Unprecedented Nucleophilic Additions of Highly Polar Organometallic Compounds to Imines and Nitriles Using Water as a Non-Innocent Reaction Medium

Article abstract of DOI:10.1002/anie.201705412

In contrast to classic methods carried out under inert atmospheres with dry volatile organic solvents and often low temperatures, the addition of highly polar organometallic compounds to non-activated imines and nitriles proceeds quickly, efficiently, and chemoselectively with a broad range of substrates at room temperature and under air with water as the only reaction medium. Secondary amines and tertiary carbinamines are furnished in yields of up to and over 99 %. The significant solvent D/H isotope effect observed for the on-water nucleophilic additions of organolithium compounds to imines suggests that the on-water catalysis arises from proton transfer across the organic–water interface. The strong intermolecular hydrogen bonds between water molecules may play a key role in disfavoring protonolysis, which occurs extensively in other protic media such as methanol. This work lays the foundation for reshaping many fundamental s-block metal-mediated organic transformations in water.

Full text of DOI:10.1002/anie.201705412

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Accepted Article
Title: Keeping the Aqueous Polar Organometallic Chemistry Dream
Alive: Unprecedented Water-catalyzed Nucleophilic Additions of
Highly Polar Organometallic Compounds to Imines and Nitriles
Authors: Giuseppe Dilauro, Marzia Dell'Aera, Paola Vitale, Vito
Capriati, and Filippo Maria Perna
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705412
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10.1002/anie.201705412
Angewandte Chemie International Edition
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Keeping the Aqueous Polar Organometallic Chemistry Dream
Alive: Unprecedented Water-catalyzed Nucleophilic Additions of
Highly Polar Organometallic Compounds to Imines and Nitriles
Giuseppe Dilauro,† Marzia Dell’Aera,† Paola Vitale, Vito Capriati,* and Filippo Maria Perna
Dedicated to Professor Roald Hoffmann on the occasion of his 80th birthday
Abstract: In contrast to classic protocols carried out under inert
atmospheres with dry volatile organic solvents and often low
temperatures, we report that the addition of highly polar
organometallic compounds to non-activated imines and nitriles
proceeds quickly, efficiently, and chemoselectively with a broad
range of substrates at room temperature and under air with water as
the only reaction medium, providing secondary amines and tertiary
carbinamines with yields up to >99%. The significant solvent D/H
isotope effect observed for the on-water nucleophilic additions of
organolithiums to imines suggests that the on-water catalysis arises
from proton transfer across the organic–water interface. The strong
intermolecular hydrogen bonds between water molecules may play a
key role in disfavouring protonolysis, which occurs extensively in
other protic media such as methanol. This work lays the foundation
for reshaping many fundamental s-block metal-mediated organic
transformations in water.
medium without further additives, thereby crossing the
considerable divide between traditionally allowed and textbook-
prohibited reactions (Scheme 1). These routes provide access to
secondary amines and tertiary carbinamines, which are often
components of bioactive compounds, synthetic materials, and
useful “building blocks” for natural products and active
pharmaceutical ingredients (APIs).[7] An alternative, sustainable
approach to amines has recently been established by Hevia and
García-Álvarez by reacting organolithium reagents with imines
and quinolines in choline-chloride-based DESs. A kinetic anionic
activation of the alkylating reagent was suggested to take place
with choline chloride, which favoured nucleophilic addition over
competitive protonolysis.[4b]
R3
H2O
R1
R1
+ R3Li
R2
N
R2
N
RT, under air
H
NH2
The discovery and the introduction of organolithium and
Grignard reagents in organic synthesis at the beginning of the
R2Met, H2O
R3Met, H2O
R1 CN
R1 R3
R2
RT, under air
RT, under air
twentieth century became, over the years,
a beacon of
Scheme 1. Organometallic nucleophilic additions to imines and nitriles using
water, at RT and under air.
opportunity to create thousands of new organic compounds by
carbon–carbon bond formation because of the high polarity of
their metal–carbon bonds.[1] The utilization of these reagents,
however, typically requires strictly anhydrous and aprotic volatile
organic solvents, inert atmospheres, and often low temperatures
(–78 °C), owing to the notorious air- and moisture-sensitivity of
s-block organometallic compounds.[1d]
The chemistry of polar organometallic compounds in
unconventional, biorenewable reaction media (e.g., “Deep
Eutectic Solvents”, DESs) has opened up new, intriguing, and
unexpected opportunities in synthesis, not only from a “green”
standpoint, but also from a mechanistic perspective.[2–5] Organic
syntheses run at organic-liquid water interfaces with water-
insoluble reactants (i.e., “on-water”) are also a fascinating area
of research.[6] Building on our recent findings on the nucleophilic
addition of Grignard and organolithium reagents to carbonyl
derivatives under “heterogeneous” conditions in water,[5c] we
present the first successful addition of highly polar
organometallic compounds at room temperature (RT) and under
air to imines and nitriles using water as the only reaction
We elected to study the reaction between commercially
available, water-insoluble aldimine 1a and n-BuLi as a model
system for the preparation of amine 2a (Table 1). First, 1.4
equiv. of n-BuLi were rapidly spread over a suspension of 1a
(0.50 mmol) in water (1 mL) under air with vigorous stirring at RT
to generate an emulsion (vortex). The mixture became orange
red upon addition of the organolithium, and turned colourless
after a few seconds. Dilution with 1 mL of cyclopentyl methyl
ether, followed by filtration, evaporation, and chromatography of
the resulting residue led to product 2a with a 96% yield (Table 1,
entry 1). Pleasingly, the reaction could also be scaled-up; by
reacting 5.5 mmol of 1a in 10 mL of water with 1.4 equiv. n-BuLi,
amine 2a formed in quantitative yield (>99%), and was isolated
by simply evaporating the organic phase without further
purification (Table 1, entry 2). Notably, due to the poor
electrophilicity of the iminic carbon atom, organolithium additions
hardly proceed in conventional ethereal or hydrocarbon solvents
in the absence of additives, and are often plagued with
competitive reduction, enolization, or coupling reactions.[8]
[*]
Dr. Giuseppe Dilauro, Dr. Marzia Dell’Aera, Dr. Paola Vitale, Dr.
Filippo M. Perna, Prof. Vito 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
Recent reports have revealed that the yields and
efficiencies of on-water reactions can be influenced by the
volume and surface area of organic droplets, and thus by the
physical mixing parameters (e.g., stirring speeds, shaking,
sonication).[9] When the organolithium addition was performed
under gentle stirring so as to minimize the area of interface
without mixing the organic and aqueous phases (i.e., static
droplets) the yield of 2a dropped to 66% (Table 1, entry 3).
E-mail: vito.capriati@uniba.it
These authors contributed equally to this work.
[†]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201705412
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COMMUNICATION
Table 1. Addition of n-BuLi to imine 1a in different solvents, at RT, and under
addition. Some experimental evidence suggests that
protonolysis of organolithium compounds by protic media does
not occur as rapidly as anticipated.[13] To investigate this aspect,
in a challenging, seemingly counterintuitive experiment, we first
spread n-BuLi (1.4 equiv.) over water (1 mL) and then added
imine 1a (0.55 mmol) after 5 s. Astonishingly, amine 2a formed
with a 20% yield (Table 1, entry 6). Thus, the water quenching
was not instantaneous, and the organolithium had a sufficient
lifetime (a few seconds) to add to the azomethine moiety.
air.[a]
Bu
solvent
Ph
Ph
+ n-BuLi
N
Ph
2a
N
Ph
RT, under air
5 sec
H
1a
Entry
Solvent
2a yield%[b]
1
2
3
4
5
6
H2O (vortex)
96
H2O (vortex)
>99[c]
66
The scope of suitable imine derivatives and commercially
available organolithium reagents was explored (Table 2). To our
delight, the optimized conditions for the synthesis of 2a could be
successfully applied to many combinations, indicative of the
considerable generality of the reaction. For example, 1.4 equiv.
of PhLi and 1a provided amine 2b with a 60% yield. Pleasingly,
as similarly observed in the addition to carbonyl compounds,[5c]
by increasing the amount of the organometallic reagent to 3
equiv., the final yield increased to 80%. The use of other
aliphatic, commercially available organolithium reagents, ranging
from MeLi to s-BuLi and even t-BuLi led to desired adducts 2c–e
in satisfactory yields (1.4 equiv.: 45–70%; 3 equiv.: 70–96%).
When an aryl-substituted imine with an electron-donating group
(1b) was used as a substrate, adducts 2f,g could be isolated in
71–80% yields by employing 3 equiv. of n-BuLi or PhLi. A
chloro-substituted arylimine (1c) was equally tolerated, and
produced desired amines 2h,i within good yields (64–97%)
when reacted with n-BuLi (1.4 equiv.) and s-BuLi (3 equiv.). The
formation of the latter adducts highlights further opportunities for
subsequent functionalization by cross-coupling reactions.
Sterically hindered N-t-butyl-substituted imine 1d readily
participated in the reaction, and delivered amines 2j–l in 62–
95% yields when 3 equiv. of n-BuLi, s-BuLi, or PhLi were used.
Notably, enolizable cyclohexylidene imine 1e also served as a
competent reaction partner providing amine 2m with a 70% yield
upon reaction with PhLi (3 equiv.). An N-benzyl-substituted
imine (1f) could also be used to produce 2n–p at excellent yields
of 80–95% with 3 equiv. of n-BuLi, s-BuLi, or PhLi. We also
explored the effectiveness of using Grignard reagents. The
addition of 1.4 equiv. of PhMgCl or i-PrMgCl·LiCl (turbo-Grignard
reagent) to 1a on water proved to be ineffective. When the
highly reactive (allyl)MgCl was alternatively used, however, the
expected N-(1-phenylbut-3-enyl)aniline (2q) could be isolated in
reasonable yields (1.4 equiv.: 40%; 3 equiv.: 75%) (see SI). We
did not investigate this type of reaction further.
Next, we examined the addition of organometallics to
nitriles, using bulk water as the only reaction medium, aimed at
preparing tertiary alkyl primary amines (termed carbinamines)
via a two-step, one-pot procedure. Generally, this addition is
limited to the first step, as the second one, involving the
corresponding poor electrophilic metalIated imines generated in
the first step, is more challenging. In only a few isolated cases, it
was reported that Grignard reagents add twice to nitriles in
conventional solvents to form tertiary carbinamines, as in the
case of allyl Grignard reagents with α-alkoxy nitriles.[14a,b] On the
other hand, tetrahydropyridine derivatives were the main
products when allyl Grignard reagents were reacted with
aromatic nitriles.[14c] The use of very harsh conditions, microwave
heating, and Lewis acids such as titanium alkoxides, somewhat
expanded the scope of the reaction so as to include two different
H2O (gentle stirring)
D2O (vortex)
57
MeOH (vortex)
H2O (vortex)
15
20%[d]
[a] Typical experimental conditions: n-BuLi (1.4 equiv.) was added at RT and
under air to a suspension/solution of imine 1a (0.50 mmol) in 1.0 mL of solvent.
[b] Isolated yield. [c] Imine 1a (5.5 mmol), 10 mL of H2O. [d] To 1.0 mL of
water, n-BuLi and imine 1a were sequentially added at RT and under air.
On-water catalysis is not well understood.[6d,e] Jung and
Marcus first proposed that on-water catalysis arises from trans-
phase H-bonding by “dangling” (that is free, not H-bonded) OH
groups at the water interface to H-bond acceptors in organic
transition states.[10] Beattie and McErlean later proposed that a
proton transfer across the organic-water interface could be the
source of such phenomena.[11a] These authors provided
compelling evidence for this hypothesis by measuring a strong
solvent D/H isotope effect for on-water aromatic aza-Claisen
rearrangements of allyl aryl amines.[11b]
We recently posited that interfacial H-bonding to water-
insoluble carbonyl compounds embedded at the organic-water
interface may provide catalytic impetus for on-water nucleophilic
additions promoted by Grignard and organolithium reagents.
This was supported by low deuterium isotope values for on-H2O
and on-D2O.[5c,6d,e] More basic nucleophilic sites in organic
molecules, however, are known to facilitate proton transfer
across the water organic interface.[6e] This postulate was
experimentally surveyed in the addition of n-BuLi to 1a by setting
up another reaction identical in every respect to the one
described above (Table 1, entry 1), but with D2O as the aqueous
phase. After 5 s, the reaction was worked up, and the product
was isolated and quantified. Remarkably, a significant solvent
deuterium isotope effect was detected: the yield of 2a dropped
considerably to 57% vs. 96% for the on-H2O reaction (Table 1,
entry 4). These reproducible data are consistent with a proton
transfer at the water-organic interface (cleavage of an O–D
bond) in the rate-limiting step, and thus with the active
participation of water.[12] On the other hand, upon replacing water
with MeOH, a higher degree of protonation was observed as the
formation of 2a was suppressed dramatically (15% yield) (Table
1, entry 5). The stronger intermolecular hydrogen bonds of water
compared to those of MeOH may play a key role in shielding the
organometallic reagent from competitive protonolysis.[5c] The
more limited ability of MeOH to engage in intermolecular
hydrogen bonds may also contribute to the less efficient
activation of the azomethine moiety towards nucleophilic
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10.1002/anie.201705412
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COMMUNICATION
organometallic nucleophiles and less reactive nitriles.[14d] Aside
from some exceptions, however, chemical yields and
selectivities were generally modest, and long reaction times (up
to 24 h) were usually required for the second addition.[14e]
Table 3. Addition of organometallics to nitriles 3a–d on water, at RT and
under air affording tertiary carbamines 4a–k.[a]
NH2
R2Li, H2O
(allyl)MgCl, H2O
R1 C N
R1
Table 2. Addition of organolithium reagents to imines 1a–f on water, under
air, and at RT, affording amine derivatives 2b–q.
RT, under air
1 min
RT, under air
5 min
R2
3a–d
4a–k
NH2
NH2
NH2
NH2
1b: R1 = Ph, R2 = 4-MeOC6H4, R3 = H
R3
R4
1c: R1 = Ph, R2 = 4-ClC6H4, R3 = H
R3
R2
H2O
Ph
Ph
4b: 80[c]
Ph
Ph
Ph
R1
+ R4Li
R1
1d: R1
1e: R1
=
=
t-Bu, R2
= = H
Ph, R3
Me
N
R2
1a–e
N
RT, under air
5 sec
Ph, R2,R3
=
-(CH2)5-
H
4a: 95[b]
4c: 60[d]
4d: 70[e] (70)[e,f]
2b–p
1f: R1 = Bn, R2 = Ph, R3 = H
NH2
NH2
NH2
Ph
Ph
Ph
Ph
Ph
Ph
4g: 92
NH2
Et
Ph
Ph
Ph
Ph
Ph
PhO
N
H
4f: 90[h]
N
Ph
N
H
4e: 87[g] (83)[f,g]
N
Me
H
H
2b: PhLi, 60[a] (80)[b] 2c: MeLi, 45[a] (70)[b] 2d: s-BuLi, 70[a] (96)[b] 2e: t-BuLi, 85[b]
OCH3 OCH3
Y
NH2
Ph
X = Cl, Y = H, 4h: 92
X = F, Y = H, 4i: 72
X = H, Y = Cl, 4j: 70
Ph
Cl
Cl
Ph
4k: 60[i]
X
[a] Isolated yields (%). [b] 2-Methyl-1-phenylbutan-1-one also formed in less
than 5% yield. [c] 1-Phenylpentan-1-one also formed with a 20% yield. [d]
Benzophenone also formed with a 35% yield. [e] Acetophenone also formed
with a 30% yield. [f] PhLi and (allyl)MgCl were sequentially added to MeCN or
Ph
Ph
Ph
Ph
N
N
Ph
2f: n-BuLi, 71[b] 2g: PhLi, 80[b]
Ph
N
N
3
3
H
H
H
H
2h: n-BuLi, 97[a] 2i: s-BuLi, 64[b]
Ph
Ph
EtCN. [g] Propiophenone was also isolated with
a 13–17% yield. [h]
Ph
N
N
Ph
N
N
3
Butyrophenone also formed with a 10% yield. [i] Benzyl phenyl ketone also
formed with a 40% yield.
H
H
H
Ph
H
2j: n-BuLi, 85[a] (95)[b] 2k: s-BuLi, 50[a] (95)[b] 2l: PhLi, 62[b] 2m: PhLi, 70[b]
Ph
Ph
Ph
When PhLi and (allyl)MgCl (3 equiv.) were added
sequentially (time interval: 1 min) to a solution of acetonitrile
(MeCN) (3b) (1 mmol) or propionitrile (EtCN) (3c) (1 mmol) or
butyronitrile (PrCN) (3d) in water, the double nucleophilic
addition again took place, thereby offering direct and
complementary access to the corresponding tertiary allyl amines
4d–f in 70–90% yields (Table 3). Thus, both in-water and on-
water methodologies could be applied to the synthesis of tertiary
carbamines.[6c] On the other hand, the yield of 4e decreased
dramatically to 12% upon sequential addition of PhLi (3 equiv.)
and (allyl)MgCl (3 equiv.) to 3c in MeOH (propiophenone was
produced with a 88% yield). PhCH2CN could be converted into
amine 4k with a 60% yield when sequentially treated with PhLi
and (allyl)MgCl (3 equiv.). Other Grignard reagents (e.g.,
MeMgCl, EtMgCl, or PhMgCl) proved to be ineffective for this
transformation.
In summary, nucleophilic addition of Grignard and
organolithium reagents to imines and nitriles, en route to
secondary amines and tertiary carbinamines, can be
conveniently carried out using bulk water as a privileged reaction
medium, working under air, at RT, with vigorous stirring.
Although in-depth mechanistic studies are needed to unveil the
intriguing role played by water, aqueous polar organometallic
chemistry has potential to become an attractive and powerful
tool in several other fundamental and applied organic processes.
Ph
N
Ph
N
Ph
N
Ph
3
H
H
H
2n: n-BuLi, 95[b] 2o: s-BuLi, 80[b]
2p: PhLi, 87[b]
[a] 1.4 equiv. of R4Li (isolated yields, %). [b] 3.0 equiv. of R4Li (isolated
yields, %).
We initiated our studies with poorly water-soluble
benzonitrile (PhCN) (3a). 3a (1 mmol) was suspended in 1 mL of
water and stirred vigorously to generate an emulsion. When the
aqueous mixture was treated with 3 equiv. of s-BuLi and 3 equiv.
of n-BuLi after 1 min of stirring, a mixture of 2-methyl-1-
phenylbutan-1-one (70%) and 1-phenyl-pentan-1-one (30%) was
isolated with complete consumption of the starting material.
Mindful of this observation, emphasis was then placed on the
use of more reactive allyl Grignard reagents in combination with
organolithiums. Pleasingly, when 3a was treated under vigorous
stirring with 3 equiv. of s-BuLi and 3 equiv. of (allyl)MgCl after 1
min in water, tertiary carbinamine 4a was isolated with a 95%
yield, whereas 2-methyl-1-phenylbutan-1-one formed at a less
1
than 5% yield (by H NMR analysis) (Table 3). When subjected
to this two-step, one-pot protocol, assorted aliphatic and
aromatic organolithium reagents such as MeLi, n-BuLi, PhLi,
and EtLi (3 equiv.) afforded the corresponding allyl-substituted
tertiary carbinamines 4b–e in satisfactory yields (60–87%), with
modest amounts of the corresponding ketones (17–35% yield)
(Table 3). Benzonitrile derivatives with electron-donating (p-
PhO), electron-withdrawing (p-Cl and o-Cl), or fluorine groups
afforded adducts 4g–j in 70–92% yields by employing 3 equiv. of
either PhLi or (allyl)MgCl. To emphasize the versatility of the
protocol, aliphatic substrates were also screened.
Acknowledgements
This work was financially supported by the University of Bari
(project code: Perna01333214Ricat), and by the Interuniversities
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10.1002/anie.201705412
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COMMUNICATION
Consortium C.I.N.M.P.I.S. (project code: COCM8470P0). The
authors are also indebted to Miss Maria Colamonico, Miss
Antonia Belviso, Mr Pasquale Mastropierro, and Mr Francesco
Messa for their contribution to the experimental work.
Keywords: azo compounds • Grignard reagents • nucleophilic
addition • organolithiums • water chemistry
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10.1002/anie.201705412
Angewandte Chemie International Edition
COMMUNICATION
Green Chemistry
COMMUNICATION
Symphony between organolithiums
and water: The title reactions allow
unprecedented access to secondary
amines and tertiary carbinamines in
very good yields using water as the
only reaction medium. These
reactions, which proceed quickly,
smoothly, and chemoselectively at
room temperature and under air, open
exciting opportunities for using highly
polar organometallics in other
Giuseppe Dilauro, Marzia Dell’Aera,
Paola Vitale, Vito Capriati*, Filippo M.
Perna
Page No. – Page No.
Keeping the Aqueous Polar
Organometallic Chemistry Dream
Alive: Unprecedented Water-
catalyzed Nucleophilic Additions of
Organolithiums and Grignard
reagents to Imines and Nitriles
fundamental and applied
transformations in aqueous media.
This article is protected by copyright. All rights reserved.