Mild nonepimerizing N -alkylation of amines by alcohols without transition metals

Article abstract of DOI:10.1021/ol201351a

A one-pot two-step sequence involving an oxidation/imine-iminium formation/reduction allowed the N-alkylation of amines by alcohols without any epimerization when optically active alcohols and amines are involved in the process.

Full text of DOI:10.1021/ol201351a

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3534–3537
Mild Nonepimerizing N-Alkylation
of Amines by Alcohols without
Transition Metals
†
Claire Guerin, Veronique Bellosta, Gerard Guillamot, and Janine Cossy*
†
‡
,†
ꢀ
ꢀ
ꢀ
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS UMR 7084,
10 rue Vauquelin, 75231-Paris Cedex 05, France, and PCAS, 23 rue Bossuet,
Z.I. la vigne aux Loups, 91160-Longjumeau, France
janine.cossy@espci.fr
Received May 19, 2011
ABSTRACT
A one-pot two-step sequence involving an oxidation/imine-iminium formation/reduction allowed the N-alkylation of amines by alcohols without
any epimerization when optically active alcohols and amines are involved in the process.
As N-alkylamines constitute a key functional group
in organic chemistry, many synthetic works have been
devoted to their synthesis.1 Traditionally, the N-alkylation
of amines is achieved either by reaction with alkylating
agents or by addition of nucleophiles or radicals on imines.1
The most commonly used method for the preparation
of secondary and tertiary amines is the substitution of
alkyl halides by amines, in the presence of a stoichiometric
amount of base.2 However, in this process polyalkyla-
tion can occur, leading to a mixture of compounds, and
undesired inorganic wastes are produced. Moreover,
many alkyl halides are toxic and not commonly encoun-
tered in Nature. The use of available, inexpensive, and
less hazardous reagents such as alcohols instead of alkyl
halides for N-alkylation of amines is a challenging and a
highly atom-efficient approach which leads only to the
formation of water as a byproduct. The “borrowing
hydrogen strategy”, also called hydrogen autotransfer,
has allowed the direct use of alcohols as alkylating agents.
This process has been applied to the formation of CꢀN
4
5
bonds,3 and the use of SiO2 and Al2O3 as catalysts
has been reported; however, both the yields and the
selectivities (monoalkylation versus bis-alkylation) are
poor. The best conditions involve transition-metal based
catalysts, including heterogeneous and homogeneous
processes. When the reaction is performed with heteroge-
neous catalysts3d such as nickel,6 copper,7 platinum,
ruthenium,8 palladium,9 gold,10 silver,11 or iron,12 the yields
are good to excellent, but generally the main drawback is
the need for harsh conditions such as high temperature
which can be detrimental for highly sensitive compounds.
Taylor et al. reported a mild one-pot oxidation/imine-
iminium formation/reduction sequence for the conversion
of benzylic, allylic, or propargylic alcohols to amines using
† ESPCI ParisTech.
‡ PCAS.
(4) (a) Brown, A. B.; Reid, E. E. J. Am. Chem. Soc. 1924, 46, 1836–
1839. (b) Narayanan, S.; Prasad, B. P. J. Chem. Soc., Chem. Commun.
1992, 1204–1205.
(5) Valot, F.; Fache, F.; Jacquot, R.; Spagnol, M.; Lemaire, M.
Tetrahedron Lett. 1999, 40, 3689–3692.
(1) (a) Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001,
57, 7785–7811. (b) Olsen, C. A.; Franzyk, H.; Jaroszewski, J. W.
Synthesis 2005, 2631–2653.
(2) Smith, M. B.; March, J. In March’s Advanced Organic Chemistry;
5th ed.; Wiley-Interscience: New York, 2001; pp 499ꢀ501 and references
cited.
(6) For recent reference with Ni, see: Garcı
´
a Ruano, J. L.; Parra, A.;
Aleman, J.; Yuste, F.; Mastranzo, V. M. Chem. Commun. 2009, 404–406.
(7) For recent references with Cu, see: (a) Martınez-Asencio, A.;
ꢀ
(3) (a) Hamid, M. H. S.; Slatford, P.; Williams, J. M. Adv. Synth.
Catal. 2007, 349, 1555–1575. (b) Nixon, T. D.; Whittlesey, M. K.;
Williams, J. M. J. Dalton Trans. 2009, 38, 753–762. (c) Dobereiner,
G. E.; Crabtree, R. H. Chem. Rev. 2010, 110, 681–703. (d) Guillena, G.;
´
ꢀ
Ramon, D. J.; Yus, M. Tetrahedron 2011, 67, 3140–3149. (b) He, J.;
Yamaguchi, K.; Mizuno, N. Chem. Lett. 2010, 39, 1182–1183.
(c) Likhar, P. R.; Arundhathi, R.; Kantam, M. L.; Prathima, P. S.
Eur. J. Org. Chem. 2009, 5383–5389.
ꢀ
Ramon, D. J.; Yus, M. Chem. Rev. 2010, 110, 1611–1641.
r
10.1021/ol201351a
Published on Web 06/08/2011
2011 American Chemical Society

MnO2 as the oxidant, a polymer-supported cyanoboro-
hydride as the reductant, and acetic acid as the additive.13
With homogeneous catalysts3 such as ruthenium14 or
iridium15 catalysts, yields in the monoalkylated amines are
good but the reaction has to be conducted in refluxing toluene
and the reaction times are usually long except under micro-
wave irradiation. By using these catalysts, the main draw-
backs are the temperature and the epimerization of optically
active alcohols involved in the N-alkylation of amines.14b
Very recently, N-alkylation of amines by direct nucleophilic
substitution at the sp3 carbon atom of alcohols was reported
using iron and amino acid catalysts, but again, elevated
temperature and long reaction times are necessary.16
Here, we report a one-pot oxidation/imine-iminium
formation/reduction sequence under mild conditions
(Scheme 1). This sequence allows the chemoselective
N-alkylation of amines with various nonactivated primary
and secondary alcohols and prevents epimerization of opti-
cally active substrates (amines or alcohols). Furthermore, no
transition metals are involved which is of importance when
medicinal chemists have to prepare amines for biological tests.
Among the various conditions reported for the oxidation
of alcohols, we selected the mild 2,2,6,6-tetramethyl-1-
Scheme 1. Oxidation/Imine-Iminium Formation/Reduction
piperidinyloxyl and [bis(acetoxy)-iodo]benzene (TEMPO-
BAIB) system17 which releases AcOH in the reaction
medium; the latter is known to be an efficient additive
for reductive aminations.18 First, we tested the sequence
for the N-alkylation of benzylamine 2a by octanol 1a.
Hence, 1a was oxidized by TEMPO (0.2 equiv) in the
presence of BAIB (1.15 equiv) in CH2Cl2 at rt. After 16 h,
2a (3 equiv) and the reducing agent (2 equiv) were both
introduced in the reaction mixture at rt. The results are
reported in Table 1. By using NaBH(OAc)3 and
NaBH3CN, which are commonly used for reductive ami-
nation of aldehydes, the desired N-alkylated amine 3a was
formed as well as the corresponding N,N-bis-alkylated
compound 4a (as a minor product) (Table 1, entries 1
and 2). The use of NaBH4 led to 3a almost quantitatively
with only traces of 4a (Table 1, entry 3). The use of 2 equiv
of benzylamine seems to be a good compromise to obtain
3a in both good yield (91%) and selectivity (ratio 3a/4a =
95/5) (Table 1, entry 5).
(8) (a) Kim, J. W.; Yamaguchi, K.; Mizuno, N. J. Catal. 2009, 263,
205–208. (b) Yamaguchi, K.; He, J.; Oishi, T.; Mizuno, N. Chem. Eur.
;
J. 2010, 16, 7199–7207. (c) Yamaguchi, K.; Mizuno, N. Synlett 2010,
2365–2382.
(9) For recent references with Pd, see: (a) Zhang, Y.; Qi, X.; Cui, X.;
Shi, F.; Deng, Y. Tetrahedron Lett. 2011, 52, 1334–1338. (b) Corma, A.;
ꢀ
Rodenas, T.; Sabater, M. J. Chem. Eur. J. 2010, 16, 254–260. (c) Xu,
;
C.-P.; Xiao, Z.-H.; Zhuo, B.-Q.; Wang, Y.-H.; Huang, P.-Q. Chem.
Commun. 2010, 46, 7834–7836.
(10) For recent references with Au, see: (a) He, L.; Lou, X.-B.; Ni, J.;
Table 1. N-Alkylation of Benzylamine with Octanol
Liu, Y.-M.; Cao, Y.; He, H.-Y.; Fan, K.-N. Chem. Eur. J. 2010, 16,
;
13965–13969. (b) Ishida, T.; Kawakita, N.; Akita, T.; Haruta, M. Gold
Bulletin 2009, 42, 267–274.
(11) (a) Shimizu, K.; Nishimura, M.; Satsuma, A. ChemCatChem
2009, 1, 497–503. (b) Cui, X.; Zhang, Y.; Shi, F.; Deng, Y. Chem. Eur.
;
J. 2011, 17, 1021–1028.
ꢀ
(12) (a) Martınez, R.; Ramon, D. J.; Yus, M. Org. Biomol. Chem.
´
2009, 7, 2176–2181. (b) Gonzalez-Arellano, C.; Yoshida, K.; Luque, R.;
Gai, P. L. Green Chem. 2010, 12, 1281–1287.
(13) Blackburn, L.; Taylor, R. J. K. Org. Lett. 2001, 3, 1637–1639.
(14) For recent references with Ru, see: (a) Watson, A. J. A.;
Maxwell, A. C.; Williams, J. M. J. J. Org. Chem. 2011, 76, 2328–2331.
(b) Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.;
Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc.
2009, 131, 1766–1774. (c) Lamb, G. W.; Watson, A. J. A.; Jolley, K. E.;
Maxwell, A. C.; Williams, J. M. J. Tetrahedron Lett. 2009, 50, 3374–
BnNH2 2a
(x equiv)
yield in
entry
“Hꢀ”
3a/4a
3aa
1
2
3
4
5
NaBH(OAc)3
NaBH3CN
NaBH4
3
3
3
1
2
74/26
85/15
97/3
n.d.b
40%
69%
quant
59%
91%
€
3377. (d) Imm, S.; Bahn, S.; Neubert, L.; Neumann, H.; Beller, M.
€
Angew. Chem., Int. Ed. 2010, 49, 8126–8129. (e) Bahn, S.; Imm, S.;
Mevius, K.; Neubert, L.; Tillack, A.; Williams, J. M. J.; Beller, M.
NaBH4
€
Chem. Eur. J. 2010, 16, 3590–3593. (f) Bahn, S.; Tillack, A.; Imm, S.;
;
Mevius, K.; Michalik, D.; Hollmann, D.; Neubert, L.; Beller, M.
NaBH4
95/5
€
ChemSusChem 2009, 2, 551–557. (g) Pingen, D.; Muller, C.; Vogt, D.
Angew. Chem., Int. Ed. 2010, 49, 8130–8133.
a Yield for isolated 3a. b n.d. = not determined.
(15) For recent references with Ir, see: (a) Suzuki, T. Chem. Rev. 2011,
111, 1825–1845. (b) Saidi, O.; Blacker, A. J.; Farah, M. M.; Marsden,
S. P.; Williams, J. M. J. Chem. Commun. 2010, 46, 1541–1543. (c) Saidi,
O.; Blacker, A. J.; Lamb, G. W.; Marsden, S. P.; Taylor, J. E.; Williams,
J. M. J. Org. Process Res. Dev. 2010, 14, 1046–1049. (d) Michlik, S.;
The reaction is general and allows the monoalkylation of
a wide range of amines.19 The results obtained with various
amines and alcohols are reported in Table 2. We have to
Kempe, R. Chem. Eur. J. 2010, 16, 13193–13198. (e) Blank, B.;
;
Michlik, S.; Kempe, R. Chem. Eur. J. 2009, 15, 3790–3799. (f) Blank,
;
B.; Michlik, S.; Kempe, R. Adv. Synth. Catal. 2009, 351, 2903–2911.
(g) Kawahara, R.; Fujita, K.; Yamaguchi, R. J. Am. Chem. Soc. 2010,
132, 15108–15111. (h) Yamaguchi, R.; Mingwen, Z.; Kawagoe, S.; Asai,
C.; Fujita, K. Synthesis 2009, 1220–1223.
(18) Baxter, E. W.; Reitz, A. B. Reductive Aminations of Carbonyl
Compounds with Borohydride and Borane Reducing Agents; John Wiley &
Sons, Inc.: 2004; Vol. 59.
(16) Zhao, Y.; Foo, S. W.; Saito, S. Angew. Chem., Int. Ed. 2011, 50,
3006–3009.
(17) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli
G. J. Org. Chem. 1997, 62, 6974–6977.
(19) For all experiments, the completion of the oxidation was
checked by TLC or GC/MS and, if necessary, additional BAIB (up to
0.75 equiv) was introduced. The amount of BAIB necessary for the
oxidation may be related to its quality.
Org. Lett., Vol. 13, No. 13, 2011
3535

point out that both NaBH4 and NaBH(OAc)3 were tested
as reducing agents and in most cases NaBH(OAc)3 was
revealed to be the best reducing agent. Benzylamine20 2a
was alkylated with ω-unsaturated primary alcohol 1b as
well as with secondary alcohols such as 1e in good yields
(g70%) (Table 2, entries 1 and 5). It is worth noting that
N-Boc-3-hydroxypiperidine 1f was quantitatively trans-
formed to the corresponding N-Boc-3-aminopiperidine
3g when primary amine 2a was used (Table 2, entry 6).
Allylamine 2b was N-alkylated in good yields by primary
or secondary alcohols without any isomerization of the
double bond (Table 2, entries 2 and 7). Furthermore, a
sterically hindered amine such as tert-butylamine 2c can be
alkylated by benzyl alcohol 1c or solketal 1d to produce the
monoalkylated amines 3d and 3e in good yields (Table 2,
entries 3 and 4).
Table 2. N-Alkylation of Primary and Secondary Amines by
Primary and Secondary Alcohols
Secondary amines 2dꢀf were also N-alkylated by pri-
mary or secondary alcohols 1a, 1b, 1c, and 1h, and the
corresponding tertiary amines 3iꢀl were isolated in good
to excellent yields (Table 2, entries 8ꢀ11). It is worth
mentioning that benzyl alcohol 1c can be used to protect
primary or secondary amines by a benzyl group under very
mild conditions, in good yields(Table 2, entries 2, 3, and 8).
This one-pot process is chemoselective, and diols such as
5 can be transformed selectively21 to the amino-alcohol 6
which, after silylation, led to 7 in 51% overall yield, with-
out isolation of any intermediates (Scheme 2).
Scheme 2. Chemoselective Amination of Diol 5
a Yields given in parentheses refer to similar experiments performed
with 2 equiv of NaBH4 instead of NaBH(OAc)3. b Yield estimated by 1H
NMR from a mixture of 3f and Bn2NH. c Only 1 equiv of amine was used
for this experiment. d Yield estimated by 1H NMR from a mixture of 3l
and Bn3N.
When the N-alkylation of amines was realized with opti-
cally active alcohols possessing a stereogenic center in the β
position such as (S)-solketal 1d, the use of a transition metal
catalyst such as a ruthenium catalyst led to an epimerization
of the stereogenic center.14b By using our conditions, no
epimerization of the stereogenic center present in the alcohol
was noticed as the N-alkylated amines 8aꢀd were isolated in
good yields and excellent enantiomeric excesses (Table 3).
Optically active amines can also be involved in this
oxidation/imine-iminium formation/reduction sequence,
without any racemization. Thus, when this sequence was
applied to benzyl alcohol 1c and optically active amine 9a
(20) In some cases when BnNH2 or Bn2NH was used, the formation
of Bn2NH or Bn3N as byproduct was observed (Table 2, entries 5 and
11). The formation of Bn2NH (respectively Bn3N) may be explained by a
partial oxidation of BnNH2 (repectively Bn2NH) followed by imine
formation and reduction.
(21) No trace of the products coming from N-alkylation by the
secondary alcohol was detected by either 1H NMR or GC/MS at
any step of the sequence.
3536
Org. Lett., Vol. 13, No. 13, 2011

Table 3. N-Alkylation of Amines by Alcohols Possessing a
Stereogenic Center in the β Position
Table 4. N-Alkylation of Amines Possessing a Stereogenic
Center in the R Position
a 10 equiv of Me2N were used because of its volatility.
(possessing a stereogenic center in the R position), 10a was
isolated in quantitative yield and with an excellent enan-
tiomeric excess (ee >96%) (Table 4, entry 1). When
optically active amines 9a and 9b were alkylated with
secondary alcohol 1g, the corresponding amines 10bꢀc
were isolated in good yields and with diastereoisomeric
ratios varying from 65/35 to 85/15 (Table 4, entries 2 and 3).
In the case of N-Boc-3-hydroxypiperidine 1f, the
N-Boc-3-aminopiperidine 10e was obtained with a diaste-
reoisomeric ratio of 80/20 in favor of the (3S)-isomer when
(S)-R-naphthylethylamine 9c was used (Table 4, entry 5).
In conclusion, we have shown that amines can be
alkylated by nonactivated alcohols in a one-pot oxidation/
imine-iminium formation/reduction sequence at rtwithout
any transition metal. This sequence of reactions, easy to
carry out, allows the formation of secondary and tertiary
amines under mild conditions in good yields and with
good functional group tolerance. Optically active amines
and alcohols can be involved in this sequence without
a Relative configuration of stereogenic centers was attributed by
comparison of NMR data with those described in literature. b Relative
configuration of stereogenic centers was attributed after hydrogenation,
as the (þ)-(S)-3-amino-1-(tert-butoxycarbonyl)piperidine is a known
coumpound. c Relative configuration of stereogenic centers was attrib-
uted by analogy with 10d.
epimerization. We are currently investigating this sequence
of reactions in order to have access to biologically active
amino compounds.
Acknowledgment. C.G. thanks PCAS for a grant, and
PCAS is gratefully acknowledged for financial support.
Supporting Information Available. Experimental pro-
cedure and characterization data of compounds 3aꢀl, 7,
8aꢀd, and 10aꢀe. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 13, 2011
3537