Highly Selective Hydrogenation of Aromatic Ketones and Phenols Enabled by Cyclic (Amino)(alkyl)carbene Rhodium Complexes

Article abstract of DOI:10.1021/jacs.5b05868

Air-stable Rh complexes ligated by strongly σ-donating cyclic (amino)(alkyl)carbenes (CAACs) show unique catalytic activity for the selective hydrogenation of aromatic ketones and phenols by reducing the aryl groups. The use of CAAC ligands is essential for achieving high selectivity and conversion. This method is characterized by its good compatibility with unsaturated ketones, esters, carboxylic acids, amides, and amino acids and is scalable without detriment to its efficiency.

Full text of DOI:10.1021/jacs.5b05868

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Highly Selective Hydrogenation of Aromatic Ketones and Phenols
Enabled by Cyclic (Amino)(alkyl)carbene Rhodium Complexes
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Yu Wei,† Bin Rao,† Xuefeng Cong,† and Xiaoming Zeng*,†,‡
†Center for Organic Chemistry, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710054, China
‡State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
Supporting Information Placeholder
yl group in the products, thus offering a straightforward and
clean route to cyclohexyl-containing ketones and cyclohexa-
nones, which are fundamental feedstock materials and widely
used as key precursors to industrially important molecules such
as caprolactam and adipic acid.19
ABSTRACT: Air-stable Rh complexes ligated by strongly σ-
donating cyclic (amino)(alkyl)carbenes (CAACs) show unique
catalytic activity for the selective hydrogenation of aromatic
ketones and phenols by reducing the aryl groups. The use of
CAAC ligands is essential for achieving high selectivity and con-
version. This method is characterized by its good compatibility
with unsaturated ketones, esters, carboxylic acids, amides, and
amino acids, and is scalable without detriment to its efficiency.
Scheme 1. Selective Hydrogenation of Aromatic Ketones
and Phenols
(a) The selective hydrogenation of aromatic ketones (two pathways)
Et
OH
5a
cat. Ru, Ir, Pd, Rh,
H2
H2
Fe, FLP...
Et
H2
OH
Et
O
ketone hydrogenation
path a
Selective hydrogenation is one of the most powerful and useful
reactions because of its synthetic significance in the creation of
pharmaceuticals, materials, and fundamental feedstock chemi-
cals.1,2 Despite considerable achievements, chemoselectivity has
long been a prominent obstacle when several unsaturated scaf-
folds are present in the same substrates.3 Compared with polar
carbonyls, the aromatic hydrocarbons are difficult substrates for
hydrogenation, probably because of the stability caused by aro-
maticity.4,5 As a result, the hydrogenation of aromatic ketones
often leads to aryl-containing alcohol products via a preferential
carbonyl reduction (Scheme 1a, path a).6 In contrast, switching
the selectivity to realize arene hydrogenation while retaining an
easily reducible carbonyl is more challenging, and has not been
achieved with structurally well-defined homogeneous catalysts
to date (Scheme 1a, path b).7 Another key problem is inhibiting
the reduction of the resulting ketones to alcohols or dehydrox-
ylated products (e.g., 4a and 5a). Especially for naturally abun-
dant phenols, efficient strategies for reducing them to cyclohex-
anones by avoiding a carbonyl reduction are rare (Scheme 1b).8,9
From both sustainable and synthetic points of view, developing
a general protocol to address these selectivity challenges would
help advance clean chemical syntheses.
2a
Et
O
1a
(CAAC)Rh(COD)Cl
4a
Et
X
CF3CH2OH, r.t.
arene hydrogenation
path b
3a
R1
R2
N
Rh
(b) The selective hydrogenation of phenols to cyclohexanones
Cl
COD
CAAC-Rh
H2
OH
OH
OH
O
(CAAC)Rh(COD)Cl
X
CF3CH2OH/H2O
isomerization
phenol hydrogenation
6a
8a
7a
A
To ensure that the arene hydrogenation occurs preferentially
over that of ketones, a suitable catalyst that allows interaction
with the aryl group via a π-coordination is required. We postu-
lated that electron-rich CAAC ligands, with their strong σ-
electron donation to the metal center, might enhance the inter-
action of the metal with the aryl by the back-donation of elec-
tron density from the filled d orbitals of the metal into the unoc-
cupied π*aryl anti-bonding orbital.12b This may favor the arene
hydrogenation with H2. Meanwhile, the electron-rich metal may
be expected to show rather low oxophilicity.20 Compared with
other transition metals, rhodium shows high reactivity towards
arene hydrogenation.1 At the outset, the impact of Rh complex-
es on the selective hydrogenation of propiophenone was evalu-
ated (Table 1). In the presence of Wilkinson’s catalyst, a trace
amount of the aryl-reduced product 3a was detected by GC-MS
analysis (entry 2). Similar results were obtained using
[Rh(cp*)Cl2]2 and RhCl3•H2O (entries 3 and 4). A complex of
[Rh(COD)Cl]2 improves the reaction to give 3a in 29% yield, but
with various by-products of 2a, 4a, and 5a (entry 5).
Recently, there has been significant progress in the rational
design of effective organometallic catalysts using σ-donating N-
heterocyclic carbenes (NHCs),10,11 and a number of elegant ex-
amples of NHC ligand-promoted hydrogenation have been re-
ported by Glorius,12 Stephan,13 Crabtree,14 and others.15 Differ-
ing from classic NHCs, cyclic (amino)(alkyl)carbenes (CAACs)
show an enhanced nucleophilicity because of a σ-donating alkyl
substituent, which was discovered by Bertrand and has received
increasing interest recently.16,17 However, the ligand effect of
CAACs in organometallic catalysis has rarely been studied.18
Herein we report the first CAAC ligand-enabled, highly selective
hydrogenation of aromatic ketones and phenols with rhodium
(Scheme 1). This method retains a synthetically valuable carbon-
Table 1. The Influence of Rhodium Complexes on the Aryl-
Selective Hydrogenation of Propiophenonea,b
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O
OH
Et
contrast, more nucleophilic CAAC bearing
a
2,4-
1
2
3
4
dimethylcyclohexenyl substituent adjacent to the carbene cen-
ter dramatically improves the conversion, giving the desired
product 3a in 80% yield with high selectivity (entry 8). To identi-
fy the coordination mode of Rh with the CAAC ligand before
catalysis, the CAAC-Rh complexes were prepared by a two-step
operation (Scheme 2). Note that the complexes are air-stable
and could be isolated by column chromatography. The 13C NMR
spectra show a greater downfield shift of the resonance for the
carbene carbons (274.7 and 272.9 ppm) than that of classic NHCs
(≈ 190 ppm).21 The structure of the (CAAC-2)Rh(COD)Cl complex
was fully characterized by single-crystal X-ray diffraction, evi-
dencing a slightly shortened Rh–Ccarbene bond (2.0128(16) Å).22
We were pleased to find that these structurally well-defined
complexes show high catalytic activity for aryl-selective hydro-
genation, leading to 3a in excellent yield and selectivity (entries
9 and 10).23,24
Et
O
H2 (0.5 Mpa)
rhodium complex (3 mol %)
2a
5a
3a
OH
+
Et
CF3CH2OH, 4 Å MS
r.t., 24 h
1a
Et
Et
5
6
4a
7
8
Yield
(3a)
Yield
(2a)
Yield
(4a)
ndc
ndc
ndc
Yield
(5a)
ndc
ndc
ndc
Entry
Rhodium complex
ndc
ndc
ndc
ndc
ndc
9
1
2
3d
none
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Rh(PPh3)3Cl
[Rh(cp*)Cl2]2
RhCl3•H2O
[Rh(COD)Cl]2
<1%
<5%
<5%
29%
9%
4
11%
25%
10%
ndc
5d
6e
10%
21%
10%
12%
[Rh(COD)Cl]2/
IMes•HCl /NaOtBu
This discovery led us to probe the scope of the aryl-selective
hydrogenation using active (CAAC)Rh(COD)Cl complexes
(Scheme 3). The phenyl group could be introduced at the α- or β-
position of the ketone with no effect on its hydrogenation and
retains the carbonyl intact (3c and 3d). The bisphenyl fragments
could be reduced simultaneously, allowing the rapid buildup of
complex biscyclohexyl structural motifs (3e–3h). As expected,
fused biscyclic ketones 3k–3n are easily accessible from readily
available benzocyclic precursors. Interestingly, the reactions
with conjugated chalcones result in a synchronous hydrogena-
tion of the unsaturated phenyl and alkenyl (3o–3q). It is particu-
larly noteworthy that the approach uniformly retains the C=O
moiety and generally achieves high conversion (76–99%). For
instance, the aromatic rings on the ester and carboxylic acid can
be reduced effectively, while keeping reactive alkoxycarbonyl
and carboxyl intact (3r and 3s). Strikingly, the hydrogenation
tolerates the synthetically valuable amidyl group, forming sub-
stituted amides such as cyclohexanecarboxamide, hexahydro-
1H-indol-2(3H)-one, and N-cyclohexylacetamide in 95–99%
yields (3t–3v). In addition, the motifs of N-protected amino acids
are also perfectly retained, offering a new avenue to functional-
ize phenyl-substituted amino acids (3w and 3x).
7e
8e
9
[Rh(COD)Cl]2/
12%
80%
<1%
ndc
ndc
ndc
<5%
<5%
<1%
<1%
11%
<1%
<1%
<1%
IPr•HCl /NaOtBu
[Rh(COD)Cl]2/
CAAC-1•2HCl /LDA
(CAAC-
1)Rh(COD)Cl
98%
(94%)f
10
(CAAC-
2)Rh(COD)Cl
96%
N
N
N
N
N
Cl
IMes•HCl
HCl2
CAAC-1•2HCl
Cl
IPr•HCl
aConditions: 1a (0.1 mmol), Rh complex (0.003 mmol), 4 Å MS
(50 mg), CF3CH2OH (2.0 mL), and H2 (0.5 Mpa) at room tempera-
ture for 24 h. bYields were determined by 1H NMR analysis. cNot
detected. d[Rh(cp*)Cl2]2 or [Rh(COD)Cl]2 (0.0015 mmol) was
e
used. [Rh(COD)Cl]2 (0.0015 mmol), iminium salt (0.004 mmol),
NaOtBu or LDA (0.004 or 0.008 mmol) in hexane or THF (2.0 mL)
were stirred at 70 °C for 12 h. After removing the solvent, the
mixture was used directly. fIsolated yield on 0.5 mmol scale.
Scheme 3. Substrate Scope for CAAC-Rh-Catalyzed Aryl-
Selective Hydrogenationa
Scheme 2. Synthesis of CAAC-Rh Complexes
Next, the effect of electron-donating NHC ligands on the se-
lective hydrogenation was explored. Unfortunately, rhodium
complex prepared in situ by treating [Rh(COD)Cl]2 with IMes•HCl
or IPr•HCl results in low conversions (entries 6 and 7). In sharp
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(CAAC-1)Rh(COD)Cl
lective reduction of bioactive estrone, allowing access to func-
tionalized bisketone 7s.
O
O
n
n
(3 mol %)
+
H2
1
2
3
4
5
6
7
8
R
R
CF3CH2OH, 4 Å MS
r.t., 24~48 h
m
m
Scheme 4. CAAC-Rh-Catalyzed Selective Hydrogenation
of Phenolsa
1
3
O
O
nBu
O
n
Me
O
OH
(CAAC-1)Rh(COD)Cl
(3 mol %)
3d, 95% (trace)c
3c, 95%b
+
H2
3a, 94% (n = 1, 0.5 Mpa)
3b, 99% (n = 5, 0.5 Mpa)
R
R
CF3CH2OH/H2O (19:1)
70 oC, 24 h
(1.0 Mpa)
(1.0 Mpa)
6
7
O
O
9
7a: R = H, 99%
(1.0 Mpa)
(2.5 Mpa)
O
OH
O
7b: R = 4-Me, 99%
3e, 90% (7%)d
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3f, 93%b
3g, 93%b
7c: R = 3-Me, 95% (trace)b
7d: R = 2-Me, 90% (8%)b
7e: R = 4-OMe, 84% (13%)b
7f: R = 2-OMe, 71% (23%)c
7g: R = 2-iPr, 95% (trace)b
7h: R = 4-iPr, 88% (71%)d,e (10%)b (2.5 Mpa)
7i: R = 4-tBu, 84% (80%)d,e (8%)b (3.5 Mpa)
7j: R = 3,5-Me, 73% (21%)b
7k: R = 2,4,6-Me, 78% (60%)d,e (14%)c (8.0 Mpa)
7l: R1 = 2-Me, R2 = 5-iPr;
(2.5 Mpa)
(2.5 Mpa)
(3.5 Mpa)
(5.0 Mpa)
(3.5 Mpa)
(2.5 Mpa)
(1.5 Mpa)
(3.0 Mpa)
O
O
6n
O
Me
O
R
(8.0 Mpa)
3j, 95%b
3i, 88%b (trace)c
3h, 85% (10%)d
7n, 65%
(2.5 Mpa)
(2.5 Mpa)
(2.0 Mpa)
(57%)d,e (20%)c
O
O
H
90% (53%)e,f (7%)b
7m: R1 = 2-iPr, R2 = 5-Me; 35% (59%)b (8.0 Mpa)
(8.0 Mpa)
H
H
H
H
(7.0 Mpa)
O
O
O
H
OH
H
O
H
H
H
OH
3k, 96%b
3l, 76%b (5%)c
3n, 98%b
3m, 95%b
(1.8 Mpa)
(2.0 Mpa)
(1.8 Mpa)
O
(2.0 Mpa)
H
O
O
H
3m, 88% (72%)d,e (10%)c
7o, 55% (42%)d,e,g (11%)b
(27%)c (5.0 Mpa)
6o
6p
6r
(2.0 Mpa)
H
3q, 95% (d.r. = 4.5:1)e
3o, 88% (7%)d
3p, 98% (d.r. = 3:1)e
(3.0 Mpa)
(4.0 Mpa)
(3.0 Mpa)
N
O
N
OH
N
OH
N
H
O
H
H
H
O
O
7r, 89% (64%)d,e (trace)b
6q
OMe
O
7q, 99%
(1.0 Mpa)
Me
O
OH
N
H
(5.0 Mpa)
N
H
O
Me
O
H
Me
H
3s, 99%b
3u, 99%b
3r, 83%b (trace)f
3t, 95%b
H
H
H
H
H
(6.8 Mpa)
(4.0 Mpa)
(1.0 Mpa)
(4.0 Mpa)
H
H
H
N
Me
CO2H
Ac
CO2H
Boc
O
HO
7s, (47%, d.r. = 1.4:1)d,e,g,h
O
HN
HN
6s
(43%)b (6.0 Mpa)
3v, 97%b
3w, 93%b
3x, 97%b
(6.0 Mpa)
aConditions: 6 (0.1 mmol), (CAAC-1)Rh(COD)Cl (0.003 mmol),
CF3CH2OH/H2O (2.0 mL), and hydrogenation was conducted
under the conditions listed in each case at 70 ºC for 24 h. The
yield was determined by GC analysis. bThe recovery of the start-
ing materials. cGC yields of the related cyclohexanol compounds.
d6 (0.5 mmol), (CAAC-2)Rh(COD)Cl (0.015 mmol), and
(6.0 Mpa)
(7.0 Mpa)
aConditions: 1 (0.5 mmol), (CAAC-1)Rh(COD)Cl (0.015 mmol), 4
Å MS (250 mg), CF3CH2OH (10 mL); reaction was conducted
under the conditions listed in each case at room temperature for
24–48 h. Isolated yields. b(CAAC-2)Rh(COD)Cl was used. GC
c
yields of the compounds that were formed by the hydrogenation
of the aromatic ring and carbonyl synchronously. GC yields of
the products that were formed by the reduction of one benzene
ring. eThe diastereomeric ratio was determined by HPLC analysis.
fTrace amount of the starting materials was detected.
e
d
CF3CH2OH/H2fO (10 mL) were used. Isolated yields are given in
g
h
parentheses. 6l (0.5 mmol). 48 h. (CAAC-1)Rh(COD)Cl (0.025
mmol) was employed, and the diastereomeric ratio was deter-
mined by HPLC analysis.
Scheme 5. Gram-Scale Hydrogenation of 1d
Inspired by these results, we examined the efficiency of this
CAAC-Rh catalyst system in the selective hydrogenation of phe-
nols to cyclohexanones. Gratifyingly, the (CAAC-1)Rh(COD)Cl
complex shows high reactivity in phenol hydrogenation in a
mixed solvent of trifluoroethanol and water (ratio of 19:1), exclu-
sively producing the product 7a in almost quantitative yield
(Scheme 4).25 Common substituents such as methyl, isopropyl,
tert-butyl, and methoxy on the phenols did not significantly in-
terfere with the performance of the complexes (7b–7i). Im-
portantly, the reaction with sterically hindered di- and trisubsti-
tuted phenols proceeded smoothly (7j–7m). Interestingly, un-
saturated phenol and phenyl are hydrogenated together in the
reaction (7n). Furthermore, polycyclic and heterocyclic sub-
strates, such as naphthols, 2-hydroxypyridine, and 2-
hydroxyquinoline, are amenable to the transformation, giving
the related ketones and lactams in good to excellent yields (7o–
7r). Notably, the protocol can be successfully applied to the se-
O
O
(CAAC-2)Rh(COD)Cl
(0.23 mol %)
Me
Me
+
H2
CF3CH2OH, r.t.
4 Å MS, 50 h
(1.0 Mpa)
3d
1d
(9.89 g, 66.78 mmol)
(88% yield, 9.08 g)
TON = 382
Finally, the selective hydrogenation is scalable and can be
conducted on the ten-gram scale with 0.23 mol% loading of
CAAC-Rh complex, the formation of 3d in 88% yield with a turn-
over number (TON) of 382 (Scheme 5).
In summary, we have developed an efficient CAAC-Rh catalyst
system for the hydrogenation of aromatic ketones and phenols
to cyclohexyl-containing ketones and cyclohexanones, through
the selective reduction of the aryl scaffolds while retaining func-
tional carbonyl groups. The unique electronic structural proper-
ties of CAAC ligands open up a new opportunity for significantly
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2004, 126, 1626–1627. (e) Chen, J.; Liu, D.; Butt, N.; Li, C.; Fan, D.;
improving selectivity and conversion by ligating to rhodium,
achieving high compatibility with a variety of C=O-containing
structural motifs, such as ketones, esters, carboxylic acids, am-
ides, and amino acids. Further studies on mechanistic under-
standing of the role of CAAC ligands and exploring chiral catalyst
systems are under way.
1
2
3
4
5
6
7
Liu, Y.; Zhang, W. Angew. Chem., Int. Ed. 2013, 52, 11632–11636. (f)
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ASSOCIATED CONTENT
8
9
Supporting Information. Detailed optimization data; experi-
mental procedures; characterization data of all new compounds;
ORTEP drawing of (CAAC-2)Rh(COD)Cl and crystallographic
data (CIF). This material is available free of charge via the Inter-
net at http://pubs.acs.org.”
(7) (a) Janurrklewlcz, K. R.; Alper, H. Organometallics 1983, 2,
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AUTHOR INFORMATION
Corresponding Author
zengxiaoming@mail.xjtu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support was provided by NSFC [No. 21202128 (X.Z.)]
and XJTU. We thank Prof. Guy Bertrand (UCSD) for the donation
of parts of iminium salts and Prof. Yan-Zhen Zheng (XJTU) for X-
ray crystallographic analysis. We also thank Prof. Frank Glorius
(WWU) and Prof. Laurean Ilies (UT) for valuable suggestions.
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806−809. (c) Eisenberger, P.; Bestvater, B. P.; Keske, E. C.; Crudden,
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(16) For a pioneering report on CAACs, see: Lavallo, V.; Canac, Y.;
Pras̈ang, C.; Donnadieu, B.; Bertrand, G. Angew. Chem., Int. Ed. 2005,
44, 5705–5709.
(17) For reviews on CAACs, see: (a) Soleilhavoup, M.; Bertrand, G.
Acc. Chem. Res. 2015, 48, 256–266. (b) Melaimi, M.; Soleilhavoup, M.;
Bertrand, G. Angew. Chem., Int. Ed. 2010, 49, 8810–8849
(18) For selected examples of CAAC ligand-based catalysis, see: (a)
Marx, V. M.; Sullivan, A. H.; Melaimi, M.; Virgil, S. C.; Keitz, B. K.;
Weinberger, D. S.; Bertrand, G.; Grubbs, R. H. Angew. Chem.; Int. Ed.
2015, 54, 1919–1923. (b) Hu, X.; Martin, D.; Melaimi, M.; Bertrand, G.
J. Am. Chem. Soc. 2014, 136, 13594–13597. (c) Zeng, X.; Kinjo, R.;
Donnadieu, B.; Bertrand, G. Angew. Chem., Int. Ed. 2010, 49, 942–
945. (d) Zeng, X.; Frey, G. D.; Kinjo, R.; Donnadieu, B.; Bertrand, G. J.
Am. Chem. Soc. 2009, 131, 8690–8696. (e) Lavallo, V.; Frey, G. D.;
Donnadieu, B.; Soleilhavoup, M.; Bertrand, G. Angew. Chem., Int. Ed.
2008, 47, 5224–5228.
REFERENCES
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(20) Karmel, I. S. R.; Fridman, N.; Tamm, M.; Eisen, M. S. J. Am.
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(21) Tapu, D.; Dixon, D. A.; Roe, C. Chem. Rev. 2009, 109, 3385–
3407.
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(22) CCDC 1058808 [(CAAC-2)Rh(COD)Cl] contains the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallo graphic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif
(23) Hg(0) poisoning experiments support a homogeneous nature
of this CAAC-Rh catalyst system. See Supporting Information.
(24) The hydrogenation of propylbenzene also occurs smoothly to
give propylcyclohexane (78% yield) under standard conditions, ex-
cluding a chelation assistance of carbonyl in the selective catalysis.
(25) Please see Supporting Information for details on the optimiz-
ing reaction parameters for the selective hydrogenation of phenols.
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H2
O
O
n
n
CF3CH2OH, 4 Å MS, r.t.
R
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m
m
iPr
24 examples
up to 99% yield
R1
N
R2
High selectivity
Scalable
iPr
Rh
Cl COD
(CAAC)Rh(COD)Cl
(3 mol %)
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O
OH
CF3CH2OH/H2O, 70 o
C
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R
19 examples, up to 99% yield
H2
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