Borrowing hydrogen in water and ionic liquids: Iridium-catalyzed alkylation of amines with alcohols

Article abstract of DOI:10.1021/op100024j

The use of [Cp*IrI₂]₂ as an efficient catalyst for the alkylation of amines by alcohols in either water or ionic liquid is described. Primary amines are converted into secondary amines, and secondary amines into tertiary amines in the absence of base, and the chemistry has been applied to the synthesis of the analgesic fentanyl. The conversion of primary amines into N-heterocycles by the reaction with diols is also described, along with the N-alkylation of sulfonamides.

Full text of DOI:10.1021/op100024j

Organic Process Research & Development 2010, 14, 1046–1049
Borrowing Hydrogen in Water and Ionic Liquids: Iridium-Catalyzed Alkylation of
Amines with Alcohols
Ourida Saidi,† A. John Blacker,‡ Gareth W. Lamb,† Stephen P. Marsden,‡ James E. Taylor,† and Jonathan M. J. Williams*,†
Department of Chemistry, UniVersity of Bath, ClaVerton Down, Bath BA2 7AY, U.K., and School of Chemistry and Institute of
Process Research and DeVelopment, UniVersity of Leeds, Leeds LS2 9JT, U.K.
Scheme 1. Alkylation of amines with alcohols using the
borrowing hydrogen strategy
Abstract:
The use of [Cp*IrI2]2 as an efficient catalyst for the alkylation
of amines by alcohols in either water or ionic liquid is
described. Primary amines are converted into secondary
amines, and secondary amines into tertiary amines in the
absence of base, and the chemistry has been applied to the
synthesis of the analgesic fentanyl. The conversion of
primary amines into N-heterocycles by the reaction with
diols is also described, along with the N-alkylation of
sulfonamides.
Since the first examples of the alkylation of amines by
alcohols using homogeneous catalysts have been published,3
there have been several ruthenium4 and iridium5 catalysts
subsequently reported. In particular, Yamaguchi and co-workers
have employed [Cp*IrCl2]2,6 for a wide range of amine
alkylation reactions. These reactions are typically run in toluene
and benefit from the addition of potassium carbonate, which
may form the iridium carbonate complex under the reaction
conditions.7 Reactions involving borrowing hydrogen processes
have recently been reviewed.8
Introduction
The alkylation of amines is usually achieved by a substitution
reaction with an alkyl halide, although these reactions can lead
to overalkylation, and the toxicity of many alkyl halides and
related alkylating agents can be problematic.1 The use of
alcohols as direct alkylating agents for amines is appealing since
the reaction is atom economical, the alcohol is likely to be less
toxic than the corresponding alkyl halide, and the only reaction
byproduct is water. Due to the poor electrophilicity of simple
alcohols, the direct reaction between amines and alcohols is
not readily achieved. The use of the borrowing hydrogen
strategy (Scheme 1) provides an alternative method for the
dehydrative coupling of amines with alcohols, and proceeds
by the temporary removal of hydrogen from a substrate alcohol
1 to provide an intermediate aldehyde 2. The electrophilic
aldehyde readily condenses with an amine, forming imine 3
under the reaction conditions. The catalyst then returns the
borrowed hydrogen to the intermediate imine, forming
the alkylated amine product 4. Herein we report the use of the
SCRAM catalyst,2 [Cp*IrI2]2, for the alkylation of amines with
alcohols using water or ionic liquid as solvent, in the absence
of base, where the first comparative study using organic,
aqueous, and ionic liquid phases for these reactions is presented.
The reaction is applied to the synthesis of the analgesic fentanyl,
to the formation of N-heterocycles from primary amines, and
to the N-alkylation of sulfonamides.
We have recently reported the use of the SCRAM catalyst,
[Cp*IrI2]2, for the oxidative conversion of aldehydes9 or
amines10 and o-aminophenol into benzoxazoles, as well as the
coupling of amines via a borrowing hydrogen pathway involv-
(3) (a) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N.
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* Author to whom correspondence may be sent. E-mail: j.m.j.williams@
bath.ac.uk.
† University of Bath.
‡ University of Leeds.
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10.1021/op100024j  2010 American Chemical Society
Published on Web 03/11/2010

Scheme 2. Alkylation reactions of amines catalyzed by
[Cp*IrI2]2
Scheme 4. Cyclization of amines with diols to form
N-heterocycles
Scheme 3. Synthesis of fentanyl using the borrowing
hydrogen approach
ing temporary imine formation.11 For example, the reaction of
2-phenylethylamine 5 with diisopropylamine affords the product
6 in excellent isolated yield (Scheme 1). In addition to the
coupling of amines, we have discovered that this catalyst is
also effective for the N-alkylation of amines by alcohols,
including the propylation of benzylamine 7 with n-propanol to
form the secondary amine 8 (Scheme 2).12 Herein we report
further details of this reaction in water and the first examples
of using ionic liquids as the medium for borrowing hydrogen
methodology. In many cases the correct choice of solvent is a
requirement in order to achieve a successful reaction.
Whilst in the fentanyl synthesis we chose to use com-
mercially available piperidine 10, we wished to examine the
synthesis of N-heterocycles by the reaction of an amine with a
suitable diol. We chose to react 1-phenylethylamine 12 with
diols 13-16 and were pleased to obtain good conversions and
reasonable isolated yields of the corresponding N-heterocycles
17-20 (Scheme 4). Using water as the solvent, we again
observed that additional base was not required in order to
activate the catalyst.
Results and Discussion
The borrowing hydrogen approach has recently been applied
to the N-alkylation of sulfonamides with alcohols,14 and we were
interested to see whether we could achieve this reaction in water
using the [Cp*IrI2]2 catalyst. In this case, we did require a base
in order to achieve reaction, presumably due to the need to
deprotonate the non-nucleophilic sulfonamide in order to
generate the intermediate sulfonyl imine. However, we were
pleased to see that the reaction in the presence of base was
successful for the alkylation of sulfonamides 21 with benzyl
alcohol 22 to give the alkylated products 23-27 with reasonable
isolated yields, except for the formation of the electron-deficient
nitro-containing sulfonamide 27 (Scheme 5).
We were interested to examine the effect of using ionic
liquids as the reaction medium for borrowing hydrogen reac-
tions, especially since the use of water as a polar solvent had
been shown to have a significant effect on these reactions. To
the best of our knowledge, there are no previous reports of
borrowing hydrogen methodology being performed in ionic
liquids. The use of ionic solvents in an industrial context has
In order to demonstrate the applicability of the amine
alkylation chemistry to the synthesis of pharmaceutically
relevant compounds, we chose to examine the synthesis of
fentanyl (9), which is an analgesic with approximately 100×
greater potency than morphine.13 Commercially available ami-
dopiperidine 10 was reacted with 2-phenylethanol 11 using 2
mol % [Cp*IrI2]2 in the absence of base to give fentanyl (9)
with a reasonable isolated yield (Scheme 3). A higher catalyst
loading and reaction time were required in comparison with
reactions using unfunctionalized substrates, and it seems
plausible that the amidopiperidine starting material and product
could act as bidentate ligands to the catalysts, reducing
reactivity.
(7) Balcells, D.; Nova, A.; Clot, E.; Gnanamgari, D.; Crabtree, R. H.;
Eisenstein, O. Organometallics 2008, 27, 2529.
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Williams, J. M. J. Dalton Trans. 2009, 753. (e) Guillena, G.; Ramo´n,
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Dobereiner, G. E.; Crabtree, R. H. Chem. ReV. 2010, 110, 681.
(9) Blacker, A. J.; Farah, M. M.; Hall, M. I.; Marsden, S. P.; Saidi, O.;
Williams, J. M. J. Org. Lett. 2009, 11, 2039.
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Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem.
Soc. 2009, 49, 1766–1774. (b) Shi, F.; Tse, M. K.; Zhou, S.; Pohl,
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J. Am. Chem. Soc. 2009, 49, 1775. (c) Shi, F.; Tse, M. K.; Cui, X.;
Go¨rdes, D.; Michalik, D.; Thurow, K.; Deng, Y.; Beller, M. Angew.
Chem., Int. Ed. 2009, 48, 5912. (d) Mart´ınez-Ascencio, A.; Ramo´n,
D. J.; Yus, M. Tetrahedron Lett. 2010, 51, 325.
(10) Blacker, A. J.; Farah, M. M.; Marsden, S. P.; Saidi, O.; Williams,
J. M. J. Tetrahedron Lett. 2009, 50, 6106.
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J. M. J. Angew. Chem., Int. Ed. 2009, 48, 7375.
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J. M. J. Chem. Commun. 2010, DOI: 10.1039/b923083a.
(13) Stanley, T. H. J. Pain Symptom Manage. 1992, 7, S3–7.
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Scheme 5. N-Alkylation of sulfonamides
Scheme 7. Beneficial effect of using an ionic liquid for
tertiary amine formation
tertiary amine products 31 and 32 was greater in the ionic liquid.
When N-benzylmorpholine 31 was formed in the ionic liquid,
94% conversion was observed and the product isolated in 85%
yield. In all cases, the correct choice of solvent was important
to obtain good conversion, and the use of toluene as solvent
afforded low conversions. We examined alternative ionic liquids
as solvents by variation of the counterion, and there was a
limited effect on conversion into N-benzylmorpholine 31,
with [BMIM]PF6 giving 94% conversion compared with
[BMIM]BF4 94%, [BMIM]SbF6 89%, [BMIM]OTf 94%, and
[BMIM]Cl 86%. The use of [BDMIM]BF4 (BDMIM )
1-butyl-2,3-dimethylimidazolium), which contains an additional
2-methyl substituent, led to a 93% conversion. In this latter case,
it is not possible for the ionic liquid to become deprotonated to
form an N-heterocyclic carbene, hence catalyst activation by
the formation of an N-heterocyclic carbene complex is not a
requirement for catalyst reactivity.
Scheme 6. Comparison of the use of toluene, water and an
ionic liquid for amine alkylation
Intrigued by the enhanced reactivity that was observed for
the formation of tertiary amines, we considered the preparation
of acyclic tertiary amines in ionic liquid. After a short reaction
time of 3 h, the reaction of dimethylamine with alcohols in water
did not lead to the formation of products 33-35. However,
using the ionic liquid [BMIM]PF6 reasonable conversions were
achieved, even though the amine was used as a 40% solution
in water. In the case of the reaction of dimethylamine with
p-methoxybenzyl alcohol, complete conversion into tertiary
amine 34 was observed in 3 h. In the reactions with di-n-
propylamine, we allowed the reactions to run for 24 h, where
only small amounts of products 36-38 were observed when
the reactions were run in water, but again, the reactions were
much more efficient when performed in [BMIM]PF6.
These observations suggest that for the formation of a
secondary amine from a primary amine, water is slightly
preferred as a solvent over the ionic liquid. However, for
formation of more hindered tertiary amines, there is a strong
preference for the reaction to be performed in ionic liquid
(Scheme 7). The mechanism involved in tertiary amine synthesis
must proceed via the reduction of an intermediate iminium
species, certainly in cases where enamine formation is not
possible. It seems unlikely that the iminium would be coordi-
nated to the metal in this case. However, in the synthesis of
secondary amines the reaction is likely to proceed via the
reduction of an imine, which is more likely to be coordinated
recently been reviewed.15 We chose to run reactions for just
3 h in order to make clear any differences in reactivity when
comparing the reaction in water with that in toluene and ionic
liquid (Scheme 6). When using the primary amine, 1-phenyl-
ethylamine 12, the alkylation reaction was more successful for
the formation of the secondary amine products 28 and 29 in
water than in either toluene or the ionic liquid [BMIM]PF6
(BMIM ) 1-butyl-3-methylimidazolium). However, when
morpholine 30 was used as the substrate, the formation of
(15) Plechkova, N. V.; Seddon, K. R. Chem. Soc. ReV. 2008, 37, 123.
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to the metal. We therefore assume that the ionic liquid favors
the iminium reduction step, although it is not clear why this is
the case. Since variation of the counterion of the ionic liquid
had a negligible effect on reactivity, it does not appear to be
important that a cationic iridium complex needs to be formed,
and we therefore speculate that it is the highly polar environment
which encourages iminium reduction.
Representative Procedure for the Alkylation of Sulfona-
mides with Benzyl Alcohol. To an oven-dried, nitrogen-purged
carousel tube containing [IrCp*I2]2 (11.7 mg, 0.01 mmol) and
K2CO3 (138 mg, 1 equiv) were added the representative
sulfonamide (1 mmol) and benzyl alcohol (1.2 mmol, 125 µL)
followed by the deionised and degassed water (2 mL). The
reaction mixture was then heated to 115 °C at reflux for 20-23
h, depending on the sulfonamide used. After the required time,
the crude mixture was extracted three times with ethyl acetate
and dried over magnesium sulfate, and the solvent was removed
under vacuum. The resulting residue was purified by column
chromatography to give the desired product.
Representative Procedure for the Reaction of Alcohol
with HNMe2 in Ionic Liquid. [Cp*IrI2]2 (11.6 mg, 0.01 mmol)
was placed in an oven-dried carousel tube and placed under an
inert atmosphere of nitrogen. [BMIM]PF6 (0.5 mL) was added
followed by the alcohol (1 mmol) and dimethylamine (40%
solution in H2O, 1.2 mmol, 0.15 mL). The tube was then heated
at 115 °C for 3 h before cooling to room temperature. Ethyl
actetate was added and the crude extracted three times with
diethylether. The combined organics were dried with MgSO4
and concentrated under reduced pressure. Conversions were
determined by analysis of the crude 1H NMR spectra.
Conclusion
In summary, we have demonstrated that [Cp*IrI2]2 is an
effective catalyst for the alkylation of amines with alcohols in
the absence of base when the reactions are run in polar media.
Sulfonamides are also N-alkylated with this catalyst, although
base is required in these reactions. The first examples of the
use of ionic liquid as solvent for borrowing hydrogen methodol-
ogy are reported and found to be especially beneficial for the
synthesis of tertiary amines.
Experimental Section
Procedure for the Alkylation of 1-Phenylethanamine with
1,4-Butanediol. To an oven-dried, nitrogen-purged carousel
tube containing [IrCp*I2]2 (11.7 mg, 0.01 mmol) were added
the 1,4-butanediol (1 mmol, 87 µL) and 1-phenylethanamine
(1 mmol, 127 µL) followed by deionised and degassed water
(2 mL). The reaction mixture was then heated to 115 °C at
reflux for 15 h. After cooling, the crude mixture was extracted
three times with ethyl acetate and dried over magnesium sulfate,
and the solvent was removed under vacuum. The resulting
residue was purified by flash chromatography eluting with
(EtOAc/hexane, 1:10) to give 1-(1-phenylethyl)pyrrolidine 1714a
as a colourless oil (135 mg, 77%); 1H NMR (300 MHz, CDCl3)
δ 7.31-7.13 (m, 5H), 3.13 (q, J ) 6.6 Hz, 1H), 2.52-2.47
(m, 2H), 2.33-2.30 (m, 2H), 1.71-1.69 (m, 4H), 1.35 (d, J )
6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 145.5, 128.3, 128.2,
127.2, 126.8, 65.9, 52.9, 23.4, 23.1; HRMS calcd for
C12H17NH+: 176.1439; Found: 176.1435.
Acknowledgment
We thank the EPSRC for funding through Grant EP/
F038321/1 and Piramal Healthcare for further support.
Supporting Information Available
Experimental procedures, characterization data, and copies
1
of H and 13C NMR spectra for isolated compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Received for review January 29, 2010.
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