Palladium-catalyzed vicinal difunctionalization of internal alkenes: Diastereoselective synthesis of diamines

Article abstract of DOI:10.1002/anie.201201719

Internal affairs: The first general palladium-catalyzed intermolecular diamination of internal alkenes employs different nitrogen sources, which add to the alkene in a regio- and diastereoselective fashion. The resulting diamination products can be converted directly into a known ligand motif. Copyright

Full text of DOI:10.1002/anie.201201719

Angewandte
Chemie
DOI: 10.1002/anie.201201719
Palladium Catalysis
Palladium-Catalyzed Vicinal Difunctionalization of Internal Alkenes:
Diastereoselective Synthesis of Diamines**
Claudio Martꢀnez and Kilian MuÇiz*
The seminal protocols by Sharpless et al. for the osmium-
(VIII)-catalyzed dihydroxylation[1,2] and aminohydroxyla-
tion[3,4] of alkenes introduced the metal-catalyzed 1,2-difunc-
tionalization of unsaturated hydrocarbons as a broadly appli-
cable concept in modern organic synthesis. Recently, palla-
dium catalysis has emerged as an conceptual alternative for
this type of intermolecular vicinal difunctionalization reaction
of alkenes.[5] While the osmium(VIII)-catalyzed reactions
proceed through the concerted transfer of two heteroatoms to
the alkene,[6] the alternative palladium-catalyzed reactions
involve the stepwise process of nucleopalladation followed by
the formation of the second carbon–heteroatom bond accom-
panied by release of the palladium catalyst. This approach
should generally enable a broader range of reactions;
however, transformations of this type such as chlorohydrin
syntheses,[7] dibrominations,[8] diacetoxylations,[9] aminoace-
toxylations,[10] and aminofluorinations[11] have so far been
applied to only terminal alkenes.
Therefore, the application of internal alkenes in difunc-
tionalization reactions remains a significant challenge in this
particular area of palladium catalysis. One reason for this is
the general problem of developing selective reaction con-
ditions that disable undesired competing pathways such as
isomerization reactions[12] and b-hydride elimination of the s-
alkyl palladium intermediates.[13] Currently, dioxygenation
reactions of substituted 2-vinyl phenols represent the only
more general oxidation reaction in this area. These reactions
were developed independently by Muzart und Sigman[14] and
show relatively broad applicability. However, they require
a 2-hydroxyphenyl substituent, which is rather difficult to
modify at later stages.
(O2CR)2 catalyst system to reactions with internal alkenes.
Herein, we now describe the successful development of the
first more generally applicable protocol for the palladium-
catalyzed intermolecular diamination of internal alkenes,
which proceeds with complete regio- and diastereoselectivity.
In view of the lack of methodology for the difunctional-
ization of internal alkenes, we started an investigation using
(Z)-b-methylstyrene (1a) as a standard substrate. The initial
attempt to transfer our conditions for the related intermo-
lecular diamination of terminal alkenes[15a] to a reaction with
substrate 1a was not successful. Imitating the diamination of
allylic ethers,[15b] we employed phthalimide (PhthNH) as the
nitrogen source in a limiting amount together with an excess
of 1a. In the presence of a combination of iodobenzene
dipivalate (PhI(OPiv)2) as the oxidant and bistosylimide as
the second nitrogen source[15a] this approach led to the desired
diamination product 2a (Table 1, entry 1). Compound 2a was
obtained as a single regio- and diastereoisomer. After some
additional experimentation we found that preheating the
catalyst precursor [Pd(NCMe)2Cl2] together with phthalimide
for a period of one hour significantly enhanced the yield
(Table 1, entry 2). When the catalyst precursor was the
corresponding benzonitrile complex, a significant increase in
yield was observed (Table 1, entry 3). A second cycle of
optimization adjusting the ratio between the iodine(III)
oxidant and the substrate 1a established conditions under
Table 1: Intermolecular regioselective diamination of (Z)-b-methylstyr-
ene (1a): optimization.
Our palladium-catalyzed intermolecular diamination
reactions of terminal alkenes[15] constitute another example
of the vicinal difunctionalization of alkenes using palladium in
a high oxidation state.[5a,b] Despite ongoing efforts, we had not
succeeded in transferring the conditions of the Pd/PhI-
Entry
Variation
Yield [%][a]
1[c]
2[c]
3
4
5
single-step procedure, 2.5 equiv 1a
2.5 equiv 1a
2.5 equiv 1a
1.1 equiv PhI(OPiv)2
1.5 equiv PhI(OPiv)2
none
20[b]
48[b]
85[b]
20
60
93
[*] Dr. C. Martꢀnez, Prof. Dr. K. MuÇiz
Institute of Chemical Research of Catalonia (ICIQ)
Av. Paꢁsos Catalans 16, 43007 Tarragona (Spain)
E-mail: kmuniz@iciq.es
Homepage: http://www.iciq.es
6
Prof. Dr. K. MuÇiz
7
8
9
10
11
5 mol% [PdCl2(NCPh)2]
3 mol% [PdCl2(NCPh)2]
2 mol% [PdCl2(NCPh)2]
1 mol% [PdCl2(NCPh)2]
distilled 1a
99
99
80
74
Catalan Institution for Research and Advanced Studies (ICREA)
Pg. Lluꢀs Companys 23, 08010 Barcelona (Spain)
[**] We thank Prof. Dr. E. Pꢂrez, Universidad Catꢃlica de Chile, for
experimental contributions and the Spanish Ministry for Economy
(CTQ2011-25027) and the Fonds der Chemischen Industrie for
financial support.
74
[a] Yield of isolated product after column chromatography. [b] Yield
based on phthalimide. [c] With [PdCl2(NCMe)2] instead of [PdCl2-
(NCPh)2].
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201719.
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which the alkene served as limiting agent and the product 2a
was isolated in 93% yield (Table 1, entries 4–6). It is
interesting to note that higher yields were obtained at lower
catalyst loadings, and quantitative yields resulted from
reactions with 5 and 3 mol% palladium, (Table 1, entries 7
and 8). Excellent results were still obtained even with catalyst
loadings of 1–2 mol% (Table 1, entries 9 and 10). An
important observation was made for a reaction using freshly
distilled alkene 1a, where a significant drop in yield was
obtained (Table 1, entry 11). Commercial (Z)-b-methylstyr-
ene contains tert-butylcatechol as a stabilizer, which sup-
presses polymerization under the present reaction temper-
ature. A control experiment revealed that in the presence of
trace amounts of palladium, freshly distilled alkene 1a
polymerizes readily within a short period of time.
Table 2 (Continued)
Under the optimized conditions, a number of (Z)-b-
alkylstyrenes could be transformed into the corresponding
diamination products (Table 2). These reactions all proceed
with complete chemo-, regio-, and diastereoselectivity. The
successful combination of phthalimide with bistosylimide as
Table 2: Scope of the palladium-catalyzed intermolecular diamination of
internal alkenes. HNPhthF =tetrafluorophthalimide.
[a] Yield of isolated product after column chromatography. [b] Reaction
on 17 mmol scale.
well as with bisphenylsulfonimide and mesyltosylimide
(HNMsTs) as the second nitrogen source was demonstrated
with the standard substrate alkene 1a (Table 2, entries 1–3).
Likewise, the reaction tolerates the more acidic tetrafluor-
ophthalimide in place of phthalimide (Table 2, entry 4),
demonstrating that the combination of the nitrogen sources
can be varied on a case-by-case basis. This variety of different
nucleophiles is without precedence for palladium-catalyzed
intermolecular reactions. In addition, the reaction can be
conveniently conducted on a larger scale: the diamination of
1a with phthalimide and bistosylimide was conducted on
a 17 mmol scale to provide the corresponding isolated
product 2a in a yield of 9 g (91%). This is the currently
largest scale preparative PdII/IV-catalyzed reaction (Table 2,
entry 1).
In additional examples the substituted b-methylstyrenes
1b and 1c yield the expected products 2e and 2 f (Table 2,
entries 5 and 6). The variety of nitrogen sources was again
demonstrated for the example of the cinnamyl methyl ether
(1d) and the four products 2g–2j were obtained in 60–84%
yield (Table 2, entries 7–10). These results are superior to
those previously recorded for the aminoacetoxylation of 1d,
which required an excess of alkene.[10] Different substituents
2
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at the arene core were investigated with alkenes 1e–1k
(Table 2, entries 11–17). These reactions proceed with accept-
able yields and with the expected complete regio- and
diastereoselectivities. The reaction of the corresponding
derivative with 4-methoxy substituent was a notable excep-
tion, leading to complete degradation under the reaction
conditions.[16] Finally, the cyclopentyl derivative 1l gives
a lower yield, which may be the consequence of steric
hindrance of the aminopalladation. The constitution and
configuration of the products was supported by X-ray single-
crystal analyses for the three compounds 2a,d,i,[17] and all
three products show identical relative configuration (unlike
for 2a,d, like for 2i).[18]
It is interesting that the described reaction conditions do
not apply to styrene (1m). The corresponding attempt
resulted in a product mixture and only phthaloyleneamide
3[19] and diamine 4 could be isolated (Scheme 1); the latter
Scheme 2. Proposed catalytic cycle.
resulting s-alkylpalladium complex A undergoes rapid,
irreversible oxidation to the palladium(IV) intermediate B,
À
which engages in the formation of the second C N bond
under net inversion of configuration at the stereogenic
benzylic position. This step regenerates the original palladi-
um(II) catalyst. An analogous sequence was recently verified
mechanistically for related primary s-benzylpalladium(IV)
intermediates and bissulfonimide as the nucleophile[23] and
for the present case this would provide the correct diastero-
meric diamination product 2.[24] It is noteworthy that this
postulated sequence is largely identical to the mechanistic
conclusions by Bꢀckvall from work on a related stoichiomet-
ric transformation dating back to the 1970s.[25]
The presence of the phthalimide group permits the facile
transformation of the generated products. Two representative
reactions leading to monosulfonylated diamines 5a,b are
depicted in Scheme 3. Thanks to their broad range of
applications, monosulfonylated diamines constitute a privi-
Scheme 1. Reaction of styrene.
results from the uncatalyzed reaction of the iodine(III)
reagent itself.[20] Since products of this type are not formed
in the reactions of the internal alkenes 1a–l, this result also
demonstrates that in these cases the palladium catalysis from
Table 2 is kinetically superior to the metal-free iodine(III)-
promoted reaction.[20]
The above-mentioned observation that catalyst loadings
of 3–5 mol% provide better results than 10 mol% can be
explained by the fact that for 1a in the presence of a higher
catalyst loading an alternative isomerization to (E)-b-meth-
ylstyrene becomes competive.[12] The latter isomer is indeed
not oxidized under the present conditions as confirmed by
a competition experiment. When a 1:1-mixture of (E)- and
(Z)-b-methylstyrene was submitted to reaction under stan-
dard conditions, selective diamination of only the Z isomer
was observed. This result should be the consequence of the
more difficult coordination of the sterically more demanding
E isomer to the palladium catalyst.
An extensive mechanistic investigation of the reaction is
still lacking. Based on the observed coherent stereochemistry
of the products, a preliminary mechanistic interpretation is
possible based on the geometry of the alkene substrate. We
currently prefer the catalytic cycle depicted in Scheme 2.
Because of the observed dependence of the reaction on the
E/Z geometry of the alkene, the initial step should consist of
coordination of the alkene to the palladium catalyst. The
subsequent aminopalladation through nucleophilic addition
of phthalimide should then proceed with trans stereochem-
istry. This step also establishes the regioselectivity of the
reaction, which is determined through the preferential
positioning of palladium in the benzylic position.[21,22] The
Scheme 3. Monosulfonylated diamines from products 2c,i. Red-
Al=Na[AlH2(OC2H4OCH3)2].
leged class of ligands,[26] which has now been made available
for the first time through a novel sequence of alkene
oxidation followed by transformation of the substituents at
the nitrogen atoms.
We have discovered a general palladium(II/IV)-catalyzed
difunctionalization reaction of internal alkenes under inter-
molecular conditions. This diamination reaction proceeds
with complete chemo-, regio-, and diastereoselectivity and
without the assistance of directing groups. The reaction
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conducted on a larger scale.
Received: March 2, 2012
Published online: && &&, &&&&
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Keywords: alkenes · amination · homogeneous catalysis ·
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Communications
Palladium Catalysis
C. Martꢁnez, K. MuÇiz*
&&&& — &&&&
Palladium-Catalyzed Vicinal
Difunctionalization of Internal Alkenes:
Diastereoselective Synthesis of Diamines
Internal affairs: The first general palla-
dium-catalyzed intermolecular diamina-
tion of internal alkenes employs different
nitrogen sources, which add to the alkene
in a regio- and diastereoselective fashion.
The resulting diamination products can
be converted directly into a known ligand
motif.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!