we decided to synthesize several new amino acid-derived
iodobenzene dicarboxylates and investigate their reactions
with unsaturated organic substrates in the presence of
tetraphenylphosphonium iodide under conditions previously
described for the reactions of DIB.2a
Amino acid-derived iodobenzene carboxylates 3 were
conveniently prepared by the exchange reaction of DIB 1
with the readily available N-protected amino acids 25
(Scheme 1).
carboxylic group. The ESI-HRMS spectra of compounds 3b
and 3d demonstrated strong [M + K]+ peaks.
We have investigated the reactivity of compounds 3 in
the reaction of iodocarboxylation of cyclohexene and dihy-
dropyran under conditions reported by Kirschning2a for DIB.
First of all, we have found that the reactivity of carboxylates
3 with alkenes is lower than the reactivity of DIB 1; only a
trace amount of the expected â-iodocarboxylate 4 was
observed after reacting reagent 3 with cyclohexene and
tetraphenylphosphonium iodide in methylene chloride under
reflux for several hours. Raising the temperature of the
reaction mixture by adding chlorobenzene (bp 132 °C)
resulted in a significant improvement of the product 4 yield
(Scheme 2).7
Scheme 1. Preparation of Dicarboxylates 3
Scheme 2. Reaction of Dicarboxylates 3 with Cyclohexene
Products 3 were isolated in good yields (Table 1) in the
form of stable, white, microcrystalline solids and were
characterized by spectroscopic data, elemental analysis, and
The optimized yields of â-iodocarboxylates 4 formed in
the reactions of compounds 3 with cyclohexene and dihy-
dropyran are listed in the Table 2. All products 4 were
isolated after column chromatography as a mixture of
nonseparable diastereomers.
Table 1. Preparation of Dicarboxylates 3a
product
yield (%)
3a
3b
3c
3d
3e
79
89b
85
80
68
Amino acid esters 4a-e were characterized by spectro-
scopic data and elemental analysis, and the structure of ester
4c was unambiguously established by single-crystal X-ray
1
analysis.8 In particular, the H NMR spectra of 4 contain
a For typical reaction conditions, see ref 6. b Prepared by reflux in
acetonitrile.
the typical signals of trans disubstituted cyclohexane as well
as the respective signals of the amino acid fragment and the
benzoyl protective group. The LC analysis of the mixture
1
high-resolution mass spectrometry.6 In particular, the H
(7) Representative Procedure. A mixture of reagent 3a (0.588 g, 1
mmol) and tetraphenylphosphonium iodide (0.466 g, 1 mmol) in methylene
chloride (20 mL) was stirred for 15 min at room temperature until the
solution turned dark red. Then, chlorobenzene (20 mL) and cyclohexene
(0.027 g, 0.33 mmol) were added and the resulting mixture was refluxed.
The reaction was monitored by TLC. When the starting materials were
consumed (approximately 10 h), the resulting solution was washed twice
with aqueous NaHSO3 (30 mL of saturated solution) and dried, and then
the solvent was removed under reduced pressure. Crude product was purified
by column chromatography (hexanes/ethyl acetate 2:1) and recrystallized
from a hexanes/ethyl acetate mixture to afford 0.105 g (79%) of analytically
pure product 4a (isolated as a mixture of nonseparable diastereomers). Mp:
135-137 °C. 1H NMR (CDCl3): δ 7.82 (d, J ) 7.2 Hz, 2H), 7.48 (m,
3H), 6.81 (br.s, 1H), 4.97 (m, 1H), 4.83 (m, 1H), 4.11 (m, 1H), 2.48 (m,
1H), 2.14 (m, 1H), 2.04 (m, 1H), 1.84 (m, 1H), 1.63 (d, J ) 7.2, 3H),
1.58-1.33 (m, 4H). 13C NMR (CDCl3): δ 172.1 (171.8), 166.7, 133.9,
131.7, 128.6, 127.0, 78.1 (77.8), 48.7, 38.2, 31.8, 30.9 (30.8), 27.2, 23.6
(23.4), 19.0 (18.6). Anal. Calcd for C16H20INO3: C, 47.89; H, 5.02; I, 31.63;
N, 3.49. Found: C, 47.84; H, 4.97; I, 31.47; N, 3.37. EI MS: m/z (%) 402
(10), [M + H]+.
NMR spectra contain the typical signals of the iodobenzene
moiety as well as the respective signals of the amino acid
fragment and the benzoyl protective group. In the 13C NMR
spectra, the most characteristic are the signals from the
(5) No reaction was observed between unprotected amino acids and DIB
due to the insolubility of amino acids in organic solvents. Protected amino
acids 2 are commercially available or can be prepared by known methods;
see: Zhdankin, V. V.; Smart, J. T.; Zhao, P.; Kiprof, P. Tetrahedron Lett.
2000, 41, 5299.
(6) Representative Procedure. A mixture of DIB 1 (0.322 g, 1 mmol)
and N-benzoyl-L-leucine 2d (0.47 g, 2 mmol) was dissolved in chloroben-
zene (40 mL). The flask was placed on a rotary evaporator, and the reaction
mixture was heated to 50 °C at aspirator vacuum. After complete evaporation
of solvent, the residue was recrystallized from ethyl acetate/hexanes and
dried in a vacuum to afford 0.538 g (80%) of analytically pure product 3d.
1
Mp: 124-126 °C. H NMR (CDCl3): δ 8.08 (dd, J1 ) 8.7 Hz, J2 ) 1.2
Hz, 2H), 7.75 (d, J ) 6.9 Hz, 4H), 7.61 (t, J ) 7.8 Hz, 1H), 7.5-7.40 (m,
8H), 6.58 (d, J ) 8.1 Hz, 2H), 4.82 (m, 2H), 1.61 (m, 6H), 0.90 (m, 12H).
13C NMR (CDCl3): δ 177.4, 167.0, 134.8, 134.1, 132.1, 131.6, 131.1, 128.5,
127.0, 122.0, 51.0, 42.2, 25.0, 22.7, 22.2. Anal. Calcd for C32H37IN2O6:
C, 57.15; H, 5.55; I, 18.87; N, 4.17. Found: C, 57.15; H, 5.65; I, 18.65; N,
4.10. ESI MS: m/z (%) 711.13 (100), [M + K]+.
(8) Compound 4c (C18H24INO3; formula weight 429.28), monoclinic,
space group P21 with a ) 9.6884(11) Å, b ) 17.902(2) Å, c ) 11.1630-
(13) Å; â ) 93.511(2)°, V ) 1932.5(4) Å3, Z ) 4; R ) 0.0513 for 8751
independent observed reflections (I > 2σ(I)); wR2 ) 0.1418 (F2, all data).
Full details on the crystal structure of 4c are available in Supporting
Information.
3614
Org. Lett., Vol. 6, No. 20, 2004
Koposov, Alexey Y
