Dearomative Allylation of Naphthyl Cyanohydrins by Palladium Catalysis: Catalyst-Enhanced Site Selectivity

Article abstract of DOI:10.1021/acs.orglett.0c00897

A dearomative allylation of naphthyl cyanohydrins with allyl borates and allyl stannanes under palladium catalysis was developed. At the initial stage of this study, the dearomative reaction (C4 substitution of the aromatics) was competing with benzyl substitution. To circumvent this issue, the use of palladium and meta-disubstituted triarylphosphine as the catalyst in a 1:1 ratio was found to enhance the site selectivity, furnishing the desired dearomatized products. Further derivatizations of products were also successful.

Full text of DOI:10.1021/acs.orglett.0c00897

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Letter
Dearomative Allylation of Naphthyl Cyanohydrins by Palladium
Catalysis: Catalyst-Enhanced Site Selectivity
Aika Yanagimoto, Masaaki Komatsuda, Kei Muto,* and Junichiro Yamaguchi*
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ABSTRACT: A dearomative allylation of naphthyl cyanohydrins
with allyl borates and allyl stannanes under palladium catalysis was
developed. At the initial stage of this study, the dearomative
reaction (C4 substitution of the aromatics) was competing with
benzyl substitution. To circumvent this issue, the use of palladium
and meta-disubstituted triarylphosphine as the catalyst in a 1:1 ratio
was found to enhance the site selectivity, furnishing the desired
dearomatized products. Further derivatizations of products were
also successful.
he chemical transformation of arenes is a fundamental
Ttopic in organic synthesis. Many transformations of
arenes have been developed, of which electrophilic aromatic
substitutions and cross-couplings are recognized as key
functionalizations of σ-bonds of aromatic cores.1 On the
other hand, the transformation of the ring itself, i.e., the
transformation of the π-bonds of arenes such as dearomative
reactions, is less studied. Nevertheless, this type of reaction can
provide high molecular complexity from simple and abundant
arenes. With recent developments in metal catalysis, several
dearomatization methods have emerged.2 For example, the
Glorius group recently achieved efficient hydrogenations of
arenes to give alicyclic compounds with a high stereo-
control.2c−f For dearomative functionalizations, however,
there are more limitations than with hydrogenations. For
example, the efficiency of the reaction significantly depends on
the electronic nature of the arenes. Although electron-rich and
electron-poor arenes can mostly be utilized as a limiting agent,3
electron-neutral arenes are regarded as inactive arenes, usually
requiring excess amounts in a reaction.4,5 Generally, only
nitroarenes,6 aryl malonates,7 and aryl iodanes8 can be utilized
for dearomative functionalizations as the limiting reagent.
We recently reported the dearomative allylation of inactive
aromatic systems initiated by a catalytic bond cleavage (Figure
1A).9 So far, we developed the dearomative allylation of benzyl
phosphates9a as well as aryl bromides9b under the influence of
a palladium catalyst. Yamamoto and Bao also developed
related reactions involving benzyl chlorides.10 These methods
enabled the dearomative functionalization of inactive arenes as
a limiting reagent. However, the obtained products were
unstable and difficult to derivatize to functionalized alicyclic
systems, ultimately restricting further synthetic application. We
postulated that this instability was caused by the highly reactive
exocyclic olefin of the products. To achieve the dearomative
Figure 1. (A) Catalytic dearomative allylation. (B) Dearomative
allylation of aromatic cyanohydrins.
synthesis of multifunctionalized alicyclic molecules, we selected
aromatic cyanohydrin phosphates as the substrate,11,12 which
possess a cyano group at the benzyl position (Figure 1B).
Importantly, because the dearomatized products have an α,β-
Received: March 10, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00897
© XXXX American Chemical Society
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A

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unsaturated cyano moiety, they are expected to be function-
alized through a conjugate addition. With this application in
mind, we herein report the development of dearomative
allylation of aromatic cyanohydrins using palladium catalysis.
We initiated this study by investigating the reaction
conditions using naphthalene cyanohydrin 1A with allyl
trifluoroborate 2a (Table 1). As a first trial, our previous
disubstituted triarylphosphines (Table 1, entries 10−13). As a
result, electron-rich m-disubstituted triarylphosphines were
found to be favorable for both reaction yield and site
selectivity, out of which m-dimethoxyphenyl phosphine L4
gave the best result (Table 1, entry 12). Delightfully, the
addition of Cs2CO3 as a base improved the reaction efficiency,
furnishing the product 3A in 70% yield with high site
selectivity (Table 1, entry 14).
a
With the optimized conditions in hand, we evaluated the
substrate scope of the reactions presented here (Scheme 1).
Table 1. Screening of Reaction Conditions
a
Scheme 1. Substrate Scope
b
entry ligand (mol %)
base
T (°C) 3A + 4A (%)
3A:4A
1
2
3
4
5
6
7
8
L1 (20)
L1 (20)
L1 (20)
L1 (10)
L1 (5)
PPh3 (5)
P(o-tol)3 (5)
P(m-tol)3 (5)
P(p-tol)3 (5)
L2 (5)
−
−
−
−
−
−
−
−
−
−
−
−
−
60
RT
4
83
82
0
61
53
36
3
46
33
35
40
44
0
0:100
49:51
−
74:26
87:13
86:14
−
91:9
88:12
91:9
91:9
95:5
−
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
9
10
11
12
13
14
L3 (5)
L4 (5)
L5 (5)
L4 (5)
Cs2CO3
70
97:3
a
Conditions: 1A (0.20 mmol), 2a (0.20 mmol), Pd(OAc)2 (5 mol
b
%), ligand, base (3.0 equiv), toluene (1.0 mL), 12 h. NMR yield.
reaction conditions for dearomative allylation of benzyl
phosphates were examined (Table 1, entry 1).9a However,
the reactivity of cyanohydrins and simple benzyl phosphates is
rather different for this catalytic system, generating only the
undesired benzyl-substituted product 4A in 83% yield. We
hypothesized that this site selectivity occurred due to the
highly electrophilic nature of the α-cyano moiety leading to
undesired benzyl substitution. Thus, the reaction temperature
was decreased from 60 °C to room temperature (RT). To our
delight, the dearomative reaction proceeded to give the desired
product (dearomative allylation product) 3A in 40% yield,
along with the undesired 4A in a 1:1 ratio (Table 1, entry 2).
Decreasing the reaction temperature to 4 °C resulted in no
reaction (Table 1, entry 3). Interestingly, when the
metal:ligand ratio was changed, decreasing the amount of
ligand improved this site selectivity (Table 1, entry 2 vs entries
4 and 5). Next, the effect of the ligand was investigated. Simple
PPh3 decreased the yield of 3A and 4A while retaining the site
selectivity (Table 1, entry 6). When using o-, m-, and p-tolyl
phosphines, it was found that m-tolyl phosphine was effective
(Table 1, entries 7−9, respectively). Encouraged by the effect
of meta substituents, we synthesized and evaluated several m-
a
Conditions: 1 (0.20 mmol), 2a (0.20 mmol), Pd(OAc)2 (5 mol %),
b
L4 (5 mol %), Cs2CO3 (3.0 equiv), toluene (1.0 mL), RT, 12 h. On
a 1.0 mmol scale. Determined by H NMR.
c
1
The reaction could be applied to C4-substituted naphthalenes.
Several C4-alkylated naphthalene cyanohydrins underwent the
reaction, giving the corresponding products 3 in moderate to
good yields with high site selectivity (3A−3C). A sterically
demanding isopropyl group was also compatible in this
reaction (3D). A strained alkyl group such as cyclopropyl
was tolerated to give 3E in moderate yield. Reactive functional
groups such as acetal (3G), ester (3I), and silyloxy (3J) groups
remained intact under the reaction conditions. Furthermore,
allyl stannane was found to be applicable as the allylating agent
in the absence of a base, furnishing 3A in good yield with high
site selectivity. It is noteworthy that these dearomatized
B
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products were reasonably stable, not decomposing during
silica-gel column chromatography. However, at this time, the
scope was limited to C4 substituents bearing naphthalenes as
well as allyl BF3K. In this regard, simple phenyl rings and
substituted allyl borates were not allowed.16
meta-disubstituted triarylphosphines have a bowl-shaped
structure, accelerating the dissociation of other ligands but
providing reaction space around the metal center.15 In line
with these reports, the use of meta-disubstituted triarylphos-
phines would support the generation of a coordinatively
unsaturated palladium species in this catalytic system.
Although o-substituted triarylphosphines are also expected to
give coordinatively unsaturated palladiums, they cannot
provide enough reaction space around the metal center,
blocking the desired transmetalation of allyl borons.16
A possible reaction mechanism is outlined in Scheme 2.13
First, oxidative addition of C−O bonds to palladium(0)
Scheme 2. Proposed Mechanism
Finally, we performed several transformations of dearomat-
ized product 3A (Scheme 4). The α,β-unsaturated cyano
Scheme 4. Derivatization of 3A
species gives benzyl-palladium B, which is in equilibrium
between σ- and π-benzyl species. Allyl borate undergoes
transmetalation, generating allyl-palladium-benzyl intermediate
C. Finally, reductive elimination forms the C−C bond at the
remote site, releasing the dearomatized products with
regeneration of the active palladium(0) species.14
At this stage, we speculate that the observed catalyst-
enhanced site selectivity may be triggered by the generation of
coordinatively unsaturated palladium species B (Scheme 3).
moiety is expected to be functionalized through several
nucleophilic additions. Although we expected that 1,4-addition
would occur when using carbon nucleophiles, the reaction
using lithioacetonitrile afforded 1,6-adduct 5 instead. A similar
regioselectivity was observed when nitromethane was reacted
with 3A in the presence of DBU, furnishing 6. This
regioselectivity is likely due to the steric repulsion of the δ,γ-
unsaturated olefin (disubstituted) versus the α,β-unsaturated
olefin (trisubstituted) to circumvent the expected 1,4-
addition.17 Furthermore, we succeeded in reductively derivatiz-
ing 3A through global hydrogenation, furnishing substituted
tetralin 7. Treatment of 3A with DIBAL was also successful to
deliver enal 8.
Scheme 3. Possible Role of the Catalyst in Site Selectivity
In summary, we developed a dearomative allylation of
aromatic cyanohydrins by a palladium catalyst. The combina-
tion of palladium and m-disubstituted triarylphosphines
enhanced site selectivity, furnishing dearomatized molecules.
Importantly, the dearomatized products could be derivatized
to a variety of substituted alicyclic systems. We believe that this
work can provide a useful synthetic entry to alicyclic molecules
and lead to an in-depth understanding of the mechanism of
related reactions. Further studies to expand the substrate
generality and elucidate the mechanism are ongoing in our
laboratory.
The reaction conditions using a 1:1 palladium:ligand ratio
would generate a coordinatively unsaturated palladium
intermediate. Thus, the allyl boron species can undergo
transmetalation to give the allyl-Pd-benzyl intermediate,
followed by reductive elimination at the C4 position to furnish
the dearomatized product.14 In contrast, when palladium and a
ligand were used in a ratio of 1:2 or more, coordinatively
saturated species D would be generated as the major catalytic
intermediate. Probably due to the highly electrophilic nature of
the cyano-bearing benzyl carbon, the allyl borons likely prefer
external attack on D, giving the benzyl-substituted compound
as the major product. meta-Disubstituted triarylphosphines
likely enforce the generation of coordinatively unsaturated
palladium B by steric repulsion. According to Tsuji’s work,
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00897.
Experimental procedures and spectroscopic data for
1
compounds, including H, 13C, and 31P NMR spectra
(PDF)
C
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AUTHOR INFORMATION
Corresponding Authors
■
Kei Muto − Department of Applied Chemistry, Waseda
University, Tokyo 169-8555, Japan; orcid.org/0000-0001-
8301-4384; Email: keimuto@aoni.waseda.jp
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Dearomative syn-1,4-Carboamination. J. Am. Chem. Soc. 2017, 139,
Junichiro Yamaguchi − Department of Applied Chemistry,
Waseda University, Tokyo 169-8555, Japan; orcid.org/
0000-0002-3896-5882; Email: junyamaguchi@waseda.jp
Authors
Aika Yanagimoto − Department of Applied Chemistry, Waseda
University, Tokyo 169-8555, Japan
Masaaki Komatsuda − Department of Applied Chemistry,
Waseda University, Tokyo 169-8555, Japan
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17787−17790. (d) Hernandez, L. W.; Klockner, U.; Pospech, J.;
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00897
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grants
JP19H02726 (to J.Y.), JP18H04661 (Hybrid Catalysis), and
JP19K15573 and The SATOMI Scholarship Foundation (to
K.M.). The Materials Characterization Central Laboratory of
Waseda University is acknowledged for HRMS measurement.
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Grignard reagents.
E
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