Construction of N-Heterocyclic Systems Containing a Fully Substituted Allylic Carbon by Palladium/Phosphine Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b03127

The unique cyclization of benzamide derivatives that contain an alkyne by a Pd(0)/dialkyl(biaryl)phosphine catalytic system is reported. The reaction efficiently provides a variety of six-membered N-heterocyclic compounds that contain a fully substituted carbon center without the need for a stoichiometric additive. Mechanistic studies suggest that this unprecedented cyclization starts with the cleavage of a propargylic C-O bond, and a 1,3-diene has been identified as a relevant intermediate.

Full text of DOI:10.1021/acs.orglett.8b03127

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Construction of N‑Heterocyclic Systems Containing a Fully
Substituted Allylic Carbon by Palladium/Phosphine Catalysis
Yohei Ogiwara,* Yui Suzuki, Kazuya Sato, and Norio Sakai*
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba
278-8510, Japan
S
* Supporting Information
ABSTRACT: The unique cyclization of benzamide deriva-
tives that contain an alkyne by a Pd(0)/dialkyl(biaryl)-
phosphine catalytic system is reported. The reaction efficiently
provides a variety of six-membered N-heterocyclic compounds
that contain a fully substituted carbon center without the need
for a stoichiometric additive. Mechanistic studies suggest that
this unprecedented cyclization starts with the cleavage of a propargylic C−O bond, and a 1,3-diene has been identified as a
relevant intermediate.
he construction of complex N-heterocycles is an
important topic in synthetic chemistry, given their
mentary strategy to both the aza-Wacker and the allylic
amination reactions, given that the electrophilic nitrogen
functions therein as the reaction site.
T
importance as core structural motifs in potentially bioactive
molecules and their role as versatile precursors for more
complex ring systems.1 A significant challenge in this field
involves the introduction of a fully substituted carbon center
bearing a vinyl substituent in the ring system. The Pd-catalyzed
intramolecular cyclization via the formation of carbon−
nitrogen bonds is regarded as one of the most reliable routes
to such compounds. The aza-Wacker cyclization of alkenes
that bear a nitrogen nucleophile by Pd(II) is a well-established
process (Scheme 1a).2,3 To perform the reaction catalytically,
an external oxidant is required for the regeneration of the
Pd(II) species from the resulting Pd(0) complex. Other
approaches are the allylic amination (Tsuji−Trost reaction)4,5
and the aza-Mizoroki−Heck reaction (Narasaka−Heck cycliza-
tion)6,7 catalyzed by Pd(0) in the presence of a base (Scheme
1b and 1c). The aza-Mizoroki−Heck reaction is a comple-
In terms of substrate generality and reaction diversity to
access complex N-heterocyclic architectures, the development
of alternative methods that generate the same motifs from
different starting substrates through unprecedented reaction
mechanisms is desirable.8 Our recent studies have examined
the Pd-catalyzed cyclization of alkynoic acids, which affords
vinyl-substituted O-heterocycles with a tetrasubstituted carbon
center.9 This novel synthetic strategy was subsequently
exploited to access a variety of N-heterocycles. In this
communication, we describe the Pd(0)-catalyzed construction
of N-heterocyclic systems with a fully substituted allylic carbon
atom from alkynes bearing a nitrogen nucleophile (Scheme
1d). The present protocol provides in principle no side
products and, therefore, avoids the use of stoichiometric
additives. Moreover, this transformation involves an unprece-
dented skeletal rearrangement. Overall, the simple method
presented herein allows producing a large variety of novel and
complex N-heterocyclic compounds.
Initially, we chose the salicylamide derivative N-phenyl-
benzamide 1a, which bears a propargyl ether moiety at the
ortho-position, as the starting substrate for the ligand screening
(Scheme 2). On the basis of our recent study on the Pd-
catalyzed cyclization of alkynoic acids,9 1a was stirred for 1 h in
toluene at 110 °C in the presence of Pd(dba)2 (10 mol %) and
tBuXPhos (20 mol %). Under these conditions, the expected
intramolecular cyclization afforded N-heterocyclic 2a with a
tetrasubstituted allylic carbon atom in 54% GC yield. After
screening the reaction conditions,10 the GC yield of 2a was
improved to 82% when JohnPhos was used as the ligand, and
2a was isolated in 77% yield.11
Scheme 1. Pd-Catalyzed Construction of N-Heterocyclic
Systems Containing a Tetrasubstituted Allylic Carbon
Center
Received: October 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03127
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Letter
a
Scheme 2. Ligand Screening
Scheme 3. Substrate Scope
The scope of this cyclization reaction was then explored
using the Pd(dba)2/JohnPhos system. As shown in Scheme 3,
a variety of substrates 1 underwent cyclization to produce the
corresponding products 2 in high yield. Substrates bearing
electron-donating and electron-withdrawing substituents on
the benzene ring (R1) or fused-aromatic rings (1b−k)
efficiently provided the corresponding products (2b−k).
Internal alkynes that bear an aryl or an alkyl substituent at
their alkynyl carbon atom (R2) (1l and 1m) also underwent
the present cyclization to afford 2l and 2m. In contrast, 2n was
not detected using terminal alkyne 1n; instead, the formation
of 2n′ with a seven-membered ring, which is a typical 7-exo-dig
adduct, was observed in 96% yield.12 The conversion of several
N-arylbenzamide derivatives (1o−s; R3 = Ar) afforded a series
of N-aryl heterocycles (2o−s). The unequivocal structural
characterization of 2s was accomplished by a single-crystal X-
ray diffraction analysis.13 Notably, primary amides (1t−v; R3 =
H) were also transformed into the corresponding products
(2t−v) that contain an unprotected nitrogen atom. On the
other hand, N-alkylbenzamide derivatives 1w (R3 = cyclo-
hexyl) and 1x (R3 = butyl) did not provide the corresponding
cyclization products 2w and 2x, but predominantly generated
1,3-dienes 3w and 3x.14
The formation of 1,3-dienes 3 was also observed in the case
of the model substrate, i.e., N-phenylbenzamide derivative 1a.
When the reaction of 1a with catalytic amounts of Pd(dba)2/
1
JohnPhos in C6D6 at 70 °C was monitored by H NMR
spectroscopy, the transient formation of 1,3-diene 3a was
observed (Figure 1a). The plots for the concentrations of the
starting substrate [1a], cyclization product [2a], and 1,3-diene
[3a] as a function of time are shown in Figure 1b. At the initial
stage of the reaction (0−30 min), 3a is generated
predominantly. Subsequently, cyclization product 2a is formed
as diene 3a is consumed.
The isolation of 1,3-diene 3a was possible by shortening the
reaction time to 1.5 min (eq 1). Then isolated diene 3a was
a
Reaction conditions: 1 (1.0 mmol), Pd(dba)2 (0.1 mmol), and
JohnPhos (0.2 mmol) in toluene (1 mL) at 110 °C for 1 h. Isolated
b
c
d
yields are shown. 0.5 mmol scale. 12 h. ORTEP drawing of 2s with
thermal ellipsoids set to 50% probability; hydrogen atoms are omitted
e
f
for clarity. 0.5 mmol scale, toluene (1 mL). 0.4 mmol scale, toluene
g
(0.8 mL). 1H NMR yield.
used as the starting substrate and catalyzed using Pd(dba)2/
JohnPhos to furnish the expected cyclization product 2a in
81% GC yield (eq 2). In their entirety, the kinetic profiles and
control experiments suggest that 1a is initially converted into
B
DOI: 10.1021/acs.orglett.8b03127
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under standard conditions, cyclization product 2l-d was
isolated in 36% yield (eq 3). 1H and 2H NMR spectral
analyses of the product revealed deuterium incorporation only
at the internal vinylic carbon atom of 2l-d (0.68 D, 0.32 H).
The reaction of deuterated N-alkylbenzamide derivative 1w-d1,
which did not afford the cyclization product, proceeded to
form 1,3-diene 3w-d in 29% isolated yield with selective
deuterium incorporation at the internal diene carbon atom,
although the deuterium content was moderate (0.40 D, 0.60
H) (eq 4). When the reaction of 1h-d1 was carried out for 5
min, both the cyclization product 2h-d and 1,3-diene 3h-d
were isolated in 79% and 9% yield, respectively (eq 5). For the
cyclization product 2h-d, deuteration of the methyl carbon
atom next to the tetrasubstituted carbon atom was also
observed (0.49 D, 2.51 H), in addition to that at the internal
vinylic carbon atom (0.32 D, 0.68 H). Furthermore, the
deuterium incorporation in diene 3h-d occurred at the internal
diene carbon atom (0.27 D, 0.73 H) and at the terminal diene
1
Figure 1. H NMR monitoring for the detection of intermediate 3a.
Reaction conditions: 1a (0.3 mmol), Pd(dba)2 (0.03 mmol), and
JohnPhos (0.06 mmol) in C6D6 (0.6 mL) at 70 °C. The
concentrations of 1a ( ), 2a ( ), and 3a ( ) were calculated
from the 1H NMR spectra using 1,3,5-trimethoxybenzene as the
internal standard.
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○
●
intermediate 3a, which subsequently undergoes cyclization
into 2a.
We then conducted deuterium-labeling experiments employ-
ing 1l-d1, 1w-d1, and 1h-d1 as the starting substrates, which
were deuterated at the nitrogen atom of their amide moieties
(eqs 3−5). At the initial stage (15 min) of the reaction of 1l-d1
Scheme 4. Possible Pathway for the Pd-Catalyzed Conversion of 1 into 2 and 3
C
DOI: 10.1021/acs.orglett.8b03127
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Letter
ORCID
carbon atom (0.16 D, 0.84 H) next to the oxygen-substituted
carbon atom.
Yohei Ogiwara: 0000-0003-1438-0916
Norio Sakai: 0000-0003-0722-4800
Notes
On the basis of these mechanistic investigations and our
previous experiments employing carboxylic acids,9 a possible
pathway is proposed in Scheme 4. Oxidative addition of the
propargylic C−O bond of 1 to Pd(0) would form η1-
propargylpalladium, which would be in equilibrium with η1-
allenyl species. From η1-allenylpalladium complex, the
generation of “O-allenyl” palladium intermediate A could
occur through the formation of a C−O bond and oxidative
addition of the N−D bond to Pd(0). Intramolecular
hydropalladation of the allene moiety in A would proceed to
afford π-allylpalladium B, which would finally undergo a
reductive elimination of the allylic C−N bond of cyclization
product 2, accompanied by deuterium migration from the
nitrogen of 1 to the internal vinylic carbon of 2. In the case of a
substrate bearing a methyl substituent at the alkynyl carbon 1
(R′ = Me), the corresponding 1,3-diene 3 would be the
observable intermediate, which can be generated from π-
allylpalladium B via reversible β-hydride elimination and N−H
reductive elimination of 3.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by JSPS KAKENHI Grant
No. JP16K21400, a research grant from the Shorai Foundation
for Science and Technology, a grant from Central Glass Co.,
Ltd. award in Synthetic Organic Chemistry, Japan, a research
grant from the Takahashi Industrial and Economic Research
Foundation, a research grant program for younger professors
from the JGC-S Scholarship Foundation, and a research grant
from the Japan Prize Foundation.
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■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03127.
Experimental procedures and characterization data for
all compounds; X-ray crystallographic data for 2s (PDF)
Accession Codes
CCDC 1571311 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, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yoheiogiwara@rs.tus.ac.jp.
*E-mail: sakachem@rs.noda.tus.ac.jp.
D
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(11) All reactions were carried out under a nitrogen atmosphere;
however, they can also be carried out in air, even though this affords
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(14) The nitrogen linker connecting the aryl and propargyl
fragments in substrate 4 was also tolerated, although the yield of
the cyclization product 5 was relatively low (28%).
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