Access to chiral tetrahydrofluorenes through a palladium-catalyzed enantioselective tandem intramolecular Heck/Tsuji-Trost reaction

Article abstract of DOI:10.1039/c9cc01379b

A palladium-catalyzed enantioselective coupling of 2,5-cyclohexadienyl-substituted aryl iodides and carbon or heteroatom nucleophiles is described. The reaction proceeded via a tandem asymmetric Heck insertion and Tsuji-Trost allylation, enabling the rapi

Full text of DOI:10.1039/c9cc01379b

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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
first methanofullerene derivatives of Sc N@D5h-C80
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DOI: 10.1039/C9CC01379B
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Access to Chiral Tetrahydrofluorenes through Palladium-Catalyzed
Enantioselective Tandem Intramolecular Heck/Tsuji–Trost Reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Ying Zhang,‡a Hong-Cheng Shen,‡a Yang-Yang Li,a Yong-Shuang Huang,b Zhi-Yong Han,a and Xiang
Wu*b
DOI: 10.1039/x0xx00000x
A
palladium-catalyzed enantioselective coupling of 2,5- tetrahydrofluorenes are ubiquitous core structures found in a
cyclohexadienyl-substituted aryl iodides and carbon or variety of biologically active natural products such as the
heteroatom nucleophiles is described. The reaction proceeded via asterogynins7 and taiwaniaquinoids8 as well as lead
a tandem asymmetric Heck insertion and Tsuji–Trost allylation, pharmaceutical compounds9 and represent key structural
enabling the rapid construction of valuable chiral elements in materials science10. Thus, efficient synthetic
tetrahydrofluorenes by using
phosphoramidite ligand.
a
chiral H8-BINOL-based methods to access optically pure tetrahydrofluorenes are still
in great demand. However, asymmetric palladium-catalyzed
tandem intramolecular Heck11/Tsuji−Trost reaction for the
The demand for the development of new methodologies to
achieve complex and valuable optically active compounds has
increased steadily in synthetic organic chemistry.1 A tandem
asymmetric Heck2/Tsuji–Trost3 reaction, the nucleophilic
substitution of π-allyl Pd intermediates formed by a Heck
carbopalladation, is a typical solution for efficiently building up
complex chiral molecules from simple and easily available
substrates.4 Recently, palladium-catalyzed cascade asymmetric
construction of enantioenriched tetrahydrofluorenes has not
yet been accomplished. Herein, we will report the first
enantioselective coupling of 2,5-cyclohexadienyl-substituted
aryl iodides and carbon or heteroatom nucleophiles catalyzed
by chiral Pd complexes for the synthesis of optically active
tetrahydrofluorenes (Fig. 1C).
Previous work:
non-enantioselective tandem Heck/Tsuji-Trost reaction
Coupling of iodobenzene, 1,4-cyclohexadiene and diethyl malonate
Pd(dba)2 (5 mol %)
(A)
difunctionalization of 1,3-dienes proceeding through
a
Ph
CH(CO2Et)2
n-Bu4NCl (1.1 equiv)
+
I
+
Ph
Heck/Tsuji–Trost process has received increasing attention for
the synthesis of structurally diverse and densely functionalized
chiral molecules, characterized by the generation of π-allyl
palladium intermediate.5 However, in contrast to 1,3-dienes,
only few nonconjugated 1,4-dienes have been successfully
employed in this type of reaction, but all giving racemic
products.6 In 1991, Larock and co-workers described a non-
enantioselective three-component coupling of iodobenzene,
1,4-cyclohexadiene and diethyl malonate through a palladium-
catalyzed tandem Heck/Tsuji–Trost reaction to furnish a trans-
product 1 (Fig. 1A).6a Then, Larock further identified that 1,4-
cyclohexadiene-tethered 2-iodobenzene could undergo
palladium-catalyzed intramolecular Heck reaction and
subsequent Tsuji–Trost reaction with diethyl malonate to
EtO2C
CO2Et
Na2CO3 (2.5 equiv)
DMSO, 80 C, 12 h
1
5 equiv
5 equiv
88% yield
(B)
Coupling of 2-iodobenzene-tethered 1,4-cyclohexadiene with diethyl malonate
CO2Me
Pd(dba)2 (10 mol %)
CO2Me
n-Bu4NCl (1.1 equiv)
+
EtO2C
CO2Et
K2CO3 (2.5 equiv)
2 equiv
DMSO, 80 C, 27 h
I
CH(CO2Et)2
2
80% yield
This work:
enantioselective tandem intramolecular Heck/Tsuji-Trost reaction
(C)
Coupling of 2-iodobenzene-tethered 1,4-cyclohexadiene with nucleophiles for the
synthesis of chiral tetrahydrofluorenes
CO2R2
CO2R2
CO2R2
R1
Pd(0)/L*
R1
R1
I
PdLnX
I
XLnPd
II
2
(Fig. 1B).6e Functionalized
CO2R2
provide tetrahydrofluorene
CO2R2
R1
NuH
R1
PdLnX
a. Department of Chemistry, University of Science and Technology of China, Hefei,
230026, China
3
4
5
Nu = C Nu
Nu = O
Nu = N
III
b. Anhui Province Key Laboratory of Advanced Catalytic Materials and Reaction
Engineering, School of Chemistry and Chemical Engineering, Hefei University of
Technology, 193 Tunxi Road, Hefei 230009, China. E-mail: wuxiang@hfut.edu.cn
Fig. 1 Tandem Heck/Tsuji-Trost Reaction.
†
Electronic Supplementary Information (ESI) available: [details of any
As shown in Fig. 1C, a Pd(II) intermediate II is generated
from the oxidative addition of a Pd(0) complex to an aryl
iodine and subsequent desymmetrizing Heck insertion
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
‡ These authors contributed equally to this work.
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COMMUNICATION
Journal Name
was carried out for 48 h. f Pd(dba)2 (0.005 mmol), L5 (0.01 mmol).
reaction.11a-c, 11e Migration of palladium of II along the carbon
chain on the same face of the ring results in the formation of a
π-allylpalladium species III. The intermediate III undergoes
backside intermolecular nucleophilic attack to afford
corresponding products 3-5. In the whole reaction process, the
chiral ligand tunes the reactivity of metal catalyst and
efficiently controls the stereoselectivity of the Heck reaction
and Tsuji–Trost allylation respectively. Therefore, the
identification of an ideal ligand turns out to be the key to
realize the asymmetric version of this reaction.
As a consequence, the chiral ligands were firstly investigated
for the Pd-catalyzed tandem reaction of methyl 1-(2-
iodobenzyl)cyclohexa-2,5-diene-1-carboxylate 6a with dibenzyl
malonate 7a (Table 1). As chiral phosphoramidite ligands were
beneficial for the palladium-catalyzed asymmetric allylic
substitutions,12 BINOL-derived phosphoramidites L1-L4 bearing
substituents at the 3,3’-positions of the binaphthyl backbone
were examined. Delightedly, in the presence of Pd(dba)2 in
CH3CN at 80 °C using K2CO3 as a base, these ligands perform
well to afford the product 3aa as a single diastereoisomer with
moderate enantioselectivities and in high yields (entries 1-4).
Particularly, the presence of electronically deficient 3,5-
ditrifluoromethylphenyl substituents at 3,3’-positions of the
binaphthyl moiety, as shown in L4, enabled the reaction to
deliver higher level of asymmetric induction (76% ee, entry 4).
A little higher ee value (79% ee) and quantitative yield were
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DOI: 10.1039/C9CC01379B
provided by H8-BINOL-based phosphoramidite L5 (entry 5).
Interestingly, the enantioselectivity could be improved to 91%
ee remarkably by conducting the reaction at 40 °C (entry 6).
The screening of bases revealed that K2CO3 was preferred for
the reaction (entries 6-10). The evaluation of solvents showed
that CH3CN was the most suitable medium for the present
reaction (entries 6, 11-14). When the temperature decreased
further to 25 °C, the highest enantioselectivity was obtained
albeit in a moderate conversion (entry 15). Importantly, by
prolonging the reaction time to 48 h and tuning the amounts
of Pd(dba)2 and L5, a higher yield of 90% was obtained with a
maintained enantioselectivity of 93% ee (entry 15 vs 14).
Under the optimized reaction conditions, a range of 2,5-
cyclohexadienyl-substituted aryl iodides 6 and malonate esters
7 were investigated (Table 2). In most cases, electron-donating
and electron-withdrawing substituents at the phenyl ring of 6
were generally well-tolerated, affording 3ba-ka as single
diastereoisomers in good yields and with excellent
enantioselectivities (entries 1-10). Probably due to steric
hindrance, 3- and 6-substituent of the substrate 6b and 6e
resulted in considerably lower enantioselectivity (entries 1 and
4). Electron-donating groups (Me or MeO) or a strong
electron-withdrawing group (CF3) at the 5-position of the
substrate degraded the conversion, affording the product in
only moderate yield but with excellent ee respectively (entries
3, 8 and 10). Ethyl and t-butyl ester derivatives 6l and 6m
could also work efficiently in the reaction (entries 11 and 12).
Moreover, the variation of ester substituents of malonates 7b-
d was also amenable to the reaction, providing corresponding
products 3ab-ad in good yields (84%-88%) and with high ee’s
(93%-94%) (entries13-15).
Table 1 Optimization of the reaction conditionsa
Pd(dba)2 (10 mol%)
CO2Me
CO2Me
L
(11 mol%)
CH2(CO2Bn)2
+
base (2.5 equiv)
I
7a
solvent, temp, 12 h
3aa
F
6a
CH(CO2Bn)2
F
F
F
F
F
F
R
R
F
P
F
F
P
O
O
Table 2 Scope of 2,5-cyclohexadienyl-substituted aryl iodides 6
and malonate esters 7a
N
O
O
N
CO2R2
CO2R2
R
6
Pd(dba)2 (5 mol%)
L5
K2CO3 (2.5 equiv)
1
R
5
R1
L1
L2
L3
L4
R = H
CH2(CO2R3)2
R1
+
(10 mol%)
R = 4-FC6H4
R = 4-NO2C6H4
R = 3,5 (CF3)2C6H3
R
3 = Bn
7a
4
2
I
-
L5
R = 3,5-(CF3)2C6H3
CH3CN, 25 C, 48 h
3 = Me
3 = Et
3 = i-Pr
3
7b
7c
7d
R
R
R
CH(CO2R3)2
6a-6m
entry ligand
base
solvent
yield(%)b,c ee (%)d
temp (C)
80
3
R1
R2
7
3
yield (%)b ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16e,f
a
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
K2CO3 CH3CN
K2CO3 CH3CN
K2CO3 CH3CN
K2CO3 CH3CN
K2CO3 CH3CN
K2CO3 CH3CN
Na2CO3 CH3CN
Ag2CO3 CH3CN
KOH
Et3N
K2CO3 DMSO
K2CO3 DMF
K2CO3 toluene
K2CO3 DCE
96
96
66
83
99
95
-
23
72
-
28
54
65
76
79
91
-
65
89
-
entry
1
2
3
4
5
6
7
8
6
80
80
80
80
40
40
40
40
40
40
40
40
40
25
25
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6a
6a
6a
3-Me
4-Me
5-Me
6-Me
4-F
4-Cl
4-Br
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
7a 3ba
7a 3ca
7a 3da
7a
7a
7a
71
86
56
75d
96
94
72
51
99
49
80
84
84
88
87
83
95
94
86d
94
96
97
97
95
94
92
90
93
94
93
3ea
3fa
3ga
7a 3ha
CH3CN
CH3CN
4-OMe
7a
7a
7a
7a
3ia
3ja
3ka
3la
9
5-Cl
5-CF3
H
H
H
H
H
42
98
-
38
80
-
10
11
12
13
14
15
t-Bu 7a 3ma
-
-
H
H
H
7b 3ab
7c 3ac
7d 3ad
K2CO3 CH3CN
K2CO3 CH3CN
44
90 (89)
96
93
Unless indicated otherwise, reactions of 6a (0.10 mmol), 7a (0.2 mmol),
Pd(dba)2 (0.01 mmol), L (0.011 mmol) and base (0.25 mmol) were carried out
in solvent (1 mL) at temperature for 12 h. bThe yields were determined by 1H-
NMR analysis of the crude products based on internal standard. Isolated
yields indicated in parentheses. d Determined by HPLC analysis. e The reaction
a Unless indicated otherwise, reactions of 6a-m (0.10 mmol), 7a-d (0.2 mmol), Pd(dba)2
(0.005 mmol), L5 (0.01 mmol) and K2CO3 (0.25 mmol) were carried out in CH3CN (1 mL)
b
c
d
at 25 C for 48 h. Isolated yields. Determined by HPLC analysis. The reaction was
carried at 40 C.
c
2 | J. Name., 2012, 00, 1-3
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Instead of malonate esters 7, aromatic phenols 8 could also
COMMUNICATION
To gain more insight into the reaction mechanism, isotope
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work as oxygen nucleophiles in the reaction under the same labeling experiments were conducted (ScDhOeIm: 1e0.120)3.9T/hCe9CrCea01c3t7io9nB
conditions. Upon the reaction with aryl iodide 6a, chiral of [D5]-6a and 7a under the standard conditions gave [D]-3aa
tetrahydrofluorenes 4 including an allylic aryl ether functional with 50% deuterium at the 3-position and 4-position on the
group could be obtained with high enantioselectivities and cylcohexene ring respectively. These results clearly
good yields (Scheme 1). Regardless of the electronic character demonstrated that the key steps of β-hydride elimination and
of the substituents at the phenols 8, reactions proceeded reinsertion had indeed occurred to give π-allyl Pd-species E
smoothly under the optimal conditions, furnishing chiral from homoallylic Pd-intermediate B which furnished the final
tetrahydrofluorenes 4aa-ae as single diastereoisomers in product by backside intermolecular nucleophilic attack
moderate yields (78−87%) with high enantioselectivities (90- (Scheme 2).
D
CO2Me
MeO2C
92% ee). Moreover, some aromatic phenols such as -napthol
and 6-hydroxyindole performed well and led to the products
with high stereochemical outcomes (4af and 4ag). Notably,
enantiopure chiral estrone could also smoothly undergo the
reaction with 6a to deliver the corresponding product 4ah with
moderate efficiency and outstanding diastereomeric excess.
The structure and absolute configuration of product 4ah was
assigned by X-ray analysis.13 The absolute configurations of all
other compounds were assigned by analogy. Alternatively,
electron-rich aniline 9a as nitrogen nucleophile was also
applicable for the reaction, providing product 5aa with 81%
D
D
standard conditions
CH2(CO2Bn)2
D
4
3
D
D
D
H
D
50% D
D
I
50% D
D
CH(CO2Bn)2
D
3aa
[D]-
6a
7a
[D5]-
90% yield
CH2(CO2Bn)2
Pd(0)
oxidative addition
backside attack
D
CO2Me
D
MeO2C
D
PdLnX
D
D
D
D
D
PdLnX
H
D
(D)H
D(H)
A
E
Heck insertion
-allyl formation
CO2Me
D
CO2Me
D
CO2Me
yield and 89% ee (eq 1).14
D

-hydride
elimination
alkene
reinsertion
CO2Me
D
D
Pd(dba)2 (5 mol%)
L5
K2CO3 (2.5 equiv)
D
CO2Me
D
D
D
D
D
XLnPd
D(H)
(10 mol%)
XLnPd
D(H)
+
ArOH
D
(D)H
D
PdLnX
H
H(D)
I
CH3CN, 25 C, 48 h
B
C
D
OAr
6a
8a 8h
-
4aa 4ah
-
Scheme 2 Isotope labeling experiments and proposed reaction
mechanism.
CO2Me
CO2Me
CO2Me
To demonstrate the practicability, we carried out a gram-
scale synthesis and derivative studies (Scheme 3). Under the
optimized reaction conditions, a reaction of 6h with 7b on 3.5
mmol scale was performed, giving 3hb in high yield (82%, 1.25
g), with excellent enantioselectivity (97% ee). Pleasingly, the
product 3hb could be transformed into various derivatives
O
O
O
O
OMe
O
4aa
80% yield, 91% ee
4ac
4ab
80% yield, 90% ee
78% yield, 90% ee
CO2Me
CO2Me
O
CO2tBu
O
CN
CO2Me
CO2Me
Pd(dba)2 (5 mol%)
L5
K2CO3 (2.5 equiv)
4ad
4ae
(10 mol%)
+
CH2(CO2Me)2
82% yield, 92% ee
87% yield, 91% ee
Br
Br
I
CO2Me
CH3CN, 25 C, 48 h
CH(CO2Me)2
3hb
82% yield, 1.25 g
97% ee
CO2Me
6h
3.5 mmol
7b
7 mmol
O
CO2Me
CO2Me
O
O
N
H
Ar
Br
4af
4ag
92% yield, 90% ee
74% yield, 87% ee
d
a
CH(CO2Me)2
(Ar= 4-OMeC6H4)
CH(CO2Me)2
CO2Me
CO2Me
13
10
70% yield, 97% ee
72% yield, >20/1 dr
97% ee
Br
Me
O
CH(CO2Me)2
O
H
CONHAr
3hb
H
CO2Me
H
4ah
70% yield, 92% de
b
c
Br
4ah
X-ray structure of
a
CH2CONHAr
(Ar= 4-BrC6H4)
57% yield, 97% ee
Scheme 1 Scope of oxygen nucleophiles. Reactions of 6a
(0.10 mmol), 8a-h (0.2 mmol), Pd(dba)2 (0.005 mmol), L5 (0.01
mmol) and K2CO3 (0.25 mmol) were carried out in CH3CN (1
mL) at 25 C for 48 h.
CH(CO2Me)2
11
93% yield, 97% ee
12
CO2Me
12
X-ray structure of
Pd(dba)2 (5 mol%)
CO2Me
Scheme 3 Scale-up experiment and transformation of the
product. Reaction conditions: a) m-CPBA, CH2Cl2; b) Pd/C, H2,
CH3OH; c) (i) NaOH, THF/H2O=1:1; (ii) Pyridine, H2O, 80 C; (iii)
4-BrC6H4NH2, EDCI, CH2Cl2; d) 4-OMeC6H4B(OH)2, Pd(PtBu3)2,
K2CO3, dioxane/H2O= 3:1, 95 C.
OMe
OMe
L5
(10 mol%)
(1)
+
K2CO3 (2.5 equiv)
CH3CN, 25 C, 48 h
HN
OMe
H2N
I
OMe
81% yield, 89% ee
6a
9a
5aa
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Org. Chem., 2017, 37, 2250-2262; (b) Y. Xiong, Y. Sun and G.
under different conditions. mCPBA-mediated epoxidation of
3hb proceeded to give the product 10 in a diastereospecific
manner. The hydrogenation of 3hb under the catalysis of Pd/C
in MeOH resulted in the saturation of the alkene and reductive
removal of bromine atom at the same time, affording the
product 11 in high yield. Hydrolysis of the esters with NaOH in
THF and H2O, subsequent decarboxylation of malonic acid
assisted by pyridine at 80 °C and followed by the condensation
with 4-bromideaniline in the presence of EDCI, provided the
diamide 12 in 57% yield in three steps.15 The Suzuki−Miyaura
coupling of 3hb with 4-methoxyphenylboronic acid under the
catalysis of Pd(PtBu3)2 proceeded cleanly to furnish the aryl
substituted tetrahydrofluorene 13.
In summary, we demonstrate a chiral Pd complex-catalyzed
asymmetric coupling of 2,5-cyclohexadienyl-substituted aryl
iodides with carbon or heteroatom nucleophiles, furnishing
the optically active tetrahydrofluorenes containing three chiral
centers as single diastereoisomers in moderate to high yields
(49−99%) with excellent enantioselectivities (83−97% ee) from
readily available starting materials. The reaction proceeds via a
Pd-catalyzed tandem intramolecular desymmetrizing Heck
insertion and allylic alkylation, oxygenation or amination,
capable of tolerating a broad scope of substrates. In the
reaction, the choice of a H8-BINOL-derived phosphoramidite
ligand bearing electron-withdrawing substituents is crucial for
successful catalysis, which not only enhances the catalytic
activity but also provides an appropriate chiral environment
for asymmetric induction. Moreover, the reaction could be
conducted in gram-scale, and the products of the reaction
could be readily converted to various useful derivatives.
We sincerely thank Prof. Liu-zhu Gong for supervision and
research facilities. We are grateful for financial support from
the National Natural Science Foundation of China (Grant No.
21672049).
View Article Online
Zhang, Tetrahedron Lett., 2018, 59, 347-355; (c) X. Wu and L.-Z.
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Conflicts of interest
There are no conflicts to declare.
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13. CCDC 1879991 (4ah) contains the ESI crystallographic data for
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14. More uncleaphiles was examied, however, poorer results were
obtained. Please see details in ESI.
15. CCDC 1879992 (12) contains the ESI crystallographic data for
this paper.
5. For selected reviews, see: (a) Z. Wu and W. Zhang, Chin. J.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9CC01379B
CO2R2
CO2R2
R1
Tandem Heck/Tsuji-Trost
R1
L5, NuH
Pd(0)/
F
I
3
Nu
single diastereoisomer
up to 99% yield
NuH
F
F
= (CO2R )2CH2
Ar1OH
R
F
P
F
3,4-(MeO)2C6H3NH2
up to 97% ee
L5
Pd(0)/
O
O
N
Nu-
R
CO2R2
CO2R2
CO2R2
L5
R = 3,5-(CF3)2C6H3
R1
R1
R1
PdLnX
PdLnX
XLnPd
A palladium-catalyzed enantioselective tandem reaction of 2,5-cyclohexadienyl-substituted aryl
iodides and carbon or heteroatom nucleophiles has been successfully established by using a
chiral H8-BINOL-based phosphoramidite ligand.