Stannyl-Lithium: A Facile and Efficient Synthesis Facilitating Further Applications

Article abstract of DOI:10.1021/jacs.5b06587

We have developed a highly efficient, practical, polycyclic aromatic hydrocarbon (PAH)-catalyzed synthesis of stannyl lithium (Sn-Li), in which the tin resource (stannyl chloride or distannyl) is rapidly and quantitatively transformed into Sn-Li reagent at room temperature without formation of any (toxic) byproducts. The resulting Sn-Li reagent can be stored at ambient temperature for months and shows high reactivity toward various substrates, with quantitative atom efficiency.

Full text of DOI:10.1021/jacs.5b06587

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Stannyl-Lithium: A Facile and Efficient Synthesis Facilitating Further
Applications
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Dong-Yu Wang,†,‡, Chao Wang,†,‡,* Masanobu Uchiyama†,‡,*
†Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo-to 113-0033, Ja-
pan;
‡Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable Resource Science, and Elements
Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama-ken 351-0198, Japan.
Supporting Information Placeholder
than 50%, since large amounts of toxic R4Sn are gen-
erated as a by-product. Therefore, existing method-
ologies require Sn-Li reagent to be prepared in excess
due to poor yield, so that it is difficult to utilize for
reactions that require exact stoichiometry. The low
atomic-efficiency of Sn-transfer results in both ex-
cess use of Sn resource and generation of considera-
ble toxic by-products, mainly including R4Sn and
R3SnSnR3. Normally, the problem of toxicity has put
off many people from using organotin compounds,
where the toxicity partly comes from the undesired
by-products and remaining excess Sn materials. If
these disadvantages could be overcome, the applica-
bility of Sn-Li chemistry would be enormously en-
hanced, and the risk of toxicity in the usage of or-
ganotin compounds would be notably reduced as
well.
ABSTRACT: We have developed a highly efficient,
practical, polycyclic aromatic hydrocarbon (PAH)-
catalyzed synthesis of stannyl lithium (Sn-Li), in
which the tin resource (stannyl chloride or distannyl)
is rapidly and quantitatively transformed into Sn-Li
reagent at room temperature without formation of
any (toxic) by-products. The resulting Sn-Li reagent
can be stored at ambient temperature for months,
and shows high reactivity toward various substrates,
with quantitative atom-efficiency.
Since the pioneering works by Wittig, Gilman, Still,
and others,1-3 stannyl lithium (Sn-Li) has long been
employed as a heavy analogue of C-Li for construct-
ing various functional molecules, including natural
products, pharmaceuticals, agrochemicals, function-
al materials and polymers.1-4 Sn-Li is also a key pre-
cursor of other Sn-metal reagents containing main
group metals (Mg, Al, Zn, B, etc.) or transition met-
als, which have a wide variety of (catalytic) reactivi-
ties.4
(A)
(C)
R2Sn
RLi
Li
R3SnX
R3SnH
RLi
+
+
+
R3Sn
Li
(B)
(D)
i
R3SnX
Pr2NLi
+
X = Halogen or SnR3
selected examples
(conditions)
yield
by trapping
method
(A)
by-product (yield)
SnCl2, PhLi
70~75%
33%
(THF, -10 oC, 15 min)
However, existing long-established methods for
preparing Sn-Li have many disadvantages: large ex-
cess consumption of Sn-sources, low yields, side re-
actions/toxic by-products, long reaction time, and
instability of the reagent as summarized by
Oehlschlager et al. (Scheme 1).5 For example, routes
(A)1 and (B)1-2 suffer from low yields, formation of
various toxic by-products, and/or long reaction time.
Although routes (C)3a and (D)3b provide better yields,
they show poor atom-economy. In route (C), an ex-
cess of highly toxic R3SnH is needed to obtain ac-
ceptable yields, and diisopropylamine is co-produced
stoichiometrically. In route (D), loss of Sn is more
nBu4Sn (45%)
SnCl2, nBuLi
nBu3SnCl (15%)
(THF, 0 oC, 15 min)
Ph3SnSnPh3, Li
(THF, r.t., 8 h)
70~75%
48%
Ph3SnSnPh3 (5~10%)
nBu6Sn2 (30%)
(B)
nBu3SnCl, Li
(THF, 0 oC, 24 h)
nBu4Sn (30%),nBu3SnCl (4%)
nBu6Sn2 (8%)
nBu3SnH, LDA
(C)
(D)
90%
80%
(THF, -30 oC, 15 min)
Pr2NH (stoichiometric to nBu3SnLi)
i
Me3SnSnMe3, MeLi
(THF, 0 oC, 8 h)
Me4Sn (stoichiometric to Me3SnLi)
Scheme 1. Current Scope and Limitations of
Methods for Synthesis of Stannyl-Lithium
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Herein, we demonstrate a new, simple, and practi- high atom-efficiency (Scheme 3-I). When the present
method was combined with zincate chemistry,9 the
stannyl zincate10 reacted smoothly with phenylacety-
lene in 1 : 1 ratio in the presence of a catalytic
amount of CuCl at 0°C to give the adduct in high
yield (Scheme 3-II), in sharp contrast to the tradi-
tional protocols for stannylzincation5,11.
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cal synthetic protocol for polycyclic aromatic hydro-
carbon (PAH)-catalyzed synthesis of Sn-Li com-
pounds from lithium metal and R3SnX (X = halogen
or SnR3), focusing in the present work mainly on the
use of naphthalene as a PAH (Scheme 2). This reac-
tion quantitatively and rapidly transforms Sn from
R3SnX to the Sn-Li moiety at room temperature
without generation of any toxic by-products; moreo-
ver, the Sn-Li reagent prepared in this way shows su-
perior reactivity and high stability under ambient
conditions, compared to Sn-Li reagent prepared with
previously reported methods.
This protocol not only provides a straightforward
method to obtain salt-free stannyl lithium, which is
very difficult with any of the previous protocols, but
also has another striking feature, that is, the stability
of the stannyl lithium solution obtained with the
new method. The reagents prepared via traditional
methods usually decompose very quickly, especially
in the presence of R3SnSnR3, an inevitable by-
product of those methods, and hence they cannot be
stored for long even at low temperature.5,12 However,
R3SnLi solutions prepared by our method have a ra-
ther long lifetime. It can be stored at room tempera-
ture for over 2 months without decomposition (Table
1). The catalytic amount of naphthalene-lithium was
proved to be important for the stability (see support-
ing information). In sharp contrast with the tradi-
tional procedures, which offer only moderate yields
of Sn-Li together with formation of various tin-
containing by-products, require the use of a large
excess of lithium (normally over 20 equivalents) and
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Naphthalene (5 mol%)
(or other PAH catalyst)
Functional
Molecules
R3Sn
X
Li
R3Sn
Li
+
THF, r.t., < 3 h
X = Halogen
or SnR3
¶ Quantitative Transformation (100% Sn-Economy) ¶ Toxic By-Product Free
¶ Stable for Long Storage at Room Temperature ¶ Diverse Applicability
Scheme 2. PAH-catalyzed Synthesis of Stannyl-
Lithium
Since direct insertion of metal always offers the
highest atom-economy in the synthesis of organome-
tallics,6 we set out to re-examine the reaction be-
tween metallic lithium and R3SnX (X = halogen or
SnR3). However, extensive studies failed to increase
the yield of Sn-Li bond formation. We next investi-
gated the naphthalene-lithium system7a-c instead of
lithium metal, with a single electron transfer (SET)
mechanism in mind. Indeed, we observed a dramatic
enhancement and acceleration of the transformation.
Encouraged by this, we extensively examined the re-
action conditions and finally found that stannyl lith-
ium could be prepared in a catalytic manner.7d As
shown in Scheme 3-I, treatment of a THF solution of
either R3SnCl or R3SnSnR3 with just lithium metal
and 5 mol% of naphthalene as a catalyst at room
temperature generated the corresponding R3SnLi
quantitatively in 3 hours, as reflected in the quanti-
tative yields of tetraorganotin products in capture
reactions with iodomethane and benzyl bromide
(capture reactions are widely used for titrating
R3SnLi solutions to calculate yields).1-3 Other PAHs,
such as anthracene and 4,4 -di-tert-butylbiphenyl
(DBB), also showed high catalytic activity. One of the
most attractive features of the new procedure is that
100% Sn-transfer was achieved; only 1 equivalent of
LiCl was co-produced when R3SnCl was employed.
Indeed, when R3SnSnR3 is used, no by-product at all
is formed. Hence, the toxicity caused by the Sn-
contained by-products could be totally removed in
this method.8 Furthermore, Sn-Li reagent prepared
by this method allowed us to introduce a stannyl
group into the final product with excellent yield and
o
long reaction periods (12 hours or longer at 0 C),
and afford rather unstable reagent solutions, the new
method provides exceptionally high efficiency and
great practical convenience.
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Scheme 3. Naphthalene-catalyzed Synthesis of especially Stille coupling. Normally, direct reaction
of C-M (e.g., C-Li) reagents with sp2 C-X (e.g., aryl
halide) is difficult, and hence chemists have used
transition metal-catalyzed cross-coupling to carry
out such C-C bond formation. However, Sn-Li spe-
cies can direct react with aryl halide to form aryltin
compounds under mild conditions. We found that
stannyl lithium (nBu3SnLi) prepared by our method
can be utilized as a potent stannyl anion equivalent
with excellent reactivity towards diverse aryl halides,
as shown in (Table 2). Firstly, this reaction is highly
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R3SnLi and Their Various Reactivity.
Table 1. Examination of Stability (Lifetime)
9
Several interesting reactions in Sn-Li chemistry
have long been neglected, probably because of the
issues with previous methods for preparing the rea-
gent. A representative case is the stannylation of aryl
halide with R3SnLi to form aryltin compounds,1c,2a, 13
which are very useful reagents for organic synthesis,
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n
atom- economical: Bu3SnLi is generated quantita-
tively from the tin source and then transformed to
stannylarene 1 in excellent to
Table 2. Stannylation of Aryl Halides with R3SnLi Prepared via Naphthalene-catalyzed Protocols and Direct Uti-
lization in Stille Coupling
quantitative yield by using aryl halide in just 1 : 1 ra-
tio. Secondly, this reaction proceeds smoothly under
mild conditions, usually being completed at ambient
temperature, whereas many existing synthetic meth-
ods of aryl stannanes (Ar-SnR3) via TM-mediated
metathesis between ArX and R3SnSnR3 require harsh
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conditions.14 Thirdly, this reaction has wide scope,
with high tolerance of electron-
14 elements are in progress. We believe this method
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represents a fundamental advance in the preparation
of heavy analogues of carbanion, which have broad
synthetic utility, and its practical convenience and
efficiency will make it widely applicable both in the
laboratory and in industry.
donating/withdrawing groups (1a-e/1f-n), bulky
groups (1b), active functional groups (1g-m), and
heterocycles (1n-r). Reaction of ArX with two C–X
bonds, such as 1p, also proceeded with high efficien-
cy. Finally, the robust and clean reaction suggests
that the prepared stannylarenes could be used for
further reaction without purification. Indeed, as ex-
pected, we found that the resultant stannylarene,
without purification, underwent Stille coupling
smoothly with aryl iodide in the presence of a cata-
lytic amount of Pd,15 affording biaryl products 2 in
high yields. In short, this system is highly advanta-
geous for creating functional molecules.
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Further applications of this method are illustrated
in Scheme 4. Diorganostannyl dichloride was trans-
formed smoothly to the corresponding dilithiostan-
n
Scheme 4. Further Applications of naphthalene-
catalyzed Synthetic Protocol.
nane species (Scheme 4-I). Treatment of Bu2SnCl2
with Li metal in the presence of a catalytic amount of
naphthalene followed by electrophilic trapping with
aryl halides afforded the desired diarylated product
in good yields.16 Up to now, only very limited exam-
ples of dianionic SnLi2 species have been reported,
such as very special cases (dilithiostannole)4f or
those limited by low yields and generation of by-
products.17 With the present method, it is possible to
prepare R2SnLi2 with more generality and high effi-
ciency, as is the case for other organo-di-metallic re-
agents.18 Germanium compounds are widely used in
optical/electronic materials, and their high cost
means that efficient synthetic methods are particu-
larly important. Germanyllithium is commonly used
for synthesis of various organogermaniums, which
was initially synthesized as early as stannyllithium
via similar methods, and was also suffering from
many disadvantages of those traditional protocols.2b
We then applied this PAH-catalytic system to ger-
manium (Scheme 4-II). By utilizing this procedure,
Ph3GeLi could be prepared efficiently and conven-
iently under mild conditions, as reflected in the ex-
cellent yields of the trapping products.
ASSOCIATED CONTENT
Supporting Information. Details for Experiments and
characterizations. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
chaowang@riken.jp; uchiyama@mol.f.u-tokyo.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This paper is dedicated to Professor Ei-ichi Negishi on
the occasion of his 80th birthday. This work was finan-
cially supported by JSPS KAKENHI (S) (No. 24229011)
(to M. U.), and JSPS TEISOKU Program (PU14008) (to
C. W.). D.-Y. W. is grateful for a scholarship provided by
the Uehara Memorial Foundation.
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