of
triphenylphosphine.
Following the most common procedure, the corresponding
benzylamine 1a-e (1 equiv) was added to a solution of
arylglyoxal 2a-h (1 equiv) in methanol, and the mixture was
stirred for 1 h.14 Cyclohexyl isocyanide 3 (1 equiv) and
2-azidobenzoic acid9 4a (1 equiv) were then added consecutively
to the imine solution, and the mixture was stirred at room
temperature for 1 h until complete precipitation of the Ugi
adducts. The mixture was chilled, and the resulting solid
products 5a-y were then filtered, recrystallized, and character-
ized by the usual spectroscopic and analytical techniques. In
turn, compounds 5a-y (1 equiv) and triphenylphosphine (1.5
equiv) were stirred under nitrogen in toluene for 24 h at room
temperature. Then the solvent was evaporated, and the residue
was purified by column chromatography using mixtures of
hexane and ethyl acetate as eluent. Solid products 6a-y were
obtained as colorless crystals and characterized by the usual
spectroscopic and analytical techniques (Scheme 1 and Table
1). From them, compound 6f was recrystallized in ethanol,
giving suitable crystals for X-ray diffraction, confirming struc-
ture 6f (Figure 1) as a racemic mixture. In the solid state, the
seven-membered ring of the benzodiazepine system adopts a
boat conformation, also found for other 3,4-dihydrobenzo[e][1,4]-
diazepin-5-one examples.15
TABLE 1. Complete List of Reagents and Products of Scheme 1
The crystal packing of 6f is supported by intermolecular
hydrogen bonds between the benzodiazepine carbonyl O[1] and
the carboxamide hydrogen N[1]H of an adjacent molecule
(Figure S1 in the Supporting Information). The all-trans
conformation of the three substituents in the 2, 3, and 4 positions
(10) Review: (a) Eguchi, S. ArkiVoc 2005, 2, 98–119, Selected examples.
(b) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.; Reddy, G. S. K.;
Raghavan, S. J. Comb. Chem. 2007, 9, 29–42. (c) Kamal, A.; Shankaraiah, N.;
Markandeya, N.; Reddy, K. L.; Reddy, Ch. S. Tetrahedron Lett. 2008, 49, 1465–
1468. (d) Kamal, A.; Shankaraiah, N.; Markandeya, N.; Reddy, Ch. S. Synlett
2008, 1297–1300.
(11) Reviews: (a) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem., Int. Ed. 2005, 44, 5188–5240. (b) Palacios, F.; Alonso, C.; Aparicio, D.;
Rubiales, G.; de los Santos, J. M. Tetrahedron 2007, 63, 523–575. (c) Fresneda,
P. M.; Molina, P Synlett 2004, 1–17, See also. (d) Gil, C.; Bra¨se, S. Chem. Eur.
J. 2005, 11, 2680–2688.
(12) (a) M. Timmer, M. S.; Risseeuw, M. D. P.; Verdoes, M.; Filippov, D. V.;
Plaisier, J. R.; van der Marel, G. A.; Overkleeft, H. S.; van Boom, J. H
Tetrahedron Asymmetry 2005, 6, 177–185. (b) Bongera, K. M.; Wennekesa, T.;
de Lavoir, S. V. P.; Esposito, D.; van den Berg, R. J. B. H. N.; Litjens, R. E. J. N.;
van der Marel, G. A.; Overkleeft, H. S. QSAR Comb. Sci. 2006, 25, 491–503.
(13) (a) San˜udo, M.; Marcaccini, S.; Basurto, S.; Torroba, T. J. Org. Chem.
2006, 71, 4578–4584. (b) Garc´ıa-Valverde, M.; Macho, S.; Marcaccini, S.;
Rodr´ıguez, T.; Rojo, J.; Torroba, T. Synlett 2008, 33–36. (c) Corres, N.; Delgado,
J. J.; Garc´ıa-Valverde, M.; Marcaccini, S.; Rodr´ıguez, T.; Rojo, J.; Torroba, T.
Tetrahedron 2008, 64, 2225–2232. (d) Marcos, C. F.; Marcaccini, S.; Menchi,
G.; Pepino, R.; Torroba, T. Tetrahedron Lett. 2008, 49, 149–152.
(14) For all experimental details about the Ugi reaction, see: Marcaccini, S.;
Torroba, T. Nature Prot. 2007, 2, 632–639.
FIGURE 1. X-ray diffraction structure of 6f (one enantiomer shown).
induces the carboxamide group in the 3-position to adopt a
rigidified axial conformation that places the two pseudopeptidic
carbonyl groups at a distance of 3.1 Å, similar to the distance
(15) See, for example: (a) Rogers-Evans, M.; Spurr, P.; Hennig, M Tetra-
hedron Lett. 2003, 44, 2425–2428. (b) Schmidt, A.; Lindner, A. S.; Shilabin,
A. G.; Nieger, M. Tetrahedron 2008, 64, 2048–2056.
2190 J. Org. Chem. Vol. 74, No. 5, 2009

SCHEME 2
FIGURE 2. Two modes of superimposition of 6f (one enantiomer,
green) to a type I′ ꢀ-turn motif (lateral chains of both structures were
not shown). (A) Parallel superimposition of the peptide backbone of
both structures. (B) Antiparallel superimposition by fitting of the
carbonyl groups.
TABLE 2. Complete List of Reagents and Products of Scheme 2
entry
R2
R4
R5
5 (%)
E1/E2
za
zb
zc
zd
H
H
H
F
H
H
H
F
H
OH
I
I
69
83
74
71
<1/99
<1/99
70/30
90/10
large number of peaks found in the spectra and introduced
uncertainty in the structure because of the various types of enol
forms that can exist from the 5a-y structures. COSY, HMQC,
and HMBC experiments on a representative example 5t (see
the Supporting Information) permitted the complete assignation
of peaks to every one of the two enol forms but did not afford
the final enol structures. We noticed that the nature of R1 did
not affect the E1/E2 proportion, but electron attractor substituents
in R2 favor a higher abundance of the E1 form better than
electron donor substituents in R2/R3 favor the E2 form. In this
way, a CF3 group in R2 gave an E1/E2 proportion of 80/20
between both enols 5v. The 1H NMR spectrum of this compound
5v showed two characteristic enolic OH signals at δ 15.6 and
15.2, whose integration permitted determination of the E1/E2
proportion (Figure S5 in the Supporting Information). The CH
of the keto form, which should appear at δ 6.0 in 1H NMR and
δ 65 in 13C NMR, was not observed. The benzylic CH2 appeared
as two pairs of doublets; for E1, the doublets appeared centered
at δ 4.03 and 3.94, but for E2 the CH2 doublets appeared at δ
5.73 and 3.85, separated by roughly 2 ppm, a very uncommon
feature. These differences should correspond to two benzyl
groups surrounded by different environments, and this charac-
teristic permitted assignement of E1/E2 mixtures of conformers.
In addition, the 13C NMR of 5v showed two peaks at the enolic
double bond region, as well as two differently heighted benzylic
methylene and cyclohexyl methyne carbon signals (Figure S6
in the Supporting Information). Careful crystallization of 5a-y
samples did not get crystals suitable for X-ray diffraction. In
order to properly describe the structure of 5a-y we performed
some additional Ugi reactions between benzylamine 1a, arylg-
lyoxals 2a and 2i, and unsubstituted or ortho-substituted benzoic
acids 4b-d to get samples of every type of enol (Scheme 2
and Table 2).
FIGURE 3. X-ray diffraction structures of 5za and 5zd (one indepen-
dent molecule).
found in most ꢀ-turn motifs (3.2-3.3 Å).16 To find out how
well the benzodiazepine ring of 6f mimics a ꢀ-turn, we
superimposed the ꢀ-turn mimetic backbone part from both
enantiomers found in the crystal cell of 6f with different
crystallographic ꢀ-turn protein examples, by fitting the two
carbonyl groups from 6f to the two central amino acid backbones
from every selected ꢀ-turn motif. Thus, δ antigen, having a type
I ꢀ-turn, LDL receptor module 5, having a type II ꢀ-turn, acetyl-
CoA carboxylase, having a type I′ ꢀ-turn, and erabutoxin B,
having a type II′ ꢀ-turn, were used.17 This revealed that the
backbone of the ꢀ-turn in every enantiomer of 6f superimposed
well with the two central amino acid backbone of type-I, I′, II,
and II′ ꢀ-turn motifs (Figure 2 and Figures S2-S4 in the
Supporting Information) by performing a parallel or, alterna-
tively, an antiparallel superimposition of the peptide chains from
both structures until perfect fitting of all four carbonyl groups.
Both modes of approach, each having some electrostatic or steric
advantages, may be useful for new drug design, in combination
with the easy availability of the synthetic approach and the large
scope of the reaction.
Previous R-amido-ꢀ-ketoamides, obtained by Ugi reactions,
existed as mixtures of keto and enol forms.18 In our case, the
Ugi products 5a-y were obtained exclusively as mixtures of
two different enol forms with no trace of the keto tautomer, on
the basis of NMR spectra in CDCl3. This fact had no
consequence on their reactivity with triphenylphosphine but
complicated the spectral assignment by NMR because of the
Compounds 5za-zb, corresponding to a single enol E1 from
their 1H NMR spectra in CDCl3, and 5zd, which was shown to
be a preferred enol E2 by NMR (CDCl3), were repeatedly
recrystallized in i-PrOH (5za-zb) or EtOH (5zd), from which
single-crystal X-ray diffraction structures of the major conform-
ers were obtained (Figure 3 and Figure S7 in the Supporting
Information). Structure 5za, where there is no ortho substitution
at the benzoyl moiety, showed a six-center quasi-cyclic enol
supported by a hydrogen bond between O1 and the hydrogen
(16) Examples in: (a) Rotondi, K. S.; Gierasch, L. M. Biopolymers 2006,
84, 13–22. (b) Marcelino, A. M. C.; Gierasch, L. M Biopolymers 2008, 89, 380–
391.
(17) Extracted from:Leader, D. P.; Milner-White, J. MotiVated Proteins
(http://motif.gla.ac.uk/motif/index.html). Code reference: delta antigen (1A92),
LDL receptor module 5 (1AJJ), acetyl-CoA carboxylase (1BDO), and erabutoxin
B (3EBX).
(18) Sung, K.; Wu, R.-R.; Sun, S.-Y. J. Phys. Org. Chem. 2002, 15, 775–
781.
J. Org. Chem. Vol. 74, No. 5, 2009 2191

from the enol O2. The benzamide moiety, containing atoms O3
and N2, was located orthogonally to the quasicyclic enol, placing
the carbonyl group at the top of the plane but pointing to the
opposite direction of both the enol and the carboxamide carbonyl
groups. The conformation is similar to a known example.18 This
conformation places the benzyl group syn to the carbonyl group;
therefore, every benzylic proton undergoes a different environ-
diazepine derivatives superimposed well with type-I, I′, II, and
II′′ ꢀ-turn motifs which, in combination to the easy availability
of the synthetic approach and the large scope of the reaction,
makes it useful for new drug design.
Experimental Section
Synthesis of 6a. 1a (132 mg, 1.23 mmol) was added to 2a (165
mg, 1.23 mmol) in MeOH (10 mL), the solution was stirred for
1 h at rt, 3 (134 mg, 1.23 mmol) and 4a (201 mg, 1.23 mmol)
were added, and the mixture was stirred for 1 day. Workup of the
solid gave 5a: 360 mg, 59%; colorless crystals (iPrOH/iPr2O); mp
169-170 °C. Then, PPh3 (157 mg, 0.6 mmol) was added under N2
to a solution of 5a (198 mg, 0.4 mmol) in toluene (10 mL); and
the mixture was stirred for 24 h at rt. Workup and chromatography
(hexane/AcOEt) gave 6a: 128 mg, 71%; colorless crystals (hexane/
1
ment, giving rise to H NMR doublets centered at δ 5.83 and
3.94 in CDCl3 and δ 5.41 and 4.38 in CD3OD, proving that
this is the preferred conformation independently of the solvent.
Thus, the conformer E2 is assigned to this conformation.
Structure 5zd, where there is a voluminous iodine atom at
the ortho position on the benzoyl moiety, showed a similar six-
center quasicyclic enol supported by a hydrogen bond between
O3 and the hydrogen from the enol O2. An additional hydrogen
bond between the benzamide carbonyl group and the hydroxyl
group of a molecule of ethanol, the solvent of crystallization,
was also found. The benzamide moiety, containing atoms O1
and N1, was located orthogonally to the quasicyclic enol, placing
the carbonyl group at the top of the plane, but this time pointing
in the same direction of both the enol and the carboxamide
carbonyl groups. This conformation places the benzyl group
anti to the neighbor carbonyl group; therefore, the environment
of every benzylic proton becomes more uniform, giving rise to
1H NMR doublets centered at δ 4.21 and 3.72 in both CDCl3
(for the main conformer) and CD3OD, proving that this is the
preferred conformation independently of the solvent. Thus,
the conformer E1 is assigned to this conformation. Therefore,
the two conformations depended strongly on the aryl substitution
and the presence of hydrogen bonds (for an additional case 5zb,
see the Supporting Information) The behavior of these com-
pounds is quite unusual but is well described by the correlation
1
AcOEt); mp 168-169 °C; H NMR (400 MHz, CDCl3) δ 7.92
(dd, J ) 1.5 Hz, J ) 7.9 Hz, 1H), 7.72-7.69 (m, 2H), 7.45-7.16
(m, 11H), 5.22 (s, 1H), 5.15 (d, J ) 14.3 Hz, 1H), 5.03 (d, J ) 8.4
Hz, 1H), 4.43 (d, J ) 14.3 Hz, 1H), 3.16-3.06 (m, 1H), 1.38-0.89
(m, 8H), 0.50-0.35 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 167.3,
164.5, 164.4, 146.2, 137.8, 136.4, 132.0, 131.0, 130.6, 129.2, 128.9,
128.7, 128.5, 127.5, 127.1, 126.1, 125.8, 59.2, 52.7, 47.9, 32.2,
32.0, 25.1, 24.5, 24.3; IR (KBr) ν˜ 3297, 1652; EIMS m/z 451 (M+,
8), 326 (100); HRMS (EI) calcd for C29H29N3O2 451.2260, found
451.2260. Anal. Calcd for C29H29N3O2: C, 77.13; H, 6.47; N, 9.31.
Found: C, 76.98; H, 6.59; N, 9.41.
Acknowledgment. We gratefully acknowledge financial
support from the Direccio´n General de Investigacio´n of Spain
(Project ref CTQ2006-15456-C04-04BQU), Junta de Castilla y
Leo´n, Consejer´ıa de Educacio´n y Cultura, y Fondo Social
Europeo (Project ref BU013A06) and the Ministry of University
and Research of Italy (PRIN 2006).
1
between the crystal conformation and the H NMR signals of
Supporting Information Available: Crystal packing of 6f,
superimposition images of 6f to type I, II, and II′ ꢀ-turn motifs,
and the commented X-ray diffraction structure of 5zb. General
procedures, spectral and analytical data, crystal structure
determinations, and spectra of all new compounds. Crystal-
lographic information files (CIF) of compounds 6f, 5za, 5zb,
and 5zd (CCDC 710906-710909). Superimposition models of
6f to type I, I′, II, and II′ ꢀ-turn motifs. This material is available
free of charge via the Internet at http://pubs.acs.org.
the benzyl methylene protons in the syn (E2) or anti (E1) position
with respect to the carbonyl oxygen, giving the assignation of
conformational structures in Tables 1 and 2.
In conclusion, we have reported a new synthesis of 5-oxo-
benzo[e][1,4]diazepine-3-carboxamides by a Ugi 4CC/Staudinger/
aza-Wittig sequence of reactions. The intermediate Ugi adducts
have been characterized as two opposite conformers of the enol
1
form, on the basis of the correlation between the H NMR
spectra and the X-ray diffraction structures of selected model
compounds. The pseudopeptidic backbone of the new benzo-
JO8025862
2192 J. Org. Chem. Vol. 74, No. 5, 2009