Robust cyclometallated Ir(iii) catalysts for the homogeneous hydrogenation of N-heterocycles under mild conditions

Article abstract of DOI:10.1039/c3cc44567d

Cyclometallated Cp*Ir(N^∧C)Cl complexes derived from N-aryl ketimines are highly active catalysts for the reduction of N-heterocycles under ambient conditions and 1 atm H₂ pressure. The reaction tolerates a broad range of other potentially reducible functionalities and does not require the use of specialised equipment, additives or purified solvent.

Full text of DOI:10.1039/c3cc44567d

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Robust cyclometallated Ir(III) catalysts for the
homogeneous hydrogenation of N-heterocycles under
mild conditions†‡
Cite this: Chem. Commun., 2013,
49, 7052
Received 18th June 2013,
Accepted 21st June 2013
Jianjun Wu, Jonathan H. Barnard, Yi Zhang, Dinesh Talwar, Craig M. Robertson
and Jianliang Xiao*
DOI: 10.1039/c3cc44567d
www.rsc.org/chemcomm
Cyclometallated Cp*Ir(N4C)Cl complexes derived from N-aryl ketimines Crabtree and co-workers reported that a [Ir(NHC)(PPh3)(COD)][PF6]
are highly active catalysts for the reduction of N-heterocycles under complex is active for the reduction of N-heterocycles at room
ambient conditions and 1 atm H2 pressure. The reaction tolerates a temperature and low H2 pressures (1–5 atm).5d However, additional
broad range of other potentially reducible functionalities and does not PPh3 was required for catalytic activity and the substrates were
require the use of specialised equipment, additives or purified solvent. limited mainly to quinolines.
We recently reported that cyclometallated Cp*Ir(N4C)Cl com-
The hydrogenation of organic substrates is one of the great success plexes are highly active catalysts for a range of hydrogen transfer
stories of homogeneous catalysis. Building on the pioneering work reactions.6 We now report that related complexes, if appropriately
of Wilkinson, Crabtree, Knowles and Noyori, highly effective functionalised, catalyse the selective reduction of N-heterocycles at
hydrogenations of CQC and CQO bonds have been developed room temperature and 1 atm H2, allowing for the operationally
and widely adopted by the synthetic community.1 However, the simple synthesis of various reduced N-heterocyclic compounds.
field of CQN hydrogenation is much less well developed and
Initially we screened complexes 1a–1l (Fig. 1) for the reduction of
utilised, particularly for N-heterocycles. Reduced heterocyclic com- 2-methylquinoline 2a in as-received 2,2,2-trifluoroethanol (TFE) at
pounds are present in many pharmaceuticals, natural products, ambient temperature (Table 1). A hydrogen balloon was used as the
organic dyes, fragrances and hydrogen storage materials, and as a hydrogen source. Surprisingly, of all the complexes 1a–1f, only the
result, efficient methods for the synthesis of these compounds are electron rich 3,4-methylenedioxy-substituted 1f showed any activity
desirable.2 Of the methods developed, the catalytic hydrogenation (entries 1–8). To assess the effect of the N-donor substituent,
of the parent unsaturated N-heterocycles with hydrogen gas is an complexes 1g–1l were screened,6 but all showed diminished activity
attractive route to these products due to the lack of stoichiometric in comparison to 1f (entries 9–14). No reaction was observed when
waste products associated with the use of reactive metals and [Cp*IrCl2]2 or no catalyst was used (entries 1–7). Notably, ligands
metal hydrides or other hydrogen sources.3
bearing the 3,4-methylenedioxy group underwent selective cyclo-
In comparison to the hydrogenation of olefins, carbonyls and metallation with [Cp*IrCl2]2 (ref. 7) to give the more hindered
imines, the hydrogenation of N-heterocycles is more challenging due products with 85 : 15–95 : 5 isomeric ratios (Fig. 2), due to the
to the aromaticity of the N-heterocycles. Transition metal catalysts ortho-directing effect of the oxygen atoms.8 In contrast, the 3-OMe
based on Rh, Ir, Ru, Os, Mo and Fe have been applied to the group of 1e resulted in selective cyclometallation para to the OMe,
homogeneous hydrogenation of N-heterocycles.4,5 Unfortunately, and 1e proved to be inactive (entries 1–7).
these reactions are often characterised by the use of high
Screening a variety of different solvents suggested that the
temperatures or hydrogen pressures, and many systems require use of TFE was essential for good catalytic activity at 1 atm H2
the use of additives such as Brønsted acids,5g chloroformates5h
or I2.5f Furthermore, to the best of our knowledge, there is no
single reported homogeneous catalyst capable of hydrogenating
quinolines, 3,4-dihydroisoquinolines, quinoxalines and indoles.
Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.
E-mail: jxiao@liv.ac.uk; Fax: +44 (0)151-7943588
† In memory of Dr Phil Hogan.
‡ Electronic supplementary information (ESI) available: Characterisation data for
Ir complexes, ligands and hydrogenation products. CCDC 933833 and 933834. For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
Fig. 1 Catalysts examined in this study (see Table 1), PMP = p-methoxyphenyl.
c3cc44567d
c
7052 Chem. Commun., 2013, 49, 7052--7054
This journal is The Royal Society of Chemistry 2013

View Article Online
Communication
ChemComm
Table 1 Optimisation of the hydrogenation of 2-methylquinolinea
Table 2 Hydrogenation of quinolines with 1fa
Entry Complex
Solvent
Conversionb (%)
Temp Time
Entry R1
R2
Prod.
(1C)
(h)
Conv.b (%)
1–7
8
1a–1e, [Cp*IrCl2]2, none TFE
1f
N.R.
>98
9
21
77
87
88
6
TFE
TFE
TFE
TFE
TFE
TFE
TFE
1
2-Me
2-Me
H
H
H
H
H
H
3a
3a
3b
3c
3d
rt
85
rt
3
16
3
>98 (96)
92 (85)
>98 (95)
>98 (97)
>98 (98)
9
1g
1h
1i
1j
1k
1l
2c
3
10
11
12
13
14
4
5
3-Me
4-Me
40
40
20
20
>98 (97),
4 : 1 dr
6
rt
3
15–17 1f
18–20 1f
21, 22 1f
MeOH, EtOH, iPrOH N.R.
DCM, THF, toluene N.R.
H2O, EtOAc
N.R.
7
8
9
rt
3
20
20
>98 (99)
>98 (93)
>98 (80)
a
Conditions: 2a (0.5 mmol), complex (1 mol%), solvent (3 mL), rt, 3 h,
H2 balloon. Conversion determined by 1H NMR of the crude reaction
b
mixture and normalising the sum of the product and starting material
integrals to 100%. A conversion of >98% was assigned when the
substrate was not observable in the spectrum. N.R. = no reaction.
40
40
10
11
12
13
14
15
H
6-CO2Et 3i
rt
40
rt
rt
rt
3
3
3
3
3
3
>98 (97)
95 (92)
>98 (97)
>98 (96)
>98 (98)
>98 (97)
2-Me 6-OMe
3j
3k
3l
H
H
H
H
6-Br
6-Cl
8-OH
8-Me
3m
3n
40
a
Conditions: substrate (0.5 mmol), 1f (1 mol%), TFE (3 mL), H2
b
balloon. As for Table 1. A conversion of >98% was assigned when
the substrate was not observable in the spectrum. Isolated yields in
c
parentheses. 0.01 mol% 1f.
Fig. 2 Molecular structures of 1f (major isomer, left) and 1g (minor isomer,
right) determined by X-ray diffraction. See the ESI‡ for details.
4-methylquinolines, which are often challenging substrates,5b,e were
pressure (entries 15–22). However, the reaction was found to occur reduced with full conversion, although a slightly elevated tempera-
slowly in MeOH at 20 bar (see the ESI,‡ S1.5 for full details), ture and prolonged time was necessary. Reduction of phenanthro-
although TFE remained the most effective solvent. TFE is known to lines gave the partially hydrogenated 1,2,3,4-tetrahydrophenan-
solvate chloride ions much more strongly than MeOH,9 and so may throlines as the exclusive products (entries 8 and 9).11 Notably,
enhance the dissociation of chloride from the coordinatively entry 6 represents the 1st homogeneous hydrogenation of 2,20-
saturated 18 electron complexes 1, creating a vacant, active site biquinoline. Acridine was reduced to the 9,10-dihydro product
on Ir(III) for H2 coordination. In line with this, the hydrogenation in (entry 7). The presence (or lack of) 2-substituents did not unduly
TFE was found to be inhibited by the addition of chloride ions affect the reaction, suggesting that the substrate and/or product
(6 fold decrease in conversion with 10% NBu4Cl) or PPh3 (no reaction does not coordinate or affect the coordination of H2 to the single
with 1% PPh3) (see ESI,‡ S1.8 for further details). In addition, as active site in TFE. The catalyst loading can be lowered. For instance,
TFE (pKa 12.4) is more acidic than MeOH (pKa 15.5) or EtOH in the reduction of 2a, a TON of 9200 (85% isolated yield) was
(pKa 15.8),10 it can hydrogen bond to substrate or product more achieved at 85 1C in 16 h and 1 atm H2 pressure, showing the robust
effectively, and thereby may help prevent them from competing nature of the hydrogenation catalyst (entry 2).
with H2 for the single vacant site on Ir(III). Indeed, 1H NMR
We also investigated the reduction of a variety of other N-hetero-
showed that upon mixing 2a with TFE in CDCl3, the chemical cycles and imines (Table 3). Quinoxalines were reduced with full
shift of the TFE hydroxyl proton changed from 2.5 to 3.5 ppm, conversions, which is, to our knowledge, the first example of
suggesting that TFE hydrogen bonds to 2a (see ESI,‡ S1.6 for homogeneous hydrogenation of these substrates under ambient
further details). Not entirely surprisingly, the use of chloride conditions (entries 1–3). Cyclic and acyclic imines were also effi-
abstracting agents (AgSbF6 and NaBArF4) did not allow the ciently hydrogenated (entries 4–10). The presence of a nitro group
reaction to proceed in MeOH at 1 atm H2 pressure (see ESI,‡ was well tolerated (entry 10). Unprotected indoles (entries 11–13),
Table S2), given the weaker hydrogen bonding ability of MeOH. which are often challenging substrates for homogeneous hydroge-
Using the optimised conditions, a variety of quinolines (includ- nation,12 could be reduced to the corresponding indolines. How-
ing substitutions at 2-, 3-, 4-, 6- and 8-positions), were hydrogenated ever, no reaction was observed for either ketone or styrene
to give the 1,2,3,4-tetrahydroquinoline products in good to excellent substrates (entries 14 and 15), showing the chemoselectivity of 1f
yields (Table 2). The reaction was found to be highly tolerant of for the reduction of CQN bonds over CQO and CQC bonds.
other functionalities, such as halides, esters, and free hydroxyl
To further demonstrate the utility of complex 1f for the
groups (entries 10 and 12–14). It is worthy to note that 3- and reduction of N-heterocycles, three widely used heterogeneous
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 7052--7054 7053

View Article Online
ChemComm
Communication
Table 3 Hydrogenation of other CQN bonds with 1fa
In conclusion, we report the reduction of a diverse range of
N-heterocyclic compounds under mild conditions (ambient
temperature, 1 atm H2) without the use of any additives. Key
to the success of the reaction is the choice of ligand and the use
of TFE as solvent. The reaction was found to be tolerant of a
wide range of other, potentially reducible, functional groups
and could be carried out using standard laboratory glassware
and non-purified solvent. Thus, our results demonstrate a
simple, yet highly selective reduction of N-heterocycles and
imines with hydrogen gas as a highly effective alternative to
the heterogeneous metal catalysts and borohydrides commonly
used for these reactions, whilst offering greatly increased
reactivity and selectivity.
Entry
Substrate
Prod.
Conv.b (%)
1c
2
3
Quinoxaline
2-Me-quinoxaline
6-Me-quinoxaline
5a
5b
5c
>98 (95)
>98 (93)
>98 (95)
4–8
5d–5h
See below
4
5
6
7
8
R1, R2 = H, R3 = Me
R1, R2 = H, R3 = Pr
R1, R2 = H, R3 = Cy
R1, R2 = MeO, R3 = Cy
R1, R2 = MeO, R3 = Ph
5d
5e
5f
5g
5h
>98 (88)
>98 (93)
>98 (89)
>98 (91)
>98 (90)
i
We thank the University of Liverpool (JHB) and Pfizer (JW)
for funding. Mass spectrometry data was acquired at the EPSRC
UK National Mass Spectrometry Facility at Swansea University.
9
5i
96 (85)
Notes and references
1 The Handbook of Homogeneous Hydrogenation, ed. J. G. de Vries and
C. J. Elsevier, Wiley-VCH, Weinheim, 2007.
10
5j
>98 (99)
´
2 (a) V. Sridharan, P. Suryavanshi and J. C. Menendez, Chem. Rev.,
11
12
13d
14
15
2-Me-indole
Indole
5-MeO-indole
4-MeO-acetophenone
4-MeO-styrene
5k
5l
5m
5n
5o
86 (83)
82 (78)
>98 (95)
N.R.
2011, 111, 7157; (b) J. D. Scott and R. M. Williams, Chem. Rev., 2002,
102, 1669; (c) R. H. Crabtree, Energy Environ. Sci., 2008, 1, 134.
3 (a) M. R. Pitts, J. R. Harrison and C. J. J. Moody, J. Chem. Soc., Perkin
Trans. 1, 2001, 955; (b) G. W. Gribble, Chem. Soc. Rev., 1998, 27, 395.
4 D.-S. Wang, Q.-A. Chen, S.-M. Lu and Y.-G. Zhou, Chem. Rev., 2012,
112, 2557.
5 (a) E. Baralt, S. J. Smith, J. Hurwitz, I. T. Horvath and R. H. Fish,
J. Am. Chem. Soc., 1992, 114, 5187; Ru: (b) T. Wang, L.-G. Zhuo, Z. Li,
F. Chen, Z. Ding, Y. He, Q.-H. Fan, J. Xiang, Z.-X. Yu and A. S.
C. Chan, J. Am. Chem. Soc., 2011, 133, 9878; (c) S.-M. Lu, X.-W. Han
and Y.-G. Zhou, J. Organomet. Chem., 2007, 692, 3065; Ir:
(d) G. E. Dobereiner, A. Nova, N. D. Schley, N. Hazari, S. J. Miller,
O. Eisenstein and R. H. Crabtree, J. Am. Chem. Soc., 2011, 133, 7547;
(e) R. Yamaguchi, C. Ikeda, Y. Takahashi and K. Fujita, J. Am. Chem.
Soc., 2009, 131, 8410; ( f ) W.-B. Wang, S.-M. Lu, P.-Y. Yang,
X.-W. Han and Y.-G. Zhou, J. Am. Chem. Soc., 2003, 125, 10536;
(g) Z.-W. Li, T.-L. Wang, Y.-M. He, Z.-J. Wang, Q.-H. Fan, J. Pan and
L.-J. Xu, Org. Lett., 2008, 10, 5265; (h) S.-M. Lu, Y.-Q. Wang,
X.-W. Han and Y.-G. Zhou, Angew. Chem., Int. Ed., 2006, 45, 2260;
(i) W.-J. Tang, J. Tan, L.-J. Xu, K.-H. Lam, Q.-H. Fan and A. S.
N.R.
a
Conditions: substrate (0.5 mmol), 1f (1 mol%), TFE (3 mL), rt, 3 h, H2
b
balloon. As for Table 1. A conversion of >98% was assigned when the
substrate was not observable in the spectrum. Isolated yields in
parentheses. 0.5 mol% 1f. N.R. = no reaction. 40 1C, 20 h.
c
d
´
C. Chan, Adv. Synth. Catal., 2010, 352, 1055; Os: ( j) R. A. Sanchez-
´
Delgado and E. Gonzalez, Polyhedron, 1989, 8, 1431; Mo: (k) G. Zhu,
Fig. 3 Synthesis and reactions of hydride 6.
K. Pang and G. Parkin, J. Am. Chem. Soc., 2008, 130, 1564; Fe:
(l) T. J. Lynch, M. Banah, H. D. Kaesz and C. R. Porter, J. Org. Chem.,
1984, 49, 1266.
6 (a) C. Wang, A. Pettman, J. Bacsa and J. Xiao, Angew. Chem., Int. Ed.,
2010, 49, 7548; (b) J. H. Barnard, C. Wang, N. G. Berry and J. Xiao,
Chem. Sci., 2013, 4, 1234; (c) Y. Wei, D. Xue, Q. Lei, C. Wang and
J. Xiao, Green Chem., 2013, 15, 629; (d) Q. Lei, Y. Wei, D. Talwar,
C. Wang, D. Xue and J. Xiao, Chem.–Eur. J., 2013, 19, 4021; (e) J. Wu,
D. Talwar, S. Johnston, M. Yan and J. Xiao, Angew. Chem., Int. Ed.,
2013, DOI: 10.1002/anie.201300292.
7 D. L. Davies, O. Al-Duaij, J. Fawcett, M. Giardiello, S. T. Hilton and
D. R. Russell, Dalton Trans., 2003, 4132.
8 K. Gao, P.-S. Lee, C. Long and N. Yoshikai, Org. Lett., 2012, 14, 4234.
9 R. R. Ryall, H. A. Strobel and M. C. R. Symons, J. Phys. Chem., 1977,
81, 253.
10 (a) P. Ballinger and F. A. Long, J. Am. Chem. Soc., 1959, 81, 1050;
(b) http://evans.harvard.edu/pdf/evans_pka_table.pdf.
11 J. Wu, D. Talwar, S. Johnston, M. Yan and J. Xiao, Angew. Chem., Int.
Ed., 2013, 52, 6983–6987.
12 (a) D.-S. Wang, Q.-A. Chen, W. Li, C.-B. Yu, Y.-G. Zhou and X. Zhang,
J. Am. Chem. Soc., 2010, 132, 8909; (b) A. Kulkarni, W. Zhou and
hydrogenation catalysts13 and five homogeneous catalysts,
including systems that have been shown to be extremely
effective for quinoline hydrogenations,5c,d,i were compared to
1f for the reduction of 2a (see ESI,‡ Table S3). Complex 1f was
found to be over 14 times more active than Rh/C which was the
most active of the heterogeneous catalysts and 6 times as active
as [IrCl(COD)]2/P-Phos/I2, which was the most active of the
other homogeneous catalysts previously reported.5i
In order to gain further information about the reaction mecha-
nism, we prepared the iridium hydride14 species 6 by treating 1f with
an excess of sodium formate in DCM–H2O (Fig. 3). Treatment of 6
with 0.2 equivalents of 2-methylquinoline 2a did not lead to the
formation of 3a. However, the reaction of 6 with 0.2 equivalents of
2-methyl quinolinium tetrafluoroborate led to the rapid formation of
the fully reduced product 3a (see ESI,‡ S1.4 for further details).
Repeating the reactions in the presence of TFE did not alter the
results. These results suggest that the protonated, instead of the
neutral quinoline, is the species that is reduced in the reaction (Fig. 3).
¨ ¨
B. Torok, Org. Lett., 2011, 13, 5124.
13 Heterogeneous Catalysis for the Synthetic Chemist, ed. R. L. Augustine,
Marcel Dekker, New York, 1996.
14 C. Wang, H.-S. T. Chen, J. Bacsa, R. A. Catlow and J. Xiao, Dalton
Trans., 2013, 42, 935.
c
7054 Chem. Commun., 2013, 49, 7052--7054
This journal is The Royal Society of Chemistry 2013