Synthesis of N -fmoc-protected amino alkyl thiocyanates/selenocyanates and their application in the preparation of 5-substituted S/Se -linked tetrazoles

Article abstract of DOI:10.1055/s-0030-1259972

A novel class of N-Fmoc-protected amino alkyl thiocyanates/selenocyanates has been prepared by thiocyanation/selenocyanation of the corresponding alkyl iodides. These thiocyanates/selenocyanates undergo a facile [2+3]-cycloaddition reaction with sodium az

Full text of DOI:10.1055/s-0030-1259972

PAPER
1447
Synthesis of N-Fmoc-Protected Amino Alkyl Thiocyanates/Selenocyanates and
Their Application in the Preparation of 5-Substituted S/Se-Linked Tetrazoles
N-Fmoc
Amino
A
l
kyl
T
hiocyan
m
ates/Selenocyanate
m
s
ina V. Sureshbabu,* Basavalingappa Vasantha, Hosahalli P. Hemantha
Room No. 109, Peptide Research Laboratory, Department of Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi,
Bangalore University, Bangalore 560001, India
Fax +91(80)22292848; E-mail: sureshbabuvommina@rediffmail.com; E-mail: hariccb@gmail.com; E-mail: hariccb@hotmail.com
Received 6 January 2011; revised 18 February 2011
protection led to a simple isolation of the free amino tetra-
Abstract: A novel class of N-Fmoc-protected amino alkyl thiocy-
zoles.7 A literature survey on S/Se-linked tetrazoles result-
ed in a handful of reports. Dondoni and co-workers
anates/selenocyanates has been prepared by thiocyanation/seleno-
cyanation of the corresponding alkyl iodides. These thiocyanates/
selenocyanates undergo a facile [2+3]-cycloaddition reaction with
synthesized S-tetrazoles bearing C-glycosyl a-amino ac-
sodium azide to afford novel N-Fmoc amino alkyl S/Se-linked tetra- ids wherein sugar-derived C-alkyl azides were first treat-
zoles.
ed with tosyl cyanide at 100 °C, followed by replacement
of the tosyl group with cysteine thiol.8 Jursic’s group re-
Key words: amino acid derivatives, thiocyanates, selenocyanates,
[2+3] cycloaddition, S/Se-linked tetrazoles
ported the synthesis of 5-alkyl- and 5-aryl-S-linked tetra-
zoles from the corresponding thiocyanates.9 Yildirir and
co-workers prepared Se-linked tetrazoles by a reaction of
aromatic selenocyanates with sodium azide.10 Though tet-
razole derivatives of amino acids have been prepared and
employed in varied applications including organic cataly-
sis,3 the chemistry has not been extended to the prepara-
tion of S/Se-linked tetrazole derivatives from amino acids.
Due to the widespread application of S/Se-linked tetra-
zolyl compounds, we reasoned that insertion of such moi-
eties in place of the carboxy group of an amino acid would
generate novel precursors for the synthesis of peptidic
drug candidates, as well as for catalyst applications.11 In
the present study, the synthesis of S/Se-linked tetrazoles
by a [2+3]-cycloaddition reaction of N-protected amino
alkyl thiocyanates/selenocyanates with sodium azide is
described.
With our previous experience in the synthesis of Na-Fmoc
amino tetrazoles from the respective nitriles, we envis-
aged that Na-Fmoc amino alkyl thiocyanates/selenocyan-
ates would be the ideal intermediates for accessing S/Se-
linked tetrazoles. Thiocyanates/selenocyanates are versa-
tile synthetic intermediates and, owing to their electro-
philic nature, they can be engaged as effective
dipolarophilic partners of an azide ion. Thiocyanato com-
pounds themselves have been used for the preparation of
a few pharmaceuticals.12 They can also serve as precur-
sors for a plethora of diverse reactions including the syn-
thesis of thio-heterocycles, thiophenols, thiocarbamates,
dithiourethanes and sulfonyl cyanides.13 Likewise, organ-
ic selenocyanates are also of interest due to their enhanced
cancer chemopreventive activities and utility as starting
materials for the synthesis of selenium-containing hetero-
cycles, diselenides and selenoketones.14
Modification of the native structure of amino acids by in-
serting heterocycles such as tetrazoles, triazoles, thiazoles
and isoxazoles through selective carboxy group transfor-
mation has been of considerable interest in biochemistry,
enzymology and pharmacology.1 In particular, tetrazoles
have been extensively studied in recent years due to their
ability to act as a metabolically stable surrogate for the
carboxy group,2 and hence have been used in designing
potential anti-inflammatory, central nervous stimulant
and hypertensive agents. They are also employed as cis-
peptide bond mimics and have found numerous applica-
tions as catalysts in asymmetric synthesis.3 Specifically,
5-S-linked tetrazoles are an important class of compounds
known for their biological and chemical potency. Due to
the presence of the alkylthio linkage, they show increased
acidity and solubility which makes them powerful activa-
tors for DNA and RNA syntheses.4 On similar lines, 5-Se-
linked tetrazoles would also represent a useful subclass
which has scarcely been addressed in the literature. The
recent surge in selenium chemistry,5 and the discovery of
several selenoproteins, prompted us to work on selenium
derivatization of amino acids, such as the 5-Se-linked tet-
razoles.
The most feasible and practical routes for the synthesis of
tetrazoles, in general, involve either reaction of a substi-
tuted halide with 1H-tetrazole or a [2+3]-cycloaddition re-
action of a nitrile with an azide ion.1a,6 Demko and
Sharpless have reported an efficient protocol for the syn-
thesis of 5-substituted amino alkyl tetrazoles by the reac-
tion of Na-Z amino nitriles with sodium azide and zinc
bromide, followed by removal of the Z group; however,
the removal of the protecting group was a challenging
task.1a–c In this regard, our use of the Fmoc group for Na-
Several methods are available for the preparation of thio-
cyanates; most of these involve substitution of a halide
with thiocyanic acid or its salt. Some of the other notable
protocols make use of thiocyanating agents such as 1-n-
butyl-3-methylimidazolium thiocyanate ([bmim]SCN),15
direct nucleophilic substitution of alcohols with the thio-
SYNTHESIS 2011, No. 9, pp 1447–1455
x
x
.
x
x
.2
0
1
1
Advanced online publication: 25.03.2011
DOI: 10.1055/s-0030-1259972; Art ID: N09811SS
© Georg Thieme Verlag Stuttgart · New York

1448
V. V. Sureshbabu et al.
PAPER
cyanate anion16 or the Mitsunobu reagent system (Ph3P– due to the ambient nature of the thiocyanate ion, was ob-
DEAD–NH4SCN).17 Similarly, selenocyanates are ac- served. This was further confirmed by comparing the
cessed by nucleophilic substitution of halides with the se- HPLC chromatograms of Fmoc-Phg-y(CH2NCS) (pre-
lenocyanate ion.18 Kachanov’s group reported a one-pot pared according to our previous report21) with Fmoc-Phg-
synthesis of selenocyanates using triselenium dicyanide y(CH2SCN) (2d, R = Ph) now in hand.29
as the selenocyanating agent.19
A single recrystallization using tetrahydrofuran–hexane
Our interest in designing peptidomimetics and unnatural elevated the purity of the samples to 99% (HPLC analy-
amino acid derivatives has led to several useful amino sis). The 13C NMR spectra of these thiocyanates have a
acid derived synthons including isocyanates of Na-Fmoc- prominent signal around 112 ppm, characteristic of SCN,
protected amino acids,20 N-urethane-protected amino while the IR spectra display a CN stretch at around 2135
alkyl isothiocyanates,21 Na-Fmoc amino alkyl cm–1.
formamides22 and N-Fmoc b-amino alkyl isonitriles.23
To demonstrate the generality of this protocol, a series of
N-Fmoc amino alkyl iodides was converted into the corre-
sponding thiocyanates 2a–e, including examples derived
from bifunctional amino acids, resulting in Fmoc-
Cys(Bn)-y(CH2SCN) (2f), Fmoc-Asp(t-Bu)-y(CH2SCN)
(2g) and Fmoc-Lys(Z)-y(CH2SCN) (2h) (Table 1). The
Though thiocyanate and selenocyanate derivatives have
prevailed in various other classes of compounds including
carbohydrates,24 to the best of our knowledge, N-protect-
ed amino alkyl thiocyanates and selenocyanates are yet to
be reported.
In the present work, the Fmoc group was selected for N- thiocyanates were stable toward long-time storage at
protection25 and potassium thiocyanate as the thiocyanat- ambient temperature, with no noticeable degradation, as
ing agent.26 The essential precursors, N-Fmoc amino alkyl confirmed by HPLC analysis. Further, the thiocyanate
iodides 1a–h (Scheme 1), were prepared via a reported moiety was also inserted in place of the side-chain hy-
protocol.27 In brief, N-Fmoc amino acids were reduced to droxy group of serine and homoserine (Figure 1; 2i, 2j).
the corresponding b-amino alcohols28 and then subjected
to the Mitsunobu reaction (Ph3P–imidazole–I2).21 In the
next step, a solution of the N-Fmoc amino alkyl iodide 1
was treated with potassium thiocyanate. Either at room
temperature or under reflux, the progress of the reaction
was not satisfactory; however, use of a catalytic amount of
tetrabutylammonium bromide drove the reaction to com-
pletion in a short duration of time. In a typical reaction, a
solution of Fmoc-Phe-y(CH2I) (1c, R = Bn) in tetrahydro-
furan was refluxed along with potassium thiocyanate and
catalytic tetrabutylammonium bromide (Scheme 1). After
completion of the reaction (TLC analysis), a simple work-
up afforded the corresponding thiocyanate 2c in good
yield with a purity of about 91%. HPLC analysis of crude
2c showed a single major peak and no trace of the corre-
sponding isothiocyanate, which otherwise can be formed
NCS
NCS
NCSe
2
3
FmocHN
COOMe
FmocHN
COOMe
FmocHN
COOMe
2j, 76%
2i, 65%
3d, 89%
Figure 1
A similar protocol was also employed for the preparation
of a few N-Fmoc amino alkyl selenocyanates, by reaction
of the corresponding alkyl iodides with potassium seleno-
cyanate (Table 1, 3a–c). The 13C NMR spectrum of 3a has
a characteristic signal at 101.9 ppm and the IR spectrum
shows a CN stretch at 2145 cm–1. The selenocyanate moi-
ety was also inserted in the w-carboxy position of Fmoc-
Glu-OMe (Figure 1, 3d).
Further, treatment of 2i and 3d in a separate set of exper-
iments with diethylamine–dichloromethane (1:1) for 45
minutes afforded the corresponding free amino methyl
esters 4i and 5d in 98% and 95% yield, respectively
(Scheme 2). On the other hand, deprotection of the methyl
ester in 2i and 3d was accomplished following a protocol
reported by Pascal and Sola;30 the free carboxy com-
pounds 6i and 7d were isolated in 85% and 75% yield, re-
spectively (Scheme 2). All of these compounds were
characterized employing mass and NMR spectroscopy.
R
R
KXCN, THF
reflux
I
XCN
FmocHN
FmocHN
2 X = S
3 X = Se
1
NHZ
Me
R =
4
COOBn
SBn
COOt-Bu
In the next set of experiments, we undertook the synthesis
of S- and Se-linked tetrazoles. In a typical study, Fmoc-
Scheme 1 Synthesis of N-Fmoc-protected amino alkyl thiocya-
nates/selenocyanates
NCX
H2N
NCX
NCX
NaOH, CaCl2
n
Et2NH
n
n
i-PrOH, H2O
CH2Cl2
COOMe
FmocHN
COOH
FmocHN
COOMe
4i X = S 98%
5d X = Se 95%
2i X = S, n = 1
3d X = Se, n = 3
6i X = S 85%
7d X = Se 75%
Scheme 2
Synthesis 2011, No. 9, 1447–1455 © Thieme Stuttgart · New York

PAPER
N-Fmoc Amino Alkyl Thiocyanates/Selenocyanates
1449
Table 1 List of the Synthesized Thiocyanates/Selenocyanates 2/3
HRMS: [M + Na]+
29
Entry
Yield
(%)
Mp
(°C)
[a]D
R
(c 0.2, MeOH) calcd (found)
XCN
FmocHN
R
X
S
1
2a
2b
2c
2d
2e
2f
Me
92
91
94
91
82
81
71
88
89
88
86
104–106
107–108
105–107
gum
+68.0
+38.1
+28.5
–2.2
361.0987
(361.0981)
2
i-Pr
S
389.1300
(389.1294)
3
Bn
S
432.1746
(432.1742)a
4
Ph
S
418.1589
(418.1588)a
5
-(CH2)3-[Pro]
CH2SBn
CH2COOt-Bu
(CH2)4NHZ
Me
S
gum
–4.2
387.1143
(387.1146)
6
S
gum
+4.0
483.1177
(483.1171)
7
2g
2h
3a
3b
3c
S
98–99
–2.4
461.1511
(461.1516)
8
S
106–108
102–103
109–110
111–113
+6.0
547.2379
(547.2373)a
9
Se
Se
Se
+12.3
+23.5
+28.3
409.0431
(409.0438)
10
i-Pr
437.0744
(437.0750)
11
i-Bu
451.0901
(451.0908)
a [M + NH4]+.
Phe-y(CH2SCN) (2c, R = Bn) was refluxed along with so- Further, S-linked tetrazoles were also incorporated in the
dium azide and zinc bromide in a water–2-propanol sys- side chain of serine and homoserine (Figure 2; 8i, 8j). In
tem (Scheme 3). The reaction was complete in 4.5 hours another example, a Se-linked tetrazole was inserted in
(TLC analysis). It is worth mentioning that, compared to place of the w-carboxy group of Fmoc-Glu-OMe
nitriles,7 thiocyanates undergo the cycloaddition reaction (Figure 2, 9d).
with sodium azide in a shorter duration of time, which can
be attributed to the electron-withdrawing nature of the S
HN
N
N
HN
N
N
HN
N
N
N
atom. A simple workup afforded the desired S-linked tet-
razole 8c as a solid in 88% yield. The protocol was ex-
tended to the preparation of a series of examples of N-
Fmoc amino alkyl S-linked tetrazoles 8a–h. In a similar
way, Se-linked tetrazoles 9a–c were prepared by a [2+3]-
cycloaddition reaction of the corresponding selenocya-
nates with sodium azide (Scheme 3, Table 2).
N
N
S
Se
S
2
3
FmocHN
COOMe
FmocHN
COOMe
FmocHN
COOMe
9d, 79%
8i, 65%
8j, 76%
Figure 2
R
NaN3, ZnBr2
R
Two S-linked tetrazoles 8a, 8e and a Se-linked tetrazole
9b were treated with diethylamine–dichloromethane (1:1)
and the free amino alkyl S/Se-linked tetrazoles 10a, 10e
and 11b, respectively, were isolated as solids (Figure 3).
The purity of these free amino derivatives was confirmed
by RP-HPLC.31
X
i-PrOH, H2O
reflux
N
FmocHN
XCN
NH
FmocHN
N
N
2 X = S
3 X = Se
8 X =S
9 X = Se
Scheme 3 Synthesis of N-Fmoc-protected amino alkyl S/Se-linked
In summary, the preparation of N-Fmoc amino alkyl thio-
cyanates/selenocyanates by reaction of the corresponding
tetrazoles
Synthesis 2011, No. 9, 1447–1455 © Thieme Stuttgart · New York

1450
V. V. Sureshbabu et al.
PAPER
Table 2 List of the Synthesized S/Se-Linked Tetrazoles 8/9
Entry
1
Tetrazole
Yield (%)
92
Mp (°C)
92–94
[a]D29 (c 0.2,
HRMS: [M + Na]+
calcd (found)
THF)
382.13 (382.05)a,b
S
S
N
8a
–21.0
+12.0
FmocHN
FmocHN
NH
NH
N
N
N
410.1651
2
3
8b
8c
87
88
gum
(410.1646)b
N
N
Ph
480.1470
(480.1465)
141–142
+9.0
S
S
N
FmocHN
NH
NH
N
N
N
Ph
444.1494
4
5
8d
8e
88
85
151–152
gum
+8.4
N
FmocHN
(444.1498)b
N
408.1494
N
S
–13.5
(408.1495)b
NH
N
Fmoc
N
N
BnS
521.1793
6
7
8
8f
85
78
78
142–143
78–80
+16.7
+11.9
+18.6
(521.1785)c
S
N
FmocHN
NH
NH
N
N
t-BuOOC
FmocHN
504.1681
(504.1686)
8g
8h
S
N
N
N
ZHN
573.2284
4
148–150
(573.2287)b
S
N
FmocHN
NH
NH
N
N
N
430.0782
Se
N
9
9a
9b
89
86
136–139
gum
+3.5
+1.6
(430.0790)b
FmocHN
FmocHN
N
480.0915
(480.0923)
10
Se
Se
N
NH
NH
N
N
N
472.1252
11
9c
85
gum
+5.6
(472.1260)b
N
FmocHN
N
a ESI-MS.
b [M + H]+.
c [M + NH4]+.
alkyl iodides with potassium thiocyanate or selenocyanate azide. Side-chain modification of a few bifunctional ami-
in the presence of tetrabutylammonium bromide is report- no acids is also reported. Free a-amino alkyl S/Se-linked
ed. The synthetic utility of these thiocyanates/selenocya- tetrazoles were isolated upon removal of the Fmoc group.
nates has been demonstrated by the preparation of a Keeping in mind the advantages of tetrazole analogues of
hitherto unreported class of 5-substituted S/Se-linked tet- amino acids, the S,Se-linked tetrazole derivatives are also
razoles via a [2+3]-cycloaddition reaction with sodium expected to deliver interesting properties.
Synthesis 2011, No. 9, 1447–1455 © Thieme Stuttgart · New York

PAPER
N-Fmoc Amino Alkyl Thiocyanates/Selenocyanates
1451
(9H-Fluoren-9-yl)methyl (S)-3-Phenyl-1-thiocyanatopropan-2-
ylcarbamate [Fmoc-Phe-y(CH2SCN), 2c]
Yield: 390 mg (94%); white solid; mp 105–107 °C; Rf = 0.35 (n-
hexane–EtOAc, 9:1).
S
N
H2N
S
N
NH
HN
NH
N
N
N
N
IR (KBr): 1708, 2135 cm–1.
10a, 97%
10e, 92%
1H NMR (400 MHz, CDCl3): d = 2.74 (d, J = 5.1 Hz, 2 H), 4.07 (d,
J = 5.7 Hz, 2 H), 4.15 (t, J = 5.7 Hz, 1 H), 4.31 (m, 1 H), 4.42 (d,
J = 6.8 Hz, 2 H), 5.35 (d, J = 5.7 Hz, 1 H), 7.16–7.62 (m, 13 H).
13C NMR (100 MHz, CDCl3): d = 33.5, 47.3, 52.3, 53.0, 62.3,
111.9, 120.1, 124.9, 125.1, 127.1, 127.9, 128.1, 129.9, 138.9, 141.4,
143.5, 156.1.
Se
N
H2N
NH
N
N
11b, 96%
Figure 3
HRMS: m/z [M + NH4]+ calcd for C25H26N3O2S: 432.1746; found:
432.1742.
All solvents were distilled prior to use and reagents were used as re-
ceived from Sigma-Aldrich. Melting points were determined on a
Büchi model 150 melting point apparatus in open capillaries and are
uncorrected. IR spectra were recorded on a Nicolet Impact 400D
(9H-Fluoren-9-yl)methyl (S)-1-Phenyl-2-thiocyanatoethylcar-
bamate [Fmoc-Phg-y(CH2SCN), 2d]
Yield: 364 mg (91%); gum; Rf = 0.35 (n-hexane–EtOAc, 9:1).
1
FT-IR spectrometer (KBr pellets, 3 cm–1 resolution). H and 13C
IR (CH2Cl2): 1703, 2139 cm–1.
NMR spectra were recorded on a Bruker AMX 400 (400 MHz)
spectrometer. High-resolution mass spectra (HRMS) were recorded
on a Micromass Q-Tof mass spectrometer. HPLC analysis was car-
ried out using an Agilent 1100 series G1311A VWD system at
l = 254 nm (flow: 0.5 mL/min, column: C18, 5 mm pore size, 4.6 ×
250 mm).
1H NMR (400 MHz, CDCl3): d = 3.40 (d, J = 6.0 Hz, 2 H), 4.15 (t,
J = 4.5 Hz, 1 H), 4.21 (m, 1 H), 4.28 (d, J = 3.2 Hz, 2 H), 5.98 (m,
1 H), 7.26–7.77 (m, 13 H).
13C NMR (100 MHz, CDCl3): d = 39.1, 47.2, 55.2, 66.9, 111.6,
124.9, 126.4, 127.1, 127.7, 128.5, 128.7, 129.2, 138.1, 141.3, 143.6,
155.5.
N-Fmoc Amino Alkyl Thiocyanates/Selenocyanates 2/3; Gener-
al Procedure
HRMS: m/z [M + NH4]+ calcd for C24H24N3O2S: 418.1589; found:
418.1588.
To a soln of a N-Fmoc amino alkyl iodide 1 (1 mmol) in THF (15
mL) were added KSCN or KSeCN (1.5 mmol) and TBAB (0.1
mmol), and the mixture was refluxed for about 3 h. After comple-
tion of the reaction (TLC), the solvent was evaporated under re-
duced pressure. The residue was diluted with EtOAc (12 mL); this
solution was washed with H2O (2 × 10 mL) and brine (10 mL), and
dried (anhyd Na2SO4). The solvent was evaporated under reduced
pressure and the residue was recrystallized (EtOAc–hexane) to ob-
tain the product 2/3 as analytically pure material.
(9H-Fluoren-9-yl)methyl (S)-2-(Thiocyanatomethyl)pyrroli-
dine-1-carboxylate [Fmoc-Pro-y(CH2SCN), 2e]
Yield: 299 mg (82%); gum; Rf = 0.25 (n-hexane–EtOAc, 9:1).
IR (CH2Cl2): 1712, 2137 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.07 (m, 4 H), 3.35 (m, 2 H), 3.59
(m, 2 H), 3.84 (m, 1 H), 4.15 (t, J = 6.0 Hz, 1 H), 4.28 (d, J = 3.6
Hz, 2 H), 7.26–7.76 (m, 8 H).
13C NMR (100 MHz, CDCl3): d = 20.6, 30.3, 35.0, 47.3, 47.8, 53.6,
(9H-Fluoren-9-yl)methyl (S)-1-Thiocyanatopropan-2-ylcar-
bamate [Fmoc-Ala-y(CH2SCN), 2a]
Yield: 311 mg (92%); white solid; mp 104–106 °C; Rf = 0.3 (n-hex-
ane–EtOAc, 9:1).
67.2, 119.8, 124.2, 125.3, 126.8, 127.4, 141.0, 144.9, 155.6.
HRMS: m/z [M + Na]+ calcd for C21H20N2NaO2S: 387.1143; found:
387.1146.
IR (KBr): 1713, 2138 cm–1.
(9H-Fluoren-9-yl)methyl (S)-1-(Benzylthio)-3-thiocyanatopro-
pan-2-ylcarbamate [Fmoc-Cys(Bn)-y(CH2SCN), 2f]
1H NMR (400 MHz, CDCl3): d = 1.24 (d, J = 4.8 Hz, 3 H), 3.02–
3.08 (m, 2 H), 3.96 (m, 1 H), 4.11–4.20 (m, 2 H), 4.21 (t, J = 3.0 Hz,
1 H), 4.99 (br, 1 H), 7.21–7.68 (m, 8 H).
13C NMR (100 MHz, CDCl3): d = 19.5, 40.2, 47.7, 52.7, 67.2,
113.0, 120.5, 125.6, 127.6, 128.3, 141.8, 144.2, 155.9.
HRMS: m/z [M + Na]+ calcd for C19H18N2NaO2S: 361.0987; found:
361.0981.
Yield: 373 mg (81%); gum; Rf = 0.35 (n-hexane–EtOAc, 9:1).
IR (CH2Cl2): 1699, 2138 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.02 (d, J = 6.2 Hz, 2 H), 3.35 (d,
J = 7.2 Hz, 2 H), 3.68 (s, 2 H), 4.12–4.30 (m, 3 H), 4.42 (br, 1 H),
5.32 (br, 1 H), 7.13–7.82 (m, 13 H).
13C NMR (100 MHz, CDCl3): d = 33.9, 36.5, 36.9, 47.1, 50.6, 66.8,
111.9, 125.0, 127.0, 127.4, 127.7, 128.7, 128.8, 130.1, 137.3, 141.3,
143.6, 155.5.
(9H-Fluoren-9-yl)methyl (S)-3-Methyl-1-thiocyanatobutan-2-
ylcarbamate [Fmoc-Val-y(CH2SCN), 2b]
Yield: 333 mg (91%); white solid; mp 107–108 °C; Rf = 0.25 (n-
hexane–EtOAc, 9:1).
HRMS: m/z [M + Na]+ calcd for C26H24N2NaO2S2: 483.1177;
found: 483.1171.
IR (KBr): 1701, 2138 cm–1.
tert-Butyl (S)-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-
4-thiocyanatobutanoate [Fmoc-Asp(t-Bu)-y(CH2SCN), 2g]
Yield: 311 mg (71%); white solid; mp 98–99 °C; Rf = 0.30 (n-hex-
ane–EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): d = 0.85 (d, J = 4.8 Hz, 6 H), 1.81 (m,
1 H), 3.05 (d, J = 6.0 Hz, 2 H), 3.55–3.68 (m, 1 H), 4.05–4.22 (m, 3
H), 4.86 (d, J = 6.0 Hz, 1 H), 7.18–7.68 (m, 8 H).
13C NMR (100 MHz, CDCl3): d = 18.6, 19.9, 31.4, 37.7, 47.7, 57.0,
67.1, 113.0, 120.5, 125.5, 127.6, 128.2, 141.8, 144.2, 156.5.
HRMS: m/z [M + Na]+ calcd for C21H22N2NaO2S: 389.1300; found:
389.1294.
IR (KBr): 1714, 2134 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29 (s, 9 H), 2.77 (d, J = 6.8 Hz,
2 H), 3.21 (d, J = 6.2 Hz, 2 H), 3.82 (m, 1 H), 4.14 (t, J = 5.6 Hz, 1
H), 4.29 (d, J = 4.4 Hz, 2 H), 5.62 (br, 1 H), 7.29–7.38 (m, 8 H).
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13C NMR (100 MHz, CDCl3): d = 26.5, 37.0, 42.3, 46.2, 48.3, 67.1,
IR (KBr): 1699, 2144 cm–1.
82.5, 111.6, 128.0, 128.2, 128.3, 128.5, 141.1, 143.4, 155.4, 171.1.
1H NMR (400 MHz, CDCl3): d = 0.92 (d, J = 6.6 Hz, 6 H), 1.84 (m,
1 H), 3.17 (d, J = 4.8 Hz, 2 H), 3.67 (m, 1 H), 4.39 (t, J = 4.4 Hz, 1
H), 4.48 (d, J = 5.4 Hz, 2 H), 4.85 (d, J = 5.6 Hz, 1 H), 7.26–7.73
(m, 8 H).
HRMS: m/z [M + Na]+ calcd for C24H26N2NaO4S: 461.1511; found:
461.1516.
(9H-Fluoren-9-yl)methyl (S)-6-{[(Benzyloxy)carbonyl]amino}-
1-thiocyanatohexan-2-ylcarbamate[Fmoc-Lys(Z)-y(CH2SCN),
2h]
Yield: 466 mg (88%); white solid; mp 106–108 °C; Rf = 0.30 (n-
hexane–EtOAc, 9:1).
13C NMR (100 MHz, CDCl3): d = 18.7, 19.9, 32.3, 33.2, 47.8, 57.2,
67.1, 102.6, 120.5, 127.6, 128.3, 141.9, 144.2, 156.7.
HRMS: m/z [M + Na]+ calcd for C21H22N2NaO2Se: 437.0744;
found: 437.0750.
IR (KBr): 1699, 2140 cm–1.
(9H-Fluoren-9-yl)methyl (S)-4-Methyl-1-selenocyanatopentan-
2-ylcarbamate [Fmoc-Leu-y(CH2SeCN), 3c]
Yield: 368 mg (86%); white solid; mp 111–113 °C; Rf = 0.30 (n-
hexane–EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): d = 1.32–1.68 (m, 6 H), 3.02 (m, 2 H),
3.56 (d, J = 3.8 Hz, 2 H), 3.85 (m, 1 H), 4.12–4.35 (m, 3 H), 5.21 (s,
2 H), 6.43 (br, 2 H), 7.23–7.56 (m, 13 H).
13C NMR (100 MHz, CDCl3): d = 21.3, 29.6, 32.1, 38.6, 40.2, 47.2,
51.2, 62.2, 66.7, 112.3, 124.9, 127.0, 127.7, 128.0, 128.1, 128.5,
128.8, 136.5, 141.3, 143.7, 155.8, 156.6.
IR (KBr): 1701, 2141 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.03 (m, 6 H), 1.31 (m, 2 H), 1.93
(m, 1 H), 3.12 (d, J = 5.9 Hz, 2 H), 3.95 (m, 1 H), 4.21–4.31 (m, 3
H), 6.53 (br, 1 H), 7.21–7.67 (m, 8 H).
HRMS: m/z [M + NH4]+ calcd for C30H35N4O4S: 547.2379; found:
547.2373.
13C NMR (100 MHz, CDCl3): d = 21.6, 22.9, 24.9, 33.5, 43.8, 47.8,
51.0, 67.2, 102.7, 121.0, 125.5, 127.6, 128.4, 141.8, 144.5, 157.5.
Methyl (R)-2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-3-
thiocyanatopropanoate [Fmoc-Ser(ySCN)-OMe, 2i]
Yield: 248 mg (65%); gum; Rf = 0.30 (n-hexane–EtOAc, 9:1).
HRMS: m/z [M + Na]+ calcd for C22H24N2NaO2Se: 451.0901;
found: 451.0908.
IR (CH2Cl2): 1705, 1735, 2135 cm–1.
Methyl (S)-2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-5-
selenocyanatopentanoate (3d)
Yield: 407 mg (89%); gum; Rf = 0.32 (n-hexane–EtOAc, 9:1).
IR (CH2Cl2): 1712, 1742, 2146 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.52 (m, 2 H), 1.85 (m, 2 H), 2.21
(t, J = 3.4 Hz, 2 H), 3.65 (s, 3 H), 4.18 (m, 1 H), 4.38 (t, J = 4.2 Hz,
1 H), 4.59 (d, J = 4.8 Hz, 2 H), 5.42 (br, 1 H), 7.18–7.72 (m, 8 H).
1H NMR (400 MHz, CDCl3): d = 3.59 (d, J = 4.4 Hz, 2 H), 3.82 (s,
3 H), 4.32 (t, J = 3.41 Hz, 1 H), 4.56 (d, J = 6.3 Hz, 2 H), 4.77 (m,
1 H), 5.97 (br, 1 H), 7.25–7.71 (m, 8 H).
13C NMR (100 MHz, CDCl3): d = 36.7, 47.7, 52.1, 53.1, 67.5,
112.1, 124.5, 125.6, 126.2, 127.1, 142.3, 144.9, 156.7, 171.9.
HRMS: m/z [M + Na]+ calcd for C20H18N2NaO4S: 405.0885; found:
405.0886.
13C NMR (100 MHz, CDCl3): d = 21.0, 27.6, 34.1, 46.7, 51.6, 55.0,
67.0, 102.1, 122.1, 125.7, 127.7, 128.3, 141.9, 144.3, 156.0, 172.0.
Methyl (S)-2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-4-
thiocyanatobutanoate [Fmoc-HSer(ySCN)-OMe, 2j]
Yield: 301 mg (76%); gum; Rf = 0.30 (n-hexane–EtOAc, 9:1).
HRMS: m/z [M + Na]+ calcd for C22H22N2NaO4Se: 481.0642;
found: 481.0649.
IR (CH2Cl2): 1738, 2139 cm–1.
Methyl (R)-2-Amino-3-thiocyanatopropanoate [H-Ser(ySCN)-
OMe, 4i]
Yield: 57 mg (98% from 2i); gum.
IR (CH2Cl2): 1735, 2135 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.48 (d, J = 5.0 Hz, 2 H), 3.82
(s, 3 H), 4.07 (m, 1 H), 5.01 (br, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 35.8, 52.1, 53.5, 112.1, 171.5.
ESI-MS: m/z [M – H]+ calcd for C5H7N2O2S: 159.02; found:
1H NMR (400 MHz, CDCl3): d = 1.98–2.11 (m, 4 H), 3.02 (m, 1 H),
3.85 (s, 3 H), 4.05–4.32 (m, 3 H), 7.07–7.59 (m, 8 H), 7.61 (d,
J = 4.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.4, 30.2, 47.6, 52.1, 53.0, 67.2,
112.8, 127.6, 127.7, 128.3, 129.4, 141.8, 144.2, 156.1, 171.1.
HRMS: m/z [M + NH4]+ calcd for C21H24N3O4S: 414.1488; found:
414.1484.
159.06.
(9H-Fluoren-9-yl)methyl (S)-1-Selenocyanatopropan-2-ylcar-
bamate [Fmoc-Ala-y(CH2SeCN), 3a]
Methyl (S)-2-Amino-5-selenocyanatopentanoate (5d)
Yield: 63 mg (95% from 3d); gum.
IR (CH2Cl2): 1742, 2146 cm–1.
Yield: 343 mg (89%); white solid; mp 102–103 °C; Rf = 0.35 (n-
hexane–EtOAc, 9:1).
IR (KBr): 1698, 2145 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.22 (m, 2 H), 1.55 (m, 2 H),
2.55 (t, J = 3.8 Hz, 2 H), 3.59 (s, 3 H), 3.68 (m, 1 H), 5.21 (br, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 21.2, 28.5, 33.9, 51.5, 53.5,
102.1, 171.8.
ESI-MS: m/z [M – H]+ calcd for C7H11N2O2Se: 234.99; found:
235.00.
1H NMR (400 MHz, CDCl3): d = 1.21 (d, J = 5.2 Hz, 3 H), 3.25 (d,
J = 4.8 Hz, 2 H), 3.91 (m, 1 H), 4.11 (t, J = 4.2 Hz, 1 H), 4.23 (d,
J = 5.8 Hz, 2 H), 5.99 (d, J = 6.2 Hz, 1 H), 7.20–7.69 (m, 8 H).
13C NMR (100 MHz, CDCl3): d = 20.7, 33.8, 47.8, 48.9, 67.8,
101.9, 120.6, 125.6, 127.7, 128.3, 141.9, 144.3, 155.8.
HRMS: m/z [M + Na]+ calcd for C19H18N2NaO2Se: 409.0431;
found: 409.0438.
(R)-2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-3-thiocy-
anatopropanoic Acid [Fmoc-Ser(ySCN)-OH, 6i]
(9H-Fluoren-9-yl)methyl (S)-3-Methyl-1-selenocyanatobutan-
2-ylcarbamate [Fmoc-Val-y(CH2SeCN), 3b]
Yield: 364 mg (88%); white solid; mp 109–110 °C; Rf = 0.30 (n-
hexane–EtOAc, 9:1).
Yield: 57 mg (85% from 2i); gum; Rf = 0.20 (CHCl3–MeOH, 8:2).
IR (CH2Cl2): 1705, 2138 cm–1.
Synthesis 2011, No. 9, 1447–1455 © Thieme Stuttgart · New York

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N-Fmoc Amino Alkyl Thiocyanates/Selenocyanates
1453
1H NMR (400 MHz, DMSO-d6): d = 3.39 (d, J = 4.6 Hz, 2 H), 4.27
(t, J = 3.8 Hz, 1 H), 4.37 (m, 1 H), 4.66 (d, J = 6.4 Hz, 2 H), 6.12
(br, 1 H), 7.25–7.71 (m, 8 H), 10.98 (br, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 35.8, 47.5, 53.5, 67.1, 111.9,
124.6, 125.8, 126.6, 127.5, 141.5, 144.5, 155.9, 172.1.
HRMS: m/z [M + Na]+ calcd for C19H16N2NaO4S: 391.0728; found:
391.0734.
1H NMR (400 MHz, DMSO-d6): d = 2.69 (d, J = 6.2 Hz, 2 H), 3.39
(d, J = 5.7 Hz, 2 H), 4.18 (t, J = 4.3 Hz, 1 H), 4.28 (d, J = 5.0 Hz, 2
H), 4.89 (m, 1 H), 6.48–6.71 (br, 1 H), 7.23–7.49 (m, 13 H), 7.67
(m, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 37.8, 39.5, 46.7, 51.9, 65.6,
125.2, 126.2, 127.1, 127.6, 128.2, 128.6, 129.2, 138.2, 140.7, 143.8,
155.6, 172.0.
HRMS: m/z [M + Na]+ calcd for C25H23N5NaO2S: 480.1470; found:
(S)-2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-5-seleno-
cyanatopentanoic Acid (7d)
Yield: 68 mg (75% from 3d); gum; Rf = 0.20 (CHCl3–MeOH, 8:2).
IR (CH2Cl2): 1712, 2140 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.32 (m, 2 H), 1.45 (m, 2 H),
2.11 (t, J = 4.0 Hz, 2 H), 3.95 (m, 1 H), 4.38 (t, J = 4.4 Hz, 1 H),
4.59 (d, J = 5.0 Hz, 2 H), 6.82 (br, 1 H), 7.18–7.72 (m, 8 H), 10.99
(br, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 21.3, 28.1, 33.8, 46.5, 54.8,
67.1, 101.5, 122.3, 125.5, 127.8, 128.5, 141.5, 144.7, 156.5, 172.7.
480.1465.
(9H-Fluoren-9-yl)methyl (S)-1-Phenyl-1-(2H-tetrazol-5-yl-
thio)ethylcarbamate [Fmoc-Phg-y(CH2SCN4H), 8d]
Yield: 403 mg (88%); white solid; mp 151–152 °C; Rf = 0.20
(CHCl3–MeOH, 8:2).
1H NMR (400 MHz, DMSO-d6): d = 3.52 (d, J = 4.8 Hz, 2 H), 4.12
(t, J = 3.8 Hz, 1 H), 4.26 (d, J = 6.4 Hz, 2 H), 4.82 (m, 1 H), 5.92
(br, 1 H), 7.26–7.68 (m, 13 H), 8.21 (br, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 37.7, 46.7, 54.2, 65.4, 120.1,
125.1, 126.3, 127.0, 127.6, 128.5, 140.7, 141.5, 143.7, 155.7, 156.8.
HRMS: m/z [M + H]+ calcd for C24H22N5O2S: 444.1494; found:
444.1498.
HRMS: m/z [M + Na]+ calcd for C21H20N2NaO4Se: 467.0486;
found: 467.0481.
N-Fmoc Amino Alkyl S/Se-Linked Tetrazoles 8/9; General Pro-
cedure
(9H-Fluoren-9-yl)methyl (S)-2-[(2H-Tetrazol-5-ylthio)meth-
yl]pyrrolidine-1-carboxylate [Fmoc-Pro-y(CH2SCN4H), 8e]
Yield: 346 mg (85%); gum; Rf = 0.20 (CHCl3–MeOH, 8:2).
1H NMR (400 MHz, DMSO-d6): d = 1.61–1.72 (m, 4 H), 3.31 (m,
2 H), 3.61 (m, 2 H), 3.80 (m, 1 H), 4.11 (t, J = 4.3 Hz, 1 H), 4.32 (d,
J = 5.7 Hz, 2 H), 7.30–7.81 (m, 9 H).
13C NMR (100 MHz, DMSO-d6): d = 22.2, 29.4, 37.5, 45.0, 47.1,
51.6, 66.7, 125.0, 126.1, 127.0, 128.8, 140.3, 143.1, 155.1, 156.2.
HRMS: m/z [M + H]+ calcd for C21H22N5O2S: 408.1494; found:
408.1495.
A mixture of a N-Fmoc amino alkyl thiocyanate/selenocyanate 2/3
(1 mmol), NaN3 (162 mg, 2.5 mmol) and ZnBr2 (222 mg, 1 mmol)
in i-PrOH–H2O (1:1, 30 mL) was heated to reflux for 4–5 h with
stirring. After cooling, the reaction mixture was acidified with 10%
HCl and diluted with EtOAc (15 mL). The aqueous layer was ex-
tracted with EtOAc (2 × 5 mL). The combined organic layer was
washed with H2O (2 × 10 mL) and brine (10 mL), and dried (anhyd
Na2SO4). The solvent was removed under reduced pressure and the
residue was either recrystallized (THF–hexane, 1:4) or column
chromatographed.
(9H-Fluoren-9-yl)methyl (S)-1-(Benzylthio)-3-(2H-tetrazol-5-
ylthio)propan-2-ylcarbamate [Fmoc-Cys(Bn)-y(CH2SCN4H),
8f]
Yield: 428 mg (85%); white solid; mp 142–143 °C; Rf = 0.25
(CHCl3–MeOH, 8:2).
1H NMR (400 MHz, DMSO-d6): d = 2.13 (d, J = 4.9 Hz, 2 H), 3.35
(d, J = 6.4 Hz, 2 H), 3.75 (s, 2 H), 4.11–4.31 (m, 3 H), 4.45 (m, 1
H), 5.31 (br, 1 H), 7.19–7.80 (m, 14 H).
13C NMR (100 MHz, DMSO-d6): d = 35.1, 36.0, 41.0, 46.7, 50.0,
65.5, 125.2, 126.9, 127.1, 127.6, 128.4, 128.9, 130.3, 138.3, 140.7,
143.8, 155.1, 156.3.
(9H-Fluoren-9-yl)methyl (S)-1-(2H-Tetrazol-5-ylthio)propan-
2-ylcarbamate [Fmoc-Ala-y(CH2SCN4H), 8a]
Yield: 351 mg (92%); white solid; mp 92–94 °C; Rf = 0.2 (CHCl3–
MeOH, 8:2).
1H NMR (400 MHz, DMSO-d6): d = 1.19 (d, J = 6.4 Hz, 3 H), 3.49
(d, J = 4.6 Hz, 2 H), 3.83 (m, 1 H), 4.18 (t, J = 5.4 Hz, 1 H), 4.27 (d,
J = 7.2 Hz, 2 H), 6.70 (br, 1 H), 7.29–7.88 (m, 9 H).
13C NMR (100 MHz, DMSO-d6): d = 19.8, 37.8, 46.2, 46.7, 66.9,
120.1, 125.1, 126.9, 127.5, 140.7, 143.8, 154.2, 155.5.
ESI-MS: m/z [M + H]+ calcd for C19H20N5O2S: 382.13; found:
382.05.
HRMS: m/z [M + NH4]+ calcd for C26H29N6O2S2: 521.1793; found:
521.1785.
(9H-Fluoren-9-yl)methyl (S)-3-Methyl-1-(2H-tetrazol-5-yl-
thio)butan-2-ylcarbamate [Fmoc-Val-y(CH2SCN4H), 8b]
Yield: 356 mg (87%); gum; Rf = 0.3 (CHCl3–MeOH, 8:2).
1H NMR (400 MHz, DMSO-d6): d = 0.87 (d, J = 5.8 Hz, 6 H), 2.32
(m, 1 H), 3.32 (d, J = 4.7 Hz, 2 H), 3.85 (m, 1 H), 3.96 (t, J = 5.2
Hz, 1 H), 4.07 (d, J = 7.1 Hz, 2 H), 6.96 (br, 1 H), 7.32–7.70 (m, 8
H), 7.98 (br, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.0, 18.9, 32.2, 36.9, 46.7,
56.2, 65.2, 120.0, 125.1, 126.9, 127.5, 140.7, 143.7, 154.8, 156.0.
HRMS: m/z [M + H]+ calcd for C21H24N5O2S: 410.1651; found:
410.1646.
tert-Butyl (S)-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-
4-(2H-tetrazol-5-ylthio)butanoate [Fmoc-Asp(t-Bu)-
y(CH2SCN4H), 8g]
Yield: 376 mg (78%); white solid; mp 78–80 °C; Rf = 0.20 (CHCl3–
MeOH, 8:2).
1H NMR (400 MHz, DMSO-d6): d = 1.34 (s, 9 H), 2.52 (d, J = 5.2
Hz, 2 H), 3.41 (m, 2 H), 4.11 (m, 1 H), 4.20 (t, J = 4.1 Hz, 1 H), 4.28
(d, J = 5.6 Hz, 2 H), 7.28–7.88 (m, 10 H).
13C NMR (100 MHz, DMSO-d6): d = 27.6, 36.5, 43.6, 46.6, 47.7,
65.4, 80.1, 120.0, 125.0, 127.0, 127.5, 140.7, 143.7, 155.4, 156.6,
169.3.
(9H-Fluoren-9-yl)methyl (S)-3-Phenyl-1-(2H-tetrazol-5-yl-
thio)propan-2-ylcarbamate [Fmoc-Phe-y(CH2SCN4H), 8c]
Yield: 403 mg (88%); white solid; mp 141–142 °C; Rf = 0.22
(CHCl3–MeOH, 8:2).
HRMS: m/z [M + Na]+ calcd for C24H27N5NaO4S: 504.1681; found:
504.1686.
Synthesis 2011, No. 9, 1447–1455 © Thieme Stuttgart · New York

1454
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PAPER
(9H-Fluoren-9-yl)methyl (S)-6-{[(Benzyloxy)carbonyl]amino}-
1-(2H-tetrazol-5-ylthio)hexan-2-ylcarbamate [Fmoc-Lys(Z)-
y(CH2SCN4H), 8h]
(9H-Fluoren-9-yl)methyl (S)-4-Methyl-1-(2H-tetrazol-5-ylsela-
nyl)pentan-2-ylcarbamate [Fmoc-Leu-y(CH2SeCN4H), 9c]
Yield: 399 mg (85%); gum; Rf = 0.25 (CHCl3–MeOH, 8:2).
Yield: 447 mg (78%); white solid; mp 148–150 °C; Rf = 0.20
(CHCl3–MeOH, 8:2).
1H NMR (400 MHz, DMSO-d6): d = 1.27–1.41 (m, 6 H), 2.66–2.81
(m, 2 H), 2.97 (d, J = 4.2 Hz, 2 H), 3.73 (br, 1 H), 4.20–4.31 (m, 3
H), 5.00 (s, 2 H), 7.29–7.51 (m, 13 H), 7.68 (s, 1 H), 7.88 (d, J = 5.7
Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 22.7, 29.1, 33.2, 37.1, 42.7,
46.7, 50.3, 65.1, 65.2, 120.0, 125.1, 127.0, 127.6, 127.8, 128.3,
137.2, 140.7, 143.7, 154.3, 155.9, 156.0.
1H NMR (400 MHz, DMSO-d6): d = 0.82 (m, 6 H), 1.21 (m, 2 H),
1.87 (m, 1 H), 3.41 (d, J = 6.4 Hz, 2 H), 3.79 (m, 1 H), 4.11 (t,
J = 4.4 Hz, 1 H), 4.24 (d, J = 5.1 Hz, 2 H), 6.29 (br, 1 H), 7.20–7.98
(m, 9 H).
13C NMR (100 MHz, DMSO-d6): d = 22.7, 24.0, 25.4, 34.4, 44.2,
47.7, 49.9, 66.0, 121.0, 126.1, 128.0, 128.5, 141.7, 144.8, 156.7,
166.9.
HRMS: m/z [M + H]+ calcd for C22H26N5O2Se: 472.1252; found:
472.1260.
HRMS: m/z [M + H]+ calcd for C30H33N6O4S: 573.2284; found:
573.2287.
Methyl (S)-2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-5-
(2H-tetrazol-5-ylselanyl)pentanoate (9d)
Methyl (R)-2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-3-
(2H-tetrazol-5-ylthio)propanoate [Fmoc-Ser(ySCN4H)-OMe,
8i]
Yield: 395 mg (79%); gum; Rf = 0.25 (CHCl3–MeOH, 8:2).
1H NMR (400 MHz, DMSO-d6): d = 1.32 (m, 2 H), 1.71 (m, 2 H),
2.05 (t, J = 3.6 Hz, 2 H), 3.55 (s, 3 H), 3.95 (m, 1 H), 4.19 (t, J = 4.2
Hz, 1 H), 4.30 (d, J = 5.2 Hz, 2 H), 6.20 (br, 1 H), 7.26–7.90 (m, 9
H).
13C NMR (100 MHz, DMSO-d6): d = 22.5, 29.1, 33.3, 47.5, 51.2,
54.2, 66.5, 124.0, 125.1, 127.0, 128.2, 141.0, 144.1, 154.9, 156.0,
171.0.
Yield: 276 mg (65%); gum; Rf = 0.30 (CHCl3–MeOH, 8:2).
1H NMR (400 MHz, DMSO-d6): d = 3.62 (d, J = 5.6 Hz, 2 H), 3.84
(s, 3 H), 4.21 (t, J = 4.7 Hz, 1 H), 4.42 (d, J = 6.4 Hz, 2 H), 4.82 (m,
1 H), 6.92 (br, 1 H), 7.31–7.71 (m, 8 H), 8.01 (br, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 33.8, 47.5, 52.9, 53.5, 67.5,
123.2, 125.2, 126.4, 127.1, 140.9, 143.1, 154.3, 157.1, 171.3.
HRMS: m/z [M + Na]+ calcd for C22H23N5NaO4Se: 524.0813;
found: 524.0818.
HRMS: m/z [M + H]+ calcd for C20H20N5O4S: 426.1236; found:
426.1232.
(S)-1-(2H-Tetrazol-5-ylthio)propan-2-amine [H-Ala-
y(CH2SCN4H), 10a]
Methyl (S)-2-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-4-
(2H-tetrazol-5-ylthio)butanoate [Fmoc-HSer(ySCN4H)-OMe,
8j]
Yield: 54 mg (97% from 8a); pale yellow solid; mp 178–180 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.22 (d, J = 6.2 Hz, 3 H), 3.13
(m, 1 H), 3.31 (d, J = 4.4 Hz, 2 H), 5.12 (br, 2 H), 7.54 (br, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 19.5, 38.5, 47.8, 155.9.
ESI-MS: m/z [M – H]+ calcd for C4H8N5S: 158.05; found: 158.09.
Yield: 334 mg (76%); gum; Rf = 0.25 (CHCl3–MeOH, 8:2).
1H NMR (400 MHz, DMSO-d6): d = 2.03 (m, 2 H), 3.31 (t, J = 3.6
Hz, 2 H), 3.75 (s, 3 H), 4.01 (m, 1 H), 4.15–4.29 (m, 3 H), 6.15 (br,
1 H), 7.12–7.62 (m, 9 H).
13C NMR (100 MHz, DMSO-d6): d = 31.0, 35.1, 47.3, 52.2, 57.0,
(S)-5-[(Pyrrolidin-2-ylmethyl)thio]-2H-tetrazole [H-Pro-
y(CH2SCN4H), 10e]
Yield: 61 mg (92% from 8e); gum.
66.9, 125.2, 126.5, 127.1, 128.0, 141.1, 144.3, 154.1, 156.0, 176.0.
HRMS: m/z [M + Na]+ calcd for C21H21N5NaO4S: 462.1212; found:
462.1217.
1H NMR (400 MHz, DMSO-d6): d = 1.50–1.69 (m, 4 H), 2.99 (m,
2 H), 3.20 (m, 1 H), 3.41 (d, J = 5.4 Hz, 2 H), 5.01 (m, 1 H), 7.68
(br, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 23.5, 32.4, 38.2, 45.3, 51.6,
154.9.
(9H-Fluoren-9-yl)methyl (S)-1-(2H-Tetrazol-5-ylselanyl)pro-
pan-2-ylcarbamate [Fmoc-Ala-y(CH2SeCN4H), 9a]
Yield: 381 mg (89%); white solid; mp 136–139 °C; Rf = 0.25
(CHCl3–MeOH, 8:2).
1H NMR (400 MHz, DMSO-d6): d = 1.27 (d, J = 6.7 Hz, 3 H), 3.43
(d, J = 6.4 Hz, 2 H), 3.81 (m, 1 H), 4.11 (t, J = 3.4 Hz, 1 H), 4.28 (d,
J = 5.7 Hz, 2 H), 5.08 (br, 1 H), 7.25–7.90 (m, 9 H).
13C NMR (100 MHz, DMSO-d6): d = 21.3, 34.7, 47.6, 47.8, 66.2,
121.0, 126.1, 127.9, 128.5, 141.6, 144.8, 154.0, 156.4.
HRMS: m/z [M + H]+ calcd for C19H20N5O2Se: 430.0782; found:
430.0790.
ESI-MS: m/z [M – H]+ calcd for C6H10N5S: 184.06; found: 184.08.
(S)-3-Methyl-1-(2H-tetrazol-5-ylselanyl)butan-2-amine [H-Val-
y(CH2SeCN4H), 11b]
Yield: 55 mg (96% from 9b); pale yellow solid; mp 186–187 °C.
1H NMR (400 MHz, DMSO-d6): d = 0.99 (d, J = 6.2 Hz, 6 H), 1.85
(d, J = 5.8 Hz, 1 H), 3.88 (d, J = 5.6 Hz, 2 H), 4.21 (m, 1 H), 5.91
(br, 2 H), 7.91 (br, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.1, 32.5, 35.9, 53.5, 155.1.
ESI-MS: m/z [M – H]+ calcd for C6H12N5Se: 234.02; found: 234.03.
(9H-Fluoren-9-yl)methyl (S)-3-Methyl-1-(2H-tetrazol-5-ylsela-
nyl)butan-2-ylcarbamate [Fmoc-Val-y(CH2SeCN4H), 9b]
Yield: 392 mg (86%); gum; Rf = 0.24 (CHCl3–MeOH, 8:2).
1H NMR (400 MHz, DMSO-d6): d = 0.85 (d, J = 6.5 Hz, 6 H), 1.81
(d, J = 5.6 Hz, 1 H), 3.38 (d, J = 5.4 Hz, 2 H), 3.93 (m, 1 H), 4.30
(t, J = 4.0 Hz, 1 H), 4.42 (d, J = 5.5 Hz, 2 H), 5.75 (m, 1 H), 7.31–
7.99 (m, 9 H).
13C NMR (100 MHz, DMSO-d6): d = 18.2, 19.1, 30.5, 32.8, 46.7,
53.1, 66.9, 120.0, 125.1, 126.9, 127.5, 140.6, 143.5, 154.9, 156.0.
Acknowledgment
We thank the University Grants Comission (UGC) [Grant No. 37-
79/2009 (SR)] and the Department of Science and Technology
(DST) (Grant No. SR/S1/OC-26/2008), New Delhi, India for finan-
cial support.
HRMS: m/z [M + Na]+ calcd for C21H23N5NaO2Se: 480.0915;
found: 480.0923.
Synthesis 2011, No. 9, 1447–1455 © Thieme Stuttgart · New York

PAPER
N-Fmoc Amino Alkyl Thiocyanates/Selenocyanates
1455
Chem. Soc. 1960, 82, 2742. (d) Blanco, J. M.; Caamano, O.;
Fernandez, F.; Gomez, G.; Lopez, C. Tetrahedron:
Asymmetry 1992, 3, 749.
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