Exploiting Synergistic Effects in Organozinc Chemistry for Direct Stereoselective C-Glycosylation Reactions at Room Temperature

Article abstract of DOI:10.1002/anie.201805758

Pairing a range of bis(aryl) zinc reagents ZnAr₂ with the stronger Lewis acidic [(ZnAr^F₂)] (Ar^F=C₆F₅), enables highly stereoselective cross-coupling between glycosyl bromides and ZnAr₂ without the use of a transition metal. Reactions occur at room temperature with excellent levels of stereoselectivity, where ZnAr^F₂ acts as a non-coupling partner although its presence is crucial for the execution of the C(sp²)–C(sp³) bond formation process. Mechanistic studies have uncovered a unique synergistic partnership between the two zinc reagents, which circumvents the need for transition-metal catalysis or forcing reaction conditions. Key to the success of the coupling is the avoidance of solvents that act as Lewis bases versus diarylzinc compounds (e.g. THF).

Full text of DOI:10.1002/anie.201805758

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Accepted Article
Title: Exploiting Synergistic Effects in Organozinc Chemistry for Direct
Stereoselective C-Glycosylation Reactions at Room Temperature
Authors: Alberto Hernan-Gomez, Samantha Orr, Marina Uzelac, Alan
Kennedy, Santiago Barroso, Xavier Jusseau, Sebastien
Lemaire, Vittorio Farina, and Eva Hevia
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805758
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10.1002/anie.201805758
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Exploiting Synergistic Effects in Organozinc Chemistry for Direct
Stereoselective C-Glycosylation Reactions at Room Temperature
Alberto Hernán-Gómez,a Samantha A. Orr,a Marina Uzelac, a Alan R. Kennedy, a Santiago Barroso,b
Xavier Jusseau,b Sébastien Lemaire,b Vittorio Farina*b and Eva Hevia*a
Abstract: Pairing a range of bis(aryl) zinc reagents ZnAr2 with the
coupling without the need of transition-metal catalysis, no
mechanistic information is available on how these reactions
actually occur.
stronger Lewis acidic [(ZnArF )] (ArF
= C6F5), enables highly
2
stereoselective cross-coupling between glycosyl bromides and ZnAr2
without the use of a transition metal. Reactions occur at room
In our aim to fill this knowledge gap, focusing on the
synthesis of pharmaceutically relevant C-glycosides,[7] herein we
combine NMR spectroscopic studies with kinetic investigations
to provide mechanistic insights into transition-metal-free cross-
coupling reactions using bis(aryl)zinc reagents. Furthermore, by
systematically probing the effect of additives in these reactions,
we disclose a new stereoselective method to access aryl-C-
glycosides which is based on the synergistic partnership of a
range of ZnAr2 nucleophiles with the strongly Lewis acidic
temperature with excellent levels of stereoselectivity, where ZnArF
2
acts as a non-coupling partner although its presence is crucial for
the execution of the C(sp2)-C(sp3) bond formation process.
Mechanistic studies have uncovered
a
unique synergistic
partnership between the two zinc reagents, which circumvents the
need for transition-metal catalysis or forcing reaction conditions. Key
to the success of the coupling is the avoidance of solvents that act
as Lewis bases vs. diarylzinc compounds (e.g. THF).
bis(pentafluorophenyl)zinc complex ZnArF (ArF = C6F5), while
2
operating at room temperature.
Cross-coupling reactions between organic halides and
organozinc nucleophiles, typified by the Negishi reaction, are
amongst the most synthetically powerful and widely used
methods for the construction of C-C bonds.[1] The use of
transition metal catalysis, most commonly employing palladium
or nickel systems, is usually imperative to facilitate these
couplings.[2] However, recent advances focusing on the
development of more sustainable and more economical
synthetic strategies have shown that in certain cases organozinc
compounds can actually participate in direct C-C bond formation.
For example, albeit under harsh reaction conditions (90-130oC,
24h), direct cross-couplings of aryl halides with bis(aryl)zinc
reagents have been reported by Uchiyama and Wang.[3] Also
extendable to organoaluminium reagents,[4] these processes
Our initial studies on the couplings of ZnAr2 reagents with
glycosyl bromide 1 were carried out using a 1:1 mixture of di-n-
butyl ether (DBE) and toluene. In these reactions the arylzinc
reagents were generated in situ by salt metathesis of ZnBr2 with
two equivalents of the relevant LiAr species, and therefore 2
equiv LiBr is also present in the reaction mixture. Although the
target C-arylated glycosides were obtained in good yields (50-
86%), forcing reaction conditions were required.[5a] Building on
the solvent effects just described, we then assessed the
reactivity of salt-free ZnPh2 (purified by sublimation) using neat
toluene as the reaction medium (Fig 1). Interestingly, under
these conditions, the coupling reaction to form 2a occurs
smoothly at room temperature and is complete in less than 5
hours (95% yield) with a high level of stereoselectivity (β/α ratio
of 89:11, Fig 1a; Table 1, entry 1).
are thought to occur via
a single-electron-transfer (SET)
mechanism. In addition, Lemaire and co-workers have reported
the direct stereoselective arylation of glycosyl bromides using
arylzinc reagents, also under quite vigorous conditions
(temperatures of 90-100oC).[5] Complementary to this work,
Ingleson has described the efficient room-temperature method
for C(sp2)-C(sp3) cross-coupling of a range of diarylzinc reagents
with benzyl and alkyl halides. In agreement with Lemaire’s work,
this study also stresses that the success of the coupling heavily
depends on the use of non-polar, non-coordinating solvents.[6]
Thus, the presence of ethereal solvents such as THF or Et2O
dramatically slows down the reactions,.[6] While these results
illustrate the ability of arylzinc reagents to engage in cross-
Figure 1. (a) Synthesis of 2a via coupling of 1 and ZnPh2. (b) Kinetic plot for
the formation of 2a and consumption of 1 over time obtained by 1H NMR
monitoring of the reaction of 1 (0.048 M) with ZnPh2 (0.024M) in [D8]-Tol at
298 K.
[a]
[b]
Dr. A. Hernán-Gómez, Dr. S. A. Orr, Dr. M. Uzelac, Dr. A. R.
Kennedy, Prof. E. Hevia
WestCHEM, Department of Pure and Applied Chemistry, University
of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, (UK)
E-mail: eva.hevia@strath.ac.uk
Dr. S. Barroso, Dr. X. Jusseau, Dr. S. Lemaire and Dr. V. Farina
Pharmaceutical Development and Manufacturing Sciences, Janssen
Pharmaceutica, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Although this selectivity is slightly lower than that observed
previously using the diarylzinc generated in situ in the
DBE:toluene solvent mixture,[4a] such selectivity can be
rationalised in similar terms, by invoking participation of the
neighbouring pivaloyl group via bicyclic oxocarbenium ion I.
Supporting information for this article is given via a link at the end of
the document.
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DOSY NMR spectroscopic studies of ZnPh2 in DBE/d8-tol
solutions indicate the formation of adduct [ZnPh2(DBE)].[8] Thus,
the significantly slower coupling reactivity observed using
DBE/toluene as a solvent may be due to the generation of a less
reactive, more coordinatively saturated, DBE- ZnPh2 adduct,
hinting at the initial interaction of the ZnAr2 with 1 as a key step
to induce the formation of I. Consistent with this interpretation,
using [ZnPh2(TMEDA)], (TMEDA= N,N,N′,N′-tetramethylethane-
1,2-diamine), where N-donor TMEDA is tightly bonded to Zn, the
formation of 2a was totally inhibited.[9]
experiments monitoring a 2:1 mixture of 1 and 4 in [D8]-toluene
over 24h show that the latter is completely inert towards cross-
coupling under the conditions studied.
Table 1. Direct arylation of 1 with ZnPh2 in the presence of additives [a]
Br
.
Ph
ZnPh2 / Additive
OPiv
OPiv
O
O
2
2
Toluene, RT, time
- ZnBr2
OPiv
OPiv
PivO OPiv
OPiv
2a
PivO
1
1H NMR monitoring of the coupling reaction to give 2a
showed that reaction rate is represented by a sigmoidal curve,
with a long induction time of over 2 hours (Fig 1b), suggesting
autocatalytic behaviour. A possible rationale could be that the
reaction is catalysed by ZnBr2 generated as a byproduct from
the reaction of ZnPh2 with 1. Being a stronger Lewis acid than
ZnPh2, ZnBr2 could then activate 1, promoting formation of the
proposed reactive intermediate cation I (Fig 1) by abstraction of
bromide to form zincate anion {ZnBr3}-.This hypothesis gained
further support when 1 was reacted with an equimolar mixture of
ZnPh2 and ZnBr2 (Table 1, entry 2). Whereas ZnBr2 is sparingly
soluble in toluene and it is therefore difficult to estimate its
concentration in this solvent, the coupling reaction is significantly
faster (2h, 70% yield) and little or no induction period is
observed (see SI for details). The possible involvement of
Grignard-like PhZnBr as a Lewis acid (instead of ZnBr2) cannot
be disregarded, as it will also be present in solution, in variable
amounts, due to the Schlenk-type equilibrium (Eq 1).[11]
Additive[a]
Time Yield
β/α
Entry
(h)
4.5
2
(%)[b]
95
70
0
ratio
89/11
91/9
1
2
3
4
5
6
7
8
None
ZnBr2 (1eq)
NBu4Br (1 eq)
ZnArF2 (1 eq)
24
1
-
99
99
99
94
98
87/13
86/14
86/14
88/12
90/10
ZnArF2 (50 mol%)
ZnArF2 (20 mol%)
ZnArF2 (10 mol%)
ZnArF2 (1eq), DBE (1 eq)
1.5
2
2.5
3.7
[a]Conditions: 1 (0.048 M), ZnPh2 (0.024 M), [D8]-Tol, 25°C. [b]Yields were
determined by 1H NMR spectroscopy using hexamethylcyclotrisiloxane as
internal standard.
1H NMR monitoring of the coupling of 1 (2 eq) with a 1:1 mixture
of ZnPh2 and 4 showed not only that 4 is unreacted at the
conclusion of the experiment, but also that no induction period is
required and a first order decay is observed (Fig 3). This made
us consider whether 4 might also operate under a catalytic
regime. However, when sub stoichiometric amounts of 4 where
employed, the reactions were significantly slower and sigmoidal
behavior for the formation of 2 was observed (Table 1, entries 5-
7).[10] This could be due partly to the possible competing co-
complexation of 4 with product 2a to form a deactivated
coordination adduct, i.e. product inhibition.[13]
Interestingly, when the reaction was carried out in neat toluene
using the ammonium salt NBu4Br (TBAB, 1 eq) as an additive,
formation of 2a is completely inhibited (Table 1, entry 3). We
later found that TBAB forms a readily isolable, anionically
activated zincate, {NBu4}{ZnPh2Br} (3)(Fig 2).[12] This result
highlights the crucial role of the Lewis acid in the reaction media.
Consistent with the solvent effects noted before,
introducing oxygen donor ligand DBE resulted in a noticeable
deceleration of the reaction rate (Table 1, entry 8).[10] This is
probably due to the formation of less active coordination adducts
Figure 2. Molecular structure of {NBu4}{ZnPh2Br} (3) with thermal ellipsoids at
[DBE(ZnArF )],[14] which ultimately diminishes the amount of
2
30% probability. Hydrogens are omitted for clarity.
solvent-free 4 available for generating oxocarbenium I.
Capitalising on these findings, we next pondered whether
addition of an external Lewis acid could also favour these
couplings, eliminating the need of an induction period (Fig 1).
These findings suggest that the enhanced reactivity using
equimolar mixtures of the ZnPh2/4 combination can be
rationalised in terms of both arylzinc reagents operating in a
unique cooperative manner, with 4 activating the glycosyl
We probed the related bis(aryl)zinc complex, ZnArF (4), where
2
the pull of highly electron withdrawing C6F5 should greatly
enhance the Lewis acidity of the Zn centre. Pleasingly, when 1
(2 eq) was reacted with an equimolar mixture of ZnPh2 and 4, 2a
bromide, facilitating formation of anomeric cation
I which
subsequently can be arylated, presumably by ZnPh2. The mild
reaction conditions and high levels of stereoselectivity obtained
contrast with those previously reported in the literature using
transition metal catalysts which require longer reaction times (up
to 12h), proceed in lower yields, and often offer lower
stereoselective control.[15,16] To confirm that our observed
was obtained selectively in
a 99% yield offering similar
stereoselectivity as when ZnPh2 was used, but in just under one
hour (Table 1, entry 4). Interestingly, no transfer of ArF unit was
observed, which demonstrates the stronger nucleophilicity of
ZnPh2 versus 4 vis a vis oxocarbenium intermediate I. In fact,
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reactivity can be unequivocally attributed to the zinc reagents,
ICP-MS analysis of ZnPh2 and 4 were carried out, which showed
extremely low concentrations[17] of trace transition-metal
impurities active in C-C bond formation processes.
family of etherate-free organozinc reagents reported in the
literature, we synthesized and characterised by NMR
spectroscopy a series of diarylzinc compounds generated by
initial lithium/halogen exchange and subsequent transmetallation
with ZnCl2 in diethyl ether, followed by filtration to remove LiCl
and evaporation of the ethereal solvent under vacuum.[10]
Without further purification, these zinc reagents were
successfully coupled with 1 at room temperature in high yields
and stereoselectivities (ratio β/α ≥90:10). Electron-rich
substituents at the aryl rings favoured the couplings, (Table 2,
Entries 1-3), affording the corresponding C-glucoside in similar
reactions times as when using reagents having electron-
withdrawing substituents (Table 2, Entries 4 and 5).[10] However,
incorporation of the highly electron-poor trifluoromethyl group on
the aryl ring inhibits the coupling reaction even under forcing
reaction conditions (110°C) (Table 2, Entry 6).[18] In addition, this
protocol proved to be compatible with steric hindrance,
generating the ortho substituted desired coupled products 2h-2j
(Table 2, Entries 7-9) at room temperature in excellent yields, in
contrast with previous studies in which synthesis of the same C-
glycosides required forcing reaction temperatures of 110°C.[5a]
Heteroaromatic zinc reagents can also be coupled, e.g.
synthesis of 2k, in 93% yield (Table 2, Entry 10).
Figure 3. (Coupling reaction of 1 (0.048 M) and ZnPh2/ZnArF (4) (0.024
2
M/0.024 M) in [D8]-Tol at 298 K. a) monitoring of reaction by 1H NMR
spectroscopy, b) First order plot of [1] vs time (min).
Table 2. Aryl Glycosides (2b-k) obtained by reaction of biaryl zinc reagents
with 1.[a]
Br
Ar
ZnAr2 / ZnArF
OPiv
OPiv
2
O
O
2
2
Toluene, RT, time
- ZnBr2
OPiv
OPiv
PivO OPiv
OPiv
PivO
2b-k
1
Entry[a]
Ar
Product
Time
(h)
Yield
(%)[b]
β/α
ratio
1
2
4-MeC6H4
4-tBu-C6H4
4-OMe-C6H4
4-Cl-C6H4
2b
2c
2d
2e
2f
1
2.5
2
99
95
99
99
98
0[c]
97
99
99
93
91/9
96/4
95/15
97/3
94/6
-
3
4
2
5
4-F-C6H4
2
6
4-CF3-C6H4
2-Me-C6H4
2-OMe-C6H4
2,6-OMe2-C6H4
2-thienyl
2g
2h
2i
12
1
7
98/2
99/1
95/5
95/5[d]
Scheme 1. Proposed 3-step mechanism of the investigated coupling reaction.
8
1[c]
4
From a mechanistic perspective, these coupling processes
can be postulated to occur via a multi-step process (Scheme 1)
with initial bromide abstraction accomplished by Lewis acidic 4,
9
2j
10
2k
2.5
giving rise to anomeric oxocarbenium ion
I and zincate
{ZnArF Br}- (A in Scheme 1) via a kinetically invisible non-
[a]Conditions: 1 (0.048 M), ZnPh2 (0.024 M), [D8]-Tol, 25°C. [b]Yields were
2
determined by 1H NMR spectroscopy using hexamethylcyclotrisiloxane as
stabilized oxocarbenium species A’ (Scheme 1). Since ZnPh2 is
also present in the reaction media, this species could be in
equilibrium with zincate {ZnPh2Br}- (B in Scheme 1), and while
this equilibrium would normally lie towards the left, giving the
stronger Lewis acidity of 4, formation of a more nucleophilic
[d]
internal standard. [c] Reaction was carried out at 85oC. 4% of 3-thienyl was
observed.
Using these conditions, we next evaluated the scope of the
reaction with different diaryl zinc reagents. Expanding the limited
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[a]Yields
were
determined
by
1H
NMR
spectroscopy
using
{ZnPh2Br}- species, capable of promoting a final, non-reversible,
electrophilic aromatic substitution step (C in Scheme 1), should
drive the reaction towards the generation of 2a, along with
PhZnBr and the recovery of 4. The discrete Wheland
intermediate C is suggested by the complete lack of reactivity of
highly electron-deficient diarylzinc compounds (Table 2, entry 6),
which would be consistent with the build-up of a positive charge
in the arylation intermediate, although this is still to be confirmed
experimentally and computationally. It should also be noted that
under these conditions, NMR studies show that the Schlenk
equilibrium affecting PhZnBr appears to be driven towards
formation of ZnPh2 and ZnBr2 (Eq 2).[19]
hexamethylcyclotrisiloxane as internal standard. [b] Reaction was carried out
at 110oC.
We explain the results as follows: the mechanism we have
proposed refers exclusively to formation of the β anomer. This
pathway would not be plausible for the formation of the α
anomer, which must be formed via the non-stabilized
oxocarbenium ion A’ (Scheme 2).
Indeed, the more stable intermediate A can only yield the β
anomer whereas A’ could lead to either α or β-product. It is
plausible that A is so stable that it reacts only with the more
reactive bromozincate ion pair B, and Ph2Zn is not nucleophilic
enough to couple with it. Although too poor a nucleophile to
react with A, Ph2Zn can react with A’, leading to mixtures of α
and β. Clearly, due to the more favourable association of 4 with
bromide ion ([A]>[B]), there are always high concentrations of
“free Ph2Zn“ in solution, leading to some stereochemical leakage
toward the “Ph2Zn pathway” and therefore some α anomer.
Bromide has the effect of scavenging much of this Ph2Zn, in
addition to complexing 4 and slowing down the reaction. The
result is predominant coupling via B and therefore mainly β
anomer.
Kinetic studies using initial rates methods at 273K offered
some support to this mechanistic hypothesis.[10] Thus, the
reaction showed first order-dependence of bromosugar 1 (Fig
S93, SI). Monitoring initial rates versus initial concentrations of
both zinc reagents, 4 and ZnPh2, showed first-order behaviour
but also displayed saturation in both cases (Figures S95-103,
SI). This is consistent with a rate-limiting oxonium formation
under “normal” synthetic conditions (step 1, Scheme 1) at high
concentration of ZnPh2, where ZnPh2 rapidly traps intermediate I
forming B and subsequently C. Contrastingly, at very low
concentration of ZnPh2 or very high concentration of 4, the C-C
coupling is rate limiting (step 2), with return of intermediate A to
the starting materials favoured over formation of intermediate
B.[20]
Finally, a brief discussion of the α/β ratios is in order. We
were puzzled that our initial studies reported[5a] almost perfect β
stereoselectivity; whereas using neat toluene with or without 4
as catalyst yields around 90% β selectivity. The most glaring
difference between the two sets of conditions is the presence or
absence of extra bromide ion with respect to that provided by
the bromosugar (as the ZnAr2 reagents were generated in situ
via salt-metathesis with 2 eq of LiAr and ZnBr2). We carried out
experiments with increasing concentrations of exogenous
bromide, opting for tetrabutylammonium bromide (TBAB) instead
of LiBr (used by Lemaire et al)[5a] owing to its much-improved
solubility in toluene. We found that bromide ion did indeed
improve selectivity while inhibiting the reaction. β-Selectivity
increased, and reaction rate decreased with increasing bromide
levels (Table 3).
{ZnArF2Br}
O
O
Ph
PivO
PivO
A'
ZnPh2
PivO
PivO
OPiv
OPiv
- ZnArF
2
OPiv
OPiv
α and β
products
{ZnArF2Br}
O
[NBu4][ZnPh2Br]
O
Ph
O
O
PivO
PivO
PivO
OPiv
PivO
- ZnArF
2
OPiv
OPiv
A
β-selectivity
Lewis Acid deactivation pathway
[NBu4][ZnArF2Br] + ZnPh2
[NBu4][ZnPh2Br] + ZnArF
2
Scheme 2. Proposed rationale for the stereoselectivity observed in the
presence of bromide anion.
In conclusion, we have disclosed a room-temperature,
diastereoselective and functional-group tolerant C(sp2)-C(sp3)
bond formation methodology for the synthesis of C-glycosides.
This involves cooperative arylation of glycosyl bromide 1 with
the synergistic partnership of an aryl zinc and the non-arylating
zinc reagent ZnArF (ArF = C6F5) (4). This methodology is
2
Table 1. Direct arylation of 1 with ZnPh2 in the presence of TBAB[a]
.
strongly inhibited by the presence of donor solvents due to
formation of coordination complexes of 4 as confirmed by NMR
and titration studies. The addition of a promoter allows a much
easier kinetic investigation, revealing a multi-step mechanism
initiated by bromine abstraction promoted by 4, followed by
bromide transfer to the arylating zinc reagent forming a more
nucleophilic zincate, which ultimately undergoes an electrophilic
aromatic substitution with the oxocarbenium electrophile, to form
the new C-C bond. Expanding the field of direct arylzinc coupling
with electrophiles, these findings have established a new type of
Zn/Zn’ synergistic behaviour whose scope and applicability
beyond glycosylation reactions are currently under investigation.
ZnPh2 / ZnArF
2
Br
Ph
OPiv
OPiv
x NBu4Br
OPiv
OPiv
O
O
2
2
Toluene, RT, time
- ZnBr2
PivO OPiv
OPiv
PivO
2a
1
Entry
x eq
Time (h)
Yield (%)[a]
β/α ratio
1
3
4
5
0
0.25
0.5
1
1
5
93
98
93
87
87/13
92/8
28
13[b]
>99/1
>99/1
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[17] Maximum concentration of 12.51 ppb/mg was observed for iron
impurities. See supporting information for full details.
Acknowledgements
[18] This contrasts with results reported when ZnAr2 (Ar = 4-CF3-C6H4)2 is
used in the presence of LiBr which furnished the relevant coupling
product in a 50% yield after 24 h at 110oC. See reference [5a].
[19] 1H NMR studies adding variable amounts of PhZnBr to a 1:1 mixture of
ZnPh2 and 4 in d8-toluene using ferrocene as an internal standard have
shown an increase in the concentration of ZnPh2 in solution, consistent
with the Schlenk-type equilibrium being driven towards formation of
ZnPh2 and ZnBr2. See SI for details.
We thank Dr. Pieter Westerduin and Dr. RajendraDeshpande for
their support of this project. We also thank Dr. Dave Armstrong
for his support on modelling the molecular volumes used in the
DOSY NMR experiments.
Keywords: zinc • arylation • cooperative effects • transition-
metal free • zincate
[20] By treating B and C as steady state intermediates, a rate law in
agreement for these observations is shown in SI.
[1]
[2]
[3]
[4]
[5]
A. De Meijere, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions,
Wiley-VCH, Weinheim, 2004.
D. Haas, J. M. Hammann, R. Greiner, P. Knochel, ACS Catal, 2016, 6.
1540
H. Minami, X. Wang, C. Wang, M. Uchiyama, Eur. J. Org. Chem. 2013,
7891.
H. Minami, T. Saito, C. Wang, M. Uchiyama, Angew. Chem. Int. Ed.
2015, 54, 4665.
(a) S. Lemaire, I. N. Houpis, T. Xiao, J. Li, E. Digard, C. Gozlan, R. Liu,
A. Gavryushin, C. Diène, Y. Wang, V. Farina, P. Knochel, Org. Lett.
2012, 14, 1480; (b) S. Barroso, S. Lemaire, V. Farina, A. K. Steib, R.
Blanc, P. Knochel, J. Org. Chem. 2016, 81, 2804.
[6]
[7]
J. J. Dunsford, E. R. Clark, M. J. Ingleson, Angew. Chem. Int. Ed. 2015,
54, 5688.
For some examples see:(a) E. C. Chao, R. R. Henry, Nat. Rev. Drug
Discovery 2010, 9, 551; (b) P. Rawat, M. Kumar, N. Rahuja, D.S.L.
Srivastava, A. Kumar, R. Maurya, Bioorg. Med. Chem. Lett. 2011, 21,
228. (c) S. Nomura, S. Sakamaki, M. Hongu, E. Kawanishi, Y. Koga, T.
Sakamoto, Y. Yamamoto, K. Ueta, H. Kimata, K. Nakayama, M. Tsuda-
Tsukimoto, J. Med. Chem. 2010, 53, 6355.
[8]
13C NMR titration experiments allowed the calculation of the association
constant (Keq) between ZnPh2 and DBE to give coordination adduct
[ZnPh2(DBE)] (Keq=2.33 M-1). See SI for details. In contrast, DOSY
NMR studies have shown that in d8-toluene solution ZnPh2 exists as a
dimer in equilibrium with its monomeric form, which is coordinatively
unsaturated and could be expected to exhibit higher Lewis-acid
reactivity.
[9]
X-ray crystallographic studies showed [ZnPh2(TMEDA)] exhibits a
monomeric structure with TMEDA coordinated as a chelate to Zn. This
structure is retained in toluene [D8]-solutions (See SI for details).
[10] See SI for details
[11] 1H NMR monitoring of the reaction of 1 with ZnPh2 showed only one set
of aromatic signals, which progressively shift towards lower field at
increasing conversions of 2. A similar trend has been previously noted
for studies on THF solutions containing EtZnCl and ZnEt2, prepared by
combining ZnEt2 and ZnCl2, see: A. J. Blake, J. Shannon, J. C.
Stephens, S. Woodward, Chem. Eur. J., 2007, 13, 2462.
[12] Ammonium zincate complex 3 was obtained in a 86% isolated yield.
DOSY NMR studies are consistent with the retention of its solid state
structure (Fig 2) in deuterated toluene.
[13] 13C NMR titration studies support product inhibition by the formation of
coordination adduct [ZnArF (2a)] (Keq=25.21 M-1). It should also be
2
noted that DOSY NMR experiments of solutions of ZnPh2 and 4 in [D8]-
toluene indicate that these two zinc compounds do not form
a
heteroleptic bis(aryl) [PhZnArF] complex but exist as separate entities.
See SI for details.
[14] 13C NMR titration studies support formation of coordination adducts
[ZnArF2(1)] and [ZnArF2(DBE)] (Keq=13.53 M-1 and 3.53 M-1
respectively), see SI for details.
[15] (a) H. Gong, M. R. Gagné, J. Am. Chem. Soc. 2008, 130, 12177; (b) H.
Gong, R. Sinisi, M. R. Gagné, J. Am. Chem. Soc. 2007, 129, 1908.
[16] L. Nicolas, P. Angibaud, I. Stansfield, P. Bonnet, L. Meerpoel, S.
Reymond, J. Cossy, Angew. Chem. Int. Ed. 2012, 51, 11101.
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10.1002/anie.201805758
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
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COMMUNICATION
A. Hernán-Gómez, S. A. Orr, M. Uzelac,
A. R. Kennedy, S. Barroso, X. Jusseau,
S. Lemaire, V. Farina* and E. Hevia*
Zn/Zn cooperation
Ar
Br
ZnArF
OPiv
OPiv
ZnAr2
+
room temperature
transition-metal free
high yielding
OPiv
OPiv
2
O
O
Arylating
reagent
Lewis acid
activator
Page No. – Page No.
stereoselective
PivO OPiv
OPiv
PivO
Exploiting Synergistic Effects in
Organozinc Chemistry for Direct
A dizinc glucose solution! Disclosing a new type of metal cooperation in
Stereoselective
C-Glycosylation
organozinc chemistry, pairing a range of bis(aryl) zinc reagents ZnAr2 with the
Reactions at Room Temperature
stronger Lewis acidic [(ZnArF )] (ArF = C6F5), enables highly stereoselective room-
2
temperature arylation of glycosyl bromides without using a transition metal catalyst.
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