Synthesis of pseudopeptidic (S)-6-amino-5-oxo-1,4-diazepines and (S)-3-benzyl-2-oxo-1,4-benzodiazepines by an Ugi 4CC Staudinger/aza-Wittig sequence

Article abstract of DOI:10.1016/j.tet.2010.06.062

Sequential Ugi reaction between p-substituted arylglyoxals, alkylamines, cyclohexyl isocyanide and 3-azido-(S)-2-(tert-butoxycarbonylamino)propanoic acid, followed by a Staudinger/aza-Wittig cyclization in the presence of triphenylphosphine, gave rise to enantiomerically pure N-cyclohexyl 4-alkyl-2-aryl-5-oxo-(S)-6-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydro-1H-1, 4-diazepine-3-carboxamides, that can be useful for new drug design. By the same sequence, p-substituted benzaldehydes, 2-aminobenzophenone, cyclohexyl isocyanide and (S)-3-phenyl-2-azidopropionic acid gave rise to N-cyclohexyl 2-((S)-3-benzyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)-(R/S) -2-arylacetamides.

Full text of DOI:10.1016/j.tet.2010.06.062

Tetrahedron 66 (2010) 6783e6788
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of pseudopeptidic (S)-6-amino-5-oxo-1,4-diazepines and (S)-3-benzyl-
2-oxo-1,4-benzodiazepines by an Ugi 4CC Staudinger/aza-Wittig sequence
,
Paulina Lecinska a, Nazaret Corres a, Daniel Moreno a, María García-Valverde a
,
*
,
Stefano Marcaccini b, Tomás Torroba a
*
a Department of Chemistry, Faculty of Science, Universidad de Burgos, 09001 Burgos, Spain
b Department of Chemistry, Polo Scientifico, Università di Firenze, 50019 Sesto Fiorentino (FI), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Sequential Ugi reaction between p-substituted arylglyoxals, alkylamines, cyclohexyl isocyanide and 3-
azido-(S)-2-(tert-butoxycarbonylamino)propanoic acid, followed by a Staudinger/aza-Wittig cyclization
in the presence of triphenylphosphine, gave rise to enantiomerically pure N-cyclohexyl 4-alkyl-2-aryl-5-
oxo-(S)-6-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydro-1H-1,4-diazepine-3-carboxamides, that can be
useful for new drug design. By the same sequence, p-substituted benzaldehydes, 2-aminobenzophenone,
cyclohexyl isocyanide and (S)-3-phenyl-2-azidopropionic acid gave rise to N-cyclohexyl 2-((S)-3-benzyl-
2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)-(R/S)-2-arylacetamides.
Received 31 May 2010
Accepted 22 June 2010
Available online 25 June 2010
Keywords:
Isocyanide
Ugi reaction
Staudinger/aza-Wittig
Diazepine
Ó 2010 Elsevier Ltd. All rights reserved.
Benzodiazepine
1. Introduction
that the sequences of classical Ugi or Passerini isocyanide multi-
component reactions, followed by post-condensation trans-
Although much less studied than the 1,4-benzodiazepine nucleus,
which is considered the paradigm of a privileged structure,1 the
1,4-diazepine nucleus has been subjected to intense research in
pharmacological,2 as well as in synthetic chemistry.3 The 1,4-dia-
zepan-2-one nucleus has been found in the naturally occurring an-
tibiotics caprazamycins and liposidomycins, which have been shown
to exhibit excellent antimicrobial activity against drug-resistant
grampositive bacteria, therefore their core synthesis has been deeply
studied.4 Chiral1,4-diazepin-2-oneshavebeenpreparedasprivileged
formations, constitute extremely powerful synthetic tools for the
preparation of structurally diverse complex molecules, among them
are heterocyclic compounds with elaborate substitution patterns,
benzodiazepine b
-turn mimetics, and pseudopeptides.1,10 As a new
contribution of this methodology, we want to report in this paper
a new short synthesis of pseudopeptidic (S)-6-amino-5-oxo-1,4-di-
azepine-3-carboxamides by the Ugi reaction between p-substituted
arylglyoxals, alkylamines, cyclohexyl isocyanide and 3-azidopro-
pionic acids, followed by a Staudinger/aza-Wittig cyclization of the
Ugi products in the presence of triphenylphosphine. The synthesis
has then been extended to (S)-3-benzyl-2-oxo-1,4-benzodiazepines.
structures in medicinal chemistry to mimic g-turn peptide secondary
structures.5 Similarly, the synthesis of the 1,4-diazepan-5-one
nucleus has been studied and chiral 1,4-diazepin-5-ones have been
used for the preparation of g-turn mimics as well as derivatives of the
antibiotic linezolid (Zyvox) and peptidomimetics.6 Finally, the 1,4-
diazepan-2,5-dione core has been synthesized for its inherently
peptidic nature in search of conformationally constrained peptido-
mimetics.7 Enantiopure bicyclic 1,4-diazepin-2,5-diones have been
synthesized through multicomponent Ugi reactions8 and a naturally
occurring example of this series has been reported.9 In general, the
synthesis of these compounds implied several steps, even though
multicomponent reactions were employed. We have recently shown
2. Results and discussion
A mixture of p-substituted arylglyoxal 2aed (1 equiv) and the
amine 3aef (1 equiv) was stirred in methanol at room temperature
for 30 min, then cyclohexyl isocyanide 4 (1 equiv) and the 2-
substituted 3-azidopropionic acid, obtained by triflyl azide diazo
transfer,11 1aec (1 equiv), were added consecutively to the imine
solution and the mixture was stirred in methanol at room tem-
perature for 2 days until solid 5aeh precipitated.12 Filtration and
recrystallization of the solid afforded N-cyclohexyl 2-[N-alkyl-N-(3-
azidopropionyl)amino]-3-oxo-3-arylpropionamides 5aeh in fair
yields (53e80%) (Scheme 1 and Table 1), that were subsequently
* Corresponding authors. Tel.: þ34 947 258088; fax: þ34 947 258831; e-mail
addresses: magaval@ubu.es (M. García-Valverde), ttorroba@ubu.es (T. Torroba).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.062

6784
P. Lecinska et al. / Tetrahedron 66 (2010) 6783e6788
O
NC
O
R3
O
O
R1
H
O
N
R1
O
OH
HN
PPh3
MeOH
r.t., 2d
O
+
+
HN
N
R1
OH
PhMe
4
N3
1a-c
H
N
R3 NH2
3a-f
r.t., 1d
R2
2a-d
R3
1
N3
1a:
R = H
R2
6a-h
1b: R1 = (S)NHCO2C(CH3)3
3a: R3 = C6H5CH2
1c: R1 = (R/S)CH3
3b: R3 = 4-ClC6H4CH2
R2
2
3c: R3 = 4-CH3OC6H4CH2
2a:
R = F
2b: R2 = OCH3
2c: R2 = H
3d: R3 = n-C4H9
5a-h
3
3e:
R = 4-FC6H4CH2
2d: R2 = CF3
3f: R3 = 4-CH3C6H4CH2
Scheme 1. 5-Oxo-1,4-diazepine-3-carboxamides by the Ugi 4CC/Staudinger/aza-Wittig sequence.
aryl-5-oxo-(S)-6-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydro-
1H-1,4-diazepine-3-carboxamides, that can be useful for new
drug design.
Table 1
Ugi products 5aeh and 1,4-diazepines 6aeh
R1
R2
R3
5 (%)
6 (%)
Benzodiazepines have been classically obtained by isocyanide
multicomponent reactions,13 sometimes by aza-Wittig reactions.1,14
The combination of Ugi or Passerini and aza-Wittig reactions
has also been very fruitful in heterocyclic synthesis.15 Some
H
H
F
C6H5CH2
5a (54)
5b (80)
5c (67)
5d (53)
5e (78)
5f (72)
5g (59)
5h (61)
6a (74)
6b (61)
6c (87)
6d (75)
6e (85)
6f (71)
6g (90)
6h (98)
OCH3
H
CF3
F
H
H
4-ClC6H4CH2
4-ClC6H4CH2
4-CH3OC6H4CH2
4-CH3OC6H4CH2
n-C4H9
(S)NHBoc
(S)NHBoc
(S)NHBoc
(S)NHBoc
(R/S)CH3
(R/S)CH3
3-substituted
(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]di-
azepin-1-yl)acetamides have been recently studied as falcipain-2
inhibitors in search of antimalarian agents,16 as well as cholecys-
tokinin (CCK-A) receptor agonists.17 Classical synthesis of the nu-
cleus usually implies several steps,18 therefore we wanted to apply
the previous Ugi 4CC-Staudinger/aza-Wittig scheme to a classical
benzodiazepine nucleus, to get new useful derivatives. The use of
chiral aminoacid derivatives opens also the possibility to obtain
a diastereoselective approach to pseudopeptidic 1,4-benzodiaze-
pin-1-yl acetamides. So, a mixture of p-substituted benzaldehyde
8aeb (1 equiv) and 2-aminobenzophenone 9 (1 equiv) was stirred
in methanol at room temperature for 30 min, then cyclohexyl iso-
4-FC6H4CH2
4-CH3C6H4CH2
H
stirred in dry toluene with triphenylphosphine (1.5 equiv) for 1
day to get N-cyclohexyl 4-alkyl-2-aryl-5-oxo-4,5,6,7-tetrahydro-
1H-1,4-diazepine-3-carboxamides 6aeh in good yields (61e98%)
after column chromatography purification (Scheme 1 and Table
1). The recrystallized products 5aeh and 6aeh were character-
ized by the usual spectroscopic and analytical techniques. DEPT,
COSY, NOESY, HMQC, and HMBC experiments of selected exam-
ples permitted to assign all NMR signals. As expected,1 products
5aeh were obtained exclusively as the enol forms, on the basis
of their NMR spectra in CDCl3. On the other hand, products 6aeh
were obtained exclusively as the 1H-tautomers, coming from the
imine to enamine tautomerization of the expected imines
formed in the Staudinger/aza-Wittig reaction. In this way, the
use of 3-azido-(S)-2-(tert-butoxycarbonylamino)propanoic acid
1b gave rise to enantiomerically pure N-cyclohexyl 4-alkyl-2-
cyanide
4 (1 equiv) and (S)-3-phenyl-2-azidopropionic acid,
obtained by triflyl azide diazo transfer from phenylalanine,11
7
(1 equiv), were added consecutively to the imine solution, and the
mixture was stirred in methanol at room temperature for 2 days
until solid 10aec precipitated.12 Filtration and recrystallization of
the solid afforded N-cyclohexyl 2-N-(S)-2-azido-3-phenyl-
propionyl-N-(2-benzoylphenyl)-(R/S)-2-arylacetamides 10aec in
fair yields (57e75%) (Scheme
2
and Table 2), that were
R4
O
R4
NC
O
H
N3
OH
O
H
N
O
O
4
7
N
N
R4
8a-c
PPh3
MeOH
r.t., 2d
HN
N3
O
O
NH2
O
N
PhMe
r.t., 1d
8a: R4 = Br
8b: R4 = Cl
4
10a-c
8c
11a-c
: R = CH3
9
Scheme 2. 5-Oxo-1,4-diazepine-3-carboxamides by the Ugi 4CC/Staudinger/aza-Wittig sequence.

P. Lecinska et al. / Tetrahedron 66 (2010) 6783e6788
6785
2112, 1634; 1H NMR (300 MHz, CDCl3)
d
15.80 (s, 1H, OH), 7.73e7.11
Table 2
Ugi products 10aec and 1,4-benzodiazepines 11aec
(m, 9H, HAr), 5.73 (d, J¼13.6 Hz, 1H), 5.46 (d, J¼7.6, 1H, NH), 3.71 (t,
J¼10.9 Hz, 1H), 3.49 (d, J¼13.6 Hz, 1H), 3.46e3.35 (m, 1H), 3.22 (dd,
J¼4.7 Hz, J¼11.4 Hz, 1H), 2.79e2.72 (m, 1H), 2.31 (s, 3H), 1.77e0.72
(m, 9H), 0.67 (d, J¼6.8 Hz, 3H), 0.34e0.20 (m,1H); 13C NMR (75 MHz,
R4
10 (%)
11 (%)
Br
Cl
CH3
10a (57)
10b (64)
10c (75)
11a (65)
11b (84)
11c (79)
CDCl3) d 177.0 (Cq),170.3 (Cq), 167.7 (Cq),138.2 (Cq), 135.4 (Cq), 133.3
(Cq), 131.2 (CHAr), 130.1 (CHAr), 129.5 (CHAr), 129.0 (CHAr), 127.9
(CHAr), 108.0 (Cq), 55.9 (CH2), 54.1 (CH2), 48.9 (CH), 37.7(CH), 32.1
(CH2), 31.8 (CH2), 25.7 (CH2), 25.1 (CH2), 25.0 (CH2), 21.3 (CH3), 14.8
(CH3); MS (EI) m/z 475 (Mþ, 11), 363 (10), 259 (49), 105 (100);
HRMS (EI) calculated for C27H33N5O3 475.2583; found 475.2580.
Anal. Calcd for C27H33N5O3: C, 68.19; H, 6.99; N, 14.73. Found: C,
68.07; H, 6.84; N, 14.88.
subsequently stirred in dry toluene with triphenylphosphine
(1.5 equiv) for 1 day to get N-cyclohexyl 2-((S)-3-benzyl-2-oxo-5-
phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)-(R/S)-2-aryla-
cetamides 11aec in good yields (65e84%) after column chroma-
tography purification (Scheme 2 and Table 2). The recrystallized
products 10aec and 11aec were characterized by the usual spec-
troscopic and analytical techniques. DEPT, COSY, NOESY, HMQC, and
HMBC experiments of selected examples permitted to assign all
NMR signals. Products 10aec and 11aec were obtained as single S
isomers in the phenylalanine moiety but as an equimolecular
mixture of R/S enantiomers in the newly formed arylglycine moiety,
therefore we did not try other examples. Although the synthesis
may be useful for new drug design, the lack of diastereoselection of
the sequence of reactions permitted only the preparation of equi-
molecular diastereomeric mixtures.
4.1.2. N-Cyclohexyl 4-benzyl-2-(4-fluorophenyl)-5-oxo-4,5,6,7-tetra-
hydro-1H-1,4-diazepine-3-carboxamide
6a. Triphenylphosphine
(157 mg, 0.6 mmol) was added under nitrogen to a solution of Ugi
adduct 5a (186 mg, 0.4 mmol) in toluene (10 ml) and the mixture
was stirred for 24 h at room temperature. Then the solvent was
evaporated under reduced pressure and the residue was purified by
column chromatography (hexane/AcOEt mixtures as eluent) to give
6a as a colorless solid (125 mg, 74%), mp 69e70 ꢀC (hexane/AcOEt);
IR (KBr, cmꢁ1) 3282, 1648, 1510; 1H NMR (400 MHz, CDCl3)
d
7.61e6.83 (m, 10H, HAr, NH), 4.94 (d, J¼8.2 Hz, 1H, NH), 4.73 (s, 2H,
CH2 benzyl), 3.65e3.62 (m, 2H), 3.53e3.48 (m, 1H), 2.79e2.77 (m,
2H), 1.56e0.68 (m, 10H); 13C NMR (100 MHz, CDCl3)
173.2 (Cq),
3. Conclusion
d
163.2 (d, J¼249.1 Hz, Cq), 164.0 (Cq), 163.9 (Cq), 143.9 (Cq), 143.8
(Cq), 137.9 (Cq), 132.3 (CHAr), 132.2 (CHAr), 130.7 (d, J¼8.3 Hz, CHAr),
128.5 (CHAr), 128.4 (CHAr), 127.4 (CHAr), 115.6 (d, J¼21.7 Hz, CHAr),
108.3 (Cq), 49.7 (CH2), 48.1 (CH2),48.0 (CH), 36.1 (CH2), 33.0 (CH2),
25.6 (CH2), 25.0 (CH2); MS (EI) m/z 421 (Mþ, 24), 330 (48), 277
(100), 278 (47), 91 (48); HRMS (EI) calculated for C25H28FN3O2
421.2166; found 421.2166. Anal. Calcd for C25H28FN3O2: C, 71.24; H,
6.70; N, 9.97. Found: C, 71.13; H, 6.54; N, 9.85.
In summary, we have described the synthesis of new enan-
tiomerically pure N-cyclohexyl (S)-4-alkyl-2-aryl-5-oxo-6-(tert-
butoxycarbonylamino)-4,5,6,7-tetrahydro-1H-1,4-diazepine-3-
carboxamides and 2-((S)-3-benzyl-2-oxo-5-phenyl-2,3-dihydro-
1H-benzo[e][1,4]diazepin-1-yl)-2-arylacetamides, obtained as
diastereomeric mixtures, by means of sequences of Ugi four
component condensations followed by Staudinger/aza-Wittig
cyclizations of the intermediate Ugi products to give the final
products. The reactions employ all commercial or easily available
starting materials, and are performed under very simple experi-
mental conditions and work-up, which makes it useful for new
drug design.
4.1.3. N-Cyclohexyl 4-(4-chlorobenzyl)-2-(4-methoxyphenyl)-5-oxo-
4,5,6,7-tetrahydro-1H-1,4-diazepine-3-carboxamide 6b. Ph3P (157 mg,
0.6 mmol) and 5b (205 mg, 0.4 mmol) reacted as in previous case to
give 6b as a pale yellow solid (114 mg, 61%), mp 72e73 ꢀC (hexane/
AcOEt); IR (KBr, cmꢁ1) 3190, 1656, 1630, 1514; 1H NMR (400 MHz,
4. Experimental section
4.1. General
CDCl3)
d
7.64e6.79 (m, 9H, HAr, NH), 4.83 (d, J¼8.3 Hz, 1H, NH), 4.70
(s, 2H, CH2 benzyl), 3.73 (s, 3H), 3.63e3.61 (m, 2H), 3.49e3.42 (m,
1H), 2.74e2.71 (m, 2H), 1.64e0.58 (m, 10H); 13C NMR (100 MHz,
CDCl3) d 173.2 (Cq), 164.4 (Cq), 164.7 (Cq), 145.1 (Cq), 136.8 (Cq), 133.0
Melting points were determined in a Gallenkamp apparatus and
are not corrected. Infrared spectra were registered in a Nicolet
Impact 410 spectrometer in potassium bromide tablets. NMR
spectra were recorded in Varian Mercury-300 and Varian Unity
Inova-400 machines, in DMSO-d6, CDCl3, CD3CN, CD3OD. Chemical
shifts are reported in parts per million with respect to residual
(Cq), 130.7 (Cq), 130.2 (CHAr), 129.9 (CHAr), 128.5 (CHAr), 114.3 (CHAr),
107.7 (Cq), 55.6 (CH3), 49.0 (CH2), 48.2 (CH2),48.0 (CH), 35.8 (CH2),
32.9 (CH2), 25.6 (CH2), 24.8 (CH2); MS (EI) m/z 467 (Mþ, 73),
468 (Mþþ1, 20), 469 (Mþþ2, 28), 342 (100), 343 (57); HRMS (EI)
calculated for C26H30ClN3O3 467.1976; found 467.1973. Anal. Calcd for
C26H30ClN3O3: C, 66.73; H, 6.46; N, 8.98. Found: C, 66.65; H, 6.59;
N, 9.15.
0
solvent protons, coupling constants (JXeX ) are reported in hertz.
Elemental analyses of C, H and N were taken in a Leco CHNS-932.
Mass spectra were taken in a Micromass AutoSpec machine, by
electronic impact at 70 eV.
4.1.4. N-Cyclohexyl 4-(4-chlorobenzyl)-2-phenyl-5-oxo-(S)-6-(tert-
butoxycarbonylamino)-4,5,6,7-tetrahydro-1H-1,4-diazepine-3-car-
boxamide 6c. Ph3P (157 mg, 0.6 mmol) and 5c (239 mg, 0.4 mmol)
reacted as in previous case to give 6c as a pale yellow solid (192 mg,
4.1.1. N-Cyclohexyl2-[N-(4-methylbenzyl)-N-(3-azido-(R/S)-2-methyl-
propionyl)amino]-3-oxo-3-phenylpropionamide 5h. A mixture of
arylglyoxal 2c (134 mg, 1 mmol) and 4-methylbenzylamine 3f
(121 mg, 1 mmol) was stirred in methanol (10 mL) at room tem-
perature for 30 min, then cyclohexyl isocyanide 4 (109 mg, 1 mmol)
and (R/S)-2-methyl-3-azidopropionic acid, obtained by triflyl azide
diazo transfer,11c 1c (129 mg, 1 mmol) were added consecutively to
the imine solution, and the mixture was stirred in methanol at room
temperature for 2 days until solid 5h precipitated. Filtration and
recrystallization of the solid in methanol afforded 5h as a colorless
solid (290 mg, 61%), mp 120e121 ꢀC (MeOH); IR (KBr, cmꢁ1) 3433,
87%), mp 79e80 ꢀC (hexane/AcOEt); [
a
]
D
20 ꢁ30.3ꢀ (c 0.49, CHCl3); IR
(KBr, cmꢁ1) 3876, 2927, 1716, 1652; 1H NMR (400 MHz, CDCl3)
d
7.65e7.17 (m, 9H, HAr), 5.86 (d, J¼5.8 Hz, 1H, NH), 5.45 (d,
J¼14.9 Hz, 1H, CH2 benzyl), 4.76 (ddd, J¼10.1 Hz, J¼5.7 Hz, J¼2.7 Hz,
1H), 4.62 (d, J¼8.2 Hz, 1H, NH), 4.19 (d, J¼14.9 Hz, 1H, CH2 benzyl),
3.93 (dd, J¼7.3 Hz, J¼2.1 Hz, 1H, NH), 3.72 (ddd, J¼10.2 Hz, J¼7.3 Hz,
J¼2.7 Hz, 1H), 3.47e3.38 (m, 1H), 3.23e3.14 (m, 1H), 1.40 (s, 9H),
1.68e0.39 (m, 10H); 13C NMR (100 MHz, CDCl3)
d 170.8 (Cq), 164.0
(Cq), 155.1 (Cq), 145.2 (Cq), 138.0 (Cq), 136.3 (Cq), 133.3 (Cq), 129.9
(CHAr), 129.2 (CHAr), 128.6 (CHAr), 128.5 (CHAr), 107.2 (Cq), 80.2 (Cq),

6786
P. Lecinska et al. / Tetrahedron 66 (2010) 6783e6788
53.1 (CH2), 53.0 (CH), 49.4 (CH2), 48.1 (CH), 32.9 (CH2), 32.4 (CH2),
28.5 (CH3), 25.5 (CH2), 24.8 (CH2), 24.7 (CH2); MS (EI) m/z 552 (Mþ,
38), 371 (100), 125 (49); HRMS (EI) calculated for C30H37ClN4O4
552.2503; found 552.2514. Anal. Calcd for C30H37ClN4O4: C, 65.15;
H, 6.74; N, 10.13. Found: C, 65.27; H, 6.89; N, 10.05.
found 484.3054. Anal. Calcd for C27H40N4O4: C, 66.91; H, 8.32; N,
11.56. Found: C, 67.09; H, 8.44; N, 11.49.
4.1.8. N-Cyclohexyl 4-(4-fluorobenzyl)-2-phenyl-5-oxo-(R/S)-6-methyl-
4,5,6,7-tetrahydro-1H-1,4-diazepine-3-carboxamide 6g. Ph3P (157 mg,
0.6 mmol) and 5g (192 mg, 0.4 mmol) reacted as in previous case to
give 6g as a colorless solid (157 mg, 90%), mp 119e120 ꢀC (hexane/
AcOEt); IR (KBr, cmꢁ1) 3436, 3262, 1631, 1514; 1H NMR (400 MHz,
4.1.5. N-Cyclohexyl 4-(4-methoxybenzyl)-2-(4-trifluoromethylphen-
yl)-5-oxo-(S)-6-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydro-1H-
1,4-diazepine-3-carboxamide 6d. Ph3P (157 mg, 0.6 mmol) and 5d
CDCl3)
d 7.58e7.08 (m, 7H, HAr), 6.92e6.88 (m, 2H, HAr), 5.42 (d,
(264 mg, 0.4 mmol) reacted as in previous case to give 6d as a pale
J¼14.8 Hz, 1H, CH2 benzyl), 4.69 (d, J¼8.3 Hz, 1H, NH), 3.99 (d,
J¼14.8 Hz, 1H, CH2 benzyl), 3.62 (d, J¼5.7 Hz, 1H, NH), 3.48e3.39
(m, 2H), 3.26 (t, J¼11.1 Hz, 1H), 3.17e3.09 (m, 1H), 1.09 (d J¼6.7 Hz,
20
yellow solid (185 mg, 75%), mp 74e76 ꢀC (hexane/AcOEt); [
a]
D
ꢁ194.8ꢀ (c 0.17, CHCl3); IR (KBr, cmꢁ1) 3421, 1641, 1511; 1H NMR
(400 MHz, CDCl3)
d
7.69e7.18 (m, 6H, HAr), 6.84e6.82 (m, 2H, HAr),
3H), 1.55e0.40 (m, 10H); 13C NMR (100 MHz, CDCl3)
d 174.4 (Cq),
5.88 (d, J¼6.0 Hz, 1H, NH), 5.48 (d, J¼14.4 Hz, 1H, CH2 benzyl),
5.01 (d, J¼8.4 Hz, 1H, NH), 4.81 (ddd, J¼9.8 Hz, 6.0 Hz, 2.3 Hz, 1H),
4.01 (d, J¼14.4 Hz, 1H, CH2 benzyl), 3.78 (s, 3H), 3.74e3.66 (m, 2H),
3.61e3.50 (m, 1H), 3.18e3.13 (m, 1H), 1.43 (s, 9H), 1.70e0.65
163.9 (Cq), 161.9 (d, J¼244.9 Hz, Cq), 144.6 (Cq), 138.6 (Cq), 134.0 (d,
J¼3.2 Hz, Cq), 129.8 (d, J¼8.0 Hz, CHAr), 129.2 (CHAr), 128.7 (CHAr),
128.2 (CHAr), 114.9 (d, J¼21.3 Hz, CHAr), 108.6 (Cq), 55.3 (CH2), 48.6
(CH2), 47.7 (CH), 37.3 (CH), 32.8 (CH2), 32.3 (CH2), 25.3 (CH2), 24.6
(CH2), 24.5 (CH2), 13.4 (CH3); MS (EI) m/z 435 (Mþ, 75), 326 (100);
HRMS (EI) calculated for C26H30FN3O2 435.2322; found 435.2329.
Anal. Calcd for C26H30FN3O2: C, 71.70; H, 6.94; N, 9.65. Found: C,
71.59; H, 6.85; N, 9.57.
(m, 10H); 13C NMR (100 MHz, CDCl3)
d 170.7 (Cq), 163.2 (Cq), 159.1
(Cq), 154.9 (Cq), 144.3 (Cq), 141.8 (Cq), 131.1 (q, J¼32.7 Hz, Cq), 129.8
(CHAr), 128.9 (CHAr), 125.4 (q, J¼3.6 Hz, CHAr), 123.7 (q, J¼272.5, Cq),
113.7 (CHAr), 106.5 (Cq), 80.2 (Cq), 55.2 (CH3), 52.8 (CH), 52.4 (CH2),
49.9 (CH2), 48.0 (CH), 32.9 (CH2), 32.7 (CH2), 28.3 (CH3), 25.3 (CH2),
24.7 (CH2), 24.6 (CH2); MS (EI) m/z 616 (Mþ, 12), 439 (100), 121 (69);
HRMS (EI) calculated for C32H39F3N4O5 616.2873; found 616.2861.
Anal. Calcd for C32H39F3N4O5: C, 62.33; H, 6.37; N, 9.09. Found: C,
62.25; H, 6.23; N, 8.92.
4.1.9. N-Cyclohexyl4-(4-methylbenzyl)-2-phenyl-5-oxo-(R/S)-6-methyl-
4,5,6,7-tetrahydro-1H-1,4-diazepine-3-carboxamide 6h. Ph3P (157 mg,
0.6 mmol) and 5h (190 mg, 0.4 mmol) reacted as in previous case to
give 6h as a colorless solid (169 mg, 98%), mp 147e149 ꢀC (hexane/
AcOEt); IR (KBr, cmꢁ1) 3443, 3261, 1636, 1505; 1H NMR (400 MHz,
4.1.6. N-Cyclohexyl 4-(4-methoxybenzyl)-2-(4-fluorophenyl)-5-oxo-
(S)-6-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydro-1H-1,4-di-
azepine-3-carboxamide 6e. Ph3P (157 mg, 0.6 mmol) and 5e
CDCl3)
d
7.61e7.04 (m, 9H, HAr), 5.44 (d, J¼14.8 Hz, 1H, CH2 benzyl),
4.76 (d, J¼8.3 Hz, 1H, NH), 3.99 (d, J¼14.8 Hz, 1H, CH2 benzyl), 3.73
(d, J¼5.0 Hz, 1H, NH), 3.52e3.40 (m, 2H), 3.30 (t, J¼11.1 Hz, 1H),
3.20e3.12 (m, 1H), 2.28 (s, 3H), 1.12 (d J¼6.7 Hz, 3H), 1.64e0.44 (m,
(244 mg, 0.4 mmol) reacted as in previous case to give 6e as a pale
20
yellow solid (193 mg, 85%), mp 76e77 ꢀC (hexane/AcOEt); [
a
]
10H); 13C NMR (100 MHz, CDCl3)
d 174.7 (Cq), 164.3 (Cq), 144.6 (Cq),
D
ꢁ40.1ꢀ (c 0.5, CHCl3); IR (KBr, cmꢁ1) 3399, 1642, 1510; 1H NMR
139.1 (Cq), 136.7 (Cq), 135.3 (Cq), 132.2 (Cq), 129.3 (CHAr), 129.0
(CHAr), 128.7 (CHAr), 128.5 (CHAr), 128.3 (CHAr), 108.8 (Cq), 55.3
(CH2), 49.4 (CH2), 47.9 (CH),37.7(CH), 33.1 (CH2), 32.6 (CH2), 25.6
(CH2), 24.9 (CH2), 24.8 (CH2), 24.9 (CH3), 13.8 (CH3); MS (EI) m/z 431
(Mþ, 86), 326 (100), 277 (52), 105 (70); HRMS (EI) calculated for
C27H33N3O2 431.2573; found 431.2578. Anal. Calcd for C27H33N3O2:
C, 75.14; H, 7.71; N, 9.74. Found: C, 75.05; H, 7.66; N, 9.64.
(400 MHz, CDCl3)
d
7.19e6.79 (m, 8H, HAr), 5.87 (d, J¼5.9 Hz, 1H,
NH), 5.44 (d, J¼14.5 Hz, 1H, CH2 benzyl), 4.89 (d, J¼8.3 Hz, 1H, NH),
4.77 (ddd, J¼10.1 Hz, J¼5.9 Hz, J¼2.6 Hz, 1H), 4.06 (d, J¼14.5 Hz, 1H,
CH2 benzyl), 3.80e3.78 (m, 1H, NH), 3.76 (s, 3H), 3.70e3.65 (m, 1H),
3.58e3.48 (m, 1H), 3.18e3.12 (m, 1H), 1.42 (s, 9H), 1.70e0.61 (m,
10H); 13C NMR (100 MHz, CDCl3)
d 170.8 (Cq), 163.8 (Cq), 163.4 (d,
J¼249.7 Hz, Cq), 159.1 (Cq), 155.1 (Cq), 144.8 (Cq), 134.2 (d, J¼3.3 Hz,
Cq), 130.8 (d, J¼8.3 Hz, CHAr), 129.9 (CHAr), 129.4 (CHAr), 115.8 (d,
J¼21.7 Hz, CHAr), 113.8 (CHAr), 106.5 (Cq), 80.2 (Cq), 55.4 (CH3), 52.8
(CH2), 52.6 (CH), 49.9 (CH2), 48.2 (CH), 33.1 (CH2), 32.9 (CH2), 28.5
(CH3), 25.5 (CH2), 24.9 (CH2), 24.8 (CH2); MS (EI) m/z 566 (Mþ, 11),
567 (Mþþ1, 6), 445 (11), 389 (65), 121 (100); HRMS (EI) calculated
for C31H39FN4O5 566.2904; found 566.2907. Anal. Calcd for
C31H39FN4O5: C, 65.71; H, 6.94; N, 9.89. Found: C, 65.84; H, 7.13; N,
9.77.
4.1.10. N-Cyclohexyl 2-N-(S)-2-azido-3-phenylpropionyl-N-(2-ben-
zoylphenyl)-(R/S)-2-(4-bromophenyl)acetamide 10a. A mixture of
p-bromobenzaldehyde 8a (185 mg, 1 mmol) and 2-aminobenzo-
phenone 9 (197 mg, 1 mmol) was stirred in methanol (10 mL) at
room temperature for 30 min, then cyclohexyl isocyanide
(109 mg, 1 mmol) and (S)-3-phenyl-2-azidopropionic acid,
obtained by triflyl azide diazo transfer from phenylalanine,11c
4
7
(191 mg, 1 mmol) were added consecutively to the imine solution
and the mixture was stirred in methanol at room temperature for 2
days until solid 10a precipitated. Filtration and recrystallization of
the solid from isopropanol-diisopropyl ether afforded N-cyclohexyl
2-N-(S)-2-azido-3-phenylpropionyl-N-(2-benzoylphenyl)-(R/S)-2-
(4-bromophenyl)acetamide 10a as a colorless solid (379 mg, 57%),
mp 169e170 ꢀC [i-PrOH/(i-Pr)2O]; IR (KBr, cmꢁ1) 3270, 2117, 1674;
4.1.7. N-Cyclohexyl
4-n-butyl-2-phenyl-5-oxo-(S)-6-(tert-butoxy-
carbonylamino)-4,5,6,7-tetrahydro-1H-1,4-diazepine-3-carboxamide
6f. Ph3P (157 mg, 0.6 mmol) and 5f (211 mg, 0.4 mmol) reacted as
in previous case to give 6f as a colorless solid (138 mg, 71%), mp
20
64e65 ꢀC (hexane/AcOEt); [
a
]
ꢁ89.3ꢀ (c 0.28, CHCl3); IR (KBr,
D
cmꢁ1) 3480, 3350, 1720, 1643, 1470; 1H NMR (400 MHz, CDCl3)
1H NMR (300 MHz, CDCl3)
d 8.07e6.78 (m, 18H, HAr), 6.06 (s, 0.5H,
d
7.65e7.29 (m, 5H, HAr), 5.83 (d, J¼5.8 Hz, 1H, NH), 4.91 (d,
CHA), 5.98 (d, J¼7.9 Hz, 0.5H, NHA), 5.92 (s, 0.5H, CHB), 5.70 (d,
J¼8.3 Hz, 1H, NH), 4.66 (ddd, J¼10.0 Hz, J¼5.8 Hz, J¼2.6 Hz, 1H),
4.12 (dt, J¼13.7 Hz, J¼7.5 Hz, 1H), 3.82 (dd, J¼7.5 Hz, J¼2.1 Hz, 1H),
3.69 (ddd, J¼10.3 Hz, J¼7.5 Hz, J¼2.6 Hz, 1H), 3.48e3.40 (m, 1H),
3.23e3.17 (m, 1H), 3.00e2.93 (m, 1H), 1.37 (s, 9H), 1.66e0.46 (m,
J¼7.8 Hz, 0.5H, NHB), 3.80e2.88 (m, 4H), 2.03e0.94 (m, 10H); 13C
NMR (75 MHz, CDCl3)
d 194.2, 193.8, 172.1, 170.7, 168.6 and 168.3
(CqA and CqB), 137.9, 137.6, 137.4, 137.1, 136.6, 136.2 and 135.9 (CqA
and CqB), 133.8, 133.7, 133.5, 133.4, 133.0, 132.9, 132.4, 132.1, 132.0,
131.9, 131.8, 131.7, 131.6, 131.0, 130.5, 130.4, 129.5, 129.3, 129.2, 128.7,
128.6, 128.5, 128.4, 129.3, 127.0 and 126.8 (CHAr A and CHAr B), 123.5
and 123.4 (CqA and CqB), 63.5 and 63.4 (CHA and CHB), 62.9 (CH),
49.3, 49.1 (CHA and CHB), 37.9, 36.1, 33.0, 32.9, 32.8, 32.7, 25.7, 25.0,
24.9, 24.8 (CH2A and CH2B); MS (EI) m/z 666 (Mþþ2, 0.3), 664 (Mþ,
0.7), 617 (8), 619 (9), 536 (19), 538 (21), 421 (45), 419 (46), 364 (95),
17H); 13C NMR (100 MHz, CDCl3)
d 170.3 (Cq), 163.8 (Cq), 154.8 (Cq),
144.2 (Cq), 138.2 (Cq), 129.3 (CHAr), 128.6 (CHAr), 128.3 (CHAr), 107.5
(Cq), 79.8 (Cq), 53.1 (CH2), 52.9 (CH), 47.8 (CH), 46.4 (CH2), 32.9
(CH2), 32.2 (CH2), 29.8 (CH2), 28.3 (CH3), 25.3 (CH2), 24.6 (CH2), 24.5
(CH2), 19.8 (CH2), 13.8 (CH3); MS (EI) m/z 484 (Mþ, 86), 284 (55), 149
(100), 83 (61); HRMS (EI) calculated for C27H40N4O4 484.3050;

P. Lecinska et al. / Tetrahedron 66 (2010) 6783e6788
6787
366 (89), 91 (100); HRMS (EI) calculated for C36H34BrN5O3
663.1845; found 663.1851. Anal. Calcd for C36H34BrN5O3: C, 65.06;
H, 5.16; N, 10.54. Found: C, 65.17; H, 5.04; N, 10.38.
4.3), 555 (Mþ, 9), 430 (96), 401 (100), 339 (70), 283 (72); HRMS (EI)
calculated for C37H37N3O2 555.2886; found 555.2874.
Acknowledgements
4.1.11. N-Cyclohexyl
2-((S)-3-benzyl-2-oxo-5-phenyl-2,3-dihydro-
1H-benzo[e][1,4]diazepin-1-yl)-(R/S)-2-(4-bromophenyl)acetamide
11a. Triphenylphosphine (157 mg, 0.6 mmol) was added under
nitrogen to a solution of Ugi adduct 10a (266 mg, 0.4 mmol) in
toluene (10 ml) and the mixture was stirred for 24 h at room
temperature. Then the solvent was evaporated under reduced
pressure and the residue was purified by column chromatography
(hexane/AcOEt mixtures as eluent) to give 11a as a colorless solid
(161 mg, 65%), mp 92e93 ꢀC (hexane/AcOEt); IR (KBr, cmꢁ1) 3429,
We gratefully acknowledge financial support from the Minis-
terio de Ciencia e Innovación, Spain (Project CTQ2009-12631-BQU),
Junta de Castilla y León, Consejería de Educación y Cultura y Fondo
Social Europeo (Projects BU023A09 and GR170).
Supplementary data
Supplementary data associated with this article can be found in
1667; 1H NMR (300 MHz, CDCl3)
d 7.80e6.89 (m, 18H, HAr), 6.65 (d,
the online version, at doi:10.1016/j.tet.2010.06.062. 1H NMR and 13
C
J¼8.4 Hz, 0.5H, NHA), 6.28 (d, J¼8.3 Hz, 0.5H, NHB), 6.07 (s, 0.5H,
NMR of compounds 5h, 6aeh, 10a and 11aec. COSY, NOESY, EXSY,
DEPT, HMBC, and HMQC experiments of selected examples of
6aeh,10a and 11aec. These data include MOL files and InChIKeys of
the most important compounds described in this article.
CHA), 5.49 (s, 0.5H, CHB), 3.86e3.70 (m, 2H), 3.56e3.38 (m, 2H),
1.94e0.74 (m, 10H); 13C NMR (75 MHz, CDCl3)
d 171.8, 170.7, 169.4,
169.0, 168.4 and 168.3 (CqA and CqB), 143.4, 139.7, 139.3, 139.1, 138.7,
138.5 (CqA and CqB), 133.9, 133.7, 132.3, 132.2, 131.9, 131.6, 131.4,
131.3, 130.8, 130.7, 130.2, 130.1, 130.0, 129.7, 129.6, 129.5, 128.8,
128.6, 128.5, 128.4, 128.3, 126.4, 126.3, 125.9, 125.6, 125.4, 123.8,
122.3 and 122.1 (CHAr A and CHAr B), 70.4 (CHB), 65.9 and 65.2 (CHA
and CHB), 63.4 (CHA), 49.1 and 49.0 (CHA and CHB), 38.0, 37.9, 33.0,
32.9, 32.7, 25.6, 24.9 and 24.8 (CH2A and CH2B); MS (EI) m/z 621
(Mþþ2, 2), 619 (Mþ, 1.6), 496 (38), 494 (42), 467 (40), 465 (35), 405
(68), 403 (64), 349 (46), 347 (48), 325 (61), 207 (100), 165 (97), 91
(79), 83 (91); HRMS (EI) calculated for C36H34BrN3O2 619.1834;
found 619.1825. Anal. Calcd for C36H34BrN3O2: C, 69.67; H, 5.52; N,
6.77. Found: C, 69.78; H, 5.64; N, 6.63.
References and notes
1. Sañudo, M.; García-Valverde, M.; Marcaccini, S.; Delgado, J. J.; Rojo, J.; Torroba,
T. J. Org. Chem. 2009, 74, 2189e2192, and references therein.
2. Review: (a) Ramajayam, R.; Giridhar, R.; Yadav, M. R. Mini-Rev. Med. Chem. 2007,
7, 793e812 Several examples in: (b) Kysil, V.; Khvat, A.; Tsirulnikov, S.;
Tkachenko, S.; Ivachtchenko, A. Tetrahedron Lett. 2009, 50, 2854e2856 See for
example: (c) Mondragón, L.; Orzáez, M.; Sanclimens, G.; Moure, A.; Armiñán,
A.; Sepúlveda, P.; Messeguer, A.; Vicent, M. J.; Pérez-Payá, E. J. Med. Chem. 2008,
51, 521e529; (d) Zhang, Y.-M.; Fan, X.; Yang, S.-M.; Scannevin, R. H.; Burke, S. L.;
Rhodes, K. J.; Jackson, P. F. Bioorg. Med. Chem. Lett. 2008, 18, 405e408.
3. See for example: Vasudevan, A.; Villamil, C. I.; Djuric, S. W. Org. Lett. 2004, 6,
3361e3364; Fujioka, H.; Murai, K.; Kubo, O.; Ohba, Y.; Kita, Y. Org. Lett. 2007, 9,
1687e1690.
4.1.12. N-Cyclohexyl
2-((S)-3-benzyl-2-oxo-5-phenyl-2,3-dihydro-
4. Caprazamycins: (a) Hirano, S.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2007, 72,
9936e9946; (b) Hirano, S.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2008, 73,
569e577. Liposidomycins: (c) Drouillat, B.; Bourdreux, Y.; Perdon, D.; Greck, C.
Tetrahedron: Asymmetry 2007, 18, 1955e1963; (d) Monasson, O.; Ginisty, M.;
Bertho, G.; Gravier-Pelletier, C.; Le Merrer, Y. Tetrahedron Lett. 2007, 48,
8149e8152.
5. (a) Iden, H. S.; Lubell, W. D. J. Org. Chem. 2007, 72, 8980e8983; (b) Iden, H. S.;
Lubell, W. D. J. Comb. Chem. 2008, 10, 691e699.
6. Synthesis: (a) Fenster, E.; Smith, B. T.; Gracias, V.; Milligan, G. L.; Aubé, J. J. Org.
1H-benzo[e][1,4]diazepin-1-yl)-(R/S)-2-(4-chlorophenyl)acetamide
11b. Ph3P (157 mg, 0.6 mmol) and 10b (248 mg, 0.4 mmol) reacted
as in previous case to give 11b as a colorless solid (194 mg, 84%), mp
104e105 ꢀC (hexane/AcOEt); IR (KBr, cmꢁ1) 3440, 1669; 1H NMR
(300 MHz, CDCl3)
NHA), 6.39 (d, J¼8.1 Hz, 0.5H, NHB), 6.39 (s, 0.5H, CHA), 6.09 (s, 0.5H,
CHB), 3.86e3.69 (m, 2H), 3.57e3.38 (m, 2H),1.90e0.76 (m,10H); 13
NMR (75 MHz, CDCl3) 171.8, 170.7, 169.3, 168.9, 168.4 and 168.3
d
7.69e6.92 (m, 18H, HAr), 6.63 (d, J¼8.3 Hz, 0.5H,
C
Chem. 2008, 73, 201e205.
g-Turn mimics: (b) Fenster, E.; Rayabarapu, D. K.;
d
Zhang, M.; Mukherjee, S.; Hill, D.; Neuenswander, B.; Schoenen, F.; Hanson, P.
R.; Aubé, J. J. Comb. Chem. 2008, 10, 230e234; (c) Wlodarczyk, N.; Gilleron, P.;
Millet, R.; Houssin, R.; Hénichart, J.-P. Tetrahedron Lett. 2007, 48, 2583e2586.
Linezolid: (d) Song, L.; Chen, X.; Zhang, S.; Zhang, H.; Li, P.; Luo, G.; Liu, W.;
Duan, W.; Wang, W. Org. Lett. 2008, 10, 5489e5492. Peptidomimetics: (e)
Gellerman, G.; Hazan, E.; Kovaliov, M.; Albeck, A.; Shatzmiler, S. Tetrahedron
2009, 65, 1389e1396.
(CqA and CqB), 143.5, 139.8, 139.4, 139.2, 138.7 and 138.6 (CqA and
CqB), 135.1, 133.3, 132.3, 132.2, 132.1, 132.0, 131.1, 130.8, 130.1, 130.0,
129.7, 129.6, 129.0, 128.7, 128.6, 128.4, 128.3 and 128.2 (CHAr A and
CHAr B), 70.4 (CHB), 65.9 and 65.3 (CHA and CHB), 63.5 (CHA), 49.1
and 49.0 (CHA and CHB), 38.1 and 37.9 (CH2A and CH2B), 33.0, 32.9,
32.7, 25.7, 24.9 and 24.8 (CH2A and CH2B); MS (EI) m/z 577 (Mþþ2,
1.6), 576 (Mþþ1, 2.0), 575 (Mþ, 3.7), 450 (79), 421 (66), 359 (100),
304 (34), 303 (57), 207 (45), 165 (40), 91 (18), 83 (16); HRMS (EI)
calculated for C36H34ClN3O2 575.2340; found 575.2330. Anal. Calcd
for C36H34ClN3O2: C, 75.05; H, 5.95; N, 7.29. Found: C, 74.87; H,
5.82; N, 7.34.
7. Peptidomimetics: (a) Lampariello, L. R.; Piras, D.; Rodriquez, M.; Taddei, M.
ꢀ
J. Org. Chem. 2003, 68, 7893e7895; (b) Süli-Vargha, H.; Schlosser, G.; Ilas, J.
J. Pept. Sci. 2007, 13, 742e748 Synthesis: (c) Xu, J.-F.; Huang, X. J. Comb. Chem.
2009, 11, 938e942; (d) Cao, J.; Huang, X. J. Comb. Chem. 2010, 12, 1e4; (e)
Springer, J.; Jansen, T. P.; Ingemann, S.; Hiemstra, H.; van Maarseveen, J. H.
Eur. J. Org. Chem. 2008, 361e367.
8. Banfi, L.; Basso, A.; Guanti, G.; Merlo, S.; Repetto, C.; Riva, R. Tetrahedron 2008,
64, 1114e1134.
9. Huang, R.-M.; Ma, W.; Dong, J.-D.; Zhou, X.-F.; Xu, T.; Lee, K. J.; Yang, X.; Xu, S.-H.;
Liu, Y. Molecules 2010, 15, 871e877.
4.1.13. N-Cyclohexyl
2-((S)-3-benzyl-2-oxo-5-phenyl-2,3-dihydro-
10. (a) Faggi, C.; García-Valverde, M.; Marcaccini, S.; Menchi, G. Org. Lett. 2010, 12,
788e791; (b) Corres, N.; Delgado, J. J.; García-Valverde, M.; Marcaccini, S.;
Rodriguez, T.; Rojo, J.; Torroba, T. Tetrahedron 2008, 64, 2225e2232; (c) García-
Valverde, M.; Macho, S.; Marcaccini, S.; Rodriguez, T.; Rojo, J.; Torroba, T. Synlett
2008, 33e36; (d) Sañudo, M.; Marcaccini, S.; Basurto, S.; Torroba, T. J. Org. Chem.
2006, 71, 4578e4584.
1H-benzo[e][1,4]diazepin-1-yl)-(R/S)-2-(4-methylphenyl)acetamide
11c. Ph3P (157 mg, 0.6 mmol) and 10c (240 mg, 0.4 mmol) reacted
as in previous case to give 11c as a colorless solid (176 mg, 79%), mp
79e80 ꢀC (hexane/AcOEt); IR (KBr, cmꢁ1) 3413, 1681; 1H NMR
11. Triflyl azide diazo-transfer: (a) Beckmann, H. S. G.; Wittmann, V. Org. Lett. 2007,
9, 1e4; (b) Yan, R.-B.; Yang, F.; Wu, Y.; Zhang, L.-H.; Ye, X.-S. Tetrahedron Lett.
2005, 46, 8993e8995; (c) Lundquist, J. T., IV; Pelletier, J. C. Org. Lett. 2001, 3,
781e783.
(300 MHz, CDCl3)
d
7.93e6.91 (m, 18H, HAr), 6.65 (d, J¼7.9 Hz, 0.5H,
NHA), 6.15 (s, 0.5H, CHB), 6.01 (d, J¼7.9 Hz, 0.5H, NHB), 5.60 (s, 0.5H,
CHA), 3.95e3.76 (m, 2H), 3.69e3.47 (m, 2H), 2.25 (s, CH3B), 2.23 (s,
CH3A), 2.01e0.71 (m, 10H); 13C NMR (75 MHz, CDCl3)
d 171.7, 170.6,
12. Extended experimental details about the Ugi reaction, in Marcaccini, S.;
Torroba, T. Nature Prot. 2007, 2, 632e639.
169.5, 169.2, 169.1 and 168.9 (CqA and CqB), 143.7, 140.1, 139.4, 138.8,
138.0 and 137.9 (CqA and CqB), 131.9, 131.7, 130.6, 130.1, 129.7, 129.6,
129.2, 128.5, 128.4, 126.8, 126.3, 125.4 and 124.0 (CHAr A and CHAr B),
70.8 (CH) 65.9 and 65.3 (CHA and CHB), 49.2 and 48.9 (CHA and
CHB), 38.1 and 38.0 (CH2A and CH2B), 32.8, 25.7, 25.1 and 24.9 (CH2A
and CH2B), 21.3 and 21.2 (CH3A and CH3B); MS (EI) m/z 556 (Mþþ1,
€
13. A recent review: (a) Domling, A. Chem. Rev. 2006, 106, 17e89 Recent examples:
(b) Shaabani, A.; Rezayan, A. H.; Keshipour, S.; Sarvary, A.; Ng, S. W. Org. Lett.
2009, 11, 3342e3345; (c) Shaabani, A.; Hajishaabanha, A. M. F.; Mofakham, H.;
Seyyedhamzeh, M.; Mahyari, M.; Ng, S. W. J. Comb. Chem. 2010, 12, 186e190; (d)
Zhou, H.; Zhang, W.; Yan, B. J. Comb. Chem. 2010, 12, 206e214.
14. A recent example: Lu, Y.; Nagashima, T.; Miriyala, B.; Conde, J.; Zhang, W.
J. Comb. Chem. 2010, 12, 125e128.

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15. See for example: (a) He, P.; Wu, J.; Nie, Y.-B.; Ding, M.-W. Eur. J. Org. Chem. 2010,
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17. See for example: Sherrill, R. G.; Berman, J. M.; Birkemo, L.; Croom, D. K.; Dezube, M.;
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M.; Freidinger, R. M.; Whitter, W. L.; Gould, N. P.; Lundell, G. F.; Homnick, C. F.;
Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.;
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1229e1239; (b) Plunkett, M. J.; Ellman, J. A. J. Am. Chem. Soc. 1995, 117,
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16. (a) Ettari, R.; Micale, N.; Schirmeister, T.; Gelhaus, C.; Leippe, M.; Nizi, E.;
Di Francesco, M. E.; Grasso, S.; Zappala, M. J. Med. Chem. 2009, 52,
2157e2160; (b) Ettari, R.; Nizi, E.; Di Francesco, M. E.; Micale, N.; Grasso,
ꢀ
S.; Zappal, M.; Vicík, R.; Schirmeister, T. ChemMedChem 2008, 3,
1030e1033; (c) Ettari, R.; Nizi, E.; Di Francesco, M. E.; Dude, M.-A.; Pradel,
ꢀ
G.; Vicík, R.; Schirmeister, T.; Micale, N.; Grasso, S.; Zappalà, M. J. Med.
Chem. 2008, 51, 988e996; (d) Micale, N.; Kozikowski, A. P.; Ettari, R.;
Grasso, S.; Zappala, M.; Jeong, J.-J.; Kumar, A.; Hanspal, M.; Chishti, A. H. J.
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