Ambient Moisture Accelerates Hydroamination Reactions of Vinylarenes with Alkali-Metal Amides under Air

Article abstract of DOI:10.1002/anie.202008512

A straightforward alkali-metal-mediated hydroamination of styrenes using biorenewable 2-methyltetrahydrofuran as a solvent is reported. Refuting the conventional wisdom of the incompatibility of organolithium reagents with air and moisture, shown here is that the presence of moisture is key in favoring formation of the target phenethylamines over competing olefin polymerization products. The method is also compatible with sodium amides, with the latter showing excellent promise as highly efficient catalysts under inert atmosphere conditions.

Full text of DOI:10.1002/anie.202008512

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Ambient Moisture Accelerates Hydroamination Reactions of
Vinylarenes with Alkali-Metal Amides under Air
Authors: Eva Hevia, Florian Mulks, Leonie Bole, Laia Davin, Alberto
Hernan-Gomez, Alan R Kennedy, and Joaquin Gracia-
Alvarez
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202008512
Link to VoR: https://doi.org/10.1002/anie.202008512

10.1002/anie.202008512
Angewandte Chemie International Edition
COMMUNICATION
Ambient Moisture Accelerates Hydroamination Reactions of
Vinylarenes with Alkali-Metal Amides under Air
Florian F. Mulks,[a]+ Leonie J. Bole,[a]+ , Laia Davin,[c] Alberto Hernán-Gómez,[c] Alan Kennedy,[c] Joaquín
García-Álvarez,*[b] and Eva Hevia*[a,c]
Dedicated to the memory of Prof Dr. Killian Muñiz
Abstract:
A
straightforward alkali-metal-mediated protocol for
of styrenes using biorenewable
transition metal catalysts. (Scheme 1).[3] Since establishing
efficient main group bimetallic catalysts for hydroamination
reactions,[4] we have become interested in developing s-block
organometallic approaches that are operationally simple for this
atom-efficient transformation dedicated to practical everyday
laboratory use. Lithium amides are simple-to-synthesize and
simple-to-use reactants for such reactions.[5] Herein we report a
new method for hydroaminations of styrenes with an exceptional
procedural simplicity with cheap and available commodity
chemicals using a biorenewable solvent compatible with the
presence of air and moisture (Scheme 1). Addition reactions to
C=C bonds proceed much slower than to their more polar C=O
and C=N counterparts, and hence, controlling the kinetics of the
desired reaction versus hydrolysis/degradation of the reactants
poses an even greater challenge.
hydroamination
2-methyltetrahydrofuran as a solvent is reported. Refuting the
conventional wisdom of the incompatibility of organolithium reagents
with air and moisture, we show that the presence of moisture is key in
favouring formation of the target phenethylamines over competing
olefin polymerisation products. The method is also compatible with
sodium amides, with the latter showing excellent promise as highly
efficient catalysts under inert atmosphere conditions.
The dogma of the need of inert conditions and cold temperatures
in reactions with polar main group organometallics has recently
been challenged. Addition reactions of Grignard reagents as well
as organolithium compounds have been established in the
presence of water, in air, and at room temperature.[1] Smooth and
expeditious reaction progress was found for addition reactions to
ketones, imines, and nitriles. It was discovered that reaction rates
with the substrate exceed that found for hydrolysis, leading to high
yields of addition products, which were subsequently hydrolysed
by the present polar reaction medium. Based on this, deep
eutectic solvents (DES) and glycerol have been shown to work
even better in these types of reaction due to their lower acidity
and lower miscibility with the organic phase.[1b-e] We have recently
been able to perform polymerisation reactions of styrenes on DES
in air using RLi reagents as initators with good results.[1e]
This prompted us to investigate lithium-mediated hydroamination
reactions of styrenes in sustainable and aerobic conditions which
require the stabilisation of reactive species for prolonged periods
of time. While hydroamination reactions have received
considerable attention in chemical research for decades, they still
remain challenging due to high activation barriers coupled with a
flat energy profile, and thus, they continue to attract further
investigation.[2] A remarkable number of catalytic protocols have
recently been developed using lithium as an alternative to
Scheme 1. Comparison of state-of-art catalytic procedures with our air- and
moisture compatible stoichiometric protocol.
Phenethylamines are valuable building blocks for general
chemical synthesis as well as for pharmaceuticals.[6] Furthermore
this study extends the applications of 2-methyltetrahydrofuran,
(2-MeTHF), which is produced from biomass degradation
products, as a prime solvent for organometallic reactions in air.[7]
Recent reports have shown that many polar organometallic
reagents are often even more soluble and more stable in 2-
MeTHF than in THF.[8] We were even able to perform fast
amidations of carboxylic acid esters and amides with lithium
amides in 2-MeTHF in air.[9] 2-MeTHF is also insoluble in water
which conveniently allows more efficient and simple aqueous
extraction of reaction crudes without prior solvent exchange.
We started this investigation by dissolving neat n-BuLi in
2-MeTHF dried over molecular sieve and added commercial
grade amines at 0 °C drop-wise over 1 min to produce 1.1–1.5 M
solutions of the lithium amides 2.[10] Being slightly more electron-
rich than parent THF, 2-MeTHF exhibited a better solubility of
lithium amides and is more suited for the intermediary storage of
the generated solutions. The commercially available solvent was
stored over molecular sieves to maintain low residual moisture.
[a]
Dr. F. F. Mulks, Miss L. J. Bole, Prof. Dr. E. Hevia
Departement für Chemie und Biochemie (DCB)
Universität Bern
Freiestrasse 3, 3012 Bern, Switzerland
E-mail: eva.hevia@dcb.unibe.ch
[+] These authors contributed equally to this work.
[b]
Dr. J. García-Álvarez
Laboratorio de Compuestos Organometálicos y Catálisis (Unidad
Asociada al CSIC). Departamento de Química Orgánica e
Inorgánica, (IUQOEM), Centro de Innovación en Química
Avanzada (ORFEO-CINQA), Facultad de Química, Universidad
de Oviedo, E-33071, Oviedo, Spain.
E-mail: garciajoaquin@uniovi.es
[c]
Dr. L. Davin, Dr. A. Hernán-Gómez, Prof. Dr. Eva Hevia
Department of Pure and Applied Chemistry
University of Strathclyde
295 Cathedral St, G11XL, Glasgow
Supporting information for this can be found under:
http://dx.doi.org/XX.XXXX/XXXX.XXXXXXXXX.
This article is protected by copyright. All rights reserved.

10.1002/anie.202008512
Angewandte Chemie International Edition
COMMUNICATION
Within only 2 h an excellent hydroamination yield of 90% was
found when stirring 1.5 eqs. of the 1 M solution of LiPip 2a with
styrene 1a under air (Table 1, Entry 1). The conventional solvents
THF and n-hexane showed reduced performance compared to 2-
MeTHF. Thus, 79% yield was found for 3a using THF (Entry 3 and
SI for details). Low solubility of amide 2a led to only 30% in n-
hexane (Entry 4, diluted to 0.5 M to counterbalance low solubility).
Neither slowing down the reaction by dilution in respect to 2a from
1 M to 0.375 M nor addition of 1 eq. of water significantly
impacted the yield, resulting in 82% (Entry 2) and 77% (Entry 5)
yields of 3a. This indicates high kinetic stability of 2a in 2-MeTHF.
The presence of 1 mL of water or ethylene glycol (EG), however,
hindered the reaction completely by likely hydrolysing 2a at a rate
faster than the hydroamination reaction (entries 6-7). Despite their
slow reaction rate, hydroamination reactions with lithium amide 2a
were compatible with glycerol (Gly) and several DESs, the non-
aqueous DESs produced fair to good yields (22–69%) although
in an 86% yield after just 10 minutes, if the speed is reduced to
500 rpm the yield observed decreases to 48% and if stirring is not
employed 2h are required to achieve a 94% conversion. Since
both lithium amide and styrene are highly soluble in 2-MeTHF, a
possible explanation for the accelerating effect observed with the
vigorous stirring could be that this facilitates the mixing with
ambient moisture. Interestingly, it should be noted that the short
reaction times observed for the formation of 3a while operating at
room temperature push this approach into the faster regimes of
known methods for lithium-mediated hydroamination of
styrenes.[3]
Previous work on s-block metal catalysed hydroamination of
styrenes have proposed that reaction occurs via initial amine
deprotonation by the metal pre-catalyst forming a reactive metal
amide, with a highly polarised M-N bond which in turn can insert
into the C=C bond of the substrate furnishing the -metallated
phenethylamine intermediate I.[11] Protonation of I by excess
sometimes suffering reproducibility issues (ChCl: choline chloride, amine, regenerates the metal amide and liberates hydroamination
Entries 9–11). It is noteworthy that stability of the lithium amide in
air for such long reaction times is surprising. Interestingly, if the
reaction of 1a with 2a is carried out in 2-MeTHF in air but placing
a drying tube charged with CaCl2 in top of the reaction vial, the
yield of 3a diminishes from 90% to a modest 35% (Entry 12),
which hints at an unexpected beneficial effect of moisture in these
reactions.
product (Scheme 2). Traces of water could quench the
lithioaminated species I from the equilibrium, which has been
discussed to be only slightly stabilised over the reactants
themselves.[12] In addition, traces of water could also react with
some lithium amide LiPip 2a (which, in our study, is present in a
0.5 eq. excess) to generate free piperidine that could
subsequently favour the protonation of I. In this regard it should
be noted that mechanistic and kinetic studies in group II metal
catalysed hydroaminations of alkenes and isocyanates have
suggested that these processes take place preferentially via an
amine-assisted concerted transition state.[13]
Table 1. Influence of the reaction time on the yield of the addition of LiPip
2a to 4-methylstyrene 1a.
Entry
1
Medium A
Medium B
Yield [%]
90
1.5 mL 2-MeTHF
4.0 mL 2-MeTHF
1.5 mL THF
-
Scheme 2. Proposed mechanism of catalytic hydroamination of styrenes with
lithium amides (L = amine or solvent molecule).[13,14]
2
-
82
3
-
79
4
3.0 mL n-hexane
1.5 mL 2-MeTHF
1.5 mL 2-MeTHF
1.5 mL 2-MeTHF
1.5 mL 2-MeTHF
1.5 mL 2-MeTHF
1.5 mL 2-MeTHF
1.5 mL 2-MeTHF
1.5 mL 2-MeTHF
-
19-32[a,b]
77
Further support for the beneficial effect of moisture in these
reactions, was found when 1a and 2a were reacted under strict
inert atmosphere conditions using dried and degassed 2-MeTHF
(30 min, 900 rpm, 1.5 eqs. of 2a), which furnished amine 3a in a
modest 28% yield (Table 2, Entry 1).
5
1 eq. H2O (18 L)
1 mL H2O
1 mL EG
6
0
7
2
8
1 mL Gly
44–69[a,b]
64[b]
Table 2. Results from addition of LiPip 2a to 4-methylstyrene 1a under dry,
wet and excess amine conditions
9
1 mL ChCl/2Gly
1 mL ChCl/2EG
1 mL ChCl/2H2O
-
10
11
12
32–46[a,b]
22[b]
35c]
Entry
Conditions
Time [min]
Yield [%]
28
Reactions performed on a 1 mmol scale stirring at 900 rpm. Mean yields of
isolated aliquots of at least two independent reactions are given. [a] A range
is given due to the spread of results. [b] Stirred at 500 rpm.[c] Carried out with
a drying tube packed with pre-dried CaCl2 attached to the top of the reaction
vial.
1
2
3
4
N2
N2
30
120
120
30
28
[a]
wet N2
75
With the air- and moisture-compatibility of this approach being the
most striking difference to other known methods, we also noted a
marked effect on the stirring speed of the reaction (Table S1, SI).
Thus while vigorous stirring (900 rpm) lead to the formation of 3a
N2 + 1.5 eqs. Pip(H)
> 99
Reactions performed on a 1 mmol scale in a total volume of 1.5 mL of 2-
MeTHF. Mean yields of isolated aliquots of at least two independent
This article is protected by copyright. All rights reserved.

10.1002/anie.202008512
Angewandte Chemie International Edition
COMMUNICATION
reactions are given. [a] A slow flow of N2 over degassed water was run over
the reaction mixture.
1
In addition, H DOSY NMR studies of 2a suggest that in D8-THF
solutions this lithium amide exists as a [(D8-THF)3Li(Pip)]
monomer (MWdet =275 g/mol, error -12%, see SI for details).[16]
Formation of small kinetically activated aggregates of 2a in these
ethereal solvents should contribute to the fast reactivity observed
in these hydroamination processes.[9] Thus, we propose that
when the reaction is carried out under air, the presence of
moisture can generate some Pip(H) that as discussed above
coordinates to 2a, which in turn reacts with styrene 1a to form
selectively hydroamination product 3a via intermediate I. This can
be subsequently quenched by PipH or traces of moisture
(Scheme 3). On the contrary, under strict inert atmosphere
conditions, using dry solvents, I reacts with free styrene (present
in solution due to the equilibrium shown in Scheme 2) initiating its
polymerisation.[1e, 15]
The same conversion was observed allowing longer reaction
times of 2 h. These low yields are in stark contrast with those
observed while working under air and in the presence of moisture,
conditions typically strictly avoided in organolithium chemistry,
which furnished 3a almost quantitatively. Interestingly if the
reaction is carried out under a nitrogen atmosphere but
introducing small amounts of water by running a nitrogen flow
over degassed water the yield increases from 28 to 75%,
supporting the idea that high conversions observed when working
in air are related to the moisture present in the reaction media
rather than oxygen. When employing a solution of LiPip 2a with a
stoichiometric excess of piperidine under inert atmosphere
conditions, using dried and degassed 2-MeTHF, we observed
> 99% yield after 30 min (Table 2, entry 4), which is consistent
with the notion that excess piperidine accelerates the reaction and
that under the conditions of our study, it can be generated by
partial hydrolysis of the employed lithium amide.
1H NMR reaction monitoring studies in D8-THF on a 1:1 mixture
of LiPip 2a and Pip(H) support the initial formation of a co-complex
(Figure 1).[14] Thus, as shown in Figure 1ii, a single set of signals
is observed for the Pip rings exhibiting a modest but noticeable
change on their chemical shifts with respect of those of 2a
(Figure1i). Addition of 0.67 eq of 1a to this mixture (replicating the
conditions of Entry 4 in Table 4) led to the quantitative formation
of hydroamination product 3a along with the recovery of the
LiPip·Pip(H) complex (Figure 1iii). We also noted that while under
inert atmosphere conditions in D8-THF, 3a can also be formed by
reacting 1a and piperidine using catalytic amounts of 2a (20
mol%,> 99% yield, 10 min, see Fig S116 in SI), in air using 2-
MeTHF as solvent, 3a was obtained only in a 16% yield. These
findings indicate that our approach only works stoichiometrically,
probably due to the competing degradation of LiPip under the
conditions employed.
Scheme 3. Reaction showing excess piperidine or ambient moisture supply is
necessary to favour hydroamination over polymerisation
We next explored the scope of this air/moisture compatible
method towards different amides (Table 3).
NMR monitoring studies also showed that addition of 1a to a
solution of 2a in D8-THF (or 2-MeTHF) in the absence of amine,
under inert atmosphere conditions, produces extensive
polymerisation of the styrene.[15]
Table 3. Reaction scope using different lithium amides
2 with
4-methylstyrene.
Entry
Amide A
Product
Yield [%]
90
1
2
3
4
5
piperidide 2a
pyrrolidide 2b
N-Me-piperazide 2c
morpholide 2d
LiNHBu 2e
3a
3b
3c
3d
-
75
>99[a]
13[a], 52[a,b]
-[b]
Reactions performed on a 1 mmol scale in 1.5 mL of 2-MeTHF. They are
stirred at 900 rpm for 30 min. Mean yields of isolated aliquots of at least two
independent reactions are given. [a] 9 mL 2-MeTHF used due to low
solubility. [b] 500 rpm, 2 h.
Figure 1. Aliphatic region from 1H NMR spectra (400 MHz) in D8-THF (i) LiPip
(2a); (ii) LiPip 2a +1 eq of Pip(H); (iii) LiPip 2a + 1 eq of Pip(H)+ 0.67 eq 1a.
At 900 rpm stirring speed and with 30 min of reaction time, we
found LiPip 2a gave 90% yield of the desired terminal amine 3a.
The 5-ring amide lithium pyrrolidide 2b gave 75% of 3b. The
This article is protected by copyright. All rights reserved.

10.1002/anie.202008512
Angewandte Chemie International Edition
COMMUNICATION
heteroatom substituted lithium N-methylpiperazide 2c and lithium
morpholide 2d were poorly soluble in 2-MeTHF. We thus diluted
them by a factor of 6 to give more uniform 0.17 M dispersions. A
virtually quantitative yield for 3c was found employing this
dispersion. On adding morpholide the reaction proceeded slower
and gave only 13% yield of 3d under our standard conditions,
which rose to 52% by stirring the reaction for 2 h at a reduced
speed of 500 rpm to slow down the moisture intake. The aliphatic
amide lithium n-butylamide 2e did not form significant amounts of
product under the original conditions nor under reduced stirring
speed (500 rpm) and longer reaction time (2 h). Broad signals in
sensitive to air and moisture than their lithium counterparts, we
found that using 2-MeTHF under air, the hydroamination product
3a is obtained in a 71% yield in just 5 min (Figure 2i). Longer
reaction times did not lead to higher conversions, suggesting that
while the hydroamination process is faster than using 2a (using
LiPip after 5 min 3a is formed in a much lower 32% yield), the
decomposition of the sodium intermediate in the presence of air
and moisture also occurs more rapidly. Showing the beneficial
and key role of moisture, if the reaction is carried out under inert
atmosphere conditions and dry solvents polymerisation of styrene
is observed.
1
the H NMR spectra of the reaction mixtures suggest that this
amide might oligomerise the styrene before the action of ambient
moisture generated enough of the corresponding amine. We also
assessed the reactivity of 2a towards several styrenes (Table 4)
Steric repulsion, unsurprisingly, leads to significant yield
reductions. With these reactions being marginally energetically
downhill, steric bulk leads to incomplete conversion of the
substrates. While we found an excellent yield of 90% for
unsubstituted styrene 1c, ortho-methyl styrene 1d gave 54% and
1,1-diphenyl styrene 1b yielded 41%. Other vinylic methyl and
phenyl substituted styrenes showed no product under the
employed conditions. Inductive and mesomeric donor
substituents generally gave excellent yields for hydroamination
with lithium piperidide 2a. 4-Methylstyrene gave 90% of 3a. Yields
of 73% for 4-OMe 3i and 93% for 3-OMe 3j are found. 3,4-
Dimethoxystyrene 1g was hydroaminated to give 97% of 3k.
Rather electron-poor styrenes worked reasonably well, with 4-
vinylbiphenyl 1h giving 59% of 3p. The 3-CF3 substituted 3m was
isolated in a 41% yield. The reactions with 4-F 1j led to a mixture
of products containing 3n in a 45% yield; whereas with 4-Cl 1k,
Figure 2. (i) Air and moisture compatible Na-mediated hydroamination of 1a in
2-MeTHF; (ii) Synthesis of 5a.0.5THF; (iii) portion of polymeric ladder structure
of 5a.0.5THF; and (iv) axial view showing helical conformation of ladder
framework (with thermal ellipsoids rendered at 50% probability, H’s omitted for
clarity and C atoms of THF molecules shown as wire frame for clarity; in (iv) C
atoms have also been omitted).
amine 3o was formed in a 64% yield.
Table 4. Reaction scope concerning various styrenes 1 with LiPip 2a.
To find out more about the constitution of NaPip, 5a (prepared by
deprotonation of piperidine via NaCH2SiMe3, 4) was recrystalised
in
a
mixture of hexane/THF affording [{Na2Pip2(THF)}∞]
(5a·0.5THF). Its structure was established by X-ray
crystallography (Figure 2ii). Exhibiting a rare polymeric ladder
structure, 5a·0.5THF is composed of four-membered {Na2N2}
rings laterally associated, with a THF bridge connecting the two
Na centres. Propagation occurs in a helical conformation with the
THF molecules coordinated on the outer side of the helix (Figure
2 iii and iv).[17],[18] Despite having this polymeric arrangement, 5a
is readily soluble in 2-MeTHF and d8-THF, which suggests the
Entry
Reactant
1b
R
Ph
H
H
H
H
H
H
H
H
H
R’
Product
3f
Yield[%]
41
1
2
3
4
5
6
7
8
9
10
H
1c
H
3g
3h
3i
85
1d
2-Me
4-OMe
3-OMe
3,4-(OMe)2
4-Ph
3-CF3
4-F
54
1e
73
1
1f
3j
93
formation of smaller aggregates. H DOSY NMR experiments in
d8-THF also suggest the formation of a monomer solvated by 3
molecules of d8-THF (MWdet =348 g/mol, error 4%, see SI for
details),[19] which is consistent with the fast reactivity seen when
reacted with 1a (Figure 2i).
1g
3k
97
1h
3l
59
1i
3m
3n
3o
41[a]
45[a]
64[a]
Inspired by these results we also pondered whether sodium alkyl
4 could act as a pre-catalyst for the hydroamination of styrenes
under inert atmosphere conditions (to avoid competing
decomposition pathways). While lithium alkyls have shown good
promise in catalytic hydroamination of olefins,[3c] the use of
sodium alkys has not been investigated. Interestingly, we found
that using just 5 mol% of 4 hydroamination of several styrenes [1a,
1c, and -Me-styrene (1l)] with a range of secondary amines [2a-
2d, HNBz2 (2f), HNMeBz (2g), HNBu2 (2h)] is accomplished in
excellent yields (72-88%) at room temperature in just 10 minutes
1j
1k
4-Cl
Reactions performed on a 1 mmol scale in 1.5 mL of 2-MeTHF. They are
stirred at 900 rpm for 30 min. Mean yields of isolated aliquots of at least two
independent reactions are given. [a] Side reactions led to contaminated
product. [
Finally, to probe the scope of this approach in terms of the nature
of the group 1 metal amide we next studied the reactivity of 1a
against NaPip (5a). While sodium amides are significantly more
This article is protected by copyright. All rights reserved.

10.1002/anie.202008512
Angewandte Chemie International Edition
COMMUNICATION
(Scheme 4). The compatibility of the sodium alkyl 4 with THF is
remarkable, just as its catalytic activity contrast with the sluggish
reactivities reported for sodium catalysed hydroamination using
Na metal or NaH as catalysts.[2a]
[2]
(a) T. E. Müller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem. Rev.
2008, 108, 3795–3892; (b) J. Seayad, A. Tillack, C. G. Hartung, M. Beller,
Adv. Synth. Catal. 2002, 344, 795–813; (c) M. C. Wood, D. C. Leitch, C.
S. Yeung, J. A. Kozak, L. L. Schafer, Angew. Chem. Int. Ed. 2007, 46,
354–358; (d) G. Tran, W. Shao, C. Mazet, J. Am. Chem. Soc. 2019, 141,
14814–14822; (e) D. C. Miller, J. M. Ganley, A. J. Musacchio, T. C.
Sherwood, W. R. Ewing, R. R. Knowles, J. Am. Chem. Soc. 2019, 141,
16590–16594; (f) S. B. Herzon, J. F. Hartwig, J. Am. Chem. Soc. 2007,
129, 6690–6691; (g) R. Kubiak, I. Prochnow, S. Doye, Angew. Chem. Int.
Ed. 2009, 48, 1153–1156; (j) M. Beller, M. Eichberger, H. Trauthwein,
Angew. Chem. Int. Ed. 1997, 36, 2225–2227.
[3]
(a) K. Kumar, D. Michalik, I. Garcia Castro, A. Tillack, A. Zapf, M. Arlt, T.
Heinrich, H. Böttcher, M. Beller, Chem. Eur. J. 2004, 10, 746–757; (b) P.
Horrillo-Martínez, K. C. Hultzsch, A. Gil, V. Branchadell, Eur. J. Org.
Chem. 2007, 2007, 3311–3325; (c) S. Germain, M. Lecoq, E. Schulz, J.
Hannedouche, ChemCatChem 2017, 9, 1749–1753; (d) R. J. Schlott, J.
C. Falk, K. W. Narducy, J. Org. Chem. 1972, 37, 4243–4245; (e) J.
Deschamp, J. Collin, J. Hannedouche, E. Schulz, Eur. J. Org. Chem.
2011, 2011, 3329–3338; (f) J. Hannedouche, E. Schulz, Chem. Eur. J.
2013, 19, 4972–4985.
[4]
[5]
L. Davin, A. Hernán-Gómez, C. McLaughlin, A. R. Kennedy, R. McLellan,
E. Hevia, Dalton Trans. 2019, 48, 8122–8130.
(a) R. E. Mulvey, S. D. Robertson, Angew. Chem. Int. Ed. 2013, 52,
11470–11487; (b) A. Pouilhès, J.-P. Baltaze, C. Kouklovsky, Synlett
2013, 24, 1805–1808.
Scheme 4. Sodium catalysed hydroamination of vinyl arenes 1c, 1d and 1l with
amines 2a-d and 2f-2h. Conversions determined by NMR spectroscopy using
ferrocene as internal standard (see SI for details); yields of isolated products
shown in brackets.
[6]
[7]
J. Swarbrick, J. C. Boylan, Encyclopedia of Pharmaceutical Technology,
Dekker: New York 1988, pp 110–116.
(a) S. Monticelli, L. Castoldi, I. Murgia, R. Senatore, E. Mazzeo,
J .Wackerlig, E. Urban, T. Langer, V. Pace, Monatsh. Chem. 2017, 148,
37–48; (b) V. Pace, P. Hoyos, L. Castoldi, P. Domínguez de María, A. R.
Alcántara, ChemSusChem 2012, 5, 1369–1379; (c) V. Pace, Aus. J.
Chem. 2012, 65, 301–302; (d) D. F. Aycock, Org. Process Res. Dev.
2007, 11, 156–159.
(a) P. Lei, Y. Ling, J. An, S. Nolan, M. Szostak, Adv. Synth. Catal. 2019,
361, 5654–5660. (b) S. Monticelli, L. Castoldi, I. Murgia, R. Senatore, E.
Mazzeo, J. Wackerlig, E. Urban, T. Langer, V. Pace, Monatsh. Chem.
2017, 148, 37–48; (c) D. F. Aycock, Org. Process Res. Dev. 2007, 11,
156–159.
To summarise, surprisingly we found that performing alkali-metal-
amide-executed intermolecular hydroamination reactions under
air can be accelerated by moisture from ambient air, instead of
being destroyed by its presence. This observation has led to the
development of an exceptionally simple procedure for vinylarene
hydroamination. Ambient moisture generates a steady supply of
the necessary free amine to coordinate and so activate the alkali-
metal amides then to quench the addition products. Formation of
small kinetically activated aggregates of the metal amides seems
to be key to enable hydroamination under these unconventional
reaction conditions.
[8]
[9]
M. Fairley, L. J. Bole, F. F. Mulks, L. Main, A. R. Kennedy, C. T. O’Hara,
J.
García-Alvarez,
E.
Hevia,
Chem.
Sci.,
2020,
DOI:
10.1039/D0SC01349H.
[10] (a) V. Snieckus, M. Rogers-Evans, Lithium Piperidide. In: e-EROS
Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons, Ltd.
Chichester 2001, pp 1–2; (b) N. Monck, P. Timm, Lithium
Dicyclohexylamide. In: e-EROS Encyclopedia of Reagents for Organic
Synthesis, John Wiley & Sons, Ltd. Chichester 2005, pp 1–2.
[11] M. S. Hill, D. J. Liptrop, C. Wheetman, Chem. Soc. Rev. 2016, 45, 972.
[12] (a) D. W. Slocum, C. A. Jennings, J. Org. Chem. 1976, 41, 3653–3664;
(b) A. G. M. Barrett, C. Brinkmann, M. R. Crimmin, M. S. Hill, P. Hunt, P.
A. Procopiou, J. Am. Chem. Soc. 2009, 131, 12906–12907.
[13] (a) C. Brinkmann, A. G. M. Barrett, M. S. Hill, P. A. Procopiou, J. Am.
Chem.Soc. 2012, 134, 2193–2207; (b) M. De Tullio, A. Hernán-Gómez,
Z. Livingstone, W. Clegg, A. R. Kennedy, R. W. Harrington, A. Antiñolo,
A. Martínez, F. Carrillo-Hermosilla, E. Hevia, Chem. Eur. J. 2016, 22,
17646–17656.
Experimental Section
Full experimental details and copies of NMR spectra are included in the
Supporting Information.
[14] X-ray crystallographic studies have already shown that LiPip can form a
coordination adduct with PipH, see G. Boche, I. Langlotz, M. Marsch, K.
Harms, N. E. S. Nudelman, Angew. Chem. Int. Ed. 1992, 31, 1205–1207.
[15] G. Ndebeka, P. Caubère, S. Raynal, S. Lécolier, Polymer 1981, 22, 347–
355; (b) G. Ndebeka, P. Caubère, S. Raynal, S. Lécolier, Polymer 1981,
22, 356–360; (c) S. Carlotti, P. Desbois, V. Warzelhan, A. Deffieux,
Polymer 2009, 50, 3057–3067; (d) A. C. Angood, S. A. Hurley, P. J. Tait, ,
J. Polym. Sci. Pol. Chem. 1973, 11, 2777–2791.
[16] In recent studies comparing the constitution of lithium anilides in THF and
Me-THF we have shown that in all cases the same level of aggregation
and solvation is observed in both solvents (see reference [9]).
Considering also the greater solubility of lithium amides in 2-MeTHF in
Acknowledgements
We thank Robert Mulvey and Marina Uzelac for useful comments.
Funding by the UK’s Engineering and Physical Sciences
Research Council (Grant number EP/S020837/1), ERC-Stg
MixMetApps and the University of Bern is also acknowledged.
comparison with THF, formation of
monomer can be proposed.
a similar [Li(Pip)(2-Me-THF)3]
Keywords: s-block metals • hydroamination • solvent effects •
air/moisture compatible • Lithium •catalysis
[17] For other examples of Na amide ladder structures see: (a) W. Clegg, K.
Henderson, L. Horsburgh, F. M. Mackenzie, R. E. Mulvey. Chem. Eur. J.
1998, 4, 53 – 56; (b) N. Kuhn, G. Henkel, J. Kreutzberg, Angew. Chem.
Int. Ed. 1990, 29, 1143-1144; (c) D. R. Baker, R. E. Mulvey, W. Clegg, P.
A. O’Neil, J. Am. Chem. Soc. 1993, 115, 6472-6473.
[18] This structure complies with the ring-laddering principle, see (a) D. R.
Armstrong, D. Barr, W. Clegg, R. E. Mulvey, D. Reed, R. Snaith, K. Wade,
Chem. Commun., 1986, 869; (b) R. E. Mulvey, Chem. Soc. Rev., 1991,
20, 167 (c) R. E. Mulvey, Chem. Soc. Rev., 1998, 27, 339.
[1]
(a) G. Osztrovszky, T. Holm, R. Madsen, Org. Biomol. Chem. 2010, 8,
3402–3404; (b) M. J. Rodriguez-Alvarez, J. Garcia-Alvarez, M. Uzelac,
M. Fairley, C. T. O'Hara, E. Hevia, Chem. Eur. J. 2018, 24, 1720–1725;
(c) C. Vidal, J. Garcia-Alvarez, A. Hernan-Gomez, A. R. Kennedy, E.
Hevia, Angew. Chem. Int. Ed. 2014, 53, 5969–5973; (d) C. Vidal, J.
Garcia-Alvarez, A. Hernan-Gomez, A. R. Kennedy, E. Hevia, Angew.
Chem. Int. Ed. 2016, 55, 16145-16148; (e) A. Sánchez-Condado, G. A.
Carriedo, A. Presa Soto, M. J. Rodríguez-Álvarez, J. García-Álvarez, E.
Hevia, ChemSusChem 2019, 12, 3134–3143; (f) F. P. Perna, P. Vitale,
V. Capriati, Curr. Opin. Green Sustain. Chem. 2020, 21, 27–33; (g) L.
Cicco, S. Sblendorio, R. Mansueto, F.M. Perna, A. Salomone, S. Florio,
V. Capriati Chem. Sci. 2016, 7, 1192–1199.
This article is protected by copyright. All rights reserved.

10.1002/anie.202008512
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
F. F. Mulks, L. J. Bole, L. Davin, A.
Hernán-Gómez, A. R. Kennedy, J.
García-Álvarez* and E. Hevia*
Page No. – Page No.
Ambient Moisture Accelerates
Hydroamination Reactions of
Vinylarenes with Alkali-Metal Amides
under Air
Moisturising for Smoother Reactions: The nemesis of organo-alkali metal
reagents, ambient moisture can remarkably accelerate the alkali-metal amide
induced hydroamination of styrenes. A practically simple aerobic procedure for
these hydroaminations under air and in renewable 2-methyltetrahydrofuran is
revealed.
This article is protected by copyright. All rights reserved.