Synthesis of 2-Amino-1,3-dienes from Propargyl Carbonates via Palladium-Catalyzed Carbon-Nitrogen Bond Formation

Article abstract of DOI:10.1021/acs.orglett.9b04413

A catalytic method to synthesize 1,3,-dienes from propargylic precursors is reported. This palladium-catalyzed carbon-nitrogen bond-forming reaction furnishes 2-amino-1,3-dienes in excellent yields (up to 98%) and shows a broad tolerance to functional group diversity. The reaction has been demonstrated for over 30 amine substrates, including anilines and indoles, and proceeds under mild neutral conditions. The resulting 1,3-dienes are of great synthetic interest because of their further reaction potential.

Full text of DOI:10.1021/acs.orglett.9b04413

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Letter
Synthesis of 2‑Amino-1,3-dienes from Propargyl Carbonates via
Palladium-Catalyzed Carbon−Nitrogen Bond Formation
Calvin Q. O’Broin and Patrick J. Guiry*
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ABSTRACT: A catalytic method to synthesize 1,3,-dienes from propargylic precursors is reported. This palladium-catalyzed
carbon−nitrogen bond-forming reaction furnishes 2-amino-1,3-dienes in excellent yields (up to 98%) and shows a broad tolerance to
functional group diversity. The reaction has been demonstrated for over 30 amine substrates, including anilines and indoles, and
proceeds under mild neutral conditions. The resulting 1,3-dienes are of great synthetic interest because of their further reaction
potential.
Scheme 1. Advances Made in Intermolecular
Decarboxylative Dienylation
he formation of carbon−nitrogen bonds presents an
T
important challenge to synthetic chemists. Between 2016
and 2018, 19 out of the 20 bestselling small-molecule
pharmaceuticals on the market possessed a nitrogen-containing
functionality, not to mention the plethora of nitrogenous
natural products that exist.1,2 To this end, numerous reports in
the literature elegantly describe different methodologies to
form C−N bonds.3 While this field has been widely explored
for a host of different functionalities, the formation of 2-amino-
1,3-dienes is relatively unexplored, with only a few examples
reported.4 1,3-Dienes are valuable synthetic handles, as they
increase the potential for molecular complexity.5 Exploitation
of the unique reactivity of propargyl electrophiles provides
access to this valuable functionality. The Tunge group has
reported dienylation with carbon nucleophiles,6 and recently
the Murakami group has published dienylation of phenols.7
However, pairing the synthetic utility of 1,3-dienes with the
ubiquity of nitrogen-containing compounds has not been
reported (Scheme 1).
The reaction was initially investigated using benzoyl-
protected aniline 1 and a slight excess of propargyl carbonate
2 with a 2 mol % loading of Pd2(dba)3·CHCl3 and a 5 mol %
loading of the diphosphine ligand dppb (Scheme 2).
Pleasingly, the reaction produced the dienylated aniline 3 in
95% yield. There were no traces of unwanted diaminated,
allenylated, or propargylated side products, as can often be
observed when propargyl electrophiles are employed.8
and iodo functionalities, with products 9 and 10 being formed
in 86% and 38%, respectively. These substrates demonstrate
the robust nature of the catalytic system and allow for the
possibility that further transition metal couplings can be
performed on the products.
A range of substituted anilines were tested to examine the
tolerance of the reaction (Scheme 3). Para-substituted aniline
substrates performed well, with both donating and with-
drawing substituents giving excellent yields of up to 98% (4−
7). N-Dienyl-4-aminostyrene product 8 was formed in 92%
yield, and the catalysis was also shown to tolerate both boryl
Received: December 9, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04413
© XXXX American Chemical Society
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a
Scheme 2. Decarboxylative Dienylation of a Model
Substrate
Scheme 4. Indole Scope
a
Scheme 3. Aniline Scope
a
Reaction conditions: amine (1.0 mmol), 2 (1.1 mmol), 2 mol %
Pd2(dba)3·CHCl3/5 mol % dppb.
the substrates. Carbazole and 3,4-dihydro-2(1H)-quinolinone
proved to be excellent substrates, affording products 35 and 37
in high yields of 86% and 93%, respectively. Again, as in the
case of the anilines, when a bis(indole) substrate was employed
the bisdienylated product 36 was formed in an excellent yield
of 85%.
To examine the general applicability of the reaction, two
bioactive compounds were tested: TBS-protected acetamino-
phen 38 and endogenous hormone melatonin 40 (Scheme 5).
a
Reaction conditions: amine (1.0 mmol), 2 (1.1 mmol), 2 mol %
b
Pd2(dba)3·CHCl3/5 mol % dppb. The reaction was run at 100 °C.
Meta and ortho substitution was also well-tolerated, with
strongly withdrawing groups and aryl bromides proving no
issue to the reaction. As examples, dienylated products 11−18
were formed in very high yields of up to 98%. Switching from
aniline to 1-aminonaphthalene furnished product 19 in 97%
yield. Heterocyclic aminopyridine and aminopyrazine sub-
strates were dienylated successfully to yield products 20 and 21
in 95% and 51% yield, respectively. Replacing the benzoyl
protecting group with acetyl and trifluoroacetyl groups allowed
the catalysis to still proceed in high yields, furnishing 22 in
92% yield and 23 in 86% yield. Sterically hindered di-ortho-
substitution was tolerated surprisingly well, providing dieny-
lated diisopropylaniline 24 in 73% yield, and bisdienylation
occurred when an m-phenylenediamine substrate was tested,
yielding 25 in an excellent yield of 92%.
a
Scheme 5. Dienylation of Biologically Active Compounds
For ortho-substituted anilines and N-acetylanilines, the
products displayed significant rotational barriers observed via
1H NMR spectroscopy. For the ortho-substituted anilines, this
restricted rotation can be explained by steric congestion, but
for the N-acetyl products, the restricted rotation can be
attributed to the double-bond character of the tertiary amide
C−N bond.9,10
With excellent results recorded for the aniline substrates, the
protocol was tested on various substituted indoles (Scheme 4).
1H-Indole was dienylated to give 26 in 61% yield.
Substitutions at the 3-, 4-, and 5-positions were all tolerated
and gave moderate to good yields, with a slight increase in
yield observed for electron-donating groups (27−34).
Interestingly, no dienylation at C-3 was observed for any of
a
Reaction conditions: amine (1.0 mmol), 2 (1.1 mmol), 2 mol %
Pd2(dba)3·CHCl3/5 mol % dppb.
Both substrates reacted with propargyl carbonate 2 to give the
corresponding dienes 39 and 41 in good yields of 80% and
71%, respectively. In the case of melatonin, no reaction at the
acetamide nitrogen was observed, showing the chemo-
selectivity of the process.
The scalability of the catalysis was measured by reacting 1 g
of 1 with propargyl carbonate 2 (Scheme 6). The catalytic
loadings were dropped to 1.0 mol % Pd0 and 2.5 mol % ligand.
B
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but no deuteration at C4. As 50% deuteration is the maximum
amount possible at either position, on the basis of the previous
experiment, this result suggests that the proton of the amine
substrate contributes more substantially to the protonation
event than the methyl protons of the propargyl carbonate but
is not the sole source. In the final experiment, when standard
aniline 1 was reacted with deuterated propargyl carbonate 45,
17% deuteration occurred at C1 and C3 of diene 48. This
conforms with the results from the previous experiment, as it
demonstrates that the propargyl carbonate also contributes to
the protonation event but less substantially than the amine
substrate. It also confirms that elimination occurs on the
methyl group of the propargyl carbonate to yield the final
diene, as C4 is fully deuterated. The likely proton source is the
ethanol byproduct of the carbonate, which in these mechanistic
studies exists in an equilibrium with its deuterated form.
A putative mechanism can thus be envisaged (Scheme 8).
First, palladium interacts with the propargyl carbonate,
Scheme 6. Gram-Scale Catalysis and Stereoselective
Dienylation
a
a
Reaction conditions: amine (1.0 mmol), carbonate (1.1 mmol), 2
mol % Pd2(dba)3·CHCl3/5 mol % dppb. Isolated yields are shown.
Dienylated product 3 was formed in 95% yield, mimicking the
smaller-scale reaction and proving the catalysis to be robust
and amenable to larger reaction scales. The use of disubstituted
propargyl carbonate 42 in the catalysis allowed the more
chemically complex dienylated product 43 to be formed in an
excellent yield of 89% with moderate control over the
stereoselectivity. This result suggests that the methyl group
can be at either terminus of the electrophile and that
substitution at the 1-position of the diene can be achieved.
With these results in hand, deuterium labeling studies were
carried out to shed some light on the mechanism of the
reaction (Scheme 7).11 When deuterated aniline 44 was
Scheme 8. Reaction Mechanism
Scheme 7. Deuterium Labeling Experiments
releasing CO2 and an ethoxide anion to form π-propargyl
complex A. The nitrogen nucleophile is then proposed to
attack this complex to give palladacyclobutene intermediate B.
The ethoxide anion neutralizes the positively charged nitrogen
atom while in turn protonating the palladacycle intermediate
to give palladium π-allyl complex C. This regenerates the
ethoxide anion, which can then deprotonate a methyl proton
to yield the final dienylated product and the palladium catalyst.
An X-ray structure of product 3 shows that the diene adopts an
s-trans conformation (Figure 1).
Finally, to demonstrate the utility and further reaction
potential of the 1,3-diene products formed, tandem dien-
employed with deuterated propargyl carbonate 45, 50%
deuteration at C1 of diene 46 was observed along with 50%
deuteration at C3 and full deuteration at C4. This
demonstrates that the N−H proton on aniline and/or the
methyl protons on the propargyl carbonate are sources of
protonation in the catalysis. When deuterated aniline 44 was
used with typical propargyl carbonate 2, 33% deuterium
incorporation at both C1 and C3 of diene 47 was observed,
Figure 1. X-ray structure of 3.
C
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ylation/Diels−Alder reactions were attempted with both
aniline and indole substrates (Scheme 9). The dienylation
AUTHOR INFORMATION
Corresponding Author
■
Patrick J. Guiry − University College Dublin, Dublin,
Ireland; orcid.org/0000-0002-2612-8569;
Email: p.guiry@ucd.ie
a
Scheme 9. Tandem Dienylation/Diels−Alder Reactions
Other Author
Calvin Q. O’Broin − University College Dublin, Dublin,
Ireland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04413
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
C.Q.O. is grateful for the award of an Irish Research Council
Enterprise Partnership Scheme Ph.D. Scholarship (EPSPG/
2016/62) with Enterprise Partner Leo Pharma. We acknowl-
edge the facilities provided by the Centre for Synthesis and
Chemical Biology (CSCB), funded by the Higher Education
Authority’s PRTLI.
a
Reaction conditions: amine (0.5 mmol), 2 (0.55 mmol), 2 mol %
Pd2(dba)3·CHCl3/5 mol % dppb, dienophile (0.55 mmol).
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ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04413.
Experimental procedures, compound characterization
data and copies of NMR spectra for all compounds
(PDF)
Accession Codes
CCDC 1962749 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
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E
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