Isoselenocyanates derived from amino acid esters: An expedient synthesis and application to the assembly of selenoureidopeptidomimetics, unsymmetrical Selenoureas and selenohydantoins

Article abstract of DOI:10.1002/psc.1276

An important class of organoselenium compounds-α-isoselenocyanato esters 4 hasbeen prepared by a reaction of α-isocyano esters with elemental selenium powder. The reaction issimple, rapid and all the isoselenocyanates havebeen isolated as stable ones after chromatographic purification. These hitherto unreported classes of molecules would be useful building blocks for the preparation of variety of selenium containing peptidomimetics. In this study, the utility of the title molecules in the preparation of selenoureidopeptidomimetics 6, unsymmetrical selenoureas 8 and selenohydantoins 10 isdemonstrated.

Full text of DOI:10.1002/psc.1276

Research Article
Received: 3 April 2010
Revised: 14 June 2010
Accepted: 15 June 2010
Published online in Wiley Online Library: 16 September 2010
(wileyonlinelibrary.com) DOI 10.1002/psc.1276
Isoselenocyanates derived from amino
acid esters: an expedient synthesis and
application to the assembly of sele-
noureidopeptidomimetics, unsymmetri-
cal Selenoureas and selenohydantoins‡
Hosahalli P. Hemantha and Vommina V. Sureshbabu∗
An important class of organoselenium compounds-α-isoselenocyanato esters 4 hasbeen prepared by a reaction of α-isocyano
esters with elemental selenium powder. The reaction issimple, rapid and all the isoselenocyanates havebeen isolated as stable
ones after chromatographic purification. These hitherto unreported classes of molecules would be useful building blocks for the
preparation of variety of selenium containing peptidomimetics. In this study, the utility of the title molecules in the preparation
c
of selenoureidopeptidomimetics 6, unsymmetrical selenoureas 8 and selenohydantoins 10 isdemonstrated. Copyright ꢀ 2010
European Peptide Society and John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article
Keywords: organoselenium compounds; isoselenocyanato esters; unsymmetrical selenoureas; selenoureidopeptidomimetics; seleno-
hydantoins
Introduction
general, generated when required and transformed further
into the desired target molecules, are somewhat unstable and
decompose over a period of time at ambient temperatures. These
key intermediates have marked applications in organic synthesis,
including carbohydrate chemistry [16,17]. Isoselenocyanates are
precursors for a number of Se-heterocycles such as selenazoles,
selenazepanes [17]. Although isoselenocyanates 4 derived from
proteinogenic amino acids is yet to be accomplished (Scheme 1),
it is well established that selenium compounds play significant
role in both chemistry as well as biology of peptides and proteins.
Among the important selenium compounds known in amino acid
chemistry [18], two prominent ones are: selenocysteine, being
considered as the 21st amino acid [19,20], often used in native
chemical ligation [21] and the corresponding selenopeptides. In
the present communication, we report isoselenocyanates derived
from amino acid esters/amides and demonstrate their utility as
building blocks in the synthesis of selenoureidopeptidomimetics
and selenohydantoins.
Ourstudiesonthesynthesisofpeptidomimeticsledtosomeuseful
intermediates such as isocyanates derived from Fmoc-Nα-amino
[1]/peptide acids [2], which were employed for the synthesis of N-
(1-Fmoc-amino alkyl)formamides [3], chiral N-Fmoc-β-amino alkyl
isonitriles [4] and ureidopeptidomimetics [2]. Recently, we have
also reported Nβ -urethane (Fmoc/Boc/Z) protected amino alkyl
isothiocyanates and demonstrated their utility in the preparation
of thioureidopeptidomimetics [5,6]. With continued interest in
this area, our attention is now drawn towards the preparation of
α-isoselenocyanato esters/amides (Figure 1), hitherto unreported
classes of building blocks useful for the assembly of selenium
containing peptidomimetics [7,8]. Various types of N-terminal
modifications of amino/peptide acid esters have been reported
in the literature leading to the generation of important class
of peptidomimetic precursors. Nowick et al., reported [9] the
synthesis of enantiomerically pure α-isocyanato esters, which
are useful precursors to several classes of peptidomimetics
[10–12]. However, isothiocyanate derivatives of amino acids
(Figure 1) were initially prepared by the treatment of amino
acid esters with carbon disulphide in THF in the presence of
triethylamine (TEA) via dithiocarbamate intermediates followed
by their decomposition [13]. The use of thiophosgene under
modified Schotten–Baumann conditions was also reported to
affordisothiocyanatopeptideesters[12].Withthisbackground,we
becameinterestedtoexploreanotheramineterminalmodification
of amino acids leading to the generation of yet another class of
intermediates – isoselenocyanato esters (Figure 1).
∗
Correspondence to: Vommina 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: hariccb@hotmail.com;sureshbabuvommina@rediffmail.com
Peptide Research Laboratory, Department of Studies in Chemistry, Central
College Campus, Bangalore University, Dr B. R. Ambedkar Veedhi, Bangalore-
560 001, India
Isoselenocyanates, such as their oxygen and sulfur analogs,
are reactive organoselenium compounds [14,15]. They are, in
‡
Dedicated to Prof. K. M. Sivanandaiah on his 75th birth anniversary.
c
J. Pept. Sci. 2010; 16: 644–651
Copyright ꢀ 2010 European Peptide Society and John Wiley & Sons, Ltd.

ISOSELENOCYANATO ESTERS
synthetic interest especially in multi-component reaction (MCR)s
which have been developed into vital tools for combinatorial syn-
thesis of drug candidates [34–40]. In particular, the α-isocyano
esters obtained by the dehydration of corresponding For-amino
esters have registered wide utility especially in MCRs for generat-
ing peptidic structures. For the dehydration of For-Xaa-esters into
isocyano esters, Ugi has employed reagents such as Phosgene or
its derivatives in the presence of a base or oxomethylenebis-(3H+-
imidazolium)bis(methanesulphonate) [35]. Danishefsky’s group
recently investigated the aspect of retaining enantiomeric purity
during dehydration of For-amino esters employing triphosgene
and a base at low temperatures [31]. It is reasonable that a
mild protocol involving neutral or slightly acidic reaction medium
is advantageous. The strong dehydrating conditions employing
excess base at higher temperature need to be completely circum-
vented. McCarthy, et al., [44] employed Burgess reagent, a well
known dehydrating agent for the conversion of several types of
formamides into isonitriles, including a few amino acid derived
ones. Sureshbabu et al., recently employed Burgess reagent for
the synthesis of chiral N-Fmoc-β-aminoalkyl isonitriles [4]. In view
of these two feasibilities, we selected two isonitriles, C-Ala-OMe
3a and C-Phe-OMe 3b as model compounds to prepare. Thus,
two separate experiments were carried out starting from For-Ala-
OMe 2a and For-Phe-OMe 2b. Both the conditions: (a) Burgess
reagent at 50 ◦C in dry CH2Cl2 for 1.5 h and (b) triphosgene (0.35
eq.)/N-methyl morpholine (NMM; 2 eq.) at −78 to −30 ◦C for about
30 min were run separately on these two model compounds. The
optical rotation values and the yield of the four products obtained
from these experiments are summarized in the Table 1. The for-
mer route has been found to give higher yield, consequently, all
the other isonitriles in this study were made employing Burgess
reagent. Two unnatural amino acids α-aminoisobutyric acid (Aib)
[45] and gabapentin (Gpn) [46], well known to be useful in de novo
design of peptides, were also selected during these studies. The
formyl compounds For-Aib-OMe and For-Gpn-OEt were prepared
using established procedures. They were then dehydrated to the
isonitriles C-Aib-OMe 3l and C-Gpn-OEt 3m as described above.
The key step of this study is the conversion of isocyano
ester 3 to the corresponding isoselenocyanato derivatives 4. In
order to investigate an appropriate condition for this conversion,
preliminaryexperimentswereconductedusingtheisonitrileC-Ala-
OMe 3a. To a solution of isonitrile 3a in THF, elemental selenium
powder was added and the resulting suspension was refluxed
in the presence of TEA. Quantitative conversion of the starting
material was observed in about an hour as adjudged by TLC.
The isoselenocyanate 4a was isolated by a simple work up
and the crude compound was isolated analytically pure by column
chromatographyin92%yield.Eitheratlowertemperatureorunder
the influence of ultrasound, this conversion was not satisfactory
(Table 2). The isoselenocyanate retains a prominent brown patch
on the TLC plate, which is a characteristic feature of most of
the selenated compounds. Further, the protocol was extended
successfully to prepare a series of isoselenocyanate derivates from
R1
OY1
X C N
O
Y1= Me, Et, Bn, tBu
Figure 1. α-Isocyanato (X O)/α-isothiocyanato (X S)/α-isoseleno-
cyanato (X Se) esters derived from amino acids.
R1
R1
Se powder
CN
COOY1
SeCN
COOY1
4a-k
TEA, THF,
reflux, 1h
78-92%
3
S
S
R1:
Y1: Me, Et, Bn
Scheme 1. Conversion of isonitriles into isoselenocyanates 4.
Results and Discussion
Synthesis of α-Isoselenocyanato Esters SeC-Xaa-OY 4
In the beginning of this study we had proposed a reaction for the
straightforward synthesis of isoselenocyanato esters starting from
appropriate α-amino acid esters by treating with either carbon
diselenide [22] or selenophosgene [23]. But, the execution of this
reactionappearedimpracticalowingtothecostandtheavailability
of the reagents. Alternatively, a reaction of isonitriles with
elemental selenium is also known to furnish isoselenocyanates
[24–26]. Although several other methods have been investigated
for the synthesis of isoselenocyanates [27–29], we had to adopt
a practically feasible protocol applicable to amino acid chemistry.
Among all the procedures, the one involving isonitrile and
selenium powder has emerged as classical protocol for general
use [17,30] because this approach gives isoselenocyanates in
satisfactory to good quantities. Elemental selenium is easy to
handle, commercially available and less expensive than other
selenating agents. Above all, isonitriles [31–40] derived from
N-formyl (For group) protected α-amino acid esters 2 [41] are
already known compounds employed as C-protected derivatives
in peptide science. Hence, we chose α-isocyano amino acid esters
3 (isonitriles derived from amino acid esters) as precursors to
isoselenocyanates to accomplish our studies (Scheme 2).
N-For-amino acids 1 were made and transformed to the corre-
sponding methyl, ethyl or benzyl esters 2 [42,43]. The next step
is the preparation of isonitriles which is the key aspect from the
point of maintaining the enantiomeric purity. Ivar Ugi has pio-
neered the chemistry of isocyanides, including those derived from
α-amino acid esters [34]. Because of the exhaustive works from
the groups of Ugi and others, isonitriles have gained tremendous
R1
R1
R1
MeOH/SOCl2 or
EtOH/SOCl2 or
Burgess
Reagent
N
COOY1
CN
COOY1
O
N
COOH
O
dry CH2Cl2,
reflux
H
H
BnOH/p-TsCl/Tolune
reflux
2
3
1
Y1= Me, Et, Bn
Scheme 2. Synthesis of isonitrile derivatives of amino acid esters 3.
c
J. Pept. Sci. 2010; 16: 644–651 Copyright ꢀ 2010 European Peptide Society and John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/psc

HEMANTHA AND SURESHBABU
Table 1. Synthesis of isocyano esters 3a and 3b under different
conditions
O
OMe
Se C N
Se C N
OEt
[α]25D (c 1, CHCl3) (% yield)
O
4l, 76 %
4m, 81 %
Entry
1
Method
C-Ala-OMe
C-Phe-OMe
Figure 2. Isoselenocyanates of Aib 4l and Gpn 4m.
Burgess reagent, dry
CH2Cl2, reflux; 1.5 h
−42.1 (95)
−52.6 (92)
2
Triphosgene/NMM
−78to −40 ◦C, 30 min
−43.8 (72)
−50.2 (80)
α-Isoselenocyanato Carboxamides 5a–f
The protocol was then extended to prepare few isoselenocyanato
carboxamidesalso. Unlikeestersandα-isocyanocarboxamidesare
stable solids and odorless but retain the isocyanide reactivity in
isocyanide based multicomponent reactions (IMCRs) [47,48]. Four
complementary protocols are available to access this important
starting material [48,49]. To implement our other objective
in making α-isoselenocyanato carboxamides 5 (Figure 3), six
known α-isocyano carboxamides were made employing known
procedure.
Briefly, For-amino acids were coupled with the desired amines
under standard peptide coupling conditions (DCC/HOBt) followed
by the dehydration of the For group into isocyano moiety
employing Burgess reagent. They were isolated in good yield
and high enantiomeric purity. Further, it was found that their
conversion to the desired isoselenocyanates 5 under the present
conditions was simple and straightforward. Thus, all the products
formed 5a–f were isolated easily with an overall yield of 68–76%.
Table 2. Synthesis of SeC-Ala-OMe 4a under various conditions
Sl.
No
Temp
(◦C)
Time
(min)
Yield
(%)
Condition
1
2
3
4
5
Thermal
65
50
30
40
50
60
95
92
57
20
53
78
Thermal
Ultrasound
Ultrasound
Ultrasound
120
120
90
other amino acid esters (methyl/ethyl/benzyl) as well. All the α-
isoselenocyanates 4b–k were obtained in good yield (78–92%;
Table 3). IsonitrilederivativesoftwounnaturalaminoacidsAiband
Gpn were also converted to the corresponding isoselenocyanates
4l and 4m (Figure 2) in 76 and 81% yields respectively. The IR
spectrum of these isoselenocyanates contain a sharp peak at
around 2248 cm−1 corresponding to the stretching frequency of
Selenoureidopeptidomimetics 6
Asimple,straightforwardandusefulapproachtoseleniumanalogs
of ureas is the reaction of isoselenocyanates with an amine.
There are several other routes reported in the literature for
the preparation of selenoureas but their general applicability
is yet to be fully demonstrated [50]. In order to illustrate
the scope of isoselenocyanates 4 and 5, the synthesis of
selenoureidopeptidomimetics 6 was undertaken (Scheme 3). It
was found that the reaction of isoselenocyanates 4 with amino
acidesters7atroomtemperatureproceededrapidlyandcomplete
starting material was generally consumed within 60 min. All the
selenoureas 6 were obtained in 67–71% yield after column
chromatographic purification and were fully characterized. In
these experiments, the hydrochloride salts of amino acid esters
were neutralized using activated zinc [51] prior to their addition
C
Se bond of NCSe. The 13C NMR of the isoselenocyanates
possesses a characteristic signal at δ 133 corresponding to
isoselenocyanate carbon, whereas the 77Se NMR had a signal
at δ −349.
These isoselenocyanates showed appreciable stability. At low
temperature they can be stored for about two weeks without any
noticeable degradation of the product. For example, there was no
change in the 1H NMR and IR spectra of SeC-Val-OMe 4c recorded
after storing for two weeks.
Table 3. List of amino acid ester derived α-isoselenocyanates 4
Se
C N-Xaa-COOY
Entry
Comp. No.
Xaa
Y
Yield (%)
HRMS Obsrd. (Calcd.)
[α]25D (c 1, CHCl3)
1
4a
4b
4c
4d
4e
4f
CH3
CH3
CH3
92
88
90
84
80
79
82
78
89
87
80
215.9554 (215.9540)
291.9860 (291.9853)
243.9855 (243.9855)
258.0017 (258.0009)
275.9563 (275.9573)
215.9556 (215.9540)
277.9683 (277.9696)
351.9875 (351.9885)
291.9867 (291.9853)
320.0155 (320.0166)
334.0330 (334.0320)
−27.5
−74.2
−44.0
−19.6
−32.2
–
2
CH2C6H5
CH(CH3)2
3
CH3
4
CH(CH3)CH2CH3
CH2CH2SCH3
H
CH3
5
CH3
6
CH2CH3
CH3
7
4g
4h
4i
C6H5
−10.2
−11.6
−67.5
−80.0
−70.2
8
CH2SCH2C6H5
CH3
CH2CH3
CH2C6H5
CH2C6H5
CH2C6H5
9
10
11
4j
CH(CH3)2
CH2CH(CH3)2
4k
c
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ISOSELENOCYANATO ESTERS
O
O
N
N
N
Se C N
Se C N
Se C N
O
O
O
5c, 76%
5b, 71%
5a, 68%
O
O
H
N
N
N
O
Se C N
Se C N
Se C N
O
O
5d, 75%
5e, 76%
5f, 70%
Figure 3. α-Isoselenocyanato carboxamides 5a–f.
R2
R1
R2 Se R1
dry CH2Cl2
Y2O
NH2
+
SeCN
COOY1
Y2OOC
N
N
COOY1
1 h, 78-86 %
H
H
O
7
4
6
Y1, Y2 = Me, Et, Bn
Scheme 3. Synthesis of selenoureidopeptides 6.
1
into the reaction mixture. However, when benzyl esters were
employed for coupling, as in the case of Phe (in 6a), the
corresponding p-toluene sulphonic acid salt was neutralized using
an equimolar quantity of NMM. No additional base was necessary
for carrying out the coupling of isoselenocyanates with amino
acid esters. The 13C NMR of selenoureas showed a signal at δ
182 corresponding to the selenocarbonyl carbon. Furthermore,
77Se NMR spectra possess peaks around δ 230–300, which also
confirms the selenocarbonyl carbon. Under the same conditions,
isoselenocyanate derived from Gpn, 4k also reacted very fast to
give the expected urea 6b (Table 4).
of ureidopeptidomimetics, H NMR analysis of the urea adducts
made using enantiomer(s)/racemate of 1-phenylethylamine was
considered to establish enantiomeric purity of the products [9]. In
this regard, (S, 3R)8e was taken as specimen example. Its epimer
(S, 3S)8e and racemate (S, 3R, S)8e were prepared by coupling (S)-
methyl 2-isoselenocyanato-3-phenylpropanoate 4b with (S) and
(R/S)-1-phenylethylamine, respectively (Figure 4). Each epimer (S,
3R)8e and (S, 3S)8e had a single distinct methyl group doublet in
their 1H NMR spectrum. The recorded values for these two isomers
are: δ 1.47 and 1.49 and 1.49 and 1.51. respectively. Further, the
δ values for methyl group’s resonance of (S, 3R, S)8e are 1.46,
1.47 and 1.48, 1.51, which revealed the presence of two epimers.
Similar studies were also made on selenourea adducts prepared
by coupling (R) and (S)-1-phenylethylamine with SeC-Phg-OMe
4g separately. In this case also, the 1H NMR spectrum showed
distinct doublets at δ 1.50 and 1.52 and 1.52 and 1.53 respectively
for (S, 3R)8f and (S, 3S)8f selenoureido epimers. These results
demonstrate the optical purity of SeC-Phe-OMe 4b as well as SeC-
Phg-OMe 4g prepared by the present protocol at levels detectable
by 1H NMR.
Unsymmetrical Selenoureas 8
In recent years, organic catalysts are being explored for various
kinds of studies in asymmetric synthesis [52]. Thioureas to a larger
extent and ureas in specific case studies have been developed as
very useful catalysts [53]. Among the unsymmetrically substituted
ureas being designed and developed, amino/peptide acid [54]
or sugar moiety [55] is selected as one of the substituents in
many catalysts where the other substituent is an aromatic moiety.
There are already a couple of reports describing the utility of
selenoureas as catalysts as well [56]. In view of these recent
advancements in organic synthesis, we extended this study to
prepare several unsymmetrical selenoureas also (Scheme 4). Thus,
the isoselenocyanates 4 were allowed to react with various amines
such as aniline, p-bromoaniline and cyclohexylamine to obtain the
designed ureas 8a–e, which were purified and characterized
(Table 4).
Synthesis of Hydantoins 10a–h
Hydantoins are an important class of biologically active molecules
[57]. Both chemistry and biology of thiohydantoins are also known
[58]. Ishihara et al., [59] demonstrated the preparation of seleno-
hydantoins derived from Val, Ala, Gly, Met, Leu and Phe by treating
the phenyl isoselenocyanate with amino acid esters at reflux. As
a final part of this study, the isoselenocyanates 4 are employed
as starting compounds for the synthesis of a few selenohydan-
toins. They were allowed to react with an amine (aniline in four
case studies, cyclohexylamine, m-toluidine, 3-chloroaniline and
3-bromoaniline in one example each) in THF at reflux for 3–4 h
(Scheme 5).
Test for Racemization
The chemistry of amino acids can involve epimerization during the
reactionsataminoaswellascarboxyfunctions.Anystudyinvolving
these substrates should be accompanied by a test for examining
the extent of racemization or otherwise. During the assembly
It was found to be a smooth reaction, complete in about
4 h. After a simple workup, the selenohydantoins 10a–h were
c
J. Pept. Sci. 2010; 16: 644–651 Copyright ꢀ 2010 European Peptide Society and John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/psc

HEMANTHA AND SURESHBABU
Table 4. List of selenoureido derivatives 6 and 8
Selenoureidopeptidomimetics 6
Compound
Unsymmetrical selenoureas 8
Compound
Entry
1
Yield (%)
71
Yield (%)
76
O
O
O
H
H
N
H
N
H
N
N
BnO
Ph
OMe
OMe
OMe
Se
6a
Se
8a
Ph
O
2
3
78
67
75
82
H
N
H
N
O
O
H
N
H
N
EtO
OEt
Se
Se
6b
8b
Ph
O
Ph Se
H
N
H
N
MeO
OMe
OBn
OMe
N
H
N
H
Se
8c
O
O
O
6c
4
5
70
55
70
72
Ph
MeO
O
H
H
Se
N
N
OMe
N
N
Se
H
H
O
Br
6d
8d
S
O
H
H
Se
O
N
N
OMe
MeO
N
N
N
Se
8e
H
H
Ph
O
O
6e
and their utility in assembling selenoureidopeptidomimetics and
selenohydantoinsisalsodemonstrated.Inviewoftheknownutility
of organoselenium compounds in biological studies, we suspect
that selenoureidopeptides also may have unrealized potential
with respect to drug design. They may appear as attractive entities
useful in asymmetric synthesis and in biological studies. In spite of
the demonstration of this type of studies in sugar chemistry, it was
not applied in peptide science. A word of caution in this regard is
‘toxicity’whichneedstobedealtwithatanappropriatetime. Inad-
dition, it seems reasonable that other bioactive compounds in this
class would be discovered whether screening efforts in this area
are thoroughly investigated. The ‘alphabets’ of isoselenocyanate
monomers may find applications in combinatorial chemistry.
R1
Se R1
R3-NH2
R3
COOY1
SeCN
COOY1
N
H
N
H
R3 = Ar, Cyclohexyl
Y1 = Me
4
8
Scheme 4. Preparation of selenoureas 8.
O
H
H
O
H
H
N
N
N
*
N
O
*
O
Se
Se Ph
Ph
(S, 3R)8e, (S, 3S)8e
(S, 3R, S)8e
(S, 3R)8f, (S, 3S)8f
(S, 3R, S)8f
Experimental
Figure 4. R, S, R/S-phenylethylamine coupled selenourea derivatives 8.
General Procedure for the Preparation of α-Isocyano Esters 3
A solution of For-amino acid ester 2 (1 mmol) in dry CH2Cl2 (8 ml)
wasrefluxedfor1.5 h, along withBurgessreagent(0.24 g, 1 mmol).
After the completion of reaction (TLC analysis), it was diluted with
CH2Cl2 (10 ml) and the organic phase was washed with aq. citric
acid (5%, 10 ml), water and brine. Evaporation of the solvent under
vacuum afforded the α-isocyano ester 3 in excellent yield and high
purity which was taken for next step as such.
obtained as pure compounds in 74–92% yields. The 77Se NMR
of 10g had a sharp signal at δ 229.46 confirming the presence
of C Se bond of selenoureido group. Characteristic peaks in IR,
1H and 13C NMR along with high resolution mass spectroscopy
(HRMS) data confirmed their structures.
Conclusions
General Procedure for the Preparation of α-Isoselenocyanato
Esters 4
A new class of isoselenocyanates derived from amino acid es-
ters/amides is described by a reaction of corresponding isonitriles
with elemental selenium. They have been isolated, characterized
The isonitrile 3 (1 mmol) was dissolved in THF (10 ml), to which
were added triethyl amine (97 µl; 0.7 mmol), Se black powder
c
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ISOSELENOCYANATO ESTERS
H
R1
Se
R4
N
TEA
THF, reflux
R1
R4 NH2
OMe
+
N
Se C N
O
4
O
10
H
H
N
H
N
Se
N
H
Se
Se
Se
N
N
N
N
N
O
O
O
O
10a, 74%
10b, 77 %
10c, 92 %
10d, 85 %
H
N
H
N
H
N
Se
Se
Se
H
Se
N
Cl
N
O
N
O
N
S
Br
N
O
10h, 76 %
S
O
10e, 82 %
Scheme 5. Synthesis of selenohydantoins 10.
10f, 88 %
10g, 94 %
(94 mg; 1.2 mmol) and the reaction mixture was refluxed for Spectral Characterization Data of Representa-
60–75 min. After the completion of the reaction, it was passed
through a pad of celite and the filtrate was concentrated. The
tive Compounds
(S)-Methyl 2-Isoselenocyanato-3-Phenylpropanoate 4b
residue was dissolved in ethyl acetate (15 ml) and the organic
layer was washed with water (10 ml × 2) and brine (10 ml).
The organic layer was concentrated by rotary evaporation under
reduced pressure and the crude residue was purified by column
chromatography (silica gel, 100–200 mesh, 10% ethyl acetate in
hexane) to afford pure isoselenocyanates 4.
Colorless gum; yield: 88%; Rf 0.78 (n-hexane-EtOAc 4 : 1); IR
(film) υmax = 2148, 1740 cm−1
;
1H NMR (CDCl3, 400 MHz):
δ = 7.26–7.42 (m, 5H), 4.64 (m, 1H), 3.83 (s, 3H), 3.22 (d,
J = 7.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ = 167.7, 135.1, 131.4,
129.9, 129.4, 128.3, 61.6,53.9, 39.9; 77Se NMR (CDCl3, 400 MHz)
δ = −348.872; HRMS (m/z) Calculated for C11H11NO2Se+Na:
291.9853; Observed: 291.9860.
General Procedure for the Preparation of Selenoureido
Compounds 6 and 8
(S)-2-Isoselenocyanato-3-Phenyl-1-(Piperidin-1-Yl)Propan-1-
One 5c
To a solution of isoselenocyanate 4 or 5 (1.5 mmol) in dry CH2Cl2
(10 ml) at room temperature was added a solution of amino
acid ester (1.8 mmol, obtained by neutralizing the corresponding
salt; treating with either commercial zinc dust [45] in case of
hydrochloride salts or using an equimolar quantity of NMM in the
case of p-toluenesulfonic acid salts) or aliphatic/aromatic amine
(1.6 mmol) and the reaction mixture was stirred at the same
temperature for an hour. After the completion of reaction (TLC),
it was diluted with CH2Cl2 (10 ml) and washed with citric acid
solution (10%, 10 ml), water (10 ml) and brine (10 ml). After the
evaporation of the solvent under reduced pressure, the crude
product was purified using column chromatography (silica gel,
100–200 mesh, 15–20% ethyl acetate in hexane) to isolate the
analytically pure selenoureas in good yields.
Gum; yield: 76%; Rf 0.50 (n-hexane/EtOAc 4 : 1); IR (film) υmax
=
2150, 1758 cm−1; H NMR (CDCl3, 400 MHz): δ = 7.14–7.39 (m,
5H), 4.16–4.20 (m, 2H), 4.04–4.08 (m, 2H), 1.97 (m, 6H); 13C NMR
(CDCl3, 100 MHz): δ = 170.8, 129.8, 129.2, 128.9, 127.9, 126.9,
69.4, 54.1, 53.3, 39.9, 24.6, 21.1, 20.9; 77Se NMR (CDCl3, 400 MHz):
δ = −376.761; HRMS (m/z) Calculated for C15H18N2OSe+Na:
345.0482; Observed: 345.0480.
1
EtO-Gpn-CSe-Gpn-OEt 6b
Colorless gum; yield: 78%; Rf 0.40 (n-hexane/EtOAc 4 : 1); IR (film)
υmax = 1756, 1545 cm−1
;
1H NMR (CDCl3, 400 MHz): δ = 7.77
(br, 1H), 6.73 (br, 1H), 4.08 (q, J = 5.1 Hz, 4H), 3.69–3.80 (m, 4H),
2.32 (s, 4H), 1.39 (br, 20 H), 1.21 (t, J = 5.4 Hz, 6H); 13C NMR
(CDCl3, 100 MHz): δ = 180.1, 173.0, 67.9, 60.7, 53.5, 37.5, 33.9, 25.8,
21.4, 14.2; 77Se NMR (CDCl3, 400 MHz): δ = 184.82; HRMS (m/z)
Calculated for C23H40N2O4Se+Na: 511.2051; Observed: 511.2043.
General Procedure for the Synthesis of Selenohydantoin 10
To a solution of isoselenocyanato methyl ester 4 (1 mmol) and
an amine (1.2 mmol) in THF (8 ml) was added TEA (410 µl;
3.0 mmol) and it was refluxed for 3 h. After completion of the
reaction, it was concentrated and the residue was dissolved in
ethyl acetate (15 ml). The organic phase was washed with citric
acid solution (10 ml, 10%), water and brine. After drying over
anhydrous sodium sulfate, the crude compound was purified
through column chromatography (silica gel 100–200 mesh, 15%
EtOAc in hexane) to afford the corresponding selenohydantoin as
colorless crystalline solid.
(S)-Methyl 2(3-Cyclohexylselenoureido)-3-Phenylpropanoate
8a
Gum; yield: 76%; Rf 0.40 (n-hexane/EtOAc 4 : 1); IR (film) υmax
=
1728, 1513 cm−1
;
1H NMR (CDCl3, 400 MHz): δ = 8.27 (br, 2H),
7.23–7.41 (m, 5H), 4.50 (m, 1H), 4.07 (s, 3H), 3.25 (d, J = 5.7 Hz, 2H),
2.94 (m, 1H), 1.92–2.25 (m, 2H), 1.78 (m, 2H), 1.65 (m, 2H), 1.32 (m,
4H); 13C NMR (CDCl3, 100 MHz): δ 185.6, 172.6, 134.0, 129.3, 128.9,
127.7, 60.7, 57.3, 36.9, 28.5, 28.0, 25.8, 24.9; HRMS (m/z) Calculated
for C17H24N2O2Se+Na: 391.0901, Observed: 391.0908.
c
J. Pept. Sci. 2010; 16: 644–651 Copyright ꢀ 2010 European Peptide Society and John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/psc

HEMANTHA AND SURESHBABU
(S)-5-Isopropyl-2-Selenoxo-3-M-Tolylimidazolidin-4-One 10c
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efficient synthesis of isothiocyanates from amines using di-tert-butyl
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Crystalline solid; yield: 92%; m.p.: 148 ◦C; Rf 0.45 (n-hexane/EtOAc
5 : 1); IR (KBr) υmax = 1750, 1524 cm−1; 1H NMR (CDCl3, 400 MHz):
δ = 8.98 (br, 1H), 7.00–7.34 (m, 4H), 3.94 (d, J = 3.3 Hz, 1H), 2.34 (s,
3H), 2.21 (m, 1H), 0.96–1.08 (dd, J = 5.4 Hz, 6H); 13C NMR (CDCl3,
100 MHz): δ = 185.6, 173.2, 139.9, 133.6, 130.9, 129.5, 129.4, 125.9,
66.7, 31.4, 21.9, 19.4, 16.8; HRMS (m/z) Calculated for C13H16N2OSe
+ Na: 319.0326; Observed: 319.0330.
Acknowledgements
We thank the Council of Scientific and Industrial Research
(grant No. 01(2323)/09/EMR-II) and Department of Science and
Technology (Grant No. SR/S1/OC-26/2008), Government of India
forfinancialsupport.WealsothanktheDepartmentsofInorganic&
Physical Chemistry, Organic Chemistry, Sophisticated Instrument
Facility, I.I.Sc., Bangalore for recording NMR and mass spectra. We
would like to thank Professor Fred Naider, CUNY, New York, USA
for useful discussion. We also acknowledge Dr K. Natarajan of Hical
Ltd., Bangalore, India for a free sample of Gpn.
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