Full text of DOI:10.1021/acs.orglett.8b01807

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Dearomative Allylation of Benzyl Phosphates
Masaaki Komatsuda, Kei Muto,* and Junichiro Yamaguchi*
Department of Applied Chemistry, Waseda University, 3-4-1 Ohkubo, Shinjuku, Tokyo 169-8555, Japan
S
* Supporting Information
ABSTRACT: Dearomative C−C bond formation of benzyl
phosphates has been developed. In the presence of a palladium/
PAr3 catalyst, benzyl phosphates reacted with allyl borates to generate
the allylated product in a dearomative fashion. The resulting
dearomatized molecules were successfully derivatized by Simmons−
Smith cyclopropanation and oxidation.
romatic molecules such as benzene and pyridine are
iconic frameworks in the field of organic chemistry and
methods using π-arene complexes,4 dihydroxygenase,5 and
A
arenophiles6 are known and some of them have been applied
to natural products synthesis,7 they often suffer from reaction
efficiency particularly in terms of the stoichiometry of metal
reagents as well as starting materials. Furthermore, catalytic
methods are currently limited.
are widely seen in functional organic compounds ranging from
pharmaceuticals to organic electronic devices. Several methods
to functionalize aromatic molecules are known, such as
electrophilic aromatic substitution and metal-catalyzed cross-
coupling. In contrast to these aromatic substitution reactions,
transformations that achieve C−C or C−heteroatom bond
formations with concomitant dearomatization are still under-
developed (Figure 1).1 These dearomative reactions are
powerful synthetic methods that build valuable alicyclic
systems and expand structural diversity. So far, such reactions
were achieved mainly by using electron-rich aromatics such as
phenols and indoles2 or electron-poor aromatics such as
azines.3 Electronically unbiased aromatics such as benzenes
and naphthalenes are still challenging substrates. Although
With these considerations in mind, we surmised that the
metal-catalyzed reaction through a π-benzyl complex inter-
mediate8 can provide a complementary dearomative method. A
π-benzyl complex is relatively easy to generate, and more
importantly, the aromatic stabilization of the parent arene is
already partially lost in the π-benzyl complex.8,9 We envisaged
that selective addition on a parent arene ring in the π-benzyl
complex intermediate could realize an efficient dearomative
functionalization. To date, the reactivity of π-benzyl complexes
is not fully understood. One example showing specific
reactivity of the complex was reported by Yamamoto, where
a Pd−π-benzyl complex underwent dearomative substitution in
the reaction between benzyl chlorides and allyl stannanes.10,11
Recently, the Bao group extended this reaction to allow for the
use of allyl silanes11e and boronic esters11f as nucleophilic
agents. We envisioned that this chemistry can be extended to
more ubiquitous benzylic alcohol derivatives through a
benzylic C−O bond cleavage.12 With facile access from the
corresponding aromatic carbonyl compounds, the reaction
would be synthetically beneficial. Herein, we report a
dearomative allylation of benzyl phosphates with allyl borates
by a palladium catalyst.
Our study began by optimizing the reaction between 1-
naphthalenemethanol derivatives 1A and allyl borate 2 as
model compounds (Table 1). Delightfully, with Pd(OAc)2,
triphenylphosphine worked to produce desired dearomatized
product 3A in moderate yield (Table 1, entry 1). Motivated by
this result, we screened a variety of ligands. Electron-donating
monodentate phosphine L1 increased the reaction efficiency to
give 3A quantitatively (Table 1, entry 2). In contrast, the
reaction yield decreased when less electron-donating phos-
phine ligands such as perfluorinated triphenylphosphine
Figure 1. (A) Dearomative functionalization of arenes. (B) Catalytic
dearomative allylation of benzene derivatives through a π-benzyl
complex intermediate.
Received: June 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01807
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Screening of Reaction Conditions
Scheme 1. Scope of Benzyl Phosphates for the Dearomative
Allylation
a
b
b
entry
ligand (X mol %)
yield of 3A (%)
yield of 1A (%)
1
2
3
4
5
6
7
8
9
PPh3 (20)
L1 (20)
P(C6F5)3 (20)
P(OPh)3 (20)
IMes·HCl (20)
63
97
trace
53
12
28
0
13
0
96
47
84
c
c
IPr·HCl (20)
72
bipy (10)
100
100
100
d
L1 (20)
0
0
none
a
Conditions: 1A (0.20 mmol), 2 (0.20 mmol), Pd(OAc)2 (5 mol %),
a
b
ligand, THF (1.0 mL), 60 °C, 12 h. 1H NMR yield determined by
using CH2Br2 as an internal standard. NaOt-Bu (20 mol %) was
added. Without Pd(OAc)2.
Conditions: 1 (0.20 mmol), 2 (0.20 mmol), Pd(OAc)2 (5 mol %),
L1 (20 mol %), THF (1.0 mL), 60 °C, 12 h.1H NMR yield
c
b
d
determined by using CH2Br2 as an internal standard. 1.0 mmol scale.
c
DPEphos (10 mol %), Cs2CO3 (3.0 equiv), and 2 (2.0 equiv) were
used.
(Table 1, entry 3) and phosphite (Table 1, entry 4) were used.
N-Heterocyclic carbene ligands also produced 3A, albeit in
lower yields (Table 1, entries 5 and 6). However, nitrogen-
based ligand was not productive (Table 1, entry 7). Without
either Pd(OAc)2 or ligand, no product was obtained (Table 1,
entries 8 and 9). In all experiments using 1A as the starting
material, the undesired coupling product at the benzylic
position was not observed. Of note here is that this reaction is
conducted using a 1:1 ratio of aromatic substrate to reagent,
compared with other dearomatizing methods that often require
excess amounts of either the arene component or the reagent.
The effect of the leaving group was examined next (Table
1B). Among phosphates, diethyl phosphate 1A gave the best
result. This reaction also allowed for the use of carbonate as a
leaving group (6A) although in slightly lower yield. However,
ester 7A unfortunately afforded no dearomatized product 3A.
Based on these results, we then surveyed the substrate scope
this case, the use of DPEphos instead of L1 and the addition of
Cs2CO3 was effective. This protocol was found to be scalable,
as seen in the reaction of 1A and 1D to produce 3A and 3D,
respectively, on 1 mmol scale.
As mentioned above, the generated products are unstable
and undergo a [1,5]-rearrangement to attain their aromatic
form, 4-allyl-1-alkylnaphthalene.15 This process is significantly
accelerated by acid, and therefore, preventing product 3 from
aromatizing during subsequent transformations can be
challenging. Among a variety of reaction conditions that we
tested, we found that Simmons−Smith-type conditions16 are
successful. Treatment of the crude mixture from the
dearomative allylation of 1D with Et2Zn/CH2I2/2,4,6-trichlor-
ophenol afforded cyclopropanated product 7D in 38% yield
over two steps. In this cyclopropanation, the exo-methylene
group selectively reacted. Furthermore, we found that the same
crude mixture of 3D underwent an unusual ketone formation
under the influence of m-CPBA, furnishing 8D in 43% yield
over two steps (Scheme 2).17
We postulate the reaction mechanism of the dearomative
allylation as follows (Scheme 3A):18 (1) oxidative addition of
the benzylic C−O bonds to Pd(0) species A generates Pd(II)
complex B, which is in equilibrium between the σ-allyl and π-
allyl species; (2) allyl borate reacts with B to give π-allyl π-
benzyl Pd(II) complex C; (3) C generates dearomatized
product 3 with the regeneration of Pd(0) to reenter the
catalytic cycle. We specifically investigate the reaction of 1A
with (E)-crotylborate 9: we obtained 10 (linear) and 11
(branched) in a ratio of 40:60, which is in a good accordance
with the generation of π-allyl palladium intermediate C in the
reaction. Although the details of the reaction from C are
1
(Scheme 1). The reaction yield was determined by H NMR
analysis because the products were unstable on silica gel.13,14
A
naphthalene with an ortho substituent (1B) generated product
in moderate yield, although the reaction required prolonged
reaction time due to steric hindrance. Secondary alcohol
derivative 1C could also be allylated in dearomative fashion,
generating 3C in 65% yield as a single E isomer. Delightfully,
this protocol allowed for the construction of quaternary
carbons starting from C4-substituted benzyl phosphates. For
example, 1D was smoothly allylated under the optimized
conditions in 65% yield. Methoxycarbonyl naphthalene 1E as
well as acenaphthene 1F also underwent the reaction. Several
biaryls (1G−1M) could be dearomatively functionalized in
good to moderate yields. Although the reaction efficiency was
decreased, simple benzene derivatives 1N could also be
transformed to the dearomatized 3N in moderate yield. In
B
DOI: 10.1021/acs.orglett.8b01807
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Derivatization of Dearomatized Product 3D
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: keimuto@aoni.waseda.jp.
*E-mail: junyamaguchi@waseda.jp.
ORCID
Kei Muto: 0000-0001-8301-4384
Junichiro Yamaguchi: 0000-0002-3896-5882
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
a
Conditions: (a) Et2Zn (1.1 equiv), CH2I2 (1.0 equiv), 2,4,6-
trichlorophenol (1.0 equiv) in CH2Cl2; (b) m-CPBA (2.0 equiv),
NaHCO3 aq in CH2Cl2.
This work was supported by JSPS KAKENHI Grant Nos.
JP16H04148 (to J.Y.), JP17K14453, and JP18H04661 (to
K.M.). The Materials Characterization Central Laboratory in
Waseda University is acknowledged for HRMS measurements.
We thank Prof. Seijiro Hosokawa for providing us with a
melting point apparatus.
Scheme 3. (A) Plausible Mechanism for the Dearomative
Allylation. (B) Dearomative Crotylation of 1A
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ASSOCIATED CONTENT
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Detailed experimental procedures, spectral data for all
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(PDF)
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DOI: 10.1021/acs.orglett.8b01807
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1
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DOI: 10.1021/acs.orglett.8b01807
Org. Lett. XXXX, XXX, XXX−XXX