In Situ Oxidation-Imine Formation-Reduction Routes from Alcohols to Amines

Article abstract of DOI:10.1021/ol015819b

(matrix presented) Manganese dioxide is employed as an in situ oxidant for the one-pot conversion of alcohols into imines. In combination with polymer-supported cyanoborohydride (PSCBH), a one-pot oxidation-imine formation-reduction sequence is reported. This procedure enables alcohols to be converted directly into both secondary and tertiary amines.

Full text of DOI:10.1021/ol015819b

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1637-1639
In Situ Oxidation−Imine
Formation−Reduction Routes from
Alcohols to Amines
Leonie Blackburn and Richard J. K. Taylor*
Department of Chemistry, UniVersity of York, Heslington, York, YO10 5DD, UK
rjkt1@york.ac.uk
Received March 9, 2001
ABSTRACT
Manganese dioxide is employed as an in situ oxidant for the one-pot conversion of alcohols into imines. In combination with polymer-
supported cyanoborohydride (PSCBH), a one-pot oxidation−imine formation−reduction sequence is reported. This procedure enables alcohols
to be converted directly into both secondary and tertiary amines.
In conventional organic synthesis the combination of a
chemical oxidant and reductant is rare, although redox
processes are well-known in biological systems. We envis-
aged a new process for the conversion of alcohols into amines
via an in situ oxidation-imine formation-reduction se-
quence (Scheme 1).1 Such a process would extend the well-
To test the viability of this proposal, we first investigated
the in situ oxidation-imine formation sequence. This is a
useful transformation in its own right, given the synthetic
utility of the product imines.4 We have previously described
the direct conversion of alcohols into alkenes using an in
situ manganese dioxide oxidation-stabilized Wittig proce-
dure.5 We therefore studied the in situ conversion of benzyl
alcohol and substituted benzyl alcohols into imines using
manganese dioxide together with a range of amines (Scheme
2 and Table 1).6 In view of the hydrolytic instability of some
of the imine products, all were routinely reduced to the
corresponding amine, the amine being fully characterized.
As shown in Table 1, imines were obtained in near
quantitative yields in all cases, confirming that under these
conditions amines and the product imines are compatible with
manganese dioxide. It should be noted that the use of (+)-
R-methylbenzylamine gave the expected amine with no loss
Scheme 1
known reductive amination procedure2 and would have the
advantage that the intermediate aldehydes and imines would
not require isolation. This should prove particularly useful
in cases where these intermediates are unstable or otherwise
difficult to handle (e.g. toxic, volatile, or prone to polym-
erization). In addition, the sequence in Scheme 1 would allow
the rapid synthesis of amines for chemical libraries and thus
find use in combinatorial chemistry.3
Scheme 2
(1) Related one-pot oxidation-reduction routes to amines can be achieved
electrolytically or via transition metal mediated processes, although harsh
conditions are required and functional group tolerance is limited. For leading
references, see: Ohtani, B.; Nakagawa, K.; Nishimoto, S.; Kagiya, T. Chem.
Lett. 1986, 1917-1920. Murahashi, S.; Kondo, K.; Hakata, T. Tetrahedron
Lett. 1982, 23, 229-232.
(2) Tarasevich, V. A.; Kozlov, N. G. Russ. Chem. ReV. 1999, 68, 55-
72, and references therein.
10.1021/ol015819b CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/05/2001

Table 1.a
Table 2.a
a General procedure: manganese dioxide (10 mmol) was added in two
portions (2 × 5 mmol) over 1 h to a solution of alcohol (1 mmol), amine
(1.5 mmol), and 4A molecular sieves (200 mg) in DCM at reflux and
allowed to stir for 24 h at reflux. The solution was filtered through Celite
and concentrated. b Yields of the imine refer to the isolated unpurified
1
product which was pure by H NMR spectroscopy. c Yields of the amine
refer to isolated unpurified product which was pure by 1H NMR spectros-
copy and was fully characterized if novel (ii, v, vi).
a General procedure: manganese dioxide (10 mmol) was added in two
portions (2 × 5 mmol) over 1 h to a solution of alcohol (1 mmol), amine
(1-3 mmol), and 4A molecular sieves (200 mg) in DCM at reflux and
allowed to stir for 24-48 h at reflux. The solution was filtered through
Celite and concentrated. b Yields of the imine refer to the isolated unpurified
product which, unless stated otherwise, was pure by 1H NMR spectroscopy.
c Yields of the amine refer to isolated unpurified product which, unless
stated otherwise, was pure by 1H NMR spectroscopy and was fully
characterized if novel (entries vii-ix). d In these cases the intermediate imine
(Z)-Hexenol also underwent efficient oxidation-imine for-
mation, but this was accompanied by a considerable amount
of alkene isomerization (entry iv): further studies are
underway to overcome this problem.
1
was contaminated with a minor byproduct (<10%) according to H NMR
Propargylic alcohols were also subjected to the in situ
oxidation-imine formation conditions (Table 2, entries v and
vi). The imines, and the amines produced after subsequent
reduction, were obtained in excellent yields. The successful
synthesis of propargylic amines affords the possibility of
obtaining Z-allylic amines by stereoselective reduction.
Having established the viability of the in situ oxidation-
imine formation reaction, our attention turned to combining
this sequence with an in situ reduction. We required a
reductant that would reduce imines selectively in the presence
of aldehydes, and felt that a heterogeneous reductant would
minimize the likelihood of reaction with manganese dioxide
and would also facilitate the workup procedure. With this
in mind, the use of polymer-supported cyanoborohydride
(PSCBH) was investigated.9,10 Initial studies were carried out
using benzyl alcohol and isobutylamine together with MnO2
(10 equiv), PSCBH (5 equiv), and acetic acid (2 equiv) as
shown in Scheme 3. The reaction mixture was then stirred
at room temperature for 48 h, filtered through silica, and
concentrated. Much to our delight the 1H NMR spectrum of
the unpurified reaction mixture indicated the presence of
N-benzyl isobutylamine in ca. 30% yield. Although the yield
spectroscopy. After reduction, the impurity was removed by acid-base
extraction.
of optical activity {[R]D 60.1 (c 0.5, EtOH); lit.7 [R]D 54.4
(c 0.5, EtOH)} as shown in entry vi. The results in Table 1
(entries vii and viii) also indicate that the presence of
electron-donating and electron-withdrawing substituents have
no adverse effect on the in situ oxidation-imine formation
reaction. Furthermore, it was established that diols can be
converted efficiently into bis-imines (entry ix).
We next investigated the use of allylic and propargylic
alcohols (Table 2), the product amines being valuable
building blocks in organic synthesis.8 As can be seen (entries
i-iii), the in situ oxidation-imine formation reaction
proceeded smoothly with cinnamyl alcohol and (E)-hexenol.
(3) Ley, S. V.; Bolli, M. H.; Hinzen, B.; Gervois, A.-G.; Hall, B. J. J.
Chem. Soc., Perkin Trans. 1 1998, 2239-2241. Ley, S. V.; Massi, A. J.
Chem. Soc., Perkin Trans. 1 2000, 3645-3654.
(4) For reviews covering the preparation and utility of imines, see:
Adams, J. P. J. Chem. Soc., Perkin. Trans. 1 2000, 125-139. Bloch, R.
Chem. ReV. 1998, 98, 1407-1438.
(5) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 3815-3818.
Blackburn, L.; Wei, X.; Taylor, R. J. K. Chem. Commun. 1999, 1337-
1338. Wei, X.; Taylor, R. J. K. J. Org. Chem. 2000, 65, 616-620.
(6) Isolated reports of this process have been published, see: Iwata, M.
Bull. Chem. Soc. Jpn. 1981, 54, 2835-2836. Medvedeva, A. S.; Safronova,
L. P.; Chichkareva, G. G.; Voronkov, M. G. Bull. Acad. Sci. USSR DiV.
Chem. Sci. 1976, 25, 107-110.
(9) With NaBH3CN itself, after extensive investigation, optimum condi-
tions afforded the amine in a maximum 40% yield; NaBH(OAc)3 was
investigated but none of the amine was produced.
(10) Hutchins, R. O.; Natale, N. R.; Taffer, I. M. Chem. Commun. 1978,
1088-1089. Commercially available from Novabiochem, catalog no. 01-
64-0337, although the reagent prepared according to the literature procedure
gave more consistent results.
(7) Juaristi, E.; Murer, P.; Seebach, D. Synthesis 1993, 1243-1246.
(8) Johannsen, M.; Jorgensen, K. A. Chem ReV. 1998, 98, 1689-1708.
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Org. Lett., Vol. 3, No. 11, 2001

Table 3. In Situ Oxidation-Imine Formation-Reductiona
Scheme 3
was moderate, it clearly indicated that the oxidation-imine
formation-reduction sequence is viable.
Optimization studies were then carried out and resulted
in an improvement of the isolated yield of N-benzyl
isobutylamine to 74% by increasing the reaction temperature
and delaying the addition of acetic acid until the oxidation
of the alcohol was essentially complete as shown by TLC
analysis. The addition of acetic acid was essential for the
reduction of the imine to the corresponding amine. The
generality of this procedure was then explored (Table 3).
As shown in Table 3, entries i-v, the in situ oxidation-
imine formation-reduction sequence proceeded efficiently
with benzyl alcohol and with an electron-rich and an electron-
deficient example. In these systems the only significant con-
taminant was the amide 2 (ca. 20%) which could be removed
by acid-base extraction. However, with 4-nitrobenzyl
alcohol (entry vi) this material was the major product (60%).
It seems likely that the intermediate aldehyde is being
converted into the corresponding cyanohydrin, which in turn
is oxidized to the acyl cyanide, which is then trapped by the
amine to give the amide via a precedented process.11 The
use of an alternative reductant should remove this problem,
and current efforts are being focused in this direction. In
addition, a second minor byproduct, dialkylated analogue 3,
was present in only small quantities (detected by mass
spectrometry and TLC).
a General procedure: manganese dioxide (10 mmol) was added in two
portions (2 × 5 mmol) over 1 h to a solution of alcohol (1 mmol), amine
(2-4 mmol), 4A molecular sieves (200 mg), and PSCBH (5 mmol) in DCM
(25 mL) at reflux. AcOH (2 mmol) was added when TLC showed all the
alcohol had essentially been oxidized (ca. 3-4 h) and the reaction mixture
was then allowed to stir for 24-64 h at reflux. The solution was filtered
through silica and concentrated. Impurities were removed by acid-base
extraction unless stated. b Purified by the formation of the N-Boc derivative
and subsequent column chromatography. c Purified by column chromatog-
raphy. d Purified by disillation.
It should be noted that the process is practically straightfor-
ward in that the oxidant and reductant are removed by
filtration and the product is isolated simply by evaporation
of the solvent. We are currently optimizing and expanding
the scope of this novel sequence and investigating its
applications in target molecule synthesis.
Finally, we established that secondary amines are also
compatible with the in situ oxidation-imine formation-
reduction sequence (Table 3, entries vii-ix). In these
examples, intermediate iminium species are formed which
undergo in situ reduction to give tertiary amines.
Acknowledgment. We thank EPSRC for funding (L.B.)
and Pfizer for additional financial support.
In summary, we have shown that activated alcohols
(benzylic, allylic, and propargylic) will undergo the man-
ganese dioxide-mediated in situ oxidation-imine formation
reaction to afford imines in excellent yields. Preliminary
studies on benzyl alcohols have also indicated the viability
of an in situ oxidation-imine formation-reduction sequence
leading to secondary and tertiary amines, demonstrating that
a chemical oxidant and reductant can coexist in the appropri-
ate circumstances.12 This sequence should be applicable to
a range of activated alcohols and may be even more general.
Supporting Information Available: Detailed experi-
mental procedures and product characterization. This material
is available free of charge via the Internet at http://pubs.ac.org.
OL015819B
(12) For other ways of utilizing potentially incompatible reagents, see:
Gelman, F.; Blum, J.; Avnir, P. J. Am. Chem. Soc. 2000, 122, 11999-
12000. Cohen, B. J.; Kraus, M. A.; Patchornik, A. J. Am. Chem. Soc. 1977,
99, 4165-4167 and references therein.
(11) Gilman, N. W. Chem. Commun. 1971, 733-734.
Org. Lett., Vol. 3, No. 11, 2001
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