Dendritic HMPA as a promoter for the mukaiyama aldol and allylation reaction

Article abstract of DOI:10.1055/s-0032-1317482

We synthesized a hexamethylphosphoramide (HMPA) analogue that was immobilized on hyperbranched polyglycerol (hPG) via a covalent approach. This polymeric analogue (hPG-HMPA) can potentially replace carcinogenic HMPA as a Lewis base additive in many reactions involving trichlorosilyl substrates. We investigated immobilized HMPA in the Mukaiyama aldol and allylation reactions. In most cases, yields and selectivities of supported and nonsupported HMPA were similar. Moreover, in the allylation reaction a positive dendritic effect could be observed, and the loading of HMPA could be lowered with hPG-HMPA to catalytic quantities (0.5 mol%). These results demonstrate that the use of HMPA can be avoided by hPG-HMPA without loss in terms of yield or selectivity. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317482

2672▌
LETTER
lDetteerndritic HMPA as a Promoter for the Mukaiyama Aldol and Allylation
Reaction
Dendritic HMPA as Promoter
Florian Mummy, Rainer Haag*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83853357; E-mail: haag@chemie.fu-berlin.de
Received: 09.08.2012; Accepted after revision: 24.09.2012
but the scope of these substitutes is mostly limited.4 Little
Abstract: We synthesized a hexamethylphosphoramide (HMPA)
has been done to replace HMPA by an immobilized ana-
analogue that was immobilized on hyperbranched polyglycerol
logue on an insoluble support.5
(hPG) via a covalent approach. This polymeric analogue (hPG-
HMPA) can potentially replace carcinogenic HMPA as a Lewis
base additive in many reactions involving trichlorosilyl substrates.
We investigated immobilized HMPA in the Mukaiyama aldol and
showed high catalytic activity.6,7 The superior solvent and
allylation reactions. In most cases, yields and selectivities of sup-
ported and nonsupported HMPA were similar. Moreover, in the al-
We have recently reported several catalysts that were sup-
ported on a soluble polymeric support and generally
coordination properties of HMPA in combination with its
practical limitations make the development of a supported
HMPA analogue most desirable.5,8 It seemed likely that
the polymeric support might show new and potentially
useful catalytic properties. We and others have shown that
dendronized catalysts often benefit from better reaction
kinetic in solution and that catalyst loadings can often be
decreased using dendritic architectures.6,7,9 The multiva-
lent presentation of HMPA also generates a high local
concentration, which is required in many reactions, where
it is currently being employed.2,3 Immobilization onto a
polymeric support also decreases the threat of HMPA in-
halation, and potential contamination by skin penetration
can at last be reduced by the polymeric support,10 whereas
the nonsupported HMPA easily penetrates the skin due to
its high swelling property.11
lylation reaction a positive dendritic effect could be observed, and
the loading of HMPA could be lowered with hPG-HMPA to cata-
lytic quantities (0.5 mol%). These results demonstrate that the use
of HMPA can be avoided by hPG-HMPA without loss in terms of
yield or selectivity.
Key words: aldol reaction, homogeneous catalysis, supported cata-
lysts, organocatalysis, HMPA, polymeric support
Hexamethylphosphoramide (HMPA) is an extremely ef-
fective polar aprotic solvent (ET = 40.9)1 with a remark-
able Lewis basicity. HMPA has been extensively used as
a cosolvent and additive for organolithium-based chemis-
try as well as in reactions promoted by samarium di-
iodide.1 Just recently it has been applied in
organocatalysis,2,3 where chiral phosphoramides have
been used for several interesting stereoselective transfor-
mations, such as in aldol and allylation reactions. It has
been demonstrated that stoichiometric quantities of phos-
phoramides are usually needed for high stereoinduction.2,3
In 1999 we introduced hyperbranched polyglycerol (hPG,
1)12 as a soluble, multifunctional, dendritic support with
applications in the field of organic synthesis13,14 and catal-
ysis.6,7,15 This polyether (Figure 1) can be easily synthe-
sized on a kilogram scale by a one-step polymerization
reaction. Due to the dendritic structure, hPG contains a
large number of primary and secondary hydroxy groups
(13.5 mmol g–1), which can be easily converted into other
functional groups by simple standard organic methods.13
Its superior properties, such as high loading capacity,
good solubility in a wide range of organic solvents (de-
pending on the surface functionalization), chemical stabil-
ity (inert ether bonds), and noncoordinating properties,
make this aliphatic polyether a promising candidate for
support of catalysts.
Unfortunately, HMPA is known as a carcinogenic and
mutagenic compound, which limits its broad use in organ-
ic synthesis. In many laboratories it has been forbidden
and it has to be handled with caution, especially as it eas-
ily penetrates the skin.1 In animal experiments it has been
shown that HMPA is metabolized by demethylation, and
the methyl groups of HMPA are responsible for the harm-
ful effects. In conclusion an HMPA analogue which can-
not be inhaled or which does not easily penetrate the skin
may serve as a potential HMPA substitute.
Due to the superior solvent effects of HMPA, many at-
tempts have been made to find a substitute for HMPA.
Several potential substitutes have been investigated in the
past such as N,N′-dimethylpropyleneurea (DMPU) and
tripyrrolidinophosphoric acid triamide (TPPA) which
were found to be good replacements for some reactions
Herein, we present the synthesis of an HMPA analogue
which is supported on a soluble dendritic polyglycerol
[hPG-HMPA (4)] and we show typical results of 4 in the
aldol and allylation reaction. Recycling experiments by
ultrafiltration are included to show the extra benefits of
hPG-HMPA.
For the immobilization of HMPA, hPG-methylamine (2)
was prepared starting from hPG-OH (1) with Mn = 10.000
g mol–1, where the OH groups of 1 were transformed into
methylamino groups. This replacement was achieved by
SYNLETT 2012, 23, 2672–2676
Advanced online publication: 19.10.2012
DOI: 10.1055/s-0032-1317482; Art ID: ST-2012-B0674-L
© Georg Thieme Verlag Stuttgart · New York
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LETTER
Dendritic HMPA as Promoter
2673
HO
uble in a variety of organic solvents (Table 1), as well as
in water, but it was insoluble in alkyl ethers.
OH
HO
O
Table 1 Solubility of hPG-HMPA Catalyst 4
O
OH
Entry
Solvent
Solubilitya
OH
O
O
1
2
3
4
5
6
7
8
CHCl3
DMF
MeOH
MeCN
H2O
+
+
+
+
+
+
–
–
HO
HO
O
O
O
O
OH
O
O
O
OH
OH
OH
O
O
O
HO
OH
OH
HO
O
CH2Cl2
Et2O
HO
1
HO
OH
THF
hPG
a Conditions: 5 mg hPG-HMPA in 1 mL of solvent.
OH
We compared the efficacy of the two systems, which were
supported HMPA 4 and monomeric HMPA 6 (Figure 2)
in the Mukaiyama aldol5 (Scheme 2 and Table 2) and al-
lylation reaction of trichlorosilyl compounds to benzalde-
hyde.
Figure 1 Hyperbranched polyglycerol (hPG, 1): The structure shown
represents a small idealized fragment of hPG (Mn = 10 000 g mol–1).
The structure is abbreviated hereafter as shown in the inset.
first converting the alcohol 1 into the mesylate13 and sub-
sequently displacing the mesylate with methylamine in an
autoclave. For the modified hPG 2 we could prove with 1H
NMR spectroscopy and elemental analysis that all mesyl-
ate groups were replaced by amine. The commercial
bis(dimethylamido)phosphoric chloride (3) was then di-
rectly coupled to the hPG 2 using n-BuLi as a base to yield
hPG-supported HMPA (4, Scheme 1).
O
P
O
P
hPG
NMe2
NMe2
Me2N
N
NMe2
Me
NMe2
4
HMPA (6)
Figure 2 Structures of polymer-supported HMPA analogue 4 and
commercial hexamethylphosphoramide 6
a, b
OSiCl3
O
OH
hPG
hPG
O
NHMe
OH
hPG-HMPA (4)
Ph
1
2
+
Ph
H
CH2Cl2, 2 h, –78 °C
7
8
9
O
c
hPG
hPG
P
N
Scheme 2 Mukaiyama aldol reaction of enol ether 7 with aldehyde
8 to β-hydroxy ketone 9
O
NMe2
NHMe
NMe2
Me
4
2
P
Cl
NMe2
NMe2
3
The aldol reaction of trichlorosiloxycyclohexene (7) to
benzaldehyde (8) showed that the yields for the supported
HMPA 4 were even slightly better than for the HMPA-
(6)-promoted reaction (Table 2, entries 2 and 3). As a con-
trol, the reaction gave very low yields (Table 2, entry 1) in
the absence of a catalyst. As result, immobilization on
HMPA led to a highly active catalyst, which was further
investigated in terms of selectivity. Polymeric catalyst 4
as well as HMPA (6) led to a syn/anti ratio of the aldol
product of 1:1 (Table 2). Whereas a ratio of >20:1 was ob-
served without a catalyst. In light of the fact that both cat-
alysts 4 and 6 gave the same stereoselective outcome, this
finding is rather surprising, especially because we have
observed in the past that selectivities usually change upon
immobilization of the catalyst.7
Scheme 1 Synthesis of hPG-supported HMPA (4): a) MsCl, pyri-
dine, 0 °C, 16 h; b) MeNH2, DMF, 60 °C, 24 h, autoclave; c) n-BuLi,
–78 °C, 12 h.
The final polymeric compound 4 was purified by ultrafil-
tration, and the degree of HMPA functionalization was
determined by 31P NMR spectroscopy using triphe-
nylphosphine oxide as an internal standard and was found
to be up to 2 mmol g–1. Two different loadings were syn-
thesized, whereby 1 mmol HMPA per gram refers to cat-
alyst 4 and 2 mmol HMPA loading refers to catalyst 5.
As its broad usability is strongly dependent on its solubil-
ity in most common organic solvents, its solubility was
tested (Table 1). The supported organocatalyst 4 was sol-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2672–2676

2674
F. Mummy, R. Haag
LETTER
Table 2 Initial Results for the Aldol Reaction Catalyzed by 4 and 6a
O
OH
hPG-HMPA (5)
SiCl3
+
syn/antib Yield
Ph
Ph
H
CH2Cl2, 1 h, r.t.
Entry
Catalyst
Loading
(mol%)
(%)c
10
8
11
1
2
3
none
0
10
10
>20:1
1:1
<5
63
60
Scheme 3 Allylation of aldehyde 8 with silane 10 to allylic alcohol 11
hPG-HMPA (4)
HMPA (6)
1:1
NMR analysis), while the catalyzed reactions were almost
finished after less than ten minutes (observed by TLC).
a Reaction conditions: catalyst (0.1 equiv), silane (1.1 equiv), and fast
addition of aldehyde 8.
The next goal was to reduce the catalyst loading. To our
surprise, we obtained nearly quantitative yield with just
0.5 mol% of dendritic catalyst 5, while the reaction cata-
lyzed by HMPA (6) was very slow and just showed less
than 2% yield after one hour (Table 4). With this experi-
ment we could nicely demonstrate how the high local con-
centration of HMPA on the polymer made reactions
feasible that usually needed higher HMPA concentra-
tions. With polymeric catalyst 5 we could present a
HMPA substitute that showed a positive dendritic effect.
b Determined by 1H NMR analysis.
c Isolated yield after column chromatography.
Secondly, when HMPA was used in solvent-like quanti-
ties a syn/anti ratio of 1:5 was observed in the product. To
increase the amount of anti product with catalyst 4, we
first optimized the reaction parameters under catalytic
conditions in accordance to literature examples (Table 3).2
The aldehyde was slowly added and diluted, diisopropyl-
ethylamine was introduced as an additive, and the aldol
reaction was performed at higher concentration. As result,
HMPA (6) led to nearly quantitative yield, and a syn/anti
ratio of 1:5 and the performance of catalyst 4 could be re-
markably improved to a yield of 93% and a ratio of 1:4.
These findings clearly show hPG-HMPA is a possible
HMPA substitute, which is as effective as the monomer
but without the negative toxic effects of 6 like inhalation.
Table 4 Application of hPG-HMPA (5) in the Allylation of Alde-
hyde 8a
Entry
Catalyst
Loading (mol%) Yield (%)b
1
2
3
4
5
none
0
0
40
<2
97
99
HMPA (6)
HMPA (6)
hPG-HMPA (5)
hPG-HMPA (5)
10
0.5
10
0.5
Table 3 Aldol Reaction under Optimized Conditions with Slow Ad-
dition of Aldehyde 8a
Entry
Catalyst
Loading
(mol%)
syn/antib
Yield
(%)b
a Reaction conditions: see experimental details.16
b Determined by 1H NMR analysis.
1
2
HMPA (6)
10
10
1:5.3
1:4.2
98
93
hPG-HMPA (4)
A potential benefit of supported catalysts is their reusabil-
ity and recyclability. To test the recyclability of hPG-
HMPA (5), allylation of benzaldehyde with allyl trichlo-
rosilane was performed in consecutive cycles and full
conversion was achieved for three runs (Table 5). After
each run the dendritic catalyst was successfully separated
from the product by ultrafiltration using a Millipore mem-
brane of regenerated cellulose with a molecular weight
cut-off of 5000 g mol–1 and methanol as solvent. It was
possible to use the same ultrafiltration membrane
throughout the whole experiment.
a Reaction conditions: see experimental details.16
b Determined by 1H NMR analysis.
Inspired by the catalytic performance of dendritic HMPA
4, we focused on the investigation of 4 in the allylation re-
action. This reaction type gives access to homoallylic al-
cohols, which are applied in natural product synthesis. In
contrast to the aldol reaction, a potential dendritic effect
can be investigated without the problems of a background
reaction.
The catalyst leaching was determined by 31P NMR analy-
sis. For the three runs, no leaching of the catalyst from the
polymeric support could be observed (Table 5).
As we could not observe a dendritic effect in the aldol re-
action we hoped that double the local concentration of
HMPA group on the polymer to 2 mmol would reinforce
a potential dendritic effect. With catalyst 5 in hand we in-
vestigated the allylation reaction of benzaldehyde with
allyl trichlorosilane (Scheme 3).3
We have been able to show with the first successful syn-
thesis of a homogeneous HMPA-supported polymeric
catalyst that dendritic polyglycerol is a suitable support
for HMPA. The high local concentration of HMPA
groups at the surface of the polymer was used to mimic a
high total concentration of HMPA in the reaction. The ex-
amples presented in this communication show that sup-
ported HMPA is a very good substitute for HMPA in
As a result, dendritic catalyst 5 gave the allylated product
in almost quantitative yield, whereas with catalyst 6 just
40% yield was observed. As a control, the reaction with-
1
out a catalyst gave no conversion after one hour (by H
Synlett 2012, 23, 2672–2676
© Georg Thieme Verlag Stuttgart · New York

LETTER
Dendritic HMPA as Promoter
2675
(9) (a) Dahan, A.; Portnoy, M. Chem. Commun. 2002, 2700.
(b) Dahan, A.; Portnoy, M. Org. Lett. 2003, 5, 1197.
(c) Kehat, T.; Portnoy, M. Chem. Commun. 2007, 2823.
(d) Dahan, A.; Portnoy, M. J. Polym. Sci., Part A: Polym.
Chem. 2005, 43, 235. (e) Mansour, A.; Kehat, T.; Portnoy,
M. Org. Biomol. Chem. 2008, 6, 3382.
(10) Marcato, P. D.; Caverzan, J.; Rossi-Bergmann, B.; Pinto, E.
F.; Machado, D.; Silva, R. A.; Justo, G. Z.; Ferreira, C. V.;
Dur, N. J. Nanosci. Nanotechnol. 2011, 11, 1880.
(11) Hansen, C. M.; Andersen, B. H. Am. Ind. Hyg. Assoc. J.
1988, 49, 301.
Table 5 Recycling of hPG-HMPA (5) in the Allylation of Benzalde-
hydea
Run
Conversion (%)b
Catalyst leachingc
1st
quant.
quant.
quant.
not detectable
not detectable
not detectable
2nd
3rd
a Reaction conditions: see experimental details,16 2 h, r.t.
b Determined by 1H NMR spectroscopy.
(12) (a) Sunder, A.; Mülhaupt, R.; Haag, R.; Frey, H. Adv. Mater.
2000, 12, 235. (b) Sunder, A.; Hanselmann, R.; Frey, H.;
Mülhaupt, R. Macromolecules 1999, 32, 4240.
c Determined by 31P NMR spectroscopy.
(13) Roller, S.; Zhou, H.; Haag, R. Mol. Diversity 2005, 9, 305.
(14) (a) Haag, R.; Sunder, A.; Hebel, A.; Roller, S. J. Comb.
Chem. 2002, 4112. (b) Hebel, A.; Haag, R. J. Org. Chem.
2002, 67, 9452.
(15) (a) Hajji, C.; Roller, S.; Beigi, M.; Liese, A.; Haag, R. Adv.
Synth. Catal. 2006, 348, 1760. (b) Beigi, M.; Haag, R.;
Liese, A. Adv. Synth. Catal. 2008, 350, 919. (c) Beigi, M.;
Roller, S.; Haag, R.; Lieses, A. Eur. J. Org. Chem. 2008,
2135.
(16) All experiments were carried out under an argon atmosphere
using dried glassware. Chemicals were purchased from
commercial suppliers and used as received unless otherwise
noted. Benzaldehyde was freshly distilled prior to use. Dry
CH2Cl2 was purchased from Sigma-Aldrich and dried via a
Solvent Purification System MB-SPS 800 from MBraun.
Column chromatography was performed on Merck Silica
Gel 60 (230–400 mesh). Ultrafiltration was performed with
a 300 mL solvent-resistant stirred cell with regenerated
cellulose membranes (molecular weight cut-off 5000 g mol–1),
both from Millipore. 1H, 13C and 31P NMR spectra were
recorded at room temperature using a Jeol ECX 400 and
Bruker AV 700. 2D spectra were recorded on a Jeol Eclipse
500. Chemical shifts (δ) were reported in parts per million
(ppm) relative to tetramethylsilane and coupling constants
(J) in hertz (Hz). The spectra were referenced against the
internal solvent (CDCl3, δ 1H = 7.26 ppm, 13C = 77.0 ppm).
O-Mesylpolyglycerol was synthesized according to the
literature procedure.13
trichlorosilyl-based transformations. In the aldol reaction
we could show that highly active catalyst 4 dramatically
enhanced the reaction rate and the selectivities.
In the allylation reaction, we could lower the catalyst ratio
to 0.5 mol% (for 5), yielding almost quantitative yield,
while HMPA (6) did not show significant conversion
(<2%) at this level of catalyst concentration. By lowering
the catalyst ratio and comparing with the monomeric
HMPA (6) we could show a positive dendritic effect in the
allylation reaction.
Recycling of the catalyst 5 was successfully achieved
three times by membrane filtration without loss of its ac-
tivity. More synthetic work to develop chiral phosphor-
amides on hPG for a catalytic asymmetric version of this
reaction is currently in progress.
Acknowledgment
The authors thank Prof. Reissig for advice and Andre Niermann for
performing ketyl-aryl coupling reactions with supported HMPA as
promoter. We acknowledge Cathleen Schlesener for technical assi-
stance. Financial support by the Deutsche Forschungsgemeinschaft
(DFG) is gratefully acknowledged.
Polyglycerylmethylamine (2): O-Mesylpolyglycerol (4.4
g, 28.6 mmol mesyl groups) was dissolved in p.a. DMF (20
mL) in a 48 mL ACE pressure tube using ultrasonication. In
the next step, MeNH2 gas (15 mL) was condensed into the
tube and sealed afterwards. The mixture was stirred and
heated up to 60 °C for 24 h. For workup the mixture was
diluted with MeOH and filtered using a glass frit. The
dissolved crude product was further purified by ultrafiltration
with MeOH as solvent and Et3N (2 mL) as an additive in the
first run. After the third run the filtrate became colorless. The
solvent was evaporated and a brown honey-like product was
obtained. Yield: 95%, 8 mmol methylamine groups per gram
polymer; 1H NMR (400 MHz, CDCl3): δ = 3.87–3.16 (br m,
PG-backbone), 2.77–2.62 (m, functionalized PG groups),
2.42–2.17 (br m, NCH3); 13C NMR (100 MHz, CDCl3): δ =
78.6–68.7 (PG), 62.0–46.0 (functionalized PG groups);
43.0–34.0 (NHMe).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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Eur. J. Org. Chem. 2004, 2988.
PG-Hexamethylphosphoramide (4):
Polyglycerylmethylamine (2) (1 g, 8 mmol) was dissolved in
anhyd THF (20 mL) in a 50 mL Schlenk tube. The clear
yellow solution was cooled to –78 °C and after 30 min,
N,N,N′,N′-tetramethylphosphorodiamidic chloride (8 mmol,
1.2 mL) was added dropwise via syringe. The reaction was
warmed to r.t. overnight and then quenched by addition of
MeOH. The crude product was purified by ultrafiltration
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2672–2676

2676
F. Mummy, R. Haag
LETTER
(membrane: 5 kDa, solvent: MeOH). 1H NMR (400 MHz,
CDCl3): δ = 3.85–3.28 (br m, PG-backbone), 2.65–2.16 (br
m, NCH3); 31P NMR (121.5 MHz, CDCl3): δ = 26.0, 27.4
ppm. Loading: 1 mmol HMPA per gram polymer;
determined by addition of triphenylphosphine oxide as
internal standard, followed by integration in the 31P spectra.
General procedure for the catalyzed aldol reaction with
slow addition of aldehyde:2 The catalyst PG-HMPA (50
mg, 0.05 mmol, 0.1 equiv) was dissolved in CH2Cl2
purified by column chromatography (SiO2, CHCl3) and was
obtained as amixture of syn and anti products as a colorless
solid. Analytical data for syn/anti ratio 1:1: 1H NMR (400
MHz, CDCl3): δ = 7.35–7.22 (m, 10 H, 2 Ph), 5.38 (d, J = 2.5
Hz, 1 H, syn-PhCHOH), 4.78 (d, J = 8.8 Hz, 1 H, anti-
PhCHOH), 3.97 (s, 1 H, anti-OH), 3.06 (s, 1 H, syn-OH),
2.64–1.25 (m, 18 H, CHax + CHeq).
General procedure for the allylation reaction of
benzaldehyde with allyl trichlorosilane: To a solution of
PG-HMPA (2 mmol HMPA/g) (50 mg, 0.1 mmol, 10 mol%)
in 0.2 mL of CH2Cl2 under N2 at r.t. was added (i-Pr)2NEt
(0.5 mL), benzaldehyde (102 µL, 1.0 mmol, 1.0 equiv), and
allyl trichlorosilane (290 µL, 2.0 mmol, 2.0 equiv). The
resulting mixture was stirred for 1 h, before it was quenched
with 2.0 mL NH4Cl solution and 2.0 mL CH2C12 were
added. The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 10mL). The combined organic
layers were washed with brine and dried over MgSO4 and
the solvent was removed in vacuo. The crude product was
analyzed by 1H NMR. 1H NMR (400 MHz, CDCl3): δ =
7.36–7.28 (m, 5 H, HCaryl), 5.86–5.76 (m, 1 H, HC-3), 5.18–
5.13 (m, 2 H, H2C-4), 4.78 (dd, J = 7.3, 5.5, 1 H, HC-1),
2.57–2.45 (m, 1 H, HC-2), 2.05 (br s, 1 H, OH)..
(0.5 mL), and the solution was cooled to –78 °C. 1-
Cyclohexenyloxytrichlorosilane (100 µL, 0.55 mmol, 1.1
equiv) was added dropwise. A solution of benzaldehyde (50
µL, 0.5 mmol, 1.0 equiv) in CH2Cl2 (0.2 mL) was then added
dropwise to the first solution with the help of a syringe pump
(speed: 0.3 mL/h). During the addition the temperature
remained constant at –78 °C. The reaction mixture was
stirred at –78 °C for an additional 60 min and then quickly
poured into cold (2 °C) sat. aq NaHCO3 (2 mL). The mixture
was allowed to warm to r.t. The phases were separated, and
the aqueous phase was extracted with CH2Cl2 (2 × 10 mL).
The organic phases were combined, dried over MgSO4,
filtered, and concentrated in vacuo. The syn/anti ratio was
determined by 1H NMR (400 MHz). The crude product was
Synlett 2012, 23, 2672–2676
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