A straightforward protocol for one-pot allylic aminations/stille couplings

Article abstract of DOI:10.1021/ol901415p

Stannylated allylic carbonates are suitable substrates for Pd-catalyzed allylic aminations. In DMF and with [Pd(allyl)Cl]₂ as catalyst, the stannylated allyl amines formed can be directly coupled with electrophiles according to the Stille proto

Full text of DOI:10.1021/ol901415p

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3518-3521
A Straightforward Protocol for One-Pot
Allylic Aminations/Stille Couplings
Christian Bukovec and Uli Kazmaier*
UniVersita¨t des Saarlandes, Institut fu¨r Organische Chemie, Im Stadtwald,
Geb. C4.2, D-66123 Saarbru¨cken, Germany
u.kazmaier@mx.uni-saarland.de
Received June 22, 2009
ABSTRACT
Stannylated allylic carbonates are suitable substrates for Pd-catalyzed allylic aminations. In DMF and with [Pd(allyl)Cl]2 as catalyst, the stannylated
allyl amines formed can be directly coupled with electrophiles according to the Stille protocol, giving rise to highly functionalized building
blocks in excellent yields.
A key topic in chemical biology and pharmaceutical chem-
istry is the design and synthesis of compound libraries, with
the focus on small molecules. Such molecules are suitable
candidates to investigate the biological function of proteins
and can be used as lead structures for the development of
drug candidates.1 The diversity-oriented synthesis (DOS)
concept, introduced by Schreiber et al.,2 is an excellent tool
to generate libraries with high substitutional, stereochemical,
and/or scaffold diversity.3 In principle, one can differentiate
three different phases. In the first step, building blocks with
orthogonal sets of functionality, suitable for subsequent
couplings, are created. In the next step, intermolecular
coupling reactions generate molecular complexity, and
subsequent cyclizations in the final step allow for the
synthesis of complex three-dimensional frameworks and
topological structures.4 For example, Meldal et al. used this
approach for the synthesis of complex peptidic structures.5
Our group is also involved in the synthesis of unusual
amino acids and peptides,6 and we developed a straightfor-
ward approach to peptide libraries based on Stille couplings.7
The Stille reaction8 is especially suited for this purpose,
because no epimerization is observed in reactions of stan-
nylated amino acids because of the neutral reaction condi-
(1) (a) Breinbauer, R.; Vetter, I. R.; Waldmann, H. Angew. Chem. 2002,
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S.; Beller, M. Tetrahedron 2005, 61, 11345–11354. (h) Brummond, K. M.;
Chen, D. Org. Lett. 2005, 7, 3473–3475. (i) Franz, A. K.; Dreyfuss, P. D.;
Schreiber, S. L. J. Am. Chem. Soc. 2007, 129, 1020–1021. (j) Thomas,
G. L.; Spandl, R. J.; Glansdorp, F. G.; Welch, M.; Bender, A.; Cockfield,
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C.; Warriner, S.; Nelson, A. Angew. Chem. 2009, 121, 110–115; Angew.
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Chem. Soc. 1998, 120, 8565–8566. (b) Schreiber, S. L. Science 2000, 287,
1964–1969. (c) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science 2003,
302, 613–618. (d) Burke, M. D.; Berger, E. M.; Schreiber, S. L. J. Am.
Chem. Soc. 2004, 126, 14095–14104.
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2007, 36, 484–491. (b) Nielsen, T. E.; Schreiber, S. L. Angew. Chem. 2008,
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10.1021/ol901415p CCC: $40.75
Published on Web 07/07/2009
 2009 American Chemical Society

tions.9 The stannylated amino acids are accessible via chelate-
Claisen rearrangement of stannylated allylic esters or via Pd-
catalyzed allylic alkylation.10 The required stannylated allylic
esters can be obtained by a Mo-catalyzed regioselective
hydrostannation of the corresponding propargylic substrates
(Scheme 1).11
because the reaction conditions for these two processes are
generally different. In addition, vinylstannanes can undergo
Pd-catalyzed cross-couplings with allylic substrates,15 and
therefore oligo- and polymerizations of the stannylated allyl
compound have to be avoided. Therefore, one has to find
reaction conditions where one of the two functionalities reacts
selectively. Very recently, Fillion et al. reported a sequential
Rh(I)-catalyzed 1,4-addition of stannylated allyl carbonates
toward alkylidene Meldrum’s acids, followed by Pd-
catalyzed intramolecular allylations.16
Scheme 1. Synthesis of Stannylated Amino Acids and Peptides
Our previous work with the chelated enolates of amino
acids and peptides indicated that the stannylated allylic
acetates and carbonates react with good nucleophiles already
at low temperatures (<-20 °C), while the Stille couplings
generally occur at temperatures around 50 °C. Unfortunately,
the strong basic reaction conditions for the enolate allylation
were not compatible with the cross-coupling conditions.
Therefore, we focused our investigations on other reactive
nucleophiles allowing a selective reaction of the allyl
fragment without affecting the vinylstannane moiety. Mal-
onates, the “standard nucleophiles” in allylic alkylations, are
unsuitable candidates, reacting in a temperature range where
decomposition of the stannylated substrate is competitive
with the nucleophilic substitution. Detailed investigations
showed that the decomposition in the presence of Pd0 toward
the corresponding allenes is a fast process as determined by
in situ NMR.17
Therefore, we next switched to the more reactive amines
(Table 1) that are suitable candidates for the synthesis of
alkaloids. To avoid double allylation, we started our inves-
tigations with piperidine as nucleophile. Interestingly, no
allylation product was obtained in THF at room temperature,
although a complete consumption of allyl carbonate 1 was
observed (entry 1). Obviously the decomposition is also faster
under these conditions, but at 0 °C a good yield of coupling
product was obtained (entry 2). Obviously THF is not the
solvent of choice for these allylations, because in the more
polar DMF no decomposition was observed even at room
temperature (entry 3). The yield could be slightly increased
if the reaction was run at 0 °C (entry 4). A further
improvement was observed after switching from [Pd(allyl)Cl]2
to Pd(PPh3)4 as catalyst (entry 5). Under these optimized
conditions we investigated the allylation of several other,
also primary, amines. While dialkylation was observed with
sterically unhindered amines, this side reaction is no issue
in allylations of sterically hindered, branched amines such
as phenylethylamine (entry 6) or amino acid esters (entry
7). Even with alaninate 2c and glycinate 2d, an excellent
yield was obtained, especially if 2 equiv of the nucleophile
was used (entries 7, 8).
This Mo-catalyzed hydrostannation can be applied to a
wide range of (electron-demanding) alkynes,12 giving rise
to orthogonal functionalized substrates such as stannylated
allylic sulfones13 or phosphonates,14 which can be subjected
to a subsequent Stille coupling/olefination protocol. With
respect to DOS the stannylated esters and carbonates (1) are
especially interesting substrates, because they can be further
modified at the allylic positions via nucleophilic substitution
and at the central position via cross-coupling with electro-
philes. Both reactions can be catalyzed by Pd, and in
principle, it should be possible to combine both couplings
to a one-pot protocol. However, this is not a trivial issue,
(6) (a) Kazmaier, U. Amino Acids 1996, 11, 283–299. (b) Kazmaier, U.;
Maier, S.; Zumpe, F. L. Synlett 2000, 1523–1535. (c) Kazmaier, U. Curr.
Org. Chem. 2003, 317–328. (d) Bauer, M.; Kazmaier, U. Recent Res. DeV.
Org. Chem. 2005, 9, 49–69. (e) Deska, J.; Kazmaier, U. Chem.sEur. J.
2007, 13, 6204–6211. (f) Deska, J.; Kazmaier, U. Curr. Org. Chem. 2008,
355–385.
(7) Deska, J.; Kazmaier, U. Angew. Chem. 2007, 119, 4654–4657;
Angew. Chem., Int. Ed. 2007, 46, 4570-4573.
(8) Stille, J. K. Angew. Chem. 1986, 98, 504–519; Angew. Chem., Int.
Ed. Engl. 1986, 25, 508-524.
(9) (a) Crisp, G. T.; Glink, P. T. Tetrahedron Lett. 1992, 33, 4649–
4652. (b) Crisp, G. T.; Glink, P. T. Tetrahedron 1994, 50, 3213–3234. (c)
Do¨rrenba¨cher, S.; Kazmaier, U.; Ruf, S. Synlett 2006, 547–550.
(10) (a) Kazmaier, U.; Schauss, D.; Pohlman, M.; Raddatz, S. Synthesis
2000, 914–916. (b) Kazmaier, U.; Schauss, D.; Raddatz, S.; Pohlman, M.
Chem.sEur. J. 2001, 7, 456–464.
(11) (a) Kazmaier, U.; Schauss, D.; Pohlman, M. Org. Lett. 1999, 1,
1017–1019. (b) Kazmaier, U.; Pohlman, M.; Schauss, D. Eur. J. Org. Chem.
2000, 2761–2766. (c) Braune, S.; Kazmaier, U. J. Organomet. Chem. 2002,
641, 26–29. (d) Wesquet, A. O.; Do¨rrenba¨cher, S.; Kazmaier, U. Synlett
2006, 1105–1109.
(15) (a) Valle, L. D.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1990,
55, 3019–3023. (b) Castano, A. M.; Ruano, M.; Echavarren, A. M.
Tetrahedron Lett. 1996, 37, 6591–6594. (c) Shirakawa, E.; Yamasaki, K.;
Yoshida, H.; Hiyama, T. J. Am. Chem. Soc. 1999, 121, 10221–10222. (d)
Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem. 2005, 117, 3551–
3554; Angew Chem., Int. Ed. 2005, 44, 3485-3488. (e) Snyder, S. A.;
Corey, E. J. J. Am. Chem. Soc. 2006, 128, 740–742.
(12) (a) Kazmaier, U.; Lucas, S.; Klein, M. J. Org. Chem. 2006, 71,
2429–2433. (b) Lin, H.; Kazmaier, U. Eur. J. Org. Chem. 2007, 2839–
2843. (c) Kazmaier, U.; Do¨rrenba¨cher, S.; Wesquet, A.; Lucas, S.;
Kummeter, M. Synthesis 2007, 320–326. (d) Lin, H.; KazmaierU. Eur. J.
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Org. Lett., Vol. 11, No. 15, 2009
3519

Table 1. Allylic Aminations of Stannylated Allyl Carbonates
entry
R1R2NH
reaction conditions
catalysta
product
yield (%)
1
2
3
4
5
6
7
8
piperidine (2a)b
piperidine (2a)b
piperidine (2a)b
piperidine (2a)b
piperidine (2a)b
1-phenylethylamine (2b)b
Ala-Ot-Bu (2c)c
Gly-Ot-Bu (2d)c
THF, rt, 1 h
THF, 0 °C, 5 h
DMF, rt, 1 h
DMF, 0 °C, 1.5 h
DMF, 0 °C, 2 h
DMF, 0 °C, 16 h
DMF, 0 °C, 16 h
DMF, 0 °C, 16 h
A
A
A
A
B
B
B
B
3a
3a
3a
3a
3a
3b
3c
3d
0
74
70
79
94
84
94
87
a Catalysts: A, 1 mol % [Pd(allyl)Cl]2, 4.5 mol % PPh3; B, 2 mol % Pd(PPh3)4. b 1.2 equiv amine used. c 2 equiv amine used.
With these stannylated allyl amines in hand we tried to
optimize the reaction conditions for the subsequent Stille
coupling (Scheme 2). Interestingly, no reaction was observed
version. The (E)-product could be obtained nearly exclusively
if the reaction was carried out in “wet” DMF (entry 4). In
this solvent, the allylic amination was significantly faster,
but the Stille coupling slowed down. After 4 h at 65 °C only
incomplete conversion was observed, and the reaction
mixture was heated to 90 °C after further 2 equiv of the
electrophile had been added. Under these conditions the
Scheme 2. Stille Couplings of Stannylated Amines
Table 2. One-Pot Allylic Alkylation/Stille Coupling
in DMF or by using Pd(PPh3)4 (the best conditions in the
allylic amination), but excellent yields were obtained with
[Pd(allyl)Cl]2/PPh3 in THF, either by conventional heating
or under microwave (MW) irradiation. In the case of the
stannylated glycine derivative 3d, the Stille coupling with
iodoacrylate gave direct access to lactame 6a.
On the basis of these encouraging results, we focused next
on the one-pot protocol of allylic aminations/Stille couplings
(Table 2). In our first attempts we used piperidine as
nucleophile and (Z)-iodoacrylate as electrophile, because both
reagents in general give clean and good coupling results.
Indeed, with this electrophile excellent yields were obtained
in absolute acetonitrile (entry 1) and DMF (entry 2) as well.
For the allylic amination the reaction mixture was warmed
from 0 °C to room temp.erature, and for the Stille coupling
the mixture was heated to 65 °C after the addition of the
electrophile. Under these conditions a partial isomerization
of the double bond was observed, which was slightly worse
in acetonitrile. To suppress this undesired process, we carried
out the reaction also at room temperature (entry 3). Although
the reaction was a little slower, under these conditions a
complete conversion was observed after 3 h, and the
isomerization could be reduced to a minimum. Obviously
the higher temperature is responsible for the (E/Z)-intercon-
a Amount of reagents used: 2 (1.2 equiv), 4b (1.05 equiv), 4c (2 equiv),
4d (2 equiv), 4e (2 equiv), 4f (1.2 equiv).
3520
Org. Lett., Vol. 11, No. 15, 2009

Table 3. Optimization of the Catalyst
entry
catalyst
ratio Pd:P yield (%) time (h)
observation
1
2
3
4
5
6
7
8
9
Pd(PPh3)4 (2 mol %)
1:4
1:2
70
82
88
39
61
86
88
92
95
48
48
20
48
16
7
16
16
16
Pd(s) after 1 h
Pd(s) after 1 h
complete conversion
Pd(s) immediately, incomplete conversion
Pd(s) immediately
Pd(s) formed slowly, complete conversion
no Pd(s), complete conversion
no Pd(s), complete conversion
complete conversion, only 1.2 equiv of 3e
(1) Pd(PPh3)4 (2 mol %); (2) [Pd(allyl)Cl]2 (1 mol %)
(1) Pd(PPh3)4 (2 mol %); (2) Pd/C (10%, 1 mol %)
(1) Pd(PPh3)4 (2 mol %); (2) [Pd(allyl)Cl]2 (3 mol %)
[Pd(allyl)Cl]2 (1 mol %), PPh3 (2 mol %)
[Pd(allyl)Cl]2 (1 mol %), PPh3 (4 mol %)
[Pd(allyl)Cl]2 (1 mol %), PPh3 (6 mol %)
1:1
1:1
1:2
1:3
1:4
1:4
[Pd(allyl)Cl]2 (1 mol %), PPh3 (8 mol %)
[Pd(allyl)Cl]2 (1 mol %), PPh3 (8 mol %)
isomerization obviously is faster than the Stille coupling.
Now, both coupling products can be obtained from the same
starting materials by simple changing of the reaction condi-
tions.
also the corresponding triflates (entry 1) and vinylbromides
(entry 2) can be used, and both primary and secondary
amines give good to excellent results.
To prove the generality of this new one-pot process, we
investigated the Stille coupling of several other electrophiles.
High yields were also obtained with iodobenzene and
p-nitrobromobenzene (entries 5 and 6), but substituents in
the O-positions seem to be detrimental (entry 7). In this case
precipitation of Pd(s) was observed, which was also the reason
for the lower yield obtained with p-bromobenzaldehyde
(entry 8).
Table 4. One-Pot Allylation/Stille Coupling under Optimized
Conditions
yield
(%)
entry
R1R2NH
R3X
product
Because this observation was made also with several other
less reactive electrophiles, we next focused on an optimiza-
tion of our catalyst system to avoid this undesired side
reaction (Table 3). p-Bromobenzaldehyde (3e) was the
investigated substrate, and 2 equiv of this electrophile was
used to ensure complete conversion. As before, piperidine
was used in a slight excess (1.2 equiv). Under the standard
conditions, formation of Pd(s) was observed after 1 h, and
prolonging the reaction time did not result in a better yield
(entry 1). The yield could be increased by adding allylpal-
ladiumchloride (entry 2) or Pd/C (entry 3) during the Stille
coupling step. Interestingly, if [allylPdCl]2 was added in such
a ratio that the overall Pd/PPh3 ratio was 1:1, a direct
precipitation of Pd(s) was observed, resulting in a minimal
conversion.
Because [allylPdCl]2 is also a good catalyst for allylic
alkylations, we tried to use this catalyst solely for both steps
and varied the amount of phosphine added (entries 5-9).
At a Pd/Pd ratio of 1:1, again Pd(s) was formed immediately
(entry 5). Increasing the amount of PPh3 resulted in a
stabilization of the catalyst, resulting in excellent overall
yields. In the presence of 4 equiv of PPh3, complete
conversion was observed even in the presence of only 1.2
equiv of the electrophile (entry 9).
1
2
piperidine (2a)
piperidine (2a)
PhOTf (4g)
(E)-ꢀ-Br-styrene
(4h)
5c
5g
94
84
3
1-phenylethylamine PhI (4c)
(2b)
t-BuNH2 (2e)
Ile-Ot-Bu (2f)
5h
73
4
5
PhI (4c)
PhI (4c)
5i
5k
89
72
In conclusion, we could show that stannylated allylic
carbonates are excellent C3 building blocks for the diversity-
oriented syntheses of functionalized amines. By careful
optimization of the reaction conditions, an allylic amination
and a subsequent Stille coupling can be performed as a one-
pot reaction. Synthetic applications of this straightforward
protocol are currently under investigation.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (Ka880/8-1) and by the
Fonds der Chemischen Industrie.
Supporting Information Available: Experimental pro-
cedures and well as analytical and spectroscopic data of
coupling products. This material is available free of charge
via the Internet at http://pubs.acs.org.
Under these optimized conditions, we investiaged a range
of further one-pot reactions (Table 4). Besides aryliodides
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Org. Lett., Vol. 11, No. 15, 2009
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