Platinum-catalyzed cross-dehydrogenative coupling reaction in the absence of oxidant

Article abstract of DOI:10.1039/c0ob00261e

A third strategy for cross-dehydrogenative coupling reaction has been reported via platinum-catalyzed sp³ C-H and sp³ C-H coupling reaction in the absence of oxidant. Nitroalkanes as well as dialkyl malonate derivatives, β-keto esters and malononitrile are active participants in this coupling reaction. Both cyclic and acyclic non-activated simple ketones are good reactants in this reaction.

Full text of DOI:10.1039/c0ob00261e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Platinum-catalyzed cross-dehydrogenative coupling reaction in the absence of
oxidant†
Xing-Zhong Shu, Yan-Fang Yang, Xiao-Feng Xia, Ke-Gong Ji, Xue-Yuan Liu and Yong-Min Liang*
Received 15th June 2010, Accepted 8th July 2010
First published as an Advance Article on the web 28th July 2010
DOI: 10.1039/c0ob00261e
Table 1 Optimization of reaction conditionsa
A third strategy for cross-dehydrogenative coupling reaction
has been reported via platinum-catalyzed sp3 C–H and sp3 C–
H coupling reaction in the absence of oxidant. Nitroalkanes
as well as dialkyl malonate derivatives, b-keto esters and
malononitrile are active participants in this coupling reaction.
Both cyclic and acyclic non-activated simple ketones are good
Entry Catalyst (mol%) Additive
Time/h Yield of 3a (%)
reactants in this reaction.
1b
2
3
4
5
PtCl2 (10%)
PtCl2 (10%)
PtCl2 (10%)
PtCl2 (10%)
PtCl2 (10%)
PtCl2 (10%)
PtCl2 (10%)
PtCl2 (10%)
PtCl2 (5%)
PtCl2 (15%)
PtCl2 (10%),
COD (20%)
PtCl2 (10%),
CO (1 atm)
K2PtCl4 (10%)
PtCl4 (10%)
no
—
—
24
16
9
24
16
34
72
The development of catalytic reactions which involve the cleavage
of C–H bonds is one of the most challenging projects in organic
synthesis.1 Despite significant progress in this area, catalytic
intermolecular transformations of sp3 C–H bonds to C–C bonds
still remain rare.2 Based on a recent literature survey, sp3 C–
H bonds adjacent to a nitrogen atom are more reactive, and
their functionalization catalyzed by transition metals has attracted
great attention.3 These reactions always involve a-C–H activation
and subsequent carbon–carbon bond formation. Among these
reactions, the oxidative cross-dehydrogenative coupling (CDC)
reaction is an attractive strategy. In this case, generation of
iminium ion intermediates followed by reactions with carbon
pronucleophiles would give a-substituted products.
HFIP (1 equiv)d
TsOH (1 equiv)
AcOH (1 equiv)
75
NRf
53
6
silica gel (50 mg)e 10
73
80
74
76
81
71
˚
˚
˚
˚
7
5 A MS (50 mg)
5 A MS (50 mg)
5 A MS (50 mg)
5 A MS (50 mg)
10
10
48
8
8c
9
10
11
˚
5 A MS (50 mg)
18
˚
12
5 A MS (50 mg)
16
65
˚
˚
˚
13
14
15
5 A MS (50 mg)
5 A MS (50 mg)
5 A MS (50 mg)
24
16
24
64
49
0
Based on recent literature precedent regarding CDC reactions,
the two pathways have been developed to achieve this trans-
formation: (i) the route using treatment with metal catalysts
in the presence of oxidants (Scheme 1a);4 (ii) the route using
treatment with oxidants (Scheme 1b).5 The former pathway was
started by Murahashi using a Ru(III) catalyst with O2 or H2O2
as oxidants.4a–c Copper-catalyzed oxidative CDC reactions were
reported by Li and others, where tBuOOH, O2, NBS and diethyl
azodicarboxylate (DEAD) are good oxidants.4d–p When rhodium
a The reaction was run with tetrahydroisoquinoline 1a (0.2 mmol) and
additive in 1 mL of CH3NO2/H2O (10 : 1) under argon at 85 ◦C. b The
reaction was run in 1 mL of CH3NO2. c The reaction was run in 1 mL of
CH3NO2/H2O (5 : 1). d HFIP is hexafluoroisopropanol. e Acidic silica gel
was used. f No reaction.
in water) was needed.4q Iron–(tBuO)2 and vanadium–tBuOOH4s
4r
systems also showed high catalytic activity in CDC reactions.
On the other hand, due to the high reactivity of the iminium
intermediate, such a complex could react with nucleophiles in
the absence of metal catalyst. Todd’s5a and our5b recent works
have shown this interesting transformation by using DDQ and
PhI(OAc)2, respectively. However, for the above two pathways, an
oxidant is always needed. Such a protocol is not ideal from the
viewpoint of atom efficiency and safety of the reaction. Herein
we report a third way via platinum-catalyzed CDC reaction in the
absence of oxidant (Scheme 1c).
t
was used, a strong oxidant such as T-HYDRO (70% BuOOH
We started by using the tetrahydroisoquinoline 1a (0.2 mmol)
with 10 mol% of PtCl2 under argon in CH3NO2 (1 mL) at 85 ◦C,
and the coupling product 3a was obtained in 34% yield after 24 h
(Table 1, entry 1). To our delight, the mixed solvent CH3NO2–
H2O (10 : 1) afforded a good yield of the desired product (Table 1,
entry 2). Addition of hexafluoroisopropanol (HFIP) improved the
reaction efficiency and product yield (Table 1, entry 3). Further
investigation of the effect of acids indicated that weakly acidic 5
Scheme 1 General pathways for CDC reaction.
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, 730000, P. R. China. E-mail: liangym@lzu.edu.cn; Fax: 0086-
931-8912582
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c0ob00261e
˚
A molecular sieves in water gave the best result (Table 1, entries
3–7). After this, studies were conducted on the amount of water
added and catalyst loading as well as other platinum catalytic
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Table 2 Coupling reaction of amines with nitroalkanesa
Table 3 Coupling reaction of tertiary amines with activated methylene
compoundsa
a The reaction was run with PtCl2 (15 mol%), 1a (0.2 mmol), 5 (2 equiv.)
in 1 mL of DMF–H2O (1 : 1) under argon in the presence of powdered 5
A MS (50 mg). b Isolated yield.
˚
acetoacetate, also gave a moderate yield of coupling compound
6c.
The direct coupling of amines with non-activated simple ketones
was also tested (Scheme 2). To achieve this coupling, a secondary
amine, L-proline, was used as an organic co-catalyst to activate
the ketones in the form of a nucleophilic enamine intermediate.6
After treating 1a with 2 equiv of cyclic ketone 7a in the presence of
PtCl2 (10 mol%) and L-proline (20 mol%) at 85 ◦C, desired product
8a was isolated in 55% yield after 48 h. When an acyclic phenyl
ketone was used, the reaction also proceeded smoothly to afford
a 53% yield of coupling product 8b. No enantiomeric excess was
observed in either example.
a The reaction was run with PtCl2 (10 mol%), tetrahydroisoquinoline 1 (0.2
mmol) in 1 mL of 2–H2O (10 : 1) under argon in the presence of powdered
5 A MS (50 mg). b Isolated yield. c The reaction was run at 80 ◦C and
˚
CH3NO2–H2O (5 : 1) was used. d Diastereomeric ratio (dr) was determined
by HPLC (OD–H), hexane–i-PrOH (80 : 20), flow rate (1.0 mL min-1).
systems but no better result obtained (Table 1, entries 8–14). No
reaction was observed in the absence of platinum catalyst (Table 1,
entry 15).
Under the optimized conditions, various b-nitroamine deriva-
tives were generated, as shown in Table 2. Tetrahydroisoquinoline
derivatives always gave moderate to high yields of the desired
products, both from nitromethane and nitroethane (3a–3e, 4a–
4d). 1-Arylpiperidines generated the desired products 3f and 3g in
73% and 85% yields, respectively, although direct functionalization
of the sp3 C–H bond in piperidine still remains one of the more
challenging areas of research.3c A 1-arylpyrrolidine also gave the
desired compound 3h in good yield. In these cases, bis-CDC
products were not observed. When a substituted five-membered
ring was used, the coupling reaction was observed at the 5-position
of N-phenyl-L-prolinol and the desired product 3i was isolated in
96% yield with alcoholic group remaining intact.
Scheme 2 Direct coupling of amine with non-activated simple ketones.
To further study the mechanism, we conducted an experiment
to detect hydrogen evolution by using an Inficon Transpector
2.7 Fortunately we detected the presence of H2 in the reaction.
The results are shown in Fig. 1. When D2O was added instead
of H2O, DH was also formed besides the formation of H2
(Fig. 1b).
On the basis of the above observations, a possible reaction mech-
anism is proposed in Scheme 3. The tertiary amine is activated
by coordination with platinum and then platinum mediated H-
abstraction generates the intermediate B.4c Subsequent reaction
of iminium intermediate B with a nucleophile affords the CDC
product, where the [Pt]–H bond is cleaved by the formation of H2.
Weak acid in the reaction system promotes this process, whereas
more H3O+ blocks the step from SM to A (Table 1, entries 3, 6, 7 vs.
In addition to nitroalkanes, this oxidant-free CDC reaction
was also applicable to activated methylene compounds (Table 3).
Dialkyl malonate derivatives and malononitrile reacted smoothly
with tertiary amines in the presence of water, affording the desired
products in moderate to good yield. b-Keto esters, such as ethyl
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Notes and references
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Fig. 1 Results of H2 detection by using an Inficon Transpector 2. H is
the fraction of H2 and HD during the detection. (a) Spectra were obtained
when CH3NO2–H2O (10 : 1) was used. (b) Spectra were obtained when
CH3NO2–D2O (10 : 1) was used.
4 For ruthenium catalysis: (a) S.-I. Murahashi, T. Nakae, H. Terai and N.
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125, 15312; (d) For copper catalysis: X. Xu and X. Li, Org. Lett., 2009,
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Scheme 3 Proposed mechanism.
4, 5). The detection of HD in the hydrogen evolution experiment
might be ascribed to the equilibrium of hydride-acceptors D2O–H+
and HDO–D+, also NuH–D2O–NuD.
In conclusion, we have reported a third strategy for cross-
dehydrogenative coupling via platinum-catalyzed sp3 C–H and sp3
C–H coupling reaction in the absence of oxidant. Nitroalkanes as
well as dialkyl malonate derivatives, b-keto esters and malononi-
trile are active participants in this coupling reaction. Both cyclic
and acyclic non-activated simple ketones are good reactants in this
reaction.
5 For metal-free CDC reactions, see: (a) A. S.-K. Tsang and M. H. Todd,
Tetrahedron Lett., 2009, 50, 1199; (b) X.-Z. Shu, X.-F. Xia, Y.-F. Yang,
K.-G. Ji, X.-Y. Liu and Y.-M. Liang, J. Org. Chem., 2009, 74, 7464.
6 For recent overviews on enamine catalysis, see: (a) P. Melchiorre, M.
Marigo, A. Carlone and G. Bartoli, Angew. Chem., Int. Ed., 2008, 47,
6138; (b) S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem. Rev.,
2007, 107, 5471.
7 Although it is difficult to detect the evolution of H2 in this reaction, we
still carried out a qualitative experiment using the Inficon Transpector
2: The reaction was carried out by using tetrahydroisoquinoline 1a (0.5
Acknowledgements
˚
mmol), PtCl2 (10% mol) and 5 A MS (100 mg) in CH3NO2–H2O or
We thank the the National Natural Science Foundation of China
(NSF-20732002, NSF-20872052, NSF-20921120404) for financial
support.
CH3NO2–D2O (2 mL) under argon in a sealed tube. When the mixture
was stirred at 85 ◦C for 6 h, the gas (2 mL) over the solution was injected
into the Hydrogen Detector Inficon Transpector 2.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 4077–4079 | 4079
©