Pd/C-Catalyzed Dehydrogenative [3+2] Cycloaddition for the Synthesis of Functionalized Tropanes

Article abstract of DOI:10.1002/ejoc.201801147

A Pd/C-catalyzed cascade approach for the synthesis of attractive benzo-fused tropanes was developed. The reaction proceeds through a sequential Pd/C-catalyzed dehydrogenative formation of azomethine ylides from amines and 1,3-dipolar cycloaddition. It allows the generation of structurally complex benzo-fused tropanes in good yields with excellent diastereoselectivities under mild reaction conditions. Preliminary results of asymmetric version of the reaction reveal that the copper catalyst and chiral monophosphoramidite ligand can furnish optically active products with moderate ee.

Full text of DOI:10.1002/ejoc.201801147

A Journal of
Accepted Article
Title: Pd/C-Catalyzed Dehydrogenative [3 + 2] Cycloaddition for the
Synthesis of Functionalized Tropanes
Authors: Hai-Jun Wang, Lei Guo, Cheng-Feng Zhu, Yun-Fei Luo, You-
Gui Li, and Xiang Wu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801147
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10.1002/ejoc.201801147
European Journal of Organic Chemistry
COMMUNICATION
Pd/C-Catalyzed Dehydrogenative [3 + 2] Cycloaddition for the
Synthesis of Functionalized Tropanes
Hai-Jun Wang,[a] Lei Guo,[a] Cheng-Feng Zhu,[a] Yun-Fei Luo,[a] You-Gui Li,[a] and Xiang Wu*[a]
CNS disorders.[8]
Abstract: A Pd/C-catalyzed cascade approach for the synthesis of
attractive benzo-fused tropanes was developed. The reaction
proceeds through a sequential Pd/C-catalyzed dehydrogenative
formation of azomethine ylides from amines and 1,3-dipolar
cycloaddition. It allows the generation of structurally complex benzo-
fused tropanes in good yields with excellent diastereoselectivities
under mild reaction conditions. Preliminary results of asymmetric
version of the reaction reveal that the copper catalyst and chiral
monophosphoramidite ligand can furnish optically active products
Figure 1. Representative benzo-fused tropanes with biological activities.
with moderate ee.
However, only a few routes have been disclosed for the
synthesis of benzo-fused tropane scaffolds.[5c,9] Among these
Introduction
approaches, [3 + 2] cycloaddition is an efficient strategy for the
[3 + 2]-Cycloaddition reactions are powerful tools for the
construction of benzo-fused tropane derivatives.[5c,9b,9g,9h,9k,9l,9n,9o]
synthesis of hetero-atoms containing five-membered cyclic
Recently, Waldmann, Antonchick and co-workers developed a
molecules.[1] Among them, azomethine ylides are commonly
direct and efficient copper-catalyzed and classical 1,3-dipolar
nitrogen-based 1,3-dipoles which represent multifunctional
cycloaddition reaction of 1,3-fused cyclic azomethine ylides and
synthons to generate pyrrolidine or pyrroline derivatives when
nitroalkenes for the synthesis of functionalized benzo-fused
reacting with unsaturated carbon−carbon bonds.[2] Moreover,
tropane scaffolds A with excellent diastereoselectivities and
azomethine ylides have high utility in the synthesis of bioactive
enantioselectivities, which have been found to be novel
heterocycles and complex natural products.[2f,2g] Usually,
inhibitors of skin cancer (Scheme 1A).[9k] In comparison, the
azomethine ylides are unstable and have to be generated in situ
oxidative dehydrogenative [3 + 2] cycloaddition, a combination of
from imines, iminium salts, aziridines and silylonium ions.[2a,2b]
two processes, including the metal catalyzed dehydrogenative
Recently, a few new oxidative processes, including photoredox
generation of azomethine ylides and subsequent 1,3-dipolar
catalysis,[3] indirect oxidation by oxygen or peroxide species[4]
cycloaddition, results in the concomitant formation of two C–C
and metal catalyzed dehydrogenation,[5] have been developed
bonds via direct oxidative functionalization of C–H bonds and is
for converting amines to azomethine ylide intermediates.
characterized by a high degree of step economy and operational
efficiency.[5c] Therefore, since we are interested in the oxidative
successfully used in the oxidative [3 + 2] cycloadditions, and
Although these azomethine ylide intermediates have been
important progress has been made in the last decade, there still
remains a great challenge for the synthesis of interesting and
important structural moieties with high efficiency and selectivity.
Benzo-fused tropanes, containing phenyl rings and tropane
moieties, exhibit a wide range of biological activities. Compound
1 is an antitumor drug candidate[6] and compound 2 has been
studied for the treatment of Type 2 diabetes[7] (Figure 1). MK-
801, the tropane core fused with two benzene rings, displays
anticonvulsant activity and gives it potential as a drug to treat
[a]
Hai-Jun Wang, Lei Guo, Dr. Cheng-Feng Zhu, Prof. Dr. Yun-Fei Luo,
Prof. Dr. You-Gui Li, and Prof. Dr. Xiang Wu*
Scheme 1. Strategic Accesses to Functionalized Benzo-fused Tropanes
Anhui Province Key Laboratory of Advanced Catalytic Materials and
Reaction Engineering, School of Chemistry and Chemical
Engineering, Hefei University of Technology, Hefei 230009, China.
E-mail: wuxiang@hfut.edu.cn
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10.1002/ejoc.201801147
European Journal of Organic Chemistry
COMMUNICATION
cycloadditions for the synthesis of structurally complex
were treated with methyl 1,2,3,4-tetrahydroisoquinoline-3-
carboxylate (3a) in the reactions (Table 2, entries 1-14).
Electron-neutral, electron-donating and electron-withdrawing
substituents were generally well-tolerated, affording 5ab−ao in
good yields and with excellent diastereoselectivity all dr > 20:1).
Particularly, due to steric hindrance, meta- and para-substituents
resulted in considerably higher yields than those of ortho-
substituents (entries 2 and 3 vs 1, entries 5 and 6 vs 4).
Additionally, 1,2,3,4,5-pentafluoro phenyl-substituted substrate
4o gave the product 5ao smoothly, albeit in a relatively lower
yield (entry 14). 2-Naphthyl-substituted nitroethene 4p also
afford the corresponding product 5ap in good yield (entry 15).
Notably, the furan- and thiophene-derived heteroaromatic
nitroalkenes reacted well to give the products 5aq and 5ar
(entries 16 and 17). Moreover, electron-rich (methoxyl) group
substituted tetrahydroisoquinolines 3b and 3c smoothly
underwent the cascade dehydrogenation/cycloaddition to furnish
the corresponding products in moderate yields (entries 18 and
19).
compounds,[10] we describe herein
a
Pd/C-catalyzed
dehydrogenative formation of azomethine ylides B from amines
and subsequent [3 + 2] cycloaddition for the synthesis of benzo-
fused tropanes (Scheme 1B). Moreover, a promising asymmetric
process using a chiral BINOL-based phosphoramidite as ligand
was developed to provide highly valuable chiral tropane
derivatives.
Results and Discussion
Initially, phenylalanine derivative 3a was employed as the
dipole precursor and trans--nitrostyrene 4a as the dipolarophile
in the dehydrogenative [3 + 2] cycloaddition. Palladium black
was first utilized to catalyze the generation of azomethine ylides
from 3a in toluene at 110 C. The desired tropane product 5aa
was isolated in 29% yield with complete diastereomeric control
(dr > 20:1) (Table 1, entry 1). Intriguingly, when Pd/C was used
as a replacement for palladium black, the yield was increased to
52% (entry 2). Then, a series of temperatures were evaluated
for the reaction and 70 °C was found to be the most suitable
operation temperature (entries 2-7). Moreover, several metal
catalysts such as Ru/C, Rh/C and Pt/C were also screened, and
a satisfactory yield of 76% was obtained using Pd/C as the
catalyst (entries 4, 8-10). A final evaluation of solvents showed
that toluene is the most suitable media to allow the reaction and
gives the highest yield (entries 4 and 12-14).
Table 2. Scope of tetrahydroisoquinolines 3 and nitroalkenes 4[a]
entry
3
R
4
5
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-CNC6H4
4-CF3C6H4
4-ClC6H4
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
5ab
5ac
5ad
5ae
5af
5ag
5ah
5ai
5aj
5ak
5al
5am
5an
5ao
5ap
5aq
5ar
60
79
71
70
78
76
83
78
80
76
81
81
80
61
76
70
58
49
45
Table 1. Optimization of the Reaction Conditions[a]
4-MeOC6H4
4-FC6H4
2,3-Cl2C6H3
3,4-(MeO)2C6H3
2,3,4,5,6-F5C6
2-naphthyl
2-furyl
entry
cat.
solvent
yield (%)[b]
temp (C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pd black
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Ru/C
Rh/C
Pt/C
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
CHCl3
110
110
90
70
60
50
rt
29
52
55
76
69
40
0
2-thienyl
C6H5
C6H5
4a
4a
5ba
5ca
[a]The reaction was carried out with 3 (0.1 mmol) and 4 (2.0 equiv) in the
presence of 10 mol % of Pd/C in toluene (1 mL) under N2 at 70 °C for 36 h.
dr > 20:1. Racemic 5 were obtained.
70
70
70
70
70
70
70
42
40
37
63
30
65
75
Pd/C
Pd/C
Pd/C
Pd/C
To explore the scope of this transformation further, we
employed tetrahydrocarbolines 6a-6e as the dipole precursors.
First, 6a was treated with nitrostyrenes 4 that had a variety of
substituting groups on the phenyl ring with different electronic
properties. The results showed that the variation has little
evident effect on the reaction outcomes (76%-90% yields, Table
2, entries 1-11). The phenyl substituent of substrate 4 could be
replaced with furan and thiophene, leading to the products 7aq
EtOAc
THF
[a]The reaction was carried out with 3a (0.1 mmol) and 4a (2.0 equiv) in the
presence of 10 mol % of metal catalysts under N2. The resulting solution was
stirred for 36 h. [b]Yield of the isolated product. Racemic 5aa was obtained.
With the optimal reaction conditions in hand, we next
surveyed the scope for both substrates 3 and 4. A variety of
nitrostyrenes 4a−r with different substituents on the phenyl ring
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10.1002/ejoc.201801147
European Journal of Organic Chemistry
COMMUNICATION
and 7ar in good yields (entries 12, 13). However, 3-indolyl
nitroethene showed lower reactivity to afford the desired product
7as in a lower yield of 26% (entry 14). Moreover, ethyl ester 6b
was also examined, providing a good yield (entry 15). When the
hydrogen atom at the C1 position of 3,4-dihydro--carboline was
changed to a methyl (6c and 6d) or phenyl (6e) group, the yields
of the reaction were reduced slightly, but essentially only a
single diastereomer (7ca, 7da[11] and 7ea) was formed (entries
16-18). Unfortunately, less reactive alkyl nitroalkenes such as
cyclohexyl- and benzyl β-substituted nitroethenes could not give
any products (See Supporting Information).
contiguous chiral centers was attained with 49% ee. Interestingly,
when the reaction proceeded at 70 C, no enantioselectivity was
observed while at 50 C the reaction did not take place (Scheme
2).
Table 3. Scope of tetrahydrocarbolines 6 and nitroalkenes 4a[a]
Scheme 2. Preliminary Asymmetric Studies..Reaction conditions: 3a (0.1
mmol), 4 (0.2 mmol), Pd/C(0.01 mmol), Cu(OAc)2 (0.01 mmol), L (0.01 mmol)
in toluene (1 mL) under N2 at 60 °C for 80 h. dr > 20:1. [a]The reaction was
entry
6
R
4
7
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
6e
C6H5
4-MeC6H4
4-NO2C6H4
4-CNC6H4
4-CF3C6H4
4-ClC6H4
4-FC6H4
2,3-Cl2C6H3
3,4-(MeO)2C6H3
2,3,4,5,6-F5C6
2-naphthyl
2-furyl
4a
4d
4g
4h
4i
7aa
7ad
7ag
7ah
7ai
86
90
83
86
76
88
86
78
85
79
87
81
84
26
76
63
54
49
carried out at 70 °C. [b]The reaction was carried out at 50 °C. NR = No
Reaction. Optical active compounds 5 were obtained.
On the basis of the experimental results above and previous
reports,[13] we proposed here a plausible reaction mechanism for
the palladium-catalyzed dehydrogenative [3 + 2] cycloaddition
(Scheme 3). Palladium catalysts have long been known to
catalyze dehydrogenation of secondary amines to imines.[14]
Initially, palladium inserts into the N–H bond followed by -H
elimination to generate the imine complex C. Then, the
corresponding cyclic imines D convert to azomethine ylides B by
1,2-prototropy. Finally, the 1,3-dipolar cycloaddition occurs
smoothly to afford tropane derivatives when the intermediates B
4j
4l
7aj
7al
4m
4n
4o
4p
4q
4r
4s
4a
4a
4a
4a
7am
7an
7ao
7ap
7aq
7ar
7as
7ba
7ca
7da
7ea
2-thienyl
3-indolyl
C6H5
C6H5
C6H5
C6H5
[a]The reaction was carried out with 6 (0.1 mmol) and 4 (2.0 equiv) in the
presence of 10 mol % of Pd/C in toluene (1 mL) under N2 at 70 °C for 36 h.
dr > 20:1. Racemic 7 were obtained.
are treated with nitroalkenes 4.
Scheme 3. Plausible Reaction Mechanism
Finally, an attempt for an asymmetric cascade via palladium
catalyzed
dehydrogenation/copper
catalyzed
dipolar
cycloaddition was conducted. Several commercially available
chiral phosphine ligands were screened (for details, see
Supporting
monophosphoramidite ligand (S,R,R)-L displayed the best
reactivity and provided the best (but moderate)
Information),
in
which
the
chiral
enantioselectivities for products in moderate yields when the
reaction proceeded at 60 C using copper acetate as the
catalyst (Scheme 2). Regardless of the electronic character of
the substituents on the phenyl ring of nitrostyrenes 4 and
heteroaromatic nitroalkenes 4, reactions proceeded smoothly,
and products with moderate ee were obtained.[12] In the case of
the product 5aa, chiral benzo-fused tropane containing four
Conclusions
In summary, we have developed
a
Pd/C-catalyzed
dehydrogenative [3 + 2] cycloaddition for the synthesis of benzo-
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10.1002/ejoc.201801147
European Journal of Organic Chemistry
COMMUNICATION
fused tropanes. The reaction proceeds through a sequential
Pd/C-catalyzed dehydrogenative formation of azomethine ylides
from amines and 1,3-dipolar cycloaddition. It allows the
generation of structurally complex benzo-fused tropanes in good
yields with excellent diastereoselectivities under mild reaction
conditions. Moreover, preliminary results of the asymmetric
version of the reaction reveal that the copper catalyst and chiral
monophosphoramidite ligand can furnish optically active
products with moderate ee.
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Experimental Section
General procedure for the synthesis of tropanes 5 or 7. Esters 3 or 6
(0.1 mmol), nitroalkenes 4 (30 mg, 0.2 mmol) and Pd/C (10.6 mg, 0.01 m
mol) were added in an oven-dried Schlenk tube. The tube was then seale
d, evacuated, and backfilled with nitrogen using standard Schlenk techni
que. Toluene (1 mL) was sequentially added by syringe at ambient temp
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Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (NNSFC) (grant 21672049) and
Hefei University of Technology.
Keywords: Palladium • Dehydrogenative • [3 + 2] Cycloaddition
• Tropanes • Asymmetric
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10.1002/ejoc.201801147
European Journal of Organic Chemistry
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Heterocyclic Chemistry
Hai-Jun Wang,[a] Lei Guo,[a] Cheng-Feng
Zhu,[a] Yun-Fei Luo,[a] You-Gui Li,[a] and
Xiang Wu* [a]
Page No. – Page No.
Text for Table of Contents
Pd/C-Catalyzed Dehydrogenative [3 +
2] Cycloaddition for the Synthesis of
Functionalized Tropanes
Described is a Pd/C-catalyzed dehydrogenative [3 + 2] cycloaddition for the synthesis of benzo-fused tropanes. The reaction proceeds
through a sequential Pd/C-catalyzed dehydrogenative formation of azomethine ylides from amines and 1,3-dipolar cycloaddition.
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