Preparation of diamines by lithiation-substitution of imidazolidines and pyrimidines

Article abstract of DOI:10.1039/b301502e

The synthesis of chiral 1,2-diamines and 1,3-diamines was achieved from the unsubstituted diamines by way of N-tert-butoxycarbonyl (Boc) substituted imidazolidines (tetrahydroimidazoles) and pyrimidines (hexahydro-1,3-diazines), which were treated with sec-butyllithium to effect deprotonation a- to the N-Boc group, followed by addition of an electrophile to give substituted products that could be hydrolysed under acidic conditions to give the substituted 1,2- or 1,3-diamines. Use of the chiral ligand (-)-sparteine promoted asymmetric deprotonation of the imidazolidine substrates to give, after hydrolysis, enantiomerically enriched 1,2-diamines.

Full text of DOI:10.1039/b301502e

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Preparation of diamines by lithiation–substitution of
imidazolidines and pyrimidines
Neil J. Ashweek,a Iain Coldham,*a Thomas F. N. Haxella and Steven Howardb
a School of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD
b GlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex,
UK CM19 5AW
Received 7th February 2003, Accepted 11th March 2003
First published as an Advance Article on the web 3rd April 2003
The synthesis of chiral 1,2-diamines and 1,3-diamines was achieved from the unsubstituted diamines by way
of N-tert-butoxycarbonyl (Boc) substituted imidazolidines (tetrahydroimidazoles) and pyrimidines (hexahydro-
1,3-diazines), which were treated with sec-butyllithium to effect deprotonation α- to the N-Boc group, followed
by addition of an electrophile to give substituted products that could be hydrolysed under acidic conditions
to give the substituted 1,2- or 1,3-diamines. Use of the chiral ligand (Ϫ)-sparteine promoted asymmetric
deprotonation of the imidazolidine substrates to give, after hydrolysis, enantiomerically enriched
1,2-diamines.
Introduction
Diamines, especially 1,2-diamines are an important class of
compounds in organic chemistry.1 They are present in many
natural products and medicinal compounds (for example in
biotin or as kappa receptor agonists). In addition, they are
valuable for the synthesis of heterocyclic compounds, as part of
Scheme 2
chiral auxiliaries and for use as catalysts, especially for catalytic
thought to be significant.6 Therefore, we were interested in
asymmetric synthesis.2 A variety of methods are known for
their formation, such as the reductive coupling of imines,
reduction or organometallic additions to imines, amination
of alkenes, ring-opening of aziridines, electrophilic amination
or functional group interconversion of diols or β-amino-
alcohols.1
studying unsymmetrical imidazolidines in which a Boc group
is attached to only one of the two nitrogen atoms. Seebach and
co-workers have reported one such approach (Scheme 3),
in which deprotonation of the imidazolidine 4 occurs on
treatment with tert-BuLi to give, after electrophilic quench,
the diastereomerically pure derivatives 5.7 Based on this work,
and that by Beak and co-workers with N-Boc-pyrrolidine,8
an asymmetric deprotonation of the unsubstituted imid-
azolidine 3 (R = alkyl) should be feasible using a chiral base.
Imidazolidine 3 has similarity to N-Boc-pyrrolidine, a sub-
strate that is well-known to undergo asymmetric deprotonation
with sec-BuLi and (Ϫ)-sparteine 6.8 This methodology allows
a direct and convenient route to enantioenriched 2-lithio-
and hence 2-substituted pyrrolidines. The chiral ligand
(Ϫ)-sparteine 6 promotes asymmetric deprotonation of the
pro-S hydrogen atom of N-Boc-pyrrolidine with very high
selectivity, although the corresponding asymmetric transform-
ation of N-Boc-piperidine is very low-yielding.9 Proton abstrac-
tion of the imidazolidine 3 (R = alkyl) would be expected to
occur adjacent to the N-Boc group at C-5 rather than at C-2
(between the two nitrogen atoms), due to the reduced acidity of
the protons α- to the tertiary amine group.10 In this paper, we
report successful asymmetric lithiation–substitution reactions
of imidazolidines 3, with a selection of R groups (including that
We were attracted to the possibility of developing a new
asymmetric synthesis of chiral diamines from α-amino-organo-
lithium compounds.3 Ideally, any simple 1,2-diamine 1 would
be converted to the desired substituted chiral 1,2-diamine 2 by a
short and operationally simple set of steps (Scheme 1). We
reasoned that this should be possible by way of the lithiated
imidazolidines 3, based on previous work in our group.4,5 In
particular, we have developed a method to prepare imidazol-
idines in one step4 and discovered that deprotonation at C-2,
between the two nitrogen atoms was possible, as outlined in
Scheme 2.5 This chemistry provided a new acyl anion equiv-
alent, although the stabilization of the intermediate organo-
lithium species afforded by the second N-Boc group was not
i
reported in a preliminary communication with R = Pr),11
together with results using a pyrimidine substrate.
Scheme 1
Scheme 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 3 2 – 1 5 4 4
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Table 1 Formation of racemic imidazolidines 7
Table 2 Formation of enantioenriched imidazolidines 7
Entry
Eϩ
E
7, Yield (%)a
Entry
Eϩ
E
7, Yield (%)a
7, er
1
2
3
4
5
6
7
8
Me3SiCl
Bu3SnCl
Ph2MeSiCl
MeI
PhNCO
Ph2CO
Me3Si
Bu3Sn
49 (79)
49 (70)
44 (81)
42 (69)
32 (55)
35b (64)
42 (68)
41 (82)
1
2
3
4
5
6
7
8
Me3SiCl
Bu3SnCl
Ph2MeSiCl
MeI
PhNCO
Ph2CO
Me3Si
Bu3Sn
40 (77)
40 (66)
44 (88)
44 (76)
20 (49)
50 (86)
40 (69)
41 (73)
93 : 7
94 : 6
94 : 6
92 : 8
86 : 14
92 : 8
50 : 50
50 : 50
Ph2MeSi
Me
CONHPh
C(OH)Ph2
CH2᎐᎐CHCH2
PhCH2
Ph2MeSi
Me
CONHPh
C(OH)Ph2
CH2᎐᎐CHCH2
PhCH2
CH2᎐᎐CHCH2Br
PhCH2Br
CH2᎐᎐CHCH2Br
PhCH2Br
a Yield in brackets refers to yield based on recovered 3. b Using Et2O as
solvent.
a Yield in brackets refers to yield based on recovered 3.
However, using the solvent Et2O gave the product 7, E =
C(OH)Ph2 (Table 1, entry 6). With ethyl chloroformate as the
electrophile, none of the product 7, E = CO2Et was formed and
instead the di-addition product 9 was obtained (29% yield),
together with recovered starting material, 3, R = iPr (62%).
Results and discussion
The imidazolidines 3, R = Me, CH2Ph and Pr were prepared
i
in one-pot from the corresponding commercially available
N-alkyl-ethylenediamines 1, R = Me, CH2Ph and iPr using con-
ditions reported previously.4 This was achieved by condensation
of the ethylenediamine with paraformaldehyde at room tem-
perature using potassium carbonate and magnesium sulfate as
dehydrating agents, followed by addition of di-tert-butyl di-
carbonate to give the imidazolidines 3 in high yield (Scheme 4).
To investigate the lithiation–substitution reaction further, a
sample of the imidazolidine 3, R = Pr in D8-THF was cooled
i
to Ϫ78 ЊC and sec-BuLi was added. Prior to addition of the
sec-BuLi, signals for the two rotamers of the imidazolidine
were clearly visible (ratio 1 : 1) by 1H or 13C NMR spectroscopy.
Addition of one equivalent of sec-BuLi resulted in the immedi-
ate disappearance of only one set of these signals, together with
the appearance of a set of broad signals.12 No change to the
NMR spectra was observed after long reaction times, on addi-
tion of further sec-BuLi or on warming to Ϫ40 ЊC (above which
temperature significant decomposition occurred). This experi-
ment indicates that only one of the two rotamers of the imid-
azolidine 3 undergoes deprotonation, and hence explains the
limitation (to 50%) in the yield of the substituted products 7–9.
Presumably, only the rotamer of the imidazolidine 3 in which
the carbonyl oxygen atom is located cis to C-5 of the imid-
azolidine undergoes reaction with sec-BuLi. This result has
implications for the deprotonation of other unsymmetrical
carbamates or carboxylic amides, the yield of which may be
limited by the slow rotation about the N–CO bond.
Scheme 4
The lithiation–substitution of the imidazolidines 3 was first
investigated in the absence of a chiral ligand. Treatment of the
imidazolidine 3, R = iPr, with sec-BuLi in THF at Ϫ78 ЊC for 1
hour, followed by addition of Me3SiCl gave the imidazolidine 7,
E = SiMe3 (49%), with no trace of the 2-substituted isomer
(Scheme 5). The imidazolidine 7, E = SiMe3, was isolated
together with substantial amounts (typically 30–50%) of
recovered starting material, 3, R = iPr. The yield of the product
7 did not improve using excess sec-BuLi, longer reaction times
or by inverse or in situ quench. Slightly lower yields of the
product 7 were obtained in the presence of the additive
TMEDA or using the solvent Et2O.
Treatment of the imidazolidine 3, R = iPr with sec-BuLi and
the chiral ligand (Ϫ)-sparteine 6 in Et2O at Ϫ78 ЊC for
1 hour, followed by addition of Me3SiCl gave the imidazolidine
7, E = SiMe3 (40%), together with recovered imidazolidine 3,
R = iPr (50% yield) (Scheme 6, Table 2). The enantiomer ratio
(er) (93 : 7) of the product 7, E = SiMe3 was determined by
NMR spectroscopy on the ring-opened Mosher amide deriv-
ative (see below). The high enantioselectivity is in line with
results on the asymmetric deprotonation of related substrates
with sec-BuLi and the chiral ligand (Ϫ)-sparteine 6.8,13 Quench-
ing with other electrophiles gave similar yields and, in most
cases, high enantioselectivities (Table 2). The enantiomer ratios
Scheme 5
Using the conditions outlined in Scheme 5, a selection of
different electrophiles was added to give a range of imidazol-
idines 7, shown in Table 1. In all cases moderate yields (up to
49%) were obtained, together with recovered starting material
3, R = iPr.
With benzophenone as the electrophile and THF as the sol-
vent, the product obtained was the imidazolidine 8 (50% yield).
Scheme 6
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 3 2 – 1 5 4 4
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were determined by NMR spectroscopy on the ring-opened
Mosher amide derivatives (see below) or by chiral HPLC
(Gilson 231 XL column, type AD). A single recrystallization of
the imidazolidine 7, E = C(OH)Ph2 gave essentially enantiopure
material. Racemic products were obtained using allyl or benzyl
bromide as the electrophile, probably as a result of a single
electron transfer process.
Evidence that the asymmetry arises from an asymmetric
deprotonation (rather than an asymmetric substitution) was
obtained by treating the racemic stannane 7, E = SnBu3 with
n-BuLi and (Ϫ)-sparteine in Et2O, followed by quenching with
Me3SiCl. This gave the product 7, E = SiMe3 (59% yield) as a
racemate, indicating that no dynamic resolution occurs under
these conditions. The configurational stability of the intermedi-
ate organolithium species was confirmed by treating the enan-
tioenriched stannane 7, E = SnBu3 (er 94 : 6) with n-BuLi in
Et2O at Ϫ78 ЊC in the absence of (Ϫ)-sparteine for 1 h, followed
by quenching with Me3SiCl to give the product 7, E = SiMe3
(63% yield, er 93 : 7). The absolute configuration of the
products is likely to be that shown in Scheme 6, which is
consistent with that determined for the asymmetric deproton-
ation of N-Boc-pyrrolidine.8 This was verified for the product 7,
E = C(OH)Ph2 by single crystal X-ray diffraction.11
Attempts to effect the deprotonation of the imidazolidine
3, R = CH2Ph using sec-BuLi in THF or in Et2O and
(Ϫ)-sparteine 6 at Ϫ78 ЊC, resulted in a mixture of unidentifi-
able products. However, the corresponding N-methyl com-
pound 3, R = Me did provide the desired substituted product 10
(Scheme 7). The product 10 was formed in similar yield (40%,
together with recovered imidazolidine 3, R = Me, 42%) to the
N-iPr analogue 7, and with the same level of enantioselectivity
(er 93 : 7, determined by chiral HPLC, assumed to have
predominantly the R-configuration).
the N-Boc compound 14. With this new imidazolidine in hand,
it was subjected to lithiation–substitution. Using sec-BuLi in
THF at Ϫ78 ЊC for 1 h (compare with conditions in Scheme 5),
followed by quenching with dimethyl sulfate, gave the product
15, but in only 24% yield, together with recovered imidazolidine
14 (69%). Increasing the time to 6 h, gave an improved yield
(48%) of the product 15 (together with 14, 50%). The 1H NMR
spectrum of the imidazolidine 14 showed the presence of both
rotamers in approximately equal amounts, and the modest yield
of the product 15 indicates that, like the N-iPr analogue, only
one rotamer is undergoing deprotonation. Unfortunately, sub-
jecting the imidazolidine 14 to the asymmetric lithiation condi-
tions using sec-BuLi in Et2O and (Ϫ)-sparteine, resulted in only
recovered starting material 14. Warming the reaction mixture to
Ϫ40 ЊC likewise gave only recovered 14, whereas at Ϫ20 ЊC
decomposition occurred. It appears that the increased steric
bulk at N-3 of the imidazolidine disfavours proton abstraction.
Similar results were obtained using the corresponding imid-
azolidine with a tert-butyl substituent at N-3, which could be
prepared in the same way as the N-cumyl compound 14 and
lithiated with sec-BuLi in THF (in the absence of sparteine)
and quenched with benzophenone (36% yield, 58% recovered
starting imidazolidine), but did not lithiate in the presence of
(Ϫ)-sparteine 6.
The results described above illustrate some of the scope and
limitations of this chemistry. Formation of the substituted
imidazolidines 7 and 10 was successful in enantiomerically
enriched form. For the formation of chiral 1,2-diamines, we
needed to hydrolyse these imidazolidines. Treatment of the
imidazolidine 7, E = SiMe3 with trifluoroacetic acid (TFA) or
B-bromocatechol borane14 in CH2Cl2 gave the unstable imid-
azolidine 16 (Scheme 9). Although the Mosher amide could be
prepared from this racemic imidazolidine [using α-methoxy-α-
(trifluoromethyl)phenylacetyl chloride in CH2Cl2 and Et3N]
in good yield, this amide was formed as a 1.2 : 1 ratio of
diastereomers and this method could not therefore be used
for the determination of enantiopurity from enantioenriched
imidazolidines.
Scheme 7
A brief attempt was made to prepare some other substituted
imidazolidines using this chemistry. Condensation of N-Boc
glycine 11 with cumylamine and dicyclohexylcarbodiimide–
hydroxybenzotriazole gave the amide 12 in quantitative yield
(Scheme 8). This carboxylic amide was sluggish to reduce, but a
reasonable yield (52%, together with 39% recovered amide 12)
of the amine 13 was obtained using boraneؒTHF complex.
Imidazolidine formation proceeded smoothly to give directly
Scheme 9
Treatment of the imidazolidine 7, E = SiMe3 with malonic
acid and pyridine,15 heating under reflux in EtOH, gave the
carbamate 17, in which the imidazolidine had been opened, but
the tert-butoxycarbonyl group remained intact (Table 3). Simi-
larly, the imidazolidines 7, E = SiMePh2, Me, CONHPh and
CH CH᎐CH all hydrolysed to the carbamates 18–21 (Table 3).
᎐
2
2
These carbamates were treated with TFA in CH2Cl2 at room
temperature to give the desired diamine products 22–26 (Table
3). These diamines could be accessed in one step by heating
the imidazolidines 7 with TFA, but the yields (unoptimized)
were lower than the two-step procedure. The Mosher amides
27, E = SiMe , SiMePh , Me, CONHPh and CH CH᎐CH were
᎐
3
2
2
2
formed in high yield from the diamines 22–26 and the ratio of
the diastereomers of 27 (1 : 1 from the racemic diamines), as
1
determined by H and 19F NMR spectroscopy, was used to
determine the enantiomer ratios given in Table 2.
Similar chemistry was applied to the homologous pyrimidine
28, prepared in one step from N-isopropyl-1,3-diaminopropane
with paraformaldehyde, followed by addition of di-tert-butyl
dicarbonate (Scheme 10). Treatment of the pyrimidine 28 with
sec-BuLi in THF at Ϫ78 ЊC for 5 hours, followed by addition of
Scheme 8
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 3 2 – 1 5 4 4
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Table 3 Hydrolysis of imidazolidines 7 using malonic acid then TFA
ide onto the carbamate had occurred. Yields of the products 29
(and 30) greater than 50% could be obtained under these condi-
tions, suggesting that there is an uneven distribution of the two
rotamers of 28 (verified by NMR spectroscopy), slightly in
favour of that with the carbonyl oxygen atom pointing towards
C-6. Small amounts of the pyrimidine 28 were recovered even
with 2.5 equivalents of sec-BuLi. These results suggest that, like
the imidazolidine substrates 3, proton abstraction is dis-
favoured at C-2, between the two nitrogen atoms. However, in
one case at higher concentration (0.3 M rather than 0.16 M,
therefore also implying less polar solvent since sec-BuLi was
added as a solution in cyclohexane), a low yield (28%) of the
2-substituted product 31 was obtained.
Product
Yield (%)
85
Product
Yield (%)
92
67
95
82
99
69
89
Attempted asymmetric deprotonation of the pyrimidine
substrate 28, using sec-BuLi and the chiral ligand (Ϫ)-sparteine
6 in Et2O, followed by addition of Me3SiCl gave only trace
amounts of the desired product 29, E = SiMe3. Some product
(up to 37% yield) was obtained using (Ϫ)-sparteine in THF,
rather than Et2O, although this was found to be racemic, as
judged by the formation of a 1 : 1 mixture of diastereomers of
the Mosher amides formed from the diamine 33 (Scheme 11). In
the same way as the imidazolidine substrates, hydrolysis of the
pyrimidine ring was possible using malonic acid and pyridine,
to give the ring-opened derivates 32 (carried out for E = SiMe3
96
87
Table 4 Formation of racemic pyrimidines 29
Entry
Eϩ
E
29, Yield (%)
and CH CH᎐CH ) (Scheme 11). Subsequent treatment with
᎐
2
2
TFA gave the diamine 33. This procedure therefore provides a
method to prepare substituted 1,3-diamines.
1
2
3
4
5
6
Me3SiCl
Bu3SnCl
Ph2MeSiCl
CH2᎐᎐CHCH2Br
PhSSPh–MeI
Ph2CO
Me3Si
Bu3Sn
Ph2MeSi
CH2᎐᎐CHCH2
60
64
64
42
39
57a
PhS
a
a Product is 30.
Scheme 11
Conclusion
Chiral substituted 1,2- and 1,3-diamines can be prepared
starting from unsubstituted 1,2- and 1,3-diamines. The un-
substituted diamines can be converted into imidazolidines or
pyrimidines in one pot and these cyclic derivatives under-
go successful lithiation–substitution α- to the N-Boc group.
Asymmetric lithiation of the imidazolidine substrates occurs in
the presence of the chiral ligand (Ϫ)-sparteine, thereby leading
to highly enantiomerically enriched products. Both rotamers of
the N-Boc imidazolidines and pyrimidines are present in solu-
tion at low temperature, but only one rotamer permits success-
ful lithiation of these unsymmetrical substrates and this limits
the yields of the substituted products. The imidazolidines and
pyrimidines can be hydrolysed to give the acyclic substituted
diamine products.
Me3SiCl gave the expected 6-substituted product 29, E = SiMe3
(Scheme 10, Table 4). Yields were best with 2–2.5 equivalents of
sec-BuLi and with TMEDA as a co-solvent. Addition of other
electrophiles gave a selection of the 6-substituted pyrimidines
29 (Table 4). Using the electrophile benzophenone, the product
30 was obtained, in which cyclization of the intermediate alkox-
Experimental
General
IR spectra were recorded as liquid films on NaCl plates
unless otherwise stated, using a Nicolet FT-IR Magna 550
Scheme 10
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 3 2 – 1 5 4 4
1535

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spectrometer. Optical rotations were recorded on an AA-1000
polarimeter using a cell of either 0.5 or 0.1 dm path length and
(ES): MHϩ, 263.1756. C15H23N2O2 requires MH, 263.1759; m/z
(CI) 263 (60%, MHϩ), 207 (100, MHϩ Ϫ C4H8) (Found: C,
68.55; H, 8.75; N, 10.55. C15H22N2O2 requires C, 68.65; H, 8.45;
N, 10.7%).
are recorded in 10Ϫ1 deg cm2
g
Ϫ1. Elemental analyses were
recorded on a Carlo Erba EA1110 elemental analyser. 1H NMR
spectra were recorded on a Bruker AC 300 MHz or a Bruker
DRX 400 MHz spectrometer using the residual solvent peak as
an internal reference. Chemical shifts are given in parts per
million. Coupling constants, J, are given in Hz. 13C NMR spectra
are recorded on the above spectrometers operating at 75 or 100
MHz respectively and are proton decoupled. Additional analy-
sis by DEPT, COSY, NOESY or HMQC experiments were
performed where necessary. Mass spectra were recorded on a
Kratos Profile HV3 or a Micromass Quattro II spectrometer or
a ThermoQuest AS2000 GCMS machine, using electron
impact (EI), chemical ionisation (CI), electrospray (ES) or field
ionisation (FI) techniques. Accurate mass measurements were
performed on the Kratos Profile spectrometer, a Finnigan
MAT 900 XLT spectrometer or a Micromass Autospec
spectrometer.
Petrol refers to light petroleum (bp 40–60 ЊC). Tetrahydro-
furan (THF) and diethyl ether (Et2O) were distilled from
sodium–benzophenone. (Ϫ)-Sparteine and N,N,NЈ,NЈ-tetra-
methylethylenediamine (TMEDA) were distilled from calcium
hydride. Flash column chromatography was performed on silica
gel 60H (230–400 mesh) (Merck 9385). Thin layer chromato-
graphy was performed on Kieselgel 60F254 0.25 mm plates,
and visualised by UV irradiation at 254 nm or potassium
permanganate dip.
3-Methylimidazolidine-1-carboxylic acid tert-butyl ester 3,
R = Me
i
In the same way as the imidazolidine 3, R = Pr, N-methyl-
ethylenediamine (1.0 mL, 11.5 mmol), paraformaldehyde
(0.34 g, 11.48 mmol) and di-tert-butyl dicarbonate (2.51 g,
11.48 mmol) gave, after purification by column chromato-
graphy on silica gel, eluting with EtOAc, the imidazolidine 3,
R = Me (1.84 g, 86%) as an oil; Rf 0.08 (EtOAc); νmax (film)/
cmϪ1 1700 (C᎐O); δ (400 MHz, CDCl , 60 ЊC, rotamers) 3.84
᎐
H
3
(2H, s, NCH2N), 3.35–3.32 (2H, m, BocNCH2CH2), 2.73–2.70
(2H, m, BocNCH2CH2), 2.29 (3H, s, N–CH3), 1.37 [9H, s,
C(CH3)3]; δC(100 MHz, CDCl3, 60 ЊC, rotamers) 153.4, 79.4,
79.1, 69.5, 54.5, 44.2, 40.0, 28.3; Found (ES): MHϩ, 187.1448.
C9H19N2O2 requires MH, 187.1446; m/z (CI) 187 (5%, MHϩ),
131 (100, MHϩ Ϫ C4H8).
(5RS )-3-Isopropyl-5-trimethylsilylimidazolidine-1-carboxylic
acid tert-butyl ester 7, E = SiMe3
To the imidazolidine 3, R = iPr (1.0 g, 4.67 mmol) in dry THF
(25 mL) under nitrogen at Ϫ78 ЊC was added sec-BuLi (4.3 mL,
5.6 mmol, 1.3 M in cyclohexane) dropwise over a period of
5 min. After 1 h, Me3SiCl (0.89 mL, 6.99 mmol) was added
slowly and the mixture was retained at Ϫ78 ЊC for a further 4 h
before being allowed to warm to room temperature. Saturated
NaHCO3(aq) (30 mL) was added, the mixture was extracted with
Et2O (3 × 30 mL) and the combined extracts were dried
(Na2SO4), evaporated and purified by column chromatography
on silica gel, eluting with petrol–EtOAc (5 : 1), to give recovered
starting material 3, R = iPr (0.38 g, 38%) and the imidazolidine
7, E = SiMe3 (0.66 g, 49%) as an oil; Rf 0.44 [petrol–EtOAc
(1 : 1)]; νmax (film)/cmϪ1 1700 (C᎐O); δ (400 MHz, CDCl , 60
3-Isopropylimidazolidine-1-carboxylic acid tert-butyl ester 3,
R = iPr
N-Isopropylethylenediamine (7.66 g, 9.32 mL, 75.0 mmol)
was added to a suspension of paraformaldehyde (2.25 g,
75.0 mmol), K2CO3 (35 g, 253 mmol) and MgSO4 (35 g,
290 mmol) in CHCl3 (250 mL) under nitrogen at room temper-
ature. After stirring for 18 h, di-tert-butyl dicarbonate (16.37 g,
75.0 mmol) was added and the mixture was stirred for a further
18 h. The mixture was filtered, evaporated, saturated brine (75
mL) was added, and the mixture was extracted with CH2Cl2
(3 × 75 mL). The combined extracts were dried (Na2SO4), evap-
orated and purified by column chromatography on silica gel,
eluting with petrol–EtOAc (1 : 1), to give the imidazolidine 3,
᎐
H
3
ЊC, rotamers) 4.25–4.23 (1H, m, NCHAHBN), 3.68–3.61 (1H,
m, NCHAHBN), 3.32–3.28 (1H, m, CHSiMe3), 3.01–2.97 (1H,
m, iPrNCHAHBCH), 2.62–2.56 (1H, m, iPrNCHAHBCH), 2.44–
2.37 (1H, m, NCHMe2), 1.45 [9H, s, C(CH3)3], 1.08 [6H, d,
J 6.0, CH(CH3)2], 0.08 [9H, s, Si(CH3)3]; δC(100 MHz, CDCl3,
60 ЊC, rotamers) 153.0, 79.3, 67.6, 53.2, 52.8, 47.1, 28.5, 21.4,
Ϫ2.4; Found (CI): MHϩ, 287.2150. C14H31N2O2Si requires MH,
287.2155; m/z (CI) 287 (95%, MHϩ), 231 (100, MHϩ Ϫ C4H8)
(Found: C, 58.93; H, 10.86; N, 9.76. C14H30N2O2Si requires C,
58.69; H, 10.55; N, 9.78%).
i
R = Pr (15.3 g, 95%) as an oil; Rf 0.16 [petrol–EtOAc (1 : 1)];
νmax (film)/cmϪ1 1700 (C᎐O); δ (400 MHz, CDCl , rotamers)
᎐
H
3
3.97 & 3.89 (2H, s, NCH2N), 3.42–3.35 (2H, m, CH2CH2-
NBoc), 2.78–2.74 (2H, m, CH2CH2NBoc), 2.40–2.34 [1H, m,
NCH(CH3)2], 1.39 [9H, s, C(CH3)3], 1.05 [6H, d, J 6.5, NCH-
(CH3)2]; δC(100 MHz, CDCl3, rotamers) 153.5, 153.4, 79.6, 79.4,
66.7, 66.6, 53.3, 53.2, 51.1, 50.3, 44.9, 44.4, 28.4, 28.3,
21.4; Found (ES): MHϩ, 215.1761. C11H23N2O2 requires MH,
215.1759; m/z (CI) 215 (56%, MHϩ), 159 (100, MHϩ Ϫ C4H8)
(Found: C, 61.9; H, 10.5; N, 12.85. C11H22N2O2 requires C,
61.65; H, 10.35; N, 13.05%).
(5S )-3-Isopropyl-5-trimethylsilylimidazolidine-1-carboxylic acid
tert-butyl ester 7, E = SiMe3
To (Ϫ)-sparteine (2.84 g, 2.79 mL, 12.13 mmol) in dry Et2O
(25 mL) under nitrogen at Ϫ78 ЊC was added sec-BuLi
(8.6 mL, 11.20 mmol, 1.3 M in cyclohexane). After 30 min, the
mixture was transferred via a cannula to a solution of the
imidazolidine 3, R = iPr (2.0 g, 9.33 mmol) in dry Et2O (25 mL)
under nitrogen at Ϫ78 ЊC. The mixture was stirred at Ϫ78 ЊC
for 2 h, and then Me3SiCl (1.78 mL, 14.00 mmol) was added,
ensuring that the temperature did not rise above Ϫ70 ЊC. The
resulting mixture was maintained at Ϫ78 ЊC for a further 4 h
and then saturated NaHCO3(aq) (50 mL) was added. The mix-
ture was extracted with Et2O (3 × 50 mL) and the combined
extracts were dried (Na2SO4), evaporated and purified by
column chromatography on silica gel, eluting with petrol–
3-Benzylimidazolidine-1-carboxylic acid tert-butyl ester 3,
R = Bn
In the same way as the imidazolidine 3, R = iPr, N-benzylethyl-
enediamine (5.0 mL, 33.3 mmol), paraformaldehyde (1.0 g, 33.3
mmol) and di-tert-butyl dicarbonate (7.26 g, 33.28 mmol) gave,
after purification by column chromatography on silica gel,
eluting with petrol–EtOAc (7 : 3), the imidazolidine 3, R = Bn
(7.87 g, 90%) as plates; mp 40.0–41.5 ЊC (from hexane–EtOAc);
Rf 0.19 [petrol–EtOAc (4 : 1)]; νmax (KBr)/cmϪ1 1690 (C᎐O);
᎐
i
δH(400 MHz, CDCl3, rotamers) 7.33–7.27 (5H, m, Ar–H),
4.00 & 3.96 (2H, s, NCH2N), 3.64 (2H, s, PhCH2N), 3.47–
3.39 (2H, m, BocNCH2CH2), 2.85–2.82 (2H, m, Boc-
NCH2CH2), 1.44 [9H, s, C(CH3)3]; δC(100 MHz, CDCl3,
rotamers) 153.6, 138.0, 137.9, 128.8, 128.7, 128.5, 127.4, 79.7,
79.5, 68.0, 67.9, 58.2, 58.1, 52.8, 52.1, 44.4, 43.8, 28.4; Found
EtOAc (5 : 1), to give recovered starting material 3, R = Pr
(0.96 g, 48%) and the imidazolidine (S)-7, E = SiMe3 (1.07 g,
40%); [α]2D3 ϩ40.4 (c 1.1 in CHCl3). Other spectroscopic data as
above for (5RS)-7, E = SiMe3. The enantiomer ratio was
1
determined to be 93 : 7 by H and 19F NMR analysis of the
Mosher amide 27, E = SiMe3.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 3 2 – 1 5 4 4
1536

View Article Online
(5RS )-3-Isopropyl-5-tributylstannylimidazolidine-1-carboxylic
acid tert-butyl ester 7, E = SnBu3
C, 70.5; H, 8.2, N, 6.95. C24H34N2O2Si requires C, 70.2; H, 8.35;
N, 6.8%).
In the same way as the imidazolidine (RS)-7, E = SiMe3, the
imidazolidine 3, R = iPr (1.0 g, 4.67 mmol), sec-BuLi (4.3 mL,
5.6 mmol, 1.3 M in cyclohexane) and Bu3SnCl (1.89 mL,
7.0 mmol) gave, after purification by column chromatography
on silica gel, eluting with petrol–EtOAc (95 : 5), the recovered
starting material 3, R = iPr (0.30 g, 30%) and the imidazolidine
7, E = SnBu3 (1.16 g, 49%) as an oil; Rf 0.41 [petrol–EtOAc
(5S )-3-Isopropyl-5-(methyldiphenylsilyl)imidazolidine-1-
carboxylic acid tert-butyl ester 7, E = SiMePh2
In the same way as the imidazolidine (S)-7, E = SiMe3, the
imidazolidine 3, R = iPr (2.0 g, 9.33 mmol), (Ϫ)-sparteine (2.84
g, 2.79 mL, 12.13 mmol), sec-BuLi (8.60 mL, 11.20 mmol, 1.3
M in cyclohexane) and Ph2MeSiCl (2.96 mL, 14.00 mmol) gave,
after purification by column chromatography on silica gel, elut-
ing with petrol–EtOAc (10 : 1), the recovered starting material
(4 : 1)]; νmax (film)/cmϪ1 1685 (C᎐O); δ (400 MHz, CDCl ,
᎐
H
3
rotamers) 4.22 (0.7H, d, J 5.5, NCHAHBN), 4.09 (0.3H, d, J 5.5,
NCHAHBN), 3.88 (0.3H, d, J 5.5, NCHAHBN), 3.64 (0.7H, d,
J 5.5, NCHAHBN), 3.45–3.41 (1H, m, CH2CHNBoc), 3.20–
3.17 (0.7H, m, CHAHBCH2NBoc), 3.05–2.97 (0.3H, m, CHA-
HBCH2NBoc), 2.85–2.80 (0.3H, m, CHAHBCH2NBoc), 2.58–
2.53 (0.7H, m, CHAHBCH2NBoc), 2.44–2.40 [1H, m, NCH-
(CH3)2], 1.51–1.46 (6H, m, 3 × CH2), 1.42 [9H, s, C(CH3)3],
1.31–1.28 (6H, m, 3 × CH2), 1.11 [6H, d, J 6.0, NCH(CH3)2],
0.91–0.85 (15H, m, 3 × CH2 & 3 × CH3); δC(100 MHz, CDCl3,
rotamers) 153.0, 152.8, 79.7, 79.0, 67.2, 66.8, 55.8, 55.3, 53.4,
53.1, 46.1, 45.1, 29.1, 28.5, 27.7, 21.6, 13.6, 9.8; Found (CI):
MHϩ, 505.2820. C23H49N2O2120Sn requires MH, 505.2816; m/z
(CI) 505 (55%, MHϩ), 447 (100, Mϩ Ϫ C4H9) (Found: C, 54.8;
H, 9.75; N, 5.3. C23H48N2O2Sn requires C, 54.9; H, 9.6; N,
5.55%).
i
3, R = Pr (0.98 g, 49%) and the imidazolidine (S)-7, E =
SiMePh2 (1.69 g, 44%); [α]2D6 ϩ12.9 (c 1.33 in CHCl3). Other
spectroscopic data as above for (5RS)-7, E = SiMePh2. The
1
enantiomer ratio was determined to be 94 : 6 by H and 19F
NMR analysis of the Mosher amide 27, E = SiMePh2.
(5RS )-3-Isopropyl-5-methylimidazolidine-1-carboxylic acid
tert-butyl ester 7, E = Me
In the same way as the imidazolidine (RS)-7, E = SiMe3, the
imidazolidine 3, R = iPr (1.0 g, 4.67 mmol), sec-BuLi (4.3 mL,
5.6 mmol, 1.3 M in cyclohexane) and methyl iodide (0.44 mL,
7.0 mmol) gave, after purification by column chromatography
on silica gel, eluting with petrol–EtOAc (5 : 1), the recovered
starting material 3, R = iPr (0.39 g, 39%) and the imidazolidine
7, E = Me (0.45 g, 42%) as an oil; Rf 0.18 [petrol–EtOAc (1 : 1)];
νmax (film)/cmϪ1 1700 (C᎐O); δ (400 MHz, CDCl , rotamers)
(5S )-3-Isopropyl-5-tributylstannylimidazolidine-1-carboxylic
acid tert-butyl ester 7, E = SnBu3
᎐
H
3
4.25–4.22 (0.5H, m, NCHAHBN), 4.15–4.00 (0.5H, m,
NCHAHBN), 3.98–3.76 (2H, m, NCHAHBN & NCH2CHN-
Boc), 3.10–1.95 (1H, m, NCHAHBCHNBoc), 2.37–2.29 (2H, m,
NCHAHBCHNBoc & NCHMe2), 1.43 [9H, s, C(CH3)3], 1.24–
1.16 (3H, m, BocNCHCH3), 1.10–1.05 [6H, m, NCH(CH3)2];
δC(100 MHz, CDCl3, rotamers) 153.8, 79.4, 67.2, 59.0, 58.2,
53.2, 52.3, 28.5, 21.5, 21.4, 19.8, 19.2; Found (ES): MHϩ,
229.1918. C12H25N2O2 requires MH, 229.1916; m/z (CI) 229
(40%, MHϩ), 171 (100, Mϩ Ϫ C4H9) (Found: C, 63.05; H, 11.0;
N, 12.05. C12H24N2O2 requires C, 63.1; H, 10.6; N, 12.25%).
In the same way as the imidazolidine (S)-7, E = SiMe3, the
i
imidazolidine 3, R = Pr (2.0 g, 9.33 mmol), (Ϫ)-sparteine
(2.84 g, 2.79 mL, 12.13 mmol), sec-BuLi (8.60 mL, 11.20 mmol,
1.3 M in cyclohexane) and Bu3SnCl (3.78 mL, 14.00 mmol)
gave, after purification by column chromatography on silica gel,
eluting with petrol–EtOAc (95 : 5), the recovered starting
material 3, R = iPr (0.78 g, 39%) and the imidazolidine (S)-7, E
= SnBu3 (1.88 g, 40%); [α]2D5 ϩ89.7 (c 1.60 in CHCl3). Other
spectroscopic data as above for (5RS)-7, E = SnBu3. The enan-
tiomer ratio was determined to be 94 : 6 by chiral HPLC using a
HP1050 LC system fitted with a Varian RI4 Refractive Index
detector with a Chiralpak AD column (250 mm × 4.6 mm id) as
the stationary phase with hexane as the mobile phase at a flow
rate of 1.0 mL minϪ1. Injection volume 20 µL of sample pre-
pared in a 1 mg mLϪ1 solution of hexane. Under these condi-
tions, the enantiomers were eluted at 4.30 min (major) and
4.95 min (minor).
(5S )-3-Isopropyl-5-methylimidazolidine-1-carboxylic acid
tert-butyl ester 7, E = Me
In the same way as the imidazolidine (S)-7, E = SiMe3, the
i
imidazolidine 3, R = Pr (2.0 g, 9.33 mmol), (Ϫ)-sparteine
(2.84 g, 2.79 mL, 12.13 mmol), sec-BuLi (8.60 mL, 11.20 mmol,
1.3 M in cyclohexane) and MeI (0.88 mL, 14.00 mmol) gave,
after purification by column chromatography on silica gel, elut-
ing with petrol–EtOAc (5 : 1), the recovered starting material 3,
R = iPr (0.84 g, 42%) and the imidazolidine (S)-7, E = Me (0.94
g, 44%); [α]2D4 ϩ31.5 (c 1.03 in CHCl3). Other spectroscopic data
as above for (5RS)-7, E = Me. The enantiomer ratio was deter-
mined to be 92 : 8 by 1H and 19F NMR and GCMS analysis of
the Mosher amide 27, E = Me.
(5RS )-3-Isopropyl-5-(methyldiphenylsilyl)imidazolidine-1-
carboxylic acid tert-butyl ester 7, E = SiMePh2
In the same way as the imidazolidine (RS)-7, E = SiMe3, the
imidazolidine 3, R = iPr (1.0 g, 4.67 mmol), sec-BuLi (4.3 mL,
5.6 mmol, 1.3 M in cyclohexane) and Ph2MeSiCl (1.48 mL,
7.0 mmol) gave, after purification by column chromatography
on silica gel, eluting with petrol–EtOAc (10 : 1), the recovered
starting material 3, R = iPr (0.46 g, 46%) and the imidazolidine
7, E = SiMePh2 (0.84 g, 44%) as an oil; Rf 0.40 [petrol–EtOAc
(5RS )-3-Isopropyl-5-phenylcarbamoylimidazolidine-1-
carboxylic acid tert-butyl ester 7, E = CONHPh
In the same way as the imidazolidine (RS)-7, E = SiMe3, the
imidazolidine 3, R = iPr (2.0 g, 9.33 mmol), sec-BuLi (8.6 mL,
11.2 mmol, 1.3 M in cyclohexane) and phenyl isocyanate
(1.5 mL, 14.0 mmol) gave, after purification by column chrom-
atography on silica gel, eluting with petrol–EtOAc (10 : 1), the
(1 : 1)]; νmax (film)/cmϪ1 1695 (C᎐O); δ (400 MHz, CDCl ,
᎐
H
3
rotamers) 7.58–7.34 (10H, m, Ar–H), 4.21–4.10 (0.5H, m,
NCHAHBN), 4.10–3.97 (0.5H, m, NCHAHBN), 3.97–3.85
(1.5H, m, NCHAHBN & NCH2CHNBoc), 3.72–3.69 (0.5H, m,
NCHAHBN), 2.89–2.85 (1H, m, NCHAHBCHNBoc), 2.72–2.69
(1H, m, NCHAHBCHNBoc), 2.37–2.31 (1H, m, NCHMe2),
1.30 & 1.19 [9H, s, C(CH3)3], 1.03 [3H, d, J 6.0, NCH(CH3)A-
(CH3)B], 0.98 [3H, d, J 6.0, NCH(CH3)A(CH3)B], 0.70 (3H, br s,
SiCH3). δC(100 MHz, CDCl3, rotamers) 154.0, 153.3, 137.5,
135.8, 135.2, 129.2, 127.7, 79.9, 79.1, 67.4, 53.9, 53.7, 52.7, 46.3,
46.0, 28.3, 28.2, 21.7, 21.6, 21.4, 21.0, Ϫ3.8, Ϫ4.6; Found (ES):
MHϩ, 411.2472. C24H35N2O2Si requires MH, 411.2468; m/z
(CI) 411 (38%, MHϩ), 277 (100, MHϩ Ϫ C4H9 Ϫ C6H5) (Found:
i
recovered starting material 3, R = Pr (0.83 g, 42%) and the
imidazolidine 7, E = CONHPh (1.40 g, 45%) as plates; mp
139.0–139.5 ЊC (from EtOAc); Rf 0.23 [petrol–EtOAc (1 : 1)];
νmax (KBr)/cmϪ1 1705 (tBuOC᎐O), 1675 (NHC᎐O); δ (400
᎐
᎐
H
MHz, CDCl3, 50 ЊC) 7.52–7.50 (2H, m, Ar–H), 7.32–7.29 (2H,
m, Ar–H), 7.11–7.07 (1H, m, Ar–H), 4.40–4.36 (1H, m, NCH2-
CHN), 4.26–4.22 (1H, m, NCHAHBN), 4.04–4.03 (1H, m,
NCHAHBN), 3.36–3.30 (1H, m, NCHAHBCHN), 2.98–2.93
(1H, m, NCHAHBCHN), 2.57–2.50 (1H, m, NCHMe2), 1.48
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 3 2 – 1 5 4 4
1537

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[9H, s, C(CH3)3], 1.14–1.12 [6H, m, NCH(CH3)2]; δC(100 MHz,
CDCl3, 50 ЊC) 169.2, 153.5, 137.9, 128.9, 124.1, 119.6, 81.5,
67.2, 60.6, 52.4, 28.3, 21.2; Found (ES): MHϩ, 334.2133.
C18H28N3O3 requires MH, 334.2131; m/z (CI) 334 (91%, MHϩ),
278 (100, MHϩ Ϫ C4H8) (Found: C, 64.75; H, 8.2; N, 12.2.
C18H27N3O3 requires C, 64.85; H, 8.15; N, 12.6%).
Other spectroscopic data as above for (5RS)-7, E = C(OH)Ph2.
The enantiomer ratio was determined to be 92 : 8 by chiral
HPLC using a Gilson 231 XL system fitted with a Chiralpak
AD column (250 mm × 4.6 mm id) as the stationary phase with
hexane–EtOH (98 : 2) as the mobile phase at a flow rate of
1.0 mL minϪ1, detection by UV absorbance at 215 nm. Injection
volume 20 µL of sample prepared in a 1 mg mLϪ1 solution of
EtOH. Under these conditions, the enantiomers were eluted at
6.01 min (major) and 7.82 min (minor). A sample was recrystal-
lised from hexane to give (R)-7, E = C(OH)Ph2 as needles;
[α]2D6 Ϫ151.1 (c 0.55 in CHCl3) and the enantiomer ratio was
determined to be >99 : 1 by chiral HPLC.
(5R)-3-Isopropyl-5-phenylcarbamoylimidazolidine-1-carboxylic
acid tert-butyl ester 7, E = CONHPh
In the same way as the imidazolidine (S)-7, E = SiMe3, the
i
imidazolidine 3, R = Pr (2.0 g, 9.33 mmol), (Ϫ)-sparteine
(2.84 g, 2.79 mL, 12.13 mmol), sec-BuLi (8.60 mL, 11.20 mmol,
1.3 M in cyclohexane) and phenyl isocyanate (3.00 mL, 14.00
mmol) gave, after purification by column chromatography on
silica gel, eluting with petrol–EtOAc (10 : 1), the recovered
starting material 3, R = iPr (1.18 g, 59%) and the imidazolidine
(R)-7, E = CONHPh (0.62 g, 20%); [α]2D4 ϩ63.3 (c 1.04 in
CHCl3). Other spectroscopic data as above for (5RS)-7,
E = CONHPh. The enantiomer ratio was determined to be
(5RS )-5-Allyl-3-isopropylimidazolidine-1-carboxylic acid
tert-butyl ester 7, E ؍ allyl
In the same way as the imidazolidine (RS)-7, E = SiMe3, the
imidazolidine 3, R = iPr (1.0 g, 4.67 mmol), sec-BuLi (4.3 mL,
5.6 mmol, 1.3 M in cyclohexane) and allyl bromide (0.59 mL,
7.0 mmol) gave, after purification by column chromatography
on silica gel, eluting with petrol–EtOAc (10 : 1), the recovered
starting material 3, R = iPr (0.38 g, 38%) and the imidazolidine
7, E = allyl (0.50 g, 42%) as an oil; Rf 0.43 [petrol–EtOAc (1 : 1)];
νmax (film)/cmϪ1 1700 (C᎐O); δ (400 MHz, CDCl , rotamers)
1
86 : 14 by H and 19F NMR analysis of the Mosher amide 27,
E = CONHPh and by chiral HPLC using a Gilson 231 XL
system fitted with a Chiralpak AD column (250 mm × 4.6 mm
id) as the stationary phase with hexane–EtOH (98 : 2) as the
mobile phase at a flow rate of 1.0 mL minϪ1, detection by UV
absorbance at 215 nm. Injection volume 20 µL of sample
prepared in a 1 mg mLϪ1 solution of EtOH. Under these condi-
tions, the enantiomers were eluted at 25.72 min (major) and
30.40 min (minor).
᎐
H
3
5.79–5.68 (1H, m, CH᎐CH ), 5.09–5.02 (2H, m, CH ᎐CH),
᎐
᎐
2
2
4.26–4.20 (0.5H, m, NCHAHBN), 4.07–4.03 (0.5H, m,
NCHAHBN), 3.95–3.74 (2H, m, NCHAHBN & NCH2CHN-
Boc), 3.00–2.84 (1H, m, NCHAHBCHNBoc), 2.70–2.45 (2H, m,
NCHAHBCHNBoc & CH ᎐CHCHAHBN), 2.40–2.34 (1H, m,
᎐
2
NCHMe ), 2.30–2.20 (1H, m, CH ᎐CHCHAHBN), 1.45 [9H, s,
᎐
2
2
C(CH3)3], 1.08–1.06 [6H, m, NCH(CH3)2]; δC(100 MHz,
CDCl3, rotamers) 153.7, 153.4, 134.7, 134.6, 117.3, 79.6,
67.3, 56.0, 55.1, 55.8, 53.2, 38.2, 37.4, 28.5, 21.5; Found (ES):
MHϩ, 255.2070. C14H27N2O2 requires MH, 255.2072; m/z
(CI) 255 (19%, MHϩ), 197 (100, Mϩ Ϫ C4H9) (Found: C, 66.15;
H, 10.7; N, 11.05. C14H26N2O2 requires C, 66.1; H, 10.3; N,
11.0%).
In the same way as the imidazolidine (S)-7, E = SiMe3,
attempted preparation of the imidazolidine (S)-7, E = allyl gave
(RS)-7, E = allyl as determined by 1H and 19F NMR analysis of
the Mosher amide 27, E = allyl.
(5RS )-5-(Hydroxydiphenylmethyl)-3-isopropylimidazolidine-1-
carboxylic acid tert-butyl ester 7, E = C(OH)Ph2
To the imidazolidine 3, R = iPr (1.0 g, 4.67 mmol) in dry Et2O
(25 mL) under nitrogen at Ϫ78 ЊC was added sec-BuLi (4.3 mL,
5.6 mmol, 1.3 M in cyclohexane) dropwise over a period of
5 min. After 3 h, benzophenone (1.53 g, 7.0 mmol) in dry Et2O
(5 mL) was added slowly and the mixture was retained at
Ϫ78 ЊC for a further 4 h before being allowed to warm to room
temperature. Saturated NaHCO3(aq) (30 mL) was added, the
mixture was extracted with Et2O (3 × 30 mL) and the combined
extracts were dried (Na2SO4), evaporated and purified by
column chromatography on silica gel, eluting with petrol–
(5RS )-5-Benzyl-3-isopropylimidazolidine-1-carboxylic acid
tert-butyl ester 7, E = CH2Ph
i
EtOAc (10 : 1), to give recovered starting material 3, R = Pr
(0.45 g, 45%) and the imidazolidine 7, E = C(OH)Ph2 (0.75 g,
40%) as needles; mp 83.5–85.5 ЊC (from hexane); Rf 0.49 [pet-
rol–EtOAc (1 : 1)]; νmax (film)/cmϪ1 1695 (C᎐O); δ (400 MHz,
In the same way as the imidazolidine (RS)-7, E = SiMe3, the
imidazolidine 3, R = iPr (1.0 g, 4.67 mmol), sec-BuLi (4.3 mL,
5.6 mmol, 1.3 M in cyclohexane) and benzyl bromide (0.83 mL,
7.0 mmol) gave, after purification by column chromatography
on silica gel, eluting with petrol–EtOAc (10 : 1), the recovered
᎐
H
CDCl3, 50 ЊC) 7.62–7.19 (10H, m, Ar–H), 4.86 (1H, m, NCH2-
CHN), 4.43 (1H, m, NCHAHBN), 3.86 (1H, m, NCHAHBN),
3.10 (1H, d, J 9.0, NCHAHBCHN), 2.68 (1H, d, J 9.0,
NCHAHBCHN), 2.61–2.55 (1H, m, NCHMe2), 1.17 [9H, s,
C(CH3)3], 1.11 [3H, d, J 6.5, NCH(CH3)A(CH3)B], 1.03 [3H, d,
J 6.5, NCH(CH3)A(CH3)B]; δC(100 MHz, CDCl3, 50 ЊC) 153.9,
146.1, 145.2, 144.0, 128.4, 128.0, 127.5, 127.4, 127.0 126.7,
126.6, 126.4, 80.7, 80.1, 67.1, 63.0, 53.2, 52.3, 27.9, 20.9, 20.8;
Found (ES): MHϩ, 397.2495. C24H33N2O3 requires MH,
397.2491; m/z (CI) 397 (64%, MHϩ), 323 (100, MHϩ Ϫ C4H9 Ϫ
OH) (Found: C, 72.45; H, 8.35; N, 6.9. C24H32N2O3 requires C,
72.7; H, 8.15; N, 7.05%).
i
starting material 3, R = Pr (0.5 g, 50%) and the imidazolidine
7, E = CH2Ph (0.58 g, 41%) as an oil; Rf 0.36 [petrol–EtOAc
(1 : 1)]; νmax (film)/cmϪ1 1695 (C᎐O); δ (400 MHz, CDCl ,
᎐
H
3
rotamers) 7.30–7.16 (5H, m, Ar–H), 4.14–3.90 (3H, m, NCH2N
i
& PrNCH2CHBn), 3.33–3.18 (1H, m, CHAHBPh), 2.73–2.70
i
(1H, m, CHAHBPh), 2.63–2.59 (2H, m, PrNCH2CH), 2.37–
2.34 (1H, m, NCHMe2), 1.50 & 1.47 [9H, s, C(CH3)3], 1.05 [6H,
d, J 6.5, NCH(CH3)2]; δC(100 MHz, CDCl3, rotamers) 153.6,
153.4, 138.8, 129.5, 129.3, 128.5, 126.3, 125.9, 79.8, 67.3, 58.2,
57.8, 55.6, 54.6, 53.4, 53.1, 40.0, 39.0, 28.5, 21.4; Found (ES):
MHϩ, 305.2230. C18H29N2O2 requires MH, 305.2229; m/z (CI)
305 (9%, MHϩ), 247 (100, Mϩ Ϫ C4H9) (Found: C, 71.25; H,
9.6; N, 9.0. C18H28N2O2 requires C, 71.0; H, 9.3; N, 9.2%).
In the same way as the imidazolidine (S)-7, E = SiMe3,
attempted preparation of the imidazolidine (S)-7, E = CH2Ph
gave (RS)-7, E = CH2Ph as determined by chiral HPLC using a
Gilson 231 XL system fitted with a Chiralpak AD column (250
mm × 4.6 mm id) as the stationary phase with hexane–EtOH
(5R)-5-(Hydroxydiphenylmethyl)-3-isopropylimidazolidine-1-
carboxylic acid tert-butyl ester 7, E = C(OH)Ph2
In the same way as the imidazolidine (S)-7, E = SiMe3, the
i
imidazolidine 3, R = Pr (2.0 g, 9.33 mmol), (Ϫ)-sparteine
(2.84 g, 2.79 mL, 12.13 mmol), sec-BuLi (8.60 mL, 11.20 mmol,
1.3 M in cyclohexane) and benzophenone (3.06 g, 14.00 mmol)
gave, after purification by column chromatography on silica gel,
eluting with petrol–EtOAc (10 : 1), the recovered starting
(96 : 4) as the mobile phase at a flow rate of 1.0 mL minϪ1
,
i
material 3, R = Pr (0.84 g, 42%) and the imidazolidine (R)-7,
detection by UV absorbance at 215 nm. Injection volume 20 µL
E = C(OH)Ph2 (1.85 g, 50%); [α]2D4 Ϫ129.7 (c 4.58 in CHCl3).
of sample prepared in a 1 mg mLϪ1 solution of EtOH. Under
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 3 2 – 1 5 4 4
1538

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these conditions, the enantiomers were eluted at 8.49 min and
8.97 min.
2.67 (1H, m, BocNCHCHAHB), 2.35 (3H, s, N–CH3), 1.19 [9H,
s, C(CH3)3]; δC(100 MHz, CDCl3, 60 ЊC, rotamers) 154.0, 146.0,
145.1, 128.7, 127.9, 127.6, 127.4, 127.3, 127.1, 126.8, 126.4,
126.2, 125.4, 80.6, 80.1, 70.6, 58.0, 55.8, 38.9, 27.9; Found (ES):
MHϩ, 369.2177. C22H29N2O3 requires MH, 369.2178; m/z (CI)
369 (100%, MHϩ) (Found: C, 71.4; H, 7.95; N, 7.5. C22H28N2O3
requires C, 71.7; H, 7.65; N, 7.6%).
(8RS )-6-Isopropyl-1,1-diphenyl-tetrahydroimidazo[1,5-c]oxazol-
3-one 8
In the same way as the imidazolidine (RS)-7, E = SiMe3, the
imidazolidine 3, R = iPr (1.0 g, 4.67 mmol) in dry THF (25 mL),
sec-BuLi (4.3 mL, 5.6 mmol, 1.3 M in cyclohexane) and benzo-
phenone (1.28 g, 7.0 mmol) in dry THF (5 mL) gave an intense
blue colour which, after purification by column chromato-
graphy on silica gel, eluting with CH2Cl2–EtOAc (10 : 1), gave
the recovered starting material 3, R = iPr (0.29 g, 29%) and the
oxazolone 8, (0.75 g, 50%) as needles; mp 117–120 ЊC (from
EtOAc); Rf 0.34 [CH2Cl2–EtOAc (4 : 1)]; νmax (KBr)/cmϪ1 1755
(5R)-5-(Hydroxydiphenylmethyl)-3-methylimidazolidine-1-
carboxylic acid tert-butyl ester 10
In the same way as the imidazolidine (S)-7, E = SiMe3, the
imidazolidine 3, R = Me (0.5 g, 2.68 mmol), (Ϫ)-sparteine
(0.82 g, 0.81 mL, 3.49 mmol), sec-BuLi (2.50 mL, 3.22 mmol,
1.3 M in cyclohexane) and benzophenone (730 mg, 4.03 mmol)
gave, after purification by column chromatography on silica gel,
eluting with petrol–EtOAc (5 : 1), the recovered starting
material 3, R = Me (0.21 g, 42%) and the imidazolidine (R)-10
(0.4 g, 40%); [α]2D4 Ϫ112.1 (c 0.78 in CHCl3). Other spectroscopic
data as above for (5RS)-10. The enantiomer ratio was deter-
mined to be 93 : 7 by chiral HPLC using a Thermo Separation
Products Spectra Series AS300 system fitted with a Chiralcel
OD column (250 mm × 4.6 mm id) as the stationary phase with
hexane–iPrOH (99.5 : 0.5) as the mobile phase at a flow rate of
1.0 mL minϪ1, detection by UV absorbance at 234 nm. Injection
volume 20 µL of sample prepared in a 1 mg mLϪ1 solution of
hexane. Under these conditions, the enantiomers were eluted at
14.76 min (minor) and 16.81 min (major).
(C᎐O); δ (400 MHz, CDCl ) 7.51–7.29 (10H, m, Ar–H), 4.81–
᎐
H
3
4.78 (1H, m, iPrNCH2CH ), 4.29 (1H, d, J 8.0, iPrNCHAHBN),
4.06 (1H, d, J 8.0, PrNCHAHBN), 2.78–2.75 (1H, m, PrN-
CHAHBCH), 2.61–2.55 (1H, m, NCHMe2), 2.09–2.05 (1H, m,
iPrNCHAHBCH), 1.02–0.98 [6H, m, NCH(CH3)2]; δC(100
MHz, CDCl3) 160.9, 142.8, 139.8, 128.7, 128.5, 128.4, 128.0,
125.9, 125.2, 86.1, 67.6, 67.4, 52.7, 52.0, 21.6, 21.1; Found (CI):
MHϩ, 323.1760. C20H23N2O2 requires MH, 323.1759; m/z (CI)
323 (100%, MHϩ) (Found: C, 74.15; H, 6.9; N, 8.55.
C20H22N2O2 requires C, 74.5; H, 6.9; N, 8.7%).
i
i
3-Isopropyl-imidazolidine-1,5,5-tricarboxylic acid 1-tert-butyl
ester 5,5-diethyl ester 9
To the imidazolidine 3, R = iPr (0.5 g, 2.33 mmol) in dry THF
(12 mL) under nitrogen at Ϫ78 ЊC was added sec-BuLi
(2.15 mL, 2.8 mmol, 1.3 M in cyclohexane) dropwise over a
period of 5 min. After 1 h, the mixture was transferred via a
cannula to a pre-cooled (Ϫ78 ЊC) solution of ethyl chloroform-
ate (0.44 mL, 4.66 mmol) in THF (8 mL) and the mixture was
retained at Ϫ78 ЊC for a further 4 h before being allowed to
warm to room temperature. Saturated NaHCO3(aq) (5 mL) was
added, the mixture was extracted with Et2O (3 × 30 mL) and the
combined extracts were dried (Na2SO4), evaporated and puri-
fied by column chromatography on silica gel, eluting with
petrol–EtOAc (10 : 1), to give recovered starting material 3,
[(1-Methyl-1-phenylethylcarbamoyl)methyl]carbamic acid
tert-butyl ester 12
To N-Boc glycine (8.54 g, 48.77 mmol) in CHCl3 (200 mL)
under nitrogen was added DCC (10.06 g, 48.77 mmol) and
HOBT (6.59 g, 48.77 mmol). The suspension was stirred for 10
min, and then cumylamine (7.00 mL, 48.77 mmol) was added.
After 18 h, the solvent was removed in vacuo, EtOAc (250 mL)
was added and the mixture was stirred for 10 min. The
solids were removed by filtration and the mixture was washed
with 10% aqueous citric acid solution (100 mL) and 10%
NaHCO3(aq) (100 mL). The organic layer was dried (Na2SO4),
evaporated and purified by column chromatography on silica
gel, eluting with CH2Cl2–MeOH–NH3 (20 : 1 : 0.1), to give the
amide 12 (14.12 g, 99%) as an oil; Rf 0.64 [CH2Cl2–MeOH–NH3
(10 : 1 : 0.1)]; νmax (film)/cmϪ1 3320 (N–H), 1670 (C᎐O); δ (400
i
R = Pr (0.26 g, 52%) and the imidazolidine 9 (0.28 g, 34%) as
an oil; Rf 0.56 [petrol–EtOAc (1 : 1)]; νmax (film)/cmϪ1 1745
(C᎐O), 1705 (C᎐O); δ (400 MHz, CDCl , rotamers) 4.29–4.12
᎐
᎐
H
3
[6H, m, (OCH2CH3)2 & NCH2N], 3.35 & 3.32 (2H, s, NCH2-
CNBoc), 2.51–2.45 [1H, m, NCH(CH3)2], 1.44 & 1.38 [9H, s,
C(CH3)3], 1.24–1.22 [6H, m, (OCH2CH3)2], 1.02–1.01 [6H, m,
NCH(CH3)2]; δC(100 MHz, CDCl3, rotamers) 168.1, 168.0,
152.3, 152.2, 80.8, 80.5, 71.2, 71.0, 67.7, 67.5, 62.0, 61.9, 60.9 &
59.5, 52.2, 28.4, 28.1, 21.2, 14.0, 13.9; Found (ES): MHϩ,
359.2173. C17H31N2O6 requires MH, 359.2182; m/z (CI) 359
(15%, MHϩ), 303 (93, MHϩ Ϫ C4H8), 258 (100, Mϩ Ϫ C3H7 Ϫ
C4H9) (Found: C, 57.0; H, 8.55; N, 7.8. C17H30N2O6 requires C,
56.95; H, 8.45; N, 7.8%).
᎐
H
MHz, CDCl3, rotamers) 7.37–7.28 (4H, m, Ar–H), 7.22–7.19
(1H, m, Ar–H), 6.78 (1H, br s, N–H), 5.50 (1H, br s, N–H), 3.70
& 3.68 (2H, s, CH2), 1.66 [6H, s, CPh(CH3)2], 1.45 [9H, s,
C(CH3)3]; δC(100 MHz, CDCl3, rotamers) 168.6, 156.4, 146.7,
128.4, 126.7, 126.6, 124.8, 124.7, 80.0, 55.9, 49.0, 29.1, 28.3;
Found (ES): MHϩ, 293.1865. C16H25N2O3 requires MH,
293.1865; m/z (CI) 293 (100%, MHϩ) (Found: C, 65.8; H, 8.05;
N, 9.5. C16H24N2O3 requires C, 65.7; H, 8.25; N, 9.6%).
[2-(1-Methyl-1-phenylethylamino)ethyl]carbamic acid tert-butyl
ester 13
(5RS )-5-(Hydroxydiphenylmethyl)-3-methylimidazolidine-1-
carboxylic acid tert-butyl ester 10
To the amide 12 (7.0 g, 23.9 mmol) in THF (70 mL) under
nitrogen at Ϫ78 ЊC was added borane tetrahydrofuran complex
(48 mL, 47.8 mmol, 1.0 M in THF). The solution was stirred
at Ϫ78 ЊC for 3 h and then at room temperature for 18 h.
Methanol (30 mL) was added and the mixture was stirred at
room temperature for a further 18 h. Concentration of the
mixture in vacuo gave an oil. The oil was treated with MeOH
(3 × 40 mL) with evaporation to dryness after each addition to
remove boric acid as trimethyl borate. Purification by column
chromatography on silica gel, eluting with petrol–EtOAc (1 : 1),
gave the recovered starting material 12 (2.7 g, 39%) and the
carbamate 13 (3.5 g, 52%) as an oil; Rf 0.10 (EtOAc); νmax (film)/
In the same way as the imidazolidine (RS)-7, E = C(OH)Ph2,
the imidazolidine 3, R = Me (0.5 g, 2.68 mmol) in dry Et2O
(13 mL), sec-BuLi (2.5 mL, 3.22 mmol, 1.3 M in cyclohexane)
and benzophenone (730 mg, 4.03 mmol) in Et2O (3 mL) gave,
after purification by column chromatography on silica gel, elut-
ing with petrol–EtOAc (5 : 1), the recovered starting material 3,
R = Me (0.25 g, 51%) and the imidazolidine 10, (0.35 g, 35%) as
cubes; mp 123–126 ЊC (from hexane); Rf 0.28 [petrol–EtOAc
(1 : 1)]; νmax (KBr)/cmϪ1 3360 (O–H), 1695 (C᎐O); δ (400 MHz,
CDCl3, 60 ЊC, rotamers) 7.60–7.58 (2H, m, Ar–H), 7.43–7.34
(4H, m, Ar–H), 7.26–7.19 (4H, m, Ar–H), 4.88–4.86 (1H, m,
BocNCHCH2), 4.35–4.32 (1H, m, NCHAHBN), 3.75–3.74 (1H,
m, NCHAHBN), 3.06–3.04 (1H, m, BocNCHCHAHB), 2.71–
᎐
H
cmϪ1 3345 (N–H), 1705 (C᎐O); δ (400 MHz, CDCl ) 7.43–7.41
᎐
H
3
(2H, m, Ar–H), 7.33–7.29 (2H, m, Ar–H), 7.26–7.20 (1H, m,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 3 2 – 1 5 4 4
1539

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Ar–H), 4.94 (1H, br s, N–H), 3.12–3.11 (2H, m, BocNCH2-
CH2), 2.44–2.41 (2H, m, BocNCH2CH2), 1.44 [15H, br s,
C(CH3)3 & CPh(CH3)2]; δC(100 MHz, CDCl3) 156.1, 147.6,
128.2, 126.3, 125.7, 79.0, 55.6, 42.7, 41.3, 29.6, 28.4; Found
(ES): MHϩ, 279.2073. C16H27N2O2 requires MH, 279.2072; m/z
(CI) 279 (3%, MHϩ), 119 (100, ϩCMe2Ph) (Found C, 69.2; H,
9.35; N, 10.25. C16H26N2O2 requires C, 69.05; H, 9.4; N,
10.05%).
(1H, m, CH2CHSiMe3), 2.81–2.75 (2H, m, NCH2CHSiMe3),
2.63–2.57 (1H, m, NCHMe2), 1.44 [9H, s, C(CH3)3], 1.04–1.00
[6H, m, NCH(CH3)2], 0.06 [9H, s, Si(CH3)3]; δC(100 MHz,
CDCl3) 156.6, 79.0, 48.6, 48.1, 41.5, 28.4, 23.1, 22.7, Ϫ3.1;
Found (ES): MHϩ, 275.2152. C13H31N2O2Si requires MH,
275.2155; m/z (CI) 275 (100%, MHϩ), 219 (74, MHϩ Ϫ C4H8)
(Found: C, 57.05; H, 11.1; N, 9.85. C13H30N2O2Si requires C,
56.9; H, 11.0; N, 10.2%).
3-(1-Methyl-1-phenylethyl)imidazolidine-1-carboxylic acid
tert-butyl ester 14
(S )-[2-Isopropylamino-1-(methyldiphenylsilyl)ethyl]carbamic
acid tert-butyl ester 18
The carbamate 13 (3.0 g, 10.78 mmol) was added to a suspen-
sion of paraformaldehyde (0.32 g, 10.78 mmol), K2CO3 (5.0 g,
36.18 mmol) and MgSO4 (5.0 g, 41.54 mmol) in CHCl3 (35 mL)
under nitrogen in a sealed tube. After 24 h at 90 ЊC, the mixture
was filtered, evaporated, added to saturated brine and extracted
with CH2Cl2 (3 × 40 mL). The combined organic extracts were
dried (Na2SO4), evaporated and purified by column chromato-
graphy on silica gel, eluting with petrol–EtOAc (4 : 1), to give
the imidazolidine 14 (2.66 g, 85%) as needles; mp 76.0–78.0 ЊC
(from hexane–EtOAc); Rf 0.29 [petrol–EtOAc (4 : 1)]; νmax
In the same way as the carbamate 17, the imidazolidine (S)-7,
E = SiMePh2 (0.5 g, 1.22 mmol), pyridine (0.30 mL, 3.66 mmol)
and malonic acid (507 mg, 4.88 mmol), gave after purification
by column chromatography on silica gel, eluting with petrol–
EtOAc (1 : 1), the carbamate 18 (326 mg, 67%) as an oil; Rf 0.23
[CH2Cl2–MeOH–NH3 (10 : 1 : 0.1)]; [α]2D5 ϩ18.6 (c 1.14 in
CHCl3); νmax (film)/cmϪ1 1695 (C᎐O); δ (400 MHz, CDCl )
᎐
H
3
7.60–7.56 (4H, m, Ar–H), 7.39–7.35 (6H, m, Ar–H), 4.46 (1H,
br s, N–H), 4.10–3.87 (1H, m, NCH2CHN), 2.90–2.86 (1H, m,
NCHAHBCHN), 2.77–2.71 (1H,
m NCHMe2), 2.67–2.62
(KBr)/cmϪ1 1690 (C᎐O); δ (400 MHz, CDCl , rotamers) 7.53–
(1H, m, NCHAHBCHN), 1.41 [9H, s, C(CH3)3], 0.97 [3H, d,
J 6.5, NCH(CH3)A(CH3)B], 0.91 [3H, d, J 6.5, NCH(CH3)A-
(CH3)B], 0.65 (3H, s, SiCH3); δC(100 MHz, CDCl3) 156.4, 135.0,
134.9, 134.6, 134.5, 129.7, 128.0, 79.2, 48.9, 47.8, 39.6, 28.3,
23.1, 22.5, Ϫ5.1; Found (CI): MHϩ, 399.2474. C23H35N2O2Si
requires MH, 399.2468; m/z (CI) 399 (100%, MHϩ), 343 (72,
MHϩ Ϫ C4H8).
᎐
H
3
7.50 (2H, m, Ar–H), 7.35 (2H, m, Ar–H), 7.24–7.22 (1H, m,
Ar–H), 4.05 & 4.00 (2H, s, NCH2N), 3.41–3.33 (2H, m, NCH2-
CH2NBoc), 2.75–2.71 (2H, m, NCH2CH2NBoc), 1.44 [15H, s,
CPh(CH3)2 & C(CH3)3]; δC(100 MHz, CDCl3, rotamers) 153.6,
146.9, 146.5, 128.1, 126.6, 126.0, 125.9, 79.5, 79.4, 61.6, 57.1,
57.0, 45.5, 44.9, 44.8, 44.4, 28.5, 24.6, 24.5; Found (ES): MHϩ,
291.2076. C17H27N2O2 requires MH, 291.2072; m/z (CI) 291
(5%, MHϩ), 119 (100, ϩCMe2Ph).
(S )-(2-Isopropylamino-1-methylethyl)carbamic acid tert-butyl
ester 19
(5RS )-5-Methyl-3-(1-methyl-1-phenylethyl)imidazolidine-1-
carboxylic acid tert-butyl ester 15
In the same way as the carbamate 17, the imidazolidine (S)-7,
E = Me (0.5 g, 2.19 mmol), pyridine (0.53 mL, 6.57 mmol) and
malonic acid (910 mg, 8.76 mmol), gave after purification by
column chromatography on silica gel, eluting with petrol–
EtOAc (1 : 1), the carbamate 19 (450 mg, 95%) as an oil; Rf 0.32
[CH2Cl2–MeOH–NH3 (10 : 1 : 0.1)]; [α]2D4 ϩ26.7 (c 0.98 in
CHCl3); νmax (film)/cmϪ1 3340 (N–H), 1700 (C᎐O); δ (400
MHz, CDCl3) 4.75 (1H, br s, N–H), 3.67–3.62 (1H, m, NCH2-
CHMe), 2.76–2.70 (1H, m, NCHMe2), 2.60–2.50 (2H, m,
NCH2CHMe), 1.39 [9H, s, C(CH3)3], 1.07 (3H, d, J 6.5, NCH2-
CHCH3), 0.98 [6H, d, J 6.5, NCH(CH3)2]; δC(100 MHz, CDCl3)
155.7, 78.9, 52.4, 48.5, 46.3, 28.4, 22.9, 19.1; Found (ES):
MNaϩ, 239.1728. C11H24N2NaO2 requires MNa, 239.1735; m/z
(CI) 217 (42%, MHϩ), 160 (100, MHϩ Ϫ C4H9) (Found: C, 61.3;
H, 11.55; N, 12.6. C11H24N2O2 requires C, 61.1; H, 11.2; N,
12.9%).
In the same way as the imidazolidine (RS)-7, E = SiMe3, the
imidazolidine 14 (100 mg, 0.34 mmol) in dry THF (1.7 mL) and
sec-BuLi (0.31 mL, 0.41 mmol, 1.3 M in cyclohexane), followed
after 6 h by Me2SO4 (0.05 mL, 0.51 mmol) gave, after purifi-
cation by column chromatography on silica gel, eluting with
petrol–EtOAc (10 : 1), the recovered starting material 14
(50 mg, 50%) and the imidazolidine 15 (50 mg, 48%) as an oil;
᎐
H
Rf 0.35 [petrol–EtOAc (10 : 1)]; νmax (film)/cmϪ1 1700 (C᎐O);
᎐
δH(400 MHz, CDCl3, rotamers) 7.53–7.51 (2H, m, Ar–H), 7.33–
7.30 (2H, m, Ar–H), 7.26–7.22 (1H, m, Ar–H), 4.10–3.88 (2H,
m, NCH2N), 3.79–3.71 (1H, m, BocNCHCH2), 2.85–2.81 (1H,
m, BocNCHCHAHB), 2.41–2.38 (1H, m, BocNCHCHAHB),
1.49 [9H, s, C(CH3)3], 1.42 [6H, s, C(CH3)2Ph], 1.26–1.22 (3H,
m, CH3CHNBoc); δC(100 MHz, CDCl3, rotamers) 153.7, 147.1,
128.1, 126.5, 126.0, 79.3, 62.1, 56.7, 52.7, 52.1, 28.5, 25.0, 24.9,
24.0, 23.9, 19.8, 19.3; Found (ES): MHϩ, 305.2231. C18H29N2O2
requires MH, 305.2229; m/z (CI) 305 (3%, MHϩ), 119 (100,
ϩCMe2Ph).
(R)-(2-Isopropylamino-1-phenylcarbamoylethyl)carbamic acid
tert-butyl ester 20
In the same way as the carbamate 17, the imidazolidine (R)-7,
E = CONHPh (0.4 g, 1.2 mmol), pyridine (0.29 mL, 3.6 mmol)
and malonic acid (500 mg, 4.8 mmol), gave after purification by
column chromatography on silica gel, eluting with petrol–
EtOAc (1 : 1), the carbamate 20 (317 mg, 82%) as an oil; Rf 0.37
[CH2Cl2–MeOH–NH3 (10 : 1 : 0.1)]; [α]2D3 Ϫ2.1 (c 1.01 in
CHCl3); νmax (film)/cmϪ1 3305 (N–H), 1675 (C᎐O); δ (400
MHz, CDCl3) 10.50 (1H, br s, N–H), 7.52–7.49 (2H, m, Ar–H),
7.32–7.28 (2H, m, Ar–H), 7.10–7.06 (1H, m, Ar–H), 5.79 (1H,
br s, N–H), 4.13–4.08 (1H, m, NCH2CHN), 3.29–3.26 (1H, m,
NCHAHBCHN), 2.91–2.85 (1H, m, NCHMe2), 2.69–2.63 (1H,
m, NCHAHBCHN), 1.47 [9H, s, C(CH3)3], 1.16–1.11 [6H, m,
NCH(CH3)2]; δC(100 MHz, CDCl3, rotamers) 169.5, 156.0,
138.1, 129.0, 124.0, 119.7, 119.6, 80.0, 53.5, 52.5, 48.9, 48.7,
28.3, 23.2, 22.8; Found (ES): MHϩ, 322.2127. C17H28N3O3
requires MH, 322.2130; m/z (CI) 322 (100%, MHϩ) (Found: C,
63.6; H, 8.6; N, 13.0. C17H27N3O3 requires C, 63.55; H, 8.5; N,
13.05%).
(1S )-(2-Isopropylamino-1-trimethylsilylethyl)carbamic acid
tert-butyl ester 17
To the imidazolidine (S)-7, E = SiMe3 (500 mg, 1.12 mmol) in
EtOH (15 mL) under nitrogen was added pyridine (0.42 mL,
5.25 mmol) and malonic acid (734 mg, 7.00 mmol) and the
mixture was heated under reflux. After 2 h, the mixture
was cooled, evaporated and the remainder of the pyridine was
removed by azeotroping with toluene. Water (10 mL)
was added and the mixture was basified to ∼ pH 14 with 2 M
NaOH(aq) (10 mL). The mixture was extracted with CH2Cl2
(3 × 50 mL) and the combined CH2Cl2 extracts were dried
(Na2SO4), evaporated and purified by column chromatography
on silica gel, eluting with petrol–EtOAc (1 : 1), to give the carb-
amate 17 (408 mg, 85%) as an oil; Rf 0.36 [CH2Cl2–MeOH–NH3
(10 : 1 : 0.1)]; [α]2D5 ϩ20.5 (c 1.05 in CHCl3); νmax (film)/cmϪ1 1685
᎐
H
(C᎐O); δ (400 MHz, CDCl ) 4.43 (1H, br s, N–H), 3.24–3.19
᎐
H
3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 3 2 – 1 5 4 4
1540

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(RS )-[1-(Isopropylaminomethyl)but-3-enyl]carbamic acid
tert-butyl ester 21
(R)-2-Amino-3-isopropylamino-N-phenylpropionamide 25
In the same was as the diamine 22, the carbamate 20 (300 mg,
0.93 mmol) and TFA (1.4 mL, 18.36 mmol) gave, after purifi-
cation by column chromatography on silica gel, eluting with
CH2Cl2–MeOH–NH3 (10 : 1 : 0.1), the diamine 25 (184 mg,
89%) as an oil; Rf 0.1 [CH2Cl2–MeOH–NH3 (10 : 1 : 0.1)]; [α]2D6
ϩ16.9 (c 1.36 in CHCl3); νmax (film)/cmϪ1 3290 (N–H), 1675
(C᎐O); δ (400 MHz, CDCl ) 10.20 (1H, br s, NHC᎐O),
In the same way as the carbamate 17, the imidazolidine (RS)-7,
E = allyl (0.4 g, 1.57 mmol), pyridine (0.38 mL, 4.72 mmol) and
malonic acid (660 mg, 6.29 mmol), gave after purification by
column chromatography on silica gel, eluting with petrol–
EtOAc (1 : 1), the carbamate 21 (370 mg, 96%) as an oil; Rf 0.34
[CH2Cl2–MeOH–NH3 (10 : 1 : 0.1)]; νmax (film)/cmϪ1 3340
᎐
᎐
H
3
(N–H), 1700 (C᎐O); δ (400 MHz, CDCl ) 5.79–5.72 (1H,
7.58–7.57 (2H, m, Ar–H), 7.54–7.27 (2H, m, Ar–H), 7.08–7.04
(1H, m, Ar–H), 3.43–3.40 (1H, m, NCH2CHN), 2.96–2.91
(1H, m, NCHAHBCHN), 2.81–2.76 (2H, m, NCHAHBCHN &
NCHMe2), 1.78 (3H, br s, N–H), 1.06 [6H, d, J 6.0, NCH-
(CH3)2]; δC(100 MHz, CDCl3) 172.6, 138.1, 128.8, 123.9, 119.4,
54.8, 50.5, 48.8, 23.1; Found (ES): MHϩ, 1222.1606. C12H20N3O
requires MH, 222.1606; m/z (CI) 222 (100%, MHϩ).
᎐
H
3
m, H C᎐CH ), 5.08–5.01 (2H, m, H C᎐CH), 4.70 (1H, br s,
᎐
᎐
2
2
N–H), 3.68–3.60 (1H, m, NCH2CH ), 2.77–2.70 (1H, m,
NCHMe2), 2.65–2.56 (2H, m, NCH2CH), 2.24–2.21 (2H, m,
H C᎐CHCH ), 1.41 [9H, s, C(CH ) ], 1.00 [6H, d, J 6.0,
᎐
2
2
3 3
NCH(CH3)2]; δC(100 MHz, CDCl3) 155.7, 134.6, 117.4, 79.0,
50.0, 48.5, 37.6, 28.4, 23.1, 23.0; Found (ES): MHϩ, 243.2067.
C13H27N2O2 requires MH, 243.2072; m/z (CI) 243 (86%, MHϩ),
187 (100, MHϩ Ϫ C4H8) (Found: C, 64.65; H, 11.15; N, 11.45.
C13H26N2O2 requires C, 64.45; H, 10.8; N, 11.55%).
(RS )-N 1-Isopropylpent-4-ene-1,2-diamine 26
In the same was as the diamine 22, the carbamate 21 (528 mg,
2.18 mmol) and TFA (3.3 mL, 43.58 mmol) gave, after purifi-
cation by column chromatography on silica gel, eluting with
CH2Cl2–MeOH–NH3 (10 : 1 : 0.1), the diamine 26 (269 mg,
87%) as an oil; Rf 0.08 [CH2Cl2–MeOH–NH3 (10 : 1 : 0.1)];
νmax (film)/cmϪ1 3330 (N–H); δH(400 MHz, CDCl3) 5.78–5.72
(S )-N 2-Isopropyl-1-trimethylsilylethane-1,2-diamine 22
To a solution of the carbamate 17 (200 mg, 0.73 mmol) in
CH2Cl2 (10 mL) at room temperature was added TFA (1.1 mL,
14.58 mmol). After 3 h, water (10 mL) was added and the mix-
ture was basified to ∼ pH 14 with 2 M NaOH(aq) (10 mL). The
mixture was extracted with CH2Cl2 (3 × 30 mL), the combined
organic extracts were dried (Na2SO4), evaporated and purified
by column chromatography on silica gel, eluting with CH2Cl2–
MeOH–NH3 (10 : 1 : 0.1), to give the diamine 22 (117 mg, 92%)
as an oil; Rf 0.06 [CH2Cl2–MeOH–NH3 (10 : 1 : 0.1)]; [α]2D6
ϩ22.6 (c 0.46 in CHCl3); νmax (film)/cmϪ1 3410 (N–H); δH(400
MHz, CDCl3) 2.81–2.75 (2H, m, NCHMe2 & NCHAHBCHSi),
2.48–2.42 (1H, m, NCHACHBCHSi), 2.28–2.24 (1H, m,
NCH2CHSiMe3), 1.54 (3H, br s, N–H), 1.06–1.04 [6H, m,
NCH(CH3)2], 0.05 [9H, s, Si(CH3)3]; δC(100 MHz, CDCl3) 50.8,
48.6, 41.9, 23.2, 22.9, 3.7; Found (ES): MHϩ, 175.1631.
C8H23N2Si requires MH, 175.1630; m/z (CI) 175 (82%, MHϩ),
116 (100, Mϩ Ϫ NCHMe2).
(1H, m, H C᎐CH ), 5.08–5.02 (2H, m, H C᎐CH), 2.82–2.79
᎐
᎐
2
2
(1H, m, NCH2CH ), 2.75–2.69 (1H, m, NCHMe2), 2.63 (1H,
dd, J 11.5, 4.0, NCHAHBCH), 2.33 (1H, dd, J 11.5, 8.5,
NCHAHBCH), 2.18–2.15 (1H, m, H C᎐CHCHAHB), 1.99–1.95
᎐
2
(1H, m, H C᎐CHCHAHB), 1.30 (3H, br s, N–H), 1.01 [6H, d,
᎐
2
J 4.5, NCH(CH3)2]; δC(100 MHz, CDCl3) 135.5, 117.2, 53.8,
50.8, 48.8, 41.0, 23.1, 23.0; Found (ES): MHϩ, 143.1548.
C8H19N2 requires MH, 143.1548; m/z (CI) 143 (100%, MHϩ).
(1S,2R)-3,3,3-Trifluoro-N-(2-isopropylamino-1-trimethylsilyl-
ethyl)-2-methoxy-2-phenylpropionamide 27, E = SiMe3
To Mosher’s acid chloride [(S)-(Ϫ)-MTPA-Cl] (108 mg, 0.43
mmol) and Et3N (0.079 mL, 0.57 mmol) in dry CH2Cl2 (2 mL)
under nitrogen at Ϫ50 ЊC was added the diamine (S)-22 (51 mg,
0.29 mmol). After 2 h, the mixture was warmed to room tem-
perature and after 18 h, saturated NaHCO3(aq) (25 mL) was
added. The mixture was extracted with CH2Cl2 (3 × 25 mL), the
combined organic extracts were dried (Na2SO4), evaporated
and purified by column chromatography on silica gel, eluting
with petrol–EtOAc (1 : 1), to give the amide (1S,2R)-27,
E = SiMe3 (105 mg, 93%) as an oil, as an inseparable mixture of
diastereomers (for diastereomer ratio measurements, the NMR
spectra and GCMS were taken on the crude reaction mixture);
Rf 0.41 [CH2Cl2–MeOH–NH3 (10 : 1 : 0.1)]; νmax (film)/cmϪ1
(S )-N 2-Isopropyl-1-(methyldiphenylsilyl)ethane-1,2-diamine 23
In the same was as the diamine 22, the carbamate 18 (460 mg,
1.16 mmol) and TFA (1.7 mL, 23.12 mmol) gave, after purifi-
cation by column chromatography on silica gel, eluting with
CH2Cl2–MeOH–NH3 (10 : 1 : 0.1), the diamine 23 (343 mg,
99%) as an oil; Rf 0.11 [CH2Cl2–MeOH–NH3 (10 : 1 : 0.1)]; [α]2D6
ϩ22.5 (c 0.53 in CHCl3); νmax (film)/cmϪ1 2965 (C–H); δH(400
MHz, CDCl3) 7.62–7.58 (4H, m, Ar–H), 7.39–7.36 (6H, m, Ar–
H), 2.95 (1H, dd, J 11.0, 3.0, NCH2CHN), 2.86 (1H, dd, J 12.0,
3.0, NCHAHBCHN), 2.77–2.70 (1H, m, NCHMe2), 2.57 (1H,
dd, J 12.0, 11.0, NCHAHBCHN), 1.45 (3H, br s, N–H), 1.02–
0.96 [6H, m, NCH(CH3)2], 0.64 (3H, s, SiCH3); δC(100 MHz,
CDCl3) 135.3, 135.2, 135.0, 134.9, 129.5, 129.4 & 128.0, 50.8,
48.5, 40.5, 23.1, 22.8, Ϫ6.4; Found (CI): MHϩ, 299.1946.
C18H27N2Si requires MH, 299.1943; m/z (CI) 299 (100%, MHϩ).
3405 (N–H), 1685 (C᎐O); δ (400 MHz, CDCl ) 7.61–7.55
᎐
H
3
(2H, m, Ar–H), 7.41–7.38 (3H, m, Ar–H), 6.81 (1H, br s,
N–H), 3.65–3.57 (1H, m, NCH2CHSiMe3), 3.47 (2.8H, s,
OCH3), 3.39 (0.2H, s, OCH3), 2.84–2.69 (3H, m, NCH2-
CHSiMe3 & NCHMe2), 1.45 (1H, br s, N–H), 1.03–0.95 [6H,
m, NCH(CH3)2], 0.10 [8.5H, s, Si(CH3)3], 0.03 [0.5H, s,
Si(CH3)3]; δC(100 MHz, CDCl3) 166.0, 133.0, 132.9, 129.3,
128.5, 128.4, 127.9, 127.5, 84.9, 84.7, 55.0, 54.9, 48.1, 48.0,
47.8, 40.9, 40.8, 23.2, 22.6, Ϫ2.8, Ϫ3.0; δF(376 MHz, CDCl3)
95.6 (minor CF3) & 95.4 (major CF3); Found (ES): MHϩ,
391.2028. C18H30F3N2O2Si requires MH, 391.2028; m/z (CI) 391
(100%, MHϩ). The diastereomer ratio of 27, E = SiMe3 was
determined to be 93 : 7 by 1H and 19F NMR and GCMS
analysis.
(S )-N 1-Isopropylpropane-1,2-diamine 24
In the same was as the diamine 22, the carbamate 19 (175 mg,
0.81 mmol) and TFA (1.2 mL, 16.18 mmol) gave, after purifi-
cation by column chromatography on silica gel, eluting with
CH2Cl2–MeOH–NH3 (10 : 1 : 0.1), the diamine 24 (65 mg, 69%)
as an oil; Rf 0.01 [CH2Cl2–MeOH–NH3 (10 : 1 : 0.1)]; [α]2D4
ϩ40.0 (c 0.11 in CHCl3); νmax (film)/cmϪ1 3420 (N–H); δH(400
MHz, CDCl3) 2.96–2.91 (1H, m, NCHMe2), 2.80–2.74 (1H, m,
NCH2CHMe), 2.60 (1H, dd, J 11.5, 4.5, NCHAHBCHMe), 2.32
(1H, dd, J 11.5, 4.5, NCHAHBCHMe), 1.59 (3H, br s, N–H),
1.07–1.04 [9H, m, NCH(CH3)2 & NCH2CHCH3]; δC(100 MHz,
CDCl3) 55.8, 48.8, 47.0, 23.1, 23.0, 22.2; Found (ES): MHϩ,
117.1392. C6H17N2 requires MH, 117.1391; m/z (CI) 117 (100%,
MHϩ).
(1S,2R)-3,3,3-Trifluoro-N-[2-isopropylamino-1-(methyldiphenyl-
silyl)ethyl]-2-methoxy-2-phenylpropionamide 27, E = SiMePh2
In the same way as amide 27, E = SiMe3, the diamine (S)-23
(85 mg, 0.29 mmol), (S)-(Ϫ)-MTPA-Cl (108 mg, 0.43 mmol)
and Et3N (0.079 mL, 0.57 mmol), gave the Mosher amide
(1S,2R)-27, E = SiMePh2 (138 mg, 93%) as an oil; Rf 0.47
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 3 2 – 1 5 4 4
1541

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[CH2Cl2–MeOH–NH3 (10 : 1 : 0.1)]; νmax (film)/cmϪ1 3400 (N–
H), 1685 (C᎐O); δ (400 MHz, CDCl ) 7.57–7.15 (15H, m, Ar–
(1H, m, NCH2CHN), 3.42 (1.6H, s, OCH3), 3.39 (1.4H, s,
OCH3), 2.78–2.65 (3H, m, NCHMe2 & NCH2CHN), 2.33–2.27
(2H, m, H C᎐CHCH ), 1.03–0.95 [6H, m, NCH(CH ) ]; δ (100
MHz, CDCl3) 166.0, 165.9, 134.2, 134.1, 133.1, 132.8, 129.3,
128.4, 127.8, 127.7, 125.3, 122.4, 117.9, 117.8, 84.3, 84.2, 83.9,
55.1, 55.0, 49.5, 48.8, 48.5, 37.1, 37.0, 23.1, 22.9; δF(376 MHz,
CDCl3) 95.2 & 95.0 (CF3); Found (ES): MHϩ, 359.1947.
C18H26F3N2O2 requires MH, 359.1946; m/z (CI) 359 (100%,
MHϩ). The diastereomer ratio of 27, E = allyl was determined
to be 50 : 50 by 1H and 19F NMR and GCMS analysis.
᎐
H
3
H), 4.37–4.30 (1H, m, NCH2CHN), 3.15 (0.2H, s, OCH3), 3.14
(2.8H, s, OCH3), 2.93–2.82 (3H, m, NCH2CHN & NCHMe2),
1.13–0.97 [6H, m, NCH(CH3)2], 0.72 (2.8H, s, SiCH3), 0.70
(0.2H, s, SiCH3); δC(100 MHz, CDCl3) 170.7, 167.1, 135.0,
134.9, 134.8, 134.0, 132.5, 130.2, 130.1, 129.4, 128.6, 128.5,
128.4, 128.3, 128.2, 127.8, 127.7, 126.5, 84.1, 83.9, 54.8, 48.3,
48.0, 47.4, 37.9, 21.7, 20.7, Ϫ5.4; δF(376 MHz, CDCl3) 93.5
(major CF3) & 92.7 (minor CF3); Found (ES): MHϩ, 515.2345.
C28H34F3N2O2Si requires MH, 515.2341; m/z (CI) 515 (100%,
MHϩ). The diastereomer ratio of 27, E = SiMePh2 was deter-
mined to be 94 : 6 by 1H and 19F NMR and GCMS analysis.
᎐
2
2
3
2
C
1-tert-Butoxycarbonyl-3-isopropylhexahydropyrimidine 28
To N-isopropyl-1,3-diaminopropane (135 mg, 1.17 mmol) in
CHCl3 (16 mL) was added MgSO4 (1 g), K2CO3 (1 g), and
paraformaldehyde (35 mg, 1.17 mmol) at room temperature.
After 24 h, di-tert-butyl dicarbonate (260 mg, 1.18 mmol) was
added. After 18 h, the mixture was filtered, evaporated and
purified by column chromatography on silica gel, eluting with
petrol–EtOAc (4 : 1 to 1 : 1), to give the carbamate 28 (230 mg,
86%) as an oil; Rf 0.22 [petrol–EtOAc (1 : 1)]; νmax (CHCl3)/cmϪ1
(1S,2R)-3,3,3-Trifluoro-N-(2-isopropylamino-1-methylethyl)-2-
methoxy-2-phenylpropionamide 27, E = Me
In the same way as amide 27, E = SiMe3, the diamine (S)-24 (33
mg, 0.29 mmol), (S)-(Ϫ)-MTPA-Cl (108 mg, 0.43 mmol) and
Et3N (0.079 mL, 0.57 mmol), gave the Mosher amide (1S,2R)-
27, E = Me (138 mg, 93%) as an oil; Rf 0.22 [CH2Cl2–MeOH–
NH3 (10 : 1 : 0.1)]; νmax (film)/cmϪ1 3325 (N–H), 1685 (C᎐O);
1695 (C᎐O); δ (400 MHz, CDCl ) 4.09 (2H, s, NCH N), 3.46
᎐
᎐
H
3
2
i
δH(400 MHz, CDCl3) 7.57–7.54 (2H, m, Ar–H), 7.40–7.36 (3H,
m, Ar–H), 7.10 (1H, br s, N–H), 4.14–4.10 (1H, m, NCH2CH ),
3.43 (0.2H, s, OCH3), 3.42 (2.8H, s, OCH3), 2.82–2.80 (1H,
m, NCHMe2), 2.73–2.67 (2H, m, NCH2CH), 2.37 (1H, br s,
N–H), 1.26–1.15 (3H, m, NCH2CHCH3), 1.06–0.95 [6H, m,
NCH(CH3)2]; δC(100 MHz, CDCl3) 166.0, 165.9, 132.9, 132.8,
129.4, 128.5, 127.6, 125.3, 122.4, 84.4, 84.3, 55.0, 54.9, 51.3,
48.6, 48.5, 45.1, 45.0, 22.8, 22.7, 22.6, 22.5, 18.5, 18.4; δF(376
MHz, CDCl3) 95.2 (minor CF3) & 95.0 (major CF3); Found
(ES): MHϩ, 333.1789. C16H24F3N2O2 requires MH, 333.1790;
m/z (CI) 333 (100%, MHϩ). The diastereomer ratio of 27, E =
(2H, br s, CONCH2CH2), 2.85–2.68 (3H, m, PrNCH2CH2
and CHCH3), 1.64–1.55 (2H, m, CH2CH2CH2), 1.48 [9H, s,
C(CH3)3], 1.09 [6H, d, J 7, CH(CH3)2]; δC(100 MHz, CDCl3)
154.3, 79.4, 62.9, 62.3, 51.2, 50.1, 48.5, 48.3, 43.9, 43.1, 28.4,
24.2, 23.4, 19.6; Found (CI): MHϩ 229.1922. C12H25N2O2
requires MH, 229.1916); m/z (CI) 229 (5%, MHϩ), 171 (100, M
t
Ϫ Bu) (Found: C, 63.1; H, 11.0; N, 12.2. C12H24N2O2 requires
C, 63.1; H, 10.6; N, 12.25%).
(RS )-1-tert-Butoxycarbonyl-3-isopropyl-6-trimethylsilylhexa-
hydropyrimidine 29, E = SiMe3
1
Me was determined to be 92 : 8 by H and 19F NMR and
To the pyrimidine 28 (75 mg, 0.33 mmol) and TMEDA (125 µL,
95 mg, 0.83 mmol) in THF (1.5 mL) was added sec-BuLi
(0.59 mL, 0.83 mmol, 1.4 M in cyclohexane) at Ϫ78 ЊC. After
5 h, TMSCl (105 µL, 90 mg, 0.83 mmol) was added and the
mixture was allowed to warm to room temperature. The mix-
ture was purified by column chromatography on silica gel, elut-
ing with petrol–EtOAc (20 : 1 to 4 : 1) to give the pyrimidine 29,
E = SiMe3 (59 mg, 60%) as an oil; Rf 0.25 [petrol–EtOAc (4 : 1)];
GCMS analysis.
(1R,2R)-3,3,3-Trifluoro-N-(2-isopropylamino-1-phenyl-
carbamoylethyl)-2-methoxy-2-phenylpropionamide 27,
E = CONHPh
In the same way as amide 27, E = SiMe3, the diamine (R)-25
(63 mg, 0.29 mmol), (S)-(Ϫ)-MTPA-Cl (108 mg, 0.43 mmol)
and Et3N (0.079 mL, 0.57 mmol), gave the Mosher amide
(1R,2R)-27, E = CONHPh (63 mg, 50%) as an oil; Rf 0.56
[CH2Cl2–MeOH–NH3 (10 : 1 : 0.1)]; νmax (film)/cmϪ1 3315
νmax (CHCl3)/cmϪ1 1675 (C᎐O); δ (400 MHz, CDCl ) 5.02
᎐
H
3
(0.3H, br s, NCH), 4.45 (0.7H, br s, NCHAHBN), 3.90 (0.7H, br
s, NCHAHBN), 3.62 (0.3H, br s, NCH), 3.45 (0.7H, br s,
NCHSi), 3.34 (0.3H, br s, NCH), 3.00–2.65 (3H, m, CH2CH2N
and CHCH3), 2.15–1.82 (1H, m, CHCHDCH2N), 1.58 (1H, dq,
J 13 and 4, CHCHDCH2N), 1.44 [9H, s, C(CH3)3], 1.08 (3H, d,
J 6.5, CHCH3), 1.06 (3H, d, J 6.5, CHCH3), 0.08 [9H, s,
Si(CH3)3]; δC(100 MHz, CDCl3) 154.5, 79.3, 62.2, 60.3, 50.8,
49.8, 48.0, 46.7, 44.6, 43.8, 28.4, 23.8, 19.7, Ϫ1.0; Found (EI):
Mϩ, 300.2232. C15H32N2O2Si requires M, 300.2233; m/z (EI)
300 (0.8%, Mϩ), 57 (100, Bu).
(N–H), 1675 (C᎐O); δ (400 MHz, CDCl ) 10.65 (1H, br s,
᎐
H
3
N–H), 7.94 (1H, s, N–H), 7.55–7.10 (10H, m, Ar–H), 4.44–4.41
(1H, m, NCH2CHN), 3.53 (2.6H, s, OCH3), 3.41 (0.4H, s,
OCH3), 3.33–3.27 (1H, m, NCHAHBCHN), 2.93–2.87 (1H, m,
NCHMe2), 2.78–2.59 (1H, m, NCHAHBCHN), 1.76 (1H, br s,
N–H), 1.15–0.89 [6H, m NCH(CH3)2]; δC(100 MHz, CDCl3)
169.5, 168.5, 137.9, 137.5, 132.8, 131.9, 129.6, 129.2, 128.7,
127.9, 127.4, 125.1, 122.2, 120.4, 119.6, 119.4, 84.4, 84.3, 84.1,
83.9, 55.3, 54.9, 52.2, 52.1, 48.9, 48.8, 47.8, 47.5, 23.2, 22.6;
δF(376 MHz, CDCl3) 93.0 (major CF3) & 92.7 (minor CF3);
Found (ES): MHϩ, 438.2005. C22H27F3N3O3 requires MH,
438.2004; m/z (CI) 438 (100%, MHϩ). The diastereomer ratio of
(RS )-1-tert-Butoxycarbonyl-3-isopropyl-6-tributylstannylhexa-
hydropyrimidine 29, E = SnBu3
27, E = CONHPh was determined to be 86 : 14 by 1H and 19
NMR analysis.
F
In the same way as the pyrimidine 29, E = SiMe3, the pyrim-
idine 28 (75 mg, 0.33 mmol), TMEDA (125 µL, 95 mg,
0.83 mmol), THF (1.5 mL), sec-BuLi (0.59 mL, 0.83 mmol, 1.4
M in cyclohexane) and Bu3SnCl (225 µL, 270 mg, 0.83 mmol)
gave, after purification by column chromatography on silica gel,
eluting with petrol–EtOAc (50 : 1 to 9 : 1), the pyrimidine 29, E
= SnBu3 (110 mg, 64%) as an oil; Rf 0.50 [petrol–EtOAc (9 : 1)];
(1R,2S )-3,3,3-Trifluoro-N-[1-(isopropylaminomethyl)but-3-
enyl]-2-methoxy-2-phenylpropionamide 27, E ؍ allyl
In the same way as amide 27, E = SiMe3, the diamine (S)-26 (41
mg, 0.29 mmol), (S)-(Ϫ)-MTPA-Cl (108 mg, 0.43 mmol) and
Et3N (0.079 mL, 0.57 mmol), gave the Mosher amide (1R,2S)-
27, E = allyl (56 mg, 54%) as an oil; Rf 0.41 [CH2Cl2–MeOH–
NH3 (10 : 1 : 0.1)]; νmax (film)/cmϪ1 3410 & 3335 (N–H), 1690
νmax (CHCl3)/cmϪ1 1675 (C᎐O); δ (300 MHz, CDCl ) 5.11
᎐
H
3
(0.3H, d, J 11, NCH), 4.32 (0.7H, d, J 11.5, NCH2N), 4.08 (1H,
d, J 11.5, NCH2N), 3.42 (0.7H, dd, J 8 and 5, NCHSn), 3.12
(0.3H, d, J 11), 3.06–3.00 (0.3H, m), 2.90–2.70 (3H, m,
NCH2CH2 and CHCH3), 1.90–1.20 [23H, m, CH2CH2N,
C(CH3)3 and Sn(CH2CH2CH2)3], 1.14–1.09 [6H, m, CH(CH3)2],
0.98–0.81 [15H, m, Sn(CH2CH2CH2CH3)3]; δC(75 MHz,
(C᎐O); δ (400 MHz, CDCl ) 7.58–7.56 (2H, m, Ar–H), 7.40–
᎐
H
3
7.38 (3H, m, Ar–H), 7.10–6.85 (1H, br s, N–H), 5.80–5.69 (1H,
m, H C᎐CHCH ), 5.14–5.00 (2H, m, H C᎐CHCH ), 4.10–4.08
᎐
᎐
2
2
2
2
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 3 2 – 1 5 4 4
1542

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CDCl3) 154.5, 79.4, 64.0, 50.3, 50.1, 45.0, 29.2, 28.3, 28.2, 27.6,
20.0, 19.3, 13.6, 11.0; Found (CI): MHϩ, 519.2986. C24H51-
N2O2120Sn requires MH, 519.2972); m/z (CI) 519 (100%, MHϩ).
80.3, 62.5, 60.1, 57.5, 56.5, 51.1, 49.4, 43.9, 29.4, 27.5, 28.1,
27.9, 20.1, 19.7; Found (CI): MHϩ, 337.1953. C18H29N2O2S
requires MH, 337.1950); m/z (CI) 337 (16%, MHϩ), 227 (100,
Mϩ Ϫ SPh).
(RS )-1-tert-Butoxycarbonyl-6-diphenylmethylsilyl-3-isopropyl-
hexahydropyrimidine 29, E = SiMePh2
(RS )-6-Isopropyl-1,1-diphenylhexahydrooxazolo[3,4-c]-
pyrimidin-3-one 30
In the same way as the pyrimidine 29, E = SiMe3, the pyrim-
idine 28 (75 mg, 0.33 mmol), TMEDA (125 µL, 95 mg,
0.83 mmol), THF (1.5 mL), sec-BuLi (0.59 mL, 0.83 mmol,
1.4 M in cyclohexane) and Ph2MeSiCl (263 µL, 288 mg,
0.83 mmol) gave, after purification by column chromatography
on silica gel, eluting with petrol–EtOAc (20 : 1 to 4 : 1), the
pyrimidine 29, E = SiMePh2 (89 mg, 64%) as an oil; Rf 0.18
[petrol–EtOAc (4 : 1)]; νmax (film)/cmϪ1 1685 (C᎐O); δ (400
MHz, CDCl3) 7.67–7.53 (4H, m, ArH), 7.45–7.28 (6H, m,
ArH), 4.98 (0.3H, br s, NCH2N), 4.51–4.37 (1H, m, NCH2N
and NCHSi), 4.22 (0.7H, br s, NCHSi), 3.91 (0.7H, d, J 11,
NCH2N), 3.40 (0.3H, br s, NCH2N), 2.80–2.50 (3H, m,
NCH2CH2 and CHCH3), 2.10–1.93 (1H, m, CH2CH2N), 1.79–
1.67 (1H, m, CH2CH2N), 1.43 [9H, s, C(CH3)3], 1.02 (3H, d, J 7,
CHCH3), 0.97 (3H, d, J 7, CHCH3), 0.70 (3H, s, SiCH3); δC(100
MHz, CDCl3) 154.5, 137.3, 136.4, 135.1, 134.8, 129.2, 129.1,
127.9, 127.7, 79.6, 61.9, 60.0, 50.8, 49.6, 47.5, 45.9, 42.7, 42.1,
28.3, 24.4, 23.8, 19.7, 19.6, Ϫ3.1, Ϫ3.6; Found (FI): Mϩ,
424.2542. C25H36N2O2Si requires M, 424.2546); m/z (FI) 424
(100%, Mϩ).
In the same way as the pyrimidine 29, E = SiMe3, the pyrim-
idine 28 (75 mg, 0.33 mmol), TMEDA (125 µL, 95 mg, 0.83
mmol), THF (1.5 mL), sec-BuLi (0.59 mL, 0.83 mmol, 1.4 M in
cyclohexane) and Ph2CO (150 mg, 0.83 mmol, in THF, 0.5 mL)
gave, after purification by column chromatography on silica gel,
eluting with petrol–EtOAc (9 : 1 to 1 : 1), the amide 30 (63 mg,
57%) as an oil; Rf 0.35 [petrol–EtOAc (1 : 1)]; νmax (CHCl3)/cmϪ1
᎐
H
1760 (C᎐O); δ (400 MHz, CDCl ) 7.54–7.52 (2H, m, ArH),
᎐
H
3
7.38–7.24 (8H, m, ArH), 4.70 (1H, dd, J 11.5 and 2,
NCHAHBN), 4.38 (1H, dd, J 11.5 and 4, PhCCH), 3.58 (1H, d,
J 11.5, NCHAHBN), 3.04 (1H, dq, J 12.5 and 2, NCHCHD-
CH2), 2.77 (1H, septet, J 6.5, CHCH3), 2.48 (1H, td, J 12.5 and
2, NCHCHDCH2), 1.40–1.22 (2H, m, NCH2CH2), 1.09 (3H, d,
J 6.5, CH3), 1.02 (3H, d, J 6.5, CH3); δC(100 MHz, CDCl3)
156.2, 142.6, 139.2, 128.5, 128.4, 128.2, 127.7, 126.0, 125.9,
86.0, 62.0, 60.3, 51.2, 46.7, 27.3, 19.3, 19.2; Found (FI): Mϩ,
336.1832. C21H24N2O2 requires M, 336.1838); m/z (FI) 336
(100%, Mϩ).
(RS )-1-tert-Butoxycarbonyl-3-isopropyl-2-trimethylsilylhexa-
hydropyrimidine 31
(RS )-6-Allyl-1-tert-butoxycarbonyl-3-isopropylhexahydro-
pyrimidine 29, E ؍ allyl
To the pyrimidine 28 (60 mg, 0.26 mmol) and TMEDA (105 µL,
80 mg, 0.70 mmol) in THF (0.4 mL) was added sec-BuLi
(0.47 mL, 0.70 mmol, 1.4 M in cyclohexane) at Ϫ78 ЊC. After
5 h TMSCl (85 µL, 76 mg, 0.70 mmol) was added and the
mixture was allowed to warm to room temperature. The mix-
ture was purified by column chromatography on silica gel, elut-
ing with petrol–EtOAc (20 : 1 to 4 : 1), to give the pyrimidine 31
(22 mg, 28%) as an oil; Rf 0.25 [petrol–EtOAc (4 : 1)]; νmax
In the same way as the pyrimidine 29, E = SiMe3, the pyrim-
idine 28 (75 mg, 0.33 mmol), TMEDA (125 µL, 95 mg,
0.83 mmol), THF (1.5 mL), sec-BuLi (0.59 mL, 0.83 mmol,
1.4 M in cyclohexane) and allyl bromide (71 µL, 100 mg,
0.83 mmol) gave, after purification by column chromatography
on silica gel, eluting with petrol–EtOAc (4 : 1), the pyrimidine
29, E = allyl (37 mg, 42%) as an oil; Rf 0.32 [petrol–EtOAc
(CHCl3)/cmϪ1 1675 (C᎐O); δ (400 MHz, CDCl ) 5.84–5.63
(1 : 1)]; νmax (CHCl3)/cmϪ1 1690 (C᎐O); δ (400 MHz, CDCl )
᎐
H
3
᎐
H
3
(1H, m, SiCH), 4.83–4.61 (1H, m, CHAHBNCO), 3.95–3.65
(1H, m, CHAHBNCO), 2.96–2.73 (3H, m, CH2NCHCH3),
1.96–1.82 (2H, m, CH2CH2CH2), 1.46 [9H, s, C(CH3)3], 1.11
(3H, d, J 6.5, CHCH3), 1.08 (3H, d, J 6.5, CHCH3), 0.12 [9H, s,
Si(CH3)3]; δC(100 MHz, CDCl3) 153.2, 80.0, 74.5, 73.6, 57.2,
56.5, 50.8, 49.2, 42.5, 31.5, 30.4, 28.4, 19.9, 0.0; Found (EI):
MHϩ, 301.2320. C15H33N2O2Si requires MH, 301.2311); m/z
(EI) 301 (12%, MHϩ), 125 (100).
5.72 (1H, ddt, J 16.5, 10 and 6.5, ᎐CH), 5.05 (1H, d, J 16.5,
᎐
᎐CHAHB), 5.02 (1H, d, J 10, ᎐CHAHB), 4.85 (1H, d, J 11.5,
᎐
᎐
NCHCHDN), 4.26 (1H, br s, NCHCH2), 3.54 (1H, d, J 11.5,
NCHCHDN), 2.88–2.82 (1H, m, NCHEHFCH2), 2.78 (1H,
septet, J 6.5, CHCH3), 2.64 (1H, br t, J 12, NCHEHFCH2)
2.45–2.37 (1H, m, ᎐CHCHGHH), 2.30–2.23 (1H, m, ᎐CHCHG-
᎐
᎐
HH), 1.99–1.89 (1H, m, NCH2CHIHJ), 1.44 [10H, m, C(CH3)3
and NCH2CHIHJ], 1.08 (3H, d, J 6.5, CHCH3), 1.06 (3H, d,
J 6.5, CHCH3); δC(100 MHz, CDCl3) 154.4, 135.1, 116.9, 79.5,
57.4, 50.4, 48.9, 43.4, 34.7, 28.4, 25.3, 19.7; Found (CI): MHϩ,
269.2227. C15H29N2O2 requires MH, 269.2229); m/z (CI) 269
(56%, MHϩ), 211 (100, Mϩ Ϫ C4H9).
(RS )-N 1-tert-Butoxycarbonyl-N 2-isopropyl-1-trimethylsilyl-1,3-
propanediamine 32, E = SiMe3
In the same way as the carbamate 17, the pyrimidine 29,
E = SiMe3 (63 mg, 0.21 mmol), malonic acid (87 mg, 0.84
mmol) and pyridine (51 µL, 0.62 mmol), gave the carbamate 32,
E = SiMe3 (52 mg, 86%) as an oil; νmax (CHCl3)/cmϪ1 3420
(RS )-1-tert-Butoxycarbonyl-3-isopropyl-6-phenylthiohexa-
hydropyrimidine 29, E = SPh
(NH), 1695 (C᎐O); δ (300 MHz, CDCl ) 4.30 (1H, br d, J 11,
᎐
H
3
In the same way as the pyrimidine 29, E = SiMe3, the pyrim-
idine 28 (75 mg, 0.33 mmol), TMEDA (125 µL, 95 mg, 0.83
mmol), THF (1.5 mL), sec-BuLi (0.59 mL, 0.83 mmol, 1.4 M in
cyclohexane) and PhSSPh–MeI [PhSSPh (180 mg, 0.83 mmol)
aged with MeI (51 µL, 42 mg, 0.83 mmol) in THF (1 mL) at
room temperature for 1 h] gave, after purification by column
chromatography on silica gel, eluting with petrol–EtOAc (9 : 1
to 4 : 1), the pyrimidine 29, E = SPh (43 mg, 39%) as an oil; Rf
SiCH), 3.12 (1H, m, CHAHBNiPr), 2.72–2.51 (3H, m, CHCHD-
CHAHBNCH ), 1.67 (1H, m, CHCHDCH2NiPr), 1.37 [9H, s,
C(CH3)3], 1.03 (3H, d, J 6.5, CHCH3), 1.01 (3H, d, J 6.5,
CHCH3), Ϫ0.02 [9H, s, Si(CH3)3]; δC(75 MHz, CDCl3) 156.6,
79.0, 48.7, 44.5, 38.1, 31.5, 28.4, 22.8, Ϫ3.6; Found (CI): MHϩ,
289.2312. C14H33N2O2Si requires MH, 289.2311); m/z (CI) 289
(22%, MHϩ), 233 (100, MHϩ Ϫ C4H8).
0.74 [petrol–EtOAc (1 : 1)]; νmax (CHCl3)/cmϪ1 1685 (C᎐O);
᎐
(RS )-N 1-tert-Butoxycarbonyl-N 2-isopropyl-1-allyl-1,3-propane-
diamine 32, E ؍ allyl
δH(400 MHz, CDCl3) 7.49–7.46 (2H, m, ArH), 7.25–7.22 (3H,
m, ArH), 6.01 and 5.74 (1H, 2 × br s, NCHS), 4.95 and 4.75
(1H, 2 × br d, J 8.5, NCHAHBN), 4.12 and 3.98 (1H, 2 × br d, J
8.5, NCHAHBN), 3.03–2.81 (3H, m, NCH2CH2 and CHCH3),
2.26–2.16 (1H, m, NCH2CHCHD), 1.82–1.64 (1H, m, NCH2-
CHCHD), 1.31–1.12 (15H, m, 5 × CH3); δC(100 MHz, CDCl3)
153.2, 153.0, 135.0, 133.8, 133.4, 133.0, 128.9, 128.2, 127.6,
In the same way as the carbamate 17, the pyrimidine 29,
E = allyl (67 mg, 0.25 mmol), malonic acid (103 mg, 1.0 mmol)
and pyridine (61 µL, 0.74 mmol), gave the carbamate 32,
E = allyl (64 mg, 100%) as an oil; νmax (CHCl3)/cmϪ1 3420 (NH),
1705 (C᎐O); δ (400 MHz, CDCl ) 5.74 (1H, ddt, J 16.5, 11 and
᎐
H
3
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1543

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7.5, ᎐CH), 5.07 (1H, d, J 16.5, ᎐CHAHB), 5.06 (1H, d, J 11,
᎐
CH2CH2CH ), 2.75 (1H, septet, J 6.5, CHCH3), 2.68–2.56 (2H,
Jimeno, J. Gavenonis, P. J. Carroll and P. J. Walsh, J. Am. Chem.
᎐
᎐
᎐CHAHB), 4.80 (1H, br d, J 8, NH), 3.77–3.66 (1H, m,
Soc., 2002, 124, 6929; A. Klapars, X. Huang and S. L. Buchwald,
J. Am. Chem. Soc., 2002, 124, 7421; M. Nakadai, S. Saito and
H. Yamamoto, Tetrahedron, 2002, 58, 8167; C. Maillet, T. Praveen,
P. Janvier, S. Minguet, M. Evain, C. Saluzzo, M. L. Tommasino and
B. Bujoli, J. Org. Chem., 2002, 67, 8191; see also F. Fache, E. Schulz,
M. L. Tommasino and M. Lemaire, Chem. Rev., 2000, 100, 2159;
Y. L. Bennani and S. Hanessian, Chem. Rev., 1997, 97, 3161.
3 P. Beak, A. Basu, D. J. Gallagher, Y. S. Park and S. Thayumanavan,
Acc. Chem. Res., 1996, 29, 552; S. V. Kessar and P. Singh,
Chem. Rev., 1997, 97, 721; R. E. Gawley, Curr. Org. Chem., 1997, 1,
71; for previous work in our group, see for example, I. Coldham,
R. Hufton and D. J. Snowden, J. Am. Chem. Soc., 1996, 118,
5322; I. Coldham and R. Hufton, Tetrahedron, 1996, 52, 12541;
N. J. Ashweek, I. Coldham, D. J. Snowden and G. P. Vennall,
Chem. Eur. J., 2002, 8, 195; I. Coldham, S. Dufour, T. F. N. Haxell,
S. Howard and G. P. Vennall, Angew. Chem., Int. Ed., 2002, 41, 3887.
4 I. Coldham, P. M. A. Houdayer, R. A. Judkins and D. R. Witty,
Synthesis, 1998, 1463.
5 I. Coldham, R. A. Judkins and D. R. Witty, Tetrahedron, 1998, 54,
14255.
6 A. R. Katritzky, R. Murugan, H. Luce, M. Zerner and G. P. Ford,
J. Chem. Soc., Perkin Trans. 2, 1987, 1695.
7 E. Pfammatter and D. Seebach, Liebigs Ann. Chem., 1991, 1323;
D. Seebach, E. Pfammatter, V. Gramlich, T. Bremi, F. Kühnle,
S. Portmann and I. Tironi, Liebigs Ann. Chem., 1992, 1145.
8 P. Beak, S. T. Kerrick, S. Wu and J. Chu, J. Am. Chem. Soc., 1994,
116, 3231; see also, ref. 3; D. Hoppe and T. Hense, Angew. Chem.,
Int. Ed., 1997, 36, 2283; A. Basu and S. Thayumanavan,
Angew. Chem., Int. Ed., 2002, 41, 716.
m, NCH ), 2.20 (2H, t, J 7.5, CH CH᎐), 1.73–1.60 (1H, m,
᎐
2
2
NCH2CHCHD), 1.50–1.30 [10H, m, C(CH3)3 and NCH2-
CHCHD] and 1.05 [6H, d, J 6.5, CH(CH3)2]; δC(100 MHz,
CDCl3) 155.8, 134.4, 117.7, 78.9, 48.7, 48.6, 43.9, 39.8, 34.9,
28.4, 22.9, 22.8; Found (CI): MHϩ, 257.2227. C14H29N2O2
requires MH, 257.2229); m/z (CI) 257 (63%, MHϩ), 201 (100,
MHϩ Ϫ C4H8).
(RS )-N-(3-Amino-3-trimethylsilylpropyl)isopropylamine 33
In the same way as the diamine 22, the carbamate 32, E = SiMe3
(52 mg, 0.18 mmol) and TFA (280 µL, 410 mg, 3.6 mmol) gave,
after extraction with CH2Cl2 (4 × 5 mL) and evaporation, the
diamine 33 (35 mg, 100%) as an oil; νmax (CHCl3)/cmϪ1 3290
(NH), 1680 (NH); δH(300 MHz, CDCl3) 4.17 (3H, br s, NH),
3.27 (1H, dt, J 11 and 5, NCHAHBCH2), 3.07 (1H, septet, J 6.5,
CHCH3), 3.05–2.92 (1H, m, NCHAHBCH2), 2.50 (1H, dd, J 9.5
and 5, NCHSi), 1.90–1.72 (2H, m, NCH2CH2), 1.26 [6H, d,
J 6.5, CH(CH3)2], 0.09 [9H, s, Si(CH3)3]; δC(75 MHz, CDCl3)
49.1, 46.8, 41.7, 30.4, 21.8, 21.7, Ϫ4.1; Found (CI): MHϩ,
189.1794. C9H24N2Si requires MH, 189.1787); m/z (CI) 189
(77%, MHϩ), 173 (100).
9 W. F. Bailey, P. Beak, S. T. Kerrick, S. Ma and K. B. Wiberg, J. Am.
Chem. Soc., 2002, 124, 1889.
Acknowledgements
10 For the deprotonation of related unsymmetrical cyclic substrates
with two heteroatoms, see A. I. Meyers, P. D. Edwards, W. F. Rieker
and T. R. Bailey, J. Am. Chem. Soc., 1984, 106, 3270; P. Beak and
E. K. Yum, J. Org. Chem., 1993, 58, 823; N. Kise, T. Urai and
J. Yoshida, Tetrahedron: Asymmetry, 1998, 9, 3125; R. E. Gawley,
Q. Zhang and A. T. McPhail, Tetrahedron: Asymmetry, 2000, 11,
2093.
We thank the EPSRC and GlaxoSmithKline for a CASE Award
(to T.F.N.H.), Mr Royston Copley for X-ray analysis, Mr
Matthew Sanders for some of the chiral HPLC analyses, Miss
Rosa Klein and Mr Ivan Prokes for some NMR spectroscopic
studies and the EPSRC mass spectrometry service at the
University of Wales, Swansea.
11 I. Coldham, R. C. B. Copley, T. F. N. Haxell and S. Howard,
Org. Lett., 2001, 3, 3799.
12 For copies of the NMR spectra, see the supporting information in
ref. 11.
References
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M. Benaglia, M. Caporale and L. Raimondi, Tetrahedron:
Asymmetry, 2002, 13, 2727.
2 For some recent uses of diamines as catalysts, see B. Mohar,
A. Valleix, J.-R. Desmurs, M. Felemez, A. Wagner and
C. Mioskowski, Chem. Commun., 2001, 2572; A. M. Costa, C.
13 D. Hoppe and T. Hense, Angew. Chem., Int. Ed., 1997, 36, 2283;
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14 R. K. Boeckman and J. C. Potenza, Tetrahedron Lett., 1985, 26,
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15 G. B. Henderson, J. Glushka, D. Cowburn and A. Cerami, J. Chem.
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 5 3 2 – 1 5 4 4
1544