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CROSS-COUPLING REACTIONS

Is sodium finally coming of age?
Given the fact that sodium is the most abundant alkali metal on Earth, the direct and indirect use of organosodium
compounds in palladium-catalysed carbon–carbon bond forming reactions is an attractive alternative forsustainable organic synthesis.

Henry N. C. WongT

he formation of carbon–carbon single
bonds is one the most importantfundamental chemical reactions
in organic synthesis, finding numerous
applications in pharmaceutical and materials
sciences. Conventionally, carbon–carbon
single bonds can be constructed by manywell-established organic transformations;especially those named metal-catalysed
cross-coupling reactions, for example, Heck–Mizoroki, Migita–Kosugi–Stille, Negishi,and Suzuki–Miyaura reactions. In thesereactions, organometallic reagents suchas organotin, organozinc or organoboron
are employed as nucleophiles, whose
preparations often involve transmetallationof organolithium compounds. The use ofsodium in cross-coupling reactions has
been considered inferior to lithium, despite
the fact that sodium is also an alkali metal,
and is the most abundant such metal in theEarth’s crust and oceans. However, since thefirst direct preparation of 3-furylsodium
from 3-iodofuran in 1933 by Gilman
and Wright1, and of phenylsodium fromchlorobenzene in 1935 by Bockmühl andEhrhart2, organosodium reagents have been
overlooked for more than 80 years.
Now, writing in Nature Catalysis,
Asako, Nakajima and Takai — chemists
from Okayama University in Japan —demonstrate that organosodium compounds
can be easily prepared from aryl chloridesor (hetero)arenes and an easily handled
sodium dispersion3. These organosodium
compounds can be converted further into
coupling partners for palladium-catalysed
Negishi or Suzuki–Miyaura cross-coupling
reactions. Direct palladium-catalysed
cross-coupling reactions employing
these organosodium compounds arealso demonstrated.
The research team initially explored thepreparation of arylsodium compounds bymaking use of sodium particles dispersedin paraffin oil with an average size
smaller than 10 μm. The concentration of
approximately 26 wt% also renders thissodium dispersion stable and easy to handle
in air. Following the method of Nobis and282att

Sodiumdispersion(250 mol%)
Hexane50 °C
5 hours

BuBuClt

Bu

Sodiumdispersion(210 mol%)

NMe2
Clbit

NaiPr
NaiPr

RNRt

Quantitative>95% yield

BuBuDtBu

NMe2NaHexane
30 °C

R

Bu

D2O

NMe2Hexane
30 °C
1 hour

Prt

Bu

But

Sodiumdispersion(250–280 mol%)

Pr
Clit

PhMe2SiCl

SiMe2Ph

86% yield(1) ZnCl 2 •TMEDA(1.2 equiv.)
Hexane30 minutes(2) Pd-PEPPSI-IPr(1 mol%)2-Cl-Naphthalene
Hexane-THF-NMP
70 °C, 5 hours
96% yield

iPriPrN

ClPdClRNCl
Pd-PEPPSI-IPr (R = i-Pr)
Pd-PEPPSI-IPent (R = i-Pentyl)c

NaTMP(1.2 equiv.)
OdOMe
NaNa

Hexane30 °C

O

Pd-PEPPSI-IPent(5 mol%)v(1) MeOBpin(1.2 equiv.)
Hexane-THF
0 °C, 10 minutes(2) 4-ClC6H4CN
Pd-PEPPSI-IPr(2 mol%)Hexane-THF-H2O
70 °C, 3 hours
94% yield

CNOOMeHexane70 °C, 3 hours
81% yield

Fig. 1 | Reactions of organosodium compounds. a, Preparation and quenching of organosodium
compounds. b, Negishi reaction. c, Suzuki–Miyaura reaction. d, Direct cross-coupling reaction.

Moormeier4, 15 organosodium compounds
were prepared and, upon quenching witheither D2O or PhMe2SiCl, deuterioarenesor phenyldimethylsilanes were afforded inyields ranging from 60% to quantitative
yield. Two examples of these conversions

Nature Catalysis | VOL 2 | APRIL 2019 | 282–283 | www.nature.com/natcatal

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are shown in Fig. 1a. For the stericallyhindered aryl chloride, 250 mol% of sodium
dispersion is required (though consideringthat sodium is a one-electron donor, thisis only 1.25 equivalents), and the reaction
temperature is also higher.
Next, the authors convertedorganosodium compounds into thecorresponding organozinc reagentsfor Negishi reaction (Fig. 1b).
Organosodium compounds underwent
transmetallation reactions by addition ofZnCl2•TMEDA (TMEDA, N,N,N′,N′tetramethylethylenediamine) to formarylzinc compounds in situ, which thenwere allowed to react with a second aryl
chloride with 0.1–3 mol% of a Pd-pyridineenhanced precatlyst preparation stabilizationand initiation (PEPPSI)-IPr catalyst, to form
the carbon(sp2)–carbon(sp2) bond. In thisway, a total of 21 cross-coupled products
were prepared with yields ranging from 70%
to 98%. Noteworthy is that the turnover
number (TON) of 920 was also obtainedfor one of these Negishi reactions. Suzuki–
Miyaura reactions were also performed
and, as shown in Fig. 1c, 2-arylbenzo[b]furan was achieved in 94% yield. In thispalladium-catalysed Suzuki–Miyaura crosscoupling reaction, benzo[b]furan-2-sodium
was prepared by a direct metallation ofbenzo[b]furan, making use of the unusual
α-hydrogen acidity of benzo[b]furan. A totalof eight examples were reported, with yieldsranging from 78% to 94%. Finally, a directcross-coupling reaction with arylsodium
compounds was also carried out. As canbe seen in Fig. 1d, the organosodium
compound was allowed to couple directlywith an aryl chloride to provide the productwith a new carbon(sp2)–carbon(sp2) bondin 81% yield. Aryl bromides can also beused, and the reaction temperature andtime for cross-coupling can be lowered to30 °C and 1 hour, respectively. A slightly
structurally different palladium catalyst,
Pd-PEPPSI-IPent (5 mol%) was usedinstead. In this direct cross-coupling
reaction, eight examples were reported, withyields ranging generally from 60% to 96%(yields were typically increased if 10 mol%of zinc salt was added). A 2.5 mmol scale
reaction was also performed, resulting in analmost similar yield, thereby pointing to thepossibility that these reactions can be scaled
up to multi-gram quantities.
One interesting implication of the workis the potential for adoption by industry. As
pointed out by the authors3: “Because of thelower reactivity of the sodium dispersion
at this concentration upon contact withwater, the permitted amount of sodium
per designated quantity of the sodium
dispersion is about 45 times larger than thatof a sodium lump in Japan, which would
make industrial applications more feasible”.
The fact that the sodium dispersion canbe measured precisely using a syringe,
while the same is not true for sodium
lump, makes the use of sodium dispersion
much more attractive and convenient. As
such, organosodium compounds would
be readily accessible under very mild
conditions in chemistry laboratories, andpresumably also at industrial settings.
These organosodium compounds would
then undergo transmetallation processes toform organozinc or organoboron species
for palladium-catalysed Negishi or Suzuki–
Miyaura reactions, or a direct palladiumcatalysed cross-coupling reaction witharyl chlorides or bromides, leading to theNature Catalysis | VOL 2 | APRIL 2019 | 282–283 | www.nature.com/natcatal

formation of new carbon(sp2)-carbon(sp2)bonds. Nonetheless, unlike organolithiumchemistry, chemists so far have not focusedso much attention on organosodium
chemistry. Therefore, suffice it to say that
more efforts are still needed in order towiden the synthetic scope of organosodiumcompounds. In view that the current
investigation still has some limitations,future efforts should be focussed on issues
such as avoiding unwanted arylsodiuminduced dehydrochlorination of aryl
chlorides, the direct use of organosodium
in metal-catalysed cross-coupling reactions,as well as in the formation of C–N, C–O
and C–S bonds, and the use of abundant
metal catalysts such as iron, zinc andnickel. Notwithstanding, this Nature
Catalysis paper from Asako, Nakajima andTakai3 serves as an inspiration to replacescarce elements such as lithium with theterrestrially abundant, inexpensive andnon-toxic sodium, for the sake of thesustainable future of the planet Earth, on
which we all reside.
❐Henry N. C. Wong

Department of Chemistry, The Chinese Universityof Hong Kong, Shatin, New Territories, Hong Kong
SAR, China.
e-mail: hncwong@cuhk.edu.hk

Published online: 11 April 2019https://doi.org/10.1038/s41929-019-0259-x
References

1. Gilman, H. & Wright, G. F. J. Am. Chem. Soc. 55, 2893–2896 (1933).
2. Bockmühl, M. & Ehrhart, G. Sodium phenyl and its derivativesand process of preparing them. US Patent 2,012,372 (1935).
3. Asako, S., Nakajima, H. & Takai, K. Nat. Catal. https://doi.
org/10.1038/s41929-019-0250-6 (2019).
4. Nobis, J. F. & Moormeier, L. F. Ind. Eng. Chem. 46, 539–544 (1954).

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