A general procedure to access methylene ether isonitrile derivatives

Article abstract of DOI:10.1055/s-0028-1083143

Isonitriles are essential building blocks for multicomponent reactions. A convenient and simple two-step synthesis of the little known methylene ether isonitrile derivatives is presented.

Full text of DOI:10.1055/s-0028-1083143

3326
PAPER
A General Procedure to Access Methylene Ether Isonitrile Derivatives
S
ynthesis of Meth
e
ylene
E
the
b
r
Isonitriles ecca L. Grange,a Craig M. Williams,*a Lin Dong,a Victoria A. Gordonb
a
School of Molecular and Microbial Sciences, University of Queensland, Brisbane 4072, Australia
Fax +61(7)33654299; E-mail: c.williams3@uq.edu.au
EcoBiotics Limited, PO Box 1, Yungaburra 4884, Australia
b
Received 29 April 2008; revised 23 June 2008
R'
RO N
Abstract: Isonitriles are essential building blocks for multicompo-
nent reactions. A convenient and simple two-step synthesis of the
little known methylene ether isonitrile derivatives is presented.
RO
N
RS
– e
N
R"
1
2
3
Key words: formamide, dehydration, isonitrile/isocyanide, multi-
component reactions
Figure 1 Isonitriles 1–3
RO
SnR3'
RO
N
TMSCN
Multicomponent reactions such as the Ugi and Passerini
reactions can rapidly provide large arrays of molecular di-
versity.1 Accessing molecular diversity is of paramount
importance in the search for new biologically active can-
didates, and multicomponent reactions provide an addi-
tional tool in this endeavour. The success of these
1
4
+
1) I–
Me3N
NHCHO
N
N
N
6
N
N
N
O
2) POCl3, Et3N
N
OH
5
reactions in delivering such diversity is, however, reliant Scheme 1
upon the size of the building block arsenal. Considering
that isonitriles play a major role in multicomponent reac-
EtOH
BnOH
H+
EtO
NHCHO
BnO
NHCHO
NH2CHO
tions, attempts to explore the synthesis of new isonitrile
CH2O
7
8
derivatives are warranted. In the course of our own work
we required methylene ether isonitriles 1. Surprisingly,
these compounds are not well known, which is in stark
contrast to the sulfur analogues 2,2 and substituted deriv-
POCl3
Et3N
BnO
NC
9
atives 3 (Figure 1).3
Scheme 2
The first of only two reports on methylene ether isonitriles
In view of this success, we now report a convenient two-
step procedure for the synthesis of methylene ether isoni-
trile derivatives 1 (Table 1) in yields ranging from 0–58%.
The yield of the product was somewhat dependent on ste-
reoelectronic effects. For example, in the benzyl series
electron-withdrawing substituents (entries 1 and 2) af-
forded products in modest yields (58 and 55%, respective-
ly), whereas electron-donating substituents decreased the
yield by more than half as seen in entries 4 and 5. This
trend is most likely due to the stabilisation of an incipient
carbocation formed in competition when the benzyl alco-
hol is in contact with the acidic media required to form the
intermediate formamide 8. Interestingly, the phenoxy (en-
try 6) derivative failed to deliver the product. Primary
aliphatics (entries 7–10) worked satisfactorily, however,
hindered secondary (entry 12) and acid labile side chains
(entry 13) did not perform particularly well.
1 describes the electrochemical conversion of organotin
methylene ethers 4 into 1 by Yoshida,4 while Sasaki5 syn-
thesised 1-(isocyanomethyloxy)benzotriazole (5) from
formamide 6 (Scheme 1).
Initially, we were attracted to the Sasaki procedure, but a
report by Threadgill6 detailing a two-step synthesis of
formamide 7, as opposed to a three-step protocol for form-
amide 6, then caught our attention. Synthesis of form-
amide 7 was straightforward, but the key to the
development of a new method for the construction of me-
thylene ether isonitrile derivatives 1 was functionalisation
of 7. After some optimisation, it was discovered that treat-
ment of 7 with benzyl alcohol in the presence of sulfuric
acid gave the benzyl derivative 8 (61%). It should be not-
ed that attempts to use the Threadgill6 procedure to direct-
ly access 8 failed. A number of protocols7 for conversion
of 8 into methylene ether isonitrile 9 were investigated,
with the most common procedure, POCl3/Et3N, giving the
best results (Scheme 2).
Pure intermediate formamides were isolated in several
cases (e.g., entries 3, 8, 10, and 12, Procedure A, see also
experimental). In all other instances, a mixture consisting
predominantly of formamide and unreacted alcohol was
subjected to dehydration (Procedure B). (Dodecyl-
oxy)methyl isonitrile (18) was generated from both pure
and impure N-[(dodecyloxy)methyl]formamide and the
SYNTHESIS 2008, No. 20, pp 3326–3330
x
x.
x
x
.
2
0
0
8
Advanced online publication: 25.09.2008
DOI: 10.1055/s-0028-1083143; Art ID: T06908SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Methylene Ether Isonitriles
3327
Table 1 Methylene Ether Isonitrile Derivatives Prepared
Entry
1b
R
Yield (%)a
58
Entry
8c
R
Yield (%)a
10
11
16
17
40
O2N
2b
55
9
64d,e
12d,f
Br
3c
4b
9
41
20
10c
11
18
19
41
*
11
12
78d,g
19d,f
MeO
5b
13
19
12c
20
23
6
14
15
0
13b
21
14
EtO
7b
42
a Isolated two step overall yield from N-[(ethoxy)methyl]formamide unless otherwise indicated.
b Procedure B.
c Procedure A.
d Estimated yield from crude 1H NMR spectrum due to compound sensitivity.
e One-step yield from N-[(ethoxy)methyl]formamide.
f Two-step overall yield from formamide.
g One-step yield from N-[(isopropyloxy)methyl]formamide.
pressed as values in ppm. GC-MS data were recorded on a Shimad-
zu GC-17A Ver.3 mass spectrometer: MS QP5050A, ionisation at
70 eV. Low resolution EI-MS measurements were recorded in pos-
itive ionisation mode on a Bruker Esquire HCT (High Capacity 3D
ion trap) instrument with a Bruker ESI source. High resolution EI-
MS data were obtained on a Finnigan MAT900. High resolution EI
accurate mass measurements were recorded in positive mode on a
Bruker MicrOTOF-Q (quadrupole - Time of Flight) instrument with
a Bruker ESI source. Accurate mass measurements were carried out
with external calibration using sodium formate as reference cali-
brant. Column chromatography was undertaken on silica gel (Flash
Silica gel 230–400 mesh) with distilled solvents. Petroleum ether
(PE) refers to the fraction boiling at 40–60 °C.
two-step yields were comparable, indicating that the pres-
ence of unreacted alcohol has no adverse effect on isoni-
trile yield.
The 13C NMR spectra of all the isonitriles synthesised fea-
tured two 1:1:1 triplets that could be attributed to the car-
bons attached to the isonitrile nitrogen. 1J(14N,13C) values
were in good agreement with those reported previously
for other isonitriles.8
In conclusion, a convenient and simple two-step synthesis
of the little known methylene ether isonitrile derivatives is
presented. Yields are moderate to low, but considering the
only alternative is electrochemical oxidation of toxic stan-
nanes, our methodology is a substantial improvement, of-
fering many new building blocks for important reactions,
such as the Ugi type.
Transetherification of N-(Ethoxymethyl)formamide (7);
N-[(Dodecyloxy)methyl]formamide; Typical Procedure A
A stirred mixture of dodecan-1-ol (2.9 g, 16 mmol), N-(ethoxy-
methyl)formamide (7; 0.80 g, 7.8 mmol) and concd H2SO4 (2 drops)
was heated at ca. 110 °C (oil bath temp.) for 1 h at atmospheric pres-
sure and then for 2 h at ca. 300 Torr. The mixture was loaded direct-
1H and 13C NMR spectra were recorded with Bruker AV300
(300.13 MHz; 75.47 MHz), AV400 (400.13 MHz; 100.62 MHz and
DRX500 (500.13 MHz; 125.77 MHz) spectrometers in CDCl3.
Coupling constants are given in Hz and chemical shifts are ex-
ly onto
a flash chromatography column [PE–EtOAc–Et3N
(75:25:0.5) → EtOAc–Et3N (100:0.5)] and the title compound was
collected as a colourless oil (0.93 g, 52%).
Synthesis 2008, No. 20, 3326–3330 © Thieme Stuttgart · New York

3328
R. L. Grange et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 8.22 (d, J = 1.4 Hz, 1 H), 8.12 (d,
J = 11.6 Hz, 1 H), 7.03 (br s, 1 H), 6.75 (br s, 1 H), 4.69 (d, J = 6.8
Hz, 2 H), 4.57 (d, J = 7.1 Hz, 2 H), 3.43 (t, J = 6.7 Hz, 2 H), 3.36 (t,
J = 6.6 Hz, 2 H), 1.51–1.45 (m, 4 H), 1.19 (m, 36 H), 0.81 (t, J = 6.7
Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 165.5, 161.8, 73.3, 68.8, 68.4,
67.7, 31.8, 29.53, 29.51, 29.47, 29.32, 29.29, 29.2, 26.0, 22.6, 14.0.
N-[(Isopropyloxy)methyl]formamide
The title compound was obtained as a colourless oil in 19% yield via
the procedure developed by Threadgill6 for N-(ethoxymethyl)form-
amide.
1H NMR (300 MHz, CDCl3): d = 8.23 (s, 1 H), 8.15 (d, J = 11.8 Hz,
1 H), 6.67 (br s, 1 H), 6.39 (br s, 1 H), 4.75 (d, J = 6.8 Hz, 2 H), 4.62
(d, J = 7.1 Hz, 2 H), 3.77 (sept, J = 6.1 Hz, 1 H), 3.69 (sept, J = 6.1
Hz, 1 H), 1.14 (d, J = 6.1 Hz, 12 H).
13C NMR (100 MHz, CDCl3): d = 165.6, 161.9, 70.8, 69.3, 68.4,
66.1, 22.0, 21.9.
EI-MS: m/z (%) = 102 (16, [M+ – CH3]), 74 (46), 58 (100), 43 (80).
ESI-MS: m/z = 266 [M + Na+].
HRMS (ESI): m/z calcd for C14H29NO2 + Na: 266.2091; found:
266.2094.
N-{[(1R)-(7,7-Dimethylbicyclo[2.2.1]hept-2-en-2-yl)methyl-
oxy]methyl}formamide
Colourless oil; yield: 51%.
Isonitriles by Dehydration of Formamides; (Dodecyloxy)methyl
Isonitrile (18); Typical Procedure A
Under argon, anhyd Et3N (2.3 mL, 17 mmol) followed by a solution
of anhyd POCl3 (0.35 mL, 3.8 mmol) in anhyd THF (2.7 mL) were
added to a stirred solution of N-[(dodecyloxy)methyl]formamide
(0.82 g, 3.4 mmol) in THF (6.0 mL) at 0 °C. The mixture was stirred
at 10 °C for 20 min and then poured onto crushed ice. The product
was extracted into Et2O (3 × 10 mL) and the combined organic
phases were washed with aq 10% Na2CO3 (20 mL), dried (MgSO4),
and concentrated in vacuo. Flash chromatography (PE–EtOAc–
Et3N, 75:25:0.5) furnished 18 (0.60 g, 79%) as a pale yellow oil.
1H NMR (300 MHz, CDCl3): d = 8.24 (d, J = 1.4 Hz, 1 H), 8.12 (d,
J = 11.6 Hz, 1 H), 6.67 (br s, 1 H), 6.46 (br s, 1 H), 5.50–5.48 (m, 2
H), 4.72 (dd, J = 6.8, 0.9 Hz, 2 H), 4.58 (d, J = 7.3 Hz, 2 H), 3.86–
3.85 (m, 2 H), 3.83–3.82 (m, 2 H), 2.41–2.32 (m, 2 H), 2.26–2.22
(m, 4 H), 2.10 (td, J = 5.4, 1.2 Hz, 2 H), 2.16–2.06 (m, 2 H), 1.25 (s,
3 H), 1.24 (s, 3 H), 1.12 (d, J = 8.6 Hz, 1 H), 1.10 (d, J = 8.7 Hz, 1
H), 0.78 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 165.3, 161.6, 144.5, 144.2, 121.4,
120.5, 71.9, 71.6, 70.1, 67.8, 43.4, 43.2, 40.72, 40.68, 37.9, 31.5,
31.4, 31.22, 31.19, 26.1, 26.0, 21.0.
1H NMR (300 MHz, CDCl3): d = 4.72 (s, 2 H), 3.59 (t, J = 6.5 Hz,
2 H), 1.59 (quint, J = 6.7 Hz, 2 H), 1.24 (m, 18 H), 0.85 (t, J = 6.5
Hz, 3 H).
ESI-MS: m/z = 232 [M + Na+].
13C NMR (75 MHz, CDCl3): d = 160.6 (1:1:1 t, J = 4.0 Hz), 72.6
(1:1:1 t, J = 5.2 Hz), 70.3, 31.8, 29.6, 29.55, 29.5, 29.4, 29.3, 29.2,
28.9, 25.8, 22.6, 14.0.
MS (EI): m/z (%) = 210 (2, [M+ – CH3]), 196 (1), 182 (1), 168 (3),
154 (2), 140 (5), 126 (3), 112 (6), 97 (35), 83 (53), 69 (52), 55 (67),
41 (100).
HRMS (ESI): m/z calcd for C12H19NO2 + Na: 232.1308; found:
232.1299.
N-[(1R,2S,5R)-(2-Isopropyl-5-methylcyclohexyloxy)meth-
yl]formamide
Colourless oil; yield: 30%.
1H NMR (300 MHz, CDCl3): d = 8.15 (d, J = 1.6 Hz, 1 H), 8.09 (d,
J = 11.6 Hz, 1 H), 7.20 (br s, 1 H), 6.95 (br s, 1 H), 4.83–4.76 (m, 1
H), 4.64–4.52 (m, 1 H), 3.19 (td, J = 10.5, 4.3 Hz, 1 H), 3.09 (td,
J = 10.5, 4.2 Hz, 1 H), 2.07–1.90 (m, 4 H), 1.58–1.49 (m, 4 H),
1.31–1.26 (m, 2 H), 1.16–1.02 (m, 2 H), 0.95–0.72 (m, 18 H), 0.67
(d, J = 6.9 Hz, 3 H), 0.65 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.5, 161.6, 77.3, 76.1, 71.0,
66.5, 48.0, 47.9, 40.8, 40.5, 34.2, 34.1, 31.3, 25.24, 25.16, 22.95,
22.93, 22.08, 22.04, 20.87, 20.80, 15.88, 15.80.
(Benzyloxy)methyl Isonitrile (9)
Colourless oil.
1H NMR (300 MHz, CDCl3): d = 7.37–7.33 (m, 5 H), 4.76 (s, 2 H),
4.70 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 161.1 (1:1:1 t, J = 4.1 Hz), 135.1,
128.5, 128.4, 128.2, 71.0 (1:1:1 t, J = 5.5 Hz), 71.0.
MS (EI): m/z (%) = 147 (7, [M+]), 117 (100), 105 (22), 91 (89), 77
(56), 65 (51), 51 (51), 41 (42).
ESI-MS: m/z = 236 [M + Na+].
HRMS (ESI): m/z calcd for C12H23NO2 + Na: 236.1621; found:
232.1621.
[(1R)-(7,7-Dimethylbicyclo[2.2.1]hept-2-en-2-yl)methyl-
oxy]methyl Isonitrile (16)
Bright yellow oil.
N-[(Benzyloxy)methyl]formamide
1H NMR (300 MHz, CDCl3): d = 5.60–5.58 (m, 1 H), 4.71 (d,
J = 12.1 Hz, 1 H), 4.66 (d, J = 12.1 Hz, 1 H), 4.05–3.95 (m, 2 H),
2.41–2.35 (m, 1 H), 2.28–2.24 (m, 2 H), 2.13 (td, J = 5.7, 1.4 Hz, 1
H), 2.12–2.07 (m, 1 H), 1.26 (s, 3 H), 1.11 (d, J = 8.7 Hz, 1 H), 0.79
(s, 3 H).
13C NMR (75 MHz, CDCl3): d = 160.5 (1:1:1 t, J = 4.1 Hz), 142.8,
123.2, 72.0, 70.8 (1:1:1 t, J = 5.4 Hz), 43.2, 40.5, 37.9, 31.4, 31.2,
25.9, 20.9.
Flash chromatographic purification [CH2Cl2–Et3N (100:0.5) →
CH2Cl2–MeOH–Et3N (90:10:0.5)] followed by removal of traces of
benzyl alcohol via Kugelrohr distillation provided the benzyl ether
as a pale yellow oil in 61% yield.
1H NMR (300 MHz, CDCl3): d = 8.29 (d, J = 1.5 Hz, 1 H), 8.16 (d,
J = 11.7 Hz, 1 H), 7.37–7.26 (m, 10 H), 6.52 (br s, 1 H), 6.34 (br s,
1 H), 4.84 (d, J = 7.0 Hz, 2 H), 4.67 (d, J = 7.3 Hz, 2 H), 4.57 (s, 2
H), 4.51 (s, 2 H).
MS (EI): m/z (%) = 191 (1, [M+]), 176 (1), 161 (3), 146 (7), 134 (9),
119 (55), 105 (40), 91 (100), 79 (54), 65 (18), 41 (77).
13C NMR (75 MHz, CDCl3): d = 165.6, 162.0, 137.4, 136.6, 128.41,
128.38, 128.2, 127.63, 127.62, 72.3, 70.3, 69.0, 67.9.
ESI-MS: m/z = 188 [M + Na+].
(1R,2S,5R)-(2-Isopropyl-5-methylcyclohexyloxy)methyl Isoni-
trile (20)
Yellow oil.
HRMS (ESI): m/z calcd for C9H11NO2 + Na: 188.0682; found:
188.0686.
1H NMR (300 MHz, CDCl3): d = 4.80 (d, J = 12.5 Hz, 1 H), 4.73 (d,
J = 12.5 Hz, 1 H), 3.40 (td, J = 10.6, 4.3 Hz, 1 H), 2.15–2.02 (m, 2
H), 1.68–1.59 (m, 2 H), 1.42–1.31 (m, 1 H), 1.26–1.17 (m, 1 H),
Synthesis 2008, No. 20, 3326–3330 © Thieme Stuttgart · New York

PAPER
Synthesis of Methylene Ether Isonitriles
3329
1.06–0.82 (m, 3 H), 0.90 (d, J = 6.5 Hz, 3 H), 0.88 (d, J = 7.1 Hz, 3
H), 0.79 (d, J = 6.9 Hz, 3 H).
HRMS (EI): m/z calcd for C10H10N2O3: 206.0686; found: 206.0694.
[(2-Phenylethyl)oxy]methyl Isonitrile (15)
Pale yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.39–7.33 (m, 2 H), 7.30–7.25 (m,
3 H), 4.69 (s, 2 H), 3.87 (t, J = 6.9 Hz, 2 H), 2.97 (t, J = 6.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 161.8 (1:1:1 t, J = 4.1 Hz), 137.6,
128.6, 128.2, 126.3, 72.4 (1:1:1 t, J = 5.7 Hz), 70.5, 35.2.
13C NMR (75 MHz, CDCl3): d = 160.0 (1:1:1 t, J = 4.2 Hz), 78.5,
69.9 (1:1:1 t, J = 5.3 Hz), 47.8, 39.5, 34.1, 31.3, 25.2, 23.0, 22.1,
20.9, 16.0.
MS (EI): m/z (%) = 180 (5, [M+ – CH3]), 138 (59), 125 (65), 110
(73), 95 (100), 81 (98), 67 (85), 55 (90), 41 (100).
(Isopropyloxy)methyl Isonitrile (19)
Orange oil.
1H NMR (300 MHz, CDCl3): d = 4.75 (s, 2 H), 3.94 (sept, J = 6.2
Hz, 1 H), 1.21 (d, J = 6.2 Hz, 6 H).
MS (EI): m/z (%) = 161 (17, [M+]), 131 (42), 116 (70), 103 (83), 91
(100), 77 (34), 65 (41), 51 (42), 41 (32).
[(Diphenylmethyl)oxy]methyl Isonitrile (13)
Yellow oil.
13C NMR (75 MHz, CDCl3): d = 160.0 (1:1:1 t, J = 4.3 Hz), 71.4,
70.0 (1:1:1 t, J = 5.4 Hz), 21.5.
1H NMR (300 MHz, CDCl3): d = 7.43–7.35 (m, 10 H), 5.85 (s, 1 H),
4.76 (s, 2 H).
(Ethoxy)methyl Isonitrile (17)
Orange oil.
1H NMR (300 MHz, CDCl3): d = 4.74 (s, 2 H), 3.67 (q, J = 7.0 Hz,
2 H), 1.23 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 160.5 (1:1:1 t, J = 4.1 Hz), 72.3
(1:1:1 t, J = 5.4 Hz), 65.5, 14.3.
13C NMR (75 MHz, CDCl3): d = 161.3 (1:1:1 t, J = 3.8 Hz), 139.3,
128.5, 128.1, 127.2, 81.1, 69.5 (1:1:1 t, J = 5.4 Hz).
MS (EI): m/z (%) = 223 (27, [M+]), 183 (20), 167 (83), 152 (16),
146 (18), 105 (100), 83 (34), 77 (37), 51 (17).
HRMS (EI): m/z calcd for C15H13NO: 223.0992; found: 223.0993.
[(4-Methoxybenzyl)oxy]methyl Isonitrile (12)
Colourless oil.
1H NMR (300 MHz, CDCl3): d = 7.27 (d, J = 8.8 Hz, 2 H), 6.89 (d,
J = 8.8 Hz, 2 H), 4.70 (s, 2 H), 4.61 (s, 2 H), 3.79 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 160.9 (1:1:1 t, J = 4.0 Hz), 159.7,
129.9, 127.0, 113.8, 70.6 (1:1:1 t, J = 5.4 Hz), 70.5, 55.0.
One-Pot Preparation of Isonitiles via Pure Transetherified
Formamides; [(4-Bromobenzyl)oxy]methyl Isonitrile (11);
Typical Procedure B
A stirred mixture of 4-bromobenzyl alcohol (2.1 g, 11 mmol), N-
(ethoxymethyl)formamide (7; 0.61 g, 5.9 mmol) and concd H2SO4
(2 drops) was heated at ca. 110 °C (oil bath temp) for 1 h at atmo-
spheric pressure and then for 2 h at ca. 300 Torr. Flash chromatog-
MS (EI): m/z (%) = 177 (20, [M+]), 147 (24), 135 (15), 121 (100),
107 (15), 91 (16), 77 (29), 40 (11).
raphy [CH2Cl2–Et3N (100:0.5)
→
CH2Cl2–MeOH–Et3N
(90:10:0.5)] provided a mixture of N-[(4-bromobenzyloxy)meth-
yl]formamide and unreacted 4-bromobenzyl alcohol. The mixture
was taken up in anhyd THF (16 mL), chilled to 0 °C and treated with
anhyd Et3N (6.7 mL, 48 mmol) followed by a solution of anhyd
POCl3 (0.93 mL, 10 mmol) in THF (7 mL). The mixture was stirred
at 10 °C for 20 min and then poured onto crushed ice. The product
was extracted into Et2O (3 × 10 mL) and the combined organic
phase was washed with aq 10% Na2CO3 (20 mL), dried (MgSO4),
and concentrated in vacuo. Flash chromatography (PE–EtOAc–
Et3N, 75:25:0.5) afforded 11 (0.74 g, 55%) as an orange oil.
[(2-Ethoxyethyl)oxy]methyl Isonitrile (21)
Colourless oil.
1H NMR (400 MHz, CDCl3): d = 4.76 (s, 2 H), 3.73–3.71 (m, 2 H),
3.58–3.56 (m, 2 H), 3.46 (q, J = 7.0 Hz, 2 H), 1.14 (t, J = 7.0 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 160.8 (1:1:1 t, J = 4.1 Hz), 72.7
(1:1:1 t, J = 5.5 Hz), 69.0, 68.9, 66.5, 14.9.
MS (EI): m/z (%) = 84 (17, [M+ – OEt·]), 73 (6), 59 (46), 44 (100),
1H NMR (300 MHz, CDCl3): d = 7.48 (d, J = 8.4 Hz, 2 H), 7.20 (d,
J = 8.4 Hz, 2 H), 4.75 (s, 2 H), 4.62 (s, 2 H).
40 (37).
13C NMR (75 MHz, CDCl3): d = 161.5 (1:1:1 t, J = 4.0 Hz), 134.2,
131.6, 129.7, 122.4, 71.2 (1:1:1 t, J = 5.6 Hz), 70.3.
Acknowledgment
MS (EI): m/z (%) = 227 (9, [M+, 81Br]), 225 (8, [M+, 79Br]), 197
(16), 195 (16), 185 (29), 183 (22), 171 (37), 169 (54), 157 (16), 155
(11), 146 (13), 116 (100), 105 (22), 89 (77), 77 (52), 63 (19), 41
(40).
The authors thank EcoBiotics Limited and the University of
Queensland for financial support.
References
HRMS (EI): m/z calcd for C9H881BrN: 226.9764; found: 226.9769;
m/z calcd for C9H879BrNO: 224.9784; found: 224.9788.
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Discovery Dev. 2003, 6, 921. (d) Tempest, P. A. Curr. Opin.
Drug Discovery Dev. 2005, 8, 776.
(2) See, for example: (a) Ranganathan, S.; Singh, W. P.
Tetrahedron Lett. 1988, 29, 1435. (b) van Leusen, A. M.;
Wildeman, J.; Moskal, J.; van Hemert, A. W. Recl. Trav.
Chim. Pays-Bas 1985, 104, 177. (c) Saikachi, H.; Sasaki,
H.; Kitagawa, T. Chem. Pharm. Bull. 1983, 31, 723.
(d) van Leusen, A. M.; Schut, J. Tetrahedron Lett. 1976,
285. (e) Schöllkopf, U.; Gerhart, F.; Hoppe, I.; Harms, R.;
Hantke, K.; Scheunemann, K. D.; Eilers, E.; Blume, E.
Liebigs Ann. Chem. 1976, 183. (f) van Leusen, A. M.;
[(3-Methyl-4-nitrobenzyl)oxy]methyl Isonitrile (10)
Pale yellow solid.
1H NMR (300 MHz, CDCl3): d = 7.91 (d, J = 8.3 Hz, 1 H), 7.28 (s,
1 H), 7.28 (d, J = 7.9 Hz, 1 H), 4.82 (s, 2 H), 4.70 (s, 2 H), 2.55 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 160.8 (1:1:1 t, J = 4.0 Hz), 148.5,
140.9, 133.8, 131.6, 125.7, 124.8, 71.7 (1:1:1 t, J = 5.7 Hz), 69.9,
20.2.
MS (EI): m/z (%) = 206 (3, [M+]), 189 (29), 159 (5), 132 (100), 119
(9), 104 (18), 91 (16), 77 (24), 65 (16), 51 (13).
Synthesis 2008, No. 20, 3326–3330 © Thieme Stuttgart · New York

3330
R. L. Grange et al.
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Synthesis 2008, No. 20, 3326–3330 © Thieme Stuttgart · New York