Multicomponent synthesis of dihydrobenzoxazepinones by coupling Ugi and Mitsunobu reactions

Article abstract of DOI:10.1039/b613056a

Various dihydrobenzo[f][1,4]oxazepin-5-ones have been convergently prepared in 2-3 steps by coupling Ugi and Mitsunobu reactions. Two alternative methodologies were used: in the first one the Ugi condensation was followed by a Mitsunobu cyclization (2 ste

Full text of DOI:10.1039/b613056a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Multicomponent synthesis of dihydrobenzoxazepinones by coupling Ugi and
Mitsunobu reactions
Luca Banfi,* Andrea Basso Giuseppe Guanti, Paulina Lecinska and Renata Riva
Received 8th September 2006, Accepted 26th September 2006
First published as an Advance Article on the web 17th October 2006
DOI: 10.1039/b613056a
Various dihydrobenzo[f ][1,4]oxazepin-5-ones have been convergently prepared in 2–3 steps by coupling
Ugi and Mitsunobu reactions. Two alternative methodologies were used: in the first one the Ugi
condensation was followed by a Mitsunobu cyclization (2 steps); in the second one an intermolecular
Mitsunobu reaction was followed by a deprotection step and then by an intramolecular Ugi reaction.
Also a “convertible” isocyanide was used.
Introduction
Multicomponent reactions1 are a powerful tool for the generation
of collections of molecules; they are extremely convergent and
produce a remarkably high increase of molecular complexity injust
one step. When the components may be varied at will, they can also
be defined as “multi diversity generation reactions,” introducing
three or more points of diversity in a single step. Among MCRs,
those based on the peculiar reactivity of isocyanides, such as the
Ugi2 and the Passerini3 reactions, have been among the most
widely used, also in an industrial context.4 While the classical
versions of these reactions lead to acyclic adducts, interesting drug-
like heterocyclic structures may be accessed by intramolecular
variants or by coupling the MCR with a subsequent secondary
transformation, taking advantage of additional functionalities
suitably placed on one or two of the components.5 In the last years
our group has reported new convergent syntheses of heterocycles
through this type of approach.6–10
As a continuation of this project, we now report two alternative,
quite short (2 or 3 steps), routes to synthesize various dihy-
drobenzo[f ][1,4]oxazepin-5-ones 5, decorated with three points
of diversity. Despite their similarity with the very common benzo-
1,4-diazepin-5-one scaffolds, these fused heterocycles have been so
far explored only rarely,11 probably because of the lack of a general
Scheme 1
method for the convergent preparation of highly substituted
derivatives.
and ethanolamine in Et2O in the presence of molecular sieves.
The general strategy exploited by us involves coupling of the
In the case of aliphatic aldehydes, the imine was actually in
well known Ugi reaction with a Mitsunobu substitution.12 Two
equilibrium with the isomeric oxazolidine. For instance, using iso-
butyraldehyde, the ratio oxazolidine–imine was 83 : 17 (NMR).
The Ugi condensation of this imine with salicylic acid, and
cyclohexyl isocyanide proceeded smoothly to afford in good yields
alternative routes may be devised: in the first one (A) the Ugi MCR
is carried out first, followed by an intramolecular Mitsunobu,
whereas in the second one (B) an intermolecular Mitsunobu is
followed by an intramolecular Ugi (Scheme 1).
the desired adduct 4a, without the need to protect the additional
functionalities (an alcoholic and a phenolic moiety). Actually, by
using O-protected ethanolamine or salicylic acid (or both) the
yield of the Ugi reaction turned out to be even lower. It should
be noted that in this multicomponent condensation, 6 different
functional groups are present simultaneously in the same pot!
The following intramolecular Mitsunobu turned out to be clean
(no significant by-product formed), but a substantial recovery
of starting material 4, even after prolonged reaction times, was
observed. We believe that the reaction is indeed fast and that the
recovered starting material derives from decomposition, during
Results and discussion
As first model for route A, we chose compound 5a (see Table 1).
In this and in the other reactions described below we always
preformed the imine by mixing equimolar quantities of aldehyde
Department of Chemistry and Industrial Chemistry, via Dode-
caneso 31, 16146, Genova, Italy. E-mail: banfi@chimica.unige.it;
Fax: +390103536118; Tel: +390103536119
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Table 1 Synthesis of dihydrobenzo-1,4-oxazepin-5-ones 5 via coupling of Ugi and Mitsunobu reactionsa
Route A
Route B
Benzoxazepinone
R1
R2
R3
Yield of 4
Yield of 5
Yield of 8
Yield of 5
5a
5b
5c
5d
5e
H
H
H
H
H
iPr
iBu
iPr
3-MeOC6H4
iPr
cyHex
cyHex
nBu
81%
51%
74%
67%
53%
65%
57%
34%
84%
44%
69%
61%
cyHex
69%
69%
45%
81%
5f
H
3-MeOC6H4
Ph
4-Pyridyl
3-MeOC6H4
3-MeOC6H4
Ph
−CH2CO2tBu
66%
63%
64%
55%
55%
79%
88%
63%
86%
45%
—
5g
5h
5i
3-Cl
3-Cl
3-MeO
3-NO2
H
cyHex
cyHex
cyHex
5l
5m
tBuCH2C(CH3)2–
< 10%
69%
77%
a Yields are of isolated products after chromatography and do not take into account the recovered starting materials.
the work-up, of an hydrolytically unstable side-product. Hypothe-
ses on the mechanism of this and other related intramolecular
Mitsunobu reactions will be reported in future papers. After a
thorough optimization (changing solvent, phosphine, azodicar-
boxylate and using various additives), we found that best results
could be achieved using DEAD (diethyl azodicarboxylate) in
the presence of Et3N. Although some starting material was still
present, the isolated yield was a satisfactory 65%. Triphenylphos-
phine and tributylphosphine gave comparable results.
CF3CH2OH as the solvent (0.2 M solution of substrate) without
the need to use high dilution conditions.
Among the isocyanides employed, there are also two “convert-
ible” isocyanides (see compounds 5e and 5m).16,17 Their use allows
in principle the production of dihydrobenzo[f ][1,4]oxazepin-5-
ones bearing an acid or ester moiety. This possibility was
demonstrated, in the case of 5e, by its high yield conversion into
methyl ester 9 (Scheme 2).16
The scope of the methodology was then explored, on varying
the aldehyde, the isocyanide, and the salicylic acid (Table 1). This
2-step protocol was found to be successful in nearly all cases
tested (5m being an exception), using salicylic acids with electron-
withdrawing or electron-donating substituents, aliphatic, aromatic
or heteroaromatic aldehydes, together with either unbulky, bulky
or even functionalized isocyanides. Although the yields were in
some cases only moderate, purification by chromatography of the
product was quite easy, since the starting material, triphenylphos-
phine oxide, and diethyl hydrazinodicarboxylate are all more polar
and well separated.
Scheme 2
Conclusion
We also tested route B, that proved to be successful too
(Scheme 1) (DBAD = di-tert-butyl azodicarboxylate). It requires
3 steps instead of 2, since two of the functions that participate
in the intramolecular Ugi reaction, temporarily blocked during
the previous Mitsunobu substitution, have to be deprotected.
Anyway this strategy turned out to afford, in some cases, better
overall yields. Moreover the introduction of two diversity inputs
only in the last step may be an advantage from the point of
view of combinatorial synthesis. Although the intramolecular
Ugi reaction of amino acids are well known,13–15 this is, to our
knowledge, the first example of such a reaction forming a seven-
membered ring. One should take into account that, according
to the accepted mechanism of the Ugi reaction,1 the final seven-
membered ring should derive from contraction of a ten-membered
intermediate, that was expected to be not easily formed, both for
entropic and enthalpic reasons. The best results were achieved with
In conclusion the presented methodology represents a new,
useful and very convergent entry into a variety of dihy-
drobenzo[f ][1,4]oxazepin-5-ones 5, decorated with 3 points of
diversity. They may be obtained in just 2 or 3 simple steps starting
from commercially available substrates, with a remarkably high
increase of structural complexity. Since the obtained scaffolds are
endowed with drug-like features, we think that libraries based on
them will prove useful in the drug discovery process.
Experimental
NMR spectra were usually taken in CDCl3 at 300 MHz (1H), and
75 MHz (13C), using TMS as internal standard for 1H NMR and
the central peak of CDCl3 (at 77.02 ppm) for 13C NMR. When
specified, they were taken in d6-DMSO. In that case the central
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◦
1
peak of DMSO (at 2.506 for H and at 39.429 ppm for 13C) was
5.58 mmol). After 2.5 h at 0 C, the solvent was evaporated and
the oily residue chromatographed through 220–400 mesh silica gel
(PE–AcOEt 7 : 3) to give the pure diprotected coupled product
(1.12 g, 84%). It was taken up in MeOH (10 mL) and water
(0.40 ml) and hydrogenated over 10% Pd–C (50 mg) at r.t. and
normal pressure. After filtration and evaporation, the amino acid
8 was obtained as a solid (410 mg, 82%) and used as such for the
subsequent intramolecular Ugi reaction.
taken as a reference. Chemical shifts are reported in ppm (d scale),
coupling constants are reported in hertz. Peak assignments were
made with the aid of DEPT, gCOSY and gHSQC experiments.
IR spectra were measured with a Perkin-Elmer 881 instrument
as CHCl3 solutions.
GC-MS were carried out on a HP-5971A instrument, using an
HP-1 column (12 m long, 0.2 mm wide), electron impact at 70 eV,
and a mass temperature of about 170 ◦C. Only m/z > 33 were
detected. All analyses were performed with a constant He flow
of 0.9 ml min−◦1 with an initial temperature of◦100 ◦C, initial time
2 min, rate 20 C min−1, final temperature 260 C, final time 4 min,
injection temperature 250 ◦C, detector temperature 280 ◦C. Rt are
in min. Melting points were measured on a Bu¨chi 535 apparatus
and are uncorrected. TLC analyses were carried out on silica gel
plates and developed at UV. Rf were measured after an elution of
7–9 cm. Chromatography was carried out on 220–400 mesh silica
gel using the “flash” methodology. Petroleum ether (40–60 ◦C) is
abbreviated as PE.
Typical procedure for the intramolecular Ugi reaction to give 5:
compound 5a
Amino acid 8 (149.1 mg, 0.823 mmol) was taken up in CF3CH2OH
(5.4 mL), treated with powdered 3 A mol. sieves, and treated with
isobutyraldehyde (88 lL, 0.964 mmol) and cyclohexyl isocyanide
(132 lL, 1.06 mmol). After stirring at r.t. for 48 h, the mixture
was evaporated to dryness and chromatographed to give pure 5a
(172 mg, 61%).
˚
Analytical data for dihydrobenzo[f ][1,4]oxazepin-5-ones 5
Compound 5a. 1H NMR (CDCl3): d 0.93 [3 H, d, CH3, J 6.6];
1.01 [3 H, d, CH3, J 6.6];1.04–1.42 [5 H, m, cyclohexyl]; 1.50–
1.96 [5 H, m, cyclohexyl]; 2.31 [1 H, d of septuplet, CH(CH3)2, Jd
11.1, Js 6.6]; 3.67 [2 H, t, CH2N, J 5.1]; 3.74 [mc, 1 H, m, CHN
cyclohexyl]; 4.22–4.39 [2 H, m, CH2O]; 4.67 [1 H, d, iPrCHN, J
11.1]; 6.09 [1 H, broad s, NH]; 7.01 [1 H, dd, H ortho to O, J 0.9,
8.1]; 7.16 [1 H, dt, H para to O, Jd 1.2, Jt 7.5]; 7.43 [mc, 1 H, m,
Typical procedure for the synthesis of Ugi products 4: compound 4a
Imine preparation. A solution of isobutyraldehyde (5 mL,
54.8 mmol) in dry diethyl ether (50 mL) was treated, at r.t., with
˚
ethanolamine (3.30 mL, 54.8 mmol) and powdered 4 A molecular
sieves (10 g). After 1 h the mixture was filtered and the filtrate
distilled at 250–300 mbar first and then at 34 mbar to give the
pure imine as a colorless liquid (3.892 g, 62%) (b.p. 60–64 ◦C at 34
mbar).
H para to C O]; 7.78 [1 H, dd, H ortho to C O, J 1.8, 8.1]. 13C
NMR (CDCl3): d 19.76, 19.47 [CH3]; 24.68, 24.76, 25.43, 32.61,
32.86 [cyclohexyl CH2]; 26.89 [CH(CH3)2]; 42.16 [CH2N]; 48.22
[CHN cyclohexyl]; 63.30 [broad, CHN]; 73.78 [CH2O]; 121.40
=
=
Ugi reaction. A solution of the imine (533 mg, 4.63 mmol) in
˚
dry MeOH (5 mL) was treated with 3 A powdered mol. sieves
=
[CH ortho to O]; 123.49 [CH para to O]; 127.04 [C–C O]; 130.97
(300 mg), salicylic acid (533 mg, 3.86 mmol), and cyclohexyl
isocyanide (400 lL, 3.22 mmol). After stirring for 48 h at r.t., the
solution was evaporated to dryness and chromatographed through
220–400 mesh silica gel (PE–acetone 7 : 3) to give pure 4a as a foam
(941 mg, 81%).
=
=
[CH ortho to C O]; 133.05 [CH para to C O]; 153.81 [C–O];
=
168.97, 169.85 [C O]. Rf 0.64 (PE–acetone 7 : 3). Found: C, 69.9;
H, 8.2; N, 8.0%. C20H28N2O3 requires: C, 69.74; H, 8.19; N, 8.13%;
IR: mmax 3006, 1666, 1628, 1458, 1042 cm−1.
Ugi adducts were checked with 1H and 13C NMR. However, due
to the presence of slowly converting conformers, the spectra were
rather complex. Only at 120 ◦C a nearly complete coalescence
was observed, but some peaks still remained rather broad. Full
characterization was therefore better performed at the stage of
dihydrobenzo[f ][1,4]oxazepin-5-ones 5.
Compound 5b. 1H NMR (d6-DMSO): d 0.91 [3 H, d, CH3,
J 6.3]; 0.93 [3 H, d, CH3, J 6.3]; 1.04–1.45 [5 H, m, cyclohexyl];
1.50–1.80 [8 H, m, cyclohexyl and CH2CH(CH3)2]; 3.47–3.70 [3
H, m, CH2N and CHN cyclohexyl]; 4.19–4.36 [2 H, m, CH2O];
5.21 [1 H, d, iBuCHN, J 7.6]; 7.03 [1 H, d, H ortho to O, J 8.1];
=
7.18 [1 H, t, H para to O, J 7.2]; 7.47 [mc, 1 H, m, H para to C O];
=
7.66 [1 H, dd, H ortho to C O, J 1.5, 8.0]; 8.03 [1 H, d, NH, J
Typical procedure for the intramolecular Mitsunobu: compound 5a
7.8].
1H NMR (CDCl3): d 0.96 [3 H, d, CH3, J 6.6]; 0.98 [3 H, d,
CH3, J 6.6]; 1.04–1.42 [5 H, m, cyclohexyl]; 1.50–1.95 [8 H, m,
cyclohexyl and CH2CH(CH3)2]; 3.48–3.64 [2 H, m, CH2N]; 3.73
[mc, 1 H, m, CHN cyclohexyl]; 4.19–4.37 [m, 2 H, CH2O]; 5.22 [1
H, t, iBuCHN, J 7.4]; 6.16 [1 H, d, NH, J 7.8]; 7.02 [1 H, dd, H
ortho to O, J 1.2, 8.1]; 7.18 [1 H, dt, H para to O, Jd 1.2, Jt 7.5];
A solution of 4a (150 mg, 0.414 mmol) in dry CH2Cl2 (5 mL)
was cooled to 0 ◦C, and treated with PPh3 (177 mg, 0.675 mmol),
Et3N (115 lL, 0.83 mmol), and diethyl azodicarboxylate (DEAD)
(98 lL, 0.62 mmol). After 1 h at 0 ◦C the solvent was evaporated
and the crude product immediately chromatographed through
220–400 mesh silica gel (PE–acetone 8 : 2 to give the pure product
5a (93 mg, 65%).
=
=
7.44 [mc, 1 H, m, H para to C O]; 7.79 [1 H, dd, H ortho to C O,
J 1.8, 7.8]. 13C NMR (d6-DMSO): d 21.93, 22.81 [CH3]; 24.49
[CH(CH3)2]; 24.57, 24.59, 25.11, 32.08, 32.14 [cyclohexyl CH2];
26.89 [C(CH3)2]; 38.40 and 41.68 [CH2N and CH2CH(CH3)2];
47.61 [CHN cyclohexyl]; 53.93 [CHN]; 73.96 [CH2O]; 121.21 [CH
Synthesis of compound 8
A solution of benzyl salicylate (749 mg, 3.28 mmol) and N-Cbz-
ethanolamine (640 mg, 3.28 mmol) in dry CH2Cl2 (5 mL) was
cooled to 0 ◦C and treated with Et3N (914 lL, 6.56 mmol), PPh3
(1.46 g, 5.58 mmol) and di-tert-butyl azodicarboxylate (1.33 g,
=
ortho to O]; 123.19 [CH para to O]; 127.45 [C–C O]; 130.77 [CH
=
=
ortho to C O]; 132.77 [CH para to C O]; 153.33 [C–O]; 168.06,
=
169.37 [C O]. Rf 0.38 (PE–AcOEt 7 : 3). Found: C, 70.5; H, 8.5;
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N, 7.7%. C21H30N2O3 requires: C, 70.36; H, 8.44; N, 7.81%; IR:
m, CH2N]; 4.24–4.39 [2 H, m, CH2O of the ring]; 4.67 [1 H, d,
CHHOSi, J 12.9]; 4.80 [1 H, d, CHHOSi, J 12.6]; 4.92 [1 H, d,
CHN, J 11.1]; 7.01 [1 H, dd, H-3, J 0.6, 7.8]; 7.09 [1 H, dt, H-4ꢀ, Jd
0.9, Jt 7.5]; 7.18 [1 H, dt, H-5, Jd 1.2, Jt 7.2]; 7.20 [1 H, dd, H-3ꢀ,
J 1.8, 7.5]; 7.31 [1 H, dt, H-5ꢀ, Jd 1.8, Jt 7.6]; 7.43 [1 H, dt, H-4, Jd
1.8, Jt 7.7]; 7.80 [1 H, dd, H-6, J 1.5, 7.8]; 8.07 [1 H, d, H-6ꢀ, J 6.5];
9.07 [1 H, s, NH]. 13C NMR (CDCl3): d 5.36 and 5.26 [(CH3)2Si];
18.31 [C(CH3)3]; 18.93 and 19.57 [(CH3)2CH]; 25.90 [C(CH3)3];
27.48 [C(CH3)2]; 42.03 [CH2N]; 63.93 [CHN]; 64.46 [CH2OSi];
73.84 [CH2O of the ring]; 121.44 [C-3]; 122.12 [C-6ꢀ]; 123.64 [C-
5]; 124.43 [C-4ꢀ]; 127.42 [C-1]; 127.91 [C-3ꢀ]; 128.32 [C-5ꢀ]; 130.45
[C-1ꢀ or C-2ꢀ]; 131.08 [C-6]; 132.99 [C-4]; 136.58 [C-1ꢀ or C-2ꢀ];
mmax 3002, 1665, 1627, 1458, 1192, 1037 cm−1.
Compound 5c. 1H NMR (CDCl3): d 0.88 [3 H, t, CH3CH2, J
7.2]; 0.95 [3 H, d, CH3, J 6.9]; 1.00 [3 H, d, CH3, J 6.3]; 1.24–1.38
[2 H, m, CH2]; 1.40–1.52 [2 H, m, CH2]; 2.31 [1 H, d of septuplet,
CH(CH3)2, Jd 11.1, Js 6.6]; 3.13–3.33 [2 H, m, CH2NH]; 3.61–3.77
[2 H, m, CH2N]; 4.27 [1 H, ddd, CHHO, J 4.8, 6.3, 11.1]; 4.35 [1 H,
ddd, CHHO, J 4.5, 5.1, 11.1]; 4.73 [1 H, d, iPrCHN, J 10.8]; 6.48 [1
H, broad s, NH]; 7.02 [1 H, dd, H ortho to O, J 1.1, 8.2]; 7.16 [1 H,
=
dt, H para to O, Jd 1.1, Jt 7.6]; 7.43 [mc, 1 H, m, H para to C O];
7.77 [1 H, dd, H ortho to C O, J 1.7, 7.6]. 13C NMR (CDCl3):
=
d 13.66 [CH3CH2]; 18.81, 19.44 [(CH3)2CH]; 19.95 [CH2]; 27.00
[CH(CH3)2]; 31.36 [CH2]; 39.07 [CH2NH]; 42.18 [CH2N]; 63.19
[broad, CHN]; 73.83 [CH2O]; 121.46 [CH ortho to O]; 123.51
=
153.78 [C-2]; 168.55 and 169.61 [C O]. Rf 0.34 (PE–acetone 86 :
14). Found: C, 67.35; H, 7.9; N, 5.7%. C27H38N2O4Si requires: C,
67.18; H, 7.94; N, 5.80%.
=
=
[CH para to O]; 127.11 [C–C O]; 130.93 [CH ortho to C O];
=
=
133.07 [CH para to C O]; 153.83 [C–O]; 169.87, 169.90 [C O].
Rf 0.52 (PE–acetone 75 : 25). Found: C, 68.05; H, 8.4; N, 8.75%.
C18H26N2O3 requires: C, 67.90; H, 8.23; N, 8.80; O, 15.07%; GC-
MS: Rt 9.66; m/z 318 (M+, 10.1); 276 (3.6); 246 (5.2); 245 (13.8);
219 (36.1); 218 (100.0); 203 (5.6); 176 (10.0); 163 (7.1); 156 (5.5);
146 (24.5); 142 (6.2); 121 (20.5); 120 (9.4); 98 (28.8); 92 (9.7); 82
(6.7); 65 (7.9); 57 (13.0); 56 (10.5); 55 (30.3); 54 (7.6); 44 (7.2); 43
(7.5); 42 (14.3); 41 (22.4).
Compound 5f. 1H NMR (CDCl3): d 1.46 [9 H, s, C(CH3)3];
3.50 [1 H, ddd, CHHN of the ring, J 3.8, 5.1, 16.0]; 3.64 [1 H, ddd,
CHHN of the ring, J 3.5, 8.0, 16.0]; 3.80 [3 H, s, OCH3]; 3.78–3.94
[2 H, m, tBuO2CCHHN + CHHO]; 4.08 [1 H, dd, tBuO2CCHHN,
J 5.7, 18.0]; 4.24 [1 H, ddd, CHHO, J 3.5, 5.1, 11.1]; 6.85–6.94
[2 H, m, NH and H-4ꢀ]; 6.97 [1 H, dd, H-3, J 0.8, 8.1]; 7.01–7.07
[2 H, m, H-2ꢀ, H-6ꢀ]; 7.14 [1 H, dt, H-5, Jd 0.9, Jt 7.5]; 7.29 [1 H,
t, H-5ꢀ, J 8.2]; 7.41 [mc, 1 H, m, H-4]; 7.82 [1 H, dd, H-6, J 1.8,
7.8]. 13C NMR (CDCl3): d 27.97 [C(CH3)3]; 42.11 [CH2CO2tBu];
43.72 [CH2N]; 55.27 [OCH3]; 60.44 [Ar-CHN]; 73.95 [CH2O];
82.15 [C(CH3)3]; 114.41 [C-2ꢀ and C-4ꢀ]; 121.28 [C-6ꢀ]; 121.39 [C-
3]; 123.36 [C-5]; 126.62 [C-1]; 129.91 [C-5ꢀ]; 131.37 [C-6]; 133.07
[C-4]; 136.39 [C-1ꢀ]; 154.12 [C-2]; 159.89 [C-3ꢀ]; 168.41, 169.47,
Compound 5d. 1H NMR (CDCl3): d 1.05–1.45 [4 H, m,
cyclohexyl]; 1.54–1.75 [2 H, m, cyclohexyl]; 1.89–2.03 [2 H, m,
cyclohexyl]; 3.52 [1 H, ddd, CHHN, J 3.6, 5.1, 15.9]; 3.63 [1 H,
ddd, CHHN, J 3.3, 7.8, 15.9]; 3.79 [3 H, s, OCH3]; 3.76–3.92 [2
H, m, CHN cyclohexyl and CHHO]; 4.26 [1 H, ddd, CHHO, J
3.9, 5.4, 11.1]; 6.06 [1 H, broad s, NH]; 6.44 [1 H, s, CHN]; 6.89
[1 H, dd, H ortho to OMe and meta to C, J 2.1, 8.1]; 6.95–7.04
=
169.54 [C O]. Rf 0.51 (CH2Cl2–AcOEt 8 : 2). Found: C, 65.65; H,
6.55; N, 6.3%. C24H28N2O6 requires: C, 65.44; H, 6.41; N, 6.36%.
=
[3 H, m, H ortho to O and meta to C O + H ortho to OMe and
C + H para to OMe]; 7.15 [1 H, dt, H para to O and meta to
Compound 5g. 1H NMR (CDCl3): d 1.05–1.45 [5 H, m,
cyclohexyl]; 1.54–1.78 [3 H, m, cyclohexyl]; 1.89–2.02 [2 H, m,
cyclohexyl]; 3.48 [1 H, ddd, CHHN, J 3.3, 5.4, 15.9]; 3.63 [1 H,
ddd, CHHN, J 3.3, 7.5, 15.9]; 3.78–3.92 [2 H, m, CHN cyclohexyl
+ CHHO]; 4.27 [1 H, ddd, CHHO, J 3.3, 5.4, 11.1]; 5.98 [1
H, d, NH, J 8.1]; 6.44 [1 H, s, ArCHN]; 6.92 [1 H, d, H-3, J
8.7]; 7.30–7.42 [5 H, m, CH phenyl + H-4]; 7.82 [1 H, d, H-6, J
2.7]. 13C NMR (CDCl3): d 24.77, 24.82, 25.41, 32.78, 32.89 [CH2
cyclohexyl]; 43.65 [CH2N]; 48.75 [CHN cyclohexyl]; 60.44 [Ar–
CHN]; 74.07 [CH2O]; 122.95 [C-3]; 127.69 [C-1]; 128.52, 128.70
=
C O, Jd 1.2, Jt 7.5]; 7.30 [1 H, t, H meta to OMe, J 7.8]; 7.42
=
=
[mc, 1 H, m, H para to C O]; 7.83 [1 H, dd, H ortho to C O,
J 1.5, 7.8]. 13C NMR (CDCl3): d 24.75, 24.81, 25.41, 32.72, 32.85
[CH2 cyclohexyl]; 43.71 [CH2N]; 48.65 [CHN cyclohexyl]; 55.30
[OCH3]; 60.25 [Ar–CHN]; 74.07 [CH2O]; 114.10 [C ortho to OMe
and para to C]; 114.43 [CH ortho to OMe and to C]; 121.16 and
121.40 [CH para to OMe and CH ortho to O]; 123.38 [CH para
=
to O]; 126.76 [C–C O]; 129.95 [CH meta to OMe]; 131.36 [CH
=
=
ortho to C O]; 133.06 [CH para to C O]; 136.96 [C–C quat.];
[C-4ꢀ and C-3]; 128.94, 129.06 [C-2ꢀ and C-3ꢀ]; 131.09 [C-6]; 132.95
=
154.09 [C–O]; 159.89 [C–OMe]; 168.26, 169.53 [C O]. Rf 0.70
ꢀ
=
[C-4]; 135.23 [C-1 ]; 152.71 [C-2]; 168.15, 168.18 [C O]. The signal
(PE–acetone 7 : 3). Found: C, 70.5; H, 7.0; N, 6.75%. C24H28N2O4
requires: C, 70.57; H, 6.91; N, 6.86%.
of C-5 is probably covered by the signals of C-2ꢀ and C-3ꢀ. Rf 0.61
(PE–acetone 8 : 2). Found: 66.8; H, 6.15; N, 6.7%. C23H25ClN2O3
requires: C, 66.90; H, 6.10; N, 6.78%.
Compound 5e.
Compound 5h. 1H NMR (CDCl3): d 1.05–1.45 [5 H, m,
cyclohexyl]; 1.54–1.76 [3 H, m, cyclohexyl]; 1.85–2.02 [2 H, m,
cyclohexyl]; 3.55 [1 H, ddd, CHHN, J 3.3, 6.9, 15.6]; 3.70 [1 H,
ddd, CHHN, J 3.3, 6.3, 15.6]; 3.83 [mc, 1 H, m, CHN cyclohexyl];
4.01 [1 H, ddd, CHHO, J 3.3, 6.3, 11.1]; 4.36 [1 H, ddd, CHHO,
J 3.3, 6.9, 11.1]; 6.58 [1 H, s, ArCHN]; 6.96 [1 H, d, H-3, J 8.4];
7.23–7.28 [3 H, m, NH + H-2ꢀ]; 7.38 [1 H, dd, H-4, J 2.7, 8.4];
7.76 [1 H, d, H-6, J 2.7]; 8.59 [2 H, d, H-3ꢀ, J 7.0]. 13C NMR
(CDCl3): d 24.75 (×2), 25.26, 32.53, 32.78 [CH2 cyclohexyl]; 43.82
[CH2N]; 48.75 [CHN cyclohexyl]; 58.86 [Ar–CHN]; 73.97 [CH2O];
123.07 [C-2ꢀ]; 123.15 [C-3]; 127.23 [C-1]; 128.63 [C-5]; 130.85
1H NMR (CDCl3): d 0.08 and 0.14 [2 × 3 H, 2 s, CH3Si]; 0.93 [9
H, s, C(CH3)3]; 1.01 [3 H, d, CH3CH, J 6.6]; 1.11 [3 H, d, CH3CH,
J 6.3]; 2.39 [1 H, d of septuplet, Jd 11.1, Js 6.6]; 3.66–3.82 [2 H,
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[C-6]; 133.28 [C-4]; 144.72 [C-1ꢀ]; 150.27 [C-2ꢀ]; 152.69 [C-2];
[C-1]; 128.22 [C-4ꢀ]; 128.68, 128.78 [C-2ꢀ, C-3ꢀ]; 131.21 [C-6];
ꢀ
=
=
166.80, 168.60 [C O]. Rf 0.20 (PE–acetone 8 : 2). Found: C, 63.4;
132.81 [C-4]; 135.43 [C-1 ]; 153.86, 155.42 [C O carbonate, C-
=
H, 5.8; N, 9.9%. C22H24ClN3O3 requires: C, 63.84; H, 5.84; N,
10.15%.
2]; 169.20, 169.26 [C O]. Rf 0.29 (PE–acetone 8 : 2). Found: C,
64.85; H, 6.25; N, 6.5%. C23H26N2O6 requires: C, 64.78; H, 6.15;
N, 6.57%.
Compound 5i. 1H NMR (CDCl3): d 1.00–1.42 [5 H, m,
cyclohexyl]; 1.50–1.75 [3 H, m, cyclohexyl]; 1.86–1.98 [2 H, m,
cyclohexyl]; 3.48–3.64 [2 H, m, CH2–N]; 3.66–3.90 [2 H, m, CHHO
and CHN cyclohexyl]; 3.77 [6 H, s, OCH3]; 4.15 [1 H, dt, CHHO,
Jd 10.5, Jt 5.3]; 6.51 [1 H, s, ArCHN]; 6.67 [1 H, d, NH, J 7.8];
6.84–7.06 [5 H, m, H-2ꢀ, H-4ꢀ, H-3, H-4, H-6ꢀ]; 7.23 [1 H, d, H-
6, J 3.0]; 7.27 [1 H, t, H-5ꢀ, J 8.0]. 13C NMR (CDCl3): d 24.66,
24.71, 25.27, 32.50, 32.65 [CH2 cyclohexyl]; 43.46 [CH2N]; 48.45
[CHN cyclohexyl]; 55.12, 55.57 [OCH3]; 60.02 [Ar–CHN]; 74.16
[CH2O]; 113.84, 113.84, 114.32, 119.75, 121.04, 122.43 [C-2ꢀ, C-
Compound 9. A solution of compound 5e (134.2 mg,
0.278 mmol) in dry MeOH (6 mL) was treated with 36%
aqueous HCl (600 lL) and stirred at room temperature for 45 h.
The solution was poured into saturated aqueous NaHCO3 and
extracted with AcOEt. Evaporation and chromatography (PE–
AcOEt 75 : 25) gave pure 9 as an oil (54.8 mg, 71%).
1H NMR (CDCl3): d 0.99 [3 H, d, CH3CH, J 6.6]; 1.04 [3 H, d,
CH3CH, J 6.6]; 2.21 [1 H, d of septuplet, Jd 10.8, Js 6.6]; 3.58–3.71
[2 H, m, CH2N]; 3.75 [3 H, s, OCH3]; 4.27–4.40 [2 H, m, CH2O];
5.17 [1 H, d, CHN, J 10.5]; 7.01 [1 H, dd, H-3, J 0.9, 8.1]; 7.16
[1 H, dt, H-5, Jd 1.2, Jt 7.5]; 7.43 [1 H, dt, H-4, Jd 1.8, Jt 7.7];
7.81 [1 H, dd, H-6, J 1.8, 78.1]. 13C NMR (CDCl3): d 19.10 and
19.41 [(CH3)2CH]; 28.81 [C(CH3)2]; 42.41 [CH2N]; 52.00 [CH3O];
61.41 [CHN]; 73.62 [CH2O]; 121.35 [C-3]; 123.67 [C-5]; 127.20
[C-1]; 131.28 [C-6]; 133.05 [C-4]; 153.70 [C-2]; 169.53 and 171.99
4ꢀ, C-3, C-4, C-6ꢀ, C-6]; 128.09 [C-1]; 129.75 [C-5ꢀ]; 137.14 [C-1ꢀ];
ꢀ
=
147.59, 155.54, 159.73 [C-5, C-2, C-3 ]; 168.26, 169.49 [C O].
Rf 0.44 (PE–acetone 75 : 25). Found: C, 68.0; H, 7.0; N, 6.2%.
C25H30N2O5 requires: C, 68.47; H, 6.90; N, 6.39%.
Compound 5l. 1H NMR (CDCl3): d 0.98 [9 H, s, C(CH3)3];
1.44 and 1.49 [2 × 3 H, 2 s, C(CH3)2]; 1.57 [1 H, d, CHHtBu, J
14.7]; 1.94 [1 H, d, CHHtBu, J 14.7]; 3.53 [1 H, ddd, CHHN, J
1.8, 6.0, 16.2]; 3.75 [1 H, ddd, CHHN, J 1.8, 7.2, 16.2]; 3.80 [3
H, s, OCH3]; 4.21 [1 H, ddd, CHHO, J 1.8, 7.2, 12.0]; 4.52 [1 H,
ddd, CHHO, J 1.8, 6.0, 12.0]; 5.86 [1 H, s, NH, J 7.8]; 6.33 [1 H, s,
ArCHN]; 6.84–7.00 [3 H, m, H-2ꢀ, H-4ꢀ, H-6ꢀ]; 7.05 [1 H, d, H-3, J
9.0]; 7.32 [1 H, t, H-5ꢀ, J 8.0]; 8.21 [1 H, dd, H-4, J 3.0, 9.0]; 8.90 [1
H, d, H-6, J 2.7]. 13C NMR (CDCl3): d 29.50, 28.95 [(CH3)2CN];
31.44 [C(CH3)3]; 31.61 [C(CH3)3]; 44.25 [CH2N]; 52.19 [CH2tBu];
55.30 [OCH3]; 56.06 [(CH3)2CN]; 61.68 [Ar–CHN]; 73.96 [CH2O];
114.32, 114.59 [C-2ꢀ, C-4ꢀ]; 121.17 [C-6ꢀ]; 122.13 [C-3]; 123.56 [C-
=
[C O]. Rf 0.35 (PE–acetone (8 : 2). Found: C, 65.3; H, 7.15; N,
4.85%. C15H19NO4 requires: C, 64.97; H, 6.91; N, 5.05%. GC-MS:
Rt 8.21; m/z 277 (M+, 5.4); 234 (32.1); 230 (7.2); 218 (100.0); 174
(3.8); 163 (64.8); 146 (14.7); 135 (5.0); 121 (15.5); 120 (11.6); 114
(12.8); 98 (5.3); 92 (6.3); 59 (7.0); 55 (7.4).
Acknowledgements
We thank MIUR and the University of Genova (PRIN 04) for
financial support.
1]; 127.72 [C-4]; 129.62 [C-6]; 130.20 [C-5ꢀ]; 136.21 [C-1ꢀ]; 142.35
ꢀ
=
[C-5]; 159.34, 160.07 [C-2, C-3 ]; 166.52, 167.94 [C O]. Rf 0.33
(PE–acetone 8 : 2). Found: C, 64.45; H, 6.95; N, 8.6%. C26H33N3O6
requires: C, 64.58; H, 6.88; N, 8.69%.
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=
=
H, d, CHHOC O, J 10.8]; 4.42 [1 H, d, CHHOC O, J 10.8];
6.56 [1 H, s, ArCHN]; 6.76 [1 H, s, NH, J 7.8]; 6.95 [1 H,
dd, H-3, J 0.9, 8.2]; 7.10 [1 H, dt, H-5, Jd 1.0, Jt 7.7]; 7.30–
7.43 [6 H, m, H-4, H-2ꢀ, H-3ꢀ, H-4ꢀ]; 7.75 [1 H, dd, H-6, J 1.6,
7.7]. 13C NMR (CDCl3): d 23.61, 23.92 [(CH3)2C]; 43.46 [CH2N];
53.35 [C(CH3)2]; 54.60 [OCH3]; 60.37 [Ar–CHN]; 71.36 [CH2O
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4240 | Org. Biomol. Chem., 2006, 4, 4236–4240
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©