Synthesis of potentially β-blocking practolol derivatives: (E + Z)-3- [4-(3-iodoprop-2-enyloxycarbonylamino)phenoxy]-1-(isopropylamino)propan-2-ol

Article abstract of DOI:10.1002/(SICI)1099-0690(200003)2000:6<1007::AID-EJOC1007>3.0.CO;2-I

The iodinatied carbamates 3 (E + Z), with potential β-blocking properties, were synthesized. The first route chosen, from 4-aminophenol and the chloroformate 7, had to be abandoned because of the formation of the oxazolidinone 10 during the epoxidation step. The aminoalcohol 17 prepared from the practolol 1 finally gave the target compounds by condensation with the iodoallylic chloroformates 8 (E + Z). The secondary Boc-protected amine function was regenerated without removing the carbamate function situated in the p-postion, by using mild reaction conditions (1 N HCl).

Full text of DOI:10.1002/(SICI)1099-0690(200003)2000:6<1007::AID-EJOC1007>3.0.CO;2-I

FULL PAPER
Synthesis of Potentially β-Blocking Practolol Derivatives: (E ؉ Z)-3-[4-(3-
Iodoprop-2-enyloxycarbonylamino)phenoxy]-1-(isopropylamino)propan-2-ol
[a]
[a]
[a]
[b]
´
Marcel Apparu,* Younes Ben Tiba, Pierre-Marc Leo, and Daniel Fagret
Keywords: β-Blockers / Protection / Deprotection / Carbamates / Oxazolidinone
The iodinatied carbamates 3 (E + Z), with potential β-
blocking properties, were synthesized. The first route
chosen, from 4-aminophenol and the chloroformate 7, had to
be abandoned because of the formation of the oxazolidinone
10 during the epoxidation step. The aminoalcohol 17 pre-
pared from the practolol 1 finally gave the target compounds
by condensation with the iodoallylic chloroformates 8 (E + Z).
The secondary Boc-protected amine function was regener-
ated without removing the carbamate function situated in the
p-postion, by using mild reaction conditions (1
N HCl).
Introduction
Results and Discussion
During our studies on β-blockers, the iodinated ana-
logues 2 (E ϩ Z) of practolol 1 were synthesized.[1,2] The
biological studies performed with this compound showed
it to be of considerable interest.[3,4] Studies carried out by
Kettmann et al. on a series of compounds structurally re-
lated to practolol, also revealed that the presence of the
carbamate function in place of the amide function increased
the blocking power by a factor of 10.[5] We therefore de-
cided to synthesize the derivatives 3 (E ϩ Z) in which R has
the same number of links and the same iodinated terminal
structure as 2 (E ϩ Z), but with an oxygen instead of
methylene bonded to nitrogen. Compound 6 (Scheme 1), an
immediate derivative of practolol, was also prepared as a
reference.
No particular problems were encountered with the syn-
thesis of 6, which had already been performed in a slightly
different way.[5] However, a few remarks should be made
concerning the epoxidation step. Contrary to what is norm-
ally observed, the phenol 4 did not disappear completely,
even after a very long reaction time: 20% still remained
after 24 h. Moreover, only the epoxide 5 was formed. From
these results, it can be deduced that the NH group was
probably more acidic than the OH group and that the
amide ion formed was not nucleophilic.
It was first planned to use an identical route to obtain 3
(E ϩ Z). In the first step, it was anticipated that the acetyl-
enic chloroformate 7, and not 8 (Scheme 2), would react
with the aminophenol. In fact, while the initial biological
studies can be carried out with the compound containing
iodine-127, if the molecule proves to be of particular inter-
est, further studies have to be carried out with the com-
pound labeled with iodine-123. At the moment, the follow-
ing sequence
is the best labeling method in the case of an iodovinylic
structure, and far superior to I/*I isotopic exchange, which
Scheme 1. a: ClCO2CH3, THF, CH3CN, room temp.; b: NAH,
DMF; c: glycidyl tosylate; d: (CH3)2CHNH2, 2-propanol, reflux
[a]
Laboratoire d’Etudes Dynamiques et Structurales de la
´
´
´
Selectivite, Universite Joseph Fourier,
BP 53, F-38041 Grenoble Cedex 9, France
Scheme 2. a: HSnBu3, AlBN, toluene, reflux; b: ICI, CH2Cl2, room
temp.; c: ClCO2CCl3, EtO2, EtN3, Ar, –30 °C
[b]
´
LER-ESA-CNRS 5077, Universite Joseph Fourier,
F-38700 La Tronche, France
Eur. J. Org. Chem. 2000, 1007Ϫ1012
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0306Ϫ1007 $ 17.50ϩ.50/0
1007

P. Benzi, L. Operti, R. Rabezzana
FULL PAPER
has produced only disappointing results.[6] Also, since iod- nucleophilic addition, which gave the most stable anion.
ine-123 has a very short half-life (13.2 h), SnBu3/I* ex- This anion, which was very basic, removed the phenolic
change must take place at the end of the synthesis. The proton from another molecule. The phenolate thus ob-
synthesis route must therefore take into account these fac- tained finally led to 10 after reaction with glycidyl tosylate.
tors.
Given that the desired results were not obtained by the
The derivative 7 was obtained relatively easily by operat- synthesis route in which the carbamate function was intro-
ing at a low temperature, starting from propargyl alcohol duced first, followed by the amino alcohol part, it was de-
and diphosgene in equimolar proportions. This excess of cided to reverse the order and first prepare compound 12
chlorinated reagent prevented the formation of the diacetyl- (Scheme 5). However, although the latter is obtained very
[7–9]
enic derivative.
easily from practolol
or 4-aminophenol, it has the dis-
While condensation of 7 with aminophenol led to the car- advantage of having two amine functions. We therefore had
bamate 9 with a very good yield, the subsequent step invol- to first find a way of protecting only the secondary amine
ving formation of the acetylenic epoxide led totally unex- function. Prugh et al. reported a simple but clever method
pectedly to 10 as the sole product (Scheme 3). Its structure for protecting a secondary amine function in the presence
was clearly identified on the basis of spectroscopic data.
of a primary amine function.[10] It involves first preparing
an imine through the action of benzaldehyde on the prim-
ary amine function, then protecting the secondary amine
function with a tert-butoxycarbonyl (Boc) group and finally
regenerating the primary amine function through hydrolysis
of the imine using acid potassium sulfate. The three opera-
tions are performed in the same flask. But this method was
developed for simple compounds with only the two amine
functions. In the case of 12, however, the presence of the
hydroxyl group could lead to complications. In fact, there
is a risk of formation of oxazolidines caused by the reaction
of the amine and alcohol functions with the benzal-
dehyde.[11] Under Prugh’s reaction conditions, compound
13 effectively leads almost quantitatively to the formation
of 14 (cis ϩ trans) (Scheme 5). However, with 12, this ring
formation did not occur and the desired compound 17 was
obtained. Protection of the secondary amine function in
this way may appear to complicate the synthesis, but it was
in fact very simple to carry out. NMR was used to monitor
the formation of 15: the signal of the aldehydic proton at
δ ϭ 10 was replaced by that of the imine at δ ϭ 8.5. Protec-
Scheme 3. a: 7, Et3N, THF, CH3CN, 5 °C, Ar; b: NaH, DMF; c:
glycidyl tosylate
Proton NMR revealed, in addition to the signals charac-
teristic of an epoxide ring and of a p-disubstituted aromatic
structure, two multiplets situated between δ ϭ 4.12–4.20
and δ ϭ 5.0–5.04. These signals, each representing two pro-
tons, showed coupling only to themselves, as indicated by
2D analysis. 13C NMR revealed the presence of three CH2O
and ϭCH2. Finally, the molar mass was 247. The formation
of 10 can, in fact, be explained quite easily in light of obser-
vations made during the preparation of 5. When carbamate
9 was added to the hydride suspension, the hydrogen carried
by the nitrogen should have been removed first to form an
amide ion; because of the favourable entropic conditions,
this led to ring formation. We were able to show that this
ring formation occurred first. This was done by performing
an hydrolysis, after completion of hydrogen evolution, and
then analyzing the results. It was found that the starting
compound had completely disappeared and only product
11 had formed. Moreover, the fact that the epoxide 10 was
obtained after addition of the tosylate, shows that the
phenolate was also formed. Scheme 4 shows the probable
route through which these results were obtained. The amide
ion formed initially reacted with the triple bond through
Scheme 5. a: 2  HCl, reflux; b: C6H5CHO, benzene, reflux; c:
Scheme 4
1008
[(CH3)3COCO]2O; d: SiO2
Eur. J. Org. Chem. 2000, 1007Ϫ1012

Ion Chemistry in XH4/Allene
FULL PAPER
tion of the secondary amine function was then achieved at ing to a cyclic radical.[13] Fragmentation of the latter would
room temperature in the same flask. The next steps were then afford the final products.
then performed in a different way from that proposed by
The compounds 3 (E ϩ Z) were finally prepared accord-
Prugh. In his case the hydrolysis was performed in the reac- ing to the route shown in Scheme 8. The iodinated allyl
tion medium, which means that the final mixture has to be chloroformates 8 (E ϩ Z) were obtained from propargyl
completely treated: evaporation of the solvent followed by alcohol[14] (Scheme 2). The stannylation conditions used
extraction with ether (to eliminate the neutral compounds), gave a E/Z ratio of approximately 80/20. The action of the
then addition of a base to free the primary amine. In our diphosgene on the iodoallyl alcohols gave the chloro-
case, after elimination of the solvent, the residue (essentially formates with a good yield, provided low-temperature reac-
16) was transferred directly to a chromatography (silica) tion conditions were used, and no attempt was made to
column where both hydrolysis of the imine and separation purify (after treatment, the crude reaction mixture con-
of the different compounds were carried out. Finally, 17 tained at least 90% of desired products). As in the case of
was obtained with a minimum yield of 75% from 12. The 19, following condensation between the amine 17 and 8 (E
action of 7 gave compound 18 (Scheme 6) without any ϩ Z), deprotection under mild conditions gave the com-
problems. This latter compound had the special character- pounds 3 (E ϩ Z) with a good overall yield.
istic of having two similar functions, since the secondary
amine function was protected in the form of a carbamate.
Reaction conditions therefore had to be found in which
only the Boc group is removed. This group can be very
easily eliminated using a 3  hydrochloric acid solution in
ethyl acetate.[12] Various tests in which the HCl concentra-
tions were gradually reduced showed that only the carba-
mate carrying the tert-butyl was removed by a 1  HCl solu-
tion in ethyl acetate. The derivative 19 was finally obtained
with an excellent yield.
Scheme 8. a: 8, Et3N, THF, CH3CN, Ar, 5 °C; b:  HCl, EtOAc
Conclusion
The carbamates 3 (E ϩ Z) were synthesized in five steps
from practolol. Iodine was introduced through condensa-
tion of the chloroformate of 3-iodoprop-2-enyl with the ap-
propriate amino alcohol. Preliminary biological studies will
determine whether these cold iodinated derivatives of prac-
tolol still have βϪblocking properties and whether they
should be labelled (with iodine-123) and studied more com-
prehensively. In this case, the synthesis route would have to
be modified so as to be able to introduce the radioactive
iodine (in electrophilic form) during the final step.
Scheme 6. a: 7, Et3N, THF, CH3CN, 5 °C, Ar; b:  HCl, ethyl
acetate; c: HSnBu3, AlBN, toluene, reflux, Ar
Experimental Section
The stannylation step which followed was unfortunately
unsuccessful: only compound 12 was recovered. Scheme 7
illustrates an attempt to justify the formation of this prod-
uct. The radical initially formed after the addition of SnBu3
to the triple bond would be subject to 1,2-migration, lead-
General Methods: Reactions were monitored by TLC using alumina
plates coated with silica gel 60F254 (Merck) and visualized using
either UV light, iodine or by charring with phosphomolybdic acid
(5% solution in ethanol). – Preparative chromatography was per-
formed with Merck silica gel (0.063–0.200 mm). – Infrared spectra
were recorded on thin films for the liquids and in nujol for the
1
solids. – H (13C) NMR spectra were obtained on 200 (50 or 62.5)
1
MHz spectrometers. Chemical shifts, for H NMR spectra, are re-
ported in δ units downfield from internal Me4Si. 13C NMR spectra
were referenced to the CDCl3 or [D6]DMSO peak at δ ϭ 77 or δ ϭ
39.5, respectively, relative to Me4Si. Multiplicities are reported as s
(singlet), d (doublet), dd (doublet of doublet) t (triplet), m (mul-
Scheme 7
tiplet). – Melting points were determined on a capillary melting
Eur. J. Org. Chem. 2000, 1007Ϫ1012
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P. Benzi, L. Operti, R. Rabezzana
FULL PAPER
1
point apparatus and are uncorrected. – Elemental analyses were
3308, 2141, 1789, 1141 cm–1. – H NMR (200 MHz, CDCl3): δ ϭ
performed by the Central Analytical Service of the CNRS. DMF 2.61–2.64 (t, H, J ϭ 2.4 Hz), 4.82–4.83 (d, 2 H, J ϭ 2.5 Hz). – 13C
˚
was distilled from (and stored over) 4A molecular sieves. THF was
distilled from sodium benzophenone ketyl immediately before use.
Toluene and benzene were distilled from sodium. Acetonitrile was
distilled from CaH2. Organic layers were dried with anhydrous
Na2SO4. Sodium hydride (60% in oil) was washed with pentane,
under argon, three times before use.
NMR (50 MHz, CDCl3): δ ϭ 58.3, 75.0, 77.6, 150.4.
3-Iodoprop-2-enyl Chloroformate [(E؉Z)-8]: The procedure was the
same as for 7. Diphosgene (0.66 mL, 5.47 mmol), 3-iodoprop-2-en-
1-ol[14] (1 g, 5.43 mmol) and triethylamine (0.77 mL, 5.52 mmol)
afforded, after filtration of the triethylammonium chloride precipit-
ate and evaporation of the solvent (in vacuo, without heating), chlo-
roformate 8 (E ϩ Z) (1.13 g, 84%) as an oil, which was used in the
next reaction without further purification. – IR: ν˜ ϭ 3061, 1777,
4-(Methoxycarbonylamino)phenol (4): To a solution of 4-amino-
phenol (2 g, 18.35 mmol) in THF/acetonitrile (1:1, 40 mL) at room
temp. under argon, was added dropwise methyl chloroformate
(0.856 g, 9.06 mmol) in THF/acetonitrile (10 mL). The reaction
was instantaneous. The hydrochloride was filtered and the solvents
were evaporated. The residue was purified by column chromato-
graphy (CHCl3/EtOAc ϭ 3:2) to give 4 (1.41 g, 93%) as white crys-
tals: m.p. 116 °C. – IR: ν˜ ϭ 3327, 1703 cm–1. – 1H NMR (200
MHz, CDCl3): δ ϭ 3.74 (s, 3 H), 5.32 (s, H), 6.46 (s, H), 6.72–6.78
and 7.15–7.19 (2d, 4 H, J ϭ 8.8 Hz). – 13C NMR (50 MHz,
CDCl3): δ ϭ 51.4, 115.1, 120.2, 130.6, 152.8, 154.2.
1610 cm–1. – H NMR (200 MHz, CDCl3): δ ϭ 4.66–4.68 (m, 1.63
1
H, E isomer), 4.86–4.89 (dd, 0.37 H, J ϭ 1.3 Hz and 5.9 Hz, Z
isomer), 6.37–6.78 (m, 2 H). – 13C NMR (50 MHz, CDCl3): δ ϭ
72.1, 73.3, 84.8, 87.7 133.1, 136.9, 150.3. – C4H4ClIO2: calcd. C
19.47, H 1.62, Cl 14.40, I 51.52; found (crude product) C 19.82, H
1.73, Cl 13.31, I 53.73.
4-(Prop-2-ynyloxycarbonylamino)phenol (9): To a solution of 4-
aminophenol (1.10 g, 9.16 mmol) and triethylamine (1.42 mL,
10.08 mmol) in THF/acetonitrile (1:1, 30 mL) was added very
slowly under argon at –35 °C a solution of compound 7 (1.09 g,
9.20 mmol) in THF/acetonitrile (1:1, 10 mL). The reaction mixture
was kept at the same temperature during the addition, then allowed
to warm to room temperature. After completion (TLC, CHCl3/
EtOAc ϭ 4:1), the precipitate was filtered and the solvent evapor-
ated in vacuo without heating. The residue was purified by chroma-
tography to give 9 (1.49 g, 85%) as white crystals: m.p. 129–130
°C. – IR: ν˜ ϭ 3333, 3290, 2123, 1703 cm–1. – 1H NMR (200 MHz,
CDCl3): δ ϭ 2.49–2.50 (t, H, J ϭ 2.4 Hz), 4.76–4.77 (d, 2 H, J ϭ
2.4 Hz), 5.11 (s, H), 6.58 (s, H), 6.74–6.78 and 7.18–7.22 (2d, 4 H,
J ϭ 8.9 Hz). – 13C NMR (62.5 MHz, [D6]DMSO): δ ϭ 51.7, 77.4,
79.2, 115.2, 120.2, 130.2, 152.8, 153.1. – C10H9NO3: calcd. C 62.82,
H 4.74, N 7.33; found C 63.18, H 4.62, N 7.03.
3-[4-(Methoxycarbonylamino)phenoxy]-1,2-epoxypropane (5): To a
slurry of NaH (0.053 g, 1.32 mmol) in dry DMF (10 mL) at 0 °C
was added dropwise under argon phenol 4 (0.200 g, 1.20 mmol) in
DMF (10 mL). When the H2 evolution stopped, glycidyl tosylate
(0.274 g, 1.20 mmol) in DMF (5 mL) was added dropwise. After
complete consumption of the phenol at room temp., the solvent
was carefully removed and the resulting crude product dissolved in
EtOAc. The solution was washed three times with water (3 ϫ 15
mL), dried, concentrated in vacuo and the residue purified by col-
umn chromatography (CHCl3/EtOAc ϭ 4.5:0.5) to furnish 5 (0.180
g, 67%) as white crystals: m.p. 105–106 °C. – IR: ν˜ ϭ 3326, 1709
1
cm–1. – H NMR (200 MHz, CDCl3): δ ϭ 2.73–2.77 (dd, H, J ϭ
4.8 and 2.7 Hz), 2.88–2.93 (dd, H, J ϭ 4.8 and 4.3 Hz), 3.31–3.38
(m, H), 3.76 (s, 3 H), 3.89–3.97 (dd, H, J ϭ 11.0 Hz and 5.6 Hz),
4.17–4.24 (dd, H, J ϭ 11.0 Hz and 3.2 Hz), 6.49 (s, H), 6.83–7.30
(m, 4 H). – 13C NMR (50 MHz, CDCl3): δ ϭ 44.7, 50.1, 52.3, 69.1,
115.0, 120.6, 131.4, 154.3, 154.8.
4-Methylene-N-[4-(2,3-epoxypropoxy)phenyl]-1-oxa-3-azolidin-2-
one (10): Compound 10 was synthesized as described for 5 starting
from 9 (0.200 g, 1.05 mmol), NaH (0.055 g, 1.24 mmol), glycidyl
tosylate (0.240 g, 1.05 mmol). After flash chromatography (CHCl3/
EtOAc ϭ 9:1) 10 was obtained as white crystals (0.160 g, 62%). –
3-[4-(Methoxycarbonylamino)phenoxy]-1-isopropylaminopropan-2-ol
6: A solution of the preceding epoxide (0.140 g, 0.62 mmol) and
isopropylamine (0.400 g, 6.76 mmol) in 2-propanol (25 mL) was
heated at reflux for 2 h. After evaporation to dryness, the residue
gave, after chromatography (EtOAc/MeOH ϭ 3:2), product 6
(0.160 g, 91%) as a white solid; m.p. 116–117 °C. – IR: ν˜ ϭ 3314,
3284, 1715 cm–1. – 1H NMR (200 MHz, [D6]DMSO): δ ϭ 0.96–
0.99 (d, 6 H, J ϭ 6.2 Hz), 2.54–2.73 (m, 3 H), 3.32 (s, 2 H), 3.78–
3.84 (m, 3 H), 6.83–7.34 (m, 4 H), 9.41 (s, H). – 13C NMR (50
MHz, [D6]DMSO): δ ϭ 22.7, 48.2, 49.9, 51.4, 68.2, 70.9, 114.6,
119.7, 132.1, 154.1, 154.2.
M.p. 95 °C. – IR: ν˜ ϭ 1771 cm–1. – H NMR (200 MHz, CDCl3)
1
δ ϭ 2.75–2.95 (m, 2 H), 3.35–3.37 (m, H), 3.91–4.00 (dd, H, J ϭ
11.2 and 5.4 Hz), 4.12–4.20 (m, 2 H), 4.23–4.30 (dd, H, J ϭ 11.2
and 2.6 Hz), 5.02–5.04 (m, 2 H), 6.99–7.04 and 7.23–7.27 (2d, 4 H,
J ϭ 8.4 Hz). – 13C NMR (62.5 MHz, CDCl3): δ ϭ 44.0, 50.0, 67.1,
69.0, 81.8, 115.6, 126.5, 128.3, 142.1, 156.2, 158.2. – C13H13NO4:
calcd. C 63.15, H 5.26, N 5.67; found C 63.33, H 5.33, N 5.53.
4-Methylene-N-(4-hydroxyphenyl)-1-oxa-3-azolidin-2-one (11):
A
solution of 9 (0.200 g, 1.05 mmol) in anhydrous DMF (5 mL) was
added dropwise at 0 °C under argon to a suspension of NaH (0.046
g, 1.15 mmol) in DMF (3 mL). When the evolution of H2 stopped
(2 h) the solution was hydrolyzed. TLC (CHCl3/EtOAc/MeOH ϭ
9:0.8:0.2) showed the presence of only one compound. The solvent
was evaporated to dryness and the residue purified by chromato-
graphy to give 11 as yellowish crystals (0.13 g, 65%). M.p. 188–190
Prop-2-ynyl Chloroformate (7): Anhydrous ether (40 mL) was intro-
duced under argon into a round-bottomed flask (500 mL) equipped
with a thermometer, an argon inlet tube, a septum and a dropping
funnel. After cooling to –10 °C in an acetone–dry ice bath, diphos-
gene (10 mL, 0.083 mol) was added with a syringe. The temperature
of the cold bath was lowered to –20 °C and propargyl alcohol (4.64
g, 0.082 mol) in ether (100 mL) was added dropwise by means of
the dropping funnel. Stirring was continued for 15 min at the same
temperature. After cooling to –30 °C, triethylamine (11.5 mL, 0.083
mol) in ether (100 mL) was added dropwise (very slowly). Stirring
was continued for a further 3 h, after which the mixture was al-
lowed to warm to room temperature and stirred overnight. After
1
°C. – H NMR (200 MHz, [D6]DMSO): δ ϭ 3.91–3.92 and 4.10–
4.11 (m, 2 H), 5.07 (m, 2 H), 6.84–6.89 and 7.09–7.14 (2d, 4 H,
J ϭ 8.7 Hz), 9.78 (s, H). – 13C NMR (50 MHz, [D6]DMSO): δ ϭ
66.9, 80.7, 116.0, 124.5, 128.6, 143.1, 155.8, 157.3. – C10H9NO3:
calcd. C 62.82, H 4.71, N 7.33; found C 62.47, H 4.91, N 7.21.
3-[4-(Amino)phenoxy]-1-isopropylaminopropan-2-ol (12): A solution
of practolol 1 (9.4 g, 35.3 mmol) in 2  HCl (200 mL) was heated
bubbling with argon for 1 h, the reaction mixture was filtered. at reflux and the evolution of the reaction monitored by TLC
Evaporation of the solvent afford 7 (6.9 g, 70%) as an oil which
was used in the next step without further purification. – IR: ν˜ ϭ
(MeOH/28% NH4OH ϭ 100:4).[8] Upon completion of the reac-
tion, the solution was made basic with NaHCO3, to pH 8. After
1010
Eur. J. Org. Chem. 2000, 1007Ϫ1012

Ion Chemistry in XH4/Allene
FULL PAPER
evaporation to dryness, the residue (solid) was extracted with
EtOAc (Soxhlet). The crude product (7.75 g) was purified by flash
resulting chlorohydrate was extracted with water. The solution was
made basic with NaHCO3 and extracted with EtOAc. The com-
chromatography (MeOH/NH4OH ϭ 100:1) to furnish 12 (7.23 g, bined extracts were dried and concentrated in vacuo. The residue
91%) as a white solid. Na2O2 could also be used to hydrolyze the
amide.[9] A mixture of 1 (3 g, 11.3 mmol) and Na2O2 (1.76 g, 31.41
mmol) in water (110 mL) was heated at reflux and the reaction
monitored by 1H NMR (disappearance of the methyl singlet at δ ϭ
was purified by chromatography (EtOAc/MeOH/27% NH4OH ϭ
4.2:0.8:0.1) to afford 19 (0.159 g, 92%) as a white powder: m.p. 96–
97 °C. – IR: ν˜ ϭ 3438, 3314, 1746 cm–1. – 1H NMR (200 MHz,
CDCl3): δ ϭ 1.36–1.40 (2 overlapping d, 6 H), 2.47–2.50 (t, H, J ϭ
2.14). After 3 h, the mixture was extracted with CHCl3. The or- 2.4 Hz), 3.00–3.40 (m, 3 H), 3.89–4.05 (m, 2 H), 4.35–4.52 (m, H),
ganic layer was worked up as usual to provide 12 (1.97 g, 78%)
after column chromatography. This second way of hydrolysis is
much easier to perform, but gives a lower yield: m.p. 115–118 °C. –
4.74–4.75 (d, 2 H, J ϭ 2.4 Hz), 5.25 (s, 2 H), 6.74–7.22 (m, 5 H). –
13C NMR (62.5 MHz, CDCl3): δ ϭ 22.8, 22.9, 49.0, 49.1, 52.6,
68.2, 70.7, 74.9, 77.9, 114.9, 120.7, 130.7, 153.0, 155.2.
–
1H NMR (200 MHz, CDCl3): δ ϭ 1.06–1.09 (d, 6 H, J ϭ 6.2 Hz), C16H22N2O4: calcd. C 62.74, H 7.19, N 9.15; found C 62.88, H
2.50–3.20 (m and br. s, 7 H), 3.86–4.05 (m, 3 H), 6.59–6.77 (2d, 4
H, J ϭ 9.7 Hz). – 13C NMR (50 MHz, CDCl3): δ ϭ 22.9, 48.8,
49.3, 68.5, 71.3, 115.6, 116.3, 140.1, 151.8.
7.27, N 9.06.
3-[4-(3-Iodoprop-2-enyloxycarbonylamino)phenoxy]-1-N(tert-
butoxycarbonyl)isopropylaminopropan-2-ol [(E ؉ Z)-20]: The pro-
cedure was the same as for 9 starting from 17 (0.163 g, 0.50 mmol),
triethylamine (0.07 mL, 0.55 mmol) and chloroformate 8 (0.123 g,
0.50 mmol) in anhydrous ether (15 mL). After flash chromato-
graphy (CHCl3/EtOAc ϭ 4:1), 20 (0.223 g, 84%) was obtained as
a very viscous oil. – IR: ν˜ ϭ 3321, 1740, 1653 cm–1. – 1H NMR
(200 MHz, CDCl3): δ ϭ 1.12–1.19 (2 overlapping d, 6 H, J ϭ 6.6
Hz), 1.49 (s, 9 H), 3.37–3.39 (d, 2 H, J ϭ 4.9 Hz), 3.75–4.80 (m, 4
H), 4.54–4.57 (dd, 1.26 H, J ϭ 5.8 Hz and 0.9 Hz, E isomer), 4.72–
4.91 (overlapping dd, 0.74 H, Z isomer), 4.91 (s, H), 6.49–6.76 (m,
3 H), 6.81–7.65 (m, 4 H). –
20.5, 20.8, 28.4, 46.8, 48.6, 66.1, 67.3, 69.9, 71.7, 80.6, 80.9, 84.9,
114.8, 120.7, 130.9, 136.0, 139.9, 153.2, 154.9, 158.1.
C20H31IN2O6: calcd. C 45.97, H 5.93, I 24.33, N 5.36; found C
45.00, H 5.67, I 26.62, N 4.92.
3-[4-(Amino)phenoxy]-1-N-(tert-butoxycarbonyl)isopropyl-
aminopropan-2-ol (17): A mixture of 12 (673 mg, 3.0 mmol), benzal-
dehyde (323 mg, 3.04 mmol) and benzene (35 mL) was heated at
reflux and the water was removed, as it was formed, by means of
a Dean–Stark apparatus. The reaction was monitored by NMR
(disappearance of the signal at δ ϭ 10 – aldehyde proton; appear-
ance of a signal at δ ϭ 8.5 – imine proton of 15). After 3 h, the
mixture was allowed to cool to room temp. and stirred for 24 h
after the addition of di-tert-butyl dicarbonate (660 mg, 3.02 mmol).
The liquid layer was evaporated in vacuo to provide 1.1 g (89%) of
a very viscous residue, essentially 16 [CHCl3/MeOH ϭ 97.5:2.5;
Rf ϭ 0.42; visualization (phosphomolybdic acid): grey spot of me-
dium intensity]. Column chromatography (silica gel: 80 g) of this
product at slow flow rate (1 mL/5 min) afforded 690 mg of a very
viscous product [CHCl3/MeOH ϭ 97.5:2.5; Rf ϭ 0.25; visualization
(phosphomolybdic acid): very intense black spot.]. Spectral analysis
13
C NMR (50 MHz, CDCl3): δ ϭ
–
3-[4-(3-Iodoprop-2-enyloxycarbonylamino)phenoxy]-1-isopropyl-
aminopropan-2-ol [(E ؉ Z)-3]: The procedure was the same as for
18. Compound 20 (0.22 g, 0.41 mmol) gave, after column chroma-
tography (EtOAc/CH3OH/27% NH4OH ϭ 4:1:0.1), compound 3
(0.126 g, 70%) as yellowish crystals; m.p. 75 °C (decomp). – IR:
ν˜ ϭ 3308, 1740 cm–1. – 1H NMR (200 MHz, CDCl3): δ ϭ 1.09–
1.12 (d, 6 H, J ϭ 6.3 Hz), 2.68–3.05 (m, 3 H), 3.39 (s, 2 H), 3.93–
4.06 (m, 3 H), 4.27–4.74 (m, 2 H), 6.48–6.80 (m, 3 H), 6.83–7.26
(m, 4 H). – 13C NMR (50 MHz, CDCl3): δ ϭ 22.9, 49.0, 49.4,
66.3, 67.9, 70.7, 80.9, 84.8, 115.0, 120.8, 130.9, 136.0, 139.9, 153.2,
155.2. – C16H23IN2O4: calcd. C 44.24, H 5.30, I 29.26, N 6.45;
found C 43.92, H 5.31, I 28.09, N 6.63.
1
proved this product to be 17 (75% based on 12). – H NMR (200
MHz, CDCl3): δ ϭ 1.14 (2 overlapping d, 6 H, J ϭ 6.4 Hz), 1.47
(s, 9 H), 3.20–4.20 (m, 9 H), 6.61–6.75 (2d, 4 H, J ϭ 9.0 Hz). – 13
C
NMR (50 MHz, CDCl3): δ ϭ 20.4, 20.7, 28.3, 46.8, 48.6, 70.2,
71.7, 80.4, 115.4, 116.3, 140.1, 151.6, 156.3. – C17H28N2O4: calcd.
C 62.96, H 8.64, N 8.64; found C 62.95, H 8.69, N 8.39.
5-Phenoxymethyl-2-phenyl-N-isopropyloxazolidine (14): This prod-
uct was prepared, as described for 15, from 13[11] (0.80 g, 3.83
mmol), benzaldehyde (0.46 g, 4.34 mmol), benzene (60 mL), but
1
not purified. H NMR (200 MHz, CDCl3): δ ϭ 0.99–1.07 (six sig-
nals, 6 H), 2.77–3.14 (m, 3 H), 3.93–4.17 (m, 2 H), 4.39–4.50 and
4.50–4.60 (2 m, H), 5.20 and 5.22 (2s, H), 6.86–6.98 (m, 3 H), 7.24–
7.40 (m, 5 H), 7.48–7.55 (m, 2 H).
[1]
M. Apparu, P. Demenge, D. Fagret, C. Ghezzi, S. Majid, J. P.
3-[4-(Prop-2-ynyloxycarbonylamino)phenoxy]-1-(N-tert-
butoxycarbonyl)isopropylaminopropan-2-ol (18): Compound 18 was
synthesized as described for 9 from 17 (0.780 g, 2.41 mmol), tri-
ethylamine (0.35 mL, 2.41 mmol) and 7 (0.284 g, 2.41 mmol) in
THF/acetonitrile (1:1, 20 mL). After flash chromatography
(CHCl3/EtOAc ϭ 9:1), 18 (0.783 g, 80%) was obtained as a very
viscous oil. – IR: ν˜ ϭ 3290 cm–1, 2252, 1727, 1672. – 1H NMR
(200 MHz, CDCl3): δ ϭ 1.12–1.19 (2 overlapping d, 6 H, J ϭ 6.7
Hz), 1.48 (s, 9 H), 2.49–2.51 (t, H, J ϭ 2.4 Hz), 3.20–3.50 (m, 3
H), 3.71–4.20 (m, 4 H), 4.76–4.77 (d, 2 H, J ϭ 2.4 Hz), 6.64 (s, H),
6.84–6.88 and 7.26–7.31 (2d, 4 H, J ϭ 9 Hz). – 13C NMR (62.5
MHz, CDCl3): δ ϭ 20.5, 20.8, 48.7, 52.7, 69.9, 71.9, 74.9, 77.2,
80.6, 114.8, 120.6, 130.7, 152.7, 155.1. – C21H30N2O6: calcd. C
62.07, H 7.39, N 6.89; found C 62.55, H 7.23, N 6.92.
Mathieu, L. Mauclaire, R. Pasqualini, M. Vidal, International
Patent WO96/00717; Chem. Abstr. 1996, 124, 288981v.
[2]
´
M. Apparu, Y. Ben Tiba, P. M. Leo, J. P Mathieu, L. Mau-
claire, J. Label. Compds. Radiopharm. 1999, 42, 1195–1202.
[3]
´
M. Apparu, Y. Ben Tiba, P. M. Leo, T. H. Dao Boulanger,
L. Mauclaire, J. P. Mathieu, E. Carbonnelle, D. Fagret, 4th
International conference on Nuclear and Radiochemistry,
Saint Malo, sept 8–13, 1996.
[4]
E. Carbonnelle, C. Ghezzy, S. Majid, V. Josserand, J. P. Ma-
thieu, M. Apparu, D. Fagret, J. Nucl. Med. 1998, 26, 50P
(suppl 5).
V. Kettmann, J. Csöllei, E. Racanska, P. Svec, Eur. J. Med.
Chem. 1991, 26, 843–851.
M. Apparu, J. C. Madelmont, in Radiopharmaceutiques,
Presses universitaires de Grenoble, Grenoble, 1998.
K. Leftheris, M. Goodman, J. Med. Chem. 1990, 33, 216–223.
B. Basil, J. R. Clark, E. C. J. Coffee, R. Jordan, A. H. Loveless,
D. L. Pain, K. R. H. Wooldridge, J. Med. Chem. 1976, 19,
399–402.
[5]
[6]
[7]
[8]
3-[4-(Prop-2-ynyloxycarbonylamino)phenoxy]-1-isopropylamino-
propan-2-ol (19): Compound 18 (0.230 g, 0.57 mmol) was dissolved
in a 1  HCl solution in EtOAc (4 mL). The mixture was stirred
at room temperature until the reaction was complete (3 h). The
[9]
H. L. Vaughn, M. D. Robbins, J. Org. Chem. 1975, 40, 1187–
1189.
Eur. J. Org. Chem. 2000, 1007Ϫ1012
1011

P. Benzi, L. Operti, R. Rabezzana
FULL PAPER
[10]
[13]
[14]
J. D. Prugh, L. A. Birchenough, M. S. Egbertson, Synthetic
J. Surzur, P. Teissier, C. R. Acad Sci. Paris, 1967, 264, 1981–
commun. 1992, 22, 2357–2360.
1984.
[11]
L. M. Weinstock, D. M. Mulvey, R. Tull, J. Org. Chem. 1976,
M. E. Jung, L. A. Light, Tetrahedron Lett. 1982, 23, 3851–
41, 3121–3124.
3854.
[12]
T. W. Greene, P. G. M. Wuts, Protective groups in organic chem-
istry, John Wiley and sons, 1991.
Received June 30, 1999
[O99401]
1012
Eur. J. Org. Chem. 2000, 1007Ϫ1012