A convenient method for the preparation of benzyl isocyanides

Article abstract of DOI:10.1055/s-2005-918517

Treatment of benzyl halides with silver salts (AgClO₄, AgBF ₄, or AgOTf) and trimethylsilyl cyanide (TMSCN) in CH ₂Cl₂ followed by cleavage of the carbon-silicon bond with aqueous NaHCO₃ or TBAF directly afforded the corresponding isocyanides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918517

PAPER
405
A Convenient Method for the Preparation of Benzyl Isocyanides
Preparation of
B
en
o
zyl Isocyanid
s
es hikazu Kitano,* Tetsuya Manoda, Teppei Miura, Kazuhiro Chiba, Masahiro Tada
Laboratory of Bio-organic Chemistry, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan
Fax +81(42)3608830; E-mail: kitayo@cc.tuat.ac.jp
Received 4 July 2005; revised 5 August 2005
1) TMSCN, AgX
Br
NC
Abstract: Treatment of benzyl halides with silver salts (AgClO4,
AgBF4, or AgOTf) and trimethylsilyl cyanide (TMSCN) in CH2Cl2
followed by cleavage of the carbon–silicon bond with aqueous
NaHCO3 or TBAF directly afforded the corresponding isocyanides.
2) TBAF or aq. NaHCO3
t-Bu
t-Bu
2
1a
Scheme 1
Key words: benzyl isocyanides, benzyl halides, silver salts, tri-
methylsilyl cyanide, perchlorate
Table 1 Reactions of 4-tert-Butylbenzyl Bromide (1a) with
TMSCN and AgX
The versatility of isocyanide is well known because it is
an important reactant for Passerini1 and Ugi2 multi-com-
ponent reactions3 and has the ability to function as a bond-
ing partner for metals in complexes.3a In addition, it is also
noteworthy that various biologically active isocyanides
have been isolated4 and synthesized.5 Isocyanides are
commonly prepared by the dehydration of formamides.3,6
However, this method is not necessarily convenient, since
preparing the formamide, including getting the precursor,
is difficult in many cases. Therefore, the development of
other simple, efficient methods to prepare isocyanides is
very important. Recently, we reported methods for pre-
paring tertiary isocyanides from alcohols7 and alkenes8
with Lewis acid and TMSCN. In addition, it is known that
1-isocyanoadamantane was synthesized from 1-haloada-
mantane with Lewis acid and TMSCN.7a,9 However, these
methods are only limited to the synthesis of tertiary isocy-
anides. During the course of our investigation on conve-
nient isocyanide synthesis, we found a new method to
prepare benzyl isocyanides. We describe herein a direct
conversion method for preparing benzyl isocyanides from
benzyl halides by using silver salts and TMSCN.
Entry
Reagent
AgClO4
AgBF4
AgOTf
Time (h)
Yield (%)a
99 (92)b
98
1
2
3
1
1
17
98
a Determined by GC analysis.
b Isolated yield.
Scheme 2 and Table 2 present the results of the reaction of
4-tert-butylbenzyl chloride (1b) and 4-tert-butylbenzyl
alcohol (1c) with TMSCN and AgClO4. These results
show that 2 was also obtained from the corresponding
benzyl chloride 1b as well as bromide 1a in good yield,
but the reaction time was longer and the yield was lower
than in the case of 1a. On the other hand, benzyl alcohol
1c was not affected under this condition. It has been re-
ported that benzyl gem-difluorides and trifluoride were
obtained from the corresponding gem-dichlorides and
10
trichloride by halogen exchange with AgBF4 and that
benzyl nitriles were prepared from the corresponding ben-
zyl chlorides with TMSCN and TiCl411 or the correspond-
ing benzyl bromides with TMSCN and TBAF.12
However, neither of the corresponding benzyl fluoride
and benzyl cyanide was observed under the conditions in
Schemes 1 and 2 and Tables 1 and 2.
The results for the reaction of 4-tert-butylbenzyl bromide
(1a) with TMSCN and silver salts (AgX) followed by
treatment with TBAF or aqueous NaHCO3 are summa-
rized in Scheme 1 and Table 1. The reactions were carried
out in CH2Cl2 with 1.5 equivalents each of AgX and
TMSCN; then, TBAF or aqueous NaHCO3 was added to
the reaction mixture as a reagent for the cleavage of the
carbon–silicon bond. 4-tert-Butylbenzyl isocyanide (2)
was obtained in excellent yields with AgClO4, AgBF4, or
AgOTf as a Lewis acid. This is similar to the case of pre-
paring isocyanide from tertiary alcohol.7b Zinc salts, such
as ZnI2, ZnBr2, or ZnCl2 was not used as a Lewis acid here
1) TMSCN, AgClO4
Y
NC
2) TBAF
t-Bu
t-Bu
1
2
Scheme 2
to obtain the desired isocyanide, in contrast to the case of Scheme 3 and Table 3 display the results of the reactions
tertiary alcohol.7a
of various benzyl bromides, which have a substituent at
the 4-position, with TMSCN and AgClO4. Each gave
good yields of the corresponding isocyanides. The desired
conversion was not affected by the halogen and acyloxy
substituents on the ring (Table 3, entries 1–3). On the oth-
er hand, substrates having an alkoxy group as a substitu-
SYNTHESIS 2006, No. 3, pp 0405–0410
Advanced online publication: 21.12.2005
DOI: 10.1055/s-2005-918517; Art ID: F11305SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
6

406
Y. Kitano et al.
PAPER
Table 2 Reactions of 4-tert-Butylbenzyl Derivatives 1 with
Table 3 Reactions of Benzyl Bromides with TMSCN and AgClO4
TMSCN and AgClO4
Entrya
Substrate
R
Product
4a
Yield (%)b
Entrya
Substrate
Y
Time (h)
Yield (%)b
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
Br
63
55
71
68
52
40
1
2
3
1a
1b
1c
Br
Cl
OH
1
17
18
99
61
Cl
4b
BzO
4c
c
–
MeO2CCH2
N(Et)Bz
succinimide
4d
a All reactions were carried out at r.t. with 1.5 equiv each of TMSCN
and AgClO4 under argon.
4e
b Determined by GC analysis.
c Not determined.
4f
a All reactions were carried out at r.t. for 1 h with 3.0 equiv each of
TMSCN and AgClO4 under argon.
ent, like 4-methoxybenzyl or 4-benzyloxybenzyl
bromides, afforded messy products (data not shown). En-
try 4 shows the result of a substrate which possesses a car-
boxylic methyl ester through a carbon chain between
benzene and the carbonyl group. The corresponding iso-
cyanide was obtained in good yield, and the carboxylic
methyl ester substituent was hardly affected under this
condition. However, the reaction of the substrate with the
carboxyl group directly as a substituent of benzene, which
is the (4-bromomethyl)benzoic acid methyl ester, never
proceeded under this condition. In addition, the nitroben-
zene derivative, which is (4-bromomethyl)nitrobenzene,
was never affected under the same condition (data not
shown). These results suggest that electron-withdrawing
substituents reduce the reactivity of this reaction. In the
case of the nitrogen functional group, which includes N-
alkylamide and imide substituents, the desired benzyl iso-
cyanides were obtained in good yields (Table 3, entries 5
and 6). However, the reaction of benzyl bromides, which
have amine and NH-amide as a substituent, afforded
messy product mixtures (data not shown). In all entries,
the observed main byproduct was the corresponding ben-
zyl alcohol that could be generated by the decomposition
of an intermediate.
b Isolated yield.
t-Bu
t-Bu
1) TMSCN, AgClO4
2) aq NaHCO3
90%
Br
NC
t-Bu
t-Bu
5
6
Scheme 4
1) TMSCN, AgClO4
Br
NC
2) aq NaHCO3
61%
MeO
MeO
NO2
NO2
7
8
Scheme 5
In order to elucidate an intermediate, a similar reaction of
1
1a was carried out in CDCl3, and H NMR was then ob-
served before adding TBAF or aqueous NaHCO3. The 1H
NMR spectrum of the intermediate was evidently differ-
ent from the simple mixture of 2 and AgClO4. In addition,
a singlet signal for 9 H, which does not belong to either
TMS or TMSCN, was observed in the 1H NMR spectrum.
This result suggests that an ionic compound 9, which has
the TMS group, exists as the intermediate in the reaction
mixture as well as in the case of the synthesis of tertiary
isocyanides.7b The reaction mechanism including the in-
termediate 9 is proposed in Scheme 6. The benzyl isocya-
1) TMSCN, AgClO4
2) aq NaHCO3
Br
NC
R
R
3
4
Scheme 3
The results for the reaction of benzyl bromides with two nide 2 was finally synthesized by the dissociation of the
substituents are displayed in Schemes 4 and 5. 3,5-Di- carbon–silicon bond.
tert-butylbenzyl bromide (5) afforded the corresponding
benzyl isocyanide 6 in high yield. In addition, 4-methoxy-
N
C
TMS
NC
Br
3-nitrobenzyl bromide (7) also afforded the correspond-
ing benzyl isocyanide 8 in good yield, although the meth-
oxy and nitro groups were included as substituents. These
results suggest that the number and position of substitu-
ents do not affect the proceeding of the reaction in the case
of the alkyl group and the reactivity depends on and varies
according to the combination of substituents when hetero
atom functional groups are included.
TMSCN
AgClO4
Z
hydrolysis
Z = ClO4 or Br
t-Bu
t-Bu
t-Bu
1a
9
2
Scheme 6
Synthesis 2006, No. 3, 405–410 © Thieme Stuttgart · New York

PAPER
Preparation of Benzyl Isocyanides
407
Mps were determined on a Mel-Temp (Laboratory Device) and are
uncorrected. NMR spectra were obtained in CDCl3 on a Jeol AL-
400 or alpha-600 spectrometer. All 1H NMR spectra are reported in
ppm relative to TMS. All 13C NMR spectra are reported in ppm rel-
ative to the central line of the triplet for CDCl3 at 77.03 ppm. IR
spectra were recorded on a Jeol Winspec-50 spectrometer. Low-
and high-resolution mass spectra were recorded on a JEOL SX-
102A spectrometer under the ionization condition (70 eV). GC
analyses were carried out on a Hewlett Packard HP 4980A fitted
with an HP-5 column (10 m × 0.53 mm i.d.). Chromatographic sep-
arations were carried out on a silica gel column (Fuji Silysia Chem-
ical BW-127ZH; 100–270 mesh) unless otherwise stated.
It has been reported that the reaction of alky iodides with
silver perchlorate affords the corresponding alkyl per-
chlorates.13 In order to further investigate the reaction
mechanism, a reaction of 3c with only AgClO4 was per-
formed. Although strict isolation was impossible because
of the instability, the generation of the corresponding ben-
1
zyl perchlorate 10 was suggested by H NMR analysis.
Then, the addition of TMSCN to the CH2Cl2 solution of
the perchlorate 10 gave the corresponding isocyanide 4c.
On the other hand, the corresponding alcohol 11 was ob-
tained when aqueous NaHCO3 was added to the CH2Cl2
solution of 10. This could be the reason that the corre-
sponding alcohols were obtained as the main byproduct in
4-Benzoyloxybenzyl Bromide (3c)14
Prepared from 4-hydroxybenzaldehyde as follows. First, 4-benzyl-
this reaction. These results suggest that the desired benzyl oxybenzyl alcohol, which was the precursor of 3c, was synthesized
by esterification of phenol with BzCl and in the presence of pyridine
followed by reduction of the aldehyde with NaBH4. Then, 3c was
obtained from the precursor by bromination of alcohol with PBr3
(1.2 equiv); white solid; yield: 78%; mp 108–109 °C.
isocyanides are obtained via the generation of the corre-
sponding perchlorate, as shown in Scheme 7.
NC
IR (KBr): 3089, 3070, 2977, 1724, 1592, 1508, 1452, 1313, 1278,
Br
OClO3
887, 713, 673, 595 cm–1.
BzO
BzO
TMSCN
1H NMR (600 MHz): d = 8.23–8.18 (m, 2 H), 7.67–7.62 (m, 1 H),
7.56–7.49 (m, 2 H), 7.49–7.43 (m, 2 H), 7.22–7.18 (m, 2 H), 4.52
(s, 2 H).
13C NMR (100.4 MHz): d = 164.77, 150.68, 135.68, 133.23,
130.11, 130.03, 129.17, 128.45, 121.96, 32.81.
4c
11
AgClO4
OH
hydrolysis
BzO
3c
BzO
10
LRMS (EI): m/z (%) = 290 (M+, 3), 211 (54), 105 (100), 77 (38).
HRMS (EI): m/z calcd for C14H11BrO2 [M+]: 289.9942; found:
289.9951.
Scheme 7
4-(Bromomethyl)phenylacetic Acid Methyl Ester (3d)15
Prepared from 4-(Bromomethyl)phenylacetic acid (1.0 g, 4.09
mmol) according to a Mitsunobu reaction in MeOH with Ph3P (1.2
equiv) and DIAD (1.2 equiv); yield: 71%.
1H NMR (600 MHz): d = 7.31–7.28 (2 H, m), 7.18–7.15 (2 H, m),
4.39 (2 H, s), 3.65 (3 H, s), 3.55 (2 H, s).
Scheme 8 shows the result of the reaction for secondary
benzyl bromide 12. The desired benzyl isocyanide 13 was
obtained in 79% yield with 13% of the corresponding ni-
trile 14 when the reaction was carried out for 1 hour. How-
ever, as the reaction time became longer, the amount of
the isocyanide 13 was reduced. Finally, the total product
was nitrile 14 after the reaction had been carried out for 24
13C NMR (150.8 MHz): d = 171.36, 136.43, 134.06, 129.47,
hours. The generation of nitrile could be attributed to the 129.04, 51.82, 40.55, 32.99.
rearrangement of the isocyano group due to the stability of
N-[4-(Bromomethyl)phenyl]-N-ethylbenzamide (3e)
the sec-benzyl cation. A similar mechanism has been re-
ported in the case of the preparation for benzyl nitrile from
the corresponding benzyl halide with TMSCN and
TiCl4.11
Prepared from 4-aminobenzyl alcohol (300 mg, 2.43 mmol) as fol-
lows. First, 4-(ethylamino)benzyl alcohol was prepared by a one-
pot reaction via reduction of the corresponding imine with acetalde-
hyde (excess) and NaBH4 (excess). Then, N-ethyl-N-[4-(hydroxy-
methyl)phenyl]benzamide, which was the precursor of 3e, was
synthesized by reacting with BzCl (2.2 equiv) and pyridine (excess)
followed by hydrolysis of ester with NaOH (1.5 equiv). Compound
3e was finally obtained from the precursor by bromination of alco-
hol with PBr3 (1.2 equiv); yellow oil; yield: 49%.
NC
CN
Br
1) TMSCN, AgClO4
2) aq NaHCO3
+
IR (neat): 3060, 3033, 2973, 2871, 1645, 1606, 1513, 1392, 1307,
1116, 698, 611 cm–1.
1H NMR (600 MHz): d = 7.30–7.21 (m, 5 H), 7.18–7.14 (m, 2 H),
7.01–6.97 (m, 2 H), 4.40 (s, 2 H), 3.97 (q, 2 H, J = 7.0 Hz), 1.22 (t,
3 H, J = 7.0 Hz).
t-Bu
13
t-Bu
14
t-Bu
12
79%
r.t., 1 h
13%
73%
r.t., 24 h
trace
13C NMR (150.8 MHz): d = 170.08, 143.23, 136.03, 129.75,
129.59, 128.59, 127.97, 127.73, 45.38, 32.50, 12.95.
Scheme 8
LRMS (EI): m/z (%) = 317 (M+, 3), 238 (86), 132 (33), 105 (100),
77 (22).
HRMS (EI): m/z calcd for C16H16BrNO [M+]: 317.0415; found:
317.0403.
In conclusion, we have developed a new method for con-
verting benzyl halides to their corresponding isocyanides.
We believe this method provides a convenient and useful
way to synthesize benzyl isocyanides.
Synthesis 2006, No. 3, 405–410 © Thieme Stuttgart · New York

408
Y. Kitano et al.
PAPER
1-[4-(Bromomethyl)phenyl]pyrrolidine-2,5-dione (3f)16
Prepared from 4-aminobenzyl alcohol (985 mg, 1.0 mmol) as fol-
lows. First, N-[4-(hydroxymethyl)phenyl]succinamic acid was pre-
pared by a reaction of the corresponding amine with succinic
anhydride. Then, 1-[4-(hydroxymethyl)phenyl]pyrrolidine-2,5-di-
one, which was the precursor of 3f, was synthesized by refluxing the
above succinamic acid in Ac2O (excess) followed by hydrolysis of
the acetate ester with BF3·OEt2 (5.0 equiv) in MeOH. Compound 3f
was finally obtained by bromination of the corresponding benzyl al-
cohol with PBr3 (1.2 equiv); yield: 25%.
1H NMR (600 MHz): d = 7.52–7.49 (m, 2 H), 7.30–7.27 (m, 2 H),
4.49 (s, 2 H), 2.90 (s, 4 H).
13C NMR (150.8 MHz): d = 175.93, 138.11, 131.78, 129.85,
126.66, 32.29, 28.38.
4-Bromobenzyl Isocyanide (4a)
Yellow oil.
IR (neat): 3086, 2925, 2854, 2144, 1727, 1706, 1592, 1486, 1438,
1409, 1346, 1072, 1012, 948, 794 cm–1.
1H NMR (600 MHz): d = 7.51 (t, 2 H, J = 8.3 Hz), 7.21 (t, 2 H,
J = 8.3 Hz), 4.58 (br s, 1 H).
13C NMR (150.8 MHz): d = 158.03 (t, J = 5.4 Hz), 131.83, 131.06,
128.04, 122.20, 44.95 (t, J = 7.5 Hz).
LRMS (EI): m/z (%) = 195 (M+, 31), 169 (17), 116 (100), 89 (37).
HRMS (EI): m/z calcd for C8H6BrN [M+]: 194.9684; found:
194.9689.
4-Chlorobenzyl Isocyanide (4b)
Yellow oil.
4-Methoxy-3-nitrobenzyl Bromide (7)
IR (neat): 3066, 2954, 2929, 2853, 2150, 1596, 1490, 1442, 1409,
1346, 1091, 952, 798 cm–1.
1H NMR (600 MHz): d = 7.40–7.35 (m, 2 H), 7.31–7.26 (m, 2 H),
4.6 (br t, 2 H, J = 1.9 Hz).
13C NMR (150.8 MHz): d = 158.19 (t, J = 5.4 Hz), 134.46, 130.75,
129.20, 128.00, 44.96 (t, J = 7.3 Hz).
LRMS (EI): m/z (%) = 151 (M+, 40), 125 (32), 116 (100), 89 (21).
Prepared from 4-hydroxy-3-nitrobenzaldehyde (1.0 g, 5.98 mmol)
as follows. First, 4-Methoxy-3-nitrobenzyl alcohol, which was the
precursor of 7, was synthesized by methylation of the phenolic
group with MeI (4.0 equiv) and K2CO3 (3.0 equiv) followed by re-
duction of the aldehyde with NaBH4 (2.0 equiv). Then, 7 was ob-
tained by bromination of the alcohol formed with PBr3 (1.2 equiv);
yield: 52%; yellow solid; 95–96 °C.
IR (KBr): 3037, 2985, 1619, 1523, 1355, 1268, 1010, 831, 624
cm–1.
1H NMR (600 MHz): d = 7.89 (d, 1 H, J = 2.1 Hz), 7.58 (dd, 1 H,
J = 8.5, 2.1 Hz), 7.08 (d, 1 H, J = 8.5 Hz), 4.47 (2 H, s), 3.97 (3 H,
HRMS (EI): m/z calcd for C8H6ClN [M+]: 151.0189; found:
151.0173.
4-Benzoyloxybenzyl Isocyanide (4c)
White solid; mp 92–93 °C.
s).
13C NMR (150.8 MHz): d = 152.60, 139.12, 134.60, 129.99,
126.05, 113.80, 56.70, 31.42.
LRMS (EI): m/z (%) = 245 (M+, 2), 197 (21), 166 (100), 150 (2),
135 (4), 120 (2), 91 (65), 69 (7).
IR (KBr): 3066, 2923, 2150, 1735, 1602, 1511, 1450, 1263, 1211,
1168, 1966, 869, 703 cm–1.
1H NMR (600 MHz): d = 8.22–8.19 (m, 2 H), 7.67–7.64 (m, 1 H),
7.54–7.51 (m, 2 H), 7.45–7.41 (m, 2 H, J = 8.8, 1.9 Hz), 7.29–7.26
(m, 2 H, J = 4.4, 2.2 Hz), 4.68 (br s, 2 H).
HRMS (EI): m/z calcd for C8H8BrNO3 [M+]: 244.9687; found:
244.9684.
13C NMR (150.8 MHz): d = 165.03, 158.18 (t, J = 4.9 Hz), 151.01,
133.79, 130.22, 129.93, 129.28, 128.65, 127.89, 122.41, 45.08 (t,
J = 7.4 Hz).
Benzyl Isocyanides 2,4,7; General Procedure
TMSCN (60 mg, 0.6 mmol) and AgClO4 (124 mg, 0.6 mmol) were
added to a solution of the appropriate benzyl halide (0.2 mmol) in
CH2Cl2 (2 mL) under argon. The reaction mixture was adequately
stirred at r.t. Then, aq sat. NaHCO3 (2 mL) was added. After stirring
for an additional 10 min, the mixture was filtered over Celite and
washed with EtOAc. The combined organic extracts were washed
with H2O and brine, and dried (MgSO4). The crude product was pu-
rified by silica gel column chromatography (hexane–EtOAc). After
removal of the solvent, a 1 M solution of TBAF in THF (1 mL) was
added to the residue. After stirring for an additional 10 min, the mix-
ture was filtered over Celite and washed with EtOAc. The combined
organic extracts were analyzed by GC. The product was isolated by
evaporation of the solvent.
LRMS (EI): m/z (%) = 237 (M+, 10), 105 (100), 77 (61), 51 (8).
HRMS (EI): m/z calcd for C15H11NO2 [M+]: 237.0790; found:
237.0796.
4-(Isocyanomethyl)phenylacetic Acid Methyl Ester (4d)
Yellow oil.
IR (neat): 3025, 2954, 2917, 2150, 1735, 1517, 1434, 1425, 1257,
1164 cm–1.
1H NMR (600 MHz): d = 7.31 (pseudo s, 4 H), 4.62 (br t, 2 H,
J = 1.8 Hz), 3.70 (s, 3 H), 3.64 (s, 2 H).
13C NMR (150.8 MHz): d = 171.83, 158.05 (t, J = 4.9 Hz), 134.54,
131.43, 130.09, 127.07, 52.29, 45.42 (t, J = 7.4 Hz), 40.89.
LRMS (EI): m/z (%) = 189 (M+, 59), 163 (3), 158 (2), 130 (100),
104 (93), 77 (19).
HRMS (EI): m/z calcd for C11H11NO2 [M+]: 189.0789; found:
189.0779.
4-tert-Butylbenzyl Isocyanide (2)
Yellow oil.
IR (neat): 3031, 2964, 2906, 2148, 1511, 1442, 1365, 1268, 1108,
1020, 821 cm–1.
1H NMR (600 MHz): d = 7.42 (d, 2 H, J = 8.4 Hz), 7.28 (d, 2 H,
J = 8.4 Hz), 4.61 (br t, 2 H, J = 1.9 Hz), 1.32 (s, 9 H).
13C NMR (150.8 MHz): d = 157.25 (t, J = 4.9 Hz), 151.64, 129.39,
126.45, 125.92, 45.28 (t, J = 7.4 Hz), 34.63, 31.28.
LRMS (EI): m/z (%) = 173 (M+, 20), 158 (100), 130 (34), 105 (18),
N-[4-(Isocyanomethyl)phenyl]-N-ethylbenzamide (4e)
Yellow oil.
IR (neat): 3058, 2971, 2935, 2869, 2150, 1641, 1612, 1513, 1390,
1120, 698 cm–1.
1H NMR (600 MHz): d = 7.31–7.27 (m, 2 H), 7.26–7.15 (m, 5 H),
7.08–7.04 (m, 2 H), 4.57 (br s, 2 H), 3.98 (q, 2 H, J = 7.3 Hz), 1.22
(t, 3 H, J = 7.3 Hz).
91 (24).
HRMS (EI): m/z calcd for C12H15N [M+]: 173.1206; found:
173.1200.
Synthesis 2006, No. 3, 405–410 © Thieme Stuttgart · New York

PAPER
Preparation of Benzyl Isocyanides
409
13C NMR (150.8 MHz): d = 170.16, 158.23 (t, J = 4.9 Hz), 143.50,
136.06, 130.51, 129.66, 128.59, 128.30, 127.82, 127.35, 45.38,
44.96 (t, J = 7.4 Hz), 12.95.
LRMS (EI): m/z (%) = 264 (M+, 34), 133 (10), 118 (25), 105 (100),
77 (43).
4-Benzoyloxybenzyl Alcohol (11)17
1H NMR (600 MHz): d = 8.21–8.19 (2 H, m), 7.64 (tt, 1 H, J = 7.4,
1.8 Hz), 7.53–7.49 (2 H, m), 7.45–7.42 (2 H, m), 7.23–7.19 (2 H,
m), 4.73 (d, 2 H, J = 3.7 Hz), 1.69 (t, 1 H, J = 3.7 Hz).
13C NMR (150.8 MHz): d = 169.15, 154.33, 142.47, 137.56,
134.12, 133.44, 132.52, 132.08, 125.78.
HRMS (EI): m/z calcd for C17H16N2O [M+]: 264.1263; found:
264.1267.
1-(1-Bromoethyl)-4-tert-butylbenzene (12)
Prepared from 4-tert-butylbenzaldehyde (1.1 g, 6.78 mmol) by re-
acting with MeMgBr (1.2 equiv) followed by bromination of the al-
cohol formed with PBr3 (1.2 equiv); yellow oil; yield: 94%.
1-[4-(Isocyanomethyl)phenyl]pyrrolidine-2,5-dione (4f)
White solid; mp 151–153 °C.
IR (KBr): 2991, 2956, 2923, 2854, 2150, 1716, 1517, 1400, 1295,
1187, 806 cm–1.
1H NMR (400 MHz): d = 7.41–7.39 (m, 2 H), 7.31–7.28 (m, 2 H),
4.62 (br s, 2 H), 2.84 (s, 4 H).
13C NMR (100.5 MHz): d = 175.46, 158.01 (t, J = 5.4 Hz), 132.31,
131.69, 127.08, 126.68, 45.00 (t, J = 7.5 Hz), 28.34.
LRMS (EI): m/z (%) = 214 (M+, 57), 188 (33), 167 (30), 149 (100),
132 (40), 105 (62), 77 (36).
HRMS (EI): m/z calcd for C12H10N2O2 [M+]: 214.0742; found:
IR (neat): 3095, 3029, 2964, 2863, 1515, 1413, 1365, 1265, 1174,
1108, 833, 599 cm–1.
1H NMR (600 MHz): d = 7.36 (4 H, pseudo s), 5.22 (q, 1 H, J = 6.9
Hz), 2.04 (d, 3 H, J = 6.9 Hz), 1.31 (9 H, s).
13C NMR (150.8 MHz): d = 151.13, 140.10, 126.41, 125.41, 49.49,
34.46, 31.20, 26.73.
LR-EIMS: m/z (%) = 240 (M+, 1), 161 (100), 146 (33), 131 (21), 91
(7).
HR-EIMS: m/z calcd for C12H17Br [M+]: 240.0513; found:
240.0519.
214.0740.
3, 5-Di-tert-butylbenzyl Isocyanide (6)
White solid; mp 40–41 °C.
1-tert-Butyl-4-[1-(isocyanoethyl)]benzene (13)
Yellow oil.
IR (neat): 3029, 2962, 2138, 1513, 1461, 1365, 1270, 833 cm–1.
1H NMR (600 MHz): d = 7.42–7.39 (m, 2 H), 7.30–7.27 (m, 2 H),
4.80 (tq, 1 H, J = 6.9, 1.9 Hz), 1.68 (dt, 3 H, J = 6.9, 1.9 Hz), 1.32
(s, 9 H).
13C NMR (150.8 MHz): d = 156.00 (t, J = 4.9 Hz), 151.36, 135.55,
125.82, 125.13, 53.51 (t, J = 6.2 Hz), 34.57, 31.28, 24.98.
LRMS (EI): m/z (%) = 187 (M+, 20), 172 (100), 144 (17), 105 (59),
77 (18).
IR (KBr): 3095, 2950, 2900, 2865, 2150, 1600, 1479, 1365, 1251,
867, 711 cm–1.
1H NMR (600 MHz): d = 7.42–7.39 (m, 1 H), 7.18–7.15 (m, 2 H),
4.62 (br s, 2 H), 1.33 (s, 18 H).
13C NMR (150.8 MHz): d = 157.28 (t, J = 4.9 Hz), 151.73, 131.53,
122.44, 120.91, 46.02 (t, J = 7.4 Hz), 34.95, 31.40.
LRMS (EI): m/z (%) = 229 (M+, 15), 214 (100), 186 (20), 131 (7),
115 (20), 91 (20).
HRMS (EI): m/z calcd for C16H23N [M+]: 229.1831; found:
HRMS (EI): m/z calcd for C16H23N [M+]: 187.1361; found:
187.1365.
229.1839.
4-(Isocyanomethyl)-1-methoxy-2-nitrobenzene (8)
Yellow solid; 82–83 °C.
2-[4-(tert-Butylphenyl)]propionitrile (14)
Colorless oil.
IR (KBr): 3031, 2940, 2150, 1623, 1525, 1438, 1348, 1251, 1180,
1016, 933, 821, 665, 549 cm–1.
1H NMR (600 MHz): d = 7.84 (d, 1 H, J = 1.8 Hz), 7.57 (dd, 1 H,
J = 8.8, 1.8 Hz), 7.15 (d, 1 H, J = 8.8 Hz), 4.64 (br s, 2 H), 3.99 (s,
3 H).
13C NMR (150.8 MHz): d = 159.07 (t, J = 3.7 Hz), 153.03, 139.62,
132.27, 124.68, 124.25, 114.27, 56.76, 44.29 (t, J = 7.4 Hz).
LRMS (EI): m/z (%) = 192 (M+, 75), 166 (26), 145 (58), 105 (54),
IR (neat): 3039, 2964, 2240, 1679, 1511, 1459, 1365, 1265, 829
cm–1.
1H NMR (600 MHz): d = 7.42–7.39 (m, 2 H), 7.29–7.26 (m, 2 H),
3.87 (q, 1 H, J = 7.3 Hz), 1.64 (d, 3 H, J = 7.3 Hz), 1.32 (s, 9 H).
13C NMR (150.8 MHz): d = 151.11, 133.98, 126.39, 126.04,
121.75, 34.55, 31.26, 30.77, 21.34.
LRMS (EI): m/z (%) = 187 (M+, 15), 172 (100), 144 (12), 105 (7),
91 (3).
HRMS (EI): m/z calcd for C16H23N [M+]: 187.1361; found:
187.1365.
91 (100), 77 (19).
HRMS (EI): m/z calcd for C9H8N2O3 [M+]: 192.0535; found:
192.0541.
Intermediate 9
Not isolated because of instability.
References
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1H NMR (600 MHz): d = 7.48–7.46 (2 H, m), 7.34–7.32 (2 H, m),
4.86 (2 H, s), 1.32 (9 H, s), 0.07 (9 H, s).
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Synthesis 2006, No. 3, 405–410 © Thieme Stuttgart · New York

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