Carbenoid insertions into benzylic C-H bonds with heterogeneous copper catalysts

Article abstract of DOI:10.1016/j.tet.2013.06.088

The copper complexes with bis(oxazoline) or azabis(oxazoline) ligands, once supported on laponite clay by electrostatic interactions, are able to catalyze the insertion of carbenoids in benzylic C-H bonds. In contrast with rhodium catalysts, they are more active with tertiary than with secondary bonds, through a similar mechanism as shown by Hammet correlation. Enantioselectivities are only moderate, with values up to 50% ee. The immobilized catalysts are partially recoverable and the best results are obtained in the case of reactions with high chemoselectivity.

Full text of DOI:10.1016/j.tet.2013.06.088

Tetrahedron 69 (2013) 7360e7364
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Carbenoid insertions into benzylic CeH bonds with heterogeneous
copper catalysts
*
ꢀ
ꢀ
~
ꢀ
Jose M. Fraile , Jose A. Mayoral, Ana Munoz, Jorge Santafe-Valero
ꢀ
ꢀ
Instituto de Síntesis Química y Catalisis Homogenea-ISQCH, CSIC-Universidad de Zaragoza, Pedro Cerbuna 12, E-50009 Zaragoza, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The copper complexes with bis(oxazoline) or azabis(oxazoline) ligands, once supported on laponite clay
by electrostatic interactions, are able to catalyze the insertion of carbenoids in benzylic CeH bonds. In
contrast with rhodium catalysts, they are more active with tertiary than with secondary bonds, through
a similar mechanism as shown by Hammet correlation. Enantioselectivities are only moderate, with
values up to 50% ee. The immobilized catalysts are partially recoverable and the best results are obtained
in the case of reactions with high chemoselectivity.
Received 19 February 2013
Received in revised form 14 June 2013
Accepted 20 June 2013
Available online 29 June 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Carbene insertion
Copper catalysts
Heterogeneous catalysis
Benzylic insertion
1. Introduction
enantioselectivities depending on the size of the formed cycle and
its substituents.8,9
The development of new synthetic methodologies for the
functionalization of CeH bonds is currently a subject of great in-
terest. The use of carbene insertion reactions is a well-established
methodology that provides new CeC bonds in a controllable
way.1 Intramolecular carbene insertions were first developed, using
dirhodium carboxylates as catalysts, whereas the usefulness of the
intermolecular version arrived with the use of donor/acceptor
diazocompounds.2 This discovery can be considered as a milestone
that changed the vision of the carbene insertion reactions as a tool
in the synthesis of compounds with a certain structural complexity.
Since then many examples of the reaction using dirhodium cata-
lysts have been described, in many cases using chiral carboxylates,
which lead to very high enantioselectivities.3
Nevertheless the use of other metals as catalysts for carbene
insertions is still rather scarce. Complexes of coinage metals (gold,
silver, and copper) have been described as useful catalysts for in-
sertions,4 even in the case of the poorly reactive methane mole-
cule.5 Copper remains as the most attractive catalyst for this kind of
reaction, given its availability and low price. In the enantioselective
version of the reaction the examples with copper catalysts are even
less abundant. The initial poor results obtained in the intra-
molecular CeH insertion of diazoesters6,7 have been only recently
Regarding copper catalyzed enantioselective intermolecular
reactions, carbene insertions into OeH bonds were firstly de-
scribed,10 whereas results were improved and extended to other
XeH bonds by using spiro-bis(oxazoline) ligands.11 After an early
attempt of enantioselective intermolecular insertion into CeH
bonds, with poor results,12 our group described for the first time
a successful intermolecular insertion into THF,13 extended to other
cyclic ethers with enantioselectivities from low to moderate
depending on the structure of the substrate.14 In fact a good part of
this moderate success is due to the use of complexes immobilized
by electrostatic interactions15 on a synthetic clay (laponite) able to
modulate not only the catalytic activity but also the stereochemical
course of the catalyzed reaction.16 Other approaches to heteroge-
neous catalysts, with or without chiral modification, have been also
attempted.17
In this paper we describe the extension of the same method-
ology to the carbene insertion reactions into benzylic CeH bonds,
using copper complexes with different bis(oxazoline) ligands
(Fig. 1) both in homogeneous phase and supported on laponite clay
by cationic exchange.
improved using
a-diazosulfones, leading from high to excellent
* Corresponding author. E-mail address: jmfraile@unizar.es (J.M. Fraile).
Fig. 1. Bis(oxazoline) (1) and azabis(oxazoline) (2) ligands used in this work.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.088

J.M. Fraile et al. / Tetrahedron 69 (2013) 7360e7364
7361
Table 1
2. Results and discussion
Results of the reaction between methyl phenyldiazoacetate (PDA) and benzylic
substrates (ethylbenzene and cumene)a
2.1. Preparation of the immobilized catalysts
Substrate
Et-benz.
Catalyst
T (ꢀC)
Yield (%)
threo/erythro
eeb (%)
Cu(OTf)2
2b-Cu(OTf)2
Rh2(OAc)4
Lap-Cu
50
50
50
50
50
65
80
50
65
80
50
65
65
65
65
65
65
65
80
65
65
65
80
65
50
50
1
1
n.d.
n.d.
72/28
73/27
83/17
81/19
77/23
81/19
83/17
83/17
83/17
d
d
Laponite was the support chosen for the preparation of the
immobilized catalysts. It is a synthetic clay with ideal formula
(Na0.5$nH2O)[(Mg5.5Li0.5)Si8(OH)4O20]. The magnesio-silicate plate-
lets (each platelet is composed by one octahedral MgO6 layer be-
n.d.
d
22
15
8
19
17
20
23
21
6
d
Lap-Cu1a
45
34
28
50
50
53
15
d
tween two tetrahedral SiO4 layers) are nanodiscs of around 0.03 mm
diameter, negatively charged due to the isomorphous substitution of
part of Mg by Li. The clay particles (tectoids) are piles of platelets with
compensating hydrated sodium cations in the interlamellar spaces
(side view in Fig. 2).18 The cationic exchange with the complex
L*Cu(OTf)2 takes place in a polar medium (methanol) able to dissolve
the leaving salt, NaOTf in this case. The bulkiness of the new cations
produces a certain degree of disorder in the final material (Fig. 2) as
well as some expansion in the interlayer space (detectable by a de-
crease in the intensity and a shift to lower angles of the 001 dif-
fraction peak in X-ray diffraction patterns of oriented samples19),
which confers a high degree of accessibility to the catalytic sites.
Lap-Cu2b
(Second run)
Cu(OTf)2
Cumene
3
1a-Cu(OTf)2
2b-Cu(OTf)2
Rh2(OAc)4
Lap-Cu
2
3
7
d
n.d.
n.d.
d
d
d
26
40
78
67
73
60
31
27
26
21d
37e,f
d
d
Lap-Cu1a
Lap-Cu1b
d
21
21
8
12
10
45
40
23
<10
50e
d
d
(Second run)
(Third run)
Lap-Cu2b
d
d
d
d
(Second run)
Rh2(S-DOSP)4
d
c
d
d
a
Substrate used as reaction solvent.
Enantioselectivity of the major diastereomer.
Ref. 21.
48% yield of dicyclopropanation product in the aromatic ring is also obtained.
Results in the reaction with pBrPDA.
24% yield of dicyclopropanation product in the aromatic ring is also obtained.
b
c
d
e
f
Fig. 2. Cationic exchange process (side view of the nanodiscs of laponite).
2.2. Reactions of cumene and ethylbenzene with phenyldiazo
acetate
The insertion into simple benzylic substrates, such as ethyl-
benzene and cumene, has shown some interesting features in the
Rh2(S-DOPS)4 catalyzed reaction. Ethylbenzene is more reactive
than cumene (5:1 ratio) with p-bromophenyldiazoacetate
(pBrPDA),20 presumably due to steric reasons. The lower reactivity
of cumene promotes the low chemoselectivity of insertion with
respect to the competitive double cyclopropanation in the aromatic
ring, with an insertion/cyclopropanation selectivity of 60/40 with
pBrPDA and 30/70 with phenyldiazoacetate (PDA).21 In parallel
with reactivity, enantioselectivity obtained with cumene is also
much lower (50% ee with pBrPDA and <10% ee with PDA) than
the excellent value obtained with ethylbenzene (86% ee with
pBrPDA20). In the case of copper catalysts, the most demanding
reactions with PDA were tested (Scheme 1), using each benzylic
substrate as reaction solvent, and the results are gathered in Table 1.
As can be seen, homogeneous copper catalysts lead to very poor
results at temperatures up to 65 ꢀC, with yields always lower than
5%. Rhodium acetate was tested for the sake of comparison, and
yield was much higher with ethylbenzene (22%), whereas reactivity
of cumene was much lower, as expected from previous results.20
Results were clearly better when heterogeneous catalysts were
used. First of all it is remarkable that cyclopropanation products
were not detected, so the chemoselectivity for insertion is com-
plete. The only by-products came from dimerization of the diazo-
compound. Yields in the range of 20e25% were obtained in the
reaction of ethylbenzene with 2b-Cu complex immobilized on
laponite between 50 and 80 ꢀC. Diastereoselectivity was always
over 80:20, similar or even higher than that obtained with Rh2(S-
DOSP)4 with pBrPDA.20 With regard to enantioselectivity it is al-
ways moderate, with values ranging 45e50% ee with both 1a and
2b ligands. The effect of temperature on enantioselectivity is
completely different in both cases, with a decrease at higher tem-
peratures, as expected, in the case of 1a, but constant enantiose-
lectivity up to 80 ꢀC, in the case of 2b. Unfortunately recovery is not
very efficient. Lap-Cu1a was analyzed after reactions with cumene
and ethylbenzene at 65 ꢀC. The analysis of the fresh catalyst
(0.23 mmol Cu/g, N/Cu ratio¼2.4, C/N ratio¼10.6) was in good
agreement with previous results.22 After reaction the amount of
copper was slightly reduced (0.19 mmol/g after cumene reaction,
0.22 mmol/g after ethylbenzene reaction), with a similar N/Cu ratio
(2.3 and 1.7, respectively) but much higher C/N ratio (around 19 in
both cases). This seems to indicate that deactivation is probably due
to poisoning, as it was observed in the analogous cyclopropanation
reactions,23 favoured by the formation of dimerization by-products
given the rather low chemoselectivity of the insertion reaction.
In contrast with Rh catalysts, cumene is more reactive than
ethylbenzene with heterogeneous copper catalysts. The competi-
tive reaction with Lap-Cu showed a ratio between cumene and
Scheme 1. Reactions of PDA with ethylbenzene and cumene.

7362
J.M. Fraile et al. / Tetrahedron 69 (2013) 7360e7364
ethylbenzene insertion products close to 2:1. At 65 ꢀC yields depend
on the ligand present in the catalyst, from 26% without ligand up to
78% with 1b. Enantioselectivity is also highly dependent on the
structure of the ligand, from 21% ee obtained with both bis(ox-
azolines) 1a and 1b, up to 45% ee reached with 2b, a value much
mechanism. Differences seem to indicate a more asynchronous
transition state in the cumene reactions, probably with a higher
charge development.
In view of that results, the reaction of pBrPDA with p-iso-
propylanisole (R¼OMe) was tested in petroleum ether as a solvent
(Table 2), instead of the own aromatic compound. Results in ho-
mogeneous phase were again very poor (ꢂ6% yield), in spite of the
higher reactivity of p-isopropylanisole. On the contrary, yields with
heterogeneous catalysts (35e40%) were similar or even better than
those obtained with cumene used as a solvent. The only exception
is Lap-Cu1b, which already led to very high yields with cumene.
Enantioselectivity also reached similar values, 20% ee with the
phenyl substituted ligand 1a and 35e40% ee with the isopropyl
substituted ligand 1b. In this case the catalysts was recovered and
reused, with similar results in the second cycle but an almost
complete deactivation in the third one. This effect has been at-
tributed to the irreversible adsorption of chelating by-products,
typically in reactions of diazocompounds with low chemo-
selectivity. Yield and enantioselectivity obtained with Lap-Cu1b are
comparable to the results described for the reaction of PDA with p-
isopropylanisole catalyzed by Rh2(S-DOSP)4, whereas the use of
Rh2(S-PTAD)4 leads to better yield but lower enantioselectivity.21
21
better than that described in the same reaction for Rh2(S-DOSP)4
and similar to that obtained with pBrPDA.20 The behaviour with
respect to recovery is slightly better than in the case of ethyl-
benzene, in agreement with the better chemoselectivity of this
reaction. Yields are kept almost constant in one or two recycles,
but in all cases enantioselectivity significantly drops. As expected
from the reactivity order, the primary benzylic position of
toluene was completely inactive to insertion, in contrast with Rh
catalysts.20,24,25
2.3. Reactions of p-substituted cumenes
Davies has described the positive effect of para substitution to
protect benzene ring,20,21,24 and at the same time electron donating
groups have shown to activate ethylbenzene.20 In view of that, the
effect of substitution has been studied in the case of cumene with
pBrPDA using heterogeneous copper catalysts (Scheme 2). First of
all the electronic effect on the reactivity was studied by competitive
reactions catalyzed by Lap-Cu1b. Cumenes substituted with donor
groups (R¼Me, OMe) were much more reactive than unsubstituted
cumene. The Hammet analysis (Fig. 3) shows a better correlation
Table 2
Results of the reaction between ethyl p-bromophenyldiazoacetate (pBrPDA) and p-
isopropylanisolea
with sþ (r2¼0.99) than with sp (r2¼0.87), with a
r
value of ꢁ1.55,
Catalyst
Yield (%)
% ee
indicating a certain development of a positive charge in the in-
sertion step. This result is analogous to that obtained with Rh cat-
Cu(OTf)2
Lap-Cu
1a-Cu(OTf)2
1b-Cu(OTf)2
Lap-Cu1a
5
36
6
d
d
alysts for ethylbenzene20
(r¼ꢁ1.27), pointing to a similar reaction
n.d.
n.d.
20
36
39
n.d.
48
11
4
41
35
36
4
48
81
Lap-Cu1b
(Second run)
(Third run)
Rh2(S-DOSP)4
Rh2(S-PTAD)4
b
b
a
In petroleum ether as a solvent, under reflux (68 ꢀC).
Result with PDA (Ref. 21) at 50 ꢀC.
b
2.4. Reaction of methyl p-bromophenyldiazoacetate with
benzyl methyl ether
In principle a secondary benzylic CeH bond in
a position of an
oxygen atom should be more reactive than the analogous bond in
ethylbenzene. Thus benzyl methyl ether was envisaged as a better
substrate for carbene insertion and it was made react with pBrPDA
in solution (Scheme 3).
Scheme 2. Reactions of pBrPDA and p-substituted cumenes.
The two diastereomers erythro-8 (like) and threo-8 (unlike) were
identified by comparison of their 1H NMR spectrum with that of
the analogous erythro and threo methyl 2,3-diphenyl-3-methoxy
propionate,26 and other related compounds.27 The higher cou-
pling constant in the CHeCH system (10.4 vs 9.6 Hz) and the higher
chemical shift of the methoxy group (3.22 vs 3.07 ppm) are in
Scheme 3. Reaction of pBrPDA and benzyl methyl ether.
Fig. 3. Hammet correlation in the reaction of pBrPDA and substituted cumenes.

J.M. Fraile et al. / Tetrahedron 69 (2013) 7360e7364
7363
agreement with the threo configuration. Moreover this identifica-
3. Conclusions
tion is also in agreement with the shielding effect of the aromatic
groups in the most stable antiperiplanar conformation (Fig. 4).28
As expected, yields were better than those obtained with eth-
ylbenzene as a solvent (Table 3). In fact, even the homogeneous
complex 1a-Cu(OTf)2 was able to promote the reaction, albeit with
low yield (20%). An important effect of the nature of the ligand was
observed, as the reaction did not take place with 1b-Cu(OTf)2.
Immobilization on laponite again significantly improves the che-
moselectivity of the process, leading to higher yields than the ho-
mogeneous catalysts, and nearly as good as Rh2(OAc)4. The same
ligand effect was present in the heterogeneous catalysts, with an
improvement from 31% yield with 1b to 87% yield with 1a.
Immobilization by electrostatic interactions improves the effi-
ciency of copper complexes with chiral bis(oxazoline) and azabi-
s(oxazoline) ligands for carbenoid insertions into benzylic CeH
bonds. Although the exact reasons are not clear, immobilized cat-
alysts may expose the catalytic sites to the reaction medium better
than the complexes, as these are insoluble in the non-polar me-
dium of the insertion reaction. Moreover, site isolation and mainly
the change of anion, from triflate to a bulkier non-coordinating
solid anion (in a similar way to the effect of BArF anion30), may
also play an important role in this improvement.
The reaction mechanism seems to be similar to that of the
rhodium catalyzed reactions, as shown by the Hammet correlation,
but the reactivity of tertiary versus secondary CeH bonds is the
opposite. Up to 78% yield can be reached with cumene, used as
reaction solvent, but the best enantioselectivity (45% ee) is ob-
tained with a less chemoselective catalyst. Slightly higher enan-
tioselectivity can be reached with ethylbenzene (50e53% ee) albeit
with lower yields. The most reactive substrate is benzyl methyl
ether (up to 87% yield with only 2:1 substrate/diazocompound
ratio), but low enantioselectivity is obtained, in contrast with cyclic
ethers, probably due to the high conformational freedom of this
substrate.
Fig. 4. Newman projections of unlike and like compounds of insertion of pBrPDA in
benzyl methyl ether.
To sum up, chiral heterogeneous copper catalysts can be highly
efficient for this kind of reactions, but new ligands have to be
designed to improve enantioselectivities.
Table 3
Results of the reaction between ethyl p-bromophenyldiazoacetate (pBrPDA) and
benzyl methyl ethera
4. Experimental section
4.1. General
Catalyst
Yield (%)
threo/erythro
eeb (%)
Lap-Cu
24
22
2
87
53
77
31
90
61/39
60/40
n.d.
68/32
68/32
70/30
68/32
57/43
d
1a-Cu(OTf)2
1b-Cu(OTf)2
Lap-Cu1a
(Second run)
(Third run)
Lap-Cu1b
26
n.d.
22
28
17
12
d
The preparation and characterization of the heterogeneous
copper catalysts have been described elsewhere.14
4.2. Carbene insertion in ethylbenzene and cumene
Rh2(OAc)4
a
In petroleum ether as a solvent, under reflux (68 ꢀC).
Enantioselectivity of the major diastereomer.
A suspension of dried heterogeneous catalyst (100 mg, around
0.02 mmol Cu) in anhydrous substrate (ethylbenzene or cumene,
10 mL) with n-decane (100 mg) as internal standard was heated at
the required temperature under an inert atmosphere. A solution of
methyl phenyldiazoacetate (176 mg, 1 mmol) in anhydrous sub-
strate (10 mL) was slowly added over 4 h with a syringe pump. Once
the addition had finished, the reaction mixture was stirred and
heated at the same temperature for 4 h. The catalyst was filtered off
and washed with anhydrous dichloromethane (5 mL). Yield and
diastereoselectivity were determined by GC and enantioselectiv-
ities were determined by HPLC. The catalyst was dried under vac-
uum and reused under the same conditions.
b
With regard to stereoselectivities, both diastereo- and enan-
tioselectivity were always low. The threo (unlike) diastereomer was
always slightly favoured over the like one, with diastereomeric
ratios in the range of 60/40 to 70/30. Values around 25% ee were
obtained with 1a as a ligand, both in solution and in solid phase.
Moreover, the catalyst Lap-Cu1a was recoverable at least twice, in
agreement with the higher chemoselectivity of this reaction. In this
case the catalyst Lap-Cu1b was analyzed after reaction, with similar
results to those of Lap-Cu1a (see above). The copper content was
only slightly lower than that of the fresh catalyst (0.19 vs
0.21 mmol/g), with similar N/Cu ratio (2.1 vs 2.3) and a significant
increase in the carbon content (C/N ratio 17.6 instead of the starting
7.7), pointing again to the poisoning with by-products.23
The insertion products were purified by flash chromatography
on silica using hexane/ethyl acetate or hexane/isopropanol mix-
tures as eluents. The two isomers of methyl 2,3-diphenylbutanoate
were identified according to the literature.31e33
These poor stereoselectivity results, mainly in comparison with
the higher enantioselectivity obtained with cyclic ethers,13,14 are
probably due to the lack of bulky groups in both reactants and to
the conformational freedom of the open chain ether. To the best of
our knowledge this reaction had not been described in the litera-
ture. The most similar example involves the reaction of PDA with
benzyl tert-butyldimethylsilyl ether, catalyzed by rhodium com-
plexes.29 In that case the typical Rh2(S-DOSP)4 catalyst led to high
yield (83%) and diastereoselectivity (95/5), but low enantiose-
lectivity (17% ee). Interestingly this and other Rh catalysts favoured
the syn (like) diastereomer. The bulkiness of the silyl group, in
contrast with the small size of the methyl one, may account for this
difference in diastereoselectivity.
4.2.1. Methyl erythro-2,3-diphenylbutanoate (erythro-3). 1H NMR
(400 MHz, CDCl3): 7.47e6.95 (m, 10H), 3.72 (d, 1H, J¼11.1 Hz), 3.46
(m, 1H), 3.37 (s, 3H), 1.02 (d, 3H, J¼7.0 Hz).
4.2.2. Methyl threo-2,3-diphenylbutanoate (threo-3). 1H NMR
(400 MHz, CDCl3): 7.47e6.95 (m, 10H), 3.71 (d, 1H, J¼11.1 Hz), 3.71
(s, 3H), 3.46 (m, 1H), 1.39 (d, 3H, J¼6.8 Hz).
4.2.3. Methyl 3-methyl-2,3-diphenylbutanoate (4).34 HRMS (ESI):
calculated (C18H20O2Na) 291.1355, found: 291.1318. 1H NMR
(400 MHz, CDCl3): 7.34e7.20 (m, 10H), 3.82 (s, 1H), 3.37 (s, 3H),
1,44 (s, 3H), 1,27 (s, 3H). 13C NMR (100 MHz, CDCl3): 173.0, 147.3,

7364
J.M. Fraile et al. / Tetrahedron 69 (2013) 7360e7364
135.6, 130.2, 128.0, 127.8, 127.3, 126.6, 126.2, 62.5, 51.4, 41.4, 26.5,
25.0.
erythro isomer (from a threo/erythro mixture): 1H NMR (400 MHz,
CDCl3): 7.91 (d, 2H, J¼8.8 Hz), 7.67 (d, 2H, J¼8.8 Hz), 7.36e7.23 (m,
5H), 4.69 (d, 1H, J¼9.6 Hz), 3.88 (m, 2H), 3.84 (d, 1H, J¼9.6 Hz), 3.07
(s, 3H), 0.96 (t, 3H, J¼7.2 Hz).
4.3. Competitive insertions
A suspension of dried Lap-Cu (60 mg, around 0.04 mmol Cu) in
a solution of the substrates (10 mmol each) in anhydrous petroleum
ether (10 mL) was heated under reflux (68 ꢀC) and under an inert
atmosphere. A solution ethyl p-bromophenyldiazoacetate (268 mg,
1 mmol) in petroleum ether (10 mL) was slowly added over 4 h with
a syringe pump. Once the addition had finished, the reaction
mixture was stirred and heated at the same temperature and the
reaction was monitored by GC-FID. The insertion products were
identified by GCeMS (m/z: ethyl 2-(4-bromophenyl)-3-methyl-3-
phenyl-butanoate (5) 360; ethyl 2-(4-bromophenyl)-3-methyl-3-
(4-methylphenyl)-butanoate (6) 374; ethyl 2-(4-bromophenyl)-3-
(4-methoxyphenyl)-3-methyl-butanoate (7) 390; in all cases the
isotopic distribution was in agreement with the molecular
formula).
Acknowledgements
This work was made possible by the generous financial support
of the Spanish ‘Ministerio de Economía y Competitividad’ (Project
CTQ2011-28124) and the ‘Diputacion General de Aragon’ (E11
Group co-financed by the European Regional Development Funds).
J.S.-V. is indebted to C.S.I.C. for a JAEpredoc grant.
ꢀ
ꢀ
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A suspension of dried heterogeneous catalyst (100 mg, around
0.02 mmol Cu) in a solution of the substrate (2 mmol) in anhydrous
petroleum ether (10 mL) with n-decane (100 mg) as internal
standard was heated under reflux (68 ꢀC) and under an inert at-
mosphere. A solution ethyl p-bromophenyldiazoacetate (268 mg,
1 mmol) in petroleum ether (10 mL) was slowly added over 4 h with
a syringe pump. Once the addition had finished, the reaction
mixture was stirred and heated at the same temperature for 4 h and
it was treated in the same way as described above.
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13. Fraile, J. M.; García, J. I.; Mayoral, J. A.; Roldan, M. Org. Lett. 2007, 9, 731.
14. Fraile, J. M.; Lopez-Ram-de-Viu, P.; Mayoral, J. A.; Roldan, M.; Santafe-Valero, J.
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Org. Biomol. Chem. 2011, 9, 6075.
15. Fraile, J. M.; García, J. I.; Mayoral, J. A. Chem. Rev. 2009, 109, 360.
16. Fraile, J. M.; García, J. I.; Herrerías, C. I.; Mayoral, J. A.; Pires, E. Chem. Soc. Rev.
2009, 38, 695.
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17. Fraile, J. M.; Mayoral, J. A.; Ravasio, N.; Roldan, M.; Sordelli, L.; Zaccheria, F. J.
The insertion products were purified by kugelrohr distillation to
eliminate the unreacted substrate, followed by flash chromatog-
raphy on silica.
Catal. 2011, 281, 273.
18. Cool, P.; Vansant, E. F. Microporous Mater. 1996, 6, 27.
19. Fraile, J. M.; García, J. I.; Harmer, M. A.; Herrerías, C. I.; Mayoral, J. A.; Reiser, O.;
Werner, H. J. Mater. Chem. 2002, 12, 3290.
20. Davies, H. M. L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org. Chem. 2002, 67, 4165.
4.4.1. Ethyl 2-(4-bromophenyl)-3-(4-methoxyphenyl)-3-methyl-bu-
tanoate (7).35 HRMS (ESI): calculated (C20H23BrO3Na) 413.0723,
found: 413.0723. 1H NMR (400 MHz, CDCl3): 7.34 (d, 2H, J¼8.5 Hz),
7.18 (d, 2H, J¼9.0 Hz), 7.07 (d, 2H, J¼8.5 Hz), 6.80 (d, 2H, J¼9.0 Hz),
3.94 (m, 2H), 3.79 (s, 3H), 3.77 (s, 1H), 1.46 (s, 3H), 1.31 (s, 3H), 1.04
(t, 3H, J¼7.6 Hz). 13C NMR (100 MHz, CDCl3): 172.3, 158.0, 139.0,
134.8, 131.9, 130.8, 127.7, 121.5, 113.3, 62.1, 60.4, 55.4, 40.9, 26.3,
25.4, 14.1.
21. Nadeau, E.; Li, Z.; Morton, D.; Davies, H. M. L. Synlett 2009, 151.
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22. García, J. I.; Lopez-Sanchez, B.; Mayoral, J. A.; Pires, E.; Villalba, I. J. Catal. 2008,
258, 378.
23. Fraile, J. M.; García, J. I.; Mayoral, J. A.; Tarnai, T.; Harmer, M. A. J. Catal. 1999,
186, 214.
24. Davies, H. M. L.; Jin, Q. Tetrahedron: Asymmetry 2003, 14, 941.
25. Thu, H.-Y.; Tong, G. S.-M.; Huang, J.-S.; Chan, S. L.-F.; Deng, Q.-H.; Che, C.-M.
Angew. Chem., Int. Ed. 2008, 47, 9747.
26. Trost, B. M.; Whitman, P. J. J. Am. Chem. Soc. 1974, 96, 7421.
27. Spassov, S. L. Tetrahedron 1969, 25, 3631.
28. Davies, H. M. L.; Ren, P. Tetrahedron Lett. 2001, 42, 3149.
29. Davies, H. M. L.; Hedley, S. J.; Bohall, B. R. J. Org. Chem. 2005, 70, 10737.
30. Slattery, C. N.; Clarke, L.-A.; Ford, A.; Maguire, A. R. Tetrahedron 2013, 69, 1297.
31. Nishimoto, Y.; Saito, T.; Yasuda, M.; Baba, A. Tetrahedron 2009, 65, 5462.
32. Adam, W.; Bosio, S. G.; Turro, N. J. J. Am. Chem. Soc. 2002, 124, 8814.
33. Gospodova, T. S.; Stefanovsky, Y. N. Monatsh. Chem. 1990, 121, 275.
34. The ethyl ester has been partially described in: Li, Y.; Huang, J.-S.; Zhou, Z.-Y.;
Che, C.-M.; You, X.-Z. J. Am. Chem. Soc. 2002, 124, 13185.
4.4.2. Ethyl
threo-2-(4-bromophenyl)-3-methoxy-3-phenyl-prop-
anoate (threo-8). 1H NMR (400 MHz, CDCl3): 7.25 (d, 2H, J¼8.4 Hz),
7.19e7.14 (m, 3H), 7.06e7.01 (m, 2H), 6.97 (d, 2H, J¼8.4 Hz), 4.63 (d,
1H, J¼10.5 Hz), 4.22 (m, 2H), 3.76 (d, 1H, J¼10.5 Hz), 3.22 (s, 3H),
1.27 (t, 3H, J¼7.2 Hz). 13C NMR (100 MHz, CDCl3): 172.3, 138.2,134.0,
131.5, 130.7, 130.6, 128.3, 127.6, 121.7, 85.9, 61.3, 59.2, 57.1, 14.3.
HRMS (ESI): calculated (C18H19BrO3Na) 385.0410, found: 385.0410.
35. In good agreement with the analogous methyl 2-(4-bromophenyl)-3-methyl-3-
phenylbutanoate described in Ref. 20.