Synthesis of two metabolites of the antiarrythmicum amiodarone

Article abstract of DOI:10.1002/1522-2675(200209)85:9<2990::AID-HLCA2990>3.0.CO;2-R

The metabolism of the potent antiarrythmic drug amiodarone (AMI; 1) has yet not been fully investigated. Recently, in vitro experiments revealed that in rabbit-liver microsomes, AMI (1) and its main metabolite MDEA (2) were biotransformed to the hydroxyla

Full text of DOI:10.1002/1522-2675(200209)85:9<2990::AID-HLCA2990>3.0.CO;2-R

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Helvetica Chimica Acta Vol. 85 (2002)
Synthesis of Two Metabolites of the Antiarrythmicum Amiodarone
by Barbara Wendta)1), Huy Riem Hab), and Manfred Hessea)*
a) Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
b) Cardiovaskul‰re Therapie-Forschung, Departement f¸r Innere Medizin, Universit‰tsspital Z¸rich,
R‰mistrasse 100, CH-8091 Z¸rich
The metabolism of the potent antiarrythmic drug amiodarone (AMI; 1) has yet not been fully investigated.
Recently, in vitro experiments revealed that in rabbit-liver microsomes, AMI (1) and its main metabolite
MDEA (2) were biotransformed to the hydroxylated derivatives 3'-OH-AMI (3) and 3'-OH-MDEA (4),
respectively. To establish the chemical structure of 3 and 4, we developed a total synthesis of these two
metabolites of AMI (1). 1H- and 13C-NMR Signal assignment from HSQC and HMBC 2D NMR data of
synthesized 4 showed that the proposed structure of metabolite 4 is correct. Even the structure of 3 was found to
be correct by comparing its HPLC/MS-MS/MS with the data described earlier.
Introduction. Amiodarone (AMI; 1) is a potent antiarrythmic and antianginal
drug. Unfortunately, the AMI therapy is accompanied by a number of side effects [1].
Because of the lack of knowledge about its metabolism, it is difficult to attach those side
effects to certain degradation products. In humans and laboratory animals, the best
known metabolite of AMI is the mono-N-deethyl-amiodarone (MDEA; 2) [2]. During
long-term therapy, the serum concentrations of this pharmacologically active metab-
olite are similar to those of AMI. It was shown that cytochrome P450 3A isoforms are
involved in the deethylation [3 5]. Recently, it was found that, in rabbit-liver
microsomes, both AMI (1) and MDEA (2) are biotransformed to 3'-OH-AMI2) (3)
and 3'-OH-MDEA2) (4), respectively [6][7]. To confirm the chemical structure of 3
and 4, we developed a synthesis of these two new metabolites of amiodarone (1).
Synthesis. For the synthesis of 3 and 4, we followed the same synthetic strategy.
First, the substituted 2-alkylbenzofuran system should be prepared (see Scheme 1),
which could later be selectively modified at the 3-position by Friedel Crafts acylation.
Instead of starting from an intact benzofuran system, we decided to follow the route of
Le Corre and Hercouet [8][9], who started from the triphenylphosphonium salt 5 and
an appropriate acid chloride. In our case, a modified procedure [10][11] was used
that involved instead of the acid chloride an activated carboxylic acid, which was
first coupled to the triphenylphosphonium salt 5 followed by intramolecular Wittig
1
)
)
Part of the planned Ph.D. Thesis of B. W., Universit‰t Z¸rich.
2
The abbreviation 3'-OH-AMI (or 3'-OH-MDEA) stands for the hydroxylated form of amiodarone (or
MDEA). The hydroxy function is located at position 3' of the butyl side chain of the benzofuran unit. The
numbering scheme is not in accordance with the IUPAC nomenclature.

Helvetica Chimica Acta Vol. 85 (2002)
2991
cyclization to the desired benzofuran 9. The protected 4-hydroxypentanoic acid 6 was
synthesized starting from g-valerolactone (see Scheme 1).
Thus, g-valerolactone was ring-opened and precipitated as its silver salt [12], which
was treated with MeI to form methyl 4-hydroxypentanoate (7) (73%). The (tert-
butyl)diphenylsilyl (TBDPS) group was chosen to protect the secondary-alcohol
function, bearing in mind that, for the later transformations, a quite stable protecting
group towards acidic and basic reaction conditions would be necessary [13]. The
optimized procedure for the protection proved to be reaction of 7 with (tert-
butyl)diphenylsilyl chloride in the presence of 1H-imidazole and catalytic amounts of
N,N-dimethylpyridin-4-amine (ˆdimethylaminopyridine; DMAP) in CH2Cl2 to give
the ester 8 in 85% yield. Saponification of 8 with aqueous KOHsolution in MeOH
afforded the desired protected 4-hydroxypentanoic acid 6.
The triphenylphosphonium salt 5 was prepared in 97% yield starting from
triphenylphosphine hydrobromide and 2-hydroxybenzenemethanol [8][9]. Its acyla-
tion with 6 by the dicyclohexylcarbodiimide/dimethylaminopyridine (DCC/DMAP)
method followed by intramolecular Wittig cyclization reaction of the obtained ester
with Et3N produced the benzofuran system 9 substituted at position 2 (76% yield over
2 steps). To obtain pure 9, it was necessary to repeat the isolation procedure (flash
chromatography) at least three times, because 9 tends to be co-eluated with DCC and
triphenylphosphine.
The Friedel Crafts acylation of 9 with p-anisoyl chloride (ˆ4-methoxybenzoyl
chloride) was carried out at 08 with SnCl4 as a Lewis acid catalyst [14][15] to give 10 in
72% yield (Scheme 2). The catalyst in CH2Cl2 was added dropwise. It was very
important to keep the reaction at low temperature (08), because otherwise the TBDPS
protecting group was cleaved. With other Lewis acids, such as AlCl3 or FeCl3, no
reaction took place even at room temperature.

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 1. Synthesis of the Benzofuran Moiety 9
a) Aq. NaOHsoln., AgNO 3, r.t. b) Mel, Et2O, reflux. c) TBDPSCI, 1H-imidazole, DMAP, CH2Cl2, r.t.; 62%
over 3 steps. d) Aq. KOHsoln., MeOH, reflux; quant. e) MeCN, reflux; 97%. f) DCC, DMAP, CH2Cl2, r.t. g)
Dioxane, Et3N, reflux; 76% over 2 steps.
For the demethylation of 10, different methods were examined. The convenient
BBr3-induced deprotection [16] led only to the substitution product 11. With other
demethylation agents, such as Me3SiCl/Na2S [17], pyridinium hydrochloride [15],
Me3SiI [18], or LiI [19], the deprotection also failed to provide 13. Following Olah×s
procedure [20] for ether cleavage with in situ generated Me3SiI (from PhSiMe3 and I2),
we obtained 12 in 31% yield. Finally, sodium ethanethiolate in DMF [21] was the
reagent of choice to cleave the methyl ether keeping the TBDPS-protected hydroxy
function of the side chain intact. With either freshly prepared NaSEt (from Na and
EtSHin DMF) or commercially available NaSEt, the reaction provided 13 in good
yield (77%). It is important to notice that only the use of freshly prepared NaSEt under
strictly O2-free conditions gave reproducible results.
The iodination of 13 was best achieved with I2, NaOAc, and NaOHin MeOH/H O
2
1.25 :1 to give 14 in quantitative yield [22] (see Scheme 3). Having 14 in hand, the
phenolic OHgroup could now be alkylated with either commercial N-(2-chloroethyl)-
diethylamine hydrochloride (15) or with a protected N-(2-iodoethyl)ethylamine.
The protected N-(2-iodoethyl)ethylamine was synthesized starting from 2-(ethyl-
amino)ethanol (Scheme 4). First, the secondary-amino function was quantitatively
transformed to carbamate 16 [23] by introducing the (tert-butoxy)carbonyl (Boc)

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2993
Scheme 2. Friedel Crafts Acylation and Methyl Ether Cleavage under Various Conditions
a) SnCl4, CH2Cl2, 08; 72%. b) BBr3, CH2Cl2, À 788 ! r.t.; 58%. c) PhSiMe3, I2, DMF, 1108; 31%. d) NaSEt,
DMF, 708; 77%.
group. To convert the OHgroup of 16 to the desired halogen substituent, several
different procedures were investigated [24 26]. The only product that could be
quantitatively isolated was 3-ethyloxazolidin-2-one (17). The formation of 17 is
promoted by the stability of the tert-butyl carbocation; transformation of the primary-
alcohol function of 16 into a leaving group leads then to the intramolecular cyclization
reaction. Even when the N-(2-chloroethyl)ethylamine hydrochloride (18)3) was tried
to be protected with (Boc)2O in the presence of Et3N, 17 was exclusively formed. To
prevent the formation of 17, we replaced the Boc group with the (benzyloxy)carbonyl
(Z) group. The Z-protected aminoethanol 19 was then transformed into the protected
N-(2-iodoethyl)ethylamine 20 in low yield. Due to the instability of both carbamates 16
and 19 under the above conditions, we decided to introduce the benzyl protecting
group.
After protection of the secondary-amino function with benzyl bromide in the
presence of Et3N in CH2Cl2 ( ! 21, 60%), the OHgroup was converted following the
standard procedure [24] to give the N-(2-iodoethyl)ethylamine 22 (Scheme 4). The
yield of this transformation was quite low (19%) due to some side reactions.
Nevertheless the coupling of 14 with both amines could now be achieved.
Following the procedure of Grain and Jammot [22], the alkylation of 14 with either
15 or 22 to 23 and 24, respectively, was quantitatively achieved in a biphasic system of
toluene/H2O with an excess of K2CO3 (Scheme 3). Other methods to alkylate the
3
)
For the preparation of 18, see [27].

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 3
a) I2, AcONa, NaOH, MeOH/H2O 1.25 :1, reflux; quant. b) K2CO3, Et2N(CH2CH2Cl) ¥ HCl (15), cat. NaI,
toluene/H2O 2 :1, reflux; quant. c) K2CO3, 22, toluene/H2O 2 :1, reflux; quant. d) 1-Chloroethyl carbon-
ochloridate, 1,2-dichloroethane, reflux, then MeOH, reflux; quant. e) Aq. HF soln. (40%), MeCN, r.t. ! reflux;
23 ! 3 ¥ HCl, 37%; 25 ! 4 ¥ HCl, 42%.
phenolic OHgroup of 14 were investigated, but neither under Mitsunobu coupling
conditions (DEAD (diethyl diazenedicarboxylate), PPh3, 19) [28][29] nor with NaHas
a base and 18 [30][31] were the desired products obtained. Having both 23 and 24 in
hand, the next steps in the synthesis of 3 and 4 were the deprotection of the 3'-OH
group and, in the case of 4, also the debenzylation of the tertiary-amino function. Because
of the diiodophenol moiety, a reductive cleavage of the benzyl group would be prob-
lematic. Therefore, we chose 1-chloroethyl carbonochloridate as a dealkylation reagent
[32]. The desired 25 with the diiodophenol moiety intact was isolated in very good yield.
First attempts to cleave the TBDPS group under standard conditions (Bu4NF, THF, room
temperature) [33] failed because of problems during the purification of 3, which could
not be separated from the excess of Bu4NF used. The deprotection was then achieved in
37% yield with 40% aqueous HF solution in MeCN [34]. Due to some instability of 3,
column chromatography had to be performed very quickly to avoid decomposition. Even
after transformation of 3 into its hydrochloride salt, the compound was very unstable in
MeOH. The same deprotection procedure with HF/MeCN was used to access 4¥HCl in
42% yield.

Helvetica Chimica Acta Vol. 85 (2002)
2995
Scheme 4
a) (Boc)2O, CH2Cl2, r.t.; quant. b) BnO(CO)Cl, K2CO3, acetone/H2O 1 :1, 08 ! r.t.; 82%. c) PPh3, 1H-
imidazole, I2, CH2Cl2, r.t.; 29%. d) PPh3, 1H-imidazole, I2, CH2Cl2, r.t.; 86%. e) PPh3, Br2, DMF, r.t.; quant. f)
(Boc)2O, Et3N, CH2Cl2, r.t.; quant. g) BnBr, Et3N, r.t.; 60%. h) Ph3P, 1 H-imidazole, I2, CH2Cl2, r.t.; 19%.
Conclusion. The spectral data (NMR, HPLC/ESI-MS, MS/MS) of our synthesized
product and the data of 4 ¥ HCl isolated from rabbit-liver microsomes [6] were found to
be identical. The spectral data (HPLC/APCI-MS/MS) of synthetic 3 ¥ HCl also proved
to be identical with the other metabolite obtained from degradation of AMI ¥ HCl in
rabbit liver microsomes [7].
By means of our synthesis, we established that the hydroxylation of amiodarone (1)
in rabbit-liver microsomes occurs at the 3'-position of the butyl side chain.
Furthermore, the most recent investigations on AMI metabolism in our laboratories
indicates that 3'-OH-MDEA (4) is present in the plasma of humans receiving AMI ¥
HCl (1 ¥ HCl) [35]. In contrast, no trace of 3'-OH-AMI (3) was detected by HPLC/
ESI-MS. With synthesized 3 ¥ HCl and 4 ¥ HCl in hand, the degradation in vitro and in
vivo can be further studied to gain more insight into the AMI metabolism. The
pharmacological properties and the toxicity of 3 ¥ HCl and 4 ¥ HCl are currently under
investigation and will be published elsewhere.
We thank the Swiss National Science Foundation for generous support. We are also grateful to Dr. L. Bigler
for HPLC/MS-MS/MS support and discussion.
Experimental Part
General. All solvents were of anal.-grade quality and were used without further purification unless
otherwise stated. THF and Et2O were dried over Na/benzophenone. DMF was stored over 4 ä molecular sieve
under N2. Flash chromatography (FC): silica gel Merck 60 (40 63 mm, 230 400 mesh). TLC: Merck precoated
silica-gel-60-F254 plates; detection by UV at 254 nm, by Schlittler reagent (H2PtCl6/HCl/KI), by Ce/Mo reagent
(Ce(SO4)2 ¥ 4H2O, aq. H3[P(Mo3O10)4] soln., aq. H2SO4 soln.) or by KMnO4 soln. M.p.: Mettler FP-5/FP-52. IR:

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Helvetica Chimica Acta Vol. 85 (2002)
1
Perkin-Elmer 297; in cmÀ1. H- and 13C-NMR: Bruker ARX-300, DRX-500, or AMX-600; chemical shifts d in
ppm rel. to the internal standard SiMe4 (CDCl3), J values in Hz. EI-MS (70 eV), CI-MS (NH3 as reactant gas)
and ESI-MS (NaI/MeOH/CH2Cl2): Finnigan-MAT 90 (EI and CI) and Finnigan TSQ-700 (ESI); in m/z (% of
base peak).
(2-Hydroxybenzyl)(triphenyl)phosphonium Bromide (5). For the preparation, see [9]. IR (CHCl3): 3670w,
3610m, 3010s, 2960s, 3420w, 2390m, 1630w, 1610w, 1600w, 1510m, 1470m, 1450m, 1430m, 1415m, 1385m, 1330w,
1220s, 1200s, 1110m, 1040m, 990w, 925m, 870m, 860m, 845m, 785s, 665s. 1H-NMR (300 MHz, CDCl3): 7.76 7.70
(m, 3 H); 7.59 7.47 (m, 12 H); 7.27 7.30 (m, 1 H); 7.01 6.90 (m, 2 H); 6.61 6.56 (m, 1 H); 4.57 (d, J ˆ 13.5,
2 H ).13C-NMR (75 MHz, CDCl3): 156.1 (s); 134.7 (d); 134.0 (dd, J(C,P) ˆ 9.5); 130.9 (d); 129.9 (d); 129.7 (d);
119.2 (d); 118.1 [sd, J(C,P) ˆ 84.7); 117.4 (d); 113.5 (sd, J(C,P) ˆ 8.6); 25.6 (td, J(C,P) ˆ 48.5). EI-MS: 292 (<1,
‡
‡
‡
‡
‡
[M À Ph] ), 262 (52, [PPh3] ), 183 (100, [PPh2] ), 152 (16), 107 (30, [M À CH2PPh3] ), 77 (39, [Ph] ), 51 (35,
‡
[C4H3] ).
(Æ)-Methyl 4-Hydroxypentanoate (7). For the synthesis, see [12]. IR (film): 3430s, 2965s, 1735s, 1435m,
1370m, 1345m, 1265m, 1170m, 1120m, 1080m, 1030w, 955w, 940w, 895w, 845w. 1H-NMR (300 MHz, C6D6): 5.49
(br. s, 1 H); 3.52 3.46 (m, 1 H); 3.32 (s, 3 H); 2.28 2.20 (m, 2 H); 1.59 1.51 (m, 2 H); 0.80 (d, J ˆ 6.2, 3 H).
.
‡
13C-NMR (75 MHz, C6D6): 174.0 (s); 66.9 (d); 51.0 (q); 34.2 (t); 30.5 (t); 23.5 (q). EI-MS: 132 (<1, M ), 117 (8,
‡
‡
‡
‡
[M À Me] ), 101 (25, [M À OMe] ), 88 (100, [M À MeCHOH] ), 85 (98), 59 (42, [COOMe] ), 57 (56), 56
(59).
(Æ)-Methyl 4-{[(tert-Butyl)diphenylsilyl]oxy}pentanoate (8). To
a soln. of 1H-imidazole (6.33 g,
93.00 mmol) and DMAP (0.68 g, 5.57 mmol) in CH2Cl2 (40 ml; filtered over neutral Al2O3 (act. 1, Woelm), 7
(4.92 g, 37.23 mmol) in CH2Cl2 (10 ml) was added. After cooling (ice/water), TBDPSCl (10.48 ml, 40.95 mmol)
was added within 20 min to this cold mixture. The mixture was allowed to reach r.t. within 6 h and stirred for 12 h
at r.t. After quenching with brine (20 ml), the org. layer was separated. The aq. layer was extracted twice with
CH2Cl2 (2 Â 30 ml). The combined org. layer was dried (MgSO4) and evaporated, and the crude product was
purified by FC (hexane/AcOEt 30 :1): pure 8 (11.74 g, 85%). Colorless liquid. IR (CHCl3): 2925s, 2880m, 2855s,
1725s, 1460m, 1435s, 1425s, 1370m, 1360m, 1340m, 1295m, 1260m, 1165m, 1130m, 1100s, 1085s, 1005m, 995m,
1
940w, 900w, 815w, 680w. H-NMR (300 MHz, CDCl3): 7.68 7.65 (m, 4 H); 7.43 7.34 (m, 6 H); 3.92 3.90 (m,
1 H); 3.62 (s, 3 H); 2.41 2.35 (m, 2 H), 1.82 1.77 (m, 2 H); 1.06 1.03 (d ‡ s, 12 H ).13C-NMR (75 MHz,
CDCl3): 173.8 (s); 135.8 (d); 134.6 (s); 134.0 (s); 129.5 (d); 129.4 (d); 127.4 (d); 127.3 (d); 68.5 (d); 51.3 (q); 34.1
t
‡
‡
(t); 29.7 (t); 26.9 (q); 22.9 (q); 19.2 (s). EI-MS: 313 (50, [M À Bu] ), 213 (100), 199 (17, [OSiPh2] ), 183 (31,
‡
[SiPh2] ).
(Æ)-4-{[(tert-Butyl)diphenylsilyl]oxy}pentanoic Acid (6). To a soln. of 8 (11.74 g, 31.68 mmol) in EtOH
(150 ml), 2m aq. KOH(56 ml, 112.00 mmol) was added. After stirring at r.t. for 14 h, the solvent was evaporated.
The white crystalline residue was dissolved in H2O (20 ml), acidified with conc. aq. HCl soln. to pH ꢀ 1, and
extracted with Et2O (3 Â 100 ml). The combined org. layer was washed with brine (100 ml), dried (MgSO4), and
evaporated. The residue was dried under h.v. for 4 h: pure 6 (11.18 g, 99%). Colorless liquid. IR (film): 3085m,
3045m, 2960s, 2930s, 2855s, 2660w, 1710s, 1590w, 1470w, 1460w, 1445w, 1425s, 1410w, 1390w, 1380m, 1360w,
1280m, 1260w, 1185w, 1130m, 1110s, 1085s, 1030w, 1020w, 1005w, 995m, 935w, 820m, 740m, 700s, 690m, 665w,
1
620w, 610s. H-NMR (300 MHz, CDCl3): 7.69 7.66 (m, 4 H); 7.41 7.33 (m, 6 H); 3.94 3.92 (m, 1 H); 2.46
2.40 (m, 2 H); 1.80 1.77 (m, 2 H), 1.07 1.04 (d ‡ s, 12 H ).13C-NMR (75 MHz, CDCl3): 179.2 (s); 135.8 (d);
135.7 (d); 134.5 (s); 133.9 (s); 129.5 (d); 129.4 (d); 127.5 (d); 127.3 (d); 68.3 (d); 33.7 (t); 29.5 (t); 26.9 (q); 22.8
‡
‡
t
‡
(q); 15.1 (s). CI-MS: 357 (100, [M ‡ H] ), 279 (20, [M À C6H5] ), 118 (6, [M À SiPh2 Bu ‡ H] ).
(Æ)-[3-(Benzofuran-2-yl)-1-methylpropoxy](tert-butyl)diphenylsilane (9). Compound
6
(2.655 g,
7.447 mmol) and DCC (3.110 g, 10.152 mmol) were dissolved in CH2Cl2 (150 ml), and 5 (3.042 g, 6.770 mmol)
and DMAP (83 mg, 0.677 mmol) were added. After stirring at r.t. for 14 h, the mixture was evaporated and the
resulting white slurry dissolved in dioxane (150 ml). Et3N (6.22 ml, 44.626 mmol) was added, and the mixture
was refluxed under N2. After cooling to r.t., the suspension was filtered over Celite, the filtrate evaporated, and
the residue was suspended in hexane (60 ml). The suspension was filtered over a pad of SiO2 and evaporated to
give the crude product, which was purified by FC (hexane/AcOEt 30 :1): 9 (2.2 g, 76%). Colorless oil with traces
(< 3%) of DCC. IR (film): 3060m, 3040m, 2960s, 2930s, 2885m, 2850m, 1600w, 1585m, 1470m, 1450s, 1425s,
1385w, 1365m, 1360m, 1250s, 1190w, 1165w, 1130s, 1110s, 1100s, 1080m, 1025m, 1005m, 995m, 950w, 935m, 820m,
795m, 750s, 740s, 700s, 685m, 620m, 610s. 1H-NMR (300 MHz, CDCl3): 7.72 7.64 (m, 4 H); 7.44 7.30 (m, 8 H );
7.19 7.15 (m, 2 H); 6.21 (s, 1 H); 4.02 3.92 (m, 1 H); 2.84 2.78 (m, 2 H); 1.98 1.80 (m, 2 H); 1.11 (d, J ˆ 6.1,
3 H); 1.07 (s, 9 H ).13C-NMR (75 MHz, CDCl3): 159.3 (s); 153.6 (s); 135.8 (d); 134.6 (s); 134.0 (s); 129.4 (d);
129.4 (d); 128.8 (s); 127.4 (d); 127.3 (d); 122.9 (d); 122.2 (d); 120.0 (d); 110.6 (d); 101.6 (d); 68.7 (d); 37.0 (t); 26.9
‡
(q); 24.1 (t); 23.0 (q); 19.2 (s). CI-MS: 207 ([M À SitBuPh2 ‡ NH4] ).

Helvetica Chimica Acta Vol. 85 (2002)
2997
(Æ)-[2-(3-{[(tert-Butyl)diphenylsilyl]oxy}butyl)benzofuran-3-yl](4-methoxyphenyl)methanone (10). To a
cool soln. (ice/water bath) of 9 (1.515 g, 3.534 mmol) and p-anisoyl chloride (631 mg, 3.71 mmol) in CH2Cl2
(100 ml) in a flame-dried flask under Ar, a pre-cooled 1m SnCl4 soln. in CH2Cl2 (3.53 ml, 3.53 mmol) was added
dropwise within 25 min. The mixture was stirred at 08 for 5 h, then quenched at 08 by adding brine (20 ml). The
aq. layer was separated and extracted with CH2Cl2 (2 Â 30 ml). The combined org. extract was washed once
more with brine (40 ml), dried (MgSO4), and evaporated. The residue was dissolved in CH2Cl2 (10 ml), SiO2
(2 g) was added, and the solvent was carefully distilled off. The crude product now coated on silica gel was
purified by FC (hexane/AcOEt 30 :1): pure 10 (1.43 g, 72%). Oil which solidified on standing. M.p. 93.3 94.68.
IR (CHCl3): 2955m, 2930m, 2855m, 1640s, 1600s, 1575m, 1510w, 1450m, 1425m, 1375m, 1360m, 1305m, 1280m,
1255s, 1245s, 1170s, 1135m, 1110s, 1070m, 1025m, 995m, 905s, 880m, 840m, 820m. 1H-NMR (300 MHz, CDCl3):
7.79 (d, J ˆ 6.8, 2 H); 7.66 7.62 (m, 4 H); 7.45 7.14 (m, 10 H); 6.91 (d, J ˆ 6.9, 2 H); 3.96 3.89 (m, 1 H); 3.84 (s,
3 H); 3.07 2.86 (m, 2 H); 2.02 1.84 (m, 2 H); 1.04 (d, J ˆ 6.2, 3 H); 1.02 (s, 9 H ).13C-NMR (75 MHz, CDCl3):
190.2 (s); 164.1 (s); 163.4 (s); 153.6 (s); 135.8 (d); 134.5 (s); 134.1 (s); 131.8 (s); 131.6 (d); 129.4 (d); 129.4 (d);
127.4 (d); 127.3 (d); 127.2 (s); 124.1 (d); 123.3 (d); 121.2 (d); 116.6 (s); 113.6 (d); 110.8 (d); 68.8 (d); 55.4 (q); 37.3
‡
‡
(t); 26.9 (q); 24.2 (t); 22.8 (q); 19.1 (s). CI-MS: 563 (100, [M ‡ H] ), 485 (46, [M À C6H5] ).
(Æ)-[2-(3-Hydroxybutyl)benzofuran-3-yl](4-methoxyphenyl)methanone (12).
A
soln. of 10 (45 mg,
0.078 mmol), Me3SiPh (18 mg, 0.120 mmol) and I2 (30 mg, 0.118 mmol) in DMF (2 ml) was heated under N2
to 1108 for 8 h. After cooling to r.t., the mixture was hydrolyzed with aq. NaHCO3 soln. (4 ml), Et2O (10 ml) was
added, the aq. layer was separated and, after acidifying with 10% aq. HCl soln. to pH 1, extracted with Et2O
(3 Â 10 ml). The combined org. extract was washed with brine (10 ml), dried (MgSO4), and evaporated.
Purification by FC (hexane/AcOEt 4 :1) gave glass-like 12 (8 mg, 31%). IR (film): 3400w, 2970w, 2920w, 1635m,
1600s, 1570s, 1510m, 1470w, 1450m, 1375m, 1310w, 1290m, 1260m, 1245s, 1235w, 1195m, 1180m, 1170s, 1110s,
1
1070m, 1030m, 1010m, 905m, 840w, 615m. H-NMR (300 MHz, CDCl3): 7.88 (d, J ˆ 8.9, 2 H); 7.58 (d, J ˆ 9.0,
1 H); 7.31 7.26 (m, 1 H); 7.20 7.14 (m, 2 H); 6.89 (d, J ˆ 9.0, 2 H); 3.91 (s, 3 H); 3.78 3.67 (m, 1 H); 3.30 3.18
(m, 1 H); 3.04 2.96 (m, 1 H); 2.08 1.81 (m, 2 H); 1.21 (d, J ˆ 6.3, 3 H). 13C-NMR (75 MHz, CDCl3): 191.1 (s);
164.4 (s); 163.8 (s); 153.6 (s); 132.2 (d); 131.1 (s); 126.6 (s); 124.3 (d); 123.3 (d); 121.1 (d); 117.5 (s); 113.7 (d);
‡
111.1 (d); 65.7 (d); 55.4 (q); 36.8 (t); 24.1 (t); 22.8 (q). CI-MS: 325 ([M ‡ H] ).
(Æ)-[2-(3-Bromobutyl)benzofuran-3-yl](4-methoxyphenyl)methanone (11). To a cooled soln. (À 788) of 10
(10 mg, 0.0178 mmol), 1m BBr3 in CH2Cl2 (20 ml, 0.020 mmol) was added. The mixture was stirred at r.t. for 4 h
and then cooled again to 108, before more 1m BBr3 in CH2Cl2 (40 ml, 0.040 mmol) was added. After stirring for
12 h at r.t., another aliquot of 1m BBr3 in CH2Cl2 (80 ml, 0.080 mmol) was added, and the mixture was kept at r.t.
for an additional 3 h. After quenching with ice-water, the aq. phase was extracted with CH2Cl2 (10 ml), the
combined org. phase was washed with brine, dried (MgSO4), and evaporated. The crude product was purified by
FC (hexane/AcOEt 2 :1): pure oily 11 (4 mg, 58%). IR (film): 3000w, 2960w, 2930w, 2840w, 1640s, 1600s, 1575s,
1510s, 1470m, 1450s, 1440m, 1420m, 1380m, 1370m, 1360m, 1310m, 1290m, 1260s, 1245s, 1180m, 1170s, 1160m,
1110m, 1030m, 1010m, 940w, 910m, 885m, 845m. 1H-NMR (300 MHz, CDCl3): 7.87 (d, J ˆ 8.9, 2 H); 7.52 7.13
(m, 4 H); 6.97 (d, J ˆ 8.9, 2 H); 4.16 4.04 (m, 1 H); 3.90 (s, 3 H); 3.28 3.00 (m, 2 H); 2.33 2.24 (m, 2 H); 1.74
(d, J ˆ 6.7, 3 H). 13C-NMR (75 MHz, CDCl3, one signal missing): 190.2 (s); 163.5 (s); 162.6 (s); 152.5 (s); 131.6
(d); 126.8 (s); 124.3 (d); 123.4 (d); 121.2 (d); 116.0 (s); 113.7 (d); 110.9 (d); 55.4 (q); 49.8 (d); 39.0 (t); 26.6 (t);
‡
26.1 (q). CI-MS: 387, 389 (41, 42, [M ‡ 1] ), 312, 314 (100, 98), 295, 297 (61, 59), 274 (67), 196 (68).
(Æ)-[2-(3-{[(tert-Butyl)diphenylsilyl]oxy}butyl)benzofuran-3-yl](4-hydroxyphenyl)methanone (13). To a
soln. of 10 (1.43 g, 2.54 mmol) in DMF (20 ml), NaSEt (4.27 g, 50.82 mmol) was added. The mixture was heated
to 708 for 17 h under N2. After cooling to 08, 10% aq. HCl soln. (20 ml) and CH2Cl2 (25 ml) were added, and the
aq. layer was separated. After extraction with CH2Cl2 (2 Â 25 ml), the combined org. layer was washed with
brine (25 ml), dried (MgSO4), and evaporated. The crude product was dried under h.v. and then purified by FC
(hexane/AcOEt 8 :1): pure, oily 13 (1.07 g, 77%). IR (film): 3330m, 3065m, 3020m, 2960s, 2925s, 2880m, 2850m,
1735w, 1705m, 1625m, 1600s, 1585s, 1510w, 1470m, 1450m, 1425s, 1375m, 1360m, 1280m, 1245s, 1165s, 1130m,
1
1110s, 1070m, 1040m, 1010m, 995m, 935w, 905m, 884m, 845m, 820m, 780w, 750m, 740m, 700s, 610s. H-NMR
(300 MHz, CDCl3): 7.74 (d, J ˆ 6.7, 2 H); 7.65 7.60 (m, 4 H); 7.45 7.13 (m, 10 H); 6.85 (d, J ˆ 6.7, 2 H); 3.94
3.85 (m, 1 H); 3.05 2.85 (m, 2 H); 1.97 1.86 (m, 2 H); 1.04 (d, J ˆ 6.1, 3 H); 1.01 (s, 9 H ).13C-NMR (75 MHz,
CDCl3): 191.6 (s); 164.7 (s); 161.0 (s); 153.6 (s); 135.8 (d); 134.5 (s); 134.1 (s); 132.1 (d); 131.1 (s); 129.5 (d);
129.4 (d); 127.6 (d); 127.5 (d); 127.1 (s); 124.3 (d); 123.4 (d); 121.1 (d); 116.6 (s); 115.5 (d); 110.9 (d); 68.8 (d);
‡
‡
37.2 (t); 26.9 (q); 24.2 (t); 22.8 (q); 19.2 (s). CI-MS: 549 (100, [M ‡ H] ), 491 (15, [M À C3H10] ), 471 (80, [M À
‡
C6H5] ).
(Æ)-[2-(3-{[(tert-Butyl)diphenylsilyl]oxy}butyl)benzofuran-3-yl](4-hydroxy-3,5-diiodophenyl)methanone
(14). A soln. of 13 (228 mg, 0.415 mmol), AcONa ¥ 3 H2O (136 mg, 0.999 mmol), and I2 (253 mg, 0.997 mmol) in

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Helvetica Chimica Acta Vol. 85 (2002)
MeOH(25 ml) was heated to reflux for 45 min. To the cooled soln. was added 0.192 m aq. NaOH(5 ml,
0.96 mmol) and H2O (15 ml). The mixture was then heated to reflux for 2 h, cooled, and stirred at r.t. for 12 h.
After quenching with aq. Na2SO3 soln. (2.00 g, 19.41 mmol; 10 ml), the solvent was evaporated, and the residue
was partitioned between Et2O (30 ml) and H2O (20 ml). The aq. layer was extracted with Et2O (2 Â 30 ml), and
the combined org. layer was washed with 10% aq. HCl soln. (10 ml), H2O (10 ml), and brine (30 ml), dried
(MgSO4), and evaporated: pure 14 (331 mg, 99%). Yellow crystals. M.p. 47.4 48.78. IR (CHCl3): 3660w, 3460m,
3060m, 2995m, 2950s, 2925s, 2880m, 2850s, 1710w, 1640s, 1585m, 1570s, 1470m, 1450s, 1425s, 1385s, 1360s, 1320m,
1280s, 1185s, 1165s, 1150s, 1130s, 1110s, 1070s, 1020m, 1005m, 995m, 935m, 905s, 855m, 820s, 695s, 610m.
1H-NMR (300 MHz, CDCl3): 8.16 (s, 2 H); 7.66 7.61 (m, 4 H); 7.47 7.21 (m, 10 H); 3.98 3.90 ( m, 1 H); 3.08
2.80 (m, 2 H); 1.97 1.89 (m, 2 H); 1.08 (d, J ˆ 6.1, 3 H); 1.00 (s, 9 H ).13C-NMR (75 MHz, CDCl3): 187.1 (s);
165.1 (s); 157.0 (s); 153.6 (s); 140.6 (d); 137.3 (s); 135.7 (d); 135.7 (d); 134.4 (s); 133.9 (s); 129.5 (d); 129.4 (d);
127.5 (d); 127.3 (d); 126.6 (s); 124.5 (d); 123.7 (d); 120.9 (d); 116.4 (s); 111.00 (d); 81.9 (d); 68.8 (d); 37.1 (t); 26.9
‡
‡
‡
(q); 24.4 (t); 22.9 (q); 19.1 (s). CI-MS: 801 (22, [M ‡ H] ), 743 (11, [M À C3H10] ), 723 (100, [M À C6H5] ).
(Æ)-[2-(3-{[(tert-Butyl)diphenylsilyl]oxy}butyl)benzofuran-3-yl]{-4-[2-(diethylamino)ethoxy]-3,5-diiodo-
phenyl}methanone (23). Compound 14 (331 mg, 0.413 mmol), N-(2-chloroethyl)diethylamine hydrochloride
(15; 78 mg, 0.453 mmol), K2CO3 (228 mg, 1.650 mmol), and traces of NaI were dissolved in toluene/H2O 2 :1
(15 ml). The soln. was stirred vigorously and heated to reflux for 5 h. After cooling, the aq. layer was extracted
with Et2O (2 Â 15 ml), the combined org. layer was washed with brine (15 ml), dried (MgSO4), and evaporated,
and the residue was dried under h.v.: pure 23 (356 mg, 96%). Yellow oil. IR (CHCl3): 2960s, 2930s, 2870m, 2850s,
1710w, 1655m, 1640s, 1585m, 1570m, 1470m, 1460m, 1450s, 1425m, 1380s, 1280m, 1260s, 1170m, 1135s, 1110s,
1070m, 1010m, 995m, 945m, 890w, 855w, 840w, 820w, 695m, 660w, 610m. 1H-NMR (300 MHz, CDCl3): 8.19 (s,
2 H); 7.67 7.63 (m, 4 H); 7.47 7.21 (m, 10 H); 4.13 (t, J ˆ 6.7, 2 H); 3.94 3.90 (m, 1 H); 3.09 (t, J ˆ 6.7, 2 H);
3.06 2.87 (m, 2 H); 2.73 (q, J ˆ 7.1, 4 H); 1.94 1.91 (m, 2 H); 1.12 (t, J ˆ 7.1, 6 H); 1.07 (d, J ˆ 6.1, 3 H); 1.02 (s,
9 H ).13C-NMR (75 MHz, CDCl3): 187.4 (s); 165.7 (s); 161.5 (s); 153.6 (s); 140.7 (d); 138.1 (s); 135.7 (d); 134.4
(s); 133.9 (s); 129.5 (d); 129.4 (d); 127.5 (d); 127.3 (d); 126.4 (s); 124.6 (d); 123.7 (d); 120.9 (d); 115.6 (s); 111.0
(d); 90.7 (s); 71.3 (t), 68.7 (d); 52.0 (t); 47.7 (t); 37.0 (t); 26.9 (q); 24.4 (t); 22.8 (q); 19.1 (s); 11.9 (q). CI-MS: 900
‡
‡
(8, [M ‡ H] ), 706 (35), 621 (100). ESI-MS: 900 ([M ‡ H] ).
tert-Butyl Ethyl-(2-hydroxyethyl)carbamate (16). For the preparation, see [23]. IR (film): 3440s (br.),
2980s, 2930s, 2860s, 1770s, 1470s, 1455s, 1410s, 1360s, 1290s, 1250s, 1215m, 1180s, 1150s, 1080s, 1050s, 970m, 880m,
860m, 795m, 770m, 760m, 735m. 1H-NMR (300 MHz, CDCl3): 3.72 (t, J ˆ 5.4, 2 H); 3.35 (t, J ˆ 5.4, 2 H); 3.26 (q,
J ˆ 7.0, 2 H); 1.45 (s, 9 H); 1.10 (t, J ˆ 7.1, 3 H) . 13C-NMR (75 MHz, CDCl3; CO signal missing): 62.3 (t); 49.7 (t);
‡
43.3 (t); 31.1 (s); 28.3 (q); 13.5 (q). CI-MS: 190 ([M ‡ H] ).
Benzyl Ethyl(2-hydroxyethyl)carbamate (19). To a soln. of 2-(ethylamino)ethanol (2 ml, 20.51 mmol) in
acetone (50 ml), a soln. of K2CO3 (5.67 g, 41.02 mmol) in H2O (50 ml) was added. After cooling to 08, benzyl
carbonochloridate (3.31 g, 21.28 mmol) was added, and the mixture was stirred at r.t. for 12 h. After acidifying
with 10% aq. HCl soln. to pH 1, the soln. was extracted with AcOEt (3 Â 70 ml). The org. extract was dried
(MgSO4) and evaporated, and the residue was dried in vacuo: pure, liquid 19 (3.77 g, 82%). IR (film): 3420s
(br.), 2970m, 2930m, 2870m, 1680s, 1475s, 1450s, 1420s, 1365m, 1275s, 1210s, 1150m, 1080m, 1050m, 990m, 905w,
1
860w, 790w, 770m, 735m, 700s. H-NMR (300 MHz, CDCl3): 7.40 7.26 (m, 5 H); 5.14 (s, 2 H); 3.75 (t, J ˆ 5.4,
2 H); 3.43 (t, J ˆ 5.5, 2 H); 3.36 (q, J ˆ 7.0, 2 H); 2.74 (br. s, 1 H); 1.13 (t, J ˆ 7.1, 3 H) . 13C-NMR (75 MHz,
CDCl3; CO signal missing): 136.6 (s); 128.4 (d); 127.9 (d); 127.7 (d); 67.1 (t); 61.9 (t); 50.1 (t); 43.2 (t); 13.7 (q).
‡
CI-MS: 224 ([M ‡ H] ).
3-Ethyloxazolidin-2-one (17). Prepared as described for 22 from 16 (0.500 g, 2.642 mmol), PPh3 (832 mg,
3.170 mmol), 1H-imidazole (216 mg, 3.170 mmol), and I2 (805 mg, 3.170 mmol) in CH2Cl2 (100 ml). After work-
up and FC (hexane/AcOEt 3 :1 ! 0 :1), pure, liquid 17 (262 mg, 86%) was isolated. For spectral data, see [36].
Benzyl Ethyl(2-iodoethyl)carbamate (20). Prepared as described for 22 from 19 (2 g, 8.958 mmol), PPh3
(2.82 g, 0.1075 mmol), 1H-imidazole (732 mg, 0.1075 mmol), and I2 (2.73 g, 0.1075 mmol) in CH2Cl2 (100 ml).
After workup and FC (hexane/AcOEt 20 :1 ! 4 :1), pure, liquid 20 (0.866 g, 29%) was isolated. IR (film):
3060w, 3020w, 2970m, 2930m, 2870w, 1755m, 1700s, 1470s, 1450s, 1415s, 1360m, 1310m, 1275s, 1230m, 1175s,
1110m, 1070m, 1025w, 990w, 970w, 810w, 790w, 770m, 750m, 730m, 695s. 1H-NMR (300 MHz, CDCl3): 7.46 7.32
(m, 5 H); 5.40 (s, 2 H); 3.65 (t, J ˆ 7.5, 2 H); 3.42 (q, J ˆ 6.8, 2 H); 3.25 3.18 (br. m, 2 H); 1.20 (t, J ˆ 6.9, 3 H).
13C-NMR (75 MHz, CDCl3; CO signals missing): 136.6 (s); 128.5 (d); 128.0 (d); 127.8 (d); 67.2 (t); 49.7 (t); 42.8
‡
‡
‡
(t); 14.8 (q); 1.6 (t). CI-MS: 351 (90, [M ‡ NH4] ), 334 (59, [M ‡ H] ), 224 (26, [M ‡ NH4 À HI] ), 206 (21,
‡
[M ‡ H À HI] ), 133 (100), 108 (53), 72.1 (82).
2-[Benzyl(ethyl)amino]ethanol (21). To a soln. of 2-(ethylamino)ethanol (3.66 g, 0.041 mmol) and Et3N
(8.30 g, 0.082 mmol) in CH2Cl2 (100 ml), BnBr (7.72 g, 0.045 mmol) was added dropwise, and the soln. was

Helvetica Chimica Acta Vol. 85 (2002)
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stirred for 14 h at r.t. After quenching with brine (20 ml), the aq. layer was extracted with CH2Cl2 (2 Â 20 ml),
the combined org. layer was dried (MgSO4) and evaporated, and the residue was dried under h.v.: 21 (4.41 g,
60%), pure enough for the next step. IR (film): 3330s (br.), 3080m, 3060m, 3020m, 2960s, 2960s, 2930s, 2870s,
2800s, 1490m, 1455s, 1370m, 1290m, 1250m, 1210m, 1180m, 1150m, 1075s, 1050s, 1030s, 980w, 910w, 870w, 770m,
730s, 700s. 1H-NMR (300 MHz, CDCl3): 7.35 7.20 (m, 5 H); 3.64 (s, 2 H); 3.56 (t, J ˆ 5.4, 2 H); 2.66 (t, J ˆ 5.4,
2 H); 2.58 (q, J ˆ 7.1, 2 H); 1.06 (t, J ˆ 7.1, 3 H) . 13C-NMR (75 MHz, CDCl3): 138.7 (s); 128.8 (d); 128.3 (d); 127.0
‡
‡
(d); 58.3 (t); 57.7 (t); 54.5 (t); 47.2 (t); 11.6 (q). CI-MS: 180 (100, [M ‡ H] ), 148 (22, [M À MeOH ‡ H] ).
Benzyl(ethyl)(2-iodoethyl)amine (22). To a soln. of PPh3 (1.76 g, 6.71 mmol) and 1H-imidazole (0.46 g,
6.76 mmol) in CH2Cl2 (100 ml), I2 (1.70 g, 6.69 mmol) was added portionwise. The suspension was stirred till all
I2 was dissolved. Then, 21 (1.00 g, 5.58 mmol) in CH2Cl2 (5 ml) was added slowly, and the suspension was stirred
for 2 h at r.t. (the flask was wrapped with Al foil to avoid exposure to light). The mixture was quenched with
brine (20 ml), the aq. layer was extracted with CH2Cl2 (2 Â 20 ml), the combined org. extract was dried (MgSO4)
and evaporated, and the crude mixture was purified by FC (hexane/AcOEt 1:1): pure 22 (303 mg, 19%).
Colorless light-sensitive liquid. IR (film): 2960s, 2920s, 2800m, 1600m, 1490w, 1450s, 1370m, 1160s, 1100m,
1070m, 1050m, 1025w, 900w, 695w, 660w. 1H-NMR (300 MHz, CDCl3): 7.45 7.28 (m, 5 H); 3.64 (s, 2 H); 3.16 (t,
J ˆ 7.7, 2 H); 2.86 (t, J ˆ 7.7, 2 H); 2.59 (q, J ˆ 7.1, 2 H); 1.06 (t, J ˆ 7.1, 3 H) . 13C-NMR (75 MHz, CDCl3): 139.4
‡
(s); 128.8 (d); 128.3 (d); 127.0 (d); 58.0 (t); 56.2 (t); 47.5 (t); 12.0 (q); 4.3 (t). CI-MS: 290 ([M ‡ H] ).
(Æ)-(4-{2-[Benzyl(ethyl)amino]ethoxy}-3,5-diiodophenyl)[2-(3-{[(tert-butyl)diphenylsilyl]oxy}butyl)ben-
zofuran-3-yl]methanone (24). A suspension of 14 (50 mg, 0.0625 mmol), 22 (19 mg, 0.0657 mmol), and K2CO3
(26 mg, 0.1875 mmol) in toluene/H2O 2 :1 (9 ml) was stirred vigorously and heated to reflux for 14 h. After
cooling, the aq. layer was extracted with Et2O (2 Â 15 ml), the combined org. layer was washed with brine
(15 ml), dried (MgSO4), and evaporated, and the yellow residue was dried under h.v. for 3 h: pure 24 (60 mg,
99%). IR (CHCl3): 3130w, 2950m, 2930s, 2880m, 2860m, 1725w, 1655m, 1650s, 1640s, 1600m, 1590m, 1570m,
1560m, 1520w, 1470m, 1460m, 1450s, 1435m, 1425m, 1370s, 1360m, 1280m, 1250m, 1170m, 1130m, 1110s, 1105s,
1070m, 1020m, 1010m, 995m, 985m, 940m, 905m, 855w, 820m, 695m, 610m. 1H-NMR (300 MHz, CDCl3): 8.15 (s,
2 H); 7.68 7.60 (m, 4 H); 7.43 7.17 (m, 15 H); 4.07 (t, J ˆ 6.6, 2 H); 3.95 3.85 (m, 1 H); 3.76 (s, 2 H); 3.07 (t,
J ˆ 6.5, 2 H); 3.04 2.78 (m, 2 H); 2.69 (q, J ˆ 7.1, 4 H); 1.96 1.83 (m, 2 H); 1.12 (t, J ˆ 7.1, 6 H); 1.07 (d, J ˆ 6.1,
3 H); 1.02 (s, 9 H ).13C-NMR (75 MHz, CDCl3): 187.5 (s); 165.7 (s); 161.5 (s); 153.6 (s); 140.7 (d)); 139.5 (s);
138.0 (s); 135.7 (d); 134.4 (s); 133.9 (s); 129.5 (d); 129.4 (d); 128.9 (d); 128.1 (d); 127.5 (d); 127.4 (d); 126.8 (d);
126.4 (s); 124.6 (d); 123.7 (d); 121.0 (d); 115.7 (s); 111.02 (d); 90.8 (s); 71.7 (t), 68.7 (d); 58.7 (t); 52.4 (t); 48.3 (t)
‡
‡
37.0 (t); 26.9 (q); 24.4 (t); 22.9 (q); 19.2 (s); 12.2 (q). ESI-MS: 962 (100, [M ‡ H] ), 984 (16, [M ‡ Na] ).
(Æ)-[2-(3-{[(tert-Butyl)diphenylsilyl]oxy}butyl)benzofuran-3-yl]{4-[2-(ethylamino)ethoxy]-3,5-diiodophe-
nyl}methanone (25). To a suspension of 24 (105 mg, 0.1092 mmol) in 1,2-dichloroethane (5 ml), 1-chloroethyl
carbonochloridate (21 mg, 0.1469 mmol) was added under N2. The mixture was heated to reflux for 2 h. To make
sure that no traces of 24 were left, additional 1-chloroethyl carbonochloridate (21 mg, 0.1469 mmol) was added,
and the mixture was refluxed for another hour. The solvent was evaporated, and the residue was dissolved in
MeOH(5 ml). After heating to reflux for 1 h, the solvent was evaporated and the residue partitioned between
CH2Cl2 (10 ml) and sat. aq. NaHCO3 soln. The aq. layer was extracted with CH2Cl2 (2 Â 10 ml). The combined
org. layer was washed with brine (15 ml), dried (MgSO4), and evaporated, and the residue was dried under h.v.
for 3 h: colorless oil (94 mg, 99%) that solidified. IR (CHCl3): 3060w, 2950s, 2920s, 2850s, 1730w, 1655m, 1640s,
1590m, 1570m, 1525w, 1460m, 1450s, 1435m, 1425m, 1370s, 1360m, 1280m, 1260m, 1240m, 1185m, 1170m, 1130s,
1
1110s, 1105s, 1070s, 1010m, 995m, 935m, 900w, 855w, 820m, 695m, 660m, 610m. H-NMR (300 MHz, CDCl3):
8.12 (s, 2 H); 7.62 7.52 (m, 4 H); 7.35 7.20 (m, 10 H); 4.12 (t, J ˆ 5.1, 2 H); 3.92 3.80 (m, 1 H); 3.10 (t, J ˆ 5.1,
2 H); 3.04 2.72 (m, 2 H); 2.75 (q, J ˆ 7.1, 2 H); 1.92 1.78 (m, 2 H); 1.13 (t, J ˆ 7.1, 3 H); 0.97 (d, J ˆ 7.1, 3 H) ;
0.94 (s, 9 H ).13C-NMR (75 MHz, CDCl3): 187.4 (s); 165.8 (s); 160.9 (s); 153.6 (s); 140.8 (d); 138.3 (s); 135.7 (d);
134.4 (s); 133.9 (s); 129.5 (d); 129.4 (d); 127.5 (d); 127.4 (d); 126.4 (s); 124.6 (d); 123.8 (d); 120.9 (d); 115.6 (s);
111.0 (d); 90.7 (s); 72.3 (t), 68.7 (d); 49.1 (t); 43.8 (t); 37.0 (t); 26.9 (q); 24.4 (t); 22.9 (q); 19.2 (s); 15.0 (q). ESI-
‡
MS: 872 ([M ‡ H] ).
(Æ)-{4-[2-(Ethylamino)ethoxy]-3,5-diiodophenyl}[2-(3-hydroxybutyl)benzofuran-3-yl]methanone Hydro-
chloride (4 ¥ HCl). To a soln. of 25 (56 mg, 0.064 mmol) in MeCN (10 ml) was added a 40% aq. HF soln.
(57 ml, 1.280 mmol). The mixture was stirred for 2 h at r.t., then heated to 608 for 4 h, and stirred afterwards for
14 h at r.t. After adding brine (10 ml), the mixture was extracted with CH2Cl2 (3 Â 20 ml), the combined org.
phase was washed with brine (20 ml), dried (MgSO4), and evaporated, and the residue was purified by FC
(CH2Cl2/MeOH/25% aq. NH3 soln. 95 :5 :0.2): pure 4 (17 mg, 42%). Yellow oil. 1H-NMR (300 MHz, CD3OD):
8.20 (s, 2 H); 7.56 7.20 (m, 4 H); 4.23 (t, J ˆ 5.5, 2 H); 3.78 3.64 (m, 1 H); 3.18 (t, J ˆ 5.5, 2 H); 3.05 2.79 (m,
2 H); 2.82 (q, J ˆ 7.2, 2 H); 1.93 1.83 (m, 2 H); 1.20 (t, J ˆ 7.2, 3 H); 1.16 (d, J ˆ 7.2, 3 H). 13C-NMR (75 MHz,

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Helvetica Chimica Acta Vol. 85 (2002)
CD3OD; one signal missing): 187.3 (s); 167.2 (s); 162.5 (s); 155.1 (s); 141.9 (d); 139.7 (s); 127.5 (s); 126.0 (d);
124.9 (d); 122.0 (d); 112.1 (d); 91.5 (s); 72.8 (t), 67.7 (d); 49.8 (t); 44.5 (t); 37.7 (t); 25.9 (t); 23.3 (q); 14.6 (q).
The free base 4 in MeOH(10 ml) was transformed into its hydrochloride by adding 5 drops of 10% aq. HCl
soln. The mixture was evaporated and then co-evaporated with MeOH(3 Â 10 ml) to remove H2O. The residue
was dried under h.v. for 3 h: 4 ¥ HCl (18 mg, 42%). White solid. M.p. 69.1 72.58. IR (CHCl3): 3430 (br.), 2960s,
2850m, 2700s, 2460m, 1655m, 1640s, 1590m, 1570s, 1555s, 1535m, 1470m, 1450s, 1430s, 1375s, 1320m, 1285s, 1240s,
1200s, 1185m, 1165m, 1120m, 1105m, 1070m, 1055m, 1015s, 960m, 940s, 935m, 905w, 840w, 820w, 700w, 660w.
1H-NMR (500 MHz, CD3OD): 8.23 (s, 2 H); 7.54 (dd, J ˆ 8.3, 0.7, 1 H); 7.38 (dd, J ˆ 7.8, 0.6, 1 H); 7.34 (ddd, J ˆ
8.3, 7.4, 1.3, 1 H); 7.24 (ddd, J ˆ 7.8, 7.4, 0.9, 1 H); 4.40 (t, J ˆ 5.0, 2 H); 3.75 3.63 (m, 1 H); 3.65 (t, J ˆ 5.0, 2 H);
3.33 3.28 (m, 2 H); 3.03 2.85 (m, 2 H); 1.94 1.82 (m, 2 H); 1.42 (t, J ˆ 7.3, 3 H); 1.16 (d, J ˆ 6.2, 3 H).
13C-NMR (125 MHz, CD3OD): 189.3 (s); 167.5 (s); 161.6 (s); 155.2 (s); 141.9 (d); 140.5 (s); 127.6 (s); 126.1 (d);
125.0 (d); 122.0 (d); 117.1 (s); 112.2 (d); 91.6 (s); 68.8 (t), 67.8 (d); 48.3 (t); 44.5 (t); 37.8 (t); 26.0 (t); 23.4 (q); 11.4
‡
(q). ESI-MS: 634 ([M ‡ H] ).
(Æ)-{4-[2-(Diethylamino)ethoxy]-3,5-diiodophenyl}[2-(3-hydroxybutyl)benzofuran-3-yl]methanone Hy-
drochloride (3 ¥ HCl). To a soln. of 23 (22 mg, 0.0245 mmol) in MeCN was added a 40% aq. HF soln. (22 ml,
0.489 mmol). The mixture was first stirred at r.t. for 14 h, then heated to 608 for 24 h. After quenching with H2O
(4 ml), CH2Cl2 (15 ml) was added, and the org. phase was separated. The aq. phase was adjusted to pH10 with
sat. NaHCO3 soln. and extracted with CH2Cl2 (2 Â 20 ml). The combined org. phase was washed with brine
(10 ml), dried (MgSO4), and evaporated. Pure 3 (6 mg, 37%) was obtained after FC (CH2Cl2/MeOH/25% aq.
NH3 soln. 95 :5 :0.2) as a yellow oil that was transformed into its hydrochloride by dissolving 3 in MeOH(4 ml)
and adding 5 drops of 10% aq. HCl soln. After evaporation, the yellow residue was dried under h.v. for 4 h:
3 ¥ HCl. 1H-NMR (500 MHz, CD3OD): 8.24 (s, 2 H); 7.55 (d, J ˆ 8.2, 1 H); 7.39 (d, J ˆ 7.8, 1 H); 7.35 (ddd, J ˆ 8.2,
7.3, 1.3, 1 H); 7.25 (ddd, J ˆ 7.8, 7.6, 0.8, 1 H); 4.46 (t, J ˆ 5.0, 2 H); 3.84 (t, J ˆ 4.8, 2 H); 3.74 3.67 (m, 1 H );
3.62 3.47 (m, 4 H); 3.03 2.88 (m, 2 H); 1.96 1.82 (m, 2 H); 1.46 (t, J ˆ 7.3, 3 H); 1.17 (d, J ˆ 6.2, 3 H).
13C-NMR (125 MHz, CD3OD, one signal missing): 189.2 (s); 167.5 (s); 161.8 (s); 155.2 (s); 141.9 (d); 140.5 (s);
127.6 (s); 126.1 (d); 125.0 (d); 122.0 (d); 117.1 (s); 111.9 (d); 91.7 (s); 67.8 (d); 67.6 (t); 52.4 (t); 37.8 (t); 26.0 (t);
‡
23.8 (q); 9.2 (q). ESI-MS: 662 ([M ‡ H] ).
REFERENCES
[1] S. N. Singh, R. D. Fletcher, S. G. Fischer, B. N. Singh, H. D. Lewis, P. C. Deedwania, B. M. Massie, C.
Colling, D. Lazzeri, New England J. Med. 1995, 333, 77.
[2] R. J. Flanagan, G. C. Storey, D. W. Holt, P. B. Farmer, J. Pharm. Pharmacol. 1982, 34, 638.
[3] H. R. Ha, P. Wyss, B. Stieger, U. A. Meyer, F. Follath, FASEB J. 1992, 6, A1845 (Abstract).
[4] G. Fabre, B. Julian, B. Sanit-Aubert, H. Joyeux, Y. Berger, Drug Metab. Dispos. 1993, 21, 978.
[5] H. R. Ha, R. Candinas, B. Stieger, U. A. Meyer, F. Follath, J. Cardiovasc. Pharmacol. 1996, 26, 533.
[6] H. R. Ha, L. Bigler, M. Binder, P. Kozlik, B. Stieger, M. Hesse, H. R. Altorfer, F. Follath, Drug Metab.
Dispos. 2001, 29, 152.
[7] H. R. Ha, L. Bigler, B. Wendt, M. Hesse, F. Follath, in preparation.
[8] A. Hercouet, M. Le Corre, Tetrahedron Lett. 1979, 23, 2145.
[9] A. Hercouet, M. Le Corre, Tetrahedron 1981, 37, 2867.
[10] B. A. McKittrick, R. Stevenson, J. Chem. Soc., Perkin Trans. 1 1984, 709.
[11] G. D. McAllister, R. C. Hartley, M. J. Dawson, A. R. Knaggs, J. Chem. Soc., Perkin Trans. 1 1998, 3453.
[12] H. Machleidt, E. Cohnen, R. Tschesche, Liebigs Ann. Chem. 1962, 655, 70.
[13] T. W. Greene, P. G. M. Wuts, −Protective Groups in Organic Synthesis×, Wiley, New York, 1991, p. 83 84,
414 416.
[14] C. F. Carvalho, M. V. Sargent, J. Chem. Soc., Perkin Trans. 1 1984, 1605.
[15] H. Kwiecien, E. Baumann, J. Heterocycl. Chem. 1997, 34, 1587.
[16] P. Kuehne, M. Hesse, Tetrahedron 1993, 49, 4575.
[17] M.-J. Shiao, L.-L. Lai, W.-S. Ku, P.-Y. Lin, J.-R. Hwu, J. Org. Chem. 1993, 58, 4742.
[18] M. E. Jung, M. A. Lyster, J. Org. Chem. 1977, 42, 3761.
[19] I. T. Harrison, J. Chem. Soc., Chem. Commun. 1969, 616.
[20] T.-L. Ho, G. Olah, Synth. Commun. 1977, 417.
[21] M. S. Newman, V. Sankaran, D. R. Olson, J. Am. Chem. Soc. 1976, 98, 3237.
[22] C. Grain, F. Jammot, to Sanofi, Paris, France, Patent 4,766,223, 1988, (Chem. Abstr. 1988, 108, 112215).

Helvetica Chimica Acta Vol. 85 (2002)
3001
[23] A. P. Krapcho, M. J. Maresch, J. Lunn, Synth. Commun. 1993, 23, 2443.
[24] L. Horner, H. Oediger, H. Hoffmann, Liebigs Ann. Chem. 1959, 626, 26.
[25] G. A. Wiley, R. L. Hershkowitz, B. M. Rein, B. C. Chung, J. Am. Chem. Soc. 1964, 86, 964.
[26] A. Hasan, C. R. Lambert, P. C. Srivastava, J. Heterocycl. Chem. 1990, 27, 1877.
[27] J. H. Parkkari, R. A. B. Bannard, I. W. Coleman, Can. J. Chem. 1965, 43, 3119.
[28] M. S. Manhas, W. H. Hoffman, B. Lal, A. K. Bose, J. Chem. Soc., Perkin Trans. 1 1975, 461.
[29] R. Liu, P. E. J. Sanderson, W. C. Still, J. Org. Chem. 1990, 55, 5184.
[30] R. Lis, T. K. Morgan, A. J. Marisca, R. P. Gomez, G. M. Lind, D. D. Davey, J. B. Phillips, M. E. Sullivan, J.
Med. Chem. 1990, 33, 2883.
[31] M. Rejzek, Z. Wimmer, D. Saman, M. Ricankova, Helv. Chim. Acta 1994, 77, 1241.
[32] B. V. Yang, D. O×Rourke, J. Li, Synlett 1993, 195.
[33] E.-J. Corey, B. B. Snidern, J. Am. Chem. Soc. 1972, 2549.
[34] R. F. Newton, D. P. Reynolds, M. A. W. Finch, D. R. Kelly, S. M. Roberts, Tetrahedron Lett. 1979, 41, 3981.
[35] H. R. Ha, L. Bigler, B. Wendt, M. Hesse, F. Follath, in preparation.
[36] N. P. Peet, S. Sunder, J. Org. Chem. 1980, 45, 536.
Received May 28, 2002