Metal-ligand cooperation in the catalytic dehydrogenative coupling (DHC) of polyalcohols to carboxylic acid derivatives

Article abstract of DOI:10.1002/chem.201101084

Several polyols, which are easily available from sugars through biochemical conversion or hydrogenolytic cleavage, are directly converted into carboxylic acids and amides. This efficient dehydrogenative coupling process, catalyzed by a rhodium(I) diolefin amido complex, is an attractive approach for the production of organic fine chemicals from renewable resources. This method tolerates the presence of several hydroxy groups and can be extended to the direct synthesis of lactams from the corresponding amino alcohols under mild conditions.

Full text of DOI:10.1002/chem.201101084

FULL PAPER
DOI: 10.1002/chem.201101084
Metal–Ligand Cooperation in the Catalytic Dehydrogenative Coupling
(DHC) of Polyalcohols to Carboxylic Acid Derivatives
Mꢀnica Trincado,* Klaus Kꢁhlein, and Hansjçrg Grꢁtzmacher*[a]
Abstract: Several polyols, which are easily available from sugars through biochem-
ical conversion or hydrogenolytic cleavage, are directly converted into carboxylic
Keywords: biomass
· cooperative
acids and amides. This efficient dehydrogenative coupling process, catalyzed by a
rhodium(I) diolefin amido complex, is an attractive approach for the production of
organic fine chemicals from renewable resources. This method tolerates the pres-
ence of several hydroxy groups and can be extended to the direct synthesis of lac-
tams from the corresponding amino alcohols under mild conditions.
effects · ligand effects · polyols ·
rhodium · sustainable chemistry ·
transfer hydrogenation
Introduction
tude of possible interactions of the substrate with the metal
center, eventually leading to the inactivation of the catalyst.
Relatively few metal-based homogeneous catalytic systems
exhibit high chemoselectivities in the oxidation of primary
and/or secondary alcohols using hydrogen transfer as a strat-
egy.[5] In sugars, this process typically affects the secondary
hydroxy functions and the precursor molecules are trans-
formed into keto-sugars.[6] There is an increasing interest in
the selective transformation of glycerol into useful building
blocks for the synthesis of fine chemicals based on simple
and selective oxidation processes.[7] The direct conversion of
an alcohol into a carbonyl compound using a dehydrogena-
tive oxidation reaction in the first step and the immediate,
subsequent conversion into another product in a tandem re-
action using a single catalyst is an attractive approach for
the direct transformation of alcohols into valuable chemi-
cals.[8]
Many organic fine chemicals, commodity chemicals, and
polymer components are currently derived from the partial
air oxidation of fossil feedstocks.[1] The rapid increase in the
price of limited fossil fuels combined with their long-stand-
ing environmental harm have led to heightened interest in
alternative renewable resources, which ideally are neutral in
carbon dioxide consumption and production.[2] In the past
few years, vast efforts have been made in the chemical
transformation of biorenewable feedstocks into valuable
and fine chemicals and fuels.[3] The more abundant and sus-
tainable alternatives to fossil carbon resources are carbohy-
drates and their polyol derivatives. The development of
highly selective and reactive transition-metal catalysts for
the conversion of highly functionalized molecules, which are
obtained from sugar-rich crops and biomass fermentation,
into fine chemicals remains a challenge.[4]
The inherent advantage of an approach based on a homo-
geneous catalytic system is better control of the process pa-
rameters leading to high selectivity compared to convention-
al transformations based on fermentation and pyrolysis pro-
cesses. An ideal homogeneous catalyst needs to be compati-
ble with the common functionalities present in biomass car-
bohydrates [(poly)hydroxyl, carbonyl, and acetal groups]
and should be stable and efficient in an aqueous environ-
ment. The design of an active and chemoselective catalytic
system for the dehydrogenation of unprotected polyhydroxy
compounds like sugars is especially burdened by the multi-
Some homogeneous catalysts based on rhodium[9] and
ruthenium[10,11] complexes have demonstrated high efficiency
in the direct synthesis of carboxylic acid derivatives from
simple primary alcohols. Milstein et al. established a PNN-
ruthenium (PNN = 2-di-tert-butylphosphinomethyl-6-diethy-
laminomethylpyridine) assisted dehydrogenative coupling
ꢀ
ꢀ
reaction (DHC) of alcohols of the type R CH2 OH + EH
ꢀ
! R CO(E) + 2H2 (E = OR, NHR, R = alkyl, aryl) under
acceptorless conditions, in which molecular hydrogen is re-
leased as a carrier of chemical energy.[11h–j] This catalyst also
allowed the direct conversion of alcohols into amides, which
is a new reaction.[11j] Later, catalysts containing ruthenium
and a N-heterocyclic carbene ligand and showing a high effi-
ciency for the transformation of alcohols into amides were
reported.[11k–p] However, only monoalcohols or special diols
with a long spacer group of at least six methylene units be-
tween the two hydroxy groups can be employed as sub-
strates with these catalysts.[12] Other dihydroxy compounds
with shorter spacer groups are not converted, most likely
due to poisoning of the ruthenium complex through chela-
tion to the metal center.
[a] Dr. M. Trincado, Prof. Dr. K. Kꢀhlein, Prof. Dr. H. Grꢀtzmacher
Department of Chemistry and Applied Biosciences
ETH-Hçnggerberg, 8093 Zꢀrich (Switzerland)
Fax : (+41)44-633-1032
E-mail: trincado@inorg.chem.ethz.ch
hgruetzmacher@ethz.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101084.
Chem. Eur. J. 2011, 17, 11905 – 11913
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Only recently has the direct synthesis of five and six mem-
bered cyclic imides from diols and a primary amine using an
in situ generated N-heterocyclic carbene (NHC) catalyst
been reported.[13] In general, these reactions require elevat-
ed temperatures and long reaction times. For the transfor-
mation of sensitive substrates it is desirable to find a catalyt-
ic system which operates at low temperatures with low cata-
lyst loadings, with high stability and chemoselectivity, which
tolerates a wide variety of functional groups by proceeding
through simple protocols, and which has an easy workup.
We reported the first experiments that allowed the chemose-
lective, homogeneously catalyzed DHC of simple primary
alcohols with water, methanol, or amines to give carboxylic
acids, methyl esters, or amides, respectively, under very mild
reaction conditions using diolefin rhodium (I) complexes 1a-
TfOH or 1a (Scheme 1).[9b–d] These reactions require a hy-
drogen acceptor. Cyclohexanone was found to be especially
suitable because it can be quantitatively regenerated from
cyclohexanol with hydrogen peroxide, H2O2, as an environ-
mentally benign secondary oxidant in a second catalytic re-
Results and Discussion
The reaction between 1,2-propanediol and benzylamine was
chosen as a model for the optimization of amidation reac-
tion conditions. A screening of catalysts was performed. We
used either a series of diolefin amine rhodium(I) complexes,
combined with a hydrogen acceptor, or several ruthenium
based catalytic systems under acceptorless conditions
(Scheme 1 and Table 1). Application of the conditions origi-
nally reported by Milstein (4 as catalyst at >1008C[11j]) only
yielded traces of product (entry 1, Table 1). Catalytic sys-
tems containing a ruthenium precursor like 5 and a NHC as
a potential ligand were found to be active for the amidation
of monoalcohols (entry 2, Table 1),[11l] but it only showed
moderate activity after 24 h, although the conversion contin-
uously increased with time without an apparent deactivation
of the catalyst (up to 46% after 48 h). Well-defined hydri-
doruthenium complexes supported by four NHC-carbene li-
gands, [RuH
4,5-dimethylimidazole-2-ylidene, ArF = C6H
bearing bidentate phosphane ligands, [HRu
ACHTUGNTERNN(UGN IEt2Me2)4]ACHTNUGTRENNNUG
[BArF ] (6, IEt2Me2 = 1,3-diethyl-
4
CHTUNGTRENNUNG
ꢀ
ꢀ
action. Hence, the overall net reaction reads: R CH2 OH
G
ꢀ
+ EH + 2H2O2 ! R CO(E) + 4H2O; E = OH, methoxy
(7, dppe = 1,2-bis(diphenylphosphanyl)ethane, OTf = tri-
flate),[15] showed little activity (entries 3 and 4, Table 1).
Based on previous findings, we investigated a number of di-
olefin amide rhodium complexes (1–3) in the catalytic DHC
of polyols.
(OMe), NHR’ (R’ = Bn). The motivation of the present
work is to contribute to the development of an efficient oxi-
dation of primary hydroxyl groups in unprotected polyols
that can complement the existing methodologies. Here we
report the activity of a series of well defined homogeneous
rhodium(I) complexes which gives remarkable results with
respect to the chemo and regioselectivity in dehydrodena-
tive catalytic processes.
The active catalyst can be generated from the precursor
(1-TfOH, 1-HCl or 2) by employing
a stoichiometric
amount of base (potassium tert-butoxide (tBuOK), lithium
bis(trimethylsilyl)amide (LiHMDS), or NaH). A difference
in the efficiency of the reaction was not observed if the cata-
lyst 1a is used directly or if it is generated in situ. Among
the solvents tested, the best results were obtained with THF
or when carrying out the reaction without a solvent but with
Scheme 1. Selection of complexes for the catalyst screening in the dehydrogenative coupling of polyols; ArF = C6H
dazole-2-ylidene, NHC=IEt2Me2 = 1,3-diethyl-4,5-dimethylimidazole-2-ylidene, OTf = triflate, PNN = 2-di-tert-butylphosphinomethyl-6-diethylamino-
3ACHTUNGTERN(NUNG CF3)2, IMe = 1,3,4,5-tetramethylimi-
methylpyridine, PACHTUNGTRENNUNG
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Rhodium-Catalyzed Dehydrogenative Coupling
FULL PAPER
Table 1. Screening with different catalysts and conditions for the amidation of 1,2-propanediol.[a]
Table 1). The yield is improved
by heating the reaction mixture
for an extended period of time
(entry 13, Table 1). Clearly, the
isolated rhodium(I) amide [Rh-
entry
Catalyst [mol%]
[RuH(PNN)(CO)] 4 (0.1)
[RuCl2A(p-cymene)]2 5 (2.5)
[RuH(IEt2Me2)4]
[BArF4] 6 (5)
[RuH(dppe)2A(OTf)] 7 (5)
1a-TfOH (0.2)
1a (0.2)
1a-TfOH (0.2)
1a (0.2)
1b-TfOH (0.2)
1c-HCl (0.2)
1c-HCl (0.2)
2 (0.1)
2 (0.1)
3 (0.2)
Ligand
Additive [mol%]
Conditions
Yield [%][b]
A
ACHTUNGTRENUN(NG PPh3)] (1a, trop2N =
1[c]
2[d]
3
G
N
–
–
reflux, 24 h
reflux, 48 h
reflux, 24 h
reflux, 24 h
rt, 4 h
rt, 12 h
rt, 4 h
rt, 1 h
rt, 12 h
rt, 12 h
608C, 12 h
rt, 12 h
608C, 12 h
rt, 12 h
0
46
9
E
N
IiPr, PCy3
–
–
–
–
–
–
–
–
–
IiPr
IiPr
–
tBuOK (15)
tBuOK (20)
tBuOK (20)
tBuOK (0.2)
–
N
N
AHCTUNGTRENNUNG
4
G
N
18
10
46
90
99
38
32
49
40
63
0
combination with methyl meth-
acrylate, provides an excellent
catalytic system for the highly
chemoselective transformation
of 1,2-propanediol to a lactic
acid amide (entry 8, Table 1).
The superior activity of the cat-
alysts for this type of reaction
under mild conditions may be
the result of the neighboring
coexistence of the Lewis basic
amido function and the Lewis
acidic metal center as a conse-
quence of the butterfly-type
structure of 1a. The amido
5[e]
6[f]
7[g]
8[h]
9
tBuOK (0.2)
–
LiHMDS (0.2)
LiHMDS (0.2)
LiHMDS (0.2)
NaH (1)
NaH(1)
10
11
12[i]
13[i]
14
–
[a] General conditions for entries 1–4: 1,2-propanediol (0.5 mmol) and BnNH2 (0.5 mmol) in toluene were
added to the catalyst and heated under an argon atmosphere; General conditions for entries 5–15: To a 1m so-
lution of 1,2-propanediol (0.5 mmol) in THF (0.5 mL), BnNH2 (1.5 mmol, 3 equiv), MMA (1.5 mmol, 3 equiv),
and the catalyst were added and stirred under an argon atmosphere; Cy = cyclohexyl, iPr = isopropyl. [b] De-
termined by GC. [c] Conditions from reference [11j]. [d] The catalyst was generated in situ using a NHC pre-
cursor (1,3-diisopropylimidazolium chloride, 5 mol%), PCy3, (5 mol%) and tBuOK in toluene.[11l] [e] With
3 equiv of cyclohexanone instead MMA. [f] The reaction was carried out with toluene as the solvent. [g] The
catalyst was generated in situ by adding a base, and the reaction was carried out with 3 equiv of BnNH2 and
3 equiv MMA in THF. The same conversion was obtained by adding 1a in its pure form. [h] The reaction was
carried out without solvent and with 6 equiv of MMA. [i] The catalyst was generated in situ by adding a NHC
precursor (1,3-diisopropylimidazolium chloride, 0.2 mol%) and NaH.
ligand acts as
a cooperative
ligand[16] in both subsequent re-
action steps: 1) the dehydro-
genation of the alcohol to the
corresponding aldehyde and 2)
the dehydrogenative coupling
an excess of benzyl amine (BnNH2) and methyl methacry-
late (MMA) as a hydrogen acceptor (entries 7 and 8,
Table 1). The influence of the ancillary ligand in the axial
position on the catalytic activity and the thermal stability of
the rhodium complex were evaluated. We found that with
triphenylphosphine (PPh3) ligands a very efficient catalytic
system was obtained (entries 7 and 8, Table 1; 90–99%
reaction between the aldehyde and the amine. A simplified
catalytic cycle consistent with our observations is outlined in
Scheme 2. In the proposed mechanism, the amido complex
[Rh
[Rh
N
ACHTUNGTRENNUNG
G
N
=
trop2NH = bis(5-H-dibenzoACHTGNUTRENNUNG
formed as key intermediates (for a detailed computational
study see reference [9b, c]). Our assumption that the amido
complex (1a) plays an active role in the catalysis is support-
ed by the fact that neither the N-methyl derivative,
yield), but triphenylphosphite (PACTHNUTRGNEUNG(OPh)3) in 1b-TfOH lead
to a less active catalyst (entry 9, Table 1).
The coordination of a strong s-donor N-heterocyclic car-
bene ligand (1,3,4,5-tetramethylimidazole-2-ylidene (IMe))
has a significant effect on the acidity of the NH function in
complex 1c-HCl.[9e] A strong base such as Li[N
ACTHNUTRGEN(NUG SiMe3)2]
(Me = methyl) is necessary to achieve the clean formation
of the corresponding rhodium amide complex. Although the
complex is remarkably stable under thermal conditions for
prolonged periods of time and neither a dissociation of the
NHC from the metal nor isomerization to the inactive spe-
cies [Rh
N
ACHTUNGTRENNUNG
5-H-dibenzo
N
L =
only a moderate yield of the amide product was obtained. A
reason for this may be the steric encumbrance of the active
site in the complex which is caused by the methyl groups at
the nitrogen atoms of the ligand (entries 10 and 11, Table 1).
Similarly, a rather low yield (40%) was obtained by pre-
paring the catalyst in situ by cleavage of the chloro bridge
dimer (2, Scheme 1) with the NHC precursor 1,3-diisopropy-
limidazolium chloride, in the presence of NaH (entry 12,
Scheme 2. Simplified catalytic cycle for the dehydrogenative coupling
(DHC) of alcohols and amines with complex 1a; R1 = alkyl, aryl; R2 =
alkyl.
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H. Grꢀtzmacher, M. Trincado, et al.
Table 2. Scope of rhodium catalyzed DHC of polyols to amides.
[Rh
(trop2NMe = bis(5-H-dibenzo-
[a,d]cyclohepten-5-yl) methyl-
ACHTUNGTRENNUNG(trop2NMe)ACHTUNGTRENNUNG(PPh3)]ACTHNUGTREN[NUGN OTf]
ACHTUNGTRENNUNG
amine),[22] nor the phosphane
diolefin (3; entry 14, Table 1)
promote the conversion of the
alcohol under identical condi-
tions. The formation and dehy-
drogenation of 1a-H2 by a hy-
drogen acceptor (A = MMA)
was proven by stoichiometric
experiments.[17]
entry
Alcohol
Product
Time at
room
temperature
Yield
[%][a]
1
2
1 h
2 h
90[b]
60[c] (83)[d]
Next, we investigated in
more detail the DHC reaction
between alcohols and amines to
the corresponding amides to
determine the scope and limita-
tions of the reaction. Indeed,
1a is a general catalyst for the
dehydrogenative coupling of
polyols with primary amines
when the reaction is conducted
under anhydrous conditions in
THF and methyl methacrylate
(MMA) is used as the hydrogen
acceptor. In the first experi-
ments, benzyl amine (BnNH2)
was employed as the coupling
partner for the synthesis of a
series of amides derived from
polyol compounds (Table 2).
The transformation of glycerol
(8b) can be carried out effi-
ciently, obtaining the bis-
3
4
5
12 h
12 h
12 h
85[e]
81[e]
90[e]
8c
8c
6
7
12 h
12 h
92[f]
96[f]
8
12 h
37[f]
[a] Yield of isolated product. [b] A (neat) mixture of the alcohol (1 equiv), BnNH2 (3 equiv), [Rh
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG(trop2N)-
ACHTUNGTRENNUNG(amide) 9b in up to 83% isolat-
ed yield when the amount of
amine (up to 8 equiv) and hy-
drogen acceptor (MMA) is in-
creased. Under the same condi-
tions, alcohols with more than
three hydroxyl groups are rela-
tively unreactive. We assume
action was performed with 6 equiv of BnNH2, 6 equiv of MMA and without solvent; 10% of N-benzyl-2,3-di-
hydroxypropanamide was also isolated. [d] With 8 equiv of BnNH2 and 6 equiv of MMA. [e] The reaction was
performed with BnNH2 (2 equiv), MMA (3 equiv) and powdered 4 ꢂ MS in DME (0.1m of alcohol). [f] The
reactions were performed in THF (0.5m of amino alcohol), with 2.5 equiv of MMA and 0.1 mol% of [Rh-
ACHUNTRGEN(NUG trop2N)ACHTUNGTNER(NUGN PPh3)].
that the limited solubility of the molecules with an extended
number of hydroxy groups in the organic solvents is respon-
sible for the low yield of products. These shortcomings are
largely overcome and the yields are greatly improved when
the reactions are carried out in the presence of powdered
molecular sieve (4 ꢂ) and by using diluted solutions (0.1m)
of the substrates in dimethoxyethane (DME). Under these
modified reaction conditions, only the primary hydroxy
function of the monomethylated sugar derivative, 1-methyl-
b-d-glucopyranose (8c), is converted, allowing the direct
and selective amidation to the glucopyranuronamides (9c–
9e). This reaction proceeds more slowly than with simple al-
cohols but shows a remarkable efficiency with several
amines (entries 3–5, Table 2), and, most importantly, all of
the stereogenic centers of the sugar molecule are preserved.
In addition to these intermolecular amidation reactions,
complex 1a is also capable of promoting the intramolecular
dehydrogenative coupling of a,w-aminoalcohols. A simple
and direct synthesis of medium-sized ring lactams can be de-
veloped (entries 6–8, Table 2). The five and six member ring
lactams 9 f and 9g are obtained in especially excellent yields
under very mild conditions. The cationic complex [Rh
ACHTUNGTRENNUNG(OTf)-
A
ACHTUNGTRENNUNG
water or water-containing solvents and can be used in com-
bination with a base as a convenient precatalyst for the syn-
thesis of carboxylates from primary alcohols and water.[9c–e]
This is a significant advantage over most catalytic systems
which require the use of an organic solvent. An efficient de-
hydrogenative coupling of polyols to the corresponding
sodium carboxylates can be performed with 1a-TfOH,
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Rhodium-Catalyzed Dehydrogenative Coupling
FULL PAPER
NaOH as the base, and a ketone as the hydrogen acceptor
(Table 3). It is convenient to use cyclohexanone as a hydro-
gen acceptor in these reactions because the formation of
cyclohexanol is exergonic, and this by-product can be easily
recycled with hydrogen peroxide using polytungstate as the
catalyst.[18]
the reaction proceeds homogeneously, although a slightly
lower yield (85%) is obtained in this transformation
(entry 4, Table 3). The high efficiency of the hydrogen trans-
fer from a primary alcohol to a ketone in an intramolecular
process is also noteworthy. This is represented by the trans-
formation of 1-hydroxy-2-propanone (8j) to the lactic acid
rac-10b, which requires only 1.5 equivalents of an additional
external hydrogen acceptor (entry 5, Table 3). Otherwise,
lactic acid can also be obtained in very good yields from
propylene oxide (entry 2, Table 3). This reaction involves a
catalytic tandem reaction, in which epoxide opening is cou-
pled to a DHC process. The dehydrogenative coupling of
glycerol with the present catalytic system is highly selective,
and one of the primary hydroxy functions of the molecule is
exclusively converted, affording glyceric acid in 98% yield
(entry 6, Table 3). To our knowledge, this marks the highest
isolated yield reported to date for the selective oxidation to
a monoacid. Alternatively, glyceric acid (10c) can also be
prepared with excellent yield from the epoxide (8i) in the
presence of an excess of base (entry 3, Table 3). Importantly,
enantiomerically pure substrates were selectively converted
to monocarboxylates without loss of the stereochemical in-
formation; the configuration at the stereocenter was com-
pletely retained. (R)-1,2-dihydroxypropane (R-8a) was con-
verted in 91% yield to give the R-configured isomer of
lactic acid (R-10b) in 5 h at room temperature (entry 4,
Table 3). Furthermore, the enantiomerically pure amino al-
cohol (8k) was quantitatively converted to b-hydroxy-a-ami-
noacid (10d) without epimerization (entry 7, Table 3). In
order to transform unprotected polyols with more than
three free hydroxy groups, a slight modification of the reac-
tion conditions was necessary; THF was added as a cosol-
vent. Under these conditions, the mono-methylated sugar
substrate (8c) could be converted to the glucoronic acid
(10e) with an acceptable yield (entry 8, Table 3). The vicinal
unprotected secondary alcohol functions remained un-
changed, and keto-sugars could not be detected. Finally, in
order to determine the efficiency of the catalytic system, the
catalyst loading was reduced to 0.01 mol% in the DHC be-
tween 1,2-dihydroxypropane and water and under identical
conditions, and a conversion of 70% to lactic acid was ach-
ieved.
Table 3. Scope of rhodium catalyzed DHC of polyols to carboxylic
acids.[a]
entry Alcohol
Product
Time at Yield
rt
(%)[b]
]
1
2 h
99
2
3
4
18 h
10 h
5 h
89[c]
95[c]
91 (85)[d]
5
6
rac-10b
14 h
8 h
92[e]
98
10c
7
8
12 h
12 h
97
66[f]
[a] A mixture of the alcohol (1.31 mmol, 1 equiv), cyclohexanone
(3.37 mmol, 2.5 equiv), H2O (1.5 mL), NaOH (1.57 mmol, 1.2 equiv), and
[RhACHTUNGTRENNUNG(OTf)ACHTUNGTRENNUNG(trop2NH)ACHTUNGTRENNUNG(PPh3)] (0.1 mol%) was stirred for the indicated time
at room temperature. [b] Yield of isolated product after acidic workup of
the recrystallized sodium salts. [c] With 2.4 equiv of NaOH. [d] The reac-
tion was performed with 5 equiv of acetone. [e] The reaction was carried
out with 1.5 equiv of cyclohexanone at 608C. [f] The reaction was per-
formed at 408C with THF as the cosolvent.
Conclusion
Moreover, we assume that the finely dispersed droplets of
the hydrogen acceptor, cyclohexanone, serve as a solvent for
the transition-metal complex in the course of the reaction.
Ethylene glycol (8g) and 1,2-propanediol (8a), major com-
modity chemicals from the hydrogenolysis of biodiesel-de-
rived glycerol, are chemoselectively and quantitatively con-
verted to 2-hydroxy acetic acid (10a, entry 1, Table 3) and 2-
hydroxypropionic acid (rac-10b)[19] in excellent yields after a
simple acidic workup of the reaction mixture. Remarkably,
acetone can also be used as an efficient hydrogen acceptor
for the DHC of 8a to lactic acid and, under these conditions,
The catalytic system composed of the diolefin amide rhodiu-
m(I) complex (1a) and a hydrogen acceptor (A) provides a
convenient route for the preparation of a wide range of car-
boxylic acid derivatives from primary alcohols under mild
conditions. Activated olefins for the synthesis of carboxylic
acids, can be employed as suitable hydrogen acceptors. As
shown in this work, a wide range of different polyhydroxyl-
ated substrates can be used in this dehydrogenative coupling
reaction, including polyols derived from renewable feed-
stock. The coupling reaction with primary amines proceeds
with especially high yields (>80%) under mild conditions.
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H. Grꢀtzmacher, M. Trincado, et al.
tiplet or unresolved, br = broad signal, coupling constant(s) in Hz, inte-
gration, interpretation. Mass spectrometric measurements were per-
formed by the mass spectrometry service of the LOC at the ETH Zꢀrich.
ETHZ on Brukerꢃs maXis (ESI/NanoSpray-Qq-TOF) for high resolution
measurements. IR spectra were measured on a Perkin–Elmer 2000 FTIR
spectrometer with a KBr beam splitter. Melting points were determined
on a Bꢀchi melting point apparatus and are reported uncorrected.
Medium size lactams, commonly embedded in the skeletons
of bioactive natural products, can be synthesized in one step
from the corresponding amino alcohol, providing an effi-
cient strategy for their synthesis. The high chemoselectivity
in the transformation of polyhydroxy compounds is remark-
able. The discrimination between primary and secondary
OH groups very likely has kinetic reasons. The primary and
sterically less hindered hydroxyl groups simply interact
General procedure for the catalyzed dehydrogenative coupling of alco-
hols to amides (Table 2): The alcohol (1.31 mmol, 1 equiv), amine (3.93–
10.48 mmol, 3–8 equiv), methyl methacrylate (3.93–7.86 mmol, 3–
ꢀ
faster with the Rh N group, the active site in the catalyst.
6 equiv), and [RhACHTNUGTRENNUG(trop2N)ACHTUTGNREN(NUNG PPh3)] (1a, 2 mg, 0.0026 mmol, 0.2 mol%) in
On the other hand, the formation of the monoacids 2-hy-
droxy acetic acid (10a) and glyceric acid (10c) may be
partly due to the biphasic reaction conditions. The amide
catalyst (1a) and the substrate are mainly dissolved in the
droplets of the hydrogen acceptor together with sufficient
amounts of water to allow a fast DHC reaction while the
product is dissolved in the aqueous phase and is thereby re-
moved from further conversion. This assumption is support-
ed by the fact that, in glycerol, both primary hydroxyl
groups are amidated to the corresponding bisamide (9b)
which is considerably less hydrophilic. The simplicity of the
catalytic process, allowing the direct chemoselective intro-
duction of a carboxylic acid or amide functionality in an
aqueous reaction medium, is appealing. Especially when a
device can be developed, in which an electrode surface acts
as a hydrogen acceptor, and the formal release of hydrogen
leads to a direct production of an electrical current as a “by-
product”. Indeed, we recently succeeded in the preparation
of organometallic fuel cells (OMFC), in which such reac-
tions can possibly be performed, and investigations along
these lines are under way.[20]
THF (1 mL) were stirred at room temperature for the time indicated in
Table 1. The reactions of 8c were performed with BnNH2 (281 g,
2.62 mmol, 2 equiv), MMA (393 mg, 3.93 mmol, 3 equiv) and powdered
4 ꢂ MS in DME (0.1m of alcohol). The reactions were monitored by
TLC. All of the volatile materials were removed under reduced pressure,
and the pure amide was isolated by chromatographic purification (9b–d
and 9 f–h) or recrystallization (9a and 9e).
General procedure for the catalyzed dehydrogenative coupling of alco-
hols to acids (Table 3): A mixture of the alcohol (1.31 mmol, 1 equiv),
water (1.5 mL), sodium hydroxide (380 mg, 6.55 mmol, 1.2 equiv), and cy-
clohexanone (321 mg, 3.28 mmol, 2.5 equiv) or acetone (380 mg,
6.55 mmol, 5 equiv) were combined in a Schlenk flask under an argon at-
mosphere. The mixture was degassed by purging with argon for 10 min
prior to the addition of [RhCAHTUNGTREN(NNUG OTf)AHCTNURGTEG(NNUN trop2NH)ACHTGUNTREN(UNNG PPh3)] (0.00131 mmol, 1 mg,
0.001 equiv) under a stream of argon. After the reaction times indicated
in Table 3 (the progress of each reaction was monitored by NMR spec-
troscopy), water was added (20 mL), and the mixture was extracted with
diethyl ether (2ꢄ20 mL). The aqueous phase was then evaporated and
the corresponding sodium salts were recrystallized and dried. Aqueous
solutions of the sodium salts were acidified with 1N HCl and the pure
acids were filtered from NaCl and dried (10a–10d). Compound 10e was
isolated by chromatographic purification.
Physical and spectroscopic data for the synthesized compounds 9a–9h
and 10a–10e: Amides 9a, 9b, and 9 f–h and carboxylic acids 10a–e were
identified by comparison with data stored in the Aldrich NMR spectra
database or with previously reported data. The 1H and 13C NMR spectra
of 9a–h and 10a–e are shown in the Supporting Information.
Experimental Section
Synthesis of compounds 9a–h and 10a–e
General: All of the reactions were carried out in flame-dried glassware
under an argon atmosphere using standard Schlenk techniques (for the
synthesis of acids) or in an argon filled glove box (Braun MB 150 B-G
system; for the synthesis of amides). Methyl methacrylate was carefully
distilled from mol sieves. Cyclohexanone was distilled from calcium hy-
dride and acetone from calcium sulfate. The alcohols employed for the
synthesis of acids were used as received. The alcohols and amines em-
ployed for the synthesis of amides were distilled and dried prior use. All
of these reagents and the organometallic complexes were stored and
N-Benzyl lactamide (9a): After the workup, the product was recrystal-
lized from THF affording a white solid (211 mg, 90%). M.p. 48–508C;
1H NMR (250 MHz, CDCl3): d=7.32–7.17 (m, 5H), 7.11 (bs, 1H), 4.44
(d, 3JH,H =6.0 Hz, 2H), 4.17 (q, 3JH,H =6.8 Hz, 1H), 1.45 ppm (d, JH,H
=
3
6.8 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) d=174.8 (C), 137.9 (C), 128.7
(CH), 128.6 (CH), 127.6 (CH), 68.4 (CH), 43.1 (CH2), 21.2 ppm (CH3);[24]
ESI MS: m/z 180.1 [M+1]+.
N,N-Dibenzyl-2-hydroxymalonamide (9a): After the workup, the residue
was purified by flash column chromatography (ethyl acetate (EtOAc)/
methanol (MeOH) 10:1 to 1:1), affording the diamide as a white solid
(234 mg, 60%). M.p. 137–1388C; 1H NMR (300 MHz, CDCl3): d=7.62
(bs, 2H), 7.35–7.23 (m, 10H), 4.50 (d, 3JH,H =2.9 Hz, 1H), 4.40 (s, 1H),
4.46 ppm (d, 3JH,H =6.8 Hz, 4H); 13C NMR (75.5 MHz, CDCl3): d=167.3
(C), 137.7 (C), 128.7 (CH), 127.6 (CH), 127.5 (CH), 71.1 (CH), 43.6 ppm
(CH2);[25] ESI MS: m/z 299.2 [M+1]+.
weighed in the glove box. The complexes [RuH
(IEt2Me2)4] (dppe)2]
[BArF4],[14] [RuH [OTf],[15] [{Rh
(OTf)(trop2NH) (trop2N)-
(PPh3)],[21][Rh
(PPh3)],[21][Rh (OPh)3)],[9c]
(OTf)(trop2NH)(P
[OTf],[22] [Rh
(OTf)(trop2NH)(IMe)] (IMe =1,3,4,5-tetramethylimida-
zole-2-ylidene),[9e] and [Rh [BArF] (trop2PPh = bis(5-H-
(trop2PPh)(PPh3)]
ACHTUNGTRENNUNG
G
E
A
R
ACHTUNGTRENNUNG
E
G
G
ACHTUNGTRENNUNG
E
G
A
[RhACHTGNUERTNNU(G trop2NMe)ACHTUNGRTEN(NUNG PPh3)]-
G
E
G
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
dibenzo-[a,d]cyclohepten-5-yl)phenylphosphane)[23] were synthesized ac-
cording to previously reported procedures. Analytical thin-layer chroma-
tography was performed using E. Merck silica gel 60 F254 plates
(0.25 mm thickness). Chromatographic purification of the amides was
performed by flash chromatography (Brunschwig silica 32–63, 60 ꢂ)
using the indicated solvents as eluents. Optical rotations were measured
in a Jasco DIP-1000 polarimeter operating at the sodium D line with a
100 mm path length cell and are reported as follows: [a]DT, concentration
(g per 100 mL). 1H NMR spectra were recorded at 300 or 250 MHz and
chemical shifts were referenced to the residual solvent peak. 13C NMR
spectra are proton decoupled and were recorded at 75.5 MHz; chemical
shifts were referenced to the solvent. Coupling constants J are given in
Hertz [Hz] as absolute values, unless specifically stated. The data is re-
ported as: s = singlet, d = doublet, t = triplet, q = quadruplet, m = mul-
N-Benzyl-2,3-dihydroxypropionamide was isolated from the crude reac-
tion mixture described above as a white solid (25 mg, 10%). M.p. 83–
858C; 1H NMR (300 MHz, [D6]DMSO): d=8.20 (t, 3JH,H =6.3 Hz, 1H),
7.30–7.10 (m, 5H), 5.55 (d, 3JH,H =5.6 Hz, 1H), 4.70 (t, 3JH,H =5.7 Hz,
1H), 4.17 (d, 3JH,H =6.3 Hz, 2H), 3.91–3.83 (m, 1H), 3.59–3.45 (m, 1H),
3.39–3.32 ppm (m, 1H); 13C NMR (75.5 MHz, [D6]DMSO): d=172.1 (C),
139.3 (C), 128.2 (CH), 127.6 (CH), 127.0 (CH), 73.40 (CH), 63.9 (CH2),
41.9 ppm (CH2);[26] ESI MS: m/z 196.1 [M+1]+.
N-Benzyl-O-methyl-b-d-glucopyranuronamide (9c): The residue ob-
tained was purified by flash chromatography (CH2Cl2/MeOH 9:1) to
afford a pale solid (331 mg, 85%). M.p. 167–1698C; [a]20D = +93.3 (c=
0.75% in DMSO); 1H NMR (300 MHz, CD3CN/D2O): d=7.61–7.53 (m,
5H), 5.06 (d, 3JH,H =3.5 Hz, 1H), 4.64 (s, 2H), 4.24 (d, 3JH,H =9.0 Hz,
11910
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 11905 – 11913

Rhodium-Catalyzed Dehydrogenative Coupling
FULL PAPER
1H), 3.88–3.75 (m, 3H), 3.62 ppm (s, 3H); 13C NMR (75.5 MHz, CD3CN/
D2O): d=171.1 (C), 138.1 (C), 129.0 (CH), 127.7 (CH), 127.6 (CH), 100.0
(CH), 73.0(CH), 71.9(CH), 71.4 (CH), 71.2 (CH), 55.7 (CH3), 42.9 ppm
(CH2); HRMS (ESI) calcd for C14H20NO6 [M+H]+ 298.1285, found
298.1282; ATR IR: n˜ =3285 w, 2923 w, 2355 w, 1665s, 1540m, 1460 w,
monia. The mixture was kept at ꢀ48C overnight, and the solid was col-
lected and washed with a mixture of water/EtOH (1:10) to afford the
pure b-hydroxyamino acid as a white solid (230 mg, 97%). M.p. 185–
1878C; [a]20D =ꢀ31.0 (c=0.1, H2O); lit. [a]20 ꢀ32.8 (c=0.1, H2O);
D
1H NMR (300 MHz, D2O): d=7.43–7.37 (m, 5H), 5.26 (d, 3JHH =4.2 Hz,
1H), 4.10 (d, 3JHH =4.1 Hz, 1H); 13C NMR (75.5 MHz, D2O): d=171.6
(C), 139.4 (C), 129.0 (CH), 129.0 (CH), 125.9 (CH), 71.2 (CH), 60.9 ppm
(CH).[32]
1045s, 1003m, 945m, 730m cmꢀ1
.
N-(4-Chlorobenzyl)-O-methyl-b-d-glucopyranuronamide (9d): The resi-
due obtained was purified by flash chromatography (CH2Cl2/MeOH 9:1)
to afford a white solid (352 mg, 81%). M.p. 165–1678C; [a]20D = +135.4
(c=0.75% in DMSO);1H NMR (300 MHz, CD3CN/D2O): d=7.32–7.21
Methyl-b-d-glucopyranosiduronic acid (10e): The residue was purified by
flash column chromatography on a short plug of silica gel (EtOAc:-
1
3
MeOH 10:1 to 1:1), affording the acid as an oil (180 mg, 66%). H NMR
(m, 4H), 4.72 (d, JH,H =3.0 Hz, 1H), 4.33 (s, 2H), 3.72 (s, 1H), 3.60–3.43
(300 MHz, D2O): d=4.23 (d, 3JH,H =8.0 Hz, 1H), 3.62 (dd, 3JH,H =9.0 Hz,
3JH,H =6.0 Hz, 1H), 3.45 (s, 3H), 3.38–3.30 (m, 2H), 3.28–3.14 ppm (m,
1H); 13C NMR (75.5 MHz, D2O): d=173.1 (C), 100.9 (CH), 74.2 (CH),
73.6 (CH), 73.6 (CH), 70.6 (CH), 58.2 ppm (CH3).[33]
(m, 3H), 3.33 ppm (s, 3H); 13C NMR (75.5 MHz, CD3CN/D2O): d=173.7
(C), 140.0 (C), 138.0 (CH), 131.9 (CH), 131.2 (CH), 102.7 (CH), 75.6
(CH), 74.6 (CH), 73.8 (CH), 73.6 (CH), 58.1 (CH3), 44.5 ppm (CH2);
HRMS (ESI-TOF) calcd for C14H19ClNO6 [M+H]+ 332.0895, found
332.0906; ATR IR: n˜ =3280 w, 2931 w, 2359 w, 1661s, 1542m, 1459 w,
1047s, 1013s, 971s cmꢀ1
.
N-Isopropyl-O-methyl-b-d-glucopyranuronamide (9e): The residue ob-
tained was recrystallized from MeOH to afford a pale solid (293 mg,
90%). M.p. 135–1378C; [a]20 = +43.9 (c=0.75% in DMSO); 1H NMR
Acknowledgements
D
(300 MHz, CD3CN/D2O): d=4.72 (d, 3JH,H =3.2 Hz, 1H), 3.96 (sept,
3JH,H =3.6 Hz, 1H), 3.83 (d, 3JH,H =9.8 Hz, 1H), 3.53–3.39 (m, 2H), 3.36
(s, 3H), 1.11 ppm (d, 3JH,H =3.2 Hz, 6H); 13C NMR (75.5 MHz, CD3CN/
D2O): d=172.9 (C), 102.7 (CH), 75.7 (CH), 74.9 (CH), 74.0 (CH), 72.8
(CH), 58.0 (CH3), 43.8 (CH), 24.2 ppm (CH3); HRMS (ESI-TOF): calcd
for C10H20NO6 [M+H]+ 250.1285, found 298.1281. ATR IR: n˜ = 3307 w,
2929 w, 1636s, 1565m, 1460 w, 1354 w, 1073s, 1054s, 1000s, 800 w, 634 w
This work was supported by the Swiss National Science Foundation and
the ETH Zꢀrich.
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cmꢀ1
.
2-Pyrrolidinone (9 f): Purification by flash column chromatography with
CH2Cl2/MeOH (100:1) as eluent afforded the product as a colorless oil
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3JH,H =7.0 Hz, 2H), 2.02–2.94 (m, 2H), 1.80–1.76 ppm (m, 2H); 13C NMR
(75.5 MHz, CDCl3): d=179.3 (C), 42.1 (CH2), 30.0 (CH2), 20.4 ppm
(CH2);[27] ESI MS: m/z 86.0 [M+1]+.
[3] a) A. Eckert, W. J. Frederick, J. P. Hallett, D. J. Leak, C. L. Liotta,
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1
(125 mg, 96%). H NMR (300 MHz, CDCl3): d=7.40 (bs, 1H), 3.20–3.15
(m, 2H), 2.25–2.19 (m, 2H), 1.66–1.62 ppm (m, 4H); 13C NMR
(75.5 MHz, CDCl3): d=172.8 (C), 41.9 (CH2), 31.3 (CH2), 22.1 (CH2),
20.1 ppm (CH2);[28] ESI MS: m/z 100.1 [M+1]+.
Azepan-2-one (9h): Purification by flash column chromatography with
CH2Cl2/MeOH (100:1) as eluent afforded the product as a white solid
(55 mg, 37%). M.p. 70–728C; 1H NMR (300 MHz, CDCl3): d=7.44 (bs,
1H), 3.09–3.04 (m, 2H), 2.33–2.29 (m, 2H), 1.60–1.47 ppm (m, 6H);
13C NMR (75.5 MHz, CDCl3): d=179.5 (C), 42.5 (CH2), 36.7 (CH2), 30.5
(CH2), 29.6 (CH2), 23.14 ppm (CH2).[29] ESI MS: m/z 114.1 [M+1]+.
Glycolic acid (10a): Obtained as a white solid (98 mg, 99%). M.p. 78–
808C; 1H NMR (300 MHz, [D6]DMSO): d =3.91 ppm (s, 2H); 13C NMR
(75.5 MHz, [D6]DMSO): d=174.6 (C), 59.9 ppm (CH2).
d-(ꢀ)-Lactic acid (10b): Obtained as a colorless oil (107 mg, 91%).
[a]20D = +13.8 (c=2.5% in 1n NaOH); (lit. [a]20D =+13.5); 1H NMR
3
(300 MHz, D2O): d=3.75 (q, 3JHH =6.9 Hz, 1H), 1.15 ppm (d, JHH
=
6.8 Hz, 3H); 13C NMR (75.5 MHz, D2O): d=177.9 (C), 63.9 (CH),
15.5 ppm (CH3).[30]
Glyceric acid (10c): After evaporation of the aqueous phase, the white
crystals of sodium glycerate were obtained by washing with acetone and
methanol. Glyceric acid was obtained, after acidification with 1n HCl, as
a viscous oil (136 mg, 98%, from glycerol; 129 mg, 95% from glycidol).
1H NMR (300 MHz, D2O): d=4.25 (t, 3JHH =3.1 Hz, 1H),), 3.73 ppm (d,
2JHH 3JHH =3.1 Hz, 1H); 13C NMR (75.5 MHz, D2O): d=177.2 (C), 72.0
(CH), 64.2 ppm (CH2).[31]
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acceptor, see: c) M. Saburi, Y. Ishii, N. Kaji, T. Aoi, I. Sasaki, S.
Yoshikawa, Y. Uchida, Chem. Lett. 1989, 563. An example where
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ACHTUNGTRENNUNG(2S, 3R)-2-Amino-3-hydroxy-3-phenylpropanoic acid (10d): After acidifi-
cation with 2n HCl solution, the water was evaporated under pressure.
After addition of water (2ꢄ10 mL) and subsequent evaporation, all of
the possible remaining HCl was removed. The residue was crystallized
from absolute ethanol. To isolate the pure amino acid, the pH of an
aqueous solution was adjusted to 7 by slow addition of 25% aqueous am-
Chem. Eur. J. 2011, 17, 11905 – 11913
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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complexes extends from hydrogenation to transfer hydrogenation of
unsaturated compounds. The complex [RuH
by anion metathesis of [RuH(dppe)2][BF4] in THF by using KOTf;
for [RuH(dppe)2][BF4], see: S. P. Nolan, T. R. Belderrain, R. H.
ACHUTGTNRNE(UNG dppe)2]AHCTUNGTREN[NGUN OTf] was made
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Grubbs, Organometallics 1997, 16, 5569.
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1
data: 1H NMR (300 MHz, [D8]THF): d=ꢀ8.15 ppm (dd, JRhH
=
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Chem. Eur. J. 2011, 17, 11905 – 11913

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Received: April 8, 2011
Published online: September 7, 2011
Chem. Eur. J. 2011, 17, 11905 – 11913
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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