Synthesis of Polycyclic Nitrogen Heterocycles via Cascade Pd-Catalyzed Alkene Carboamination/Diels-Alder Reactions

Article abstract of DOI:10.1021/acs.orglett.5b00896

Cascade Pd-catalyzed alkene carboamination/Diels-Alder reactions between bromodienes and amines bearing two pendant alkenes are described. These transformations generate 4 bonds, 3 rings, and 3-5 stereocenters to afford polycyclic nitrogen heterocycles wi

Full text of DOI:10.1021/acs.orglett.5b00896

Letter
pubs.acs.org/OrgLett
Synthesis of Polycyclic Nitrogen Heterocycles via Cascade Pd-
Catalyzed Alkene Carboamination/Diels−Alder Reactions
Derick R. White and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States
*
S Supporting Information
ABSTRACT: Cascade Pd-catalyzed alkene carboamination/Diels−Alder
reactions between bromodienes and amines bearing two pendant alkenes are
described. These transformations generate 4 bonds, 3 rings, and 3−5
stereocenters to afford polycyclic nitrogen heterocycles with high
diastereoselectivity.
olycyclic scaffolds that contain a nitrogen heterocycle fused
to a six-membered carbocycle are common features of
many biologically active molecules. These structures are
Scheme 1. Cascade Carboamination/Diels−Alder Reaction
P
displayed in natural products such as the yohimbine alkaloids
1
(
e.g., reserpine, 1) and molecules of potential pharmaceutical
2
relevance such as thrombin receptor antagonist 2.
Scheme 2. Preliminary Experiment: Optimal Conditions
addition, a few prior examples of Pd-catalyzed cross-coupling/
Diels−Alder reactions supported the overall feasibility of this
Our group has previously illustrated that Pd-catalyzed alkene
carboaminations between aryl or alkenyl halides or triflates and
alkenes bearing pendant nitrogen nucleophiles are a concise,
efficient, and stereoselective means of generating nitrogen
6
transformation. Importantly, given the broad scope of the
carboamination reactions, this strategy should not be limited to
the synthesis of polycyclic pyrrolidine derivatives such as 5, but
rather a much broader array of heterocyclic architectures could
be obtained by employing different alkene-tethered nucleo-
philes.
In our initial experiments we elected to employ 9-
bromoanthracene as the bromodiene substrate, as this
compound is commercially available and would allow us to
explore the diastereoselectivity (relative face selectivity) of the
Diels−Alder reaction in a simple system with no possible
stereoisomers resulting from endo- vs exo-cycloaddition. As
shown in Scheme 2, after exploring a range of phosphine
3
,4
heterocycles. We reasoned that coupling our Pd-catalyzed
alkene carboamination method with a Diels−Alder cyclo-
addition could provide a rapid and efficient approach to the
synthesis of polycyclic heterocycles with a high degree of
stereocontrol. As shown in Scheme 1, a γ-aminoalkene
derivative such as 3, which bears a second pendant alkene
unit, could be coupled with a bromodiene in the presence of a
Pd-catalyst and a base to afford intermediate 4. This
intermediate could then undergo a Diels−Alder [4 + 2]
5
cycloaddition to yield 5. Our prior studies have illustrated that
most Pd-catalyzed alkene carboamination reactions proceed
with high diastereoselectivity, and examples of stereocontrolled
intramolecular Diels−Alder reactions are well-established. In
Received: March 27, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00896
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Organic Letters
Letter
Table 1. Cascade Carboamination/Diels−Alder Reactions of
Scheme 3. Limitations
a
Amides and Hydroxylamines
Pd(OAc) and Dpe-Phos. Other phosphine ligands provided
2
various amounts of Heck arylation side product 6 or failed to
efficiently promote the carboamination step.
Once suitable reaction conditions had been identified we
began to explore the scope of this one-pot reaction sequence.
Since chemical yields were modest in some instances, a few
different phosphine ligands were examined for most substrate
combinations. The Dpe-Phos ligand provided satisfactory
results in most cases, but for some substrates other ligands
such as Xantphos, Cy Dpe-Phos, or RuPhos proved superior.
4
As shown in Table 1, pentenylamine derivatives 3a−b bearing a
N-crotonyl group or an N-cinnamyl group were coupled with 9-
bromoanthracene to afford polycyclic products 5a−b with high
8
diastereoselectivity. The presence of a phenyl substituent
adjacent to the N-atom was tolerated in the reaction of 3c,
although the desired product 5c was generated with lower, but
still useful, diastereoselectivity (5:1 dr). A similar outcome was
observed in the reaction of 3-phenylhydroxylamine derived
substrate 7 (3.5:1 dr). In both of these cases the diminished
stereocontrol occurred during the Diels−Alder step, as the
diasteromeric products differed in the configuration of the
stereocenters generated in the cycloaddition relative to those
formed in the carboamination step. Substrates 8a−b obtained
via acylation of 2-allylaniline also underwent the carboamina-
tion/Diels−Alder reaction sequence to afford 10a and 10b in
moderate yield and high dr. In most instances satisfactory
outcomes were achieved simply through extended heating of
the reaction mixture at a constant temperature (usually 130
°
C). However, for substrate 7 the best results were obtained
when the carboamination step was conducted at 90 °C until the
substrate had been completely consumed, at which point 1
equiv of LiOTf was added and the temperature was raised to
9
facilitate the cycloaddition.
Although the cascade reactions between 9-bromoanthracene
and 3a−c, 7, and 8a−b were reasonably efficient, efforts to
extend these transformations to other bromodienes were less
successful. For example, the Pd-catalyzed carboamination of 3a
with 2-bromofuran proceeded in good yield to afford 11
a
Conditions: 1.0 equiv of substrate, 2.0 equiv of 9-bromoanthracene,
.0 equiv of t-BuONa, 4 mol % Pd(OAc) or 2 mol % Pd (dba) , 8
2 2 3
b
2
mol % ligand, xylenes (0.07 M), 24 h. Diastereomeric ratio of isolated
material. Diasteromeric ratios were similar for crude reaction mixtures
c
unless otherwise noted. Isolated yield (average of two experiments).
d
(
Scheme 3, eq 1), but the Diels−Alder cycloaddition of this
The reaction was conducted at 90 °C for 24 h until the
carboamination step had proceeded to completion, then 1 equiv of
LiOTf was added to the reaction mixture, and the temperature was
increased to 130 °C for an additional 24 h. Diastereomeric ratio and
yield for initial purification in which diastereomers were not separated.
One pure diastereomer was isolated following a second chromatog-
raphy
compound was not achieved even under forcing conditions
10
(170 °C, microwave irradiation). Efforts to employ non-
aromatic bromodienes such as 1-bromo-4-phenylbutadiene in
the carboamination reactions of 3a−c, 7, or 8a−b led to the
formation of complex mixtures of products even at relatively
low temperatures (Scheme 3, eq 2).
e
Given these limitations, we elected to explore the reactivity
of urea or sulfamide derived substrates, as our prior studies had
illustrated these types of substrates can be efficiently coupled
with various alkenyl bromides. As shown in Table 2, N,N′-
7
ligands, palladium precatalysts, and reaction conditions for the
coupling of 3a with 9-bromoanthracene we discovered that the
best results were obtained using a catalyst composed of
B
DOI: 10.1021/acs.orglett.5b00896
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Cascade Carboamination/Diels−Alder Reactions of
Scheme 4. Transformations of Phenylenediamine
Derivatives
a
Ureas and Sulfamides
had been consumed, at which time the temperature was raised
7
to promote the Diels−Alder reaction. This protocol helped to
minimize competing base-mediated alkene isomerization.
Substrate 12b was successfully coupled with nonaromatic
bromodienes to yield 13e and 13f. However, in these cases
diastereoselectivity was poor (ca. 1:1), presumably due to a low
preference for exo- vs endo-cycloaddition pathways. Finally,
cyclohexadienyl triflate also proved to be a viable electrophile in
a cascade reaction with 12b; product 13g was generated in 30%
yield and 19:1 dr. In this case use of modified reaction
conditions, in which t-BuOLi and PhCF were employed as
3
base and solvent, provided results superior to those obtained
using standard conditions.
Finally, we briefly explored the formation of six-membered
heterocycles using the cascade reaction sequence. Phenylenedi-
amine derivatives 14a−b were converted to polycyclic products
1
5a−c in moderate to good yield with excellent diastereose-
lectivity (Scheme 4, eqs 3−4). Unfortunately, efforts to employ
nonaromatic bromodienes with these substrates did not provide
satisfactory results.
In conclusion, we have developed a concise approach to the
stereocontrolled synthesis of polycyclic heterocycles via a
cascade Pd-catalyzed alkene carboamination/Diels−Alder re-
action sequence. The transformations effect the formation of 4
bonds, 3 rings, and 3−5 stereocenters with high levels of
diastereoselectivity in most cases examined. Future studies will
be directed toward expanding the scope of these reactions to a
broader array of diene electrophiles and further exploration of
the substrate scope.
a
Conditions: 1.0 equiv of substrate, 2.0 equiv of bromodiene, 2.0 equiv
of t-BuONa, 2 mol % Pd (dba) , 8 mol % ligand, xylenes (0.07 M), 24
h. Diastereomeric ratio of isolated material. Diasteromeric ratios were
similar for crude reaction mixtures unless otherwise noted. Isolated
yield (average of two experiments). The reaction was conducted at 70
2
3
b
c
d
°
C for 24 h until the carboamination step had proceeded to
completion, and then the temperature was increased to 130 °C for
an additional 24 h. The reaction was conducted for 48 h. The
reaction was conducted using P(2-furyl) as a ligand. The reaction
e
f
g
3
was conducted using 4 mol % Pd(OAc) , 12 mol % CPhos, 2 equiv t-
BuOLi, and trifluorotoluene (0.7 M).
2
ASSOCIATED CONTENT
Supporting Information
■
*
S
Experimental procedures, characterization data for all new
diallylureas and sulfamides proved to be viable substrates for
the cascade Pd-catalyzed carboamination/Diels−Alder reac-
tions, with a broader substrate scope than was observed with
1
13
compounds, and copies of H and C NMR spectra for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b00896.
3
a−c, 7, and 8a−b. Reactions of 12a or 12b with 9-
bromoanthracene or 2-bromofuran proceeded in moderate to
good yield and high diastereoselectivity to afford polycyclic
products 13a−d. In some instances the best results were
obtained when the carboamination step was conducted at
relatively low temperature (70 °C) until the starting material
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jpwolfe@umich.edu.
C
DOI: 10.1021/acs.orglett.5b00896
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Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the NIH (GM 071650) for financial support
of this work.
■
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DOI: 10.1021/acs.orglett.5b00896
Org. Lett. XXXX, XXX, XXX−XXX