Selective synthesis of isocyanides from secondary alcohols by a new type of oxidation-reduction condensation

Article abstract of DOI:10.1246/cl.2005.1124

Selective synthesis of isocyanides from secondary alcohols via alkyl diphenylphosphinites is established by a new type of oxidation-reduction condensation in controlling the ambident reactivity of cyanide anion. In the presence of ZnO, isocyanides are obtained exclusively in moderate to high yields. Copyright

Full text of DOI:10.1246/cl.2005.1124

1124
Chemistry Letters Vol.34, No.8 (2005)
Selective Synthesis of Isocyanides from Secondary Alcohols
by a New Type of Oxidation–Reduction Condensation
Kouta Masutani,y;yy Tomofumi Minowa,y;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received May 10, 2005; CL-050616)
Selective synthesis of isocyanides from secondary alcohols
via alkyl diphenylphosphinites is established by a new type of
oxidation–reduction condensation in controlling the ambident
reactivity of cyanide anion. In the presence of ZnO, isocyanides
are obtained exclusively in moderate to high yields.
Table 1. Additive effect
CN
NC
Ph
Ph
(EtO)2P(O)CN (1.0 equiv.)
DMBQ (1.5 equiv.)
OPPh2
1
+
Ph
(1.5 equiv.)
Additive (2.0 equiv.)
CHCl3 (0.10 M), rt, 24 h
Isocyanides are the class of compounds which possess for-
mally divalent carbon that exhibit unique reactivities.1 By mak-
ing the best use of their characteristics, isocyanides have been
employed in multicomponent reactions such as Passerini2 and
Ugi3 reactions, synthesis of heterocycles4 as well as ligands of
transition metal complexes.5 Isocyanides can be prepared by var-
ious methods such as nucleophilic displacement of alkyl halides
by silver cyanide,6 dehydration of formamides,7 carbylamine re-
action,8 or reduction of isocyanates or isothiocyanates.9 Since
these reactions are often carried out under basic conditions or
at high reaction temperatures, it is desired to develop more con-
venient synthetic reactions that proceed under mild conditions.
It was previously reported from our laboratory that the prep-
aration of nitriles from primary alcohols was accomplished via a
new type of oxidation–reduction condensation using 2,6-dimeth-
yl-1,4-benzoquinone (DMBQ) and diethyl cyanophosphonate.10
In the course of our study on the application of this condensation
reaction to the secondary alcohols, formation of an isocyanide
happened to be observed. This incident prompted us to study a
selective preparation of isocyanides. In this communication,
we would like to report a selective synthesis of isocyanides from
the corresponding secondary alcohols via a new type of oxida-
tion–reduction condensation process.
During the study on cyanation of 4-phenyl-2-butanol with
diethyl cyanophosphonate in CHCl3, it was found unexpectedly
that the corresponding isocyanide 2 was formed in 23% yield
along with the aimed nitrile 1 (Scheme 1). Formation of iso-
cyanides by the conventional cyanations of the secondary alco-
hols with cyanide ion has not yet been known.11 Since cyanide
anion works as an ambident nucleophile12 and upon considering
the Pearson’s HSAB principle,13 it was figured that either nitriles
or isocyanides would be formed selectively in the presence of an
additive such as inorganic salt: that is, hard metal salts interact
2
Yield
Yield
Entry
Entry
Additive
Additive
(1:2)/%a
(1:2)/%a
6
7
Ag2O
HgO
CdO
ZnO
ZnO
None
Li2SO4
Na2CO3
Mg(OTf)2
CaO
88
(74 : 26)
88
(79 : 21)
80
(82 : 18)
72
(84 : 16)
48
0
0
1
2
3
4
5
8
68
(<5 : >95)
9
57
(<5 : >95)
82b,c
(<5 : >95)
10
(81 : 19)
aIsolated as a mixture of isomers. Numbers in parentheses
are ratios of isomers determined by comparing the peak of
1
b
the methine proton of each isomer in H NMR analysis. The
reaction was carried out in CH2Cl2 (1.0 M). c1.0 equiv. of
ZnO was used.
preferentially at the hard position of nitrogen of cyanide to
provide niriles whereas soft metal salts interact at soft C-position
to afford isocyanides.
The effect of inorganic salts was then examined in order to
form either nitrile or isocyanide selectively (Table 1). In the first
place, reactions were tried by using various alkali metal and al-
kaline earth metal salts (Table 1, Entries 2–5). However, the de-
sired nitrile was not obtained in a good yield, which was contrary
to our expectation. Then, the same reaction was carried out in the
presence of heavy metal salts (Table 1, Entries 6–9), and to our
surprise, it was found that the corresponding isocyanide was ob-
tained exclusively when ZnO and CdO were used as additives
(Table 1, Entries 8 and 9). Despite CdO afforded the isocyanide
in higher yield, further optimization of the case with ZnO
was tried from the environmental-benign point of view. Under
the optimized conditions (1.0 M of CH2Cl2 and 1.0 equiv.
of ZnO), the desired isocyanide was obtained in 82% yield
(Table 1, Entry 10).
OH
OPPh2
n-BuLi, Ph2PCl
THF, 0 °C, 1 h
Ph
Ph
+
CN
NC
(EtO)2P(O)CN, DMBQ
CHCl3, rt, 24 h
Next, cyanation of several secondary alcohols was tried
under the optimized conditions (Table 2). Alkyl diphenyl phos-
phinites derived from 1-phenyl-2-propanol and 1-phenyl-3-pen-
tanol provided the corresponding isocyanides in good yields
Ph
Ph
2: 23%
1: 65%
Scheme 1.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.8 (2005)
1125
Table 2. Selective formation of isonitriles from various second-
ary alcohols with ZnO as an additive
was washed with saturated aqueous NaHCO3 solution and then
with brine, and was dried over anhydrous sodium sulfate. After
filtration and evaporation, the resulted residue was purified by
preparative TLC to afford the corresponding isocyanide.
Thus, selective synthesis of isocyanides from secondary
alcohols by a new type of oxidation–reduction condensation
was achieved in the presence of ZnO.16 Further study on this
type of selective condensation reaction is now in progress.
(EtO)2P(O)CN (1.0 equiv.)
DMBQ (1.5 equiv.)
Ph2PCl, Et3N
DMAP
ROPPh2
ROH
Entry
RNC
ZnO (1.0 equiv.)
CH2Cl2, rt, 24 h
THF, rt, 2 h
(1.5 equiv.)
Yield/%
ROH
OH
ROPPh2
RNC
63a
This study was supported in part by the Grant of the 21st
Century COE Program, Ministry of Education, Culture, Sports,
Science and Technology (MEXT).
1
2
3
4
5
6
7
quant.
Ph
Ph
OH
95
82
89
63
72
78
81
40b
References and Notes
1
a) ‘‘Isonitrile Chemistry,’’ ed. by I. Ugi, Academic Press,
New York (1971). b) M. Suginome and Y. Ito, in ‘‘Science of
Synthesis,’’ ed. by S.-I. Murahashi, Thieme, Stuttgart (2004),
Vol. 19, p 445.
OH
OH
PMBO
2
3
L. Banfi and R. Riva, Org. React., 65, 1 (2005).
A. Domling and I. Ugi, Angew. Chem., Int. Ed. Engl., 39, 3168
quant.
71
TBDPSO
¨
(2000).
OH
OH
4
5
a) S. Marcaccini and T. Torroba, Org. Prep. Proced. Int., 25,
141 (1993). b) D. van Leusen and A. M. van Leusen, Org.
React., 57, 417 (2001).
a) P. M. Treichel, Adv. Organomet. Chem., 11, 21 (1973). b) Y.
Yamamoto, Coord. Chem. Rev., 32, 193 (1980). c) E. Singleton
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a) W. Lieke, Ann. Chem. Pharm., 112, 316 (1859). b) H. L.
Jackson and B. C. McKusick, Org. Synth., Coll. Vol. IV, 438
(1963).
a) I. Ugi and R. Meyr, Chem. Ber., 93, 239 (1960). b) I. Ugi, R.
Meyr, M. Lipinski, F. Bodensheim, and F. Rosendahl, Org.
Synth., Coll. Vol. V, 300 (1973).
a) A. W. Hoffmann, Ann. Chem. Pharm., 144, 114 (1867). b)
G. W. Gokel, R. P. Widera, and W. P. Weber, Org. Synth., Coll.
Vol. VI, 232 (1988).
O
N
86
OH
99
Ph
6
7
8
9
b
a1.5 mL of CH2Cl2 was used. The reaction time was 3 h.
OH
OPPh2
NC
Ph2PCl, Et3N, DMAP
Ph
99% ee (R)
THF, rt, 2 h
Ph
Ph
(EtO)2P(O)CN, DMBQ
ZnO, CH2Cl2, rt, 24 h
T. Mukaiyama, H. Nambu, and M. Okamoto, J. Org. Chem., 27,
3651 (1962).
96% ee (S)
Scheme 2.
10 T. Mukaiyama, K. Masutani, and Y. Hagiwara, Chem. Lett., 33,
1192 (2004).
(Table 2, Entries 1 and 2). Monoprotected diols having p-
methoxybenzyl group or tert-butyldiphenylsilyl group also
provided the desired isocyanides in satisfactory yields (Table 2,
Entries 3 and 4). On the other hand, heterocyclic rings such as
benzofuran and N-methyl indole were not affected under the
above conditions (Table 2, Entries 5 and 6). The corresponding
isocyanide was obtained in 40% yield from 1-phenylethanol
(Table 2, Entry 7).
Cyanation of an optically active secondary alcohol was next
examined in order to know for certain the stereochemistry of the
reaction. It was found then that the inversion of configuration
was observed if (R)-4-phenyl-2-butanol was used as the substrate
(Scheme 2).14
Typical experimental procedure is as follows: to a stirred
suspension of dry ZnO (3N5, purchased from KANTO
KAGAKU) (0.50 mmol), alkyl diphenylphosphinite15 (0.75
mmol) and diethyl cyanophosphonate (0.50 mmol) was added
a dichloromethane solution (0.50 mL) of 2,6-dimethyl-1,4-ben-
zoquinone (0.75 mmol) at room temperature under argon
atmosphere. After 24 h, the reaction mixture was quenched with
saturated aqueous NaHCO3 solution and the aqueous layer was
extracted with dichloromethane. The combined organic layer
11 a) H. Loibner and E. Zbiral, Helv. Chim. Acta, 59, 2100 (1976).
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´
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´
´
ˆ
Kawamura, H. Kaku, and S. Ito, Tetrahedron Lett., 40, 7355
(1999). e) N. Iranpoor, H. Firouzabadi, B. Akhlaghinia, and
N. Nowrouzi, J. Org. Chem., 69, 2562 (2004).
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Iffland, J. Am. Chem. Soc., 77, 6269 (1955). b) O. A. Reutov,
I. P. Beletskaya, and A. L. Kurts, in ‘‘Ambident Anions,’’
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Pearson, J. Chem. Educ., 45, 581, 643 (1968). c) T.-L. Ho,
Chem. Rev., 75, 1 (1975). d) T.-L. Ho, in ‘‘Hard and Soft Acids
and Bases Principle in Organic Chemistry,’’ Academic Press,
New York (1977).
14 The absolute configuration of the isocyanide was determined
by conversion to the known amine and comparison of the sign
of specific rotation.
15 The preparation of various secondary alkyl diphenylphos-
phinites, see: K. Ikegai, W. Pluempanupat, and T. Mukaiyama,
Chem. Lett., 34, 638 (2005).
16 Cyanation of a primary alcohol such as 3-phenyl-1-propanol
gave ca. 2:1 ratio of the corresponding isocyanide and nitrile.
Published on the web (Advance View) July 9, 2005; DOI 10.1246/cl.2005.1124