One-Pot Synthesis of Decahydropyrene via Tandem C-H Activation/Intramolecular Diels-Alder/1,3-Dipolar Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.6b02768

A novel decahydropyrene synthesis has been successfully developed involving a tandem rhodium-catalyzed C-H activation/intramolecular Diels-Alder reaction/1,3-dipolar cycloaddition cascade process by using diazole as a traceless directing group. The advantage of this one-pot strategy is a quite simple, efficient, highly stereoselective, and unique product structure.

Full text of DOI:10.1021/acs.orglett.6b02768

Letter
pubs.acs.org/OrgLett
One-Pot Synthesis of Decahydropyrene via Tandem C−H Activation/
Intramolecular Diels−Alder/1,3-Dipolar Cycloaddition
Hui Lin and Lin Dong*
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan
University, Chengdu 610041, China
S
* Supporting Information
ABSTRACT: A novel decahydropyrene synthesis has been
successfully developed involving a tandem rhodium-catalyzed C−
H activation/intramolecular Diels−Alder reaction/1,3-dipolar
cycloaddition cascade process by using diazole as a traceless
directing group. The advantage of this one-pot strategy is a quite
simple, efficient, highly stereoselective, and unique product
structure.
Scheme 1. Strategies to Polycyclic Structures
andem reactions, sometimes referred to as domino
reactions, are attractive strategies for the construction of
T
complex bridged or polycyclic structures bearing several
contiguous stereocenters from simple precursors without the
need to isolate intermediates.1 Especially with the rapid
development of the C−H activation reaction in the past
decades,2 tandem reactions following the first rhodium-catalyzed
C−H bond cleavage have been extensively studied due to the
high efficiency and atom-economy.3,4 For example, various
amides or oximes coupling with multiple alkynes to obtain
polycyclic heteroaromatic compounds via a multiple chelation-
assisted ortho-C−H bond cleavage process and annulation in
one-pot have been discovered by many groups.4 Despite the
significant developments, cascade reactions via rhodium-
catalyzed C−H activation to build a more complex polycyclic
system still face huge challenges. Therefore, exploring a versatile
and novel cascade route is highly desirable.
Recently, decahydropyrene has received certain attention by
virtue of its unique molecular struture; however, traditional
approaches for the synthesis of these structures usually suffer
from low yields, complex operations, and inadequate structural
modification (Scheme 1, eq 1).5 Very recently, a powerful
intramolecular [4 + 2]/[3 + 2] cycloaddition cascade reaction
was utilized in the total synthesis of a series of indole alkaloids
(Scheme 1, eq 2).6 Inspired by the structure of decahydropyrene
derivatives and based on this cascade work, herein, we report a
highly efficient and powerful strategy for the one-pot synthesis of
a series of decahydropyrenes through a tandem rhodium-
catalyzed C−H activation/intramolecular Diels−Alder reaction/
1,3-dipolar cycloaddition cascade process (Scheme 1, eq 3). It is
worth mentioning that the diazole in this cascade reaction can act
as a traceless directing group,2p,7 releasing N2 during the
pericyclic cascade after the Rh catalyst.
We commenced our examination by investigating the cascade
annulation of 1,3,4-oxadiazole 1a and (4-methylpent-4-en-1-yn-
1-yl)benzene 2a. Although 3aa should be the key intermediate in
the proposed cascade reactions, the initial experiments were
performed by optimizing the reaction conditions for the first
Received: September 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02768
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions To Form
Intermediate 3aa
Scheme 2. Substrate Scope of 1,3,4-Oxadiazoles
a
b
entry
cd
t (°C)
acid
AcOH
additive
yield of 3aa (%)
,
1
2
3
4
5
6
7
8
9
110
110
100
100
100
100
100
100
100
100
100
31
34
63
62
63
69
63
74
46
74
80
cd
,
PivOH
cd
,
PivOH
cd
,
PhOCH2COOH
PhOCH2COOH
PhOCH2COOH
PhOCH2COOH
PhOCH2COOH
PhOCH2COOH
PhOCH2COOH
PhOCH2COOH
d
Cu(OAc)2
CuOAc
Cu(acac)2
AgCO3
10
11
AgOAc
a
Reaction conditions unless otherwise specified: 0.03 mmol of 1a, 2.2
equiv of 2a, 8 mol % of [Cp*Rh(CH3CN)3](SbF6)2, 0.5 mL of DCE,
1 equiv of acid, 0.4 equiv of additive, 11 h, under air. [RhIII] =
b
c
d
[Cp*Rh(CH3CN)3](SbF6)2. Isolated yield of 3aa. Under Ar. With
5 mol % of [Cp*Rh(CH3CN)3](SbF6)2.
a
Table 2. Optimization of the One-Pot Reaction Conditions
a
Reaction conditions unless otherwise specified: 0.03 mmol of 1, 2.2
equiv of 2a, 8 mol % of [Cp*Rh(CH3CN)3](SbF6)2, 0.5 mL of DCE,
1 equiv of PhOCH2COOH, 0.4 equiv of AgOAc, 100 °C, 10−24 h,
under air. Subsequently, 0.4 mL of mesitylene was directly added to
the mixture, and the temperature was increased to 240 °C, 6−11 h.
Isolated yield of 4.
b
entry
additive/equiv
solvent
mesitylene
yield of 4aa (%)
1
2
3
4
5
6
7
8
9
27
17
20
NP
40
48
65
90
80
1,2-dichlorobenzene
diphenyl oxide
mesitylene
ortho-C−H activation step (Table 1, step I).8 Compared to other
acids, PhOCH2COOH gave the higher yield (Table 1, entries 1−
3). Lowering the reaction temperature and even being open to
the air did not influence the reaction efficiency (Table 1, entries 4
and 5). Raising the catalytic loading gave a slightly better yield
(Table 1, entry 6). Among the additives investigated, AgOAc was
the best choice to afford 3aa in 80% yield (Table 1, entries 7−
11).
Next, reaction conditions of the one-pot process to directly
generate decahydropyrene product 4aa without isolated
intermediate 3aa are examined with the best conditions of C−
H activation in hand (Table 2). To our delight, the cascade
polycyclic product 4aa can be detected when we directly added
high-boiling-point solvents into the mixture of step I and then
increased the temperature to 240 °C (Table 2, entries 1−3).
However, low yields imply that the acid environment in step I
might affect the cascade reaction to continue smoothly.
Throughout further additive screening, 3 equiv of K2CO3 was
best suited for this [4 + 2]/−N2/[3 + 2] reaction, giving the final
product 4aa in 90% yield (Table 2, entries 4−9). It is possible
that a pH value in step II was crucial to this cascade cyclization
reaction. The structure of the final product 4aa was characterized
by X-ray crystallography (Figure 1).9
NaOAc/1
Na2CO3/1
K2CO3/1
K2CO3/2
K2CO3/3
K2CO3/4
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
a
Reaction conditions unless otherwise specified: 0.03 mmol of 1a, 2.2
equiv of 2a, 8 mol % of [Cp*Rh(CH3CN)3](SbF6)2, 0.5 mL of DCE,
1 equiv of PhOCH2COOH, 0.4 equiv of AgOAc, 100 °C, 11 h, under
air (step I). Subsequently, 0.4 mL of solvent was directly added to the
mixture of step I, and the temperature was increased to 240 °C, 10 h
b
(step II). [RhIII] = [Cp*Rh(CH3CN)3](SbF6)2. Isolated yield of 4aa.
Figure 1. X-ray crystal structure of 4aa.
With the optimized one-pot reaction conditions in hand, we
explored the generality of the substrate scope of 1,3,4-
B
DOI: 10.1021/acs.orglett.6b02768
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
group were suitable coupling partners but were proven to be less
efficient in this cascade reaction, applying the desired products
4ah and 4ai only in low yields due to the steric hindrance.
Furthermore, a phenyl group instead of a methyl group was
installed in the alkene, leading to 4aj in 52% yield. Meanwhile,
attempts to use butyl substituent 2k as a coupling partner failed.
To make better use of this special structure of decahydropyr-
enes, we subjected it to further transformation (Scheme 4). As
we expected, 4aa could be oxidized to diepoxy product 5 in high
total yield by m-CPBA, while four isomers were detected. After
recrystallization, one of the isomers can be observed (5′).
In summary, we have successfully developed a unique cascade
annulation for the one-pot synthesis of decahydropyrenes from
1,3,4-oxadiazoles and 1,4-enynes (a special case of alkynes) by
using diazole as a traceless directing group. This powerful
methodology involves multistep reactions and various trans-
formations: (1) tandem rhodium-catalyzed ortho-C−H activa-
tion; (2) [4 + 2] cycloaddition reaction; (3) nitrogen release; (4)
[3 + 2] cascade cycloaddition reaction. Furthermore, this cascade
cyclization strategy allows the formation of six new C−C bonds,
three new rings together with an oxygen bridge ring. This type of
structure is the first constructed by using transition-metal-
catalyzed cascade reactions. Further applications of decahy-
dropyrenes are still under investigation in our laboratory.
Scheme 3. Substrate Scope of Alkynes
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02768.
Experimental procedures, structural proofs, and NMR
spectra (PDF)
a
Reaction conditions unless otherwise specified: 0.03 mmol of 1a, 2.2
equiv of 2, 8 mol % of [Cp*Rh(CH3CN)3](SbF6)2, 0.5 mL of DCE, 1
equiv of PhOCH2COOH, 0.4 equiv of AgOAc, 100 °C 10−24 h,
under air. Subsequently, 0.4 mL of mesitylene was directly added to
the mixture, and the temperature was increased to 240 °C, 6−11 h.
Isolated yield of 4.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dongl@scu.edu.cn.
Notes
Scheme 4. Oxidization of Decahydropyrene 4aa
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from the NSFC
(21572138).
■
REFERENCES
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(9) Crystallographic data for 4aa: CCDC 1509293, C35H34O3, M =
502.62, space group P1, cell: a = 9.4048(4) Å, b = 11.0851(4) Å, c =
̅
13.4547(4) Å, α = 76.126(3)°, β = 82.803(3)°, γ = 86.051(3) °,
temperature = 291 K, calcd 1.237 mg/mm3.
D
DOI: 10.1021/acs.orglett.6b02768
Org. Lett. XXXX, XXX, XXX−XXX