Synthesis of pseudopeptidic [(5H)-6-oxodibenzo[b,f][1,5]diazocine-5-yl]arylglycinamides by an Ugi 4CC/Staudinger/aza-Wittig sequence

Article abstract of DOI:10.1016/j.tet.2007.12.028

Sequential Ugi reaction between p-substituted benzaldehydes, 2-acetyl or 2-benzoylanilines, cyclohexyl or benzyl isocyanides, and 2-azidobenzoic acid, followed by a Staudinger/aza-Wittig cyclization in the presence of triphenylphosphine afforded pseudopep

Full text of DOI:10.1016/j.tet.2007.12.028

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2225e2232
www.elsevier.com/locate/tet
Synthesis of pseudopeptidic [(5H)-6-oxodibenzo[b,f][1,5]diazocine-5-
yl]arylglycinamides by an Ugi 4CC/Staudinger/aza-Wittig sequence
a
Nazaret Corres , Jacinto J. Delgado , Marıa Garcıa-Valverde , Stefano Marcaccini ,
b
a,
c
*
Teresa Rodrıguez , Josefa Rojo , Tomas Torroba
´
´
a
a
a,
*
´
´
a Departamento de Qu´ımica, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Ba~nuelos s/n, 09001-Burgos, Spain
b SCAI, Centro de IþDþi, Universidad de Burgos, Plaza Misael Ba~nuelos s/n, 09001 Burgos, Spain
c Dipartimento di Chimica Organica ‘Ugo Schiff’, Universita` degli Studi di Firenze, 50019 Sesto Fiorentino (FI), Italy
Received 12 November 2007; received in revised form 5 December 2007; accepted 7 December 2007
Available online 15 December 2007
Abstract
Sequential Ugi reaction between p-substituted benzaldehydes, 2-acetyl or 2-benzoylanilines, cyclohexyl or benzyl isocyanides, and 2-azido-
benzoic acid, followed by a Staudinger/aza-Wittig cyclization in the presence of triphenylphosphine afforded pseudopeptidic [(5H)-6-oxodiben-
zo[b,f][1,5]diazocine-5-yl]arylglycinamides.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Isocyanide; Ugi reaction; Staudinger/aza-Wittig; Diazocine
1. Introduction
any further practical development.7 We have recently shown
that the sequences of classical Ugi or Passerini isocyanide
multicomponent reactions, followed by post-condensation
transformations, constitute extremely powerful synthetic tools
for the preparation of structurally diverse complex molecules,
among them are heterocyclic compounds with elaborate
substitution patterns, constrained peptides, peptide mimetics,
and pseudopeptides.8 As a new contribution of this metho-
dology, we want to report in this paper a new synthesis
of pseudopeptidic [(5H)-6-oxo-dibenzo[b,f][1,5]diazocine-5-
yl]arylglycinamides by the Ugi reaction between p-substituted
benzaldehydes, 2-acetyl or 2-benzoylanilines, cyclohexyl or
benzyl isocyanides, and 2-azidobenzoic acid, followed by
a Staudinger/aza-Wittig cyclization of the Ugi products in
the presence of triphenylphosphine.
The dibenzo[b,f][1,5]diazocine nucleus is a privileged
structure found in the Troger’s base1 and its analogs,2 that
¨
are mainly intended for supramolecular chemistry. Other de-
rivatives are much more scarce, with the exception of the
dibenzo[b,f][1,5]diazocine-6,12-diones (dianthranilides), eas-
ily accessible from anthranilic acids.3 Such dilactams have
been of interest as chemosensitizers and reversal agents in
multidrug resistance,4 and in conformational studies.3b,d,e
Polycyclic benzodiazocines of natural origin are potent inhib-
itors of protein kinase C and cyclic nucleotide-dependent pro-
tein kinases, used in experimental pharmacology,5 and simple
benzodiazocines have been used as homologues of benzodi-
azepine drugs.6 Because of its structural similarity with diaze-
pam and oxazepam, dibenzo[b,f][1,5]diazocine-6(5H)-one
derivatives have attracted some interest for long time, but
the lack of a secure method for their synthesis has stopped
2. Results and discussion
A mixture of p-substituted benzaldehyde 1aec (1 equiv), 2-
benzoyl- or 2-acetylaniline 2a,b (1 equiv), cyclohexyl or ben-
* Corresponding authors. Tel.: þ34 947258088; fax: þ34 947258831.
zyl isocyanide9 3a,b (1 equiv), and 2-azidobenzoic acid10
(1 equiv) was stirred in methanol at room temperature for
4
´
E-mail addresses: magaval@ubu.es (M. Garcıa-Valverde), ttorroba@ubu.
es (T. Torroba).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.028

2226
N. Corres et al. / Tetrahedron 64 (2008) 2225e2232
two days until solid 5aeh precipitated.11 Filtration and re-
crystallization of the solid afforded N-cyclohexyl (or benzyl)
2-[N-(2-benzoyl(or acetyl)phenyl)-N-(2-azidobenzoyl)amino]-
2-arylacetamides 5aeh in good yields (48e89%) (Scheme 1
and Table 1), which were subsequently stirred in dry tolu-
ene with triphenylphosphine (1.5 equiv) for one day to get
N-cyclohexyl (or benzyl) 2-aryl-2-{12-phenyl(or methyl)-(5H)-
6-oxodibenzo[b,f][1,5]diazocine-5-yl}acetamides 6aeh in good
yields (54e93%) (Scheme 1 and Table 1).
consisted of a racemic mixture of two enantiomeric E-
˚
rotamers associated by two H-bonds [H(1A)/O(1): 2.59 A,
N(1)eH(1A)/O(1): 162.8ꢀ]. One enantiomer is shown in
Figure 2. The racemic unit cell, showing the H-bonds that sup-
ports the packing, is shown in Figure 3.
Although we employed reaction conditions that were selec-
tive for the cyclization of the intermediate iminophosphorane
with the ketone group,13 the formation of the diazocine ring
was undoubtedly probed from the EI HRMS patterns of 6aeh,
R1
R2
R3
NH
O
OH
N3
O
O
H
NH2
R3
NH
O
O
N
NC
R3
R2
+
+
MeOH
r.t., 2d
PPh3
PhMe
r.t., 1d
+
O
O
N
R1
1a-c
O
3a-b
R1
4
2a-b
2a: R1= Ph 3a: R3= c-C6H11
N3
5a-h
1a: R1= Cl
1b: R1= Br
1c: R1= OMe
N
2b: R1= Me 3b: R3= CH2Ph
R2
6a-h
Scheme 1. Dibenzo[b,f][1,5]diazocine-5-yl arylglycinamides by the Ugi 4CC/Staudinger/aza-Wittig sequence.
The recrystallized products 5aeh and 6aeh were charac-
as, for example, detection of m/z peak 235.087 corresponding
ꢁ
terized by the usual spectroscopic and analytical techniques.
COSY, NOESY, EXSY, DEPT, HMBC, and HMQC experi-
ments of selected examples permitted to assign all NMR
signals.
to the ring fragment (C15H11N2Oþ , calcd m/z 235.087) in 6h.
1H and 13C NMR spectra of 6aeh were much complicated
by the presence of four diastereoisomers coming from the
planar chiral ring3b and the restricted rotation of the arylgly-
cine group bonded to the amide ring nitrogen. At higher tem-
1H and 13C NMR spectra of 5aeh were complicated by the
presence of diastereotopic protons, coming from the restricted
rotation of the tertiary amide bond in every racemic mixture,
and the axial chirality due to the hindered anilide, giving
rise to the presence of atropisomers. Assuming the general
rule that groups cis to oxygen are shifted downfield,12 we
assigned the E geometry to the downfield signals and the Z
geometry to the upfield signals, from which the Z/E ratio was
obtained (Table 1). The rather complicated spectra were much
simplified at increasingly high temperatures, in which signals
coalesced to finally show a single racemic structure for each
product, such as 5a shown in Figure 1.
1
peratures the signals coalesced. Thus, at 80 ꢀC, the H NMR
Cl
O
NH
O
O
O
HE
NH
O
N
N
Hz
O
N3
Cl
N3
Z-5a
E-5a
The Z/E ratio depended on the benzoyl or acetyl substitu-
ent, being inverted by the presence of one or the other group,
and depended strongly on the solvent polarity. For example,
5h showed a Z/E ratio of 20:80 in CDCl3 and 93:7 in
CD3OD, therefore the presence of H-bonds may account for
the results. Single crystal X-ray diffraction of one of the sam-
ples, 5d, confirmed the expected structure. The unit cell
120°C
110°C
100°C
80°C
70°C
Table 1
Ugi products 5aeh and dibenzodiazocines 6aeh
R1
R2
R3
5 (%)
Z/E
6 (%)
50°C
20°C
Cl
Br
Ph
Ph
c-C6H11
c-C6H11
c-C6H11
CH2Ph
5a (62)
5b (55)
5c (89)
5d (48)
5e (70)
5f (60)
5g (68)
5h (61)
74:26
74:26
75:25
75:25
20:80
20:80
18:82
20:80
6a (81)
6b (57)
6c (75)
6d (54)
6e (93)
6f (57)
6g (81)
6h (68)
HZ
HE
OMe
Br
Ph
Ph
Cl
Br
Me
Me
Me
Me
c-C6H11
c-C6H11
c-C6H11
CH2Ph
8.00
7.50
7.00
6.50
6.00
OMe
Br
Figure 1. Selected region of 1H NMR spectra of 5a in deuterated chlorobenz-
ene at different temperatures.

N. Corres et al. / Tetrahedron 64 (2008) 2225e2232
2227
80°C
Cl
Ha
NH
70°C
50°C
O
O
N
N
6a
Ph
25°C
3.50
Figure 4. Ha region of the 1H NMR spectra of 6a in deuterated chlorobenzene
at different temperatures.
Figure 2. Single crystal X-ray diffraction structure of 5d.
400
350
3.90
3.80
3.70
3.6
spectrum of 3a showed only large signals corresponding to
two rotamers (Fig. 4).
1
Figure 5. Cyclohexyl methyne region of the H NMR spectra of 6f in CDCl3
(left) and CD3OD (right).
A similar transition of signals was obtained by changing the
polarity of the solvent. Thus, 1H NMR spectrum of 6f in
CDCl3 showed four signals for the cyclohexyl methyne proton
next to the NH group, but in CD3OD it showed only two large
signals, therefore the presence of H-bonds in CDCl3, which
are broken in CD3OD, may be the cause of the latter behavior
(Fig. 5).
oxodibenzo[b,f][1,5]diazocine-5-yl}acetamides by means of
a sequence of Ugi four component condensation followed by
a Staudinger/aza-Wittig cyclization of the intermediate Ugi
products to give the final products. The reaction employs all
commercial or easily available starting materials, performed
under very simple experimental conditions and does not re-
quire chromatographic work-up, but only recrystallization of
the products, therefore being appropriate for combinatorial
schemes.
3. Conclusion
In summary, we have described the synthesis of new N-cy-
clohexyl (or benzyl) 2-aryl-2-{12-phenyl(or methyl)-(5H)-6-
4. Experimental
4.1. Synthesis of N-cyclohexyl (or benzyl) 2-[N-(2-benzoyl(or
acetyl)phenyl)-N-(2-azidobenzoyl)amino]-2-arylacetamides
5aeh
A mixture of 2-azidobenzoic acid 4 (163 mg, 1 mmol) and
the corresponding p-substituted benzaldehyde 1aec (1 mmol),
aniline 2a,b (1 mmol), and isocyanide 3a,b (1 mmol) was
stirred in methanol (20 mL) at room temperature for two
days until a solid precipitated (addition of diisopropylether
was sometimes necessary). Filtration and recrystallization
from the appropriate solvent afforded acetamides 5aeh.
4.1.1. N-Cyclohexyl 2-[N-(2-benzoylphenyl)-N-(2-azido-
benzoyl)amino]-2-(4-chlorophenyl)acetamide 5a
Yellow crystals (367 mg, 62%), mp 163e165 ꢀC (isopropyl-
ethereisopropanol). IR (KBr, cmꢂ1): 3333 (NH), 3024 (CAre
1
H), 2132 (N3), 1678 (C]O), 1664 (C]O), 1635 (C]O). H
NMR (400 MHz, CDCl3) d 7.64e7.44 (m, 2.26H, 2HArþ0.26H
NH, rot. A), 7.35e7.01 (m, 13HAr), 6.73e6.63 (m, 2.74H,
2HArþ0.74H NH, rot. B), 6.01 (s, 0.26H, rot. A), 5.90 (s,
0.74H, rot. B), 3.93e3.83 (m, 0.74H, rot. B), 3.57e2.66 (m,
Figure 3. Crystal packing of 5d unit cell showing a racemic mixture of two
enantiomeric E-rotamers associated by two H-bonds.

2228
N. Corres et al. / Tetrahedron 64 (2008) 2225e2232
0.26H, rot. A), 2.08e0.83 (m, 10H). 13C NMR (100 MHz,
CDCl3) d 194.2 (Cq), 168.5 (Cq, rot. A), 168.0 (Cq, rot. B),
139.7 (Cq), 136.8 (Cq), 134.4 (Cq), 133.3 (CHAr), 32.8 (CHAr),
132.5 (CHAr), 131.4 (CHAr), 131.3 (CHAr), 130.8 (CHAr), 130.5
(CHAr), 130.4(CHAr), 129.9(CHAr),128.6(CHAr),128.4(CHAr),
128.3 (CHAr), 127.2 (CHAr, rot. B), 127.0 (CHAr, rot. A), 124.4
(CHAr), 118.9 (CHAr, rot. B), 118.5 (CHAr, rot. A), 68.4 (CH,
rot. B), 66.8 (CH, rot. A), 49.1 (CH, rot. A), 48.6 (CH, rot. B),
33.2 (CH2), 33.0 (CH2), 25.9 (CH2), 25.1 (CH2). MS (EI) m/z
563 (MþꢂN2, 11.8), 437 (100), 320 (47), 271 (73). Anal. Calcd
for C34H30ClN5O3: C, 68.97; H, 5.11; N, 11.83. Found: C,
69.06; H, 5.19; N, 11.67.
4.1.4. N-Benzyl 2-[N-(2-benzoylphenyl)-N-(2-azido-
benzoyl)amino]-2-(4-bromophenyl)acetamide 5d
Yellow crystals (310 mg, 48%), mp 172e174 ꢀC (isopropa-
noleDMF). IR (KBr, cmꢂ1): 3356 (NH), 2125 (N3), 1691
(C]O), 1653 (C]O), 1635 (C]O). 1H NMR (400 MHz,
CDCl3) d 8.09 (t, J¼5.5 Hz, 0.25NH, rot. B), 7.70e6.89 (m,
20HAr), 6.73e6.60 (m, 2.75H, 2HArþ0.75NH, rot. A), 6.07
(s, 0.25H, rot. B), 6.06 (s, 0.75H, rot. A), 4.60 (dd, J¼4.2,
13.6 Hz, 0.75H, rot. A), 4.56 (dd, J¼4.2, 13.6 Hz, 0.75H, rot
A), 4.39 (dd, J¼5.5, 14.6 Hz, 0.25H, rot. B), 4.29 (dd,
J¼5.5, 14.6 Hz, 0.25H, rot. B). 13C NMR (100 MHz,
CDCl3) d 195.3 (Cq, rot. B), 194.2 (Cq, rot. A), 169.6 (Cq,
rot. A), 168.6 (Cq, rot. B), 168.4 (Cq, rot. B), 168.1 (Cq, rot.
A), 140.0 (Cq, rot. B), 139.7 (Cq, rot. A), 138.4 (Cq, rot. A),
138.2 (Cq, rot. B), 137.2 (Cq), 136.7 (Cq), 135.1 (Cq), 133.3
(CHAr), 132.6 (CHAr), 131.6 (CHAr), 131.5 (CHAr), 131.4
(CHAr), 130.9 (CHAr, rot. B), 130.8 (CHAr, rot. A), 130.5
(CHAr, rot. B), 130.4 (CHAr, rot. A), 130.0 (CHAr, rot. B),
129.8 (CHAr, rot. A), 128.8 (CHAr, rot. A), 128.6 (CHAr, rot.
B), 128.3 (CHAr), 128.0 (CHAr), 127.5 (CHAr), 127.3
(CHAr), 124.5 (CHAr, rot. B), 124.3 (CHAr, rot. A), 122.9
(Cq, rot. A), 122.4 (Cq, rot. B), 118.4 (CHAr, rot. B), 118.4
(CHAr, rot. A), 68.2 (CH, rot. B), 66.8 (CH, rot. A), 44.3
(CH2, rot. A), 44.1 (CH2, rot. B). MS (EI) m/z 617
(Mþþ2ꢂN2, 5.9), 615 (MþꢂN2, 5.5), 483 (100), 364 (75),
271 (28). Anal. Calcd for C35H26BrN5O3: C, 65.22; H, 4.07;
N, 10.87. Found: C, 65.10; H, 4.19; N, 10.74. Crystal data
for compound 5d: C35H26BrN5O3, MW¼644.52, triclinic,
4.1.2. N-Cyclohexyl 2-[N-(2-benzoylphenyl)-N-(2-azido-
benzoyl)amino]-2-(4-bromophenyl)acetamide 5b
Yellow crystals (350 mg, 55%), mp 170e172 ꢀC (isopropyl
ethereisopropanol). IR (KBr, cmꢂ1): 3329 (NH), 2126 (N3),
1644 (C]O), 1653 (C]O), 1661 (C]O). 1H NMR
(400 MHz, CDCl3) d 7.65e7.51 (m, 2.74H, 2HArþ0.74NH,
rot. A), 7.43e7.00 (m, 13HAr), 6.77e6.59 (m, 2.26H,
2HArþ0.26NH, rot. B), 5.99 (s, 0.26H, rot. B), 5.87 (s,
0.74H, rot. A), 3.81e3.75 (m, 0.26H, rot. B), 3.69e3.63 (m,
0.74H, rot. A), 2.13e1.10 (m, 10H). 13C NMR (100 MHz,
CDCl3) d 207.0 (Cq), 194.0 (Cq), 168.2 (Cq), 139.5 (Cq), 136.5
(Cq), 133.5 (Cq), 133.2 (Cq), 133.0 (CHAr), 132.2 (CHAr), 131.3
(CHAr), 131.1(CHAr), 130.9(CHAr),130.6(CHAr),130.3(CHAr),
130.2 (CHAr), 129.6 (CHAr), 128.0 (CHAr), 127.0 (CHAr), 124.2
(CHAr), 118.3 (Cq), 68.2 (CH, rot B), 66.6 (CH, rot. A), 48.8
(CH, rot. A), 48.4 (CH, rot. B), 33.0 (CH2), 32.8 (CH2), 25.6
(CH2), 24.8 (CH2). MS (EI) m/z 609 (Mþþ2ꢂN2, 5.9), 607
(MþꢂN2, 5.5), 483 (78), 363 (47), 271 (100). Anal. Calcd for
C34H30BrN5O3: C, 64.15; H, 4.75; N, 11.00. Found: C, 63.98;
H, 4.87; N, 10.88.
˚
˚
˚
P-1, a¼11.489(3) A, b¼11.599(3) A, c¼12.230(3) A, a¼
3
ꢀ
ꢀ
ꢀ
˚
74.893(5) , b¼77.874(5) , g¼89.569(5) ; V¼1536.5(7) A ,
Z¼2, Dcalcd¼1.393 g cmꢂ1, m(Mo Ka)¼1.382 mmꢂ1. Yellow
prism (0.50ꢃ0.50ꢃ0.25) mm3. 14,829 measured reflections,
5360 independent (Rint¼0.0467), 3099 observed (I>2s(I)).
R1¼0.0512, wR2¼0.1421 (all data). CCDC 667058 contains
the supplementary crystallographic data for this paper. These
data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html or from the Cambridge Crystallographic
Data Center, 12, Union Road, Cambridge CB2 1EZ, UK;
fax: þ44 (1223) 336033; email: deposit@ccdc.cam.ac.uk.
4.1.3. N-Cyclohexyl 2-[N-(2-benzoylphenyl)-N-(2-
azidobenzoyl)amino]-2-(4-methoxyphenyl)acetamide 5c
Yellow crystals (523 mg, 89%), mp 166e168 ꢀC (isopropyl
ethereisopropanol). IR (KBr, cmꢂ1): 3336 (NH), 2129 (N3),
1634 (C]O), 1660 (C]O), 1672 (C]O). 1H NMR
(400 MHz, CDCl3) d 7.79e7.68 (m, 1.75H, 1HArþ0.75NH,
rot. B), 7.57e6.93 (m, 12HAr), 6.76e6.45 (m, 4.25H,
4HArþ0.25NH, rot. A), 5.94 (s, 0.25H, rot. A), 5.89 (s,
0.75H, rot. B), 3.91e3.83 (m, 0.25H, rot. A), 3.74e3.60 (m,
0.75H, rot. B), 3.60 (s, 0.75H, rot. A), 3.07 (s, 2.25H, rot. B),
2.05e1.10 (m, 10H). 13C NMR (100 MHz, CDCl3) d 193.8
(Cq), 169.0 (Cq), 159.2 (Cq), 139.5 (Cq), 136.7 (Cq), 133.4
(Cq), 132.7 (CHAr), 132.5 (CHAr), 132.4 (CHAr), 131.5 (Cq),
131.0 (CHAr), 130.8 (CHAr), 130.6 (CHAr), 130.2 (CHAr),
130.1 (CHAr), 129.6 (CHAr), 129.4 (CHAr), 128.0 (CHAr), 127.8
(CHAr), 126.6 (CHAr), 124.0 (CHAr), 118.2 (CHAr), 113.6
(CHAr, rot. B), 113.2 (CHAr, rot. A), 68.5 (CH, rot. B), 66.3
(CH, rot. A), 55.1 (CH3, rot. B), 55.0 (CH3, rot. A), 48.7 (CH,
rot. A), 48.2 (CH, rot. B), 33.0 (CH2), 32.8 (CH2), 25.6 (CH2),
24.8 (CH2). MS (EI) m/z 559 (MþꢂN2, 1.6), 432 (47), 271
(100). Anal. Calcd for C35H33N5O4: C, 71.53; H, 5.66; N,
11.92. Found: C, 71.45; H, 5.81; N, 11.82.
4.1.5. N-Cyclohexyl 2-[N-(2-acetylphenyl)-N-(2-azido-
benzoyl)amino]-2-(4-chlorophenyl)acetamide 5e
Yellow crystals (371 mg, 70%), mp 155e157 ꢀC (isopropyl
ethereisopropanol). IR (KBr, cmꢂ1): 3348 (NH), 2130 (N3),
1684 (C]O), 1670 (C]O), 1652 (C]O). 1H NMR
(400 MHz, CDCl3) d 7.44e7.00 (m, 10.2H, 10HArþ0.2NH,
rot. B), 6.96e6.78 (m, 2.8H, 2HArþ0.8NH, rot. A), 6.04 (s,
0.8H, rot. A), 6.01 (s, 0.2H, rot. B), 3.93e3.84 (m, 0.8H,
rot. A), 3.69e3.60 (m, 0.2H, rot. B), 2.26 (s, 0.6H, rot. B),
2.06 (s, 2.4H, rot. A), 1.96e1.10 (m, 10H). 13C NMR
(100 MHz, CDCl3) d 198.5 (Cq, rot. A), 168.7 (Cq, rot. B),
168.6 (Cq, rot. A), 168.5 (Cq, rot. A), 167.5 (Cq, rot. B), 138.0
(Cq, rot. B), 137.7 (Cq, rot. A), 136.7 (Cq, rot. B), 136.4 (Cq,
rot. A), 136.1 (Cq, rot. B), 135.5 (Cq, rot. A), 134.4 (Cq, rot.
A), 134.1 (Cq, rot. B), 133.0 (CHAr), 132.5 (CHAr), 132.2
(CHAr), 131.1 (CHAr, rot. A), 130.9 (CHAr, rot. B), 130.7
(CHAr), 129.9 (CHAr), 128.8 (Cq), 128.6 (CHAr, rot. A), 128.5

N. Corres et al. / Tetrahedron 64 (2008) 2225e2232
2229
(CHAr, rot. B), 128.1 (CHAr), 124.7 (CHAr), 118.3 (CHAr, rot.
4.1.8. N-Benzyl 2-[N-(2-acetylphenyl)-N-(2-azido-
B), 118.0 (CHAr, rot. A), 66.6 (CH, rot. B), 65.2 (CH, rot. A),
49.0 (CH, rot. A), 48.6 (CH, rot. B), 33.4 (CH2), 33.1 (CH2),
29.3 (CH3, rot. B), 29.0 (CH3, rot. A), 25.8 (CH2), 25.2
(CH2), 25.1(CH2). MS (EI) m/z 501 (MþꢂN2, 3.1), 375
(100), 258 (80), 209 (28). Anal. Calcd for C29H28ClN5O3: C,
65.72; H, 5.32; N, 13.21. Found: C, 65.61; H, 5.39; N, 13.11.
benzoyl)amino]-2-(4-bromophenyl)acetamide 5h
Light red crystals (355 mg, 61%), mp 143e145 ꢀC (isopro-
panoleDMF). IR (KBr, cmꢂ1): 3360 (NH), 2132 (N3), 1697
(C]O), 1673 (C]O), 1639 (C]O). 1H NMR (400 MHz,
CD3OD) d 7.85 (dd, J¼1.2, 7.9 Hz, 1H), 7.50 (dd, J¼1.5,
7.9 Hz, 1H), 7.40e6.88 (m, 11H, 10HArþ1NH), 6.14 (s,
0.07H, rot. B), 6.05 (s, 0.93H, rot. A), 4.51 (d, J¼15.2 Hz,
0.93H, rot. A), 4.44 (d, J¼15.2 Hz, 0.93H, rot. A), 4.40e
4.35 (m, 0.14H, rot. B), 2.28 (s, 0.21H, rot. B), 2.18 (s,
2.79H, rot. A). 13C NMR (100 MHz, CD3OD) d 200.7 (Cq),
172.2 (Cq), 170.4 (Cq), 139.7 (Cq), 138.4 (Cq), 138.1 (Cq),
136.6 (Cq), 134.8 (CHAr), 134.3 (CHAr), 133.9 (Cq), 133.4
(CHAr), 132.6 (CHAr), 132.1 (CHAr), 131.9 (CHAr), 131.3
(CHAr), 129.9 (CHAr), 129.5 (CHAr), 129.3 (CHAr), 128.4
(CHAr), 128.1 (CHAr), 125.4 (CHAr), 123.8 (Cq), 119.1
(CHAr), 66.6 (CH), 44.3 (CH2), 29.2 (CH3). MS (EI) m/z
555 (Mþþ2ꢂN2, 4), 553 (MþꢂN2, 4), 421 (41), 302 (28),
209 (100). Anal. Calcd for C30H24BrN5O3: C, 61.86; H,
4.15; N, 12.02. Found: C, 62.01; H, 4.19; N, 11.87.
4.1.6. N-Cyclohexyl 2-[N-(2-acetylphenyl)-N-(2-azido-
benzoyl)amino]-2-(4-bromophenyl)acetamide 5f
Colorless crystals (345 mg, 60%), mp 152e154 ꢀC (iso-
propyl ethereisopropanol). IR (KBr, cmꢂ1): 3334 (NH),
2125 (N3), 1656 (C]O), 1654 (C]O), 1620 (C]O). 1H
NMR (400 MHz, CDCl3)
d
7.68e7.64 (m, 1.2H,
1HArþ0.2NH, rot. B), 7.44e6.86 (m, 11HAr), 6.81 (d,
J¼8.1 Hz, 0.8H, rot. A), 6.04 (s, 0.8H, rot. A), 6.02 (s,
0.2H, rot. B), 3.96e3.84 (m, 0.8H, rot. A), 3.71e3.60 (m,
0.2H, rot. B), 2.27 (s, 0.6H, rot. B), 2.07 (s, 2.4H, rot. A),
2.10e1.15 (m, 10H). 13C NMR (100 MHz, CDCl3) d 200.2
(Cq, rot. B), 199.2 (Cq, rot. A), 168.4 (Cq, rot. B), 168.3 (Cq,
rot. A), 168.2 (Cq, rot. A), 167.1 (Cq, rot. B), 167.9 (Cq), 137.5
(Cq), 136.2 (Cq), 135.3 (Cq), 133.1 (CHAr), 132.7 (CHAr), 132.2
(CHAr),132.0(CHAr), 131.3(CHAr),131.2(CHAr),130.9(CHAr),
130.4 (CHAr), 129.6 (CHAr), 128.7 (CHAr), 128.4 (CHAr),
124.4 (CHAr), 122.5 (CHAr), 118.1 (Cq, rot. B), 117.8 (Cq, rot.
A), 66.4 (CH, rot. B), 65.1 (CH, rot. A), 48.8 (CH, rot. A), 48.4
(CH, rot. B), 33.1 (CH2), 32.8 (CH2, rot. B), 29.1 (CH3, rot. B),
28.8 (CH3, rot. A), 25.6 (CH2), 24.9 (CH2), 24.8 (CH2). MS
(EI) m/z 547 (Mþþ2ꢂN2, 7.8), 545 (MþꢂN2, 7.5), 421 (78),
302 (35), 209 (100). Anal. Calcd for C29H28BrN5O3: C, 60.63;
H, 4.91; N, 12.19. Found: C, 60.69; H, 5.08; N, 12.05.
4.2. Synthesis of N-cyclohexyl (or benzyl) 2-aryl-2-{12-
phenyl(or methyl)-(5H)-6-oxodibenzo[b,f][1,5]diazocine-
5-yl}acetamides 6aeh
A mixture of acetamides 5aeh (1 mmol) in dry toluene
(15 mL) was treated with triphenylphosphine (393 mg,
1.5 mmol) in dry toluene (5 mL). The mixture was stirred
for one day. Then the solvent was evaporated and the residue
was treated with hexane. The solid obtained was recrystallized
from the appropriate solvent yielding the corresponding diben-
zodiazocinones 6aeh.
4.1.7. N-Cyclohexyl 2-[N-(2-acetylphenyl)-N-(2-azido-
benzoyl)amino]-2-(4-methoxyphenyl)acetamide 5g
4.2.1. N-Cyclohexyl 2-(4-chlorophenyl)-2-{12-phenyl-(5H)-
6-oxodibenzo[b,f][1,5]diazocine-5-yl}acetamide 6a
Colorless crystals (358 mg, 68%), mp 147e149 ꢀC (iso-
propyl ethereisopropanol). IR (KBr, cmꢂ1): 3335 (NH),
2126 (N3), 1642 (C]O), 1668 (C]O), 1692 (C]O). 1H
NMR (400 MHz, CDCl3) d 7.75 (dd, J¼1.1, 7.9 Hz, 1H,
Colorless crystals (444 mg, 81%), mp 136e138 ꢀC (hexa-
neeethyl acetate). IR (KBr, cmꢂ1): 3420 (NH), 1660
(C]O), 1652 (C]O), 1633 (C]N). 1H NMR (400 MHz,
CDCl3) d 8.70 (br s, 0.25H, NH, isom. C), 8.29 (d,
J¼7.95 Hz, 0.30H, NH, isom. B), 8.03 (d, J¼7.45 Hz,
0.38HAr, isom. A), 7.85 (br s, 0.38H, NH, isom. A), 7.74e
6.32 (m, 16H, 15.68HArþ0.32H CH, isom. CþD), 6.10 (s,
0.30H, CH, isom. B), 6.05e5.85 (m, 1H, HAr), 5.08 (s,
0.82HArþ0.18NH,
rot.
B),
7.40e6.50
(m,
12H,
11.18HArþ0.82H NH, rot. A), 6.07 (s, 0.82H, rot. A), 5.92
(s, 0.18H, rot. B), 3.96e3.80 (m, 0.82H, rot. A), 3.78e3.65
(m, 0.18H, rot. B), 3.74 (s, 0.54H, rot. B), 3.69 (s, 2.46H,
rot. A), 2.28 (s, 0.54H, rot. B), 2.02 (s, 2.46H, rot. A),
2.09e1.00 (m, 10H). 13C NMR (100 MHz, CDCl3) d 200.1
(Cq, rot. B), 198.1 (Cq, rot. A), 169.0 (Cq, rot. A), 168.5
(Cq, rot. B), 168.3 (Cq, rot. A), 168.0 (Cq, rot. B), 159.3
(Cq), 137.5 (Cq), 136.2 (Cq), 135.7 (Cq), 132.7 (CHAr),
132.4 (CHAr), 131.7 (CHAr), 131.1 (Cq), 130.2 (CHAr), 129.3
(CHAr), 129.0 (CHAr), 128.6 (CHAr), 128.1 (CHAr), 125.5
(CHAr), 124.3 (CHAr), 118.0 (CHAr, rot. B), 117.4 (CHAr,
rot. A), 113.6 (CHAr, rot. B), 113.1 (CHAr, rot. A), 64.8
(CH), 55.2 (CH3, rot. B), 55.1 (CH3, rot. A), 48.7 (CH, rot.
A), 48.2 (CH, rot. B), 33.1 (CH2), 32.8 (CH2), 29.2 (CH3,
rot. B), 28.7 (CH3, rot. A), 25.6 (CH2), 25.9 (CH2), 24.8
(CH2). MS (EI) m/z 497 (MþꢂN2, 14), 371 (100), 209 (89).
Anal. Calcd for C30H31N5O4: C, 68.55; H, 5.94; N, 13.32.
Found: C, 68.66; H, 6.13; N, 13.20.
0.38H, CH, isom. A), 3.91e3.84 (m, 0.38H, CHcyclohexyl
,
isom. A), 3.70e3.65 (m, 0.30H, CHcyclohexyl, isom. B),
3.51e3.45 (m, 0.25H, CHcyclohexyl, isom. C), 3.22 (br s,
0.07H, CHcyclohexyl, isom. D), 2.09e0.65 (m, 10H). 13C
NMR (100 MHz, CDCl3) d 196.7, 196.4, 172.2, 169.2,
168.8, 167.9, 148.8, 148.1, 143.2, 140.7, 137.2, 135.6,
134.8, 133.2, 133.1, 133.0, 132.9, 132.8, 132.3, 132.1,
131.9, 131.7, 131.5, 131.3, 131.1, 130.8, 130.5, 129.3,
129.0, 128.9, 128.8, 128.3, 128.2, 128.1, 128.1, 128.0,
125.8, 125.5, 121.6, 121.4, 117.0, 116.9, 116.6, 70.1, 68.4,
67.8, 48.9, 48.7, 48.4, 41.6, 36.3, 33.4, 33.2, 33.1, 33.0,
32.7, 32.7, 32.6, 29.3, 26.0, 25.9, 25.9, 25.5, 25.4, 25.3,
25.2, 22.8, 20.7, 19.7, 19.0. MS (EI) m/z 547 (Mþ, 2), 422
(21), 277 (100), 201 (20). HRMS (EI) calcd for C34H30ClN3O2

2230
N. Corres et al. / Tetrahedron 64 (2008) 2225e2232
547.2027, found 547.2031. Anal. Calcd for C34H30ClN3O2: C,
74.51; H, 5.52; N, 7.67. Found: C, 74.42; H, 5.58; N, 7.56.
1662 (C]O), 1633 (C]N). 1H NMR (400 MHz, CDCl3)
d 10.21 (br s, 0.15H, NH, isom. D), 8.69 (t, J¼5.1 Hz,
0.24H, NH, isom. C), 8.32 (br s, 0.28H, NH, isom. B),
8.01e5.86 (m, 23.05H, 22HArþ0.33NH, isom. Aþ0.72H
CH, isom. A, C, D), 5.50 (s, 0.28H, CH, isom. B), 4.60e
4.10 (m, 1.70H, CH2, isom. A, B, C), 3.32e3.23 (m, 0.30H,
CH2, isom. D). 13C NMR (100 MHz, CDCl3) d 170.0, 169.9,
169.5, 142.4, 139.2, 139.0, 138.8, 138.7, 137.2, 137.1,
133.1, 133.0, 132.9, 132.3, 132.2, 132.0, 131.7, 131.5,
131.3, 131.1, 131.0, 130.8, 130.6, 130.4, 130.1, 129.8,
129.3, 129.0, 128.9, 128.8, 128.5, 128.3, 128.1, 128.0,
127.9, 127.0, 126.9, 125.9, 125.6, 125.3, 121.9, 117.1,
116.9, 116.7, 69.2, 68.4, 67.3, 43.9. MS (EI) m/z 601
(Mþþ2, 79), 599 (Mþ, 73), 469 (44), 364 (77), 362 (75),
209 (69), 91 (100). HRMS (EI) calcd for C35H26BrN3O2
599.1208, found 599.1129. Anal. Calcd for C35H26BrN3O2:
C, 70.00; H, 4.36; N, 7.00. Found: C, 70.11; H, 4.44; N, 6.87.
4.2.2. N-Cyclohexyl 2-(4-bromophenyl)-2-{12-phenyl-(5H)-
6-oxodibenzo[b,f][1,5]diazocine-5-yl}acetamide 6b
Yellow crystals (338 mg, 57%), mp 137e139 ꢀC (hexanee
ethyl acetate). IR (KBr, cmꢂ1): 3432 (NH), 1660 (C]O),
1652 (C]O), 1634 (C]N). 1H NMR (400 MHz, CDCl3)
d 8.68 (br s, 0.26H, NH, isom. C), 8.24 (d, J¼7.8 Hz,
0.31H, NH, isom. B), 7.85 (br s, 0.41H, NH, isom. A),
8.04e5.85 (m, 17.69H, 17HArþ0.69H CH, isom. A, C, D),
5.06 (s, 0.31H, CH, isom. B), 3.91e3.84 (m, 0.41Hcyclohexyl
,
isom. A), 3.68e3.63 (m, 0.31Hcyclohexyl, isom. B), 3.51e3.43
(m, 0.26Hcyclohexyl, isom. C), 3.21 (br s, 0.02Hcyclohexyl
,
isom. D), 2.03e0.85 (m, 10H). 13C NMR (100 MHz,
CDCl3) d 196.6, 196.3, 174.5, 173.2, 172.2, 169.0, 168.7,
167.8, 148.2, 148.1, 140.8, 137.2, 136.0, 135.3, 134.8,
133.2, 133.0, 132.9, 132.9, 132.8, 132.6, 132.4, 132.3, 132.1,
131.6, 131.5, 131.2, 131.1, 131.0, 131.0, 130.9, 130.8, 130.5,
130.4, 130.2, 130.0, 129.8, 129.5, 129.3, 129.0, 128.9, 128.8,
128.6, 128.3, 128.2, 127.9, 125.8, 125.5, 121.8, 121.5, 117.0,
70.1, 68.4, 67.8, 48.9, 48.7, 48.4, 33.3, 33.1, 33.1, 32.7, 32.7,
32.5, 31.8, 29.3, 26.0, 25.9, 25.4, 25.3, 25.2, 22.9, 22.8. MS
(EI) m/z 593 (Mþþ2, 3), 591 (Mþ, 3), 467 (43), 277 (100),
201 (25), 119 (53). HRMS (EI) calcd for C34H30BrN3O2
591.1521, found 591.1531. Anal. Calcd for C34H30BrN3O2:
C, 68.92; H, 5.10; N, 7.09. Found: C, 69.07; H, 5.24; N, 6.88.
4.2.5. N-Cyclohexyl 2-(4-chlorophenyl)-2-{12-methyl-(5H)-
6-oxodibenzo[b,f][1,5]diazocine-5-yl}acetamide 6e
Colorless crystals (452 mg, 93%), mp 159e161 ꢀC (hexa-
neeethyl acetate). IR (KBr, cmꢂ1): 3429 (NH), 1684
1
(C]O), 1629 (C]N). H NMR (400 MHz, CDCl3) d 8.90
(br s, 0.15H, NH, isom. D), 8.44 (br s, 0.24H, NH, isom. C),
8.19 (d, J¼8.2 Hz, 0.27H, NH, isom. B), 7.82e6.35 (m,
13.07H, 12HArþ0.34H NH, isom. Aþ0.73H CH, isom. A,
C, D), 5.23 (s, 0.27H, CH, isom. B), 3.93e3.86 (m, 0.34H,
CHcyclohexyl, isom. A), 3.77e3.69 (m, 0.27H, CHcyclohexyl
,
4.2.3. N-Cyclohexyl 2-(4-methoxyphenyl)-2-{12-phenyl-
isom. B), 3.55e3.45 (m, 0.24H, CHcyclohexyl, isom. C),
3.34e3.26 (m, 0.15H, CHcyclohexyl, isom. D), 2.73, 2.31,
2.25, 2.20 (s, 3H, CH3, isom. A, B, C, D), 2.10e0.93 (m,
10H). 13C NMR (100 MHz, CDCl3) d 174.5, 173.2, 168.9,
168.5, 148.2, 140.9, 138.6, 134.9, 134.7, 133.4, 133.3,
132.9, 132.8, 132.5, 132.4, 132.3, 132.1, 132.0, 131.9,
131.8, 131.5, 131.2, 131.1, 130.9, 130.2, 130.1, 129.9,
129.2, 129.1, 129.0, 128.9, 128.8, 128.7, 128.1, 128.0,
127.9, 127.8, 127.5, 127.3, 127.1, 126.7, 126.3, 125.2,
121.9, 121.2, 119.2, 117.1, 116.4, 67.5, 48.8, 48.6, 33.3,
32.7, 29.7, 29.3, 25.9, 25.2, 25.2. MS (EI) m/z 487 (Mþþ2,
2.4), 485 (Mþ, 6), 380 (75), 359 (56), 277 (100), 201 (23).
HRMS (EI) calcd for C29H28ClN3O2 485.1870, found
485.1860. Anal. Calcd for C29H28ClN3O2: C, 71.67; H, 5.81;
N, 8.65. Found: C, 71.58; H, 5.92; N, 8.58.
(5H)-6-oxodibenzo[b,f][1,5]diazocine-5-yl}acetamide 6c
Colorless crystals (408 mg, 75%), mp 143e145 ꢀC (hexa-
neeethyl acetate). IR (KBr, cmꢂ1): 3429 (NH), 1674
(C]O), 1665 (C]O), 1632 (C]N). 1H NMR (400 MHz,
CDCl3) d 8.77 (d, J¼7.2 Hz, 0.32H, NH, isom. C), 8.45 (d,
J¼8.4 Hz, 0.32H, NH, isom. B), 7.87 (br s, 0.32H, NH,
isom. A), 8.03e5.87 (m, 17.68H, 17HArþ0.68H CH, isom.
A, C, D), 5.17 (s, 0.32H, CH, isom. B), 3.67 (br s, 0.32H,
CHcyclohexyl, isom. A), 3.79 (br s, 0.32H, CHcyclohexyl, isom.
B), 3.69, 3.63, 3.58, 3.56 (s, 3H, CH3, isom. A, B, C, D),
3.50 (br s, 0.32H, CHcyclohexyl, isom. C), 3.24 (br s, 0.04H,
CHcyclohexyl, isom. D), 2.08e0.82 (m, 10H). 13C NMR
(100 MHz, CDCl3) d 174.7, 173.5, 173.4, 172.3, 170.1,
170.0, 159.0, 158.9, 147.9, 147.8, 142.9, 137.5, 137.4,
133.8, 133.3, 133.1, 133.0, 132.9, 132.8, 132.5, 132.2,
132.1, 132.0, 131.9, 131.8, 131.6, 131.5, 131.4, 131.3,
131.2, 131.0, 130.8, 130.4, 130.3, 130.2, 129.8, 129.5,
129.3, 129.1, 129.0, 128.9, 128.8, 128.7, 128.3, 128.1, 127.9,
125.7, 125.2, 124.9, 121.6, 117.0, 116.9, 113.5, 113.4, 69.1,
69.1, 67.9, 55.3, 48.7, 48.6, 48.3, 33.3, 33.1, 32.9, 32.8,
32.7, 26.0, 25.5, 25.3, 25.2, 25.2. MS (EI) m/z 543 (Mþ,
1.1), 417 (91), 277 (100). Anal. Calcd for C35H33N3O3: C,
77.32; H, 6.12; N, 7.73. Found: C, 77.46; H, 6.24; N, 7.61.
4.2.6. N-Cyclohexyl 2-(4-bromophenyl)-2-{12-methyl-(5H)-
6-oxodibenzo[b,f][1,5]diazocine-5-yl}acetamide 6f
Colorless crystals (302 mg, 57%), mp 144e146 ꢀC
(hexaneeethyl acetate). IR (KBr, cmꢂ1): 3432 (NH), 1684
1
(C]O), 1633 (C]N). H NMR (400 MHz, CDCl3) d 8.90
(br s, 0.15H, NH, isom. D), 8.44 (br s, 0.23H, NH, isom. C),
8.16 (d, J¼8.0 Hz, 0.29H, NH, isom. B), 7.84e5.95 (m,
13.04H, 12HArþ0.33H NH, isom. Aþ0.71H CH, isom. A,
C, D), 5.20 (s, 0.29H, CH, isom. B), 3.92e3.85 (m, 0.33H,
4.2.4. N-Benzyl 2-(4-bromophenyl)-2-{12-phenyl-(5H)-6-
oxodibenzo[b,f][1,5]diazocine-5-yl}acetamide 6d
Yellow crystals (324 mg, 54%), mp 197e199 ꢀC (ethyl
acetateeDMF). IR (KBr, cmꢂ1): 3440 (NH), 1671 (C]O),
CHcyclohexyl, isom. A), 3.74e3.68 (m, 0.29H, CHcyclohexyl,
isom. B), 3.53e3.45 (m, 0.23H, CHcyclohexyl, isom. C),
3.33e3.28 (m, 0.15H, CHcyclohexyl, isom. D), 2.74, 2.31,
2.26, 2.21 (s, 3H, CH3, isom. A, B, C, D), 2.10e0.48 (m,

N. Corres et al. / Tetrahedron 64 (2008) 2225e2232
2231
10H). 13C NMR (100 MHz, CDCl3) d 174.5, 173.1, 172.3,
168.8, 168.5, 148.7, 148.2, 141.0, 138.8, 137.7, 136.9,
136.4, 135.5, 135.1, 133.4, 132.9, 132.7, 132.3, 132.2,
132.1, 131.9, 131.8, 131.1, 131.0, 130.9, 130.8, 130.5,
130.2, 129.9, 129.0, 128.9, 128.8, 128.2, 128.1, 127.3,
127.1, 126.7, 126.3, 125.2, 124.4, 123.7, 122.0, 121.8,
121.7, 121.3, 119.2, 117.1, 116.4, 116.3, 69.1, 67.7, 67.6,
50.1, 49.0, 48.5, 33.3, 33.0, 32.6, 31.8, 29.7, 29.3, 28.7,
25.9, 25.3. MS (EI) m/z 531 (Mþþ2, 1.5), 529 (Mþ, 1.5),
380 (100), 277 (62). Anal. Calcd for C29H28BrN3O2: C,
65.66; H, 5.32; N, 7.92. Found: C, 65.49; H, 5.21; N, 7.79.
29.1, 28.8. MS (EI) m/z 539 (Mþþ2, 3), 537 (Mþ, 3), 405
(23), 277 (100), 201 (16). HRMS (EI) calcd for C30H24BrN3O2
537.1052, found 537.1028. Anal. Calcd for C30H24BrN3O2: C,
66.92; H, 4.49; N, 7.80. Found: C, 66.99; H, 4.53; N, 7.69.
Acknowledgements
We gratefully acknowledge financial support from the
´
Direccion General de Investigacion of Spain (Project ref.
CTQ2006-15456-C04-04BQU) and Junta de Castilla y Leon,
´
´
´
´
Consejerıa de Educacion y Cultura, y Fondo Social Europeo
(Project ref. BU013A06).
4.2.7. N-Cyclohexyl 2-(4-methoxyphenyl)-2-{12-methyl-
(5H)-6-oxodibenzo[b,f][1,5]diazocine-5-yl}acetamide 6g
Colorless crystals (390 mg, 81%), mp 155e157 ꢀC (hexa-
neeethyl acetate). IR (KBr, cmꢂ1): 3431 (NH), 1683
Supplementary data
1H NMR and 13C NMR of compounds 5aeh and 6aeh.
COSY, NOESY, EXSY, DEPT, HMBC, and HMQC experi-
ments of selected examples of 5aeh and 6aeh. Supplemen-
tary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2007.12.028.
1
(C]O), 1627 (C]N). H NMR (400 MHz, CDCl3) d 8.88
(br s, 0.15H, NH, isom. D), 8.51 (br s, 0.25H, NH, isom. C),
8.41 (d, J¼8.2 Hz, 0.28H, NH, isom. B), 7.86e5.91 (m,
13.04H, 12HArþ0.32H NH, isom. Aþ0.72H CH, isom. A,
C, D), 5.43 (s, 0.28H, CH, isom. B), 3.95e3.50 (m, 0.85H,
CHcyclohexyl, isom. A, B, C), 3.34e3.30 (m, 0.15H, CHcyclohexyl
,
References and notes
isom. D), 3.75, 3.70, 3.73, and 3.65 (s, 3H, CH3, isom. A, B, C,
D), 2.74, 2.35, and 2.15 (s, 3H, CH3, isom. A, B, C, D), 2.05e
0.86 (m, 10H). 13C NMR (100 MHz, CDCl3) d 174.7, 174.6,
173.3, 172.4, 172.4, 172.4, 170.5, 170.0, 169.9, 169.6, 169.5,
169.2, 160.0, 159.1, 159.0, 148.0, 147.9, 140.6, 140.4, 138.6,
137.6, 137.3, 137.0, 136.4, 133.7, 133.5, 133.4, 133.1, 133.0,
132.9, 132.8, 132.7, 132.5, 132.3, 132.2, 132.1, 132.0, 131.9,
131.8, 131.7, 131.5, 131.3, 130.9, 130.6, 130.5, 130.3, 130.0,
129.7, 129.0, 128.9, 128.8, 128.8, 128.7, 128.6, 128.4128.2,
128.0, 127.2 127.0, 126.9, 126.5, 126.1, 125.0, 124.3, 121.1,
117.2, 116.3, 113.9, 113.4, 113.3, 113.2, 112.9, 68.2, 68.0,
64.0, 63.9, 55.5, 55.3, 55.3, 55.2, 48.8, 48.7, 48.3, 33.4, 33.3,
33.0, 32.9, 29.9, 29.4, 29.3, 26.8, 26.0, 25.9, 25.8, 25.7, 25.6,
25.5, 25.3, 25.2, 24.9. MS (EI) m/z 481 (Mþ, 3), 380 (40), 355
(100), 277 (70), 201 (16). HRMS (EI) calcd for C30H31N3O3
481.2365, found 481.2375. Anal. Calcd for C30H31N3O3: C,
74.82; H, 6.49; N, 8.73. Found: C, 74.91; H, 6.57; N, 8.61.
1. Recent examples: (a) Didier, D.; Sergeyev, S. Eur. J. Org. Chem. 2007,
3905e3910; (b) Yuan, C.-X.; Tao, X.-T.; Ren, Y.; Li, Y.; Yang, J.-X.;
Yu, W.-T.; Wang, L.; Jiang, M.-H. J. Phys. Chem. C 2007, 111, 12811e
12816.
2. A recent example: Leganza, A.; Bezze, C.; Zonta, C.; Fabris, F.; De
Lucchi, O.; Linden, A. Eur. J. Org. Chem. 2006, 2987e2990.
3. See for example: (a) Acs, P.; Muller, E.; Rangits, G.; Lorand, T.; Kollar, L.
¨
Tetrahedron 2006, 62, 12051e12056; (b) Olszewska, T.; Gdaniec, M.;
Po1onski, T. J. Org. Chem. 2004, 69, 1248e1255; (c) Hassner, A.; Sun,
B.; Gellermann, G.; Meir, S. Tetrahedron Lett. 2004, 45, 1377e1379;
(d) Hoorfar, A.; Ollis, W. D.; Price, J. A.; Stephanatou, J. S.; Stoddart,
J. F. J. Chem. Soc., Perkin Trans. 1 1982, 1649e1699; (e) Edge, S. J.;
Ollis, W. D.; Stephanatou, J. S.; Stoddart, J. F. J. Chem. Soc., Perkin
Trans. 1 1982, 1701e1714. Dilactams from Ugi reactions: (f) Ebert,
B. M.; Ugi, I. K. Tetrahedron 1998, 54, 11887e11898. Polycyclic dilac-
tams: (g) Eguchi, S.; Matsuehita, Y.; Takeuchi, H. J. Org. Chem. 1992, 57,
697e6979.
4. Nonnenmacher, E.; Brouant, P.; Mrozek, A.; Karolak-Wojciechowska, J.;
Barbe, J. J. Mol. Struct. 2000, 522, 263e269.
5. See for example: (a) Nakayama, T.; Harada, N.; Asano, M.; Nomura, N.;
Saito, T.; Mishima, A.; Okajima, K. J. Pharmacol. Exp. Ther. 2007, 322,
582e590; (b) Culmsee, C.; Gerling, N.; Landshamer, S.; Rickerts, B.;
Duchstein, H. J.; Umezawa, K.; Klumpp, S.; Krieglstein, J. Mol. Pharma-
col. 2005, 68, 1006e1017; (c) Mixcoatl-Zecuatl, T.; Flores-Murrieta, F. J.;
Granados-Soto, V. Eur. J. Pharmacol. 2006, 531, 87e95.
4.2.8. N-Benzyl 2-(4-bromophenyl)-2-{12-methyl-(5H)-6-
oxodibenzo[b,f][1,5]diazocine-5-yl}acetamide 6h
Colorless crystals (366 mg, 68%), mp 167e169 ꢀC (ethyl
acetateeDMF). IR (KBr, cmꢂ1): 3432 (NH), 1691 (C]O),
1666 (C]O), 1626 (C]N). 1H NMR (400 MHz, CDCl3)
d 10.43 (br s, 0.34H, NH, isom. D), 8.68 (br s, 0.15H, NH,
isom. C), 8.22 (br s, 0.16NH, isom. B), 7.69e6.05 (m,
18.19H, 17HArþ0.35NH, isom. Aþ0.84H CH, isom. A, C,
D), 5.76 (s, 0.16H, CH, isom. B), 4.50e4.02 (m, 1.32H,
CH2, isom. A, B, C), 3.20 (dd, J¼14.8, 5.1 Hz, 0.68H, CH2,
isom. D), 2.21, 2.18, 2.13 (s, 3H, CH3, isom. A, B, C, D).
13C NMR (100 MHz, CDCl3) d 172.9, 170.1, 147.6, 139.1,
139.0, 137.7, 137.1, 133.2, 133.1, 133.0, 132.9, 132.8,
132.4, 132.3, 132.1, 131.0, 130.9, 130.6, 130.2, 129.7,
129.6, 129.4, 129.2, 129.1, 129.0, 128.9, 128.8, 128.6,
128.5, 128.4, 128.2, 127.9, 127.8, 127.0, 123.1, 122.3, 122.0,
119.6, 116.5, 67.6, 67.3, 67.3, 43.8, 43.5, 43.4, 29.5, 29.2,
6. Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem., Int. Ed.
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´
´
642e646; (b) Pessoa-Mahana, H.; Martınez-Aranguiz, K. G.; Araya-Ma-
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´
See also: (d) Sigaut, F.; Didierdefresse, B.; Levy, J. Tetrahedron 2000, 56,
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8. (a) Marcaccini, S.; Torroba, T. Multicomponent Reactions; Zhu, J., Bien-
´
ayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; Chapter 2,
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~
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2232
N. Corres et al. / Tetrahedron 64 (2008) 2225e2232
(c) Alternative procedure: Ugi, I.; Meyr, R.; Lipinski, M.; Bodesheim, F.;
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Rosendahl, F. Org. Synth. Coll. Vol. 1973, 5, 300; (d) Ugi, I.; Meyr, R.;
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Santos, J. M. Tetrahedron 2007, 63, 523e575; (b) Brase, S.; Gil, C.;
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Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188e
5240. A benzodiazocine via Staudinger/aza-Wittig ring closing: (c)
O’Neil, I. A.; Murray, C. L.; Potter, A. J.; Kalindjian, S. B. Tetrahedron
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11. Extended experimental details about the Ugi reaction, in: Marcaccini, S.;
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