Palladium-Catalyzed Chemoselective Oxidative Addition of Allyloxy-Tethered Aryl Iodides: Synthesis of Medium-Sized Rings and Mechanistic Studies

Article abstract of DOI:10.1021/acs.orglett.1c01238

This Letter describes a Pd-catalyzed Tsuji-Trost-type/Heck reaction with allyloxy-tethered aryl iodides and aziridines. The strategy provides efficient access to benzannulated medium-sized rings via intermolecular cyclization. The substrate aryl iodide ha

Full text of DOI:10.1021/acs.orglett.1c01238

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Letter
Palladium-Catalyzed Chemoselective Oxidative Addition of Allyloxy-
Tethered Aryl Iodides: Synthesis of Medium-Sized Rings and
Mechanistic Studies
Ce Liu,∥ Yuke Li,∥ Wei-Yu Shi, Ya-Nan Ding, Nian Zheng, Hong-Chao Liu, and Yong-Min Liang*
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ABSTRACT: This Letter describes a Pd-catalyzed Tsuji−Trost-type/Heck
reaction with allyloxy-tethered aryl iodides and aziridines. The strategy
provides efficient access to benzannulated medium-sized rings via intermo-
lecular cyclization. The substrate aryl iodide has two oxidative addition sites,
that is, the aromatic C−I bond and the allyl−oxygen bond. The chemoselective
oxidative addition of allyl−oxygen bonds is favored, followed by the activation
of aromatic C−I bonds. Aziridine plays a key role. Mechanistic studies shed
light on the reaction pathway.
Scheme 1. Project Background and Pd-Catalyzed Oxidative
Addition of Allyloxy-Tethered Aryl Iodides
edium-sized rings (8- to 11-membered rings) are
Mcommonly found in a range of bioactive natural
products.1 Some important natural products containing the
medium-sized ring system include (+)-laurencin, heliannuol A,
brazilone, and rhazinilam, and so on.2−5 Although medium-
sized rings have much promise in medicinal chemistry and the
pharmaceutical industry, the construction of the frameworks is
still challenging owing to unfavorable entropic factors and
transannular interactions.6 To overcome these difficulties,
many excellent synthetic strategies have been developed, such
as transition-metal-catalyzed cyclization, ring expansion, ring-
closing metathesis, lactonization and lactamization, and so
on.1,7 Among the studies of transition-metal-catalyzed
cyclization,7a,c,f,k many transformations proceed via intra-
molecular cyclization within a single molecule. Thus substrates
must be carefully designed, and they usually bear a long tether.
Herein a novel synthesis of benzannulated medium-sized rings
by palladium-catalyzed intermolecular cyclization with readily
accessible allyloxy-tethered aryl iodides and three-membered
aziridines heterocycles was studied.
In the past 30 years, alkene-tethered aryl iodides have been
exploited as substrates via palladium-catalyzed intramolecular
Heck-type reactions and C−H bond activations in domino
processes.8 Among these reports, numerous seminal works
have been published by Shi,9 Lautens,10 and others11 that used
iodoarenes with alkyl ether moieties (1) as substrates (Scheme
1a) to synthesize valuable heterocyclic and fused polycyclic
compounds. The previously mentioned reports are generally
triggered by the Heck-type reaction to generate σ-alkylpalla-
dium species A first, and this can be further functionalized
(Scheme 1a). On the basis of our interest in the field11b and
our previous report on the synthesis of indolines (Scheme
1b),12 we envisioned that the migration of aziridine 2a to give
the five-membered palladacycle E (similar to palladacycle B)
then gives the eight-membered palladacycle F (similar to
palladacycle C) followed by reductive elimination to produce
the spiro-fused benzoazepine derivative 3 (pathway i, Scheme
1c). To probe this conjecture, we carried out experimental
explorations. Interestingly and unexpectedly, nine- and eight-
membered medium-sized heterocyclic compounds 4 and 5
were isolated in a one-pot process (Scheme 1c) rather than the
expected compound 3. It is likely that Pd(0) reacts with allyl−
oxygen bonds to generate the π-allylpalladium species G first;
Received: April 12, 2021
Published: May 14, 2021
https://doi.org/10.1021/acs.orglett.1c01238
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4311−4316
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a
then, in the presence of aziridine 2a, the allylamine compound
6 is formed via a Tsuji−Trost-type reaction, which is followed
by a Heck reaction to produce heterocyclic compounds
(pathway ii, Scheme 1c).
Table 1. Substrate Scope for Annulation with 1 and 2
However, the development of such a transformation faces a
considerable challenge. The substrate aryl iodide 1 has two
oxidative addition sites, that is, the aromatic C−I bond and the
allyl−oxygen bond. The direct oxidative Heck-type reaction is
a strongly competitive process (Scheme 1a). Aryl iodide 1 itself
could easily produce a carboiodination product (R ≠ H),10
spiro-fused benzocyclobutene (R = aryl),11c or Heck-type
product (R = H)13 via a σ-alkylpalladium species. On the other
hand, aryl iodide 1 is also an allyl compound. In the presence
of a suitable nucleophile, a substrate containing a leaving group
in the allylic position can proceed via the Tsuji−Trost reaction
to provide a new substituted allyl compound.14 According to
the results of this palladium-catalyzed chemoselective oxidative
addition of allyloxy-tethered aryl iodides (pathway ii, Scheme
1c), the addition of aziridine 2a is helpful in the formation of a
π-allylpalladium species to produce allylamine product 6.
Aziridine itself is an electrophilic reagent.15 However, when its
three-membered ring is opened by the nucleophilic 2-
iodophenolate ion, the newly generated amino group can act
as a nucleophilic reagent to complete the Tsuji−Trost reaction.
In addition, with the retention of aromatic C−I bonds, studies
about Pd-catalyzed deprotection of allyl ethers of phenols have
been reported.16
Aryl iodide 1a and 1-tosylaziridine 2a were used as starting
substrates to explore this palladium-catalyzed chemoselective
oxidative addition reaction. (See the Supporting Information
(SI), Table S1.) After a series of reaction parameters was used,
the desired heterocyclic compounds were observed in up to
61% yield (4aa + 5aa). We found that the nine-membered ring
product 4aa, formed through a 9-endo-trig cyclization,
accounted for the higher proportion (4aa/5aa 12.5:1).17 Of
the phosphine ligands examined, the use of bidentate
phosphine ligands was found to be crucial, and CyDPEphos
gave the best yields (Table S1). The scope for one-pot
annulations with aryl iodides 1 and aziridines 2 was then
investigated under Condition A (Table 1). Considering the
regioselectivity of the products, the dimethyl-substituted
substrate 1a was the best choice (12.5:1) compared with
substrates 1b−1f (entries 1 and 7−11). The configurations of
products 4ba and 5ba were determined by X-ray analysis. (See
the SI.) A gram-scale reaction with 1b (5 mmol) and 2a was
carried out, and the desired products 4ba and 5ba were
isolated in 46% yield (4ba/5ba 5:1; for detailed information,
see the SI). With 1a as the aryl iodide partner, the
transformations of several aziridines with different aryl sulfonyl
groups on the nitrogen atom were also studied (entries 2−6).
They all performed well and afforded the respective cyclization
products in moderate yields with good selectivity. In particular,
when aziridines 2c and 2e were involved, only single isomers of
the nine-membered ring products 4ac and 4ae were generated,
respectively (entries 3 and 5, >20:1). However, when the
phenyl ring bore electron-withdrawing groups, such as 1g and
1h, only Tsuji−Trost-type products were isolated.18 In
addition, reactions of aryl iodide 1i and allylamine 1j did not
proceed well.
a
Condition A: 1 (0.2 mmol, 1.0 equiv), 2 (1.5 equiv), [Pd(allyl)Cl]2
(5 mol %), CyDPEphos (20 mol %), and KOAc (2.0 equiv) in
CH3CN (4 mL) at 105 °C in an oil bath for 24 h. Yields were
calculated by ratio. Isolated yields. Ratios were determined by H
NMR.
b
c
d
1
Scheme 2. Synthesis of Allylamine 6ba at Low Temperature
performed, and the results are detailed in Table S2. The use
of a bidentate phosphine ligand was crucial for the allyl
amination reaction, and dppe was proven to be the best ligand.
Allylamine products 6aa and 6ba were isolated in 85 and 90%
yields, respectively (Table 2). The configuration of product
6ba was unambiguously determined by X-ray analysis.
Substituted groups at the two-position of the allyl bonds of
the substrates (1k and 1l) were also tolerated, and good yields
resulted (6ka, 70%; 6la, 74%).19
To understand the reaction mechanism, we carried out a
series of control experiments (Scheme 3). When substrate 6ba
proceeded under Condition A, cyclization products 4ba and
5ba were isolated in up to 59% yield (4ba/5ba 5:1, Scheme
3a). Combined with the results in Schemes 2 and 3a, it is
reasonable to state that the intermolecular cyclization reaction
When the temperature was lowered to 80 °C, in addition to
cyclization products 4ba and 5ba, allylamine derivative 6ba
with reactive functional groups (Ar−I and CC bonds) was
observed (72%, Scheme 2). A new optimization was
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species).20 One can speculate that (1) the transformation
(Scheme 3c) involved a chemical equilibrium between phenol
ion 10 and π-allylpalladium species H and (2) under certain
circumstances, π-allylpalladium species and σ-alkylpalladium
species can exist in the same reaction system. Moreover, 0.5
equiv of sodium phenolate 7 was added to the allyl amination
reaction under Condition B (Scheme 3d), and in addition to
allylamine derivative 6ba (66% yield, based on 1b), the new
allylamine product 11 was obtained (35% yield, based on 7).
Furthermore, when 5.0 equiv of 7 was added, virtually only
product 11 was isolated (96%, based on 1b, Scheme S2). No
amount or trace amounts of Heck cyclization products 12 were
observed (Scheme 3d and Scheme S2). Combined with the
results in Scheme 3c,d, these results indicated that the addition
of aziridine 2a was helpful in the formation of a π-
allylpalladium species to produce allylamine products.
a
Table 2. Scope of Allylamine Derivatives 3
a
Condition B: 1 (0.2 mmol, 1.0 equiv), 2a (1.5 equiv), [Pd(allyl)Cl]2
(5 mol %), and dppe (20 mol %) in CH3CN (2 mL) at 30 °C in an
oil bath for 24 h. Isolated yields. DtBPF was used as the phosphine
ligand. DtBPF = 1,1′-bis(ditert-butylphosphino) ferrocene.
b
Inspired by Le Floch’s report,21 density functional theory
(DFT) was used to understand the mechanism of the Tsuji−
Trost-type reaction and Heck cyclization with aryl iodide 1b in
Figure 1. Aryl iodide 1b coordinates with palladium through
the CC (i1A) or C−I (i1B) bond. i1A is more stable than
Scheme 3. Control Experiments
proceeds via a sequential Tsuji−Trost-type reaction (6ba) and
Heck reaction (4ba and 5ba). After experimental exploration
(Table S3), the desired cyclization products were obtained in
up to 75% yield when XPhos was utilized (4ba/5ba 3.1:1,
Scheme 3b). After considering the results in Tables S1−S3, we
found that bidentate phosphine ligands were beneficial for the
Tsuji−Trost-type reaction, whereas Buchwald phosphine
ligands favored the Heck reaction. Next, aryl iodide 1f and
sodium phenolate (7) were mixed under Condition B (Scheme
3c). Not only was the anion exchange product allyl phenyl
ether 8 isolated (via a π-allylpalladium species) but also Heck
cyclization products 9 were observed (via a σ-alkylpalladium
Figure 1. Computed free-energy profile. (a) The red path represents
the palladium-catalyzed Tsuji−Trost-type reaction with aziridine. (b)
The green path represents the β-H elimination pathway. The energies
are in kilocalories per mole.
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i1B, with a 7.2 kcal/mol energy difference. For the palladium-
catalyzed Tsuji−Trost-type reaction (red path, Figure 1a), the
C−O bond of i1A breaks with a barrier of 16.0 kcal/mol,
forming i3A and i4A. The O atom of i3A attacks the three-
membered ring compound 2a with a barrier of 19.5 kcal/mol.
The C−N bond of i8A forms with barrier of 19.3 kcal/mol.
The rate-determining step (rds) is that from i1A to i5A-ts,
with a barrier of 23.0 kcal/mol. For comparison, the
monodentate ligand PPh3 was used to calculate the β-H
elimination path (green path, Figure 1b). The oxidation
addition reaction barrier is quite small with a barrier of only 1.3
kcal/mol from i1B to i3B. The five-membered ring formation
reaction occurs from i4B to i6B with a barrier 27.7 kcal/mol.
The barrier of β-H elimination is 10.5 kcal/mol from i6B to
i8B. The rds is 27.7 kcal/mol, which is 4.7 kcal/mol higher
than in the case of the pathway involving the π-allyl
intermediate.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01238.
■
sı
Complete experimental procedures and characterization
data for the prepared compounds (PDF)
Accession Codes
CCDC 2011199, 2011201, and 2011212 contain 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 Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
A plausible mechanism is proposed that is consistent with
the experimental results previously mentioned (Scheme 4).
AUTHOR INFORMATION
Corresponding Author
■
Yong-Min Liang − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China;
orcid.org/0000-0001-8280-8211; Email: liangym@
lzu.edu.cn
Scheme 4. Proposed Mechanism
Authors
Ce Liu − State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, China; State Key
Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, China
Yuke Li − Department of Chemistry and Centre for Scientific
Modeling and Computation, Chinese University of Hong
Kong, Hong Kong, China
Wei-Yu Shi − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Ya-Nan Ding − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Nian Zheng − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Hong-Chao Liu − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
The Pd(0) species undergoes oxidative addition of aryl iodide
1b to produce π-allylpalladium complex I. Then, the
nucleophilic 2-iodophenolate ion is trapped by electrophilic
aziridine 2a. Next, the newly generated π-allylpalladium species
J undergoes reductive elimination to yield the desired
allylamine product 6ba and regenerate the Pd(0) catalyst.
Finally, cyclization products 4ba and 5ba are isolated through
the Heck reaction with allylamine 6ba.22
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01238
Author Contributions
∥C.L. and Y.L. contributed equally.
In summary, a palladium-catalyzed chemoselective oxidative
addition of allyloxy-tethered aryl iodides with aziridines has
been developed. The aryl iodide substrate has two oxidative
addition sites, that is, the aromatic C−I bond and the allyl−
oxygen bond. By adjusting the reaction conditions, Pd(0) can
be made to react first with the allyl−oxygen bond to generate a
π-allylpalladium species; then, this forms new C−O and C−N
bonds with aziridines to obtain allylamine derivatives. This is
followed by the production of nine- and eight-membered
benzannulated medium-sized rings via the Heck reaction in
one pot. Because the reaction proceeds by way of a favored π-
allylpalladium species, it seems that the special electrophilic
partner aziridine plays a very important role. Preliminary
mechanistic studies and DFT calculations shed light on the
reaction pathway. Further applications of this method for
syntheses of other heterocycles are underway.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Bo-Sheng Zhang, Dr. Ping-Xin Zhou, and Dr.
Dao-Qian Chen for helpful discussions. Support from the
National Natural Science Foundation of China (NSF grant
nos. 21772075 and 21532001) is acknowledged.
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(19) For more studies about substrates 1k and 1l, see Scheme S3.
(20) Yields were determined by GC-MS. For more studies, see
Scheme S2.
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