One-pot synthesis of isocyanides from alcohols

Article abstract of DOI:10.1055/s-0031-1289592

A one-pot reaction of alcohols with trimethylsilyl cyanide and methanesulfonic acid with subsequent neutralization by triethylamine and dehydration by tosyl chloride and pyridine gave the corresponding isocyanides in moderate-to-high yields. This method was used to synthesize tertiary and benzylic isocyanides from the corresponding alcohols. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289592

PAPER
3997
One-Pot Synthesis of Isocyanides from Alcohols
One-Pot
k
Synthesis of
uIsocyanides from
A
O
lcohols kada, Yoshikazu Kitano*
Laboratory of Bio-organic Chemistry, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509,
Japan
Fax +81(42)3675700; E-mail: kitayo@cc.tuat.ac.jp
Received 30 August 2011; revised 4 October 2011
Ritter reaction with trimethylsilyl cyanide and methane-
Abstract: A one-pot reaction of alcohols with trimethylsilyl cya-
sulfonic acid, neutralization with triethylamine, and dehy-
nide and methanesulfonic acid with subsequent neutralization by
dration with tosyl chloride and pyridine. We therefore
report a convenient one-pot synthesis of isocyanides from
triethylamine and dehydration by tosyl chloride and pyridine gave
the corresponding isocyanides in moderate-to-high yields. This
method was used to synthesize tertiary and benzylic isocyanides alcohols via formamides that does not require any metallic
from the corresponding alcohols.
reagent.
Key words: isocyanides, alcohols, Ritter reactions
One-pot formation of an isocyanate 2 from adamantan-1-
ol (1) was achieved by treatment with a Brønsted acid and
1.3 equivalents of trimethylsilyl cyanide (step 1), fol-
Isocyanides are versatile compounds that have been em-
ployed in many synthetically useful transformations, such
as Passerini or Ugi multicomponent reactions.1 As an ex-
pansion of the versatility of isocyanides as substrates, a
two-component coupling reaction of an isonitrile with a
carboxylic acid or a thio acid can be used in peptide syn-
thesis.2 In addition, many isocyanides with biological ac-
tivities have been isolated3 or synthesized.4 The most
widely used method for preparing isocyanides is dehydra-
tion of the corresponding formamides,1c,5 but difficulties
in obtaining the appropriate formamide precursors often
make this method inconvenient. It is therefore desirable to
develop an alternative simple and efficient method for
synthesizing isocyanides. We recently developed a meth-
od for synthesizing tertiary isocyanides from alcohols by
using stoichiometric amounts of trimethylsilyl cyanide
and a zinc or silver salt.6 A variety of isocyanides can be
obtained in high yields when silver perchlorate is used as
the Lewis acid in this reaction.6b However, the use of sto-
ichiometric amounts of metallic reagents in large-scale
syntheses is neither economically nor ecologically desir-
able. This prompted us to develop a new method for syn-
thesizing isocyanide from alcohols without the use of
metallic reagents.
lowed by neutralization with triethylamine (step 2), and
dehydration with the appropriate base and dehydrating
agent (step 3). The results obtained by using various com-
binations of Brønsted acids, bases, and dehydrating agents
are summarized in Table 1. The desired reaction proceed-
ed when either methanesulfonic acid or trifluoroacetic
acid was used as the Brønsted acid in step 1 (Table 1; en-
tries 1–4); however, the reaction did not proceed in the
presence of sulfuric acid because the neutralization step
after the modified Ritter reaction was inefficient. Trifluo-
roacetic acid also caused problems as a Brønsted acid, be-
cause although the starting material was completely
converted into the corresponding formamide within 24
hours in step 1, the desired product was obtained in poor
yield because the dehydration in step 3 was inefficient
(entry 4). Methanesulfonic acid was therefore selected as
the optimal Brønsted acid for step 1. For 0.5 mmol of al-
cohol 1, the optimum amount of acid was found to be 300
mL per milliliter of dichloromethane. When the amount of
methanesulfonic acid was decreased from 300 mL to 100
mL per milliliter of dichloromethane, the alcohol–form-
amide conversion became inefficient (entries 1 and 2) and
the yield of the desired product decreased considerably.
However, there was no change in the yield when the
amount of methanesulfonic acid was increased to 500 mL
per milliliter of dichloromethane. With regard to the neu-
tralization process in step 2, although pyridine could be
used as the base, triethylamine was chosen because dense
fumes were generated in the reaction vessel when pyridine
was added. In step 3, the conditions for dehydration were
optimized for both pyridine/tosyl chloride and triethyl-
amine/phosphoryl chlorides. When triethylamine was
used in conjunction with phosphoryl chlorides, such as
phenoxyphosphoryl dichloride [PhOP(O)Cl2], ethoxy-
phosphoryl dichloride [EtOP(O)Cl2], diphenoxyphospho-
ryl chloride [(PhO)2P(O)Cl], or diethoxyphosphoryl
chloride [(EtO)2P(O)Cl], neutralization proceeded
smoothly and dehydration occurred efficiently to give the
desired product (entries 5–8). However, pyridine with to-
Recently, Chen and co-workers reported a modified Ritter
reaction for the synthesis of formamides from the corre-
sponding alcohols in the presence of trimethylsilyl cya-
nide and sulfuric acid.7 Encouraged by the results of their
study, we developed a new method for synthesizing isocy-
anides from alcohols via the corresponding formamide in-
termediates, because we believed that this conversion
could proceed by a one-pot process involving dehydration
of the formamide after the modified Ritter reaction. De-
tailed investigations showed that the desired alcohol–
isocyanide conversion occurs in three steps: a modified
SYNTHESIS 2011, No. 24, pp 3997–4002
x
x.
x
x
.
2
0
1
1
Advanced online publication: 04.11.2011
DOI: 10.1055/s-0031-1289592; Art ID: F84511SS
© Georg Thieme Verlag Stuttgart · New York

3998
I. Okada, Y. Kitano
PAPER
syl chloride was found to be the optimal base and dehy- product 4j. This was attributed to nucleophilic substitu-
drating agent combination because it produced a higher tion by the chloride ion generated from tosyl chloride.
yield of the product and required smaller amounts of re-
Table 2 One-Pot Reactions of Various Alcohols with Trimethylsi-
lyl Cyanide and Methanesulfonic Acid, Followed by Neutralization
with Triethylamine and Dehydration with Tosyl Chloride and Pyri-
agents than did the triethylamine with phosphoryl chlo-
ride combinations.
dine
Table 1 Optimization of the Reaction Conditions
1) TMSCN (1.3 equiv), MsOH (0.3 mL)
OH
NC
CH2Cl2 (1 mL)
1) TMSCN (1.3 equiv), acid
R
OH
3a–q 2) Et3N (10.0 equiv)
3) pyridine (2.0 equiv), TsCl (1.2 equiv)
R
NC
4a–q
2) Et3N (10.0 equiv)
3) base, dehydrating agent
1
2
Entrya
Substrate
Yieldb (%)
86
Entrya Acid
(step 1)b
Base
Dehydrating
Yieldd
(%)
(step 3)c
agent (step 3)c
OH
1
1f
2
3
4
5
6
7
8
MsOH
(100 mL)
pyridine
(2.0 equiv)
TsCl
12
88
89
17
82
70
25
92
4
(1.2 equiv)
3a
OH
OH
MsOH
(300 mL)
pyridine
(2.0 equiv)
TsCl
2
94
92
(1.2 equiv)
MeO
4
3b
MsOH
(500 mL)
pyridine
(2.0 equiv)
TsCl
(1.2 equiv)
3c
AcO
TFA
pyridine
(2.0 equiv)
TsCl
4
(300 mL)e
(1.2 equiv)
3c
O
MsOH
(300 mL)
Et3N
(2.0 equiv)
PhOPOCl2
(2.0 equiv)
OH
N
4
91
4
MsOH
(300 mL)
Et3N
(5.0 equiv)
EtOPOCl2
(2.0 equiv)
O
3d
MsOH
(300 mL)
Et3N
(2.0 equiv)
(PhO)2POCl
(5.0 equiv)
OH
5
6
93
53
94
94
93
91
FmocHN
4
MsOH
(300 mL)
Et3N
(5.0 equiv)
(EtO)2POCl
(5.0 equiv)
3e
OH
a Reaction conditions: adamantan-1-ol (1; 0.5 mmol), CH2Cl2 (1 mL);
the second step of the reaction was carried out for a short time.
b Step 1 was carried out for 2 h.
AcHN
4
3f
c Step 3 was carried out for 2 h.
d Determined by GLC.
OH
e Step 1 was carried out for 24 h.
7
F
4
4
4
4
3g
We then examined the scope of this reaction under the op-
timized conditions. Table 2 shows the results for one-pot
syntheses of the corresponding isocyanides from various
tertiary and benzylic alcohols. Under the optimized condi-
tions, all the tertiary alcohols that we examined were
smoothly converted into the corresponding isocyanides in
good-to-excellent yields with negligible amounts of
byproducts (entries 1–14). Various functional groups,
such as ether, ester, imide, carbamate, amide, or halide,
were well tolerated under these conditions (entries 2–10).
However, alcohol 3f, which contained an acetamide
group, gave the desired isocyanide in moderate yield (en-
try 6). For reasons that are unclear, a measurable amount
of the corresponding alkene was obtained in this case as a
byproduct. Furthermore, when iodide 3j was used as the
starting material, increasing the reaction time resulted in
the formation of the chloride 4h in addition to the desired
OH
8
Cl
3h
OH
9
Br
3i
OH
10d
I
3j
OH
80
11
(cis/trans = 75:25)e
3k
Synthesis 2011, No. 24, 3997–4002 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Isocyanides from Alcohols
3999
Table 2 One-Pot Reactions of Various Alcohols with Trimethylsi-
lyl Cyanide and Methanesulfonic Acid, Followed by Neutralization
with Triethylamine and Dehydration with Tosyl Chloride and Pyri-
dine (continued)
Entries 15–17 show the results for some substituted ben-
zylic alcohols. Monosubstituted benzylic alcohols 3o and
3p gave the desired isocyanides in moderate yields. 4-(Ni-
trophenyl)methanol did not give the corresponding
isocyanide (data not shown), but (4-methoxy-3-nitrophe-
nyl)methanol (3q) gave the desired isocyanide in moder-
ate yield. The relatively low yields of benzylic
isocyanides were attributed to inefficient formamide syn-
thesis in step 1. In addition, these results suggest that elec-
tron-withdrawing substituents on the benzene ring reduce
the reactivity of benzylic alcohols. On the other hand, the
primary alcohol dodecan-1-ol and the secondary alcohol
dodecan-2-ol gave the corresponding formates in moder-
ate yield as the major products, together with small
amounts of corresponding mesylates. Under reaction con-
ditions similar to those used in step 1, dodecan-1-ol was
converted into dodec-1-yl formate in 86% yield together
with a 3% yield of the corresponding mesylate (75% con-
version), whereas dodecan-2-ol was converted into
dodec-2-yl formate in 34% yield together with an 8%
yield of the corresponding mesylate (71% conversion).
These conversions required longer reaction times than
those of tertiary or benzylic alcohols, and were carried out
over three days.
1) TMSCN (1.3 equiv), MsOH (0.3 mL)
CH2Cl2 (1 mL)
R
OH
3a–q 2) Et3N (10.0 equiv)
3) pyridine (2.0 equiv), TsCl (1.2 equiv)
R
4a–q
NC
Entrya
Substrate
Yieldb (%)
OH
80
12
(cis/trans = 75:25)e
3l
OH
78
13
14
(cis/trans = 30:70)e
AcO
3m
OH
71
(cis/trans = 30:70)e
AcO
3n
OH
A proposed mechanism for the formation of the formate is
shown in Scheme 1. Protonation of trimethylsilyl isocya-
nide, which is the equilibrium product of trimethylsilyl
cyanide,8 and subsequent nucleophilic addition of an alco-
hol yields intermediate A. This intermediate is hydrolyzed
to the corresponding formate during workup.
15
16
54e
36
3o
OH
OH
BzO
3p
H+
TMS
N
C
TMS
N
CH
RO
TMS CN
17
52
MeO
H
NO2
O
H
C
hydrolysis
3q
TMS
N
R
O C H
a Steps 1 and 3 of the reaction were carried out for 2 h each.
b Isolated yield.
OR
A
c Step 1 of the reaction was carried out for 1 h.
d Step 3 of the reaction was carried out for 1 h.
e Determined by GLC.
Scheme 1
A practical application of this reaction was demonstrated
by conversion of 154 mmol of alcohol 3d into desired iso-
cyanide 4d in 85% yield.
The stereoselectivity of the reaction was examined by us-
ing 1-methylcyclohexan-1-ol derivatives, containing a
tert-butyl group (3k and 3l) or an acetoxy group (3m and
3n) at the 4-position. In both cases, reactions of stereoiso-
meric alcohols gave the same products in approximately
the same ratios, and the major isomer in both cases con-
tained an axially oriented isocyano substituent (entries
11–14). However, the orientation of the isocyano group at
the 4-position was dependent on the type of functional
group sharing that position. This tendency is also ob-
served in the case of direct formation of isocyanides from
alcohols by treatment with trimethylsilyl cyanide and sil-
ver perchlorate,6b although the ratio of the isocyanides 4k
(cis) and 4l (trans) was different.
In conclusion, we have developed a convenient one-pot
method for converting alcohols into the corresponding
isocyanides without using a metallic reagent. This method
can be used for the efficient and practical synthesis of var-
ious isocyanides.
NMR spectra were recorded in CDCl3 on a JEOL alpha-600 spec-
trometer or a JEOL AL-400 spectrometer. All 1H NMR spectra are
reported in ppm relative to TMS. All 13C NMR spectra are reported
in ppm relative to the central line of the triplet for CDCl3 at 77.0
ppm. IR spectra were recorded on a JEOL WINSPEC-50 spectrom-
eter. Electrospray ionization (ESI) and direct analysis in real time
(DART) mass spectra were recorded on a JEOL JMS-T100 mass
spectrometer. Chromatographic separations were carried out on a
Synthesis 2011, No. 24, 3997–4002 © Thieme Stuttgart · New York

4000
I. Okada, Y. Kitano
PAPER
9H-Fluoren-9-ylmethyl (11-Hydroxy-11-methyldodecyl)car-
silica gel column (Fuji Silysia Chemical BW-127ZH; 100–270
mesh or Kanto Chemical 60N; 63–210 mm) unless otherwise stated.
bamate (3e)
N2H4·H2O (1.1 mL, 23.0 mmol) was added to a soln of alcohol 3d
(3.96 g, 11.5 mmol) in MeOH (100 mL) and the mixture was re-
fluxed for 25 h. Brine (200 mL) was then added and the mixture was
extracted with EtOAc (400 mL). The combined extracts were
washed with H2O and brine then dried (MgSO4) and concentrated
under reduced pressure. The resulting amine 6 was used in the next
reaction without further purification.
Physical data for compounds 2,9 4b,10 4d,6b 4e,10 4g,10 4h,10 4i,10
6b
4j,10 4k,6b 4l, 4m6b 4n,6b 4o,11 4p,11 and 4q11 were identical to
those reported in the literature. Compounds 3d,12 3i,12 3k,6b 3l,6b
3m,6b 3n,6b and 3p11 were prepared according to literature proce-
dures.
2-Methyldodecan-2-ol (3a)
5% Pd/C (94.0 mg) was added to a soln of 2-methyldodec-11-en-2-
ol6b (2.02 g, 10.2 mmol) in EtOAc (20 mL) and the mixture was
stirred at r.t. for 22 h under H2. The resulting mixture was filtered
through Celite, and the filtrate was concentrated under reduced
pressure. The residue was purified by column chromatography [sil-
ica gel, EtOAc–hexane (1:5)] to give a colorless oil; yield: 1.67 g
(82%).
Amine 6 (713 mg, 3.40 mmol) was dissolved in CH2Cl2 (4 mL), N-
(9-fluorenylmethoxycarbonyloxy)succinimide (1.33 g, 4.08 mmol)
was added, and the mixture was stirred at r.t. for 2 h. Brine (50 mL)
was then added and the mixture was extracted with EtOAc (200
mL). The combined extracts were washed with H2O and brine then
dried (MgSO4) and concentrated under reduced pressure. The resi-
due was purified by column chromatography [silica gel, EtOAc–
hexane (1:3)] to give a white solid; yield: 1.05 g (49%); mp 77–
79 °C.
IR (NaCl): 3370 (br), 2960, 2926, 2852, 1468, 1377, 1186, 1149
cm–1.
IR (KBr): 3360 (br), 2972, 2927, 2848, 1689, 1527, 1450, 1377,
1250, 1230, 1146, 1014 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.48–1.43 (m, 2 H), 1.37–1.16 (m,
23 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (150 MHz, CDCl3): d = 70.9, 44.0, 31.9, 30.2, 29.6, 29.6,
29.6, 29.3, 29.1, 24.3, 22.6, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C13H28NaO: 223.2038;
found: 223.2034.
1H NMR (600 MHz, CDCl3): d = 7.76 (d, J = 7.3 Hz, 2 H), 7.59 (d,
J = 7.3 Hz, 2 H), 7.40 (t, J = 7.3 Hz, 2 H), 7.31 (t, J = 7.3 Hz, 2 H),
4.73 (br s, 1 H), 4.40 (t, J = 7.4 Hz, 2 H), 4.22 (t, J = 7.4 Hz, 1 H),
3.21–3.16 (m, 2 H), 1.53–1.43 (m, 4 H), 1.37–1.24 (m, 14 H), 1.22–
1.19 (m, 7 H).
13C NMR (150 MHz, CDCl3): d = 156.4, 144.0, 141.3, 127.6, 126.9,
125.0, 119.9, 70.9, 66.4, 47.3, 43.9, 41.0, 30.1, 29.9, 29.5, 29.4,
29.4, 29.2, 29.2, 26.7, 24.3.
HRMS (ESI): m/z [M + Na]+ calcd for C28H39NNaO3: 460.2828;
found: 460.2838.
2-Methyl-11-methoxydodecan-2-ol (3b)
KF (895 mg, 15.4 mmol) was added to a soln of 11-hydroxy-11-
methyldodecyl tosylate (5)10 in MeOH (20 mL) and the mixture was
stirred at r.t. for 29 h. Brine (80 mL) was then added and the mixture
was extracted with EtOAc (160 mL). The combined extracts were
washed with H2O and brine then dried (MgSO4) and concentrated
under reduced pressure. The residue was purified by column chro-
matography [silica gel, EtOAc–hexane (1:3)] to give a colorless oil;
yield: 136 mg (27%).
N-(11-Hydroxy-11-methyldodecyl)acetamide (3f)
Ac2O (880 mL, 9.3 mmol) was added to a soln of amine 6 (1.0 g,
4.65 mmol) in pyridine (10 mL) and the mixture was stirred at r.t.
for 20 h. Brine (70 mL) was then added and the mixture was extract-
ed with EtOAc (140 mL). The combined extracts were washed suc-
cessively with 3 M aq HCl, sat. aq NaHCO3, and brine then dried
(MgSO4) and concentrated under reduced pressure. The residue was
purified by column chromatography [silica gel, EtOAc–
MeOH (1:10)] to give a white solid; yield: 725 mg (61%); mp 61–
62 °C.
IR (NaCl): 3400 (br), 2970, 2927, 2854, 1466, 1375, 1120 cm–1.
1H NMR (600 MHz, CDCl3): d = 3.36 (t, J = 7.1 Hz, 2 H), 3.30 (s,
3 H), 1.56 (quint, J = 7.1 Hz, 2 H), 1.47–1.43 (m, 2 H), 1.37–1.24
(m, 15 H), 1.22–1.19 (m, 6 H).
13C NMR (150 MHz, CDCl3): d = 73.0, 71.0, 58.5, 44.0, 30.2, 29.6,
29.6, 29.6, 29.5, 29.5, 29.2, 26.1, 24.3.
HRMS (ESI): m/z [M + Na]+ calcd for C14H30NaO2: 253.2143;
found 253.2142.
IR (KBr): 3250 (br), 3095, 2978, 2964, 2933, 2924, 2852, 1645,
1564, 1464, 1367, 1292, 1228, 1203, 1188, 1186, 1153 cm–1.
1H NMR (600 MHz, CDCl3): d = 5.45 (br s, 1 H), 3.23 (dd, J = 13.6,
7.0 Hz, 2 H), 1.97 (s, 3 H), 1.52–1.44 (m, 4 H), 1.37–1.25 (m, 15 H),
1.21 (s, 6 H).
13C NMR (150 MHz, CDCl3): d = 170.0, 70.9, 43.9, 39.6, 30.1, 29.5,
29.5, 29.4, 29.2, 29.1, 29.1, 26.8, 24.2, 23.2.
HRMS (ESI): m/z [M + Na]+ calcd for C15H31NNaO2: 280.2252;
found: 280.2270.
11-Methyl-11-hydroxydodecyl Acetate (3c)
AcOH (633 mL, 11.0 mmol) and Et3N (1.53 mL, 11.0 mmol) were
added successively to a soln of alcohol 3i (1.03 g, 3.69 mmol) in
DMF (30 mL), and the mixture was stirred at 80 °C for 20 h. Brine
(50 mL) was then added and the mixture was extracted with EtOAc
(150 mL). The combined extracts were washed with sat. aq
NaHCO3 and brine then dried (MgSO4) and concentrated under re-
duced pressure. The residue was purified by column chromatogra-
phy [silica gel, EtOAc–hexane (1:3)] to give a colorless oil; yield:
516 mg (54%).
11-Fluoro-2-methyldodecan-2-ol (3g)
KF (6.20 g, 106.7 mmol) was added to a soln of tosylate 5 (1.51 g,
4.08 mmol) in ethylene glycol (30 mL) and the mixture was stirred
at r.t. for 7 d. Brine (100 mL) and H2O (50 mL) were then added and
the mixture was extracted with EtOAc (250 mL). The combined ex-
tracts were washed with H2O and brine then dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
column chromatography [silica gel, EtOAc–hexane (1:4)] to give a
colorless oil; yield: 381 mg (43%).
IR (NaCl): 3428 (br), 2968, 2931, 2854, 1741, 1468, 1367, 1242,
1038 cm–1.
1H NMR (600 MHz, CDCl3): d = 4.05 (t, J = 7.1 Hz, 2 H), 2.05 (s,
3 H), 1.62 (quint, J = 7.1 Hz, 2 H), 1.48–1.43 (m, 2 H), 1.37–1.25
(m, 14 H), 1.23–1.18 (m, 7 H).
13C NMR (150 MHz, CDCl3): d = 171.2, 70.9, 64.6, 43.9, 30.1, 29.5,
29.4, 29.2, 29.2, 29.2, 28.5, 25.8, 24.3, 20.9.
IR (NaCl): 3400 (br), 2927, 2854, 1468, 1377, 1151, 1055, 1043,
1003 cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C15H30NaO3: 281.2093;
found: 281.2084.
Synthesis 2011, No. 24, 3997–4002 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Isocyanides from Alcohols
4001
1H NMR (600 MHz, CDCl3): d = 4.44 (dt, J = 47.4, 6.2 Hz, 2 H),
1.73–1.64 (m, 2 H), 1.48–1.43 (m, 2 H), 1.42–1.26 (m, 14 H), 1.22–
1.19 (m, 7 H).
13C NMR (150 MHz, CDCl3): d = 84.2 (d, J = 163.8 Hz), 71.0, 44.0,
30.4, 30.3, 30.1, 29.6, 29.5, 29.2, 25.1, 25.1. 24.3.
IR (KBr): 3263 (br), 2939, 2846, 1624, 1529, 1348, 1261, 1039,
1012 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.85 (d, J = 2.3 Hz, 1 H), 7.54 (dd,
J = 8.7 and 2.3 Hz, 1 H), 7.07 (d, J = 8.7 Hz, 1 H), 4.68 (d, J = 5.9
Hz, 2 H), 3.96 (s, 3 H), 1.93 (br s, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C13H27FNaO: 241.1944:
found 241.1940.
13C NMR (150 MHz, CDCl3): d = 152.2, 139.2, 133.3, 132.7, 124.0,
113.6, 63.5, 56.6.
HRMS (ESI): m/z [M + Na]+ calcd for C8H9NNaO4: 206.0429:
found 206.0431.
11-Chloro-2-methyldodecan-2-ol (3h)
TsCl (3.66 g, 19.2 mmol) was added to a soln of 11-methyldodecan-
1,11-diol10 (2.77 g, 12.8 mmol) in pyridine (50 mL) and the mixture
was stirred at r.t. for 15 h. Brine (200 mL) was then added and the
mixture was extracted with EtOAc (200 mL). The combined ex-
tracts were washed successively with 3 M aq HCl, sat. aq NaHCO3,
and brine then dried (MgSO4) and concentrated under reduced pres-
sure. The residue was purified by column chromatography [silica
gel, EtOAc–hexane (1:1)] to give a slightly yellow oil; yield: 760
mg (25%).
Isocyanides 4: General Procedure
TMSCN (80 mL, 0.65 mmol) and MsOH (300 mL) were added suc-
cessively to a soln of the appropriate alcohol (0.5 mmol) and the
mixture was stirred at r.t. for 2 h before Et3N (700 mL, 5.0 mmol)
and then pyridine (81 mL, 1.0 mmol) and TsCl (114 mg, 0.6 mmol)
were added to the mixture. The mixture was then stirred for a further
2 h at r.t. Sat. aq NaHCO3 (30 mL) was added and the mixture was
extracted with EtOAc (100 mL). The combined extracts were
washed successively with 1 M aq HCl, sat. aq NaHCO3, and brine
then dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel) to give
the pure isocyanide.
IR (NaCl): 3380 (br), 2966, 2929, 2854, 1466, 1375, 1157 cm–1.
1H NMR (600 MHz, CDCl3): d = 3.53 (t, J = 7.0 Hz, 2 H), 1.77
(quint, J = 7.0 Hz, 2 H), 1.48–1.39 (m, 4 H), 1.37–1.26 (m, 12 H),
1.23–1.19 (m, 7 H).
13C NMR (150 MHz, CDCl3): d = 71.0, 45.1, 43.9, 32.6, 30.1, 29.5,
1,1-Dimethylundecyl isocyanide (4a)
Colorless oil.
IR (NaCl): 2981, 2925, 2854, 2138, 1467, 1369 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.58–1.52 (m, 2 H), 1.48–1.41 (m,
2 H), 1.39 (t, J = 1.8 Hz, 6 H), 1.37–1.23 (m, 14 H), 0.88 (t, J = 7.0
Hz, 3 H).
13C NMR (150 MHz, CDCl3): d = 152.8 (t, J = 5.0 Hz), 57.3 (t,
J = 5.0 Hz), 42.4, 31.8, 29.5, 29.5, 29.4, 29.4, 29.2, 28.9, 24.0, 22.6,
14.0.
29.4, 29.4, 29.2, 28.8, 26.8, 24.3.
HRMS (ESI): m/z [M + Na]+ calcd for C13H27ClNaO: 257.1648:
found 257.1651.
11-Iodo-2-methyldodecan-2-ol (3j)
KI (995 mg, 6.0 mmol) was added to a soln of tosylate 5 (739 mg,
1.99 mmol) in MeCN (20 mL) and the mixture was stirred at r.t. for
4 h. Brine (80 mL) was then added and mixture was extracted with
EtOAc (160 mL). The combined extracts were washed with succes-
sively with H2O and brine then dried (MgSO4) and concentrated un-
der reduced pressure. The residue was purified by column
chromatography [silica gel, EtOAc–hexane (1:3)] to give a color-
less oil; yield: 596 mg (92%).
HRMS (DART): m/z [M + H]+ calcd for C14H28N: 210.2222; found:
210.2236.
11-Isocyano-11-methyldodecyl Acetate (4c)
IR (NaCl): 3360 (br), 2968, 2927, 2852, 1466, 1375, 1365, 1167
cm–1.
1H NMR (600 MHz, CDCl3): d = 3.19 (t, J = 7.3 Hz, 2 H), 1.82
(quint, J = 7.3 Hz, 2 H), 1.48–1.44 (m, 2 H), 1.41–1.25 (m, 14 H)
1.23–1.18 (m, 7 H).
13C NMR (150 MHz, CDCl3): d = 70.1, 43.9, 33.5, 30.4, 30.1, 29.5,
29.4, 29.3, 29.2, 28.5, 24.3, 7.3.
Colorless oil.
IR (NaCl): 2983, 2929, 2856, 2129, 1738, 1468, 1367, 1240, 1039
cm–1.
1H NMR (600 MHz, CDCl3): d = 4.05 (t, J = 6.6 Hz, 2 H), 2.05 (s,
3 H), 1.65–1.58 (m, 2 H), 1.57–1.53 (m, 2 H), 1.48–1.26 (m, 20 H).
13C NMR (150 MHz, CDCl3): d = 171.1, 152.8 (t, J = 5.0 Hz), 64.5,
57.3 (t, J = 5.0 Hz), 42.4, 29.4, 29.4, 29.4, 29.3, 29.1, 28.9, 28.5,
25.8, 24.1, 20.9.
HRMS (ESI): m/z [M + Na]+ calcd for C13H27INaO: 349.1004:
found 349.1002.
HRMS (ESI): m/z [M + Na]+ calcd for C16H29NNaO2: 290.2096;
found: 290.2106.
(4-Methoxy-3-nitrophenyl)methanol (3q)
NaBH4 (380 mg, 10.0 mmol) was added to a soln of 4-(hydroxy-
methyl)-2-nitrophenol (355 mg, 2.26 mmol) in MeOH (30 mL) and
the mixture was stirred at r.t. for 4 h. Brine (30 mL) and 3 M aq HCl
(20 mL) were then added and the mixture was extracted with EtOAc
(100 mL). The combined extracts were washed successively with 3
M aq HCl, H2O, and brine then dried (MgSO4) and concentrated un-
der reduced pressure. The residue (332 mg) was dissolved in DMF
(20 mL) then K2CO3 (790 mg 5.72 mmol) and MeI (950 mL, 15.2
mmol) were added and the mixture was stirred at 35 °C for 40 h.
Brine (30 mL) was then added and the mixture was extracted with
EtOAc (100 mL). The combined extracts were washed successively
with H2O and brine, then dried (MgSO4) and concentrated under re-
duced pressure. The residue was purified by column chromatogra-
phy [silica gel, EtOAc–hexane (1:1)] to give a yellow solid: yield:
282 mg (68%); mp 62–63 °C.
N-(11-Isocyano-11-methyldodecyl)acetamide (4f)
Slightly yellow oil.
IR (NaCl): 3300 (br), 2981, 2926, 2854, 2129, 1651, 1556, 1468,
1369, 1294, 1225 cm–1.
1H NMR (600 MHz, CDCl3): d = 5.46 (br s, 1 H), 3.23 (dd, J = 6.8
and 3.4 Hz, 2 H), 1.97 (s, 3 H), 1.66–1.23 (m, 24 H).
13C NMR (150 MHz, CDCl3): d = 170.0, 152.6 (t, J = 5.0 Hz), 57.3
(t, J = 5.0 Hz), 42.3, 39.5, 29.4, 29.3, 29.3, 29.2, 29.1, 28.9, 28.9,
26.8, 23.9, 23.1.
HRMS (ESI): m/z [M + Na]+ calcd for C16H30N2NaO: 289.2256;
found: 289.2267.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Synthesis 2011, No. 24, 3997–4002 © Thieme Stuttgart · New York

4002
I. Okada, Y. Kitano
PAPER
(4) (a) Kitano, Y.; Ito, T.; Suzuki, T.; Nogata, Y.; Shinshima,
K.; Yoshimura, E.; Chiba, K.; Tada, M.; Sakaguchi, I.
J. Chem. Soc., Perkin Trans. 1 2002, 2251. (b) Kitano, Y.;
Yokoyama, A.; Nogata, Y.; Shinshima, K.; Yoshimura, E.;
Chiba, K.; Tada, M.; Sakaguchi, I. Biofouling 2003,
19 (Suppl. 1), 187. (c) Nogata, Y.; Kitano, Y.; Yoshimura,
E.; Shinshima, K.; Sakaguchi, I. Biofouling 2004, 20, 87.
(d) Kitano, Y.; Nogata, Y.; Shinshima, K.; Yoshimura, E.;
Chiba, K.; Tada, M.; Sakaguchi, I. Biofouling 2004, 20, 93.
(e) Kitano, Y.; Akima, C.; Yoshimura, E.; Nogata, Y.
Biofouling 2011, 27, 201.
(5) (a) Baldwin, J. E.; O’Neil, I. A. Synlett 1990, 603.
(b) Launay, D.; Booth, S.; Clemens, I.; Merritt, A.; Bradley,
M. Tetrahedron Lett. 2002, 43, 7201. (c) Porcheddu, A.;
Giacomelli, G.; Salaris, M. J. Org. Chem. 2005, 70, 2361.
(d) Kim, S.; Yi, K. Y. Tetrahedron Lett. 1986, 27, 1925.
(e) Creedon, S. M.; Crowley, H. K.; McCarthy, D. G.
J. Chem. Soc., Perkin Trans. 1 1998, 1015. (f) Bose, D. S.;
Goud, P. R. Tetrahedron Lett. 1999, 40, 747.
Acknowledgment
This work was partially supported by a Grant-in-Aid for the Encou-
ragement of Young Scientists (B) from the Ministry of Education,
Science, Sports, and Culture.
References
(1) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. (b) Ugi,
I.; Betz, W.; Fetzer, U.; Offerman, K. Chem. Ber. 1961, 94,
2814. (c) Isonitrile Chemistry; Ugi, I., Ed.; Academic Press:
New York, 1971. (d) Dömling, A.; Ugi, I. Angew. Chem.
Int. Ed. 2000, 39, 3168. (e) Ugi, I.; Dömling, A. In
Combinatorial Chemistry: A Practical Approach; Fenniri,
H., Ed.; Oxford University Press: Oxford, 2000, 287.
(f) Dömling, A. Curr. Opin. Chem. Biol. 2000, 4, 318.
(g) Ugi, I.; Werner, B.; Dömling, A. In Targets in
Heterocyclic Systems: Chemistry and Properties; Attanasi,
O. A.; Filippone, P., Eds.; Società Chimica Italiana: Rome,
2000.
(2) (a) Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130,
5446. (b) Li, X.; Danishefsky, S. J. Nat. Protoc. 2008, 3,
1666. (c) Li, X.; Yuan, Y.; Berkowitz, W. F.; Todaro, L. J.;
Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 13222.
(d) Li, X.; Yuan, Y.; Kan, C.; Danishefsky, S. J. J. Am.
Chem. Soc. 2008, 130, 13225. (e) Wu, X.; Li, X.;
Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 1523.
(f) Yuan, Y.; Zhu, J.; Li, X.; Wu, X.; Danishefsky, S. J.
Tetrahedron Lett. 2009, 50, 2329. (g) Rao, Y.; Li, X.;
Danishefsky, S. J. J. Am. Chem. Soc. 2009, 131, 12924.
(h) Wu, X.; Stocdill, J. L.; Wang, P.; Danishefsky, S. J.
J. Am. Chem. Soc. 2010, 132, 4098. (i) Wu, X.; Park, P. K.;
Danishefsky, S. J. J. Am. Chem. Soc. 2011, 133, 7700.
(3) (a) Fusetani, N. Nat. Prod. Rep. 2004, 21, 94. (b) Garson,
M. J.; Simpson, J. S. Nat. Prod. Rep. 2004, 21, 164.
(6) (a) Kitano, Y.; Chiba, K.; Tada, M. Tetrahedron Lett. 1998,
39, 1911. (b) Kitano, Y.; Chiba, K.; Tada, M. Synthesis
2001, 437.
(7) Chen, H. G.; Goel, O. P.; Kesten, S.; Knobelsdolf, J.
Tetrahedron Lett. 1996, 37, 8129.
(8) (a) Booth, M. R.; Frankiss, S. G. J. Chem. Soc., Chem.
Commun. 1968, 1347. (b) Reetz, M. T.; Chatziiosifidis, I.;
Künzer, H.; Müller-Starke, H. Tetrahedron 1983, 39, 961.
(c) Zieger, H. E.; Wo, S. J. Org. Chem. 1994, 59, 3838.
(9) Sasaki, T.; Eguchi, S.; Katada, T. J. Org. Chem. 1974, 39,
1239.
(10) Kobayashi, G.; Saito, T.; Kitano, Y. Synthesis 2011, 3225.
(11) Kitano, Y.; Manoda, T.; Miura, T.; Chiba, K.; Tada, M.
Synthesis 2006, 405.
(12) Kitano, Y.; Nogata, Y.; Matsumura, K.; Yoshimura, E.;
Chiba, K.; Tada, M.; Sakaguchi, I. Tetrahedron 2005, 61,
9969.
Synthesis 2011, No. 24, 3997–4002 © Thieme Stuttgart · New York