Isocyanide based multicomponent reactions of oxazolidines and related systems

Article abstract of DOI:10.1016/j.tet.2010.05.083

N-Alkyloxazolidines react in a multicomponent reaction with carboxylic acids and isocyanides to give N-acyloxyethylamino acid amides. The previously reported reaction conditions were improved using a design of experiments approach (DoE). Under the optimis

Full text of DOI:10.1016/j.tet.2010.05.083

Tetrahedron 66 (2010) 6496e6507
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Isocyanide based multicomponent reactions of oxazolidines and related systems
,
a,
Robert W. Waller a, Louis J. Diorazio b, Brian A. Taylor b, William B. Motherwell a , Tom D. Sheppard
*
*
a Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London, WC1H 0AJ, UK
b AstraZeneca Process R&D, AstraZeneca, Silk Road Business Park, Macclesfield, SK10 2NA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Alkyloxazolidines react in a multicomponent reaction with carboxylic acids and isocyanides to give
N-acyloxyethylamino acid amides. The previously reported reaction conditions were improved using
a design of experiments approach (DoE). Under the optimised conditions, good yields of the N-acyloxy-
ethylamino acid amide products are obtained both via a three- or four-component approach from N-
alkylethanolamines, aldehydes/ketones, isocyanides and carboxylic acids. The reaction of oxazolidines
without a nitrogen substituent was found to give either the expected Ugi products or the N-acyloxyethy-
lamino acid amides depending on the choice of reaction conditions. Optimised reaction conditions were
also developed for the ring-expansion of oxazolidines to morpholin-2-ones via reaction with an isocyanide
followed by hydrolysis. The mechanistic pathway of the multicomponent reaction was briefly investigated
using an 18O labelling experiment. The carboxylic acid component can be replaced bya range of other acidic
nucleophiles including thiobenzoic acid, thiophenol or 5-phenyltetrazole, which are incorporated via an
alternative pathway. These latter reactions can also be applied to 2-aminotetrahydrofurans, 2-amino-
tetrahydropyrans or 4-hydroxybut-2-one, further extending the structural diversity of the multicompo-
nent reaction products.
Received 1 March 2010
Received in revised form
17 May 2010
Accepted 21 May 2010
Available online 26 May 2010
In celebration of the award of the Tetra-
hedron Prize to Professor Steven Ley
Keywords:
Multicomponent reactions
Isocyanides
Design of experiments
Oxazolidines
Ring-opening reactions
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
provide ample evidence of the burgeoning interest in this rapidly
evolving research area, partly fuelled by the unique intellectual
Multicomponent reactions (MCRs) are convergent reactions
between three or more reactants in which all or most of the atoms
in the starting materials form part of the final product.1 They are
inherently atom economical processes in which relatively complex
products can be obtained in a one-pot reaction from simple starting
materials and thus exemplify many of the desired features of an
‘ideal synthesis’. Within this framework, isocyanide based multi-
component reactions (IMCRs) have provided a wealth of highly
useful sequences for the assembly of compound libraries of
particular interest to the pharmaceutical industry, and those which
incorporate amino acid or hydroxyacid motifs through the use of
the well known Ugi2 and Passerini3 reactions have proven to be
especially valuable. The replacement of the carbonyl component in
these reactions with a cyclic acetal unit could provide access to
alternative multicomponent pathways, although reactions have, to
date, been limited to simple isocyanide insertion into one of the
CeO bonds.4 However, the application of bis-secondary diamines,5
N,O-acetals6 and glycolaldehyde dimer7 in novel IMCRs has been
reported. Numerous reviews in recent years on the development
and application of isocyanide based multicomponent reactions
challenges posed by their design.8
We recently reported a novel three-component reaction (3-CR)
between N-alkyl oxazolidines, isocyanides and carboxylic acids
(Scheme 1).6 As part of our ongoing investigations into isocyanide
based multicomponent reactions (IMCR), we now describe, in full
detail, the optimisation of this reaction via a design of experiments
(DoE) approach, enabling the reaction to be carried out successfully
as a four-component reaction in which the oxazolidine is generated
in situ from a carbonyl compound and an ethanolamine. We also
describe a mechanistic study and the extension of these multi-
component reactions to a wider range of N,O-acetals and nucleo-
philic components.
R5
O
R1
R2
TsOH
H
N
O
N
R4
N
C
R5CO2H
R3
O
N
R4
MeCN
R1
R2
2
3
R3
O
1a-1g
4a-4p
1a R1= 4-MeC6H4, R2=H, R3=Me
1e R1= 4-MeC6H4, R2=H, R3=CH2Ph
1b R1= C6H13, R2=H, R3=Me
n
1f R1,R2= (CH2)5, R3=Me
1c R1= 4-MeOC6H4, R2=H, R3=Me 1g R1= 4-MeC6H4, R2=H, R3= Bu
1d R1= 4-O2NC6H4, R2=H, R3=Me
t
* Corresponding authors. E-mail addresses: w.b.motherwell@ucl.ac.uk (W.B.
Motherwell), tom.sheppard@ucl.ac.uk (T.D. Sheppard).
Scheme 1.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.083

R.W. Waller et al. / Tetrahedron 66 (2010) 6496e6507
6497
2. Results and discussion
When the reaction was carried out in the absence of the
carboxylic acid, 5a was obtained in 36% yield. A possible mecha-
nism for this bifurcated reaction pathway is shown in Scheme 3.
Trapping of the iminium ion by the isocyanide leads to nitrilium
cation 7, which can be expected to exist in equilibrium with cyclic
iminoether 8. Nucleophilic attack of a carboxylic acid on nitrilium
2.1. Three-component MCR of oxazolidines, isocyanides and
carboxylic acids
Initial reactions were carried out using an N-alkyloxazolidine, an
isocyanide and a carboxylic acidwith 10%TsOH as catalyst(Scheme 1)
and gave reasonable to good yields of the N-acyloxyethylamino acid
amides (Table 1) when the reactions were carried out at reflux in
MeCN.6 A wide variety of oxazolidines,9 isocyanides and carboxylic
acids were well tolerated and this reaction gives a complimentary
structural skeleton to the ubiquitous Ugi and Passerini reactions.
Thus, oxazolidines derived from both aromatic and aliphatic alde-
hydes bearing a variety of nitrogen substituents could be employed,
together with alkyl and aryl isocyanides and alkyl or benzoic acids.
The yields were good in most cases, although reactions with aryl
isocyanides or those with a bulky nitrogen substituent gave lower
conversions. The reaction was extremely slow at room temperature
and in the absence of an acid catalyst.
cation
7 will lead to the multicomponent product 4 after
subsequent acyl transfer in intermediate 9 (path A). Alternatively,
attack of the carboxylic acid on 8 could lead directly to the multi-
component product 4 via nucleophilic ring-opening (path B).10
Finally, competing hydrolysis of the cyclic intermediate 8 will
lead to the morpholin-2-one product 5. The 4-CR presumably leads
to the formation of a significant amount of morpholin-2-one due to
the generation of 1 equiv of water during the oxazolidine formation
step.
R4
R4
N
C
HO
R3
R3
N
N
O
N
R3
N
R1
R2
R1
R2
HO
R1
R2
1
6
Table 1
R5CO2H
Path A
7
Three-component reactions of oxazolidines, isocyanides and carboxylic acids
Oxazolidinone R4
R5
Yield (%) Product
O
R5
R4
N
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1c
1d
1e
1f
tBu
Ph
Et
Ph
Ph
Ph
Et
66
64
71
73
80
78
48
4a
4b
4c
4d
4e
4f
4g
4h
4i
O
tBu
O
cC6H11
R1
N
R4
9
R3
N
iPr
HO
tBu
N
R3
R2
R1 R2
8
R5CO2H
Path B
tBu
cC6H11
Ph
H2O
Acyl migration
R5
tBu
2-(3-Indole)ethyl 44
Et
O
R4
NH
O
2,6-Dimethylphenyl
2-Chloro-6-methylphenyl Ph
42
29
68
47
44
63
20
54
R1
4j
4k
4l
O
tBu
tBu
tBu
tBu
tBu
tBu
Ph
Ph
Ph
Ph
Me
Me
O
N
R3
4
R2
N
R3
O
4m
4n
4o
4pa
R1 R2
5
1g
1a
Scheme 3.
The reaction was carried out in iPrOH (see Scheme 7).
a
2.3. Design of experiments (DoE) optimisation of the
multicomponent reaction
2.2. Four-component MCR via in situ oxazolidine formation
After the successful development of the three-component
reaction between an N-alkyloxazolidine, isocyanide and carboxylic
acid (Scheme 1), we reasoned that an in situ preparation of the
N-alkyloxazolidine in the presence of an isocyanide and carboxylic
acidda four-component reaction (4-CR)dshould also be feasible. A
brief study indicated that oxazolidine formation was essentially
complete under the reaction conditions after 30 min.
Unfortunately, the reaction between n-heptanal, N-methyl-
ethanolamine, tert-butyl isocyanide and benzoic acid gave a disap-
pointing 13% yield of the desired four-component product 4e
(Scheme 2). Lactone 5a was isolated as the major product (25%)
from this reaction. Close examination of the NMR spectra of the
crude reaction mixtures of the earlier three-component reactions
indicated that small quantities of morpholin-2-one products were
also present, presumably due to traces of water in the reaction
mixture.
At this stage in our investigation, we decided to use a Design of
Experiments (DoE) approach11 in order to improve the yield of both
the three- and four-component reactions. Initially we looked at
developing conditions for the 3-CR, with the intention of being able
to subsequently carry out the reaction as a four-component re-
action, whilst minimising the formation of 5. DoE selects a wide
ranging and diverse set of experiments in which the factors are
independent of each other yet may be varied simultaneously. This
results in a causal predictive model, which quantifies the impor-
tance of each factor plus any factor/factor interactions. DoE has seen
extensive use in process chemistry in recent years and may be both
more thorough and efficient than classical one variable at a time
(OVAT) methods.11 The 3-CR to produce 4m (Scheme 4) was chosen
as a good substrate for the DoE process as it resulted in a moderate
Ph
O
O
N
O
n-C6H13
N
O
H
N
N
O
4m
+
Ph
N
OH
Ph
TsOH
MeCN
OH
n-C6H13
H
4e
+
t
O
Bu
C
O
t
13%
BuNC
PhCO2H
5a
5b
25%
1e
Scheme 2.
Scheme 4.

6498
R.W. Waller et al. / Tetrahedron 66 (2010) 6496e6507
yield of 44%, giving plenty of scope for yield improvement, as well
as a good chromophore for HPLC UV detection. MODDE 7Ô soft-
ware was used to design a set of reactions. The factors chosen for
variation and the levels employed are shown in Table 2. The effect
of the factors on the yield of both 4m and 5b was investigated.
20
15
10
5
Isopropanol
MeCN
Ethyl
Acetate
0
Table 2
Variables considered, with levels employed in design (DOE #1)
-5
Conc.
Variable
Temperature (ꢀC)
(ꢁ)
60
0.2
1
2
1
0
(þ)
80
0.4
1.5
10
1.5
-10
-15
-20
A
B
C
D
E
F
N/A
0.3
1.25
6
1.25
d
Anisole
Solvent concentration (M)
Benzoic acid (equiv)
Acid catalyst (mol %)
Isocyanide (equiv)
Solvent Type (four types)a
d
d
Graph 1. Scaled and centred coefficients for 4m yield.
a
(i)-Anisole (ii)-EtOAc (iii)-iPrOH (iv)-MeCN.
10
5
MeCN
We embarked upon a mixed level fractional factorial experi-
mental design (resolution III), with one factor at four levels and five
factors at two levels allowing main factors to be assessed for im-
portance, this was carried out as 16 experiments plus four control
experiments (Table 3). Yields of 4m and 5b were determined by
HPLC UV peak area integration relative to 1,1,1-trifluorotoluene
internal standard.
pTsOH
Anisole
Ethyl
Acetate
0
Table 3
Isopropanol
Isocyanide
Benzoic
Acid
-5
-10
Experimental plan and results (DOE #1)
#
A
B
C
D
E
F
Yield 4m (%)
Yield 5b (%)
1
2
3
4
5
6
7
8
ꢁ
þ
ꢁ
þ
þ
ꢁ
þ
ꢁ
þ
ꢁ
þ
ꢁ
ꢁ
þ
ꢁ
þ
ꢁ
ꢁ
þ
þ
ꢁ
ꢁ
ꢁ
ꢁ
þ
þ
þ
þ
ꢁ
ꢁ
ꢁ
ꢁ
þ
þ
þ
þ
0
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
þ
þ
þ
þ
þ
þ
þ
þ
0
þ
þ
ꢁ
ꢁ
ꢁ
ꢁ
þ
þ
þ
þ
ꢁ
ꢁ
ꢁ
ꢁ
þ
þ
0
þ
þ
ꢁ
ꢁ
þ
þ
ꢁ
ꢁ
ꢁ
ꢁ
þ
þ
ꢁ
ꢁ
þ
þ
0
i
48
44
65
67
38
36
64
61
47
38
74
68
54
33
68
57
41
42
40
38
26
23
18
30
18
16
30
36
27
17
14
21
24
13
25
29
18
18
19
18
ii
iii
iv
i
ii
iii
iv
i
ii
iii
iv
i
ii
iii
iv
ii
ii
ii
ii
Graph 2. Scaled and centred coefficients for 5b yield.
and disfavours the formation of 5b. A lower loading of TsOH is also
desirable, as it has no effect on the yield of 4m, whilst a higher level
favours the formation of side product 5b. The lower temperature of
60 ꢀC may also be used, as there is no benefit indicated by the use of
a higher temperature. However it should again be noted that initial
work showed that this reaction was very slow at room temperature
or in the absence of an acid catalyst. The new conditions obtained
from the DoE study were expected to reduce the amount of lactone
5b produced by hydrolysis of intermediate 8. We therefore in-
vestigated whether we could apply these conditions to the four-
component reaction. Initial experiments to determine the rapidity
of the oxazolidine formation in isopropanol were encouraging,
with over 80% conversion to the oxazolidine observed within
30 min under the reaction conditions. Satisfyingly when the 4-CR
was attempted between an ethanolamine, aldehyde, isocyanide
and carboxylic acid, a yield akin to the 3-CR was obtained in most
cases (Table 4).
9
10
11
12
13
14
15
16
17
18
19
20
0
0
0
0
0
0
0
0
0
0
0
0
The data was analysed using MODDE 7Ô software by a partial
least squares fitting model (PLS). This resulted in two models, the
first for 4m where R2¼0.922 and Q2¼0.844 and a second model for
5b where R2¼0.897 and Q2¼0.711, respectively. The data from the
models is viewed as a scaled and centred coefficient plot where
the sign and size of each coefficient bar shows the relative effect on
the yield and thus the relative importance of the factor in the model.
For the formation of 4m, temperature and equivalents of benzoic
acid, TsOH and isocyanide had no statistical effect within the
parameters investigated. Graph 1 shows that choice of solvent is the
most significant factor affecting the yield of 4m, with isopropanol
and to a lesser degree acetonitrile, being superior. Concentration of
reactants had a smaller effect within the range investigated.
Table 4
Four-component reactions of aminoalcohols, aldehydes, isocyanides and carboxylic
acids
R1
R2
R3
R4
R5
Yield (%)
Product
4-MeeC6H4
nC6H13
4-MeOeC6H4
4-O2NeC6H4
nC6H13
H
H
H
H
H
Me
Me
Me
Me
Me
tBu
Ph
Ph
Ph
Ph
Ph
68
56
66
30
43
4a
4e
4k
4l
tBu
tBu
tBu
cC6H11
4g
Graph 2 indicates that the factors affecting the yield of lactone
5b are solvent and TsOH loading. The use of acetonitrile as solvent
and a higher loading of TsOH results in an increased yield of 5b. The
two models together reveal that for a cleaner higher yielding
preparation of 4m in the presence of some water, isopropanol
should be selected as solvent, since it favours the formation of 4m
2.4. Application of bifunctional substrates
The new reaction conditions were also applied to the synthesis
of medium ring products in moderate yield via incorporation of the

R.W. Waller et al. / Tetrahedron 66 (2010) 6496e6507
6499
bifunctional acid/aldehyde components 10 and 11 (Scheme 5).12
Table 6
Experimental plan and yields of 5b (DOE #2)
These reactions were unsuccessful at high temperature, but the
multicomponent reaction products 12e14 were obtained in mod-
erate yield on stirring the reactions for prolonged periods at room
temperature.
#
A
B
C
4h (%)
22h (%)
44h (%)
1
2
3
4
5
6
7
8
9
10
ꢁ
ꢁ
þ
þ
ꢁ
ꢁ
þ
þ
0
ꢁ
ꢁ
ꢁ
ꢁ
þ
þ
þ
þ
0
i
ii
i
ii
i
ii
i
ii
i
i
0
0
4
8
0
0
7
12
4
5
15
3
26
23
16
7
33
24
28
30
26
4
38
29
27
9
51
36
41
43
O
O
OH
CO2H
CHO
H
N
TsOH
R2
R1
i-PrOH
RT
N
R2
0
0
10
2-7 days
N
C
HN
R1
O
c
12 R1
=
C6H11, R2 = Me 33%
The results of the second DoE (Graph 3) showed that solvent
type is again an important factor, with DMSO superior to sulfolane.
The loading of TsOH is also a factor, with a greater loading resulting
in a higher yield. Isocyanide loading again had no effect within the
levels studied. When the loading of TsOH was increased to 1.1 equiv,
reasonable yields of morpholinones 5aec could be obtained
(Scheme 6).
13 R1 = Bu, R2 = CH2Ph 25%
t
O
O
O
CO2H
OH
O
H
N
TsOH
H
i-PrOH
RT
2 days
N
t
O
HN
Bu
N
C
11
t
Bu
O
20
14 49%
DMSO
15
Scheme 5.
10
5
2.5. Design of experiments (DoE) optimisation
of morpholinone synthesis
Sulfolane
0
pTsOH
We then directed our attention to optimising the conditions for
the ring-expansion of oxazolidines to morpholinones by the re-
action of an oxazolidine with tert-butyl isocyanide (Scheme 6).
Model 2 in DoE #1 (Graph 2) indicates that the formation of 5b is
favoured by a polar aprotic solvent (acetonitrile) and a higher
loading of TsOH. These factors were further investigated using
a second design of experiments (DoE) process. The selected vari-
ables in this study were solvent type (two levels), TsOH acid catalyst
loading and isocyanide loading (Table 5). Preliminary studies of
polar aprotic solvents suggested sulfolane and DMSO to be superior
solvents to MeCN for the study; DMF was unsuitable. A full factorial
experimental design (resolution V) with three factors with each at
two levels, allowing main factors and interaction between factors to
be assessed for importance, was carried out as eight experiments
plus two control experiments (Table 6). Yields of 5b were
determined by HPLC UV peak area integration relative to 1,1,1-tri-
fluorotoluene internal standard at the three reaction times given in
Table 6. The data was analysed to give a model where R2¼0.892 and
Q2¼0.781.
-5
-10
-15
Graph 3. Scaled and centred coefficients for morpholin-2-one formation.
2.6. Mechanistic studies
Scheme 3 shows two feasible, alternative mechanisms for the
reaction between an N-alkyloxazolidine, an isocyanide and a car-
boxylic acid to give the 4-CR product 4. To clarify the mechanism,
18O-labelled acetic acid was used as the acid component in an MCR
with oxazolidinone 1a and tert-butyl isocyanide to give 4p-18O2
(Scheme 7).
O
N
O
NC
R2
n
TsOH
H
N
5a R1
=
C6H13, R2 = Me, 69%
N
N
C AcOH
O
t
5b R1 = 4-MeC6H4, R2 = CH2Ph, 60%
5c R1 = 4-MeC6H4, R2 = Me, 55%
i-PrOH
O
N
N
Bu
R2
O
DMSO
TsOH
75 °C, 24h
O
O
R1
1
R1
1a
4p 54%
4p-18O2 47%
Scheme 6.
Scheme 7.
Table 5
Variables considered, with levels employed in DOE #2
The position of the labelled oxygen atoms in the product of this
reaction will be different depending on the mechanistic pathway
followed (Scheme 8). Both carbonyl oxygens in the product will be
labelled if path A is followedd(attack of the acylium ion by the
carboxylic acid anion followed by O-acyl migration), while both
oxygen atoms in the ester group will be labelled via path B (acid
catalysed ring-opening by nucleophilic attack at the sp3 carbon).
Variable
(ꢁ)
0
(þ)
50
1.5
d
A
B
C
Acid catalyst (mol %)
Isocyanide (equiv)
10
1
30
1.25
Solvent Type (two types)a
d
d
a
(i)-DMSO (ii)-Sulfolane.

6500
R.W. Waller et al. / Tetrahedron 66 (2010) 6496e6507
Careful comparison of the mass spectrum of the product from the
labelling experiment with the unlabelled product 4p strongly
suggested that product 4p-18O2 contains 18O labels at the two
carbonyl oxygens, as evidenced by the mass observed for the
fragment 19. This indicates that carboxylic acids react via route
Adtrapping the acylium ion with subsequent O-acyl migration,
which may occur in either the intra- or inter-molecular mode.
a complex mixture of products. However, Ugi reactions using un-
protected ethanolamine have been reported to occur in high yield
in MeOH at room temperature in the absence of an acid catalyst.14
After optimisation of our reaction conditions using DoE, we decided
to reinvestigate the reaction of oxazolidine 21a, expecting to
see the formation of Ugi product 23 as previously reported
(Scheme 10).14 We were therefore extremely surprised to obtain
moderate yields of the O-acyl migration product 22a, with no
detectable quantity of the Ugi product 23 (Scheme 10). This is
somewhat unexpected, as acyl transfer to the amino group in the
intermediate would be expected to be much faster than acyl
transfer to the hydroxyl group due to the greater nucleophilicity of
nitrogen and the more favourable 5-exo-trig transition state (as
opposed to 7-exo-trig arrangement required for the O-acyl trans-
fer). Interestingly, when the same reaction was carried out in
methanol at room temperature, only the Ugi product 23 was
obtained. A series of experiments were carried out to investigate
the effect of temperature, solvent type and concentration on the
yields of the two possible products of this reaction. By varying the
solvent and/or temperature mixtures, of the two products could be
obtained. The TsOH catalyst is unnecessary for either reaction, in
fact resulting in slightly lower yields (Table 7).
t
Bu
HO
t
N
N
Bu
N
C
O
N
N
15
Ar
H
16
HO
18O
R
R
1a
18O
18OH
18O
Me
N
18
O
17
t
N
OH
N
Bu
N
R
R
18O
Acyl migration
N
18OH
N
18O
18O
O
18O
18O
O
R1
N
N
O
N
H
H
R2
HN
O
tBu
PhCOOH
21a
N
C
N
H
O
4p-18O2
22a R1= H, R2= COPh
23 R1= COPh, R2= H
18O
18O
18O
H
N
N
Scheme 10.
N
O
O
H
Table 7
Three-component reactions of oxazolidine 21a
4p-18O2
325
222
Temp (ꢀC) Solvent Conc. (M) Time (h) TsOH (mmol) 22a (%) 23 (%)
19
(321)
(220)
82
25
82
25
82
78
65
45
25
25
25
iPrOH
MeOH
iPrOH
MeOH
MeCN
EtOH
1
0.4
1
0.4
1
1
0.4
0.4
1
1
0.4
18
42
18
42
18
18
18
18
42
42
42
2
2
0
0
2
0
0
0
0
0
0
57
d
70
d
d
30
d
d
d
d
d
d
Scheme 8.
81
d
90
d
The cyclic intermediate 20 could be isolated in 73% yield when
2,6-dimethylphenyl isocyanide was reacted with 1b in the absence
of a carboxylic acid (Scheme 9). It is thought that the electronic
stabilisation provided by the aryl group, together with the in-
creased steric hindrance due to the presence of the methyl groups
results in a higher stability. Heterocycle 20 was stable in air for
more than three months at room temperature but could be
converted into product 4i by heating with propionic acid in the
presence of TsOH in iPrOH.
32
80
84
71
66
60
MeOH
MeOH
EtOH
iPrOH
iPrOH
In general lower temperatures and the use of more polar sol-
vents favoured the Ugi product 23, whereas heating in less polar
alcohols led to a preference for the O-acyl migration product 22a.
Our initial hypothesis was that the ester product 22a was formed by
acyl transfer from nitrogen to oxygen when the reaction was
heated. However, on heating Ugi product 23 to reflux for 18 h in the
presence of 10% TsOH only trace amounts of the ester 22a were
observed. No conversion was observed at all in the absence of the
acid catalyst suggesting that the ester 22a cannot be derived from
amide 23 in the multicomponent reaction. A possible explanation is
that the nitrogen atom is able to act as a general base for the OH in
refluxing iPrOH, but this process is disfavoured by hydrogen
bonding to the solvent in MeOH. Moderate to good yields of the
esters 22aed could be obtained from the ethanolamine derived
oxazolidines 21a and 21b (Scheme 11 and Table 8).13
EtCO2H
TsOH
N
TsOH
O
n
4i
N
O
C6H13
N
C
i
i
PrOH
PrOH
38%
N
n-C6H13
20 73%
1b
Scheme 9.
2.7. Use of oxazolidines derived from ethanolamine
Initial attempts during the early stages of our research to use
oxazolidine (21a)13 in the 3-CR with MeCN as solvent resulted in

R.W. Waller et al. / Tetrahedron 66 (2010) 6496e6507
6501
formation of a stable
a
-adduct after nucleophilic attack on the
O
O
HN
O
R3
N
C
H
N
acylium ion. Potentially, almost any nucleophile could be in-
corporated into the reaction, through suitable choice of conditions,
as the ring-opening process is likely to be thermodynamically
favourable due to formation of the stable amide bond. This novel
reaction pathway is complementary to both the Mumm rear-
rangement in the Ugi reaction and the Smiles rearrangement in
recently reported IMCRs of phenols and related derivatives.16
R3
N
H
O
R4
R1 R2
R4COOH
R1
R2
22a-22d
21a R1= 4-MeC6H4, R2= H
21b R1= Me, R2= Me
Scheme 11.
2.9. Extension to other N,O-acetals
Table 8
Three-component reactions of ethanolamine derived oxazolidines, isocyanides and
carboxylic acids
We briefly examined the extension of these novel multicom-
ponent reactions to N,O-acetals 27 and 28 (Scheme 13).17 Pleasingly,
the three-component reactions between these systems, tert-butyl
isocyanide and 5-phenyl-1H-tetrazole led to the formation of the
expected multicomponent products 29 and 30 in good yield. These
reactions presumably proceed via ring-opening of the in-
termediates 31 and 32, respectively.
Oxazolidinone
R3
R4
Yield (%)
Product
21a
21b
21b
21b
tBu
Ph
90
38
37
37
22a
22b
22c
22d
tBu
2-(3-Indole)-ethyl
Ph
Ph
cC6H11
tBu
N
N
2.8. Alternative nucleophiles for the oxazolidine 3-CR
Ph
t
N
Bu
N
C
N
O
N
N
Thioacids have been previously employed in isocyanide based
multicomponent reactions as alternatives to carboxylic acids.15 We
were keen to examine their use in an oxazolidine MCR to determine
whether the softer nature of the thioacid might favour the alter-
native ring-opening pathway (path B, Scheme 3).10 Pleasingly,
when thiobenzoic acid was employed in a 3-CR with oxazolidine 1a
and tert-butyl isocyanide, product 24 was obtained in 20% yield, in
which the intermediate 8 has undergone an SN2 ring-opening re-
action (Scheme 12).
29
N
O
N
N
74%
Ph
27
NH
NH
N
t
Bu
TsOH, MeCN
N
N
t
Bu
N
N
C
N
N
O
N
Ph
O
N
O
30
Ph
NH
28
O
83%
NH
N
t
Bu
TsOH, MeCN
O
R3
N
O
O
N
R3
t
O
Bu
Nu
N
C
t-Bu
N
N
TsOH
MeCN
N
H
Nu
N
R1
1a, 1b,
1f, 21a
R2
R1
R2
O
N
N
t
t
Bu
Bu
H
31
32
O
N
Scheme 13.
Ph
N
Nu =
S
S
Ph
N
Ph
26a-26b
24
25a-25c
Similar reactions could also be carried out via four-component
condensation of benzylamine, 4-hydroxybut-2-one 33, tert-butyl
isocyanide and either thiophenol or 5-phenyl-1H-tetrazole to give
the products 34 and 35 (Scheme 14). These reactions are likely to
involve the formation of intermediate 36, generated by trapping of
an in situ formed iminium ion with the isocyanide.
Scheme 12.
This result led us to investigate other soft nucleophiles as
potential components for the oxazolidine IMCR (Scheme 12 and
Table 9). Gratifyingly, multicomponent products could also be
obtained successfully with thiophenol and 5-phenyltetrazole. In
the latter case, only a single regioisomer (assigned as 26 on the
basis of NOE experiments) of the tetrazole product was obtained.
We are currently investigating the scope of this variation of our
3-CR as the incorporation of aromatic heterocycles as components
in an MCR could be of great potential utility in pharmaceutical
library synthesis. The role of the cyclic intermediate 8 as a trap for
a diverse range of nucleophiles, circumvents one of the major
limitations of Ugi-type reactions: the requirement for the
O
t
Ph
Bu
NH2
C
CONH Bu
OH
t
Ph
N
H
Nu
N
NuH
33
tBu
N
N
N
Ph
N
N
Nu =
S
O
36
Ph
34
53%
35
Ph
N
H
26%
Scheme 14.
Table 9
Three-component reactions of oxazolidines, isocyanides and nucleophiles
3. Conclusions
R1
R2
R3
Nu
Yield (%)
Product
4-MeC6H4
nC6H13
H
H
Me
Me
Me
H
Me
Me
PhCSOH
PhSH
PhSH
PhSH
5-Phenyl-1H-tetrazole
5-Phenyl-1H-tetrazole
20
59
29
6
71
67
24
In summary, oxazolidines clearly constitute a powerful and
flexible scaffold for a diverse set of multicomponent trans-
formations, leading to potentially useful structural diversity in
a single reaction step. A wide range of ethanolamines, carbonyl
compounds, isocyanides and carboxylic acids can be employed in
either three- or four-component reaction sequences. These
25a
25b
25c
26aa
26ba
(CH2)5
4-MeC6H4
H
H
H
nC6H13
4-MeC6H4
a
The product was assigned as the 1,4 substituted tetrazole isomer.

6502
R.W. Waller et al. / Tetrahedron 66 (2010) 6496e6507
reactions can be extended to incorporate a variety of nucleophiles in
place of the carboxylic acid component including thiols and tetra-
zoles and the use of other N,O-acetals is also feasible. Further work is
underway to explore the full scope of these novel multicomponent
reactions of N,O-acetals and to extend them to other systems.
was removed under reduced pressure and the crude product was
purified by column chromatography to yield the product.
4.4.1. 2-[(tert-Butylcarbamoyl-p-tolylmethyl)methylamino]ethyl
benzoate 4a. Yield: 66% (method A), 68% (method C); colourless oil;
Rf 0.23 (Petrol/EtOAc, 2:1); IR (film) nmax 3400e3100 (br), 2928,
4. Experimental
1718, 1665, 1604, 1514, 1365 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 1.27
(9H, s, tBu), 2.27 (3H, s, tolyleCH3), 2.34 (3H, s, NeCH3), 2.67e2.88
(2H, m, NeCH2), 4.00 (1H, s, CH), 4.33e4.65 (2H, m, CH2eO), 6.93
(1H, br s, NH), 7.05e7.60 (9H, m, Ar); 13C NMR (75 MHz, CDCl3)
4.1. General methods
Melting points were performed on a Reichert Thermovar hot
stage apparatus and are uncorrected. Boiling points were measured
during distillation. 1H NMR spectra were recorded at 300 MHz on
a Bruker AMX300 spectrometer at 300 K and 13C NMR spectra were
recorded at 75 MHz on a Bruker AMX300 spectrometer at 300 K
unless otherwise stated. Macherey-Nagel 0.20 mm silica gel 60
UV254 plates were used for TLC. Infrared spectra were carried out on
a Shimadzu FTIR 8700 and were recorded as a thin film or a NujolÒ
mull in between NaCl disks. Mass spectra and accurate mass
measurements were recorded using a Micromass 70-SE magnetic
sector spectrometer at the University College London Chemistry
department. Unless stated, chemicals were used as purchased and
without further purification. Unless otherwise stated, all reactions
were performed under an atmosphere of nitrogen using oven dried
glassware, which was cooled under a flow of nitrogen prior to use.
DMSO was distilled from calcium hydride. Benzene was distilled
from sodium benzophenone ketyl. THF, CH2Cl2, Et2O, MeCN, tolu-
ene and n-hexane, were prepared as anhydrous, degassed solvents
from an anhydrous engineeringÒ zeolite drying apparatus. Meth-
anol from was distilled from magnesium methoxide. Anhydrous
isopropanol was purchased from Sigma/Aldrich. Petrol refers to
light petroleum ether bp 40e60 ꢀC.
Oxazolidines 1aeg and 21aeb were prepared from the corre-
sponding carbonyl compounds and the appropriate aminoalcohol
by: (i) repeated concentration of an ethanol solution; (ii) heating
under Dean/Stark conditions in the presence of a trace amount of
iodine; or (iii) stirring in ether in the presence of MgSO4.6,9,13 N,O-
Acetals 28 and 29 were prepared from 1,2-dihydrofuran and 1,2-
dihydropyran, respectively, according to a literature procedure.17
Spectroscopic data for these compounds were identical to those
previously reported.
d 21.1, 28.6, 40.5, 50.7, 53.5, 62.4, 75.6, 128.4, 129.0, 129.2, 129.7,
130.1, 132.9, 133.1, 137.8, 166.5, 170.8; HRMS (CI): [MþH]þ,
C23H31N2O3 requires 383.23347, found 383.23425.
4.4.2. 2-[(tert-Butylcarbamoyl-p-tolylmethyl)methylamino]ethyl
propionate 4b. Yield: 64% (method A); colourless oil; Rf 0.26 (Petrol/
EtOAc, 2:1); IR (film) nmax 3404 (br), 3054, 2970, 2926, 2826, 1737,
1664, 1513, 1456 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 1.08 (3H, t, J
7.7 Hz, CH2eCH3), 1.28 (9H, s, tBu), 2.14 (3H, s, PheCH3), 2.25 (3H, s,
NeCH3), 2.27 (2H, q, J 7.7 Hz, CH2eCH3), 2.54 (2H, t, J 5.8 Hz, NeCH2),
3.76 (1H, s, CH), 4.10 (2H, t, J 5.8 Hz, OeCH2), 6.23 (1H, br s, NH),
7.03e7.10 (4H, m, AreH); 13C NMR (100 MHz, CDCl3)
d 9.5, 21.5, 28.0,
40.7, 51.0, 53.9, 62.3, 76.3, 129.2, 129.5, 133.6, 138.1, 171.2, 174.7;
HRMS: [MþH]þ, C19H31N2O3 requires 335.23346, found 335.23240.
4.4.3. 2-[(Cyclohexylcarbamoyl-p-tolylmethyl)methylamino]ethyl
benzoate 4c. Yield: 71% (method A); pale yellow oil; Rf 0.14 (Petrol/
EtOAc, 2:1); IR (film) nmax 3310 (br), 2922, 2952, 1726, 1651, 1562,
1460 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 0.95e1.81 (10H, m, cyclo-
hexyl), 2.27 (3H, s, AreCH3), 2.29 (3H, s, NeCH3), 2.67e2.81 (2H, m,
NeCH2), 3.60e3.78 (1H, m, CHNHCO), 4.00 (1H, s, CH), 4.30e4.43
(2H, m, CH2eO), 6.93 (1H, br s, NH), 7.03e7.54 (7H, m, Ar),
8.00e8.05 (2H, m, Ar); 13C NMR (75 MHz, CDCl3)
d 21.1, 24.8, 25.4,
32.7, 40.5, 50.7, 53.5, 62.3, 75.6, 128.4, 129.0, 129.2, 129.7, 130.1,
132.9, 133.1, 137.8, 166.5, 170.8; HRMS: [MþNa]þ, C25H32N2NaO3
requires 431.23105, found 431.23051.
4.4.4. 2-[(Isopropylcarbamoyl-p-tolylmethyl)methylamino]ethyl
benzoate 4d. Yield: 73% (method A); colourless oil; Rf 0.25 (Petrol/
EtOAc, 2:1); IR (film) nmax 3420 (br), 2985, 2968, 1739, 1651, 1506,
1452 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 1.00 (3H, d, J 6.6 Hz,
CHeCH3), 1.07 (3H, d, J 6.6 Hz, CHeCH3), 2.28 (3H, s, NeCH3 or
PheCH3), 2.29 (3H, s, NeCH3 or PheCH3), 2.63e2.70 (1H, m,
NeCHH), 2.72e2.80 (1H, m, NeCHH), 3.96 (1H, s, C]OCH),
4.2. General procedure for 3-CR in MeCN (method A)
Oxazolidine (2 mmol), carboxylic acid (2 mmol), para-toluene-
sulfonic acid (38 mg, 0.2 mmol) and isocyanide (2 mmol) were
added to MeCN (5 mL) and heated at reflux under an atmosphere of
nitrogen for 18e24 h until completion by TLC. Excess solvent was
removed under reduced pressure and the crude product was
purified by column chromatography to yield the product.
3.99e4.05 (1H, m, CHe(CH3)2), 4.35e4.41 (1H, m OeCHH),
4.46e4.52 (1H, m, OeCHH), 6.91 (1H, d, J 8.3 Hz, NH), 7.10 (2H, d, J
7.6 Hz, AreH), 7.16e7.20 (2H, m, AreH), 7.39e7.48 (2H, m, AreH),
7.56e7.62 (1H, m, AreH), 8.04e8.09 (2H, m, AreH); 13C NMR
(100 MHz, CDCl3) d 21.0, 22.4, 40.4, 40.7, 53.4, 62.2, 62.3, 75.1, 128.3,
128.8, 129.1, 129.5, 130.0, 132.9, 133.0, 137.7, 166.4, 170.5; HRMS:
[MþH]þ, C22H29N2O3 requires 369.2178, found 369.2177.
4.3. Optimised general procedure for 3-CR in iPrOH (method B)
4.4.5. 2-[(tert-Butylcarbamoylheptyl)methylamino]ethyl
benzoate
Oxazolidine (2 mmol), carboxylic acid (2 mmol), para-toluene-
sulfonic acid (8 mg, 0.04 mmol) and isocyanide (2 mmol) were
added to iPrOH (2 mL) and heated at reflux under an atmosphere of
nitrogen for 18e24 h until completion by TLC. Excess solvent was
removed under reduced pressure and the crude product was
purified by column chromatography to yield the product.
4e. Yield: 80% (method A), 56% (method C); colourless oil; Rf 0.34
(Petrol/EtOAc, 2:1); IR (film) nmax 3365 (br), 3026, 2948, 2926, 2856,
1724, 1674, 1506, 1452 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 0.74 (3H,
t
t, J 6.9 Hz, CH3), 1.16 (9H, s, Bu), 1.17e1.41 (6H, m, CH2) 1.44e1.59
(2H, m, CH2), 1.62e1.77 (2H, m, CH2), 2.23 (3H, s, NeCH3),
2.77e2.87 (3H, m, NeCH2 & CH), 4.32e4.47 (2H, m, CH2eO), 6.62
(1H, br s, NH), 7.26e7.96 (5H, m, Ph); 13C NMR (75 MHz, CDCl3)
4.4. Optimised general procedure for 4-CR in iPrOH (method C)
d 14.0, 22.5, 27.2, 27.4, 28.6, 29.5, 31.6, 38.3, 50.2, 53.7, 62.7, 68.9,
128.3, 129.5, 130.0, 133.0, 166.4, 172.2; HRMS: [MþH]þ, C22H37N2O3
Aldehyde/ketone (2 mmol), aminoalcohol (2 mmol), para-tol-
requires 377.28040, found 377.28061.
uenesulfonic acid (8 mg, 0.04 mmol), carboxylic acid (2 mmol) and
i
isocyanide (2 mmol) were added to PrOH (2 mL) and heated at
4.4.6. 2-[(tert-Butylcarbamoylheptyl)methylamino]ethyl propionate
reflux under an atmosphere of nitrogen for 18e24 h. Excess solvent
4f. Yield: 78% (method A); colourless oil; Rf 0.21 (Petrol/EtOAc,

R.W. Waller et al. / Tetrahedron 66 (2010) 6496e6507
6503
2:1); IR (film) nmax 3330 (br), 2951, 2930, 2958, 1746, 1662, 1510,
1456 cmꢁ1 1H NMR (CDCl3, 300 MHz)
0.77 (3H, t, J 6.6 Hz,
133.2, 137.6, 166.4, 171.3; HRMS: [MþH]þ, C25H34ClN2O3 requires
;
d
445.2258, found 445.2266.
CH3), 1.05 (3H, t, J 7.5 Hz, propyleCH3), 1.13e1.23 (6H, m, CH2),
t
1.25 (9H, s, Bu), 1.39e1.54 (2H, m, CH2), 1.60e1.72 (2H, m, CH2),
4.4.11. 2-{[tert-Butylcarbamoyl-(4-methoxyphenyl)methyl]methyl-
amino}ethyl benzoate 4k. Yield: 68% (method A), 66% (method C);
colourless oil; Rf 0.40 (Petrol/EtOAc, 2:1); IR (film) nmax 3390 (br),
2.19 (3H, s, NeCH3), 2.25 (2H, q, J 7.5 Hz, C]OeCH2), 2.53e2.71
(2H, m, NeCH2), 2.77 (1H, dd, J 7.3, 5.3 Hz, CH), 4.04 (2H, t, J
6.5 Hz, OeCH2), 6.78 (1H, br s, NH); 13C NMR (75 MHz, CDCl3)
2980, 2970, 2930, 2885, 1716, 1678, 1510, 1452 cmꢁ1 1H NMR
;
d
9.0, 14.0, 22.7, 27.3, 27.5, 28.7, 29.2, 30.0, 38.4, 51.0, 53.3, 62.0,
(CDCl3, 300 MHz) d
1.27 (9H, s, tBu), 2.33 (3H, s, NeCH3), 2.67e2.85
68.9, 172.3, 174.3; HRMS: [MþH]þ, C18H37N2O3 requires
(2H, m, NeCH2), 4.02 (3H, s, OMe), 4.06 (1H, s, CH), 4.32e4.62 (2H,
m, CH2eO), 6.78 (2H, d, J 6.8 Hz, m-PhOMe), 7.04 (1H, br s, NH), 7.17
(2H, d, J 6.8 Hz, AreH), 7.32e7.53 (3H, m, AreH), 8.00 (2H, d, J
329.28040, found 329.28191.
4.4.7. 2-[(1-Cyclohexylcarbamoylheptyl)methylamino]ethyl benzoate
4g. Yield: 48% (method A), 43% (method C); colourless oil; Rf 0.26
(Petrol/EtOAc, 2:1); IR (film) nmax 3400e3250 (br), 2930, 2955,1717,
8.5 Hz, AreH); 13C NMR (75 MHz, CDCl3)
d 28.5, 40.4, 50.6, 53.4,
55.2, 62.3, 75.1, 113.8, 128.1, 128.4, 129.6, 130.1, 130.2, 132.5, 133.1,
159.4, 166.4, 170.9; HRMS: [MþH]þ, C23H31N2O4 requires
399.22837, found 399.22720.
1647, 1510, 1452 cmꢁ1 1H NMR (CDCl3, 300 MHz):
; d 0.86 (3H, t, J
7.0 Hz, CH3), 0.88e1.05 (3H, m, alkyl), 1.20 (9H, m, alkyl), 1.32e1.80
(8H, m, alkyl), 2.27 (3H, s, NeCH3), 2.83e2.97 (3H, m, NeCH2 and
CH), 3.53e3.61 (1H, m, CH), 4.28e4.42 (2H, m, CH2eO), 6.82 (1H, d,
J 8.5 Hz, NH), 7.36e7.41 (2H, m, AreH), 7.47e7.51 (1H, m, AreH)
4.4.12. 2-{[tert-Butylcarbamoyl-(4-nitrophenyl)methyl]methyl-
amino}ethyl benzoate 4l. Yield: 47% (method A), 30% (method C);
orange oil; Rf 0.40 (Petrol/EtOAc, 2:1); IR (film) nmax 3300 (br), 3060,
7.96e8.01 (2H, m, AreH); 13C NMR (75 MHz, CDCl3)
d
14.0, 22.6,
2990, 2895, 2805, 1716, 1682, 1521, 1452 cmꢁ1 1H NMR (CDCl3,
;
24.8, 25.4, 27.3, 27.5, 29.5, 31.7, 32.8, 33.1, 38.4, 47.5, 53.8, 62.6, 68.5,
128.4, 129.6, 130.1, 133.1, 166.5, 171.9; HRMS: [MþH]þ, C24H39N2O3
requires 403.29605, found 403.29553.
300 MHz) d
1.26 (9H, s, tBu), 2.30 (3H, s, NeCH3), 2.67e2.88 (2H, t, J
5.6 Hz NeCH2), 4.18 (1H, s, CH), 4.41(2H, m, CH2eO), 6.98 (1H, br s,
NH), 7.39e7.47 (4H, m, AreH), 7.52e7.57 (1H, m, AreH), 8.01 (2H, d,
J 8.6 Hz, AreH), 8.12 (2H, d, J 8.6 Hz, AreH); 13C NMR (75 MHz,
4.4.8. 3-(1H-Indol-3-yl)-2-[(1-tert-butylcarbamoylheptyl)methyl-
aminoethyl propionate 4h. Yield: 44% (method A); colourless oil;
Rf 0.12 (Petrol/EtOAc, 2:1); IR (film) nmax 3300 (br), 3387 (br),
CDCl3) d 28.5, 40.0, 51.0, 53.8, 61.9, 74.7, 123.5, 128.5, 129.6, 129.9,
130.2, 133.3, 143.0, 147.5, 166.4, 169.1; HRMS: [MþNa]þ,
C22H27N3NaO5 requires 437.19099, found 437.19266.
3020, 2959, 2930, 2858, 1732, 1666, 1514, 1456 cmꢁ1 1H NMR
;
(CDCl3, 300 MHz)
d
0.89 (3H, t, J 6.8 Hz CH3), 1.20e1.32 (8H, m,
4.4.13. 2-[Benzyl-(tert-butylcarbamoyl-p-tolylmethyl)amino]ethyl
benzoate 4m. Yield: 44% (method A); colourless oil; Rf 0.28 (Petrol/
EtOAc, 4:1); IR (film) nmax 3342 (br), 2924, 1717, 1678, 1510,
t
CH2), 1.37 (9H, s, Bu), 1.50e1.64 (1H, m, CHHealkyl), 1.68e1.82
(1H, m, CHHealkyl), 2.26 (3H, s, NeCH3), 2.62e2.72 (2H, m,
NeCH2), 2.75 (2H, t, J 7.5 Hz, COeCH2), 2.87 (1H, t, J 5.4 Hz, CH),
3.13 (2H, t, J 7.5 Hz, C]CeCH2), 4.17 (2H, t, J 5.6 Hz, OeCH2), 6.92
(1H, s, NH), 6.97 (1H, s, C]CH), 7.11 (1H, t, J 7.2 Hz, Ar), 7.18 (1H,
t, J 7.1 Hz, Ar), 7.34 (1H, d, J 7.8 Hz, Ar), 7.69 (1H, d, J 7.7 Hz, Ar),
1364 cmꢁ1; 1H NMR (CDCl3, 300 MHz) 1.26 (9H, s, tBu), 2.34 (3H, s,
d
PheCH3), 2.79e2.98 (2H, m, NeCH2), 3.53e3.58 (1H, d, J 4.7 Hz,
PheCH2), 3.87e3.92 (1H, d, J 4.7 Hz, benzylic CH2), 4.20e4.49 (2H,
m, CH2eO), 4.39 (1H, s, CH), 6.96 (1H, br s, NH), 7.13e7.98 (14H, m,
8.84 (1H, br s, NH indole); 13C NMR (75 MHz, CDCl3)
d
14.1, 20.8,
AreH); 13C NMR (75 MHz, CDCl3)
d 21.2, 28.7, 49.2, 50.9, 56.3, 62.6,
22.7, 27.3, 27.6, 28.8, 29.6, 31.7, 35.1, 38.5, 50.5, 53.4, 62.3, 69.1,
111.4, 114.3, 118.5, 119.1, 121.76, 121.82, 127.1, 136.5, 172.6, 173.5;
HRMS: [MþH]þ, C26H41N3O3 requires 443.31479, found
443.31388.
70.2, 127.4, 128.4, 128.5, 129.0, 129.7, 129.9, 130.2, 132.1, 133.1, 137.6,
138.8, 166.5, 170.8; HRMS: [MþH]þ, C29H35N2O3 requires
459.26475, found 459.26337.
4.4.14. 2-[(1-tert-Butylcarbamoylcyclohexyl)methylamino]ethyl ben-
zoate 4n. Yield: 63% (method A); colourless oil; Rf 0.63 (Petrol/
EtOAc, 2:1); IR (film) nmax 3380 (br), 2973, 2944, 2870, 1710, 1680,
4.4.9. 3-{[1-(2,6-Dimethylphenylcarbamoyl)heptyl]methylamino}
ethyl propionate 4i. Yield: 42% (method A); colourless oil; Rf 0.40
(Petrol/EtOAc, 2:1); IR (film) nmax 3300 (br), 3020, 2955, 2928, 2856,
1505, 1465 cmꢁ1 1H NMR (CDCl3, 300 MHz) 1.19 (9H, s, tBu),
; d
1738, 1674, 1468 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
0.88 (3H, t, J
1.30e1.37 (2H, m, CH2) 1.51e1.91 (8H, m, CH2), 2.21 (3H, s, NeCH3),
2.68 (2H, t, J 6.0 Hz, NeCH2,), 4.28 (2H, t, J 6.1 Hz CH2eO), 6.22 (1H,
br s, NH), 7.04e7.41 (3H, m, Ar), 7.92 (2H, d, J 9.4 Hz, Ar); 13C NMR
6.6 Hz, CH3), 1.02 (3H, t, J 7.5 Hz, COCH2CH3), 1.25e1.58 (10H, m,
CH2), 1.63e1.78 (1H, m, CH2), 1.88e2.00 (1H, m, CH2), 2.21 (6H, s,
AreCH3), 2.45 (3H, s, NeCH3), 2.91 (2H, m, NeCH2,), 3.25 (1H, t, J
6.5 Hz, CH), 4.22 (2H, t, J 5.5 Hz, CH2eO), 7.01 (3H, s, Ar), 8.65 (1H, br
(75 MHz, CDCl3)
d 22.9, 25.9, 28.6, 30.2, 36.0, 49.8, 50.1, 63.7, 66.4,
128.3, 129.9, 130.1, 132.9, 166.3, 174.4; HRMS: [MþH]þ, C21H33N2O3
s, NH); 13C NMR (75 MHz, CDCl3)
d
8.9, 14.1, 18.7, 22.6, 27.33, 27.38,
requires 361.24910, found 361.24790.
29.6, 31.7, 38.8, 54.0, 62.1, 68.6, 126.8, 128.8, 134.1, 134.9, 171.4,
174.4; HRMS: [MþNa]þ, C22H36N2NaO3 requires 399.26235, found
399.26169.
4.4.15. 2-[tert-Butyl-(tert-butylcarbamoyl-p-tolyl-methyl)amino]
ethyl acetate 4o. Yield: 20% (method A); colourless needles mp
90e91 ꢀC (CHCl3); Rf 0.40 (Petrol/EtOAc, 2:1); IR (KBr Disc) nmax
3314 (br), 2968, 2924, 1738, 1670, 1506, 1456 cmꢁ1; 1H NMR (CDCl3,
4.4.10. 2-{[1-(2-Chloro-6-methylphenylcarbamoyl)heptyl]methyl-
amino}ethyl benzoate 4j. Yield: 29% (method A); colourless oil; Rf
0.18 (Petrol/EtOAc, 2:1); IR (film) nmax 3280 (br), 2961, 2919, 2874,
t
t
300 MHz)
d 1.16 (9H, s, Bu), 1.41 (9H, s, Bu), 2.00 (3H, s, CO2CH3),
2.28 (3H, s, CH3 tolyl), 2.30e2.41 (1H, m, NeCHH), 2.81e2.92 (1H,
m, NeCHH), 3.58e3.67 (1H, m, OeCHH), 3.78e3.87 (1H, m,
OeCHH), 4.55 (1H, s, CH), 7.01 (2H, d, J 8.1 Hz, Ph), 7.08 (2H, d, J
1719, 1637, 1467 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 0.77 (3H, t, J
6.9 Hz, CH2CH3), 1.16e1.28 (6H, m, CH2), 1.32e1.47 (2H, m, CH2),
1.65e1.75 (1H, CH2), 1.87e1.94 (1H, m, CH2), 2.10 (3H, s, NeCH3),
2.55 (3H, s, PheCH3), 3.13 (2H, t, J 5.6 Hz, NeCH2), 3.53 (1H, dd, J 7.1,
6.0 Hz, CH), 4.45e4.90 (2H, t, J 5.6 Hz, OeCH2), 7.05e7.32 (2H, m,
Ar), 7.44e7.49 (2H, m, AreH), 7.57e7.61 (1H, m, Ar), 7.95e8.00 (1H,
m, AreH), 8.11 (2H, m, AreH), 8.70 (1H, br s, NH); 13C NMR
8.1 Hz, Ph), 7.83 (1H, br s, NH); 13C NMR (75 MHz, CDCl3)
d 21.1, 27.9,
28.7, 42.8, 50.6, 56.7, 65.2, 66.6, 129.5, 130.2, 134.4, 137.3, 170.7,
174.0; HRMS: [MþH]þ, C21H35N2O3 requires 363.26475, found
363.26552.
(100 MHz, CDCl3)
d
13.9, 18.9, 22.5, 27.2, 27.5, 29.3, 31.5, 38.4, 53.6,
4.4.16. 2-[(tert-Butylcarbamoyl-p-tolylmethyl)methylamino]ethyl
62.0, 68.3, 127.0, 127.5, 128.17, 128.23, 129.0, 129.4, 130.0, 132.9,
acetate 4p. Yield: 54% (method B); colourless oil; Rf 0.40 (2:1

6504
R.W. Waller et al. / Tetrahedron 66 (2010) 6496e6507
Petrol/EtOAc); IR (thin film) nmax 3330 (br), 2987, 2943, 2872, 2875,
13C NMR (CDCl3)
d 28.5, 51.5, 51.8, 56.9, 64.9, 71.0, 127.3, 127.7, 128.4,
1732, 1667, 1515, 1455 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
1.28 (9H,
128.4, 128.7, 128.9, 129.1, 130.2, 130.8, 134.4, 137.5, 168.9, 173.7;
HRMS (EI): [MþH]þ, C22H27N2O3 requires 367.20217, found
367.20211; LRMS (EI): 389 (100, MþNa), 367 (64, MþH), 390 (23),
369 (9), 368 (8), 181 (7).
t
s, Bu), 2.09 (3H, s, COCH3), 2.16 (3H, s, tolyleCH3), 2.23 (3H, s,
NeCH3), 2.54 (2H, t, J 5.6 Hz, NeCH2), 3.76 (1H, s, CH), 4.09 (2H, t, J
5.6, OeCH2), 6.95 (1H, br s, NH), 7.11 (2H, d, J 8.0 Hz, Ar), 7.23 (2H, d,
J 8.0 Hz, Ar); 13C NMR (CDCl3, 100 MHz)
d 21.1, 21.2, 28.7, 40.2, 51.5,
53.5, 61.9, 75.5, 127.5, 128.8, 129.1, 133.0, 138.8, 167.4, 169.2; HRMS:
[MþH]þ, C18H29N2O3 requires 321.2173, found 321.2155; LRMS:
[MþH]þ, 176 (100), 321 (78, MþH), 220 (54), 343 (17, MþNa), 177
(12), 221 (8).
4.5.3. 11-Methyl-7-oxo-6,7,9,10,11,12-hexahydro-5,8-dioxa-11-aza-
benzocyclodecene-12-carboxylic acid tert-butylamide 14. 2-(Meth-
ylamino)-ethanol (161
ml, 2 mmol), TsOH (8 mg, 0.04 mmol) and
tert-butyl isocyanide (226
ml, 2 mmol) were added to a solution of
2-formylphenoxyacetic acid (360 mg, 2 mmol) in anhydrous iPrOH
(1.5 mL). The mixture was stirred for 48 h at rt. Excess solvent was
removed under reduced pressure and the residue was purified by
flash chromatography (1:1 Petrol/EtOAc) to give 14 as a white solid,
which was recrystallised from iPrOH to give colourless prisms
(317 mg, 49%); mp 140e143 ꢀC; Rf 0.20 (1:1 Petrol/EtOAc); IR (KBr
4.4.17. 2-[(tert-Butylcarbamoyl-p-tolylmethyl)methylamino]ethyl
acetatee18O2 4p-18O2. Yield: 47% (method B); colourless oil; Rf 0.37
(Petrol/EtOAc, 2:1); IR (film) nmax 3360 (br), 2966, 2920, 2884, 1708,
1643, 1512, 1456 cmꢁ1; 1H NMR (CDCl3, 300 MHz) 1.28 (9H, s, tBu),
d
2.00 (3H, s, COCH3), 2.15 (3H, s, tolyleCH3), 2.24 (3H, s, NeCH3),
2.57e2.62 (2H, m, NeCH2), 3.83 (1H, s, CH), 4.10 (2H, t, J 5.7 Hz,
OeCH2), 6.99 (1H, br s, NH), 7.04e7.23(4H, m, AreH); 13C NMR
Disc) nmax 3356, 2944, 1742, 1674, 1508, 1487, 1448 cmꢁ1
;
1H NMR
t
(CDCl3)
d
1.30 (9H, s, Bu), 2.44 (3H, s, NeCH3), 2.53 (1H, dt, J 15.5,
(75 MHz, CDCl3)
d
20.9, 21.0, 28.5, 40.0, 50.6, 53.3, 61.6, 75.5, 128.6,
2.3 Hz, NeCHH), 2.71e2.82 (1H, m, NeCHH), 4.24 (2H, dd, J 6.9,
1.7 Hz, OeCH2), 4.40 (1H, d, J 13.4 Hz, OCHHC]O), 4.58 (1H, d, J
13.4 Hz, OCHHC]O), 4.79 (1H, s, CH), 6.66 (1H, br s, NH), 6.98e7.07
(2H, m, Ar), 7.18 (1H, td, J 7.7, 1.6 Hz, Ar), 7.26 (1H, dd, J 7.6, 1.4 Hz,
128.8, 129.0, 129.2, 137.7, 137.9, 170.3 (br), 170.7; HRMS: [MþH]þ,
C18H29N2O18O2 requires 325.22630, found 325.22528.
Fragmentation of the [MþH]þ ion, m/z 321 was achieved by in-
source collision induced dissociation (CID). The in-source CID mass
spectrum for the labelled compound 4p-18O2 showed the fragment
ion at m/z 222, consistent with [MþHꢁC4H9NHC18OH]þ, a loss of
103 Da. The in-source CID mass spectrum for the non-labelled
compound 4p showed the fragment ion at m/z 220, consistent with
[MþHꢁC4H9NHCOH]þ, a loss of 101 Da.
Ar); 13C NMR (CDCl3)
d 28.6, 38.8, 50.4, 50.6, 60.6, 66.8, 72.8, 121.2,
124.5, 128.6, 129.5, 130.9, 156.8, 168.1, 171.1; HRMS (EI): [MþH]þ,
C17H25N2O4 requires 321.18143, found 321.18214; LRMS (EI): 321
(100 MþH), 322 (18), 343 (10, MþNa), 220 (7), 276 (5), 298 (4).
4.6. General procedure for morpholin-2-one synthesis
4.5. Multicomponent reaction of acid/aldehydes
Oxazolidine (2 mmol), TsOH (419 mg, 2.2 mmol) and tert-butyl
isocyanide (226 ml, 2 mmol) were added to reagent grade DMSO
4.5.1. 5-Methyl-1-oxo-3,4,5,6-tetrahydro-1H-benzo[f][1,4]oxazocine-
6-carboxylic acid cyclohexylamide 12. 2-(Methylamino)-ethanol
(5 mL) and heated to 75 ꢀC under an atmosphere of nitrogen for
24 h. The reaction was cooled to rt and satd NaHCO3(aq) (5 mL) and
EtOAc (5 mL) were added. The organic layer was separated and the
aqueous layer was further extracted with EtOAc (2ꢂ5 mL). The
combined organic layers were then washed with brine (5 mL),
dried (MgSO4), filtered and evaporated under reduced pressure and
purified by column chromatography (Petrol/EtOAc).
(161
(202
m
m
l, 2 mmol), TsOH (8 mg, 0.04 mmol) and cyclohexyl isocyanide
l, 2 mmol) were added to a solution of 2-carboxybenzaldehyde
i
(300 mg, 2 mmol) in anhydrous PrOH (1.5 mL). The mixture was
stirred for 48 h at rt under N2. Excess solvent was removed under
reduced pressure and the residue was purified by flash chromatog-
raphy (2:1 Petrol/EtOAc) to give 12 as a white solid, which was
recrystallised from methanol to give colourless needles (202 mg,
33%); mp 146e148 ꢀC; Rf 0.12 (2:1 Petrol/EtOAc); IR (KBr Disc) nmax
4.6.1. 3-Hexyl-4-methylmorpholin-2-one 5a. Yield: 69%; colourless
oil; Rf 0.25 (2:1 Petrol/EtOAc); IR (thin film) nmax 2963, 2931, 2874,
3309, 2936, 2854, 1717, 1634, 1539, 1454 cmꢁ1
;
1H NMR (CDCl3)
2867,1738,1552,1459 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 0.83 (3H, t, J
d
1.08e1.37 (5H, m, cy), 1.51e1.88 (5H, m, cy), 2.32 (3H, s, NeCH3), 2.94
6.8 Hz, CH2CH3), 1.23e1.32 (7H, m, alkyl), 1.45e1.54 (1H, m, alkyl),
1.70e1.78 (1H, m, alkyl),1.88e2.02 (1H, m, alkyl), 2.30 (3H, s, NeCH3),
2.60 (1H, ddd, J 12.8, 11.1, 3.3 Hz, NeCHH), 2.84 (1H, dt, J 9.8, 2.7 Hz,
NeCHH), 2.99 (1H, t, J 4.9 Hz, CH), 4.23e4.27 (1H, ddd, J 10.8, 3.2,
2.3 Hz, OeCHH), 4.38 (1H, td, J 10.9, 3.1 Hz, OeCHH); 13C NMR (CDCl3,
(1H, ddd, J 14.2, 7.3, 3.8 Hz, NeCHH), 3.07 (1H, ddd, J 14.2, 4.0, 3.8 Hz,
NeCHH), 3.69 (1H, dtd, J 10.5, 8.5, 3.9 Hz, cy), 3.84 (1H, ddd, J 12.6, 5.8,
3.8 Hz, OeCHH), 4.07 (1H, ddd, J 12.6, 7.3, 4.0 Hz, OeCHH), 4.27 (1H, s,
CH), 6.96 (1H, d, J 8.2 Hz, NH), 7.04e7.06 (1H, m, Ar), 7.28e7.32 (3H, m,
Ar); 13C NMR (CDCl3)
d
24.6, 25.4, 32.7, 32.9, 42.4, 48.1, 55.5, 64.8, 70.6,
75 MHz) d 14.0, 22.6, 24.7, 29.3, 30.1, 31.7, 43.1, 51.1, 67.0, 67.7, 170.5;
128.3, 128.6, 130.2, 130.8, 134.9, 168.3, 173.4; HRMS: [MþH]þ,
C18H25N2O3 requires 317.18652, found 317.18574; MS: (EI) 339 (100,
MþNa), 317 (83, MþH), 340 (17), 318 (13), 202 (12), 221 (7).
HRMS: [MþH]þ, C11H22NO2 requires 200.16505, found 200.16432.
4.6.2. 4-(4-Benzyl)-3-p-tolyl-morpholin-2-one 5b. Yield: 60%; col-
ourless oil; Rf 0.45 (2:1 Petrol/EtOAc); IR (thin film) nmax 3018, 2973,
4.5.2. 5-Benzyl-1-oxo-3,4,5,6-tetrahydro-1H-benzo[f][1,4]oxazocine-
1742, 1512, 1452 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 2.27 (3H, s,
6-carboxylic acid tert-butylamide 13. 2-(Benzylamino)-ethanol
PheCH3), 2.55 (1H, ddd, J 12.7, 11.0, 3.2 Hz, NeCHH), 2.90 (1H, dt, J
12.7, 2.7 Hz, NeCHH), 3.08 (1H, d, J 13.3 Hz, PheCHH), 3.71 (1H, d, J
13.3 Hz, PheCHH), 4.14 (1H, s, CH), 4.27 (1H, ddd, J 10.8, 3.2, 2.4 Hz,
OeCHH), 4.46 (1H, td, J 11.0, 3.2 Hz, OeCHH), 7.11 (1H, m, Ar), 7.14
(1H, m, Ar), 7.16e7.19 (3H, m, Ar), 7.21e7.24 (2H, m, Ar), 7.36e7.39
(284
(226
m
m
l, 2 mmol), TsOH (8 mg, 0.04 mmol) and tert-butyl isocyanide
l, 2 mmol) were added to solution of 2-carbox-
a
ybenzaldehyde (300 mg, 2 mmol) in anhydrous iPrOH (1.5 mL). The
mixture was stirred for 7 days at rt under N2. Excess solvent was
removed in vacuo and the residue was purified by flash chroma-
tography (3:2 Petrol/EtOAc) to give 13 as a pale yellow oil (179 mg,
25%); Rf 0.40 (1:1 Petrol/EtOAc); IR (thin film) nmax 3340 (br), 2984,
(2H, m, Ar); 13C NMR (CDCl3, 100 MHz)
d 21.5, 47.1, 59.2, 69.0, 70.7,
127.9, 128.7, 129.20, 129.23, 129.9, 134.9, 137.5, 138.6, 169.3; HRMS:
[MþH]þ, C18H20NO2 requires 282.14940, found 282.14894.
2924, 2885, 1716, 1667, 1486, 1408 cmꢁ1
;
1H NMR (CDCl3)
d
1.29
t
(9H, s, Bu), 2.82 (1H, ddd, J 14.2, 6.2, 4.2 Hz, NeCHCH), 3.19 (1H,
ddd, J 14.2, 6.7, 4.8 Hz, NeCHH), 3.78 (2H, s, AreCH2), 3.88 (1H, ddd,
J 12.5, 6.8, 4.2 Hz, OeCHH), 4.11 (1H, ddd, J 12.4, 6.3, 4.8 Hz,
OeCHH), 4.41 (1H, s, CH), 6.42 (1H, br s, NH), 7.29e7.42 (9H, m, Ar);
4.6.3. 4-Methyl-3-p-tolylmorpholin-2-one 5c. Yield: 55%; colour-
less oil; Rf 0.10 (1:1 Petrol/EtOAc); IR (thin film) nmax 2951, 2795,
1738, 1514, 1456 cmꢁ1
;
1H NMR (CDCl3, 400 MHz)
d
2.19 (3H, s,
AreCH3/NeCH3), 2.32 (3H, s, AreCH3/NeCH3), 2.79e2.84 (1H, m,

R.W. Waller et al. / Tetrahedron 66 (2010) 6496e6507
6505
NeCHH), 3.00 (1H, ddd, J 12.7, 3.0, 1.9 Hz, NeCHH), 3.87 (1H, s, CH),
4.37e4.45 (1H, ddd, J 10.8, 3.2, 2.0 Hz, OeCHH), 4.64 (1H, td, J 11.3
3.5 Hz, OeCHH), 7.15 (2H, d, J 8.0 Hz, AreH), 7.27 (2H, d, J 8.0 Hz,
300 MHz) d 0.83e1.04 (4H, m, Cy), 1.27 (6H, s, (CH3)2), 1.44e1.61
(4H, m, Cy), 1.70e1.79 (2H, m, Cy), 2.83 (2H, t, J 5.4 Hz, NeCH2),
3.56e3.64 (1H, tdt, J 10.6, 8.9, 3.9 Hz CHNHCO), 4.35 (2H, t, J 5.4 Hz,
OeCH2), 7.21 (1H, bd, J 8.4 Hz, CONH), 7.41 (2H, dd, J 8.5, 7.4 Hz,
AreH), 7.53 (1H, tt, J 7.4, 1.3 Hz, AreH), 8.00 (2H, br d, J 8.5 Hz,
AreH); 13C NMR (CDCl3, 100 MHz)
d 21.2, 43.6, 51.0, 68.4, 72.3,
128.7, 129.3, 134.4, 138.1, 168.9; HRMS: [MþH]þ, C12H16NO2
requires 206.11810, found 206.11854.
AreH); 13C NMR (CDCl3, 75 MHz)
d 24.8, 25.5, 25.7, 33.0, 42.7, 47.5,
58.5, 64.9, 128.4, 129.6, 130.0, 133.1, 166.5, 175.2; HRMS: [MþH]þ,
4.6.4. (Z)-(2,6-Dimethylphenyl)-(3-heptyl-4-methylmorpholin-2-yli-
C19H29N2O3 requires 333.21782, found 333.21810.
dene)amine
20. 2-Hexyl-3-methyloxazolidine
1b
(342 mg,
2 mmol), TsOH (8 mg, 0.04 mmol) and 2,6-dimethylphenyl iso-
cyanide (262 mg, 2 mmol) were added to anhydrous PrOH (2 mL)
4.7.4. 2-(1-tert-Butylcarbamoyl-1-methylethylamino)ethyl benzoate
22d. Yield: colourless oil (224 mg, 37%); Rf 0.35 (1:1 Petrol/EtOAc);
IR (thin film) nmax 3330 (br), 2995, 2940, 2880, 1720, 1665, 1510,
i
and heated at reflux under an atmosphere of nitrogen for 17 h.
Excess solvent was removed under reduced pressure and the crude
product was purified by column chromatography (10:1 Petrol/
EtOAc) to yield 20 as a colourless oil (421 mg, 73%); Rf 0.23 (6:1
Petrol/EtOAc); IR (thin film) nmax 3021, 2957, 2957, 2854, 1624, 1477,
1406 cmꢁ1; 1H NMR (CDCl3)
d
1.27 (9H, s, tBu), 1.28 (6H, s, 2ꢂCH3),
2.86 (2H, t, J 5.5 Hz, NeCH2), 4.37 (2H, t, J 5.6 Hz, OeCH2), 7.13 (1H,
br s, NH), 7.43 (2H, t, J 7.5 Hz, m-Ar), 7.52 (1H, m, p-Ar), 8.01 (2H, d, J
7.5 Hz, o-Ar); 13C NMR (CDCl3)
d 25.6, 28.6, 42.6, 50.1, 58.9, 65.0,
1443 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
0.99 (3H, t, J 6.4 Hz,
128.4, 129.6, 130.0, 133.1, 166.6, 175.6; HRMS (CI): [MþH]þ,
C17H27N2O3 requires 307.20216, found 307.20284; LRMS (CI): 206
(100), 307 (63, MþH), 111 (16), 149 (15), 113 (15), 207 (14).
CH2CH3),1.33e1.51 (6H, m, alkyl),1.58e1.74 (2H, m, alkyl),1.93e2.04
(1H, m, alkyl), 2.17 (6H, s, Phe(CH3)2), 2.21e2.34 (1H, m, alkyl), 2.48
(3H, s, NeCH3), 2.65 (1H, ddd, J 12.8, 9.4, 3.8 Hz, NeCHH), 2.92 (1H,
dt, J 12.8, 3.5 Hz, NeCHH), 3.32 (1H, t, J 4.8 Hz, CH), 4.05e4.22 (2H, m,
4.7.5. N-(tert-Butylcarbamoyl-p-tolylmethyl)-N-(2-hydroxyethyl)
benzamide 23. 2-p-Tolyl-oxazolidine 21a (327 mg, 2 mmol), ben-
OeCH2), 6.83 (1H, t, J 7.6 Hz, AreH), 7.04 (2H, d, J 7.6 Hz, AreH); 13
C
NMR (CDCl3, 75 MHz)
d
14.2, 18.9, 22.7, 25.4, 29.7, 31.8, 32.0, 43.5,
zoic acid (244 mg, 2 mmol) and tert-butyl isocyanide (226 ml,
51.1, 65.2, 66.4, 122.6, 127.5, 128.3, 145.4, 155.8; HRMS (CI): [MþH]þ,
2 mmol) were added to anhydrous methanol (5 mL) at room tem-
perature and stirred for 42 h under an atmosphere of nitrogen.
Excess solvent was removed under reduced pressure and the crude
product was purified by column chromatography (2:1 Petrol/
EtOAc) to yield 23 (660 mg, 90%) as colourless needles; Rf 0.16 (2:1
Petrol/EtOAc); mp 138e139 ꢀC (iPrOH/Petrol); IR (KBr Disc) nmax
3406 (br), 3317, 3027, 2993, 2981, 2931, 1665, 1618, 1542, 1450,
C19H31N2O requires 303.24364, found 303.24371.
4.7. General procedure for reaction of N-unsubstituted
oxazolidines to give 22aed
Oxazolidine 21 (2 mmol), benzoic acid (2 mmol) and tert-butyl
isocyanide (2 mmol) were added to anhydrous PrOH (2 mL) and
i
1419 cmꢁ1; 1H NMR (DMSO-d6, 400 MHz, 373 K) 1.35 (9H, s, tBu),
d
heated at reflux under an atmosphere of nitrogen for 18 h. Excess
solvent was removed under reduced pressure and the crude
product was purified by column chromatography (4:1 Petrol/
EtOAc) to yield the ester 22.
2.33 (3H, s, PheCH3), 3.13e3.27 (2H, m, NeCH2), 3.39e3.49 (2H, m,
OeCH2), 4.45 (1H, br s, OH), 5.58 (1H, s, CH), 7.20e7.26 (4H, m,
AreH), 7.38 (1H, br s, NH), 7.43e7.48 (5H, m, AreH); 13C NMR
(100 MHz, DMSO-d6, 373 K) d 19.9, 27.9, 47.5, 50.1, 58.6, 63.9, 125.9,
127.6, 128.34, 128.40, 128.5, 132.9, 136.6, 136.7, 168.5, 171.5; HRMS:
4.7.1. 2-[(tert-Butylcarbamoyl-p-tolylmethyl)amino]ethyl benzoate
22a. Yield: 90%; Rf 0.36 (2:1 Petrol/EtOAc); colourless oil (516 mg,
70%); Rf 0.36 (2:1 Petrol/EtOAc); IR (thin film) nmax 3370 (br), 2985,
[MþH]þ, C22H29N2O3 requires 369.21782, found 369.21828.
4.8. Incorporation of other nucleophilic components
2930, 2880,1716,1670,1514,1452 cmꢁ1; 1H NMR (CDCl3)
d 1.28 (9H,
s, tBu), 2.07 (1H, br s, NH), 2.28 (3H, s, tolyleCH3), 2.88e3.02 (2H, m,
NeCH2), 4.08 (1H, s, CH), 4.34e4.41 (2H, m, OeCH2), 6.96 (1H, s,
NH), 7.10 (2H, d, J 7.8 Hz, Ar), 7.22 (2H, d, J 8.1 Hz, Ar), 7.38e7.55 (3H,
4.8.1. S-{2-[(tert-Butylcarbamoyl-p-tolylmethyl)methylamino]ethyl}
thiobenzoate 24. Oxazolidine 1a (355 mg, 2 mmol), thiobenzoic
acid (259
ml, 2 mmol), TsOH (38 mg, 0.2 mmol) and tert-butyl iso-
m, Ar), 8.00 (2H, d, J 8.3 Hz, Ar); 13C NMR (CDCl3)
d
21.1, 28.7, 47.1,
cyanide (166 mg, 226 ml, 2 mmol) were added to MeCN (5 mL) and
50.6, 64.3, 67.7, 126.8, 128.4, 129.1, 129.5, 130.0, 133.1, 136.6, 137.7,
166.5, 171.2; HRMS (FAB): [MþH]þ, C22H29N2O3 requires 369.21781,
found 369.21690; LRMS (FAB): 369 (100, MþH), 268 (61), 370 (27),
154 (23), 176 (13).
heated at reflux under an atmosphere of argon for 24 h. Excess
solvent was removed under reduced pressure and the crude
product was purified by column chromatography (4:1 Petrol/
EtOAc) to yield 24 as a pale yellow oil; Rf 0.33 (Petrol/EtOAc, 2:1); IR
(thin film) nmax 3444 (br), 3007, 2970, 2898, 1667, 1662, 1506, 1470;
t
4.7.2. 2-(1-(tert-Butylamino)-2-methyl-1-oxopropan-2-ylamino)
ethyl 3-(1H-indol-3-yl)propanoate 22b. Yield: 38%; colourless
prisms, mp 112e114 ꢀC (iPrOH); Rf 0.11 (Petrol/EtOAc/Et3N,
50:50:1); IR (KBr Disc) nmax 3354, 3318, 3171, 2974, 2923,1730,1645,
1H NMR (CDCl3, 400 MHz)
d
1.24 (9H, s, Bu), 2.15 (3H, s, NeCH3),
2.22 (3H, s, AreCH3), 3.02 (2H, t, J 6.7 Hz, NeCH2), 3.09e3.21 (2H,
m, SeCH2), 3.81 (1H, br s, CH), 7.02 (2H, d, J 8.0 Hz, AreH), 7.09 (2H,
d, J 8.0 Hz, AreH), 7.34e7.38 (2H, m, AreH), 7.47e7.51 (1H, m,
1521, 1456 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
1.22 (6H, s, (CH3)2),
AreH), 7.87e7.89 (2H, m, AreH); 13C NMR (100 MHz, CDCl3)
d 21.5,
1.27 (9H, s, tBu), 2.04 (1H, s, NH), 2.67 (2H, t, J 5.5 Hz, NeCH2), 2.75
(2H, t, J 7.5 Hz, COeCH2), 3.12 (2H, t, J 7.5 Hz, IndoleeCH2),
3.61e4.36 (2H, m, OeCH2), 7.00 (1H, d, J 2.2 Hz, AreH), 7.11e7.22
(2H, m, AreH), 7.28 (1H, br s, NH amide), 7.34 (1H, d, J 8.0 Hz, AreH),
7.59 (1H, d, J 7.7 Hz, AreH), 8.51 (1H, br s, NH indole); 13C NMR
27.6, 29.0, 39.9, 51.0, 54.5, 75.5, 127.1, 128.5, 128.9, 130.0, 132.8,
133.4, 136.8, 137.5, 170.5, 191.2; HRMS: [MþH]þ, C23H31N2O2S
requires 399.2106, found 399.2109.
4.8.2. 2-[Methyl-(2-phenylsulfanylethyl)amino]octanoic acid tert-
(CDCl3, 75 MHz)
d
20.7, 25.5, 28.7, 34.9, 42.3, 50.1, 58.8, 64.5, 111.3,
butylamide 25a. Oxazolidine 1b (342 mg, 2 mmol), thiophenol
114.5, 118.6, 119.2, 121.6, 122.0, 127.1, 136.4, 173.4, 175.6; HRMS (CI):
(205
(166 mg, 226
m
l, 2 mmol), TsOH (19 mg, 0.1 mmol) and tert-butyl isocyanide
[MþH]þ, C21H32N3O3 requires 374.24437, found 374.24483.
ml, 2 mmol) were added to anhydrous MeCN (1 mL)
and heated at reflux under an atmosphere of nitrogen for 24 h.
Excess solvent was removed under reduced pressure and the crude
product was purified by column chromatography (8:1 Petrol/
EtOAc) to yield 25a as a colourless oil (428 mg, 59%); Rf 0.21 (6:1
4.7.3. 2-(1-Cyclohexylcarbamoyl-1-methylethylamino)ethyl benzo-
ate 22c. Yield: 37%; yellow oil; Rf 0.19 (Et2O); IR (thin film) nmax
3320 (br), 2930, 2871, 1720, 1661, 1514, 1463 cmꢁ1; 1H NMR (CDCl3,

6506
R.W. Waller et al. / Tetrahedron 66 (2010) 6496e6507
Petrol/EtOAc); IR (thin film) nmax 3430 (br), 2958, 2927, 2856, 1674,
5-phenyl-1H-tetrazole (292 mg, 2 mmol), TsOH (19 mg, 0.1 mmol)
and tert-butyl isocyanide (226 l, 2 mmol) were added to anhy-
1510, 1481, 1456 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
0.81 (3H, t, J
m
6.7 Hz, CH2CH3),1.21 (7H, br s, alkyl),1.28 (9H, s, tBu),1.34e1.59 (2H,
m, alkyl), 1.64e1.73 (1H, m, alkyl), 2.19 (3H, s, NeCH3), 2.71 (2H, t, J
6.6 Hz, NeCH2), 2.81 (1H, dd, J 5.5, 7.1 Hz, CH), 2.99 (2H, t, J 6.6 Hz,
drous MeCN (5 mL) at rt and then heated at reflux under an
atmosphere of nitrogen for 24 h. Excess solvent was removed under
reduced pressure and the crude product was purified by column
chromatography (80:10:1 Petrol/EtOAc/Et3N) to yield 26b as a col-
ourless oil (441 mg, 67%); Rf 0.11 90:30:1 (Petrol/EtOAc/Et3N); IR
SeCH2), 7.10e7.29 (5H, m, Ph); 13C NMR (CDCl3, 75 MHz)
d 14.1,
22.6, 27.2, 27.5, 28.7, 29.2, 31.7, 32.7, 37.4, 50.4, 53.7, 68.7, 126.0,
128.9, 129.2, 136.4, 172.4; HRMS: [MþH]þ, C21H37N2OS requires
365.26265, found 365.26202.
(thin film) nmax 3190 (br), 2966, 2873, 1668, 1514, 1466, 1452 cmꢁ1
;
1H NMR (CDCl3)
d
1.56 (9H, s, tBu), 2.26 (3H, s, NeCH3), 2.33 (3H, s,
tolyleCH3), 2.85e2.92 (1H, m, CH3NCHH), 2.99 (1H, m, CH3NCHH),
3.84 (1H, s, CH), 4.62e4.68 (1H, m, NeCHH), 4.72e4.81 (1H, m,
NeCHH), 6.61 (1H, s, NH), 6.92 (2H, d, J 8.2 Hz, Ar), 7.02 (2H, d, J
7.8 Hz, Ar), 7.49e7.60 (3H, m, Ar), 8.13e8.16 (2H, m, Ar); 13C NMR
4.8.3. 1-[Methyl(2-phenylsulfanylethyl)amino]cyclohexanecarboxylic
acid tert-butylamide 25b. Oxazolidine 1f (311 mg, 2 mmol), thio-
phenol (205
ml, 2 mmol), TsOH (19 mg, 0.1 mmol) and tert-butyl
isocyanide (166 mg, 226
m
l, 2 mmol) were added to anhydrous
(CDCl3) d 21.1, 28.5, 40.1, 50.7, 51.1, 53.1, 75.4, 126.8, 127.4, 128.8,
MeCN (1 mL) and heated at reflux under an atmosphere of nitrogen
for 24 h. Excess solvent was removed under reduced pressure and
the crude product was purified by column chromatography (6:1
Petrol/EtOAc) to yield 25b as a colourless oil (154 mg, 22%); Rf 0.4
(6:1 Petrol/EtOAc); IR (thin film) nmax 3450 (br), 2959, 2931, 2873,
128.9, 129.3, 130.4, 132.6, 137.9, 165.2, 170.3; HRMS (ESþ): [MþH]þ,
C23H31N6O requires 407.25593, found 407.25580; LRMS (ES): 407
(100, MþH), 429 (39, MþNa), 408 (26), 430 (8), 379 (7).
4.8.7. N-tert-Butyl-5-(5-phenyl-2H-tetrazol-2-yl)-2-(pyrrolidin-1-
yl) pentanamide 29a and N-tert-butyl-5-(5-phenyl-1H-tetrazol-1-
yl)-2-(pyrrolidin-1-yl) pentanamide 29b, (15:1 mixture). 1-(Tetra-
hydrofuran-2-yl)pyrrolidine 27 (282 mg, 2 mmol), 5-phenyl-1H-
tetrazole (292 mg, 2 mmol), TsOH (8 mg, 0.04 mmol) and tert-butyl
2860,1728,1464 cmꢁ1; 1H NMR (CDCl3, 300 MHz) 1.32 (9H, s, tBu),
d
1.39e1.77 (10H, m, cy), 2.23 (3H, s, NeCH3), 2.70 (2H, br t, J 7.0 Hz,
NeCH2), 3.03 (2H, br t, J 7.0 Hz, SeCH2), 6.71 (1H, br s, NH),
7.14e7.34 (5H, m, AreH); 13C NMR (CDCl3, 75 MHz)
d 23.0, 26.0,
28.7, 30.3, 33.5, 34.5, 66.6, 125.9, 128.9, 129.0, 136.8, 175.6; HRMS:
isocyanide (226 ml, 2 mmol) were added to anhydrous MeCN (2 mL)
[MþH]þ, C20H33N2OS requires 349.23135, found 349.23170.
and heated at reflux for 42 h under an atmosphere of N2. Excess
solvent was removed under reduced pressure and the residue was
purified by flash column chromatography (2:1 Petrol/EtOAc) to give
29a and 29b (15:1 mixture) as a colourless oil (548 mg, 74%); Rf 0.23
(2:1 Petrol/EtOAc); IR (thin film) nmax 3335 (br), 2964, 2888, 1663,
4.8.4. N-tert-Butyl-2-(2-phenylsulfanylethylamino)-2-p-tolylaceta-
mide 25c. Oxazolidine 22a (163 mg, 2 mmol), thiophenol (205
2 mmol), TsOH (8 mg, 0.02 mmol) and tert-butyl isocyanide
(166 mg, 226 l, 2 mmol) were added to anhydrous MeCN (2 mL)
ml,
m
1520, 1464, 1450 cmꢁ1; compound 29a: 1H NMR (CDCl3, 500 MHz)
t
and heated at reflux under an atmosphere of nitrogen for 24 h.
Excess solvent was removed under reduced pressure and the crude
product was purified by column chromatography (2:1 Petrol/
EtOAc) to yield 25c as a colourless oil (40 mg, 6%); Rf 0.19 (2:1
Petrol/EtOAc); IR (thin film) nmax 3330 (br), 2974, 2905, 2865, 1662,
d
1.28 (9H, s, Bu), 1.48e1.57 (1H, m, CHCHH), 1.65e1.69 (4H, m,
CH2eCH2), 1.69e1.77 (1H, m, CHCHH), 2.01e2.08 (1H, m, CHH),
2.08e2.18 (1H, m, CHH), 2.38e2.44 (4H, m, CH2eNeCH2), 2.62 (1H,
dd, J 8.7, 4.3 Hz, CH), 4.60 (1H, ddd, J 13.6, 8.2, 6.9 Hz, NeCHH), 4.64
(1H, ddd, J 13.6, 8.2, 6.9 Hz, NeCHH), 6.54 (1H, br s, NH), 7.38e7.42
1515, 1480, 1454 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
1.32 (9H, s, tBu),
(3H, m, Ar), 8.06 (2H, dd, J 8.2, 1.9 Hz, Ar); compound 29b: 1H NMR
t
1.91e2.04 (1H, br s, NH), 2.37 (3H, s, AreCH3), 2.84 (2H, m, SeCH2),
3.02e3.08 (2H, m, NHeCH2), 3.97 (1H, s, CH), 7.13e7.37 (9H, m,
(CDCl3, 500 MHz)
d
1.24 (9H, s, Bu), 1.48e1.57 (1H, m, CHHCH2N),
1.65e1.69 (4H, m, CH2eCH2), 1.69e1.77 (1H, m, CHCHH), 2.01e2.08
(1H, m, CHH), 2.08e2.18 (1H, m, CHH), 2.38e2.44 (4H, m,
CH2eNeCH2), 2.52 (1H, dd, J 8.8, 4.5 Hz, CH), 4.38e4.43 (2H, m,
NeCH2), 6.52 (1H, br s, NH), 7.46e7.50 (3H, m, Ar), 7.61e7.65 (2H,
AreH); 13C NMR (75 MHz, CDCl3)
d 21.2, 28.7, 34.5, 47.2, 50.7, 67.7,
126.4, 127.0, 129.0, 129.5, 129.7, 131.8, 136.7, 137.6, 171.2; HRMS:
[MþH]þ, C21H29N2OS requires 357.20006, found 357.20142.
m, Ar); compound 29a: 13C NMR (CDCl3, 125 MHz)
d
23.06, 25.3,
28.46, 28.53, 51.3, 52.7, 60.13, 68.9, 126.6, 127.3, 128.7, 130.0, 164.8,
171.83; compound 29b: 13C NMR (CDCl3, 125 MHz)
23.06, 25.8,
4.8.5. 2-{Methyl[2-(5-phenyltetrazol-1-yl)ethyl]amino}octanoic acid
tert-butylamide 26a. Oxazolidine 1b (343 mg, 2 mmol), 5-phenyl-
1H-tetrazole (292 mg, 2 mmol), TsOH (19 mg, 0.1 mmol) and tert-
d
28.46, 28.50, 47.6, 51.2, 60.13, 68.7, 123.8, 128.5, 129.1, 131.1, 154.1,
171.72; HRMS (CI): [MþH]þ, C20H31N6O requires 371.25592, found
371.25524; LRMS (CI): 270 (100, MþH), 371 (88, MþH), 104 (64),
225 (41), 173 (27), 189 (25).
butyl isocyanide (226 ml, 2 mmol) were added to anhydrous MeCN
(5 mL) at rt and then heated at reflux under an atmosphere of
nitrogen for 24 h. Excess solvent was removed under reduced
pressure and the crude product was purified by column chroma-
tography (80:10:1 Petrol/EtOAc/Et3N) to yield 26a as a colourless oil
(565 mg, 71%); Rf 0.35 (90:30:1 Petrol/EtOAc/Et3N); IR (thin film)
4.8.8. N-tert-Butyl-2-morpholino-6-(5-phenyl-2H-tetrazol-2-yl)hex-
anamide 30a (major) and N-tert-butyl-2-morpholino-6-(5-phenyl-
1H-tetrazol-1-yl)hexanamide 30b (minor), (10:1 mixture).
4-(Tetrahydro-2H-pyran-2-yl)morpholine 28 (342 mg, 2 mmol), 5-
phenyl-1H-tetrazole (292 mg, 2 mmol), TsOH (8 mg, 0.04 mmol)
nmax 3335 (br), 2955, 2920, 2862, 1665, 1518, 1460 cmꢁ1
;
1H NMR
t
(CDCl3)
d
0.74 (3H, t, J 6.8 Hz, CH2CH3), 1.11 (9H, s, Bu), 1.16e1.28
(8H, m, alkyl), 1.33e1.44 (1H, m, alkyl), 1.57e1.68 (1H, m, alkyl), 2.17
(3H, s, NeCH3), 2.76 (1H, dd, J 7.1, 5.8 Hz, CH), 3.03 (1H, ddd, J 13.6,
7.0, 5.2 Hz, CH3NCHH), 3.13 (1H, ddd, J 13.6, 7.0, 5.2 Hz, CH3NCHH),
4.58 (1H, ddd, J 13.9, 7.0, 5.2 Hz, NeCHH), 4.67 (1H, ddd, J 13.9, 7.0,
5.1 Hz, NeCHH), 6.26 (1H, s, NH), 7.31e7.39 (3H, m, Ar), 8.00e8.05
and tert-butyl isocyanide (226 ml, 2 mmol) were added to anhy-
drous MeCN (2 mL) and heated at reflux for 18 h under an atmo-
sphere of N2. Excess solvent was removed under reduced pressure
and the residue was purified by flash column chromatography
(90:10:1 Petrol/EtOAc/Et3N) to give 30a and 30b (10:1 Mixture) as
a colourless oil (663 mg, 83%); Rf 0.44 (90:10:1 Petrol/EtOAc/Et3N);
(2H, m, Ar); 13C NMR (CDCl3)
d 14.0, 22.5, 27.0, 27.4, 28.5, 29.2, 31.6,
37.3, 50.3, 51.3, 53.9, 68.6, 126.7, 127.3, 128.8, 130.3, 165.0, 171.6;
HRMS (CI): [MþH]þ, C22H37N6O requires 401.30287, found
401.30378; LRMS (CI): 401 (100, MþH), 300 (80), 104 (53), 402 (26),
255 (23), 272 (20).
IR (thin film) nmax 3320 (br), 2963, 2952, 2863, 1663, 1533, 1464,
t
1452 cmꢁ1; compound 30a: 1H NMR (CDCl3)
d
1.16 (9H, s, Bu),
1.22e1.1.37 (2H, m, CH2), 1.39e1.48 (2H, m, CHCH2), 1.78e1.86 (2H,
m, CH2), 2.27e2.41 (4H, m, CH2eNeCH2), 2.55 (1H, t, J 6.7 Hz, CH),
3.55 (4H, t, J 4.8 Hz, CH2eOeCH2), 4.26 (2H, t, J 7.2 Hz, NeCH2), 6.62
(1H, br s, NH), 7.38e7.42 (3H, m, Ar), 7.49e7.54 (2H, m, Ar);
4.8.6. N-tert-Butyl-2-(methyl(2-(5-phenyl-2H-tetrazol-2-yl)ethyl)
amino)-2-p-tolylacetamide 26b. Oxazolidine 1a (355 mg, 2 mmol),

R.W. Waller et al. / Tetrahedron 66 (2010) 6496e6507
6507
compound 30b: 1H NMR (CDCl3)
d
1.17 (9H, s, tBu), 1.22e1.1.37 (2H,
407.25593, found 407.25612; LRMS (EI): 407 (100 MþH), 360 (92),
m, CH2), 1.50e1.59 (2H, m, CHCH2), 1.88e2.00 (2H, m, CH2),
2.27e2.41 (4H, m, CH2eNeCH2), 2.55 (1H, t, J 6.7 Hz, CH), 3.55 (4H,
t, J 4.8 Hz, CH2eOeCH2), 4.50 (2H, t, J 7.0 Hz, NeCH2), 6.61 (1H, br s,
NH), 7.28e7.37 (3H, m, Ar), 7.96e7.99 (2H, m, Ar); compound 30a:
338 (54), 429 (30), 317 (27), 261 (22).
Supplementary data
13C NMR (CDCl3,)
d
23.2, 27.2, 28.6, 29.3, 50.54, 52.7, 67.06, 69.5,
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.05.083.
126.6, 127.4, 128.8, 130.1, 164.8, 171.2; compound 30b: 13C NMR
(CDCl3)
d 23.4, 27.0, 28.6, 29.5, 47.7, 50.54, 67.06, 69.3, 123.8, 128.6,
129.2, 131.1, 154.2, 170.9; HRMS (FAB): [MþH]þ, C21H33N6O2 re-
quires 401.26649, found 401.26566; LRMS (FAB): 154 (100), 401
(62, MþH), 155 (24), 153 (15), 307 (14), 402 (13).
References and notes
1. Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH: Weinheim,
2005.
2. Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8.
3. Passerini, M. Gazz. Chim. Ital. 1921, 51, 126; Passerini, M. Gazz. Chim. Ital. 1931, 61,
964.
4.8.9. N-tert-Butyl-2-methyl-2-phenylamino-4-phenyl-
sulfanylbutyramide 34. 4-Hydroxybutanone (172
zylamine (219 l, 2 mmol), thiophenol (205 l, 2 mmol), TsOH
(4 mg, 0.02 mmol) and tert-butyl isocyanide (226 l, 2 mmol) were
ml, 2 mmol), ben-
4. Ito, Y.; Imai, H.; Segoe, K.; Saegusa, T. Chem. Lett.1984, 937; Pellissier, H.; Meou, A.;
Gil, G. Tetrahedron Lett. 1986, 27, 2979; Pellissier, H.; Gil, G. Tetrahedron Lett. 1988,
29, 6773; Yoshioka, S.; Oshita, M.; Tobisui, M.; Chatani, N. Org. Lett. 2005, 7, 3697;
Tobisu, M.; Kitakima, A.; Yoshioka, S.; Hyodo, I.; Oshita, M.; Chatani, N. J. Am.
Chem. Soc. 2007, 129, 11431.
5. Giovenzana, G. B.; Tron, G. C.; Di Paola, S.; Menegotto, I. G.; Pirali, T. Angew. Chem.,
Int. Ed. 2006, 45, 1099; Pirali, T.; Callipari, G.; Ercolano, E.; Genazzani, A. A.;
Giovenzana, G. B.; Tron, G. C. Org. Lett. 2008, 10, 4199.
6. Diorazio, L. J.; Motherwell, W. B.; Sheppard, T. D.; Waller, R. W. Synlett 2006,
2281.
7. Kim, Y. B.; Choi, E. H.; Keum, G.; Kang, S. B.; Lee, D. H.; Koh, H. Y.; Kim, Y. Org.
Lett. 2001, 3, 4149; Banfi, L.; Basso, A.; Guanti, G.; Lecinska, P.; Riva, R. Mol.
Divers. 2008, 12, 187; Mossetti, R.; Pirali, T.; Tron, G. C. J. Org. Chem. 2009, 74,
4890.
m
m
m
added to anhydrous MeCN (5 mL) and heated at 45 ꢀC for 18 h
under an atmosphere of N2. Excess solvent was removed under
reduced pressure and the residue was purified by flash column
chromatography (7:1 Petrol/EtOAc) to give 34 (373 mg, 53%) as
a pale yellow oil; Rf 0.32 (2:1 Petrol/EtOAc); IR (thin film) nmax 3345
(br), 3012, 2998, 2887, 2952, 2913, 1668, 1583, 1480, 1439 cmꢁ1; 1H
NMR (CDCl3)
d
1.34 (9H, s, tBu), 1.37 (3H, s, CH3), 1.97e2.04 (2H, m,
CH2), 2.14 (1H, s, NH), 2.91 (1H, ddd, J 13.1, 9.9, 6.4 Hz, SeCHH), 2.98
(1H, ddd, J 13.1, 9.9, 6.7 Hz, SeCHH), 3.53 (1H, d, J 12.6 Hz, ArCHH),
3.68 (1H, d, J 12.6 Hz, AreCHH), 7.13 (1H, tt, J 6.2, 1.5 Hz, Ar),
8. Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc.
Chem. Res. 1996, 29, 123; Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.d
7.25e7.39 (10H, m, ArþNH); 13C NMR (CDCl3)
d 22.5, 28.6, 28.8,
€
Eur. J. 2000, 6, 3321; Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168;
€
Domling, A. Curr. Opin. Chem. Biol. 2002, 6, 306; Nair, V.; Rajesh, C.; Vinod, A. U.;
38.6, 47.5, 50.4, 62.0, 126.1, 127.3, 127.9, 128.7, 129.0, 129.1, 129.2,
136.2, 140.0, 174.0; HRMS (EI): [MþH]þ, C22H31N2OS requires
371.21571, found 371.21583; LRMS (EI): 371 (100 MþH), 372 (22),
393 (20, MþNa), 212 (8), 270 (6), 395 (5).
Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899;
€
Zhu, J. Eur. J. Org. Chem. 2003,1133; Ugi, I.; Werner, B.; Domling, A. Molecules 2003,
€
8, 53; Domling, A. Chem. Rev. 2006, 106, 17; El Kaïm, L.; Grimaud, L. Tetrahedron
2009, 65, 2153; Banfi, L.; Riva, R.; Basso, A. Synlett 2010, 23.
9. Bergmann, E. J. Am. Chem. Soc. 1951, 73, 5662; Laurent, P. A.; de Almeida, R. C. F.
Bull. Soc. Chim. Fr. 1967, 570; Shimizu, K.; Ito, K.; Skiya, M. Chem. Pharm. Bull.
1974, 22, 1256; Northrop, R. C.; Russ, P. L. J. Org. Chem. 1975, 40, 558; Saba, S.;
Domkowski, P. W.; Firooznia, F. Synthesis 1990, 921; Tararov, V. I.; Kadyrov, R.;
Riermeier, T. H.; Boerner, A. Synthesis 2002, 375.
10. For previous example of nucleophilic ring-opening of cyclic iminoethers with
thiols/thiobenzoic acid see: Fry, E. P. J. Org. Chem.1950,15, 438; Wehrmeister, H. L.
J. Org. Chem. 1963, 28, 2587; Wehrmeister, H. L. J. Org. Chem. 1963, 28, 2589.
11. Carlson, R.; Carlson, J. E. Design and Optimisation in Organic Synthesis, 2nd ed.;
Elsevier: Amsterdam, 2005.
4.8.10. 2-(Benzylamino)-N-tert-butyl-2-methyl-4-(5-phenyl-2H-tet-
razol-2-yl)butanamide 35. 4-Hydroxybutanone (172
benzylamine (219 l, 2 mmol), 5-phenyl-1H-tetrazole (292 mg,
2 mmol), TsOH (4 mg, 0.02 mmol) and tert-butyl isocyanide (226 l,
ml, 2 mmol),
m
m
i
2 mmol) were added to PrOH (5 mL) and heated at 45 ꢀC for 18 h
under an atmosphere of N2. Excess solvent was removed under
reduced pressure and the residue was purified by flash column
chromatography (4:1 Petrol/EtOAc) to give 35 as a colourless oil
(211 mg, 26%); Rf 0.36 (2:1 Petrol/EtOAc); IR (thin film) nmax 3370
12. Zhang, Z.; Jacobson, A.; Rusche, J. R.; Herlihy, W. J. Org. Chem. 1999, 64, 1074.
13. Fife, T. H.; Hagopian, L. J. Am. Chem. Soc. 1968, 90, 1007; Saavedra, J. E. J. Org.
Chem. 1985, 50, 2379.
14. Ley, S. V.; Taylor, S. J. Bioorg. Med. Chem. Lett. 2002, 12, 1813; Liu, L.; Li, C. P.;
Siska, F.; Vito, F. Bioorg. Med. Chem. Lett. 2004, 14, 2221; Banfi, L.; Basso, A.;
Guanti, G.; Lecinska, P.; Riva, R. Org. Biomol. Chem. 2006, 4, 4236; Banfi, L.;
Basso, A.; Guanti, G.; Kielland, N.; Repetto, C.; Riva, R. J. Org. Chem. 2007, 72,
2151.
(br), 3048, 3007, 2953, 2937, 2867, 1661, 1516, 1451, 1362 cmꢁ1; 1H
t
NMR (CDCl3)
d
1.38 (9H, s, Bu), 1.46 (3H, s, CH3), 2.41 (1H, ddd, J
14.2, 8.7, 6.2 Hz, CHH), 2.50 (1H, ddd, J 14.2, 8.5, 7.0 Hz, CHH), 3.55
(1H, d, J 12.7 Hz, AreCHH), 3.68 (1H, d, J 12.7 Hz, AreCHH), 4.70
(1H, ddd, J 13.8 8.6, 6.2 Hz, NeCHH), 4.87 (1H, ddd, J 13.8, 8.7, 7.0 Hz,
NeCHH), 7.19e7.25 (5H, m, Ar), 7.41 (1H, br s, NH), 7.44e7.49 (3H,
€
15. Heck, S.; Domling, A. Synlett 2000, 424.
16. El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44, 7961; El Kaïm, L.;
Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006, 8, 4019; El Kaïm, L.; Gizolme, M.;
Grimaud, L.; Oble, J. Synlett 2007, 465; El Kaïm, L.; Gizolme, M.; Grimaud, L.; Oble, J.
J. Org. Chem. 2007, 72, 4169; Barthelon, A.; El Kaïm, L.; Gizolme, M.; Grimaud, L. Eur.
J. Org. Chem. 2008, 5974.
m, Ar), 8.06e8.14 (2H, m, Ar); 13C NMR (CDCl3)
d 23.1, 28.7, 37.7,
47.5, 49.6, 50.7, 61.4, 126.8, 127.3, 127.4, 127.7, 128.6, 128.9, 130.3,
139.5, 165.1, 173.4; HRMS (EI): [MþH]þ, C23H30N6O requires
17. Cheng, X.; King Kuok, H. Tetrahedron 2001, 57, 5445.