LiBF4: A mild and novel reagent for the O-H insertion reactions of α-diazoketones

Article abstract of DOI:10.1016/S0040-4039(03)01361-3

Lithium tetrafluoroborate (10 mol%) is found to catalyze efficiently the O-H insertion reactions of α-diazoketones with various alcohols including benzylic, allylic, propargylic and cyclopropyl carbinols to produce the corresponding α-alkoxy ketones in excellent yields with high selectivity. A solution of 10 mol% of LiBF₄ in acetonitrile provides a convenient reaction medium to carry out the O-H insertion reactions under mild and neutral conditions.

Full text of DOI:10.1016/S0040-4039(03)01361-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5691–5694
LiBF4: a mild and novel reagent for the OꢀH insertion reactions
of a-diazoketones
J. S. Yadav,* B. V. S. Reddy and P. Vishnumurthy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received 3 February 2003; revised 20 May 2003; accepted 30 May 2003
Abstract—Lithium tetrafluoroborate (10 mol%) is found to catalyze efficiently the OꢀH insertion reactions of a-diazoketones with
various alcohols including benzylic, allylic, propargylic and cyclopropyl carbinols to produce the corresponding a-alkoxy ketones
in excellent yields with high selectivity. A solution of 10 mol% of LiBF4 in acetonitrile provides a convenient reaction medium to
carry out the OꢀH insertion reactions under mild and neutral conditions.
© 2003 Elsevier Ltd. All rights reserved.
a-Diazocarbonyl compounds find widespread applica-
tions in organic synthesis especially in natural product
synthesis.1 The ready availability, relative stability and
facile decomposition of a-diazocarbonyl compounds
under thermal, photochemical, acid, base and transition
metal catalysis conditions make them useful intermedi-
ates in organic synthesis.2 Furthermore, a-diazoketones
undergo a variety of transformations such as cyclo-
propanation, aziridine formation, ylide formation,
CꢀH, XꢀH insertion reactions and cyclization reac-
tions.3 These reactions are chemoselective, which allow
new carbonꢀcarbon and carbonꢀhetero atom bond for-
mation under mild conditions. Recently, asymmetric
versions of diazocarbonyl reactions have also been
reported to produce enantiomerically pure compounds.4
Typically, transition metal catalysts such as Rh, Ru,
Os, Pt and Cu salts are employed to promote the
insertion reactions of a-diazocarbonyl compounds.5
Although, diazocarbonyl reactions are typically cata-
lyzed by transition metal salts, new catalytic systems
are being continuously explored in search of improved
efficiencies and cost effectiveness. Both protic acids as
well as Lewis acids and metal triflates have been
reported for OꢀH insertion reactions of a-diazocar-
bonyl compounds with alcohols.6,7 However, the devel-
opment of mild and neutral alternatives such as lithium
tetrafluoroborate would extend the scope and generality
of OꢀH insertion reactions of a-diazocarbonyl
compounds.
The catalytic properties of lithium perchlorate in
diethyl ether (LPDE) as a mild Lewis acid are well
documented and involve specific solute–Li interactions
with complexation to the diethyl ether and the less
−
nucleophilic bulky counterion ClO4 . However, the
inherently hazardous nature of perchlorate limits its use
to specific cases only on a small scale. An alternative
catalytic media was recently proposed. Acetonitrile
solutions of LiBF4 are safe and efficient catalytic media
for various organic transformations. The catalytic
applications of lithium tetrafluoroborate have recently
been reviewed.8
Herein, we wish to report the use of lithium tetra-
fluoroborate as a novel Lewis acid catalyst for OꢀH
Scheme 1.
Keywords: a-diazoketones; insertion reactions; lithium salts; a-alkoxy ketones.
* Corresponding author. Fax: +91-40-27160512; e-mail: yadav@iict.ap.nic.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01361-3

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Table 1. LiBF4-catalyzed OꢀH insertion reactions of a-diazoketones with alcohols

J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 5691–5694
5693
Acknowledgements
insertion reactions of a-diazocarbonyl compounds with
a range of alcohols to produce a-alkoxy ketones in
excellent yields under very mild conditions (Scheme 1).
B.V.S. thanks the CSIR, New Delhi, for the award of a
fellowship.
Accordingly, treatment of diazoacetophenone with allyl
alcohol in the presence of 10 mol% lithium tetra-
fluoroborate in acetonitrile afforded 2-allyloxy-1-
phenyl-1-ethanone in 95% yield (entry a). This
remarkable catalytic activity of lithium tetra-
fluoroborate provided the incentive for further study of
reactions with other a-diazocarbonyl compounds. Inter-
estingly, various a-diazoketones reacted smoothly with
a variety of alcohols in the presence of 10 mol% LiBF4
at ambient temperature to give the corresponding a-
alkoxy ketones as the products of OH insertion. Both
aromatic and aliphatic diazoketones afforded the
respective a-alkoxy ketones. The cis-cyhalothric acid
derived diazoketone also gave similar results (entries
n–p, Table 1). In all cases, the reactions proceeded
efficiently at ambient temperature. The method is clean
and the products are obtained in high yields with high
selectivity.9 No side product arising from a Wolff rear-
rangement was observed under these reaction condi-
tions. Other side products such as a-halo ketones (the
products of halide insertion) arising especially when
Lewis acids such as indium or aluminium halides are
used, were not detected under these conditions. To
determine the efficiency of this procedure, we have also
performed the reactions with various other lithium salts
such as lithium perchlorate and lithium triflate. Among
these catalysts, lithium tetrafluoroborate was found to
be the most effective. In contrast to LPDE (where the
Li+ acts as a Lewis acid), the role of LTAN (lithium
tetrafluoroborate in acetonitrile) as catalyst is ascribed
to its low stability making it similar to BF3. Acetonitrile
can form a complex CH3CN+–BF3 which acts as the
catalytic species.8 The limited solubility of LiBF4 in
common organic solvents restricted an extensive solvent
study. Furthermore, the reactions were also carried out
using 10 mol% LiClO4 in acetonitrile to compare its
efficiency with lithium tetrafluoroborate. In this reac-
tion media, high temperature (refluxing acetonitrile)
and longer reaction times (8–15 h) were typically
required to achieve comparable yields to those obtained
with LiBF4. A comparison of the efficiency of both
catalytic media showed that LiClO4 can be adequately
replaced by LiBF4 which is much easier and safer to
handle and even affords better yields in most cases. The
scope of this method is illustrated with respect to
various diazoketones and a range of alcohols and the
results are presented in Table 1.
References
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9. General procedure: A mixture of a-diazoketone (2 mmol),
alcohol (2 mmol), LiBF4 (0.2 mmol) in acetonitrile (10
mL) was stirred at room temperature for the appropriate
time (Table 1). After completion of the reaction as indi-
cated by TLC, the reaction mixture was quenched with
water and extracted with ethyl acetate (2×15 mL). Evapo-
ration of the solvent followed by purification on silica gel
(Merck, 100–200 mesh, ethyl acetate–hexane, 0.5–9.5)
afforded the pure a-alkoxy ketone.
In summary, an acetonitrile solution of lithium tetra-
fluoroborate was shown to be a highly efficient and
convenient catalytic medium for OꢀH insertion reac-
tions of a-diazoketones with alcohols to produce a-
alkoxy ketones. In addition to its simplicity and mild
reaction conditions, this method provides high yields of
products with high selectivity making it a useful and
attractive strategy for the preparation of a-alkoxy
ketones of synthetic importance.
Spectroscopic data for selected products: 3e: 1H NMR
(200 MHz, CDCl3) l: 0.15–0.25 (m, 2H), 0.48–0.57 (m,
2H), 1.0–1.15 (m, 1H), 3.35 (d, 2H, J=6.5 Hz), 4.60 (s,
2H), 7.45 (d, 2H, J=8.0 Hz), 7.90 (d, 2H, J=8.0 Hz). IR
(KBr) w: 3084, 2924, 1695, 1590, 1488, 1401, 1283, 1226,
1132, 1092, 980, 826 cm−1. EIMS: m/z: 224 M+, 154, 139,
125, 111, 75, 55, 39. HRMS calcd for C12H13ClO2:
224.0604. Found: 224.0639.

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3m: 1H NMR (200 MHz, CDCl3) l: 0.90 (t, 3H, J=6.5
3p: H NMR (200 MHz, CDCl3) l: 1.25 (s, 3H), 1.38 (s,
3H), 2.30 (dd, 1H, J=8.1, 8.5 Hz), 2.58 (d, 1H, J=8.1
Hz), 3.99–4.05 (m, 4H), 5.20–5.30 (m, 2H), 5.80–5.97 (m,
1H), 6.98 (d, 1H, J=8.5 Hz). IR (KBr) w: 3080, 2929,
1711, 1651, 1412, 1291, 1139, 953, 732 cm−1. EIMS: m/z:
296 M+, 225, 197, 161, 141, 71, 41. HRMS calcd for
C13H16ClF3O2: 296.0790. Found: 296.0827.
Hz), 1.20–1.39 (m, 20H), 1.50–1.70 (m, 2H), 2.45 (t, 2H,
J=6.5 Hz), 4.0 (s, 2H), 4.60 (s, 2H), 7.15–7.20 (m, 5H). IR
(KBr) w: 3085, 2923, 2854, 1721, 1655, 1461, 1274, 1115,
721 cm−1. EIMS: m/z: 332 M+, 212, 128, 105, 91, 77, 57,
43. HRMS calcd for C22H36O2: 332.2715. Found:
332.2751.