Carbenylative Amination and Alkylation of Vinyl Iodides via Palladium Alkylidene Intermediates

Article abstract of DOI:10.1021/acs.orglett.5b02820

Most palladium-catalyzed reactions involving insertion of alkylidenes with α-hydrogens undergo β-hydride elimination from alkylpalladium(II) intermediates to form alkenes. Vinyl iodides were shown to generate η³-allylpalladium intermediates that resist β-hydride elimination, preserving the sp³ center adjacent to the carbene moiety. Acyclic stereocontrol (syn/anti) for carbenylative amination and alkylation reactions was low, suggesting a lack of control in the migratory insertion step. Highly hindered carbene precursors inexplicably led to formation of Z-alkenes with high levels of stereocontrol.

Full text of DOI:10.1021/acs.orglett.5b02820

Letter
pubs.acs.org/OrgLett
Carbenylative Amination and Alkylation of Vinyl Iodides via
Palladium Alkylidene Intermediates
Ilandari Dewage Udara Anulal Premachandra, Thi A. Nguyen, Chengtian Shen, Eugene S. Gutman,
and David L. Van Vranken*
Department of Chemistry, University of California, 1102 Natural Sciences 2, Irvine, California 92697-2025, United States
*
S Supporting Information
ABSTRACT: Most palladium-catalyzed reactions involving insertion of alkylidenes with
α-hydrogens undergo β-hydride elimination from alkylpalladium(II) intermediates to form
3
alkenes. Vinyl iodides were shown to generate η -allylpalladium intermediates that resist β-
3
hydride elimination, preserving the sp center adjacent to the carbene moiety. Acyclic
stereocontrol (syn/anti) for carbenylative amination and alkylation reactions was low, suggesting a lack of control in the
migratory insertion step. Highly hindered carbene precursors inexplicably led to formation of Z-alkenes with high levels of
stereocontrol.
alladium-catalyzed carbenylative insertion processes are
gaining increasing attention, as they are analogous to widely
In rare instances, three-component carbenylative insertions
P
have been observed to out-compete β-hydride elimination using
1
3
7−9
used carbonylative insertion processes. Three-component
carbenylative cross-coupling reactions offer a powerful method
for joining molecular fragments through one-carbon units,
similar to three-component carbonylative cross-coupling reac-
tions. In initial applications, diazo compounds served as the
major carbene precursors, but more recently, N-tosylhydrazone
anions have been used to expand the scope of carbene precursors
η -to η -allyl or oxa-allyl transitions, but the generality of this
approach has not previously been demonstrated. Palladium
catalysts have been used to unite vinyl iodides with nucleophiles
and carbene precursors incapable of β-hydride elimination:
9
,10
trimethylsilyl, carboxyalkyl, aryl, and vinyl (Figure 1). In this
work, we demonstrate that simple alkylidene groups can
efficiently engage in three-component carbenylative cross-
coupling reactions of vinyl iodides without β-hydride elimi-
nation. Furthermore, we demonstrate the utility of N-
trisylhydrazones as alkylidene precursors that react faster than
the corresponding N-tosylhydrazones.
1
to include benzylidene and alkylidene derivatives. When there
are hydrogens adjacent to the carbene center, carbene insertion is
usually followed by β-hydride elimination, which out-competes
nucleophilic trapping and erases any stereochemical information
created in the carbene insertion step (Scheme 1).
Scheme 1. β-Hydride Elimination Out-Competes
Nucleophilic Trapping
Figure 1. Carbenylative amination and alkylation with alkylidene
carbenes without β-hydride elimination.
We initiated the investigation of carbenylative insertion
reactions of ω-aminovinyl iodide 1 and isobutyraldehyde N-
tosylhydrazone 2a using conditions similar to those used in our
previous work on carbenylative amination of benzaldehyde
Most palladium-catalyzed carbene insertion processes involve
RPdX complexes derived from oxidative addition of aryl
2
3
(pseudo)halides and benzylic and allylic halides. In other
10b
tosylhydrazones (Scheme 2). The only product isolated from
processes, RPdX complexes arise from addition of nucleophiles
10b,11
4
the reaction was the known dimer 4 (31%),
and a large
to Pd(II). Regardless of how the migratable group ends up on
amount of unreacted vinyl iodide 1 (68%) was recovered. We
speculated that the low solubility of the lithiated N-
the Pd(II) intermediate, migration to the alkylidene ligand
ultimately results in substituted olefins due to the rapidity of β-
hydride eliminations. Two-component reactions of Pd(0)
alkylidenes with carbon monoxide or isonitriles lead to ketenes
Received: September 29, 2015
5
,6
or ketenimines, respectively, without β-hydride elimination.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02820
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Organic Letters
Letter
tosylhydrazone was responsible for its failure to engage in the
reaction. When the corresponding N-trisylhydrazone 3 was
employed as the alkylidene precursor, the lithiated N-
trisylhydrazone exhibited better solubility in the reaction and
afforded the desired pyrrolidine 5 in 15% yield. From there, the
conditions were optimized to afford pyrrolidine 5 in 91% yield,
and there was no evidence of dimer 4 or products resulting from
elimination of the alkylidene α proton.
tosylhydrazone and lithium tert-butoxide was increased, leading
to a 75% isolated yield of the carbenylative amination product 9.
When the E isomer of vinyl iodide 8a was employed in the
reaction, the product was obtained in lower yield (55%).
Previously, it had been shown that Z-vinyl iodides and E-vinyl
iodides give comparable yields in intramolecular carbenylative
10b
aminations.
The reaction is believed to involve intermolecular attack of
3
piperidine on an η -allylpalladium intermediate on the least
13
hindered side of the allyl fragment. When fewer equivalents of
lithium tert-butoxide were used, allylamine 9 (55%) was
accompanied by the allylic regioisomer 10 (25%). The poor
regioselectivity is probably attributable to the faster palladium-
catalyzed equilibration of the protonated forms of allylic amines
Scheme 2. Intramolecular Carbenylative Amination with an
Alkylidene Precursor
14
9
and 10 (Scheme 5). To test this hypothesis, we exposed
product 9 to the less basic conditions, without the vinyl iodide
starting material, for 20 h and found it to produce an 80:20
mixture of allylamines 9 and 10.
Alkenylcyclopentanes are found in a variety of natural
products, such as brefeldin C, doproston B, isopulo’upone, and
amaminol A. To test the potential for carbon nucleophiles in the
intramolecular carbenylative insertion reaction, substrate 6 was
synthesized and subjected to the optimized reaction conditions
Scheme 5. Allylamines Slowly Isomerize under the Conditions
of the Reaction
(Scheme 3). The lithium enolate of malonate 6 produces the
Scheme 3. Intramolecular Carbenylative Alkylation with an
Alkylidene Precursor
In theory, regioisomer 9 should be highly favored under
3
kinetic conditions regardless of how one accesses the η -
allylpalladium intermediate. When the vinyl iodide, rather than
the N-tosylhydrazone, is substituted with a secondary alkyl
group, the amine still prefers to attack at the least hindered side of
the allylic system. Reaction of vinyl iodide 11 with N-
tosylhydrazone 2b generated allylamine 12 (Scheme 6),
analogous to the preferred formation of regiosomer 9 over 10.
The net transformation is a carbenylative cross-coupling, similar
to a carbonylative cross-coupling reaction with carbon monoxide.
corresponding alkenylcyclopentane 7 in 57% yield. The low yield
is probably attributable to the sensitivity of the substrate.
Srivastava and co-workers have previously shown related ε-
iodovinylmalonates to be highly sensitive to alkoxides. When
malonate 6 was exposed to potassium carbonate, lithium tert-
butoxide, or potassium tert-butoxide at 80 °C for 1 h, increasing
levels of decomposition (17%, 52%, and 100%, respectively)
were observed.
12
Scheme 6. Carbenylative Cross-Coupling with a Hindered
Vinyl Iodide
A three-component version of the reaction was tested using
piperidine as the external nucleophile and Z-vinyl iodide 8a
(Scheme 4). Under the conditions optimized for intramolecular
Scheme 4. Intermolecular Carbenylative Amination with
Alkylidene Precursors
With optimized conditions for the intermolecular carbenyla-
tive cross-coupling reaction in hand, we next set out to explore
variations in the alkylidene precursor 2a−d, the vinyl iodide, 8a
and 8b, and the nucleophile (Scheme 7). The sulfonylhydrazone
anions compete with other nucleophiles in the reaction by
3
15
trapping with vinyl iodide 1, none of the desired allylamine 9 was
observed. Under these conditions, trisylhydrazone 3 was too
reactive as a carbene source. When N-tosylhydrazone 2a was
used along with 4 equiv of piperidine, the desired allylamine 9
was obtained in 44% yield. The triethylamine additive can be
omitted from the reaction conditions. Under the optimized
conditions, 5 equiv of piperidine was used and the amount of N-
attacking the η -allylpalladium intermediate, and formation of
N-allylated hydrazone 23 accounts for 20−30% of the mass
balance based on NMR of the crude reaction mixtures. In the
absence of a nucleophile, a mixture of diene products, resulting
from β-hydride elimination, was observed along with adduct 23
(22%). Diethyl malonate afforded comparable yields and
resulted in a 13:1 regioisomeric mixture of allylic alkylation
B
DOI: 10.1021/acs.orglett.5b02820
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Organic Letters
Letter
Scheme 7. Scope of Intermolecular Carbenylative Alkylation
and Amination with Alkylidene Precursors
asymmetric 1,2-migrations to discrete acyclic carbocations,
which are structurally analogous to late metal carbenes; none
involve an adjacent stereogenic center.
16
The effect of adjacent stereogenic centers in migratory carbene
insertions was evaluated by utilizing chiral alkyl N-trisylhy-
drazones 24a−f in intramolecular carbenylative aminations
(
Table 1). Unfortunately, the products were obtained as nearly
Table 1. Stereoselectivity in Carbenylative Amination
products (13ab). Not surprisingly, when Meldrum’s acid was
utilized as the nucleophile, none of the desired adduct 14ab was
obtained, probably due to the weaker nucleophilicity of the
conjugate base (pK ′ = 4.97). Butylamine and benzylamine gave
a
modest yields of the desired coupling products 15ab and 16ab,
respectively. The cyclic secondary amines, pyrrolidine, piper-
idine, and morpholine, gave good yields (17ab−19ab). The
superiority of cyclic amines in three-component carbenylative
equal mixtures of syn and anti diastereomers. N-Trisylhydrazones
2
4a and 24b afforded pyrrolidines 25a and 25b, respectively, in
good yields, but thioether 24c gave none of the desired product,
and 85% of the vinyl iodide was recovered. N-Boc-pyrrolidine
9
,10a
amination reactions was demonstrated in previous studies.
2
4d gave a slight preference for the one diastereomer of 25d.
The stereochemistry of the major diastereomer of 25d was
The carbenylative amination and alkylation reactions proceed
with high chemoselectivity; oxidative addition across the Ar−Br
bond was not observed. We next explored the tolerance of
different alkyltosylhydrazones, and the coupling reactions
furnished yields up to 78% (20cb, 21ba, and 22db).
assigned as anti by converting the inseparable mixture to the
corresponding bis-N-benzyl-bis-pyrrolidines; the major diaster-
eomer was shown to be identical to the known meso (anti) isomer
11
2
6 (Scheme 8). To our surprise, when sterically encumbered
Valdes
́
and co-workers have previously shown that palladium-
catalyzed reactions of N-tosylhydrazones derived from α-chiral
1b
Scheme 8. Assignment of Relative Stereochemistry by
Conversion to Known Bis-pyrrolidine
ketones proceed with preservation of stereochemistry. Since
carbenylative amination reactions create new stereogenic centers
it is possible to assess the potential for acyclic stereocontrol. The
Felkin−Anh model reliably predicts the acyclic stereocontrol in
nucleophilic additions to carbonyls with α-chiral centers (Figure
2a). Chiral centers might also affect 1,2-migration reactions in
alkylpalladium carbene complexes, but that behavior has never
been studied. There have been surprisingly few studies of
N-trisylhydrazones 24e and 24f were employed the products
were obtained as the Z alkenes (J ≤ 7.9 Hz) with none of the
expected E alkene products (Table 1, entries 5 and 6). To test the
effect of steric encumbrance on alkene geometry, the hindered N-
tosylhydrazone 27 was tested and shown to give only the E
product 28 (Scheme 9). Thus, sterics alone is not sufficient to
explain formation of Z products 25e and 25f.
Figure 2. Acyclic stereocontrol: (a) nucleophilic addition to carbonyls,
(
b) 1,2-migration to palladium carbenes.
C
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Organic Letters
Letter
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02820.
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Experimental details, characterization of new compounds,
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AUTHOR INFORMATION
Corresponding Author
■
*
(
6
E-mail: david.vv@uci.edu.
Notes
(
1
(
6
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
T.A.N. was supported by GAANN P200A120070.
■
(
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