Ugi multicomponent reaction followed by an intramolecular nucleophilic substitution: Convergent multicomponent synthesis of 1-sulfonyl 1,4-diazepan-5-ones and of their benzo-fused derivatives

Article abstract of DOI:10.1021/jo062626z

A short, two-step approach to the synthesis of diazepane or diazocane systems, based on a Ugi multicomponent reaction followed by a subsequent intramolecular S_N2 reaction was studied. 1 -Sulfonyl tetrahydrobenzo[e]-1,4-diazepin-1-ones 1 were ob

Full text of DOI:10.1021/jo062626z

Ugi Multicomponent Reaction Followed by an Intramolecular
Nucleophilic Substitution: Convergent Multicomponent Synthesis of
1-Sulfonyl 1,4-Diazepan-5-ones and of Their Benzo-Fused
Derivatives
Luca Banfi,* Andrea Basso, Giuseppe Guanti, Nicola Kielland, Claudio Repetto, and
Renata Riva*
Dipartimento di Chimica e Chimica Industriale, Via Dodecaneso 31, I-16146 GenoVa, Italy
banfi@chimica.unige.it; riVa@chimica.unige.it
ReceiVed December 21, 2006
A short, two-step approach to the synthesis of diazepane or diazocane systems, based on a Ugi
multicomponent reaction followed by a subsequent intramolecular SN2 reaction was studied. 1-Sulfonyl
tetrahydrobenzo[e]-1,4-diazepin-1-ones 1 were obtained in very high yield through a Ugi multicomponent
reaction followed by Mitsunobu cyclization. On the other hand, aliphatic 1-sulfonyl 1,4-diazepan-5-ones
2 could be obtained employing different cyclization conditions (sulfuryl diimidazole). A similar approach
toward diazocane rings using hydroxamates as nucleophiles was less successful, affording only O-cyclized
adducts or unexpected side products. A mechanistic explanation of the observed outcomes is proposed.
Introduction
We are particularly interested in coupling the Ugi reaction
with aliphatic substitutions.7,11,12 While brilliant examples of
Ugi reactions followed by SNAr reactions have been re-
cently reported,1,13-17 less attention has been devoted to SN2
reactions.18-25
Multicomponent reactions (MCRs)1 are, for their intimate
nature, extremely convergent, producing a remarkably high
increase of molecular complexity in just one step. Therefore,
especially when the components may be varied at will, they
are very well suited for the generation of libraries. 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 heterocyclic structures may be accessed by intramo-
lecular variants or by coupling the MCR with a subsequent
secondary transformation, taking advantage of additional func-
tionalities 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 latter approach.6-11
(6) Anthoine-Dietrich, S.; Banfi, L.; Basso, A.; Damonte, G.; Guanti,
G.; Riva, R. Org. Biomol. Chem. 2005, 3, 97-106.
(7) Banfi, L.; Basso, A.; Guanti, G.; Paravidino, M.; Riva, R. QSAR
Comb. Sci. 2006, 25, 457-460.
(8) Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Tetrahedron Lett. 2003,
44, 7655-7658.
(9) Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Tetrahedron Lett. 2004,
45, 6637-6640.
(10) Basso, A.; Banfi, L.; Guanti, G.; Riva, R. Tetrahedron 2006, 62,
8830-8837.
(11) Banfi, L.; Basso, A.; Guanti, G.; Lecinska, P.; Riva, R. Org. Biomol.
Chem. 2006, 4, 4236-4240.
(12) Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Tetrahedron 2006, 62,
4331-4341.
(13) Cristau, P.; Vors, J. P.; Zhu, J. Tetrahedron 2003, 59, 7859-7870.
(14) Cristau, P.; Vors, J. P.; Zhu, J. P. Org. Lett. 2001, 3, 4079-4082.
(15) Cristau, P.; Vors, J. P.; Zhu, J. P. Tetrahedron Lett. 2003, 44, 5575-
5578.
(1) Zhu, J.; Bienayme´, H. Multicomponent Reactions; Wiley: Weinheim,
2005.
(2) Doemling, A.; Ugi, I. Angew. Chem., Int. Ed. Engl. 2000, 39, 3169-
3210.
(16) Tempest, P.; Ma, V.; Kelly, M. G.; Jones, W.; Hulme, C.
Tetrahedron Lett. 2001, 42, 4963-4968.
(3) Banfi, L.; Riva, R. Org. React. 2005, 65, 1-140.
(4) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.-Eur. J.
2000, 6, 3321-3329.
(17) Tempest, P.; Pettus, L.; Gore, V.; Hulme, C. Tetrahedron Lett. 2003,
44, 1947-1950.
(5) Doemling, A. Chem. ReV. 2006, 106, 17-89.
(18) Ugi, I.; Schmid, T. J. Prakt. Chem. 1997, 339, 652-655.
10.1021/jo062626z CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/20/2007
J. Org. Chem. 2007, 72, 2151-2160
2151

Banfi et al.
SCHEME 1
The Ugi condensation of these two bifunctionalized compo-
nents with a series of isocyanides proceeded smoothly to afford
in moderate to good yields the desired adduct 9 or 10 (Table
1). It should be noted that, in this multicomponent condensation,
6 different functional groups are present simultaneously in the
same pot and that protection of the hydroxy group was not
necessary. The yield was lower than 60% only in the cases of
entries 1, 4, 14, 17, and 21. In the case of entries 1 and 14, the
reason was the relatively easy self-condensation of valeralde-
hyde, isovaleraldehyde, or of their imines under the reaction
conditions. This side process was not completely avoided by
the use of freshly distilled imine and by the presence of
molecular sieves in the reaction media. The moderate yield
obtained in entries 4, 17, and 21 is probably due to the great
bulkiness of the isocyanide.
The NMR spectra of all the Ugi products 9 and 10 were
complicated by the conformational equilibrium between the two
rotamers around the tertiary amide bond. Only at temperatures
> 110 °C did complete or nearly complete coalescence occur.
Having in hand the sulfonylamino alcohols 9 and 10, we
subjected them to normal Mitsunobu conditions (DEAD or
TBAD, PPh3 in THF) (methods A-C) (Scheme 3, Table 2). In
the case of 9 the reaction turned out to be quite clean forming
the expected 1-sulfonyl tetrahydrobenzo[e]-1,4-diazepin-1-ones
1 in good to excellent yields. We could therefore prepare a small
collection of these compounds. In some cases we preferred the
use of di-tert-butyl azodicarboxylate (DBAD, methods B and
C) simply for an easier separation of the product from the
hydrazo dicarboxylate byproduct. The yield was actually very
similar using TBAD or DEAD. Although in the first tests we
included also Et3N in the reaction mixture (methods A and B),
according to what found in the analogous cyclization of
phenols,11 we later found that the presence of Et3N was not
really necessary, and that the same yields were obtained also
without it (method C). Apart from entries 1 and 2, the cyclization
yields were always excellent (around 90%).
In the case of the â-alanine-derived compound 10a (used as
model for preliminary studies) the outcome was more complex.
Under the usual Mitsunobu conditions the reaction was fast and
reached completion in few minutes at 0 °C. However, to our
surprise, the expected product 2a was formed in only 32% yield
and was accompanied as a major product (55%) by the bicyclic
adduct 11a. The latter was formed with a remarkable stereo-
selectivity (15:1 diastereomeric ratio). The structure of 11a was
assigned on the basis of NMR spectra (see the Supporting
Information).
We reasoned that interesting heterocyclic scaffolds could be
produced in a straightforward manner by already introducing a
suitable nucleophile and an alcoholic moiety in two of the four
components of the Ugi reaction and by performing a subsequent
intramolecular Mitsunobu reaction.26 We have recently described
the straightforward synthesis of benzoxazepinones using phenols
as nucleophiles. We now describe our approaches toward
compounds of general formula 1-4 (Scheme 1), employing
sulfonamides and hydroxamates as nucleophiles for the Mit-
sunobu reaction. In all cases our plan involved inclusion of the
nucleophilic moiety into the carboxylic components of the Ugi
MCR.
Results and Discussion
As sulfonamide derivatives we employed the four carboxylic
acids 7a,b27,28 and 8a,b,29,30 easily synthesized from anthranilic
acid or â-alanine (Scheme 2). Imines 5 were obtained by mixing
equimolar quantities of the appropriate aldehyde and ethanol-
amine in Et2O in the presence of molecular sieves. The imines
derived from aliphatic aldehydes were purified by distillation,
whereas those derived from aromatic aldehydes were used as
1
such, after evaporation of the solvent. Interestingly, H NMR
showed that the compounds derived from condensation of
ethanolamine with aliphatic saturated aldehydes were actually
equilibrium mixtures of the imine 5 and of the isomeric
oxazolidines 6, with the latter prevailing (the exact ratios are
reported in the experimental section and in the Supporting
Information).
(19) Marcaccini, S.; Pepino, R.; Cruz Pozo, M. Tetrahedron Lett. 2001,
42, 2727-2728.
We tried to improve the yield of 2a by changing various
reaction parameters (phosphine, azodicarboxylate, solvent) but
without success. Thus we turned to completely different
conditions. However, on treating 10 with methanesulfonyl
chloride and Et3N in CH2Cl2 at -30 f 0 °C, exclusively the
bicyclic compound 11a was formed, with no trace of 2a. After
various unsuccessful attempts, our attention was drawn by N,N′-
sulfuryl diimidazole. This reagent was introduced as an alterna-
tive to the Mitsunobu reaction by Hanessian in the 80s,31,32 but
since then, to our knowledge, it has never been employed again
in an intramolecular fashion.
(20) Umkehrer, M.; Kolb, J.; Burdack, C.; Ross, G.; Hiller, W.
Tetrahedron Lett. 2004, 45, 6421-6424.
(21) Neo, A. G.; Delgado, J.; Polo, C.; Marcaccini, S.; Marcos, C. F.
Tetrahedron Lett. 2005, 46, 23-26.
(22) Golebiowski, A.; Klopfenstein, S. R.; Shao, X.; Chen, J. J.; Colson,
A. O.; Grieb, A. L.; Russell, A. F. Org. Lett. 2000, 2, 2615-2617.
(23) Golebiowski, A.; Jozwik, J.; Klopfenstein, S. R.; Colson, A. O.;
Grieb, A. L.; Russell, A. F.; Rastogi, V. L.; Diven, C. F.; Portlock, D. E.;
Chen, J. J. J. Comb. Chem. 2002, 4, 584-590.
(24) Rossen, K.; Sager, J.; DiMichele, L. M. Tetrahedron Lett. 1997,
38, 3183-3186.
(25) de Greef, M.; Abeln, S.; Belkasmi, K.; Doemling, A.; Orru, R. V.
A.; Wessjohann, L. A. Synthesis 2006, 3997-4004.
(26) Hughes, D. L. Org. Reactions 1992, 42.
To our satisfaction, treatment of 10a with N,N′-sulfuryl
diimidazole in the presence of a suitable base gave cleanly only
the diazepanone 2a, without any formation of 11a. The reaction
(27) Surman, M. D.; Mulvihill, M. J.; Miller, M. J. Org. Lett. 2002, 4,
139-141.
(28) Dannhardt, G.; Fiebich, B. L.; Schweppenhaeuser, J. Eur. J. Med.
Chem. Chim. Ther. 2002, 37, 147-162.
(29) Wang, J.; Hou, Y. J. Chem. Soc. Perkin Trans 1 1998, 1919-1923.
(30) Ciolli, C. J.; Kalagher, S.; Belshaw, P. J. Org. Lett. 2004, 6, 1891-
1894.
(31) Hanessian, S.; Couture, C.; Wiss, H. Can. J. Chem. 1985, 63, 3613.
(32) Vate`le, J.-M.; Hanessian, S. Tetrahedron 1996, 52, 10557-10568.
2152 J. Org. Chem., Vol. 72, No. 6, 2007

Ugi Multicomponent Reactions
SCHEME 2
TABLE 1. Results of Ugi Reaction of Imines 5, Isocyanides, and â-Sulfonylamino Acids 7 or 8
entry
product
carboxylic acid
R1
R2
R3
yield
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
7a
7a
7a
7a
7b
7b
7b
7b
IBu
cyHex
nBu
Bn
tBuCH2CMe2-
Bn
cyHex
nBu
cyHex
p-Tol
p-Tol
p-Tol
p-Tol
Me
Me
Me
Me
48%
63%
88%
35%
70%
77%
57%
67%
3-BrC6H4
cyHex
cyHex
3-BrC6H4
iPr
9g
9h
Ph
2-furyl
9
9i
7a
iPr
pTol
69%
10
11
12
13
14
15
16
17
18
19
20
9j
7b
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
cyHex
iPr
cyHex
iPr
tBuO2C-CH2-
cyHex
Bn
tBu
Bn
cyHex
tBu
tBuCH2CMe2-
nBu
cyHex
Me
62%
67%
69%
95%
25%
62%
70%
52%
62%
77%
90%
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
nBu
4-ClC6H4
3-MeOC6 H4
3-MeOC6 H4
3-MeOC6 H4
2-furyl
3-MeOC6 H4
tBuO2C-CH2-
21
10k
8a
iPr
p-Tol
45%
22
23
10l
10m
8b
8b
iPr
Ph
Bn
cyHex
2-(NO2)C6H4-
2-(NO2)C6H4-
80%
79%
SCHEME 3
was optimized on changing the base and the solvent. With Et3N,
DBU (1,8-diazabicyclo[5,4,0]undec-7-ene), or K2CO3 no reac-
tion occurred. With nBu4NF the reaction took place but
sluggishly. Best results were obtained with 1.2 equiv of NaH
or NaHMDS (NaN(SiMe3)2) in DMF. 2a was isolated in 68%
yield and easily purified by chromatography (whereas separa-
tion of 2a from 11a after classical Mitsunobu was rather
difficult).
J. Org. Chem, Vol. 72, No. 6, 2007 2153

Banfi et al.
TABLE 2. Results of Cyclization of Hydroxysulfonamides 9-10a
entry
product
method
R1
R2
R3
yield (1 or 2)
yield (11)
yield (12)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
A
B
C
A
B
C
C
C
iBu
cyHex
nBu
Bn
tBuCH2CMe2-
Bn
cyHex
nBu
cyHex
p-Tol
p-Tol
p-Tol
p-Tol
Me
Me
Me
Me
51%
70%
85%
82%
98%
95%
91%
92%
3-BrC6H4
cyHex
cyHex
3-BrC6H4
iPr
1g
1h
Ph
2-furyl
9
1i
C
iPr
p-Tol
91%
10
11
12
13
14
15
16
17
18
19
20
21
1j
C
A
D
D
D
D
D
D
D
D
D
D
cyHex
iPr
iPr
cyHex
iPr
nBu
4-ClC6H4
3-MeOC6 H4
3-MeOC6 H4
3-MeOC6 H4
2-furyl
tBuO2C-CH2-
cyHex
cyHex
Bn
tBu
Bn
cyHex
tBu
Me
93%
32%
68%
55%
52%
46%
52%
60%
62%
42%
27%
30%b
2a
2a
2b
2c
2d
2e
2f
2g
2h
2i
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
55%
18%
10%
10%
22%
14%
18%
tBuCH2CMe2-
nBu
cyHex
2j
3-MeOC6 H4
tBuO2C-CH2-
30%
45%
22
2k
D
iPr
p-Tol
23
24
2l
2m
D
D
iPr
Ph
Bn
cyHex
2-(NO2)C6H4-
2-(NO2)C6H4-
36%
41%
50%
28%
a Yields are of isolated products after chromatography and do not take into account the recovered starting materials. Method A: DEAD, PPh3, Et3N,
THF, 0 °C. Method B: TBAD, PPh3, Et3N, THF, 0 °C. Method C: TBAD, PPh3, THF, 0 °C. Method D: sulfuryl diimidazole, NaHMDS or NaH, DMF,
room temperature, 4-18 h. b In this case separation of 2j from 12j proved difficult and was not performed.
Also in this case, in order to assess the scope of the protocol,
we varied the aldehyde, the isocyanide, and the sulfonyl group
(see Table 2). The methodology proved to be reasonably general.
However, in several cases, the cyclization reaction furnished a
byproduct, whose structure did not correspond to the bicyclic
compound 11 but instead to the ketopiperazine 12. The
assignment of this structure was made on the basis of NMR
spectra (see the Supporting Information). With sulfonamido
alcohols derived from aliphatic aldehydes, usually this byproduct
was formed in little amount, but when an aromatic isocyanide,
namely, the “convertible” Linderman isocyanide,33 was em-
ployed (entry 22) the ketopiperazine 12 was formed exclusively.
Substantial amount of this side product were also observed in
entries 21, 23, and 24. It seems that the formation of ketopip-
erazine is favored by a higher acidity of the amide derived from
the isocyanide, by an increased steric bulk of the sulfonamide,
and in part when sulfonamido alcohols are derived from
aromatic aldehydes.
The short preparation of 1 and 2 (just two steps) opens the
way to the synthesis of collections of compounds arising from
decoration of the 1-sulfonyl-1,4-diazepan-5-one and of the
1-sulfonyl tetrahydrobenzo[e]-1,4-diazepin-1-one scaffolds. These
heterocycles, despite their close resemblance to important drugs,
have been very little explored so far in medicinal chemis-
try.27,34,35 Although in the case of 2 the overall yields are in
some cases only moderate, the possibility to obtain in just two
simple steps relatively complex structures, with the introduction
of three diversity points, makes this protocol well suited for
the preparation of collections of potentially bioactive substances.
Another nucleophile that can be employed in Mitsunobu
reactions is the hydroxamate. So we decided to explore its use
in this strategy, including it once again into the carboxylic
component of an Ugi reaction. We reasoned that monohydrox-
amates of malonic acids would have been problematic due to
the presence of further relatively acidic protons at the R-position.
Therefore we chose monohydroxamates of succinic acid instead,
with the goal to obtain the unprecedented mesocyclic scaffolds
3 or 4 (substituted diazocanediones).
The acid 13 was easily obtained by reaction of succinic
anhydride with O-benzyl hydroxylamine (Scheme 4).36 The Ugi
condensation with imine 5b and benzyl isocyanide afforded in
moderate yield the adduct 14. Also in this case protection of
the alcoholic moiety was not necessary.
When 14 was treated under the standard Mitsunobu conditions
(DEAD, PPh3, 0 °C) two new products were rapidly formed.
However, the main one was not the expected 1,4-diazocane-
5,8-dione 3a nor the isomeric compound 15a. Identification of
this new unexpected product was not easy, because it tended to
decompose in part upon chromatography or in the presence of
traces of acids (even upon simple dissolution in CDCl3, due to
the likely presence of traces of DCl) giving the imide 17. On
the other hand, in the presence of Et3N, it was converted back
into starting material 14. Eventually, after fast chromatography
and quick NMR analysis in DMSO-d6, we could obtain a clean
spectrum of 16a, which was consistent with the isomerized ester.
This structure is also in agreement with the observed conversion
(33) Linderman, R. J.; Binet, S.; Petrich, S. R. J. Org. Chem. 1999, 64,
336-337.
(34) Huang, W.; Naughton, M. A.; Yang, H.; Su, T.; Dam, S.; Wong, P.
W.; Arfsten, A.; Edwards, S.; Sinha, U.; Hollenbach, S.; Scarborough, R.
M.; Zhu, B.-Y. Bioorg. Med. Chem. Lett. 2003, 13, 723-728.
(35) Santilli, A. A.; Osdene, T. S. J. Org. Chem. 1964, 29, 1998-2003.
(36) Ames, D. E.; Grey, T. F. J. Chem. Soc. 1955, 631-636.
2154 J. Org. Chem., Vol. 72, No. 6, 2007

Ugi Multicomponent Reactions
SCHEME 4
SCHEME 5
into 17 under acid conditions and 14 under basic conditions.
The yield of this compound could not be established precisely,
but it was clearly the main product. A minor product (this time
completely stable) was isolated in 25% yield from the reaction
mixture. It was recognized as the O-cyclized adduct 15a. It is
well known that hydroxamates are ambident nucleophiles and
that they can cyclize under Mitsunobu conditions either to cyclic
hydroxamates or to iminolactones.37-40 In our case, the 1H and
13C NMR spectra are definitely more consistent with the
iminolactone structure 15 than with the expected cyclic hy-
droxamate 3. In particular the 13C spectrum shows three
quaternary carbons at 175.1, 171.0, and 156.2 ppm. The last
value fits better with an iminolactone than with a cyclic
hydroxamate. There is a CH2 at 68.5 ppm, suggesting a CH2O
group. Finally, at 1H NMR, the same CH2 gives signals at 4.39
and 4.07 ppm, values that seem too high for a CH2N group. In
the spectra of 15a, there is only one set of signals, indicating
that it is probably just one of the possible diastereoisomers
around the CdN double bond. We think that the other one is
formed in little amount and therefore we were not able to isolate
it. We tried to improve the yield of 15a, but without success:
using di-iso-propyl azodicarboxylate (DIAD) or di-tert-butyl
azodicarboxylate (DBAD) the situation was even worse and
nearly no adduct 15a was formed.
We explored the same reaction also on the more complex
substrates 22a,b, hoping that the pyrrolidine ring could furnish
a steric bias favoring the desired cyclization (Scheme 5). These
compounds were obtained starting from the chiral, enantiomeri-
cally pure, pyrroline 18, whose preparation and use in Ugi
reactions were recently reported by us.9 The reaction of 18 with
the aspartic derivative 19 and benzyl isocyanide proceeded in
high yield to give a 2:1 trans:cis diastereoisomeric mixture.9
Conversion of the benzyl ester into the corresponding hydrox-
amate and removal of the silyl protecting group gave the
alcohols 22a,b, which could be conveniently separated and fully
characterized at this stage.
They were independently submitted to Mitsunobu conditions
and were found to give a completely different outcome. The
cis compound gave only one significant product 23a, in good
yields. This adduct was recognized as the O-cyclized product
by its NMR spectra. On the contrary, cyclization of the trans
compound 22b gave a mixture of two isomeric products in a
68:32 ratio. This reaction was best carried out with DIAD, since
the diethyl hydrazo dicarboxylate coeluted with the product.
However the same mixture was formed also with DEAD.
Although these two isomers did not separate on thin-layer
chromatography (TLC) or with high-performance liquid chro-
matography (HPLC), they gave distinct NMR signals that did
not merge even at 120 °C. The most important feature of these
isomers at NMR is the presence of only three carbonyl signals
at 171.3/172.6, 165.2/166.0, and 154.8, instead of the expected
four. Moreover, there is a quaternary signal at 108.4/109.7. The
1H NMR shows clearly the presence of the NHBn hydrogen
and the absence of OH groups or of other amidic NHs (apart
(37) Maurer, P. J.; Miller, M. J. J. Am. Chem. Soc. 1983, 105, 240-
245.
(38) Panday, S. K.; Langlois, N. Tetrahedron Lett. 1995, 36, 8205-
8208.
(39) Takahashi, H.; Hitomi, Y.; Iwai, Y.; Ikegami, S. J. Am. Chem. Soc.
2000, 122, 2995-3000.
(40) Langlois, N.; Calvez, O. Tetrahedron Lett. 2000, 41, 8285-8288.
J. Org. Chem, Vol. 72, No. 6, 2007 2155

Banfi et al.
SCHEME 6
from the NHBoc). On standing in solution, especially in the
presence of water, 24b tended to decompose, indicating a
relatively facile hydrolysis. These and other data indicate the
structure 24b depicted in Scheme 5 as the most likely one. The
presence of a new stereogenic center explains the formation of
two isomers, while the 108.4/109.7 signal is in agreement with
the orthoester-type carbon.
in the presence of a base (Et3N), which increases the amount
of the anion present in solution.
On the other hand, with aliphatic sulfonamides and hydrox-
amates, the alternative path B becomes predominant and the
oxazolinium ion 30 is formed preferentially. The same oxazo-
linium ion can be formed also through a third pathway (path
C), where the system DEAD/PPh3 acts on the cyclic intermediate
31 provoking a formal elimination of water.
The fate of the oxazolinium ion 30 depends on the overall
structure. In the case of the hydroxamates studied in this work
(Scheme 7), the length of the chain bearing the NuH group
allows attack by this group to the CdN bond to give the spiro
compounds 34. Although this product was not isolated starting
from the simpler substrate 14, we think that it may undergo a
facile hydrolysis during workup to give the ester 16a. On the
contrary, starting from the more complex substrate 22b, a spiro
compounds analogue to 34 could be isolated. The higher
bulkiness of substituents and the presence of the additional
pyrrolidine ring makes this adduct more stable, although we
observed its facile hydrolysis on standing (see above).
Although interesting, the results obtained with the hydroxy
hydroxamates 14 and 22 are not very promising from the
synthetic point of view. The yield of the cyclized product is
heavily dependent from subtle structural or stereochemical
variations, and moreover, the O-cyclized products are favored.
The resulting iminolactones are not very attractive from the point
of view of medicinal chemistry because of their likely metabolic
instability.
However, the results collected allow us to try to rationalize
the outcome of these Mitsunobu reactions. Scheme 6 shows a
general mechanistic hypothesis that can be applied to the
nucleophiles described in this paper (sulfonamides and hydrox-
amates) but also to the previously described phenols.11 We think
that side reactions as well as the recovery of starting material
(observed in the case of phenols as nucleophiles) can be
explained through the formation of an oxazolinium ion inter-
mediate 30.
In the case of aliphatic sulfonamides, this type of cyclization
would lead to a four-membered ring and is disfavored. Therefore
the oxazolinium ion 34 is attacked by the secondary amide to
give 11a.
Finally, in the case of phenols derived from salicylic acid,11
probably because of conjugation of the aryl with the CdN
double bond in the oxazolinium ions 30, both type of cyclization
are disfavored and 30 is hydrolyzed during workup giving back
the starting material.
The competition between path A and paths B or C is expected
to be operating also using other activation methods. Actually,
as already stated above, reaction of 10a with methanesulfonyl
chloride and Et3N gave exclusively the bicyclic adduct 11. A
mechanism analogous to path B can account for this behavior.
A question now arises: why the situation is completely reversed
with sulfuryl diimidazole? After all, sulfuryl imidazole is
believed to react with alcohols under basic conditions to give
sulfonyl derivatives not very different from methanesulfonates.32
However we think that the mechanism of the reaction of alcohols
The starting materials exist in two interconverting conformers
deriving from rotation around the tertiary amide bond. Only
one of these conformers (25) can be converted into the desired
cyclization product 28 (path A). On the other hand, in the other
conformation 26, activation of the hydroxy group will give the
intermediate 29. In this structure only the oxygen of the tertiary
amide can act as a nucleophile, forming the oxazolinium cation
30 (path B). Intermediate 29 is obviously in equilibrium with
the conformer 27. Therefore the competition between the two
paths depends on various factors, such as the position of the
conformational equilibrium, the ring size formed from path A,
and the acidity of the NuH group. The scale of acidity should
be: aromatic sulfonamides, phenols, aliphatic sulfonamides,
hydroxamates. Therefore aromatic sulfonamides and phenols
form an anion more easily and path A predominates, especially
2156 J. Org. Chem., Vol. 72, No. 6, 2007

Ugi Multicomponent Reactions
SCHEME 7
SCHEME 8
with sulfuryl diimidazole may be different from that with
sulfonyl chlorides. The imidazolide anion is a poor leaving group
and therefore reaction with the alkoxide should be accelerated
if an acid species protonates the pyridine-type imidazole nitrogen
during substitution. Under the conditions employed there are
only two possible acid species: the sulfonamide and the
secondary amide, the former being much more acidic. Scheme
8 shows a possible mechanism.
In this hypothesis the rate-limiting step is the formation of
the activated alcohol 39. For its formation the sulfonamido group
plays the double role of basic catalyst (provoking the formation
of the alcoholate 37) and of acid catalyst, favoring imidazole
expulsion during the nucleophilic attack of the alcoholate to
sulfuryl diimidazole. Therefore only the “correct” conformation
may react. In this conformation only path A is possible, because
path B will require a conformational change. Also the formation
of ketopiperazines can be explained by this picture. In this case
it is the secondary amide that plays the role of basic-acid
catalyst. It is interesting to note that the reaction promoted by
the secondary amide may take place in both conformations. The
side reaction leading to ketopiperazines should be disfavored
by the lower acidity of the amide compared to the sulfonamides.
However, the fact that it forms a six-membered ring (instead
of a seven-membered ring) and that it can occur on both
conformers, makes it competitive in some cases with the desired
pathway, especially when the amide acidity is increased, such
as in entries 21 and 22 of Table 2.
obtainment of relatively complex heterocyclic scaffolds in few
steps. Although coupling the Ugi reaction with a known organic
transformation like the Mitsunobu reaction may seem a trivial
exercise, one should always bear in mind that we are working
on complex highly functionalized structures, and that the two
amidic groups arising from the Ugi reaction do not always
behave as mere spectators: they can indeed heavily interfere
with the “normal” expected course of the reaction. Fine-tuning
of the conditions and a thorough assessment of the scope of
these synthetic methodologies have to be pursued before
claiming the synthetic utilities of these tandem reactions. In our
case, we have proved that the very short (2 steps) synthesis of
tetrahydrobenzo[e]-1,4-diazepin-1-ones and of 1-sulfonyl 1,4-
diazepan-5-ones with 3 diversity inputs is indeed possible by
coupling Ugi and Mitsunobu reactions. The addition of further
diversity inputs (using substituted ethanolamines and substituted
anthranilic acids) is in progress. On the contrary, the attempted
synthesis of 1,4-diazocane-5,8-diones was less successful. In
any case the collected results allowed us to propose a possible
mechanistic rationalization, which may be precious for future
developments.
Experimental Section
General Procedure for the Synthesis of Imines 5-Oxazo-
lidines 6 from Aliphatic Aldehydes and Ethanolamine. 2-(2-
Methylpropylideneamino)ethanol 5a/2-Isopropyloxazolidine 6a.
A solution of isobutyraldehyde (5 mL, 54.8 mmol) in dry diethyl
ether (50 mL) was treated, at room temperature, with ethanolamine
(3.30 mL, 54.8 mmol) and powdered 4-Å 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
Conclusions
The results discussed in this paper show the power of coupling
Ugi MCRs with post-condensation transformations for the rapid
J. Org. Chem, Vol. 72, No. 6, 2007 2157

Banfi et al.
1
colorless liquid (3.892 g, 62%) (bp 60-64 °C at 34 mbar). H
ortho to CH3, J 8.1]; 7.40-7.60 [5 H, m, aromatics]; 7.65 [1 H, d,
H ortho to CdO, J 7.5]. 13C NMR: δ 21.6 [CH3Ar]; 22.0, 23.3
[(CH3)2CH]; 24.5 (2), 25.4, 32.6, 32.7 [CH2 cyclohexyl]; 25.1
[CH(CH3)2]; 41.7 [CH2N]; 48.0 [cyHex-CHNH]; 53.3 [CH2N]; 54.4
[iBu-CHN]; 127.5 [CH ortho to SO2]; 128.9 [CH meta to C)O]
129.7 [CH meta to SO2]; 130.4 [CH ortho to CdO]; 131.4 [CH
meta to CdO]; 132.3 [CH para to CdO]; 134.3, 134.4, 136.5, 143.7
[quaternary aromatic]; 168.8, 169.5 [CdO]. IR: νmax 3419 (broad),
2996, 2935, 2854, 1663, 1630, 1598, 1504, 1449, 1406, 1348, 1256,
NMR showed a 17:83 ratio between 5a and 6a. 5a: δ 1.07 [6 H,
d, CH(CH3)2, J 6.9]; 2.43 (mc)[1 H, m, CH(CH3)2]; 3.50 (mc) [2
H, m, CH2OH]; 3.79 [2 H, t, CH2N, J 5.3]; 7.61 [1 H, d, CH)N,
J 4.2]. 6a: δ 0.98 and 1.00 [2 × 3 H, 2d, CH(CH3)2, J 6.6]; 1.77
[1 H, octuplet, CH(CH3)2, J 6.3]; 3.00 [1 H, dt, CHH-N, Jt 7.6, Jd
11.7]; 3.23 [1 H, ddd, CHH-N, J 4.8, 6.6, 11.7]; 3.60-3.76 [2 H,
m, CH2O]; 4.07 [1 H, d, O-CH-N, J 6.3]. GC-MS: Rt 2.46; m/z
115 (M+, 0.9); 100 (2.9); 84 (31.4); 72 (100.0); 70 (21.8); 56 (11.8);
55 (11.2); 45 (25.8); 44 (30.6); 43 (9.8); 42 (10.6); 41 (15.8); 39
(9.3).
General Procedure for the Synthesis of Imines 5 from
Aromatic Aldehydes and Ethanolamine. As above, but, after
filtration of molecular sieves, the solution was evaporated to
dryness. After further stripping at 1 mbar for 2-3 h, the crude
imine was used as such for the Ugi reaction. NMR in selected cases
showed that only the imine form 5 was present.
1155, 1116, 1086, 1050 cm-1
.
N-Cyclohexyl-3-methyl-2-(7-oxo-4-tosyl-1,4-diazepan-1-yl)bu-
tanamide 2a. Foam. Rf 0.51 in PE/AcOEt 4:6. Found: C, 61.7; H,
7.9; N, 9.25. C23H35N3O4S requires C, 61.44; H, 7.85; N, 9.35. 1H
NMR: δ 0.78 and 0.91 [2 × 3H, 2d, (CH3)2CH J 6.9, 6.3]; 1.00-
1.85 [10H, m, cyclohexyl]; 2.19 [1H, d of septuplet, CH(CH3)2, Js
6.5, Jd 11.1]; 2.42 [3H, s, ArCH3]; 2.36-2.48 [1H, m, H-3]; 2.56
[1H, t, H-7, J)11.5]; 2.74 [1H, dd, H-6, J 14.7, 6.9]; 2.86 [1H,
ddd, H-6, J 14.7, 10.8, 1.8]; 3.50-3.64 [2H, m, CHNH of
cyclohexyl + H-2]; 3.73-3.92 [3H, m, H-2, H-7, H-3]; 4.35 [1H,
d, iPrCHNH, J)11.1]; 5.82 [1H, d, NH, J)8.1]; 7.31 [2 H, d, CH
ortho to CH3, J 8.1]; 7.61 [2 H, CH meta to CH3, J 8.1]. 13C NMR:
δ 18.5 and 19.4 [CH(CH3)2]; 21.5 [Ar-CH3]; 24.6 [2 × CH2
cyclohexyl]; 25.3 [CH2 cyclohexyl]; 25.9 [CH(CH3)2]; 32.66 and
32.68 [2C, CH2 cyclohexyl]; 37.9 [C-6 of the ring)]; 43.7 [C-7 of
the ring]; 43.9 [C-2 of the ring]; 47.8 [CHN cyclohexyl]; 49.2 [C-3
of the ring]; 62.7 [iPr-CHN]; 127.4 and 129.8 [aromatic CH]; 133.6
and 143.8 [aromatic C quat.]; 168.7 and 174.3 [CdO]. IR: νmax
3685, 3419, 3028, 2930, 2855, 2402, 1667, 1638, 1504, 1434, 1364,
General Procedure for the Ugi Reactions to give 9-10. The
freshly prepared imine is dissolved in dry MeOH (0.7 M) and added
with powdered 3-Å molecular sieves (30 mg/mL). Acid 7 or 8 (0.9
equiv) and the appropriate isocyanide (0.8 eq) are then added in
sequence. After 24 h the solution is filtered and evaporated. It is
taken up in AcOEt or CH2Cl2 (when the residue is not soluble in
AcOEt) and washed with saturated aqueous NaHCO3. After drying
(Na2SO4) and evaporation, the crude product is chromatographed
on silica gel (220-400 mesh) with CH2Cl2/Me2CO (about 85:15)
or petroleum ether/Me2CO (about 6:4). The purity of the Ugi
1
products was assessed by H and 13C NMR as well as by TLC.
1340, 1307, 1242, 1158, 1094, 971, 905, 821 cm-1
.
The NMR spectra showed a double set of signals due to confor-
mational equilibria. Only at 110 °C did the coalescence occur.
However, some signals were still broad. For this reason we preferred
to carry out the complete characterization on the cyclized products
1 and 2.
General Procedure for the Intramolecular Mitsunobu: To
Give Compounds 1. Method A. A solution of 9 (0.414 mmol) in
dry THF (5 mL) was cooled to 0 °C and treated with PPh3 (177
mg, 0.675 mmol), Et3N (115 µL, 0.83 mmol), and DEAD (98 µL,
0.62 mmol). After 5 min the cooling bath was removed and the
mixture stirred at room temperature for 1-6 h until disappearence
of the substrate. The solvent was evaporated and the crude product
immediately chromatographed through 220-400 mesh silica gel
(petroleum ether/acetone) to give the pure product.
Method B. Exactly as above but using TBAD instead of DEAD.
Method C. Exactly as above but without addition of Et3N.
General Procedure for the Cyclization of 10 to Give 2
(Method D). The substrate 10 was dissolved in DMF (0.18 M)
and treated subsequently with 1.5 equiv of N,N′-sulfuryldiimidazole
and 1.2 equiv of NaH (60% in mineral oil) or sodium hexameth-
yldisilazide (0.6 M in toluene). After 18 h, the reaction was
quenched with 5% aqueous NH4H2PO4 + 1 M HCl (10:1). The
pH was adjusted to 3. Extraction with AcOEt, drying (Na2SO4),
and evaporation gave a crude product that was chromatographed
on silica gel (220-400 mesh) typically with CH2Cl2/Me2CO 95/5
or 9/1 or with petroleum ether/AcOEt 4/6 + 1-2% EtOH. The
latter solvent mixture was better suited when separation from the
side product 12 turned difficult. In most cases, analytically pure
samples could be obtained by trituration from Et2O /PE.
Selected Data for Compounds 1-2. N-Cyclohexyl-2-(2,3-
dihydro-5-oxo-1-tosyl-1H-benzo[e] [1,4]diazepin-4(5H)-yl)-4-
methylpentanamide 1a. White solid. Mp: 158.8-161.5 °C. Rf 0.43
(PE/AcOEt 6:4). Found: C, 65.4; H, 7.3; N, 8.1. C28H37N3O4S
requires C, 65.73; H, 7.29; N, 8.21. 1H NMR: δ 0.72-0.85 [1 H,
m, CHHiPr]; 0.86 [3 H, d, CH3, J 6.6]; 0.89 [3 H, d, CH3, J 6.3];
1.03-1.48 [7 H, m, CH2 cyclohexyl + CH(CH3)2]; 1.50-1.80 [4
H, m, CH2 cyclohexyl]; 1.80-1.95 [1 H, m, CHHiPr]; 2.41 [3 H,
s, CH3]; 3.17 [1 H, ddd, CHHN, J 4.2, 11.4, 15.6]; 3.50-3.62 [1
H, m, CHHN]; 3.60-3.72 [1 H, m, cyHex-CHN]; 3.73-3.84 [1
H, m, CHHN]; 3.95 [1 H, dt, CHHN, Jd 4.8, Jt 12.00]; 4.59 [1 H,
dd, CHCH2, J 4.2, 10.5]; 6.16 [1 H, d, NH, J 8.4]; 7.23 [2 H, d, H
N1-(1-(Benzylcarbamoyl)-3-methylbutyl)-N4-(benzyloxy)-N1-
(2-hydroxyeth yl)succinamide 14. It was prepared in 50% yield
from 5b/6b and acid 13 following the general procedure for Ugi
reactions. Rf 0.32 (CH2Cl2/Me2CO 7:3). Found: C, 66.3; H, 7.45;
N, 8.85. C26H35N3O5 requires C, 66.50; H, 7.51; N, 8.95. 1H
NMR: (DMSO-d6, 110 °C): δ 0.91, 0.93 [2 × 3H, 2 d, (CH3)2-
CH2 J 5.4, 6.0]; 1.48-1.66 [2H, m, CH2CH(CH3)2]; 1.84 [1H,
octuplet, CH(CH3)2 J 7.2]; 2.37 [2 H, t, CH2CdO, J 6.9]; 2.56-
2.76 [2H, m, CH2CdO]; 3.30-3.65 [4H, m, OCH2CH2N]; 4.31
[2H, d, HNCH2Ph J 5.7]; 4.52, 4.66 [2H, 2 s (broad), CHN and
OH]; 4.82 [2H, s, PhCH2O]; 7.18-7.45 [10H, m, CH aromatics];
7.99 [1H, s, NHCH2Ph]; 10.55 [1H, s, NH hydroxamate]. 13C NMR
(DMSO-d6, 110 °C): δ 21.5, 21.9 [(CH3)2CH]; 24.0 [CH(CH3)2];
27.4, 27.5 [2 × CH2CdO]; 37.7 [CH2N]; 42.0 [CH2CH(CH3)2];
46.8 [PhCH2N]; 56.7 [CHN]; 59.2 [CH2OH]; 76.6 [PhCH2O]; 125.9,
126.5, 127.3, 127.4, 127.5, 127.9 [aromatic CH]; 135.5, 138.7
[aromatic quat. C]; 169.6, 170.2, 171.9 [3 × CdO].
Mitsunobu Reaction of Compound 14. It was carried out under
the conditions of method A described above. Chromatography
(PE/acetone 7:3 to 6:4) gave compounds 15a (faster eluting, 25%)
plus compound 16a (35%). It should be noted that 16a tended to
decompose in part during chromatography giving 17 or 14.
N-Benzyl-2-(8-benzyloxyimino-5-oxo-1,4-oxazocan-4-yl)-4-
methylpentanamide 15a. Rf 0.63 in CH2Cl2/AcOEt 1:1. Found:
C, 69.0; H, 7.45; N, 9.15. C26H33N3O4 requires C, 69.16; H, 7.37;
N, 9.31. 1H NMR: δ 0.90, 0.93 [2 × 3H, 2 × d, (CH3)2CH, J 6.6];
1.41-1.62 [2H, m, CHH-CH(CH3)2 and CH(CH3)2]; 1.81 [1H,
dt, CHH-CH(CH3)2, Jt 7.5, Jd 13.5]; 2.47-2.74 [4H, m, H-6 and
H-7]; 3.51 [1H, dt, H-3, Jt 3.9, Jd 16.5]; 3.62 [1H, ddd, H-3, J 3.0,
8.1, 16.2]; 4.08 [1H, ddd, H-2, J 3.0, 8.4, 12.3]; 4.38 [1H, ddd,
H-2, J 3.3, 4.8 12.3]; 4.30 and 4.44 [2H, AB part of ABX system,
CH2Ph, JAB 14.7, JAX 5.6, JBX 6.1]; 4.98 [2H, s, PhCH2O]; 5.03
[1H, t, CHN, J 7.5]; 6.96 [1H, t, NH, J 5.85]; 7.20-7.40 [10H, m,
aromatic CH]. 13C NMR: δ 22.4, 22.8 [CH3]; 24.7 [CH(CH3)2],
30.5, 32.7 [C-6 and C-7]; 36.6 [C-3]; 43.5 [CH2CH(CH3)2]; 45.2
[NCH2Ph]; 54.4 [CHN]; 68.5 [CH2O (C-2)]; 76.3 [PhCH2O]; 127.4,
127.7, 128.0, 128.1, 128.4, 128.6 [CH benzyl]; 137.1 e 137.9 [quat.];
156.2 [CdN]; 171.0, 175.1 [CdO].
2-(1-(Benzylcarbamoyl)-3-methylbutylamino)ethyl 3-(Benzyl-
oxycarbamoyl)propanoate 16a. Note: it is difficult to obtain in
2158 J. Org. Chem., Vol. 72, No. 6, 2007

Ugi Multicomponent Reactions
completely pure form this compound, because it tends to convert
into 17 or back into 14. We could obtain a nearly pure sample by
fast chromatography and examine it as soon as possible exclusively
at NMR. 1H NMR (DMSO-d6, room temperature): δ 0.84, 0.87 [2
× 3H, 2 d, (CH3)2CH, J 6.6]; 1.23-1.41 [2H, m, CH2CH(CH)3];
1.66 [1H, nonuplet, CH2CH(CH3)2 J 6.6]; 2.24 [2H, t, CH2CdO];
2.50-2.75 [2H, m, CH2CdO]; 3.08 [1 H, t, CHN, J 7.3]; 3.20-
3.50 [2 H, m, CH2N (covered by the water signal)]; 4.03 [2 H, t,
CH2O, J 5.8]; 4.30 [2 H, d, NHCH2Ph]; 4.77 [2 H, s, OCH2Ph];
7.20-7.43 [10 H, m, aromatics]; 8.43 [1 H, t, NH, J 6.2]; 11.07 [1
H, s, NHO]. Note: the NH signal of the secondary amine is not
seen because it exchanges rapidly with water contained in DMSO-
d6. 13C NMR (DMSO-d6, room temperature): δ 22.3, 22.8 [CH3-
CH]; 24.3 CH(CH3)2]; 26.9, 28.5 [CH2CdO]; 41.8, 42.6, 45.9
[CH2N + CH2CH(CH3)2]; 60.2 [CHN]; 63.8 [CH2O]; 76.8 [PhCH2O];
126.7, 127.1, 128.21 (2 superimposed signals), 128.24, 128.7
[aromatic CH]; 135.9, 139.6 [quat.]; 168.2, 172.1, 174.4 [CdO].
tert-Butyl (S)-3-((Benzyloxy)carbonyl)-1-((5R,S)-2-(benzylcar-
bamoyl)-5-(tert-butyldimethylsilyl(oxymethyl))pyrrolidin-1-yl)-
1-oxopropan-2-ylcarbamates 20a,b. Compound 18 (453 mg, 2.12
mmol) was dissolved in dry MeOH (7.1 mL). Then benzyl
isocyanide (310 µL, 2.54 mmol) and Boc-L-Asp(OBn)-OH 19 (755
mg, 2.33 mmol) were added, and the resulting solution was stirred
at room temperature for 1.25 h. After solvent evaporation under
reduced pressure, the residue was dissolved in AcOEt and washed
with saturated NaHCO3; the organic layer was finally washed with
brine and dried over Na2SO4. After solvent removal the crude was
purified by chromatography with CH2Cl2/AcOEt 95:5 f CH2Cl2/
AcOEt 4:6 + 1% MeOH to give 20a,b (1.180 g, 85%) as a white
foam. D.r., determined by HPLC, was 34:66 20a (cis, Rt 14.82 min):
20b (trans, Rt 13.56 min).
AB system, PhCH2O JAB)12.6]; 7.16-7.34 [11H, m, aromatics,
NHBoc]; 8.11 (m) [1H, broad t, CONHCH2, J)5.3]; 8.71 (M) [1H,
broad t, CONHCH2, J)5.5]. 13C NMR (taken in DMSO-d6 at 50
MHz at room temperature): δ -5.70, -5.63, and -5.58 [2C, Si-
(CH3)2]; 17.8 [SiC(CH3)3]; 24.7 (M), 26.7 (m), 27.0 (m), and 30.1
(M) [2C, C-3, C-4]; 25.6 (m) and 25.7 (M) [3C, SiC(CH3)3]; 28.0
[3C, OC(CH3)3]; 35.1 (M) and 36.1 (m) [CH2CO2Bn]; 41.8 (m)
and 42.2 (M) [NHCH2Ph]; 48.4 (m) and 48.8 (M) [CHNHBoc];
58.3 (m), 59.2 (M), 60.2 (M), and 60.4 (m) [2C, C-2, C-5]; 61.6
(M), 63.5 (m), 65.3 (M), and 65.4 (m) [2C, CH2OSi, OCH2Ph];
78.0 (M) and 78.6 (m) [OC(CH3)3]; 126.5, 126.6, 126.7, 127.0,
127.5, 127.7, 127.8, 128.09, 128.15, and 128.2 [10C, aromatic CH];
135.9 (m), 136.0 (M), 138.9 (M), and 139.3 (m) [2C, aromatic
quat.]; 155.0 (M) and 155.2 (m) [CdO Boc]; 169.9, 170.0, 170.4,
171.2, 171.5, and 171.8 [3C, CdO]. IR: νmax 3425, 2951, 2926,
2855, 1727, 1649, 1493, 1426, 1368, 1245, 1157, 1109, 835 cm-1
.
tert-Butyl (S)-3-(((Benzyloxy)amino)carbonyl)-1-((5R,S)-2-
(benzylcarbamoyl)-5-(hydroxymethyl)pyrrolidin-1-yl)-1-oxopro-
pan-2-ylcarbamates 22a,b. (1) Hydrogenolysis of benzyl ester. A
solution of 20a,b (316 mg, 0.48 mmol) in 95% EtOH (6 mL) was
treated with 10% Pd/C (36 mg) and hydrogenated at room
temperature for 3.5 h. The catalyst was filtered and the solvent
removed in vacuo. The oily residue was taken up twice, first with
dry toluene and then with dry CH2Cl2 to give a white solid that
was directly submitted to the following coupling. Rf 0.28 (cis) and
0.43 (trans) in PE/AcOEt 1:1 + 2% AcOH. (2) Coupling reaction
to give 21a,b. Crude acid was dissolved in dry CH2Cl2/DMF 3:1
(12 mL) and treated with N-benzylhydroxylamine hydrochloride
(116 mg, 0.72 mmol) and triethyl amine (370 µL, 2.66 mmol). After
cooling to 0 °C, PyBOP [(benzotriazol-1-yloxy)tripyrrolidinophos-
phonium hexafluorophosphate] (302 mg, 0.58 mmol) was added
and the resulting solution was allowed to stir at room temperature
for 1 h. The mixture was partitioned between water and AcOEt
and extracted. The organic layers were washed with brine and dried
over Na2SO4. The solvent was removed, and the crude was purified
by chromatography with PE/AcOEt 1:1 + 2% iPrOH f 2:8 + 2%
iPrOH to give 21a,b (288 mg, 89%) as a white foam. Rf 0.38 (cis)
and 0.50 (trans) in PE/AcOEt 1:1 + 2% iPrOH. (3) Silyl ether
removal. A solution of 21a,b (288 mg, 0.43 mmol) in CH3CN (2.5
mL) was cooled to 0 °C and treated with HF (40%, 125 µL). After
1.5 h at 0 °C, the reaction was quenched with solid NaHCO3 (250
mg), diluted with water, and extracted with AcOEt. The organic
layers were washed with brine and dried over Na2SO4. The solvent
was removed, and the crude product was purified by chromatog-
raphy with CH2Cl2 + 8% iPrOH f CH2Cl2 + 10% iPrOH to give
22a (80 mg) and 22b (144 mg) as white foams, with a 94% overall
yield. Compound 22a. Rf 0.46 in CH2Cl2 + 8% iPrOH. Found: C,
62.55; H, 6.80; N, 10.15. C29H38N4O7 requires C, 62.80; H, 6.91;
The following transformations have been performed on the
diastereomeric mixture. However, analytically pure samples of both
20a and 20b have been obtained by chromatography and were
independently characterized. Compound 20a. Rf 0.23 in CH2Cl2/
AcOEt 8:2 + 0.5% MeOH. Found: C, 64.35; H, 7.90; N, 6.50.
C35H51N3O7Si requires C, 64.29; H, 7.86; N, 6.43. [R]D ) -35.8
1
(c 3.14). H NMR: (taken in DMSO-d6 at 200 MHz. At room
temperature, two conformations in a 77 (M ) major):23 (m )
minor) ratio were observed; at 100 °C just one conformer but with
very broad signals can be detected): δ (room temperature) 0.002
[6H, s, Si(CH3)2]; 0.84 [9H, s, SiC(CH3)3]; 1.37 [9H, s, OC(CH3)3];
1.53-2.82 [6H, m, CH2CO2, H-3, H-4]; 3.44-4.46 [7H, m, CH2-
OSi, CHNHBoc, NHCH2Ph, H-2, H-5]; 4.68-5.08 [2H, m,
PhCH2O]; 7.10 (m) [1H, d, NHBoc, J)7.6]; 7.18-7.40 [10H, m,
aromatics]; 7.48 (M) [1H, d, NHBoc, J)7.2]; 8.10 (M) [1H, broad
s, CONHCH2]; 8.35 (m) [1H, broad s, CONHCH2]; 13C NMR (taken
in DMSO-d6 at 50 MHz at r. t.): δ -5.7 and -5.6 [2C, Si(CH3)2];
17.9 [SiC(CH3)3]; 25.7 [3C, SiC(CH3)3]; 26.7 (M), 26.8 (M) and
29.6 (m) [2C, C-3, C-4]; 28.0 [3C, OC(CH3)3]; 36.2 [CH2CO2Bn];
41.8 (M), and 42.6 (m) [NHCH2Ph]; 48.1 (M) and 49.2 (m)
[CHNHBoc]; 58.9 (M), 59.8 (m), 60.5 (M), and 61.0 (m) [2C, C-2,
C-5]; 63.0 (M), 63.6 (m), and 65.5 (M+m) [2C, CH2OSi, OCH2-
Ph]; 78.4 (M) and 78.5 (m) [OC(CH3)3]; 126.5, 126.7, 127.1, 127.7,
127.9, 128.1, 128.2, and 128.3 [10C, aromatic CH]; 135.8 (M+m),
139.0 (m), and 139.2 (M) [2C, aromatic quat.]; 155.0 [CdO Boc];
169.9, 170.1, 170.8, and 171.3 [3C, CdO]. IR: νmax 3675, 3421,
3005, 2954, 2856, 1721, 1655, 1494, 1420, 1367, 1292, 1188, 1161,
1094, 811 cm-1. Compound 20b. Rf 0.40 in CH2Cl2/AcOEt 8:2 +
0.5% MeOH. Found: C, 64.50; H, 7.80; N, 6.55. C35H51N3O7Si
1
N, 10.10. [R]D ) -32.9 (c 2.12). H NMR: (taken in DMSO-d6.
At room temperature two prevailing conformations in a 83 (M )
major):17 (m ) minor) ratio were observed; at 100 °C just one
conformer but with very broad signals can be detected): δ (room
temperature) 1.38 [9H, s, OC(CH3)3]; 1.72-2.48 [6H, m, CH2-
CONHOBn, H-3, H-4]; 3.23-4.78 [9H, m, CH2OH, PhCH2O,
CHNHBoc, NHCH2Ph, H-2, H-5]; 5.01 (m) [1H, broad t, OH,
J)4.8]; 5.07 (M) [1H, broad t, OH, J)4.7]; 6.85 [1H, d, NHBoc
(m or M), J)7.5]; 7.19-7.39 [11H, m, aromatics, NHBoc (m or
M)]; 8.32 (M) [1H, broad t, CONHCH2, J)5.7]; 8.61 (m) [1H,
broad t, CONHCH2, J)5.9]; 11.04 (M) [1H, broad s, ONHCO];
11.08 (m) [1H, broad s, ONHCO]. 13C NMR (taken in DMSO-d6
at room temperature): δ 27.3 (M), 27.5 (M), 28.9 (m), and 29.7
(m) [2C, C-3, C-4]; 28.0 [3C, OC(CH3)3]; 34.8 [CH2CONHOBn];
41.7 (M) and 42.5 (m) [NHCH2Ph]; 48.2 (M) and 49.3 (m)
[CHNHBoc]; 59.5, 60.4, and 61.1 [2C, C-2, C-5]; 62.1 [CH2OH];
76.8 [OCH2Ph]; 78.3 [OC(CH3)3]; 126.5, 126.7, 127.0, 128.1, 128.2,
and 128.7 [10C, aromatic CH]; 135.8 (M+m), 138.9 (m), and 139.2
(M) [2C, aromatic quat.]; 155.5 (m) and 155.0 (M) [CdO Boc];
166.5 (m) and 166.6 (M) [CONHOBn]; 170.8, 171.5, and 172.0
[2C, CdO]. IR: νmax 3677, 3353, 2975, 1695, 1655, 1493, 1434,
1
requires C, 64.29; H, 7.86; N, 6.43. [R]D ) +28.7 (c 2.10). H
NMR: (taken in DMSO-d6 at 200 MHz. At room temperature, two
conformations in a 70 (M ) major):30 (m ) minor) ratio were
observed; they do not collapse even at 100 °C): δ (room
temperature) -0.001 and 0.025 [2 × 3H, 2s, Si(CH3)2]; 0.85 (M)
and 0.84 (m) [9H, s, SiC(CH3)3]; 1.37 (M) and 1.33 (m) [9H, s,
OC(CH3)3]; 1.67-2.86 [6H, m, CH2CO2, H-3, H-4]; 3.23-4.88
[7H, m, CH2OSi, CHNHBoc, NHCH2Ph, H-2, H-5]; 4.82 and 4.91
(m) [2H, AB system, PhCH2O JAB)12.8]; 5.03 and 5.09 (M) [2H,
J. Org. Chem, Vol. 72, No. 6, 2007 2159

Banfi et al.
1368, 1159, 1073 cm-1. Compound 22b. Rf 0.27 in CH2Cl2 + 8%
iPrOH. Found: C, 62.85; H, 6.85; N, 10.20. C29H38N4O7 requires
C, 62.80; H, 6.91; N, 10.10. [R]D ) +19.9 (c 0.85). H NMR:
(M) and 79.1 (m) [OC(CH3)3]; 126.6, 126.9, 127.6, 128.1, 128.16,
and 128.21 [10C, aromatic CH]; 137.3 and 139.2 [2C, aromatic
quat.]; 153.5, 154.8, 170.4, and 171.0 [4C, CdO(or N)]. IR: νmax
3685, 3462, 3000, 1703, 1670, 1631, 1602, 1492, 1416, 1368, 1292,
1
(taken in DMSO-d6. At room temperature two prevailing conforma-
tions in about a 1:1 ratio were observed; they do not collapse even
at 100 °C): δ (room temperature) 1.30 and 1.37 [9H, 2s,
OC(CH3)3]; 1.73-2.54 [6H, m, CH2CONHOBn, H-3, H-4]; 3.07-
4.87 [10H, m, CH2OH, PhCH2O, CHNHBoc, NHCH2Ph, H-2, H-5,
OH one conformer]; 4.99 [1H, broad t, OH one conformer, J)4.8];
7.10 [1H, d, NHBoc one conformer, J)7.8]; 7.15 [1H, d, NHBoc
one conformer, J)6.6]; 7.21-7.40 [10H, m, aromatics]; 7.93 [1H,
broad t, CONHCH2 one conformer, J)5.7]; 8.71 [1H, broad s,
CONHCH2 one conformer]; 10.80 [1H, broad s, ONHCO one
conformer]; 10.99 [1H, broad s, ONHCO one conformer]. 13C NMR
(taken in DMSO-d6 at room temperature): δ 24.5, 26.7, 27.2, and
29.7 [2C, C-3, C-4]; 28.0 and 28.0 [3C, OC(CH3)3]; 33.3 and 34.4
[CH2CONHOBn]; 41.7 and 42.4 [NHCH2Ph]; 48.5 and 48.9
[CHNHBoc]; 58.9, 59.7, 60.0, and 60.6 [2C, C-2, C-5]; 62.4 [CH2-
OH]; 76.9 [OCH2Ph]; 78.2 and 78.6 [OC(CH3)3]; 126.46, 126.55,
126.7, 127.0, 127.2, 128.1, 128.17, 128.24, 128.69, and 128.74
[10C, aromatic CH]; 135.8, 135.9, 139.0, and 139.3 [2C, aromatic
quat.]; 155.0 and 155.4 [CdO Boc]; 166.6 and 166.7 [CONHOBn];
170.0, 170.7, 171.4, and 171.8 [2C, CdO]. IR: νmax 3667, 3362,
1159, 1017, 859, 720 cm-1
.
Compound 24b. The same conditions used for the preparation
of 23a were used, starting from 22b (74 mg, 0.13 mmol), but
employing DIAD (74 µL, 0.37 mmol) instead. Chromatography
with PE/Et2O 7:3 + 2% MeOH afforded 24b (49 mg, 68%) as a
pale-yellow foam. Rf 0.41 in Et2O + 2% MeOH. Found: C, 64.95;
H, 6.70; N, 10.50. C29H36N4O6 requires C, 64.91; H, 6.76; N, 10.44.
1
[R]D ) +25.8 (c 2.39). H NMR: (taken in DMSO-d6. At room
temperature two epimers in a 65 (M ) major):35 (m ) minor)
ratio were observed; at 90 °C the same ratio was maintained but
the signals become sharper): δ (90 °C) 1.20-2.44 [4H, m, H-3,
H-4]; 1.42 and 1.44 [9H, s, OC(CH3)3]; 1.83 and 2.57 (M) [AB
part of ABX system, CH2CHNHBoc, JAB)11.1, JAX)6.0, JBX)5.7];
2.33 and 2.61 (m) [AB part of ABX system, CH2CHNHBoc,
JAB)16.4, JAX)8.1 JBX)8.9]; 3.48 (t, J ) 7.4), 3.66 (dt, J ) 8.0
and 12.6), 3.91 (quintuplet, J ) 7.0), 3.98 (quintuplet, J ) 9.4),
4.08 (t, J ) 7.2), 4.17-4.38 (m) and 4.56 (quadruplet, J ) 8.8)
[7H, CH2O, CHNHBoc, NHCH2Ph, H-2, H-5]; 4.91 and 5.05 (m)
[2H, AB system, OCH2Ph, JAB)10.0]; 5.06 and 5.12 (M) [2H, AB
system, OCH2Ph, JAB)9.9]; 6.68 (m) [1H, broad s, NHBoc]; 6.89
(M) [1H, broad d, NHBoc, J)8.1]; 7.16-7.48 [10H, m, aromatics];
7.84 (m) [1H, broad s, CONHCH2]; 8.36 (m) [1H, broad s,
CONHCH2]. 13C NMR (taken in DMSO-d6 at room trmperature):
δ 28.0 (m) and 28.1 (M) [3C, OC(CH3)3]; 28.6 (M), 29.4 (m), 30.1
(m), and 30.3 (M) [2C, C-3, C-4]; 33.5 (m) and 34.7 (M) [CH2-
CHNHBoc]; 41.9 (M) and 42.1 (m) [NHCH2Ph]; 45.1 (m) and 49.5
(M) [CHNHBoc]; 60.5 (M), 60.9 (m), 63.4 (m), and 64.8 (M) [2C,
C-2, C-5]; 70.3 (M) and 74.4 (m) [CH2O ring]; 78.4 (m) and 79.1
(M) [OCH2Ph]; 78.6 [OC(CH3)3]; 108.4 (M) and 109.7 (m) [OCN-
(N)(C)]; 126.6, 126.7, 127.0, 128.17, 128.21, 128.24, 128.4, 128.6,
128.77, 128.80, and 129.3 [10C, aromatic CH]; 134.4 (M), 135.2
(m), 139.0 (m), and 139.1 (M) [2C, aromatic quat.]; 154.8 [CdO
Boc]; 165.2 (M) and 166.0 (m), 172.6 (m), and 173.3 (M) [2C,
CdO]. IR: νmax 3673, 3422, 3371, 3000, 1708, 1603, 1492, 1367,
3005, 1680, 1490, 1429, 1368, 1190, 1023 cm-1
.
tert-Butyl (5S,8S,10aR)-8-(Benzylcarbamoyl)-3-benzyloxyimino-
octahydro-6-oxo-1H-pyrrolo[2,1-c][1,4]oxazocin-5-ylcarbam-
ate 23a. A solution of 22a (80 mg, 0.14 mmol) in dry THF (10
mL) was treated with PPh3 (113 mg, 0.43 mmol) and DEAD (64
µL, 0.41 mmol). After 1.5 h of stirring at room temperature the
solvent was removed in vacuo, and the crude was purified by
chromatography with PE/AcOEt 4:6 + 0.7% MeOH to give 23a
(54 mg, 70%) as a white foam. Rf 0.40 in PE/AcOEt 4:6 + 0.7%
MeOH. Found: C, 64.85; H, 6.90; N, 10.30. C29H36N4O6 requires
1
C, 64.91; H, 6.76; N, 10.44. [R]D ) +43.3 (c 0.88). H NMR:
(taken in DMSO-d6. At room temperature two conformations in a
87 (M ) major):13 (m ) minor) ratio were observed; at 90 °C the
signals almost collapsed to give one rotamer): δ (90 °C) 1.40 [9H,
s, OC(CH3)3]; 2.01-2.18 [2H, m, H-3 or H-4]; 1.85-1.97 [1H, m,
H-3 or H-4]; 1.74-1.78 [1H, m, H-3 or H-4]; 2.45 and 2.79 [2H,
AB part of ABX system, CH2CHNHBoc, JAB)14.5, JAX)11.7,
JBX)5.2]; 4.12 [1H, dd, CHHO, J)1.8, 11.4]; 4.30 and 4.37 [2H,
AB part of ABX system, NHCH2Ph, JAB)15.2, JAX)6.1, JBX)5.8];
4.28-4.42 [1H, m, H-5]; 4.49 [1H, d, CHHO, J)11.7]; 4.59 [1H,
t, H-2, J)6.9]; 4.70 [1H, center of m, CHNHBoc]; 4.86 and 4.95
[2H, AB system, OCH2Ph, J)11.7]; 6.59 [1H, broad s, CHNHBoc];
7.21-7.80 [10H, m, aromatics]; 7.87 [1H, broad s, CONHCH2].
13C NMR (taken in DMSO-d6 at room temperature): δ 26.8, 27.7,
and 27.8 [2C, C-3, C-4]; 28.1 [3C, OC(CH3)3]; 34.5 (m) and 35.3
(M) [CH2CHNHBoc]; 41.9 [NHCH2Ph]; 49.2 [CHNHBoc]; 59.8
and 61.1 [2C, C-2, C-5]; 73.5, 73.9, and 75.0 [2C, CH2O]; 78.2
1247, 1159, 1041, 907, 862 cm-1
.
Acknowledgment. We wish to thank the University of
Genoa, M.U.R.S.T. (COFIN 04), and Fondazione San Paolo
for financial assistance and Mr. Vito Vece for his precious
collaboration to this work.
Supporting Information Available: General experimental
methods. Characterizations of all compounds 5-6, 1, and 2 as well
as of compounds 11a and 12b. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO062626Z
2160 J. Org. Chem., Vol. 72, No. 6, 2007