Chemoselective alcoholysis of lactide mediated by a magnesium catalyst: An efficient route to alkyl lactyllactate

Article abstract of DOI:10.1039/c1dt10087d

Alkyl-(S,S)-O-lactyllactate was prepared by chemoselective alcoholysis of lactide LA mediated by a magnesium catalyst. When ROH reacted with LA it yielded the ring-opened product R-(S,S)-O-lactyllactate exclusively, which remained intact as long as LA was present in the reaction mixture. Consumption of LA caused the reaction to proceed further giving R-(S)-lactate.

Full text of DOI:10.1039/c1dt10087d

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Chemoselective alcoholysis of lactide mediated by a magnesium catalyst: an
efficient route to alkyl lactyllactate†
Agnieszka Grala, Jolanta Ejfler, Lucjan B. Jerzykiewicz and Piotr Sobota*
Received 17th January 2011, Accepted 18th February 2011
DOI: 10.1039/c1dt10087d
Alkyl-(S,S)-O-lactyllactate was prepared by chemoselective
alcoholysis of lactide LA mediated by a magnesium catalyst.
When ROH reacted with LA it yielded the ring-opened
product R-(S,S)-O-lactyllactate exclusively, which remained
intact as long as LA was present in the reaction mixture.
Consumption of LA caused the reaction to proceed further
giving R-(S)-lactate.
laneamine), are highly efficient initiators for lactide
polymerization.6 Here we report the use of tetrahedral magnesium
complex [Mg(tbpca)2] where (Htbpca = N-[methyl(2-hydroxy-
3,5-di-tert-butyphenyl)]-N-methyl-N-cyclohexylamine) as the
catalyst for the alcoholysis of LA. This study demonstrated
unique chemistry that allows for facile chemoselective catalytic
incorporation of ROH into LA and pure alkyl lactyllactate
formation. As shown in Scheme 1, MgBu2 treated with 2
equivalents of Htbpca in toluene cleanly afforded the monomeric
tetrahedral magnesium compound [Mg(tbpca)2] (1, 87%) by
butane elimination. This was isolated as a colorless air and
moisture sensitive solid or crystals in high yield, readily soluble
in hydrocarbons, dichloromethane and thf. The aminephenolate
ligand Htbpca was prepared following the Mannich reaction
between N-cyclohexylamine, formaldehyde and substituted
phenol as described in the literature.7
Lactide (L-LA, D-LA, rac-LA), a cyclic dimmer, is one of
the simplest chiral compounds derived from lactic acid. It is
made from the fermentation of carbohydrates such as corn - a
renewable feedstock. A valuable reagent for organic syntheses,1
and a useful monomer for polymerization,2 very recently it has
become a desirable starting material for the syntheses of lactate
and lactyllactate esters.3 The esters produced by alcoholysis of LA
catalyzed by metal complexes have attracted great interest since
they open up environmentally-friendly routes to alkyl lactates -
compounds widely used in the cosmetic and food industries.4
Earlier syntheses of alkyl lactates required a protective strategy, a
stoichiometric amount of metal complexes, long reaction times
and high temperatures.5 Claborn5b later discovered that alkyl
lactyllactate can be produced by heating a mixture of a dry lactate
and the desired anhydrous alcohol in the range 70–90 ◦C for ca. 6 to
8 h in the presence of an acid catalyst under anhydrous conditions.
The problem with these methods is the formation of polymer
by-products and selectivity. Recently, Phomphrai used lithium,
sodium, potassium and calcium alkoxide catalysts generated in
situ to make a range of alkyl lactates from lactides and alcohols.3b
However, the reaction course of LA transformation to alkyl (S,S)-
lactyllactate decelerated after 20–30 min to achieve conversion
from 48 to 84% for MOR where M = Li, Na and K, respectively,
due to the aggregation of the active catalyst. For calcium alkoxide
Ca(OR)2 the reaction proceeded further and in 10 min methyl
(S)-lactate was formed exclusively.
Scheme 1 Synthesis of [Mg(tbpca)2].
The structure of 1 was confirmed by elemental analysis and
NMR spectroscopy, as well as X-ray crystallography. The 1H
NMR spectra of 1 were routine (see ESI†) and showed one set
of resonances for aryl protons at 7.66 and 7.08 ppm, two singlets
of tert-butyl groups at 1.78 and 1.56 ppm and a signal assigned to
N-methyl protons at 2.02 ppm. The methylene protons from the
phenyl-CH2–N linker appeared as broad singlets at 4.12 and 3.44
ppm. The molecular structure of 1 is shown in Fig. 1 and selected
bond lengths and angles are given in Table 1S.† X-ray analysis
shows that the magnesium compound is a molecular monomer
with the four-coordinated magnesium centre surrounded by two
pairs of N,O atoms from two aminephenolate ligands forming a
distorted tetrahedron. Although such coordination seems typical
for magnesium, to our surprise only two monomeric four-
coordinated magnesium complexes were found in the CCDC.8
In the standard procedure the magnesium compound 1, lactide
L-LA and dry ethanol in the molar ratio 1/50/200 was added
Recently our group has reported that the aminephenolate
magnesium compounds, [Mg(tbpoa)2] (Htbpoa = N-[methyl(2-
hydroxy-3,5-di-tert-butylphenyl)]-N-methyl-N-methyl-1,3-dioxo-
Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383,
Wroclaw, Poland. E-mail: plas@wchuwr.pl; Fax: +48 (71) 328 23 48;
Tel: +48 (71) 375 73 06
† Electronic supplementary information (ESI) available: Experimental
details, characterizing data and X-ray structure determination. CCDC
799087. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1dt10087d
4042 | Dalton Trans., 2011, 40, 4042–4044
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Fig. 2 1H NMR (C6D6, RT) spectrum of the alcoholysis of L-lactide
catalysed by [Mg(tbpca)2], (* signals of Htbpca). Reaction conditions
[Mg(tbpca)2]/L-LA/EtOH = 1/50/200, solvent CH2Cl2, [Mg(tbpca)2] =
0.003 M, RT.
Fig. 1 View of [Mg(tbpca)2]. Hydrogen atoms are omitted. Key bond
◦
˚
lengths (A) and angles ( ): Mg(1)–O(1) 1.896(2), Mg(1)–O(2) 1.896(2),
Mg(1)–N(1) 2.193(2), Mg(1)–N(2) 2.193(2), O(1)–Mg(1)–O(2) 133.19(7),
O(1)–Mg(1)–N(1) 95.04(6), O(1)–Mg(1)–N(2) 99.80(6), O(2)–Mg(1)–N(1)
99.80(6), O(2)–Mg(1)–N(2) 95.04(6), N(1)–Mg(1)–N(2) 142.09(7).
at room temperature in dichloromethane. After 1 h the reaction
was quenched with acetic acid and the product was isolated
1
by distillation under vacuum. The H NMR spectra shows two
quartets (4.27, 5.04 ppm) and doublets (1.21, 1.46 ppm) due to
methine and methylene protons of pure ethyl-(S,S)-O-lactyllactate
as well as resonances for the ethyl group, triplet (0.88 ppm)
and quartet (3.86 ppm), respectively (Fig. 2, Table 2, entry 1).
Furthermore, when the reaction was carried out for 3 days
at room temperature the solution consisted of 70% of ethyl-
(S,S)-O-lactyllactate and 30% ethyl-(S)-lactate (Table 2, entry
2). Surprisingly, the analogous reaction with methanol is much
faster and more complex. After 5 min besides methyl-(S,S)-O-
lactyllactate (93.5%) methyl-(S)-lactate (6.5%) was also observed
(Table 2, entry 3). To explain the reaction pathway and formation
of intermediates in this multiple-step process the reaction course
between 1, LA and MeOH (1/50/200) in toluene was recorded at
room temperature and various time intervals, generally up to 7 h
and monitored by 1H NMR (Fig. 3). The characteristic feature of
Fig. 3 1H NMR spectra presented for methine protons recorded at
273 K at various time intervals: a = 2 min, b = 4 min, c = 2 h, d = 7
h. Reaction condition: C6D6, RT [Mg(tbpca)2]/LA/MeOH = 1/50/200.
ꢀ methyl-(S,S)-O-lactyllactate, o methyl-(S)-lactate, * CH2Cl2.
1
the H NMR spectrum is the disappearance of L-LA substrate
and formation of two reaction products, first methyl-(S,S)-O-
lactyllactate, which is formed as long as lactide is present in the
reaction mixture; subsequently methyl-(S)-lactate appears. This
indicates that the highly active compound 1 is able to catalyze not
only the reaction between LA and alcohol but also the reaction
among methyl-(S,S)-O-lactyllactate and ROH. In the first step
the MeOH reacted with L-LA giving the ring-opened product
methyl-(S,S)-O-lactyllactate exclusively (Scheme 2, cycle A). This
remained intact as long as L-LA is present in the reaction mixture.
As soon as L-LA is completely consumed the methyl-(S,S)-O-
lactyllactate reacts with MeOH giving methyl-(S)-lactate (cycle
B).
The study demonstrated that catalyst 1 had remarkable chemos-
electivity and could specifically form methyl-(S)-lactate from
methyl-(S,S)-lactyllactate only in the absence of L-LA. For the
purpose of screening the catalyst activity, different alcohols
(BnOH, EtOH, MeOH, Pr-OH, BuOH) were examined in the
alcoholysis reaction of L-lactide as shown in Table 1 (entry 8–10).
All reactions proceed catalytically to give the corresponding alkyl-
Scheme 2 Proposed mechanism for the alcoholysis and polymerisation
of L-lactide.
(S,S)-O-lactyllactates with moderate yield. These observations
suggested that the conversion of LA to alkyl lactyllactates, alkyl
lactate or PLA depends on catalyst/LA/alcohol ratio as well as
of the polarity of alcohol.
i
n
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Table 1 Summary of alcoholysisa
of L-lactide using [I],
further giving methyl-(S)-lactate. The product selectivity and its
easily extendable range might make this method convenient for
wider application.
[Mg(tbpca)2]/catalyst
Entry
t (h)
ROH
A-LL
A-L
L-LA
1
2
3
4
5
6
7
8
1
EtOH
EtOH
98.0
70.0
93.5
71.0
62.0
27.0
0.5
50.0
48.0
75.5
0
0
2.0
0
0
0
0
0
0
50.0
52.0
24.5
0
Acknowledgements
72
0.08
0.5
1
3
6
2
3
18
0.25
30.0
6.5
29.0
38.0
63.0
99.5
0
0
0
0
MeOH
MeOH
MeOH
MeOH
MeOH
nBuOH
iPrOH
BnOH
BnOH8
We gratefully acknowledge the financial assistance of the Minister
of Science and Higher Education (Grants Nos. N204 185539 and
N 209027940).
Notes and references
9
10
1 (a) R. Datta and M. Henry, J. Chem. Technol. Biotechnol., 2006, 81,
1119; (b) T. Kitazaki, A. Tasaka, H. Holono, Y. Matsushita and K. Itoh,
Chem. Pharm. Bull., 1999, 47, 360; (c) E. Roulland, C. Monneret and J.
C. Florent, Tetrahedron Lett., 2003, 44, 4125.
2 (a) O. Dechy-Cabaret, B. Martin-Vaca and D. Bourissou, Chem. Rev.,
2004, 104, 6147; (b) J. Wu, T. L. Yu, C. T. Chen and C. C. Lin, Coord.
Chem. Rev., 2006, 250, 602; (c) W. C. Huang and C. C. Lin, Inorg. Chem.,
2009, 48, 728; (d) C. A. Wheaton, P. G. Hayes and B. J. Ireland, Dalton
Trans., 2009, 4832; (e) V. Poirier, T. Roisnel, J. F. Carpentire and Y.
Sarazin, Dalton Trans., 2009, 9820.
11b
a General reaction condition: [1] = 0.003, T = 25 ◦C, [1]/L-LA/ROH
= 1/50/200, A-LL: alkyl-(S,S)-O-lactyllactate, A-L: alkyl-(S)-lactate.
b Polymerization reaction conditions: [1]/L-LA/BnOH = 1/100/1, prod-
uct PLA 100%.
A blank test was also performed in which no catalyst was
added; no reaction was observed. Furthermore, it was found that
compound 1 is also a very effective initiator for the ring-opening
polymerization of L-LA. When 1 was allowed to react with 100
equiv. of L-LA and 1 equiv. of benzyl alcohol in toluene at room
temperature, polymerization with 100% conversion was achieved
in 15 min and produces PLA with the expected molecular weight
Mw = 15 560 and low polydispersity PDI = 1.10 characteristic of
well controlled living propagation.
In summary, we have developed a new, simple and efficient
strategy for the preparation of a well-defined magnesium catalyst
for selective conversion of lactides to alkyl-(S,S)-lactyllactates and
to PLA in high yields. The study demonstrated that catalyst 1
is stable, and alkyl-(S,S)-O-lactyllactate is formed only in the
presence of L-LA. In the absence of LA the reaction proceeds
3 (a) N. Y. Jeon, S. J. Ko, K. Won, H. Y. Kang, B. T. Kim, Y. S. Lee
and H. Lee, Tetrahedron Lett., 2006, 47, 6517; (b) K. Phomphrai,
S. Pracha, P. Phonjanthuek and M. Pohmakotr, Dalton Trans., 2008,
3048.
4 H. V. Claborn, US Pat., 2 371 281, 1945.
5 (a) G. Martino-Gauchi, R. Teissier, US Application Publication
20060014976, 2006; (b) H. V. Claborn, US Pat 2 371 281, 1945; (c) Z.
Zhong, S. Schneiderbauer, P. J. Djikstra, M. Westerhausen and J. Feijen,
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7 J. Ejfler, S. Szafert, K. Mierzwicki, L. B. Jerzykiewicz and P. Sobota,
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8 (a) K. W. Henderson, G. W. Honeyman, A. R. Kennedy, R. E. Mulvey,
J. A. Parkinson and D. C. Sherrington, Dalton Trans., 2003, 1365; (b) J.
Ejfler, K. Krauzy-Dziedzic, S. Szafert, L. B. Jerzykiewicz and P. Sobota,
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4044 | Dalton Trans., 2011, 40, 4042–4044
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The Royal Society of Chemistry 2011
©