Boosting Conjugate Addition to Nitroolefins Using Lithium Tetraorganozincates: Synthetic Strategies and Structural Insights

Article abstract of DOI:10.1002/chem.202001294

We report the first transition metal catalyst- and ligand-free conjugate addition of lithium tetraorganozincates (R₄ZnLi₂) to nitroolefins. Displaying enhanced nucleophilicity combined with unique chemoselectivity and functional group tolerance, homoleptic aliphatic and aromatic R₄ZnLi₂ provide access to valuable nitroalkanes in up to 98 % yield under mild conditions (0 °C) and short reaction time (30 min). This is particularly remarkable when employing β-nitroacrylates and β-nitroenones, where despite the presence of other electrophilic groups, selective 1,4 addition to the C=C is preferred. Structural and spectroscopic studies confirmed the formation of tetraorganozincate species in solution, the nature of which has been a long debated issue, and allowed to unveil the key role played by donor additives on the aggregation and structure of these reagents. Thus, while chelating N,N,N’,N’-tetramethylethylenediamine (TMEDA) and (R,R)-N,N,N’,N’-tetramethyl-1,2-diaminocyclohexane (TMCDA) favour the formation of contacted-ion pair zincates, macrocyclic Lewis donor 12-crown-4 triggers an immediate disproportionation process of Et₄ZnLi₂ into equimolar amounts of solvent-separated Et₃ZnLi and EtLi.

Full text of DOI:10.1002/chem.202001294

A Journal of
Accepted Article
Title: Boosting Conjugate Addition to Nitroolefins Using Lithium
Tetraorganozincates: Synthetic Strategies and Structural Insights
Authors: Marzia Dell'Aera, Filippo Maria Perna, Paola Vitale, Angela
Altomare, Alessandro Palmieri, Lewis C. H. Maddock, Leonie
J. Bole, Alan R. Kennedy, Eva Hevia, and Vito Capriati
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To be cited as: Chem. Eur. J. 10.1002/chem.202001294
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10.1002/chem.202001294
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Boosting Conjugate Addition to Nitroolefins Using Lithium
Tetraorganozincates: Synthetic Strategies and Structural Insights
Marzia Dell’Aera,[a],[b] Filippo Maria Perna,[a] Paola Vitale,[a] Angela Altomare,[b] Alessandro Palmieri,[c]
Lewis C. H. Maddock,[d] Leonie J. Bole,[e] Alan R. Kennedy,[d] Eva Hevia,* [e] and Vito Capriati*[a],[f]
Dedication ((optional))
Abstract: We report the first transition metal catalyst- and ligand-free
conjugate addition of lithium tetraorganozincates (R4ZnLi2) to
nitroolefins. Displaying enhanced nucleophilicity combined with
unique chemoselectivity and functional group tolerance, homoleptic
aliphatic and aromatic R4ZnLi2 provide access to valuable nitroalkanes
in up to 98% yield under mild conditions (0 °C) and short reaction time
(30 min). This is particularly remarkable when employing β-
nitroacrylates and β-nitroenones, where despite the presence of other
electrophilic groups, selective 1,4 addition to the C=C is preferred.
Structural and spectroscopic studies confirmed the formation of
tetraorganozincate species in solution, the nature of which has been
a long debated issue, and allowed to unveil the key role played by
donor additives on the aggregation and structure of these reagents.
Thus, while chelating N,N,N',N'-tetramethylethylenediamine
(TMEDA) and (R,R)-N,N,N',N'-tetramethyl-1,2-diaminocyclohexane
(TMCDA) favour the formation of contacted-ion pair zincates,
macrocyclic Lewis donor 12-crown-4 triggers an immediate
disproportionation process of Et4ZnLi2 into equimolar amounts of
solvent-separated Et3ZnLi and EtLi.
functionalities including carbonyl derivatives by the Nef reaction,
amines by reduction, nitrile oxides, nitriles, hydroxylamines, and
imines by other transformations.[1] Several nucleophiles, which
include carbon, oxygen, phosphorus, nitrogen, sulfur and cyanide
anions, have been hitherto successfully employed.[2] The
conjugate addition of various organometallic reagents provides a
complementary powerful method for nitro-alkylation. While the
effectiveness of these transformations is known to be poor when
highly reactive organolithium and Grignard reagents are used,
with concomitant undesirable side reactions and low yields which
often imply the presence of additives,[3] the alternative use of
organozinc reagents as milder and “softer” nucleophiles offers
distinct advantages particularly as a result of their lower basicity
and broad functional group tolerance.[4]
The addition of alkylzinc halides or dialkylzinc reagents to
nitroalkenes has been the subject of intensive investigation in the
last years, especially with reference to their asymmetric variant.[5]
The 1,4-addition process is the normal pathway followed by these
reagents, albeit restricted to alkyl-, benzyl-, and allylzinc reagents
because of their poor kinetic reactivity. The intriguing replacement
of the vinylic nitro group by an alkyl group remains a complication
encountered upon treating 2-arylnitroethenes with dialkylzinc
compounds in the absence of a Lewis acid and in ethereal
solvents. Such an unexpected vinylic C–C coupling was first
described by Seebach and coworkers in some seminal papers,[6]
and has also been noticed to take place by Dilman and coworkers
in the copper-catalysed reaction of gem-difluorinated organozinc
reagents with β-nitrostyrenes.[7]
Introduction
Nitroalkenes are established Michael acceptors and unique and
versatile building blocks in organic synthesis due to the markedly
electron-deficient character of the nitro group. The latter can be
easily and advantageously transformed into a legion of diverse
Alkali-metal zincate complexes of general composition
R3ZnLi (1) and R4ZnLi2 (2) can be prepared either using the co-
complexation approach from R2Zn and RLi or by reacting RLi with
ZnCl2 in a suitable stoichiometric ratio (Scheme 1). By enabling
metal-metal' cooperativities, these systems offer synergistic
reactivities which cannot be replicated by their monometallic
counterparts.[8]
[a]
Dr. M. Dell’Aera, Dr. P. Vitale, Dr. F. M. Perna, Prof. V. Capriati
Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari
“A. Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125
Bari, Italy
E-mail: vito.capriati@uniba.it
Dr. M. Dell’Aera, Dr. A. Altomare
Istituto di Cristallografia (IC-CNR), Via Amendola 122/o, I-70125
Bari, Italy
Prof. A. Palmieri
Dipartimento di Scienze Chimiche, Università di Camerino, Via S.
Agostino 1, I-62032 Camerino (Italy)
Dr. L. C. H. Maddock, Dr. A. R. Kennedy
Department of Pure and Applied Chemistry, University of
Strathclyde Glasgow, G1 1XL, UK
[b]
[c]
[d]
[e]
n = 1
n = 2
n = 3
n = 4
R3ZnLi (1)
R4ZnLi2 (2)
ZnCl2
+
nRLi
R2Zn
+
nRLi
-2 LiCl
Dr. L. J. Bole, Prof. E. Hevia
Department für Chemie und Biochemie, Universität Bern, CH3012,
Bern, Switzerland
Scheme 1. Formation of lithium zincate complexes 1 and 2 by reaction of RLi
with R2Zn or ZnCl2.
E-mail: eva.hevia@dcb.unibe.ch
[f]
Prof. Vito Capriati
Pioneering work by Uchiyama, Sakamoto, and Kondo
revealed that, owing to their dianion-type character, the 18-
electron, tetraorganozincate complexes 2 (also referred to as
higher-order zincates), showed a much more pronounced kinetic
activity over their triorgano analogues 1 in some fundamental
organic transformations such as (i) deprotonative metalations, (ii)
halogen (or tellurium) zinc exchange reactions followed by
trapping reactions with electrophiles or intramolecular epoxide
opening, Michael addition and carbozincation reactions, and (iii)
copper- and palladium-catalysed C–C bond-forming reactions.[9]
Dipartimento di Chimica, Istituto di Chimica dei Composti
Organometallici (ICCOM) – CNR, Università di Bari “A. Moro”, Via
E. Orabona 4, I-70125 Bari, Italy
CCDC 196165, 1951656, 1977196 and 1977197 contain the
supplementary crystallographic data for this paper. These data are
provided free of charge by the Cambridge Crystallographic Data
Centre.
Supporting information for this article is given via a link at the end
of the document.
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10.1002/chem.202001294
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In contrast to triorganozincates,[8,10] however, the applications of
tetraorganozincates in transition-metal-catalyst-free C–C bond-
forming processes have received relatively little attention, aside
from a recent report by Hevia and coworkers describing the direct
arylation of electron-deficient N-heterocyclic compounds using
acridine as a case study.[11] Moreover, in spite of the pronounced
aptitude of tetraorganozincates towards anion transfer reactions,
key questions about their nucleophilic properties and the ability to
promote direct conjugate addition to Michael acceptors still
remain unanswered.
Filling this important gap in the knowledge, herein we profit
on the exceptional functional group tolerance and enhanced
nucleophilic power of tetraorganozincates, and report their first
applications for regioselective addition to nitroolefins. Key
features of this study include (i) no co-ligand, additive or transition
metal catalyst is required; (ii) mild reaction conditions (0 °C) and
short reaction times (30 min); (iii) high chemoselectivity and broad
substrate scope, and (iv) nitroalkanes isolated in up to 98% yield.
Furthermore, structural and spectroscopic studies on these
mixed-metal organometallic reagents provide insights on the
unique reactivity observed.
Under the best conditions of Table 1 (entry 6), addition of a
substoichiometric amount of 4c (0.6 equiv) to 3a still provided only
5ac in 89% yield (Table 1, entry 8), whereas 4b (1.2 equiv)
furnished a mixture of 5ac and 6 in a 91:9 ratio (Table 1, entry 9).
It should be noted that the formation of tetraorganozincate
complexes in solution, as postulated by Uchiyama and
Sakamoto,[9] where Zn is bonded to four anionic ligands, has
previously been a debated issue because of the strong coulombic
repulsion, which should make these species thermodynamically
unfavored.[17] Contrastingly, DFT studies on systems containing t-
Bu groups suggest that the disproportionation of t-Bu3ZnLi into t-
Bu4ZnLi2 and t-Bu2Zn is favoured in THF.[18] More recently,
Koszinowski has pointed out that “the formulas LiZnR3 and
Li2ZnR4 refer to the overall composition of the reactive mixtures
but do not necessarily reflect the stoichiometry of the actual
species present in solution”.[19] Detailed NMR spectroscopic
studies carried out by Berger and Mobley with 13C-enriched
reagents, indeed, allowed to ascertain that addition of 2 equiv of
MeLi to Me2Zn generated an equilibrium mixture of Me3ZnLi and
Me4ZnLi2, though strongly shifted toward the former product.[20]
Thus, in some cases, the reactive species could be the higher
energy tetraorganozincate complex, which would explain the
chemical reactivities reported by Uchiyama and Sakamoto for
these complexes[9] and also our own results discussed herein.
Results and Discussion
Table 1. Addition of organozinc species 4 to nitroolefin 3a under different
conditions.[a]
As part of our ongoing research towards nucleophilic
addition of polar organometallic compounds to carbonyl
compounds,[12a–d] imines,[12e,f] styrene derivatives,[12g] amides,[12h]
and nitriles[12f,i] in the so-called Deep Eutectic Solvents (DESs)[13]
and water, we first investigated the addition of Et2Zn (4a) (1.0 M
in hexanes) (1.2 equiv) to conjugated nitroolefin 3a (0.5 mmol) in
two prototypical choline chloride (ChCl)/glycerol (Gly) (1:2
mol/mol) and ChCl/urea (1:2 mol/mol) eutectic mixtures. By
running the reaction at room temperature (RT, 25 °C) and under
air, only the starting nitroolefin 3a was quantitatively recovered
(Table 1, entries 1,2). The use of D-(–)-fructose as the hydrogen
bond donor in combination with ChCl (2:1 mol/mol), in a sonicator
bath (40 kHz; 50 W) (due to the increased viscosity of the reaction
medium at RT), led to a complete disappearance of olefin 3a with
formation of a mixture of 5ac and 6 in a 80:20 ratio, with olefin 6
being the result of the nucleophilic displacement of the nitro group
by the ethyl group (Table 1, entry 3). It is worth noting that, under
the aforementioned conditions, the nucleophilic addition of 4a
took place smoothly within 30 min reaction time in the absence of
any additional ligand and/or a copper source, which are usually
essential ingredients for this reaction.[14] DESs are known to act
not only as solvents but also as catalytic active species
contributing to exalting the electrophilicity/nucleophilicity of a
certain reaction partner by hydrogen-bonding interactions.[13c,15]
Upon switching 4a for zincate Et3ZnLi (4b) in the fructose-based
eutectic mixture, the 5ac/6 ratio became 90:10 (full conversion)
(Table 1, entry 4). Similar results were obtained at RT with the
use of the more nucleophilic zincate complex Et4ZnLi2, (4c)
prepared by mixing 2 equiv of EtLi (0.5 M benzene/cyclohexane)
with Et2Zn (see Supporting Information) (Table 1, entry 5).
organozinc
NO2
NO2
Et
4a: Et2Zn
4b: Et3ZnLi
4c: Et4ZnLi2
species (4)
+
solvent, T
30 min
Ph
Ph
Et
Ph
3a
5ac
6
Entry
4
Solvent
T (°C)
Conv. (%)
5ac:6[b]
[c]
1
2
3
4
5
6
7
8
9
4a
4a
4a
4b
4c
4c
4c
4c
4b
ChCl/Gly
25
25
25
25
25
0
0
–
[c]
ChCl/urea
0
–
D-(–)-fructose/ChCl[d]
D-(–)-fructose/ChCl[d]
D-(–)-fructose/ChCl[d]
full
full
full
full
full
90
full
80:20
90:10
90:10
>98:2[f]
90:10
>98:2[g]
91:9
[e]
–
[e]
–
25
0
[e]
–
[e]
–
0
[a] Reaction conditions: 1.0 g DES per 0.5 mmol of 3a; ChCl/Gly (1:2 mol/mol);
ChCl/urea (1:2 mol/mol); D-(–)-fructose/ChCl (2:1 mol/mol); 1.2 equiv organozinc
species. [b] Ratio determined by 1H NMR analysis of the crude reaction mixture.
[c] No reaction. [d] Reaction performed in a sonicator bath. [e] With no additional
solvents. [f] 98% yield of isolated product. [g] 4c: 0.6 equiv; 89% yield of isolated
product.
Given the scarcity of structural and spectroscopic data on
the constitution of tetraorganozincates,[21] 4c was isolated as a
colourless oil and characterised by multinuclear magnetic
resonance studies, including DOSY experiments (see Supporting
Information for details). Supporting the formation of Et4ZnLi2, a
distinct quartet at -0.40 ppm is observed in the 1H NMR spectrum
in [D8]-toluene solution for the Zn-CH2 groups. Consistent with the
increased anionic character, this resonance is significantly
shielded compared to that observed for 4b (at -0.13 ppm) and to
that of Et2Zn (at 0.17 ppm). Contrasting with previous work from
Mobley and Berger on Me4ZnLi2 species (vide supra), low
temperature NMR studies of 4c showed no evidence of a dynamic
Remarkably, the one-shot, rapid addition of 4c to 3a,
performed at 0 °C, under nitrogen and with no additional solvents,
produced adduct 5ac in 98% isolated yield as the sole product
(Table 1, entry 6). Of note, either the strict exclusion of air or
lowering the temperature to 0 °C, proved to be crucial to increase
even more the yield of 5ac and to completely suppress the
formation of 6 as a by-product (contrasting with the results
observed when the reaction is carried out at RT; Table 1, entry 7).
Organozinc compounds are known to be able to initiate the
formation of alkyl radicals through the reaction with oxygen,[16] and
the alkyl substitution at the vinylic carbon is supposed to take
place via a radical pathway.[7] This could explain our own results.
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equilibrium between this tetraorganozincate and 4b in [D8]-
tetraorganozincates 7a and 8 proved to be active towards the
transfer of an ethyl group to 3a, although they showed diminished
reactivity in comparison to donor-free 4c, thereby affording 5ac in
76 and 70% yield, respectively.[25]
toluene solutions (even at -50 oC).
nEtLi
+
Et2Zn
n = 2
n = 1
Et3ZnLi
4b
Et4ZnLi2
4c
N
(2 equiv)
N
TMEDA
(2 equiv)
N
Et
Et
Et
Et
Zn
N
N
N
N
N
N
EtLi
Li
Li
Zn Et
Li
N
Et
Et
7b
Figure 1. Molecular structures of [Et4ZnLi2(TMEDA)2] (7a) (LHS) and
[{Li(TMEDA)2}+{ZnEt3}−] (7b) (RHS). Hydrogen atoms are omitted for clarity and
thermal ellipsoids are rendered at 50% probability.
7a or 8
=
N
TMEDA, 7a; (R,R)-TMCDA, 8
N
NMe2
NMe2
TMEDA =
Me2N
(R,R)-TMCDA =
NMe2
Scheme 2. Synthesis of lithium zincates 4b,c, 7a,b and 8.
In an attempt to trap and structurally characterise a
tetraethylzincate intermediate, 2 equiv of the bidentate N-donor
ligands TMEDA (N,N,N',N'-tetramethylethylenediamine) and of
chiral
(R,R)-TMCDA
[(R,R)-N,N,N',N'-tetramethyl-1,2-
diaminocyclohexane] were added to in situ prepared solutions of
4c with the aim of facilitating crystallisation. These reactions led
to the isolation of [Et4ZnLi2(N-N)2] (N-N = TMEDA, 7a; (R,R)-
TMCDA, 8) as crystalline solids in 70 and 82% yields, respectively
(Scheme 2). The molecular structures of 7a and 8 were
established by X-ray crystallographic studies confirming the
presence of the Et4ZnLi2 fragment (Figures 1 and 2).
Addition of 2 equiv of TMEDA to triorganozincate 4b
furnished [{Li(TMEDA)2}+{ZnEt3}−] (7b) which can be
quantitatively transformed into 7a by addition of 1 equiv of EtLi
(Scheme 2). Comparison of the 1H NMR spectra of TMEDA
adducts 7a and 7b in [D8]toluene showed the same trend in the
chemical shifts for the Zn-CH2 groups as that observed for 4b and
4c (vide supra) (δ: -0.25 ppm for 7a vs 0.15 ppm for 7b) consistent
with the increased anionic character of tetraorganozincate 7a. It
should also be noted that 1H and 7Li NMR monitoring of solutions
of 7a showed no evidence of disproportionation of this
tetraorganozincate into 7b and EtLi (see Supporting Information
for details). X-ray crystallographic studies established a solvent-
separated ion pair structure for 7b, with Zn being coordinated to
three ethyl groups in a trigonal planar environment with an
average Zn-C bond distance of 2.036 Å, whereas Li being
Figure 2. Molecular structure of [Et4ZnLi2(R,R)-TMCDA)2] (8). Hydrogen atoms
are omitted for clarity and thermal ellipsoids are rendered at 50% probability.
Having established the optimal conditions for the
chemoselective nucleophilic addition of 4c to olefin 3a, we sought
to capitalise on this process by exploring the scope of this reaction
(Table 2). Assorted arylnitroolefins with a methyl substituent (3b),
a fluorine atom (3d), electron-withdrawing (chlorine, bromine,
trifluoromethyl) (3c, 3f, 3g) or electron-donating groups (MeO)
(3e) at the ortho-, meta-, and para-positions could be efficiently
reacted with aliphatic tetraorganozincates such as Et4ZnLi2 (4c),
n-Bu4ZnLi2 (4d), n-Hexyl4ZnLi2 (4e), i-Pr4ZnLi2 (4f) and t-Bu4ZnLi2
(4g) delivering the expected adducts 5ad, 5bc–5gc, 5bd, 5ed,
5be, 5bf, and 5ag in very good yields (65–98%). Nitroolefins
decorated with electron-rich heterocycles (2-furyl, 2-thienyl) (3h,i)
also served as competent electrophilic partners, and afforded in
the reaction with 4c the adducts 5hc and 5ic in 75–85% yield.
Next, we focused on the challenging conjugate addition promoted
by an aromatic organozincate reagent like Ph4ZnLi2 (4h).[11]
Arylation of β-nitrostyrenes has been realised so far only via
Rh(II)- or Pd(II)-catalysed addition reactions with boronic acids or
arylsiloxanes.[26] In some preliminary experiments, we found that
the addition of PhLi to nitroolefin 3a gave only a complex mixture,
whereas Ph2Zn resulted totally unreactive. Highlighting the
remarkable synergistic power of these bimetallic reagents,
addition of 4h to 3a provided adduct 5ah in 96% yield. Similarly,
the addition of 4h to nitroolefins 3b–i proceeded smoothly and
delivered the desired diarylated adducts 5bh–5ih in 50–70% yield.
Trimethoxy and dimethylamino aryl derivatives 3j,k reacted
smoothly as well with 4h to give functionalised nitroalkanes 5jh
and 5kh, each in an excellent yield (98%). Gratifyingly, heteroaryl
organozincate (2-thienyl)4ZnLi2 (4i) also proved to be a competent
nucleophilic partner, and in the reaction with nitroolefins 3f and 3k
led to the addition products 5fi and 5ki in satisfactory yields (69–
89%). These examples of transition metal-free arylation reactions
expand even further the synthetic potential of tetraorganozincate
reagents as versatile reagents, combining an enhanced
nucleophilic power with an exceptional functional group tolerance
and selectivity, for promoting important C–C bond-forming
reactions.
solvated by two chelating TMEDA ligands in
a distorted
tetrahedral geometry (Figure 1). This motif is reminiscent of that
+
−
reported by Stalke for {{Li(diglyme)2} {ZnMe3} }, which is obtained
by mixing MeLi and Me2Zn in equimolar amounts with diglyme.[22a]
Contrastingly, 7a and
8
display contacted-ion pair
arrangements in the classical Weiss motif mould,[23] with trinuclear
arrangements adopting a pseudolinear disposition where each Et
bridge connects the central Zn to an outer Li atom (Figures 1,2).
Since both structures are closely related, only 8, which is a rare
example of a chiral zincate, will be described here (see
Supporting Information for full structural details). As expected,
due to this bridging coordination of the Et groups, the Zn-C
distances in 8 are elongated (mean value, 2.125 A) with respect
to those found in 7b. Each Li completes its distorted tetrahedral
coordination by binding to a chelating TMCDA donor. DOSY NMR
studies are consistent with the retention of this structure in [D8]-
toluene solution (see Supporting Information). As far as we can
ascertain, this is the first example of a structurally defined zincate
with
a
chiral donor.[24] It should be noted that both
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Table 2. Nucleophilic addition of tetraorganozincates 4c–i to nitroolefins 3a–k: scope of the reaction.[a]
3a: Ar = Ph; 3b: Ar = 4-tolyl; 3c: Ar = 4-ClC6H4; 3d: Ar = 4-FC6H4;
3e: Ar = 2-MeOC6H4; 3f: Ar = 3-BrC6H4; 3g: Ar = 4-CF3C6H4; 3h: Ar = 2-furyl;
3i: Ar = 2-thienyl; 3j: Ar = 3,4,5-(MeO)3C6H2; 3k: Ar = 4-Me2NC6H4
R4ZnLi2 (4) (1.2 equiv)
NO2
NO2
with no additional solvents
5
4c: R = Et; 4d: R = n-Bu; 4e: R = n-Hexyl;
4f: R = i-Pr; 4g: R = t-Bu; 4h: R = Ph; 4i; R = 2-thienyl
Ar
R
3
Ar
0 °C, 30 min
NO2
NO2
NO2
NO2
NO2
NO2
NO2
OMe
Br
3
F3C
Me
Cl
F
5ad: [65%, 3a, 4d
66%, 3a, n-Bu4ZnNa2 (16)]
5bc: (90%, 3b, 4c)
5cc: (89%, 3c, 4c) 5dc: (90%, 3d, 4c) 5ec: (80%, 3e, 4c) 5fc: (98%, 3f, 4c)
5gc: (80%, 3g, 4c)
NO2
3
NO2
5
NO2
NO2
NO2
NO2
NO2
3
NO2
OMe
S
O
Me
Me
Me
5ah: (96%, 3a, 4h)[b]
5bd: (98%, 3b, 4d) 5ed: (98%, 3e, 4d) 5be: (90%, 3b, 4e) 5bf: (70%, 3b, 4f) 5ag: (73%, 3a, 4g)
5hc: (75%, 3h, 4c) 5ic: (85%, 3i, 4c)
NO2
NO2
NO2
NO2
NO2
NO2
NO2
OMe
Br
o
F3C
F
Me
Cl
5bh: (60%, 3b, 4h)
5ch: (60%, 3c, 4h) 5dh: (70%, 3d, 4h) 5eh: (50%, 3e, 4h) 5fh: (69%, 3f, 4h)
5gh: (70%, 3g, 4h) 5hh: (60%, 3h, 4h)
NO2
S
NO2
NO2
NO2
S
NO2
MeO
MeO
Br
S
Me2N
5ki: (89%, 3k, 4i)
Me2N
5kh: (98%, 3k, 4h)
OMe
5ih: (60%, 3i, 4h)
5jh: (98%, 3j, 4h)
5fi: (69%, 3f, 4i)
[a] Yields of isolated product. [b] With PhLi: complex mixture; with Ph2Zn: no reaction.
Table 3. Nucleophilic addition of 4c to β-nitroacrylates 9a–e and β-nitroenones
12a–c.[a]
chemoselectivity with 4c leading to adducts 10ac, 10bc, 10cc,
10dc, and 13ac (in which either the ester or the carbonyl moiety
remained untouched) in 70–98% yield. In the case of nitroacrylate
9e and β-nitroenones 12b,c, spontaneous hydrolysis of the nitro
group (Nef reaction) took place during the work-up procedure,[29]
thereby providing β-ketoester 11ec and β-diketones 14bc and
14cc, respectively, as the final products in 70–80% yield.
Since only homoleptic zincates were used in these reactions,
we next assessed the selectivity on transfer of the anionic moiety
to 3a by using heteroleptic systems which combine
simultaneously aryl and alkyl groups (Scheme 3). Using a co-
complexation approach as depicted in Scheme 1, R2Ph2ZnLi2 (R=
CH2SiMe3, 4j) was prepared in situ by mixing Ph2Zn and RLi in a
1:2 ratio in hexane (Scheme 3). The monosilyl CH2SiMe3 group
was chosen as previous studies on zinc-catalysed additions of
Grignard reagents to carbonyl compounds from Ishihara have
described this group as a dummy ligand with poor transfer
R1
R1
Et
R1
Et
O
NO2
OR2
10
or
OR2
Et
R1
Et
R1
R1
NO2
OR2
NO2
R2
12
11
Et4ZnLi2 (4c)
O
O
O
or
with no additional
solvents
0 °C, 30 min
NO2
R2
13
9
or
O
O
R2
14
O
O
9a: R1 = PhCH2CH2, R2 = Et; 9b: R1 = CH3(CH2)5, R2 = i-Pr; 9c: R1 = CH3(CH2)4, R2 = Et;
9d: R1 = Et, R2 = Pr; 9e: R1, R2 = Et; 12a: R1 = PhCH2CH2, R2 = Ph;
12b: R1 = Et, R2 = Ph; 12c: R1 = Et, R2 = t-Bu
NO2
NO2
OEt
NO2
OPr
NO2
Oi-Pr
Ph
2
4
5
OEt
Et
Et
Et
Et
O
O
O
O
10ac: 70%[b] 10bc: 98%[c] 10cc: 88%[d] 10dc: 89%[c]
capabilities when part of
a
magnesium triorganozincate
O
O
NO2
Ph
O
Ph
2
complex.[30] The reaction of 4j with nitroolefin 3a afforded 5ah in
a modest 20% yield [contrasting with the almost quantitative yield
(96%) observed when using Ph4ZnLi2 (4h) as an arylating
reagent; Scheme 3, Table 2], being the major product of the
reaction the alkyl-substituted adduct 5aj (41% yield) resulting
from the transfer of a monosilyl group. The yield for 5aj could be
increased to 88% when using homoleptic (CH2SiMe3)4ZnLi2 (4k).
While these studies showed poor control of the selectivity when
using heteroleptic reagents, they also revealed that by forming
more reactive lithium tetra(organo)zincates it is possible to
activate, the bulky and usually inert, CH2SiMe3 group to engage
in addition reactions.[31]
Ph
t-Bu
OEt
Et
Et
Et
13ac: 77%[e]
Et
O
O
O
O
14cc: 70%[f]
11ec: 80%
14bc: 80%
[a] Yields of isolated product; 0.5 mmol 9, 1.2 equiv Et4ZnLi2 (4c). [b]
Separable mixture (60:40) of diastereomers. [c] Inseparable mixture (60:40)
of diastereomers. [d] Separable mixture (43:57) of diastereomers. [e]
Separable mixture (45:55) of diastereomers. [f] In CD3Cl solution, 14cc was
found to equilibrate to the corresponding enolic form (see Experimental).
To further quantify the synthetic scope of this protocol, we
also investigated the reactivity of tetraorganozincate 4c towards
β-nitroacrylates,[27a,b] which are useful building blocks en route to
β2-amino acids,[28] and β-nitroenones.[27c,d] As shown in Table 3,
the phenylethyl-, the hexyl-, the pentyl- and the ethyl-substituted
nitroacrylates 9a–d and the aliphatic and aromatic β-nitroenones
12a–c reacted with good reaction efficiency and high
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3a was reacted with sodium zincate n-Bu4ZnNa2 (16) (prepared
by co-complexation of 2 equiv of n-BuNa with n-Bu2Zn) which
afforded alkylation product 5ad in a 66% yield, almost identical to
that observed when using the lithium analog n-Bu4ZnLi2 (4d)
(65%) (Table 2).
NO2
Ph
NO2
R
NO2
NO2
Ph4ZnLi2 (4h)
R2Ph2ZnLi2 (4j)
+
0 °C, 30 min
0 °C, 30 min
Ph
Ph
3a
Ph
Ph
Ph
5ah: 20%
5aj: 41%
5ah: 96%
R4ZnLi2 (4k)
0 °C, 30 min
NO2
R = CH2SiMe2
2 RLi
+
R2Ph2ZnLi2 (4j)
Ph2Zn
Ph
R
Conclusions
5aj: 88%
In summary, the first transition metal-catalyst- and ligand-free
nucleophilic additions of lithium tetraorganozincates to nitroolefins
to provide valuable nitroalkanes are described. These reactions
take place smoothly, with high chemoselectivity, under mild
conditions (0 °C) and with a broad substrate scope without
additional solvents. Structural and spectroscopic studies probing
the constitution of these bimetallic systems support the formation
of highly nucleophilic lithium tetra- and trialkyl-zincates and
highlight the influence that donor additives can have not only in
the aggregation and structure of these reagents but also in their
stoichiometry. Further extension of this bimetallic research to its
asymmetric version is currently being pursued in our laboratories.
Scheme 3. Assessing arylation/alkylation reactions of 3a using heteroleptic and
homoleptic zincates.
Finally, in an attempt to glean some information on the
potential involvement of lithium in these transformations and on
whether its possible interaction with the unsaturated organic
substrate could also be an important factor on favoring these C-C
bond-forming processes, 4c was reacted with 3a in the presence
of 4 equiv of 12-crown-4 (which is known to block the Li
coordination sites). Under these conditions, 5ac was obtained in
almost identical yield (95%) than in the absence of this
macrocyclic Lewis donor (98%), suggesting that Li plays a
secondary role in these alkylations, providing stabilisation to the
anionic zincate intermediates. Interestingly, in a recent paper, the
fast, direct conjugate addition of organozinc halides to non-
enolizable enones observed in 1,2-dimethoxyetane (DME) has
been rationalised in terms of the ability of DME to chelate with
both its oxygen atoms one of the Li ions present in the transition
state. This contributes to lower the activation energy of the
reaction with respect to what has been seen for THF.[32]
Acknowledgements
This work was carried out under the framework of the National
PRIN project “Unlocking Sustainable Technologies Through
Nature-Inspired Solvents (Code: 2017A5HXFC_002) and
financially supported by MIUR, the Interuniversity Consortium
C.I.N.M.P.I.S., the University of Bari (codes: PernaF.18
FondiAteneo15-16, VitaleP.18 Fondi Ateneo 15-16) and the
European Research Council (ERC-Stg MixMetApps to EH). The
authors are also indebted to Albermarle for the generous gift of
chemicals, to Professor Dieter Seebach for valuable, insightful
discussions, and to Dr. Alba Rubino and Dr. Lucia Caruso for their
contribution to the experimental section.
Further investigations on the constitution of 4c, upon the
addition of
2
equiv of 12-crown-4, also revealed that
a
disproportionation
process was induced furnishing
triorganozincate [{Li(12-crown-4)2}+{ZnEt3}-] (15) as a crystalline
solid along with EtLi. X-ray crystallographic studies confirmed the
solvent-separated structure of 15 with the lithium atom being
coordinatively saturated, sandwiched between two crown ether
ligands, and Zn coordinated to three ethyl groups forming the
same anion present in 7b (Figure 3). It should be noted that while
previous work in alkali-metal zincate chemistry has unlocked the
key role that donor additives can play in aggregation and structure
of these bimetallic systems,[22] the formation of 15 is a rare
example where the Lewis donor (12-crown-4) also facilitates a
disproportionation process. The similar yields obtained in the
formation of 5ac, when 3a is reacted with tetraorganozincate 4c
or triorganozincate 15, mirror the conversions reported in Table 1
when comparing the reactivities of 4c and 4b (vide supra).
Keywords: zincate • addition • lithium • nitroolefins • arylation
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Organozinc chemistry
COMMUNICATION
The
organozinc
metamorphosis
of
Marzia Dell’Aera, Filippo Maria Perna,
Paola Vitale, Angela Altomare,
reagents!
Transforming neutral R2Zn into
nucleophilic R4ZnLi2 zincate
complexes enabled chemoselective
alkylation/arylation of nitroolefins to
give 1,4-addition adducts in up to
Alessandro Palmieri, Lewis C. H.
Maddock, Leonie J. Bole, Alan R.
Kennedy, Eva Hevia,* Vito Capriati*
Page No. – Page No.
98%
spectroscopic
confirmed the dianionic-type nature
of these species and the key role of
donor additives in their aggregation
and structure.
yield.
Structural
and
Boosting Conjugate Addition to
investigations
Nitroolefins
Using
Lithium
Tetraorganozincates:
Synthetic
Strategies and Structural Insights
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