Synthesis of aryl trimethylstannanes from aryl amines: A sandmeyer-type stannylation reaction

Article abstract of DOI:10.1002/anie.201304579

Sandmeyer-type stannylation: Stille coupling is one of the most powerful coupling reactions for C-C bond formation, whereas there are only limited methods to access aryl stannane compounds. A mild stannylation process based on a Sandmeyer-type transformation using aromatic amines as the starting materials is described. DCE: 1,2-dichloroethane. Copyright

Full text of DOI:10.1002/anie.201304579

Angewandte
Chemie
DOI: 10.1002/anie.201304579
Synthetic Methods
Synthesis of Aryl Trimethylstannanes from Aryl Amines:
A Sandmeyer-Type Stannylation Reaction**
Di Qiu, He Meng, Liang Jin, Shuai Wang, Shengbo Tang, Xi Wang, Fanyang Mo, Yan Zhang,*
and Jianbo Wang*
The cross-coupling reaction with organotin reagents, namely
the Stille coupling reaction, has been well-established as
[1,2]
À
a powerful C C bond forming method in organic synthesis.
À
Moreover, the Ar Sn bond can also be employed in various
À
À
functional-group transformations, such as C N, C F, and
C OCF3 bond formation.[3] The wide application of Stille
À
coupling has created considerable need for the easy access to
aryl stannane compounds. However, the methods for the
synthesis of functionalized aryl stannane compounds are still
very limited. The traditional method for preparing aryl
stannane compounds is by the reaction of aryl magnesium,
-lithium, or -zinc reagents with trialkyl tin chloride (Scheme
1a).[4] A different strategy is the nucleophilic substitution
between aryl halides or aryl ammonium salts and trialkyl
stannyl anion (Scheme 1b).[5] Moreover, palladium-catalyzed
direct stannylation from aryl halides/ArOTf has also been
reported, which uses hexaalkyl distannane as the tin source
(Scheme 1c).[6]
Scheme 1. Synthetic methods for aryl triaryl stannanes.
tinuation of our interest in this type of diazonium salt-based
transformation, we have proceeded to develop a new route to
aryl stannane compounds through similar Sandmeyer-type
transformation (Scheme 1d).
The Sandmeyer-type transformation is a classical and
valuable approach in which the amino group can be converted
into various functional groups, such as halogen, cyano,
hydroxy, and sulfonate groups.[7] These transformations have
been routinely applied both in the research laboratory and in
industrial production. The common reaction intermediates in
these transformations are aryl diazonium salts, which have
been recently explored in various new transformations.[8–10]
We have recently reported a new approach towards aryl
boronic pinacol esters with aromatic amines as starting
materials.[9] This transformation, which is a novel metal-free
borylation, is under the Sandmeyer-type reaction conditions
by using alkyl nitrite as diazotizing reagent.[11] In view of the
importance of aryl stannane compounds and also as a con-
At the outset, we carried out the stannylation under the
reaction conditions similar to our previously reported Sand-
meyer-type borylation with MeCN as solvent.[9] To our
disappointment, we could only observe trace expected
stannylation product 2a (Table 1, entry 1). Most starting
Table 1: Optimization of reaction conditions.[a]
Entry
Additive (equiv)
Yield [%][b]
1
2
3
4
5
6
7
none
none
trace[c]
38[d]
62
72
66
BF3·OEt2 (1)
TsOH (1)
AlCl3 (1)
AcOH (1)
TsOH (1.2)
[*] D. Qiu, H. Meng, L. Jin, S. Wang, S. Tang, X. Wang, F. Mo,
Dr. Y. Zhang, Prof. Dr. J. Wang
40
76
Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry, Peking University
Beijing 100871 (China)
[a] Unless otherwise noted, the reaction conditions are as follows: aryl
amine (0.3 mmol), tBuONO (1.5 equiv), (SnMe3)3 (1.1 equiv),
1,2-dichloroethane (DCE; 1.5 mL), 4 h. [b] Yield of isolated product.
[c] The reaction was carried out in MeCN; 1a was recovered unchanged.
[d] The reaction was carried out in DCE with 10 equivalents of tBuONO.
E-mail: yan_zhang@pku.edu.cn
wangjb@pku.edu.cn
Prof. Dr. J. Wang
The State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
material (1a) remained unchanged under these conditions.
The yield of 2a could be significantly improved when excess
tert-butyl nitrite was employed and the solvent was switched
to DCE (Table 1, entry 2). Notably, the yield of 2a was
diminished when extending the reaction time or raising the
reaction temperature. It was then confirmed that the product
354 Fenglin Lu, Shanghai 200032 (China)
[**] The project is supported by the 973 Program (No. 2012CB821600)
and NSFC (Grant No. 21272010).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304579.
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2a was not stable at high temperature and the aryl stannane
product could react with alkyl nitrite under these conditions.
We then decided to carry out the reaction at 08C, and we also
reasoned that adding an acidic additive should facilitate the
diazotization process. To our delight, the reaction was
significantly improved by adding 1 equivalent of BF3·OEt2
(Table 1, entry 3). Other acids were then subsequently
examined, and p-toluenesulfonic acid (TsOH) was shown to
provide optimal results (Table 1, entries 4,7).
loss of products in the purification. Notably, the side-products
of the reaction, which are mostly hydrodeamination products
and tBuOSnMe3, can be easily removed from the desired
stannylation products.
To demonstrate the practical usefulness of this method,
the stannylation reaction has been carried out on a gram scale
for two substrates 1b and 1c, as shown in Equation (1) and
Equation (2). The corresponding stannylation products 2b
With the optimized reaction conditions in hand, we then
proceeded to expand the scope of substrates to a series of
functionalized aniline derivatives (Scheme 2). Moderate to
and 2c were obtained in acceptable yields on about a 2 gram
scale.
Heterocyclic aryl stannane compounds have also been
found great importance in organic synthesis, especially for
pharmaceuticals. Thus, we expanded the scope of this
stannylation to the synthesis of aromatic heterocyclic amine
derivatives. The results shown in Scheme 3 indicate that
Scheme 2. Scope of aniline derivatives. Reaction conditions: aryl
amine (0.3 mmol), tBuONO (0.6 mmol), (SnMe3)2 (0.33 mmol), TsOH
(0.36 mmol), DCE (1.5 mL), 4 h. [a] Yield of isolated product after
column chromatography. [b] Room temperature. [c] The reaction was
carried out for 12 h at room temperature.
Scheme 3. Scope of heterocyclic amine derivatives. If not otherwise
noted, the reaction conditions are as follows: aryl amine (0.3 mmol),
tBuONO (0.6 mmol), (SnMe3)2 (0.33 mmol), TsOH (0.36 mmol), DCE
(1.5 mL), 4 h. [a] Yield of isolated product after column chromatogra-
phy. [b] The reaction was carried out for 24 h. [c] TsOH (0.45 mmol)
was used.
good yields were obtained under the reaction conditions. The
stannylation has shown excellent tolerance to both electron-
withdrawing and electron-donating groups on the aromatic
ring, including nitro (2b), methyl (2c), cyano (2d), halogen
stannylation of electron-deficient rings affords relatively high
yields under the standard conditions (4a–e). However, longer
time is required for the diazotization process of these
substrates. In the case of 4e, the diminished yield may be
attributed to the steric effects of the chloride substituent. As
for the amine substrates bearing electron-rich substituents,
the corresponding stannylation products could only be
isolated in low yield owing to the easy oxidation of the
substrates (4h).
À
(2e, 2 f, 2g), formyl (2h), acetyl (2i), methoxy/BocO (2j,
2k), methylthio (2l), trifluoromethyl (2m), and azo groups
(2o). Along with the para-substituted anilines, more compli-
cated substrates, such as those substituted by alkenyl (2t),
alkynyl (2u), and amido (2z) groups, were subjected to this
reaction, and moderate yields were obtained. In the case of 2s
and 2v, the diminished yields were presumably due to steric
effects. For the fluoro- and trifluoromethyl-substituted ani-
lines, the diminished yields were attributed to the low boiling
points of the products (2v, 2w and 2y), which resulted in the
Since purification of aryl stannane compounds is tedious
and some aryl stannanes are not stable on a silica gel column,
it is thus desirable to perform the cross-coupling reaction
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without purification of the crude aryl stannane products. The
sequential Sandmeyer-type stannylation and Pd-catalyzed
Stille coupling reaction was then explored. Upon completion
of the stannylation, the reaction system was filtered to remove
the insoluble precipitates, followed by removing the DCE
solvent in vacuum. The crude product was then subjected to
the Stille reaction to afford the coupling products in moderate
to high yields (Scheme 4).
Scheme 5. Synthesis of p-terphenyl derivatives from p-aminoaniline.
Scheme 4. Sequential stannylation and Pd-catalyzed Stille cross-
coupling reactions. Reaction conditions for the first step: aryl amine
(0.5 mmol), tBuONO (1.0 mmol), (SnMe3)2 (0.55 mmol), TsOH
(0.60 mmol), DCE (2 mL), 4 h; second step: Ar’Br (1.2 equiv),
[Pd(PPh3)4] (5 mol%), toluene (3 mL). [a] Yield of isolated final product
after column chromatography. [b] The yield in bracket refers to the
reaction using PhI for the second step. [c] Reaction for the first step
was carried out at room temperature.
When 10 mol% TEMPO was used, the yield of 2a dropped
from 76% to 63%. The reaction was completely blocked if
excess TEMPO (150 mol%) was added. This experiment
indicates the involvement of radical intermediates in the
reaction mechanism.
A radical mechanism has been proposed to account for
this stannylation reaction (Scheme 6).[12,13] First, diazotization
Further demonstration of the usefulness of this Sand-
meyer-type stannylation is the concise synthesis of p-ter-
phenyl derivatives 9a–e from p-aminoaniline 6 (Scheme 5).
One of the two amino groups of p-aminoaniline 6 was first
converted into a boron group with our previously established
metal-free borylation method.[9b] Subsequently, the stannyla-
tion converted the remaining amino group into a trimethyl-
stannyl group. With the aromatic substrate 8 bearing both
boron and tin groups, consecutive cross-couplings were
carried out by first performing a Stille cross-coupling with
[Pd(PPh3)4] catalyst and ArBr. Upon completion of the Stille
coupling, Ar’Br, K2CO3, and EtOH–H2O were added and
reflux was continued for 6 h. The consecutive cross-coupling
afforded p-terphenyl derivatives 9a–e in moderately good
yields.
Scheme 6. Proposed reaction mechanism.
To gain insights into the reaction mechanism, we have
carried out the reaction in the presence of radical scavenger
TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) [Eq. (3)].[9b]
of the amino group with tBuONO generates diazonium salt A
(Scheme 6a). This is followed by single electron transfer
(SET) from (Me3Sn)2 to A, generating radical anion species B
and radical anion species C (Scheme 6b).[14] From B, aryl
radical D is formed, while C reacts with tert-butoxide anion to
generate trimethylstannyl radical E (Scheme 6c and d).
Reaction of the aryl radical D with (Me3Sn)2 affords the
stannylation product and trimethylstannyl radical
E
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(Scheme 6e).[15] An alternative pathway to stannylation
product is direct combination of radical D and E (Scheme 6 f).
In conclusion, we have developed a Sandmeyer-type
stannylation reaction to synthesize aryl trimethylstannane
derivatives. The reaction is under mild conditions and affords
the stannylation products in moderate to good yields in most
cases. The reaction tolerates a wide range of functional
groups. In view of the importance of arylstannane compounds
in cross-coupling reactions, we expect that this novel stannyl-
ation method will find applications in organic synthesis.
Further expansion of the substrate scope as well as the
detailed mechanistic study is currently underway in our
laboratory, and the results will be reported in due course.
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Received: May 28, 2013
Revised: July 13, 2013
Published online: September 6, 2013
Keywords: aryl stannanes · cross-coupling · diazonium salts ·
.
À
a report on catalytic aromatic C H bond stannylation, see:
Sandmeyer reaction · Stille coupling reaction
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