Simple preparation of N-protected chiral-amino alkyl thiols from corresponding iodides employing sodium trithiocarbonate

Article abstract of DOI:10.1080/00397911.2011.595522

A simple protocol for the preparation of N-protected amino alkyl thiols is reported that employs a reaction of sodium trithiocarbonate (Na ₂CS₃) with N-protected amino alkyl iodides. Na ₂CS₃ is easy to prepare and the protocol circumvents the use of strong bases and multiple steps. All the thiol compounds made were obtained as enantiopure samples and were characterized employing NMR and mass spectrometry.

Full text of DOI:10.1080/00397911.2011.595522

Synthetic Communications1, 43: 228–235, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.595522
SIMPLE PREPARATION OF N-PROTECTED CHIRAL
b-AMINO ALKYL THIOLS FROM CORRESPONDING
IODIDES EMPLOYING SODIUM TRITHIOCARBONATE
Chilakapati Madhu, H. P. Hemantha, T. M. Vishwanatha, and
V. V. Sureshbabu
Peptide Research Laboratory, Department of Studies in Chemistry,
Central College Campus, Bangalore University, Bangalore, India
GRAPHICAL ABSTRACT
Abstract A simple protocol for the preparation of N-protected amino alkyl thiols is reported
that employs a reaction of sodium trithiocarbonate (Na2CS3) with N-protected amino alkyl
iodides. Na2CS3 is easy to prepare and the protocol circumvents the use of strong bases and
multiple steps. All the thiol compounds made were obtained as enantiopure samples and
were characterized employing NMR and mass spectrometry.
Keywords Alkyl iodide; chiral b-amino alkyl thiol; sodium trithiocarbonate
INTRODUCTION
There is growing interest in the preparation of chiral b-amino alkyl thiols,
which have a marked existence in medicinal and synthetic chemistry.[1,2] Naturally
occurring amino thiols such as cysteine, homocysteine, and penicillamine are
involved in several biological processes.[3] Mercapto derivatives possess useful
physicochemical and pharmacokinetic properties by virtue of their acidity and metal
affinity.[4] Furthermore, amino alkyl thiols serve as precursors for chiral sources in
Received May 2, 2011.
Address correspondence to V. V. Sureshbabu, Peptide Research Laboratory, Department of
Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi,
Bangalore 560 001, India. E-mail: sureshbabuvommina@rediffmail.com, hariccb@gmail.com, hariccb@
hotmail.com
228

CHIRAL b-AMINO ALKYL THIOLS
229
Scheme 1. Various approaches reported for the synthesis of b-amino alkyl thiols.
asymmetric reactions and have been found to be better substituents than amino
alcohols in several asymmetric syntheses.[5] They are useful components for various
thio derivatives such as thiocarbamates, taurins, and S-heterocycles.[6] Because of
their synthetic applications in the construction of a diverse class of thia-
peptidomimetics, development of protocols for the preparation of b-amino thiols
is of considerable interest. One of the most frequently employed protocols for the
preparation of 2-amino thiols is the hydrolysis of corresponding thioacetates using
strong bases NaOH, KOH, NaOMe, or K2CO3.[7,8] Ethylenediamine-mediated
hydrolysis of O-ethyl thiocarbonate was employed for the preparation of Boc-
Leu-w[CH2SH].[9] Recently, we reported a facile synthesis of N-protected chiral
b-amino alkyl thiols by reaction of corresponding iodides with thiourea at reflux fol-
lowed by the hydrolysis of the resulting isothiouronium salt with sodium pyrosulfite
in a two-step protocol.[10] Various protocols employed to access b-amino alkyl thiols
are summarized in Scheme 1.
RESULTS AND DISCUSSION
Presently, our group is exploring further synthetic applications of these chiral
thiol intermediates for assembling novel peptidomimetics. For example, the synthesis
of selenothiocarbamates and dithiocarbamate-linked peptidomimetics is in progress.
Thus, owing to the extensive application of N-protected amino alkyl thiols, we
became interested in establishing simpler routes to prepare chiral-b-amino alkyl
thiols from amino acids. During this quest, we came across sodium trithiocarbonate
(Na2CS3),[12] which was employed to transfer alkyl halides into mercaptans via a SN2
displacement.13 Surprisingly, this potential reagent has received only scant attention.
The mild reaction conditions, simplicity of reagent preparation, and reaction efficacy
prompted us to explore its applicability for the preparation of N-protected amino
alkyl thiols from their iodo precursors.
The reagent was prepared by mixing a known quantity of sodium sulfide with
slight excess of CS2 in water according to the reported protocol.[12] The resulting

230
C. MADHU ET AL.
brick-red solution was stored at rt. On the other hand, N-protected amino acid was
reduced to alcohol and then converted to its iodide under Mitsunobu conditions
(PPh3=imidazole=I2).[14] For the preparation of N-protected b-amino thiols, in a
typical reaction Z-Phe-w[CH2-I] 1a was treated with the stock solution of Na2CS3
in dioxane at 50 ꢀC (Scheme 2). About 1.5 h was sufficient for complete consumption
of the starting material (thin-layer chromatographic TLC, analysis), after which the
thiol product 2a was isolated by an acidic workup followed by column chromato-
graphy in 88% yield. The product was identified by comparing its TLC and
high-performance liquid chromatographic (HPLC) data with the authentic sample
and later confirmed through mass and NMR spectroscopy.
The reproducibility and efficacy of the protocol was then demonstrated by pre-
paring a series of b-amino alkyl thiols from Z- as well as Boc-protected amino alkyl
iodides in affordable yields and purities (Table 1). However, the mild basic nature of
the reagent caused cleavage of the Fmoc group to an extent of 20–30% (TLC) during
the reaction, because of which N-Fmoc-amino alkyl thiols (2j and 2k) were obtained
in fairly poor yields. All the compounds were characterized by mass and NMR tech-
niques. Importantly, during these preparations, no sulfide formation was detected
that otherwise would arise by the reaction of thiols with unreacted alkyl iodides in
the reaction mixture (LC-MS analysis). The HPLC analysis of crude samples showed
that the compounds are enantiomerically pure. To check the enantiomeric purity
of the thiols, in a case study, crude samples of Z-L-Leu-w[CH2-SH] and Z-D-
Leu-w[CH2-SH] were analyzed through HPLC (HPLC particulars: Agilent 1100
series having G1311A VWD at k ¼ 254 nm, flow 0.5 mL=min, column: Chiralcell
OD-H, pore size 5 mm, diameter ꢁ length ¼ 4.6 ꢁ 250 mm; method: gradient n-
hexane–ethanol in 45 min). Major peaks corresponded to thiol compound eluted
at distinct tR values (16 min and 23 min respectively), which evidenced the presence
1
of a single isomer in each sample. Further, H NMR spectra of a pair of isomeric
thiols prepared starting from Boc-L-Ala-OH and its D-isomer had distinct methyl
doublets, thus confirming the presence of a single isomer in each sample.
In the reaction, the alkyl iodide first reacts with sodium trithiocarbonate
to afford monoalkyl trithiocarbamic acid salt, which upon acidification yields
monoalkyl trithiocarbonate. This is unstable and undergoes spontaneous decompo-
sition into the desired thiol (Scheme 3). In one report, CS2 released at the end of
the reaction was recovered, which provides direct evidence for the proposed
mechanism.[12]
Scheme 2. Conversion of N-protected b-amino alkyl iodides to thiols.

CHIRAL b-AMINO ALKYL THIOLS
231
Table 1. List of N-protected b-amino alkyl thiols 2
HRMS [M þ Na]þ
Entry
a
Thiol 2
Yield (%)
85
[a][25] (c ¼ 0.1, CHCl3)
Calcd.
Observed
276.1042
ꢂ21.5
276.1034
b
86
ꢂ15.7
290.1191
290.2136
c
78
75
ꢂ9.6
þ8.1
274.0878
370.0911
274.1443
370.1152
d
e
f
62
76
67
ꢂ10.75
ꢂ26.65
ꢂ5.7
382.1089
214.0878
242.1191
382.1135
214.0251
241.9774
g
h
i
70
65
ꢂ23.85
ꢂ4.05
290.1191
256.1347
290.0598
256.1256
j
48
55
ꢂ13.9
ꢂ12.4
380.1087a
412.1347
380.0922
412.1355
k
a[M þ K]þ.

232
C. MADHU ET AL.
Scheme 3. Mechanism of transformation of alkyl iodide into thiol.
CONCLUSION
We have employed sodium trithiocarbonate (Na2CS3) as a useful reagent for
the one-step conversion of N-protected amino alkyl iodides into corresponding
thiols. The reaction is simple, and the reagent is easy to prepare and handle. Unlike
most of the earlier protocols, which require either multiple steps, strong bases, or iso-
lation of intermediates, the present approach delivers the product in a simple and
economic way. We hope that the protocol attracts considerable attention as a
method of choice for fulfilling the increasing demand for chiral b-amino alkyl thiols
in synthetic and biomedical applications.
EXPERIMENTAL
All solvents were freshly distilled before use. Amino acids were used as received
from Sigma-Aldrich Company. TLC analysis was carried out using precoated
silica-gel G254 plates. The reaction mixture was purified by column chromatography
over silica gel (200–300). 1H and 13C NMR spectra were recorded at 300 and 75 MHz
respectively, with tetramethylsilane (TMS) as internal standard. Mass spectra were
recorded on HRMS.
Preparation of Na2CS3
CS2 (4.25 mL, 1.1 eq) was added to a solution of Na2S (5 g, 64 mmol) in water
(30 mL), and the reaction mixture was maintained at 40 ꢀC for 1 h. The resulting
brick-red solution was stored at rt.
Preparation of N-Protected Chiral b-Amino Alkyl Thiols 2a–j: General
Procedure
N-Protected alkyl iodide (1.26 mmol) was dissolved in dioxane (5 mL), and
sodium trithiocarbonate solution (1.5 eq, 0.95 mL) was added. The homogeneous
solution was heated to 50 ꢀC (Scheme 2). About 1.5 h was sufficient for complete
consumption of the starting material (TLC analysis). The reaction mixture was acidi-
fied with 5% diluted HCl extracted into EtOAc (10 mL ꢁ 2). The organic phase was
washed with water and brine and concentrated in vacuo. The residue was purified via
column chromatography.
Z-Val-w[CH2SH] (2a). 1H NMR (300 MHz, CDCl3): d 7.13 (br, 1H), 6.94–7.1
(m, 5H), 5.17 (s, 2H), 3.7 (m, 1H), 2.85 (m, 2H), 2.43 (br, 1H), 2.34 (m, 1H), 1.05 (d,
6H, J ¼ 4.1 Hz); 13C NMR (75 MHz, CDCl3): 155.5, 141.3 128.8, 127.6, 127.3, 65.1,

CHIRAL b-AMINO ALKYL THIOLS
233
51.3, 44.0, 32.4, 28.9, 22.8l. HRMS (m=z) calc. for C13H19NO2S 276.1034; found
276.1042 [M þ Na]þ.
Z-Leu-w[CH2SH] (2b). 1H NMR (300 MHz, CDCl3): d 6.8 (br, 1H), 6.98–7.2
(m, 5H), 5.2 (s, 2H), 3.85 (m, 1H), 2.79 (m, 2H), 2.4 (br, 1H), 1.89 (m, 1H), 1.65 (m,
2H), 0.9 (d, 6H, J ¼ 2.3 Hz); 13C NMR (75 MHz, CDCl3): 155.5, 141.3, 128.8, 127.6,
127.3, 65.1, 51.3, 44.0, 32.4, 28.9, 22.5. HRMS (m=z) calc. for C14 H21NO2S
290.1191; found 290.2136 [Mþ þ Na].
Z-Pro-w[CH2SH] (2c). 1H NMR (300 MHz, CDCl3): d 6.98–7.21 (m, 5H),
5.11 (s, 2H), 3.51 (m, 1H), 3.3 (t, 3H, J ¼ 3.9 Hz), 2.83 (m, 2H), 2.47 (br, 1H),
1.71 (m, 2H) 1.59 (m, 2H); 13C NMR (75 MHz, CDCl3): 156.9, 141.3, 128.9,
127.7, 127.0, 65.7, 56.1, 47.6, 31.0, 28.9, 21.8. HRMS (m=z) calc. for C13H17NO2S
274.0878; found 274.1443 [Mþ þ Na].
Z-Cys(S-Bzl)-w[CH2SH] (2d). 1H NMR (300 MHz, CDCl3): d 6.94–7.2 (m,
10), 6.83 (br, 1H), 5.2 (s, 2H), 3.9 (m, 1H), 3.51 (s, 2H), 2.81 (m, 2H), 2.65(d, 2H,
J ¼ 4.3 Hz), 2.23 (br, 1H); 13C NMR (75 MHz, CDCl3): 154.9, 142.1, 136.3, 129.5,
129.0, 128.8, 127.4, 127.3, 66.3, 57.2, 39.5, 37.2, 31.0. HRMS calc. for C18H21NO2S2
370.0911; found 370.1152 [Mþ þ Na].
Z-Asp(OBzl)-w[CH2SH] (2e). 1H NMR (300 MHz, CDCl3): d 7.24–7.28 (m,
10H) 5.34 (br, 1H), 5.1.4 (s, 2H), 5.04 (s, 2H), 4.08 (m, 1H), 2.70 (m,2H), 2.61 (d,
2H, J ¼ 2.3 Hz), 1.55 (br, 1H); 13C NMR (75 MHz, CDCl3): 171.2, 154.1, 139.2,
138.3, 128.1, 127.8, 127.6, 127.4, 127.1, 126.5, 60.2, 57.3, 54.7, 39.2, 32.1. HRMS
(m=z) calc. for C19H21NO4S 382.1089; found 382.1135 [Mþ þ Na].
Boc-Ala-w[CH2SH] (2f). 1H NMR (300 MHz, CDCl3): d 6.9 (br, 1H), 4.9 (m,
1H), 2.8 (m, 2H), 2.59 (br, 1H), 1.6 (d, 3H, J ¼ 6.9 Hz), 1.38 (s, 9H); 13C NMR
(75 MHz, CDCl3): 155.9, 77.3, 51.2, 33.8, 28.3, 19.3. HRMS calc. for C8H17NO2S
214.0878; found 214.0251 [Mþ þ Na].
Boc-Val-w[CH2SH] (2g). 1H NMR (300 MHz, CDCl3): d 7.1 (br, 1H), 3.9 (m,
1H), 2.78 (m, 2H), 2.45 (br, 1H), 2.36 (m, 1H), 1.4 (s, 9H), 1.1 (d, 6H, J ¼ 4.2 Hz);
13C NMR (75 MHz, CDCl3): 155.7, 76.9, 643, 32.7, 29.9, 28.5, 17.2. HRMS (m=z)
calc. for C10H21NO2S 242.1191; found 241.9774 [Mþ þ Na].
Boc-Phe-w[CH2SH] (2h). 1H NMR (300 MHz, CDCl3): d 7.11–7.25 (m, 5H),
4.64 (br, 5H), 4.11 (m, 1H), 2.86 (d, 2H, J ¼ 4.5 Hz), 2.52 (m, 2H), 2.02 (br, 1H), 1.33
(s, 9H); 13C NMR (75 MHz, CDCl3): 155.3, 138.9, 129.2, 128.2, 126.1, 77.7, 54.4,
37.6, 28.3. HRMS (m=z) calc. for C14H21NO2S 290.1191; found 290.0598 [Mþ þ Na].
Fmoc-Val-w[CH2SH] (2i). 1H NMR (300 MHz, CDCl3): d 7.3–7.8 (m, 8H),
6.9 (br, 1H), 4.68 (d, 2H, J ¼ 6.5 Hz), 4.39 (t, 1H, J ¼ 3.7 Hz), 3.7 (m, 1H), 2.72
(m, 2H), 2.34 (br, 1H), 2.34 (m, 1H), 1.1 (d, 6H, J ¼ 4.28 Hz); 13C NMR (75 MHz,
CDCl3): 156.1, 143.8, 142.1, 128.9, 128.5, 126.5, 66.1, 63.4, 46.8, 32.6, 30.1, 17.2
HRMS calc. for C20H23NO2S 380.1087; found 380.0922 [Mþ þ K].
Fmoc-Phe-w[CH2SH] (2j). 1H NMR (300 MHz, CDCl3): d 6.95–7.9 (m, 13H),
6.83 (br, 1H), 4.6 (m, 1H), 4.59 (d, 2H, J ¼ 6.2 Hz), 4.35 (t, 1H, J ¼ 3.3 Hz), 2.83 (m,
2H), 2.75 (d, 2H, J ¼ 4.2 Hz), 2.39 (br, 1H); 13C NMR (75 MHz, CDCl3): 143.5,

234
C. MADHU ET AL.
141.1, 139.0, 128.5, 128.3, 128.1, 127.9, 126.3, 125.8, 66.8, 56.7, 48.5, 40.9, 31.2.
HRMS (m=z) calc. for C24H23NO2S 412.1347; found 412.1355 [Mþ þ Na].
ACKNOWLEDGMENTS
The authors thank the University Grants Commission, New Delhi (UGC), for
financial support [F. No. 37-79=2009 (SR)]. The departments of Inorganic and
Physical Chemistry (IPC) and Organic Chemistry at IISc, Bangalore, are thanked
for the compound characterization data. Timely help from H. N. Gopi, IISER,
Pune, during the preparation of the manuscript is gratefully acknowledged.
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