Iodine monochloride-amine complexes: An experimental and computational approach to new chiral electrophiles

Article abstract of DOI:10.1002/chem.200500507

Lactonizations are important steps in many synthetic sequences. Sub-strate-controlled reactions that use chiral auxiliaries or chiral alkenes have already been studied in depth. This study focuses on stereoselective reagent-controlled iodolactonizations,

Full text of DOI:10.1002/chem.200500507

FULL PAPER
DOI: 10.1002/chem.200500507
Iodine Monochloride–Amine Complexes: An Experimental and
Computational Approach to New Chiral Electrophiles
Jürgen Haas, Stewart Bissmire, and Thomas Wirth*[a]
Abstract: Lactonizations are important
steps in many synthetic sequences. Sub-
strate-controlled reactions that use
chiral auxiliaries or chiral alkenes have
already been studied in depth. This
study focuses on stereoselective re-
agent-controlled iodolactonizations, by
application of a new method that uses
complexes of iodine monochloride and
various donor molecules. (R)-1,2,3,4-
Tetrahydro-1-naphthylamine and other
amines with similar structures were
found to be efficient in the iodocycliza-
tion of 4-aryl-4-pentenoic acids. Calcu-
lations were performed on complexes
of
(R)-1,2,3,4-tetrahydro-1-naphthyl-
amine with XCl (X=I, H) to identify
possible reactive species in these iodo-
cyclizations. Calculations were carried
out at various levels of theory, includ-
ing B3LYP/6-31+G (d,p) by using a
modified SDD basis set for iodine.
Keywords: computer chemistry
·
electrophiles · iodine · iodolactoni-
zation · stereoselective synthesis
Introduction
therefore, we focused our attention on complexes of ICl and
various donor molecules. Although it is known that oxygen-
containing compounds like carbonyl compounds,[4] ethers,[5]
and nitrogen-containing molecules[6] can form 1:1 complexes
with ICl, we found that complexes of enantiomerically pure
primary amines are suitable reactive and selective electro-
philic species for iodolactonizations. Recently, we reported
preliminary results on stereoselective iodolactonizations of
4-phenyl-4-pentenoic acid 1 and other substrates by employ-
ing mixtures of enantiomerically pure amines with ICl as re-
agents[7] (Scheme 1). (R)-1,2,3,4-Tetrahydro-1-naphthyl-
amine 3 and other amines with similar structure, such as
(R)-1-phenyl-1-ethylamine 4, were found to be efficient
amines for the iodolactonization, yielding lactones 2 with up
to 45% ee. Chiral halonium ion complexes with dihydroqui-
nidine[8] or 2-menthyl-pyridine[9] have been reported for ster-
eoselective iodo- and bromolactonizations, although only
Reactions of double bonds with electrophilic reagents play
an important role in many transformations in organic syn-
thesis. Electrophile-promoted cyclizations of unsaturated
substrates are an important transformation in heterocyclic
chemistry, and much effort has been devoted to the control
of such cyclizations and the development of enantioselective
versions. Stereocontrol can be achieved by using substrate-
controlled reactions, albeit with the disadvantage of having
to remove the chiral auxiliary after the reaction. Most of the
reactions described to date are limited to this variant. Enan-
tiomerically pure electrophilic reagents can, however, gener-
ate new stereogenic centers under reagent-controlled condi-
tions.
We have already investigated selenium[1] and hypervalent
iodine reagents[2] for this purpose, and now report the use of
chiral iodine electrophiles for reagent-controlled stereoselec-
tive iodocyclizations. Iodocyclizations have been studied ex-
tensively, and this transformation serves as an important key
reaction in many syntheses.[3] Iodine monochloride (ICl) is
about 400 times more reactive than elemental iodine and,
[a] Dr. J. Haas, S. Bissmire, Prof. Dr. T. Wirth
School of Chemistry, Cardiff University
Cardiff, CF10 3AT (UK)
Fax : (+44)29-2087-6968
E-mail: wirth@cf.ac.uk
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Scheme 1. Reagent-controlled stereoselective iodolactonization.
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low enantiomeric ratios (up to 57:43) were obtained. Re-
cently, the first example of a catalytic enantioselective iodo-
cyclization of unsaturated alcohols was reported,[10] and re-
sults with chiral phase-transfer catalysts in iodolactoniza-
tions were also described.[11]
Results and Discussion
To understand the nature of the stereoselective induction in
this iodolactonization, and to be able to further optimize the
chiral reagent, we investigated and analyzed the amine–ICl
mixtures in a number of ways. Elemental analysis of the
yellow powder, which precipitated from mixing 3 and ICl in
dichloromethane, indicated a 1:1 composition.[12] Unfortu-
nately, it was impossible to obtain further information from
powder diffraction analysis. A titration of amine 4 with ICl
was monitored by performing NMR spectroscopy, in which
the resonance of the benzylic proton at 4.15 ppm showed a
shift to a higher field, which reverted after the addition of
more than one equivalent of ICl (Figure 1, left). This behav-
ior indicates a more complex reaction than a simple 1:1
adduct formation. By contrast, the chemical shift of the
methyl protons (1.42 ppm) does not show this behavior
(Figure 1, right).
Figure 2. UV/Vis spectra of a 1:1 mixture of amine 3 and ICl (1”10ꢀ5
in CH2Cl2 at RT).
m
7% ee. Reversing the order of the amines (first 4, then 3)
resulted in (R)-2 with 6% ee. These values are very close to
the expected 10% ee for (R)-2, in which an equal participa-
tion of amines 3 and 4 in the reaction is assumed. However,
the addition of 4 to a preformed complex of 3 and ICl at
ꢀ788C, instead of at room temperature, resulted in (R)-2
with 10% ee, and reversing the order of the amines yielded
1% ee (R)-2.[14] This shows that, even at ꢀ788C, the ex-
change of the amine ligands on the iodine cation is rapid, al-
though an equilibrium with equal contributions of both
amines was not reached and slightly different results were
obtained.
To gain further insight into the reaction between primary
amine 3 and ICl, quantum chemical studies were performed
by using the Gaussian 98 programme package.[15] Molecules
containing heavy elements pose a great problem in ab initio
calculations, because these elements contain a large number
of core electrons, which, although unimportant in a chemical
sense, must be characterized by using a large number of
basis functions to properly describe the valence orbitals.
This difficulty can be overcome by the use of effective core
potentials (ECP). These functions model the core electrons
and prevent the valance electrons from collapsing into the
core.[16] The valence electrons are then treated explicitly,
yielding results comparable in quality to all-electron calcula-
tions at a fraction of the computational cost. To design an
ECP, a good quality all-electron wave function must be gen-
erated first. This is usually achieved by using a numerical
Hartree–Fock or a relativistic Dirac–Hartree–Fock calcula-
tion. The valance orbitals are then replaced by pseudo orbi-
tals, which are designed to behave correctly on the outer
part, but lack the nodal structure in the core region that is
observed in regular orbitals. Finally, the core electrons are
replaced by a potential that is designed so that the solutions
of the Schrçdinger equation produce valence orbitals,
matching the pseudo orbitals. These potentials effectively in-
clude relativistic effects, which effect mainly core electrons.
In the SDD basis set used for iodine in our calculations, the
46 electron (krypton) core of iodine is described by using an
ECP.[17] The two s-electrons are described at a double zeta
level, and the five p-electrons at a triple zeta level. To im-
prove results in the following calculations, a set of d-orbitals
optimized in the ICl–ethene complex was added. The expo-
Figure 1. Titration of phenylethylamine 4 with ICl (ratio of 4:ICl is indi-
cated) monitored by conducting NMR spectroscopy (300 MHz, CDCl3,
RT).
A 1:1 mixture of amine 3 and ICl was then observed by
performing UV/Vis spectroscopy over a period of time. The
spectra displayed significant changes during the first 30 min
after mixing, but thereafter, remained almost unchanged.
Two isosbestic points at 237 and 262 nm indicate that at
least two species are in equilibrium (Figure 2).[13]
The stability and dynamics of the amine–ICl complexes
under different conditions were investigated by conducting a
series of crossover experiments with the unsaturated acid 1
as a substrate. Amine 3 yielded (R)-2 with 45% ee, whereas
amine 4 gave the opposite enantiomer, (S)-2, in 26% ee.
One equivalent of 4 was added (at RT) to a preformed 1:1
complex of amine 3 and ICl, and the subsequent iodolacto-
nization of 1, performed at ꢀ788C, generated (R)-2 with
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Iodine Monochloride–Amine Complexes
FULL PAPER
nent of the d-type Gaussian function was varied in a series
of single point MP2 calculations on ICl with simultaneous
geometry optimization. A cubic fit to the data resulted in an
optimum value for the exponent (see below). A further shell
of sp diffuse functions was added for a better description of
long-range effects important for complexations (e.g., polar-
izability). The exponent for these was estimated by extrapo-
lating beyond the values for the 6–311+G diffuse functions
in halogens up to bromine[18] (Table 1).
transfer must be investigated. Interactions between iodine
and double bonds are of interest in investigating the addi-
tion to the double bond in lactonization reactions. Results
obtained by using the LANL2DZ basis set in combination
with B3LYP are also included (Table 2).
ꢀ
Table 2. Comparison of experimental and calculated X ICl bond lengths
[Š].
Exptl B3LYP/
B3PW91/
MP2/
B3LYP/
SDD+pd SDD+pd
SDD+pd LANL2DZ
N2·ICl
3.180 3.144
3.120
2.712
3.011
2.878
2.727
2.567
0.163
3.096
3.063
3.217
3.094
2.822
2.613
0.034
3.242
2.918
3.163
3.044
3.951
2.602
0.091
Table 1. Data for optimization of the exponent a.
CO·ICl
C2H2·ICl
C2H4·ICl
HCN·ICl
NH3·ICl
sum of
3.011 2.820
3.115 3.098
3.032 2.989
2.850 2.780
2.711 2.601
0.057
Exponent a
I–C distance [Š]
Energy [a.u.]
0.15
0.2
0.25
0.3
2.386
2.371
2.365
2.364
2.368
ꢀ471.57067
ꢀ471.57327
ꢀ471.57367
ꢀ471.57276
ꢀ471.57129
0.35
squares
error
variance (r2)
0.70
0.42
0.77
0.65
A cubic fit of energy plotted against exponent leads to
the function described in Equation (1):
Results of statistical analysis showed that the B3LYP cal-
culations with the modified basis set perform best among
the DFT methods tested. Although MP2 performs best stat-
istically, there is no constant trend in error (some bond
lengths are overestimated, whereas others are underestimat-
ed). MP2 calculations, even on the small molecules, were
found to be significantly more time-consuming than those
carried out by using B3LYP. Therefore, MP2 methods were
rejected in favor of B3LYP calculations with the modified
basis set for iodine.
fðxÞ ¼ ꢀ1:09 x3 þ 1:08779 x2 ꢀ 0:331693 x ꢀ 471:542
ð1Þ
Differentiation shows that an exponent of a=0.237 leads
to a minimum in energy (Figure 3).
Ab initio calculations at different levels of theory (MP2/
SDD, B3LYP/SDD, B3LYP/LANL2DZ, B3LYP/6–31G-
(d,p) with SDD+pd for iodine) were used to investigate
species that could be involved in the formation of the chiral
amine–ICl complexes. The formation of 5 is a straightfor-
ward donor–acceptor reaction between amine 3 and ICl.
Species 6 involves a proton–iodine exchange on the nitro-
gen, which is likely to be facilitated by the formation of an
HCl complex with another molecule amine. This explains
the need for a second equivalent of amine, and is supported
by the calculated energy of the amine–HCl complex. Experi-
mentally, we found that the second equivalent of amine can
be replaced by another base.[7] The second molecule of ICl
that is necessary to form 7 or 8 must originate from 5, as all
of the ICl is assumed to be used initially in the formation of
5. This means that the reactions leading to 7 and 8 are side
reactions. The formation of 7 can take place only if it is
either assisted by the formation of an amine–HCl complex,
or if the complexation energy of 7 is much higher than that
of 5. Transition states A–D connecting the different com-
plexes have also been considered (Scheme 2).
Figure 3. Plot of energy versus a with cubic fit.
For higher accuracy, all other elements were treated at a
higher level of theory. The 6–31G basis set was used with
polarized and diffuse functions for the same reasons as
those mentioned above.
A set of preliminary calculations was conducted to com-
pare the results obtained from calculations performed by
using the modified basis set in B3LYP, B3PW91, and MP2
with experimental results. Experimental data were obtained
from a study carried out by Legon on a series of interactions
between iodine monochloride and simple Lewis bases.[19]
Comparison of results was restricted to interactions between
ICl and nitrogen, and ICl and unsaturated carbon atoms,
and both of these interactions are relevant to this study. Ni-
trogen–iodine interactions are important for the formation
of the reactive species, in which both complexation and
Initial calculations were carried out by using methyl-
amine–ICl complexes at various levels of theory. The geo-
metries and energies at the MP2/SDD level and MP2/6–
31G(d,p) levels (with SDD for iodine) are almost identical,
and all subsequent calculations with the tetrahydronaphthyl
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T. Wirth et al.
(CPCM) was applied to the calculations of complexes 5 and
6.[21] The results obtained by using the CPCM model allow
similar conclusions as the results obtained from the previous
calculations. The energies of the complexes are lower, indi-
cating a stabilization by the solvent. Solvents with a relative-
ly high dielectric constant e seem to stabilize the complexes
most efficiently, as shown in Table 4.
Table 4. Total energies [kJmolꢀ1] obtained (relative to free amine 3) by
using the CPCM solvent model.
Benzene Diethyl Dichloromethane Acetonitrile
ether
Scheme 2. Different amine–ICl complexes.
e [pFmꢀ1
5 total energy
B3LYP/SDD
5 total energy
B3LYP/SDD+pd
6 total energy
B3LYP/SDD
6 total energy
B3LYP/SDD+pd
]
2.25
ꢀ107.1
4.36
8.93
36.64
ꢀ123.1
ꢀ119.9 ꢀ119.6
moiety were performed at the lower MP2/SDD level. The
[a]
ꢀ87.8
ꢀ41.3
ꢀ23.3
ꢀ103.3 ꢀ106.0
–
ꢀ
length of the N I bond ranges from 2.14 to 2.52 Š. A slight-
ly higher NBO[20] charge was found on the iodine in 6 (0.3 e,
ꢀ52.1
ꢀ33.9
ꢀ51.3
ꢀ36.5
ꢀ54.1
ꢀ
ꢀ
direct N I bond) compared to 5 (0.2 e, R* NH2·ICl). A ro-
tational analysis around the carbon–nitrogen bond for com-
plexes 5 and 6 was performed. Because the nitrogen atom in
6 is a chiral center, both diastereomers were investigated.
The structures shown in Figure 4 represent the energetic
[a]
–
[a] Not available.
The solvent plays an important role in the formation of
the complexes and also in the subsequent addition to the
alkene. The strong influence of the solvent on both reactivi-
ty and selectivity was already apparent from our preliminary
experiments. Selectivity in the iodolactonization of 1 is
thought to arise from complex 5 when the reaction mixture
of ICl and 3 is cooled to ꢀ788C and the reaction is com-
menced immediately. When the mixture of ICl and 3 was
stirred at room temperature for 30 min before the addition
of 1 at ꢀ788C, which gave higher selectivities, 6 alone, or as
a mixture together with 5, may be the dominant source of
selectivity. This hypothesis is supported by the isolation of
a-tetralone after longer reaction times (>30 min) for ICl
and 3. The a-tetralone might originate from 6 after elimina-
tion of an HI moiety to the imine and hydrolysis in the sub-
sequent aqueous workup.
Figure 4. Calculated structures of 5 and 6.
minima of all conformations calculated. Details can be
found in the Supporting Information. At all levels of theory,
the barrier to overcome C was too high to be achieved at
room temperature, and D could not be located at all. The
relative energies of complexes and transition states are
given in Table 3.
Because the stereoselectivity of the iodolactonization can
be influenced drastically by changing the solvent used in the
reaction, the conductor polarizable continuum model
Based on the most successful 1,2,3,4-tetrahydro-1-naph-
thylamine scaffold, various compounds with similar structure
(the enantiomerically pure amines 9–14, Figure 5) were pre-
pared and investigated in the iodolactonization reaction. Al-
though secondary or tertiary amines led to racemic iodolac-
Table 3. Total energies (relative to free amine 3) of complexes and tran-
sition states.
Total energies
[kJmolꢀ1
5
A
6
B
7
C
8
]
B3LYP/LANL2DZ ꢀ88.6 29.5 ꢀ33.0
ꢀ0.2 ꢀ12.4 100.1 55.1
B3LYP/SDD
MP2/SDD
ꢀ92.0 29.5 ꢀ28.6
ꢀ87.2 49.6 ꢀ46.3
4.5
ꢀ2.7 105.9 63.5
[a]
ꢀ13.0 ꢀ44.9
–
6.9
B3LYP/SDD+pd[b] ꢀ72.5 79.1 ꢀ14.6[c]
–
ꢀ31.7 134.5 61.8
[a]
[a] Not available. [b] 6–31G(d,p) basis set used for all atoms apart from I.
[c] Relative energy of the amine·HCl complex is ꢀ60.8 kJmolꢀ1
.
Figure 5. Enantiomerically pure amines 3 and 9–14.
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Iodine Monochloride–Amine Complexes
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tone 2 in previous experiments, a series of N-monosubstitut-
ed and N,N-disubstitued derivatives 9 were investigated sys-
tematically.
Some selectivity was observed with the alkyl-substituted
compounds 9a and 9b, but substituents on the nitrogen
atom obviously strongly influence its ability to coordinate to
iodine monochloride. Only racemic lactone was observed
with amines 9c and 9d (Table 5). Amines 10 and 11[22] were
ous thermodynamic properties.[23c,d,24] The correlation of
Hammett sþp constants with the calculated NBO charges at
C1 of iodiranium ions 15 has an r2 value of 0.86, which is
much better than that obtained by using Hammett sp con-
stants (r2 =0.53),[25] and confirms a positive charge stabilized
in the benzylic position (see Supporting Information for
data). The correlation of the enantiomeric excess of iodolac-
tonizations of unsaturated acids of type 16, displaying differ-
ent substituted aromatic moieties (Scheme 3), with the
Hammett sþp values also shows a good correlation (r2 =
0.88), as depicted in Figure 7.
Table 5. Iodolactonizations of 1 obtained by using enantiomerically pure
amines 9–14.
Amine
2 (ee)
Amine
2 (ee)
3
4
45% (R) 10
26% (S) 11
41% (R)
3% (R)
30% (R)
19% (R)
0%
9a (R1 =H, R2 =Me) 20% (R) 12
9b (R1 =R2 =Me)
13% (R) 13
9c (R1 =H, R2 =Boc)
9d (R1 =H, R2 =Ts)
0%
0%
14a R=O-menthyl
14b R=3,5-dinitrobenzoyl
0%
Scheme 3. Iodolactonization of electronically modified acids 16.
investigated as electronically modified derivatives of 3.
Amine 10 did show slightly reduced selectivities, whereas 11
interestingly led to almost racemic iodolactone. An interac-
tion of the iodine atom with the ring-nitrogen atom might
be the reason for an almost racemic product 2.
To gain a better insight into the face-selectivity of the ini-
tial step, iodiranium moieties of type 15 were calculated and
optimized at a B3LYP/SDD level of theory. The more with-
drawing (higher Hammett value) a substituent in the 4-posi-
tion of the aromatic moiety of 1, the shorter the bond be-
1
ꢀ
Figure 7. Correlation of Hammett spþ values with enantioselectivities in
the iodolactonization of unsaturated acids 16.
tween the iodine atom and the benzylic carbon atom (C I)
in the iodiranium intermediates 15 (Figure 6). Interestingly,
Because interactions between 1 and the amine–ICl com-
plex might influence the selectivity, the cyclization of corre-
sponding esters and amides was investigated. tert-Butyl ester
18 (Figure 8) could be cyclized only with ICl, but the expect-
ed lactone 2 was not formed by using the amine–ICl com-
plex of the stereoselective protocol described above.[7] The
reactivity of the 2:1 amine–ICl complex is too low for the
conversion of 18 into lactone 2, but by changing to an ami-
ne:ICl ratio of 1:1.5, 2 was obtained in 66% yield with 34%
ee. Only amide 19a (Figure 8) was reactive when the stereo-
selective lactonization protocol was used (amine:ICl ratio of
2:1) to give 2 in 37% ee, albeit in a low yield (43%), which
might be due to the low solubility of 19a in dichlorome-
thane. All other amide derivatives 19b–d remained unreact-
Figure 6. Differently substituted iodiranium ions 15.
this also correlates with higher selectivities observed in the
iodolactonization of differently substituted, unsaturated car-
boxylic acids 1. This iodolactonization appears, therefore, to
be one of the rare examples in stereoselective synthesis in
which only electronic factors of a substrate can remarkably
influence selectivities. In most enantioselective reactions,
steric factors play the major role, and electronic effects are
only rarely studied.[23]
All optimized geometries showed an unsymmetric iodira-
nium ion 15 irrespective of the substituent R. The distance
1
of C2 to I remains constant at 2.24 Š, whereas the C
ꢀ
I
bond lengths are significantly longer and vary from 2.97 to
3.04 Š, depending on the substituent R. Hammett correla-
tions have been applied frequently to not only reaction
rates, but also to NMR shifts, enantioselectivities, and vari-
Figure 8. Ester 18 and amides 19 used in iodocyclizations.
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T. Wirth et al.
General procedure for iodocyclizations: The enantiomerically pure
amine (0.46 mmol) was dissolved in CH2Cl2 (3 mL) and stirred with ICl
(0.23 mmol, 0.23 mL of a 1m solution in CH2Cl2) for 35 min at 338C.
After cooling to ꢀ788C, the unsaturated carboxylic acid 1 (0.115 mmol),
dissolved in CH2Cl2 (1 mL), was added. After 10 min, aqueous Na2S2O3
(10%) was added and the reaction mixture was allowed to warm up to
room temperature. The reaction mixture was extracted with CH2Cl2 (2”
6 mL) and the combined organic layers were dried with MgSO4. The
product 2[26] was purified by performing preparative TLC (tert-butylmeth-
yl ether/pentane 1:2).
ed when the stereoselective lactonization protocol was used,
and only an iodine solution in aqueous THF could affect the
lactonization.
The fact that ester 18 and amide 19 can be cyclized with
selectivities comparable to the cyclization of the acid 1 (R=
Ph) implies that the stereoselecting step is the face-selective
attack of the double bond by the amine–ICl complex, rather
than a precomplexation in an acid–base reaction prior to
lactonization. A reaction of the solid amine–ICl complex
and the carboxylic acid 1 in a solid-state reaction also led to
lactone 2. Grinding the two solids in a mortar produced lac-
tone 2 with 14% ee, and the selectivity could be increased
to 34% ee by cooling with liquid nitrogen.
The synthesis of the unsaturated acid 20 with a tetrasub-
stituted double bond was performed by using a Claisen rear-
rangement. The subsequent iodolactonization proceeded at
a similar reaction rate and identical selectivites (45% ee) in
the lactone 21 were obtained (Scheme 4).
General procedure for the synthesis of 4-aryl-4-pentenoic acid esters:
The boronic acid (4 mmol), KF (12 mmol, 936 mg), and [Pd2(dba)3]
(0.06 mmol, 55 mg) were dissolved in THF (3 mL), then 4-bromo-4-pen-
tenoic acid tert-butyl ester[27] (4.4 mmol, 1.03 g) or 4-bromo-4-pentenoic
acid ethyl ester[28] (4.4 mmol, 911 mg), and tris-(o-tolyl)phosphine
(0.16 mmol, 49 mg) were added. After 4–10 h, the reaction was filtered
over celite. The celite pad was washed with diethyl ether (250 mL). After
evaporation of the solvent, the crude product was purified by performing
flash chromatography (silica gel, tert-butylmethyl ether/pentane 1:10). All
products obtained were clear, colorless oils.
4-Phenyl-4-pentenoic acid (1): For spectral data, see reference [29].
5-Iodomethyl-5-phenyl-dihydrofuran-
2-one (2): For spectral data, see Sup-
porting Information of reference [7].
(R)-N-Methyl-1,2,3,4-tetrahydro-1-
naphthylamine (9a): For preparation
and spectral data, see reference [30].
(R)-N,N-Dimethyl-1,2,3,4-tetrahydro-
1-naphthylamine (9b): For preparation
and spectral data, see reference [31].
Scheme 4. Synthesis and lactonization of acid 20 with a tetrasubstituted double bond.
(R)-1,2,3,4-Tetrahydronaphthyl
car-
bamic acid tert-butyl ester (9c): (R)-
1,2,3,4-tetrahydro-1-naphthylamine
(7 mmol, 1 g) and Et3N (1.5 mL) were
Conclusion
dissolved in CH2Cl2 (10 mL), cooled to 08C, and di-tert-butyldicarbonate
(9 mmol, 1.96 g) was added and allowed to warm to RT. After stirring for
10 h, the reaction was diluted with H2O (50 mL) and extracted with
CH2Cl2 (3”30 mL). After evaporation of the solvent and the perfor-
mance of flash chromatography (silica gel, tert-butylmethyl ether/pentane
1:2), 9c was obtained quantitatively (1.75 g, 100% yield). M.p. 76–788C;
1H NMR (CDCl3, 400 MHz): d=1.95–1.86 (m, 1H), 1.95–1.86 (m, 1H),
2.73–2.57 (m, 2H), 4.75 (m, 2H), 6.96–6.92 (m, 1H), 7.09–7.02 (m, 2H),
7.26–7.21 ppm (m, 1H); IR: n˜ =3328, 3054, 3013, 1694, 1494, 1454, 1391,
1174 cmꢀ1; MS (EI): m/z (%): 248 (25) [M+H+], 218 (45), 158 (50), 148
(100), 130 (55), 100 (78); HRMS: calcd for C15H22O2N [M+]: 248.1644;
found: 248.1644.
The formation of chiral electrophilic complexes between pri-
mary amines and ICl was investigated, and the existence of
two possible chiral complexes was hypothesized and sup-
ported by the results of ab initio and DFT calculations. By
combining all the data obtained from NMR titrations, UV/
Vis studies, crossover experiments, and ester as well as
amide lactonizations, we conclude that the stereoselecting
step is most likely to be the attack of the double bond with-
out previous reagent–substrate interaction via the carboxylic
acid moiety. The formation and the charge distribution of
unsymmetric iodiranium ions were successfully related to
the Hammett substituent constants. This study should now
lead to the development of new and more efficient chiral
ICl complexes for a broad range of reagent-controlled ster-
eoselective iodocyclizations.
(R)-4-Methyl-N-(1,2,3,4-tetrahydronaphth-1-yl)benzenesulfonamide (9d):
For preparation and spectral data, see reference [32].
(R)-1-Azido-7-methoxy-1,2,3,4-tetrahydronaphthalene: (S)-1-Hydroxy-7-
methoxy-1,2,3,4-tetrahydronaphthalene[33] (110 mg, 0.62 mmol) was dis-
solved in toluene (2.3 mL) and diphenylphosphorylazide (166 mg,
0.68 mmol) was added. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)
(160 mg, 1 mmol) was then added and the reaction was stirred overnight
at room temperature. The reaction mixture was then partitioned between
CH2C12 and saturated NH4C1, washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The resulting clear yellow oil was
purified by performing flash chromatography (silica gel, tert-butylmethyl
ether/pentane 1:9) to yield (R)-1-azido-7-methoxy-1,2,3,4-tetrahydro-
naphthalene (86 mg, 68% yield); 1H NMR (CDCl3, 250 MHz): d=1.62–
1.93 (m, 4H), 2.49–2.73 (m, 2H), 3.72 (s, 3H), 4.66 (t, J=6.3 Hz, 1H),
6.58–6.74 (m, 2H), 6.89–7.02 ppm (m, 1H); 13C NMR (CDCl3,
62.5 MHz): d=19.4, 28.0, 29.2, 55.4, 59.7, 113.3, 114.8, 129.4, 130.4, 134.7,
157.8 ppm; IR (neat): n˜ =2932, 2835, 2361, 2341, 2096, 1614, 1505, 1456,
1254, 1149, 1039, 808, 668 cmꢀ; MS (EI): m/z (%): 203 (10) [M+], 174
(9), 161 (100), 146 (12), 128 (8), 115 (15), 89 (9), 74 (7), 51 (16); HRMS:
calcd for C11H14N3 [M++H]: 204.2511; found: 204.2513.
Experimental Section
All reactions were performed under an argon atmosphere with anhy-
drous solvents. The 1H and 13C NMR spectra were recorded in CDCl3 by
using TMS as an internal standard. Melting points are uncorrected. The
enantiomerically pure amines 3, 4, and 12 are commercially available.
NMR titration of 1-phenyl-1-ethylamine 4 with ICl: A solution of 4
(585 mL, 0.057m in CDCl3) was placed in an NMR tube. A solution of ICl
(0.85m in CDCl3) was added in amounts of 10 mL and an NMR spectrum
(300 MHz) was recorded after each addition.
5782
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 5777 – 5785

Iodine Monochloride–Amine Complexes
FULL PAPER
(R)-7-Methoxy-1,2,3,4-tetrahydronaphthylamine (10):[34] 1-Azido-7-me-
thoxy-1,2,3,4-tetrahydronaphthalene (86 mg, 0.39 mmol) was dissolved in
anhydrous methanol, and 10% palladium on charcoal (2 mg) was added.
The solvent was then thoroughly degassed and saturated with H2. The re-
action mixture was stirred for 30 min. Purification by performing prepa-
181 (25), 180 (100), 168 (33), 154 (31), 84 (16), 69 (15), 57 (16), 43 (21),
40 (25); HRMS: calcd for C14H16N [M++H]: 198.1277; found: 198.1280.
(3R,4R)-trans-4-(3,5-Dinitrobenzamido)-3-propyl-1,2,3,4-tetrahydrophen-
anathrene (14b): (3R,4R)-trans-4-(3,5-Dinitrobenzamido)-3-propenyl-
1,2,3,4-tetrahydrophenanathrene (500 mg, 1.15 mmol) was dissolved in a
1:1 mixture of dry THF/2-propanol (5 mL). Wilkinsons catalyst (0.5
mol%) was added and the mixture was stirred under hydrogen for 48 h.
The solvent was removed under reduced pressure and the product was
purified by performing flash chromatography (silica gel, petroleum ether/
1
rative TLC (ethyl acetate/MeOH 4:1) yielded 20 mg (38%) 10; H NMR
(CDCl3 250 MHz): d=1.78–2.01 (m, 4H), 2.68–2.78 (m, 2H), 3.90 (s,
3H), 3.95 (t, J=6 Hz, 1H), 6.76 (m, 1H), 7.00 ppm (m, 2H); 13C NMR:
d=19.5, 28.4, 29.7, 31.8, 49.7, 55.4, 112.3, 114.2, 129.0, 130.1, 157.9 ppm.
1
(R)-8-Amino-5,6,7,8-tetrahydroquinoline (11): rac-8-Hydroxy-5,6,7,8-tet-
rahydroquinoline[22] was separated into the enantiomers by performing
HPLC (Daicel Chiracel OD, 21 mm”250 mm), at 6 mLminꢀ1 with 2-
propanol/hexane 1:4 as eluent. Rf (S)=18 min, Rf (R)=24 min. The (S)-
enantiomer was converted into amine 11 by following the procedure in
reference [22].
Et2O 4:1); H NMR (CDCl3, 400 MHz): d=0.89 (t, J=7.6 Hz, 3H), 1.14–
1.31 (m, 1H), 1.41–1.72 (m, 4H), 1.92–2.04 (m, 2H), 2.94–3.10 (m, 2H),
5.98 (dd, J=9.5, 3.4 Hz, 1H), 6.26 (d, J=9.5 Hz, 1H), 7.10 (d, J=8.5 Hz,
1H) 7.33 (t, J=7.3 Hz, 1H), 7.43 (dt, J=7.8, 1.1 Hz, 1H), 7.42 (d, J=
8.5 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 8.73 (d, J=
2.0 Hz, 2H), 8.95 ppm (t, J=2.1 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d=14.8, 20.9, 24.0, 30.8, 34.9, 39.8, 48.1, 121.4, 132.0, 125.9, 127.5, 127.7,
128.1, 129.1, 130.9, 132.3, 132.8, 135.8, 138.2, 148.8, 162.2 ppm; IR (KBr):
n˜ =3339, 7632, 1541, 1526, 1345, 1083, 913, 804, 729 cmꢀ1; MS: m/z (%):
433.3 (37) [M]+, 432.3 (100), 210.1 (20), 166.8 (24), 62.0 (8); HRMS:
calcd for C24H24N3O5 [M++H]: 434.1710; found: 434.1715.
1,2,3,4-Tetrahydrophenanthren-4-ol: NaBH4 (62 mg, 1.68 mmol) was
added to a solution of 2,3-dihydrophenanthren-4(1H)-one[35] (300 mg,
1.53 mmol) in MeOH at 08C. The reaction mixture was warmed to room
temperature and stirred for 6 h. The solvent was evaporated and the resi-
due was treated with saturated aqueous NH4Cl (3 mL) and then extract-
ed with CH2Cl2 (4”3 mL). The combined organic layers were dried over
MgSO4 and the solvent was removed under reduced pressure to yield
298 mg (98%) of 1,2,3,4-tetrahydrophenanthren-4-ol; 1H NMR (CDCl3,
400 MHz): d=1.68–2.04 (m, 3H), 2.11–2.20 (m, 1H), 2.71–2.89 (m, 2H),
5.31 (t, J=3.3 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 7.34 (dt, J=7.4, 0.7 Hz,
1H), 7.46 (dt, J=7.0, 1.4 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.68 (d, J=
8.1 Hz, 1H), 8.13 ppm (d, J=8.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d=17.2, 30.3, 31.7, 63.5, 123.4, 125.1, 126.6, 128.0, 128.2, 128.6, 132.0,
132.4, 132.6, 135.3 ppm; MS (EI): m/z (%): 198 (83) [M+], 180 (100), 164
(62), 152 (27), 140 (77), 115 (38) 90 (26), 76 (21), 63 (25); HRMS: calcd
for C14H18ON [M++NH4]: 216.1383; found: 216.1385.
4-p-Tolyl-4-pentenoic acid ethyl ester: Yield: 34%, colorless oil;
1H NMR (CDCl3, 400 MHz): d=1.27 (t, J=7.2 Hz, 3H), 2.38 (s, 3H),
2.50 (t, J=7.8 Hz, 2H), 2.86 (t, J=7.8 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H),
5.08 (s, 1H), 5.31 (s, 1H), 7.17 (d, J=8.0 Hz, 2H), 7.34 ppm (d, J=
8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz): d=14.6, 21.9, 30.9, 33.8, 60.8,
112.4, 126.4, 129.5, 133.8, 139.4, 147.1, 173.6 ppm; IR (neat): n˜ =3104,
3041, 2979, 1735, 1628, 1492, 1370 cmꢀ1; MS: m/z (%): 218 (42) [M+],
145 (100), 129 (50), 115 (92), 91 (13), 77 (7), 55 (9); HRMS: calcd for
C14H19O2 [M++H]: 219.1385; found: 219.1386.
4-p-Tolyl-4-pentenoic acid (16b): 4-p-Tolyl-4-pentenoic acid ethyl ester
(1.28 mmol, 280 mg) was stirred in a 1m LiOH solution in aqueous EtOH
(60%) for 10 h. After evaporation, dilution with water, and extraction
with CH2Cl2, the organic extracts were dried over MgSO4. After evapora-
tion of the solvent and recrystallization (petroleum ether), 90 mg (55%
yield) of 13b was obtained. For spectral data, see Supporting Information
of reference [7].
4-Azido-1,2,3,4-tetrahydrophenanthrene:
Mesyl
chloride
(50 ml,
0.404 mmol) was added to a solution of 1,2,3,4-tetrahydrophenanthren-4-
ol (20 mg, 0.101 mmol), 4-dimethylaminopyridine (DMAP) (74 mg,
0.606 mmol), and NaN3 (328 mg, 5.05 mmol) in CH2Cl2 (3 mL) at 08C.
After 30 min, the reaction mixture was allowed to warm to room temper-
ature and DMSO (1.5 mL) was added. The mixture was stirred for 3 d
and then quenched with water. The aqueous phase was extracted with
CH2Cl2 (3”3 mL) and the combined organic layers were washed with sa-
turated aqueous NaCl (4”5 mL) and dried over MgSO4. The solvent was
removed under reduced pressure and the crude product was purified by
performing flash chromatography (silica gel, diethyl ether/petroleum
ether 2:1) to yield 17 mg (75%) of product. The racemate was separated
by subjecting it to preparative HPLC (Daicel Chiracel OD, 21 mm”
4-(4-Chlorophenyl)-4-pentenoic acid tert-butyl ester: Yield: 60%, color-
less oil; 1H NMR (CDCl3, 400 MHz): d=1.36 (s, 9H), 2.30 (t, J=7.7 Hz,
2H), 2.69 (t, J=7.6 Hz, 2H), 5.02 (s, 1H), 5.20 (s, 1H), 7.40–7.28 ppm
(m, 4H); 13C NMR (CDCl3, 100 MHz): d=28.1, 30.5, 34.2, 80.4, 113.2,
128.4, 129.0, 133.3, 139.2, 146.0, 178.4 ppm; IR (neat): n˜ =3083, 2978,
1729, 1628, 1492, 1455, 1148 cmꢀ1; MS: m/z (%): 284 (40) [M++NH4],
228 (100), 194 (18), 165 (8), 108 (18), 91 (13); HRMS: calcd for
C15H23ClO2N [M++NH4]: 284.1417; found: 284.1426.
250 mm, 5 mLminꢀ1 158C), Rf (R)=10.1 min, [a]2D0 =+278 (c=0.35,
,
CHCl3); Rf (S)=18.8 min, [a]2D0 =ꢀ276 (c=0.35, CHCl3); 1H NMR
(CDCl3, 400 MHz): d=1.82–2.05 (m, 3H), 2.22–2.38 (m, 1H), 2.77–2.98
(m, 2H), 5.04 (s, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.39 (dt, J=5.6, 1.3 Hz,
1H), 7.48 (dt, J=7.1, 0.6 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.73 (d, J=
7.5 Hz, 1H), 8.0 ppm (d, J=8.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d=16.9, 28.6, 28.8, 53.9, 121.7, 124.3, 125.8, 126.1, 126.7, 127.6, 127.8,
131.1, 131.4, 135.1 ppm; IR (thin film): n˜ =3051, 2938, 2094, 1626, 1602,
1510, 1430, 1292, 1263, 1233, 1190, 1058, 901, 848, 814, 743 cmꢀ1; HMRS:
calcd for C14H13N3 [M+]: 223.1104; found: 223.1101.
4-(4-Chlorophenyl)-4-pentenoic acid (16c): 4-(4-Chlorophenyl)-4-pente-
noic acid tert-butyl ester (2 mmol, 500 mg) and silica (10 g) were refluxed
in toluene (5 mL) for 2 h.[36] After filtration over celite, a basic extraction
with 1n NaOH and extraction with CH2Cl2 after acidification with 1n
HCl yielded 250 mg (60%). For spectral data, see Supporting Informa-
tion of reference [7].
4-(4-Trifluoromethylphenyl)-4-pentenoic acid tert-butyl ester: Yield:
64%, colorless oil; 1H NMR (CDCl3, 400 MHz): d=1.36 (s, 9H), 2.32 (t,
J=7.7 Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 5.12 (s, 1H), 5.30 (s, 1H), 7.40
(d, J=8.2 Hz, 2H), 7.49 ppm (d, J=8.9 Hz, 2H); 13C NMR (CDCl3,
100 MHz): d=28.1, 30.5, 34.2, 80.4, 113.2, 124.5 (1JCF =260 Hz), 125.7,
126.9, 130.0 (2JCF =30 Hz), 144.8, 146.5, 172.6 ppm; IR (neat): n˜ =3086,
3005, 2980, 1730, 1616, 1573, 1455, 1368, 1325, 1150 cmꢀ1; MS: m/z (%):
318 (100) [M++NH4], 262 (67), 228 (5), 199 (18), 115 (11), 77 (6.5);
HRMS: calcd for C16H23F3O2N [M++NH4]: 318.1681; found: 318.1676.
(R)-1,2,3,4-Tetrahydrophenanthrene-4-amine (13): (R)-4-Azido-1,2,3,4-
tetrahydrophenanthrene (86 mg, 0.39 mmol) was dissolved in anhydrous
methanol, and 10% palladium on charcoal (2 mg) was added. The sol-
vent was then thoroughly degassed and saturated with H2. The reaction
mixture was stirred for 30 min. The solution was filtered through celite
and the solvent was removed under reduced pressure. Purification by
using preparative TLC with ethyl acetate/MeOH 4:1 yielded 20 mg
1
4-(4-Trifluoromethylphenyl)-4-pentenoic acid (16d): 4-(4-Trifluorome-
thylphenyl)-4-pentenoic acid tert-butyl ester (1.1 mmol, 270 mg) and
silica (10 g) were refluxed in toluene (5 mL) for 2 h.[36] After filtration
over celite, a basic extraction with 1n NaOH and 1n HCl yielded 280 mg
(93%). For spectral data, see Supporting Information of reference [7].
(26%) 13; [a]2D0 =22 (c=1, CHCl3); H NMR (CDCl3, 400 MHz): d=1.7–
2.05 (m, 4H), 2.76–2.90 (m, 2H), 4.64 (s, 1H), 7.10 (d, J=8.4 Hz, 1H),
7.34 (dt, J=7.1, 0.9 Hz, 1H), 7.44 (dt, J=7.0, 1.3 Hz, 1H), 7.56 (d, J=
8.4 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 8.08 ppm (d, J=8.5 Hz, 1H);
13C NMR (CDCl3, 100 MHz): d=17.1, 30.3, 31.9, 44.5, 123.3, 124.8, 126.4,
127.1, 128.2, 128.8, 132.0, 132.7, 133.9, 134.8 ppm; IR (thin film): n˜ =2926,
2360, 1508, 1442, 1262, 806, 742, 668 cmꢀ1; MS: m/z (%): 198 (13) [M+],
Iodolactones (17): For spectral data, see Supporting Information of refer-
ence [7].
Chem. Eur. J. 2005, 11, 5777 – 5785
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5783

T. Wirth et al.
4-Phenyl-4-pentenoic acid tert-butyl ester (18): 1H NMR (CDCl3,
400 MHz): d=1.38 (s, 9H), 2.42 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz,
2H), 5.38 (s, 1H), 5.58 (s, 1H), 7.18–7.38 ppm (m, 5H).
then concentrated under reduced pressure. After recrystallization, methyl
5-methyl-4-phenylhex-4-enoate was obtained (431 mg, 40% yield);
1H NMR (CDCl3, 400 MHz): d=1.45 (s, 3H), 1.72 (s, 3H), 2.18 (t, J=
7.8 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H), 3.53 (s, 3H), 6.98 (m, 2H), 7.12 (m,
1H), 7.20 ppm (m, 2H); 13C NMR (CDCl3, 62.5 MHz): d=20.5, 22.6,
30.0, 33.2, 51.8, 126.5, 128.3, 128.4, 129.0, 129.4, 129.5, 133.6, 143.2,
174.2 ppm.
Procedure for the synthesis of 19a and 19b: 4-Phenyl-4-pentenoic acid 2
(400 mg, 2.27 mmol) was dissolved in THF (5 mL). Carbonyldiimidazole
(368 mg, 2.27 mmol) was added dropwise in THF (5 mL). The reaction
was stirred for 30 min, then heated to reflux for 30 min, and cooled to
room temperature. p-Toluenesulfonamide (428 mg, 2.5 mmol) [methane-
sulfonamide 260 mg, 2.5 mmol] was added in one portion, and 1,8-
diazabicyclo[5.4.0]undec-7-ene (339 ml, 2.27 mmol) dissolved in THF
(2 mL) was added. The product was poured onto 1m HCl and extracted
with tert-butylmethyl ether (3”20 mL). The combined organic phases
were dried over MgSO4 and concentrated under reduced pressure. Flash
chromatography with ethylacetate/pentane (1:2) and then CH2Cl2/metha-
nol (100:1) yielded 19a (367 mg, 50%) [19b: 430 mg, 75%].
5-Methyl-4-phenylhex-4-enoic acid (20): Methyl 5-methyl-4-phenylhex-4-
enoate (280 mg, 1.28 mmol) was dissolved in a 5:1 mixture of THF and
water. LiOH (118 mg, 2.82 mmol) was added and the mixture was heated
to reflux for 16 h. The reaction mixture was neutralized with 5n HCl and
extracted with CH2Cl2 (3”10 mL). The combined organic layers were
dried over MgSO4, the solvent removed under reduced pressure, and the
product purified by performing column chromatography (petroleum
ether/Et2O 4:1) to obtain 20 in 97% yield (257 mg); 1H NMR (CDCl3,
400 MHz): d=1.43 (s, 3H), 1.72 (s, 3H), 2.15 (t, J=7.8 Hz, 2H), 2.61 (t,
J=7.8 Hz, 2H), 6.98 (m, 2H), 7.12 (m, 1H), 7.20 ppm (m, 2H); 13C NMR
(CDCl3, 62.5 MHz): d=20.1, 22.3, 29.4, 32.8, 126.2, 128.1, 129.1, 129.2,
132.9, 142.7, 180.1 ppm; IR (thin film): n˜ =3074, 2909, 2360, 1709, 1490,
1441, 1295, 1214, 1122, 1072, 1026, 929, 768, 702 cmꢀ1; MS: m/z (%): 204
(92) [M+], 143 (68), 128 (100), 115 (71), 91 (45), 73 (32), 65 (28), 51 (37);
HRMS: calcd for C13H16O2 [M+]: 204.2682; found: 204.2687.
N-(4-Phenyl-4-pentenoyl)-4-toluenesulfonamide (19a): M.p. 74–768C;
1H NMR (CDCl3, 300 MHz): d=2.39 (m, 5H), 2.71 (t, J=8.4 Hz, 2H),
4.96 (s, 1H), 5.20 (s, 1H), 7.30–7.23 (m, 7H), 7.92 ppm (d, J=8.4 Hz,
2H); 13C NMR (CDCl3, 75 MHz): 21.5, 29.5, 34.9, 113.1, 125.9, 127.6,
128.3, 128.8, 129.5, 135.4, 139.9, 145.0, 145.9, 170.7 ppm; IR: n˜ =3346,
1826, 1712, 1496, 1428, 1440, 1340, 1477, 1086, 103, 91, 850, 815, 779, 704,
666 cmꢀ1; MS: m/z (%): 330 (100) [M+], 174 (38), 155 (25), 131 (28), 117
(12), 103 (10), 91 (58), 77 (20), 55 (26), 43 (18); HRMS: calcd for
C18H20NO3S [M++H]: 330.1119; found: 330.1161.
5-(2’-Iodo-2’methylethyl)-5-phenyldihydrofuran-2-one (21): This was syn-
thesized from 20 by using the standard iodolactonization procedure;
1H NMR (CDCl3, 400 MHz): d=1.8 (s, 3H), 2.03 (s, 3H), 2.36–2.52 (m,
2H), 2.67–2.79 (m, 2H), 7.28–7.39 ppm (m, 5H); 13C NMR (CDCl3,
62.5 MHz): d=20.3, 20.8, 28.3, 32.5, 41.6, 83.2, 123.8, 127.3, 129.3, 139.7,
173.6 ppm.
N-(4-Phenyl-4-pentenoyl)-methylsulfonamide (19b): M.p. 121–1248C;
1H NMR (CDCl3, 300 MHz): d=2.46 (t, J=7.8 Hz, 2H), 2.88 (t, J=
7.8 Hz, 2H), 3.21 (s, 3H), 5.12 (s 1H), 5.34 (s, 1H), 7.41–7.26 ppm (m,
5H); 13C NMR (CDCl3, 75 MHz): 29.9, 35.3, 41.5, 113.9, 129.1, 727.9,
128.6, 139.8, 146.1, 171.3 ppm; IR: n˜ =3246, 3082, 3052, 3031, 2983, 2932,
2883, 1811, 1718, 1700, 1626, 1466, 1332, 1182, 1126, 980, 901, 894, 869,
779, 518, 509 cmꢀ1; MS: m/z (%): 254 (100) [M+], 174 (9), 159 (27),
131.(34), 117 (14), 91 (17), 89 (10); HRMS: calcd for C12H16NO3S [M+
+H]: 254.0851; found: 254.0851.
Acknowledgements
Procedure for the synthesis of 19c and 19d: DMAP (28 mg, 0.227 mmol)
was dissolved in CH2Cl2 (2 mL), and N-(3-dimethylaminopropyl)-N’-
ethyl-carbodiimide hydrochloride (EDCI) (436 mg, 2.27 mmol) dissolved
in CH2Cl2 (5 mL) was added at 08C. 4-Phenyl-4-pentenoic acid (400 mg,
2.27 mmol) dissolved in CH2Cl2 (5 mL) was added dropwise. Propylamide
(205 mL, 2.27 mmol) [benzylamide 273 mL, 2.27 mmol] was added slowly
to the reaction. The mixture was warmed to room temperature over 2 h,
poured onto water, and extracted with CH2Cl2 (3”20 mL). The combined
organic phases were washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. Flash chromatography with tert-butyl-
methyl ether/pentane (1:1) yielded 19c (346 mg, 70%) [19d: 400 mg,
66%].
We thank Prof. Barbara Alberts (University of Hamburg, Germany) for
analytical data, Prof. Andrew N. French (Albion College, Michigan,
USA) for valuable discussions and assistance in the synthesis of 14, Dr.
Sîan Howard and Dr. David J. Willock (Cardiff University) for support
in developing the SDD+pd basis set, Prof. Olaf G. Wiest (University of
Notre Dame, South Bend, USA) for valuable discussions, and the CSCS
Supercomputing Center, the CLRC, the University of Basel, and Cardiff
University for support. We thank Regis Technology for the donation of
the Whelk-O1 alkene. We also thank the EPSRC National Mass Spec-
trometry Service Centre, Swansea, for mass spectrometric data and the
Swiss National Foundation (SNF) and EPSRC for funding this project.
N-Propyl-4-phenyl-4-pentenamide (19c): M.p. 54–568C; 1H NMR
(CDCl3, 300 MHz): d=0.89 (t, J=8.1 Hz, 3H), 1.50–1.43 (m, 2H), 2.29
(t, J=8.1 Hz, 2H), 2.85 (t, J=8.1 Hz, 2H), 3.15 (q, J=6.6 Hz, 2H), 5.09
(s, 1H), 5.29 (s, 1H), 5.74 (s, 1H), 7.41–7.23 ppm (m, 5H); 13C NMR
(CDCl3, 100 MHz): d=11.3, 22.7, 31.1, 35.3, 41.1, 112.9, 126.0, 127.5,
128.3, 140.4, 147.1, 172.2 ppm; IR: n˜ =3303, 3079, 2958, 2872, 1956, 1894,
1798, 1638, 1542, 1492, 1444, 1372, 1339, 1263, 1232, 1169, 1025, 895, 777,
704 cmꢀ1; MS: m/z (%): 218 (100) [M+], 132 (16), 117 (7), 60 (13), 55
(12), 43 (34); HRMS: calcd for C14H20NO [M++H]: 218.1500; found:
218.1548.
N-Benzyl-4-phenyl-4-pentenamide (19d): M.p. 88–908C; 1H NMR
(CDCl3, 300 MHz): d=2.30 (t, J=7.5 Hz, 2H), 2.83 (t, J=7.5 Hz, 2H),
4.32 (d, J=5.4 Hz, 2H), 5.06 (s, 1H), 5.26 (s, 1H), 6.04 (s, 1H), 7.36–
7.18 ppm (m, 10H); 13C NMR (CDCl3, 75 MHz): d=31.0, 35.2, 43.4,
113.0, 126.0, 127.3, 127.5, 127.6, 128.3, 128.5, 138.2, 140.3 ppm; IR: n˜ =
3298, 3050, 2947, 1952, 1881, 1805, 1786, 1752, 1632, 1551, 1493, 1454,
1381, 1223, 1160, 1075, 1029, 996, 890, 778, 747, 695 cmꢀ1; MS: m/z (%):
266 (80) [M++H], 147 (5), 131 (10), 117 (7), 106 (11), 91 (9); HRMS:
calcd for C18H20NO [M++H]: 265.1467; found: 265.1543.
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5784
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Chem. Eur. J. 2005, 11, 5777 – 5785

Iodine Monochloride–Amine Complexes
FULL PAPER
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Received: May 5, 2005
Published online: July 22, 2005
Chem. Eur. J. 2005, 11, 5777 – 5785
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5785