Electrophilic α-thiocyanation of chiral and achiral N-acyl imides. A convenient route to 5-substituted and 5,5-disubstituted 2,4-thiazolidinediones

Article abstract of DOI:10.1016/j.bmcl.2008.02.034

Electrophilic α-thiocyanation of N-acyl carboximides using N-thiocyanatosuccinimide and hydrolytic cyclization of the adducts affords 5-substituted and 5,5-disubstituted 2,4-thiazolidinediones in good overall yields. α-Thiocyanation of chiral N-acyl carboximides proceeds with excellent diastereoselectivity, although partial racemization occurs during subsequent cyclization.

Full text of DOI:10.1016/j.bmcl.2008.02.034

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Bioorganic & Medicinal Chemistry Letters 18 (2008) 1768–1771
Electrophilic a-thiocyanation of chiral and achiral N-acyl imides.
A convenient route to 5-substituted and 5,5-disubstituted
2,4-thiazolidinediones
J. R. Falck,* Shuanhu Gao, Ravi Naga Prasad and Sreenivasulu Reddy Koduru
Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Received 14 January 2008; revised 8 February 2008; accepted 13 February 2008
Available online 16 February 2008
Abstract—Electrophilic a-thiocyanation of N-acyl carboximides using N-thiocyanatosuccinimide and hydrolytic cyclization of the
adducts affords 5-substituted and 5,5-disubstituted 2,4-thiazolidinediones in good overall yields. a-Thiocyanation of chiral N-acyl
carboximides proceeds with excellent diastereoselectivity, although partial racemization occurs during subsequent cyclization.
ꢀ 2008 Elsevier Ltd. All rights reserved.
The 2,4-thiazolidinedione (TZD) moiety is extensively
utilized as a carboxylic acid mimetic to improve the met-
abolic stability and therapeutic profile of bioactive
agents.1 TZDs are often prepared from the parent car-
boxylates via a three-step sequence of a-halogenation,
nucleophilic displacement with thiourea2 or KSCN,3
and hydrolytic ring closure, although this route can be
problematic for 5,5-disubstituted thiazolidinediones4
and/or if sensitive functionality is present.5 Conse-
quently, we sought an alternative procedure and report
herein the direct a-thiocyanation of N-acyl carboximides
1 (R@H) using N-thiocyanatosuccinimide6 (2) and
hydrolytic cyclization of adduct 3 to TZDs 4 in good
overall yields (Eq. 1). Notably, a-thiocyanation of chiral
1 (R@PhCH2A) proceeded with excellent diastereoselec-
tivity, although partial racemization occurred during
cyclization to 4.
forts to add 2 to enolic intermediates generated from
carboxylic acids and esters routinely afforded little if
any of the desired a-thiocyanate adduct. N-Acyl carbox-
imides7 1 (R@H), in sharp contrast, reacted smoothly
with 2 following the Evans’ protocol7 (Method A8) to
give 3 in good yields (Table 1).9 The reaction was com-
patible with an electron rich aryl (Entry 1), sulfur het-
erocycle (Entry 2), terminal and disubstituted
acetylenes (Entries 3 and 4), terminal olefin (Entry 5),
and vinyl dibromide (Entry 6). a-Phenoxy carboximide
23 (Entry 7), on the other hand, proved recalcitrant as
the boron enolate, but could be coaxed to react with 2
by way of its lithium salt (Method B8).
Cyclization to the corresponding TZDs 4 (Table 1) was
best done with a two-step, one-pot process via initial
methoxide addition to the thiocyanate with concomitant
annulation and then acidic hydrolysis of the resultant 2-
methoxythiazol-4(5H)-ones.10 Not surprisingly, 25 was
hydrolytically labile and could not be isolated in any sig-
nificant amount. Analogous a-thiocyanations of 4(R)-
phenylmethyl-2-oxazolidinones7 26 (Entry 1) and 28
(Entry 2) via Method A proceeded in good yields and
with virtually complete diastereoselectivities (Table 2).
By analogy with comparable boron enolate azidations
and brominations, adducts 27 and 29 were assigned
the 2R-stereochemistry. a,a-Disubstituted carboxamides
30a11 and b (Entry 3) reacted sluggishly under the same
conditions, so we adapted Kobayashi’s protocol12
[LDA, Ti(O-i-Pr)3Cl] for the a-thiocyanation (Method
C8). The same chromatographically separable 1:1 mix-
ture of diastereomers 31a and b was obtained starting
ð1Þ
Based upon earlier studies by Toste et al.,6 we selected
N-thiocyanatosuccinimide (2) as a convenient source
of S-electrophilic thiocyanate. However, extensive ef-
Keywords: Thiocyanate; Thiazolidinedione; Enolate; Asymmetric;
Heterocycle.
*
Corresponding author. Tel.: +1 214 648 2406; fax: +1 214 648
6455; e-mail: j.falck@UTSouthwestern.edu
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.02.034

J. R. Falck et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1768–1771
1769
Table 1. a-Thiocyanation of N-acyl imides and hydrolytic cyclization
Entry Carboximide a-Thiocyanate
Yield (%) TZD
Yielda (%)
1
78b
78
66
62
2
3
74b
69b
4
5
71b
68
71
72b
6
7
71b
68
54c
0
a (i) NaOMe, MeOH, 0 ꢁC; (ii) 2 N HCl, rt.
b Prepared via Method A.
c Prepared via Method B.
Table 2. Asymmetric a-thiocyanation of N-acyl imides
Entry Carboximide
a-Thiocyanate
Yield (%)
d.r.a
99:1
1
83b
2
74b
99:1
3
66c
1:1
Stereochemical assignments are tentative.
a Determined by 1H/13C NMR.
b Prepared via Method A.
c Prepared via Method C.

1770
J. R. Falck et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1768–1771
Scheme 1. Reagents and conditions: (a) Pt(Me2POH)3 (25 mol%), THF/H2O (2:1), 40 ꢁC, 2 h; (b) LDA (1.2 equiv), THF/Et2O (2:1), ꢀ78 ꢁC, 2 h.
Elem. 2006, 181, 1039; (b) Hu, B.; Malamas, M.; Elling-
boe, J.; Largis, E.; Han, S.; Mulvey, R.; Tillett, J. Bioorg.
Med. Chem. Lett. 2001, 11, 981; (c) Singh, S. P.; Parmar,
S. S.; Raman, K.; Stenberg, V. I. Chem. Rev. 1981, 81, 175;
(d) Gaupp, S.; Effenberger, F. Tetrahedron: Asymmetry
1999, 10, 1777.
from either 30a or b. All efforts to convert thiocyanates
27 and 29 to TZDs using the above and related hydro-
lytic conditions induced complete racemization at the
C(2)-stereogenic centers. Reasoning that the a-hydrogen
would be less prone to epimerization if the thiocyanate
was transformed into a thiocarbamate, we developed
an exceptionally mild procedure utilizing the Ghaffar–
Parkins’ catalyst in THF/water.13 In practice, 32 was ob-
tained from 27 in excellent yield and with no indication
6. Toste, F. D.; De Stefano, V.; Still, I. W. J. Synth.
Commun. 1995, 25, 1277.
7. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L.
J. Am. Chem. Soc. 1990, 112, 4011.
1
of epimerization by H/13C NMR analysis (Scheme 1).
8. Method A: n-Bu2BOTf (1 M solution in CH2Cl2, 1.1 mmol)
was added with stirring to a 0 ꢁC solution of N-acyl imide 1
(1 mmol) in CH2Cl2 (10 mL) under an argon atmosphere
followed by neat (i-Pr)2NEt (1.2 mmol). After 1 h, the
resultant slurry was cooled to ꢀ78 ꢁC and a solution of 2
(2 mmol) in CH2Cl2 (12 mL) was slowly added via syringe.
After 1.5 h, the reaction was quenched using pH 7
phosphate buffer (3.5 mL) and 30% H2O2 (22 mmol).
Hydrogen peroxide was omitted during the quenching of
adducts 9, 21, and 29. Extractive isolation and purification
by SiO2 chromatography gave a-thiocyanate 3 in the
indicated yields (Table 1).
Unfortunately, cyclization to 33, even at low tempera-
ture, resulted in some loss of C(2)-stereochemical integ-
rity as determined by chiral HPLC.14,15
As anticipated, cyclizations of thiocyanates 31a and b,
which lack epimerizable a-hydrogens, using either of
the above annulation procedures were uneventful and
the derived 5,5-disubstituted TZDs 34a and b were se-
cured as single enantiomers14 in ca. 70% yield.
Method B: A precooled (ꢀ78 ꢁC) solution of N-acyl imide 1
(1 mmol) in dry THF (10 mL) was added via cannula to a
stirring, ꢀ78 ꢁC solution of LDA (1.2 mmol) in dry THF
(6 mL) under an argon atmosphere. After stirring for
30 min, a freshly prepared solution of 2 (2 mmol) in dry
THF (3 mL) was added dropwise and the reaction mixture
was allowed to stir for 2 h at ꢀ78 ꢁC. The reaction mixture
was quenched with saturated aq NH4Cl (10 mL) and
extracted with EtOAc (3· 15 mL). The combined organic
extracts were washed with brine, dried (Na2SO4), concen-
trated in vacuo, and the residue was purified by SiO2
column chromatography to give a-thiocyanate 3 in the
indicated yield (Table 1). Method C: A precooled (ꢀ78 ꢁC)
solution of N-acyl imide 30a or b (1 mmol) in dry THF
(15 mL) was added via cannula to a stirring, ꢀ78 ꢁC
solution of LDA (2 mmol) in dry THF (12 mL) under an
argon atmosphere. After 30 min, Ti(O-i-Pr)3Cl (4 mmol,
1 M solution in hexane) was added and the reaction
mixture was warmed to ꢀ40 ꢁC. After 1 h, the mixture
was re-cooled to ꢀ78 ꢁC and a freshly prepared solution of
2 (2 mmol) in dry THF (3 mL) was added dropwise. After
2 h at ꢀ78 ꢁC, the reaction mixture was quenched with
saturated aq NH4Cl (10 mL) and extracted with EtOAc (3·
15 mL). The combined organic extracts were washed with
brine, dried (Na2SO4), concentrated in vacuo, and the
residue was purified by PTLC to give 31a and b (66%
combined yield, 1:1). PTLC: benzene/ether (96:4), 31a and
b Rf ꢁ 0.67 and 0.61, respectively. The absolute configura-
Acknowledgments
Financial support provided by the Robert A. Welch
Foundation and NIH (GM31278, DK38226).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.2008.
02.034.
References and notes
1. (a) Boyd, A. S. Int. J. Derm. 2007, 46, 557; (b) McIntyre,
R. S.; Soczynska, J. K.; Woldeyohannes, H. O.; Lewis, G.
F.; Leiter, L. A.; MacQueen, G. M.; Miranda, A.; Fulgosi,
D.; Konarski, J. Z.; Kennedy, S. H. Expert Opin.
Pharmacother. 2007, 8, 1615; (c) Elte, J. W. F.; Blickle,
J. F. Eur. J. Inter. Med. 2007, 18, 18.
1
tions of 31a and b are based upon comparisons of H/13C
2. Momose, Y.; Maekawa, T.; Yamano, T.; Kawada, M.;
Odaka, H.; Ikeda, H.; Sohda, T. J. Med. Chem. 2002, 45,
1518.
3. Sohda, T.; Mizuno, K.; Kawamatsu, Y. Chem. Pharm.
Bull. 1984, 32, 4460.
4. Doran, W. J.; Shonle, H. A. J. Org. Chem. 1938, 3, 193.
5. Alternative syntheses: (a) Metwally, M.; Etman, H.;
Keshk, E.; Fekry, A. Phosphorus, Sulfur Silicon Relat.
NMR and are tentative.
9. Spectral and physical data for representative compounds:
Compound 5: pale yellow solid, mp 78.8–80.6 ꢁC; TLC:
EtOAc/hexane (3:7), Rf ꢁ 0.39; 1H NMR (CDCl3,
300 MHz) d 7.11 (d, 2H, J = 8.4 Hz), 6.82 (d, 2H,
J = 8.4 Hz), 4.32 (t, 2H, J = 8.1 Hz), 3.98 (t, 2H,
J = 8.1 Hz), 3.78 (s, 3H), 2.94 (t, 2H, J = 7.8 Hz), 2.63 (t,
2H, J = 7.8 Hz), 1.96 (apparent p, 2H, J = 7.5 Hz); 13C

J. R. Falck et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1768–1771
1771
D
NMR (CDCl3, 100 MHz) d 173.5, 158.0, 153.7, 133.8,
129.6, 113.9, 62.25, 55.4, 42.7, 34.7, 34.4, 26.3.
69.9, 55.5, 55.4, 45.4, 37.6, 32.6, 31.9; ½aꢂ25 ꢀ110.1 (c 1.05,
CHCl3).
Compound 28: mp 46.8–48.2 ꢁC; TLC: EtOAc/hexane
Compound 6: TLC: EtOAc/hexane (3:7), Rf ꢁ 0.37; 1H
NMR (CDCl3, 300 MHz) d 7.09 (d, 2H, J = 6.3 Hz), 6.82
(d, 2H, J = 6.3 Hz), 4.82 (t, 1H, J = 9.3 Hz), 4.51–4.36 (m,
2H), 4.23–3.92 (m, 2H), 3.77 (s, 3H), 2.85–2.65 (m, 2H),
2.53–2.25 (m, 2H); 13C NMR (CDCl3, 100 MHz) d 167.9,
158.2, 153.1, 131.1, 129.4, 113.9, 109.2, 62.4, 55.2, 45.1,
42.5,32.6, 31.6.
1
(2:3), Rf ꢁ 0.40; H NMR (CDCl3, 400 MHz) d 7.34–7.12
(m, 6H), 6.92 (dd, 1H, J = 3.5, 5.2 Hz), 6.83 (d, 1H,
J = 3.5 Hz), 4.68–4.63 (m, 1H), 4.19–4.14 (m, 2H), 3.27
(dd, 1H, J = 13.6, 3.2 Hz), 3.04–2.92 (m, 4H), 2.75 (dd,
1H, J = 13.2, 9.6 Hz), 2.12–2.02 (m, 2H); 13C NMR
(CDCl3, 75 MHz) d 172.8, 153.5, 144.3, 135.4, 129.5,
129.1, 127.5, 126.9, 124.7, 123.4, 66.3, 55.2, 38.0, 34.8,
Compound 7: mp 74.2–76.6 ꢁC; TLC: EtOAc/hexane
D
1
(3:7), Rf ꢁ 0.48; H NMR (CDCl3, 400 MHz) d 8.02 (br
29.2, 26.2; ½aꢂ25 ꢀ48.1. (c 1.01, CHCl3).
s, 1H, NH), 7.08 (d, 2H, J = 8.8 Hz), 6.83 (d, 2H,
J = 8.8 Hz), 4.17 (dd, 1H, J = 16, 4.4 Hz), 3.78 (s, 3H),
2.83–2.65 (m, 2H), 2.53–2.44 (m,1H), 2.23–2.13 (m, 1H);
13C NMR (CDCl3, 75 MHz) d 174.7, 170.3, 158.6, 131.2,
129.8, 114.4, 55.5, 50.9, 35.0, 32.4.
Compound 29: Pale yellow solid, mp 62.8–64.2 ꢁC; TLC:
EtOAc/hexane (1:4, 2 elutions), Rf ꢁ 0.30; 1H NMR
(CDCl3, 300 MHz) d 7.14–7.38 (m, 6H), 6.92 (dd, 1H,
J = 3.6, 5.1 Hz), 6.84 (d, 1H, J = 3.6 Hz), 4.79 (t, 1H,
J = 9 Hz), 4.71–4.61 (m, 1H), 4.23 (d, 2H, J = 4.8 Hz),
3.32 (dd, 1H, J = 13.5, 2.7 Hz), 3.10–3.05 (m, 2H), 2.90
(dd, 1H, J = 13.5, 9.3 Hz), 2.70–2.38 (m, 2H); 13C NMR
(CDCl3, 75 MHz) d 167.7, 153.3, 141.9, 134.7, 129.7,
129.3, 127.8, 127.3, 125.6, 124.3, 109.2, 66.9, 55.5, 45.2,
Compound 8: mp 76.7–77.7 ꢁC; TLC: EtOAc/hexane
(2:3), Rf ꢁ 0.4; 1H NMR (CDCl3, 300 MHz) d 7.10 (d,
1H, J = 5.1 Hz), 6.91 (dd, 1H, J = 5.1, 3.3 Hz), 6.81 (d,
1H, J = 3.3 Hz), 4.39 (t, 2H, J = 7.8 Hz), 4.00 (t, 2H,
J = 7.8 Hz), 2.99 (t, 2H, J = 7.2 Hz), 2.91 (t, 2H,
J = 7.2 Hz), 2.05 (apparent p, 2H, J = 7.2 Hz); 13C NMR
(CDCl3, 75 MHz) d 173.1, 153.7, 144.4, 126.9, 124.7,
123.4, 62.2, 42.6, 34.5, 29.3, 26.3.
D
37.6, 32.5, 26.7; ½aꢂ25 ꢀ79.25 (c 0.81, CHCl3).
10. TZD cyclization procedure: NaOMe (2.5 mmol) added
with stirring to a 0 ꢁC solution of a-thiocyanate 3
(1 mmol) in dry MeOH/THF (4:1, 50 mL). After 1 h, the
reaction mixture was acidified with 2 N HCl to pH 2. After
stirring at rt for 3 h, the organic solvent was removed in
vacuo and the aqueous residue was extracted with EtOAc
(3· 10 mL). The combined organic extracts were washed
with water, dried, concentrated in vacuo and the residue
purified by SiO2 chromatography to give 2,4-thiazolidin-
edione 4 in the indicated yields (Table 1).
Compound 9: TLC: EtOAc/hexane (3:7), Rf ꢁ 0.35; 1H
NMR (CDCl3, 400 MHz) d 7.13–7.05 (d, 1H, J = 5.2 Hz),
6.91 (dd, 1H, J = 5.1, 3.3 Hz), 6.82 (d, 1H, J = 3.3 Hz),
4.84 (t, 1H, J = 8 Hz), 4.49–4.40 (m, 2H), 4.11–3.96 (m,
2H), 3.06–3.02 (m, 2H), 2.57–2.35 (m,2H); 13C NMR
(CDCl3, 100 MHz) d 167.9, 153.4, 141.9, 127.3, 125.6,
124.3, 109.3, 62.8, 45.1, 42.8, 32.7, 26.7.
Compound 10: mp 67.7–70.2 ꢁC; TLC: EtOAc/hexane
(3:7, 3 elutions), Rf ꢁ 0.38; 1H NMR (CDCl3, 400 MHz) d
8.95 (s, 1H, NH), 7.17 (d, 1H, J = 4.8 Hz), 6.93 (dd, 1H,
J = 4.8, 3.4 Hz), 6.83 (d, 1H, J = 3.4 Hz), 4.25 (dd, 1H,
J = 9.6, 4.4 Hz), 3.22–2.86 (m, 2H), 2.61–2.53 (m, 1H),
2.30–2.17 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 175.3,
171.0, 141.6, 127.3, 125.7, 124.4, 50.6, 35.0, 27.4.
11. Imide 30 was prepared from racemic 2-methyl-3-phenyl-
propanoic acid and diastereomers 30a and
b were
separated chromatographically [TLC: EtOAc/hexane
(3:7), 30a and b Rf ꢁ 0.40 and 0.38, respectively]. The
absolute configuration of 30a was established by sapon-
ification [LiOH/H2O2, THF/H2O (2:1), 0 ꢁC] and com-
parison of the free acid optical rotation with the
literature value: Lentz, N. L.; Peet, N. P. Tetrahedron
Lett. 1990, 31, 811.
Compound 26: mp 70.8–71.6 ꢁC; TLC: EtOAc/hexane
1
(2:3), Rf ꢁ 0.44; H NMR (CDCl3, 300 MHz) d 7.35–7.19
(m, 5H), 7.13 (d, 2H, J = 9 Hz), 6.83 (d, 2H, J = 9 Hz),
4.69–4.59 (m, 1H), 4.12–4.21 (m, 2H), 3.78 (s, 3H), 3.28
(dd, 1H, J = 13.2, 3.3 Hz), 3.08–2.88 (m, 2H), 2.74 (dd,
1H, J =13.2, 3.3 Hz), 2.68–2.63 (m, 2H), 2.04–1.93 (m,
2H); 13C NMR (CDCl3, 100 MHz) d 172.9, 157.7, 153.3,
135.2, 133.4, 129.3, 128.8, 127.2, 113.6, 66.0, 55.1, 54.9,
12. Murata, Y.; Kamino, T.; Hosokawa, S.; Kobayashi, S.
Tetrahedron Lett. 2002, 43, 8121.
13. Ghaffar, T.; Parkins, A. W. Tetrahedron Lett. 1995, 36,
8657.
14. Chiral HPLC of 33: Chiralpakꢂ AD (250 · 4.6 mm),
hexane/i-PrOH/AcOH (5:1:0.01), flow rate 1 mL/min,
230 nm, Rt ꢁ 9.86 and 14.61 min. For 34a and b:
Rt ꢁ 6.4 and 13.7 min, respectively.
D
37.7, 34.8, 34.1, 25.9; ½aꢂ23 ꢀ43.7 (c 1.34, CHCl3).
Compound 27: mp 108.3–109.9 ꢁC; TLC: EtOAc/hexane
1
(3:7), Rf ꢁ 0.30; H NMR (CDCl3, 300 MHz) d 7.35–7.20
15. The interconversion of 5-substituted TZD enantiomers
under various conditions has been noted before: Welch, C.
J.; Kress, M. H.; Beconi, M.; Mathre, D. J. Chirality 2003,
15, 143; Shen, Z.; Bakhtiar, R.; Komuro, M.; Awano, K.;
Taga, F.; Colletti, A.; Hora, D.; Feeney, W.; Iliff, S.;
Franklin, R. B.; Vincent, S. Rapid Commun. Mass
Spectrom. 2005, 19, 1125, also see Refs. 2 and 3.
(m, 5H), 7.10 (d, 2H, J = 8.8 Hz), 6.82 (d, 2H, J = 8.8 Hz),
4.76 (t, 1H, J = 7.2 Hz), 4.63–4.56 (m, 1H), 4.24–4.16 (m,
2H), 3.76 (s, 3H), 3.29 (dd, 1H, J = 13.6, 3.2 Hz), 2.86–
2.79 (m, 2H), 2.75–2.67 (m, 2H), 2.55–2.45 (m, 1H), 2.39–
2.28 (m, 1H); 13C NMR (CDCl3, 100 MHz) d 168.0, 158.6,
153.3, 134.7, 131.7, 129.8, 129.7, 129.3, 127.8, 114.3, 109.4,