Ionic Ga-Complexes of Alkylidene- And Arylmethylidenemalonates and Their Reactions with Acetylenes: An In-Depth Look into the Mechanism of the Occurring Gallium Chemistry

Article abstract of DOI:10.1021/jacs.8b08913

A new synthetic concept was suggested in the chemistry of substituted methylidenemalonates that enables their utilization as 1,2-zwitterionic synthons. This strategy is to generate liquid ionic Ga complexes from methylidenemalonates and GaHal₃with a strict 3/4 composition and then use them in further synthesis. A number of complexes with different metal halides have been synthesized and studied in detail. The unique properties of gallium among all metals have been demonstrated and explained. On the basis of the discovered new class of gallium complexes of methylidenemalonates, a number of novel reactions with acetylenes have been elaborated, which are unknown in the conventional chemistry of methylidenemalonates. The main demonstrated process is a three-component addition to a triple bond involving halide anions, leading to the formation of polyfunctional vinyl halides with highE-selectivity. The mechanism has been studied experimentally in fine detail. Application of specially optimized⁷¹Ga NMR spectroscopy makes it possible to take an in-depth look into the gallium chemistry in a new light. In particular, the key participation of GaHal₄^-anions in the occurring transformations has been established.

Full text of DOI:10.1021/jacs.8b08913

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Article
Ionic Ga-Complexes of Alkylidene- and Arylmethylidenemalonates,
and Their Reactions with Acetylenes. An In-depth Sight
into the Mechanism of the Occurring Gallium Chemistry.
Roman A. Novikov, Dmitry A. Denisov, Konstantin V. Potapov,
Yaroslav V. Tkachev, Evgeny V. Shulishov, and Yury V. Tomilov
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08913 • Publication Date (Web): 02 Oct 2018
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Ionic Ga-Complexes of Alkylidene- and Arylmethylidenemalonates,
and Their Reactions with Acetylenes. An In-depth Sight into the Mech-
anism of the Occurring Gallium Chemistry.
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Roman A. Novikov,*,§,†,‡ Dmitry A. Denisov,§,† Konstantin V. Potapov,† Yaroslav V. Tkachev,‡ Evgeny
V. Shulishov,† and Yury V. Tomilov*,†
† N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russian
Federation
‡ Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov st., 119991 Moscow, Russian Federa-
tion
KEYWORDS. Gallium, Methylidenemalonates, Ionic Complexes, Acetylenes, Trans-Addition, Vinyl Halides, 71Ga NMR.
ABSTRACT: A new synthetic concept was suggested in the chemistry of substituted methylidenemalonates, which enables
their utilization as 1,2-zwitterionic synthons. This strategy is to generate liquid ionic Ga complexes from methylidenemalo-
nates and GaHal3 with a strict 3/4 composition, and then use them in further synthesis. A number of complexes with differ-
ent metal halides have been synthesized and studied in detail. The unique properties of gallium among all metals have been
demonstrated and explained. Based on the discovered new class of gallium complexes of methylidenemalonates, a number
of novel reactions with acetylenes has been elaborated, which are unknown in conventional chemistry of methylidenemalo-
nates. The main demonstrated process is a three-component addition to a triple bond involving halide anions and leading to
the formation of polyfunctional vinyl halides with high E-selectivity. The mechanism has been studied experimentally in fine
detail. Application of specially optimized 71Ga NMR spectroscopy makes it possible to take an in-depth look into the gallium
–
chemistry in a new light. In particular, the key participation of GaHal4 anions in the occurring transformations has been
established.
many types to be altered completely. Using common com-
INTRODUCTION
pounds such as alkenes,7 acetylenes,8 aldehydes,9 diazo
ethers,10 etc. in the reactions, diverse carbo- and heterocy-
clic structures can be assembled on the basis of 1,2-
zwitterions 2 generated (Scheme 1). No doubt, the 1,2-
zwitterionic chemistry of DAC is already a very important
and significant concept in synthesis.
Donor-acceptor cyclopropanes (DACs)1 are a broad class
of substituted three-membered carbocycles.2 They are
known for their capability to undergo small ring opening
to act as 1,3-zwitterionic synthones.3 Owing to this feature,
they are currently popular in organic synthesis4 and have
become quite ordinary building blocks. However, current
challenges of organic synthesis require that ever more so-
phisticated and nontrivial methods be developed for syn-
thesizing complex polyfunctional structures from simple
starting compounds in a minimum number of stages. This
is required because of the increasing demands for the crea-
tion of new biologically active compounds, pharmaceutical
agents, functional materials, catalysts, etc. It might seem
that DACs have been studied so well1–4 that their chemistry
is already exhausted in the sense of creating something
fundamentally new. However, this is by no means true, and
new studies currently continue to appear where quite non-
trivial ways of their application are considered.5
Scheme 1. Utility of the gallium 1,2-zwitterions in D–A
cyclopropane chemistry.
One of these cutting-edge approaches6 that appeared
and was actively developed in the past few years involves
the use of DACs as sources of 1,2-zwitterions.7–10 The
method is based on the use of gallium compounds and al-
lows the reaction pathways of DACs 1 with substrates of
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Taking into consideration the above facts and the obvi- 1/1 intermediate complex at –70 °С by means of spectros-
1
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8
ous structural limitations for generation of 1,2-zwitterions
from DACs, an obvious question arises: can such 1,2-
zwitterions be generated from the corresponding unsatu-
rated precursors? The answer seems self-evident: substi-
tuted methylidenemalonates would be very convenient
sources since 1,2-zwitterions are in fact their complexes
with a strongly polarized double bond (Scheme 2). Every-
thing appears very simple, but no developments of this
kind have been reported in the literature. This concept is
certainly rather close to the classical Michael chemistry of
alkylidenemalonates, but would these reactions occur in a
similar way? Moreover, yet another question arises: would
gallium halides manifest their unique properties here as
well, and if yes, to what extent?
copy). If the reagents are mixed in a smaller ratio than 3/4,
then the NMR spectra contain a double set of signals that
belong to the individual complex 5 and the free ligand 3. It
is interesting to note that pure complex 5 is a liquid; ap-
parently it is some analogue of ionic liquids.15,16
Scheme 3. Formation of the different type of complexes
with metal halides from DACs and methylidenemalo-
nates.
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Scheme 2. Concept of this work.
RESULTS AND DISCUSSION
At the first step, it was necessary to study the possible
formation of methylidenemalonate complexes with various
metal halides. It was found that methylidenemalonates 3
are rather good bidentate ligands that readily coordinate
metal atoms at the two carbonyls of the ester groups. This
causes a polarization of the C=C bond, and its strength can
1
be monitored by the downfield shifts of CH in the H and
13C NMR spectra.6b In most cases, 1/1 covalent complexes
4 are formed, e.g., with SnCl4, TiCl4, ZnCl2, etc. (Scheme 3).
The coordination of the metal in these complexes is not
very strong, as the gradual change in the chemical shifts
upon varying the reagent ratio confirms. ZnCl2 is coordi-
nated much more weakly.
Quite a different picture is observed in the complexation
with GaCl3. In this case, ionic complex 5 with a strict 3/4
composition is formed, in which three methylidenemalo-
nate ligands are coordinated to one gallium atom (Scheme
3). They replace three chloride ions at that gallium atom,
–
which then form three GaCl4 anions. The structure of the
complex was thoroughly studied using NMR spectroscopy
(Figures 1 and 2), including that on 71Ga atoms,11,14 and 2D
experiments (see also Supp. Inf.). Complexes with similar
structures have been reported in only a few cases,12,13 and
we studied them just recently using model ligands, diethyl
malonate and cyclopropanedicarboxylate, as an example.14
It was found that complexes 5 had a surprisingly stable
and beneficial structure. They were readily formed upon
mixing the reagents even at low temperatures and did not
decompose on heating up to 100 °C (we failed to detect the
Figure 1. Characteristic NMR spectra for ionic Ga complex 5b
(X=Br) in CD2Cl2 (left). H NMR spectra of neat 5b and its so-
1
lution in CD2Cl2 at +30 °C. (right). 71Ga NMR spectrum (after
deconvolution) of neat 5b demonstrated two types of Ga at-
oms in the complex (middle). Samples of complexes 5a–c in
NMR tubes in CD2Cl2; at the bottom of the tubes neat liquid Ga
complexes can be seen that are analogs of ionic liquids.
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Figure 2. 71Ga NMR spectra of complexes 2a (top, ref. [6b])
and 5a (bottom) demonstrating a fundamental difference in
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the environment of Ga atoms. Small and highly symmetrical
GaCl4– anions have a much narrower signal with a characteris-
tic chemical shift of ca. +250 ppm.
Figure 3. 1H NMR spectra for complexes 5a,b (Hal = Cl, Br) at
different temperatures in the range from –50 °C to +30 °C
(CH and CO2Me regions are shown); these spectra show the
presence of two stereoisomers A and B in solution at low
temperatures, while at temperatures above –20 °С they are
averaged due to rotation around the polarized C-C double
bond. At the top, isomers A and B are presented, as well as
their simplified projection in an orange frame.
The C=C double bond in the malonate moiety of complex
5 is strongly polarized, much more strongly than upon
coordination of malonate 2 with SnCl4 or TiCl4 (complexes
4), despite the fact that three malonate ligands at once are
bound to one gallium atom in complex 5. The strength of
polarization matches that in complex 2 formed from a
DAC,6b though the structure of this complex differs from
that of the GaCl3 complex with methylidenemalonates (5a–
e).

+
We have also carried out detailed studies of complex 5a
by mass spectrometry method (ESI-HRMS) (Scheme 4).
Unfortunately, it turned out that this method is poorly
suited for the study of such complexes, since they are un-
stable under the conditions of the extremely dilution nec-
essary for the recording of mass spectra. Thus, using ESI-
HRMS we were able to detect the GaCl4-anions (in negative
masses), as well as the free ligand 3a and its dimer in mi-
nor amounts (Scheme 4). The cation part of any gallium
complexes could not be detected (using any solvents in-
cluding common MeCN and CH2Cl2). EI-MS was failed to
detect any species except the ligand 3a. In order to study
the nature of the destruction of complexes 5, we have car-
ried out the reaction of 5a with a large excess of acetoni-
trile. 71Ga NMR studies show the ligand exchange in the
cationic part of 5a with preservation of GaCl4-anions
(Scheme 4). Herewith, an octahedral cation [Ga3+(MeCN)6]
is formed.
The complexation of methylidenemalonates 3 with AlCl3
or EtAlCl2 gives rise to a mixture of a few hardly identifia-
ble complexes and is apparently of intermediate nature. In
–
this case, partial formation of AlCl4 anions within the
complexes is also observed.
There is a very interesting situation with the stereo-
chemistry of complexes 5. The fact is that the ligand 3 is
not symmetrical in terms of R-substituent. As a result, from
the theoretical point of view complexes 5 can exist as two
stereoisomers A and B with different relative positions of
the C=CH(R) fragments (Figure 3). From statistical consid-
erations the ratio of stereoisomers A and B should be 1/3.
These facts are excellent confirmed by detailed studies of
the complexes 5 by means of NMR spectroscopy at various
temperatures (Figure 3). At temperatures below –20 °C, 4
signals of each type are observed in the spectra with equal
intensities (for both CH fragments and for each of the MeO-
groups). From the considerations of symmetry, isomer B
should give three signals, and isomer A — a single signal
with tripled intensity. Taking into account the ratio of the
isomers of A and B as 1/3, this gives the observed picture
(Figure 3). When heated to +30 °C, all 4 signals collapse
into one for all types of groups. It is very important fact,
because it is an evidence of the strong polarization of C=C
double bond and its high semi-double character, which
allows it to rotate at temperatures above –20 °C.
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Scheme 5. Formation of complexes with Ga halides
from DACs and isomeric benzylmethylidenemalonates.
1
2
3
Scheme 4. Mass spectrometric studies of complex 5a,
and its partial decomposition by MeCN.
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The formation of ionic complexes 5 from methyli-
denemalonates allows their usual reactivity to be changed
completely. The next stage involved a study of their new
interesting chemistry. In this paper, we focused our atten-
tion on the carbocationic processes characteristic of the
gallium chemistry of DACs7,8 — mainly reactions with
acetylenes that allow a number of new processes to be
performed (Scheme 6). Apparently, it is just the first chap-
ter of their new interesting gallium chemistry.
Benzylmethylidenemalonates (1´) noticeably differ from
other substituted methylidenemalonates 3 in their behav-
ior upon reaction with Ga halides, and are similar in this to
D–A cyclopropanes 1 (Scheme 5). They can form two types
of complexes 2 and 5 depending on the conditions, one of
the main of which is the used excess of Ga halide. Here-
with, the initially formed complexes 2 transform into ionic
complexes 5 under certain conditions. The latter precipi-
tate as a thick oil and are not very stable in this state. They
are easily dimerized and oligomerized by analogy with D-A
cyclopropanes.3g The processes of formation of complexes
2/5 have been studied in detail by NMR spectroscopy on
the example of reaction of 1a and 1a´ with GaCl3 (Scheme
5). And the previous data6,7b were refined and supple-
mented. NMR spectra for both complexes are similar to
those shown in Figure 2. Benzylmethylidenemalonates 1´
with other aryl substituents react similarly.6,7b Also, we
have synthesized the stable ionic complex 5g based on
sterically hindered ortho,ortho-Me2-substituted malonate
1b´ and GaBr3 (Scheme 5), used for additional structural
assignments. Obtained structural data allow to look deeper
at the "gallium" reactions of D–A cyclopropanes, which
have a significant synthetic utility.7–10 It should be noted
that the 1/1 gallium complexes like 2 from other methyli-
denemalonates are highly unstable and were not detected.
Scheme 6. Some reactions of ionic Ga complexes 5.
The reaction with acetylenes 6 was found to be a con-
venient model process for studying and demonstrating the
synthetic potential of ionic gallium complexes 5. In this
case, it is not necessary to generate this complex before-
hand: it is sufficient to mix all the reagents at once, which
simplifies the synthetic protocol. Apart from GaCl3, it was
interesting to study the behavior of other Lewis acids and
metal halides in this reaction (Table 1). It should be noted
that, despite its simplicity, the combination of these sub-
strates was not reported in literature. However, a number
of similar examples was described, especially the intramo-
lecular version of the reactions or the use of specific types
of malonates but without the participation of gallium(III).17
In the present work, the main process that we designed is
a three-component addition to a triple bond involving hal-
ide anions and leading to formation of polyfunctional vinyl
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halides. Vinyl halides are very convenient building blocks
Table 2. Optimization of the reaction conditions. a
1
2
in organic synthesis and promising compounds for further
modifications.18
Table 1. Screening of different Metal Chlorides. a
3
4
5
6
7
8
9
Metal Chloride
(1 equiv.)
Yield,
(%) b
Entry
T, (°C) t, (h)
Entry
Metal Chloride
GaCl3
Yield, (%) b,c
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1
EtAlCl2
EtAlCl2
EtAlCl2
EtAlCl2
GaCl3
–78
0
1
0
1 d
2
70
25
37
26
39
<5
0
2
2
19
21
37
45
60
62
64
70
39
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34
AlCl3
3
rt
0.33
2
3
EtAlCl2
Et2AlCl
FeCl3
4
rt
4
5
rt
2
5
6
GaCl3
0
0.5
3
6
SnCl4
7
GaCl3
0
7
TiCl4
8
GaCl3
–10
–20
–78
–78
0
0.5
1
8
ZnCl2
0
9
GaCl3
9
InCl3
0
10
11
12
13
14 c
15 d
16 e
GaCl3
0.5
1
10
GeCl4
0
GaCl3
11
SbCl5
0
GaCl3 (0.7 equiv.)
GaCl3 (1.5 equiv.)
GaCl3
0.5
2
a
General conditions: 0.75 mmol of 3a in 7–8 mL CH2Cl2;
rt
b
c
treatment of the r.m.: HCl/H2O (5–10%). NMR yields. Max-
imum (optimized) yields are given. d –20 °С, 1 h.
0
0.5
0.5
2
GaCl3
0
We used benzylidenemalonate and phenylacetylene as
the model substrates (Table 1). The reaction was found to
be quite sensitive to the nature of the Lewis acids. Moreo-
ver, like in the DAC chemistry, gallium halides were unique
in this process, too. It was GaCl3 that showed the best yield
of the target (3-chloroallyl)malonate 7a (up to 70% ac-
cording to NMR spectra). Its efficiency was much higher
than that of the other metal chlorides, many of which failed
to give the target product at all. Of the other Lewis acids,
chloroethylalanes, AlCl3 and FeCl3 proved to be the most
successful: with these, the yields of chloroallylmalonate 6a
were 25–39%. Only traces of the product were observed in
the presence of SnCl4, whereas the reactions using TiCl4,
ZnCl2, InCl3, GeCl4, or SbCl5 failed to give 7a altogether.
Either the reaction did not occur at all, or polymerization
of the starting substrates was observed. Moreover, consid-
erable decarboxylation of the starting malonate to give a
cinnamic ester was observed in the presence of SnCl4.
GaCl3
rt
a
General conditions: 0.75 mmol of 3a in 7–8 mL CH2Cl2;
treatment of the r.m.: HCl/H2O (5–10%). NMR yields. 6a
was added 5 min later after mixing of 3a and GaCl3 at 0 °C.
Treatment of the r.m.: 1 mL MeOH was added at 0 °C.
b
c
d
e
1
equiv. 6a was used.
A similar picture is observed with metal bromides and
iodides. Acceptable yields of the corresponding bromo-
and (iodoallyl)malonates 7s,t are obtained only if GaBr3 or
GaI3 are used (Scheme 7), whereas AlBr3, AlI3, ZnBr2, ZnI2,
BBr3, and PBr3 do not give any decent results. Activation
with other Lewis acids, such as Sc(OTf)3, Ga(OTf)3,
BF3·Et2O, or TfOH, does not give any identifiable products
of acetylene addition.
A detailed optimization of the process conditions was
performed for GaCl3 and EtAlCl2 (Table 2). The optimum
temperature range lies within –20 to 25°С, while the se-
quence of reagent mixing has almost no effect on the yield
of the final product. We succeeded in achieving a 37%
yield with EtAlCl2, and an almost two times higher yield
(70%) with GaCl3. Though Al compounds do promote this
reaction, the product yields are not so valuable from syn-
thetic point of view, and we failed to increase them any
further.
Apparently, the reason lies in the specific ionic structure
of the reactive intermediate Ga complex, whereas the com-
plexes formed by the other metal halides have covalent
–
structures. Furthermore, the GaCl4 counterions present in
the complex structure are apparently the key element for
the transfer of chloride anions. The latter statement ex-
plains the formation of products in the reactions using
aluminum and iron chlorides, since the latter can give
–
–
AlCl4 and FeCl4 anions involved in chlorine transfer.
However, the lack of selective formation of 5 type com-
plexes in these cases strongly decreases the yield of (3-
chloroallyl)malonates.
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Scheme 7. Scope of the main process to give (3- esting that cyclopropyl-substituted substrates can be used
1
2
3
4
5
6
haloallyl)malonates.
in this reaction without opening the three-membered ring.
Disubstituted acetylenes enter the reaction much worse
and require more drastic conditions. For example, oct-4-
yne gives the target product 7p in only 20% yield, whereas
diphenylacetylene does not react with alkylidenemalo-
nates even under very drastic conditions.
The reaction occurs with high E-selectivity in the majori-
ty of examples considered. In this case, a Z-isomer is
formed due to isomerization of the E-isomer under acidic
reaction conditions or during chromatography on SiO2,
which sometimes results in an isomer mixture.
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In this process, instead of alkylidenemalonates, one can
also use benzylideneacetoacetic ester 8a or substituted
methylideneacetylacetones 8b,c that give substituted ke-
toesters or 1,3-diketones 9a–c (Scheme 8). Moreover, an
additional set of diastereomers is formed in the case of
ketoester 8a.
Scheme 8. Reactions of 2-methylidene-1,3-ketoesters
or 1,3-diketones with acetylenes under the action of
GaCl3.
Apart from the main process of three-component as-
sembly of (3-haloallyl)malonates, other interesting reac-
tions can also be performed based on the gallium complex-
es 5 that we developed. In fact, the reaction of al-
kylphenylacetylenes 6i,j with benzylidenemalonate 3a in
the presence of GaCl3 gives products of [3+2]-annulation of
the malonate substrate to the aromatic ring in high yields
(Scheme 9). In this case, a mixture of two isomeric indenes
10 and 10´ with different positions of the double bond is
formed.
If an alkylidenemalonate that cannot undergo [3+2]-
annulation is used in this reaction instead of benzyli-
denemalonate, a side process occurs than involves cycliza-
tion on the ester group to give a single diastereomer of 6-
membered lactone 11 (Scheme 10). It should be noted that
the formation of 6-membered lactones 11 was found to be
rather a typical process in the reactions of methylidenema-
lonates with acetylenes. They are often formed as side
products if certain substrates are combined, and their con-
tent can be increased to quite a decent level by optimizing
the conditions (Scheme 10). Furthermore, the fact that
lactones 11 are formed is important for the description of
the mechanistic part of the processes.
After having identified the optimum conditions we ex-
plored the versatility of our new three-component process.
Its scope was found to be quite extensive (Scheme 7). The
reaction is of general character and readily occurs with
diverse aryl- and alkyl-substituted methylidenemalonates
3, as well as aryl- and alkyl-acetylenes 6, to give the corre-
sponding (3-chloroallyl)malonates 7. Application of galli-
um bromide or iodide makes it possible to obtain the cor-
responding bromo or iodo derivatives 7q–v. The highest
yields (up to 95%) are obtained by combining alkyli-
denemalonates with aliphatic alkynes. The use of aryl-
substituted acetylenes decreases the yields of (3-
haloallyl)malonates, though aryls with both donor and
acceptor substituents can be used in this case. It is inter-
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Scheme 9. [3+2]-Annulation with alkylphenyl-
acetylenes.
Scheme 11. Some follow-up chemistry.
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Scheme 10. Examples of the formation of 6-membered
lactones.
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Of special interest is the mechanistic part that is im-
portant from theoretical point of view for understanding
various processes in the organic chemistry of gallium.
Nearly all mechanistic and computational studies known in
the literature that deal with “gallium”-catalyzed reactions
present a considerably simplified picture of transfor-
mations that occur in reality.17h,19 A serious problem also
lies in the ways for studying the mechanisms of this kind,
considering the complexity of the intermediate gallium
complexes (of type 5) that are generated. Computational
methods are of little help since it is often unknown what
should be calculated.20 Obviously, a holistic methodology
needs to be created, including, among other things, detec-
tion of intermediate gallium complexes and adaptation of
71Ga NMR spectroscopy11 for direct observation of gallium
nuclei during a reaction.
The obtained compounds contain various functional
groups that can be easily modified using standard
synthetic protocols (Scheme 11). For example, compound
7j can be readily decarboxylated under Krapcho reaction
conditions to give 12. A halide atom at the double bond in
products
7
opens up rich prospects for further
modifications by cross coupling reactions, especially
considering the facility of incorporating bromine or iodine
(Sonogashira and Stille reactions, for example).
Furthermore, functional groups previously incorporated
into starting acetylene or methylidenemalonates can also
be potentially used.
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Scheme 12. The proposed mechanism closest to reality, and key NMR data for its reconstruction.
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As a result, we created a mechanistic picture to describe
the occurring processes that is the closest to reality
(Scheme 12). As one can see, the real observed processes
are extremely complicated. And they all occur in a single
flask! As mentioned above, ionic complex 5 (I-1), in which
three methylidenemalonate molecules are coordinated at
once on one gallium atom, is the key intermediate. The
formation of this complex is a separate stepwise process.21
It starts with the coordination of methylidenemalonate 3
with GaX3 that exists in solution as a Ga2X6 dimer. The re-
sulting complex A is immediately coordinated with the
second methylidenemalonate molecule with elimination of
the second gallium atom as a GaX4 anion to give intermedi-
ate ionic complex B. The latter subsequently undergoes the
ligand exchange once more to give the key complex 5 (I-1),
which has the highest stability. Complex B can be detected
by NMR spectroscopy during the reaction in CDCl3, where-
as it is highly unstable in CD2Cl2.
dination with the MeO group (intermediate D), thus de-
termining the stereospecificity of the subsequent addition
of a halogen atom. The observed formation of a second
stereoisomer occurs due to isomerization of the E-isomer
7 formed initially.
The halogen atom transfer mechanism is one of the key
points of this process. It occurs by a stereospecific attack of
–
GaX4 on the vinyl carbocation. As a result, free GaX3 is
eliminated and a C–Hal bond is formed (intermediates E
and then I-2). In this case the solution contains no free
halide ions, as confirmed by 35Cl and 81Br NMR spectrosco-
–
py. The transfer of chloride ions via GaCl4 anions was ob-
–
served directly using 71Ga NMR spectroscopy; GaCl4 ani-
ons give a characteristic narrow signal at +250 ppm that is
easily distinguishable from the other forms of gallium.11
The concentration of GaCl4– drops strongly during the reac-
tion (ideally to 0 if the reaction occurs quantitatively),
whereas at the starting instant of time the predominant
fraction of gallium exists precisely in this form.
This is followed by the main process, i.e., addition of an
acetylene molecule. Since the C=C double bond in complex
5 (I-1) is strongly polarized, the acetylene attacks the car-
bocationic center to give an unstable vinyl cation (inter-
mediate C). The latter can be stabilized due to weak coor-
The next interesting point is that there are three methyl-
idenemalonate molecules on a gallium cation, all of which
successively enter the reaction without destroying the
frame of Ga3+. As a result, a number of complicated inter-
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mediate complexes exist, I-1 –> I-2 –> I-3 –> I-4, the latter and in the transfer of halogen atoms. This partially ex-
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5
6
7
8
being a complex of three product molecules in enolate
form. The shift of H NMR signals of the CH moiety in the
polarized malonate double bond gradually changes upfield
from 9.13 to 8.88 ppm in the series I-1 –> I-2 –> I-3, indi-
cating that the positive charge on the central gallium cati-
on gradually decreases.
plains the exceptional features of gallium compounds in
processes of this kind. These results will undoubtedly be
useful later in further studies on the organic chemistry of
gallium and will perhaps expand this field of chemistry
considerably. For example, GaCl3 is a unique reagent in the
DAC chemistry that modifies the direction of reaction.6–10 It
is possible that they are also complex and follow scenarios
similar to those described above.
1
However, the process does not yet end in complex I-4.
When C–Hal bonds are formed, a lot of free reactive GaX3 is
released (intermediate I-2). It decomposes the I-4 complex
due to a cascade of trans-ligandation processes, to eventu-
ally give the gallium enolate of the I-5 product. It is already
rather stable under the reaction conditions and is only
decomposed later upon hydrolysis of the reaction mixture.
It should be noted that complexes I-1–I-4, enolate I-5 and
the final product 7 strongly differ in molecular mass, which
allows one to distinguish them easily and reliably by diffu-
sion NMR spectroscopy (DOSY).22 Using the DOSY tech-
nique, it is possible to measure the diffusion coefficients of
the dissolved molecules easily and directly from the NMR
experiment. Diffusion coefficients are related to the speed
of molecular motions in solution and depend on the size of
dissolved compounds. In the first approximation diffusion
of molecules only depends on their molecular masses,
hence one can estimate the solute molecular masses rather
precisely by measuring the diffusion coefficient.22
As an elegant completion of this work, we have per-
formed a number of additional mechanistic experiments
(Table 3). The latter had also the mission of a preliminary
search for an approach to the catalytic implementation of
the above described gallium chemistry, as well as the addi-
tion of other nucleophiles besides the halide anions. All
obtained results are in excellent consistency with the pro-
posed mechanistic scheme, and carry a lot of additional
confirming information. Two key aspects should be noted:
1) the necessity of using the gallium(III) salts; and 2) the
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–
key and essential role of GaHal4 anions in the transport of
nucleophiles. Also, the process can be carried out in a
"semi-catalytic" version using Ga(OTf)3 as a catalyst, and
–
Bu4N+ GaI4 as a nucleophile source (as an example) (En-
tries 12, 13; and Scheme 14). It should be noted that the
replacing gallium with another metal (Sc, Sn) leads to the
impossibility of realization of the process (Entries 2, 3, 14,
–
15). Similarly acts the replacement of Bu4N+ GaI4 by
Other reactions of complexes 5 with acetylenes follow
similar scenarios. For example, indenes 6 are formed upon
an intramolecular electrophilic attack on the aromatic ring
in intermediate C/F with a certain combination of substit-
uents. Lactones 11 are formed upon intramolecular cy-
clization on the carbonyl group (intermediate G), showing
that intramolecular coordination of the ester group to the
vinyl carbocation actually takes place.
Bu4N+ I– (Entries 10, 12). As a consequence, the addition of
sources of other anions (NaN3, KCN, KSCN, ZnCl2) doesn't
lead to their insertion in the product even in trace amounts
in model reaction of 3k with 6b and Ga(III) salts (Entries 4,
–
5, 7, 8, 18). The creation of tetrahedral GaNu4 anions is
required for the successful introduction in the reactions of
other nucleophiles (Nu) besides halide anions. This ap-
proach was perfectly implemented in a preliminary ver-
sion for the SCN– anions (Entries 19, 20; and Scheme 14).
In this case as sources of the latter we used Ga(SCN)3 and
Diastereoselectivity of the formation of lactones 11 is
excellent. Corresponding stereochemical model is present-
ed on Scheme 13. Cis-selectivity is set in the hydrolysis
stage of pyran H, which is formed after cyclization of the
intermediate G. Apparently, hydrolysis occurs intramo-
lecularly by bound H2O molecule in the gallium complex I.
Steric hindrance of the R-substituent blocks the access of
water from one side, and the intramolecular attack pro-
vides high diastereoselectivity.
–
Bu4N+ Ga(SCN)4 , which are similar in properties to its hal-
ogen analogs.
Scheme 14. “Semi-catalytic” version of the main pro-
cess, and approach to transfer of different nucleo-
philes.
Scheme 13. Stereochemical model for the formation of
lactones 11.
In total, six intermediate complexes (B & I-1 – I-5) were
detected quite reliably by means of NMR (Scheme 12).
These complexes are very useful for understanding the
–
essence of the occurring processes. The GaX4 anions play
the key role, both in the formation of reactive complexes
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Page 10 of 12
lonates as 1,2-zwitterionic synthons. The developed strat-
1
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5
6
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8
egy is to generate ionic Ga complexes from methylidene-
malonates and gallium halides with a strict 3/4 composi-
tion. These complexes are ionic liquids and they are used
in further syntheses. We synthesized a number of com-
plexes with different metal halides and showed that galli-
um possessed unique properties among all metals. Based
on the discovered new class of ionic gallium complexes of
methylidenemalonates, a number of novel reactions with
acetylenes have been elaborated. The main process is a
three-component addition to a triple bond involving halide
anions and leading to the formation of polyfunctional vinyl
halides with high E-selectivity. The mechanism has been
studied in fine detail, including the use of specially opti-
mized 71Ga NMR spectroscopy to take a look into the galli-
um chemistry, which involves the key participation of
GaHal4– anions.
Table 3. Additional mechanistic experiments, and ap-
proach toward catalytic version and transfer of differ-
ent nucleophiles.
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Entry MXn
Nu–-sourse Conditions Nu
(mol.%) a (equiv.) a
Product
(Yield) b
1
2
3
4
GaCl3
SnCl4
–
rt, 2h
Cl
–
7m (97%)
no product
no product
–
rt, 2 h
rt, 2 h
rt, 1.5 h
ASSOCIATED CONTENT
SnCl4
GaCl3
TMSCl
–
Supporting Information. 1H, 13C, 71Ga, 119Sn and 2D NMR
spectra for metal complexes and pure products (PDF)
This material is available free of charge via the Internet at
http://pubs.acs.org.
KCN
(5 equiv.)
Cl
7m (26%)
conv. 56%
5
6
7
8
GaCl3
NaN3
(5 equiv.)
rt, 1 h
Cl
–
7m (90%)
AUTHOR INFORMATION
Corresponding Authors
* E-mail: novikovfff@bk.ru.
* E-mail: tom@ioc.ac.ru.
Ga(OTf)3
(20%)
–
40 °C, 6 h
40 °C, 2 h
40 °C, 2 h
n/r c
Ga(OTf)3 ZnCl2
(10%)
–
n/r
(2 equiv.)
Ga(OTf)3 NaN3
(10%)
–
n/r
ORCID
Roman A. Novikov: 0000-0002-3740-7424
Yury V. Tomilov: 0000-0002-3433-7571
9
GaI3
–
rt, 2h
I
7u (95%)
10
Ga(OTf)3 Bu4N+ I–
40 °C, 2 h
–
n/r
Author Contributions
§ Roman A. Novikov and Dmitry A. Denisov contributed equal-
ly.
(10%)
(2 equiv.)
11
12
GaCl3
(10%)
Bu4N+ I–
(2 equiv.)
40 °C, 2 h
–
n/r
Notes
Ga(OTf)3 Bu4N+ GaI4– 40 °C, 2 h
(10%)
I
7u (15%)
conv. 17%
The authors declare no competing financial interest.
13
14
–//–
–//–
40 °C, 12 h I
7u (75%)
ACKNOWLEDGMENT
Sc(OTf)3
(10%)
Bu4N+ GaI4– 40 °C, 2 h
–
n/r
This work was supported by the Russian Science Foundation
(grant no. 14-13-01054-P). High resolution mass spectra were
recorded in the Department of Structural Studies of N. D. Zel-
insky Institute of Organic Chemistry RAS, Moscow. Dr. Roman
A. Novikov and Dr. Yaroslav V. Tkachev thank the Program of
fundamental research for state academies for 2013–2020
years (№ 01201363817) for support of NMR studies (Engel-
hardt Institute of Molecular Biology, Russian Academy of Sci-
ences).
15
16
SnCl4
GaCl3
Bu4N+ GaI4– rt, 2h
Bu4N+ GaI4– 40 °C, 2 h I + Cl 7u (47%)
1.5/1 7m (31%)
–
n/r
17
18
19
GaCl3
Bu4N+ I–
KSCN
–
40 °C, 2 h Cl
rt, 2 h Cl
7m (80%)
7m (60%)
GaCl3
Ga(SCN)3
40 °C, 4 h, SCN 15a (45%)
4 Å MS
ABBREVIATIONS
DAC, Donor-Acceptor Cyclopropane.
20
Ga(OTf)3 Bu4N+
(20%)
40 °C, 8 h, SCN 15a (40%)
Ga(SCN)4 4 Å MS
–
a 1 equiv. by default. b NMR yields. c n/r = no reaction.
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In conclusion, we suggest a new synthetic protocol,
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(6)
Main works on DACs as 1,2-zwitterions: (a) Novikov, R.
A.; Tarasova, A. V.; Korolev, V. A.; Timofeev, V. P.; Tomilov, Y. V.
Angew. Chem. Int. Ed. 2014, 53, 3187. (b) Novikov, R. A.; Balakirev,
D. O.; Timofeev, V. P.; Tomilov, Y. V. Organometallics 2012, 31,
8627. (c) Novikov, R. A.; Tarasova, A. V.; Tomilov, Y. V. Synlett
2016, 27, 1367.
(19) Some calculations of Ga(III) & In(III)-mediated reac-
tions: (a) Michelet, B.; Thiery, G.; Bour, C.; Gandon, V. J. Org. Chem.
2015, 80, 10925–10938. (b) Zhuo, L.-G.; Zhang, J.-J.; Yu, Z.-X. J.
Org. Chem. 2012, 77, 8527–8540. (c) Zhuo, L.-G.; Shi, Y.-C.; Yu, Z.-
X. Asian J. Org. Chem. 2014, 3, 842–846.
(7)
Reactions with alkenes: (a) Novikov, R. A.; Tarasova, A.
V.; Korolev, V. A.; Shulishov, E. V.; Timofeev, V. P.; Tomilov, Y. V. J.
Org. Chem. 2015, 80, 8225. (b) Zotova, M. A.; Novikov, R. A.; Shu-
lishov, E. V.; Tomilov, Y. V. J. Org. Chem. 2018, 83, 8193.
(8)
Reactions with acetylenes: (a) Novikov, R. A.; Tarasova,
(20) Tu, P.-K.; Zhou, L.; Kirillov, A. M.; Fang, R.; Yang, L. Org.
Chem. Front. 2018, 5, 1702–1717.
(21) El-Hellani, A.; Monot, J.; Guillot, R.; Bour, C.; Gandon, V.
A. V.; Denisov, D. A.; Borisov, D. D.; Korolev, V. A.; Timofeev, V. P.;
Tomilov, Y. V. J. Org. Chem. 2017, 82, 2724. (b) Novikov, R. A.;
Borisov, D. D.; Tarasova, A. V.; Tkachev, Y. V.; Tomilov, Y. V. Angew.
Chem. Int. Ed. 2018, 57, 10293–10298.
Inorg. Chem. 2013, 52, 506–514.
(22) Diffusion Ordered Spectroscopy (DOSY): (a) Johnson, C.
S. Jr. Prog. Nucl. Magn. Reson. Spectrosc. 1999, 34, 203. (b)
Pregosin, P. S.; Kumar, P. G. A.; Fernandez, I. Chem. Rev. 2005, 105,
2977. (c) Macchioni, A.; Ciancaleoni, G.; Zuccaccia, C.; Zuccaccia, D.
Chem. Soc. Rev. 2008, 37, 479.
(9)
Reactions with aldehydes: (a) Borisov, D. D.; Novikov, R.
A.; Tomilov, Y. V. Angew. Chem. Int. Ed. 2016, 55, 12233. (b) Bo-
risov, D. D.; Novikov, R. A.; Tomilov, Y. V. Tetrahedron Lett. 2017,
58, 3712.
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