Flexible stereoselective functionalizations of ketones through umpolung with hypervalent iodine reagents

Article abstract of DOI:10.1002/anie.201400405

The functionalization of carbonyl compounds in the α-position has gathered much attention as a synthetic route because of the wide biological importance of such products. Through polarity reversal, or "umpolung", we show here that typical nucleophiles, such as oxygen, nitrogen, and even carbon nucleophiles, can be used for addition reactions after tethering them to enol ethers. Our findings allow novel retrosynthetic planning and rapid assembly of structures previously accessible only by multistep sequences. A Nu approach: An efficient α-functionalization of ketones with a range of simple and useful nucleophiles is possible by using hypervalent iodine reagents (see scheme; Nu′ can be the Nu itself or a protected form of this nucleophile group).

Full text of DOI:10.1002/anie.201400405

Angewandte
Chemie
DOI: 10.1002/anie.201400405
Umpolung
Flexible Stereoselective Functionalizations of Ketones through
Umpolung with Hypervalent Iodine Reagents**
Pushpak Mizar and Thomas Wirth*
Abstract: The functionalization of carbonyl compounds in the
a-position has gathered much attention as a synthetic route
because of the wide biological importance of such products.
Through polarity reversal, or “umpolung”, we show here that
typical nucleophiles, such as oxygen, nitrogen, and even carbon
nucleophiles, can be used for addition reactions after tethering
them to enol ethers. Our findings allow novel retrosynthetic
planning and rapid assembly of structures previously acces-
sible only by multistep sequences.
R
eactions of carbonyl compounds are among the most
exploited transformations in chemistry. Apart from direct
Scheme 1. Nucleophilic addition to enolates with reversed polarity.
=
E+ =electrophile; NuÀ =nucleophile; IIII =iodine(III) reagent; Y,
Z=substituents.
reactions of the C O moiety, their facile deprotonation at the
adjacent carbon atom (a-position) makes enolates and their
derivatives such as silyl enol ethers easily accessible. They are
used almost exclusively as versatile nucleophiles for reactions
with alkyl, aryl, or heteroatom electrophiles to achieve
functionalizations in the a-position.[1] Polarity inversions are
alternative, much less developed, approaches for the synthesis
of otherwise difficult to access target molecules. The develop-
ment of a flexible method for the a-functionalization of
ketones with a range of nucleophilic coupling partners would
provide a very useful alternative. We make use of the high
electrophilicity as well as the high nucleofugality of hyper-
valent iodine reagents for the umpolung[2] of silyl enol ethers,
thereby allowing a range of nucleophiles to react in a clean
transformation (Scheme 1).[3] The ability to generate novel
stereogenic centers in such a process is also highly promising.
The synthetic advantage of adding nucleophiles to the a-
position of carbonyl compounds through umpolung reactions
has also been utilized in various other strategies.[4] This is
exemplified by organocatalytic formation of enamines with
aldehydes[5] and ketones[6] through activation with phos-
phates[7] or by electrochemical reactions.[8] Stepwise methods
by initial introduction of a leaving group in the a-position
followed by nucleophilic displacement have also been used to
access the substituted derivatives.[9]
Synthetic transformations mediated by hypervalent iodine
have received growing attention in recent years.[10,11] This is
not surprising, considering that these reagents are polyvalent
electrophiles[12] and mild oxidants. They are a good alter-
native to the toxic transition metals often used to effect
similar transformations and have already been used to
perform a-functionalizations of ketones.[13,14] Hypervalent
iodine moieties are sometimes referred to as hypernucleo-
fuges, because of their high dissociation rates compared to
standard leaving groups such as triflates.[15] To facilitate such
reactions further, we have introduced tethers between the
nucleophile and the enol ether. Temporary tethers have long
been used to switch intermolecular reactions to intramolec-
ular ones and thereby take advantage of the high degrees of
regio- and stereocontrol arising from the less flexible
transition states.
By using this strategy it is also possible to synthesize
acyclic molecules by tethering the reactants and removing the
linker group after the intramolecular reaction. Silicon is
a popular choice when considering temporary tethers to link
two reaction components.[16] This popularity is due to several
factors, mainly because the acyclic silicon derivatives are
facile to synthesize through the formation of either silyl ethers
or acetals containing a wide range of functionalities. Addi-
tionally, the silicon tether remains inert in most reactions and
can be easily and selectively removed after the reaction by
either aqueous work-up or treatment with tetrabutylammo-
nium fluoride. Thus, it is often referred to as being a “traceless
silicon tether”.[17]
[*] Dr. P. Mizar, Prof. Dr. T. Wirth
School of Chemistry, Cardiff University
Park Place, Main Building, Cardiff CF10 3AT (UK)
E-mail: wirth@cf.ac.uk
Homepage: http://www.cf.ac.uk/chemy/wirth
[**] This project was supported by an EU Marie Curie fellowship to P.M.
(DIALMEC, No. 298642). Support from the School of Chemistry,
Cardiff University is also gratefully acknowledged. We thank the
EPSRC National Mass Spectrometry Facility, Swansea, for mass
spectrometric data.
For initial studies, compound 1a (R = Ph, Nu = NEt2) was
treated with different hypervalent iodine reagents in the
presence or absence of activating Lewis acids to yield the
corresponding a-aminated product 2a, with the tethered silyl
moiety cleaved during the work-up. As shown in Table 1
Supporting information for this article (all synthetic methods
including spectroscopic and analytical data) is available on the
WWW under http://dx.doi.org/10.1002/anie.201400405.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Table 1: Optimization of reaction conditions.
(entries 2–6), the reaction proceeds much faster in the
presence of a Lewis acid through activation of the iodine
reagent, but the yields decreased substantially. The use of
iodine triacetate[18] (Table 1, entry 7) allows a fast work-up
without the necessity to remove iodobenzene, but using this
highly reactive reagent results in the acetate also reacting as
a nucleophile to produce 8a as a side product. The reaction
with (diacetoxyiodo)benzene [PhI(OAc)2] as the reagent
proceeds very smoothly at room temperature without the
necessity of any Lewis acid to yield 2a in up to 94% yield
(Table 1, entry 8). A one-pot procedure for this sequence has
also been developed.
We then examined the scope of the carbon–nitrogen bond
formation under the established reaction conditions. As
shown in Table 1, many nitrogen-containing dimethylsilyl
enol ethers were prepared, which all participated in a straight-
forward manner in the amination reaction, thereby furnishing
the corresponding amines with high efficiency. The method is
very efficient with aromatic, aliphatic, and cyclic ketones, and
the a-aminated products 2 are obtained in good yields. The
nature of the substituents has almost no effect on the overall
course of the reaction. Electron-rich aromatic substituents
(2 f) are tolerated as well as elec-
Entry
Reagent(s)
Solvent
2a
yield [%]
1
2
3
4
5
6
7
8
PhI(OCOCF3)2
MeCN
MeCN
MeCN
MeCN[a]
69
PhI(OCOCF3)2, TMSOTf
PhI(OCOCF3)2, BF3·OEt2
PhI(OAc)2, BF3·OEt2
PhI(OAc)2, BF3·OEt2
PhI(OAc)2, BF3·OEt2
I(OAc)3
<10
<5
20
[a]
CH2Cl2
70
CH2Cl2
CH2Cl2
CH2Cl2
45
57[b]
94
PhI(OAc)2
[a] Reaction performed at 08C. [b] In addition to 2a, compound 8a is
formed in 23% yield.
The method also allowed carbon–carbon coupling reac-
tions by using an enolate as the nucleophile and as the
electrophile in the same reaction, thus providing direct access
tron-poor substituents (2r). Al-
Table 2: Reaction of enol ethers 1 with nitrogen and oxygen nucleophiles.
though the thermodynamic control
of enolate formation allows the
selective synthesis of 2n, a kinetic
control of the enolate formation
could deliver the amino functional-
ity at the ring carbon atom.
The method was extended to
the synthesis of secondary amines
3, primary amines 4, and also
towards alcohols 5, ethers 6 and 7,
and esters 8 by using other suitable
nucleophiles on the tethered linker
(Table 2). The yields in the synthesis
of secondary amines 3 on using tosyl
amide as the nucleophile were low
but increased to good levels when
the tosyl amide was protected with
a trimethylsilyl moiety. A bis(trime-
thylsilyl)amine moiety tethered to
the silicon atom was used as the
nucleophile for the direct synthesis
of primary amines 4. The trimethyl-
silyl groups are cleaved during
work-up, thereby leading directly
to the unprotected a-aminoketones
4 as products. To ensure complete
and fast cleavage, the work-up
is carried out with one equivalent
of tetrabutylammonium fluoride
(TBAF). Aliphatic ketones also
show good yields with various
oxygen nucleophiles to furnish free
alcohols 5, ethers 6 and 7, or with
the oxygen atom protected as an
ester (acetate) in 8.
[a] Synthesis of compounds 2, 7, 8: CH2Cl2; 3–6: CH2Cl2/CH3CN 1:1.
2
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
Table 3: Synthesis of 1,4-diketones 10.
to highly versatile 1,4-dicarbonyl derivatives. This process was
initially reported in 1935[19] and since that time also used
frequently in stereoselective reactions,[20] but almost exclu-
sively involving metal enolates. A major limitation lies with
the lack of methods that allow for the selective and controlled
coupling of enolates under metal-free conditions and only
a few reactions describe the dimerization of trimethylsilyl
enol ethers to form 1,4-diketones.[21–24] We have expanded the
use of bis(silyl enol ethers) 9[25,26] to coupling reactions for the
easy synthesis of aliphatic and bicyclic 1,4-diketones
(Scheme 2). The 1,4-diketones 10 are obtained in good
Entry
Product
R
Yield [%]
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10 f
10g
10h
Me
tBu
Ph
4-MeOC6H4
2-BrC6H4
–
–
–
75
79
89
82
78
85[a]
82[a]
80[a]
[a] The meso isomer is formed in about 5% yield.
Table 4: Optimization of the enantioselective reaction to 2i.
Scheme 2. Coupling of bis(enol ethers) 9 to 1,4-diketones 10.
yields after the necessary activation of the hypervalent
iodine reagent with boron trifluoride etherate. The reaction
was sluggish when the reagent was not activated with boron
trifluoride etherate. In the case of cyclic precursors, the
coupled products (10 f–10h) are produced as racemates with
the meso isomers as minor side products (ca. 5%). New
stereogenic centers can be generated in reactions with cyclic
or substituted enol ethers.
Chiral lactate-based hypervalent iodine reagents devel-
oped by the research groups of Fujita[27] and Ishihara[28] have
recently been used for highly efficient diaminations,[29,30]
aminofluorinations,[31] aminohydroxylations,[32] and rear-
rangement reactions.[33] Although methods exist for stereose-
lective a-hydroxylations,[34] the direct and stereoselective
introduction of a simple amino moiety next to ketones would
allow novel synthetic strategies to build up important
structural features. We show that the chiral reagent 14,
which has been used for the stereoselective functionalization
of double bonds,[28–33] can be used for highly enantioselective
Entry
Reagent
Solvent/additives
T [8C]
2i
2i
ee [%]
yield [%]
1
2
3
4
5
6
7
8
9
11[28]
12[36]
13[27]
14[28]
14
14
14
14
14
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN, BF3·OEt2
CH2Cl2, BF3·OEt2
CH3CN, TMSOTf
CH2Cl2/CH3CN 1:1
CH2Cl2/CH3CN 1:1
CH2Cl2/CH3CN 1:1
25
25
25
25
21
35
30
45
24
40
trace
65
81
32
45
60
69
7
35
–
68
79
41
À48
25
À48
0
25
10
14
50
60
an additive in CH3CN/CH2Cl2 (1:1; Table 4, entry 9). Higher
or lower temperatures led to lower selectivities; the use of
a Lewis acid as an additive for the activation of the reagent
also strongly affected the selectivity (Table 4, entries 5–7).
Interestingly, carrying out the reaction at reaction temper-
atures between 08C and 508C (Table 4, entries 8–10) showed
the highest enantioselectivity to be obtained at room temper-
ature. The chiral reagent was used in stoichiometric amounts,
but the reduced aryl iodide can be recovered after the
reaction without loss of optical purity and can be reused.
The examples in Table 5 demonstrate that this approach is
superior to the classical substitution of a-halo ketones,[37] as
high stereoselectivities have not been reported in such
multistep approaches. A recent report used a-oxytosyl
ketones as oxyallyl cation precursors for reactions with
nucleophiles.[9] We show that not only secondary alcohols
and amines, but also chiral tertiary alcohol derivatives (5g,
5h, 8e, 8 f) and tertiary amines (4k, 4l) are accessible and
À
À
C O and C N bond formations when cyclic enol ethers 1 are
used as substrates. The stereoselective coupling of bisenol
ethers to form diketones 10 by employing chiral hypervalent
iodine reagents was also carried out (Table 3). However, the
enantiomers could not be separated.[35]
The direct and stereoselective synthesis of unprotected a-
hydroxyketones or a-aminoketones from enol ethers is highly
valuable as it allows the rapid generation of chiral building
blocks. Different chiral hypervalent iodine compounds and
various reaction conditions have been investigated in the
synthesis of 2i (Table 4). The screen of different reagents 11–
14 established 14 to be the most efficient chiral iodine(III)
compound. The highest selectivity was obtained when Ishi-
hara amide 14 was used at room temperature in the absence of
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Table 5: Stereoselective reactions of cyclic enol ethers 1 introducing
nitrogen and oxygen nucleophiles by using lactate-based hypervalent
iodine reagent 14. Yields are given in brackets.
using hypervalent iodine reagents. This provides rapid access
to nitrogen- and oxygen-substituted ketones in a simple
operation. Products, including amino acid derivatives, are
obtained with high stereoselectivities by using chiral hyper-
valent iodine reagents for the a-functionalization of ketones
in a transition-metal-free protocol.
Received: January 14, 2014
Revised: March 18, 2014
Published online: && &&, &&&&
Keywords: amination · hydroxylation · hypervalent iodine ·
.
stereoselective synthesis · umpolung
[1] J. Otera, Modern Carbonyl Chemistry, Wiley-VCH, Weinheim,
2000.
[2] D. Seebach, Angew. Chem. 1979, 91, 259 – 278; Angew. Chem.
Int. Ed. Engl. 1979, 18, 239 – 258.
[3] a) R. M. Moriarty, O. Prakash, M. P. Duncan, J. Chem. Soc.
Chem. Commun. 1985, 420; b) R. M. Moriarty, O. Prakash, M. P.
Duncan, R. K. Vaid, H. A. Musallam, J. Org. Chem. 1987, 52,
150 – 153; c) R. M. Moriarty, R. K. Vaid, V. T. Ravikumar, B. K.
Vaid, T. E. Hopkins, Tetrahedron 1988, 44, 1603 – 1607.
[4] O. Miyata, T. Miyoshi, M. Ueda, ARKIVOC 2013, ii, 60 – 81.
[5] V. Jha, N. B. Kondekar, P. Kumar, Org. Lett. 2010, 12, 2762 –
2765.
[6] T. Miyoshi, T. Miyakawa, M. Ueda, O. Miyata, Angew. Chem.
2011, 123, 958 – 961; Angew. Chem. Int. Ed. 2011, 50, 928 – 931.
[7] A. G. Smith, J. S. Johnson, Org. Lett. 2010, 12, 1784 – 1787.
[8] J. Mihelcic, K. D. Moeller, J. Am. Chem. Soc. 2003, 125, 36 – 37.
[9] M. N. Vander Wal, A. K. Dilger, D. W. C. MacMillan, Chem. Sci.
2013, 4, 3075 – 3079.
[10] “Hypervalent Iodine Chemistry”: Topics in Current Chemistry,
Vol. 224 (Ed.: T. Wirth), Springer, Berlin, 2003.
[11] V. V. Zhdankin, Hypervalent Iodine Chemistry, Wiley, Chiches-
ter, 2014.
obtained in good stereoselectivities (77–90% ee). Under the
same reaction conditions, b-keto esters permitted the syn-
thesis of cyclic amino acid derivatives 4m–4p in enantiose-
lectivities above 90%. Traditionally, such compounds are
synthesized by multistep sequences.[38] The absolute config-
uration of the reaction products was confirmed to be R in
every case by comparison with known compounds.[39] It is
therefore assumed that the chiral reagent 14 (Ishihara amide)
reacts preferentially from the Re face of the cyclic silyl enol
ether, thereby resulting in the R stereochemistry in all
reaction products shown in Table 5.
The method is very convenient for the synthesis of 2-
amino ketones under benign and extremely simple reaction
conditions. The hypervalent iodine reagent is added to
a solution of the substrate at room temperature. After
a short reaction time (2–4 h), the cleavage of the silyl linker
and protecting group proceeds during the work-up at room
temperature under almost neutral reaction conditions. The
removal of nitrogen protecting groups usually involves the
use of drastic reaction conditions or transition-metal cata-
lysts.[40,41] The products obtained with the method presented
herein are stable and can be obtained efficiently with or
without subsequent purification steps. Under the reaction
conditions shown here, it seems that a catalytic procedure
using a stoichiometric oxidant and catalytic amounts of
a chiral iodine(I) precursor is not feasible as it is known
that oxidants such as mCPBAwill directly react with silyl enol
ethers.[34]
[12] M. Brown, U. Farid, T. Wirth, Synlett 2013, 24, 424 – 431.
[13] For a recent review, see E. A. Merritt, B. Olofsson, Synthesis
2011, 517 – 538.
[14] For early studies, see a) a-oxytosylation: G. F. Koser, A. G.
Relenyi, A. N. Kalos, L. Rebrovic, R. H. Wettach, J. Org. Chem.
1982, 47, 2487 – 2489; b) a-hydroxylation: R. M. Moriarty, H.
Hu, S. C. Gupta, Tetrahedron Lett. 1981, 22, 1283 – 1286.
[15] M. Ochiai, Top. Curr. Chem. 2003, 224, 5 – 68.
[16] a) M. Bols, T. Skrydstrup, Chem. Rev. 1995, 95, 1253 – 1277;
b) L. R. Cox, S. V. Ley in Templated Organic Synthesis (Eds.: F.
Diederich, P. J. Stang), Wiley-VCH, Weinheim, 2000, pp. 275 –
395.
[17] a) J. F. Reichwein, S. T. Iacono, M. C. Patel, B. L. Pagenkopf,
Tetrahedron Lett. 2002, 43, 3739 – 3741; b) A. V. Gulevich, F. S.
Melkonyan, D. Sarkar, V. Gevorgyan, J. Am. Chem. Soc. 2012,
134, 5528 – 5531.
[18] R. C. Cambie, D. Chambers, P. S. Rutledge, P. D. Woodgate, J.
Chem. Soc. Perkin Trans. 1 1977, 95, 2231 – 2235.
[19] D. Ivanoff, A. Spassoff, Bull. Soc. Chim. Fr. 1935, 2, 76 – 78.
[20] A. G. Csꢀkꢁ, J. Plumet, Chem. Soc. Rev. 2001, 30, 313 – 320.
[21] R. Moriarty, O. Prakash, M. P. Duncan, J. Chem. Soc. Perkin
Trans. 1 1987, 559 – 561.
[22] a) V. V. Zhdankin, M. Mullikin, R. Tykwinski, B. Berglund, R.
Caple, N. S. Zefirov, A. S. Kozꢂmin, J. Org. Chem. 1989, 54,
2605 – 2608; b) V. V. Zhdankin, R. Tykwinski, B. Berglund, M.
Mullikin, R. Caple, N. S. Zefirov, A. S. Kozꢂmin, J. Org. Chem.
1989, 54, 2609 – 2612.
In summary, we present a novel and broadly applicable
strategy for the a-functionalization of carbonyl derivatives
[23] H.-Y. Jang, J.-B. Hong, D. W. C. MacMillan, J. Am. Chem. Soc.
2007, 129, 7004 – 7005.
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
[24] T. D. Beeson, A. Mastracchio, J.-B. Hong, K. Ashton, D. W. C.
MacMillan, Science 2007, 316, 582 – 585.
[25] M. Schmittel, A. Burghart, W. Malisch, J. Reising, R. Sçllner, J.
Org. Chem. 1998, 63, 396 – 400.
[26] M. D. Clift, C. N. Taylor, R. J. Thomson, Org. Lett. 2007, 9, 4667 –
4669.
[27] M. Fujita, Y. Yoshida, K. Miyata, A. Wakisaka, T. Sugimura,
Angew. Chem. 2010, 122, 7222 – 7225; Angew. Chem. Int. Ed.
2010, 49, 7068 – 7071.
[33] U. Farid, F. Malmedy, R. Claveau, L. Albers, T. Wirth, Angew.
Chem. 2013, 125, 7156 – 7160; Angew. Chem. Int. Ed. 2013, 52,
7018 – 7022.
[34] B.-C. Chen, P. Zhou, F. A. Davies, E. Ciganek, Org. React. 2003,
62, 1 – 356.
[35] In preliminary experiments we found that the product 10 f
obtained using chiral reagent 14 showed optical rotation.
[36] U. H. Hirt, M. F. H. Schuster, A. N. French, O. G. Wiest, T.
Wirth, Eur. J. Org. Chem. 2001, 1569 – 1579.
[28] M. Uyanik, T. Yasui, K. Ishihara, Angew. Chem. 2010, 122, 2221 –
2223; Angew. Chem. Int. Ed. 2010, 49, 2175 – 2177.
[29] C. Rçben, J. A. Souto, Y. Gonzꢀlez, A. Lishchynskyi, K. MuÇiz,
Angew. Chem. 2011, 123, 9650 – 9654; Angew. Chem. Int. Ed.
2011, 50, 9478 – 9482.
[37] M. Marigo, S. Bachmann, N. Halland, A. Braunton, K. A.
Jørgensen, Angew. Chem. 2004, 116, 5623 – 5626; Angew. Chem.
Int. Ed. 2004, 43, 5507 – 5510.
[38] K. Shibatomi, Y. Soga, A. Narayama, I. Fujisawa, S. Iwasa, J.
Am. Chem. Soc. 2012, 134, 9836 – 9838.
[30] J. A. Souto, C. Martꢃnez, I. Velilla, K. MuÇiz, Angew. Chem.
2013, 125, 1363 – 1367; Angew. Chem. Int. Ed. 2013, 52, 1324 –
1328.
[31] W. Kong, P. Feige, T. de Haro, C. Nevado, Angew. Chem. 2013,
125, 2529 – 2533; Angew. Chem. Int. Ed. 2013, 52, 2469 – 2473.
[32] U. Farid, T. Wirth, Angew. Chem. 2012, 124, 3518 – 3522; Angew.
Chem. Int. Ed. 2012, 51, 3462 – 3465.
[39] Compounds 4i, 4o, 4p, 5d–5h, 6d, and 8d are confirmed to have
R absolute configuration.
[40] T. Miura, T. Biyajima, T. Fujii, M. Murakami, J. Am. Chem. Soc.
2012, 134, 194 – 196.
[41] T. Miura, M. Morimoto, M. Murakami, Org. Lett. 2012, 14,
5214 – 5217.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Umpolung
A Nu approach: An efficient a-function-
alization of ketones with a range of
simple and useful nucleophiles is possi-
ble by using hypervalent iodine reagents
(see scheme; Nu’ can be the Nu itself or
a protected form of this nucleophile
group).
P. Mizar, T. Wirth*
&&&& — &&&&
Flexible Stereoselective
Functionalizations of Ketones through
Umpolung with Hypervalent Iodine
Reagents
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!