A stereocontrolled route to protected isocyanates from alcohols

Article abstract of DOI:10.1016/j.tet.2004.12.042

Full details are given for a modified Mitsunobu approach to the formation of N-alkylated 1,2,4-dithiazolidine-3,5-diones 2 from a wide range of alcohols 10 with predominantly, inversion of configuration. The resulting products 2 can be regarded as protected isocyanates 6.

Full text of DOI:10.1016/j.tet.2004.12.042

Tetrahedron 61 (2005) 2141–2148
A stereocontrolled route to protected isocyanates from alcohols
Daniel J. Cane-Honeysett,a Michael D. Dowleb and Mark E. Wooda,
*
aDepartment of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 14 October 2004; revised 1 December 2004; accepted 17 December 2004
Available online 18 January 2005
Abstract—Full details are given for a modified Mitsunobu approach to the formation of N-alkylated 1,2,4-dithiazolidine-3,5-diones 2 from
a wide range of alcohols 10 with predominantly, inversion of configuration. The resulting products 2 can be regarded as protected iso-
cyanates 6.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
that it is possible to use the parent heterocycle, 1,2,4-
dithiazolidine-3,5-dione 4 and its corresponding potassium
salt 5 as the nucleophile in substitution reactions with
reactive alkyl halides. These studies have also highlighted
the fact that such imides 2 can also be regarded as a masked
form of an isocyanate 6, which can be released on treatment
with triphenylphosphine, under anhydrous conditions
(Scheme 2).7,8 In addition to representing a protected form
of a primary amine therefore, alkylated 1,2,4-dithiazolidine-
3,5-diones 2 are also versatile and potentially very useful,
synthetic intermediates.
Amongst the plethora of protecting groups that have been
developed for primary amines 1,1 the dithiasuccinoyl imide
or 1,2,4-dithiazolidine-3,5-dione 2 (abbreviated to RNDts)
stands out in that it can be cleaved under unusual conditions.
For example, such imides 2 can be converted back into
primary amines 1 using mild thiolysis, under basic
conditions2 or using phosphorus(III) reagents under partly
aqueous conditions3 (Scheme 1).
The 1,2,4-dithiazolidine-3,5-dione heterocycle is, however,
stable under strongly acidic, mildly basic and photochemi-
cal cleavage conditions and hence, this group has been used
in orthogonal protection strategies in peptide4 and amino-
glycoside5 synthesis. N-Alkylated 1,2,4-dithiazolidine-3,5-
diones 2 can be prepared from primary amines 1 via the
treatment of their corresponding alkoxythiocarbamates 3
with chlorocarbonylsulfenyl chloride (Scheme 1).6
Our findings on the use of 4 in Mitsunobu-type alkylations
of alcohols have also been reported (in preliminary form).9
Herein, we give full experimental details and a discussion of
the methods used in this synthetic procedure.
Imide derivatives and phthalimide in particular, have seen
wide usage as nitrogen nucleophiles in Mitsunobu amina-
tion reactions.10 In order to circumvent the problems that are
sometimes encountered in the cleavage of N-alkylated
phthalimides, a variety of other imide and related
As an alternative, straightforward route to N-alkylated
1,2,4-dithiazolidine-3,5-diones 2, we have recently shown
Scheme 1. Reagents and conditions: (i) EtOCS2CH2CO2H or EtOCS2CSOEt; (ii) ClCOSCl; (iii) HOCH2CH2SH, Et3N or Ph3P, H2O.
Keywords: 1,2,4-Dithiazolidine-3,5-diones; Mitsunobu amination; Isocyanates; Urethanes; Amino acids.
* Corresponding author. Tel.: C44 1392 263450; fax: C44 1392 263434; e-mail: m.e.wood@exeter.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.042

2142
D. J. Cane-Honeysett et al. / Tetrahedron 61 (2005) 2141–2148
Scheme 2. Reagents and conditions: (i) R-Hal; (ii) Ph3P, PhCH3, 6.
derivatives have also been developed for use as protected
amine nucleophiles.11 The ability of N-alkylated 1,2,4-
dithiazolidine-3,5-diones 2 to act as protected amines or
isocyanates, coupled with the remarkably high acidity of
the parent heterocycle 4 (pKaZ2.85),7–9 suggested that
conducting investigations into the behaviour of 4 under
Mitsunobu amination conditions would be worthwhile.
We therefore carried out a systematic study of the use of 7 in
reactions between 4 and a range of alcohols 10 (Scheme 4).
These were chosen in order to compare results with those
obtained in traditional and modified14 Mitsunobu reactions
with phthalimide.
2. Results and discussion
Initial experiments were carried out using benzyl alcohol, 4,
triphenylphosphine and diethyl azodicarboxylate (DEAD)
(Scheme 3). As expected, these reaction conditions
appeared only to result in degradation of 4, presumably by
reaction with triphenylphosphine and none of the desired
product 2d could be detected. An attempt to avoid this
degradation by pre-mixing the triphenylphosphine and
DEAD, followed by sequential addition of benzyl alcohol
10d and 4, also failed.
Scheme 4. Reagents and conditions: 7, CH2Cl2.
Initial experiments were carried out with three simple
secondary alcohols. The results obtained are detailed in
Table 1 with comparative yields and enantiomeric excesses,
where available, being given for similar reactions of these
alcohols with phthalimide under standard Mitsunobu
conditions (Scheme 5) and using Barrett’s imidate ester
method (Scheme 6).
Isopropyl 10a and R-sec-butyl 10b alcohols gave an
acceptable (51%) isolated yield of the corresponding
N-alkylated 1,2,4-dithiazolidine-3,5-diones 2a and 2b,
respectively. In the latter case, the ee of the product was
found to be 71% and this is consistent with the observation
that incomplete inversion is sometimes observed with
betaine reagent 7.12 Whilst R-2-octanol 10c gave a good
yield of the desired product 2c, we were unable to determine
the enantiomeric excess by chiral HPLC, although further
reactions of this product (see later) suggested that 2c had an
ee of 97%.
Scheme 3. Reagents and conditions: Ph3P, EtO2C–N]N–CO2Et.
Castro et al. had reported the unexpected formation of
betaine 7 in attempted Mitsunobu reactions with sulfamide
8 as the nucleophile (Fig. 1)12 and showed that it could
be used effectively to promote stereoselective Mitsunobu-
type reactions between carboxylic and nitrogen acids
and alcohols. Most importantly, Brummond and Lu
showed that 7 could be used to mediate a Mitsunobu-type
reaction with the phosphine-sensitive thiazolidinedione 9
(Fig. 1).13
Analogous reactions of a number of allylic and benzylic
alcohols were also investigated (Table 2).
Benzyl alcohol 10d gave a very good (80%) yield of the
desired N-alkylated 1,2,4-dithiazolidine-3,5-dione 2d. A
higher yield was expected from this reactive alcohol and
indeed, this result is directly comparable with the 75% yield
obtained in a standard Mitsunobu reaction between benzyl
alcohol 10d and phthalimide.17 R-a-Methylbenzyl alcohol
10e gave a lower yield (50%) of 2e than that obtained for the
corresponding phthalimide derivative (73%) produced using
Barrett’s imidate ester method.14a Interestingly however,
both processes resulted in some racemisation, the products
Figure 1.

D. J. Cane-Honeysett et al. / Tetrahedron 61 (2005) 2141–2148
Table 1. Mitsunobu-type reactions with secondary alcohols
2143
Alcohol 10 (equiv)a
Product 2
Yieldb (%)
ee (%)
Comparable reactions with phthalimide
Yield (%)
c7515
ee (%)
51
—
—
—
d
10a (0.21)
10b (0.89)
2a
—
51
76
71
c75 (G)14
—
—
92
d
2b
97e
c7514
O99
96
d
—
10c (0.93)
2c
a Equivalent of 10 relative to 4.
b Based on 10.
c Using typical Mitsunobu conditions.
d Using Barrett’s imidate ester method.
e Determined from urethane 11a (see text).
having similar ee’s (70 and 72%, respectively), suggesting
that Mitsunobu-type reactions of 10e probably involve
significant SN1 character. Racemic 2-cyclohexen-1-ol 10f
gave a lower yield (38%) of the desired product 2f although
this is comparable with the imidate ester result obtained by
Barrett et al. with potassium phthalimide (34%). In
comparison, Sammes et al. have reported a 57% yield for
the preparation of N-cyclohex-2-enyl phthalimide under
standard Mitsunobu conditions.18 Crotyl alcohol 10g gave
an acceptable yield of the desired product 2g in an E/Z ratio
which remained unchanged from the starting alcohol 10g.
For this alcohol, no products arising from allylic trans-
position could be detected. In contrast, racemic 3-buten-l
10h gave a mixture of products in a relatively low (39%)
yield. Here, the ratio of direct alcohol displacement/allylic
transposition was found to be 2:1 with 2g being obtained in
Scheme 5. Reagents and conditions: R0O2C–N]N–CO2R0, Ph3P, solvent.
Scheme 6. Reagents and conditions: (i) CH3CN, 0 8C; (ii) KPhth, 60–70 8C.
Table 2. Mitsunobu-type reactions with benzylic and allylic alcohols
Alcohol 10 (equiv)a
Product(s) 2
Yieldb (%)
ee (%)
Comparable reactions with phthalimide
Yield (%)
c7516
ee (%)
80
50
—
71
—
—
2d
10d (0.83)
d
—
c
—
d7313a
—
72
2e
2f
10e (0.92)
10f (0.83)
38
—
c57 (G)17
d34 (G)13a
—
—
c
57
—
—
—
—
—
10g (0.84)
d
—
(E/ZZ12:1) 2g
c
39 (overall)
—
d98 (G)13a
—
—
2h
2g
10h (1.00)
(E/ZZ2:1)
a Equivalent of 10 relative to 4.
b Based on 10.
c Using typical Mitsunobu conditions.
d Using Barrett’s imidate ester method.

2144
D. J. Cane-Honeysett et al. / Tetrahedron 61 (2005) 2141–2148
Table 3. Mitsunobu-type reactions with hydroxyesters
Alcohol 10 (equiv)a
Product 2
Yieldb (%)
52
ee (%)
92
Comparable reactions with phthalimide
Yield %
ee %
c,d4518
e2513b
O99%
—
2i
10i (0.83)
c
37
71
—
—
—
e
—
10j (0.90)
2j
a Equiv. of 10 relative to 4.
b Based on 10.
c Using typical Mitsunobu conditions.
d Yield for reaction with S-ethyl lactate.
e Using Barrett’s imidate ester method.
an E/Z ratio of 2:1. Interestingly, in comparison, Barrett et
al. reported a very high (98%) yield in the imidate ester
reaction of 10h with potassium phthalimide, with no allylic
transposition being observed.14b
enantiomeric excess of 92%. This result compares favour-
ably with the analogous preparation of S-N-phthaloyl
alanine ethyl ester under Mitsunobu conditions, using a
solid-supported azodicarboxylate, where a 45% yield and O
99% ee have been reported for the reaction between S-ethyl
lactate and phthalimide.19 (Note: a 58% yield was originally
reported for the standard Mitsunobu reaction between
racemic ethyl lactate and phthalimide.17) In comparison,
the reaction between S-methyl lactate 2i and potassium
phthalimide under imidate ester conditions, has been
reported to give a low (25%) yield of N-phthaloyl alanine
methyl ester with complete racemisation.14b
In order to investigate our methodology in the context of the
preparation of protected a- and b-amino acids, reactions
between S-methyl lactate 10i and S-ethyl 3-hydroxybutyrate
10j and 1,2,4-dithiazolidine-3,5-dione 4 and betaine 7 were
also carried out (Table 3).
S-Methyl lactate 10i gave a 52% yield of 2i, with an
S-Ethyl 3-hydroxybutyrate 10j gave a disappointing (37%)
yield of the corresponding protected b-amino acid 2j with
some racemisation having occurred. The low yield, in this
instance, is however, perhaps not surprising, given the
propensity of such b-hydroxy esters to undergo elimination
under Mitsunobu reaction conditions.10a Unfortunately,
comparative literature data for reactions between phthali-
mide and 3-hydroxybutyrates are not available.
Scheme 7. Reagents and conditions: Ph3P (1.00 equiv), R0OH (0.80–
1.07 equiv), PhCH3, reflux.
Table 4. Urethane preparation
Imide 2
Alcohol (equiv)
PNB–OH (0.80)
Product 11
Yield (%)
a92
ee (%)
97
Imide 2 ee (%)
b
2b
11a
11b
Bn–OH (0.85)
PNB–OH (0.85)
Bn–OH (1.07)
a25
a79
c59
69
69
90
70
70
92
2e
2e
11c
2i
11d
PNB–OH (1.05)
c89
71
71
2j
11e
a Based on benzylic alcohol.
b Could not be determined by chiral HPLC.
c Based on N-alkyl-1,2,4-dithiazolidine-3,5-dione 2.

D. J. Cane-Honeysett et al. / Tetrahedron 61 (2005) 2141–2148
2145
A number of the N-alkylated 1,2,4-dithiazolidine-3,5-dione
products 2 were converted, through the intermediate
(detectable but not isolated/characterised) isocyanates 6,
into urethane-protected amines 11 (Scheme 7).
Activity AA-1000 automatic polarimeter in a 1dm path
length cell.
Infrared spectra were recorded using a Nicolet Magna 550
spectrometer with only major absorbances being quoted,
using the abbreviations: w, weak; m, medium; s, strong and
br, broad. Thin film samples were prepared by evaporation
of a dilute chloroform sample of the compound on a sodium
chloride plate.
Our previously reported procedure8 was employed, in which
a mixture of the N-alkylated 1,2,4-dithiazolidine-3,5-dione
2 was heated with an equimolar quantity of triphenylphos-
phine and a benzylic alcohol (0.80–1.07 equiv) in toluene,
under reflux. Table 4 summarises the results of these studies,
with yields being calculated, in all cases, from the minor
component in the reaction.
1H NMR spectra were obtained using Bru¨cker AM300,
ACF300 and Advance DRX400 spectrometers at operating
frequencies of 300 and 400 MHz. Chemical shifts are
quoted in ppm relative to tetramethylsilane with referencing
to the residual protonated solvent peak. Coupling constants
are given to the nearest 0.5 Hz. The abbreviations: s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet and br, broad
are used.
As mentioned earlier, we had been unable to determine
the enantiomeric excess in 2c, which was derived from
R-2-octanol but the enantiomers of the 4-nitrobenzyl
urethane 11a proved to be separable by chiral HPLC,
indicating a 97% ee Importantly, for all of the urethanes 11
isolated, the enantiomeric excess was determined to be the
same as the starting alcohol 10, within experimental error,
suggesting that the intermediate isocyanates 6 were
configurationally stable under the reaction conditions
employed.
13C NMR spectra were obtained using either a Bru¨cker
ACF300 or Bru¨cker Advance DRX400 spectrometer at
operating frequencies of 75 and 100 MHz, respectively.
Chemical shifts are quoted in ppm relative to tetramethyl-
silane, with referencing to the solvent peak. Assignments
are derived from DEPT editing.
The preparation of the urethane-protected alanine methyl
ester derivative 11d from the S-methyl lactate-derived
1,2,4-dithiazolidine-3,5-dione 2i allowed us to confirm that
inversion of configuration was the predominant pathway
in the original Mitsunobu-type reaction. The formation of
protected b-amino ester 11f illustrates the potential use of
the overall methodology in the synthesis of b-amino acids.
Mass spectra were determined using Thermoquest Finnigan
TRACE 2000 GC–MS and Micromass GCT instruments or
by the EPSRC National Mass Spectrometry Service
Centre, Swansea, UK in electron impact (EI), ammonia
chemical ionisation (CI) and positive ion electrospray
(ESC) modes.
Analytical thin layer chromatography was carried out using
glass or aluminium-backed plates coated with Merck
Kieselgel 60 F254, with plates being visualised by quenching
of UV fluorescence or by staining with iodine or potassium
permanganate as appropriate. Flash chromatography
was carried out using BDH silica gel with particle size
40–63 mm.
3. Conclusions
Overall, we have shown that the structurally simple
heterocycle, 1,2,4-dithiazolidine-3,5-dione 4 provides an
excellent isocyanate synthetic equivalent in Mitsunobu-type
reactions using a wide variety of alcohols. The methodology
developed has, therefore, significant potential to be of use in
the synthesis of amines, ureas and also many nitrogen-
containing heterocycles. The stability of this heterocyclic
system to strongly acidic, mildly basic and photochemical
conditions provides the possibility of carrying an isocyanate
through a series of synthetic steps in a protected form,
greatly expanding the number of possibilities for using this
highly reactive functional group in synthesis.
Solvents and reagents were used as supplied commercially
or purified using standard procedures as appropriate.
Petroleum ether refers to the fraction of light petroleum
ether boiling between 40 and 60 8C.
Solvents were removed under reduced pressure using a
Bu¨chi R110 Rotovapor, equipped with a water and/or dry
ice condenser as appropriate.
4. Experimental
4.1. General
4.2. Mitsunobu-type N-alkylation of 1,2,4-dithiazolidine-
3,5-dione 4—general procedure
The alcohol 10 (typically ca 0.74 mmol) was added to a
stirred solution of 1,2,4-dithiazolidine-3,5-dione 4 (typi-
cally 0.82 mmol) and betaine reagent 712 in dichloro-
methane (2 cm3) at room temperature. After stirring at this
temperature for 18 h, the solvent was evaporated in vacuo
and the resulting residue was purified by flash chromatog-
raphy on silica gel (typically eluting with 90% petroleum
ether–10% ethyl acetate) to give the title compound 2.
Enantiomeric excesses were determined by chiral HPLC,
using a Chiralcelw ODe column, eluting with 9:1 v/v
hexane-propan-2-ol. Detection was carried out at a wave-
length of 254 nm.
Melting points were determined using a Gallenkamp
MPD350 apparatus and are uncorrected.
Specific rotations were determined using an Optical
4.2.1. 4-Isopropyl-1,2,4-dithiazolidine-3,5-dione 2a. Using

2146
D. J. Cane-Honeysett et al. / Tetrahedron 61 (2005) 2141–2148
the general procedure above with isopropyl alcohol 10a
(300 mL, 3.93 mmol), 1,2,4-dithiazolidine-3,5-dione 4
(110 mg, 0.82 mmol) and betaine 7 (345 mg, 0.84 mmol)
in dichloromethane (2 cm3) gave 2a (74 mg, 51%). as a
colourless oil. Data as reported previously.8
4.2.6. (G)-4-Cyclohex-2-enyl-1,2,4-dithiazolidine-3,5-
dione 2f. Using the general procedure above with (G)-2-
cyclohexen-1-ol 10f (67 mL, 0.68 mmol), 1,2,4-dithiazo-
lidine-3,5-dione 4 (110 mg, 0.82 mmol) and betaine 7
(345 mg, 0.84 mmol) in dichloromethane (2 cm3) gave 2f
(56 mg, 38%), as a white solid; (Found MHC (CI)
216.0158, C8H10NO2S2 requires 216.0153); mp 89–91 8C;
nmax (thin film)/cmK1 2980–2740 (w), 1646 (s), 1296 (m),
1167 (m) and 1134 (m); dH (400 MHz; CDCl3) 1.62–2.25
(6H, complex, (CH2)3), 4.98–5.11 (1H, m, alkene CH), 5.46
(1H, dd, JZ2, 12 Hz, NCH) and 5.89–6.01 (1H, m, alkene
CH); dC (100.6 MHz; CDCl3) 21.8, 24.0, 25.5 ((CH2)3),
56.3 (NCH), 124.4, 131.4 (alkene CH) and 167.3 (C]O);
m/z (CI) 216 (MHC, 16%), 164 (36), 136 (100) and 123 (24).
4.2.2. S-4-sec-Butyl-1,2,4-dithiazolidine-3,5-dione 2b.
Using the general procedure above with R-sec-butyl alcohol
10b (67 mL, 0.73 mmol), 1,2,4-dithiazolidine-3,5-dione 4
(110 mg, 0.82 mmol) and betaine 7 (345 mg, 0.84 mmol)
in dichloromethane (2 cm3) gave 2b (74 mg, 51%) as a
colourless oil, 71% ee (determined by chiral HPLC); [a]D21
C24 (cZ1, CHCl3); nmax (thin film)/cmK1 3044–2883 (w),
1736 (s), 1646 (s), 1454 (m), 1311 (w), 1223 (m), 1189 (w),
1034 (w), 949 (m) and 692 (s); dH (300 MHz; CDCl3) 0.86
(3H, t, JZ8 Hz, CH3CH2), 1.42 (3H, d, JZ8 Hz, CH3CH),
1.72–1.84 (1H, m, CHAHB), 1.94–2.06 (1H, m, CHAHB) and
4.39–4.49 (1H, m, CH); dC (100.6 MHz; CDCl3) 14.2, 17.4
(CH3), 32.3 (CH2) and 56.6 (CH); m/z (EI) 191 (MC, 12%),
135 (14), 99 (21), 73 (100) and 64 (33).
4.2.7. E-4-But-2-enyl-1,2,4-dithiazolidine-3,5-dione 2g.
Using the general procedure above with crotyl alcohol
10g (commercial E/Z mixture, 59 mL, 0.69 mmol), 1,2,4-
dithiazolidine-3,5-dione 4 (110 mg, 0.82 mmol) and betaine
7 (345 mg, 0.84 mmol) in dichloromethane (2 cm3) gave 2g
(74 mg, 57%), as a yellow oil; (Found MHC (CI) 189.9998,
C6H8NO2S2 requires 189.9996); nmax (thin film)/cmK1
3060–2960 (m), 1718 (s), 1656 (m), 1420 (w), 1360 (w),
1340 (w), 1290 (m), 1140 (w), 1020 (w), and 980 (w); dH
(400 MHz; CDCl3) 1.70 (3H, dd, JZ1, 6 Hz, CH3), 4.28
(2H, dd, JZ1, 7 Hz, CH2), 5.38–5.55 (1H, m, alkene CH)
and 5.76–5.89 (1H, m, alkene CH); dC (100.6 MHz; CDCl3)
17.7 (CH3), 47.7 (CH2), 122.1, 132.9 (2!alkene CH) and
167.3 (C]O); m/z (CI) 190 (MHC, 16%), 164 (18), 136
(100) and 98 (8). 1H NMR indicated that the product
contained a small quantity of Z-4-but-2-enyl-1,2,4-dithiazo-
lidine-3,5-dione (E/Z ratioZ12:1). The only 1H NMR
signals for this stereoisomer which could be positively
identified were: dH (400 MHz; CDCl3) 1.74 (3H, d, JZ
6 Hz, CH3) and 4.40 (2H, d, JZ7 Hz, CH2).
4.2.3. S-4-(1-Methylheptyl)-1,2,4-dithiazolidine-3,5-
dione 2c. Using the general procedure above with R-2-
octanol 10c (120 mL, 0.76 mmol), 1,2,4-dithiazolidine-3,5-
dione 4 (110 mg, 0.82 mmol) and betaine 7 (345 mg,
0.84 mmol) in dichloromethane (2 cm3) gave 2c (142 mg,
76%) as a brown oil, enantiomers inseparable by chiral
HPLC; [a]2D1 C14 (cZ1, CHCl3); (Found MC (EI)
247.3810, C10H17NO2S2 requires 247.3795); nmax (thin
film)/cmK1 3030–2834 (w), 1734 (s), 1685 (s), 1516 (w),
1375 (w), 1221 (m), 1136 (w) and 1059 (w); dH (300 MHz;
CDCl3) 0.87 (3H, t, JZ8 Hz, CH3CH2), 1.11–1.36 (8H,
complex, (CH2)4) 1.45 (3H, d, JZ8 Hz, CH3CH), 1.55–1.79
(1H, m, CHAHBCH), 1.94–2.12 (1H, m, CHAHBCH) and
4.42–4.58 (1H, m, CH); dC (75.1 MHz; CDCl3) 14.0, 17.3
(CH3), 22.5, 26.5, 28.8, 31.6, 32.2 ((CH2)5), 56.6 (CH) and
167.7 (C]O); m/z (EI) 247 (MC, 7%), 155 (13), 135 (11),
129 (44) and 64 (100).
4.2.8. (G)-4-(1-Methylallyl)-1,2,4-dithiazolidine-3,5-
dione 2h and E/Z-4-but-2-enyl-1,2,4-dithiazolidine-3,5-
dione 2g. Using the general procedure above with (G)-3-
buten-2-ol 10h (64 mL, 0.74 mmol), 1,2,4-dithiazolidine-
3,5-dione 4 (110 mg, 0.74 mmol) and betaine 7 (345 mg,
0.84 mmol) in dichloromethane (2 cm3) gave a 2:1 mixture
of 2h and 2g (55 mg, 39%), as an oil; (Found MHC (CI)
189.9998, C6H8NO2S2 requires 189.9996); nmax (thin film)/
cmK1 2926 (w), 1734 (m), 1686 (s), 1516 (w), 1311 (w), and
1059 (w); For 2h: dH (400 MHz; CDCl3) 1.56 (3H, d, JZ
6.8 Hz, CH3), 5.00–5.08 (1H, m, NCH), 5.25–5.31 (2H,
complex, CH]CH2) and 6.07–6.18 (1H, m, CH]CH2); dC
(100.6 MHz; CDCl3) 16.8 (CH3), 57.4 (CH), 118.6
(CH]CH2), 134.5 (CH]CH2) and 167.2 (C]O); Data
for 2g as described above with the E/Z ratio being 1:2.
4.2.4. 4-Benzyl-1,2,4-dithiazolidine-3,5-dione 2d. Using
the general procedure above with benzyl alcohol 10d
(70 mL, 0.68 mmol), 1,2,4-dithiazolidine-3,5-dione 4
(110 mg, 0.82 mmol) and betaine 7 (345 mg, 0.84 mmol)
in dichloromethane (2 cm3) gave 2d (74 mg, 80%) as an
off-white solid. Data as reported previously.20
4.2.5. S-4-(1-Phenylethyl)-1,2,4-dithiazolidine-3,5-dione
2e. Using the general procedure above with R-a-methyl-
benzyl alcohol 10e (90 mL, 0.75 mmol), 1,2,4-dithiazo-
lidine-3,5-dione 4 (110 mg, 0.82 mmol) and betaine 7
(345 mg, 0.84 mmol) in dichloromethane (2 cm3) gave 2e
(90 mg, 50%), as a brown oil, 70% ee (determined by
chiral HPLC); [a]D21 K32 (cZ1, CHCl3); (Found MHC (CI)
240.0168, C10H10NO2S2 requires 240.0153); nmax (thin
film)/cmK1 3033–2844 (w), 1732 (s), 1630 (m), 1595 (m),
1554 (m), 1505 (w), 1426 (w), 1297 (m), 1190 (w), 1024 (w)
and 723 (m); dH (400 MHz; CDCl3) 1.78 (3H, d, JZ7 Hz,
CH3), 5.73 (1H, q, JZ7 Hz, CH) and 7.24–7.44 (5H,
complex, phenyl-H); dC (100.6 MHz; CDCl3) 16.0 (CH3),
57.6 (CH), 128.3, 128.7, 128.9 (phenyl CH), 137.9 (phenyl
ipso-C) and 167.8 (C]O); m/z (CI) 240 (MHC, 9%), 192
(9), 164 (18), 151 (100) and 47 (87).
4.2.9. R-Methyl 2-(3,5-dioxo-1,2,4-dithiazolidin-4-
yl)propionate 2i. Using the general procedure above with
S-methyl lactate 10i (65 mL, 0.68 mmol), 1,2,4-dithiazoli-
dine-3,5-dione 4 (110 mg, 0.82 mmol) and betaine 7
(345 mg, 0.84 mmol) in dichloromethane (2 cm3) gave 2i
(78 mg, 52%), as an oil, 92% ee (determined by chiral
HPLC); [a]2D1 C44 (cZ1, CHCl3). All other data as
described previously for racemic 2i.8
4.2.10. R-Ethyl 3-(3,5-dioxo-1,2,4-dithiazolidin-4-yl)-
butyrate 2j. Using the general procedure above with

D. J. Cane-Honeysett et al. / Tetrahedron 61 (2005) 2141–2148
2147
S-ethyl 3-hydroxybutyrate 10j (98 mL, 0.74 mmol), 1,2,4-
dithiazolidine-3,5-dione 4 (110 mg, 0.82 mmol) and betaine
7 (345 mg, 0.84 mmol) in dichloromethane (2 cm3) gave 2j
(68 mg, 37%), as a yellow oil, 71% ee (determined by
chiral HPLC); [a]D21 K7 (cZ1, CHCl3); (Found MHC (CI)
250.0210, C8H12NO4S2 requires 250.0208); nmax (thin film)/
cmK1 1733 (m), 1635 (s), 1456 (w), 1375 (w), 1275 (m),
1173 (m), 1144 (m), 1068 (w), 804 (w) and 698 (m); dH
(300 MHz; CDCl3) 1.23 (3H, t, JZ7 Hz, CH3CH2), 1.48
(3H, d, JZ7 Hz, CH3CH), 2.70 (1H, dd, JZ6, 17 Hz,
CHAHBCO2Et), 3.18 (1H, dd, JZ9, 17 Hz, CHAHBCO2Et),
4.11 (2H, dq, JZ1, 7 Hz, CH2CH3) and 4.88–4.96 (1H, m,
CHN); dC (75.1 MHz; CDCl3) 14.1, 17.4 (2!CH3), 36.5
(CH2CO2Et), 51.7 (CHN), 61.0 (CH2O) and 167.5, 170.2
(2!C]O); m/z (CI) 250 (MHC, 7%), 206 (10), 204 (100),
156 (13), 116 (53) and 112 (27).
301.1188); nmax (thin film)/cmK1 3158–2839 (w), 1705 (s),
1606 (w), 1522 (s), 1450 (w), 1348 (s), 1240 (m), 1061 (m),
1014 (w), 852 (w), 739 (w) and 700 (m); dH (400 MHz;
CDCl3) 1.51 (3H, d, JZ7 Hz, CH3CH), 4.79–4.91 (1H, br
m, CH), 5.08 (1H, br s, NH), 5.15, 5.17 (2!1H, AB, JZ
14 Hz, ArCH2), 7.21–7.41 (5H, complex, phenyl-H) and
7.49, 8.20 (2!2H, AA0BB0, JZ8 Hz, aryl-H); dC
(100.6 MHz; CDCl3) 22.4 (CH3), 50.9 (CH), 65.2 (CH2),
123.7, 125.9, 127.5, 128.2, 128.4 (aryl C–H), 143.1, 144.0
(2!aryl ipso C) and 155.0 (C]O); m/z (CI) 301 (MHC,
5%), 295 (13), 280 (16), 279 (100), 201 (10) and 105 (37).
4.3.4. R-Benzyloxycarbonyl alanine methyl ester 11d.
Using the general procedure7 with R-methyl 2-(3,5-dioxo-
1,2,4-dithiazolidin-4-yl) propionate 2i (100 mg,
0.45 mmol), triphenylphosphine (120 mg, 0.46 mmol) and
benzyl alcohol (50 mL, 0.48 mmol) in toluene (2 cm3) gave
11d (63 mg, 59% based on R-methyl 2-(3,5-dioxo-1,2,4-
dithiazolidin-4-yl) propionate 2i) as a white, powdery solid,
90% ee (determined by chiral HPLC); mp 45–46 8C (lit.23
47–48.5 8C); All other data in agreement with literature
values.23
4.3. Urethane 11 formation from 4-alkylated 1,2,4-
dithiazolidine-3,5-diones 2
A general procedure for urethane formation has been
reported.8
4.3.1. S-(4-Nitrobenzyl)-1-methylheptyl carbamate 11a.
Using the general procedure8 with S-4-(1-methylheptyl)-
1,2,4-dithiazolidine-3,5-dione 2b (120 mg, 0.49 mmol),
triphenylphosphine (130 mg, 0.50 mmol) and 4-nitrobenzyl
alcohol (60 mg, 0.39 mmol) in toluene (2 cm3) gave 11a
(111 mg, 92% based on 4-nitrobenzyl alcohol) as an oil,
97% ee (determined by chiral HPLC); [a]2D1 C23 (cZ1,
CHCl3); (Found MHC (CI) 309.1816, C16H25N2O4 requires
309.1814); nmax (thin film)/cmK1 3031–2856 (w), 1732 (s),
1611 (w), 1532 (s), 1452 (w), 1355 (s), 1243 (m), 1201 (m),
1111 (w), 1060 (w), 1024 (w), 740 (w) and 659 (s); dH
(400 MHz; CDCl3) 0.86 (3H, d, JZ7 Hz, CH3CH), 1.14
(3H, d, JZ7 Hz, CH3CH), 1.18–1.49 (10H, complex,
(CH2)5), 3.63–3.74 (1H, m, CHN), 4.66 (1H, br d, JZ
8 Hz, NH), 5.17 (2H, s, CH2Ar) and 7.49, 8.20 (2!2H,
AA0BB0, JZ9 Hz, aryl-H); dC (100.6 MHz; CDCl3) 14.1,
21.2 (2!CH3), 22.6, 25.9, 29.1, 31.8, 37.1 ((CH2)5), 47.4
(CHN), 64.9 (CH2Ar), 123.7, 128.0 (aryl C–H), 144.3,
147.5 (2!aryl ipso C) and 155.2 (C]O); m/z (CI) 309
(MHC, 17%), 296 (19), 295 (100), 185 (8), 154 (60), 113
(13) and 106 (28).
4.3.5. R-Ethyl 3-(4-nitrobenzyloxycarbonylamino) buty-
rate 11e. Using the general procedure7 with R-ethyl 3-(3,5-
dioxo-1,2,4-dithiazolidin-4-yl) butyrate 2j (150 mg,
0.60 mmol), triphenylphosphine (164 mg, 0.63 mmol) and
4-nitrobenzyl alcohol (96 mg, 0.63 mmol) in toluene
(2 cm3) gave 11e (166 mg, 89% based on R-ethyl 3-(3,5-
dioxo-1,2,4-dithiazolidin-4-yl) butyrate 2j) as a brown oil,
71% ee (determined by chiral HPLC); [a]2D1 C5 (cZ1,
CHCl3); (Found MHC (CI) 311.1235, C14H19N2O6 requires
311.1243); nmax (thin film)/cmK1 3050–2836 (w), 1734 (br
s), 1608 (w), 1536 (s), 1456 (w), 1348 (s), 1247 (m), 1194
(w), 1109 (w), 1066 (m), 1028 (w), 852 (w) and 739 (w); dH
(300 MHz; CDCl3) 1.18 (3H, t, JZ7 Hz, CH3CH2), 1.19
(3H, d, JZ7 Hz, CH3CH), 2.46 (2H, d, JZ6 Hz, CH2CH),
3.96–4.06 (1H, m, CHCH3), 4.07 (2H, q, JZ7 Hz,
CH2CH3), 5.11 (2H, s, ArCH2), 5.36 (1H, br d, JZ7 Hz,
NH) and 7.43, 8.14 (2!2H, AA0BB0, JZ9 Hz, aryl-H); dC
(75.1 MHz; CDCl3) 14.6 (CH3), 20.7 (CH3), 40.7 (CHCH2),
44.6 (NCH), 61.1 (CH3CH2), 64.3 ArCH2), 124.1, 128.4
(aryl C–H), 144.5, 147.9 (2!aryl ipso C), 155.4 (urethane
C]O) and 171.9 (ester C]O); m/z (CI) 311 (MHC, 86%),
295 (23), 265 (100), 223 (12), 158 (24), 132 (18), 116 (77)
and 112 (33).
4.3.2. S-Benzyl-1-phenylethylcarbamate 11b. Using the
general procedure8 with S-4-(1-phenylethyl)-1,2,4-dithi-
azolidine-3,5-dione 2e (140 mg, 0.59 mmol), triphenyl-
phosphine (155 mg, 0.59 mmol) and benzyl alcohol
(60 mL, 0.50 mmol) in toluene (2 cm3) gave 11c (32 mg,
25% based on benzyl alcohol) as an oily solid, 69% ee
(determined by chiral HPLC); [a]2D1 K34 (cZ1, CHCl3)
(literature [a]2D1 C44 (cZ0.59, CHCl3) for R-enantio-
mer21). All other data in agreement with literature values.22
Acknowledgements
The authors gratefully acknowledge GlaxoSmithKline for
an Industrial CASE award to D.J.C.-H., the EPSRC
National Mass Spectrometry Service Centre (University of
Wales Swansea, UK) for mass spectrometric work.
4.3.3. S-(4-Nitrobenzyl)-1-phenylethyl carbamate 11c.
Using the general procedure8 with S-4-(1-phenylethyl)-
1,2,4-dithiazolidine-3,5-dione 2e (140 mg, 0.59 mmol),
triphenylphosphine (155 mg, 0.59 mmol) and 4-nitrobenzyl
alcohol (76 mg, 0.50 mmol) in toluene (2 cm3) gave 11c
(118 mg, 79% based on 4-nitrobenzyl alcohol) as a brown
oil, 69% ee (determined by chiral HPLC); [a]2D1 K41 (cZ1,
CHCl3); (Found MHC (CI) 301.1174, C16H17N2O4 requires
References and notes
1. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.

2148
D. J. Cane-Honeysett et al. / Tetrahedron 61 (2005) 2141–2148
2. Barany, G.; Merrifield, R. B. J. Am. Chem. Soc. 1980, 102,
3084–3095.
13. Brummond, K. M.; Lu, J. L. J. Org. Chem. 1999, 64,
1723–1726.
14. (a) Barrett, A. G. M.; Braddock, C. D.; James, R. A.;
Procopiou, P. A. Chem. Commun. 1997, 433–434. (b) Barrett,
A. G. M.; Braddock, C. D.; James, R. A.; Koike, N.;
Procopiou, P. A. J. Org. Chem. 1998, 63, 6273–6280.
15. Dandapani, S.; Curran, D. P. Tetrahedron 2002, 50,
3855–3864.
3. Barany, G.; Merrifield, R. B. Anal. Biochem. 1979, 95,
160–170.
4. Albericio, F.; Barany, G. Int. J. Pept. Protein. Res. 1987, 30,
177–205.
5. Jensen, K. J.; Hansen, P. R.; Venugopal, D.; Barany, G. J. Am.
Chem. Soc. 1996, 118, 3148–3155.
16. Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc. 1972,
94, 679–680.
6. Barany, G.; Merrifield, R. B. J. Am. Chem. Soc. 1977, 99,
7363–7365.
17. Wada, M.; Sano, T.; Mitsunobu, O. Bull. Chem. Soc. Jpn.
1973, 46, 2833–2835.
7. Cane-Honeysett, D. J.; Dowle, M. D.; Wood, M. E. Synlett
2000, 1622–1624.
18. Sammes, P. G.; Thetford, D. J. Chem. Soc., Perkin Trans. 1
1989, 655–661.
8. Wood, M. E.; Cane-Honeysett, D. J.; Dowle, M. D.; Coles,
S. J.; Hursthouse, M. B. Org. Biomol. Chem. 2003, 1,
3015–3023.
19. Arnold, L. D.; Assil, H. I.; Vederas, J. C. J. Am. Chem. Soc.
1989, 111, 3973–3976.
9. Wood, M. E.; Cane-Honeysett, D. J.; Dowle, M. D. J. Chem.
Soc., Perkin Trans. 1 2002, 2046–2047.
20. Slomczy’nska, U.; Barany, G. J. Heterocycl. Chem. 1984, 21,
241–246.
10. (a) Mitsunobu, O. Synthesis 1981, 1–28. (b) Hughes, D. L.
Org. React. (N. Y.) 1992, 42, 335–656. (c) Hughes, D. L. Org.
Prep. Proced. Int. 1996, 28, 127–164.
21. Takayama, S.; Lee, S. T.; Hung, S.-C.; Wong, C.-H. Chem.
Commun. 1999, 127–128.
22. Stafford, J. A.; Gonzales, S. S.; Barrett, D. G.; Suh, E. M.;
Feldman, P. L. J. Org. Chem. 1998, 63, 10040–10044.
23. Miyazawa, T.; Kayoko, T.; Eosatsu, E.; Yanagihara, R.;
Yamada, T. J. Chem. Soc., Perkin Trans. 1 2001, 87–94.
11. Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1991, 24, 285–289.
12. Castro, J. L.; Matassa, V. G.; Ball, R. G. J. Org. Chem. 1994,
59, 2289–2291.