Ligand-controlled regiodivergent π-allyl palladium catalysis enables a switch between [3+2] and [3+3] cycloadditions

Article abstract of DOI:10.1039/c9cc00611g

Reported herein is the use of ligands to tune the regioselectivity and reactivity of palladium-catalyzed [3+2] and [3+3] cycloadditions. Diverse synthesis with vinylethylene carbonates (VECs) as well as free naphthols has been explored to construct four different valuable polycyclic frameworks in a broad substrate scope.

Full text of DOI:10.1039/c9cc00611g

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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DOI: 10.1039/C9CC00611G
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Ligand-Controlled Regiodivergent π-Allyl Palladium Catalysis
Enables a Switch between [3+2] and [3+3] Cycloadditions
Yu Xia,a Qiao-Fei Bao,a Yuke Li,b Li-Jing Wang,c Bo-Sheng Zhang,a Hong-Chao Liu,a and Yong-Min
Received 00th January 20xx,
Accepted 00th January 20xx
Liang*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
a)
Reported reactivities of VECs
Reported herein is the use of ligands to tune the regioselectivity
and reactivity of palladium-catalyzed [3+2] and [3+3]
cycloadditions. Diverse synthesis with vinylethylene carbonates
(VECs) as well as free naphthols has been explored to construct
four different valuable polycyclic frameworks in a broad substrate
scope.
electrophile
PdLn
O
R
O
O
R
O
R
[Pd]
O
R
O
O
-C
2
nucleophile
OH
Nu
R
Nu
PdLn
O
Nu
OH
R
R
Transition-metal-catalyzed cycloadditions constitute one of
the most significant classes of organic reactions for building the
challenging but synthetically valuable cyclic framworks that
exist in natural products, bioactive reagents and
pharmaceutical molecules.1 Within this class of reactions,
catalytic [3+2]1d,2 and [3+3]3 cycloadditions have enabled the
highly efficient construction of midsize carbocycles and
heterocycles. Meanwhile free naphthols, frequently-used as
starting materials in cycloaddition, also have been a focal point
of attention for chemists. The [3+2] and [3+3] transformations
with free naphthols are expedient strategies to access
naphthofuran and benzochromene structural motifs that are
widely distributed compounds in biologically active products.4
Because of the different reactivities of 1-naphthol and 2-
naphthol, it is difficult for them to be used in cycloadditions at
the same time. Therefore, the development of novel and
efficient synthetic methods to improve the reactivity of 1-
naphthol and 2-naphthol is highly desired. Transition-metal
catalytic strategies that allow the divergent synthesis of
skeletally diverse cycloadditions in particular, are desirable
methodologies.
b) This work
: ligand-controlled regiodivergent cycloaddition with VECs and naphthols
R
R
OH
O
O
[Pd]
dppp
[Pd]
Brettphos
O
Base
solvent
Base
solvent
O
O
O
R
O
R
high regioselectivity and reactivity for VECs
diverse synthesis for naphthols
simply switch the ligands
R
Scheme 1 Regioselectivity and reactivity of VECs
Vinylehtylene carbonates (VECs), regarded as π-allyl
surrogates upon decarboxylation, have found various
applications in organic chemistry.5 Because of the diverse
reactivities of π-allyl species, nucleophilic additions6 and
electrophilic cycloadditions7 are feasible to deliver
functionalized building blocks to their desired locations
(Scheme 1a). Recently, Zhang et al. have developed diversified
[3+2] cycloadditions with various electrophilic partners.8 Zhao
and co-workers reported some cycloaddition methods to
synthesize highly functionalized rings of different sizes.9
Although eminent approaches have been made regarding the
regioselectivity of the π-allyl, the regiodivergent nature of π-
allyl is seldom reflected in cycloaddition reactions. And with
respect to the cycloaddition with VECs and nucleophiles, we
urgently need to fill the gap in this field. Alternatively, under
specific conditions, nucleophilic internal or terminal attack has
enabled the construction of versatile alcohol compounds with
high stereo- and regioselectivity. In this regard, the Kleij’s group
employed a series of nucleophiles, such as phenol, thiophenol
and aniline, to realize π-allyl asymmetric synthesis.10 Notably,
most nucleophiles attack the Pd-π-allyl intermediate at one of
the two terminal carbons, so the π-allyl central carbon atom is
aY. Xia, Q.-F. Bao, B.-S. Zhang, H.-C. Liu, Prof. Y.-M. Liang, State Key Laboratory of
Applied Organic Chemistry, School of Chemistry and Chemical
Engineering,Lanzhou University, Lanzhou 730000 (P. R. China)
E-mail: liangym@lzu.edu.cn liangym@lzu.edu.cn
bDepartment of Chemistry and Centre for Scientific Modeling and Computation,
Chinese University of Hong Kong, Shatin, Hong Kong, China
cKey Laboratory of Medicinal Chemistry, and Molecular Diagnosis of the Ministry of
Education, College of Chemistry & Environmental Science, HeBei University, 180
Wusi Donglu, Baoding 071002, P. R. China.
†Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization data and copies of NMR spectra. CCDC 1890681, 1890679 and
1890680. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/x0xx00000x
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J. Name., 2013, 00, 1-3 | 1
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70% yield and 16:1 selectivity. Fortunately, the use of bidentate
ligands DPEphos or dppp switched the main product to 5a in
View Article Online
DOI: 10.1039/C9CC00611G
Table 1. Optimization of the reaction conditions.a
moderate yield and excellent regioselectivity (>20:1) (entries 8–
9). No better results were obtained after screening on the
palladium catalysts (entries 10–11). The subsequent
adjustment of the Pd catalyst/ligand loading ratio produced
better yield and superior selectivity (entry 12). Additionally, it
should be noted that the loading of 1.0 mol% Pd catalyst and
2.0 mol% ligand was also tolerated to give 4a in 60% yield with
high regioselectivity (entry 13). Meanwhile 2-naphthol (2a) was
entirely compatible with these reaction conditions (entry 14),
which replaced the 1a as the starting material. The optimized
reaction conditions (denoted reaction condition A): 1 (0.2
mmol), 3 (0.4 mmol), [Pd(C3H5)Cl]2 (2.5 mol%), Brettphos (5.0
mol%), K2CO3 (2.0 equiv), toluene (2 ml), 90 °C, 12 h.
With the optimized reaction conditions in hand, we first
explored the scope of 1-naphthol’s [3+2] cycloaddition (Table
2). A range of 1-naphthols containing electron-donating groups
performed well in obtaining the corresponding products (4a–
4d) in good yield with excellent regioselectivity (>20:1).
Unfortunately, because of the influence of palladium(0)
oxidative addition by chloro group, substrate 1e failed to give
the corresponding product 4e. The group of F on the naphthol
performed in this reaction (66% yield and reselectivity 2:1 for
4f). Notably, 1,6-dihydroxynaphthalene was tolerated to give a
novel tetracyclic compound at a yield of 52% (4g). Afterwards,
a series of VECs, including electron-donating groups at the
phenyl ring, worked smoothly in this transformation in 63–73%
yield (4h–4k). Alternatively, VECs of containing electron-
withdrawing group, with the exception of the chloro group (3l),
also gave the corresponding products in 63–71% yield (4m–4n).
Substitutions of polyaromatics as well as dioxolane fused
phenyl ring, performed well, and were in good yield (4o–4p).
Heteroaryl substituted VEC was also compatible to afford the
product 4q (yield for 58%).
Ph
Ph
or
O
[Pd] (5 mol%)
ligand (10 mol%)
OH
O
O
O
O
+
O
O
K2CO3 (2.0 equiv.)
solvent, 90 oC, 12 h
Ph
3a
PCy2
1a
4a
5a
Brettphos
Entry
[Pd]
Ligand
Solvent
Yield
(%)b
61
[4a:5a]c
1
2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
Pd(OAc)2
XPhos
XPhos
XPhos
PPh3
MeCN
toluene
1,4-dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
12:1
16:1
-
66
trace
42
3
4
1:1
5
P-(2-furyl)3
Brettphos
Davephos
DPEphos
dppp
37
3:1
6
70
16:1
15:1
1:>20
1:>20
14:1
10:1
25:1
20:1
>20:1
7
51
8
40
9
55
10
11
12d
13e
14d,f
Brettphos
Brettphos
Brettphos
Brettphos
Brettphos
59
.
Pd2(dba)3 CHCl3
55
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
73
60
77
aReactions were carried out using 1a (0.2 mmol), 3a (0.4 mmol), [Pd] (5.0 mol%),
ligand (10.0 mol%), K2CO3 (2.0 equiv), solvent (2 ml), 90 °C, 12 h. bIsolated yields.
cRegioselectivity determined by 1H-NMR analysis of crude reaction mixture. d [Pd]
(2.5 mol%), ligand (5.0 mol%). [Pd] (1.0 mol%), ligand (2.0 mol%), 24h. 1a was
replaced by 2-naphthol (2a).
e
f
rarely involved in any reaction.11 Therefore, taking advantage
of central carbon enables π-allyl to extend applications in
organic synthesis.
Based on the studies of regioselectivity and regio diversity,12
ligand-controlled strategy is a challenging but straightforward
way to our destination. We envisaged controlling the
coordination of the catalyst to the π-allyl and the selectivity of
nucleophilic addition through adjusting the steric and
electronic effect of ligand. One remarkable feature of our
design is that naphthol as a C,O-bis(nucleophile)s is difficult to
react with umpolung VECs.9c,13 Therefore catalyst-π-allyl
system can be tuned by ligand without other influences in
general. Meanwhile taking care of both 1-naphthol and 2-
naphthol can greatly improve applicability of the reactions.
On the basis of this catalytic cycloaddition design plan,
therefore we began by employing classical palladium/ligand
system and 1-naphthol (1a)/phenyl VEC (2a) as partners to
explore the reactions (Table 1). Encouragingly, our anticipated
annulation products 4a and slight 5a were obtained in common
yield 61% with 12:1 regioselectivity (entry 1). Subsequently,
various solvents were executed; the yield and selectivity were
slightly improved by using toluene (entries 2–3). Further
experiments on the effect of the ligands were carried out
(entries 4–9). By using small steric ligands, such as PPh3 and P-
(2-furyl)3, the regioselectivity dramatically declined. Then, the
bulky ligands were examined, producing the desired product in
To further ascertain the scope of the chosen reaction
conditions, we investigated the 2-naphthol’s [3+2]
Table 2 Substrate scope with respect to the 1-naphthol’s [3+2] cycloaddition.a,b
R2
O
OH
[Pd(C3H5)Cl]2 (2.5 mol%)
brettphos (5 mol%)
O
O
O
R1
+
K2CO3 (2.0 equiv.)
toluene, 90 oC, 12 h
R1
R2
1
3
4
Ph
Ph
Ph
Ph
O
O
O
O
MeO
c4a 73%
4b 68%
4c 69%
4a
4d 66%
4h (R = 4-Me):
70%
4i (R = 4-OMe): 71%
Ph
O
Ph
R
4j (R = 4-tBu):
4k (R= 3-OMe):
4l (R = 4-Cl):
73%
69%
trace
71%
63%
O
O
O
Ph
R
4md (R = 4-F):
4ge 52%
4e (R= 6-Cl): trace
4fd (R= 4-F): 66%
4n (R = 4-CF3):
O
O
S
O
O
O
4o 70%
4p 62%
4q 58%
b
aReaction condition A. Isolated yields are shown. Unless otherwise noted, the
regioselectivity ratio = >20:1.cThe gram scale reaction of 4a sees ESI. dThe
regioselectivity ratio of 4f = 2:1 and 4k = 14:1. e3a (0.6 mmol), K2CO3 (3.0 equiv).
2 | J. Name., 2012, 00, 1-3
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Table 4 Substrate Scope with Respect to [3+3] cycloaddition.a,b
cycloadditions (Table 3). The fundamental structure of the 2-
naphthol was explored, thus affording a corresponding product
in 77% yield with excellent regioselectivity (>20:1) (6a). The
presence of electron-donating groups on 2-naphthol, such as
methyl and methoxy, performed well (75–77% yield for 6b–6c).
The bromo group on the 2-naphthol failed to give a
naphthofuran compound (6d). Gratifyingly, 7-hydroxyquinoline
participated in this reaction to deliver 6e in moderate yield.
Meanwhile, the 2,3-dihydroxynaphthalene also underwent
View Article Online
DOI: 10.1039/C9CC00611G
R2
O
[Pd(C3H5)Cl]2 (2.5 mol%)
dppp (5 mol%)
O
OH
O
O
R1
+
K2CO3 (2.0 equiv.)
PhCF3, 90 oC, 12h
R1
R2
1
3
5
Ph
Ph
Ph
O
Ph
Ph
O
O
O
O
R
MeO
5e (R = 6-Cl): 35%
5f (R = 4-F): 41%
5a 65%
5b 56%
5c 50%
5d 47%
5h (R
5i (R
5j (R = 4-tBu):
5k (R = 4-F):
5l (R
5m (R = 4-CF3):
=
=
4-Me):
4-OMe): 44%
54%
Ph
O
R
55%
60%
40%
33%
O
O
= 4-Cl):
smoothly, affording
a unique product with a double
N
5n (R = 3-OMe): 52%
cycloaddition (62% yield for 6f). For the variation on the VEC 3,
both electron-donating and electron-withdrawing groups at
the para- or meta- position on the phenyl group were achieved
in moderate to excellent yield (6g–6m). Remarkably,
substitutions of heteroaryl, polyaromatic even dioxolane fused
phenyl ring were applied with good yield results (6n–6p).
Screening on the alkyl VECs, cyclohexyl was tolerated to give 6q
in 31% yield. But the methyl VEC failed to obtain the
corresponding product 6r. The structure of 6n was confirmed
by X-ray crystal structure analysis (see ESI).
Subsequently, the scope of [3+3] cycloaddition with
naphthols was investigated (Table 4) under the optimal
conditions B (Screening the conditions B sees ESI). Toward this
end, we studied the effect of electrons on the 1-naphthol.
Whether investigating electron-donating or electron-
withdrawing groups on the naphthol, they all afforded the
products in 35–65% yield (5a–5f). It is noteworthy that 4-
hydroxyindole could provide the cycloaddition product in a
moderate yield (5g). Next, various electron-donating and
electron-withdrawing substituents at para- or meta- positions
on the phenyl group of VECs were all tolerated and gave 33–
60% yield (5h–5n). Ultimately, VECs, containing thienyl,
naphthyl, dioxolane and cyclohexyl ring, also produced the
desired products (5o–5r). In spite of unsatisfied regioselectivity
of 2-naphthol’s [3+3] cycloaddition, we also explored the effect
of substituents in order to improve the reaction.
5g 45%
5o 52%
O
O
S
O
O
O
5r 20%
5q 38%
5p 45%
OMe
F
R
O
O
O
O
O
5wc (R = cyclohexyl): 38%
5xc (R = methyl):
48%
5s 60% (2:3)
5u 66% (14:1)
5v 67% (5:1)
5t 70% (10:1)
aReaction conditions B (screening the conditions B sees ESI). Isolated yields are
shown. bUnless otherwise noted, the regioselectivity ratio = >20:1. cThe
regioselectivity ratio 5w = 12:1 and 5x = 3:1.
Compared with the unsubstituted substrate 3a,
monosubstituted substrates bearing electron-withdrawing and
electron-donating groups enhanced the selectivity of
cycloaddition (5s–5v). Especially, the electron-donating groups
dramatically improved the reaction regioselectivity. And the
alkyl VECs such as cyclohexyl and methyl group reacted under
the reaction conditions but showed different selectivity (5w
and 5r). The structure of 5j was confirmed by X-ray crystal
structure analysis (see ESI).
A plausible mechanism for the [3+2] and [3+3] cycloaddition
is depicted in Scheme 2, which features ligand-controlled π-allyl
regioselectivity.10d,14 The catalytic cycle is initiated by Pd-π-allyl
intermediate A, formed from Pd(0) and 3a. Under the action of
the base, the nucleophile 1a attacks the internal carbon atom
of Pd-allyl A to afford vinylpalladium B. The intermediate B
undergoes reductive elimination of Pd(II)Ln to deliver the
tertiary allylic aryl ether C. An aromatic Claisen rearrangement
occurs smoothly under this reaction condition, producing the
intermediate D. The previously freed Pd(0) reacts with D via
Table 3 Substrate scope with respect to 2-naphthol’s [3+2] cycloadditiona,b
R2
O
[Pd(C3H5)Cl]2 (2.5 mol%)
OH
brettphos (5 mol%)
O
O
O
R1
+
K2CO3 (2.0 equiv.)
toluene, 90 oC, 12 h
R1
R2
2
3
6
Ph
Ph
Ph
Ph
Ph
4a
3a
O
O
O
O
O
N
MeO
CO2
PdH
Ph
O
Pd(0)Ln
Br
O
6a 77%
6b 75%
6c 80%
6d trace
6e
A
57%
Ph
Ph
PdLn
H
PR3
6g (R
6h (R = 4-OMe): 81%
=
4-Me):
88%
P
Pd PR3
A
R
O
base
P
h
Ph
O
Ph
O
t
a
s
o
Pd
Ph
P
1a
6i (R
6j (R
=
=
4-tBu):
4-Cl):
75%
30%
78%
63%
h
p
t
t
e
r
O
B
O
O
6k (R = 4-F):
6l (R
4-CF3):
O
H
=
PdLn
6m (R = 3-OMe): 68%
G
P
Ph
7
F
6fc 62%
a
6n 80%
t
h
Ph
d
p
p
O
O
B
O
p
O
Ph
O
B
S
O
5a
PdLn
E
O
O
O
Ph
HO
O
Pd(0)Ln
OH
Ph
Pd(0)Ln
OH
6o 55%
6p 75%
6q 31%
6r trace
Aromatic Claisen
Rearrangement
D
C
b
aReaction conditions A and isolated yields are shown. Unless otherwise noted,
the regioselectivity ratio = >20:1. C3a (0.6 mmol) and K2CO3 (3.0 equiv).
Scheme 2 Proposed Mechanism
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allylation once again and then obtains the alternative
intermediate E. On one hand, by using Brettphos as ligand,
oxygen ion selectively attacks the internal carbon atom to
afford [3+2] cycloaddition product 4a (Path A). On the other
hand, under the control of ligand dppp, oxygen ion selectively
attacks π-allylpalladium intermediate at its central carbon atom
rather than external carbon atom to form the cyclicpalladium
G. Regrettably, we did not detect the product 7 of direct
reductive elimination. Following by β-H elimination and
reductive elimination, the desired product 5a is produced and
Pd(0) is regenerated to the next reaction cycle (Path B).
In summary, we here present an efficient and diverse
cycloaddition between naphthols and VECs under
palladium/ligand catalysis. By simply switching the ligands, an
unprecedented π-allyl regiodivergent is realized to enable [3+2]
and [3+3] cycloadditions. Meanwhile, both 1-naphthols and 2-
naphthols are also tolerated in this method, thus greatly
improving the economics of the reactions. The compatibility
with gram scale reaction further enhanced the synthetic
practicality of this method. These discoveries shed light on the
development of new catalytic domino reactions for challenging
π-allyl regiodivergent and regioselectivity via ligand-controlled
methodologies.
5
6
7
8
9
We thank the National Natural Science Foundation of China
(21532001 and 21772075).
Conflicts of interest
There are no conflicts to declare.
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