Synthesis of isonitriles from N-substituted formamides using triphenylphosphine and iodine

Article abstract of DOI:10.1055/s-0034-1379111

Treatment of N-substituted formamides with the reagent combination of triphenylphosphine and molecular iodine, in the presence of a tertiary amine, quickly produces the corresponding isocyanides in high yields under ambient conditions. The process employs readily available and low-cost reagents, a convenient synthetic procedure, and mild reaction conditions for the synthesis of various alkyl and aryl isocyanides.

Full text of DOI:10.1055/s-0034-1379111

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 0049–0054
paper
49
X. Wang et al.
Paper
Synthesis
Synthesis of Isonitriles from N-Substituted Formamides Using
Triphenylphosphine and Iodine
Synthesis of Isonitriles under Mild Conditions
Xia Wang
Ph3P, I2, tertiary amine
CH2Cl2, r.t., 1–2 h
R
R
N
C
N
O
Qing-Gang Wang
Qun-Li Luo*
H
R = aryl, alkyl
14 examples, 78–90%
Key Laboratory of Applied Chemistry of Chongqing Municipality,
College of Chemistry and Chemical Engineering, Southwest
University, Chongqing 400715, P. R. of China
qlluo@swu.edu.cn
+
8
6
2
(
3
6
)
8
2
5
4
0
0
0
Received: 18.07.2014
Accepted after revision: 18.08.2014
Published online: 17.09.2014
formamides using acyl halides of group IV–VI elements in
the presence of a base as the dehydrating agent.5a Among
these dehydrating reagents, acyl halides of group IV ele-
ments, typically, phosgene and its related compounds, are
particularly efficacious, but their application is limited due
to their extreme toxicity and/or high costs.6 At the same
time, sulfonyl chlorides (which are acyl halides of group VI
elements) with low toxicity, are also efficient dehydrating
reagents in the presence of bases for the preparation of iso-
cyanides from formamides, but these reagents are mainly
used for the dehydration of N-alkyl-substituted formamides
rather than the N-aryl-substituted counterparts.7 Conse-
quently, a system utilizing phosphoryl trichloride and an
organic base is most commonly used.3c However, phosphor-
yl trichloride is a specific controlled hazardous substance
under a series of legal regulations in China8 and Japan.9 For
ordinary users in China, to obtain such reagents requires a
purchase license for highly toxic chemicals issued by the lo-
cal public security bureau. Therefore, efficient methods for
the preparation of isocyanides employing readily accessible
and cheap dehydrating reagents with low toxicity are at-
tractive.9,10 In our previous research,11 we found that N,N-
dimethylformamide (DMF) was not suitable for the amida-
tion of carboxylic acids promoted by trimethyl phosphite
and iodine, whereas N-methyl-2-pyrrolidone (NMP) gave
good results. During further examination of this observa-
tion, we found that the combination of triphenylphosphine
and iodine was an efficient dehydrating system toward for-
mamides, which could be used for the preparation of isocy-
anides under ambient conditions. This finding has led to the
development of a practical method for convenient access to
isonitriles by using inexpensive and readily available re-
agents of low toxicity.
DOI: 10.1055/s-0034-1379111; Art ID: ss-2014-f0453-op
Abstract Treatment of N-substituted formamides with the reagent
combination of triphenylphosphine and molecular iodine, in the pres-
ence of a tertiary amine, quickly produces the corresponding isocya-
nides in high yields under ambient conditions. The process employs
readily available and low-cost reagents, a convenient synthetic proce-
dure, and mild reaction conditions for the synthesis of various alkyl and
aryl isocyanides.
Key words isonitriles, formamides, dehydration, triphenylphosphine,
iodine
Isonitriles are very important functionalities in organic
synthesis due to the presence of an isocyano group with
ambiphilic reactivity, which enables them to react with
electrophiles, nucleophiles, and radicals.1 The diverse range
of transformations in which isocyanides participate have
covered multicomponent reactions, metal-catalyzed isocy-
anide insertions and polymerizations.2 Their important
synthetic utility encompasses the synthesis of complex am-
ides, polypeptides and glycopeptides of biological impor-
tance, the formation of substituted nitrogen-containing
heterocycles, and the enantioselective construction of chi-
ral heterocyclic compounds.3
Despite their wide range of utility in organic synthesis,
the commercial supply of isonitriles is relatively limited,
and only the simplest, unfunctionalized examples can be
purchased. In most cases, access to isonitriles relies heavily
on their preparation in the laboratory.4 Therefore, more
convenient methods for the preparation of isocyanides
would provide a solution to this problem. Reliable prepara-
tive routes to these compounds mainly include the dehy-
dration of formamides and the carbylamine reaction of
amines;5 the standard method involves the dehydration of
We began our studies on the dehydration of formamides
by using the combination of trimethyl phosphite and iodine
(Table 1). It was disclosed in previous research11 that the in
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X. Wang et al.
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Synthesis
Table 1 Dehydration of Formamides Promoted by Phosphorus(III) Compoundsa
H
O
N
NC
conditions
R
R
1a–c
2a–c
Entry
R
Conditionsb
Results
60%d
1c
2
4-MeO
4-MeO
4-MeO
4-Br
1a/P(OMe)3/I2/Et3N = 1:4.5:4.5:13.5 (added in portions), ice-bath to r.t., 4 h
1a/P(OMe)3/I2/DIPA = 1:3:3:9 (added in portions), ice-bath to r.t., 4 h
1a/P(OEt)3/I2/DIPEA = 1:2:2:6, ice-bath to r.t., 2 h
partial conversione
partial conversione
partial conversione
no reactione
3
4
1b/P(OMe)3/I2/DIPEA = 1:2:2:6, ice-bath to 30 °C, 24 h
1a/P(OMe)3/I2/DMAP = 1:2:2:6, ice-bath to r.t., 2.5 h
1c/P(OMe)3/I2/Et3N = 1:2:2:6, ice-bath to r.t., 12 h
5
4-MeO
2-O2N
4-MeO
6
no reactione
7c
1a/Ph3P/I2/Et3N = 1:1.5:1.5:3, r.t., 1 h
90%d
a Formamide 1 (0.1 mmol) was used unless otherwise stated.
b DIPA = diisopropylamine; DIPEA = N,N-diisopropylethylamine; DMAP = 4-(N,N-dimethylamino)pyridine.
c Formamide 1a (1 mmol) was used.
d Yield of isolated product.
e Monitored by thin-layer chromatography (TLC).
situ reaction of trialkyl phosphites and iodine formed alkyl
iodophosphates, which were efficient activating reagents
for the carboxyl group. However, the carboxyl activation did
not occur in N,N-dimethylformamide, whereas N-methyl-2-
pyrrolidone and other common organic solvents gave good
results.11 We deduced that the deactivation of iodophos-
phates in N,N-dimethylformamide resulted from the reac-
tion of the iodophosphate with the formamide. In addition,
chlorophosphate compounds are known to be efficient re-
agents for the dehydration of formamides.9 Thus, we hoped
that the combination of trimethyl phosphite and iodine
could be used as a dehydrating system for the preparation
of isonitriles. When N-(4-methoxyphenyl)formamide (1a,
R = OMe) or N-(4-bromophenyl)formamide (1b, R = Br) was
employed as the substrate, the dehydration took place (Ta-
ble 1, entries 1–4), but the conversions were incomplete,
even with an excess of the dehydrating system (Table 1, en-
try 1). Improved results could not be obtained despite at-
tempting several optimization experiments (Table 1, en-
tries 2–6). We speculate that a possible reason behind this
lack of reactivity lay in the fact that the alkyl iodophos-
phates were unstable in the present reaction system and
were inclined to undergo rapid conversion into the inactive
form(s), which led to incomplete conversion of the sub-
strate. We then turned to the combination of triphenyl-
phosphine and iodine as the reagents. Fortunately, this
combination was very efficient (Table 1, entry 7). Interest-
ingly, the dehydration of formamides promoted by triphen-
ylphosphine and carbon tetrachloride (CCl4) (halohydrocar-
bon solvent, 60 °C, 2.5 h) has been reported previously,10c
but there are no related studies on the use of triphenyl-
phosphine and iodine, although the latter is faster and more
convenient (see below).
We next examined the dehydration of N-(4-bromophe-
nyl)formamide (1b) as a model system to optimize the reac-
tion conditions. As shown in Table 2, the reactions in many
of the common aprotic solvents, such as halohydrocarbons,
ether and hydrocarbon, generated isonitrile 2b in good to
excellent yields (Table 2, entries 2–6). However, when the
dehydration was conducted in N,N-dimethylformamide,
only a trace amount of the product was observed (Table 2,
entry 1). Among the tested solvents, dichloromethane gave
the best performance (Table 2, entry 6). Therefore, dichloro-
methane was the solvent of choice for further investiga-
tions. Screening the base indicated that the dehydration re-
action could be accomplished with common organic bases
(Table 2, entries 6–11), but not with inorganic bases (Table
2, entries 12–14). Among the tested common organic bases,
tertiary amines such as triethylamine and N,N-diisopropyl-
ethylamine proved to be superior (Table 2, entries 6 and 7
vs 8–11). Therefore, we established optimized conditions
for the dehydration of formamides using the combination
of triphenylphosphine and iodine for the preparation of iso-
nitriles. The reaction was complete within one hour in di-
chloromethane using triphenylphosphine (1.5 equiv) and
iodine (1.5 equiv) in the presence of triethylamine or N,N-
diisopropylethylamine (3.0 equiv) at room temperature.
Under the optimized conditions, the substrate scope of
our protocol was examined. The results, which are summa-
rized in Scheme 1, demonstrate the generality of this meth-
od. A wide range of N-aryl- and N-alkyl-substituted forma-
mides were quickly converted into the expected isonitriles
in good to excellent yields. N-Aryl-substituted substrates
containing an electron-withdrawing or an electron-donat-
ing group on the benzene ring gave good results. Various
functional groups, such as ether, halo, nitro, ester, and
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X. Wang et al.
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Synthesis
Table 2 Optimization of the Reaction Conditions for the Dehydration
of N-(4-Bromophenyl)formamide (1b)a
Ph3P, I2 , Et3N
R
R
N
C
N
H
1a–n
O
CH2Cl2, r.t., 1 ha
2a–n
Ph3P, I2, base
Br
NC
Br
NHCHO
solvent, r.t., time
NC
NC
NC
1b
Solvent
2b
NO2
Yieldb
MeO
Br
Entry
Base
Time
2b 90%
2c 84%
2a 90%
2d 90%
2g 85%
1
DMF
Et3N
Et3N
5 h
5 h
5 h
8 h
1 h
1 h
1 h
1 h
5 h
5 h
4 h
5 h
5 h
5 h
trace
80%
84%
82%
84%
90%
87%
69%
56%
52%
60%
NC
NC
NC
2c
3c
4
THF
CHCl3
toluene
DCE
Et3N
EtO2C
BnO
2f 86%
Et3N
2e 83%
5
Et3N
NC
NC
NC
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et3N
O2N
Cl
7
DIPEA
DIPA
Cl
2i 79%
8
2h 86%
9
DBU
NC
O2N
NC
NC
10
11
12
13
14
DABCO
DMAP
KOH
O2N
OMe
2l 82%
2j 86%
2k 82%
no reaction
no reaction
no reaction
NC
K2CO3
Na2CO3
NC
FmocHN
BocHN
2m 89%b
2n 78% (2 h)b
a Reaction conditions: 1b (1.0 mmol), Ph3P (1.5 mmol), I2 (1.5 mmol), base
(3.0 mmol), solvent (3 mL), r.t. (unless otherwise stated).
b Yield of isolated product.
Scheme 1 Substrate scope for the preparation of isonitriles via the de-
hydration of formamides using the combination of triphenylphosphine
and iodine. a Reagents and conditions: 1 (1 mmol), Ph3P (1.5 mmol), I2
(1.5 mmol), Et3N (3 mmol), CH2Cl2 (3 mL), unless noted otherwise. The
products were purified on silica gel. b Conditions as above, but with
DIPEA (3 mmol) as the base instead of Et3N
c Ph3P (2.0 mmol), I2 (2.0 mmol) and Et3N (4.0 mmol) were employed.
alkoxycarbonylamino, were only slightly affected under
these conditions. The positional isomers of substituted N-
phenylformamides afforded the expected products in simi-
lar yields (Scheme 1, 2c vs 2i and 2j, and 2g vs 2h). Other o-
mono and o,o-disubstituted N-phenylformamides also gave
good results (2k and 2l), which indicated that steric effects
adjacent to the formamido group did not significantly affect
the progress of the reactions.
It should be noted that the dehydrations of both acid-
and alkali-sensitive substrates produced the expected iso-
nitriles in good yields, without the side-chain protecting
groups being affected (2m and 2n). Due to the fact that
most syntheses of isonitriles take place under alkaline con-
ditions, related examples containing an alkali-sensitive
group are rare.9,10a Accordingly, Sureshbabu et al. reported
that substrates containing an alkali-sensitive 9-fluorenyl-
methyloxycarbonylamino (FmocNH) moiety could be dehy-
drated using the Burgess reagent in dichloromethane at re-
flux temperature under neutral reaction conditions.10a They
pointed out that the methods employing phosphorus(V)
oxychloride/pyridine and triphenylphosphine/carbon tetra-
chloride did not produce satisfactory results. Compared
with Sureshbabu’s method, our protocol did not require an
expensive water-sensitive reagent, or a heating device,
since our reactions were conducted at room temperature
and used reagents that were stable toward moisture. More-
over, the combined cost of triphenylphosphine and iodine is
less than 10% that of the Burgess reagent,12 whereas the de-
hydrating efficiency of our approach was equivalent to that
of Sureshbabu’s method. In addition, Kitano’s method for
isonitrile synthesis gave good results with acid- and alkali-
sensitive substrates using chlorophosphate compounds as
the dehydrating reagent,9 however, chlorophosphate com-
pounds are not as stable as triphenylphosphine and iodine
toward moisture, which is disadvantageous when storing
reagents.
Gratifyingly, when analytical grade dichloromethane
was employed (as received commercially), the reaction
yields were of no significant difference. Moreover, purifica-
tion of the products was very simple (column chromatogra-
phy); even the purification of relatively highly polar 2m
could be achieved easily using polar dichloromethane as the
eluent. Removal of the triphenylphosphine oxide by-prod-
uct from reactions which employ triphenylphosphine is of-
ten troublesome. However, in our case, all the target com-
pounds were easily separated from polar triphenylphos-
phine oxide due to the fact that isocyanides are of relatively
low polarity.
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X. Wang et al.
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Synthesis
H
N
1b
Ar
CHO
O
H
PPh3
I2
Et3N
Et3N
I
I
1b
I
PPh3
I
I
Ar NC
2b
N
Ph3P
PPh3
CDCl3
Ar
A
B
δP −4.25 ppm
Ph3PO + Et3N•HI
Et3N•HI
C
δ
P −16.4 ppm
δ
P 43.8 ppm
Ar = 4-BrC6H4
δ
P 29.8 ppm
Scheme 2 Postulated pathway for the synthesis of an isonitrile mediated by triphenylphosphine
To establish the mechanism of the current process we
used 31P NMR spectroscopy to monitor the progress of the
reaction. As shown in Scheme 2, the 31P NMR signal of
triphenylphosphine appeared at δ = –4.25 in deuterochloro-
form. When an equimolar amount of iodine was added to
the solution, a signal appeared at δ = –16.4, which was due
to the ‘spoke’ species A.13a When formamide 1b was intro-
duced into the mixture, this signal was slightly shifted to
δ = –14.0, and a new minor signal appeared at δ = 43.8.
Bricklebank et al. investigated the reaction of triphenyl-
phosphine with iodine in detail in deuterochloroform; they
revealed that the chemical shift of the ionic structure,
[Ph3PI]+, appeared at δ = 44.8 and was mostly not affected
by its counterions.13b Thus, we speculated that the signal at
δ = 43.8 resulted from complex B or from similar structures,
in which the key structural feature was a [Ph3PI]+ cation,
and the addition of formamide 1 accelerated the ionization
of the ‘spoke’ species A to form the ionic complex B.13b,c Af-
ter triethylamine had been added, the signal at δ = –14.0
shifted to δ = –16.5, and that at δ = 43.8 quickly disap-
peared. At the same time, a new resonance appeared at δ =
29.8, which was assigned to triphenylphosphine oxide. The
addition of triethylamine gradually weakened the intensity
of the signal at δ = –16.5 and simultaneously led to an in-
crease in the intensity of the signal at δ = 29.8. After five
hours at room temperature, no further perceptible change
was observed in the 31P NMR spectrum. This observation
was consistent with the consumption of formamide 1b
along with the formation of isonitrile 2b and triphenyl-
phosphine oxide, which was monitored by TLC. Thus, the
formation of isonitrile 2b was presumed to occur via α-
elimination of a proton and triphenylphosphine oxide from
intermediate phosphonium salt C with the aid of a base,
similar to the triphenylphosphine/carbon tetrachloride me-
diated mechanism proposed by Appel et al.10c Bae and co-
workers investigated the synthesis of O6-(benzotriazol-1-
yl)inosine nucleosides promoted by the reagent combina-
tion of triphenylphosphine and iodine. They proved that the
signal due to the nucleoside phosphonium salt appeared at
δ = 66.2.13d However, the 31P NMR spectroscopic signal of
phosphonium salt intermediate C was not observed in our
system, which is most possibly due to its low concentration.
In conclusion, the dehydration of various N-substituted
formamides with the reagent combination of triphenyl-
phosphine and molecular iodine afforded smoothly the cor-
responding isocyanides in high yields. Electronic effects and
steric hindrance resulting from substituents on the aromat-
ic ring did not affect significantly the progress of these re-
actions. Both acid- and alkali-sensitive substrates produced
the expected isonitriles in good yields without the side-
chain protecting groups being affected. We believe that this
method represents a mild, convenient, efficient and cost-
effective route to prepare various isocyanides.
Commercially available reagents were used as received. Formamides
1a, 1b, 1d, 1g and 1h were prepared using the direct formic acid ami-
dation method,14a formamides 1c, 1i and 1j were obtained using ZnO-
catalyzed formic acid amidation,14b formamides 1e, 1f and 1l were
synthesized via ethyl formate amidation,9 and formamide 1k was pre-
pared using the mixed anhydride method.14c Formamides 1m and 1n
were prepared according to the literature.14d All solvents for chro-
matographic separations were distilled before use. Petroleum ether
(PE) refers to the fraction boiling in the 60–90 °C range. Column chro-
matography was carried out using Haiyang 200–300 mesh silica gel
(Qingdao, China). FT-IR spectra (wavelength range = 4000–400 cm–1
were obtained using Bruker TENSOR-27 FT-IR Spectrometer
)
a
(Bruker). Samples were prepared as KBr pellets. 1H and 13C NMR spec-
tra were recorded on Bruker 300 MHz or 600 MHz spectrometers at
293 K. Chemical shifts (δ) were internally referenced to the residual
solvent signals (CDCl3 at 7.26 ppm for 1H, and at 77.00 ppm for 13C)
relative to tetramethylsilane. Data are reported as follows: multiplici-
ty (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad, br s = broad singlet), coupling constant(s) (Hz), integration. The
structures of all the known products were confirmed by comparison
with the spectroscopic data of authentic samples. The yields in Table
2 and Scheme 1 refer to those of isolated products (average of two
runs).
Isocyanides 2; General Procedure
To a stirred solution of formamide 1 (1.0 mmol) and I2 (381 mg, 1.5
mmol) in CH2Cl2 (3 mL) was added Ph3P (394 mg, 1.5 mmol), followed
by the dropwise addition of Et3N (415 μL, 301 mg, 3 mmol). The mix-
ture was stirred at r.t. until the consumption of the formamide was
complete (TLC monitoring, typically 1 h), and then diluted with
CH2Cl2 (10 mL) and washed with ice-cold sat. aq Na2S2O3 solution (10
mL). The aq phase was extracted with CH2Cl2 (2 × 10 mL). Each por-
tion of the organic phase was sequentially washed with deionized
H2O (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and fil-
tered. The combined organic phase was concentrated under reduced
pressure and purified by column chromatography (silica gel, typically
PE as the eluent) to give the corresponding isocyanide 2. Any devia-
tions from this procedure are noted in Table 2 and Scheme 1.
4-Methoxyphenyl Isocyanide (2a)10b
Yield: 119 mg (90%); brown oil.
IR (KBr): 2125 (s) cm–1
.
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X. Wang et al.
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Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.19 (d, J = 8.7 Hz, 2 H), 6.78 (d, J = 8.9
Hz, 2 H), 3.72 (s, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.47 (dd, J = 7.9 Hz, 1.3 Hz, 1 H), 7.42
(dd, J = 7.6 Hz, 1.3 Hz, 1 H), 7.39–7.26 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 162.4 (t, J = 5.8 Hz), 159.4, 127.2, 118.8
(t, J = 14.9 Hz), 114.1, 55.1.
13C NMR (75 MHz, CDCl3): δ = 168.9 (br), 130.6, 130.2, 130.0, 127.8,
127.4, 125.3 (t, J = 15.4 Hz).
4-Bromophenyl Isocyanide (2b)15a
4-Nitrophenyl Isocyanide (2i)10b
Yield: 164 mg (90%); white amorphous solid.
Yield: 117 mg (79%); white amorphous solid.
IR (KBr): 2125 (m) cm–1
.
IR (KBr): 2130 (s) cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.53 (d, J = 8.6 Hz, 2 H), 7.25 (d, J = 8.4
1H NMR (300 MHz, CDCl3): δ = 8.29 (d, J = 8.9 Hz, 2 H), 7.58 (d, J = 8.8
Hz, 2 H).
Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 165.8 (t, J = 6.2 Hz), 132.6, 127.8, 125.4
(t, J = 13.8 Hz), 123.3.
13C NMR (151 MHz, CDCl3): δ = 170.0 (br), 147.6, 131.3 (t, J = 12.0 Hz),
127.5, 125.0.
2-Nitrophenyl Isocyanide (2c)15b
3-Nitrophenyl Isocyanide (2j)15d
Yield: 124 mg (84%); yellow amorphous solid.
Yield: 127 mg (86%); white amorphous solid.
IR (KBr): 2125 (w) cm–1
.
IR (KBr): 2142 (m) cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.11 (dd, J = 1.4 Hz, 8.2 Hz, 1 H), 7.73
(dt, J = 1.3 Hz, 7.7 Hz, 1 H), 7.67–7.57 (m, 2 H).
1H NMR (300 MHz, CDCl3): δ = 8.28 (d, J = 8.1 Hz, 1 H), 8.22 (s, 1 H),
7.74 (d, J = 8.0 Hz, 1 H), 7.66 (t, J = 8.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 173.8 (br), 144.1 (br), 134.2, 130.1,
129.8, 125.5, 120.9 (t, J = 16.9 Hz).
13C NMR (75 MHz, CDCl3): δ = 167.6 (br), 148.2, 132.1, 130.6, 127.1 (t,
J = 11.9 Hz), 124.1, 121.5.
4-Methylphenyl Isocyanide (2d)15c
2,6-Dimethylphenyl Isocyanide (2k)14c
Yield: 105 mg (90%); brown oil.
Yield: 108 mg (82%); white amorphous solid.
IR (KBr): 2125 (s) cm–1
.
IR (KBr): 2122 (s) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.25 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 8.2
1H NMR (600 MHz, CDCl3): δ = 7.18 (t, J = 7.6 Hz, 1 H), 7.09 (d, J = 7.6
Hz, 2 H), 2.37 (s, 3 H).
Hz, 2 H), 2.42 (s, 6 H).
13C NMR (151 MHz, CDCl3): δ = 163.5 (t, J = 5.6 Hz), 139.6, 129.9,
126.1, 124.1 (t, J = 13.5 Hz), 21.2.
13C NMR (151 MHz, CDCl3): δ = 167.8 (br), 134.8, 128.6, 127.7, 126.7
(t, J = 12.9 Hz), 18.8.
4-Benzyloxyphenyl Isocyanide (2e)9
2-Methoxy-4-nitrophenyl Isocyanide (2l)9
Yield: 174 mg (83%); pale yellow amorphous solid.
Yield: 146 mg (82%); light yellow amorphous solid.
IR (KBr): 2125 (s) cm–1
1H NMR (600 MHz, CDCl3): δ = 7.45–7.38 (m, 4 H), 7.38–7.33 (m, 1 H),
7.31 (d, J = 8.9 Hz, 2 H), 6.94 (dt, J = 8.9 Hz, 2.6 Hz, 2 H), 5.08 (s, 2 H).
13C NMR (150.9 MHz, CDCl3): δ = 163.0 (br), 159.0, 136.1, 128.7,
128.3, 127.7, 127.4, 119.8 (t, J = 13.4 Hz), 115.5, 70.4.
.
1H NMR (300 MHz, CDCl3): δ = 7.86 (dd, J = 8.9 Hz, 2.1 Hz, 1 H), 7.84
(br s, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 4.05 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 173.0 (br s), 155.5, 148.4, 128.1, 121.1
(t, J = 14.4 Hz), 115.8, 107.1, 56.8.
tert-Butyl (2-Isocyanoethyl)carbamate (2m)15e
Ethyl 4-Isocyanobenzoate (2f)15a
The product was purified by column chromatography on silica gel
[PE→PE–EtOAc, 80:20 (v/v)].
Yield: 151 mg (86%); pale brown amorphous solid.
Yield: 151 mg (89%); light yellow oil.
IR (KBr): 2128 (s) cm–1
1H NMR (600 MHz, CDCl3): δ = 8.07 (dt, J = 8.7 Hz, 2.0 Hz, 2 H), 7.43 (d,
J = 8.6 Hz, 2 H), 4.39 (q, J = 7.1 Hz, 2 H), 1.39 (t, J = 7.1 Hz, 3 H).
.
IR (KBr): 2150 (s) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 5.15 (s, 1 H), 3.49 (br s, 2 H), 3.34 (br s,
2 H), 1.42 (s, 9 H).
13C NMR (151 MHz, CDCl3): δ = 157.4 (br), 155.6, 80.0, 41.9 (t, J = 5.9
13C NMR (151 MHz, CDCl3): δ = 167.2 (br), 164.9, 131.3, 130.8, 129.9
(t, J = 13.1 Hz), 126.4, 61.5, 14.2.
Hz), 39.7, 28.2.
4-Chlorophenyl Isocyanide (2g)15a
(9H-Fluoren-9-yl)methyl (2-Isocyanoethyl)carbamate (2n)10a
Yield: 117 mg (85%); white solid.
The product was purified by column chromatography on silica gel
(PE→CH2Cl2).
IR (KBr): 2128 (s) cm–1
1H NMR (300 MHz, CDCl3): δ = 7.41–7.26 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 165.4 (br), 135.2, 129.6, 127.5, 124.8 (t,
J = 13.3 Hz).
.
Yield: 228 mg (78%); white amorphous solid.
IR (KBr): 2152 (m) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.78 (d, J = 7.5 Hz, 2 H), 7.59 (d, J = 7.4
Hz, 2 H), 7.41 (t, J = 7.4 Hz, 2 H), 7.33 (t, J = 7.4 Hz, 2 H), 5.42 (s, 1 H),
4.44 (d, J = 6.8 Hz, 2 H), 4.22 (t, J = 6.8 Hz, 1 H), 3.51 (t, J = 4.6 Hz, 2 H),
3.44–3.39 (m, 2 H).
2-Chlorophenyl Isocyanide (2h)15d
Yield: 118 mg (86%); white solid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 49–54

54
X. Wang et al.
Paper
Synthesis
13C NMR (151 MHz, CDCl3): δ = 157.7 (t, J = 11.3 Hz), 156.2, 143.6,
141.2, 127.7, 127.0, 124.9, 119.9, 66.9, 47.1, 41.7 (t, J = 5.3 Hz), 40.1.
(6) Obrecht, R.; Herrmann, R.; Ugi, I. Synthesis 1985, 400.
(7) Karl, R.; Lemmen, P.; Ugi, I. Synthesis 1989, 718.
(8) For example, POCl3 is included in the List of Hazardous Chemi-
cals issued by the Chinese State Administration of Work Safety
as well as the Highly Toxic Chemicals Directory jointly issued by
eight ministries of the Chinese Government.
Acknowledgment
(9) Kobayashi, G.; Saito, T.; Kitano, Y. Synthesis 2011, 3225.
(10) (a) Sureshbabu, V. V.; Narendra, N.; Nagendra, G. J. Org. Chem.
2009, 74, 153. (b) Porcheddu, A.; Giacomelli, G.; Salaris, M.
J. Org. Chem. 2005, 70, 2361. (c) Appel, R.; Kleinstück, R.; Ziehn,
K.-D. Angew. Chem., Int. Ed. Engl. 1971, 10, 132.
The authors thank the National Natural Science Foundation of China
(No. 20971105) and the Fundamental Research Funds for the Central
Universities (XDJK2012B011) for financial support.
Supporting Information
(11) Luo, Q.-L.; Lv, L.; Li, Y.; Tan, J.-P.; Nan, W.; Hui, Q. Eur. J. Org.
Chem. 2011, 6916.
(12) Price ratios are based on the amount of 25 g from the current
J&K Scientific Catalog in China, calculated from the price per
mole of each reagent. Price ratios calculated from other com-
mercial chemicals catalogs were similar.
(13) (a) Godfrey, S. M.; Kelly, D. G.; McAuliffe, C. A.; Mackie, A. G.;
Pritchard, R. G.; Watson, S. M. J. Chem. Soc., Chem. Commun.
1991, 1163. (b) Bricklebank, N.; Godfrey, S. M.; Mackie, A. G.;
McAuliffe, C. A.; Pritchard, R. G.; Kobryn, P. J. J. Chem. Soc.,
Dalton Trans. 1993, 101. (c) Núñez, R.; Farràs, P.; Teixidor, F.;
Viñas, C.; Sillanpää, R.; Kivekäs, R. Angew. Chem. Int. Ed. 2006,
45, 1270; and references therein. (d) Bae, S.; Lakshman, M. K.
J. Org. Chem. 2008, 73, 1311.
(14) (a) Bandgar, B. P.; Kinkar, S. N.; Chobe, S. S.; Mandawad, G. G.;
Yemul, O. S.; Dawane, B. S. Arch. Appl. Sci. Res. 2011, 3, 246.
(b) Hosseini-Sarvari, M.; Sharghi, H. J. Org. Chem. 2006, 71,
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4270. (d) Wang, W.-h.; Zhang, T.; Xu, P. J. Chin. Pharm. Sci. 2003,
12, 66.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379111.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 49–54