Palladium-catalyzed stille-type coupling of N -acyl iminium ions with distannanes: A Multicomponent synthesis of α-amidostannanes

Article abstract of DOI:10.1021/cs401164z

The palladium-catalyzed three-component coupling of imines, acid chlorides, and hexabutyldistannane is described. This results in the synthesis of various α-amidostannanes in good yields, without the use of strong nucleophilic organometallic reagents. The reaction is believed to proceed via a Stille-type cross coupling of an in situ-generated N-acyl iminium salt with Bu ₃SnSnBu₃ and reaches completion within 1 h at ambient temperature using simple, unligated Pd₂dba₃ as a catalyst. Combining the formation of α-amidostannanes with lithiation and carboxylation allows the overall synthesis of amino acid derivatives in two steps from imines, acid chlorides, and CO₂.

Full text of DOI:10.1021/cs401164z

Research Article
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Palladium-Catalyzed Stille-Type Coupling of N‑Acyl Iminium Ions
with Distannanes: A Multicomponent Synthesis of
α‑Amidostannanes
Boran Xu and Bruce A. Arndtsen*
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 2K6
S
* Supporting Information
ABSTRACT: The palladium-catalyzed three-component cou-
pling of imines, acid chlorides, and hexabutyldistannane is
described. This results in the synthesis of various α-
amidostannanes in good yields, without the use of strong
nucleophilic organometallic reagents. The reaction is believed
to proceed via a Stille-type cross coupling of an in situ-generated N-acyl iminium salt with Bu3SnSnBu3 and reaches completion
within 1 h at ambient temperature using simple, unligated Pd2dba3 as a catalyst. Combining the formation of α-amidostannanes
with lithiation and carboxylation allows the overall synthesis of amino acid derivatives in two steps from imines, acid chlorides,
and CO2.
KEYWORDS: palladium catalysis, organostannanes, iminium ions, cross coupling, amino acids
Scheme 1. Multicomponent Synthesis of Substituted Amides
ransition metal-catalyzed multicomponent coupling re-
actions have attracted interest in the design of new
T
synthetic methods.1 A useful feature of these transformations is
the ability of the metal catalyst both to activate simple and
unreactive building blocks toward reaction and at the same time
to control how several of these are assembled. These can
provide routes for coupling multiple basic units directly to
products, where a single metal catalyst mediates several bond-
forming operations in a single reaction. A wide range of metal-
catalyzed multicomponent coupling reactions have been
developed.2 One variant that we have been actively developing
involves the use of iminium ions in palladium-catalyzed cross
coupling reactions. While imines are typically not viable
electrophiles in cross coupling reactions, we demonstrated
several years ago that acid chlorides can induce imines both to
undergo facile oxidative addition and to be coupled with
transmetalation with organostannanes to generate α-substituted
amides.3 This reaction presumably proceeds via the initial in situ
generation of N-acyl iminium salts, which undergo oxidative
addition to palladium (Scheme 1). We and others have
demonstrated that this general platform can provide mild
routes for the creation of a range of substituted amides from
three or more available units.4,5
In considering this reactivity, we noted that addition of
palladium to the N-acyl iminium salts converts this typically
strongly electrophilic substrate into a more covalent, palladated
intermediate A. α-Metalated amines and amides are useful
building blocks in synthesis, as they provide access to
umpolung reactivity relative to the typically electrophilic
reactivity at carbon imines.6 Important examples are α-
aminostannanes, which can serve as precursors to amino-
substituted carbon nucleophiles (Scheme 2).7 Subsequent
reaction with electrophiles can provide a flexible platform for
synthesizing a diverse range of α-substituted amines, amino
alcohols, or amino acids. The synthesis of aminostannanes
typically requires the addition of nucleophilic Bu3Sn− to imines
or aminosulfones.8 These tin reagents are highly reactive
compounds that must first be generated or, as demonstrated by
Sato, generated in situ via the use of TMSSnBu3 and
stoichiometric fluoride.9
As an alternative, it is well established that distannanes can
participate in palladium-catalyzed cross coupling reactions with
aryl and vinyl halides to generate organotin reagents.10
Considering the similarity between classic Stille couplings and
that shown in Scheme 1, we became interested in the potential
of acid chlorides to induce imines to participate in palladium-
catalyzed coupling with distannanes, as a mild approach to
generating α-amidostannanes. The results of these studies are
reported below. This has provided a convenient route for the
Received: December 8, 2013
Revised: February 1, 2014
Published: February 3, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/cs401164z | ACS Catal. 2014, 4, 843−846

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Research Article
creates an intermediate, A, in which there is presumably only
one coordination site available. The association of a strongly
coordinating phosphine to this site could inhibit trans-
metalation of A with the stannane.11,12 Consistent with this,
the use of simple 5% Pd2dba3CHCl3 without an added ligand
leads to the rapid formation of amidostannane 1a in a moderate
40% yield (entry 7). Slightly increasing the amount of acid
chloride employed (1.5 equiv) allows the synthesis of 1a in
good overall yield (entry 8). Despite employing no activating
ligands, the reaction is rapid and occurs at ambient temperature
and within 1 h. The catalyst loading can be decreased to 1.5
mol % without any loss of yield (entry 9). Other organometallic
reagents can also be employed in this reaction, such as
(SnMe3)2 or Bu3SnSiMe3 (entry 10 or 11, respectively), albeit
with lower yields. In the case of Bu3SnSiMe3, a mixture of
stannyl and silylated products is formed.13
Scheme 2. Synthesis and Utility of α-Aminostannanes
As shown in Table 2, this reaction can be readily diversified.
A variety of N-substituted imines are compatible with this
coupling, including those with common protecting groups, such
N-benzyl, N-allyl, and N-2,4-dimethoxybenzyl units (entries 1,
2, and 8, respectively). Both electron-donating and -with-
drawing units can be employed on the imine carbon (entries
9−14). However, C-aliphatic imines are not amenable to the
reaction, and imines derived from α,β-unsaturated aldehydes
lead to mixtures of products. In addition to benzoyl chloride,
functionalized aryl and even furanyl and thiophenyl acid
chlorides can be employed (entries 4−7). Chloroformates, on
the other hand, were not reactive under these conditions. The
reaction is also compatible with substrates that can undergo
other palladium-catalyzed transformations. For example, imines
containing both terminal olefinic (entries 2 and 4) and aryl
bromide (entry 10) functionalities react selectively with the
distannane to form 1. These units can be problematic in
palladium catalysis because of their potential to participate in
Heck or cross coupling reactions. The selectivity in this case is
presumably driven by the rapid oxidative addition of the in situ-
generated N-acyl iminium salt, and the subsequent rapid
transmetalation with the distannane, and leaves these functional
groups available as synthetic handles for other metal-catalyzed
transformations. The reaction is also easily scalable and can be
performed on a 1 mmol scale without an appreciable loss of
yield (entry 1).
As an illustration of the potential utility of this reaction, it is
established that α-aminostannanes can undergo facile Sn−Li
exchange for subsequent reaction with electrophiles.7,8 This
reactivity can also be applied to the amidostannanes 1. The
addition of n-butyllitium to 1 leads to the in situ generation of
the lithiated amide, which can be trapped with CO2 to form the
carboxylated 2 in good synthetic yields (Scheme 3). Overall,
this provides a route for the preparation of a variety of
trisubstituted α-amido acid derivatives in two synthetic steps
from imines, acid chlorides, and CO2.9a
In conclusion, we have reported a mild, palladium-catalyzed
method for generating α-amidostannanes from imines, acid
chlorides, and (SnBu3)2. This reaction proceeds at ambient
temperature, shows good functional group compatibility, and is
easily diversified. Studies directed toward the application of this
approach to other metalated products are currently underway.
preparation of metalated amides from three simple and/or
commercially available reagents (imines, acid chlorides, and
Bu3SnSnBu3) that can be readily diversified and does so
without the need to employ presynthesized or strongly
nucleophilic substrates.
Table 1 details our attempts to generate α-amidostannane 1a
from imine, acid chloride, and Bu3SnSnBu3. Phosphine-
Table 1. Catalyst Development for Multicomponent
a
Coupling
entry
catalyst
ligand
yield (%)
1
2
3
4
5
6
7
−
−
−
−
−
−
−
−
10% Pd(PPh3)4
5% Pd2dba3·CHCl3
5% Pd2dba3·CHCl3
5% Pd2dba3·CHCl3
10% CuCl
15% P(tBu)3
15% PPh3
15% PCy3
−
−
−
−
−
5% Pd2dba3·CHCl3
5% Pd2dba3·CHCl3
1.5% Pd2dba3·CHCl3
1.5% Pd2dba3·CHCl3
1.5% Pd2dba3·CHCl3
40
70
73
33
38
b
8
b
9
bc
,
10
11
bd
,
a
General: imine (0.1 mmol), acid chloride (0.1 mmol), (SnBu3)2 (0.1
1
mmol), Pd, and L as indicated, 2 mL of THF, 1 h. Yield by H NMR
relative to a benzyl benzoate standard. Use of 0.15 mmol of acid
chloride and (SnBu3)2. With (SnMe3)2 to yield SnMe3-substituted
product. With Me3SiSnBu3 and a 16 h reaction time.
b
c
d
coordinated palladium catalysts such as Pd(PPh3)4 or
Pd2dba3/PR31do not mediate the formation of 1a (entries 1−
5). Instead, H nuclear magnetic resonance (NMR) analysis
shows the bisstannane and the in situ-formed N-acyl iminium
salt essentially unreacted. Copper catalysts, which we have
found to behave like palladium in the coupling of N-acyl
iminium salts with organostannanes, are also ineffective (entry
6).4c
We postulated that the lack of coupling in these systems is
due to the presence of phosphine. In contrast to typical
palladium-catalyzed cross coupling reactions with aryl halides,
the oxidative addition of N-acyl iminium salts to palladium
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Research Article
d
Table 2. Substrate Scope in α-Amidostannane Synthesis
a
b
c
d
On a 1 mmol scale. With 5 mol % Pd. Acid chloride (0.35 mmol), (SnBu3)2 (0.35 mmol), and 5 mol % Pd. General: imine (0.2 mmol), acid
chloride (0.3 mmol), (SnBu3)2 (0.3 mmol), and 1.5% Pd2dba3·CHCl3 in 3 mL of THF for 16 h. Isolated yields.
Scheme 3. Synthesis of α-Amido Acid Derivatives
AUTHOR INFORMATION
Corresponding Author
*E-mail: bruce.arndsten@mcgill.ca.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NSERC, CFI, and the FQRNT-supported Centre for
Green Chemistry and Catalysis for their financial support. B.X.
thanks the FQRNT and Hydro-Queb
́
ec for predoctoral
fellowships.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Details of experimental procedures and H and 13C NMR
1
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