Aminoborohydrides. 14. Lithium aminoborohydrides in the selective reduction or amination of alkyl methanesulfonate esters

Article abstract of DOI:10.1021/ol0167659

formula presented Lithium aminoborohydride (LAB) reagents initiate the amination or reduction of alkyl methanesulfonate esters, as dictated by reaction conditions. Alkyl methanesulfonate esters treated with unhindered LABs provide tertiary amines in excellent yield. Reduction to the corresponding alkane is achieved using a hindered LAB reagent or by forming the highly reactive Super-Hydride reagent in situ using LAB and a catalytic amount of triethylborane. The reduction methodology disclosed herein is a safe and convenient alternative to existing synthetic methods.

Full text of DOI:10.1021/ol0167659

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3915-3918
Aminoborohydrides. 14. Lithium
Aminoborohydrides in the Selective
Reduction or Amination of Alkyl
Methanesulfonate Esters
Shannon Thomas, Tai Huynh, Vanessa Enriquez-Rios, and Bakthan Singaram*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Cruz,
Santa Cruz, California 95064
singaram@chemistry.ucsc.edu
Received September 17, 2001
ABSTRACT
Lithium aminoborohydride (LAB) reagents initiate the amination or reduction of alkyl methanesulfonate esters, as dictated by reaction conditions.
Alkyl methanesulfonate esters treated with unhindered LABs provide tertiary amines in excellent yield. Reduction to the corresponding alkane
is achieved using a hindered LAB reagent or by forming the highly reactive Super-Hydride reagent in situ using LAB and a catalytic amount
of triethylborane. The reduction methodology disclosed herein is a safe and convenient alternative to existing synthetic methods.
Alkyl and aryl methanesulfonate esters are important reagents
in organic synthesis.1 They have excellent leaving group
properties, are readily available, and are common intermedi-
ates for the deoxygenation of alcohols to their parent
alkanes.2 Deoxygenation of alcohols to alkanes is a common
synthetic transformation that is usually achieved by reducing
the sulfonate ester derivatives with lithium aluminum hydride
(LAH).3 LAH reductions of primary alkyl sulfonates gener-
ally proceed with satisfactory results, whereas sterically
hindered alkyl sulfonates treated with LAH suffer from
unfavorable side reactions (elimination and sulfer-oxygen
bond cleavage).3 For reactions where LAH cannot be used,
lithium triethylborohydride (LiEt3BH or Super-Hydride) is
an excellent alternative.4 However, for complete reduction,
2 equiv of the highly reactive LiEt3BH is required and
oxidation of the resulting trialkylborane complicates the
workup procedure in a large-scale reaction.
Lithium aminoborohydride (LAB) reagents have recently
emerged as a new class of powerful and selective reducing
agents5 that could potentially carry out the deoxygenation
of alcohols to their alkanes. However, under certain circum-
stances, LABs preferentially transfer their amine functionality
over a hydride. For example, both unsubstituted and substi-
tuted benzyl halides treated with LAB reagents at 0 °C give
the corresponding tertiary amine-borane complexes, whereas
the same reaction at 65 °C affords toluene products.6 There
is thus a difference in the reactivity of LAB reagents toward
(4) (a) Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1976, 41, 3064.
(b) Super-Hydride is a registered trademark of Sigma-Aldrich Chemical
Co.
(5) Fisher, G. B.; Harrison, J.; Fuller, J. C.; Goralski, C. T.; Singaram,
B. Tetrahedron Lett. 1992, 33, 4533.
(6) Collins, C. J.; Lanz, M.; Goralski, C. T.; Singaram, B. J. Org. Chem.
1999, 64, 2574.
(1) Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85.
(2) March, J. AdVanced Organic Chemisty, 4th ed; Wiley and Sons: New
York, 1992; pp 441-442.
(3) Gaylord, N. G. Reduction with Complex Metal Hydrides; Interscience
Publishers: New York, 1956; pp 855-875.
10.1021/ol0167659 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/08/2001

alkyl halides with temperature. Additionally, LAB reagents
undergo a unique reaction with 2-halobenzonitriles.7 During
this reaction, reduction of the nitrile is accompanied by
amination at the carbon bearing the halogen, and 2-ami-
nobenzylamines are obtained. Clearly, LAB reagents are
capable of mediating the transfer of both their amine and
hydride functionalities; exploring and ultimately controlling
this dual reactivity is desired. Herein we report the controlled
reactivity of LABs toward alkyl sulfonates as modulated by
temperature, steric bulk, and the in situ generation of Super-
Hydride.
addition to these two species, LiBH4 (δ -43, quin.) and H2-
BNR2 (δ 0, t) are present. This difference in boron species
with temperature can be accounted for by the more efficient
metal hydride transfer reaction at 65 °C between the more
Lewis acidic boron of the tertiary amine-borane and the
less Lewis acidic boron of the LAB reagent.9 In this way,
LiBH4 is generated along with the amino-borane side
product for reactions run at high temperature (Figure 1). Such
Primary alkyl methanesulfonates treated with unhindered
LAB reagents at 0 and 25 °C provide only the corresponding
tertiary amines; no reduction products are observed by GC
analysis. Under these reaction conditions, LABs are exclu-
sively amine transfer agents. For example, 3-phenylpropyl
methanesulfonate 1 provides tertiary amines 2 in excellent
yield with a variety of LAB reagents after an acidic
methanolic workup procedure (Table 1). However, when the
Table 1. Amination Reactions of Primary Alkyl Sulfonates
with Various Lithium Aminoborohydride Reagentsa
Figure 1. Temperature dependent differences in boron species
generated during the reaction of 1 with LAB. Species characterized
by coupled and decoupled 11B NMR spectra.
differences in reactivity with temperature have previously
been reported for metal hydride transfer reactions.10
Controlling the competitive reduction vs amination reac-
tivity of LAB reagents toward alkyl sulfonates is particularly
appealing considering the current methods for reducing alkyl
sulfonate esters to alkanes. However, to make reduction the
dominant reaction, the ability of the LAB reagent to transfer
its amine moiety must be suppressed. A sterically hindered
LAB reagent (lithium diisopropylaminoborohydride) should
be less likely to transfer its amine functionality in an SN2
fashion, and hydride transfer would thus be expected. Indeed,
even at 25 °C, primary alkyl sulfonates undergo only
reduction with a sterically hindered LAB reagent.
Although lithium diisopropylaminoborohydride initiates
reduction for primary alkyl sulfonates, it is not suitable for
secondary alkyl sulfonates, which are recovered unchanged
after prolonged exposure at reflux temperature. For example,
3-phenylpropyl methanesulfonate 1 treated with lithium
diisopropylaminoborohydride is reduced to 3-phenylpropane
3 in 30 min at 25 °C, but cyclohexylmesylate 4 is not
a 10 mmol of 1, 2.5 equiv of LAB, acidic methonolic workup liberates
borane from originally formed amine-borane, providing amine products
(CAUTION! hydrogen eVolution!). See ref 6 for further experimental
details. Compounds identified by proton and carbon NMR. b Prepared from
corresponding amine-borane, see ref 5 for a detailed procedure. c Isolated
yield. No other products observed by GC analysis.
same reaction is performed at 65 °C, reduction to the
corresponding alkane is a competitive reaction.
11B NMR identifies the boron species that are generated
during the reaction, and temperature dependent differences
are detected. At 0 °C, only the residual LAB reagent (δ -16,
q) and the amine-borane complex of the tertiary amine
product (δ -14, q) are evident.8 At reflux temperature, in
(7) Thomas, S.; Collins, C. J.; Cuzens, J. R.; Spiciarich, D.; Goralski,
C. T.; Singaram, B. J. Org. Chem. 2001, 66, 1999.
(8) Aliquots were removed from the reaction flask via canunula needle,
were run neat, and were referenced to BF3:OEt2 (δ ) 0) for 11B NMR
spectra.
(9) Harrison, J.; Alvarez, S. G.; Godjoian, G.; Singaram, B. J. Org. Chem.
1994, 59, 7193.
(10) Brown, H. C.; Singaram, B.; Singaram, S. J. Organomet. Chem.
1982, 239, 43.
3916
Org. Lett., Vol. 3, No. 24, 2001

The in situ generation of LiEt3BH for the reduction of
alkyl methanesulfonates proved to be quite successful. Using
1.5 equiv of LAB and 20 mol % of Et3B, reduction of both
primary and secondary alkyl mesylates is accomplished in
very high yield. For example, when 3-phenylpropyl meth-
anesulfonate 1 is treated with 20 mol % of Et3B and 1.5
equiv of LiH3BN(Me)2, 3-phenylpropane 3 is the only
observable product (Figure 3). After only 15 min at reflux
Figure 2. Representative reduction of primary alkyl sulfonates with
lithium diisopropylaminoborohydride. Analysis by GC; yield
reported was determined using a suitable internal standard and
authentic product sample. No other products were detected.
Figure 3. Reduction of primary alkylsulfonic ester with LiH3-
BNMe2 and 20 mol % of Et3B.
susceptible to reduction (Figure 2). To achieve reduction for
secondary mesylates, a more powerful reducing agent is
necessary.
temperature, a 94% yield of the reduction product is obtained,
with no other observable products by GC analysis. Not only
is the methodology for generating LiEt3BH in situ using LAB
successful, but it is also applicable to secondary and alicyclic
methanesulfonate esters. These hindered mesylates are typi-
cally more difficult to reduce, as we had experienced with
the unsuccessful reduction of cyclohexylmesylate 4 with our
hindered LAB reagent. However, after subjecting cyclo-
hexylmesylate 4 to the modified procedure of generating
LiEt3BH via LAB, cyclohexane 5 was generated in 95%
yield. This new reduction methodology provides results
comparable with those of the original methodology.4,11 Using
our methodology, cyclohexylmesylate 4 is reduced to cy-
clohexane 5 in 95% yield, with only a trace amount of
cylcohexene 6 present in the reaction mixture and no
cyclohexanol 7 detected by GC analysis. With the original
methodology, a 68% yield of cyclohexane 5 was reported,
with a 12% yield of the elimination product cyclohexene 6
(Table 2). Generating LiEt3BH in situ using LAB and a
LiEt3BH is an exceptionally powerful nucleophilic reduc-
ing agent capable of reducing even hindered alkyl sul-
fonates.11 However, it is not without its disadvantages, which
are 2-fold: The original procedure requires 2 equiv of LiEt3-
BH, presumably due to the formation of the unreactive
complex Et6B2H-Li+,12 and an oxidation step in the workup
procedure is required.13 Generating LiEt3BH in situ elimi-
nates the disadvantages that are associated with this reagent,
yet maintains the advantages inherent in using such a
powerful, nucleophilic reducing agent.
Since lithium hydride transfer has been reported between
LAB reagents and hindered trialkylorganoboranes, producing
lithium trialkylborohydrides,9 conceivably a similar exchange
reaction between LAB and Et3B should generate LiEt3BH.
The LAB reagent would act as a lithium hydride transfer
reagent with Et3B, producing LiEt3BH, with aminoborane
as a side product. The newly formed LiEt3BH would then
become the reducing species. Since Et3B is regenerated
during reduction of the alkyl sulfonate, theoretically only a
catalytic amount of Et3B is required. In this way, the primary
hydride source is from LAB reagent, which is nonpyrophoric.
LAB reagents are an ideal lithium hydride source for the
proposed generation of LiEt3BH. They are simple to prepare,
are easily handled, and can be stored in an ampule for
prolonged periods of time without undergoing decomposition.
Unlike LiH, LABs would provide a homogeneous reaction
environment, and the reduction product could easily be
obtained by performing a simple workup procedure.14
Additionally, LAH is not suitable for such a metal hydride
exchange reaction with Et3B as it suffers from practical
complications resulting from gel formations due to the
required addition of triethylenediamine (TED), which pre-
cipitates aluminum hydride as TED‚AlH3.10
Table 2. Reduction of Cyclohexyl Sulfonates with Various
Hydride Reducing Agents
a 1.5 equiv of LAB, 20 mol % of Et3B. Precent study, solutions were
0.1 M in sulfonate, reaction time 4 h. Analysis by GC using internal
standard. b 2.1 equiv of LiEt3BH, reaction time 4 h. Reference 12.
(11) Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J. Org. Chem. 1980,
45, 1.
(12) Holder, R. W.; Mattuno, M. G. J. Org. Chem. 1977, 42, 2166.
(13) CAUTION! Trialkylboranes are known to be extremely pyrophoric.
LiEt3BH generates triethyl borane upon loss of a hydride. Using a catalytic
amount of Et3B for the in situ generation of LiEt3BH substantially decreases
the amount of pyrophoric material for a given reduction.
catalytic amount of Et3B is thus a new and useful methodol-
ogy that is complimentary to existing synthetic methods.
Org. Lett., Vol. 3, No. 24, 2001
3917

transfer of their amine functionality and tertiary amines 2
are obtained in excellent yield (Figure 4).
The reduction methodology reported herein highlights the
synthetic advantages LiEt3BH offers. Moreover, the con-
trolled reactivity of LAB reagents toward alkyl methane-
sulfonate esters demonstrates their dual properties as both
hydride and amine transfer reagents.
Acknowledgment. We thank the GAANN foundation for
a research fellowship for S.T., the Callery Chemical Com-
pany for their generous donation of dimethylamine-borane
and pyrrolidine-borane, and the donors of the Petroleum
Research Fund, administered by the American Chemical
Society. We gratefully acknowledge a research grant from
the Dow Chemical Co.
Figure 4. Representative selective reduction or amination of alkyl
sulfonate 1-mesyl-3-phenylpropane 1 as mediated by lithium
dimethylaminoborohydride. Analysis by GC; yield reported was
determined using a suitable internal standard and authentic product
samples.
Supporting Information Available: Proton and carbon
spectra for compounds 2a-e. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0167659
The dual properties of LAB reagents are governed by
reaction conditions in their reactivity toward alkyl methane-
sulfonate esters, providing control over reduction vs amina-
tion of the title compounds. By treating the alkyl sulfonate
1 with both LAB and a catalytic amount of Et3B, or by
employing a sterically hindered LAB reagent, reduction to
the alkane 3 is accomplished. Alternatively, using a sterically
unhindered LAB in the absence of Et3B, LABs mediate the
under a stream of nitrogen. The sidearm and reflux condenser are fitted
with rubber septum and secured with copper wire. The apparatus is kept
under a stream of nitrogen run through an oil bubbler. The flask is charged
with 10 mL of dry THF (distilled from sodium-benzophenone), followed
by 1 mmol of 3-phenylpropyl methanesulfonate 1, 1 mmol of internal
standard (mesitylene), and 0.2 mmol of Et3B. The solution is allowed to
reach reflux temperature, at which time 1.5 mmol of 1 M LiH3BNMe2 is
added dropwise. See refs 5, 6, or 7 for a more detailed description of LAB
handling and quenching. (CAUTION!, if quenched with 3 M HCl, hydrogen
eVolution!) After 15 min, a 0.1 mL aliquot is removed from the reaction
mixture and placed in 1 mL of pentane (LAB and amine-boranes are
insoluble in pentane). The sample is filtered through a syringe filter and
analyzed by GC. Yields reported are GC yields, utilizing an internal standard
and corrected for detector response.
(14) Procedure for the preparation of 3-phenylpropane 3 from
3-phenylpropyl methanesulfonate 1 is representative. An oven-dried 50
mL round-bottom flask with a sidearm is equipped with a magnetic stir bar
and reflux condenser. The apparatus is assembled while hot and cooled
3918
Org. Lett., Vol. 3, No. 24, 2001