Synthesis of α-hydroxy carboxylic acids via a nickel(II)- Catalyzed hydrogen transfer process

Article abstract of DOI:10.1002/adsc.201100241

A new catalytic system for β-alkylation of lactic acid with primary alcohols has been developed. In the presence of nickel(II) acetate tetrahydrate [Ni(OAc)₂(H₂O)₄] and base, lactic acid reacts with primary alcohols to afford the corresponding coupled α-hydroxy carboxylic acids in good to excellent yields via a hydrogen transfer process without any hydrogen acceptor or hydrogen donor. Copyright

Full text of DOI:10.1002/adsc.201100241

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DOI: 10.1002/adsc.201100241
Synthesis of a-Hydroxy Carboxylic Acids via a Nickel(II)-
Catalyzed Hydrogen Transfer Process
Guo Tanga,b,* and Chien-Hong Chenga,*
a
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan R.O.C.
Fax : (+886)-3-5724-698; e-mail: chcheng@mx.nthu.edu.tw
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005,
b
Peopleꢀs Republic of China
Fax : (+86)-592-218-5780; e-mail: t12g21@xmu.edu.cn
Received: March 31, 2011; Revised: May 6, 2011; Published online: August 11, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100241.
Abstract: A new catalytic system for b-alkylation of
lactic acid with primary alcohols has been devel-
oped. In the presence of nickel(II) acetate tetrahy-
plex for the synthesis of a-hydroxy carboxylic acids
could be an environmentally more friendly route than
the one using aldehydes and sodium cyanide as the
reagents.
drate [NiACHTUNGTRENNUNG(OAc)2ACHTUNGTRENNUNG(H2O)4] and base, lactic acid reacts
with primary alcohols to afford the corresponding
coupled a-hydroxy carboxylic acids in good to ex-
cellent yields via a hydrogen transfer process with-
out any hydrogen acceptor or hydrogen donor.
Our continued interest in nickel-catalyzed reactions
recently[7] prompted us to explore the possibility of
using low-cost nickel complexes as the catalysts for
hydrogen transfer process reactions. We found that
the air stable NiACTHNUGTRENNUG(OAc)2CAHTUNGTREN(NGUN H2O)4 complex can catalyze
the b-alkylation lactic acid with primary alcohols to
give the corresponding products in good yields.
This nickel-catalyzed b-alkylation of lactic acid de-
pends greatly on the reaction conditions. To optimize
the conditions, we examined the effect of solvent,
base, and ligand on the reaction yield (Table 1).
Benzyl alcohol (1a) and lactic acid were used as the
Keywords: hydrogen transfer process; a-hydroxy
carboxylic acids; lactic acid; nickel-catalyzed reac-
tion; primary alcohols
a-Hydroxy carboxylic acids are broadly used in the substrates in these studies. The catalytic reaction did
cosmetics and pharmaceutical industries.[1] The main not proceed or proceeded very slowly at 1208C (en-
method for the synthesis of this type of compounds is tries 1–5). When a mixture of 1a (3.0 mmol) and lactic
via the cyanation of aldehyde followed by hydrolysis acid (3.60 mmol) was heated in the presence of
as shown in the literature.[2] However, the aldehydes Ni
N
2ACHTUNGTERN(NUNG H2O)4 (5 mol%) and KOH (5.40 mmol) at
Catalytic b-alkylation of secondary alcohols with (entry 10). Product 3a is an important building block
primary alcohols is a convenient way to make higher for the production of a large variety of angiotensin-
alcohols. Only few examples of this type of catalytic converting enzyme (ACE) inhibitors.[8] Under similar
reactions are reported in the literature.[3,4] Most of the reaction conditions, the addition of a phosphine
homogeneous catalysts used for these reactions are ligand such as dppm, dppe or PPh3 resulted in 85–
Ru complexes[4] and Ir complexes under nitrogen con- 92% product yields (Table 1, entries 7–9). NiCl2 or
ditions.[5] The base-mediated b-alkylation of alcohols NiBr2 was also effective for the benzylation of lactic
under aerobic conditions without transition metal cat- acid (entries 17 and 18).
alysts was also reported by Crabtree.[6] In addition, al-
An advantage of this nickel(II)-catalyzed b-alkyla-
though that many secondary alcohols were employed tion of lactic acid is that the reaction can also success-
for the b-alkylation catalyzed by these complexes, no fully proceed under aerobic conditions. As shown in
a-hydroxy carboxylic acids as the substrates has been entry 11, when 1a and 2 were heated in the presence
investigated.
of NiACHTGUNTREUNN(G OAc)2ACHTUNGRTNE(NUNG H2O)4 under an atmosphere pressure of
Direct condensation of simple lactic acid with pri- air, the reaction gave 3a in 87% yield. In a control re-
mary alcohols catalyzed by an air-stable metal com- action, benzyl alcohol and 2-hydroxypropionic acid in
1918
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Synthesis of a-Hydroxy Carboxylic Acids via a Nickel(II)-Catalyzed Hydrogen Transfer Process
Table 1. Optimization of b-alkylation of lactic acid.[a]
Entry
Catalyst
Ni(Ni(OAc)2
Ligand
Base
Solvent
T
Yield [%]
1
2
3
4
5
6
G
dppm
dppm
dppm
dppm
dppm
dppm
dppm
dppe
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
K2CO3
K3PO4
DBU
KOH
KOH
t-BuOH
H2O
PhMe
BuOH
100
120
120
120
120
140
155
155
155
155
155
180
165
155
155
155
155
155
0
0
0
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
–
N
16
13
20
90
85
92
90
87
85
6
8
12
0
90
85
ethyl glyme
–
–
–
–
–
–
–
–
–
–
–
–
–
7[b]
8[b]
9[b]
10[b]
11[c]
12[c]
13[c]
14[c]
15[c]
16[c]
17[c]
18[c]
Ph3P
–
–
–
–
–
–
–
–
–
Ni
Ni
Ni
U
NiCl2
NiBr2
[a]
Unless otherwise mentioned, the reaction was carried out with 1a (3.0 mmol), 2a (3.60 mmol), NiACTHNUTRGENN(UG OAc)2ACHTUNGTRENNUNG(H2O)4
1
(0.150 mmol, 5 mol%), KOH (5.40 mmol), and N2 for 30 h in a sealed tube. Yields were determined by H NMR.
Heated under a nitrogen atmosphere (one atm at room temperature) at 1558C for 3 h.
Heated under aerobic conditions at 1558C for 3 h; then at 1808C for 0.5 h.
[b]
[c]
the presence of KOH but without Ni
G
G
Encouraged by this result, we decided to try out
were heated at 1658C for 3 h under aerobic condi- the reaction of various primary alcohols with lactic
tions, to afford 3a in only 6% yield (entry 13). The acid. The results are shown in Table 2. 4-Methyl- and
result indicates that a nickel catalyst is essential to 4-tert-butylbenzyl alcohols reacted similarly to afford
achieve high yield of product 3a even when the reac- the corresponding a-hydroxy carboxylic acids 3b and
tion was carried out under aerobic conditions (one 3c in excellent yields. Treatment of lactic acid with
atm at room temperature).[6] In the absence of a base, various methoxy-substituted benzyl alcohols led to
the catalytic reaction did not proceed. Various bases the formation of products 3d–3f in 65–85% yields.
were tested for the catalytic reaction. Among them, These products are important building blocks for pre-
KOH gave the highest yield of product 3a (en- ventives and remedies for diabetes pharmaceuticals.[9]
tries 10–16). Other bases such as K3PO4, K2CO3 and 4-Chloro- and 4-bromobenzyl alcohols were examined
DBU were less effective, giving 3a in very low yield. for their reactivity with lactic acid under similar reac-
The choice of temperature is also vital to the catalytic tion conditions and gave the expected products 3g
reaction (entries 5–9). When the temperature was and 3h in 93 and 59% yields, respectively. These two
below 1408C (entries 1–6), product 3a was detected in products are known to be intermediates for several
0–20% yields. However, when the temperature was important pharmaceuticals.[9a,10] Substituted benzyl al-
raised to 1558C, the b-alkylation of lactic acid could cohols with electron-donating 2,3-dimethoxy and elec-
be carried out in the absence of solvents and the reac- tron-withdrawing trifluoromethyl groups and thienyl-
tion gave 3a in 90% yield. It is critical to keep the methyl alcohol also reacted smoothly with lactic acid
temperature higher than 1558C, because the mixture to afford products 3f, 3j and 3k, respectively, in 50–
is turned into a cream; the potassium lactate generat- 90% yield. However, a much higher reaction temper-
ed appears to be melted and the mixing of reaction ature of 175–1808C in the presence of less basic
components is better above this temperature. When K3PO4 was required for the reactions. It is noteworthy
the temperature was raised to 1808C, b-alkylation of that 2-hydroxy-4-(4-(trifluoromethyl)phenyl)butanoic
lactic acid was completed within 30 min in the pres- acid (3j), a soluble epoxide hydrolase inhibitor,[11] was
ence of Ni
G
G
obtained in 90% yield. The present catalytic reaction
was also successfully applied to aliphatic alcohols,
Adv. Synth. Catal. 2011, 353, 1918 – 1922
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1919

Guo Tang and Chien-Hong Cheng
COMMUNICATIONS
Table 2. Nickel-catalyzed alkylation of lactic acid with pri-
albeit in lower yields. Thus, 3-phenylpropanol and 1-
octanol reacted with lactic acid to afford the corre-
sponding a-hydroxy carboxylic acid 3m and 3n in 30
and 40% yields, respectively.
mary alcohols.[a]
Our catalytic system is also effective for the alkyla-
tion of 2-alkanols with benzyl alcohol giving the cor-
responding b-alkylated products (3o–3q) in 75–85%
yields under nitrogen atmosphere (Scheme 1). In a
control reaction, benzyl alcohol and 1-phenylethanol
in toluene in the presence of KOH, but without
NiACHTUNGRTENN(UG OAc)2ACHTUNGTRNEN(UGN H2O)4 and dppm, were heated at 1158C for
30 h and the corresponding alkylation product 3o was
obtained in merely 12% yield.
A possible mechanism for this Ni(II) complex-cata-
lyzed b-alkylation of lactic acid with primary alcohols
is described in Scheme 2. The initial key step involves
the b-hydrogen elimination of alkoxide–NiX to give
aldehyde, potassium pyruvate and a hydridonikel spe-
cies. The cross-aldol reaction of the aldehyde with po-
tassium pyruvate generated affords the a,b-unsaturat-
ed ketone intermediate. Successive transfer hydroge-
nation of C=C and C=O double bonds of the a,b-un-
saturated ketone by the hydridonikel species generat-
ed in the first step leads to the final product. In this
catalytic reaction, the addition of a hydrogen donor
or acceptor is not necessary, unlike the RuCl2ACHTUNGTRENNUNG(PPh3)3
catalytic system, making our system a more atom eco-
nomical process.
In summary, we have shown a new efficient system
for the b-alkylation of lactic acid with primary alco-
hols catalyzed by air-stable Ni(II) complexes. Many
biologically active a-hydroxy carboxylic acids can be
synthesized in high yields using this nickel system as
the catalyst.
[a]
Reaction conditions: primary alcohol (3.0 mmol), lactic
acid (3.60 mmol), NiACHTNUGTRENNU(G OAc)2ACHTUNTGREN(NGUN H2O)4 (0.150 mmol), KOH
(5.40 mmol), 155–1658C, 3 h, under aerobic conditions.
Isolated yield based on the primary alcohol used.
Experimental Section
[b]
[c]
Typical Procedure for the Synthesis of 3a–3n
Primary alcohol (3.0 mmol), lactic acid (3.60 mmol), Ni-
ACHTUNGTRENNUNG(OAc)2ACHTUNGTRENNUNG(H2O)4 (0.150 mmol), K3PO4 (14.4 mmol), 175-
To an ice-cooled solution of KOH (5.40 mmol) in H2O
(6.0 mL) and toluene (10.0 mL) in a 25-mL round-bottom
flask equipped with a Dean–Stark apparatus, lactic acid
(3.60 mmol) was added slowly. The reaction mixture was
1808C, 3 h, under aerobic conditions. Isolated yield based
on primary alcohol.
1) Reaction conditions as in footnote[a]; 2) methanol
(20.0 mL), H2SO4 (3.0 mL), reflux 3 h.
Scheme 1. Nickel-catalyzed b-alkylation of secondary alcohols with benzyl alcohols. Reaction conditions: 1 (1.2 mmol), 2
(1.0 mmol), dppm (0.050 mmol), Ni(OAc)2A(H2O)4 (0.050 mmol), KOH (3.0 mmol), toluene (3.0 mL), in a sealed tube, 1158C,
N2 1 atm (ambient room pressure), 30 h. Isolated yield based on 2.
A
CHTUNGTRENNUNG
1920
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Adv. Synth. Catal. 2011, 353, 1918 – 1922

Synthesis of a-Hydroxy Carboxylic Acids via a Nickel(II)-Catalyzed Hydrogen Transfer Process
Scheme 2. A possible catalytic reaction pathway.
stirred for 50–70 min in a 1358C silicon oil bath to remove
[2] a) M. F. Parisi, G. Gattuso, A. Notti, F. M. Raymo,
the water in the mixture. Primary alcohol (3.0 mmol) and
NiACHTUNGTRENNUNG(OAc)2ACHTUNGTRENNUNG(H2O)4 (0.150 mmol) were then added into the
R. H. Abeles, J. Org. Chem. 1995, 60, 5174–5179;
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flask. The reaction mixture was stirred at 155–165C for 3 h
and subsequently water (50.0 mL) was added. The solution
was extracted with toluene (2ꢂ20.0 mL). The water phase
was acidified with concentrated HCl to pH<3.0, then ex-
tracted with EtOAc (3ꢂ30.0 mL) and combined with the or-
ganic solution. The organic layer was washed with brine (2ꢂ
10.0 mL), dried with sodium sulfate, and filtered. The filtrate
was evaporated under vacuum. The crude product was puri-
fied on a silica gel column using hexane-ethyl acetate (1/5–
1/1 v/v) as eluent to give the corresponding pure product
3a–3n.
[3] Reviews: a) G. Guillena, D. J. Ramꢄn, M. Yus, Angew.
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[4] a) C. S. Cho, B. T. Kim, T.-J. Kim, S. C. Shim, J. Org.
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Supporting Information
Experimental details and copies of NMR spectra of all com-
pounds are available as Supporting Information.
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Acknowledgements
[7] a) K. K. Majumdar, C.-H. Cheng, Org. Lett. 2000, 2,
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We thank National Science Council, Taiwan (NSC-96-
2113M-007-020MY3) and Fujian, China (2009HZ0004-1) for
support of this research.
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