The Journal of Organic Chemistry
Article
3.89−3.97 (m, 1H, H4), 3.74 (s, 3H, CO2CH3), 3.68−3.72 (m, 1H,
H5B), 2.61 (br s, 1H, NH,- averaged with cis isomer NH), 0.91 (s, 9H,
C(CH3)3); 13C{1H} NMR (100 MHz, CDCl3) major isomer (cis): δ
173.0 (CO2CH3), 100.0 (C2), 68.4 (C4), 59.6 (C5), 52.7 (CO2CH3),
33.3 (C(CH3)3), 25.3 (C(CH3)3); minor isomer (trans): 173.2
(CO2CH3), 99.3 (C2), 69.0 (C4), 59.5 (C5), 52.5 (CO2CH3), 34.6
(C(CH3)3), 25.0 (C(CH3)3); IR (neat) νmax/cm−1 3316, 2955, 1740;
HRMS (TOF, ESI+) m/z: [M+H]+ Calcd for C9H18NO3 188.1281;
Found 188.1285.
washed with buffer at pH 5, 7, and 9 (see details in Supporting
Information). Only the sample subjected to the pH 5 buffer gave
rise to the SCRFK cross-peaks, while those from the higher pH
buffers did not (Figure S7). Scalar cross-relaxation peaks were
observed across a range of solvents including CD2Cl2, CDCl3,
C6D6, and toluene, although the exception was DMSO which
appeared to inhibit these peaks, likely due to hydrogen-bonding
perturbing the NH exchange process.
The likely involvement of bimolecular exchange was also seen
to influence the proton spectrum of 4d as a function of solution
concentration (Figure 5). An increase was seen to lead to
broadening of the NH resonance of both isomers with
corresponding exchange decoupling of neighboring protons,
indicative of an increase in exchange rate. Correspondingly,
scalar cross-relaxation cross-peaks were observed only at the
higher concentration for this sample. Slight shift changes are also
apparent in the spectra of Figure 5 as a function of concentration,
most notably for the NH and the adjacent CH protons, which
suggests association, potentially through intermolecular hydro-
gen bonding involving amino and carbonyl groups. Such
association may promote the bimolecular exchange process
and serve to enhance the appearance of scalar cross-relaxation.
Thus, sample concentration will also likely dictate conditions
under which scalar cross-relaxation peaks may be seen in NOESY
spectra when proton exchange is involved, alongside temperature
and solvent acidity.
Methyl (2RS,4S,5R)-2-(tert-Butyl)-5-methyl-1,3-oxazolidine-4-car-
boxylate (4b). Yield (1.84 g, 77%); yellow oil; inseparable 1:1
1
diastereomers. Rf (50% EtOAc in DCM) 0.64; H NMR (400 MHz,
CDCl3) (2R,4S,5R) isomer: δ 4.29 (s, 1H, H2), 3.78−3.88 (m, 1H, H5),
3.75 (s, 3H, CO2CH3), 3.46 (d, 1H, J = 7.2 Hz, H4), 2.69 (br s, 1H, NH,
averaged with 2S,4S,5R isomer NH), 1.33 (d, 3H, J = 6.0 Hz, C(5)CH3),
0.97 (s, 9H, C(CH3)3); (2S,4S,5R) isomer: 4.38 (s, 1H, H2), 3.78−3.88
(m, 1H, H5), 3.77 (s, 3H, CO2CH3), 3.36 (d, 1H, J = 7.2 Hz, H4), 2.69
(br s, 1H, NH, averaged with 2R,4S,5R isomer NH), 1.37 (d, 3H, J = 6.0
Hz, C(5)CH3), 0.90 (s, 9H, C(CH3)3); 13C{1H} NMR (100 MHz,
CDCl3) (2R,4S,5R) isomer: δ 172.1 (CO2CH3), 98.9 (C2), 76.4 (C5),
65.9 (C4), 52.6 (CO2CH3), 34.7 (C(CH3)3), 24.9 (C(CH3)3), 20.0
(C(5)CH3); (2S,4S,5R) isomer: 172.8 (CO2CH3), 98.3 (C2), 77.4
(C5), 67.2 (C4), 52.5 (CO2CH3), 33.7 (C(CH3)3), 25.3 (C(CH3)3),
19.1 (C(5)CH3); IR (neat) νmax/cm−1 3315, 2957, 1741; HRMS (TOF,
ESI+) m/z: [M+Na]+ Calcd for C10H19NNaO3 224.1257; Found
224.1266.
Methyl (2RS,4S)-2-(tert-Butyl)-1,3-thiazolidine-4-carboxylate
(4c).29 Yield (2.32 g, 98%); yellow oil; inseparable 2.6:1 cis and trans
1
diastereomers. Rf (75% EtOAc in DCM) 0.61; H NMR (500 MHz,
CDCl3) major isomer (cis): δ 4.43 (s, 1H, H2), 3.78 (dd, 1H, J = 9.7, 6.7
Hz, H4), 3.75 (s, 3H, CO2CH3), 3.23 (t, 1H, J = 10.2, 6.7 Hz, H5A), 2.65
(t, 1H, J = 10.0 Hz, H5B), 2.40 (br s, 1H, NH, averaged with trans isomer
NH), 1.04 (s, 9H, C(CH3)3); minor isomer (trans): 4.50 (s, 1H, H2),
4.11 (t, 1H, J = 6.0 Hz, H4), 3.72 (s, 3H, CO2CH3), 3.08 (t, 1H, J = 10.6,
6.4 Hz, H5A), 2.99 (dd, 1H, J = 10.6, 5.6 Hz, H5B), 2.40 (br s, 1H, NH,
averaged with cis isomer NH), 0.95 (s, 9H, C(CH3)3); 13C{1H} NMR
(100 MHz, CDCl3) major isomer (cis): δ 171.9 (CO2CH3), 81.9 (C2),
65.5 (C4), 52.5 (CO2CH3), 37.5 (C5), 34.1 (C(CH3)3), 27.1
(C(CH3)3); minor isomer (trans): 172.5 (CO2CH3), 79.9 (C2), 65.1
(C4), 52.5 (CO2CH3), 37.1 (C5), 36.0 (C(CH3)3), 26.7 (C(CH3)3); IR
(neat) νmax/cm−1 3317, 2954, 1740; HRMS (TOF, ESI+) m/z: [M
+Na]+ Calcd for C9H17NNaO2S 226.0872; Found 226.0880.
Methyl (2RS,4R)-2-Phenyl-1,3-thiazolidine-4-carboxylate (4d).
Yield (2.37 g, 91%); colorless oil; inseparable 1.6:1 cis and trans
diastereomers; Rf (25% ethyl acetate in petroleum ether) 0.48; 1H NMR
(500 MHz, CDCl3) major isomer (cis): δ 7.56−7.47 and 7.41−7.31 (m,
5H, Ar−CH), 5.57 (s, 1H, H2), 3.99 (dd, 1H, J = 9.0, 7.0 Hz, H4), 3.80
(s, 3H, CO2CH3), 3.47 (dd, 1H, J = 10.43, 7.0 Hz, H5A), 3.12 (dd, 1H, J
= 10.3, 9.0 Hz, H5B), 2.70 (br. s, 1H, NH, averaged with trans isomer
NH); minor isomer (trans): δ 7.41−7.31 (m, 5H, Ar−CH), 5.82 (s, 1H,
H2), 4.22 (dd, 1H, J = 7.1, 5.8 Hz, H4), 3.79 (s, 3H, CO2CH3), 3.39 (dd,
1H, J = 10.6, 7.1 Hz, H5A), 3.21 (dd, 1H, J = 10.6, 5.8 Hz, H5B), 2.70 (br.
s, 1H, NH, averaged with cis isomer NH); 13C{1H} NMR (100 MHz,
CDCl3) major isomer (cis): δ 171.6 (CO2CH3), 138.2 (Ar−C), 128.7,
128.5, 127.5 (Ar-CH), 70.9 (C2), 64.3 (C4), 52.6 (CO2CH3), 39.2
(C5); minor isomer (trans): δ 172.2 (CO2CH3), 141.2 (Ar−C), 128.7,
127.9, 127.0 (Ar-CH), 72.6 (C2), 65.6 (C4), 52.6 (CO2CH3), 38.2
(C5); IR (neat) νmax/cm−1 3314, 2952, 1736; HRMS (TOF, ESI+) m/z:
[M+Na]+ Calcd for C11H13NNaO2S 246.0559; Found 246.0563.
Methyl (2RS,4R)-2-(4-Bromophenyl)-1,3-thiazolidine-4-carboxy-
late (4e). Yield (5.60 g, 94%); colorless oil; inseparable 1.4:1 cis and
trans diastereomers; Rf (20% ethyl acetate in petroleum ether) 0. 23; 1H
NMR (500 MHz, C6D6) major isomer (cis): δ 7.39 (d, 2H, J = 8.5 Hz,
Ar−CH), 7.30 (d, 2H, J = 8.4 Hz, Ar−CH), 5.40 (s, 1H, H2), 3.87 (app
t, 1H, J = 7.9 Hz, H4), 3.70 (s, 3H, CO2CH3), 3.35 (dd, 1H, J = 10.4, 7.1
Hz, H5A), 3.00 (dd, 1H, J = 10.3, 8.9 Hz, H5B), 2.90−2.32 (br. s, 1H,
NH, averaged with trans isomer NH); minor isomer (trans): δ 7.34 (d,
2H, J = 8.5 Hz, Ar−CH), 7.26 (d, 2H, J = 8.4 Hz, Ar−CH), 5.66 (s, 1H,
H2), 4.03 (app t, 1H, J = 6.5 Hz, H4), 3.69 (s, 3H, CO2CH3), 3.27 (dd,
1H, J = 10.6, 7.1 Hz, H5A), 3.06 (dd, 1H, J = 10.6, 6.1 Hz, H5B), 2.90−
CONCLUSIONS
■
The appearance of anomalous cross-peaks in the NOESY spectra
of oxazolidines and thiazolidines has been attributed to scalar
cross-relaxation of the first kind that arises when the J-couplings
between correlated protons are slowly modulated. These cross-
peaks have opposite sign to positive NOEs and an appearance
similar to chemical exchange peaks, although they do not arise
between mutually exchanging protons. For these systems, they
are shown to arise from proton on−off exchange at the amino
nitrogen which leads to modulation of proton scalar couplings,
and their appearance is therefore sensitive to solution conditions
that will influence this exchange rate, including sample
temperature, solution acidity, and solute concentration. The
presence of such peaks in (1D and 2D) NOESY spectra will likely
occur in any system in which scalar couplings are modulated at an
appropriate rate (on the millisecond time scale), with likely
mechanisms including conformational interconversion, nitrogen
inversion, and proton exchange.
EXPERIMENTAL SECTION
■
Synthesis. General Procedure for the Synthesis of Oxazolidine
and Thiazolidine Compounds.26 To the relevant methyl ester
hydrochloride (1.0 equiv) in petroleum ether, triethylamine (1.5
equiv) and aldehyde (1.2 equiv) were added. The mixture was heated at
reflux with continuous removal of water using a Dean−Stark head for 18
h. The white precipitate was then filtered and washed with Et2O. The
combined filtrates were concentrated under reduced pressure to give the
oxazolidine or thiazolidine. All aryl substituted thiazolidines were
purified by flash column chromatography (SiO2, EtOAc/Petroleum
ether).
Methyl (2RS,4S)-2-(tert-Butyl)-1,3-oxazolidine-4-carboxylate
(4a).27,28 Yield (5.85 g, 97%); yellow oil; inseparable 1.4:1 cis and
1
trans diastereomers. Rf (85% EtOAc in DCM) 0.64; H NMR (400
MHz, CDCl3) major isomer (cis): δ 4.07 (s, 1H, H2), 3.89−3.97 (m, 2H,
H5A + H4), 3.76 (s, 3H, CO2CH3), 3.68−3.72 (m, 1H, H5B), 2.61 (br s,
1H, NH, averaged with trans isomer NH), 0.98 (s, 9H, C(CH3)3); minor
isomer (trans): 4.32 (s, 1H, H2), 4.11 (app t, 1H, J = 7.6 Hz, H5A),
E
J. Org. Chem. XXXX, XXX, XXX−XXX