Tris(acetylacetonato)rhodium(III)-catalyzed α-alkylation of ketones, β-alkylation of secondary alcohols and alkylation of amines with primary alcohols

Article abstract of DOI:10.1002/adsc.201300061

The tris(acetylacetonato)rhodium(III) catalyst is shown to be a versatile catalyst in the presence of DABCO (1,4-diazabicyclo[2.2.2]octane) as ligand for the α-alkylation of ketones followed by transfer hydrogenation, for the one-pot β-alkylation of secondary alcohols with primary alcohols and for the alkylation of aromatic amines in the presence of an inorganic base in toluene. Copyright

Full text of DOI:10.1002/adsc.201300061

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DOI: 10.1002/adsc.201300061
Tris(acetylacetonato)rhodium(III)-Catalyzed a-Alkylation of
G
Ketones, b-Alkylation of Secondary Alcohols and Alkylation of
Amines with Primary Alcohols
Ponnam Satyanarayana,a Ganapam Manohar Reddy,a
Hariharasharma Maheswaran,a,* and Mannepalli Lakshmi Kantama
a
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad, India
Fax : (+91)-40-2719-3510; phone: (+91)-40-2719-1532; e-mail: maheswaran_dr@yahoo.com
Received: January 23, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300061.
Abstract: The tris(acetylacetonato)rhodium
alyst is shown to be a versatile catalyst in the pres- an inorganic base in toluene.
ence of DABCO (1,4-diazabicyclo[2.2.2]octane) as
ligand for the a-alkylation of ketones followed by Keywords: alcohols; amines; 1,4-diazabicyclo-
transfer hydrogenation, for the one-pot b-alkylation [2.2.2]octane (DABCO); ketones; transfer hydroge-
of secondary alcohols with primary alcohols and for nation; tris(acetylacetonato)rhodium(III) complex
ACHTUNGTREN(NUNG III) cat- the alkylation of aromatic amines in the presence of
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Introduction
tion resulting in the loss of a water molecule, and sub-
sequent hydrogenation of the resulting enone to yield
Alcohols are one of the most basic and important the coupled secondary alcohol as product (see
classes of organic compounds because they have Scheme 2). Both the a-alkylation of ketones and the
a wide range of applications.[1] a-Alkylation of eno- b-alkylation of sec-alcohols with primary alcohols
lates derived from ketones with electrophiles such as were first reported by Cho et al. with RuCl2ACHTUNGTRENNUNG(PPh3)3
alkyl halides is the conventional method to form alco- catalyst at 80–1008C in dioxane.[3] In this work, it was
[1,2]
À
hols with extended C C bonds.
The metal-cata- mandatory to use stoichiometric amounts of a sacrifi-
lyzed a-alkylation of ketones and/or b-alkylation of cial hydrogen acceptor such as 1-dodecene as hydro-
sec-alcohols with primary alcohols is attracting much gen trap to avoid reduction of the product ketones.
attention (Scheme 1) lately because of its critical ad- Cho et al. have reported that in the absence of a sacri-
vantage over the conventional a-alkylation method ficial hydrogen acceptor a mixture of both product
involving enolates, which suffers from problems with ketones and alcohols was obtained. The Pd/C[4]
waste salts.
system can also be used as a catalyst in combination
The metal-catalyzed alkylation reaction has posi- with 1-decene as hydrogen trap to avoid overreduc-
tioned itself as a green process in terms of atom econ- tion of the alkylated ketone. Furthermore use of
omy, avoidance of protecting groups, and waste mini-
mization. It is to be noted that the b-alkylation of sec-
alcohols with primary alcohols is a multistep process
that involves a dehydrogenation reaction of the alco-
hol to the ketone or aldehyde, followed by aldol reac-
À
Scheme 2. Borrowing hydrogen process in C C coupling of
alcohols.
À
Scheme 1. General scheme for C C coupling of alcohols.
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Ru[3a,b,5] and Ir[6] metal-based catalysts have also been
reported for this purpose, and they have shown sensi-
ble reactivity by modest alterations of the original re-
action conditions. For example, a chiral bimetallic Ru-
Ir catalyst combination has enabled the enantioen-
riched a-alkylation of ketones.[7a] Both iridium and
ruthenium complexes with chelating N-heterocyclic
carbene[7b] complexes as well as ruthenium and iridi-
um terpyridine[7c] complexes have also been reported
for the direct b-alkylation of a secondary alcohol with
primary alcohols. Saito et al. has reported using
a Cu(I)/H2/NaOH system for the direct b-alkylation
Scheme 3. Borrowing hydrogen concept illustrated for N-
alkACTHNUGRTENUNGylation of amine.
of secondary alcohol with primary alcohols.[8] Reac- This overall process is termed borrowing hydrogen[26]
tions involving metal nanoparticles of Ni,[9] Pd[10] (vi- which is clearly elaborated in the mechanistic scheme
ologen polymers) and heterogeneous Pd/AlO(OH)[11] shown in Scheme 3. Recently Xu et al. reported that
catalysts have also been reported for ketone and alco- the direct alkylation of amines was catalyzed by Wil-
hol coupling reactions allowing ketones to become kinsonꢁs catalyst and promoted by air.[27] This reaction
the major products. It is to be noted that here the car- has been shown to provide a mixture of both sec-
bonyl functionality remains unreduced, and thus the amine and imine.
corresponding alcohols are very rarely produced. Re-
Given the critical importance of both alcohols and
cently it has been reported that pincer-type N-hetero- sec-amines, herein, we report a phosphorus-free, very
cyclic carbene/Pd complexes[12] give high yields of the low loading (1.0 mol%) of commercially available
corresponding alcohols. The Ag/Al2O3 heterogeneous tris(acetylacetonato)rhodiumACTHNUTRGNEUGN(III) complex/DABCO/
catalyst system has also been reported for the selec- base-based catalytic system for the a-alkylation of ke-
tive synthesis of ketones but not alcohols using tones, and direct one-pot b-alkylation of secondary al-
a b-alkylation method.[13] Ryu et al. have reported cohols with primary alcohols. These reactions produce
the selective ketone product formation using alcohols as the final product, no ketone was formed
RuHCl(CO)ACHTUNGTRENNUNG(PPh3)3 catalyst for the a-alkylation reac- during the reaction. These reactions are atom eco-
tion for a variety of ketones and primary alcohols.[14] nomical as we use only stoichiometric amounts of re-
Interestingly, Ru-based catalysts in general have been agents. Notably, our reaction requires the use of
shown to give either a mixture of alcohols and ketone DABCO which is a sterically hindered, mild base
or alcohols as the major component of the product which is eco-friendly, highly reactive, and inexpen-
mixture.[5]
sive.[28] Using the same catalytic system we also report
the direct C N bond formation via N-alkylation of ar-
omatic amines under mild conditions using an inor-
ganic base and DABCO. These studies form the focus
of this paper.
À
Alkylation of Amines with Primary Alcohol
Nitrogen-containing molecules, particularly amines
and their derivatives, have more important functions
in chemical and biological sciences.[15] Direct metal- Results and Discussion
catalyzed N-alkylation of amines with primary alco-
hols provides an efficient route to new sec-amines. Initial experiments were carried out by choosing ace-
Grigg et al. and Watanabe et al. independently re- tophenone, 1-phenylethanol and 4-methoxyphenylme-
À
ported the first examples of direct C N bond forma- thanol as model substrates for optimizing the reaction
tion with alcohols.[16] Recent reports have led to more conditions for the a-alkylation of ketones and for the
active catalysts and milder conditions, which were b-alkylation of secondary alcohols with primary alco-
based on various metal ions such as Ru,[17] Ir,[6f,7b,18] hols in the presence of 1 mol% rhodium as metal
Pt,[19] Au,[20] Ag,[21] Pd,[22] Ni,[23] Cu,[24] and Fe.[25]
A
source, with DABCO as organic ligand additive, base
drawback of some of these reported catalytic systems and toluene as solvent. Two different rhodium cata-
is that the reaction tends to give a mixture of both lysts were evaluated for this study and they are
imine and sec-amine as products.[6f,7b,21c,27,30] The for- tris(acetylacetonato)rhodium
ACHTUNGTRENNUNG
mation of imines from the reaction can be understood
ACHUTGTNRNEUGrN hodiumACHTGNUTRENNUNG
from the fact that an alcohol can be activated by the (B) was used in the presence of a ligand and a strong
metal ion as the corresponding aldehyde, then in situ base such as KO-t-Bu in toluene, the desired coupled
condensation of amine with aldehyde to give imines product
3-(4-methoxyphenyl)-1-phenylpropan-1-ol
which is followed by a transfer hydrogenation reac- was obtained in 55% yield (Table 1, entry 1). By em-
tion to yield the secondary amine as final product. ploying identical reaction conditions, when 1-phenyl-
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Tris(acetylacetonato)rhodiumACTHNUGRTENUNG(III)-Catalyzed a-Alkylation of Ketones, b-Alkylation of Secondary Alcohols
Table 1. Optimization of reaction conditions for the a-alky-
lation of ketone and b-alkylation of secondary alcohols with
primary alcohol.[a]
mary alcohol to get good yields of the coupled alcohol
products. Instead of strong inorganic bases, we have
also employed the much milder potassium carbonate
as base; interestingly, no detectable products were ob-
tained. (Table 1, entry 7). We have also performed the
reaction in the absence of inorganic base and absence
of rhodium source, for the a-alkylation reaction
À
(Table 1, entries 8–10), once again no detectable C C
coupled products were obtained. Therefore, for these
reactions both inorganic base and rhodium metal
source are essential to promote the reaction. Interest-
ingly, when the rhodium metal source is changed from
trichlororhodium
ACHTUNGTRENN(UNG III) (B) to tris(acetylacetonato)-
rhodium(III) (A), in the presence of DABCO and
AHCTUNGTRENNUNG
KO-t-Bu base, we have obtained yields as high as
91% for the coupled product 3-(4-methoxyphenyl)-1-
phenylpropan-1-ol (Table 1, entry 11). However, we
have noted when the inorganic base used for this re-
action is KOH instead of KO-t-Bu, the yield of the
coupled product rose to 98% for the a-alkylation re-
action (Table 1, entry 12). Similarly, the b-alkylation
reaction under similar reaction conditions gave yields
as high as 98% for the coupled alcohol product
(Table 1, entry 14) but at the expense of the required
reaction time which was 14–16 h. When the reaction
was performed in the presence of DBU as organic
ligand additive instead of DABCO, we obtained only
70% yield of the a-alkylated alcohol product
(Table 1, entry 13).
[a]
Reaction conditions: acetophenone (1 mmol, 0.5M in tol-
uene) 4-methoxyphenylmethanol (1 mmol, 0.5M in tolu-
ene), metal source (1.0 mol%), base (1 mmol), DABCO
(50 mol%) and 2 mL of toluene at 1108C, for 4–6 h.
[b]
Isolated yield of addition product.
[c]
Phenylethanol (1 mmol),
4-methoxyphenylmethanol
(1 mmol) and reaction time was 14-16 h
Acetonitrile used as solvent.
Considerable amount of aldehyde obtained.
[d]
[e]
Thus, the optimum reaction conditions for both a-
alkylation and b-alkylation reactions are the use of
equimolar amounts of ketone or sec-alcohol with pri-
mary alcohols, tris(acetylacetonato)rhodium
ACHTUNGTRENN(UNG III) (A),
ACHTUNGTRENNUNGethanol (secondary alcohol) was used as substrate in KOH base, DABCO ligand in toluene solvent at
place of a ketone, a direct b-alkylation of the secon- 1108C. Using the optimized reaction conditions in
dary alcohol with a primary alcohol readily occurs, hand, a-alkylation reactions of ketones with primary
À
and this results in the C C coupled product of 3-(4- alcohols using various ketones were examined to ex-
methoxyphenyl)-1-phenylpropan-1-ol in 42% yield plore the scope of the reaction (Scheme 4, Table 2).
(Table 1, entry 2). It is clear from Table 1, entries 1 As can be seen, this protocol is applicable for the re-
and 2, that both the reactions give rise to same cou- actions of a variety of aromatic ketones as well as ali-
pled alcohol product. When the a-alkylation reaction phatic ketones with aromatic alcohols, and these stud-
was carried out in the presence of KOH as base, the ies illustrate the scope of the present catalytic system.
yield of addition product has been slightly increased Among various ketone substrates studied, to our de-
to 61% (Table 1, entry 3). When the same reaction light the reaction proceeded smoothly, and excellent
was carried out in acetonitrile as solvent, a significant yields were obtained between aromatic ketones like
drop in yield of the product to 32% was observed acetophenone, 1-(4-methoxyphenyl)ethanone and 1-
(Table 1, entry 4). When the a-alkylation reaction was (6-methoxynapthalen-2-yl)ethanone with aromatic al-
performed in the absence of DABCO we have ob- cohols like phenylmethanol, 4-(methoxyphenyl)me-
tained only a very poor yield (15%) of the coupled al- thanol and p-tolylmethanol (Table 2, entries 1–6 and
cohol product (Table 1, entry 5). Similar results with
poor yield of the product were obtained with b-alky-
lation reactions under similar reaction conditions
(Table 1, entry 6). From the above results it can be in-
ferred that DABCO plays a crucial role in promoting
the reaction. It is also clear that the solvent toluene is
the best solvent for both a-alkylation of ketones and
b-alkylation reactions of secondary alcohol with pri- ondary alcohols with primary alcohols.
Scheme 4. a-Alkylation of ketones and b-alkylation of sec-
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Table 2. RhACHTUNGTRENNUNG(III)-catalyzed a-alkylation of ketones with pri-
piophenone and 2-methylpropan-1-ol, only a moderate
yield of product 2,4-dimethyl-1-phenylpentan-1-ol was
obtained (Table 2, entry 9) as a mixture of diastereo-
mers in a 50:50 ratio. We could not find literature ref-
erences that have descriptions about observed diaste-
reoselectivity ratios for entries 8 and 9 in Table 2. It is
very likely that no one has synthesized these com-
pounds before in the literature. The a-alkylation of
cyclohexanone with phenylmethanol also gave a mod-
erate yield of 62% of alcohol product as 2-(4-methox-
ybenzyl)cyclohexanol (Table 2, entry 10). It can be
clearly seen that when the reaction is conducted be-
tween an aliphatic ketone such as 4-methylpentan-2-
one with an aromatic alcohol like phenylmethanol
and 4-(methoxyphenyl)methanol, the isolated yields
of the desired products were nearly 58–61%. (Table 2,
entries 11 and 12). Thus, the conclusion drawn from
these studies is that aromatic ketones and aromatic
mary alcohols.[a]
À
primary alcohols give highest yields for the C C cou-
pled product, however, we have obtained only a mod-
erate yields when aliphatic ketones are used with aro-
matic and aliphatic primary alcohols under our opti-
mized experimental conditions (Table 2, entries 10–
12). As discussed earlier, Ryu et. al. have reported se-
lective ketone product formation using the
Ru(H)(Cl)(CO)ACHTNUTRGNE(UNG PPh3)3 catalyst for a-alkylation reac-
tions of a variety of ketones and primary alcohols
using similar substrate stoichiometry (1:1) and cata-
lyst loading (1.0 mol%).[14] In contrast, in our work,
we use a similar substrate stoichiometry and catalyst
loading and have obtained exclusively alcohols as the
product during a-alkylation reactions using a commer-
cially available catalyst A. This result strongly suggest
that a RhACTHNUTRGNEUG(N III) species even in small amounts pro-
motes the reduction of not only the double bond but
also the keto functionality during the reaction.
Being encouraged by the above results, we next ex-
amined the one-pot b-alkylation of various secondary
alcohols with primary alcohols under our optimized
reaction conditions (Scheme 4). The b-alkylation of
secondary alcohols like 1-phenylethanol, and 1-(4-me-
thoxyphenyl)ethanol with primary alcohols like phe-
nylmethanol, 4-(methoxyphenyl)methanol and p-tolyl-
[a]
Reaction conditions: ketone (1 mmol, 0.5M in toluene),
primary alcohol (1 mmol, 0.5M in toluene), KOH
(1 mmol), catalyst A (1 mol%) DABCO (0.5 mmol) and
2 mL of toluene.
Isolated yields.
Reaction time was 24 h and 50:50 diastereomeric mix-
[b]
[c]
tures of products formed
entry 13). When the reaction was performed between methanol gave excellent yields of the corresponding
propiophenone and 4-methoxyphenylmethanol, we coupled alcohol products (Table 3, entries 1–5).
have obtained 3-(4-methoxyphenyl)-2-methyl-1-phe-
When the reaction was performed between an aro-
nylpropan-1-ol as product in good yields with a longer matic secondary alcohol like 1-(6-methoxynapthalene-
reaction time (24 h). In this case, the product was elu- 2-yl)ethanol and a primary aromatic alcohol such as
cidated as a mixture of diastereomers in a 50:50 ratio p-tolylmethanol also gave excellent yield as high as
(Table 2, entry 7).The best diastereoselectivity ever 92% (Table 3 entry 7). Notably, a previous report for
noted for this compound, synthesized via the same ap- this reaction gave only 65% yield with RuCl
proach, is approxiately 50:50.[8] However, when the catalyst[3a] whilst we have obtained a much higher
reaction was conducted between propiophenone and yield using the commercially available Rh(acac)3 cata-
2ACHTUNGTRENNUNG(PPh3)3
AHCTUNGTRENNUNG
3-phenylpropan-1-ol we have obtained 2-methyl-1,5- lyst. The use of a secondary alcohol, such as 1-phenyl-
diphenylpentan-1-ol only in moderate yield (57%) as propanol with 4-methoxyphenylmethanol, for the re-
the diastereomeric product in a 50:50 ratio (Table 2 action gave a good yield of the desired product which
entry 8). When the reaction was performed using pro- is elucidated as a diastereoisomeric mixture in a 50:50
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Tris(acetylacetonato)rhodiumACTHNUGRTENUNG(III)-Catalyzed a-Alkylation of Ketones, b-Alkylation of Secondary Alcohols
Table 3. RhACHTUNGTRENNUNG(III)-catalyzed b-alkylation of secondary alcohols
(1 mol%) under benign reaction conditions in toluene
at 1108C.
with primary alcohols.[a]
It is to be noted that with the exception of en-
tries 8–10 in Table 3, the reactions of all the substrates
have been reported in the literature. However, the
yields obtained with many of our substrates with our
catalyst system are much higher than those reported
in the literature. Given the fact that the b-alkylation
reaction is very important, we have made a compari-
son of our work with those of important works that
were reported previously using the substrates de-
scribed in Table 3. The details of these results are
shown in Table 4. As can be seen in Table 4, a large
excess of base and catalyst is needed to promote the
reaction for Ru- and Ir-based catalysts. In these
works, it has been reported that the yields for the
products are much lower than those reported in the
present work when aromatic sec-alcohols, alicyclic al-
cohols are used with aromatic alcohols.[3a,5b,6a] In addi-
tion, our catalyst system is both commercially avail-
able and it requires only stoichiometric use of re-
agents using 1.0 mol% of the catalyst for promoting
the b-alkylation reaction.
During the course of this study, we have discovered
that the optimized reaction conditions for both a-al-
kylation of ketones and b-alkylation of secondary al-
cohols can also be extendable to the direct N-alkyla-
tion of various aromatic amines with aromatic alco-
hols to synthesize exclusively sec-amines (Scheme 5).
The results of this study are presented in Table 5.
Quite notably, when the direct amination reaction
was performed in the presence of catalyst B between
p-toluidine and 4-(methoxyphenyl)methanol no prod-
uct was isolated (Table 5, entry 1). Interestingly when
the same reaction was performed in the presence of
[a]
Reaction conditions: Secondary alcohol (1 mmol, 0.5M in
toluene), primary alcohol (1 mmol, 0.5M in toluene), cat-
alyst A (1.0 mol%), KOH (1 mmol), DABCO (0.5 mmol)
and 2 mL of toluene at 1108C, for 12–16 h.
[b]
Isolated yield of addition product.
[c]
Diastereomeric mixture.[3a,5a]
Table 4. Comparison of the b-alkylation of secondary alco-
hols by different methods.
ratio (Table 3, entry 6). For this reaction, the previous
report by S. Saito et al. has shown a similar 50:50 dia-
stereoselectivity for the product.[8] Similarly, the reac-
tion of a-tetralol with 4-(methoxyphenyl)methanol
and phenylmethanol gave the corresponding alkylated
alcohols as diastereoisomeric mixtures in a 50:50 ratio
in good yields (Table 3, entries 8 and 9).[6a] For reac-
tions between 1-phenylpropanol and 3-phenylpropa-
nol only a 47% yield of a 50:50 diastereomeric prod-
uct was obtained (Table 3, entry 10). Similar diaste-
reomeric product formation in a 50:50 ratio has been
reported previously by other researchers for the reac-
tion of a-tetralol with 4-methoxyphenylmethanol and
phenylmethanol as well as reaction of 1-phenylpropa-
nol with 4-methoxyphenylmethanol.[8,6a] Given that
excellent results were obtained for the a-alkylation of
ketones and the b-alkylation of secondary alcohols
with primary alcohols, it is apparent that the catalytic
system is very efficient at low catalyst loading
[a]
Conditions: reagents loading in mol%, R=Ph, Nap,
PhCH2; R’ =Ph, PhCH2CH2.
[b]
Present work.
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Similarly, the reaction performed between 4-ethylani-
line and phenylmethanol has given good yields as
high as 92% of N-benzyl-4-ethylaniline product
(Table 5, entry 5).When thereaction was conducted
between aniline with phenylmethanol and 4-methoxy-
phenylmethanol, excellent yields of the corresponding
amines were obtained – as high as 95% (Table 5, en-
tries 6 and 7). Under our optimized reaction condi-
tions, 4-iodoaniline also reacts smoothly with p-tolyl-
methanol and gives an excellent yield of the product
4-iodo-N-(4-methylbenzyl)aniline (Table 5, entry 8).
Interestingly, our methodology is also suitable for sul-
fonamides in a coupling reaction with primary aro-
matic alcohols which are an important class of com-
pounds in agrochemical and pharmaceutical chemis-
try.[29,25a] In addition, this reaction could be used as
a protecting group strategy for amines due to the
easily removable sulfonyl group on the nitrogen so
that they lead to the formation of primary amines.
For example, when the reaction was performed be-
tween 4-methylbenzenesulfonamide and 4-(methoxy-
Scheme 5. N-Alkylation of amines with primary alcohols.
Table 5. RhACHTUNGTRENNUNG(III)-catalyzed N-alkylation of amines with pri-
mary alcohols.[a]
À
phenyl)methanol, the C N cross-coupled N-(4-meth-
ylbenzyl)-4-methylbenzenesulfonamide product was
obtained in 88% yield (Table 5, entry 9). To the best
of our knowledge, the only work to date that reports
such high yields for sec-amines from 4-methylbenze-
nesulfonamide and 4-methoxyphenyl)methanol is that
by Yu and Xu et al.[27]
We wish to propose a possible mechanism for the
b-alkylation reaction on the lines that are reported
using [IrCpCl2]2 complexes.[6a] The probable mecha-
nism of RhACTHNUGRTNEUNG(III) complex-catalyzed b-alkylation of
secondary alcohols with primary alcohols is described
in Scheme 6. We propose that the first step of the re-
action would involve the oxidation of primary and
secondary alcohols to aldehydes and ketones accom-
panied by the generation of a hydrido rhodium spe-
cies. We propose that this step occurs upon the reac-
[a]
Reaction conditions: aromatic alcohol 1 mmol (0.5M in
toluene), aromatic amine 1 mmol (0.5M in toluene), cat- tion of alcohols in the presence of KOH and
alyst (1.0 mol%), KOH, (1 mmol), DABCO
(0.5 mmol), toluene 2 mL.
Isolated yields;
Reaction performed in the presence 1.0 mol% of catalyst
B; product not detected (n.d).
Solvent used is acetonitrile
A
RhACHTNURTGENN(UG acac)3 to generate a RhCAHTUNGTRNE(NUGN alkoxide) species which
undergoes a b-hydrogen elimination reaction to pro-
vide ketones, aldehydes, and hydrido rhodium species.
Then, the base-mediated cross-aldol condensation be-
tween aldehyde and ketone would occur to give an
a,b-unsaturated ketone. Then, the successive transfer
hydrogenation of C=C and C=O double bonds of the
[b]
[c]
[d]
catalyst A instead of catalyst B using acetonitrile as a,b-unsaturated ketone by the hydrido rhodium spe-
solvent only the imine [(E)-4-methoxy-N-(4-methyl- cies would occur to give the product. In this catalytic
benzylidene)aniline] was isolated as product (Table 5, system, the hydrido rhodium species generated at the
entry 2). However, when the same reaction was con- stage of the oxidation of alcohols are consumed at the
ducted in toluene we have discovered that only 4-me- stage of the reduction of a,b-unsaturated ketone.
thoxy-N-(4-methylbenzyl)aniline,
formed as major product (Table 5, entry 3). As can be not required; thereby making our RhAHCUTNGTRENNUNG
a
sec-amine, is Hence, additions of hydrogen donor and acceptor are
(III)-based cata-
seen from Table 5, 4-ethylaniline reacts smoothly lytic system a highly atom economical process.
under our experimental conditions with 4-methoxy-
phenylmethanol and gives an excellent yield of 4-
ethyl-N-(4-methoxybenzyl)aniline (Table 5, entry 4).
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Tris(acetylacetonato)rhodiumACTHNUGRTENUNG(III)-Catalyzed a-Alkylation of Ketones, b-Alkylation of Secondary Alcohols
Typical Procedure for a-Alkylation of Ketones with
Primary Alcohols
A pressure tube was charged with a mixture of acetophe-
none (1 mmol, 0.5M in toluene) and 4-methoxyphenylme-
thanol (1 mmol, 0.5M in toluene), DABCO (50 mol%),
KOH (1 mmol) and catalyst A (1.0 mol%). The reactants
were stirred in 2 mL of toluene at 1108C for 4 h. The prog-
ress of the reaction was monitored by TLC. After the com-
pletion of reaction, it was quenched using brine solution and
extracted with ethyl acetate (3ꢂ50 mL). The combined or-
ganic extracts were dried over anhydrous sodium sulfate
and filtered. Then, the solvent was evaporated under re-
duced pressure to give the crude product which was subject-
ed to silica gel column chromatography using hexanes/ethyl
acetate mixture as eluent to afford 3-(4-methoxyphenyl)-1-
phenylpropan-1-ol; yield: 98%.
Typical Procedure for b-Alkylation of Secondary
Alcohols with Primary Alcohols
A pressure tube was charged with a mixture of 1-phenyl-
AHCTUNGTREGeNNNU thanol (1.0 mmol, 0.5M in toluene), (4-methoxyphenyl)me-
thanol (1.0 mmol, 0.5M in toluene), DABCO (50 mol%),
KOH (1.0 mmol), and catalyst A (1.0 mol%). The reactants
were stirred in 2 mL of toluene at 105–1108C for 12–16 h.
The progress of the reaction was monitored by TLC analy-
sis. After the completion of reaction, it was quenched using
brine solution, and extracted with ethyl acetate (3ꢂ50 mL).
The combined organic extracts were dried over anhydrous
sodium sulfate and filtered. Then, the solvent was evaporat-
ed under reduced pressure to give the crude product which
was subjected to silica gel column chromatography using
hexanes/ethyl acetate mixture as eluent to afford 3-(4-me-
thoxyphenyl)-1-phenylpropan-1-ol; yield: 98%.
Scheme 6. Possible mechanism for RhACTHNUTRGNEUNG(III) complex-cata-
lyzed b-alkylation of secondary alcohols with primary alco-
hols.
Conclusions
In summary, we have demonstrated that the Rh-
ACHTUNGTRENNUNG(acac)3/DABCO/KOH catalyst is very efficient and
useful system for the a-alkylation of ketones, the b-al-
kylation of secondary alcohols and also the alkylation
of amines with primary alcohols in the absence of any
Typical Procedure for N-Alkylation of Amines with
Primary Alcohols
extra additives or external H2 source. We have also A pressure tube was charged with a mixture of p-toluidine
(1.0 mmol, 0.5M in toluene), 4-(methoxyphenyl)methanol
1.0 mmol (0.5M in toluene), DABCO (50 mol%), KOH
shown that the present catalyst system enables
a highly atom economical process that can be extend-
able to the direct N-alkylation of various aromatic
amines with aromatic alcohols to synthesize exclusive-
ly sec-amines.
(1.0 mmol) catalyst
A (1.0 mol%). The reactants were
stirred in 2 mL of toluene at 105–1108C for 12–16 h. The
progress of the reaction was monitored by TLC analysis.
After the completion of reaction, it was quenched using
brine solution, and extracted with ethyl acetate (3ꢂ50 mL).
The combined organic extracts were dried over anhydrous
sodium sulphate and filtered. Then, the solvent was evapo-
rated under reduced pressure to give the crude product
which was purified by column chromatography using hex-
anes/ethyl acetate mixture as eluent to afford 4-methoxy-N-
(4-methylbenzyl)aniline; yield: 94%.
Experimental Section
Materials and Analysis
All chemicals and solvents were purchased from commercial
1
vendors and used as received. The H NMR and 13C NMR
spectra were recorded on a Varian (400 MHz) or an Avance
(300 MHz) spectrometer. Tetramethylsilane (d=0.00 ppm)
1
was used as internal standard for H NMR. 13C NMR were
referenced to the residual solvent signal (CDCl3, 77.0 ppm).
Merck silica gel 60–120 mesh was used for column chroma-
tography using hexanes/ethyl acetate solvent mixture.
Acknowledgements
PSN and GMR thank the Council of Scientific and Industrial
Research, New Delhi, India for fellowship and financial sup-
port.
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FULL PAPERS
10 Tris(acetylacetonato)rhodiumACTHNUGRTNEUNG(III)-Catalyzed a-Alkylation
of Ketones, b-Alkylation of Secondary Alcohols and
Alkylation of Amines with Primary Alcohols
Adv. Synth. Catal. 2013, 355, 1 – 10
Ponnam Satyanarayana, Ganapam Manohar Reddy,
Hariharasharma Maheswaran,*
Mannepalli Lakshmi Kantam
10
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