Copper-Catalyzed Asymmetric Allylic Alkylation of β-Keto Esters with Allylic Alcohols

Article abstract of DOI:10.1002/adsc.201601139

The asymmetric allylic alkylation reaction of β-keto esters catalyzed by copper complex tBuBOX-Cu(OTf)₂ employing allylic alcohols as environmentally friendly electrophilic partner, is herein described. This new protocol renders in general the

Full text of DOI:10.1002/adsc.201601139

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DOI: 10.1002/adsc.201601139
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Copper-Catalyzed Asymmetric Allylic Alkylation of b-Keto Esters
with Allylic Alcohols
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Paz Trilloa and Alejandro Baezaa,*
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Departamento de Quımica Organica, Facultad de Ciencias, and Instituto de Sıntesis Organica (ISO), Universidad de
Alicante, Apdo 99, 03080 Alicante, Spain
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Fax: +34 96 5903549
Phone: +34 96 5903549; e-mail: alex.baeza@ua.es
Received: October 17, 2016; Revised: January 20, 2017; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201601139
there are only a handful of works reported in the
literature on this respect being, most of them,
Abstract: The asymmetric allylic alkylation reac-
tion of b-keto esters catalyzed by copper complex
tBuBOX-Cu(OTf)2 employing allylic alcohols as
environmentally friendly electrophilic partner, is
herein described. This new protocol renders in
general the corresponding allylic products with two
consecutive all-carbon stereocenters in good both
yields and enantioselectivities and with low to
catalyzed by expensive transition-metal based catalytic
systems.[3–5] In addition, even scarcer is the use of
unsymmetrical 1,3-dicarbonyl compounds, such as b-
keto esters, which would render two consecutive all-
carbon stereocenters, as nucleophiles.[6]
Continuing with our investigations about the use of
p-activated alcohols, able to form stable carbocationic
intermediates, in asymmetric alkylation reactions
modest diastereoselection. The regioselectivity of
the process seems to be governed by the formation
through an SN1-type process,[7–9] we decided to inves-
of the most stable olefin according to the results
tigate the copper(II) catalyzed asymmetric alkylation
of b-keto esters employing allylic alcohols as alkylat-
obtained when non-symmetrically substituted alco-
hols were employed. The scope, limitations and
mechanistic aspects of the process are also dis-
cussed.
ing agents (Scheme 1). The results of this study are
herein disclosed.[10]
Keywords: Asymmetric Allylic Alkylation; Allylic
Alcohols; b-Keto esters; Copper; Bisoxazolines
40 The catalytic asymmetric allylic substitution reaction
41 is a well-established and widespread methodology
42 successfully employed in organic synthesis, which
43 allows the introduction of a vast amount of different
44 nucleophiles in an enantioselective fashion and the
45 creation of new chiral allylic entities containing at
46 least one stereogenic center.[1]
Scheme 1. Alkylation of b-keto esters with activated alco-
hols.
47
In the last decade, great efforts have been con-
48 ducted on this important transformation in order to
49 replace the traditionally employed alcohol derivatives
50 (such as carbonates, acetates, phosphates…) as sub-
51 strates, for the more readily available and environ-
As starting point, we decided to look for the
52 mentally friendly allylic alcohols.[2] However, despite optimal reaction conditions by checking the reaction
53 the enormous progresses already accomplished in the between (E)-1,3-diphenylprop-2-en-1-ol (1), which a
54 area, the asymmetric allylic alkylation reaction, also priori would give rise to a carbocationic intermediate
55 known as asymmetric Tsuji-Trost reaction, of 1,3- that possesses multiple resonance structures and hence
56 dicarbonyl compounds, employing such substrates is seemingly stable, and keto ester 3a using Cu(OTf)2 as
57 still undeveloped and, to the best of our knowledge, copper(II) salt. Based on our previous experience with
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the alkylation of such dicarbonyl compounds with considerable drop in both conversion and enantiose-
benzylic alcohols,[7] Box-type ligands L1–L3, toluene lectivity was obtained (Table 1, entry 7).
and low temperatures (À158C in this case) were the
Once the optimal reaction conditions were estab-
ligands, solvent and the temperature of choice respec- lished, different 1,3-keto esters were tested using
tively.[11] To our disappointment the reaction produced alcohol 2 as substrate (Table 2). As previously men-
the desired product but as racemic mixture when using tioned, 5a was obtained in good yields, poor diaster-
L1 and L2 (Table 1, entries 1 and 2). The reason of eoselection and high enantioselectivities in both
this behavior might be ascribed to the still high diastereomers (Table 2, entry 1). Lower yields, even
reactivity of the carbocationic intermediate (E= + when the reaction was carried out at 08C and using
10 2.70),[12,13] which apparently favors the racemic back- 15 mol% of catalyst loading, were obtained when keto
11 ground reaction catalyzed by the in situ generated ester 3b was tested. However, a quite good d.r. was
12 TfOH (see Scheme 2).[14] With this hypothesis in mind obtained (85/15) obtaining, additionally, an excellent
13 we decided to switch the allylic alcohol to (E)-1,3-bis 95% ee for the major diastereoisomer (Table 2,
14 (4-methoxyphenyl)prop-2-en-1-ol (2), which would entry 2). Attempts to further increase diastereo- and
15 give rise to a significantly more stable carbocationic enantioselectivities by introducing a bulky group, such
16 specie (E=À1.45).[12] By doing so, we were pleased to as tert-butyl, in both the keto (3c) and the ester
17 observe the formation of product 5a in high con- moiety (3d) turned out to be unsuccessful, since the
18 version and enantioselectivities, although with poor reaction failed at low temperatures. The correspond-
19 diastereoselectivity, as expected from a reaction in- ing products, 5c and 5d, were only obtained at room
20 volving a carbocationic intermediate, when tBuBOX temperature with poor or null enantioselection, albeit
21 (L1) was the ligand employed (Table 1, entry 3). good diastereoselectivity was observed in the former
22 Changing the ligand to PhBOX (L2) and iPrPyBOX case (Table 2, entries 3 and 4). Next, acyclic a-methyl
23 (L3) resulted in worsening results (Table 1, entries 4 substituted keto ester 3e, which would give rise to the
24 and 5). In addition, as somehow expected from our generation of an all carbon quaternary stereogenic
25 previous work, the reaction using L1 paired with Cu center was evaluated,[15] but the reaction failed under
26 (OAc)2 did not take place (Table 1, entry 6). Finally, optimized conditions. However, at 08C good diastereo
27 attempts to enhance the diastereomeric ratio by low- and enantioselectivities (75/25 and 74%/82% ee
28 ering temperature down to À508C were unfruitful respectively) were achieved although unfortunately
29 since in spite of a slight amelioration achieved, a with a modest 45% yield (Table 2, entry 5). Rising up
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the temperature to 258C increased significantly the
yield but, as expected, provoked an important detri-
ment in the d.r. and the ee of product 5e (Table 2,
entry 6). Next, cyclic keto esters were tested. Firstly,
six-membered substrate 3f was assayed, obtaining
product 5f in moderate yield and good enantioselec-
tivities for both diastereoisomer (Table 2, entry 7). To
our delight, the reaction afforded the allylation
product 5g in good yield and with an 85:15 diatereo-
meric ratio, reaching, in addition, high ee’s for both
diastereomers, 81% and 95%, respectively when 3g
was employed (Table 2, entry 8). In view of the good
results obtained with the cyclic keto esters, the more
sterically demanding benzocondensed analogs 3h and
3i were next tested. However, the reaction became
sluggish and only at room temperature the corre-
sponding products were obtained, but as racemic
mixtures in both cases (Table 2, entries 9 and 10).
Next, in order to expand the applicability of the
process we decided to evaluate other allylic alcohols
as alkylating agents in the reaction with keto ester 3a
(Table 3). Firstly, different open chained allylic alco-
hols possessing an electron donating group were
selected. Thus, when alcohol 6 was tested the corre-
sponding product 14a was only obtained in poor yield,
and low diastereo- and enantioselection, even when
the reaction was performed at 258C and using
15 mol% of catalyst loading (Table 2, entry 1). With
Table 1. Optimization of the reaction conditions.[a]
Entry L CuX
Product Conv. [%][b] d.r. [b] ee [%][c]
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7
L1 Cu(OTf)2
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85
80
92
85
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50/50
50/50
60/40 94/80
55/45 33/18
50/50 15/<10
rac.
rac.
L2 Cu(OTf)2
L1 Cu(OTf)2
L2 Cu(OTf)2
L3 Cu(OTf)2
L1 Cu(OAc)2
L1 Cu(OTf)2
<15
–
–
75[d]
65/35 85/76
[a] Unless otherwise specified, the reaction conditions were: 1
or 2 (0.15 mmol), 2a (0.225 mmol, 1.5 equiv.), Cu(OTf)2
(10 mol%) and ligand (12 mol%) in 1.5 mL of PhMe at
À158C.
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[b] Determined by H NMR of the crudes.
[c] Determined by HPLC using chiral column Daicel Chir-
alpak ADÀH (see supporting information for details).
[d] Reaction performed at À508C.
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Table 2. Reaction of 2 with different b-keto esters[a].
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[a] Unless otherwise specified, the reaction conditions were: 2 (0.15 mmol), 3 (0.225 mmol, 1.5 equiv.), Cu(OTf)2 (10 mol%)
and tBuBOX (12 mol%) in 1.5 mL of PhMe at À158C.
51 [b] Isolated yields after flash chromatography.
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[c] Determined by H NMR of the crudes.
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[d] Determined by HPLC using chiral columns (see supporting information for details).
[e] Reaction performed with of Cu(OTf)2 (15 mol%) and tBuBOX (17 mol%).
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[f] Not isolated, estimation of the crude yield from H NMR data.
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Table 3. Alkylation of 3a with different alcohol[a].
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[a] Unless otherwise specified, the reaction conditions were: alcohol (0.15 mmol), 3a (0.225 mmol, 1.5 equiv.), Cu(OTf)2
(10 mol%) and tBuBOX (12 mol%) in 1.5 mL of PhMe.
[b] Isolated yields after flash chromatography.
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[c] Determined by H NMR and/or GC of the crudes.
[d] Determined by HPLC using chiral columns (see supporting information for details).
[e] Reaction performed with of Cu(OTf)2 (15 mol%) and tBuBOX (17 mol%).
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[f] Not isolated, estimation of the crude yield from H NMR data.
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the aim of generating a more stable carbocationic most stable olefin.[16] Finally the SN1-type reaction
intermediate, the allylic alcohol 7 containing an extra would take place in a enantiospecific way onto the
methyl group was synthesized. The reaction of such planar carbocationic intermediate which would ex-
alcohol with keto ester 3a gave rise to the formation plain the low d.r. observed in most of the cases.[17]
of regioisomers, being the product 16a, which arise Regarding the stereochemistry of the new formed all-
from a double bond isomerisation, the major one. carbon stereogenic centers, and despite several trials
Unfortunately, this last product was obtained in a performed, we were not able to determine the
52:48 diastereomeric ratio and with low enantioselec- absolute configuration of these new synthesized prod-
tivities. By the contrary, a modest 46% ee was ucts. Nevertheless, R configuration at the center
10 observed for the minor regiosiomer 15a (Table 2, placed in the keto ester moiety could be assumed.
11 entry 2). Attempts to favour the formation of this last This hypothesis arise from the fact that the catalytic
12 regioisomer by lowering the temperature (08C) were complex and the b-keto esters employed in this work
13 unfruitful and under these conditions the yield are exactly the same as those employed in our
14 dropped considerably. On the other hand, as somehow previous work, in which the R-configured alkylated b-
15 expected, the enantioselectivity was increased up to keto ester products seemed to be obtained when
16 68% (Table 2, entry 3). Disappointingly, the use of xanthydrols were the alkylating agents.[7]
17 alcohol 8, which after dehydration would give rise to
18 the formation of a rather stable, although sterically
19 crowded, carbocationic intermediate (E= +0.98),[12]
20 gave rise to the corresponding product 17a as racemic
21 mixtures and only when 15 mol% of catalyst loading
22 and 258C were employed (Table 2, entry 4).
23
Next, since the results with acyclic allylic alcohols
24 were unsuccessful, we decided to evaluate the behav-
25 ior of allylic cyclic alcohols. We were pleased to
26 observe that, under optimized conditions, alcohol 10
27 produced the allylation product 20 as a sole regioisom-
28 er in high yield and diastereo- and enantioselectivity
29 (Table 3, entry 6). Encouraged by this result, alcohol
30 11 was then tested and, despite the fact of obtaining
31 high diastereo- and enantioselectivity for compound
32 21, low yields were obtained even when the reaction
33 was performed at room temperature (Table 3, entry 7).
34 As somehow expected the replacement of the phenyl
35 group by a methyl one caused the reaction failure
36 (Table 3, entry 8).
37
Concerning the regiochemical course of the proc-
38 ess, the results observed in the reaction of 3a with
39 alcohols 7, 10 and 11 (Table 3, entry 2, 3, 6 and 7)
40 clearly point towards a rearrangement of the allylic
41 alcohol. This isomerization, which has been previously
42 observed by us[9c,d] and other groups when using such
43 substrates in the presence of a Lewis or Brønsted
44 acid,[16] could take place before the reaction with the
Scheme 2. Proposed reaction mechanism.
In summary, in this work we have disclosed the
45 b-keto ester. Thus, the formation of the most energeti- application of the complex Cu(OTf)2-tBuBOX as
46 cally favorable olefin seems to govern the regiochem- catalyst for the asymmetric allylic alkylation of b-keto
47 istry of the reaction rather than the stability of the esters employing allylic alcohols as alkylating agents.
48 carbocationic intermediate.
Once the regiochemical outcome was established presented seems to be somehow narrow, this simple
Although the scope of the methodology herein
49
50 and assuming that an SN1-type reaction occurred, a and environmentally benign process avoids the use of
51 tentative mechanism was proposed as follows expensive transition metal complex and generates
52 (Scheme 2). Firstly, the catalytic system tBuBOX-Cu only water as by-product. By using this new protocol
53 (OTf)2 would coordinate the keto ester through the different keto esters were successfully alkylated,
54 enolate, hence liberating a substoichiometric amount generating two consecutive all carbon stereogenic
55 of TfOH which would be enough not only to form the centers. The best results, in terms of both yield and
56 corresponding carbocation but also to promote the enantioselectivity, were achieved in those cases where
57 alcohol isomerization towards the formation of the a stable carbocationic intermediate was formed. The
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e) M. Bandini, G. Cera, M. Chiarucci, Synthesis 2012,
44, 504; f) M. Bandini, Angew. Chem. 2011, 123, 1026;
Angew. Chem. Int. Ed. 2011, 50, 994. For selected recent
examples about the use of allylic alcohols in enantiose-
lective processes, see: e) M. A. Schafroth, G. Zuccarello,
S. Krautwald, D. Sarlah, E. M. Carreira, Angew. Chem.
2014, 126, 14118–14121; Angew. Chem. Int. Ed. 2014, 53,
13898–13091; f) D. Banerjee, K. Junge, M. Beller,
Angew. Chem. 2014, 126, 13265–13269; Angew. Chem.
Int. Ed. 2014, 53, 13049–13053; g) J. Y. Hamilton, N.
Hauser, D. Sarlah, E. M. Carreira, Angew. Chem. 2014,
126, 10935–10938; Angew. Chem. Int. Ed. 2014, 53,
10759–10762; h) X. Huo, G. Yang, D. Liu, Y. Liu, I. D.
Gridnev, W. Zhang, Angew. Chem. 2014, 126, 6894–
6898; Angew. Chem. Int. Ed. 2014, 53, 6776–6780; i) S.
Krautwald, M. A. Schafroth, D. Sarlah, E. M. Carreira,
J. Am. Chem. Soc. 2014, 136, 3020–3023; i) Y. Hamilton,
D. Sarlah, E. M. Carreira, J. Am. Chem. Soc. 2014, 136,
3006–3009; j) M. Zhuang, H. Du, Org. Biomol. Chem.
2014, 12, 4590–4593; k) A. Gualandi, L. Mengozzi,
C. M. Wilson, P. G. Cozzi, Synthesis 2014, 46, 1321; l) S.
Krautwald, D. Sarlah, M. A. Schafroth, E. M. Carreira,
Science 2013, 340, 1065–1068 and references cited there-
in.
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reaction mechanism seems to proceed through an SN1-
type reaction, which could explain the low diastereo-
selection observed in the majority of cases. In
addition, the results observed suggest an TfOH
catalyzed in situ isomerization of the alcohol towards
the most energetically stable olefin prior the reaction
to occur, thus governing the regioselectivity of the
process.
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Experimental Section
General procedure for the asymmetric allylic
alkylation of b-keto esters with allylic alcohols.
Onto an evacuated, oven-dried and septum-capped flask
containing But-BOX ligand (L1, 5.4 mg, 0.018 mmol,
12 mol%) and Cu(OTf)2 (5.4 mg, 0.015 mmol, 10 mol%)
under argon atmosphere, toluene (0.5 mL) was added. The
complex was stirred at 258C for 90 min. After this time, the
flask was placed in a cooling bath at the corresponding
temperature and stirred for 10 min. Then, b-keto ester
(0.21 mmol, 1.5 equiv.) was added and stirred for an addi-
tional 10 min. Next, a solution of the corresponding alcohol
(0.15 mmol) in toluene (1 mL) was finally added and the
reaction mixture stirred for 15 h. After this time, saturated
NH4Cl (3 mL) was added and the mixture extracted with
ethyl acetate (33 5 mL). The organic phases were dried
(MgSO4) and evaporated. The crudes were purified by flash
chromatography. NOTE: Slight to moderate racemization
was observed in some cases after flash chromatography was
carried out. In addition, the chiral adducts MUST be kept in
the freezer (À208C) to avoid racemization.
[3] For examples of transition metal catalyzed processes,
see: a) K. Miyata, M. Kitamura, Synthesis, 2012, 44,
2138–2146; b) K. Miyata, H. Kutsuna, S. Kawakami, M.
Kitamura, Angew. Chem. 2011, 123, 4745–4749; Angew.
Chem. Int. Ed. 2011, 50, 4649–4653; c) S. Reimann, T.
Mallat, A. Baiker, J. Catal. 2007, 252, 30–38.
[4] For an organocatalyzed process, see: P.-S. Wang, X.-L.
Zhou, L.-Z. Gong, Org. Lett. 2014, 16, 976–979.
[5] For a recent example of the combined used of metal
and organocatalysis, see: H. Zhou, L. Zhang, C. Xu, S.
Luo, Angew. Chem. 2015, 127, 12836–12839; Angew.
Chem. Int. Ed. 2015, 54, 12645–12648.
[6] For a previous study from our group using an organo-
catalytic approach, see: P. Trillo, A. Baeza, C. Nꢁjera,
Synthesis 2014, 46, 3399–3407.
Acknowledgements
University of Alicante (VIGROB-173, GRE12-03), and
´
Spanish Ministerio de Economıa
y
Competitividad
(CTQ2015-66624-P) are gratefully acknowledged for financial
support (Project).
[7] P. Trillo, A. Baeza, C. Nꢁjera, Adv. Synth. Catal. 2013,
355, 2815–2821.
[8] For recent reviews about racemic SN1-type reaction with
alcohols, see: a) A. Baeza, C. Nꢁjera, Synthesis, 2014,
46, 25–34; b) E. Emer, R. Sinisi, M. Guiteras-Capdevila,
D. Petruzzielo, F. De Vicentiis, P. G. Cozzi, Eur. J. Org.
Chem. 2011, 647–666.
[9] For contributions from our group about allylic substitu-
tion using alcohols through SN1-type reactions, see:
a) A. Grau, A. Baeza, E. Serrano, J. Garcꢂa-Martꢂnez,
C. Nꢁjera, ChemCatChem 2015, 7, 87–93; b) P. Trillo, A.
Baeza, C. Nꢁjera, ChemCatChem. 2013, 5, 1538–1542;
c) P. Trillo, A. Baeza, C. Nꢁjera, J. Org. Chem. 2012, 77,
7344–7354; d) P. Trillo, A. Baeza, C. Nꢁjera, Eur. J. Org.
Chem. 2012, 2929–2934; e) X. Giner, P. Trillo, C. Nꢁjera,
J. Organomet. Chem, 2010, 696, 357–361.
[10] The copper-catalyzed asymmetric allylic alkylation of b-
keto esters employing allylic alcohols has been previ-
ously reported but using 2 equiv. of BF3·Et2O and CsI in
order to convert the hydroxyl group in the correspond-
ing iodide: Q.-H. Deng, H. Wadepohl, L. H. Gade, J.
Am. Chem. Soc. 2012, 134, 2946–2949.
References
[1] For selected examples of recent reviews on this subject,
see: a) Transition Metal Catalyzed Enantioselective
Allylic Substitution in Organic Synthesis, Vol. 38 (Ed.:
U. Kazmaier), Chemistry; Springer: Heidelberg, 2012;
b) B. M. Trost, Org. Process. Res. Dev. 2012, 16, 185–
194; c) G. Helmchen, U. Kazmaier, S. Fçster in Catalytic
Asymmetric Synthesis, 3rd ed., (Ed.: I. Ojima), Wiley:
Hoboken, NJ, 2010, pp. 497–642 and references cited
therein.
[2] For recent reviews about the use of allylic alcohols in
enantioselective processes, see: a) M. Dryzhakov, E.
Richmond, J. Moran, Synthesis 2016, 48, 935–959; b) A.
Gualandi, L. Mengozzi, C. M. Wilson, P. G. Cozzi
Chem. Asian J. 2014, 9, 984; c) B. Sundararaju, M.
Achard, C. Bruneau, Chem. Soc. Rev. 2012, 41, 4467,
4483; d) M. Chiarucci, M. di Lillo, A. Romaniello, P. G.
Cozzi, G. Cera, M. Bandini, Chem. Sci. 2012, 3, 2859;
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[11] Binap and phosphoramidites were also essayed, but no
reaction, or if so racemic mixtures, were obtained.
[12] The E values (electrophilicity parameters in Mayrꢃs
scale) are related with carbocation stability and hence
with the reactivity. Thus, lower E value implies higher
stability and lower reactivity. E (1+)= +2.70; E (2+)
=À1.45; E (8+)= +0.98. Extracted from: a) K. Trosh-
in, C. Shindele, H. Mayr, J. Org. Chem. 2011, 76, 9391–
9408; b) H. Mayr, B. Kempf, A. R. Ofial, Acc. Chem.
Res. 2003, 36, 66–77; c) However, the reactivity–selec-
tivity principle should not be taken as a general rule
and must be regarded with care. For a comprehensive
analysis of polar organic reactivity, see: H. Mayr,
Tetrahedron 2015, 71, 5095–5111.
[13] For selected reviews about electrophilicity and reactiv-
ity of stabilized carbocations, for example see: a) P. G.
Cozzi, F. Benfatti, Angew. Chem. 2010, 122, 264–267;
Angew. Chem. Int. Ed. 2010, 49, 256; b) H. Mayr, A. R.
Ofial, J. Phys. Org. Chem. 2008, 21, 584–595; c) H.
Mayr, A. R. Ofial, Pure Appl. Chem. 2005, 77, 1807–
1821.
metals, for example, see: a) Y. Liu, H. Hu, H. Zheng, Y.
Xia, X. Liu, L. Lin, X. Feng, Angew. Chem. 2014, 126,
11763–11766; Angew. Chem. Int. Ed. 2014, 53, 11579–
11582; b) H.-G. Chen, B. Feng, L.-Y. Chen, W. Guo, X.-
Y. Yu, L.-Q. Lu, J.-R. Chen, W.-J. Xiao, Chem.
Commun. 2014, 50, 2873-2875. c) W.-B. Liu, C. M.
Reeves, B. M. Stoltz, J. Am. Chem. Soc. 2013, 135,
17298–17301; d) W.-B. Liu, C. M. Reeves, S. C. Virgil,
B. M. Stoltz, J. Am. Chem. Soc. 2013, 135, 10626–10629;
e) M. Kawatsura, D. Ikeda, Y. Komatsu, K. Mitani, T.
Tanaka, J. Uenishi, Tetrahedron 2007, 63, 8815-8824.
[16] For recent examples of Brønsted or Lewis acid
catalyzed rearrangement of allylic alcohols, see: a) P.-F.
Li, H.-L. Wang, J. Qu, J. Org. Chem. 2014, 79, 3955–
3962; b) J. Li, C. Tan, J. Gong, Z. Yang, Org. Lett. 2014,
16, 5370–5273; c) K. Chen, H. J. Chen, J. Wong, J. Yang,
S. A. Pullarkat, ChemCatChem 2013, 5, 3882–3888;
d) J. A. McCubbin, S. Voth, O. V. Krokhin, J. Org.
Chem. 2011, 76, 8537–8542; e) H. Zheng, M. Lejkowski,
D. G. Hall, Chem. Sci. 2011, 2, 1305–1310.
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[17] Based on experimental evidences a similar catalytic
system was previously postulated by us for the alkyla-
tion of b-keto esters with xanthydrols (see ref. 7) and
also by the group of Nishibayashi for the Cu(OTf)2-
BOX alkylation of b-keto phosphonates with benzylic
alcohols: M. Shibata, M. Ikeda, K. Motoyama, Y.
Miyake, Y. Nishibayashi, Chem. Commun. 2012, 48,
9528–9530.
[14] Our group (see ref. 9d) have reported the TfOH
catalyzed alkylation of different 1,3-dicarbonyl com-
pounds using allylic alcohol 1. For the use of other
different Brønsted acids for the same reaction see ref. 8.
[15] The construction of all-carbon consecutive quaternary
and tertiary stereocenters still remain a difficult task
and usually requires the use of expensive transition
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