Carbamoylimidazolium and thiocarbamoylimidazolium salts: Novel reagents for the synthesis of ureas, thioureas, carbamates, thiocarbamates and amides

Article abstract of DOI:10.1016/j.tet.2005.05.056

Carbamoylimidazolium salts act as efficient N,N-disubstituted carbamoylating reagents. These salts are readily prepared by the sequential treatment of secondary amines with N,N′-carbonyldiimidazole (CDI) and iodomethane. The carbamoylimidazolium salts are more efficient carbamoyl transfer reagents than the intermediate carbamoylimidazoles, as a result of the 'imidazolium' effect. Kinetic studies on the base promoted hydrolysis of both carbamoylimidazoles and carbamoylimidazolium salts reveal over a hundred-fold rate acceleration. The salts react with amines, thiols, phenols/alcohols, and carboxylic acids in high yields, without the need for subsequent chromatographic purification of the products, producing ureas, thiocarbamates, carbamates, and amides, respectively. Analogous thiocarbamoylimidazolium salts were also synthesized from secondary amines and N,N′-thiocarbonyldiimidazole (TCDI), followed by methylation with iodomethane.

Full text of DOI:10.1016/j.tet.2005.05.056

Tetrahedron 61 (2005) 7153–7175
Carbamoylimidazolium and thiocarbamoylimidazolium salts:
novel reagents for the synthesis of ureas, thioureas, carbamates,
thiocarbamates and amides
Justyna A. Grzyb,a Ming Shen,a Chiaki Yoshina-Ishii,a W. Chi,b R. Stanley Brownb
and Robert A. Bateya,
*
aDepartment of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ont., Canada M5S 3H6
bDepartment of Chemistry, Queen’s University, Kingston, Ont., Canada K7L 3N6
Received 17 June 2004; revised 5 May 2005; accepted 16 May 2005
Available online 15 June 2005
Dedicated to the memory of Dr. Bruce Graham, former Director of Research and Development, Crompton Chemical, Guelph, Ontario.
Abstract—Carbamoylimidazolium salts act as efficient N,N-disubstituted carbamoylating reagents. These salts are readily prepared by the
sequential treatment of secondary amines with N,N0-carbonyldiimidazole (CDI) and iodomethane. The carbamoylimidazolium salts are more
efficient carbamoyl transfer reagents than the intermediate carbamoylimidazoles, as a result of the ‘imidazolium’ effect. Kinetic studies on
the base promoted hydrolysis of both carbamoylimidazoles and carbamoylimidazolium salts reveal over a hundred-fold rate acceleration.
The salts react with amines, thiols, phenols/alcohols, and carboxylic acids in high yields, without the need for subsequent chromatographic
purification of the products, producing ureas, thiocarbamates, carbamates, and amides, respectively. Analogous thiocarbamoylimidazolium
salts were also synthesized from secondary amines and N,N0-thiocarbonyldiimidazole (TCDI), followed by methylation with iodomethane.
q 2005 Published by Elsevier Ltd.
1. Introduction
synthesis requires the use of toxic phosgene. In addition,
they are highly reactive, prone to hydrolysis, and their
relative instability does not render them suitable for long-
term storage and archiving. These considerations are
particularly important where ‘off the shelf’ reagents or a
series of combinatorial ‘building blocks’ are required.
The reaction of nucleophiles with acyl transfer reagents,
such as acid chlorides, is one of the most important classes
of functionalization reaction used in organic synthesis. Such
reactions are also important for the generation of
combinatorial libraries,1 both using solid-phase organic
synthesis (SPOS)2 and parallel solution-phase techniques.3
The corresponding transfer of an electrophilic carbamoyl
group (R1R2NC]O) to nucleophiles is used in the
formation of ureas, carbamates and thiocarbamates. A
variety of reagents are useful synthetic equivalents to
carbamoyl cations (Fig. 1). Isocyanates 1 are used as
monosubstituted carbamoyl transfer reagents (R1NHC]O),
and act as synthetic equivalents to monosubstituted
carbamoyl cations. Carbamoyl chlorides 2 are the most
commonly used synthetic equivalents to disubstituted
carbamoyl cations. Unfortunately, there are significant
drawbacks associated with the use of carbamoyl chlorides.
They have limited commercial availability and their
As a solution to these problems, we envisaged the use of
carbamoylimidazolium salts 3 as N,N0-disubstituted carba-
moyl cation equivalents (Fig. 1).4 The corresponding
carbamoylimidazoles 4, are much less reactive towards
nucleophilic attack and have to be activated as carbamoyl-
imidazolium salts. Such activation of carbonylimidazole as
carbonylimidazolium salts has been demonstrated pre-
viously in a number of systems.5,6–9 Acylimidazolium
salts were shown, initially by Jencks, to be more reactive
than acylimidazoles in their reactions with nucleophiles.6
Keywords: Carbamoylimidazolium salts; Thiocarbamoylimidazolium salts;
Ureas; Thioureas; Carbamates; Thiocarbamates; Amides.
Figure 1. N-monosubstituted and N,N0-disubstituted carbamoyl cation
equivalents.
*
Corresponding author. Tel./fax: C1 416 978 5059;
e-mail: rbatey@chem.utoronto.ca
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.05.056

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Similarly, alkoxycarbonylimidazolium salts are also acti-
vated towards nucleophilic attack by amines.7 Rapoport
has applied this strategy in the selective protection of the
amino functionality in nucleosides, as amides, carbamates,
and thiocarbamates.8 Dicationic 1,10-carbonylbis(3-methyl-
imidazolium) ions have been used for alkoxycarbonylations
of amino acids for peptide and ester bond forming
reactions.9
The stability of different salts in solution and in the solid-
state by using 1H NMR analysis was observed. The
carbamoylimidazolium salts 3a, 3c and 3h derived from
tetrahydroquinoline, N-methylaniline and O,N-dimethylhy-
droxylamine, respectively, were chosen as test compounds
for stability studies. The stability of the compounds in the
solid state was evaluated using freshly prepared salts, stored
at rt without exclusion of air and moisture. The same
compounds were also evaluated as stock solutions in CDCl3
stored at rt. Salt 3a is a very stable, non-hygroscopic,
crystalline solid, which can be stored for extended periods
of time without discoloration. There are only trace amounts
of decomposition products appearing after 3 months of
storage either in CDCl3 solution or in solid state. Salt 3c is a
very hygroscopic yellow foam. However, NMR studies
showed that the salt remained at the same purity level even
after 3 months. A CDCl3 solution of 3c showed only trace
amount of decomposition product after 3 months of storage.
Salt 3h, a white crystalline solid, was the least stable
compound, with significant color change occurring after
several days of storage in the solid state. However,
decomposition can be avoided by storing the solid in a
freezer at K20 8C. Decomposition was also observed in the
CDCl3 solution of salt 3h after 24 h showing 12%
contamination with the decomposition product. After 48 h,
the decomposition caused significant color change and some
precipitation.
We now outline a full study on the use of carbamoylimi-
dazolium salts 3 as N,N0-disubstituted carbamoyl transfer
reagents, as well as the use of the corresponding sulfur
analogs. Specifically, we show their application to the
synthesis of ureas, thioureas, carbamates, thiocarbamates,
and amides using solution-phase methods (Scheme 1).4
There has also been a recent application of these reagents in
polymer-supported chemistry.10
2. Results and discussion
Carbamoylimidazolium salts 3 are readily prepared from
N,N0-carbonyldiimidazole (CDI) via a two-step procedure.
CDI, used as the phosgene equivalent in this synthesis, is a
commercially available and easily handled crystalline
solid.5 Stable and isolable carbamoylimidazoles 4 were
obtained in high yields by refluxing the secondary amines
with CDI in THF for 16 h (Table 1, 4a–4e). The reaction of
L-proline benzylester hydrochloride, morpholine, O,N-
dimethylhydroxylamine and 1,4-dioxa-8-aza-spiro[4.5]-
decane with CDI under refluxing conditions afforded
undesirable byproducts. However, when these reactions
were stirred at rt in dichloromethane, the desired carba-
moylimidazoles were cleanly formed in high yields
(Table 1, 4f–4i). After simple aqueous work-up, the
carbamoylimidazoles 4 were reacted with MeI in aceto-
nitrile at rt for 24 h. The carbamoylimidazolium salts 3 were
obtained after evaporation of the solvent and volatile
reagents.
X-ray crystallographic and IR data, clearly show the
structural effects of the well-known imidazolium effect.
X-ray crystallographic analysis of the salt 3b shows a
˚
relatively short C(5)–N(3) bond (1.327(6) A) and a longer
11
C(5)–N(1) bond (1.466(6) A) (Fig. 2). This reflects the
˚
greater double bond character of the C(5)–N(3) bond. The
C(5)–N(1) bond is longer and weaker because the lone-pair
of electrons on the imidazolium nitrogen does not have a
significant resonance effect with the carbonyl group, since it
is part of the aromatic p-system of the imidazolium ring.
These C–N bond distances compare to values of approxi-
˚
mately 1.371–1.379 A for simple tetrasubstituted ureas, and
˚
A wide variety of carbamoylimidazolium salts 3 have been
prepared for which the analogous carbamoyl chlorides are
not commercially available. Since our goal was the
development of carbamoyl transfer reagents suitable for a
range of synthetic applications, including combinatorial
library synthesis, the long-term thermal, hydrolytic and air
stability of the salts is an important practical consideration.
1.325–1.346 A for amides. The degree of pyramidalization
of N(3) is intermediate between that of idealized sp3 and sp2
hybridization geometries (such as in aliphatic amines and
amides, respectively). The infra-red C]O stretch absorp-
tion frequencies of the carbamoylimidazolium salts 3
usually lie in the range of 1710–1730 cmK1, whereas
those of the carbamoylimidazoles 4 occur some 30 cmK1
lower, in the range of 1680–1700 cmK1, indicative of a
Figure 2. Solid-state structure of the carbamoylimidazolium cation of salt
3b as determined by X-ray crystallographic analysis.11 Displacement
ellipsoids are drawn at the 30% probability level and H atoms are shown as
spheres of arbitrary radii.
Scheme 1.

J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
Table 1. Carbamoylimidazole 4a and carbamoylimidazolium salt 3b formation
7155
Carbamoylimidazole
Yield (%)c
88
Carbamoylimidazole
Yield (%)c
Quant.
4a
3a
4b
3b
88
87
Quant.
Quant.
4c
3c
4d
3d
92
Quant.
4e
3e
87
Quant.
98
96d
4f
3f
90d
82
4g
3g
3h
96d
95d
93
96
4h
4i
3i
a Secondary amine (1.0 equiv) and CDI (1.1 equiv) in THF were refluxed for 16 h.
b Carbamoylimidazole and MeI (4.0 equiv) in acetonitrile were stirred for 24 h.
c Isolated yields without flash chromatography.
d Secondary amine (1.0 equiv), CDI (1.1 equiv) (triethylamine (1 equiv) in case of HCl salt was added) in CH2Cl2 were stirred at rt for 24 h.
stronger C]O bond in the 3 compared to 4. The stronger
C]O bond in the salts presumably offsets a correspond-
ingly weaker C(]O)–N(imidazole) bond.
The results show that hydroxide promoted hydrolysis of
carbamoylimidazolium salts 3 occurs over 100-fold more
rapidly than the corresponding carbamoylimidazoles. These
results compare with a second order rate constant of 1.5!
105 MK1 sK1 measured for the hydroxide promoted
hydrolysis of CH3CO–ImMeC (acetylimidazolium ion),
measured at mZ0.2 (NaCl).6
2.1. Reactivity studies of carbamoylimidazolium salts 3:
base promoted hydrolysis
A hydrolysis study of the carbamoylimidazolium salts 3 and
carbamoylimidazoles 4 was undertaken both to give a guide
to their hydrolytic stability, but more importantly to provide
kinetic data for their reactivity with the simple nucleophile
hydroxide. Thus, second order rate constants for the
hydroxide promoted hydrolysis of carbamoylimidazoles
and carbamoylimidazolium salts were measured at 25 8C
using UV/visible spectroscopic measurements, by observ-
ing the rate of change in absorbance at 230 nm (Table 2,
Entries 1 and 2), 225 nm (Table 2, Entries 3 and 5), 235 nm
(Table 2, Entries 4 and 6), 270 nm (Table 2, Entry 7) and
265 nm (Table 2, Entry 8).
2.2. H/D exchange studies of carbamoylimidazolium
salts 3
The imidazolium salts 3 are very weak acids, as indicated by
H/D exchange at the C-2 position of the imidazolium ring
(Fig. 3). For example, compound 3i undergoes deuterium
exchange in CD3OD, with complete exchange occurring
1
after approximately 24 h, as measured by H NMR. The
addition of tertiary amine bases, such as triethylamine, to a
solution of the salts 3 in CD3OD accelerates the H/D
exchange process, with full deuterium exchange occurring

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J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
Table 2. Second order rate constants for the aqueous hydroxide promoted
hydrolysis of carbamoylimidazoles 4 and carbamoylimidazolium salts 3 at
TZ25 8C, mZ0.1 (KCl)
and trisubstituted ureas, the most significant of which
involves treatment of amines with isocyanates.14 However,
there are only a few methods for the formation of
unsymmetrical tetrasubstituted ureas.15 The most well estab-
lished method involves treatment of a carbamoyl chloride
with a secondary amine.16 Katritzky has demonstrated the
use of 1,10-carbonylbisbenzotriazole5 as a phosgene
equivalent for the synthesis of unsymmetrical tetrasubsti-
tuted ureas under refluxing conditions.17
Entry
Compounds
k2 (MK1 sK1
)
4g
1
0.34G0.14
3g
4i
2
3
96G13
Reaction of carbamoylimidazolium salts 3 with secondary
amines is an experimentally straightforward and general
protocol for the synthesis of unsymmetrical tetrasubstituted
ureas. Addition of secondary amines to a solution of
carbamoylimidazolium salts in dichloromethane in the
presence of triethylamine, afforded tetrasubstituted ureas
in high yields (Table 3). A range of different secondary
amines were successfully reacted forming the ureas 5a–h in
excellent yields. Similarly, the addition of primary amines
to the salts 3 afforded the corresponding trisubstituted ureas
5i–l. In most cases, the detectable byproducts, N-methyl-
imidazole and triethylamine hydrochloric acid, can be
removed by washing the organic phase with dilute acid. This
greatly facilitates the purification protocol, and we have
previously demonstrated that this method is amenable for
the semi-automated solution-phase parallel synthesis of
ureas.4c X-ray crystallographic analysis of the tetrasubsti-
tuted urea 5b shows C(6)–N(8) and C(6)–N(1) bond
0.11G0.04
4
38.0G7.9
3i
4b
5
6
7
0.094G0.037
31.1G5.3
3b
0.038G0.008
4a
˚
˚
distances of 1.381(3) A and 1.354(3) A, respectively,
(Fig. 4). The preferential conjugation of N(8) with the
aromatic system of the tetrahydroquinoline ring results in
smaller resonance effect between the carbonyl group and
N(8), which is reflected by the longer C(6)–N(8) bond
distance.
8
16.0G0.9
3a
within 1 h. The use of a triethylamine/CD3OD combination
results in the formation of the corresponding carbamates
after approximately 20 h, through nucleophilic attack of
CD3OD vide infra. The H/D exchange process presumably
occurs through the intermediacy of an imidazol-2-ylidene
carbene (Fig. 3). The weak acidity of the salts 3 has been
exploited by our laboratories for the formation of N-
carbamoyl substituted heterocyclic carbene Pd(II)
complexes.12 Also, Hlasta has reported the nucleophilic
addition reaction of these carbenes to aldehydes, via in situ
generated carbamoylimidazolium salts.13
Unfortunately, the experimental procedure developed for
aliphatic amines is not suitable for the reaction of more
weakly nucleophlic amines, such as anilines. However,
reaction as the anilide anions, which are much more reactive
nucleophliles, provides a convenient synthetic protocol for
the formation of the corresponding ureas. Thus, pretreat-
ment of the anilines with a strong base such as n-BuLi (or
KHMDS), followed by addition of the salts 3 generates the
corresponding ureas 6 (Table 4).
2.4. Synthesis of carbamates 7 and 8
Organic carbamates represent an important class of
compounds in pharmacology, agriculture18 and in synthetic
chemistry as protecting groups for amines.19 The standard
method for their formation involves transfer of an
electrophilic alkoxy carbonyl group to a nucleophilic
amine. In certain cases, the alternate process of reacting a
nucleophilic alcohol with an electrophilic carbamoylation
reagent may be desirable. Examples of this latter process
include the use of phosgene derivatives such as isocyanates
or carbamoyl chlorides,20 which upon attack by alcohols
generates N-mono- and N-disubstituted carbamates, respect-
ively. Several alternative methods that avoid the use of toxic
materials have also been developed.21 We envisaged that
the salts 3, while relatively unreactive with alcohols, would
react with nucleophlic alkoxides to produce the correspond-
ing carbamates 7/8. In the case of phenols, tertiary amines
2.3. Synthesis of tri- and tetrasubstituted ureas 5 and 6
The initial synthetic targets that we envisaged for the
reactions of the salts 3 were for the generation of ureas.
There are numerous methods for the synthesis of mono-, di-
Figure 3. H/D exchange of carbamoylimidazolium salts 3 at the C-2
position via imidazol-2-ylidene carbenes.

J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
Table 3. Synthesis of ureas 5a from carbamoylimidazolium salts 3 and amines
7157
Urea
Yield (%)b
Urea
Yield (%)b
96
82
74
5a
5g
89
5b
5h
5i
77
96
84
89
5c
5j
5d
5e
81
78
Quant.
5k
5l
70
5f
a Imidazolium salt 3 (1.0 equiv), amine (or HCl salts) (1.0 equiv) and triethylamine (1.0 equiv, or 2.0 equiv for HCl salts) in CH2Cl2 were stirred at rt for 24 h.
b Isolated yields.
are suitable bases for the in situ generation of the reactive
phenoxides. Thus, heating the substrates overnight at reflux
in acetonitrile, in the presence of one molar equivalent of
triethylamine, gave the corresponding carbamates 7 in
excellent yields (Table 5). Again, the byproducts are easily
removed by washing the organic phase with dilute acid.
Using this method carbamates 7 were obtained with
sufficiently high purity such that chromatographic purifi-
cation was not required.
Aliphatic alcohols react slowly with carbamoylimidazolium
salts even under reflux conditions in the presence of
triethylamine. The lower acidity of aliphatic alcohols
presumably prevents the formation of the alkoxide anion
under these conditions, which would serve as the reactive
nucleophile. Less acidic alcohols will react with carbamoyl-
imidazolium salts, when first converted into more nucleo-
philic sodium alkoxides. Thus, formation of the alkoxides
by the treatment of a mixture of the alcohol and the
carbamoylimidazolium salt 3 in THF/DMF with NaH led to
the formation of the desired carbamates 8 after stirring at rt
for 24 h. Formation of Cbz and Alloc carbamates from
amines is thus possible via the corresponding carbamoyl-
imidazolium salts, therefore, providing another strategy for
the formation of these synthetically important carbamate
protecting groups.
The use of alcohols as solvents in the presence of
triethylamine at rt also results in carbamate formation, as
exemplified by the addition of 2,2,2-trifluoroethanol with 3i
in the presence of triethylamine at rt, to give carbamate 8b
(Table 5), as well as by the addition of CD3OD to 3i, vide
supra. Under these conditions it is likely that base assisted
Figure 4. Solid-state structure of the tetrasubstituted urea 5b as determined
by X-ray crystallographic analysis. Displacement ellipsoids are drawn at
the 30% probability level and H atoms are shown as spheres of arbitrary
radii.

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Table 4. Aryl substituted ureas 6a synthesized from carbamoylimidazolium salts 3 and anilines
Amide
Yield (%)b
Amide
Yield (%)b
6a
90
97
6e
6f
96
97
76
70
6b
6c
6g
6d
87
65
6h
a Amine (1.0 equiv) and n-BuLi (1.5 equiv) in THF were stirred at rt for 1 h. Imidazolium salt 3 (1.2 equiv) was then added and the reaction stirred for 18 h.
b Isolated yields.
attack of the alcohols to 3 occurs, rather than by direct attack
of alkoxides.
importance, particularly for small-scale synthesis.25
Although these coupling reagents usually give good results,
they are often expensive, some are toxic, while others are
not very soluble in organic solvents, and the amide products
require chromatographic purification from the coupling
reagent byproducts.
2.5. Synthesis of thiocarbamates 9
Thiocarbamates are generally prepared from carbamoyl
chlorides and thiols,22 chlorothiolformates and amines23 or
via the thione–carbamate rearrangement.24 Unfortunately,
the necessary intermediates are typically prepared from
phosgene or thiophosgene. Now the thiocarbamates 9 can be
easily synthesized in a similar manner to the carbamate
analogs described above (Table 6). Addition of one
equivalent of either alkylthiols or thiophenols to
carbamoylimidazolium salts 3 at rt in chloroform or
dichloromethane, in the presence of triethylamine,
provided the desired thiocarbamates 9 in excellent
yield and purity. The successful reaction of an N-protected
cysteine (Table 6, 9e) suggests that this reaction may be
useful for the functionalization of thiol residues in peptide
chemistry.
The carbamoylimidazolium salts 3 react with carboxylic
acids in the presence of triethylamine, in acetonitrile at rt, to
form tertiary amides 10 in excellent yields (Table 7). The
desired products are of sufficient purity after aqueous work-
up that chromatographic purification is not required. For
example, this approach provides a very convenient approach
for the synthesis of Weinreb amides 10h–l from the
corresponding imidazolium salt 3h.4d
These reactions are noteworthy, in that the carbamoylimi-
dazolium salts 3 act as coupling reagents, leading to the
formation of an activated acyl transfer agent, while
simultaneously generating a nucleophilic secondary
amine, which then react together to form the tertiary amides
10. In essence, the salts 3 serve as preactivated amine
reagents that are capable of reacting directly with carboxylic
acids, without the requirement for the introduction of
additional coupling reagents. This is an unusual approach,
the best analogy for which, is the reaction of carboxylic
acids with isocyanates at 60 8C, to give secondary amides.
The isocyanates similarly act as coupling reagent and amine
source.26
2.6. Synthesis of tertiary amides 10
The amide functional group is one of the most important
functionalities in organic chemistry, due to its presence in
natural products, pharmaceutical and other biologically
active compounds. The most common method of synthesiz-
ing amides involves reaction of an amine with an activated
derivative of a carboxylic acid, such as an acid chloride. In
many cases the use of acid chlorides is not favourable, since
they can be difficult to work, are not easily stored, and lead
to undesirable side reactions. Thus, the more general
method of combining an amine and a carboxylic acid in
the presence of various coupling reagents, has grown in
2.7. Synthesis of thiocarbamoylimidazolium salts 12
The success of carbamoylimidazolium salts 3 as N,N-
disubstituted carbamoyl transfer reagents, encouraged us to

J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
7159
Table 5. Carbamate 7a and 8b synthesized from carbamoylimidazolium salts 3 and phenols or alcohols
Carbamate
Yield (%)c
93
Carbamate
Yield (%)c
57
95d
83
7a
8a
71
94
7b
8b
8c
7c
8d
88
78
7d
7e
8e
86
94
63
83
7f
8f
a Imidazolium salt 3 (1.0 equiv), phenol (1.0 equiv) and triethylamine (1.0 equiv) in acetonitrile were refluxed for 18 h.
b Imidazolium salt 3 (1.0 equiv), alcohol (1.0 equiv) and NaH (1.0 equiv) in THF/DMF (1:1) were stirred at rt for 24 h.
c Isolated yields.
d Imidazolium salt 3 (1.0 equiv) and triethylamine (1.0 equiv) in CF3CH2OH were stirred at rt for 18 h.
Table 6. Thiocarbamates 9a synthesized from carbamoylimidazolium salts 3 and thiols
Thiocarbamate
Yield (%)b
Thiocarbamate
Yield (%)b
9a
9b
86
91
9d
84
92
71
94
9e
9f
9c
a Imidazolium salt 3 (1.0 equiv), thiol (1.0 equiv) and triethylamine (1.0 equiv) in CH2Cl2 or CHCl3 were stirred at rt for 18 h.
b Isolated yield.

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Table 7. Amides 10a synthesized from carbamoylimidazolium salts 3 and carboxylic acids
Amide
Yield (%)b
Amide
Yield (%)b
10j
92
92
10a
10k
10b
75
97
94
93
86
92
10c
10l
10d
10m
96
99
10n
10e
10f
95
75
87
62
10o
10g
10p
10h
94
95
80
82
10q
10i
10r
a Imidazolium salt (1.0 equiv), carboxylic acid (1.0 equiv) and triethylamine (1.0 equiv) were stirred at rt for 16 h.
b Isolated yields.
investigate the use of the analogous sulfur based thiocarba-
moylimidazolium salts 12. We anticipated that these salts
would act as N,N-disubstituted thiocarbamoyl transfer
reagents. The need for such reagents is particularly acute,
since thiocarbamoyl chlorides are currently used for this
purpose, the synthesis of which requires the use of highly
toxic thiophosgene.
Recrystallization is required to obtain the pure products 12.
Althoughthe compounds are not stable as oils, the recrystallized
products are yellow crystals, which can be stored for extended
periods of time without decomposition (Table 8).
2.8. Synthesis of unsymmetrical tri- and tetrasubstituted
thioureas 13
The thiocarbamoylimidazolium salts 12 can be readily
prepared by analogous chemistry to that employed for the
synthesis of 3, using thiocarbonyldiimidazole (TCDI) as
the precursor. Thus, reaction of secondary amines with
TCDI proceeded in dichloromethane at rt to give
thiocarbamoylimidazoles 11, which are usually viscous
yellow or brown oils. Alkylation of the unpurified
thiocarbamoylimidazoles 11 with 4 equiv of MeI in
acetonitrile gave the crude products 12 as brown oils.
An example of the utility of thiocarbamoylimidazolium salts
12 as N,N-disubstituted thiocarbamoyl transfer reagents is
exemplified by their reactivity with primary and secondary
amines, to give tri- and tetrasubstituted thioureas 13, examples
of which are known to be biologically interesting. By far the
most common method of preparing thioureas is the reaction of
isothiocyanates with amines.27 TCDI has also been employed
in thiourea synthesis, but the addition of the second amine
requires heating and the reaction most likely proceeds through

J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
Table 8. Thiocarbamoylimidazole 11a and thiocarbamoylimidazolium salt 12b formation
7161
Thiocarbamoylimidazole
Yield (%)c
96
Imidazolium salt
Yield (%)c
78
65
11a
12a
11b
12b
90
11c
12c
90
Quant.
76
Quant.
11d
12d
a Secondary amine (1.0 equiv) and TCDI (1.1 equiv) in CH2Cl2 were stirred at rt for 2 h.
b Thiocarbamoylimidazole (1.0 equiv) and MeI (4.0 equiv) in acetonitrile were stirred at rt for 24 h.
c Isolated yields.
an isothiocyanate.28 Reaction of 12 with secondary amines in
dichloromethane at rt results in the formation of thioureas 13
(Table 9). The salts 12 are less reactive than the salts 3, since
replacement of the oxygen by sulfur lowers their electro-
philicity. This has practical implications, as demonstrated by
the lower reaction yields of 13 obtained with primary amines
(Table 9, compound13f), comparedto reactions withthe more
nucleophilic secondary amines (Table 9, compound 13e).
Thiocarbamoylimidazolium salt 12d was observed to show
very poor reactivity with diallylamine and pyrrolidine. These
results show that thiocarbamoylimidazolium salts are good
thiocarbamoyl transfer reagents, offering a more practical
solution than the use of thiocarbamoyl chlorides, which is
particularly useful for the formation of tetrasubstituted
thioureas.
2.9. Application of carbamoylimidazolium salts 3 in
target oriented synthesis
We envisaged that reaction of diethyl phosphonoacetic acid
with the salts 3 would lead to the formation of diethyl
phosphonoacetamides, which can then be used in
Table 9. Thioureas 13a synthesized from thiocarbamoylimidazolium salts 12 and amines
Thiourea
Yield (%)b
Quant.
Thiourea
Yield (%)b
13a
13e
71
13b
13c
13a
Quant.
94
45
21
13f
84
13d
a Thiocarbamoylimidazolium salts 12 (1.0 equiv), secondary amines (1.2 equiv) and triethylamine (1.2 equiv) in CH2Cl2 were stirred at rt for 24 h.
b Isolated yields.

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carbamoylimidazoles in greater then 95% yield after
column chromatography, which was necessary to remove
some of the byproducts from the TBDMSCl protection step.
18a and 18b were then methylated with methyl iodide
according to the standard procedure to generate the
carbamoylimidazolium salts 19a and 19b in quantitative
yields. The installation of the phosphonate moiety necessary
for the Wadsworth–Horner–Emmons reaction was accom-
plished through the amide bond forming reaction between
19a and 19b and diethyl phosphonoacetic acid at 50 8C to
give 20a and 20b in 92 and 91% yield, respectively.
Scheme 2. (a) Diethyl phosphonoacetic acid, NEt3, MeCN, reflux, 1 day;
(b) isobutyraldehyde, LiCl, DBU, MeCN, rt, 16 h.
Wadsworth–Horner–Emmons reactions to form a,b-unsa-
turated amides or lactams. Reaction of the carbamoylimi-
dazolium salts with diethyl phosphonoacetic acid in the
presence of triethylamine results in the formation of diethyl
phosphonoacetamides 14, which can be used in either inter-
or intramolecular Wadsworth–Horner–Emmons reactions
with aldehydes and ketones (Scheme 2). For example,
conversion of 3g to the morpholine derived diethyl
phosphonoacetamide 14, followed by treatment with
isobutyraldehyde yielded a,b-unsaturated amide 15 as the
E-isomer.
The final fused bicycles were obtained through deprotection
to the alcohols 21a and b with TBAF, followed by oxidation
with the Dess–Martin reagent to give aldehydes 22a and b,
which had to be chromatographed through a very short silica
column to minimize decomposition. Oxidation using Swern
conditions, TPAP/NMO, and PCC were less effective. The
final cyclization was carried out with sodium hydride in
THF at 0 8C to give the products 23a and 23b in 82 and 75%
yield. Attempts to cyclize the aldehyde 22a directly or with
minimal amount of purification gave very low yields.
A similar approach was used in a model synthesis of the
fused bicyclic lactams 23a and 23b (Scheme 3). 23a is an
intermediate in the synthesis of indolizidines such as
2-epilentiginosine and lentiginosine,29 while 23b can be
used in the synthesis of quinolizidine ring systems, and is an
intermediate in the synthesis of leontiformine and leonti-
formidine.30 The synthesis of 23a and 23b began with the
protection of 2-piperidinemethanol or 2-piperidineethanol
with TBDMSCl in 99 and 98% yield, respectively, without
purification. The protected amines 17a and 17b were
reacted with CDI in CH2Cl2 at rt to generate the
3. Conclusions
Carbamoylimidazolium salts behave as convenient N,N0-
disubstituted carbamoyl transfer reagents, showing
increased reactivity over carbamoylimidazoles as a result
of the imidazolium effect. These compounds, as well as their
thiocarbamoylimidazolium counterparts, are readily pre-
pared by a simple two-step procedure from the correspond-
ing secondary amines, and are obtained in excellent yield
and purity following straightforward work-up procedures.
The salts serve as useful ‘building blocks’ which can be
utilized to generate a variety of functional groups, such as
ureas, thioureas, carbamates, thiocarbamates, and amides,
under mild reaction conditions. We are currently applying
this methodology to the formation of combinatorial
libraries.
4. Experimental
4.1. General
THF was distilled from sodium metal/benzophenone ketyl
under nitrogen. CH2Cl2 and CH3CN were distilled from
CaH2 under nitrogen. All other commercial reagents were
used as received (Aldrich, Fischer Scientific Ltd or BDH).
All glassware was flame-dried and allowed to cool under a
1
stream of dry nitrogen. Melting points are uncorrected. H
and 13C NMR were recorded at 400 and 100 MHz,
respectively, on a Varian Unity 400 spectrometer and
Gemini 200 MHz spectrometer. Proton chemical shifts were
internally referenced to the residual proton resonance in
CDCl3 (d 7.26) or CD3OD (d 3.31) or DMSO-d6 (d 2.50).
Carbon chemical shifts were internally referenced to the
deuterated solvent signals in CDCl3 (d 77.20) or CD3OD (d
49.00) or DMSO-d6 (d 39.50). Phosphorus chemical shifts
were referenced to 85% phosphoric acid (external). FT-IR
spectra were recorded on a Perkin-Elmer Spectrum 1000,
with samples loaded as neat films on NaCl plates or as KBr
Scheme 3. (a) TBDMSCl, pyr, CH2Cl2, rt, 4 h; (b) CDI, CH2Cl2, rt, 1 day;
(c) MeI, MeCN, rt, 1 day; (d) Diethyl phosphonoacetic acid, NEt3, MeCN,
50 8C, 1 day; (e) TBAF, THF, rt, 30 min; (f) o-C6H4COOI(OAc)2 (i.e.,
Dess–Martin periodinane reagent), CH2Cl2, rt, overnight; (g) NaH, THF,
0 8C, 40 min.

J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
7163
discs. Low-resolution mass spectra were recorded on a Bell
and Howell 21-490 spectrometer, and high resolution
spectra were recorded on an AEI MS3074 spectrometer.
Specific optical rotation was determined on a Perkin-Elmer
243B Polarimeter under the conditions indicated using the
sodium D line (589 nm). Analytical thin-layer chromato-
graphy (TLC) was performed on pre-coated silica gel plates,
(Silicycle, Inc.), visualized with a UV254 lamp (Spectro-
line, Longlife Filter) and stained with 20% phosphomolyb-
dic acid in ethanol or ninhydrin. Spectral data are provided
for all new compounds and for compounds which lack full
characterization in the literature.
137.2, 136.9, 129.8, 129.1, 127.8, 126.8, 117.8, 51.7, 48.6,
20.6; IR (neat) 2975, 1690, 1414, 1217, 1069, 1020, 965,
754 cmK1; MS (EI) m/z (rel. intensity) 243 (1), 176 (25), 92
(10), 91 (100), 85 (14), 83 (23), 68 (6), 65 (7), 51 (9); HRMS
(EI) m/z Calcd (MC) 243.1367, found 243.1372.
4.2.5. 1-(Pyrrolidin-1-ylcarbonyl)-1H-imidazole (4e).32
White solid; mp 50–52 8C; H NMR (400 MHz, CDCl3) d
1
8.01 (1H, s), 7.36 (1H, br s), 7.08 (1H, br s), 3.64–3.61 (4H,
m), 2.00–1.97 (4H, m); 13C NMR (100 MHz, CDCl3) d
149.8, 136.9, 129.6, 117.7, 48.9 (br), 25.7 (br); IR (KBr
pellet) 2976, 1694, 1417, 1102, 843 cmK1
.
4.2. General procedure for the preparation of
carbamoylimidazoles 4a–4e
4.2.6. Benzyl 1-(1H-imidazol-1-ylcarbonyl)-L-prolinate
(4f).4a,c To a solution of CDI (0.890 g, 5.50 mmol) in
CH2Cl2 (15 mL) was added L-proline benzyl ester hydro-
chloride (1.21 g, 5.00 mmol) and triethylamine (0.700 mL,
5.00 mmol). The mixture was stirred for 48 h at rt, then
washed with water (2!20 mL). The organic layer was dried
over anhydrous MgSO4, filtered and the solvent was
removed under vacuum to yield 4g as colorless, viscous
oil (1.44 g, 96%); 1H NMR (200 MHz, CDCl3) d 8.02 (1H,
s), 7.35 (6H, br s), 7.07 (1H, s), 5.20 (2H, m), 4.67 (1H, m),
3.76 (2H, m), 2.35 (1H, m), 2.06 (3H, m); 13C NMR
(50 MHz, CDCl3) d 170.7, 149.4, 136.5, 135.1, 129.4,
128.3, 128.1, 127.8, 117.3, 66.8, 60.6, 49.5, 29.1, 24.6; IR
(neat) 3583, 3469, 3122, 2980, 2957, 1746, 1682, 1417,
1171, 1100, 901 cmK1; MS (EI) m/z (rel. intensity) 299 (1),
232 (12), 164 (12), 160 (6), 158 (11), 91 (100), 70 (21);
HRMS (EI) m/z calcd (MC) 299.1270, found 299.1255;
[a]2D3 K618 (c 1.00, CH2Cl2).
To a suspension of N,N0-carbonyldiimidazole (CDI,
60.0 mmol) in THF (100 mL) was added the amine
(55.0 mmol). The mixture was refluxed for 16 h. Removal
of solvent under vacuum gave a viscous oil, which was
dissolved in CH2Cl2 (100 mL) and washed with water (2!
100 mL). The organic layer was dried over anhydrous
MgSO4, filtered and concentrated in vacuo to yield the
carbamoylimidazole 4a–e.
4.2.1. 1-(1H-Imidazol-1-ylcarbonyl)-1,2,3,4-tetrahydro-
quinoline (3,4-dihydro-2H-quinolin-1-yl)-imidazol-1-yl-
methanone (4a).4a,c Yellow solid; mpZ71–73 8C; 1H
NMR (400 MHz, CDCl3) d 7.65 (1H, d, JZ1.0 Hz), 7.18
(1H, m), 7.06 (1H, m), 6.98 (1H, m), 6.92 (1H, m), 6.89 (1H,
m), 6.64 (1H, m), 3.86 (2H, t, JZ6.5 Hz), 2.82 (2H, t, JZ
6.5 Hz), 2.07 (2H, m); 13C NMR (100 MHz, CDCl3) d
150.0, 137.8, 137.5, 131.9, 129.6, 129.1, 127.1, 125.9,
123.2, 118.3, 45.9, 26.7, 24.1; IR (KBr pellet) 3122, 2958,
1691, 1578, 1492, 1396, 1215, 1100, 916 cmK1; MS (EI) m/z
(rel. intensity) 227 (46), 160 (94), 142 (13), 132 (100), 117
(11), 77 (17); HRMS (EI) m/z calcd (MC) 227.1059, found
227.1051.
4.3. General procedure for the preparation of
carbamoylimidazoles with CH2Cl2 as solvent
To a cooled (cold water bath) solution of CDI (44.0 mmol)
in CH2Cl2 (30 mL) was added the amine (40.0 mmol)
dropwise. After the solids dissolved, giving a slightly
yellowish clear solution, the water bath was removed, and
the mixture stirred for a further 24 h. The reaction was
diluted with CH2Cl2 (20 mL), and quenched with water
(50 mL). The aqueous layer was extracted with CH2Cl2 (4!
50 mL), the combined organic layers dried over anhydrous
MgSO4, filtered and concentrated in vacuo to yield
carbamoylimidazoles 4g–4i.
4.2.2. 2-(1H-Imidazol-1-ylcarbonyl)-1,2,3,4-tetrahydro-
isoquinoline (4b).4c Yellow solid; mpZ82–83 8C; 1H
NMR (400 MHz, CDCl3) d 7.94 (1H, s), 7.26–7.08 (6H,
m), 4.75 (2H, s), 3.82 (2H, t, JZ6.0 Hz), 3.04 (2H, t, JZ
6.0 Hz); 13C NMR (100 MHz, CDCl3) d 150.8, 136.6, 133.4,
131.5, 129.5, 128.6, 127.0, 126.5, 126.0, 117.6, 48.1, 44.2,
28.3; IR (KBr pellet) 3098, 2898, 1681, 1428, 1240, 1162,
1104, 1077, 1052, 933 cmK1; MS (EI) m/z (rel. intensity) 227
(69), 160 (100), 142 (49), 130 (10), 117 (36), 103 (14), 91 (12);
HRMS (EI) m/z calcd (MC) 227.1061, found 227.1059.
4.3.1. 4-(1H-Imidazol-1-ylcarbonyl)morpholine (4g).4c,33
White solid; mpZ83–84 8C; 1H NMR (400 MHz, CDCl3) d
7.85 (1H, s), 7.17 (1H, m), 7.08 (1H, m), 3.73 (4H, m), 3.61
(4H, m); 13C NMR (100 MHz, CDCl3) d 150.4, 136.4,
129.4, 117.5, 65.9, 46.3.
4.2.3. N-Methyl-N-phenyl-1H-imidazole-1-carboxamide
(4c).4c,31 Yellow solid; mpZ62–63 8C; 1H NMR (400 MHz,
CDCl3) d 7.54 (1H, s), 7.38–7.29 (3H, m), 7.11–7.07 (2H,
m), 6.81–6.76 (2H, m), 3.45 (3H, s); 13C NMR (100 MHz,
CDCl3) d 149.3, 142.0, 136.8, 129.3, 127.9, 127.1, 125.1,
117.7, 39.2; IR (KBr pellet) 3126, 2949, 1702, 1592, 1492,
4.3.2. N-Methoxy-N-methyl-1H-imidazole-1-carboxa-
1
mide (4h).4d Colorless oil; H NMR (400 MHz, CDCl3) d
8.24 (1H, s), 7.55 (1H, m), 7.03 (1H, m), 3.66 (3H, s), 3.37
(3H, s); 13C NMR (100 MHz, CDCl3) d 148.6, 137.1, 128.6,
118.0, 60.6, 33.8; IR (neat) 3121, 2938, 1690, 1421, 1227,
1061, 965, 735 cmK1; MS (EI) m/z (rel. intensity) 155
(100), 125 (34), 95 (38), 88 (55), 68 (63); HRMS (EI) m/z
Calcd (MC) 155.0695, found 155.0700.
1458, 1385, 1294, 1253, 1118, 1096, 1026, 983 cmK1
.
4.2.4. N-Benzyl-N-isopropyl-1H-imidazole-1-carboxa-
mide (4d).4c Foamy yellow oil; 1H NMR (400 MHz,
CDCl3) d 7.90 (1H, s), 7.38 (2H, m), 7.31 (3H, m), 7.21
(1H, s), 7.04 (1H, s), 4.58, (2H, s), 4.16 (1H, m), 1.35 (3H,
s), 1.34 (3H, s); 13C NMR (100 MHz, CDCl3) d 151.9,
4.3.3. 8-(1H-Imidazol-1-ylcarbonyl)-1,4-dioxa-8-aza-
spiro[4.5]decane (4i).4c White solid; mpZ121–123 8C;

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1H NMR (400 MHz, CDCl3) d 7.83 (1H, s), 7.16 (1H, m),
7.06 (1H, m), 3.96 (4H, s), 3.65 (4H, m), 1.75 (4H, m); 13C
NMR (100 MHz, CDCl3) d 150.6, 136.7, 129.5, 117.8,
106.1, 64.4, 44.5, 34.9; IR (KBr pellet) 3112, 2869, 2855,
1700, 1464, 1427, 1361, 1243, 1098, 1026, 913 cmK1; MS
(EI) m/z (relative intensity) 237 (22), 170 (100), 142 (82), 99
(37), 98 (27), 70 (19); HRMS (EI) m/z Calcd (MC)
237.1113, found 237.1111.
617 cmK1; MS (FAB) m/z (relative intensity) 259 (9), 258
(50), 180 (5), 176 (21), 173 (17), 132 (6), 92 (9), 91 (100),
83 (14); HRMS (FAB) m/z Calcd (MCK127) 258.1621,
found 258.1620.
4.4.5. 3-Methyl-1-(pyrrolidin-1-ylcarbonyl)-1H-imida-
1
zol-3-ium iodide (3e). White solid; mpZ102–105 8C; H
NMR (400 MHz, CDCl3) d 10.40 (1H, s), 7.83 (1H, m), 7.55
(1H, m), 4.31 (3H, s), 2.07 (4H, br m), 2.05 (4H, m); 13C
NMR (100 MHz, CDCl3) d 145.0, 136.8, 123.8, 121.2, 51.0
(br), 49.6 (br), 38.3, 26.6 (br), 34.4 (br); IR (KBr pellet)
3446, 3078, 1716, 1404, 1257, 1136, 827; MS (FAB) m/z
(relative intensity) 180 (100), 98 (81), 83 (15); HRMS
(FAB) m/z Calcd (MCK127) 180.1137, found 180.1139.
4.4. General procedure for the preparation of
carbamoylimidazolium salts 3
To a solution of carbamoylimidazole 4 (8.00 mmol) in
acetonitrile (15 mL) was added methyl iodide (32.0 mmol).
The mixture was stirred at rt for 24 h. The solvent was
removed under vacuum to yield the carbamoylimidazolium
salt 3a–i.
4.4.6. Benzyl 1-[(3-methyl-1H-imidazol-3-ium-1-yl)car-
1
bonyl]-L-prolinate iodide (3f).4a,c Foamy yellow oil; H
NMR (200 MHz, CDCl3) d 10.30 (1H, s), 7.78–7.32 (7H, m),
5.18 (2H, br s), 4.70 (1H, br s), 4.24 (3H, br s), 4.12–3.93 (2H,
m), 2.49 (1H, br s), 2.12 (3H, m); 13C NMR (50 MHz, CDCl3)
d 169.8, 145.1, 136.2, 134.7, 128.3, 128.1, 127.7, 123.9, 120.4,
68.0, 61.5, 51.4, 37.7, 29.9, 25.4; IR (neat) 3448, 3069, 1728,
1584, 1537, 1407, 1175, 1094 cmK1; MS (FAB) (rel.
intensity) 314 (100), 173 (66), 154 (11), 136 (10), 107 (6),
91 (69); HRMS (FAB) m/z calcd (MCK127) 314.1505,
found 134.1499; [a]2D3 K448 (c 1.01, CH2Cl2).
4.4.1. 1-(3,4-Dihydroquinolin-1(2H)-ylcarbonyl)-3-
methyl-1H-imidazol-3-ium iodide (3a).4a,c Yellow solid;
mp 97–99 8C; H NMR (400 MHz, CDCl3) d 9.90 (1H, s),
1
7.61 (1H, s), 7.25–7.22 (2H, m), 7.15 (1H, m), 7.08 (1H, m),
6.95 (1H, d, JZ8.0 Hz), 4.12 (3H, s), 3.93 (2H, t, JZ
6.5 Hz), 2.93 (2H, t, JZ6.5 Hz), 2.11 (2H, m); 13C NMR
(50 MHz, DMSO-d6) d 146.4, 138.3, 135.9, 132.2, 129.0,
126.3, 125.9, 123.3, 123.2, 121.2, 46.7, 36.4, 25.7, 22.9; IR
(KBr pellet) 3438, 3074, 2937, 1722, 1583, 1535, 1493,
1459, 1356, 1014, 749 cmK1; MS (FAB) m/z (relative
intensity) 242 (100), 160 (40), 154 (83), 138 (29), 137 (52),
136 (61), 132 (14), 120 (12), 107 (23), 91 (12); HRMS
(FAB) m/z Calcd (MCK127) 242.1293, found 242.1296.
4.4.7. 3-Methyl-1-(morpholin-4-ylcarbonyl)-1H-imida-
zol-3-ium iodide (3g).4c White solid; mpZ165–166 8C;
1H NMR (400 MHz, DMSO-d6) d 9.61 (s, 1H), 8.04 (s, 1H),
7.87 (s, 1H), 3.91 (s, 3H), 3.66 (s, 4H), 3.52 (s, 4H); 13C NMR
(100 MHz, DMSO-d6) d 146.5, 137.4, 123.5, 120.9, 65.3,
46.2, 36.5; IR (KBr pellet) 3115, 2862, 1718, 1437, 1244,
1145, 1117, 996; MS (FAB) m/z (relative intensity) 196 (100),
185 (14), 175 (5), 115 (10), 114 (50), 111 (5); HRMS (FAB) m/z
calcd (MCK127) 196.1086, found 196.1103.
4.4.2. 1-(3,4-Dihydroisoquinolin-2(1H)-ylcarbonyl)-3-
methyl-1H-imidazol-3-ium iodide (3b).4c Yellow solid;
1
mpZ166–168 8C; H NMR (400 MHz, DMSO-d6) d 9.63
(1H, br s), 8.09 (1H, br s), 7.89 (1H, br s), 7.22 (4H, br s),
4.75 (2H, br s), 3.94 (3H, m), 3.72 (2H, br s), 2.96 (2H, br s);
13C NMR (100 MHz, DMSO-d6) d 146.8, 137.3, 133.9,
131.5, 128.1, 126.7, 126.4, 126.1, 123.5, 120.8, 47.5 (br),
44.2, 36.5, 27.6; IR (KBr pellet) 3144, 3078, 2968, 1711,
1408, 1354, 1150, 1132, 978 cmK1; MS (FAB) m/z (relative
intensity) 242 (100), 190 (3), 144 (5), 117 (5), 160 (39);
HRMS (FAB) m/z calcd (MCK127) 242.1293, found
242.1284.
4.4.8. 1-{[Methoxy(methyl)amino]carbonyl}-3-methyl-
1H-imidazol-3-ium iodide (3h).4d White solid; mpZ
115–117 8C; H NMR (400 MHz, DMSO-d6) d 10.11 (1H,
1
s), 7.88 (1H, m), 7.77 (1H, m), 4.30 (3H, s), 3.94 (3H, s),
3.43 (3H, s); 13C NMR (100 MHz, DMSO-d6) 144.6, 138.1,
123.9, 121.4, 63.6, 38.6, 35.1; IR (KBr pellet) 3063, 1714,
1459, 1385, 1160, 1085, 954, 739, 725 cmK1; MS (ESI) m/z
(rel. intensity) 170 (100), 139 (10); HRMS (ESI) m/z calcd
(MCK127) 170.0924, found 170.0916.
4.4.3. 3-Methyl-1-{[methyl(phenyl)amino]carbonyl}-1H-
imidazol-3-ium iodide (3c).4a,c Yellow solid, mp 95–98 8C;
1H NMR (400 MHz, CDCl3) d 9.71 (1H, s), 7.55 (1H, br s),
7.37–7.31 (5H, m), 7.01 (1H, br s), 4.02 (3H, s), 3.45 (3H,
s); 13C NMR (100 MHz, CDCl3) d 145.0, 139.7, 137.2,
129.8, 128.3, 125.7, 122.8, 120.2, 40.3, 37.1; IR (KBr pellet)
3457, 3076, 1732, 1594, 1494, 1372, 1271, 1152, 983,
920 cmK1; MS (FAB) m/z (rel. intensity) 217 (20), 216
(100), 154 (14), 136 (11), 107 (6), 93 (7); HRMS (FAB) m/z
calcd (MCK127) 216.1137, found 216.1130.
4.4.9. 1-(1,4-Dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-3-
methyl-1H-imidazol-3-ium iodide (3i).4c White solid; mp
169–172 8C; 1H NMR (400 MHz, DMSO-d6) d 9.58 (s, 1H),
8.03 (m, 1H), 7.87 (m, 1H), 3.91 (m, 7H), 3.54 (s, 4H), 1.76
(s, 4H); 13C NMR (100 MHz, DMSO-d6) d 146.5, 137.4,
123.5, 120.9, 105.6, 63.9, 44.4 (br), 36.5, 33.8; IR (KBr
pellet) 3078, 2886, 1735, 1573, 1534, 1419, 1369, 1218,
1138, 1092, 1027 cmK1; MS (FAB) m/z (relative intensity)
252 (100), 185 (63), 170 (83), 142 (75), 126 (10); HRMS
(FAB) m/z Calcd (MCK127) 252.1348, found 252.1355.
4.4.4. 1-{[Benzyl(isopropyl)amino]carbonyl}-3-methyl-
1
1H-imidazol-3-ium iodide (3d).4c Yellow foam; H NMR
(400 MHz, CDCl3) d 10.58 (1H, m), 7.31–7.07 (7H, m),
4.88 (2H, s), 4.44 (1H, m), 4.14 (3H, s), 1.45 (3H, s), 1.43
(3H, s); 13C NMR (100 MHz, CDCl3) d 147.3, 136.8, 136.0,
129.3, 128.2, 126.8, 123.7, 120.4, 52.7, 49.2, 37.9, 20.6; IR
(neat) 3063, 1723, 1536, 1414, 1342, 1171, 1138, 748,
4.5. Kinetics of hydroxide promoted hydrolysis of 3
and 4
Stock solutions of 3 and 4 (0.02 M in MeCN) were prepared,
then sealed with rubber septa and placed in a freezer. Buffer

J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
7165
solutions were made using HCl (pH 2.0–3.11), EPPS (pH
7.9–8.7), CHES (pH 9.2–9.8), CAPS (pH 10.29–11.10) and
NaOH (pH 11.98). Concentrations of 0.010, 0.020, and
0.030 M were used for CAPS, CHES and EPPS, and in all
cases the ionic strength of the solutions was held at 0.10 by
the addition of KCl.
m), 6.94–6.90 (1H, m), 3.66 (2H, t, JZ6.0 Hz), 3.47 (3H, s),
3.01 (3H, s), 2.73 (2H, t, JZ6.5 Hz), 1.96–1.90 (2H, m); 13C
NMR (100 MHz, CDCl3) d 160.7, 139.6, 128.9, 128.5,
125.8, 122.9, 121.9, 59.5, 45.6, 35.8, 26.6, 23.6; IR (neat)
2932, 1663, 1493, 1374, 965 cmK1; MS (EI) m/z (rel.
intensity) 220 (42), 160 (91), 142 (16), 132 (100), 117 (19),
77 (19); HRMS (EI) m/z calcd (MC) 220.1212, found
220.1220.
The second order rate constants for the hydroxide promoted
hydrolysis of carbamoylimidazoles and carbamoylimidazo-
lium salts were measured at 25 8C by observing the rate of
change in absorbance at 230 nm (Table 2, Entries 1 and 2),
225 nm (Table 2, Entries 3 and 5), 235 nm (Table 2, Entries
4 and 6), 270 nm (Table 2, Entry 7) and 265 nm (Table 2,
Entry 8), using an OLIS modified Cary-17 UV/visible
spectrophotometer. Reactions were initiated by injecting
10 mL of the substrate solution into 2.5 mL of the buffer
solution, which had been thermally equilibrated in the
instrument cell holder for 10 min. Absorbance versus time
profiles were fit by NLLSQ methods using Prism software to
give pseudo-first order rate constants. Second order rate
constants were determined by dividing the pseudo-first
order rate constant by the concentration of hydroxide and
are given in Table 2.
4.6.4. 1-[(4-Benzylpiperazin-1-yl)carbonyl]-1,2,3,4-tetra-
1
hydroquinoline (5d).4a,c White solid; mp 171–173 8C; H
NMR (200 MHz, CDCl3) d 7.55–6.90 (9H, m), 4.02 (2H, br
s), 3.67–3.57 (6H, m), 2.88–2.70 (6H, m), 2.01–1.88 (2H,
m); 13C NMR (50 MHz, CDCl3) d 159.1, 139.6, 130.7,
129.6, 129.2, 128.9, 128.7, 128.3, 126.4, 122.7, 119.9, 60.7,
50.9, 45.2, 42.9, 26.5, 23.3; IR (KBr pellet) 2940, 1640,
1578, 1492, 1300, 1260, 1202, 1176 cmK1; MS (EI) m/z
(rel. intensity) 335 (15), 203 (26), 160 (22), 146 (24), 132
(37), 91 (100); HRMS (EI) m/z calcd (MC) 335.1998, found
335.1990.
4.6.5. Benzyl 1-[(4-benzylpiperazin-1-yl)carbonyl]-L-
1
prolinate (5e).4a Yellow oil; H NMR (200 MHz, CDCl3)
d 7.66–7.29 (10H, m), 5.30–5.02 (2H, m), 4.69–4.57 (1H,
m), 4.11–3.68 (6H, m), 3.46–3.21 (4H, m), 2.95–2.30 (3H,
m) 2.00–1.78 (3H, m); 13C NMR (50 MHz, CDCl3) d 172.4,
160.8, 135.5, 131.3, 130.0, 129.1, 128.5, 128.3, 128.2,
127.9, 66.6, 61.0, 59.8, 50.4, 49.6, 42.5, 29.2, 25.5; IR (neat)
2950, 2451, 1741, 1634, 1418, 1276, 1174, 1081, 1031, 957,
922, 734, 700, 644 cmK1; MS (EI) m/z (relative intensity)
407 (25), 275 (15), 203 (16), 159 (26), 146 (35), 134 (34),
132 (39), 120 (12), 108 (16), 91 (100); HRMS (EI) m/z calcd
(MC) 407.2209, found 407.2199; [a]2D3 K24.08 (c 1.01,
CH2Cl2).
4.6. General procedure for the preparation of tri- or
tetrasubstituted ureas 5
To a solution of carbamoylimidazolium salt 3 (1.00 mmol)
in CH2Cl2 (10 mL) was added the primary or secondary
amine (1.00 mmol) and triethylamine (1.00 mmol). The
mixture was stirred at rt for 24 h, then washed with 1.0 N
HCl (2!5 mL) and brine (5 mL), the organic layer was
dried (MgSO4), filtered and concentrated in vacuo to yield
urea 5a–l.
4.6.1. N-Methyl-N-phenyl-3,4-dihydroisoquinoline-
2(1H)-carboxamide (5a).4a Clear oil; 1H NMR
(400 MHz, CDCl3) d 7.41–6.91 (9H, m), 4.41 (2H, s),
3.57 (2H, t, JZ6.0 Hz), 3.51 (3H, s), 2.71 (2H, t, JZ
6.0 Hz); 13C NMR (100 MHz, CDCl3) d 160.9, 146.6,
134.5, 133.5, 129.3, 128.4, 126.1, 126.0, 125.8, 124.4,
123.8, 47.6, 43.5, 39.5, 28.2; IR (neat) 2928, 1594, 1493,
1440, 1403, 1259, 1113, 928 cmK1; MS (EI) m/z (rel.
intensity) 266 (95), 235 (11), 208 (62), 189 (13), 160 (100),
142 (69), 132 (56), 117 (55), 107 (73), 91 (23); HRMS (EI)
m/z calcd (MC) 266.1419, found 26.1426.
4.6.6. Benzyl 1-{[(2S)-2-(methoxycarbonyl)pyrrolidin-1-
yl]carbonyl}-L-prolinate (5f). Yellow oil; 1H NMR
(200 MHz, MeOH-d4) d 7.34–7.23 (5H, m), 5.21–5.04
(2H, m), 4.83–4.37 (3H, m), 3.69 (3H, m), 3.58–3.53 (3H,
m), 2.29–2.18 (2H, m), 1.98–1.71 (6H, m); 13C NMR
(50 MHz, CDCl3) d 173.3, 172.6, 158.4, 136.2, 128.5,
127.7, 126.5, 65.6, 63.0, 60.1, 60.0, 51.6, 48.2, 28.9, 28.9,
24.9; IR (neat) 2953, 2880, 1740, 1616, 1438, 1343, 1279,
1173, 1096, 1042, 1004, 914, 752, 699 cmK1; MS (EI) m/z
(relative intensity) 360 (5), 301 (20), 225 (77), 160 (30), 156
(35), 142 (15), 128 (100), 108 (41), 91 (76); HRMS (EI) m/z
calcd (MC) 360.1685, found 360.1682; [a]2D3 K25.88 (c
1.00, MeOH).
4.6.2. Methyl 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)-
L-prolinate (5b).4a,c Yellow oil; 1H NMR (400 MHz,
CDCl3) d 7.33 (1H, m), 7.10 (2H, m), 6.90 (1H, m), 4.56
(1H, t, JZ7.5 Hz), 3.81–3.69 (4H, m), 3.42–3.36 (1H, m),
3.12–3.02 (2H, m), 2.75–2.62 (2H, m), 2.24 (1H, m), 2.00
(1H, m), 1.88–1.74 (4H, m); 13C NMR (100 MHz, CDCl3) d
173.3, 158.3, 140.1, 129.2, 128.3, 126.4, 122.1, 120.8, 59.8,
51.9, 48.9, 44.8, 29.5, 26.8, 25.1, 23.8; IR (neat) 2951, 2880,
1745, 1640, 1579, 1495, 1403, 1174, 1026 cmK1; MS (EI)
m/z (rel. intensity) 288 (49), 229 (23), 160 (37), 128 (100);
HRMS (EI) m/z calcd (MC) 288.1474, found 288.1474;
[a]2D3 C125.28 (c 1.02, CH2Cl2).
4.6.7. Benzyl 1-{[3-(hydroxymethyl)piperidin-1-yl]car-
bonyl}-L-prolinate (5g). Yellow oil; H NMR (200 MHz,
1
CDCl3) (rotamers) d 7.35–7.28 (5H, m), 5.24–5.06 (2H, m),
4.71–4.59 (2H, m), 3.61–3.05 (8H, m), 2.30 (1H, m), 2.08–
1.25 (8H, m); 13C NMR (50 MHz, DMSO-d6) (rotamers) d
172.5, 172.5, 161.2, 142.4, 136.1, 128.3, 127.9, 127.5,
126.5, 126.3, 65.4, 63.6, 63.6, 62.8, 59.9, 59.8, 49.5, 49.2,
49.2, 49.1, 46.5, 46.2, 38.5, 38.2, 29.0, 27.0, 24.9, 24.8,
24.4, 24.1; IR (neat) 3406, 2931, 2820, 1735, 1615, 1435,
1353, 1303, 1169, 1082, 1028, 748, 699 cmK1; MS (EI) m/z
(rel. intensity) 347 (6), 212 (88), 204 (7), 142 (100), 114
(33), 98 (17), 91 (57), 81 (18), 70 (92); HRMS (EI) m/z
Calcd (MC) 346.1893, found 346.1904.
4.6.3.
1(2H)-carboxamide (5c). Yellow oil; 1H NMR
(400 MHz, CDCl3) d 7.25–7.23 (1H, m), 7.09–7.05 (2H,
N-Methoxy-N-methyl-3,4-dihydroquinoline-

7166
J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
4.6.8. N-Methoxy-N-methyl-1,4-dioxa-8-azaspiro[4.5]
decane-8-carboxamide (5h). Yellow oil; 1H NMR
(400 MHz, CDCl3) d 3.87 (4H, s), 3.47 (3H, s), 3.43 (4H,
t, JZ6.0 Hz), 2.84 (3H, s), 1.60 (4H, t, JZ6.0 Hz); 13C
NMR (100 MHz, CDCl3) d 161.6, 106.9, 64.2, 58.5, 43.4,
36.3, 34.9; IR (neat) 2959, 1648, 1473, 1437, 1260,
1099 cmK1; MS (EI) m/z (rel. intensity) 230 (9), 170
(100), 142 (98), 99 (29); HRMS (EI) m/z calcd (MC)
230.1267, found 230.1255.
m/z (rel. intensity) 204 (100), 173 (17), 106 (27), 98 (86), 55
(54); HRMS (EI) m/z Calcd (MC) 204.1263, found 204.1258.
4.7.2. N-Methyl-N-phenyl-1,4-dioxa-8-azaspiro[4.5]
decane-8-carboxamide (6c). Yellow oil; RfZ0.55 (1:9
Hexane/EtOAc); H NMR (400 MHz, CDCl3) d 7.30–7.25
1
(2H, m), 7.07–7.04 (3H, m), 3.85 (4H, s), 3.25 (4H, t, JZ
6.0 Hz), 3.17 (3H, s), 1.45 (4H, t, JZ6.0 Hz); 13C NMR
(100 MHz, CDCl3) d 161.1, 147.2, 129.7, 124.7, 123.9,
107.3, 64.5, 43.9, 39.8, 34.7; IR (KBr pellet) 2960, 2880,
4.6.9. N-Allyl-3,4-dihydroquinoline-1(2H)-carboxamide
(5i).4a,4c,34 White solid; mpZ55–57 8C; 1H NMR
(400 MHz, CDCl3) d 7.36–7.12 (4H, m), 5.84 (1H, m),
5.18 (2H, m), 3.92 (2H, d, JZ5.0 Hz), 3.81 (2H, t, JZ
6.0 Hz), 2.73 (2H, t, JZ6.5 Hz), 2.01–1.88 (2H, m); 13C
NMR (75 MHz, CDCl3) d 156.6, 139.4, 135.4, 132.5, 129.7,
126.7, 124.4, 123.4, 115.9, 43.6, 43.5, 27.2, 24.0; IR (neat)
1648, 1595, 1496, 1432, 1254, 1109, 1033, 945, 761 cmK1
;
MS (EI) m/z (rel. intensity) 276 (73), 170 (65), 142 (100),
106 (32), 77 (37); HRMS (EI) m/z calcd (MC) 276.1474,
found 276.1471.
4.7.3. N-Methoxy-N,N0-dimethyl-N0-phenylurea (6d).
Yellow oil; RfZ0.5 (6:4 Hexane/EtOAc); 1H NMR
(300 MHz, CDCl3) d 7.35–7.28 (2H, m), 7.16–7.12 (3H,
m), 3.19 (3H, s), 2.90 (3H, s), 2.82 (3H, s); 13C NMR
(75 MHz, CDCl3) d 161.7, 145.8, 129.0, 126.0, 126.0, 58.0,
40.3, 34.0; IR (KBr pellet) 2934, 1669, 1596, 1497, 1465,
1371, 1122, 1054, 764, 697 cmK1; MS (EI) m/z (relative
intensity) 194 (25), 163 (27), 134 (100), 106 (59), 77 (31);
HRMS (EI) m/z calcd (MC) 194.1058, found 194.1058.
3325, 2947, 1654, 1512, 1321, 1202, 912 cmK1
.
4.6.10. Ethyl N-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)
glycinate (5j). White solid; mpZ49–50 8C; 1H NMR
(400 MHz, CDCl3) d 7.43 (1H, m), 7.26–7.14 (2H, m),
7.06 (1H, m), 5.67 (1H, br m), 4.20 (2H, q, JZ7.0 Hz), 4.05
(2H, d, JZ5.5 Hz), 3.78 (2H, t, JZ6.0 Hz), 2.77 (2H, t, JZ
6.5 Hz), 1.94 (2H, m), 1.29 (3H, t, JZ7.0 Hz); 13C NMR
(100 MHz, CDCl3) d 171.1, 156.5, 139.1, 132.6, 129.7,
126.9, 124.7, 123.4, 61.5, 43.7, 42.9, 27.2, 24.1, 14.4; IR
(KBr pellet) 3385, 2983, 1751, 1643, 1507, 1395, 1195,
1034 cmK1; MS (EI) m/z (relative intensity) 262 (84), 217
(8), 189 (10), 160 (18), 133 (100), 118 (17), 103 (5); HRMS
(EI) m/z calcd (MC) 262.1317, found 262.1328.
4.7.4. 1-(1,4-Dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-
1,2,3,4-tetrahydroquinoline (6e). Yellow oil; RfZ0.45
(1:9 Hexane/EtOAc); H NMR (400 MHz, CDCl3) d 7.01–
1
6.92 (3H, m), 6.80 (1H, t, JZ7.0 Hz), 3.84 (4H, s), 3.50
(2H, t, JZ6.0 Hz), 3.31 (4H, t, JZ6.0 Hz), 2.67 (2H, t, JZ
6.5 Hz), 1.90–1.83 (2H, m), 1.58 (4H, t, JZ5.5 Hz); 13C
NMR (100 MHz, CDCl3) d 159.8, 140.8, 129.0, 127.4,
126.3, 121.8, 119.5, 106.9, 64.2, 45.5, 43.7, 34.7, 26.9, 23.4;
IR (KBr pellet) 2955, 2880, 1649, 1493, 1417, 1246, 1096,
946, 754 cmK1; MS (EI) m/z (rel. intensity) 302 (95), 170
(81), 142 (100), 132 (42), 98 (26); HRMS (EI) m/z calcd
(MC) 302.1630, found 302.1632.
4.6.11. N-[2-(3,4-Dimethoxyphenyl)ethyl]-1,4-dioxa-8-
azaspiro[4.5]decane-8-carboxamide (5k).4c,35 Yellow
oil; 1H NMR (400 MHz, CDCl3) d 7.24 (1H, m), 6.63
(2H, m), 4.76 (1H, t, JZ5.5 Hz), 3.86 (4H, s), 3.76 (6H, s),
3.33 (6H, m), 2.67 (2H, t, JZ7.0 Hz), 1.55 (4H, m); 13C
NMR (100 MHz, CDCl3) d 157.0, 148.4, 147.0, 131.6,
120.3, 111.6, 110.9, 106.6, 63.9, 55.4, 55.3, 42.0, 41.6, 35.6,
34.3; IR (neat) 3334, 2960, 1614, 1515, 1232, 1142,
4.7.5. N-Phenyl-1,4-dioxa-8-azaspiro[4.5]decane-8-car-
boxamide (6f). White solid; mpZ138–139 8C; RfZ0.3
(4:6 Hexane/EtOAc); H NMR (300 MHz, CDCl3) d 7.33–
1030 cmK1
.
1
7.18 (4H, m), 7.00–6.92 (2H, m), 3.94 (4H, s), 3.53 (4H, t,
JZ5.5 Hz), 1.67 (4H, t, JZ5.5 Hz); 13C NMR (75 MHz,
CDCl3) d 154.9, 139.2, 128.6, 122.8, 120.2, 106.9, 64.5,
42.6, 35.1; IR (KBr pellet) 3319, 2958, 1638, 1535, 1445,
1240, 1111, 945, 753 cmK1; MS (EI) m/z (rel. intensity) 262
(77), 217 (15), 170 (54), 142 (100), 119 (16); HRMS (EI) m/z
calcd (MC) 262.1317, found 262.1314.
4.7. General procedure for the preparation of tri- or
tetrasubstituted ureas 6
To a solution of amine (1.00 mmol) in THF (6 mL) was
added n-BuLi (1.50 mmol), and the reaction was stirred for
1 h. Then the carbamoylimidazolium salt 3 (1.20 mmol)
was added. The mixture was stirred at rt for 18 h, then
diluted with CH2Cl2 (20 mL) and washed with 0.2 N HCl
(20 mL). The aqueous layer was extracted with CH2Cl2 (3!
25 mL). The combined organic layers were washed with
0.2 N HCl (2!20 mL) and brine (15 mL), the organic layer
dried (MgSO4), filtered and concentrated in vacuo. The
products were obtained following column chromatography.
4.7.6. N-(4-Chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]
decane-8-carboxamide (6g). Peach solid; mpZ199–
201 8C; RfZ0.35 (4:6 Hexane/EtOAc); 1H NMR
(300 MHz, CDCl3) d 7.29–7.19 (4H, m), 6.56 (1H, s),
3.98 (4H, s), 3.56 (4H, t, JZ6.0 Hz), 1.74 (4H, t, JZ
6.0 Hz); 13C NMR (75 MHz, CDCl3) d 154.4, 137.7, 128.8,
128.0, 121.2, 106.9, 64.7, 42.9, 35.2; IR (KBr pellet) 3341,
1639, 1534, 1494, 1240, 1116, 1089, 946 cmK1; MS (EI) m/z
(relative intensity) 296 (59), 251 (9), 170 (73), 153 (23), 142
(100), 98 (28); HRMS (EI) m/z calcd (MC) 296.0928, found
296.0921.
4.7.1. N-Methyl-N-phenylpyrrolidine-1-carboxamide
(6a). Peach solid; mpZ64–66 8C; RfZ0.5 (100% EtOAc);
1H NMR (300 MHz, CDCl3) d 7.31–7.26 (2H, m), 7.10–7.07
(3H, m), 3.21 (3H, s), 3.04 (4H, t, JZ6.5 Hz), 1.69–1.64 (4H,
m); 13C NMR (75 MHz, CDCl3) d 159.7, 146.4, 129.3, 125.0,
124.6, 48.1, 39.9, 25.7; IR (KBr pellet) 2972, 2875, 1638,
1594, 1499, 1431, 1383, 1248, 1106, 764, 703 cmK1; MS (EI)
4.7.7. N-(4-Methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]
decane-8-carboxamide (6h). Beige solid; mpZ154–156 8C;

J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
7167
RfZ0.2 (1:1 Hexane/EtOAc); 1H NMR (300 MHz, CDCl3) d
7.17 (2H, d, JZ9.0 Hz), 6.75 (2H, d, JZ9.0 Hz), 6.72 (1H, s),
3.93 (4H, s), 3.72 (3H, s), 3.45 (4H, t, JZ5.5 Hz), 1.65 (4H, t,
JZ5.5 Hz); 13C NMR (75 MHz, CDCl3) d 155.6, 155.3, 132.1,
122.6, 113.9, 107.0, 64.5, 55.6, 42.6, 35.1; IR (KBr pellet) 3318,
2958, 1634, 1513, 1421, 1235, 1109, 1034, 946, 822 cmK1; MS
(EI) m/z (rel. intensity) 292 (100), 247 (13), 170 (33), 149 (68),
142 (98), 98 (30); HRMS (EI) m/z calcd (MC) 292.1423, found
292.1422.
142 (76), 99 (25), 70 (14); HRMS (EI) m/z calcd (MC)
264.1110, found 264.1110.
4.8.5. Phenyl methyl(phenyl)carbamate (7e).4b,36 White
solid; mpZ56–58 8C; 1H NMR (400 MHz, CDCl3) d 7.70–
7.20 (10H, m), 3.48 (3H. s); 13C NMR (75 MHz, CDCl3) d
154.1, 151.5, 143.1, 129.4, 129.2, 126.7, 126.0, 125.5,
121.8, 38.3; IR (KBr pellet) 1735, 1600, 1560, 1260, 1239,
1233 cmK1
.
4.8.6. 3-Nitrophenyl 3,4-dihydroquinoline-1(2H)-car-
4.8. General procedure for the preparation of carbamate
7 from phenols
1
boxylate (7f).4b Yellow solid; mpZ78–80 8C; H NMR
(400 MHz, CDCl3) d 8.08–8.04 (2H, m), 7.74 (1H, br s),
7.55–7.51 (2H, m), 7.24–7.06 (3H, m), 3.93 (2H, m), 2.85
(2H, t, JZ6.5 Hz), 2.05 (2H, t, JZ6.5 Hz); 13C NMR
(100 MHz, CDCl3) d 152.1, 151.3, 148.5, 137.1, 130.5,
129.7, 128.6, 128.1, 126.0, 124.4, 123.7, 120.2, 117.3, 45.3,
27.0, 23.3; IR (KBr pellet) 2949, 1725, 1493, 1349, 1117,
991 cmK1; MS (EI) m/z (rel. intensity) 298 (41), 160 (100),
142 (13), 132 (78), 117 (10), 77 (10); HRMS (EI) m/z calcd
(MC) 298.0954, found 298.0944.
To a solution of carbamoylimidazolium salt 3 (1.00 mmol)
in acetonitrile (6 mL) was added the phenol (1.00 mmol)
and triethylamine (1.00 mmol). The reaction was refluxed
overnight. The solvent was removed under vacuum and the
residue was dissolved in CH2Cl2 (15 mL) and 0.1 M HCl
(15 mL) was added. The aqueous layer was extracted with
CH2Cl2 (3!15 mL). The combined organic layers were
washed with water (20 mL) and brine (20 mL). The organic
layer was dried (MgSO4), filtered and concentrated in vacuo
to yield carbamate 7a–f.
4.9. General procedure for the preparation of carbamate
8 from alcohols
4.8.1. 2-Naphthyl morpholine-4-carboxylate (7a).4b Clear
oil; 1H NMR (400 MHz, CDCl3) d 7.85–7.78 (3H, m), 7.58
(1H, m), 7.49–7.42 (2H, m), 7.29–7.26 (1H, m), 3.77–3.74
(4H, m), 3.71 (2H, br s), 3.59 (2H, br s); 13C NMR
(100 MHz, CDCl3) d 153.5, 148.6, 133.5, 131.0, 129.0,
127.5, 127.3, 126.2, 125.3, 121.2, 118.2, 66.3, 66.2, 44.6,
43.9; IR (KBr pellet) 2956, 2853, 1722, 1418, 1230, 1161,
1115, 1063 cmK1; MS (EI) m/z (relative intensity) 257 (71),
144 (11), 127 (14), 114 (100), 70 (51); HRMS (EI) m/z
Calcd (MC) 257.1052, found 257.1045.
To a solution of carbamoylimidazolium salt 3 (2.00 mmol)
and alcohol (2.00 mmol) in THF/DMF (2:1, 12 mL) was
added portionwise NaH (2.20 mmol, 80% in mineral oil).
The solution was stirred at rt for 1 day. H2O (10 mL) and
Et2O (20 mL) were added, and the organic layer was washed
with H2O (2!10 mL). The organic layer was dried
(MgSO4), filtered and concentrated in vacuo. The oil was
purified by flash column chromatography (CH2Cl2) to yield
carbamate 8e–f.
4.9.1. 3-Methylbut-2-en-1-yl 1,4-dioxa-8-azaspiro[4.5]
decane-8-carboxylate (8a).4b Yellow oil; 1H NMR
(200 MHz, CDCl3) d 5.30–5.27 (1H, m), 4.52 (2H, d, JZ
7.0 Hz), 3.90 (4H, s), 3.49–3.47 (4H, m), 1.69 (3H, s), 1.64
(3H, s), 1.61–1.58 (4H, m); 13C NMR (50 MHz, CDCl3) d
155.3, 137.9, 119.4, 106.9, 64.3, 62.2, 41.8, 34.7, 25.6, 17.9;
IR (neat) 2961, 2879, 1694, 1428, 1231, 1112 cmK1; MS
(EI) m/z (rel. intensity) 255 (37), 196 (16), 186 (3), 170 (19),
142 (27), 99 (41); HRMS (EI) m/z calcd (MC) 255.1471,
found 255.1468.
4.8.2. 2-Bromophenyl morpholine-4-carboxylate (7b).4b
1H White solid, mp 62–63 8C; 1H NMR (400 MHz, CDCl3)
d 7.57–7.05 (4H, m), 3.74 (6H, m), 3.56 (2H, m); 13C NMR
(100 MHz, CDCl3) d 152.4, 148.4, 133.0, 128.3, 126.9,
124.0, 116.3, 66.5, 45.0, 44.2; IR (KBr pellet) 2917, 1715,
1214, 763 cmK1; MS (EI) m/z (relative intensity) 206 (89),
156 (8), 114 (100), 70 (59); HRMS (EI) m/z calcd (MC)
286.0079, found 286.0083.
4.8.3. 2-Bromophenyl 1,4-dioxa-8-azaspiro[4.5]decane-
8-carboxylate (7c).4b Yellow oil; 1H NMR (400 MHz,
CDCl3) d 7.54–7.52 (1H, m), 7.29–7.02 (3H, m), 3.94 (4H,
s), 3.78–3.63 (4H, m), 1.79–1.74 (4H, m); 13C NMR
(100 MHz, CDCl3) d 152.2, 148.4, 132.8, 128.2, 126.6,
124.0, 116.3, 106.5, 64.2, 42.7, 42.4, 35.0, 34.5; IR (neat)
2960, 1732, 1423, 1214, 1104, 945, 750 cmK1; MS (EI) (rel.
intensity) 341 (5), 262 (15), 170 (77), 142 (100), 99 (38);
HRMS (EI) m/z calcd (MC) 341.0263, found 341.0270.
4.9.2. 2,2,2-Trifluoroethyl 1,4-dioxa-8-azaspiro[4.5]
decane-8-carboxylate (8b).4b Yellow oil; 1H NMR
(200 MHz, CDCl3) d 4.42 (2H, q, JZ8.5 Hz), 3.91 (4H,
s), 3.53–3.52 (4H, m), 1.64–1.63 (4H, m); 13C NMR
(50 MHz, CDCl3) d 153.1, 123.1 (q, JZ277.5 Hz), 106.5,
64.3, 61.3 (q, JZ54.0 Hz), 42.4, 42.1, 34.8, 34.5; IR (neat)
2966, 1714, 1474, 1232, 1166, 962 cmK1; MS (EI) m/z (rel.
intensity) 269 (74), 210 (19), 186 (100), 170 (23), 99 (65);
HRMS (EI) m/z calcd (MC) 269.0875, found 269.0873.
4.8.4. Pyridin-3-yl 1,4-dioxa-8-azaspiro[4.5]decane-8-
carboxylate (7d).4b White solid; mpZ102–103 8C; 1H
NMR (400 MHz, CDCl3) d 8.36–8.33 (2H, m), 7.47–7.44
(1H, m), 7.27–7.23 (1H, m), 3.87 (4H, s), 3.83–3.52 (4H,
m), 1.87–1.28 (4H, m); 13C NMR (100 MHz, CDCl3) d
152.3, 147.6, 145.8, 143.2, 128.9, 123.3, 106.1, 64.1, 42.3,
42.1, 34.6, 34.2; IR (KBr pellet) 2892, 1723, 1219, 1108,
958 cmK1; MS (EI) m/z (rel. intensity) 264 (3), 170 (100),
4.9.3. 3-Methylbut-2-en-1-yl 3,4-dihydroisoquinoline-
2(1H)-carboxylate (8c).4b Yellow oil; 1H NMR
(200 MHz, CDCl3) d 7.24–7.14 (4H, m), 5.40–5.33 (1H,
m), 4.63–4.60 (4H, m), 3.71–3.65 (2H, m), 2.86–2.80 (2H,
m), 1.75 (3H, s), 1.71 (3H, s); 13C NMR (50 MHz, CDCl3) d
155.6, 137.8, 134.4, 133.2, 128.5, 126.2, 126.1, 125.9,
119.4, 62.2, 45.5, 41.3, 28.7, 25.6, 17.8; IR (neat) 2930,

7168
J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
1703, 1428, 1227, 1118, 984 cmK1; MS (EI) m/z (relative
intensity) 245 (5), 176 (47), 132 (36), 104 (19), 69 (100);
HRMS (EI) m/z Calcd (MC) 245.1416, found 245.1415.
signal); 19F NMR (376 MHz, CDCl3) d K131 (2F, m),
K150 (1F, m), K161 (2F, m); IR (KBr pellet) 1664, 1517,
1470, 1295, 1094, 976 cmK1; MS (EI) m/z (relative
intensity) 359 (17), 199 (24), 160 (100), 132 (78), 118
(19); HRMS (EI) m/z calcd (MC) 359.0403, found
359.0419.
4.9.4. 3-Methylbut-2-en-1-yl methyl(phenyl)carbamate
1
(8e).4b Clear oil; H NMR (200 MHz, CDCl3) d 7.25 (5H,
m), 5.33 (1H, m), 4.61 (2H, d, JZ7.0 Hz), 3.30 (3H, s), 1.73
(3H, s), 1.68 (3H, s); 13C NMR (50 MHz, CDCl3) d 155.6,
143.3, 137.8, 128.6, 125.6, 125.4, 119.3, 62.4, 37.4, 25.5,
17.8; IR (neat) 2934, 1707, 1598, 1498, 1386, 1353, 1298,
1277, 1153 cmK1; MS (EI) m/z (rel. intensity) 219 (3), 175
(3) 160 (9), 151 (24) 107 (59), 69 (100); HRMS (EI) m/z
calcd (MC) 219.1259, found 219.1251.
4.10.4. S-Cyclohexyl 3,4-dihydroquinoline-1(2H)-car-
1
bothioate (9d).4b Clear oil; H NMR (200 MHz, CDCl3) d
7.72 (1H, d, JZ8.0 Hz), 7.20–7.02 (3H, m), 3.76 (2H, tr,
JZ6.0 Hz), 3.49 (1H, m), 2.75 (2H, tr, JZ6.5 Hz), 2.07–
1.15 (12H, m); 13C NMR (50 MHz, CDCl3) d 168.3, 138.1,
131.3, 128.6, 125.8, 124.9, 124.8, 45.0, 44.2, 33.5, 26.9,
26.2, 25.6, 23.6; IR (neat) 2930, 1646, 1580, 1488, 1446,
1362, 1295, 1197, 1162, 1089 cmK1; MS (EI) m/z (rel.
intensity) 275 (89), 193 (25), 172 (47), 160 (69), 133 (100),
83 (37); HRMS (EI) m/z calcd (MC) 275.1344, found
275.1335.
4.9.5. Benzyl methyl(phenyl)carbamate (8f).4b,37 Yellow
oil; 1H NMR (200 MHz, CDCl3) d 7.40–7.20 (10H, m), 5.20
(2H, s), 3.35 (3H, s); 13C NMR (75 MHz, CDCl3) d 155.6,
143.5 (d), 136.8, 129.0, 128.6, 128.0, 127.8, 126.3, 125.9,
67.4, 37.9; IR (neat) 2950, 1705, 1596, 1496, 1387, 1348,
1152 cmK1
.
4.10.5. Methyl N-acetyl-S-(3,4-dihydroquinolin-1(2H)-
1
ylcarbonyl)-L-cysteinate (9e).4b Yellow foam; H NMR
(200 MHz, CDCl3) d 7.61–7.59 (1H, m), 7.15–7.06 (3H, m),
6.73 (1H, d, JZ5.5 Hz), 4.73–4.69 (1H, m), 3.78–3.69 (5H,
m), 3.33 (2H, d, JZ6.0 Hz), 2.72 (2H, t, JZ6.5 Hz), 1.97–
1.91 (5H, m); 13C NMR (50 MHz, CDCl3) d 170.7, 169.9,
167.8, 137.4, 131.7, 128.6, 125.9, 125.5, 124.5, 52.9, 52.4,
45.4, 32.0, 26.6, 23.5, 22.9; IR (neat) 3290, 2950, 1760,
1682, 1647, 1372, 1296, 1090 cmK1; MS (EI) m/z (rel.
intensity) 336 (44), 277 (19), 193 (6), 160 (100), 144 (13),
132 (93); HRMS (EI) m/z calcd (MC) 336.1144, found
336.1140.
4.10. General procedure for the preparation of thiocar-
bamate 9
To a suspension of carbamoylimidazolium salt 3
(1.00 mmol) in CH2Cl2 (6 mL) was added the thiol
(1.00 mmol) and triethylamine (1.00 mmol). After stirring
at rt overnight, the reaction was diluted with CH2Cl2 (5 mL)
and 0.1 M HCl (10 mL). The aqueous layer was extracted
with CH2Cl2 (3!10 mL) and the combined organic layers
were washed with H2O (10 mL) and brine (15 mL). The
organic layer was dried (MgSO4), filtered and concentrated
in vacuo. The crude material was purified by flash column
chromatography (98:2 Hexane: ethyl acetate) to yield the
thiocarbamate 9a–f.
4.10.6. S-Cyclohexyl 1,4-dioxa-8-azaspiro[4.5]decane-8-
carbothioate (9f).4b White solid; mpZ56–57 8C; 1H NMR
(200 MHz, CDCl3) d 3.87 (4H, s), 3.51–3.34 (5H, m), 1.91–
1.88 (2H, m), 1.63–1.37 (7H, m), 1.34–1.16 (5H, m); 13C
NMR (50 MHz, CDCl3) d 166.7, 106.8, 64.3, 44.7, 43.6,
41.4, 34.7, 33.5, 25.9, 25.4; IR (KBr pellet) 2931, 1644,
1447, 1263, 1033, 914 cmK1; MS (EI) m/z (rel. intensity)
285 (18), 252 (20), 204 (66), 170 (100), 142 (80), 99 (32);
HRMS (EI) m/z calcd (MC) 285.1399, found 285.1408.
4.10.1. S-Phenyl methyl(phenyl)thiocarbamate (9a).4b,38
White solid; mpZ66–67 8C; 1H NMR (200 MHz, CDCl3) d
7.60–7.40 (10H, m), 3.37 (3H, s); 13C NMR (50 MHz,
CDCl3) d 167.4, 141.8, 135.4 (d), 129.5 (d), 129.4, 129.0
(d), 128.8 (d), 128.6 (d), 128.2 (d), 38.5; IR (neat) 2950,
1666, 1592, 1484, 1443, 1341, 1272, 1106 cmK1
.
4.11. General procedure for the preparation of amides
10 from carboxylic acids
4.10.2. S-Dodecyl 3,4-dihydroquinoline-1(2H)-car-
1
bothioate (9b).4b Clear oil; H NMR (200 MHz, CDCl3) d
7.72–7.70 (1H, m), 7.17–7.06 (3H, m), 3.78 (2H, t, JZ
6.0 Hz), 2.90 (2H, t, JZ7.0 Hz), 2.75 (2H, t, JZ6.5 Hz),
2.00–1.94 (2H, m), 1.63–1.58 (2H, m), 1.39–1.24 (18H, m),
0.86 (3H, t, JZ7.0 Hz); 13C NMR (50 MHz, CDCl3) d
168.6, 138.1, 131.3, 125.8, 125.8, 124.9, 124.7, 45.0, 31.8,
30.8, 29.9, 29.5, 29.5, 29.4, 29.4, 29.2, 29.1, 28.9, 26.8,
23.6, 22.6, 14.0; IR (neat) 2852, 1661, 1489, 1295, 1194,
1090, 937 cmK1; MS (EI) m/z (relative intensity) 361 (79),
193 (12), 160 (100), 132 (50), 118 (6); HRMS (EI) m/z
Calcd (MC) 361.2439, found 361.1444.
To a suspension of 3 (1.00 mmol) in acetonitrile (6 mL)
were added the carboxylic acid (1.00 mmol) and triethyl-
amine (1.00 mmol). The reaction was stirred at rt overnight.
The solvent was removed in vacuo and the residue dissolved
in CH2Cl2 (15 mL) and 0.2 N HCl (15 mL) was added. The
aqueous layer was extracted with CH2Cl2 (3!15 mL). The
combined organic layers were washed with 0.2 N HCl
(15 mL), 0.5 M K2CO3 (25 mL), and brine (20 mL), dried
(MgSO4), filtered and concentrated in vacuo to give the
amide 10a–l.
4.10.3. S-(Pentafluorophenyl) 3,4-dihydroquinoline-
1(2H)-carbothioate (9c).4b White solid; mpZ78–79 8C;
1H NMR (400 MHz, CDCl3) d 7.70–7.66 (1H, m), 7.23–
7.18 (3H, m), 3.85 (2H, t, JZ6.5 Hz), 2.81 (2H, t, JZ
6.5 Hz), 2.11–1.98 (2H, m); 13C NMR (100 MHz, CDCl3) d
162.2, 150.3 (m), 145.3 (m), 140.2 (m), 137.2, 135.1 (m),
132.5, 128.9, 126.3, 124.5, 45.9, 26.6, 23.6 (1 missing
4.11.1. 4-(4-Methylpentanoyl)morpholine (10c).4d,39
Yellow oil; H NMR (300 MHz, CDCl3) d 3.60–3.37 (8H,
m), 2.25–2.20 (2H, m), 1.55–1.39 (3H, m), 0.83 (6H, d, JZ
6.5 Hz); 13C NMR (75 MHz, CDCl3) d 172.2, 67.1, 66.8,
46.2, 42.0, 34.2, 31.3, 28.0, 22.5; IR (neat) 2956, 1651,
1429, 1273, 1116, 1030, 851 cmK1; MS (EI) m/z (rel.
intensity) 170 (10), 142 (15), 129 (100), 114 (30), 86 (41),
1

J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
7169
57 (63); HRMS (EI) m/z calcd (MHC) 186.1494, found
186.1495.
4.11.8. Benzyl [2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-
oxoethyl]carbamate (10o).4d White solid; mpZ84–86 8C;
1H NMR (300 MHz, CDCl3) d 7.30–7.24 (5H, m), 5.90 (1H,
s), 5.06 (2H, s), 3.97 (2H, d, JZ4.0 Hz), 3.90 (4H, s), 3.64
(2H, t, JZ5.5 Hz), 3.37 (2H, t, JZ5.5 Hz), 1.65–1.60 (4H,
m); 13C NMR (75 MHz, CDCl3) d 166.0, 156.0, 136.3,
128.3, 127.8, 127.8, 106.4, 66.6, 64.3, 42.4, 42.2, 40.0, 35.0,
34.4; IR (KBr pellet) 3306, 2962, 2878, 1717, 1635, 1520,
1443, 1218, 1058, 734 cmK1; MS (EI) m/z (rel. intensity)
334 (24), 243 (27), 170 (41), 142 (84), 108 (38), 99 (100);
HRMS (EI) m/z calcd (MC) 334.1529, found 334.1529.
4.11.2. Benzyl [(1S)-1-benzyl-2-morpholin-4-yl-2-
oxoethyl]carbamate (10e).4d,40 Yellow oil; 1H NMR
(300 MHz, CDCl3) d 7.32–7.17 (10H, m), 6.17 (1H, d,
JZ8.5 Hz), 5.12–5.01 (2H, m), 4.89–4.81 (1H, m), 3.66–
3.22 (6H, m), 3.07–2.82 (4H, m); 13C NMR (75 MHz,
CDCl3) d 170.2, 156.0, 136.6, 136.5, 129.8, 128.8, 128.7,
128.3, 128.2, 127.4, 67.0, 66.6, 66.2, 51.6, 46.2, 42.5, 40.4;
IR (neat) 3289, 1716, 1636, 1528, 1455, 1231, 1114,
751 cmK1; MS (EI) m/z (rel. intensity) 368 (3), 254 (60),
217 (53), 210 (62), 91 (100); HRMS (EI) m/z calcd (MC)
368.1736, found 368.1726.
4.11.9. Benzyl [(1S)-1-(1,4-dioxa-8-azaspiro[4.5]dec-8-
ylcarbonyl)-3-methylbutyl]carbamate (10p). Yellow oil;
1H NMR (300 MHz, CDCl3) d 7.33–7.26 (5H, m), 5.74 (1H,
d, JZ9.0 Hz), 5.06 (2H, s), 4.80–4.72 (1H, m), 3.95 (4H, s),
3.76–3.53 (4H, m), 1.76–1.65 (5H, m), 1.51–1.38 (2H, m),
0.99 (3H, d, JZ6.5 Hz), 0.91 (3H, d, JZ6.5 Hz); 13C NMR
(75 MHz, CDCl3) d 170.5, 156.0, 136.3, 128.3, 127.9,
127.9, 106.7, 66.9, 64.6, 64.6, 49.2, 43.6, 43.1, 40.5, 35.7,
34.9, 24.9, 23.6, 22.2; IR (thin film) 3293, 2958, 1715, 1640,
1531, 1454, 1231, 1100, 1044, 945 cmK1; MS (EI) m/z (rel.
intensity) 390 (2), 334 (3), 220 (24), 176 (45), 142 (28), 91
(100); HRMS (EI) m/z calcd (MC) 390.2155, found
390.2168.
4.11.3. N-Methoxy-N-methyl-4-oxo-4-phenylbutanamide
1
(10i).4d,41 Yellow oil; H NMR (300 MHz, CDCl3) d 7.64
(2H, d, JZ7.0 Hz), 7.49–7.36 (3H, m), 3.70 (3H, s), 3.27
(2H, t, JZ6.5 Hz), 3.14 (3H, s), 2.84 (2H, t, JZ6.5 Hz); 13C
NMR (75 MHz, CDCl3) d 199.1, 173.4, 137.0, 133.2, 128.7,
128.2, 61.4, 33.2, 32.4, 26.3.
4.11.4. N-{2-[Methoxy(methyl)amino]-2-oxoethyl}-4-
methylpentanamide (10j).4d Yellow oil; 1H NMR
(300 MHz, CDCl3) d 3.62 (3H, s), 3.11 (3H, s), 2.35 (2H,
t, JZ7.5 Hz), 1.60–1.40 (3H, m), 0.85 (6H, d, JZ6.5 Hz);
13C NMR (75 MHz, CDCl3) d 150.0, 61.4, 33.7, 32.4, 30.1,
28.0, 22.5; IR (neat) 2957, 1669, 1467, 1345, 1177,
1001 cmK1; MS (EI) m/z (rel. intensity) 144 (12), 103
(48), 99 (79), 81 (100), 61 (99); HRMS (EI) m/z calcd (MC)
159.1259, found 159.1253.
4.11.10. 1-(Phenylacetyl)-1,2,3,4-tetrahydroquinoline
1
(10q).43 Yellow oil; H NMR (400 MHz, CDCl3) d 7.27–
7.12 (9H, m), 3.87 (2H, s), 3.80 (2H, t, JZ6.5 Hz), 2.60
(2H, br s), 1.89 (2H, t, JZ6.5 Hz); 13C NMR (100 MHz,
CDCl3) d 170.9, 139.3, 135.5, 128.9, 128.6, 128.5, 126.8,
126.2, 125.7, 124.9, 43.2, 41.4, 26.6, 24.1 (1 carbon
missing); IR (thin film) 3029, 2946, 1652, 1580, 1492,
1383, 1165, 1074, 760, 719 cmK1; MS (EI) m/z (rel.
intensity) 251 (95), 160 (26), 133 (100), 117 (18), 91 (60);
HRMS (EI) m/z calcd (MC) 251.1310, found 251.1310.
4.11.5. 2-Iodo-N-methoxy-N-methylbenzamide (10l).4d,42
1
White solid; mpZ55–58 8C; H NMR (400 MHz, CDCl3,
50 8C) d 7.83–7.80 (1H, m), 7.38–7.34 (1H, m), 7.26–7.24
(1H, m), 7.09–7.05 (1H, m), 3.51 (3H, br s), 3.31 (3H, br s);
13C NMR (100 MHz, CDCl3, 50 8C) d 141.7, 139.1, 130.4,
127.8, 127.4, 92.5, 61.2, 32.7 (1 missing signal); MS (EI) m/z
(rel. intensity) 291 (18), 231 (100), 203 (31), 104 (8), 76
(26); HRMS (EI) m/z Calcd (MC) 290.9756, found
290.9760.
4.11.11. Benzyl [2-(3,4-dihydroquinolin-1(2H)-yl)-2-
oxoethyl]carbamate (10r). Yellow oil; 1H NMR
(300 MHz, CDCl3) d 7.35–7.13 (9H, m), 5.78 (1H, s),
5.10 (2H, s), 4.15 (2H, d, JZ4.5 Hz), 3.76 (2H, br s), 2.72
(2H, br m), 2.00–1.92 (2H, m); 13C NMR (75 MHz, CDCl3)
d 168.1, 156.4, 137.8, 136.6, 129.0, 128.6, 128.2, 128.2,
126.6, 126.1, 124.3, 67.0, 44.0, 43.6, 26.8, 23.7 (1 carbon
missing); IR (thin film) 3326, 2947, 1722, 1660, 1492, 1404,
1237, 1048, 759 cmK1; MS (EI) m/z (rel. intensity) 324
(42), 216 (18), 160 (27), 133 (100), 91 (60); HRMS (EI) m/z
calcd (MC) 324.1474, found 324.1479.
4.11.6. 8-(Phenylacetyl)-1,4-dioxa-8-azaspiro[4.5]decane
1
(10m).4d Yellow oil; H NMR (300 MHz, CDCl3) d 7.25–
7.16 (5H, m), 3.85 (4H, d, JZ2.0 Hz), 3.68 (2H, s), 3.65
(2H, t, JZ6.0 Hz), 3.43 (2H, t, JZ6.0 Hz), 1.58 (2H, t, JZ
6.0 Hz), 1.37 (2H, t, JZ5.5 Hz); 13C NMR (75 MHz,
CDCl3) d 169.5, 135.3, 128.9, 128.7, 127.0, 107.0, 64.6,
44.4, 41.3, 40.1, 35.4, 34.8; IR (neat) 2962, 2878, 1630,
1440, 1360, 1250, 1097, 1029 cmK1; MS (EI) m/z (rel.
intensity) 261 (73), 170 (100), 142 (80), 118 (37), 91 (77);
HRMS (EI) m/z calcd (MC) 261.1365, found 261.1368.
4.12. General procedure for the preparation of
thiocarbamoylimidazoles
To
a
suspension of N,N0-thiocarbonyldiimidazole
(5.50 mmol) in CH2Cl2 (5 mL) was added amine
(5.00 mmol). The mixture was stirred at rt for 2 h. The
reaction mixture was then diluted with CH2Cl2 (100 mL)
and washed with water (3!20 mL). The organic layer was
dried (MgSO4), filtered and concentrated in vacuo to yield
the product thiocarbamoylimidazole 11a–d.
4.11.7. 8-Propionyl-1,4-dioxa-8-azaspiro[4.5]decane
1
(10n).4d White solid; mp 59–60 8C; H NMR (300 MHz,
CDCl3) d 3.86 (4H, s), 3.58 (2H, t, JZ6.0 Hz), 3.41 (2H, t,
JZ6.0 Hz), 2.25 (2H, m), 1.56 (4H, m), 1.03 (3H, t, JZ
7.5 Hz); 13C NMR (75 MHz, CDCl3) d 172.2, 107.0, 64.6,
43.5, 39.8, 35.7, 34.9, 26.6, 9.7; IR (KBr pellet) 2961, 2873,
1648, 1419, 1226, 1075, 928, 816 cmK1; MS (EI) m/z (rel.
intensity) 199 (72), 142 (35), 99 (100), 86 (35), 57 (53);
HRMS (EI) calcd (MC) 199.1208, found 199.1214.
4.12.1. 8-(1H-Imidazol-1-ylcarbonothioyl)-1,4-dioxa-8-
azaspiro[4.5]decane (11a). Beige solid; mpZ89–92 8C;
1H NMR (200 MHz, CDCl3) d 7.81–7.80 (1H, m), 7.14–7.13

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J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
(1H, m), 7.02 (1H, m), 3.95–3.94 (8H, m), 1.80 (4H, br s); 13
C
3.91 (3H, s), 3.87–3.67 (6H, br m); 13C NMR (50 MHz, DMSO-
d6) d 171.9, 137.5, 123.8, 121.2, 65.4 (br), 52.0, 36.6; IR (KBr
pellet) 3065, 1507, 1437, 1242, 1052, 963 cmK1; MS (FAB)
m/z (rel. intensity) 121 (51), 185 (100), 175 (12), 130 (45).
NMR (50 MHz, CDCl3) d 178.2, 137.0, 129.4, 119.0, 105.6,
64.3, 49.4, 34.6; IR (KBrpellet)3114, 1507, 1362, 1238, 1079,
935 cmK1; MS (EI) m/z (rel. intensity) 253 (97), 186 (100),
158 (91), 142 (27), 99 (66); HRMS (EI) m/z calcd (MC)
253.0885, found 253.0876.
4.13.3. 3-Methyl-1-(pyrrolidin-1-ylcarbonothioyl)-1H-
imidazol-3-ium iodide (12c). Yellow solid; mpZ178–
180 8C; H NMR (400 MHz, CDCl3) d 10.25 (1H, br m),
1
4.12.2. 4-(1H-Imidazol-1-ylcarbonothioyl)morpholine
1
(11b). White solid; mpZ84–90 8C; H NMR (200 MHz,
7.91 (1H, br m), 7.60 (1H, br m), 4.25 (3H, s), 4.07 (2H, br
m), 3.89–3.86 (2H, m), 2.18–2.11 (4H, m); 13C NMR
(100 MHz, CDCl3) 168.6, 136.1, 123.7, 121.9, 56.2, 55.4,
38.2, 26.8, 24.7; IR (KBr pellet) 3064, 1579, 1516, 1447,
1331, 1193, 956, 855 cmK1; MS (FAB) m/z (rel. intensity)
196 (92), 114 (100); HRMS (FAB) m/z calcd (MCK127)
196.0908, found 196.0908.
CDCl3) d 7.78 (1H, s), 7.10–7.09 (1H, m), 6.98–6.97 (1H,
m), 3.82–3.67 (8H, m); 13C NMR (50 MHz, CDCl3) d 178.4,
137.1, 129.8, 118.9, 66.0, 51.7; IR (KBr pellet) 2975, 1487,
1436, 1362, 1304, 1239, 1115, 1029, 962 cmK1; MS (EI) m/z
(rel. intensity) 197 (80), 130 (100), 111 (7), 86 (89); HRMS
(EI) m/z calcd (MC) 197.0623, found 197.0625.
4.12.3. 1-(Pyrrolidin-1-ylcarbonothioyl)-1H-imidazole
(11c). Yellow oil; H NMR (400 MHz, CDCl3) d 7.97–
4.13.4. 1-(3,4-Dihydroquinolin-1(2H)-ylcarbonothioyl)-
3-methyl-1H-imidazol-3-ium iodide (12d). Yellow solid;
mpZ199–204 8C; 1H NMR (400 MHz, CDCl3) d 9.65 (1H,
s), 7.65 (1H, s), 7.59 (1H, s), 7.36 (1H, d, JZ9.0 Hz), 7.23
(1H, m), 7.06 (1H, m), 6.91 (1H, d, JZ8.0 Hz), 4.20 (2H, t,
JZ6.5 Hz), 3.86 (3H, s), 2.88 (2H, t, JZ6.0 Hz), 2.09–2.06
(2H, m); 13C NMR (100 MHz, CDCl3) 171.6, 138.4, 137.6,
134.6, 128.8, 127.6, 127.0, 123.4, 123.1, 121.6, 53.6, 36.5,
25.8, 23.7; MS (FAB) m/z (rel. intensity) 258 (45), 236 (20),
176 (100), 160 (29), 146 (35).
1
7.96 (1H, m), 7.33–7.32 (1H, m), 7.07–7.06 (1H, m), 3.91
(2H, br m), 3.65 (2H, br m), 2.05 (4H, br m); 13C NMR
(100 MHz, CDCl3) d 175.7, 137.0, 129.6, 118.9, 54.9, 53.7,
26.7, 24.6; IR (neat) 3114, 2975, 1694, 1495, 1358, 1281,
1043, 954, 825, 746 cmK1; MS (EI) m/z (rel. intensity) 181
(81), 114 (100), 84 (12), 72 (59), 55 (33); HRMS (EI) m/z
calcd (MC) 181.0674, found 181.0677.
4.12.4. 1-(1H-Imidazol-1-ylcarbonothioyl)-1,2,3,4-tetra-
hydroquinoline (11d). Beige solid; mpZ75–77 8C; 1H
NMR (400 MHz, CDCl3) d 7.93 (1H, s), 7.74 (1H, s), 7.26–
7.23 (2H, m), 7.12 (3H, br m), 4.96 (2H, s), 4.03 (2H, m),
3.08 (2H, m); 13C NMR (100 MHz, CDCl3) d 177.0, 139.1,
137.3, 132.6, 129.2, 128.4, 127.0, 126.4, 122.3, 119.3, 52.2,
26.4, 24.2; IR (KBr pellet) 3118, 1652, 1471, 1233, 1062,
928 cmK1; MS (EI) m/z (rel. intensity) 143 (100), 215 (17),
176 (55), 142 (33), 117 (48); HRMS (EI) m/z calcd (MC)
243.0830, found 243.0831.
4.14. General procedure for the synthesis of thioureas 13
To a solution of thiocarbamoylimidazolium salt 12
(0.50 mmol) in CH2Cl2 (1.0 mL) was added a primary or
secondary amine (0.600 mmol) and triethylamine
(0.60 mmol). The reaction was stirred at rt for 2 h, and
diluted with CH2Cl2 (10 mL). The mixture was washed with
1N HCl solution (2!5 mL) and brine. The aqueous layer
was extracted with CH2Cl2 (3!10 mL). The combined
organic layers were washed with H2O (10 mL) and brine
(10 mL), dried (MgSO4), filtered and concentrated in vacuo
to afford thiourea 13a–e.
4.13. General procedure for the preparation of
thiocarbamoylimidazolium salts 12
To a solution of thiocarbamoylimidazole (8.00 mmol) in
acetonitrile (15 mL) was added methyl iodide (32.0 mmol).
The mixture was stirred at rt for 24 h. The solvent was
removed under vacuum to yield the thiocarbamoyl
imidazolium salt 12a–d as a yellow viscous oil. Recrystal-
ization in methanol/ethyl acetate gave yellow crystals.
4.14.1. 4-(Pyrrolidin-1-ylcarbonothioyl)morpholine
(13a). Yellow oil; 1H NMR (400 MHz, CDCl3) d 3.75
(4H, t, JZ4.5 Hz), 3.67–3.63 (4H, m), 3.46 (4H, t, JZ
4.5 Hz), 1.94–1.91 (4H, m); 13C NMR (100 MHz, CDCl3) d
190.7, 66.8, 53.2, 51.4, 25.6; IR (neat) 2965, 2854, 1434,
1346, 1269, 1215, 1115, 1030, 872 cmK1; MS (EI) m/z (rel.
intensity) 200 (100), 167 (37), 143 (30), 130 (11), 114 (61),
96 (10), 86 (53), 70 (45); HRMS (EI) m/z calcd (MC)
200.0983, found 200.0992.
4.13.1.
1-(1,4-Dioxa-8-azaspiro[4.5]dec-8-ylcarbo-
nothioyl)-3-methyl-1H-imidazol-3-ium iodide (12a).
Yellow solid; mpZ192–196 8C; 1H NMR (200 MHz,
DMSO-d6) d 9.62 (1H, s), 8.09–80.8 (1H, m), 7.86–7.84
(1H, m), 4.17 (2H, br s), 3.93 (4H, s), 3.90 (3H, s), 3.63 (2H,
br s), 1.89–1.80 (4H, br m); 13C NMR (50 MHz, DMSO-d6)
d 172.0, 137.2, 123.7, 121.2, 105.2, 64.0, 50.0, 36.4, 34.0
(br); IR (KBr pellet) 2962, 1639, 1457, 1236, 1097,
906 cmK1; MS (FAB) m/z (rel. intensity) 268 (59), 227
(6), 186 (100), 158 (31), 142 (13); HRMS (EI) m/z calcd
(MCK127) 268.1120, found 268.1136.
4.14.2. 2-(Pyrrolidin-1-ylcarbonothioyl)-1,2,3,4-tetrahy-
droisoquinoline (13b). Yellow oil; H NMR (400 MHz,
1
CDCl3) d 7.19–7.10 (4H, m), 4.65 (2H, s), 3.73–3.66 (6H,
m), 3.00 (2H, t, JZ6.0 Hz), 1.94–1.91 (4H, m); 13C NMR
(100 MHz, CDCl3) d 189.8, 134.6, 133.7, 128.6, 126.6,
126.4, 126.3, 53.2, 53.0, 49.0, 29.0, 25.6; IR (neat) 2967,
1667, 1435, 1207, 1107, 920, 751 cmK1; MS (EI) m/z (rel.
intensity) 246 (73), 161 (22), 147 (20), 132 (100), 117 (41),
103 (17), 90 (18), 83 (17), 70 (42); HRMS (EI) m/z calcd
(MC) 246.1192, found 246.1191.
4.13.2. 3-Methyl-1-(morpholin-4-ylcarbonothioyl)-1H-
imidazol-3-ium iodide (12b). Yellow solid; mpZ205–
210 8C; H NMR (200 MHz, DMSO-d6) d 9.65 (1H, s),
1
4.14.3. 8-(Morpholin-4-ylcarbonothioyl)-1,4-dioxa-8-
azaspiro[4.5]decane (13c). White solid; mpZ94–96 8C;
8.10–8.09 (1H, m), 7.88–7.87 (1H, m), 4.13–3.99 (2H, br s),

J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
7171
1H NMR (400 MHz, CDCl3) d 3.86 (4H, s), 3.61–3.55 (8H,
m), 3.45–3.43 (4H, m), 1.67–1.64 (4H, m); 13C NMR
(100 MHz, CDCl3) d 193.5, 106.6, 66.1, 64.2, 51.8, 49.0,
4.14.8. 4-[(2E)-4-Methylpent-2-enoyl]morpholine (15).
To a suspension of LiCl (1.24 mmol) in acetonitrile
(15 mL) was added 14 (1.24 mmol) followed by 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU, 1.04 mmol) and
isobutyrylaldehyde (1.04 mmol). The reaction was stirred
at rt for 16 h. The solvent was then removed in vacuo and
the crude product dissolved in CH2Cl2 and washed with
0.1 N HCl, brine, dried (MgSO4), and concentrated in
vacuo. The crude product was purified by column
chromatography (100% EtOAc) to give a yellow oil
34.5; IR (neat) 2849, 1644, 1427, 1232, 1094, 854, 754 cmK1
;
MS (EI) m/z (rel. intensity) 272 (100), 239 (29), 215 (17), 186
(34), 154 (22), 142 (19), 127 (11), 99 (22), 86 (56), 72 (11);
HRMS (EI) m/z calcd (MC) 272.1204, found 272.1195.
4.14.4. 8-[(4-Benzylpiperazin-1-yl)carbonothioyl]-1,4-
dioxa-8-azaspiro[4.5]decane (13d). White foam; 1H
NMR (400 MHz, CDCl3) d 7.31–7.24 (5H, m), 3.94 (4H,
s), 3.65–3.58 (8H, m), 3.53 (2H, s), 2.52–2.50 (4H, m),
1.75–1.73 (4H, m); 13C NMR (100 MHz, CDCl3) d 193.2,
136.9, 129.1, 128.2, 127.3, 106.8, 64.3, 62.6, 52.4, 51.2,
49.2, 34.7; IR (neat) 2955, 1883, 1475, 1422, 1357, 1236,
1138, 1086, 1034 cmK1; MS (EI) m/z (rel. intensity) 361
(42), 328 (20), 238 (33), 229 (76), 215 (36), 186 (56), 159
(58), 146 (42), 99 (28), 91 (100); HRMS (EI) m/z calcd
(MC) 361.1830, found 361.1824.
1
(85%); H NMR (300 MHz, CDCl3) d 6.75 (1H, dd, JZ
15.0 Hz, JZ7.0 Hz), 6.05 (1H, dd, JZ15.0 Hz, JZ1.5 Hz),
3.57–3.47 (8H, br m), 2.39–2.32 (1H, m), 0.96 (6H, d, JZ
6.5 Hz); 13C NMR (75 MHz, CDCl3) d 165.7, 153.2, 116.5,
66.8, 46.1, 42.3, 31.2, 21.6; IR (thin film) 2961, 2857, 1658,
1620, 1432, 1270, 1229, 1116, 975, 846 cmK1; MS (EI) m/z
(rel. intensity) 183 (25), 168 (18), 140 (68), 97 (100), 86
(30); HRMS (EI) m/z calcd (MC) 183.1259, found
183.1264.
4.15. General procedure for TBDMS protection of
alcohol 16
4.14.5. N-Butyl-N-methylmorpholine-4-carbothioamide
(13e). Yellow oil; H NMR (400 MHz, CDCl3) d 3.72–
1
3.66 (4H, m), 3.56 (2H, t, JZ7.5 Hz), 3.38–3.35 (4H, m),
3.03 (3H, s), 1.60–1.53 (2H, m), 1.24 (2H, sextet, JZ
7.5 Hz), 0.87 (3H, t, JZ7.0 Hz); 13C NMR (100 MHz,
CDCl3) d 194.6, 66.4, 54.6, 51.9, 40.4, 29.1, 19.8, 13.7; IR
To a solution of 2-piperidinemethanol (17.3 mmol) in CH2Cl2
(35 mL) was added imidazole (34.7 mmol). After stirring for
5 min., t-butyldimethylsilyl chloride (19.1 mmol) was added
andthe reactionmixturewas stirred atrtfor 4.5 h. Thereaction
mixture was diluted with CH2Cl2 and saturated aqueous
NaHCO3. The aqueous layer was extracted with CH2Cl2 (!4).
The combined organic layers were washed once with H2O,
dried (MgSO4), filtered and concentrated in vacuo to give 17.
(neat) 2928, 1495, 1455, 1392, 1248, 1116, 1029, 875 cmK1
;
MS (EI) m/z (rel. intensity) 216 (67), 183 (23), 159 (18), 130
(48), 98 (37), 86 (100), 74 (35), 57 (29); HRMS (EI) m/z calcd
(MC) 216.1301, found 216.1296.
4.14.6. N-[2-(3,4-Dimethoxyphenyl)ethyl]morpholine-4-
carbothioamide (13f). Yellow solid, mp 79–81 8C; 1H
NMR (400 MHz, CDCl3) d 6.78–6.76 (1H, m), 6.70–6.68
(2H, m), 5.52 (1H, br m), 3.88 (2H, td, JZ7.0 Hz, JZ
5.5 Hz), 3.83 (3H, s), 3.82 (3H, s), 3.65 (8H, br s), 2.85 (2H,
t, JZ7.0 Hz); 13C NMR (100 MHz, CDCl3) d 182.4, 149.0,
147.7, 131.1, 120.5, 111.7, 111.2, 66.0, 55.8, 55.8, 47.2,
46.8, 34.5; IR (KBr pellet) 3373, 2932, 1515, 1261, 1235,
1141, 1025 cmK1; MS (EI) m/z (rel. intensity) 310 (10), 223
(27), 164 (99), 151 (100), 107 (8), 87 (6), 72 (7); HRMS (EI)
m/z calcd (MC) 310.1362, found 310.1351.
4.15.1. 2-(tert-Butyldimethylsilanyloxymethyl)piperidine
1
(17a).4d Yellow oil; H NMR (400 MHz, CDCl3) d 3.51–
3.47 (1H, m), 3.38–3.34 (1H, m), 3.06–3.02 (1H, m), 2.62–2.52
(2H, m), 1.76–1.72 (1H, m), 1.57–1.24 (4H, m), 1.09–0.90
(1H, m), 0.85 (9H, s), 0.01 (6H, s); 13C NMR (100 MHz,
CDCl3) d 68.1, 58.4, 46.8, 28.6, 26.6, 26.1, 24.6, 18.4,
K5.2; IR (thin film) 3343, 2931, 1472, 1463, 1330, 1089,
930, 837, 777 cmK1; MS (EI) m/z (rel. intensity) 230 (3),
214 (7), 172 (27), 84 (100), 73 (8); HRMS (EI) m/z calcd
(MHC) 230.1940, found 230.1947.
4.16. General procedure for formation of
carbamoylimidazole 18
4.14.7. Diethyl (2-morpholin-4-yl-2-oxoethyl)phospho-
nate (14).44 To a suspension of 3f (4.00 mmol) in dry
MeCN (24.0 mL) were added diethyl phosphonoacetic acid
(4.00 mmol) and triethylamine (4.00 mmol). The reaction
mixture was refluxed for 24 h. The solvent was removed in
vacuo and the residue was dissolved in CH2Cl2 and washed
with 0.2 N HCl. The aqueous layer was extracted with
CH2Cl2 (!3). The combined organic layers were washed
with 0.2 N HCl, 0.5 M K2CO3, and brine, dried (MgSO4),
and concentrated in vacuo. Product 14 was obtained without
further purification as a yellow oil (76%); 1H NMR
(400 MHz, CDCl3) d 4.11–4.07 (4H, m), 3.66–3.49 (8H,
m), 2.98 (2H, d, JZ22.0 Hz), 1.26 (6H, t, JZ7.0 Hz); 13C
NMR (100 MHz, CDCl3) d 163.5 (d, JZ6.0 Hz), 66.9, 66.8,
62.8 (d, JZ7.0 Hz), 47.5, 42.5, 33.4 (d, JZ132.0 Hz), 16.5
(d, JZ7.0 Hz); 31P (121 MHz, CDCl3) d 22.11; IR (thin
film) 2981, 2859, 1644, 1442, 1258, 1115, 1032, 970, 788
cmK1; MS (EI) m/z (relative intensity) 235 (64), 179 (92),
125 (66), 86 (89), 57 (100); HRMS (EI) m/z Calcd (MHC)
266.1157, found 266.1155.
To a solution of 17 (13.9 mmol) in CH2Cl2 (28 mL) was
added CDI (15.2 mmol). The reaction mixture was stirred at
rt for 1 day, diluted with H2O and the aqueous layer was
extracted with CH2Cl2 (!3). The combined organic layers
were washed with H2O (!2), dried (MgSO4), filtered and
concentrated in vacuo. The product was obtained following
column chromatography.
4.16.1. [2-(tert-Butyldimethylsilanyloxymethyl)piperi-
din-1-yl]imidazol-1-yl-methanone (18a).4d Pale yellow
oil; RfZ0.5 (3:7 Hexane/EtOAc); 1H NMR (500 MHz,
CDCl3) d 7.90 (1H, s), 7.25 (1H, s), 7.02 (1H, m), 5.26 (1H,
br s), 3.94 (1H, t, JZ10.0 Hz), 3.58–3.55 (1H, m), 3.07–
3.02 (1H, m), 1.74–1.55 (6H, m), 0.84 (9H, s), 0.03 (3H, s),
0.02 (3H, s); 13C NMR (125 MHz, CDCl3) d 152.2, 137.2,
129.4, 118.3, 61.0, 55.7, 41.8, 26.0, 25.8, 25.5, 19.7, 18.4,
K5.3; IR (thin film) 3120, 2931, 1694, 1422, 1385, 1249,

7172
J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
1103, 1003, 839, 779 cmK1; MS (EI) m/z (relative intensity)
323 (1), 308 (6), 266 (100), 256 (27), 178 (58), 73 (44);
HRMS (EI) m/z Calcd (MC) 323.2029, found 323.2035.
combined organic layers were washed with H2O, 0.5 M
K2CO3, brine, dried (MgSO4), filtered and concentrated in
vacuo. The product was obtained following column
chromatography.
4.16.2. {2-[2-(tert-Butyldimethylsilanyloxy)ethyl]piperi-
din-1-yl}imidazol-1-yl-methanone (18b).4d Pale yellow
oil; RfZ0.55 (3:7 Hexane/EtOAc); H NMR (500 MHz,
4.18.1. Diethyl {2-[2-(tert-Butyldimethylsilanyloxy-
1
methyl)piperidin-1-yl]-2-oxoethyl}phosphonate (20a).4d
1
CDCl3) d 7.87 (1H, s), 7.22 (1H, s), 7.06 (1H, s), 4.44 (1H,
br s), 3.90–3.87 (1H, m), 3.67–3.62 (2H, m), 3.13 (1H, t, JZ
12.5 Hz), 2.04–1.98 (1H, m), 1.87–1.83 (1H, m), 1.75–1.67
(5H, m), 1.57–1.54 (1H, m), 0.86 (9H, s), K0.01 (6H, s);
13C NMR (125 MHz, CDCl3) d 151.3, 137.1, 129.6, 118.1,
60.3, 51.5, 42.4, 33.2, 28.7, 26.1, 26.0, 19.1, 18.5, K5.1,
K5.2; IR (thin film) 3117, 2856, 1682, 1472, 1246, 1201,
1099, 989, 828, 775 cmK1; MS (EI) m/z (rel. intensity) 322
(5), 280 (100), 270 (22), 198 (11), 184 (20), 73 (27); HRMS
(EI) m/z calcd (MKHC) 336.2107, found 336.2115.
Yellow oil; RfZ0.2 (100% EtOAc); H NMR (400 MHz,
CDCl3) (rotamers) d 4.55–4.50 (1H, m), 4.25–4.07 (4H, m),
3.88–3.81 (1H, m), 3.56–3.46 (2H, m), 3.08–2.79 (2H, m),
2.59–2.51 (1H, m), 1.78–1.35 (6H, m), 1.33–1.28 (6H, m),
0.85 (2.67H, s), 0.83 (6.33H, s), 0.02 (4.2H, s), K0.01
(1.8H, s); 13C NMR (100 MHz, CDCl3) (rotamers) d 164.7
(d, JZ5.5 Hz), 163.7 (d, JZ5.0 Hz), 62.6 (d, JZ6.0 Hz),
62.5 (d, JZ6.0 Hz), 62.4 (d, JZ7.0 Hz), 62.0 (d, JZ
6.0 Hz), 61.4, 60.7, 44.0, 37.0, 33.8 (d, JZ133.0 Hz), 33.8
(d, JZ133.0 Hz), 25.8, 25.8, 25.8, 25.6, 25.2, 24.3, 19.8,
19.0, 18.1, 16.3 (d, JZ6.0 Hz), 16.3 (d, JZ6.0 Hz), K5.5,
K5.6; 31P NMR (121 MHz, CDCl3) (rotamers) d 23.68,
22.78; IR (thin film) 2932, 2858, 1638, 1443, 1254, 1102,
1027, 969, 838, 779 cmK1; MS (EI) m/z (rel. intensity) 409
(5), 350 (46), 322 (19), 262 (100), 172 (38), 84 (90); HRMS
(EI) m/z calcd (MHC) 408.2335, found 408.2332.
4.17. General procedure for formation of
carbamoylimidazolium salts 19
To a solution of 18 (27.7 mmol) in MeCN (55 mL) was
added MeI (110.8 mmol) and the reaction mixture was
stirred at rt for 1 day. The solvent was evaporated in vacuo
to give the product.
4.18.2. Diethyl (2-{2-[2-(tert-butyldimethylsilanyloxy)
ethyl]piperidin-1-yl}-2-oxoethyl)phosphonate (20b).4d
Yellow oil; RfZ0.5 (95:5 EtOAc/MeOH); 1H NMR
(300 MHz, CDCl3) (rotamers) d 4.79 (0.3H, br s), 4.54–
4.48 (0.7H, br m), 4.33–4.27 (0.7H, br m), 4.18–4.04 (3.3H,
m), 3.62–3.42 (3H, m), 3.05–2.79 (2H, m), 2.54–2.44 (1H,
m), 1.86–1.81 (2H, m), 1.73–1.50 (6.3H, m), 1.36–1.24
(5.7H, m), 0.86 (6.3H, s), 0.84 (2.7H, s), 0.02 (1.8H, s), 0.00
(4.2H, m); 13C NMR (75 MHz, CDCl3) (rotamers) d 163.8
(d, JZ5.0 Hz), 162.9 (d, JZ5.0 Hz), 62.7 (d, JZ6.0 Hz),
62.6, 62.5 (d, JZ6.5 Hz), 62.0 (d, JZ6.5 Hz), 61.1, 59.1,
50.4, 46.5, 43.0, 37.1, 34.0 (d, JZ132.0 Hz), 33.6 (d, JZ
133.5 Hz), 33.3, 33.2, 29.5, 28.8, 26.4, 26.2, 25.8, 19.5,
19.2, 18.5, 16.7 (d, JZ6.0 Hz), 16.7 (d, JZ6.5 Hz), K5.9,
K5.0; 31P NMR (121 MHz, CDCl3) (rotamers) d 23.55,
22.84; IR (thin film) 2931, 2858, 1640, 1444, 1255, 1095,
1024, 967, 835, 777 cmK1; MS (EI) m/z (rel. intensity) 422
(8), 365 (81), 336 (100), 308 (27), 243 (39); HRMS (EI) m/z
calcd (MHC) 422.2492, found 422.2480.
4.17.1. 3-[2-(tert-Butyldimethylsilanyloxymethyl)piper-
idine-1-carbonyl]-1-methyl-3H-imidazol-1-ium iodide
1
(19a).4d Foamy yellow solid; very hygroscopic; H NMR
(400 MHz, CDCl3) d 9.97 (1H, s), 7.69 (1H, s), 7.67 (1H, s),
4.39–4.37 (1H, m), 4.24 (3H, s), 4.07–4.02 (1H, m), 3.95
(1H, t, JZ10.5 Hz), 3.63–3.59 (1H, m), 3.12–3.05 (1H, m),
2.20–2.10 (1H, m), 1.70–1.46 (5H, m), 0.84 (9H, s), 0.058
(3H, s), 0.054 (3H, s); 13C NMR (100 MHz, CDCl3) d 147.3,
136.3, 123.8, 120.7, 60.2, 55.8 (br), 41.7 (br), 37.6, 25.4,
25.0, 24.2, 18.6, 17.8, K5.8, K5.9; IR (thin film) 3076,
2951, 1723, 1537, 1418, 1252, 1150, 1100, 1004, 839, cmK1
;
MS (ESI) m/z (rel. intensity) 338 (9), 270 (7), 256 (100), 197
(31); HRMS (ESI) m/z calcd (MCK127) 338.2258, found
338.2265.
4.17.2. 3-{2-[2-(tert-Butyldimethylsilanyloxy)-ethyl]
piperidine-1-carbonyl}-1-methyl-3H-imidazol-1-ium
iodide (19b).4d Foamy light yellow solid; very hygroscopic;
1H NMR (400 MHz, CDCl3) d 10.06 (1H, s), 7.72 (1H, s),
7.66 (1H, s), 4.62 (1H, br s), 4.25 (3H, s), 3.85 (1H, br s),
3.67–3.64 (2H, m), 3.34 (1H, br s), 2.07–1.61 (8H, m), 0.82
(9H, s), K0.01 (6H, s); 13C NMR (100 MHz, CDCl3) d
146.5, 137.1, 124.2, 121.1, 60.2, 52.6 (br), 44.0 (br), 38.2,
32.8, 28.5 (br), 26.0, 25.8, 18.5, 18.3, K5.2; IR (thin film)
4.19. General procedure for TBDMS deprotection to
alcohol 21
To a solution of 20 (14.7 mmol) in THF (70 mL) was added
tetrabutylammonium fluoride (17.7 mmol). The reaction
mixture was stirred at rt for 30 min, quenched with H2O and
extracted with CH2Cl2 (!4), dried (MgSO4), filtered and
concentrated in vacuo. The product was obtained following
column chromatography.
2930, 2857, 1720, 1639, 1420, 1255, 1098, 836, 776 cmK1
;
MS (ESI) m/z (rel. intensity) 352 (11), 271 (27), 270 (100);
HRMS (ESI) m/z calcd (MCK127) 352.2414, found
352.2427.
4.19.1. Diethyl {2-[2-(hydroxymethyl)piperidin-1-yl]-2-
4.18. General procedure for formation of amide 20
oxoethyl}phosphonate (21a).4d Yellow oil; yield: 94%;
RfZ0.3 (9:1 EtOAc/MeOH); H NMR (400 MHz, CDCl3)
1
To a solution of 19 (6.29 mmol) in MeCN (38 mL) were
added diethylphosphonoacetic acid (6.92 mmol) and Et3N
(6.92 mmol). The reaction mixture was stirred at 50 8C for
1 day. The solvent was removed in vacuo and the crude
product was partitioned between CH2Cl2 and H2O. The
aqueous layer was extracted with CH2Cl2 (!4). The
(rotamers) d 4.51 (1H, br s), 4.23 (1H, br d, JZ13.5 Hz),
3.91–3.84 (4H, m), 3.65 (1H, br t, JZ10.5 Hz), 3.52–3.14
(2.6H, m), 2.96–2.68 (1.7H, m), 2.43 (0.7H, br t, JZ
12.5 Hz), 1.56–1.22 (6H, m), 1.19–1.02 (6H, m); 13C NMR
(125 MHz, CDCl3) (rotamers) d 164.8 (d, JZ5.5 Hz), 164.1
(d, JZ5.5 Hz), 62.9 (d, JZ6.0 Hz), 62.8 (d, JZ6.5 Hz),

J. A. Grzyb et al. / Tetrahedron 61 (2005) 7153–7175
7173
62.5 (d, JZ6.5 Hz), 62.5 (d, JZ6.0 Hz), 60.8, 60.5, 55.9,
50.9, 43.4, 37.2, 33.8 (d, JZ132.0 Hz), 33.6 (d, JZ
132.0 Hz), 26.1, 25.7, 25.3, 24.9, 19.6, 19.3, 16.4, 16.3;
31P NMR (121 MHz, CDCl3) (rotamers) d 23.72, 23.00; IR
(thin film) 3412, 2939, 2869, 1624, 1446, 1245, 1025, 972,
787 cmK1; MS (EI) m/z (rel. intensity) 294 (8), 263 (72),
262 (100), 248 (16), 84 (92); HRMS (EI) m/z calcd (MHC)
294.1470, found 294.1461.
(3H, m), 2.67–2.39 (2H, m), 1.75–1.34 (7H, m), 1.18 (6H, t,
JZ7.0 Hz); 13C NMR (75 MHz, CDCl3) (rotamers) d 200.3,
199.5, 163.8 (d, JZ5.5 Hz), 163.2 (d, JZ5.5 Hz), 62.5 (d,
JZ6.5 Hz), 62.3 (d, JZ6.5 Hz), 48.4, 44.5, 44.2, 43.8, 42.8,
37.2, 33.5 (d, JZ132.5 Hz), 33.3 (d, JZ132.5 Hz), 29.3,
28.2, 25.5, 25.2, 18.9, 18.5, 16.2 (d, JZ6.5 Hz); 31P NMR
(121 MHz, CDCl3) (rotamers) d 21.63, 20.92; IR (thin film)
2939, 2867, 1721, 1631, 1250, 1024, 970 cmK1; MS (EI) m/z
(rel. intensity) 305 (9), 179 (17), 150 (28), 126 (100), 98
(74), 84 (80); HRMS (EI) m/z calcd (MC) 305.1392, found
305.1396.
4.19.2. Diethyl {2-[2-(2-hydroxyethyl)piperidin-1-yl]-2-
oxoethyl}phosphonate (21b).4d Yellow oil; RfZ0.3 (9:1
EtOAc/MeOH); H NMR (400 MHz, CDCl3) (rotamers) d
1
4.89–4.86 (0.7H, m), 4.56–4.52 (0.3H, br m), 4.37–4.4.36
(0.3H, br m), 4.22–4.11 (3.7H, m), 3.82–3.70 (1.7H, m),
3.65–3.58 (1.3H, m), 3.43–3.01 (3.7H, m), 2.63–2.56 (0.3H,
br m), 2.09–1.94 (1.3H, m), 1.78–1.46 (7H, m), 1.40–1.30
(5.7H, m); 13C NMR (75 MHz, CDCl3) (rotamers) d 165.4
(d, JZ6.0 Hz), 63.1 (d, JZ6.5 Hz), 62.8 (d, JZ3.5 Hz),
62.7 (d, JZ3.5 Hz), 62.4 (d, JZ6.0 Hz), 58.2, 58.0, 50.6,
45.6, 43.2, 37.2, 33.7 (d, JZ132.0 Hz), 32.9 (d, JZ
134.0 Hz), 32.6, 32.4, 29.2, 29.0, 25.9, 25.6, 19.3, 16.4 (d,
JZ6.5 Hz); 31P NMR (121 MHz, CDCl3) (rotamers) d
23.83, 22.31; IR (thin film) 3441, 2942, 1626, 1448, 1247,
1025, 975, 788 cmK1; MS (EI) m/z (rel. intensity) 308 (14),
307 (10), 262 (78), 179 (20), 128 (100), 84 (65); HRMS (EI)
m/z calcd (MHC) 308.1623, found 308.1638.
4.21. General procedure for the Wadsworth–Horner–
Emmons reaction
To a solution of 22 (0.515 mmol) in THF (10 mL) at 0 8C
was added NaH (0.515 mmol) and the reaction mixture was
stirred at 0 8C for 40 min. The crude reaction mixture
was diluted with CH2Cl2 and H2O and the aqueous layer
was extracted with CH2Cl2 (!5). The combined organic
layers were washed with brine, dried (MgSO4), filtered and
concentrated in vacuo. The product was obtained following
column chromatography.
4.21.1. 6,7,8,8a-Tetrahydroindolizin-3(5H)-one (23a).4d,29
1
Yellow oil; RfZ0.3 (100% EtOAc); H NMR (400 MHz,
CDCl3) d 7.00–6.96 (1H, m), 6.13–6.01 (1H, m), 4.27–4.23
(1H, m), 3.86–3.82 (1H, m), 2.84–2.77 (1H, m), 2.10–2.06
(1H, m), 1.92–1.87 (1H, m), 1.74–1.70 (1H, m), 1.54–1.43
(1H, m), 1.36–1.20 (1H, m), 1.05–0.94 (1H, m); 13C NMR
(100 MHz, CDCl3) d 169.0, 147.1, 127.5, 61.5, 39.4, 30.8,
25.4, 23.6.
4.20. General procedure for oxidation of alcohol to the
aldehyde 22
To a solution of 21 (3.75 mmol) in CH2Cl2 (37 mL) was
added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-
(1H)-one (Dess–Martin reagent, 4.50 mmol). The reaction
mixture was stirred at rt for 16 h. The reaction mixture was
filtered through Celite, and the filtrate diluted with 0.5 M
K2CO3 and extracted with CH2Cl2 (!4). The combined
organic layers were washed with brine, dried (MgSO4),
filtered and concentrated in vacuo. The product was
obtained after column chromatography.
4.21.2. 1,6,7,8,9,9a-Hexahydro-4H-quinolizin-4-one
1
(23b).4d,30 Yellow oil; RfZ0.48 (100% EtOAc); H NMR
(400 MHz, CDCl3) d 6.46–6.42 (1H, m), 5.88–5.85 (1H, m),
4.50–4.46 (1H, m), 3.45–3.38 (1H, m), 2.55–2.45 (2H, m),
2.22–2.13 (1H, m), 1.83–1.78 (1H, m), 1.74–1.70 (2H, m),
1.52–1.35 (3H, m); 13C NMR (100 MHz, CDCl3) d 165.6,
138.2, 124.7, 54.9, 43.1, 33.5, 31.2, 24.9, 24.1; IR (thin film)
2934, 2856, 1667, 1613, 1429, 1321, 1272, 1154, 826,
814 cmK1; MS (EI) m/z (rel. intensity) 151 (67), 136 (9),
122 (30), 84 (100), 68 (27); HRMS (EI) m/z calcd (MC)
151.0997, found 151.0994.
4.20.1. Diethyl [2-(2-formylpiperidin-1-yl)-2-oxoethyl]
phosphonate (22a).4d Yellow oil; RfZ0.14 (100%
EtOAc); H NMR (400 MHz, CDCl3) (rotamers) d 9.66
1
(0.2H, s), 9.51 (0.8H, s), 5.18 (0.7H, br d, JZ5.5 Hz), 4.73–
4.61 (0.3H, br m), 4.24–4.08 (4H, m), 3.93–3.89 (1H, br m),
3.23–2.94 (3H, m), 2.64–2.57 (0.2H, m), 2.42–2.25 (0.8H,
br m), 1.83–1.47 (4H, m), 1.39–1.25 (7H, m); 13C NMR
(100 MHz, CDCl3) (rotamers) d 200.9, 200.0, 165.2, 165.1,
63.6, 62.8 (d, JZ6.5 Hz), 62.7 (d, JZ6.5 Hz), 59.3, 45.8,
40.5, 33.9 (d, JZ131.0 Hz), 33.5 (d, JZ133.0 Hz), 25.2,
24.7, 24.6, 23.4, 20.9, 20.8, 16.4 (d, JZ6.5 Hz); 31P NMR
(121 MHz, CDCl3) d 20.65; IR (thin film) 2940, 2866, 1731,
1639, 1444, 1249, 1025, 972, 833, 787 cmK1; MS (EI) m/z
(rel. intensity) 292 (5), 262 (49), 179 (9), 151 (8), 123 (12),
84 (100); HRMS (EI) m/z calcd (MC) 291.1236, found
291.1230.
Acknowledgements
This work was supported by the Natural Science and
Engineering Research Council (NSERC) of Canada,
Crompton Co. and the Environmental Science and
Technology Alliance Canada (ESTAC). R.A.B. gratefully
acknowledges additional support through a Premier’s
Research Excellence Award. M. S. acknowledges additional
support through a Pestcon Graduate Scholarship. We thank
Dr. A. B. Young for mass spectrometric analyses, and
Dr. A. J. Lough for X-ray crystallographic analysis. We
thank Dr. V. Santhakumar for preliminary experiments,
and Professor Scott Taylor (University of Waterloo),
Dr. Sheldon Park (Crompton Co.) and Dr. Mark A.
Dekeyser (Crompton Co.) for useful discussions.
4.20.2. Diethyl {2-oxo-2-[2-(2-oxoethyl)piperidin-1-yl]
ethyl}phosphonate (22b).4d Yellow oil; RfZ0.15 (100%
EtOAc); H NMR (300 MHz, CDCl3) (rotamers) d 9.63
1
(0.3H, s), 9.54 (0.7H, s), 5.22–5.16 (0.6H, m), 4.61–4.55
(0.2H, br m), 4.44–4.38 (0.2H, br m), 4.06–3.96 (4H, m),
3.69–3.64 (0.7H, br m), 3.37–3.25 (0.3H, m), 3.06–2.85

7174
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2003, 59, 1339–1348. (d) Mongin, F.; Trecourt, F.; Gervais,
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B.; Mongin, O.; Queguiner, G. J. Org. Chem. 2002, 67,
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