Unusual Azetidine or Oxazine Formation upon Reaction of O-Ethyl Dithiocarbonate with 1,2,3-Triphenyl-3-Phthalimidopropyl Iodides; Erythro Selectivity in the Reaction of lodotrimethylsilane with Phthalimidopropanols

Article abstract of DOI:10.1039/a802677g

Reaction of isomeric 1,2,3-triphenyl-3-phthalimidopropanols with hexamethyldisilane and iodine gave highly selectively iodides 3 with 1,2-erythro configuration which treated with O-ethyl dithiocarbonate yielded from ET-3 the xanthate ester 4, the trans,trans-dihydrooxazine 5 and the olefin 6 as major products while from EE-3 the cis,trans-azetidine 7 was obtained in 75% yield.

Full text of DOI:10.1039/a802677g

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658 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 658±659$
Unusual Azetidine or Oxazine Formation upon
Reaction of O-Ethyl Dithiocarbonate with
1,2,3-Triphenyl-3-Phthalimidopropyl Iodides;
Erythro Selectivity in the Reaction of
Iodotrimethylsilane with Phthalimidopropanols$
M. E. Ivanova, V. B. Kurteva, M. J. Lyapova* and I. G. Pojarlieff
Institute of Organic Chemistry, Bulgarian Academy of Sciences, ul. Acad. G. Bonchev block 9,
So®a 1113, Bulgaria
Reaction of isomeric 1,2,3-triphenyl-3-phthalimidopropanols with hexamethyldisilane and iodine gave highly selectively
iodides 3 with 1,2-erythro configuration which treated with O-ethyl dithiocarbonate yielded from ET-3 the xanthate ester
4, the trans,trans-dihydrooxazine 5 and the olefin 6 as major products while from EE-3 the cis,trans-azetidine 7 was
obtained in 75% yield.
Our long standing interest in diastereomers with three
adjacent chiral centers has been focused on amino-
propanols.1 In an extention to aminothiols we attempted
to prepare 1,2,3-triphenyl-3-phthalimidopropyl dithiocarbo-
nates from the respective alcohols 1 via the chlorides 2.
The latter proved too unreactive to O-ethyl dithiocarbonate
and for this reason the iodides, 3, were prepared from 1
with iodotrimethylsilane. High yields were obtained and,
contrary to the usually observed inversion of con®guration,2
this reaction showed high erythro selectivity with the
sterically hindered alcohols studied by us: EE-1 gave a
single 3-phthalimido iodide of retained con®guration while
both TT- and ET-1 gave ET-3. This stereochemical result
can be rationalized by the involvement of a carbenium
ion. As is the case with methine protons next to sp2
carbons,3 the preferred conformation for the cation should
be the one with eclipsed hydrogen and a partial double
bond. With such a model (A) the preferred attack should
be from the side of the smaller substituent Ph, compared to
C-3.
Reaction of the iodides 3 with ethyl dithiocarbonate in
dry ethanol gave the desired phthalimidopropyl dithio-
carbonate 4 as a major product only in the case of ET-3
accompanied by considerable amounts of the unexpected
oxazine 5 and the elimination product 6. With the EE iso-
mer of 3, however, a high yield of the cis,trans-azetidine 7
was obtained.
The structure of the cyclic products was deduced from
their spectral properties indicating opening of the phthal-
imide ring and formation of an ester function. Acid hydro-
lysis of oxazine 5 to TT-3-amino-1,2,3-triphenylpropanol
con®rmed reliably its structure. The 13C NMR signals for
C-2 and C-4 of the azetidine 7 coinciding at d 61.88 are
incompatible with an oxazine structure where one carbon
is bonded to O and the other one to N and thence a large
di€erence in the chemical shifts is expected. For oxazine 5
the resonances of the two carbons are separated by 18 ppm.
Heating the iodides in ethanol in the absence of dithio-
carbonate brought about degradation but none of the cyclic
products, implying that dithiocarbonate is involved by
adding to a carbonyl. The intermediate forms the oxazine
ring by rear attack followed by ethanolysis. For azetidine
formation the intermediate breaks down to produce an
amide anion. The conformations of the iodides on Scheme 1
are the preferred ones6 and correlate with cyclization reac-
tivities: in the ET isomer O can be trapped by direct
attack, in the EE isomer changing to an unfavourable
Scheme 1
conformation presumably allows time for break down to
amide anion.
Cyclization of addition intermediates has been
observed in the reaction of aldimine anions with N-(2-
*To receive any correspondence.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

View Article Online
J. CHEM. RESEARCH (S), 1998 659
Table 1 1H NMR chemical shifts (d) and coupling constants
(in Hz, in parentheses)
EE-3. From EE-1, as a single diastereoisomer (NMR), yield 95%,
‡
mp 145±147 8C (decomp.); ꢀ~max 1710, 1760 cm 1; MS (Cl) [M ‡ 1]
m/z 544, 416, 269, 254, 236, 180, 150, 128.
H-2a
H-3(J23)
ET-3. (a) From ET-1,5 crude yield 420 mg, mp 177±179 8C
Compound
H-1(J12
)
‡
(chloroform±hexane, 59%); ꢀ~max 1710, 1760 cm 1; MS (EI) [M I]
415, 269, 268, 254, 236, 180, 150, 128, 127.
EE-1b
4.82(2.8)
4.69
4.77
6.21 (13.2)
6.11(12.2)
ET-1c
5.08(4.20)
5.083(4.5)
5.084(3.1)
5.525(6.9)
5.136(3.6)
5.421(3.6)
5.030(10.4)h
6.415(1.9)k,l
5.033(5.4)n
4.280(2.9)
TT-1d
EE-3
4.956
4.021
4.665
5.250
5.319
3.136i
6.076(11.9)
5.931(11.9)
5.810(11.6)
5.490(12.6)
5.666(12.3)
5.491(10.7)j
6.484(1.9)k,l
5.590(9.9)p
6.213(12.3)
(b) From TT-1, as a mixture of ET-3/ET-1/TT-1 in a ratio of
4.4:1:1.2 (NMR) 480 mg.
Reaction of Phthalimido Iodide ET-3 with Potassium O-ethyl
Dithiocarbonate.ÐET-3 (4.9 g, 9 mmol) and KS2C(OEt) (4.3 g,
27 mmol) in dry ethanol (400 ml) was re¯uxed for 6 h. After
removal of the solvent in vacuo the residue was extracted with
CH2Cl2±water, the organic layer washed with brine, dried (Na2SO4)
and evaporated. The crude reaction product which showed on
TLC more than eight closely moving spots was separated by
¯ash chromatography on Silica gel (ether±hexane 1:4 as eluent)
giving four major products: trans,trans-5,6-dihydro-4H-2 (2-ethoxy-
ET-3
EE-4e
ET-4f
trans,trans-5g
Z-6
cis,trans-7m
EE-8q
3.812o
4.432
aCouplings not shown. bOH 1.78(6.0). cOH 1.98(4.6). dOH
f
2.096(4.5). eCH2 4.504, CH3 1.232. CH2 4.470, CH3 k1.225.
carbonylphenyl)-4,5,6-triphenyl-1,3-oxazine
128±130 8C (diisopropyl ether); ꢀ~max 1673, 1715 cm
5 (800 mg, 22%), mp
13C NMR
i
j
gCH2 4.237, CH3 1.282. hH-4(J45). H-5. H-6(J56). J13
.
1
;
lNo NOE enhancement was observed. mCH2, 4.202, CH3 1.230.
nH-2(J23). oH-3. pH-4(J45). qCH2 3.203, CH3 1.960.
(DEPT) C-2 ꢁ 157.21, C-4 64.29, C-5, 53.33, C-6 81.83, COO
‡
167.63, CH2 61.10, CH3 14.17; MS (CI) [M ‡ 1] m/z 462, 416, 284,
236, 180, 149 (Found: C, 80.82; H, 5.74; N, 3.18. C31H27NO3,
requires C, 80.67; H, 5.90; N, 3.03%); ET S-O-ethyl-1,2,3-triphenyl-
bromoethyl)phthalimides.4 The involvement of the amide
anion in the formation of the azetidine is supported by
the presence of stilbene observed in the fragmentation of a
similar system.1
propyl-3-phthalimido dithiocarbonate 4 (1.4 g, 38%), mp 162±163 8C
1
(ether±pentane); ꢀ~max 1050, 1710, 1760 cm
;
ꢂmax 385 nm
‡
(SCSOC2H5); MS(EI) [M SCSOC2H5] m/z 416, 268, 236, 180,
122(SCSOCH2H5) (Found: C, 71.54; H, 5.20; N, 2.50; S, 11.81.
C32H27NO3S requires C, 71.48; H, 5.06; N, 2.60; S, 11.92%);
The relative con®gurations at C-2, C-3 are not a€ected
in these reactions and so are known from the starting
phthalimido propanols 1.5 Azetidine 7 shows vicinal proton
couplings of 5.4 and 9.9 Hz thus revealing a cis,trans con-
®guration because with equal substituents in positions 2 and
4 the other alternative, the cis,cis isomer, would show equal
constants. Slow rotation on the NMR timescale can be
excluded as it would have doubled the signals of cis,trans-7.
The oxazine 5 shows the characteristic large couplings
of the trans,trans isomer. The most likely intramolecular
cyclization by inversion at C-1 assigns the relative con-
®gurations of the idodides as given in Scheme 1.
The con®gurations of the dithiocarbonates 4 were only
tentatively assigned. In the case EE-3 the con®guration of
the ether 8 was unequivocally assigned by synthesis from
the alcohol EE-1 and ethyl iodide and its con®guration can
be explained by the model given for the iodides. The same
pathway will provide EE-dithiocarbonate from EE-3 and
the ET isomer for ET-3.
z-1,2,3-triphenyl-3-phthalimidoprop-1-ene
6 (864 mmg, 24%), mp
197±199 8C (chloroform±hexane); ꢀ~max 1710, 1760 cm 1; MS(CI)
416, 268, 236, 180 (Found: C, 83.89; H, 5.00; N, 3.59. C29H21NO2
requires C, 83.83; H 5.09; N, 3.37).
Reaction of Phthalimido Iodide EE-3 with Potassium O-ethyl
Dithiocarbonate.ÐA solution of EE-3 (2.71 g, 5 mmol) and
KS2C(OEt) (2.7 g, 15 mmol) in absolute ethanol (150 ml) was
treated in a manner to that described for ET-3 to leave a residue,
which was recrystallized from diisopropyl ether to give 1.04 g
of cis,trans-N-(2-ethoxycarbonylbenzoyl)-2,3,4-triphenylazetidine 7.
A further 0.69 g could be isolated from the evaporated mother-
liquor after separation on Silica gel (ether±hexane 1:4 as eluent),
,
13C NMR
1
total yield 75%, mp 145±147 8C; ꢀ~max 1660, 1715 cm
C-2 and C-4 ꢁ 61.88 (common signal), C-3, 48.52, CO 156.93, COO
168.30, CH2 61.23, CH3 14.17; MS (CI) [M ‡ 1] m/z 462, 282, 177
‡
(Found: C, 80.54; H, 5.92; N, 3.24. C31H27NO3, requires C, 80.67;
H, 5.90; N, 3.03%). Four other products were isolated from the
column: EE-O-ethyl S-1,2,3-triphenyl-3-phthalimidopropyl dithio-
carbonate 4 (90 mg, 3.4%), mp 182±184 8C (diisopropyl ether);
ꢀ~max 1050, 1710, 1760 cm 1; ꢂmax 385 nm (SCSOC2H5); MS(EI)
[M-CS2] m/z 460, [M-SCSOC2H5] 415, 324, 268, 236, 178,
151, 77(CS2); EE-ethyl 1,2,3-triphenyl-3-phthalimidopropyl ether 8
(120 mg, 5.2%), mp 222±224 8C (diisopropyl ether); ꢀ~max 1100,
1710, 1760 cm 1; ESI-FTICR MS m/z 462.2049 (M ‡ 1, theoreti-
cally 462.2064, C31H28NO3) identical with the product obtained
from EE-1 (1 mmol), NaH (4 mmol) and ethyl iodide (4 mmol) in
THF (5 ml) for 6 h at room temperature in 83% yield; 6 (30 mg,
1.4%), identical with the product obtained from ET-3 in the same
reaction; trans-stillbene (60 mg, 6.7%), identical with an authentic
sample.
Experimental
The melting points were measured in capillaries, the IR spectra
on a Specord IR 75 or Bruker IFS 113v instrument in chloro-
form unless stated otherwise, UV spectra on a Specord UV Vis
spectrometer in ethanol, NMR spectra on a Bruker DRX 250 in
deuteriochloroform (chemical shifts are quoted in ppm as d values)
and mass spectra on a JEOL JMS-D 300 spectrometer.
EE-1,2,3-Triphenyl-3-phthalimidopropanol 1.ÐA solution of EE-3-
amino-1,2,3-triphenylpropanol7 (303 mg, 1 mmol) and phthalic
anhydride (148 mg, 1 mmol) in dry pyridine (1 ml) was re¯uxed for
2 h. After cooling the mixture was poured onto ice and allowed
to stand overnight. The separated material was triturated with
10% HCl (50 ml), the solid formed was collected and recrystallized
from ethanol to give compound EE-1 (516 mg, yield 95%), mp
Received, 8th April 1998; Accepted, 30th June 1998
Paper E/8/02677G
References
1 V. B. Kurteva, M. J. Lyapova and I. G. Pojarlie€, J. Chem. Res.
(S), 1993, 270 and references cited therein.
2 G. A. Olah and S. C. Narang, Tetrahedron, 1982, 38, 2225.
3 U. Berg, T. Liljefors, M. Roussel and J. Sandstrom, Acc. Chem.
Res., 1985, 18, 80.
4 N. De Kimpe, Z. Yao, L. De Buyck, R. Verhe and N. Schamp,
Bull. Soc. Chim. Belg., 1986, 95, 197.
5 M. J. Lyapova and M. E. Ivanova, Compt. Rend. Acad. Bulg.
Sci., 1982, 35, 1669.
6 V. S. Dimitrov, V. B. Kurteva, M. J. Lyapova, B. P. Mikhova
and I. G. Pojarlie€, Magn. Reson. Chem., 1988, 26, 564.
7 M. J. Lyapova and B. J. Kurtev, Chem. Ber., 1969, 102, 3739;
1971, 104, 131.
‡
217±218 8C; ꢀ~max 1710, 1760, 3400 cm 1; MS (Cl) [M ‡ 1] m/z 434,
416, 374, 270, 254, 210 (Found: C, 80.12; H, 5.35; N, 3.18.
C29H23NO3, requires C, 80.35; H, 5.35; N, 3.23%).
Diastereomeric 1,2,3-Triphenylpropyl-3-phthalimido Iodides (3):
General Procedure.ÐIodine (254 mg, 1 mmol) and hexamethyl-
disilane (0.2 ml, 1 mmol) were added to a stirred solution of the
appropriate phthalimidopropanol (434 mg, 1 mmol) in dry chloro-
form (5 ml) under argon. After 4 h of stirring at room temperature
the reaction mixture was rapidly extracted with 10% Na2S2O3 (aq),
the organic layer was washed with brine, dried (Na2SO4) and
evaporated to dryness under reduced pressure.