Synthesis of Isoselenocyanates

Article abstract of DOI:10.1055/s-0035-1560481

Isoselenocyanates were synthesized by two methods under phase-transfer conditions (50% aq NaOH, CH₂Cl₂, Aliquat 336); the first started from isocyanides and selenium and gave isoselenocyanates in 61-89% yields, while the second started from amines and used chloroform and selenium, by applying sequentially the Hofmann isonitrile synthesis and the addition of selenium, in 4-70% yields.

Full text of DOI:10.1055/s-0035-1560481

SYNTHESIS
0
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1
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3
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1
0
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, 85–96
paper
85
J. Zakrzewski et al.
Paper
Synthesis
Synthesis of Isoselenocyanates
NCSe
N
Jerzy Zakrzewski*
NCSe
NCSe
Bogumiła Huras
NCSe
N
Anna Kiełczewska
N
·
·
O
Me
O
·
Institute of Industrial Organic Chemistry, Annopol 6, 03-236
Warsaw, Poland
zakrzewski@ipo.waw.pl
O
Cl
NCSe
Se, 50% aq NaOH
Aliquat 336
R-NC
NCSe
F3C
NCSe
R-NCSe
NCSe
Se, 50% aq NaOH
Aliquat 336, CHCl3
R-NH2
NCSe
Me
NCSe
CH2NCSe
NCSe
Received: 03.06.2015
Accepted after revision: 25.08.2015
Published online: 29.10.2015
The direct addition of selenium to isocyanides using
black, finely powdered, elemental selenium in an organic
solvent is the most typical method for the synthesis of
isoselenocyanates.9,10,34–41
DOI: 10.1055/s-0035-1560481; Art ID: ss-2015-t0358-op
Abstract Isoselenocyanates were synthesized by two methods under
phase-transfer conditions (50% aq NaOH, CH2Cl2, Aliquat 336); the first
started from isocyanides and selenium and gave isoselenocyanates in
61–89% yields, while the second started from amines and used chloro-
form and selenium, by applying sequentially the Hofmann isonitrile
synthesis and the addition of selenium, in 4–70% yields.
In our previous research, we have obtained isoselenocy-
anates (bearing nitroxyl25 and aryl26 moieties) from isocya-
nides. Unfortunately, we observed unreproducible results
when the addition of selenium to isocyanides with black,
finely powdered, elemental selenium occurred either in
chloroform or in tetrahydrofuran in the presence of tri-
ethylamine (see below).
Key words isoselenocyanates, isocyanides, selenium, phase-transfer
catalysis
Thus, alternative synthetic approaches to isoselenocya-
nates seem to be attractive. As a result of our search for
these methods, we propose a new method for isoselenocya-
nate synthesis involving the use of an aqueous/organic bi-
phasic system operating under strong alkaline conditions
for the addition of selenium to aromatic, aliphatic, and cy-
cloaliphatic (including a cage adamantyl moiety, as well as
five- and six-membered nitroxides) isocyanides or directly
to the corresponding amines.
The methods for the synthesis of isocyanides and
isoselenocyanates (known from the literature and de-
scribed in this paper) are summarized in Scheme 1.
Isocyanides 3a–l were synthesized by a Hofmann isoni-
trile synthesis using amines 1a–l as starting materials to-
gether with chloroform and 50% aqueous sodium hydroxide
solution in the presence of the ammonium salt Aliquat 336
(Table 1).
The synthetic significance of isoselenocyanates lies
mainly in the fact that they are essential precursors/inter-
mediates of biologically active organoselenium compounds:
heterocycles,1–4 selenoureas, and selenocarbamates.5–11
Isoselenocyanates, as well as their above-mentioned trans-
formation products: heterocyclic compounds, selenoureas,
and selenocarbamates, show significant biological activity.
Isoselenocyanates themselves have anticancer proper-
ties.12–14 Heterocyclic compounds (with ebselen and/or its
derivatives as the best known example) show anticancer15
and antibacterial activity.16–18 Selenoureas demonstrate
free-radical scavenging, enzyme inhibition, and anticancer
activity, which have been recently reviewed.19 Selenoureas
are reported to be superoxide radical scavengers20 and to
inhibit the capacity of peroxidase-catalyzed reactions;21
they also have antioxidant,22–24 pesticidal,25–27 antibacterial
and antifungal,23 anti-urease,28,29 and anti-thyroid30 activi-
ty. Selenocarbamates show antiproliferative,31 cytotoxic,32
antioxidant,22 pesticidal,25,27 and effective superoxide anion
scavenger33 activity.
The synthesized isocyanides 3a–l were transformed
into isoselenocyanates 4a–l. Firstly, we examined the con-
version of isocyanides 3 into isoselenocyanates 4 using
black, finely powdered, elemental selenium in chloroform
or in tetrahydrofuran in the presence of triethylamine. The
results are summarized in Table 2.
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J. Zakrzewski et al.
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Synthesis
R-NH2
1a–l
g: 4-Cl-2-MeC6H3
N
O
Se, 50% aq NaOH
CHCl3
aliquat 336
·
a:
50% aq NaOH
CHCl3
aliquat 336
B
h: Bn
N
·
O
Se, CHCl3
b:
HCOOEt
Se, THF, Et3N
i: n-C5H11
R-NCSe
R-NC
A
4a–l
Se, 50% aq NaOH
aliquat 336, CH2Cl2
N
·
3a–l
c:
O
d: Ph
COCl2 or
ClCO2CCl3
Et3N
Se
COCl2 or
ClCO2CCl3
Et3N
j:
N
N
e: 3-MeC6H4
f: 4-F3CC6H4
k: t-Bu
N
N
5
·
O
·
O
l:
R-NHCHO
2a–c
Scheme 1 Synthesis of isoselenocyanates 4a–l
Table 1 Hofmann Isonitrile Synthesis of 3a–l
50% aq NaOH, CHCl3
CH2Cl2, Aliquat 336
R-NH2
R-NC
2
3
Entry
Product
Temperature, time
Purification
Yield (%)
1
2
3
3aa
3ba
3ca
reflux, 24 h
reflux, 3 h
chromatography (benzene; benzene–MeOH, 95:5)
chromatography (benzene–EtOAc, 95:5)
chromatography (benzene–MeOH, 95:5)
65
7
1642 943
12–15 °C, 45 min
reflux, 1.5 h
40 °C, 1.5 h
4
3d
3e
3f
chromatography (hexane)
66b 30b
58
5
vacuum distillation (72 °C/12 Torr; 80 °C/15 Torr; 83 °C/18 Torr)
vacuum distillation (56–60 °C/10 Torr)
chromatography (benzene)
6
40–45 °C, 4 h
reflux, 5 h; r.t., 12 h
reflux, 2.5 h
41–43 °C, 2 h
reflux, 4 h
60
7
3g
3h
3i
78
8
chromatography (hexane–EtOAc, 9:1)
chromatography (hexane–EtOAc, 9:1)
65
9
30
10
11
12
3j
chromatography (hexane; hexane–EtOAc, 9:1; hexane–EtOAc, 4:1; EtOAc) 57
3k
3l
40 °C, 4 h
vacuum distillation (89–92 °C)
40
72
40 °C, 4 h
chromatography (hexane–EtOAc, 4:1)
a Dehydration of the corresponding formylamine using diphosgene gave nitroxyl isocyanides 3a–c in 90% (3a) and 68% (3b) (see experimental section); dehydra-
tion using phosgene42 gave 3c in 84% yield and using diphosgene25 gave 3c in 78% yield.
b Isolated by column chromatography in 66% yield; isolated by vacuum distillation in 30% yield.26
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J. Zakrzewski et al.
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Table 2 Synthesis of Isoselenocyanates Using Elemental Selenium in
Boiling Chloroform (see General Procedure 1, GP1) and in Boiling Tetra-
hydrofuran in the Presence of Triethylamine (see General Procedure 2,
GP2)
If the starting isocyanides 4-(trifluoromethyl)phenyl
isocyanide (3f) and 4-chloro-2-methylphenyl isocyanide
(3g) were used as chromatographically purified com-
pounds, the time taken for the addition of selenium was
long, and, in the case of the reaction of 4-(trifluorometh-
yl)phenyl isocyanide (3f) to give 4-(trifluoromethyl)phenyl
isoselenocyanate (4f) the yields were negligible. For the
same reason, the start of the reaction with selenium in the
conversion of 3a,b,f,g into 4a,b,f,g was also delayed (Table 2,
entries 2, 4, 8, 9, and 14); if isocyanides 3f and 3g were used
as crude, unpurified compounds, then the reaction time to
achieve accepted yields of 4f,g were short (Table 2, entries
10–13 and 15–18).
These phenomena were the immediate reasons to look
for a reliable and efficient method for effective and predict-
able isoselenocyanates synthesis. We observed that the se-
lenium dissolved and reacted with sodium hydroxide aque-
ous solution and underwent disproportionation according
to the equation: 3 Se + 6 HO– → SeO32– + 2 Se2– + 3 H2O.45–47
Hence we examined the addition of selenium to isocya-
nides in a biphasic system, using 50% aqueous sodium hy-
droxide solution and dichloromethane and a quaternary
ammonium salt (Aliquat 336) as the catalyst (phase-trans-
fer catalysis conditions, PTC, Scheme 1, route A, Table 3).
The yields varied from medium to good (depending on the
isocyanide used as the starting compound). According to
the equation, the Se2– anion may be considered as a direct
agent, which is the effective nucleophilic agent attacking
the isocyanide carbon atom.
GP1: Se, CHCl3
GP2: Se, Et3N, THF
R-NCSe
R-NC
4
3
Entry
Product
GP1
Yield (%)
GP2
Time (h)
Time (h)
Yield (%)
1
4a
4a
4b
4b
4c
4d
4e
4f
2.5
127b
3
19a
5c
4
79
–
2
–
3
13a
25c
3825,44
9126
90
22b
66
–
4
54b
–
5
70
19.5b
2.5
3
61
92
74
18
–
6
24b
28b
30.5b
22b
2.5
2.5
0.75
2.5
29b
2.5
2.5
2.5
2.5
19
7
8
3c
5
9
4f
2c
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4f
48a
49a
47a
70a
51c
63a
53a
57a
65a
60
–
–
4f
–
–
4f
–
–
4f
–
–
4g
4g
4g
4g
4g
4h
4i
7
74
–
–
–
–
–
–
–
–
Table 3 Synthesis of Isoselenocyanates 4a–l from Isocyanides 3a–l in
an Aqueous/Organic Biphasic System (General Procedure 3, GP3)
7
76
48
63
40
56
–
24b
25b
30
66
5
4j
36
9
Se, 50% aq NaOH
CH2Cl2, Aliquat 336
4k
4l
18
5
R-NC
R-NCSe
30
18
10
3
4
4l
30b
16
–
a Starting isocyanides used as crude, unpurified compounds (the yields are
calculated based on the corresponding amines).
Entry
Product Temp, time
Column chromatography
mobile phase
Yield
(%)
b A delay in the initiation of the reaction with selenium is observed.
c Starting isocyanides used as chromatographically purified compounds.
1
4a
4b
4c
4c
4d
4e
4f
r.t., 4 h
benzene, benzene–MeOH (9:1) 66
2
r.t., 4 h
benzene, benzene–EtOAc (9:1)
89
63
60
89
77
61
86
67
75
74
65
72
3
reflux, 4 h
r.t., 2.5 h
r.t., 1.5 h
r.t., 2.5 h
r.t., 4 h
benzene
benzene
hexane
hexane
hexane
hexane
hexane
hexane
hexane
pentane
hexane
In our hands, the reactions with selenium both in chlo-
roform and in tetrahydrofuran in the presence of triethyl-
amine were occasionally unreproducible and unpredict-
able.
Using the same isocyanide, the time taken for the reac-
tion to occur could vary from hours to days from experi-
ment to experiment.
There was a delay in the initiation of the reaction with
selenium. Sometimes, no isoselenocyanate was detected
during the initial period of the reaction (lasting at least sev-
eral hours). It may be rationalized by the extreme heteroge-
neity of the reaction system (black, finely powdered, ele-
mental selenium in the organic solutions of an isocyanide).
4
5
6
7
8
4g
4h
4i
r.t., 1.5 h
r.t., 2 h
9
10
11
12
13
r.t., 3 h
4j
r.t., 1.5 h
r.t., 4 h
4k
4l
reflux, 3 h
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Synthesis
Efficient addition of selenium to isocyanides under
phase-transfer catalysis conditions prompted us to apply
the same phase-transfer catalysis conditions to the direct,
one-pot addition of selenium to the corresponding primary
amines. We selenized the starting amines 1a–l under
phase-transfer catalysis conditions in a one-pot reaction
using simultaneously chloroform and 50% aqueous sodium
hydroxide solution in the presence of the quaternary am-
monium salt Aliquat 336 as the catalyst, and after a short
period of time selenium was added (Scheme 1, route B, Ta-
ble 4). Selenium should be added after the complete in situ
conversion of the amines 1a–l into the isocyanides 3a–l,
otherwise the simultaneous presence of the amine 1a–l
and isoselenocyanate 4a–l may lead to the formation of
symmetrical selenoureas (RNH)2C=Se. The yields of nitroxyl
isoselenocyanates 4a–c synthesized by direct addition of
selenium to nitroxyl amines 1a–c were low (Table 4). Syn-
thesis of 4a–c by the addition of selenium to isocyanides
3a–c was much more effective.
the expected isoselenocyanate 4c (9%) while the reaction at
room temperature gave the carbodiimide 5 (12%), which
was isolated and characterized.
It should be noted that the starting amine should be
fairly soluble in the organic phase. Attempted reactions of
completely insoluble amines (5-aminouracil, tyrosine) with
selenium under phase-transfer catalysis conditions failed.
In general, except for 3a, the yield of the direct reaction
of selenium with amines 1b–l to isoselenocyanates 4b–l us-
ing phase-transfer catalysis conditions, was approximately
equal to the combined yield of two steps, i.e. the yield of the
Hofmann isonitrile reaction of amines 1b–l to isocyanides
3b–l multiplied by the yield of the reaction of selenium in
the phase-transfer catalysis conditions of isocyanides 3b–l
to isoselenocyanates 4b–l. It led to the conclusion, that the
efficacy of the direct addition of selenium to amines is sim-
ilar to the two-step reaction: Hofmann isonitrile reaction
and addition of selenium to resulting isocyanides under
phase-transfer catalysis conditions.
The structure of the synthesized isocyanides 3a–l and
isoselenocyanates 4d–l were confirmed using EI-MS, ESI-
Table 4 Synthesis of Isoselenocyanates 4 from Amines 1 in an Aque-
ous/Organic Biphasic System (General Procedure 4, GP4)
1
MS, HRMS-EI and HRMS-ESI spectrometry, as well as H,
13C, and 77Se NMR, and IR spectroscopy.
1. 50% aq NaOH, CHCl3
CH2Cl2, Aliquat 336
2. Se
The 1H and 13C NMR spectra of nitroxyl isocyanides 3a–c
were recorded in the presence of a drop of a reducing agent
[in fact the spectra of the corresponding hydroxylamines
3a(OH)–c(OH) were recorded]. In this research phenylhy-
drazine was used,48 however, sometimes the use of hydra-
zobenzene49,50 and pentafluorophenylhydrazine51 have also
been reported.
R-NH2
R-NCSe
1
4
Entry Product Temp, time
Column chromatog- Yield
raphy
(%)
mobile phase
Step 1
Step 2
The couplings of both hydrogen and carbon atoms
bound to the nitrogen atom of the NC group were recog-
nized as sharp, not-broadened triplets with equal intensi-
1
2
4a
4b
r.t., 4 h
r.t., 1.5 h
r.t., 1.5 h
hexane–EtOAc (9:1)
4
reflux, 2 h
benzene, benzene–
EtOAc (9:1)
10
9a
1
ties of lines visible in the H and 13C NMR spectra of some
isocyanides: 3c(OH), 3h, 3i, 3k (1H NMR), and for: 3a(OH)–
c(OH), 3d, 3e, 3h–j (13C NMR). The coupling is caused by the
spin quantum number I = 1 of the 14N nucleus.
3
4c
4d
4e
4f
reflux, 4 h
reflux, 2 h
reflux, 3 h
reflux, 4 h
reflux, 4 h
reflux, 1.5 h
reflux, 1.5 h
reflux, 1 h
benzene
4
hexane–EtOAc (9:1) 70
5
hexane
hexane
hexane
hexane
53
27
73
37
28
50
46
48
The triplets of hydrogen atoms of CH–NC [3c +
phenylhydrazine = 3c(OH)], CH2–NC (3i), (CH3)3C–NC (3k),
and carbon atoms of CH–NC [3c + phenylhydrazine =
3c(OH)] and CH2–NC (3i) are presented in the graphical
presentation of the spectra (see the Supporting Informa-
tion).
A strong, characteristic absorption in the IR spectra of
isocyanides 3a–l was observed in the range 2151–2123 cm–1
(stretching vibration).52 The structure of the isoselenocya-
nates 4a–c bearing a nitroxyl moiety were confirmed using
only EI-MS, ESI-MS, HRMS-EI, HRMS-ESI, and IR. Recording
of NMR spectra in the presence of phenylhydrazine is im-
possible due to the reaction of isoselenocyanate group with
phenylhydrazine. It should be noted that in the 13C NMR
spectra, no signals were attributed to an isoselenocyanate
group.26,53 The signal of isoselenocyanate group in 77Se NMR
6
reflux, 1.5 h
reflux, 1 h
7
4g
4h
4i
8
reflux, 2.5 h reflux, 1 h
9
reflux, 4 h
reflux, 4 h
reflux, 4 h
reflux, 0.75 h pentane
reflux, 1.25 h hexane
10
11
12
4j
4k
4l
reflux, 1.5 h
pentane
hexane
reflux, 2.5 h reflux, 2 h
a If step 2 was performed at r.t. then the product was 5 in 12% yield.
The selenium addition step was carried out at either the
boiling point (4c–l) or at room temperature (five-
membered nitroxyl isoselenocyanates 4a,b). In the case of
4-amino-2,2,6,6-tetramethylpiperidin-1-oxyl (1c, TEMPO-
NH2), performing the reaction with selenium reflux led to
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was observed at δ = –278 to –298 for ArNCSe 4d–g), and at
δ = –345 to –358 for aliphatic and cycloaliphatic isoseleno-
cyanates 4h–l.54
The molecular peak is clearly visible in all mass spectra
of the target isoselenocyanates 4a–k. Adamantyl isoseleno-
cyanate 4l is the exception (m/z 241, 8%), probably due to
the dominating signal of the adamantyl cation [m/z 135
(100%)].
ing a Micromass LCT apparatus. IR spectra were recorded on an FT/IR
Jasco 420 spectrophotometer. 1H and 13C NMR data were collected us-
ing a Varian UNITYplus 200 or 500 spectrophotometers (at 200 or 500
MHz, respectively). 77Se NMR data were recorded using a Bruker DRX
500 Advance (95 MHz). The 1H and 13C NMR spectra of nitroxyl isocy-
anides 3a–c were recorded in a presence of a drop of phenylhydrazine
(in fact the spectra of corresponding hydroxylamines 3a(OH)–3c(OH)
were recorded).48 EPR data were recorded using a Bruker ESP 300 E
apparatus.
A characteristic, strong, broad absorption at 2100–2160
cm–1 is visible in the IR spectra of 4a–l that confirms the
presence of the NCSe group (asymmetrical NCSe stretching
vibration53).
In conclusion: using phase-transfer catalysis conditions,
we developed an effective and reproducible method for the
synthesis of isoselenocyanates, involving the addition of se-
lenium either to isocyanides or directly to amines.
3-Carbamoyl-2,2,5,5-tetramethylpyrrolidin-1-oxyl
A solution of 2,2,6,6-tetramethyl-4-oxopiperidin-1-oxyl69,70 (90.0 g,
0.529 mol) and KOH (89.1 g, 1.59 mol) in 25% aq NH3 (2650 mL) was
placed in a glass reactor of 20-L capacity equipped with a bottom
valve, an efficient mechanical stirrer, a reflux condenser, a dropping
funnel, and a thermometer. A solution of I2 (134.4 g, 0.529 mol) in
benzene (2650 mL) was added dropwise with vigorous stirring to the
solution of 2,2,6,6-tetramethyl-4-oxopiperidin-1-oxyl at 25 °C. Decol-
orization of each drop was observed before the subsequent drop was
added. The addition of the I2 solution took more than 3 h. NaCl (530 g)
was then added. Stirring was stopped and the layers were separated
using the bottom valve; the benzene layer was discarded. The aque-
ous layer was returned to the reactor and extracted with 16 portions
of CH2Cl2 (7.5-L total). The combined CH2Cl2 extracts were dried (an-
hyd MgSO4). Evaporation gave crude 3-carbamoyl-2,2,5,5-tetrameth-
ylpyrrolidin-1-oxyl (52 g, 53%); mp 163–166 °C. The crude product
was sufficiently pure to be used in further steps. It may be purified by
crystallization (EtOAc) to give yellow crystals; yield: 48.5 g (50%); mp
168–170.5 °C (Lit.68 162–164 °C); Rf = 0.38 (benzene–acetone, 1:1).
Starting amines 1d–l were purchased from Aldrich, Alfa-Aesar, and
Fluorochem. Nitroxyl amine TEMPO-NH2 (1c) and its precursors were
synthesized according to literature procedures: 4-(acetylamino)-
2,2,6,6-tetramethylpiperidine and 4-acetylamino-2,2,6,6-tetrameth-
ylpiperidin-1-oxyl
(TEMPO-NHCOCH3),55–62
4-amino-2,2,6,6-te-
tramethylpiperidin-1-oxyl (1c, TEMPO-NH2).56–58,61,62 Nitroxyl amines
PROXYL-NH2 (1a),58,61,63,64 and PROXYL-CH2NH2 (1b),58,65,66 and their
precursor 3-carbamoyl-2,2,5,5-tetramethylpyrrolidin-1-oxyl (PROX-
YL-CONH2)58,67,68 were synthesized according to literature procedure
with some modifications (for the protocols, see below). The following
protocols for TEMPO derivatives 2c, 3c, and 4c, and phenyl isoseleno-
cyanate (4d) have been previously described: 4-(formylamino)-
2,2,6,6-tetramethylpiperidin-1-oxyl (2c, TEMPO-NHCHO) in 96%
yield from 4-amino-2,2,6,6-tetramethylpiperidin-1-oxyl (1c, TEMPO-
NH2) and ethyl formate;42 4-isocyano-2,2,6,6-tetramethylpiperidin-1-
oxyl (3c, TEMPO-NC) in 16% yield from 4-amino-2,2,6,6-tetrameth-
ylpiperidin-1-oxyl (1c, TEMPO-NH2) using CHCl3 and NaOH under
PTC catalysis;42 4-isocyano-2,2,6,6-tetramethylpiperidin-1-oxyl (3c,
TEMPO-NC) from 4-(formylamino)-2,2,6,6-tetramethylpiperidin-1-
oxyl (2c, TEMPO-NHCHO) in 84% and 78% yield using either phos-
gene42 or diphosgene,25 respectively; 4-isoselenocyanato-2,2,6,6-te-
tramethylpiperidin-1-oxyl (4c, TEMPO-NCSe) in 38% yield25,44 from
the corresponding isocyanide 3c (TEMPO-NC), and black, finely pow-
dered, elemental selenium in boiling CHCl3; phenyl isocyanide (3d) in
66% yield from the Hofmann isonitrile reaction using aniline (1d),
CHCl3, and NaOH under PTC catalysis;26 phenyl isoselenocyanate (4d)
in 91% yield26 from the corresponding isocyanide 3d and black, finely
powdered, elemental selenium in boiling CHCl3.
3-Amino-2,2,5,5-tetramethylpyrrolidin-1-oxyl (1a, PROXYL-NH2)
3-Carbamoyl-2,2,5,5-tetramethylpyrrolidin-1-oxyl (9.3 g, 0.05 mol)
was added either to a solution of Br2 (11.3 g, 0.07 mol) and NaOH
(12.1 g) in H2O (130 mL) at 5 °C, or to NaOCl (146.8 g) [obtained by the
saturation of NaOH (16.3 g) in water (175 mL) with gaseous Cl2 (7 g)]
at 5 °C. The solution was stirred at 5 °C for 1 h and at 70 °C for 1–2 h.
The solution was cooled to 5 °C and KOH (100 g) was added at 5–20
°C. The mixture was extracted with Et2O (1 × 100 mL, 1 × 60 mL, 1 ×
35 mL). The combined Et2O extracts were dried (anhyd MgSO4) and
evaporated to obtain crude 1a. The crude product was purified by ei-
ther column chromatography (EtOAc) to give 1a (2.7 g, 34%) or by dis-
tillation under reduced pressure to give 1a (4.13 g, 52%) as a yellow
oil; bp 65.5–66 °C/0.6 Torr (Lit.61,64 75–80 °C/1 Torr); mp 44–46 °C
(Lit.71 34–35 °C); Rf = 0.24 (benzene–acetone, 1:1).
IR (film): 3378, 3312, 2970, 2929, 2870, 1464, 1361, 1106, 860 cm–1
.
MS (EI, 70 eV): m/z (%) = 157 (15, M), 143 (4), 141 (4), 112 (4), 98 (10),
84 (100), 70 (15), 56 (55).
TLC was carried out on silica gel Merck Alurolle 5562 or Alufolien
5554; mobile phases: hexane–EtOAc (9:1); benzene–EtOAc (9:1); ben-
zene–MeOH. TLC visualization was achieved using UV 254 nm light
and/or I2 vapor; visualization of isoselenocyanates: UV 254 nm and ir-
radiation with UV lamp for 5–10 min (red spots) or spraying with 1%
ethanolic PdCl2 (dark brown spots on pale beige background); visual-
ization of isocyanides: UV 254 or 1% ethanolic AgNO3, UV/IR (white
spots on a dark background). Column chromatography was per-
formed on silica gel 0.040–0.063 mm, 230–400 mesh: Merck
1.09385.1000 or Zeochem 60 hyd. EI-MS data (70 eV) were recorded
on an AMD 604 and Agilent Technologies 5975 B mass spectrometers.
HRMS-EI data were recorded by using an AMD 604 mass spectrome-
ter. MS-ESI and HRMS-ESI (MeOH as a solvent) were recorded by us-
3-(Aminomethyl)-2,2,5,5-tetramethylpyrrolidin-1-oxyl (1b, PROX-
YL-CH2NH2)
3-Carbamoyl-2,2,5,5-tetramethylpyrrolidin-1-oxyl (17.03 g, 0.092
mol) was reduced with LiAlH4 (21.9 g, 0.576 mol) (added in 3 × 7.3 g
portions in equidistant time intervals) in anhyd Et2O (2400 mL) under
reflux for 12 h (with vigorous magnetic stirring). The mixture was
cooled to 5 °C. Under vigorous stirring, the mixture was decomposed
slowly and thoroughly with water (22.2 mL), 15% aq NaOH solution
(22.2 mL), and finally with water again (48 mL) at 5–10 °C. The white
precipitate was filtered off and leached with boiling Et2O (2 × 450
mL); the combined ether solutions were dried (anhyd MgSO4). Evapo-
ration of the solvent gave the crude amine 1b (13.95 g) as a yellow oil;
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it was purified by vacuum distillation to give pure 1b (8.1 g, 52%) as a
yellow oil; bp 40–66 °C/0.05–0.01 Torr, 84–87 °C/0.8 Torr (Lit.65 55
°C/0.1 Torr); Rf = 0.17 (benzene–acetone, 1:1).
benzene, benzene–EtOAc, 9:1) to give 3a (1.5 g, 90%) as a yellow oil or
3b (1.228 g, 68%) as an orange oil solidifying in the refrigerator; mp
31–34 °C. For the spectral characterization of 3a and 3b, see below.
IR (film): 3370, 3303, 2971, 2929, 2867, 1463, 1362 cm–1
.
3-Methylphenyl Isocyanide (3e) (Hofmann Isonitrile Reaction)
MS: m/z (%) = 171 (100, M), 157 (38), 142 (6), 126 (16), 109 (22), 95
The solution of m-toluidine (1e, 32.1 g, 0.3 mol) and CHCl3 (49.7 g,
33.6 mL, 0.416 mol) in CH2Cl2 (140 mL) was placed in a reactor
equipped with an efficient mechanical stirrer. Aliquat 336 (5.2 g,
0.013 mol) and 50% aq NaOH (152 g, 100 mL, 1.9 mol) were added to
the solution. The biphasic mixture was vigorously stirred at boiling
point (40 °C) for 1.5 h. TLC monitoring (benzene–MeOH, 9:1) indicat-
ed that no starting amine remained. The mixture was cooled to r.t.
and the layers were separated. The organic layer was washed with
water (100 mL), 1 M HCl (200 mL), and sat. aq NaHCO3 solution (200
mL), and dried (anhyd MgSO4). The drying agent was filtered off and
the volatiles were evaporated. The residue was distilled under vacu-
um to give 3e (20.25 g, 58%) as a dark-greenish liquid with a pungent
odor; bp 72 °C/12 Torr, 80 °C/15 Torr, 83 °C/18 Torr; Rf = 0.61 (ben-
zene–MeOH, 9:1). Alternatively, crude 3e may be purified by column
chromatography (hexane–EtOAc, 85:15).
(8), 74 (18), 70 (42).
3-(Formylamino)-2,2,5,5-tetramethylpyrrolidin-1-oxyl (2a, PROX-
YL-NHCHO) or 3-[(Formylamino)methyl]-2,2,5,5-tetramethylpyr-
rolidin-1-oxyl (2b, PROXYL-CH2NHCHO), General Procedure
This procedure is analogous to that in the literature.42 PROXYL-
NHCHO 1a or PROXYL-CH2NHCHO 1b (0.02 mol) was refluxed with a
large excess of ethyl formate (~50 mL) for 5 h. The formation of 2a or
2b was monitored by TLC (benzene–MeOH, 9:1, 3:1). Excess ethyl for-
mate was evaporated under reduced pressure. The crude, dark, yellow
oil (~100%) may be used for the next step without purification. Col-
umn chromatography (silica gel, benzene) gave pure 2a or 2b.
3-(Formylamino)-2,2,5,5-tetramethylpyrrolidin-1-oxyl (2a, PROX-
YL-NHCHO)
IR (film): 2121, 1600, 1486, 784, 683 cm–1
.
Dark orange oil that solidified in a refrigerator; yield: 0.37 g (100%;
starting 1a: 0.002 mol); Rf = 0.30 (CCl4–EtOAc, 1:1).
IR (KBr): 3300, 2975, 1671, 1526, 1465, 1374, 1220 cm–1
MS (EI, 70 eV): m/z (%) = 185 (M+, 8), 155 (15), 99 (100), 95 (20), 84
(9), 70 (44), 56 (40), 41 (23).
HRMS (EI, 70 eV): m/z [M]+ calcd for C9H17N2O2: 185.12900; found:
185.12849.
1H NMR (200 MHz, CDCl3): δ = 2.35 (s, 3 H), 7.10–7.30 (m, 4 H, C6H4).
13C NMR (50 MHz, CDCl3): δ = 21.15 (CH3), 123.50 (CH), 126.28 (t,
J = 13.4 Hz, CNC), 126.89 (CH), 129.25 (CH), 130.25 (CH), 139.74 (C),
163.57 (t, J = 5.95 Hz, NC).
MS (EI, 70 eV): m/z (%) = 117 (M+, 100), 116 (79), 90 (51), 89 (37), 63
(11).
.
HRMS (EI, 70 eV): m/z [M]+ calcd for C8H7N: 117.05785; found:
117.05748.
3-[(Formylamino)methyl]-2,2,5,5-tetramethylpyrrolidin-1-oxyl
(2b, PROXYL-CH2NHCHO)
4-(Trifluoromethyl)phenyl Isocyanide (3f) (Hofmann Isonitrile
Reaction)
Dark yellow oil; yield: 0.37 g (92%; starting 1b: 0.002 mol); Rf = 0.24
(CCl4–EtOAc, 1:1).
The solution of 4-(trifluoromethyl)aniline (1f, 10 g, 0.062 mol), and
CHCl3 (10.4 g, 7 mL, 0.087 mol) in CH2Cl2 (50 mL) was placed in a reac-
tor equipped with an efficient mechanical stirrer. Aliquat 336 (0.7 g,
0.0017 mol) and 50% aq NaOH (30.7 g, 20.2 mL, 0.38 mol) were added
to the solution. The biphasic mixture was vigorously stirred at boiling
point (40 °C) for 4 h. TLC monitoring (benzene–MeOH, 9:1) indicated,
that no starting amine remained. The mixture was cooled to r.t., water
(20 mL) was added, the layers were separated, and the aqueous layer
was washed with CH2Cl2 (2 × 15 mL). The combined organic layers
were washed with 1 M HCl (40 mL) and sat. aq NaHCO3 solution, and
dried (anhyd MgSO4). The drying agent was filtered off and the vola-
tiles were evaporated. The residue (11.1 g) was distilled under vacu-
um to give 3f (6.41 g, 60%) as a dark-bluish liquid with a pungent
odor; bp 56–60 °C/10 Torr; Rf = 0.38 (hexane–EtOAc, 9:1), 0.66 (ben-
zene–MeOH, 9:1) visualization: UV, 1% ethanolic AgNO3, UV/IR). Al-
ternatively, the crude 3f may be purified by column chromatography:
hexane–EtOAc, 20:1.
IR (film): 3293, 2973, 1672, 1538, 1462, 1381, 1360 cm–1
MS (EI, 70 eV): m/z (%) = 199 (M+, 20), 185 (9), 169 (14), 126 (32), 113
(100), 98 (44), 74 (27), 69 (37), 68 (46), 55 (20), 41 (35).
HRMS (EI, 70 eV): m/z [M]+ calcd for C10H19N2O2: 199.14465; found:
.
199.14396.
3-Isocyano-2,2,5,5-tetramethylpyrrolidin-1-oxyl (3a, PROXYL-NC)
or 3-(Isocyanomethyl)-2,2,5,5-tetramethylpyrrolidin-1-oxyl (3b,
PROXYL-CH2NC); Dehydration with Diphosgene; General Procedure
To a magnetically stirred solution of PROXYL-NHCHO 2a or PROXYL-
CH2NHCHO 2b (0.01 mol), Et3N (2.55 g, ~3.53 mL, 25.3 mmol), and
CH2Cl2 (10 mL) cooled in an ice bath, diphosgene (333 μL) was added
dropwise with a syringe with the temperature below 10 °C. Further
portions of diphosgene (167 μL each) were added every 1–1.5 h. The
formation of 3a or 3b was monitored using TLC [Rf = 0.6 to 0.7 (ben-
zene–MeOH, 9:1)]. The addition of diphosgene was terminated when
no starting 2a or 2b was observed by TLC (4 h at 2–5 °C, 3–4 portions
of diphosgene, 167 μL each). Then the mixture was stirred at r.t. for 1
h, transferred into a pear-shaped flask, CH2Cl2 was evaporated under
reduced pressure, and finally benzene (20 mL) was added. The result-
ing suspension was vigorously stirred, and the precipitate of Et3N·HCl
was filtered off. The precipitate was thoroughly washed with benzene
(2 ×). The benzene filtrate was concentrated under reduced pressure,
and the dark yellow residue (3a: 1.8–2 g; 3b: ~3.1 g) was subjected to
column chromatography (3a: benzene, benzene–MeOH, 95:5; 3b:
IR (film): 2128, 1614, 1325, 1180, 1132, 1105, 1067, 846 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.51 (d, J = 8.4 Hz, 2 H, CHAr), 7.70 (d,
J = 8.4 Hz, 2 H, CHAr).
13C NMR (50 MHz, CDCl3): δ = 123.24 (q, JCF = 271 Hz, CF3), 126.82 (q,
JCF = 3.55 Hz, CAr), 126.95, 131.18, 131.85, 167.14 (NC).
MS (EI, 70 eV): m/z (%) = 171 (M+, 100), 152 (49), 121 (74), 102 (15),
75 (22), 50 (17).
HRMS (EI, 70 eV): m/z [M]+ calcd for C8H4NF3: 171.02958; found:
171.03029.
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tert-Butyl Isocyanide (3k) (Hofmann Isonitrile Reaction)
vigorously stirred under reflux for the time given in Table 1. The con-
sumption of the amine and the formation of the isocyanide were both
monitored by TLC. The mixture was cooled to r.t., then water (50 mL)
and CH2Cl2 (50 mL) were added. The organic layer was separated and
dried (anhyd MgSO4). The drying agent was filtered off, and the sol-
vent was evaporated under reduced pressure. The residue was puri-
fied by column chromatography (hexane–EtOAc, 9:1) to give the iso-
cyanides 3a,b,g–j.
The solution of tert-butylamine (1k, 14.6 g, 21.1 mL, 0.2 mol) and
CHCl3 (30.24 g, 20.4 mL, 0.25 mol) in CH2Cl2 (100 mL) was placed in a
reactor of 200-mL capacity equipped with an efficient mechanical
stirrer, a reflux condenser, and a thermometer. Aliquat 336 (0.5 g,
0.0012 mol) and 50% aq NaOH (91.2 g, 60 mL, 1.14 mol) were added
to the solution. The mixture was vigorously stirred at boiling point
(40 °C) for 4 h. The mixture was cooled to r.t., water (100 mL) was
added, the layers were separated, and the aqueous layer was washed
with CH2Cl2 (2 × 50 mL). The combined organic layers were washed
with 1 M HCl (100 mL) and sat. aq NaHCO3 solution (100 mL), and
dried (anhyd MgSO4). The drying agent was filtered off and the vola-
tiles were evaporated. The residue distilled under vacuum to give 3k
(6.64 g, 40%) as a volatile liquid solidifying in a refrigerator; bp 89–
92 °C (Lit.72 92–93 °C/725 Torr).
3-Isocyano-2,2,5,5-tetramethylpyrrolidin-1-oxyl (3a, PROXYL-NC)
Following the general procedure for the Hofmann isonitrile reaction
(for conditions see Table 1) or using formylamine 2a and diphosgene
(for the procedure, see above) in 90% yield; yellow oil; yield: 109 mg
(65%; starting 1a: 0.001 mol); mp ~18 °C; Rf = 0.56 (benzene–MeOH,
9:1).
IR (film): 2986, 2135, 1476, 1372, 1240, 1215, 859, 759 cm–1
.
IR (film): 2979, 2143, 1698, 1464, 1367, 684.
1H NMR (200 MHz, CDCl3): δ = 1.45 [t, J = 2.1 Hz, 9 H, (CH3)3CNC].
13C NMR (50 MHz, CDCl3): δ = 30.89 (3 CH3), 54.25 (C), 152.57 (NC).
MS (EI, 70 eV): m/z (%) = 168 (7), 167 (4), 166 (10, 2 M73), 164 (7), 85
(44), 83 (M+, 68), 68 (42, M-CH3), 57 (100, t-C4H9+), 47 (20), 41 (77).
1H NMR (200 MHz, CDCl3–PhNHNH2, 3a-OH): δ = 1.13 (s, 3 H, CH3),
1.22 (s, 3 H, CH3), 1.24 (s, 3 H, CH3), 1.25 (s, 3 H, CH3), 1.88–2.02 [m, 1
H, HHC-CH(NC)], 2.17 [dd, J = 12.8, 7.8 Hz, 1 H, HHC-CH(NC)], 3.66 [t,
J = 7.9 Hz, 1 H, CH(NC)].
13C NMR (50 MHz, CDCl3–PhNHNH2, 3a-OH): δ = 20.34 (CH3), 24.43
(CH3), 27.47 (CH3), 27.62 (CH3), 42.77 (CH2), 57.27 (t, J = 7.1 Hz,
CHNC), 61.50 (C), 65.80 (C), 156.96 (t, J = 6.1 Hz, CHNC).
MS (ESI): m/z (%) = 413 (3), 322 (12), 289 (30), 233 (35), 195 (25), 158
(10), 106 (100, M + Na).
HRMS (ESI): m/z [M + Na]+ calcd for C5H9NNa: 106.0633; found:
106.0632.
MS (EI, 70 eV): m/z (%) = 167 (M+, 71), 152 (39), 122 (46), 112 (38), 95
(26), 82 (59), 74 (42), 56 (100), 41 (70).
HRMS (EI, 70 eV): m/z [M]+ calcd for C9H15N2O: 167.11844; found:
167.11772.
1-Adamantyl Isocyanide (3l) (Hofmann Isonitrile Reaction)
1-Adamantylamine (1l, 2.27 g, 0.015 mol), Aliquat 336 (0.15 g,
0.00037 mol), CHCl3 (1.8 g, 1.2 mL, 0.015 mol), and CH2Cl2 (7.5 mL)
were placed in a reactor equipped with an efficient mechanical stir-
rer; 50% aq NaOH (6.84 g, 4.5 mL, 0.0855 mol) was added to the mix-
ture. The biphasic mixture was vigorously stirred at boiling point
(40 °C) for 4 h. TLC monitoring (hexane–EtOAc, 9:1) indicated that no
starting amine remained. The mixture was cooled to r.t., water (15
mL) was added, the layers were separated, and the aqueous layer was
washed with CH2Cl2 (2 × 15 mL). The combined organic layers were
washed with 1 M HCl (20 mL) and sat. aq NaHCO3 solution, and dried
(anhyd MgSO4). The drying agent was filtered off and the volatiles
were evaporated. The residue (2.023 g) was subjected to column chro-
matography (hexane–EtOAc, 4:1) to give 3l (1.73 g, 72%) as a white
solid; mp 183–185 °C (Lit.74 186–188 °C); Rf = 0.41 hexane–EtOAc,
9:1), 0.57 (benzene–MeOH, 9:1), visualization UV, 1% ethanolic
AgNO3, UV/IR).
3-(Isocyanomethyl)-2,2,5,5-tetramethylpyrrolidin-1-oxyl (3b,
PROXYL-CH2NC)
Following the general procedure for the Hofmann isonitrile reaction
(for conditions see Table 1) or using formylamine 2b and diphosgene
(for the procedure, see above) in 68% yield; orange oil that solidified
in a refrigerator; yield: 24 mg (7%; starting 1b: 0.002 mol); mp 31–
34 °C; Rf = 0.56 (benzene–EtOAc, 1:1).
IR (film): 2974, 2149, 1462, 1365, 1249, 1160, 928 cm–1
.
1H NMR (200 MHz, CDCl3–PhNHNH2, 3b-OH): δ = 1.02 (s, 3 H, CH3),
1.17 (s, 3 H, CH3), 1.19 (s, 3 H, CH3), 1.22 (s, 3 H, CH3), 1.49 [t, J = 11.6
Hz, 1 H, HHCCH(CH2NC)], 1.92 [dd, J = 12.6 Hz, J = 7.4 Hz, 1 H, HH-
CCH(CH2NC)], 2.0–2.6 [m, 1 H, CH2CH(CH2NC)], 3.15–3.50 [m, 2 H,
CH2CH(CH2NC)].
13C NMR (50 MHz, CDCl3–PhNHNH2, 3b-OH): δ = 18.43 (CH3), 26.54
(CH3), 27.06 (CH3), 27.81 (CH3), 40.23 (CH2), 42.55 (t, J = 6.4 Hz,
CH2NC), 42.83 (CH), 61.26 (C), 64.94 (C), 156.63 (t, J = 10.4 Hz,
CH2NC).
MS (EI, 70 eV): m/z (%) = 181 (M+, 29), 166 (10), 149 (8), 126 (16), 69
(100), 56 (27), 41 (49).
HRMS (EI, 70 eV): m/z [M]+ calcd for C10H17N2O: 181.13409; found:
181.13393.
IR (KBr): 2918, 2858, 2123, 1454, 1077 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.62–1.72 (m, 6 H, 3 CH2), 2.0–2.06 (m,
6 H, 3 CH2), 2.06–2.16 (m, 3 H, 3 CH).
13C NMR (50 MHz, CDCl3): δ = 28.75 (3 CH), 35.54 (3 CH2), 43.60 (3
CH2), 54.28 (C), 151.62 (NC).
MS (EI, 70 eV): m/z (%) = 161 (M+, 17), 135 (100, [Ad – H]+), 104 (6), 93
(10), 92 (8), 91 (9), 79 (16), 77 (9).
HRMS (EI, 70 eV): m/z [M]+ calcd for C11H15N: 161.12045; found:
161.11971.
4-Isocyano-2,2,6,6-tetramethylpiperidin-1-oxyl (3c, TEMPO-NC)
Hofmann isonitrile reaction;42 yield: 16%; phosgene in benzene solu-
tion as a dehydrating agent;42 yield: 84%; diphosgene as a dehydrating
agent;25 yield: 78%; red crystals; Lit.25,42 mp 142–144 °C (hexane),
Lit.43 mp 133–134 °C, Lit.75 mp 143.5–144.5 °C; Rf = 0.65 (benzene–
MeOH, 9:1).
Isocyanides 3a–d,g–j; Hofmann Isonitrile Reaction of Amines
1a–d,g–j; General Procedure
A mixture of amine 1a,b,g–j (0.05 mol), CHCl3 (8 g, 5.4 mL, 0.067
mol), CH2Cl2 (33 mL), Aliquat 336 (0.67 g, 0.00167 mol), and 50% aq
NaOH (22.8 g, 15 mL, 0.285 mol) was vigorously stirred; an exother-
mic effect was observed. When the effect has ceased, the mixture was
IR (KBr): 2968, 2948, 2913, 2143, 1467, 1390, 1365, 1355, 1242, 1181,
675, 570 cm–1
.
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1H NMR (200 MHz, CDCl3–PhNHNH2, 3c-OH): δ = 1.11 [s, 6 H,
(CH3)2CN(OH)C(CH3)2], 1.19 (s, 6 H, (CH3)2CN(OH)C(CH3)2], 1.74 (t,
J = 12.3 Hz, 2 H, H2CCH(NC)CH2), 2.0 (dd, J = 12.3 Hz, J = 3.3 Hz, 2 H,
H2CCH(NC)CH2), 3.75 (ttt, J = 12.0, 4.0, 2.0 Hz, 1 H, CH(NC)].
13C NMR (125 MHz, CDCl3–PhNHNH2, 3c-OH): δ = 19.56 (2 CH3), 31.86
(2 CH3), 45.37 (t, J = 6.6 Hz, CHNC), 45.48 (2 CH2), 58.45 (2 C), 154.79
(t, J = 4.9 Hz, CHNC).
MS (EI, 70 eV): m/z = 181 (M+, 31), 167 (18), 126 (9), 124 (24), 109
(35), 94 (100), 81 (36), 68 (74), 67 (67), 55 (52), 41 (98).
HRMS (EI, 70 eV): m/z [M]+ calcd for C10H17N2O: 181.13409; found:
181.13370.
Pentyl Isocyanide (3i)
Following the general procedure for the Hofmann isonitrile reaction
(for conditions see Table 1) gave a yellow oil; yield: 0.44 g (30%; start-
ing 1i: 0.015 mol); Rf = 0.44 (hexane–EtOAc, 9:1), 0.65 (benzene–
MeOH, 9:1).
IR (film): 2959, 2863, 2149, 1456 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 0.93 (t, J = 7.2 Hz, 3 H, CH3), 1.25–1.52
(m, 4 H, 2 CH2), 1.6–1.78 (m, 2 H, CH2), 3.39 (tt, J = 6.6, 2.0 Hz, 2 H,
CH2NC).
13C NMR (50 MHz, CDCl3): δ = 13.98 (CH3), 21.98 (CH2), 28.60 (CH2),
28.97 (CH2), 41.73 (t, J = 6.3 Hz, CH2NC), 155.71 (t, J = 5.7 Hz, NC).
EPR (aN, [G]): 15.49 G (toluene), 15.77 G (CH2Cl2), 15.83 G (DMSO),
g = 2.0060.
MS (EI, 70 eV): m/z (%) = 96 (5, M – 1), 82 (26), 69 (51), 68 (42), 57
(23), 55 (75), 42 (100), 41 (95).
Phenyl Isocyanide (3d)
Cyclododecyl Isocyanide (3j)
Following the general procedure for the Hofmann isonitrile reaction
(for conditions see Table 1), the product was isolated either by column
chromatography or by vacuum distillation as a yellowish liquid; yield:
66% (column chromatography);26 30% (vacuum distillation);26 bp 68–
69.5 °C/22 Torr, 35–38 °C/0.7 Torr (Lit.76 43–44 °C/1.5 Torr, Lit.77
64 °C/22 Torr); Rf = 0.66 (benzene–MeOH, 9:1).
Following the general procedure for the Hofmann isonitrile reaction
(for conditions see Table 1) gave a yellow liquid; yield: 2.77 g (57%;
starting 1j: 0.025 mol); Rf = 0.50 (benzene–MeOH, 9:1).
IR (film): 2933, 2850, 2135, 1470, 1450, 1346, 721 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.33 (s, 16 H, 8 CH2), 1.2–1.9 (m, 6 H, 3
CH2), 3.55–3.75 (center: 3.65) (sym m, 1 H, CHNC).
13C NMR (50 MHz, CDCl3): δ = 21.05 (CH2), 23.27 (CH2), 23.37 (CH2),
23.81 (CH2), 23.93 (CH2), 30.48 (CH2), 51.46 (t, J = 5.5 Hz, CHNC),
153.88 (t, J = 5.1 Hz, CHNC).
IR (film): 2126 (NC), 1588, 1486, 1455, 754, 684, 513 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.30–7.42 (m, 5 H, C6H5).
13C NMR (75 MHz, CDCl3): δ = 126.18 (CHAr), 126.46 (t, J = 13.4 Hz,
CNC), 129.18, 129.25, 164.00 (t, J = 5.7 Hz, CNC).
MS (EI, 70 eV): m/z (%) = 192 (40, M – 1), 178 (15), 164 (48), 150 (100),
138 (20), 136 (78), 122 (53), 108 (49), 96 (79), 82 (85), 81 (64), 67
(65), 55 (85), 41 (99).
MS (EI, 70 eV): m/z (%) = 103 (M, 100), 77 (35), 76 (49), 51 (18), 50
(17).
MS (ESI): m/z (%) = 459 (3), 248 (30, M + Na + CH3OH), 216 (100, M +
Na).
4-Chloro-2-methylphenyl Isocyanide (3g)
Following the general procedure for the Hofmann isonitrile reaction
(for conditions see Table 1) gave a dark solid; yield: 3.73 g (78%; start-
ing 1g: 0.032 mol); mp 40–47 °C; Rf = 0.62 (benzene–MeOH, 9:1).
HRMS (ESI): m/z [M + Na]+ calcd for C13H23NNa: 216.1728; found:
216.1732.
IR (KBr): 3433, 2124, 1628, 1482, 1177, 1117, 886, 831, 622 cm–1
1H NMR (200 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3), 7.15–7.30 (m, 3 H).
13C NMR (50 MHz, CDCl3): δ = 18.61 (CH3), 127.05 (CH), 127.70 (CH),
130.66 (CH), 135.07 (C), 136.86 (C), 167.24 (NC).
MS (EI, 70 eV): m/z (%) = 153 (17), 151 (M+, 54), 116 (100), 89 (41), 63
(13), 62 (7).
HRMS (EI): m/z [M]+ calcd for C8H6NCl: 151.01888; found: 151.01893.
.
Isoselenocyanates 4a,b,e–l; General Procedure 1
Isocyanides 3a,b,e–l, black, finely powdered, elemental selenium (1:2
mol/mol), and CHCl3 (1.5 mL/1 mmol of isocyanide 3a,b,e–l) were
stirred with gentle reflux for the time given in Table 2. The formation
of 4 was monitored using TLC. Unreacted selenium was filtered off,
then the filtrate was evaporated. The crude product was subjected to
column chromatography (benzene–MeOH, 95:5) to give isoselenocya-
nates 4a,b,e–l.
Benzyl Isocyanide (3h)
Isoselenocyanates 4a–l; General Procedure 2
Following the general procedure for the Hofmann isonitrile reaction
(for conditions see Table 1) gave a pale brown liquid; yield: 3.57 g
(65%; starting 1h: 0.047 mol); Rf = 0.24 (hexane–EtOAc, 9:1).
Equimolar (0.003 mol) amounts of isocyanide 3a–l, black, finely pow-
dered, elemental selenium, and Et3N, in THF (10 mL) were heated at
boiling point for the time given in Table 2. The progress of the reac-
tion was monitored by TLC. The mixture was allowed to cool to r.t.
Unreacted selenium was filtered off under reduced pressure using a
Büchner funnel and filter paper. Silica gel (70–230 mesh, 10 g) was
added to the filtrate, and the resulting mixture was evaporated to
dryness under reduced pressure. The mixture was moistened with
THF and evaporated to dryness again. The powdered residue was
placed on the top of the bed of silica gel and subjected to column
chromatography to give isoselenocyanates 4a–l.
IR (film): 3034, 2151, 1497, 1454, 1352, 735, 695.
1H NMR (200 MHz, CDCl3): δ = 4.62 (t, J = 2.0 Hz, 2 H, CH2NC), 7.28–
7.45 (m, 5 H, C6H5).
13C NMR (50 MHz, CDCl3): δ = 45.75 (t, J = 7.1 Hz, CH2NC), 126.84
(CH), 128.84 (CH), 129.21 (CH), 132.56 (C), 157.74 (CH2NC).
MS (EI, 70 eV, deposited on graphite): m/z (%) = 117 (M+, 100), 116
(47), 91 (64, C7H7+), 90 (66), 89 (41), 77 (9), 65 (15), 63 (17), 51 (14),
50 (11).
MS (ESI): m/z (%) = 227 (30), 140 (100, M + Na).
Isoselenocyanates 4a–l; General Procedure 3
HRMS (ESI): m/z [M + Na]+ calcd for C8H7NNa: 140.0476; found:
140.0481.
Isocyanide 3a–l (0.015 mol), CH2Cl2 (75 mL), 50% aq NaOH solution
(6.84 g, 4.5 mL, 0.0855 mol), Aliquat 336 (0.2 g, 0.0005 mol), and
black, finely powdered, elemental selenium (1.26 g, 0.016 mol) were
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vigorously stirred at r.t. (4a–k) or refluxed (4c,l) for the time given in
Table 3. The isoselenocyanate formation was monitored by TLC. The
mixture was cooled to r.t., then water (30 mL) was added, and unre-
acted selenium was filtered off under reduced pressure using a
Büchner funnel and filter paper. The organic layer was separated and
dried (anhyd MgSO4). The drying agent was filtered off, and the sol-
vent was evaporated under reduced pressure. The residue was puri-
fied by column chromatography (see Table 3) to give the isoselenocy-
anates 4a–l.
4-Isoselenocyanato-2,2,6,6-tetramethylpiperidin-1-oxyl (4c, TEM-
PO-NCSe)
Red crystals; yield: 38% (GP1),25,44 159 mg (61%; GP2, starting 3c:
0.001 mol), 1.11 g (63%; GP3, reflux, starting 3c: 0.0068 mol), 0.34 g
(60%; GP3, r.t., starting 3c: 0.0022 mol), 180 mg (9%; GP4, starting 1c:
0.0075 mol); mp 158–160 °C; Rf = 0.0.75 (benzene–MeOH, 9:1).
IR (KBr): 2161 cm–1
.
MS (EI, 70 eV): m/z (%) = 261 (M+, 35), 259 (17), 175 (14), 154 (42),
140 (19), 124 (26), 109 (24), 94 (29), 81 (20), 69 (100), 55 (41), 41
(75).
HRMS (EI): m/z [M]+ calcd for C10H17N2O80Se: 261.0506; found:
261.0514.
Isoselenocyanates 4a–l; General Procedure 4
A mixture of amine 1a–l (0.015 mol), CHCl3 (2.4 g, 1.62 mL, 0.02 mol),
CH2Cl2 (10 mL), Aliquat 336 (0.2 g, 0.0005 mol), and 50% aq NaOH
(6.84 g, 4.5 mL, 0.086 mol) was vigorously stirred; an exothermic ef-
fect was observed. When the effect had ceased, the mixture was vig-
orously stirred (4a) or refluxed (4b–l) for the time given in Table 4.
The consumption of the amine was monitored by TLC. The mixture
was cooled to r.t., and black, finely powdered, elemental selenium (1.5
g, 0.019 mol) was added. The reagents were vigorously stirred at r.t.
(4a,b) or refluxed (4c–l) for the time given in Table 4. The isoseleno-
cyanate formation was monitored by TLC. The mixture was cooled to
r.t., then water (15 mL) and CH2Cl2 (15 mL) were added, and the unre-
acted selenium was filtered off under reduced pressure using a
Büchner funnel and filter paper. The organic layer was separated and
dried (anhyd MgSO4). The drying agent was filtered off, and the sol-
vent was evaporated under reduced pressure. The residue was puri-
fied by column chromatography (see Table 4). Silica gel (10 g) was
added to the crude isoselenocyanate in CH2Cl2. After evaporation, the
silica gel containing the crude product was placed on the top of the
chromatographic column and eluted with the mobile phase (Table 4)
to give the isoselenocyanates 4a–l. In the case of 4c, if the reaction
with selenium carried out at r.t., bis(2,2,6,6-tetramethyl-1-oxylpiper-
idin-4-yl)carbodiimide (5) was isolated (12%).
EPR (aN [G]): 15.46 G (toluene), 15.73 G (CH2Cl2), 15.80 G (DMSO),
g = 2.0061 (toluene), g = 2.0060 (CH2Cl2), g = 2.0059 (DMSO).
Bis(2,2,6,6-tetramethyl-1-oxylpiperidin-4-yl)carbodiimide (5)
Red crystals; yield: 205 mg (12%; starting 1c: 0.01 mol); mp 165–167
°C (hexane) (Lit.78 165–167 °C); Rf = 0.47 (benzene–MeOH, 9:1).
IR (KBr): 2975, 2927, 2126, 1468, 1375, 1365, 1350, 1243, 1183, 638,
560.
MS (EI, 70 eV): m/z (%) = 350 (70, M), 264 (25), 234 (28), 219 (37), 208
(35), 178 (47), 163 (42), 155 (38), 154 (48), 152 (34), 140 (77), 124
(100), 111 (36), 109 (52), 100 (56), 98 (39), 83 (50), 82 (47), 74 (27),
69 (94), 67 (38), 56 (82), 55 (87), 41 (92).
Phenyl Isoselenocyanate (Isoselenocyanatobenzene, 4d)
Oil; yield: 91% (GP1),26 0.53 g (92%; GP2, starting 3d: 0.0031 mol),
1.29 g (89%; GP3, starting 3d: 0.008 mol), 1.90 g (70%; GP4, starting
1d: 0.015 mol); Rf = 0.82 (hexane–EtOAc, 9:1).
IR (film): 2116, 2040, 1589, 1487, 749, 683 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 7.22–7.42 (m, 5 H, C6H5).
13C NMR (50 MHz, CDCl3): δ = 126.03 (CHAr), 128.08 (CHAr), 129.55
(CHAr), 139.00 (CAr).
3-Isoselenocyanato-2,2,5,5-tetramethylpyrrolidin-1-oxyl (4a,
PROXYL-NCSe)
77Se NMR (95 MHz): δ = –297.07 (295.979).
MS (EI, 70 eV): m/z (%) = 185 (18), 183 (M+, 100), 181 (49), 103 (28),
Yellow oil that solidified in a refrigerator; yield: 48 mg (19%; GP1,
starting 3a: 0.00104 mol), 0.816 g (79%; GP2, starting 3a: 0.0042
mol), 1.96 g (66%; GP3, starting 3a: 0.012 mol), 22 mg (4%; GP4, start-
ing 1a: 0.0025 mol); mp 33 °C; Rf = 0.25 (hexane–EtOAc, 4:1), 0.58
(benzene–MeOH, 9:1).
77 (77), 51 (30), 50 (14).
3-Methylphenyl Isoselenocyanate (4e)
IR (film): 2964, 2128, 1726, 1690, 1650, 1463, 1365, 1260, 1098,
Yellowish oil; yield: 24.8 g (90%; GP1, starting 3e: 0.141 mol), 0.426 g
(74%; GP2, starting 3e: 0.003 mol), 2.25 g (77%; GP3, starting 3e:
0.015 mol), 1.58 g (53%; GP4, starting 1e: 0.015 mol); Rf = 0.30 (hex-
ane), 0.54 (hexane–EtOAc, 9:1).
IR (film): 2106, 1602, 1483, 779, 681, 625 cm–1
1H NMR (200 MHz, CDCl3): δ = 2.34 (s, 3 H, CH3), 7.03–7.30 (m, 4 H).
1020, 801 cm–1
.
MS (EI, 70 eV): m/z (%) = 249 (10), 247 (M+, 57), 161 (43), 111 (32), 95
(33), 74 (33), 69 (74), 56 (93), 55 (100), 41 (88).
HRMS (EI, 70 eV): m/z [M]+ calcd for C9H15N2OSe : 247.03496; found:
247.03537.
.
13C NMR (50 MHz, CDCl3): δ = 21.30 (CH3), 123.24 (CH), 126.76 (CH),
129.19 (CH), 129.46 (CH), 135.60 (t, J = 4.6 Hz, CNCSe), 139.93 (C).
77Se NMR (95 MHz): δ = –298.86.
3-(Isoselenocyanatomethyl)-2,2,5,5-tetramethylpyrrolidin-1-oxyl
(4b, PROXYL-CH2NCSe)
Dark-orange oil; yield: 35 mg (25%; GP1, starting 3b: 0.000552 mol),
258 mg (66%; GP2, starting 3b: 0.0015 mol), 1.86 g (89%; GP3, start-
ing 3b: 0.008 mol), 156 mg (10%; GP4, starting 1b: 0.0058 mol);
Rf = 0.22 (benzene–MeOH, 9:1), 0.58 (benzene–EtOAc, 1:1).
MS (EI, 70 eV): m/z (%) = 199 (12), 197 (M+, 68), 195 (33), 117 (24),
116 (20), 91 (100, C7H7+), 65 (37).
HRMS (EI): m/z [M]+ calcd for C8H7NSe: 196.97437: found: 196.97378.
IR (film): 2960, 2920, 2138, 1461, 1365, 1340, 1248, 683 cm–1
.
MS (EI, 70 eV): m/z (%) = 261 (M+, 52), 259 (26), 126 (25), 74 (21), 69
4-(Trifluoromethyl)phenyl Isoselenocyanate (4f)
(100), 56 (14), 55 (18), 41 (43).
HRMS (EI, 70 eV): m/z [M]+ calcd for C10H17N2OSe: 261.05061; found:
261.05104.
Pale creamy solid; yield: 7.4 g (70%; GP1, starting 3f: 0.042 mol), 132
mg (18%; GP2, starting 3f: 0.003 mol), 1.38 g (61%; GP3, starting 3f:
0.009 mol), 0.673 g (27%; GP4, starting 1f: 0.01 mol); mp 65–68 °C;
Rf = 0.52 (hexane–EtOAc, 9:1).
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IR (KBr): 3432, 2137, 1610, 1325, 1134, 1065, 840 cm–1
.
77Se NMR (95 MHz): δ = –357.679.
1H NMR (200 MHz, CDCl3): δ = 7.40 (dd, J = 8.4, 0.6 Hz, 2 H, CHAr), 7.65
(dd, J = 8.4, 0.6 Hz, 2 H, CHAr).
MS (EI, 70 eV, deposited on graphite): m/z (%) = 179 (13), 177 (M+, 75),
175 (37), 120 (14), 55 (27), 43 (100), 41 (50).
13C NMR (125 MHz, CDCl3): δ = 123.79 (q, JCF = 270.88 Hz, CF3), 126.43,
126.86 (q, JCF = 3.9 Hz, CAr), 129.77 (q, JCF = 32.6 Hz, CAr), 133.16.
HRMS (EI, 70 eV): m/z [M]+ calcd for C6H11NSe: 177.0057; found:
177.0059.
77Se NMR (95 MHz): δ = –278.02.
MS (EI, 70 eV): m/z (%) = 253 (19), 251 (M+, 97), 249 (49), 171 (8), 152
Cyclododecyl Isoselenocyanate (4j)
Oil that solidified in a refrigerator; yield: 98 mg (36%; GP1, starting 3j:
0.001 mol), 171 mg (63%; GP2, starting 3j: 0.001 mol), 0.93 g (74%;
GP3, starting 3j: 0.0046 mol), 2.02 g (50%; GP4, starting 1j: 0.015
mol); mp 34–36 °C; Rf = 0.87 (hexane–EtOAc, 9:1).
(16), 145 (100), 125 (13), 121 (12), 95 (17), 75 (19), 50 (11).
HRMS (EI, 70 eV): m/z [M]+ calcd for C8H4NF380Se: 250.94610; found:
250.94526.
IR (KBr): 2934, 2851, 2138, 1468, 718 cm–1
1H NMR (200 MHz, CDCl3): δ = 1.2–1.5 (m, 18 H), 1.60–1.95 (m, 4 H),
3.86 (sym m, 1 H).
13C NMR (50 MHz, CDCl3): δ = 21.12 (CH2), 23.17 (CH2), 23.30 (CH2),
.
4-Chloro-2-methylphenyl Isoselenocyanate (4g)
Pale yellow solid; yield: 16.6 g (65%; GP1, starting 3g: 0.11 mol), 0.34
g (74%; GP2, starting 3g: 0.002 mol), 2.18 g (86%; GP3, starting 3g:
0.011 mol), 1.68 g (73%; GP4, starting 1g: 0.01 mol); mp 46–49 °C;
Rf = 0.53 (hexane–EtOAc, 9:1).
23.93 (CH2), 24.04 (CH2), 30.44 (CH2), 55.92 (CH).
IR (KBr): 3435, 2094, 1474, 1134, 1186, 894, 819 cm–1
.
77Se NMR (95 MHz): δ = –354.615.
1H NMR (200 MHz, CDCl3): δ = 2.38 (s, 3 H, CH3), 7.15–7.27 (m, 3 H).
MS (EI, 70 eV): m/z (%) = 273 (M+, 45), 271 (23), 167 (49, C12H23+), 111
(51), 97 (89), 83 (79), 69 (81), 55 (100), 41 (79).
HRMS (EI, 70 eV): m/z [M]+ calcd for C13H23NSe: 273.0996; found:
13C NMR (50 MHz, CDCl3): δ = 18.46 (CH3), 127.24 (CH), 127.35 (CH),
130.78 (CH), 133.68 (C), 137.31 (C).
273.1001.
77Se NMR (95 MHz): δ = –298.200.
MS (EI, 70 eV): m/z (%) = 233 (36), 231 (M+, 82), 229 (40), 196 (16),
151 (100), 125 (14), 116 (38), 99 (10), 89 (46), 63 (22).
tert-Butyl Isoselenocyanate (4k)
Creamy solid; yield: 445 mg (18%; GP1, starting 3k: 0.015 mol), 0.65 g
(40%; GP2, starting 3k: 0.01 mol), 2.645 g (65%; GP3, starting 3k:
0.025 mol), 1.123 g (46%; GP4, starting 1k: 0.015 mol); mp 50–53 °C
(Lit.80 51–53 °C); Rf = 0.39 (hexane–EtOAc, 9:1).
HRMS (EI, 70 eV): m/z [M]+ calcd for C8H6ClNSe: 230.93540; found:
230.93635.
Benzyl Isoselenocyanate (4h)
IR (film): 2981, 2126, 2066, 1459, 1367, 1230, 1180, 667 cm–1
1H NMR (200 MHz, CDCl3): δ = 1.48 (s, 3 CH3).
13C NMR (50 MHz, CDCl3): δ = 30.58 (3 CH3), 59.30 (C).
77Se NMR (95 MHz): δ = –345.793.
.
Yellow oil; yield: 177 mg (60%; GP1, starting 3h: 0.0015 mol), 0.39 g
(76%; GP2, starting 3h: 0.0026 mol), 1.51 g (67%; GP3, starting 3h:
0.0115 mol), 1.1 g (37%; GP4, starting 1h: 0.015 mol); Lit.80 mp –8 °C;
Rf = 0.56 (hexane–EtOAc, 9:1).
IR (film): 3031, 2138, 1604, 1496, 1453, 1340, 732, 604 cm–1
.
MS (EI, 70 eV, deposited on graphite): m/z (%) = 163 (M+, 24), 161 (12),
149 (10), 112 (13), 111 (14), 97 (23), 85 (40), 83 (43), 71 (48), 70 (33),
69 (35), 57 (100, t-C4H9+), 56 (34), 55 (56), 43 (68), 41 (92).
1H NMR (200 MHz, CDCl3): δ = 4.78 (s, 2 H), 7.25–7.45 (m, 5 H, C6H5).
13C NMR (50 MHz, CDCl3): δ = 49.21 (CH2NCSe), 127.12 (CH), 128.87
(CH), 129.30 (CH), 133.08 (C).
HRMS (EI, 70 eV): m/z [M]+ calcd for C5H9NSe: 162.9900; found:
162.9906.
77Se NMR (95 MHz): δ = –348.805.
MS (EI, 70 eV, deposited on graphite): m/z (%) = 199 (11), 197 (M+, 58),
195 (29), 117 (15), 116 (14), 91 (100), 65 (43), 63 (19), 51 (14).
1-Adamantyl Isoselenocyanate (4l)
Pale yellow plates; yield: 160 mg (18%; GP1, starting 3l: 0.0037 mol),
0.2 g (56%; GP2, starting 3l: 0.0015 mol), 0.69 g (72%; GP3, starting 3l:
0.004 mol), 4.05 g (48%; GP4, starting 1l: 0.035 mol); mp 208–211 °C;
Rf = 0.45 (hexane–EtOAc, 9:1).
MS (ESI, –’ve): m/z (%) = 228 (30), 196 (100, M – H), 194 (25).
HRMS (ESI): m/z [M – H] calcd for C8H6NSe: 195.9665; found:
195.9674.
IR (KBr): 2915, 2853, 2112, 1304, 1077 cm–1
1H NMR (500 MHz, CDCl3): δ = 1.67 (tt, J = 15.5, 2.7 Hz, 6 H, 3 CH2),
2.03 [d, J = 2.7 Hz, 6 H, (CH2)3CN], 2.13 (br s, 3 H, 3 CH).
13C NMR (125 MHz, CDCl3): δ = 29.04 (CH), 35.40 (CH2), 43.30 (CH2),
59.18 (C–N).
77Se NMR (95 MHz): δ = –349.641.
MS (EI, 70 eV): m/z (%) = 241 (M+, 8), 239 (4), 135 (100, [Ad – H]+), 107
(7), 93 (21), 79 (24).
HRMS (EI, 70 eV): m/z [M]+ calcd for C11H15NSe: 241.03697; found:
.
Pentyl Isoselenocyanate (4i)
Orange liquid; yield: 153 mg (66%; GP1, starting 3i: 0.0013 mol), 136
mg (48%; GP2, starting 3i: 0.0016 mol), 1.62 g (75%; GP3, starting 3i:
0.012 mol), 0.746 g (28%; GP4, starting 1i: 0.015 mol); Rf = 0.87 (hex-
ane–EtOAc, 9:1).
IR (film): 2957, 2146, 1449, 1342 cm–1
1H NMR (200 MHz, CDCl3): δ = 0.88–0.98 (m, 3 H, CH3), 1.24–1.5 (m, 4
H, 2 CH2), 1.66–1.82 (m, 2 H, CH2), 3.61 (t, J = 6.6 Hz, 2 H).
.
13C NMR (50 MHz, CDCl3): δ = 14.04 (CH3), 22.06 (CH2), 28.80 (CH2),
29.32 (CH2), 45.67 (CH2NCSe).
241.03634.
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Acknowledgment
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This work was financially supported by a Grant N N209 044739, Na-
tional Science Centre, Poland. We would like to thank Mrs Bogusława
Wantusiak and Mrs Barbara Zdunek for assistance in the syntheses of
all described compounds. We are grateful to Mrs Hanna Konopka for
performing the IR measurements.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560481. Spectra of isocyanides
3a–l and isoselenocyanates 4a–l are provided.
S
u
p
p
ortiInfogrmoaitn
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p
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