Selective primary aniline synthesis through supported Pd-catalyzed acceptorless dehydrogenative aromatization by utilizing hydrazine

Article abstract of DOI:10.1039/d1cc01686e

By utilizing hydrazine (N₂H₄) as the nitrogen source in the presence of a hydroxyapatite-supported Pd nanoparticle catalyst (Pd/HAP), various primary anilines can be selectively synthesized from cyclohexanonesviaacceptorless dehydrogenative aromatization. The strong nucleophilicity of N₂H₄and the stability of the hydrazone intermediates can effectively suppress the formation of the undesired secondary aniline byproducts.

Full text of DOI:10.1039/d1cc01686e

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Selective primary aniline synthesis through
supported Pd-catalyzed acceptorless
dehydrogenative aromatization by utilizing
hydrazine†
Cite this: Chem. Commun., 2021,
57, 6530
Received 30th March 2021,
Accepted 1st June 2021
Wei-Chen Lin, Takafumi Yatabe * and Kazuya Yamaguchi
*
DOI: 10.1039/d1cc01686e
rsc.li/chemcomm
By utilizing hydrazine (N2H4) as the nitrogen source in the presence of a selective synthesis of primary anilines is still quite difficult because
hydroxyapatite-supported Pd nanoparticle catalyst (Pd/HAP), various pri- undesirable secondary anilines are easily formed via reductive
mary anilines can be selectively synthesized from cyclohexanones via amination, that is, condensation of the desired primary anilines
acceptorless dehydrogenative aromatization. The strong nucleophilicity with cyclohexanones or cyclohexylimine intermediates followed by
of N2H4 and the stability of the hydrazone intermediates can effectively Pd-catalyzed hydrogenation of the secondary imine intermediates.
suppress the formation of the undesired secondary aniline byproducts.
In our group’s recent reports, primary anilines can be selectively
synthesized from aqueous NH3 and cyclohexanones in the presence
Primary anilines are widely utilized for pharmaceuticals, agrochem- of supported Pd nanoparticle catalysts (Fig. 1b);7 however, the
icals, electronic materials, dyes, and polymers.1 To date, several utilization of styrene as the hydrogen acceptor is necessary to inhibit
synthetic methods to obtain primary anilines have been developed, the reductive amination. Otherwise, secondary anilines were pro-
for example, nitration of arenes followed by reduction of duced as the major products due to the stronger nucleophilicities of
nitrobenzenes,2 and cross-coupling such as the Ullmann reaction the desired primary anilines than that of NH3.7 In terms of atom
or the Buchwald–Hartwig reaction of NH3 with benzene derivatives economy, acceptorless dehydrogenative aromatization is more ideal,
(e.g., aryl halides or aryl boronic acids).3 Recently, phenols have also theoretically producing H2 and H2O as the byproducts. Our
been utilized to produce primary anilines with NH3 or N2H4 as the group also reported the cyclohexanone oxime formation from
nitrogen source.4 Although these synthetic methods are efficient,
some disadvantages are still present—pre-functionalized aromatic
compounds are required, and this functionalization step is some-
times restricted to specific ortho/meta/para positions according to
the different substituents on the aromatic rings (Fig. 1a).
In this decade, dehydrogenative aromatization catalyzed by Pd
species has been widely applied to synthesize various arenes from
non-aromatic substrates.5 By utilizing six-membered carbocyclic
compounds, the regioselective installation of substituents at ortho/
meta/para positions can be easily conducted through well-developed
synthetic methods, such as nucleophilic addition of enolates,
Michael addition, and the Diels–Alder reaction. Therefore, various
aromatic compounds with the desired substituents can be synthe-
sized more efficiently. Until now, this strategy has been successfully
used in the synthesis of arylamines such as secondary or tertiary
anilines via in situ condensation of amines with cyclohexanones
followed by dehydrogenation to form aromatic rings.6 However, the
Department of Applied Chemistry, School of Engineering, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. E-mail: kyama@appchem.t.u-tokyo.ac.jp,
yatabe@appchem.t.u-tokyo.ac.jp; Fax: +81-3-5841-7220
† Electronic supplementary information (ESI) available: Experimental details,
additional experimental results, characterization data, and spectral data of
Fig. 1 Synthesis of primary anilines.
compounds (PDF). See DOI: 10.1039/d1cc01686e
6530 | Chem. Commun., 2021, 57, 6530–6533
This journal is © The Royal Society of Chemistry 2021

View Article Online
Communication
ChemComm
condensation of NH2OH with cyclohexanones followed by acceptor- region revealed that the Pd nanoparticles mainly existed as Pd0
less dehydrogenative aromatization using supported Pd nanoparti- (Fig. S2, ESI†). The X-Ray diffraction (XRD) patterns showed that
cle catalysts to synthesize primary anilines (Fig. 1b).8 In this case, the HAP structure was maintained after loading the Pd nano-
however, the selectivity to the desired primary anilines is not yet particles (Fig. S3, ESI†). Thus, the HAP-supported Pd nanoparticle
perfect due to the formation of cyclohexylimines as the intermedi- catalyst was successfully prepared.
ates, which inevitably produced secondary anilines albeit in small
Then, we carried out the acceptorless dehydrogenative aroma-
amounts (of about 10%) via reductive amination. Recently, homo- tization from hydrazine monohydrate (N2H4ꢀH2O) and 4-
geneously catalyzed acceptorless dehydrogenative aromatization has methylcyclohexanone (1a) in the presence of various supported
also been developed to synthesize primary anilines using a photo- Pd catalysts to form p-toluidine (2a) with N,N-dimethyl-
redox Ir–Co system;9 however, thermal reaction systems for accep- acetamide (DMA) as the solvent (Table 1). The DMA solution of
torless dehydrogenative aromatization to primary anilines with quite 1a and N2H4ꢀH2O was first stirred at room temperature to perform
high selectivity are hitherto unknown.
the condensation between 1a and N2H4ꢀH2O. Due to the strong
Another potentially attractive nitrogen source is N2H4, which nucleophilicity of N2H4, it was confirmed that after stirring for
possesses strong nucleophilicity to react readily with ketones,10 only 15 min, 1a was fully consumed with the formation of the
forming hydrazones as the stable products.11 Therefore, we hydrazone intermediates (3a and 4a). Then, the catalyst was added
developed a new strategy for the selective synthesis of primary to the solution and the dehydrogenative aromatization reaction
anilines by using N2H4 as the nitrogen source with supported was started at 160 1C under an Ar atmosphere. Among these
Pd nanoparticles as the catalyst. Herein, a one-pot condensa- supported Pd catalysts indicated in Table 1, Pd/HAP showed the
tion reaction between N2H4 and cyclohexanones followed by highest activity; 87% yield of 2a was obtained without the
acceptorless dehydrogenative aromatization to selectively pro- formation of secondary anilines (5a and 6a) (Table 1, entry 1).
duce primary anilines has been achieved in the presence of a HAP support alone did not promote the dehydrogenation reac-
hydroxyapatite-supported Pd nanoparticle catalyst (Pd/HAP) tion, confirming that Pd nanoparticles were active species for this
(Fig. 1c). Due to the strong nucleophilicity of N2H4 and the reaction (Table 1, entry 8). After the Pd/HAP-catalyzed reaction, H2
stability of the hydrazone intermediates, cyclohexanones were and NH3 were detected in the gas phase by GC-MS analysis,
quickly consumed, and condensation of the desired primary indicating that 2a was synthesized via acceptorless dehydrogena-
anilines with cyclohexanones or other intermediates did not tive aromatization of 3a and 4a. In the cases of basic supports,
occur. Therefore, secondary aniline byproducts were hardly such as CeO2 and layered double hydroxide (LDH), the yields of
produced, and various primary anilines were successfully the detected products became lower (Table 1, entries 3 and 4). The
synthesized with quite high selectivity through the present physical mixture of Pd/HAP and LDH also led to the decrease of
Pd/HAP-catalyzed acceptorless dehydrogenative aromatization. product yields (Table S1, entry 2, ESI†). The Fourier transform
Initially, the Pd/HAP catalyst was prepared via the deposition– infrared spectroscopy (FT-IR) results of Pd/LDH showed a band
precipitation of Pd species on HAP, followed by NaBH4 reduction. around 1500 cm-1 after the reaction (Fig. S4, ESI†), indicating that
The transmission electron microscopy (TEM) analyses of the there were possibly intermediates or products adsorbed on the
prepared Pd/HAP indicated that the Pd species were dispersedly surface of basic supports, which led to lower product yields. Acidic
supported on HAP as nanoparticles with an average diameter of supports, such as Al2O3, ZrO2, and TiO2, led to the formation of
3.89 nm (standard deviation: 1.10 nm) (Fig. S1, ESI†). The X-Ray small amounts of 5a and 6a (Table 1, entries 2, 6, and 7), and
photoelectron spectroscopy (XPS) spectrum around the Pd 3d these supports also promoted the further condensation of the
Table 1 Effect of catalystsa
Conv. [%]
Yield [%]
Entry
Catalyst
1a
2a
3a
4a
5a
6a
1
2
3
4
5
6
7
8b
Pd/HAP
Pd/Al2O3
Pd/CeO2
Pd/LDH
Pd/C
Pd/ZrO2
Pd/TiO2
HAP
499
499
499
499
499
499
499
499
87
77
63
58
58
39
3
o1
o1
o1
o1
o1
o1
o1
4
o1
o1
o1
o1
o1
o1
29
o1
1
o1
o1
16
2
o1
o1
o1
o1
23
1
4
o1
o1
o1
91
o1
a
Reaction conditions: (first step) 1a (0.5 mmol), N2H4ꢀH2O (1.0 mmol), DMA (2 mL), r.t., open air, 15 min. (second step) catalyst (Pd: 3 mol% to 1a),
b
160 1C, Ar (1 atm), 1 h. HAP (60 mg). Conversions and yields were determined by GC analysis using n-hexadecane as the internal standard.
This journal is © The Royal Society of Chemistry 2021
Chem. Commun., 2021, 57, 6530–6533 | 6531

View Article Online
ChemComm
Communication
produced 2a with DMA solvent, which also resulted in lower yields 5a and 6a (Table S1, entry 4, ESI†). The above results revealed that
of 2a (Table S2, ESI†). Adding acetic acid into the present Pd/HAP- HAP, a support with weak basicity,12 was the most suitable for the
catalyzed system also led to low 2a yield and selectivity (Table S1, present acceptorless dehydrogenative aromatization to selectively
entry 3, ESI†). The use of Pd/C led to the significant formation produce 2a without any additives.
of undesirable 5a and 6a (Table 1, entry 5). The study by Li and
Metals other than Pd, such as Pt and Ru, were examined,
co-workers has indicated that Pd/C promotes the reduction of the and they showed no catalytic activity for the dehydrogenation
hydrazone intermediates in the presence of H2O, to form reaction (Table S3, ESI†). Decreasing the temperature to 150 1C
cyclohexylamines.4b The produced cyclohexylamines then reacted or 140 1C significantly lowered the rate of the dehydrogenative
with 2a, leading to the formation of 5a and 6a. It is possible that aromatization (Table S4, ESI†). Various solvents, such as DMA,
H2O acted as the weak acid to promote the reduction of the N-methyl-2-pyrrolidone (NMP), diethylene glycol dimethyl
hydrazone intermediates. In fact, adding 4A-MS into the present ether (diglyme), and mesitylene, were also examined, and DMA
Pd/C-catalyzed system successfully suppressed the formation of was the most suitable solvent for the present reaction
(Table S5, ESI†). This Pd/HAP-catalyzed system was confirmed
to be truly heterogeneous by hot filtration experiment (Fig. S5,
Table 2 Substrate scopea
ESI†) and inductively coupled plasma atomic emission spectro-
scopy (ICP-AES) analysis, and the catalyst can be reused despite
the loss of its catalytic activity possibly due to Pd nanoparticle
aggregation (Fig. S6, ESI†).13
Under the optimized reaction conditions in hand, we next
investigated the substrate scope of the present Pd/HAP-
catalyzed system. The dehydrogenative aromatization reactions
were started after the complete conversion of cyclohexanones to
hydrazone intermediates at room temperature except in the
case of 2,6-dimethylcyclohexanone. As a result, a variety of
primary anilines shown in Table 2 were selectively synthesized
with no detection of secondary anilines except for entry 11
(Table S6, ESI†). Cyclohexanone and its derivatives with alkyl
and phenyl substituents were efficiently converted to the
corresponding primary anilines (Table 2, entries 1–7). The more
sterically hindered substrate, 2,6-dimethylcyclohexanone, was
also converted to the corresponding primary aniline (Table 2,
entry 8). The steric hindrance made it difficult for both the
condensation step and the dehydrogenation step to proceed
(Table S7, ESI†). A hydroxyphenyl-substituted cyclohexanone
was also applicable (Table 2, entry 9). Cyclohexanones posses-
sing a trifluoromethyl, an alkoxy, an ester, or an amide group
were tolerated in the present reaction system without hydro-
genolysis of these functional groups (Table 2, entries 10–13).14
Substrates possessing an acetal, a tert-butyldimethylsilyl (TBS),
or a tert-butoxycarbonyl (Boc) protecting group were also con-
verted into the corresponding primary anilines (Table 2, entries
14–16). When using cyclohexanediones in our previous
Pd-catalyzed system using NH3, aminophenols were formed
as the major products.7 In contrast, applying cyclohexane-
diones to this reaction led to the formation of benzenediamines
because N2H4 can easily attack both ketone sites in these
substrates (Table 2, entries 17 and 18).
To verify the reaction pathway, several control experiments
were conducted. First, the time profile of the reaction between
1a and N2H4ꢀH2O was examined (Fig. S7, ESI†). Before the
reaction was started at 160 1C, it was found that 1a had
been fully consumed, and hydrazones 3a and 4a were formed
through condensation of 1a with N2H4ꢀH2O. When the solution
was heated to 160 1C in the presence of Pd/HAP, 3a and 4a
were gradually converted to 2a with a trace amount of cyclo-
hexanone phenylhydrazone (7a) formed as the intermediate.
a
Reaction conditions: (first step) substrate (0.5 mmol), N2H4ꢀH2O
(1.0 mmol), DMA (2 mL), r.t., open air, 15 min. (second step) Pd/HAP
b
(Pd: 3 mol% to substrate), 160 1C, Ar (1 atm). 30 min for the first step.
c
d
e
Pd/HAP (Pd: 9 mol% to substrate). N2H4ꢀH2O (3.0 mmol). 4A-MS
f
(100 mg) was added. N2H4ꢀH2O (2.0 mmol). Yields were determined by
GC analysis. The isolated yields are shown in parentheses.
6532 | Chem. Commun., 2021, 57, 6530–6533
This journal is © The Royal Society of Chemistry 2021

View Article Online
Communication
ChemComm
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 (a) B. Amini and S. Lowenkron, Aniline and Its Derivatives, Kirk-
Othmer Encyclopedia of Chemical Technology, 2003, vol. 2, pp. 783–
809; (b) P. F. Vogt and J. J. Gerulis, Amines, Aromatic, Ullmann’s
Encyclopedia of Industrial Chemistry, vol. 2, 2012, pp. 699–718.
2 R. S. Downing, P. J. Kunkeler and H. van Bekkum, Catal. Today,
1997, 37, 121–136.
3 (a) Q. Shen and J. F. Hartwig, J. Am. Chem. Soc., 2006, 128,
10028–10029; (b) D. S. Surry and S. L. Buchwald, J. Am. Chem. Soc.,
2007, 129, 10354–10355; (c) J. Kim and S. Chang, Chem. Commun.,
2008, 3052–3054; (d) H. Rao, H. Fu, Y. Jiang and Y. Zhao, Angew.
Chem., Int. Ed., 2009, 48, 1114–1116; (e) P. Ruiz-Castillo and
S. L. Buchwald, Chem. Rev., 2016, 116, 12564–12649;
( f ) J. Schranck and A. Tlili, ACS Catal., 2018, 8, 405–418.
4 (a) T. Cuypers, P. Tomkins and D. E. De Vos, Catal. Sci. Technol.,
2018, 8, 2519–2523; (b) Z. Qiu, L. Lv, J. Li, C.-C. Li and C.-J. Li, Chem.
Sci., 2019, 10, 4775–4781; (c) Z. Qiu, H. Zeng and C.-J. Li, Acc. Chem.
Res., 2020, 53, 2395–2413; (d) Z. Qiu and C.-J. Li, Chem. Rev., 2020,
120, 10454–10515.
Fig. 2 Control experiments of reactions in the presence of 2a or 10a
under the following conditions: (first step) 1b (0.5 mmol), N2H4ꢀH2O
(1.0 mmol), DMA (2 mL), r.t., open air, 15 min; (second step) 2a or 10a
(0.5 mmol), Pd/HAP (Pd: 3 mol% to 1b), 160 1C, Ar (1 atm), 1 h.
5 (a) Y. Izawa, D. Pun and S. S. Stahl, Science, 2011, 333, 209–213;
(b) S. A. Girard, H. Huang, F. Zhou, G.-J. Deng and C.-J. Li,
Org. Chem. Front., 2015, 2, 279–287; (c) A. V. Iosub and S. S. Stahl,
ACS Catal., 2016, 6, 8201–8213; (d) X. Liu, J. Chen and T. Ma,
Org. Biomol. Chem., 2018, 16, 8662–8676.
6 (a) K. Taniguchi, X. Jin, K. Yamaguchi, K. Nozaki and N. Mizuno,
Chem. Sci., 2017, 8, 2131–2142; (b) Y. Koizumi, K. Taniguchi, X. Jin,
K. Yamaguchi, K. Nozaki and N. Mizuno, Chem. Commun., 2017, 53,
10827–10830; (c) S. Takayama, T. Yatabe, Y. Koizumi, X. Jin,
K. Nozaki, N. Mizuno and K. Yamaguchi, Chem. Sci., 2020, 11,
4074–4084.
7 Y. Koizumi, X. Jin, T. Yatabe, R. Miyazaki, J. Hasegawa, K. Nozaki,
N. Mizuno and K. Yamaguchi, Angew. Chem., Int. Ed., 2019, 58,
10893–10897.
8 X. Jin, Y. Koizumi, K. Yamaguchi, K. Nozaki and N. Mizuno, J. Am.
Chem. Soc., 2017, 139, 13821–13829.
Then, although phenylhydrazines were not detected in the
time profile, control experiments with phenylhydrazine (8b)
and 1,2-diphenylhydrazine (9b) as the starting materials in
the present reaction system were carried out (Fig. S8, ESI†).
Both 8b and 9b were fully converted to the corresponding
primary aniline (2b) with 499% selectivity via reductive N–N
bond cleavage, indicating that 8b and 9b were the possible
intermediates produced from the dehydrogenation of the
corresponding hydrazones. In addition, the reaction of cyclo-
hexanone (1b) with N2H4ꢀH2O in the presence of 2a was carried
out (Fig. 2). In this case, 2b was selectively obtained without the
formation of secondary anilines 5ab and 6ab. On the other
hand, for the reaction of 1b with N2H4ꢀH2O in the presence of
4-methylcyclohexylamine (10a), secondary anilines 5ab0 and 5a
were produced in significant amounts (Fig. 2). These results
indicated that in the cases of catalysts giving 5a and 6a shown
in Table 1, 5a and 6a were derived from the coupling of 2a with
10a, which was proposed to be produced from the hydrogeno-
lysis of hydrazones 3a and 4a.4b Therefore, the hydrazone
intermediates were proved to be stable enough in the present
Pd/HAP-catalyzed reaction system, where cyclohexylamines
were not produced during the reaction, leading to the high
selectivity to the desired primary anilines. Besides, the results
also indicated that primary anilines were not produced through
the dehydrogenation of cyclohexylamines. From these results,
we summarized the pathway of this reaction in Fig. S9, ESI.†
This work was financially supported by JSPS KAKENHI Grant
No. 19H02509 and 20K22547.
´
9 S. U. Dighe, F. Julia, A. Luridiana, J. J. Douglas and D. Leonori,
Nature, 2020, 584, 75–81.
10 (a) A. Furst, R. C. Berlo and S. Hooton, Chem. Rev., 1965, 65, 51–68;
(b) E. F. Rothgery, Hydrazine and Its Derivatives, in Kirk-Othmer
Encyclopedia of Chemical Technology, 2004, vol. 13, pp. 562–607;
(c) T. A. Nigst, A. Antipova and H. Mayr, J. Org. Chem., 2012, 77,
8142–8155.
¨
11 (a) D. K. Kolmel and E. T. Kool, Chem. Rev., 2017, 117, 10358–10376;
´
(b) P. Rulliere, G. Benoit, E. M. D. Allouche and A. B. Charette,
Angew. Chem., Int. Ed., 2018, 57, 5777–5782.
12 (a) T. Tsuchida, J. Kubo, T. Yoshioka, S. Sakuma, T. Takeguchi and
W. Ueda, J. Catal., 2008, 259, 183–189; (b) S. Diallo-Garcia,
M. B. Osman, J.-M. Krafft, S. Casale, C. Thomas, J. Kubo and
G. Costentin, J. Phys. Chem. C, 2014, 118, 12744–12757.
13 For the details of the leaching test and reuse test, see the ESI†.
14 In the case of cyclohexanones with electron-withdrawing groups,
hydrogenation of the hydrazone intermediates occurs comparatively
easily to cause low selectivity to the desired primary anilines, which
can be inhibited by the addition of 4A-MS (Table S8, ESI†).
This journal is © The Royal Society of Chemistry 2021
Chem. Commun., 2021, 57, 6530–6533 | 6533