Domino Hydrogenation-Reductive Amination of Phenols, a Simple Process To Access Substituted Cyclohexylamines

Article abstract of DOI:10.1021/acs.orglett.5b01842

Phenols can be efficiently reduced by sodium formate and Pd/C as the catalyst in water and in the presence of amines to give the corresponding cyclohexylamines. This reaction works at rt for 12 h or at 60 °C under microwave dielectric heating for 20 min. With the exception of aniline, primary, secondary amines, amino alcohols, and even amino acids can be used as nucleophiles. The reductive process is based on a sustainable hydrogen source and a catalyst that can be efficiently recovered and reused. The protocol was developed into a continuous-flow production of cyclohexylamines in gram scale achieving very efficient preliminary results (TON 32.7 and TOF 5.45 h^-1).

Full text of DOI:10.1021/acs.orglett.5b01842

Letter
pubs.acs.org/OrgLett
Domino Hydrogenation−Reductive Amination of Phenols, a Simple
Process To Access Substituted Cyclohexylamines
Varsha R. Jumde,† Elena Petricci,† Chiara Petrucci,‡ Niccolo Santillo,† Maurizio Taddei,*,†
̀
and Luigi Vaccaro*,‡
†Dipartimento di Biotecnologie, Chimica e Farmacia, Universita
̀
degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy
‡Laboratory of Green Synthetic Organic Chemistry, CEMIN − Dipartimento di Chimica, Biologia e Biotecnologie, Universita
̀
di
Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy
S
* Supporting Information
ABSTRACT: Phenols can be efficiently reduced by sodium formate
and Pd/C as the catalyst in water and in the presence of amines to
give the corresponding cyclohexylamines. This reaction works at rt
for 12 h or at 60 °C under microwave dielectric heating for 20 min.
With the exception of aniline, primary, secondary amines, amino
alcohols, and even amino acids can be used as nucleophiles. The
reductive process is based on a sustainable hydrogen source and a
catalyst that can be efficiently recovered and reused. The protocol
was developed into a continuous-flow production of cyclohexyl-
amines in gram scale achieving very efficient preliminary results
(TON 32.7 and TOF 5.45 h−1).
Scheme 1. Reductive Strategies towards Cyclohexylamines
implification of organic synthetic processes and develop-
Sment of sustainable protocols are some of the major goals in
contemporary synthetic organic chemistry. Amines are very
useful compounds, as they behave as synthetic tools to prepare
pharmaceutically relevant derivatives.1 In addition, many active
principal drugs, agrochemicals, and other specialty chemicals
feature the amine as a functional group.2 Cyclohexylamines are a
relevant part of the amine family including anticonvulsants,
kinase inhibitors, antidiabetics, and antiviral compounds.3
Reductive amination of carbonyl compounds is one of the
most useful methods to prepare substituted amines.4 Among a
plethora of synthetic procedures available for reductive
amination,5 one of the milder and most environmentally benign
transformations is hydrogenation of the amine-carbonyl
compound mixture over a heterogeneous transition metal
catalyst.6 This reaction can be carried out in water or other
“green” solvents using gaseous H2 or other hydrogen sources.7 A
substantial improvement in this transformation is the generation
of the carbonyl compound starting from alcohols under
conditions compatible with the reductive amination. The red−
ox cycle of alcohol oxidation and contemporary reduction of the
corresponding imine/iminium salt done by the same catalyst has
been largely explored and extensively reviewed.8 With a
cyclohexylamine as the synthetic target, while reductive
amination starts from cyclohexanone (path a in Scheme 1), the
hydrogen transfer approach is based on dehydrogenation of
cyclohexanol to cyclohexanone and further reduction of the
condensation product with the amine (path b in Scheme 1).
On the other hand, cyclohexanol and cyclohexanone can be
obtained in turn by hydrogenation of phenol. This reaction may
occur through a 6-electron process that directly produces
cyclohexanol or a 4-electron reduction to 1-hydroxycyclohexene
that immediately tautomerizes to the corresponding cyclo-
hexanone. Gas phase hydrogenation over a Pd catalyst is one of
the most effective ways to produce cyclohexanone, but high
temperature and pressure of H2 are required,9 while dehydrogen-
ative aromatization of cyclohexanone to arylethers or arylamines
is also possible.10 The use of more complex Pd-based catalysts or
reaction media may allow the reaction to occur under milder
conditions,11 and recently, the use of hydrogen precursors in
water has been reported.12 In addition, under vapor phase
conditions (250−300 °C for 3 h) phenol and ammonia can
produce mixtures of aniline, cyclohexylamine, N-cyclohexylani-
line, and N,N-dicyclohexylamine.13
Following our interest in developing sustainable protocols
based on heterogeneous catalysis (for heterocycle synthesis and
cross-coupling reactions),14,15 we report here the direct trans-
formation of phenols into substituted cyclohexylamines in an
Received: June 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01842
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
efficient domino process carried out under mild and environ-
mentally benign conditions. While this work was in progress, Li
and co-workers published a Pd catalyzed reductive coupling of
phenols with anilines in toluene at 100 °C.16 We have also proved
that the protocol can be used as a trustworthy approach to
continuous-flow production. In our experience, the application
of flow technology has proven to be an effective tool for the
exploitation of heterogeneous catalysis in alternative reaction
media, allowing achievement of high environmental efficiency.17
Although several protocols for the continuous-flow reductive
amination of aldehydes, ketones, and nitriles have been recently
reported,18 to the best of our knowledge, this is the first example
of one-pot hydrogenation of phenol and subsequent amination
carried out in batch and/or in continuous flow conditions.
The first exploration of the reaction mode was carried out on
phenol and butylamine using Pd/C as the catalyst and different
hydrogen donor sources. As water is reported to accelerate the
hydrogenation of phenol,11 aqueous HCOONa was first
explored as a reducing agent. We were pleased to obtain
acceptable yields of N-butyl-cyclohexylamine 3, although in a
mixture with some cyclohexanol and unreacted cyclohexanones
(Table 1, entry 1). The use of other organic solvents and other
organic hydrogen donors gave worse results (Table 1, entry 2);
thus, we decided to investigate the influence of catalyst and
hydrogen source equivalents on the product distribution.
Increasing the amount of sodium formate gave better results in
terms of conversion and yield of the isolated product. Working
with a 9% mol amount of Pd/C and 20 equiv of HCOONa with
respect to the amount of phenol gave 100% conversion; no
cyclohexanol was observed, <5% of cyclohexenone was still
present in the crude, and cyclohexylamine 3 was isolated in 80%
yield (Table 1, entry 3). Comparable results were obtained
doubling the equivalents of catalyst or sodium formate (Table 1,
entries 4 and 5), while a contemporary increase of both
components gave no improvements in conversion (data not
reported in Table 1). A small increment of the reaction
temperature gave a decisive gain of yields. After warming the
reaction at 60 °C for 6 h, product 3 was obtained in 96% isolated
yield while, when the reaction was submitted to microwave
(MW) dielectric heating, the same result, in term of conversion
and isolated yield of 3, was obtained after 20 min (Table 1,
entries 6 and 7). The use of MWs also permitted a reduction in
the amount of Pd/C employed down to 5% mol (Table 1, entry
8). This quantity, however, was the lowest possible for a
complete conversion, even at higher temperatures, from the
results reported in Table 1, entries 9 and 10. Also the influence of
the nature of Pd/C was studied when carrying out the reaction
with different types of nanosized Pd/C catalysts. Better and more
reproducible results were obtained with the SA and JM1 type
catalysts (Table 1, entry 11). Finally, direct hydrogenation with
H2 gas was also tried under the same reaction conditions
employed with HCOONa. A much lower conversion of phenol
was observed at rt after 24 h under 1 atm of H2 and even under
MW dielectric heating at 60 °C under 3 atm of H2 (Table 1,
entries 14 and 15).19 In conclusion of this explorative section,
three different protocols are possible for a synthetically useful
conversion of phenol into N-butylcyclohexylamine: (i) 0.09
equiv of Pd at rt for 12 h; (ii) 0.09 equiv of Pd at 60 °C for 6 h;
(iii) 0.05 equiv of Pd at 60 °C under MW dielectric heating for 20
min.
Table 1. Reductive Amination of Phenol: Reaction Condition
Optimization
b
Pd/C
equiv
H-donor
a
conv.
(%)
yield
(%)
With the third protocol selected as the most effective
procedure, the substrate scope was investigated (Scheme 2, Pd
entry
1
equiv
conditions
rt, 12 h
c
h
0.09
10
10
20
20
40
20
20
20
20
20
63
46
d
c
2
0.09
rt, 12 h
10
−
80
Scheme 2. Substrate Scope of Reductive Amination under
MW Dielectric Heating
c
i
3
0.09
rt, 12 h
100
100
100
100
100
100
86
c
i
4
0.18
rt, 12 h
87
c
i
5
0.09
rt, 12 h
84
c
i
6
0.09
60 °C, 6 h
96
c
i
7
0.09
60 °C MW, 20 min
60 °C MW, 20 min
60 °C MW, 20 min
100 °C MW,
20 min
96
c
i
8
0.05
96
c
h
9
0.03
79
c
h
10
0.03
82
75
e
i
11
12
13
14
15
0.09
20
20
20
rt, 12 h
100
100
85
95
f
h
0.09
rt, 12 h
80
g
h
0.09
rt, 12 h
55
c
j
0.09
H2
rt, 24 h
22
−
−
c
k
0.09
H2
60 °C MW, 20 min
20
a
(Phenol 1.5 mmol), butylamine (3 mmol) and the catalyst were
mixed in 10 mL of H2O and submitted to the reaction conditions in
b
table. Conversion based on the amount of phenol still present in the
c
crude reaction mixture determined by GC/MS. SA: Pd/C 10 wt %
d
loading, matrix activated carbon support (Aldrich). Reaction done in
e
MeOH with cyclohexene as H donor. JM1: Pd 10 wt % on activated
f
carbon paste type 487, moisture 55% (Johnson Matthey). JM2: Pd 10
wt % on activated carbon paste type 87L, moisture 56% (Johnson
g
Matthey). JM3 Pd 10 wt % on activated carbon paste type 434,
h
moisture 53% (Johnson Matthey). GC yield calcd on benzyl alcohol
i
j
a
b
as internal standard (see Supporting Information). Isolated yield. 1
Reaction done in MeOH/H2O 30:70 v/v. cis/trans ratio determined
c
k
atm. 3 atm.
by GC/MS analysis. trans/cis ratio determined by GC/MS analysis.
B
DOI: 10.1021/acs.orglett.5b01842
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
source SA or JM1). Other primary amines different from
butylamine were also effective in this transformation (see
compounds 4 and 5 in Scheme 2). Secondary amines reacted
also very well giving good yields of the phenol reductive
amination products 6−8. A potential limitation was observed
when the lipophilicity of reagents and products increased and
complete solubility in water was no longer possible. In these
cases, addition of MeOH to the solution (up to 30% v/v respect
to the water) allowed the reaction to proceed successfully. This
approach was employed to obtain compounds 6 and 9, where
(L)-phenylalanine methyl ester works as the nucleophile. The
reaction could be carried out also on substituted phenols giving
access to substituted cyclohexylamines (compounds 10−14 in
Scheme 2). In general, electron-donating substituents on the
aromatic rings were found to promote the reaction, while the
presence of electron-withdrawing substituents gave a consistent
decrement of the yields as observed, when methyl p-
hydroxybenzoate was submitted to our reaction conditions.
Indeed, amine 14 was formed in low yield and most of the
starting material (recoverable) remained unchanged even after a
longer reaction time. With substituted phenols the stereo-
selectivity of the reaction was analogous to that observed in the
reductive amination of substituted cyclohexanones with H2, as
verified when compounds 10, 12, 13, and 14 were prepared
starting from the corresponding substituted cyclohexanones.20
The reaction could be successfully carried out also on β-
naphtol that gave the corresponding N-substituted-1,2,3,4-
tetrahydronaphth-2-ylamines 16 and 17 in acceptable yields.
When aniline was used as the nucleophile, the major product of
the reaction was N-cyclohexylaniline 18 (Scheme 3) independ-
access to cyclohexylamines. The availability of reductive
protocols based on a sustainable hydrogen source is timely and
highly desirable. Effective dehydrogenation of formic acid to
hydrogen and CO2 could contribute particularly strongly to the
development of low-carbon economy, where formic acid offers a
versatile entry into the chemical supply chain.21 Formic acid and
derivatives are in fact major products of biomass processing, and
they have already been identified as a potential H2 storage
material due to the high gravimetric energy density, nontoxicity,
and capability of being safely handled in aqueous solutions.
Given these considerations and the observation that the process
has a soft impact on the catalyst efficiency, we decided to focus on
defining a continuous flow protocol. The Pd/C catalyst (SA in
Table 1) was packed in two glass columns, while the mixture of
phenol 1, butylamine 2, and sodium formate in water was
prepared in a flask, acting as a reservoir connected to an HPLC
pump. The catalyst columns were placed in a thermostated
chamber and heated at 60 °C while the reactant mixture was
continuously pumped at a flow rate of 0.4 mL min−1. Initially, the
mixture streaming from the catalyst column was collected
cyclically into the reservoir for 30 min, to achieve homogeneous
filling of the solid-containing columns. After reaching a stationary
state, the conversion of 1 to 3 reached 98% and the reacted
mixture was continuously collected while being periodically
monitored by GLC. The resulting aqueous mixture was extracted
with ethyl acetate and the combined organic layers were
subsequently washed with NaOH 5% solution to remove
unreacted phenol (Scheme 4).
Scheme 4. Synthesis of 3 under Continuous Flow Conditions
Scheme 3. Reaction with Aniline
ently from the nature of the starting phenol. Under our reaction
conditions, aniline was more reactive than phenol, producing the
intermediate cyclohexanone that immediately bound the
unreacted aniline to give compound 18 that is not further
reduced on the aromatic ring. Compound 18 was also formed by
reacting aniline alone with Pd/C and HCOONa in H2O or when
aniline was used, in place of phenol, in the presence of the more
nucleophilic butylamine 2 (Scheme 3). The possibility of
recycling the Pd/C catalyst in batch was investigated in the
reaction between phenol and piperidine as a model. The
separation of the catalyst was carried out by filtration of the crude
reaction mixture, and the Pd catalyst was washed with water and
used directly in the next run. The recycling experiments showed
that at least five consecutive reactions could be run without a
noticeable decrease in activity. The use of the recycled Pd/C in
other catalytic processes was also investigated. Hydrogenation of
1-pentenoic acid (H2 gas, 1 atm in MeOH/H2O 1:1, rt, 12 h) and
alkylation of p-nitrotoluene (H2 gas, 1 atm, MeOH, rt, 24 h) with
acetonitrile occurred without differences in terms of yields and
purities using both recycled and fresh Pd/C.15a
During 6 h of operation, 1.88 g of 1 were reacted, with a 90%
isolated yield of the amine 3. It should be noted that, under
continuous flow conditions, only 1.1 mmol of Pd were required
to convert 40 mmol of phenol, corresponding to a ratio of 2.7
mol %, which represents further improvement with respect to
our best batch conditions (5 mol % under MW heating). With
the flow protocol we were able to achieve TON and TOF values
of 32.7 and 5.45 h−1 respectively. The flow procedure was
extended to the reaction between 4-methoxyphenol and
butylamine, to prepare amine 7, obtaining comparable results
in terms of yield (Scheme 4).
In conclusion, we have developed an efficient procedure for
the reductive amination of phenols in water under mild
sustainable conditions. The reaction proceeds with commercially
available Pd/C, and the heterogeneous catalyst can be recycled
several times. The process proved to be robust enough to be
applied to a continuous flow procedure that allowed substituted
cyclohexylamine on a larger scale to be obtained, with a reduced
The Pd catalyzed reductive amination of phenols with
HCOONa in the presence of amine provides a mild sustainable
C
DOI: 10.1021/acs.orglett.5b01842
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01842.
Characterization data and copies of the 1H and 13C NMR
spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: maurizio.taddei@unisi.it.
*E-mail: luigi.vaccaro@unipg.it.
Notes
(12) (a) Chen, A.; Li, J.; Chen, J.; Zhao, G.; Ma, L.; Yu, Y.
ChemPlusChem 2013, 78, 1370−1378. (b) Cheng, H.; Liu, R.; Wang, Q.;
Wu, C.; Yu, Y.; Zhao, F. New J. Chem. 2012, 36, 1085−1090.
(13) Hamada, H.; Yamamoto, M.; Kuwahara, Y.; Matsuzaki, T.;
Wakabayashi, K. Bull. Chem. Soc. Jpn. 1985, 58, 1551−1555.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research has been developed and partially financed within
the National Project “BIT3G”−Italian Green Chemistry Cluster.
The support of University of Perugia and Regione Toscana
(Project POR CRO FSE 2007-2013 Asse IV, Capitale Umano) is
also gratefully acknowledged.
(14) (a) Taddei, M.; Mura, M. G.; Rajamaki, S.; De Luca, L.;
̈
Porcheddu, A. Adv. Synth. Catal. 2013, 355, 3002−3013. (b) Linciano,
P.; Pizzetti, M.; Porcheddu, A.; Taddei, M. Synlett 2013, 24, 2249−2254.
(c) Pizzetti, M.; De Luca, E.; Petricci, E.; Porcheddu, A.; Taddei, M. Adv.
Synth. Catal. 2012, 354, 2453−2464.
(15) (a) Ballerini, E.; Curini, M.; Gelman, D.; Lanari, D.; Piermatti, O.;
Pizzo, F.; Santoro, S.; Vaccaro, L. ACS Sustainable Chem. Eng. 2015, 3,
1221−1226. (b) Petrucci, C.; Cappelletti, M.; Piermatti, O.; Nocchetti,
M.; Pica, M.; Pizzo, F.; Vaccaro, L. J. Mol. Catal. A: Chem. 2015, 401,
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DOI: 10.1021/acs.orglett.5b01842
Org. Lett. XXXX, XXX, XXX−XXX