Green Protocol for the O-H Insertion of α-Diazoketones with Alcohols and Water Using Ionic Liquid [Bmim]BF4

Article abstract of DOI:10.1246/cl.2003.1060

α-Diazoketones undergo readily O-H insertion reactions with alcohols and water in hydrophilic [bmim]BF₄ ionic liquid in the absence of any acid catalyst to furnish α-alkoxy and α-hydroxy ketones in excellent yields under neutral conditions. The recovered ionic liquid can be easily reused in four to five cycles with consistent in activity. The use of ionic liquid helps to avoid the use of acid catalysts as well as environmentally unfavorable volatile organic solvents.

Full text of DOI:10.1246/cl.2003.1060

1
060
Chemistry Letters Vol.32, No.11 (2003)
Green Protocol for the O–H Insertion of ꢀ-Diazoketones with Alcohols and Water
Using Ionic Liquid [Bmim]BF4
ꢀ
J. S. Yadav, B. V. S. Reddy, and M. Srinivas
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received August 4, 2003; CL-030720)
ꢀ
-Diazoketones undergo readily O–H insertion reactions with
BF -
4
alcohols and water in hydrophilic [bmim]BF4 ionic liquid in the
absence of any acid catalyst to furnish ꢀ-alkoxy and ꢀ-hydroxy ke-
tones in excellent yields under neutral conditions. The recovered
ionic liquid can be easily reused in four to five cycles with consis-
tent in activity. The use of ionic liquid helps to avoid the use of
acid catalysts as well as environmentally unfavorable volatile or-
ganic solvents.
N N
+
(
)n
n = 3 = [hmim]PF
n = 5 = [octmim]PF4
4
n = 1 = [bmim]BF4
Figure 1.
ticular process. Since ionic liquids are entirely composed of ions,
they can provide an ideal reaction medium for reactions that in-
volve reactive ionic intermediates. Owing to the stabilization of
charged intermediates by ionic liquids, they can promote enhanced
selectivities and reaction rates. As a result of their green creden-
tials and potential to enhance reaction rates and selectivities, ionic
ꢀ-Hydroxy ketones are useful intermediates in organic syn-
1
thesis especially in asymetric aldol reactions. ꢀ-Diazoketones
are versatile building blocks for the synthesis of many biologically
10
liquids are finding increasing applications in organic synthesis.
2
active natural products. The ready availability, relative stability,
However, there are no examples of the use of ionic liquids for
the O–H insertion of diazoketones with alcohols and water.
With an ever-increasing quest for exploration of newer reac-
tions in ionic liquids, we report herein for the first time the use
of ionic liquids as green solvents for the O–H insertion reactions
of ꢀ-diazocarbonyl compounds with water and alcohols to afford
ꢀ-hydroxy- and ꢀ-alkoxy ketones in excellent yields. For example,
treatment of diazoacetophenone with water at 80 C in the absence
of any acid catalyst in [bmim]BF afforded 2-hydroxy acetophe-
none in 85% yield (Scheme 1).
and facile decomposition of ꢀ-diazocarbonyl compounds under
acid or thermal or photochemical conditions make them useful in-
termediates in organic synthesis. Furthermore, ꢀ-diazoketones
undergo a variety of transformations such as cyclopropanation,
aziridine formation, ylide formation, C–H, X–H insertion reactions
and cyclization reactions. The carbene reactions are chemoselec-
tive, which allow new carbon–carbon and carbon–hetero atom
bond formation under mild conditions. Recently, asymmetric ver-
sion of diazo insertions have also been reported to afford enantio-
3
4
ꢁ
4
5
merically enriched compounds. Typically, transition metal cata-
lysts such as Rhodium and Copper salts are employed to
promote the insertion reactions of ꢀ-diazocarbonyl compounds.
The reaction proceeds smoothly in [bmim]BF4 ionic liquid
without the need of any acid catalyst. The remarkable catalytic ac-
tivity of [bmim]BF prompted us to study it further in reactions
6
4
Although, diazoinsertion reactions are typically catalyzed by tran-
sition metal salts, new catalytic systems are being continuously ex-
plored in search of improved efficiencies and cost effectiveness.
Both protic acids and Lewis acids including metal triflates have
been reported for the O–H insertion of ꢀ-diazocarbonyl com-
with other ꢀ-diazocarbonyl compounds. Interestingly, a variety
of ꢀ-diazoketones reacted efficiently with water and alcohols un-
der the reaction conditions to give the corresponding ꢀ-hydroxy-
and ꢀ-alkoxy ketones as products of O–H insertion. Diazoketone
derived from cyhalothric acid also gave similar results. Both aro-
matic and aliphatic diazoketones afforded the respective ꢀ-alkoxy-
and ꢀ-hydroxy ketones in excellent yields with high selectivity. A
variety of substrates including tert-butyl, isopropyl, allylic, ben-
zylic, propargylic alcohols, and cyclopropyl carbinols underwent
smoothly O–H insertion reactions with ꢀ-diazoketones to give
the corresponding ꢀ-alkoxy ketones (Table 1). The products could
be easily separated by simple extraction with diethyl ether. No side
product arising from Wolff rearrangement was observed under
these reaction conditions. Other side products such as ꢀ-halo ke-
tones (as products of halide insertion) arising especially from
Lewis acids such as indium or aluminium halides, were not detect-
ed under these conditions. To compare the efficacy of ionic liquids,
we have carried out the reactions both in hydrophobic [bmim]PF6
and hydrophilic [bmim]BF4 ionic liquids. Among them,
7
pounds. However, most of these methods often involve the use
of acid catalysts which always demand aqueous work-up for the
catalyst separation, recycling and disposal. Furthermore, some of
them involve the use of harsh conditions, expensive reagents and
suffer from the lack of simplicity and also the yields and selectiv-
ities reported are far from satisfactory owing to the occurance of
several side reactions. In view of the increasing synthetic impor-
tance of ꢀ-hydroxyketones as synthons in asymmetric aldol reac-
tions, the development of simple, convenient, and environmentally
friendly approaches are desirable. In recent times, ionic liquids
have emerged as a substitute and alternative solvents for the immo-
8
bilization of transition metal catalysts, Lewis acids, and enzymes.
They are being used as green solvents with interesting properties
such as tunable polarity, high thermal stability, immiscibility with
a number of organic solvents, negligible vapor pressure, and ease
[bmim]BF was found to be the most effective and giving the best
4
9
of recyclability. They are referred to as ‘designer solvents’ as their
O
O
[
Bmim]BF4
properties such as hydrophilicity, hydrophobicity, Lewis acidity,
viscosity, and density can be altered by the fine-tuning of parame-
ters such as the choice of organic cation, inorganic anion, and the
length of alkyl chain attached to an organic cation (Figure 1).
These structural variations offer flexibility to the chemist to
devise the most idealized solvent, catering to the needs of any par-
N2
OR
R
+
R'-OH
R
80 °C
2
3
1
R ' = H, alkyl, benzyl, cyclopropyl, allyl, propargyl
Scheme 1.
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.11 (2003)
1061
Table 1. [Bmim]BF4-catalyzed OH-insertion reactions of ꢀ-diazo ke-
tones
as acetonitrile and chloroform. In these organic solvents in the ab-
sence of Lewis acids, the diazoketones were unreacted and com-
pletely recovered even under refluxing conditions. In ionic liquid
even in the absence of acid catalyst, the reactions proceeded
smoothly with high efficiency. It is noteworthy to mention that
O–H insertion of ꢀ-diazoketones with alcohols proceeds smoothly
at room temperature when using 5 mol % of bismuth triflate in
α
−Diazoketone
Alcohol
2
Producta
3
Reaction Tme Yield
b
Entry
1
/h
/%
O
O
a
b
Cl
N2
Cl
OH
H O
2
4.5
3.5
86
CF3
CF
3
O
O
ꢁ
Cl
Cl
O
O
90
85
[bmim]BF4. In the absence of catalyst, high temperature (80 C)
OH
"
CF3
and longer reaction times (3.5–6 h) are typical to achieve compara-
ble yields to those obtained with 5 mol % of Bi(OTf)3 in
[bmim]BF4. The scope of this method is illustrated with various di-
azoketones and a wide range of alcohols and the results are pre-
sented in the Table.
In summary, [bmim]BF4 ionic liquid has been employed for
the first time as an efficient and recyclable reaction media for the
O–H insertion of ꢀ-diazoketones with alcohols and water to afford
c
d
OH
OH
5.0
4.5
6.0
"
"
CF3
O
87
82
Cl
O
CF3
e
f
Cl
O
O
"
"
OH
OH
2
Cl
Cl
O
O
Cl
CF3
CF3
5.0
84
ꢀ-alkoxy- and ꢀ-hydroxy-ketones respectively. Ionic liquid plays
O
a dual role of catalyst and the promoter. The diazoketones (electro-
philic carbenes) show increased reactivity in ionic liquids thereby
reducing the reaction times and improving the yields. The simple
experimental and product isolation procedures combined with ease
of recovery and reuse of ionic liquids is expected to contribute to
the development of green strategy for the preparation of ꢀ-alkoxy-
and ꢀ-hydroxy ketones.
N2
O
g
H O
OH
5.0
4.0
85
91
O
O
h
OH
O
O
"
Ph
4
.5
87
i
j
Ph
OH
OH
"
"
O
O
5.0
92
83
BVS thanks CSIR, New Delhi, for the award of fellowship.
O
O
O
O
4
.5
k
OH
References and Notes
"
"
1
a) J. K. Whitsell and C. M. Buchanan, J. Org. Chem., 51, 5443 (1986). b) B. M.
Trost, H. Ito, and E. R. Silcoff, J. Am. Chem. Soc., 123, 3367 (2001). c) T.
Hoffmann, T. Zhong, B. List, D. Shabat, J. Anderson, S. Gramatikova, R. A.
Lerner, and C. F. Barbas, III, J. Am. Chem. Soc., 120, 2768 (1998).
Ph
Ph OH
OH
5.0
5.5
85
82
l
O
O
O
OH
O
N2
2
3
4
a) A. Padwa and M. D. Weingarten, Chem. Rev., 96, 223 (1996). b) A. Padwa,
Top. Curr. Chem., 189, 121 (1997). c) M. A. Calter, Curr. Org. Chem., 1, 37
m
Cl
Cl
(1997).
n
o
4.5
5.0
90
83
a) M. P. Doyle, M. A. McKervey, and T. Ye, ‘‘Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds from Cyclopropanes to Ylides,’’
Wiley-InterScience, New York (1998).
a) T. Ye and M. A. McKervey, Chem. Rev., 94, 1091 (1994). b) A. Padwa and S.
A. Hornbuckle, Chem. Rev., 91, 263 (1991). c) M. P. Doyle, Chem. Rev., 86, 919
"
OH
Cl
Cl
O
O
O
O
Ph
"
Ph OH
(1986).
M. P. Doyle and M. A. McKervey, Chem. Commun., 1997, 983.
a) E. Aller, D. S. Brown, G. G. Cox, D. J. Miller, and C. J. Moody, J. Org.
Chem., 60, 4449 (1995). b) S. Sengupta, D. Das, and D. S. Sarma, Tetrahedron
Lett., 37, 8815 (1996). c) C. J. Moody and D. J. Miller, Tetrahedron, 54, 2257
p
4.0
OH
89
"
5
6
Cl
a
1
b
All products were charactarized by H NMR, IR and MS. Isolated and
unoptimized yields.
(
3
1998). d) A. Demonceau, C. A. Lemoine, and A. F. Noels, Tetrahedron Lett.,
7, 1025 (1996).
results. Similar results were also obtained with ionic liquids having
longer alkyl chains such as 1-hexyl-3-methylimidazolium tetra-
fluoroborate [hmim]BF4 or 1-octyl-3-methylimidazolium tetra-
fluoroborate [octmim]BF4. These air and moisture stable ionic liq-
7
a) P. J. Giddings, D. I. John, and E. J. Thomas, Tetrahedron Lett., 1978, 995. b)
S. V. Pansare, R. P. Jain, and A. Bhattacharyya, Tetrahedron Lett., 40, 5255
(1999). c) S. Muthusamy, S. A. Babu, and C. Gunanathan, Tetrahedron Lett.,
4
R. Sheldon, Chem. Commun., 2001, 2399.
a) T. Welton, Chem. Rev., 99, 2071 (1999). b) P. Wasserscheid and W. Keim,
Angew. Chem., Int. Ed., 39, 3772 (2000).
10 C. M. Gordon, Appl. Catal., A, 222, 101 (2001).
3, 3133 (2002). d) K. Jones and T. Toutounji, Tetrahedron, 57, 2427 (2001).
ꢁ
8
9
uids can be easily recovered and reused after activation at 80 C for
3
–4 h. Thus, activated [bmim]BF4 ionic liquid was recycled for
several times with consistent in activity, even after fourth cycle
the product 3b was obtained with the similar yield and purity of
those obtained in the first cycle. No trace of impurites derived from
ionic liquids were detected by GLC analysis of the products. Ionic
liquids used in this study were obtained from Fluka and also pre-
pared from the readily available and inexpensive N-methyl imida-
zole, 1-chlorobutane, and sodium hexafluorophosphate or sodium
tetrafluroborate and their purity was determined by comparing of
1
1
General procedure: A mixture of ꢀ-diazoketone (1 mmol) and alcohol (2 mmol)
or water (3 mmol) in 1-butyl-3-methylimidazolium tetrafluoroborate (3 mL)
were stirred at 80 C for the appropriate time (Table 1). After completion of
ꢁ
the reaction, as indicated by TLC, the reaction mixture was extracted with
diethyl ether (3 ꢃ 10 mL). The combined ether extracts were concentrated in
vacuo and the resulting product was directly charged onto a small silica gel
column and eluted with a mixture of ethyl acetate:n-hexane (2:8) to afford pure
alkoxy or hydroxy ketone. The remaining ionic liquid was further washed with
ether and recycled in subsequent runs. Spectroscopic data for selected pro-
ducts:3b: 1H NMR (200 MHz, CDCl ) ꢁ: 1.25 (s, 3H), 1.38 (s, 3H), 2.30 (dd,
1
3
their H NMR spectra with commercial samples. The purity of
[
1
H, J ¼ 8:1, 8.5 Hz), 2.58 (d, 1H, J ¼ 8:1 Hz), 3.99–4.05 (m, 4H), 5.20–5.30
bmim]PF6 ionic liquid is ꢂ97:0% (NMR). The use of ionic liquids
(
m, 2H), 5.80–5.97 (m, 1H), 6.98 (d, 1H, J ¼ 8:5 Hz). IR (KBr) ꢂ 3080,
À1 þ
as reaction medium for this reaction avoids the use of moisture sen-
sitive reagents or heavy metal Lewis acids or solid acids as promot-
ers thereby minimizing the production of toxic or corrosive acid
waste during workup. In order to compare the efficiency of ionic
liquids, the reactions were also conducted in organic solvents such
2929, 1711, 1651, 1412, 1291, 1139, 953, 732 cm . EIMS: m=z: 296 M ,
1
225, 197, 161, 141, 71, 41. 3p: H NMR (200 MHz, CDCl3) ꢁ : 0.15–0.25
(
m, 2H), 0.48–0.57 (m, 2H), 1.0–1.15 (m, 1H), 3.35 (d, 2H, J ¼ 6:5 Hz), 4.60
(s, 2H), 7.45 (d, 2H, J ¼ 8:0 Hz), 7.90 (d, 2H, J ¼ 8:0 Hz). IR (KBr) ꢂ 3084,
À1
2
m=z: 224 M, 154, 139, 125, 111, 75, 55, 39.
924, 1695, 1590, 1488, 1401, 1283, 1226, 1132, 1092, 980, 826 cm . EIMS:
þ
Published on the web (Advance View) October 20, 2003; DOI 10.1246/cl.2003.1060