A rhodium catalyzed cycloisomerization and tandem Diels-Alder reaction for facile access to diverse bicyclic and tricyclic heterocycles

Article abstract of DOI:10.1039/c9sc00980a

A regioselective distal cycloisomerization of 1,6-allenenes was successfully developed to afford six-membered ring exocyclic 1,3-dienes employing a rhodium/diphosphine catalyst system. Deuterium labelling experiments and DFT calculations were performed to provide insights into the reaction mechanism of this unprecedented transformation. In addition, one-pot tandem Diels-Alder reactions with various dienophiles could readily construct diverse bicyclic and tricyclic nitrogen heterocycles, which are ubiquitous core scaffolds for a variety of natural products and bioactives. High efficiency and exclusive chemo and regioselectivities for a broad substrate scope were achieved under mild conditions using a low catalyst loading of 0.5 mol%.

Full text of DOI:10.1039/c9sc00980a

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DOI: 10.1039/C9SC00980A
ARTICLE
Rhodium catalyzed cycloisomerization and tandem Diels-Alder
reaction for facile access to diverse bicyclic and tricyclic
heterocycles
Received 00th January 20xx,
Accepted 00th January 20xx
Yirong Zhou,a,b Ali Nikbakht, Felix Bauer and Bernhard Breit*
a
a
a
DOI: 10.1039/x0xx00000x
A regioselective distal cycloisomerization of 1,6-allenenes was successfully developed to afford six-membered ring exocyclic
,3-dienes employing a rhodium/diphosphine catalytst system. Deuterium labelling experiments and DFT calculations were
1
performed to provide insights into the reaction mechanism of this unprecedented transformation. In addition, one-pot
tandem Diels-Alder reactions with various dienophiles could readily construct diverse bicyclic and tricyclic nitrogen
heterocycles, which are ubiquitous core scaffolds for a variety of natural products and bioactives. High efficiency as well as
exclusive chemo- and regioselectivities for a broad substrate scope were achieved under mild conditions using a low catalyst
loading of 0.5 mol%.
Transition metal catalyzed cycloisomerization reactions have cycloisomerization to construct useful cyclic 1,3-dienes by using
proved to be synthetically useful and elegant methods to our rhodium/diphosphine catalytic system. Herein, we present
construct structurally diverse all carbon and heterocyclic an unprecedented rhodium catalyzed regioselective distal
frameworks in high efficiency as well as excellent atom and step cycloisomerization of 1,6-allenenes to provide six-membered
1
economy. In particular, cycloisomerization reactions of linear ring exocyclic 1,3-dienes exclusively (Scheme 1b). Based on
di-unsaturated systems with a suitable linker chain, such as 1,6- deuterium labelling experiments and DFT calculations a
2
3
4
5
6
diynes, 1,6-enynes, allenynes, bisallenes, and allenedienes
plausible reaction mechanism could be elucidated. Moreover, a
have been intensely investigated. Furthermore, readily one-pot tandem Diels-Alder reaction with various dienophiles
available 1,6-allenenes have attracted extensive synthetic furnished diverse bicyclic and tricyclic nitrogen heterocycles in
1
4
interest and their cycloisomerization has been successfully high atom- and step-economy. Such fused bicyclic and tricyclic
realized to access diverse heterocycles by employing various nitrogen containing heterocycles constitute privileged core
7
8
transition metal catalysts, including nickel, palladium,
skeletons for a variety of natural products and drugs as well as
9
10
11
ruthenium, rhodium and gold, etc. To the best of our fluorescent probes (Fig. 1), which highlights the manifold
knowledge, all the previously reported examples involved a potential applications of this new methodology in medicinal and
proximal allene π-bond activation and produced five- material chemistry.
1
5
membered ring dienes as major product (Scheme 1a). In view of
1
2
a) Previous work: proximal π-bond activation
diversity-oriented synthesis, it is therefore in high demand to
develop a new versatile catalytic system to furnish alternative
cycloisomerization products which enable for subsequent
multiple functionalizations.
R1
R1
R1
R1
[Ru]
[Au]
[Rh]
X
R1
R1
X
X
[Rh]
·
R2
R2
Recently, our group has made significant progress on the
development of rhodium catalyzed atom-efficient addition
reactions of various pronucleophiles to unactivated allenes and
X
R1
X
[Au]
R2
R1
X = NR, C(CO2R)2
1
3
R2
alkynes to provide enantioenriched branched allylic products.
To further expand the synthetic potential, we envisioned that
,6-allenene would be an interesting substrates for
R
b) This work: distal π-bond activation
1
·
[
Rh(COD)Cl]2
R
R
R
R
DPEphos
X
a. Institut für Organische Chemie und Biochemie
X
X
dienophiles
D-A Reaction
Albert-Ludwigs-Universität, Alberstr. 21, 79104 Freiburg (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
Key Laboratory of Functional Small Organic Molecules, Ministry of Education,
College of Chemistry and Chemical Engineering
X = NR, C(CO2R)2
b.
Scheme 1 Transition metal catalyzed cycloisomerizations of allenenes.
Jiangxi Normal University, Nanchang, 330022, China
†Electronic Supplementary Information (ESI) available: CCDC 1579171 (2a) and
CCDC 1834751 (4c). Experimental procedures and detailed characterization data of
all new compounds. See DOI: 10.1039/x0xx00000x
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Journal Name
H
H
Me
With the optimized reaction conditions in hand, the
substrate scope was explored. The results are shown in Table 2.
HO2C
HN
View Article Online
DOI: 10.1039/C9SC00980A
O
N
PO3H2
N
4
-tBuC6HSO2
Bn
First, substrates having different protecting groups at the
nitrogen linker atom were investigated (2a to 2g). Thus, in
addition to sulfonyl groups, easily removable Boc and Cbz
carbamates were well tolerated. Second, a variety of allenenes
with an all-carbon linker were examined (2h to 2n). In these
LY235959
N-methyl-D-aspartate
NMDA) antagonist
glucocorticoid receptor
antagonist
OMe
(
dextromethorphan
H
H
OTMB
O
N
N
Et
o
OMe
CO2Me
cases, a slight increase of the reaction temperature to 80 C was
H
Cl
NH
O
necessary in order to complete the cycloisomerization process.
Different ester functions, such as methyl, ethyl and benzyl were
all compatible in this reaction (2h to 2j). Moreover, a group of
masked hydroxyl functions were also suitable for the
transformation (2l to 2n). It is noteworthy that an interesting
diene product 2k with a spiro ketal structure was obtained in
good yield.
MeO
(
-)-reserpine
solvatochromic fluorophore
Fig. 1 Selected examples for drugs and natural product containing bicyclic or tricyclic
nitrogen heterocycles as core structures.
To test our hypothesis, unactivated terminal 1,6-allenene
a was chosen as a privileged model substrate for initial
reactivity assays. Surprisingly, in contrast to literature reported Table 2 Substrate scope for the cycloisomerization to access exocyclic 1,3-dienesa
1
results, no proximal coupled five-membered ring 1,3-diene
product (as shown in Scheme 1a) was detected. Conversely, a
completely new kind of six-membered ring exocyclic 1,3-diene
was obtained as the sole product with exclusive regioselectivity
and in good yield. The molecular structure of product 2a was
unambiguously confirmed by X-ray crystallographic analysis.
This unexpected preliminary result induced us to systematically
optimize the reaction conditions (Table 1). Firstly, several
solvents were examined for the new cycloisomerization
reaction (Table 1, entries 1-3) with DCE (1,2-dichloroethane)
proving to be superior to THF (tetrahydrofuran) and toluene.
Further investigations on the reaction temperature revealed
•
2
.5 mol% [Rh(COD)Cl]2
5.0 mol% DPEphos
X
DCE (0.1 M), 60 or 80 o
C
X
1
2
O
O
N
O
N
N
S
S
S
O
O
O
O2N
Cl
MeO
2b, 78%
2c, 81%
2d, 73%
O
MeO2C
2
o
N
N
N
that 60 C was most suitable for this new transformation. The
yield decreased with either higher or lower temperatures (Table
S
Cbz
Boc
MeO C
Me
O
2
e, 70%
2f, 64%
2g, 61%
2h, 66%
1
, entry 5). Finally, the best result (80% yield) was obtained
employing a lower substrate concentration of 0.1 M (Table 1,
entry 6).
EtO2C
BnO2C
BnO2C
O
EtO2C
Me
Me
O
Table 1 Reaction conditions optimization for the cycloisomerization to access exocyclic
2
i, 63%
2j, 75%
2k, 71%
1
,3-dienesa
BnO
BnO
BzO
TBDPSO
TBDPSO
2n, 81%
·
2.5 mol% [Rh(COD)Cl]2
.0 mol% DPEphos
5
BzO
2m, 86%
TsN
solvent (0.2 M), T o
TsN
C
2
l, 82%
1a
2a
CCDC 1579171 (2a)
aThe reactions were carried out on a 0.2 mmol scale of 1 in the presence of 2.5 mol% of
[Rh(COD)Cl] and 5.0 mol% of DPEphos in DCE (2.0 mL) for 20 h. For products 2b to 2g,
the reactions were performed at 60 ° C. For products 2h to 2n, the reactions were
Temp./oC
b
2
Entry
Solvent
DCE
Yield [%]
performed at 80 °C. All the yields were isolated yields.
1
2
3
4
5
6c
80
80
80
95
60
60
65
58
55
51
75
80
To gain deeper insights into the reaction mechanism of this
new cycloisomerization reaction, a series of deuterium labelled
substrates was prepared and subjected to standard reaction
conditions (Scheme 2). The results with substrates 1a-1 and 1a-
THF
Toluene
DCE
2
indicated that the deuterium atoms at terminal positions of
DCE
alkene and allene completely remained in their original position.
Hence, these carbon-hydrogen bonds should not change during
the process (equation 1 and 2). However, the deuterium atom
at the internal position of the alkene in 1a-3 completely shifted
into the 5 position of the piperidine ring (2a-3), which indicated
that an isomerization step might be involved to form the
exocyclic carbon-carbon double bonds (equation 3).
DCE
a
The reactions were carried out on a 0.2 mmol scale of 1a in the presence of 2.5 mol% of
b
[
Rh(COD)Cl]
2
and 5.0 mol% of DPEphos in DCE (1.0 mL) at Temp./°C for 20 h. Isolated
c
yield. 2.0 mL DCE was used (0.1 M).
2
| J. Name., 2012, 00, 1-3
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complete catalytic cycle for the traditional 5-membered ring
cylcoisomerization were performed. However, the energy
View Article Online
DOI: 10.1039/C9SC00980A
·
2
.5 mol% [Rh(COD)Cl]2
5
.0 mol% DPEphos
barrier of the rate determining step was found to be
TsN
TsN
D
(1)
DCE , 80 oC, 52%
1
6
8
0% D
significantly higher and is therefor unfavored.
D
D
D
Considering that exocyclic 1,3-dienes 2 are potentially good
reaction partners in Diels-Alder reactions, we anticipated that
in the presence of suitable dienophiles, a one-pot tandem
cycloisomerization/Diels-Alder reaction could be developed.
This could become an efficient synthetic method to prepare
1
a-1 D 80% D
2a-1
D
94% D
D
9
4% D
·
2.5 mol% [Rh(COD)Cl]2
5.0 mol% DPEphos
D
(
2)
TsN
DCE , 80 oC, 62%
TsN
16
diverse bicyclic and tricyclic nitrogen heterocycles. Indeed, as
1
a-2
2a-2
summarized in Table 3, we found that a wide range of 1,6-
allenenes reacted smoothly in the presence of the rhodium
catalyst and N-phenyl maleimide to furnish the desired tricyclic
heterocycles 4 in good yields along with exclusive regio-, and
diastereoselectivities. The constitution and relative
configuration of 4c were determined by X-ray crystallographic
analysis, while the others were assigned by analogy. For the
protected amide allenenes (4a-4g), as low as 0.5 mol% of
rhodium catalyst was sufficient to achieve full conversion.
Comparable yields showed that the protecting groups on the
nitrogen atom exhibited negligible influences on the reaction.
For carbon-linked allenene substrates (4h-4o) a slightly
increased catalyst loading of 1 mol% was needed to allow for
smooth and complete transformation. Various functional
H
D
5
100% D
·
2.5 mol% [Rh(COD)Cl]2
5
.0 mol% DPEphos
(
3)
TsN
D
TsN
DCE , 80 oC, 58%
100% D
1a-3
2a-3
Scheme 2 Deuterium labelling experiments.
To shed further light on the mechanism of this new
cylcoisomerization reaction, DFT computations were
performed.16 Based on the labeling experiments and the DFT
calculations the mechanism depicted in Scheme 3 is proposed.
Starting from a monomeric [ClRh(DPEphos)] complex ([Rh]) the
substrate 1a could coordinate to form the chelate intermediate
I1. An oxidative coupling via TS1 furnishes the -allyl
intermediate I2. This is followed by a β-hydride elimination (TS2) Table 3 Substrate scope for the cycloisomerization and tandem Diels-Alder reaction
a
to give the -allyl hydride complex I3. Isomerization to the -
allyl intermediate I4 (via TS3) and reductive elimination (via TS4)
delivers product 2a and regenerates the rhodium catalyst.
O
.
O
0
.5 or 1.0 mol% [Rh(COD)Cl]2
1.0 or 2.0 mol% DPEphos
X
+
N
Ph
N Ph
THF or DCE (0.2 M), 80 o
C
X
O
3a
O
1
4
N
H
[Rh]
Ts
Ts
N
•
H
2a
O
N
[
Rh]
1a
Ts
TS4
N
Ph
H
[
N
Rh]
R
O
•
H
[Rh]
N
Ts
N
R = 4-MeC6H4SO2,
4a, 83%
Ts
I4
R = 4-NO2C6H4SO2, 4b, 79%
R = 4-ClC6H4SO2, 4c, 76%
R = 4-MeOC H SO , 4d, 71%
I1
CCDC 1834751 (4c)
•
Ts
N
H
[
Rh]
6
4
2
H
[Rh]
N
R = 2,4,6-triMeC H SO , 4e, 70%
6 2 2
Ts
TS1
R = Ms, 4f, 72%
TS3
R = Boc, 4g, 61%
O
O
O
H [Rh]
N
Ts
RO C
N
O
Ph
H
[Rh]
2
N Ph
N
Ph
Ts
I3
RO2C
I2
O
Ph
O
H
R = Me, 4h, 78%
R = Et, 4i, 79%
R = Bn, 4j, 71%
4k, 66%
[
Rh]
N
Ts
PPh2
Rh
TS2
O
[
Rh] =
O
PPh2 Cl
O
N
Ph
RO
N
Ph
O
Scheme 3 Proposed mechanism for the rhodium-catalyzed cycloisomerization of
O
RO
1
,6-allenenes to six-membered exocyclic 1,3-dienes.
Me
Me
O
R = Bn, 4m, 67%
R = Bz, 4n, 73%
R = TBDPS, 4o, 62%
O
4l, 75%
Fig. 2 displays the energy profile of the reaction. The
highest energetic barriers are the oxidative coupling to form the
five-membered metallacycle (TS1) with a G of 14.6 kcal/mol
aThe reactions were carried out on a 0.2 mmol scale of 1 with 1.0 equivalent of 3a at
0 °C for 20 h. For products 4b to 4g, the reactions were performed in THF (1.0 mL) using
and 1.0 mol% of DPEphos. For products 4h to 4o, the reactions
8
(
M06/def2SVP), and the reductive elimination step (TS4) with a 0.5 mol% of [Rh(COD)Cl]
2
2
were performed in DCE (1.0 mL) using 1.0 mol% of [Rh(COD)Cl] and 2.0 mol% of

G of 14.5 kcal/mol (M06/def2SVP). The calculated reaction
DPEphos. All the yields were isolated yields.
mechanism is in accord with the results of the deuterium
labelling experiments. Furthermore, calculations of the
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DOI: 10.1039/C9SC00980A
Fig. 2 Computed catalytic cycle of the Rh catalyzed cycloisomerization of 1,6-allenenes to six-membered exocyclic 1,3-dienes. All energies(PCM-
M06/def2SVP//BP86/def2SVP) given with respect to energies of the [ClRh(DPEphos)] complex and the substrate.
groups, such as ester, ketone, ketal and ethers were all well
tolerated.
Thus, a series of N-aryl maleimides with either elelctron
poor or electron rich aryl substituents behaved well and
Next, the scope of dienophiles for the rhodium catalyzed provided the tandem products in good to high yields (6a-6n). A
domino cycloisomerization/Diels-Alder reaction was evaluated. variety of aryl halides including F, Cl, Br and even I were well
As illustrated in Table 4, a wide range of symmetrical tolerated enabling a subsequent derivatization through diverse
dienophiles proved suitable, providing the desired tricyclic and cross coupling methods (6e-6h). Other well behaving
bicyclic heterocycles in good to high yields.
dienophiles where benzoquinone (6o), the diphenyl ketone
derived from fumaric acid (6p), dimethyl fumarate (6q), trans-
dicyano ethylene (6r), acetylene dicarboxylate (6s), tetra-cyano
ethylene (6f) and azo dicarboxylate (6u).
The obtained fused tricyclic heterocyclic products contain
an internal tetra-substituted alkene function, which permits a
variety of functionalization reactions. Towards this goal the
tricyclic products 4a and 4h were selected for preliminary
studies (Scheme 4).
Table 4 Substrate scope for various dienophilesa
•
0
.5 or 2.0 mol% [Rh(COD)Cl]2
R
R
R
R
1.0 or 4.0 mol% DPEphos
TsN
+
THF or DCE (0.2 M), 80 o
TsN
C
1a
5
6
dienophiles
O
O
O
O
OH
O
Ph
Ph
H
N
R
TsN
10 mol% Pd/C
30 bar H2,
EtOH, 80 o
C
RuCl , NaIO4
N Ph
TsN
TsN
N
Ph
3
TsN
X
THF/H2O
O
H
OH
O
O
O
O
R = H, 6a, 92%
R = Me, 6b, 87%
R = Et, 6c, 68%
R = Bn, 6d, 64%
O
X = NTs, 10a, 70%, single isomer
X = C(CO2Me)2, 10h, 62%, single isomer
6o, 65%
6p, 87%
7
, 94%, single isomer
N
Ph
X
O
Pb(OAc)4
DCM
X = NTs, 4a
R = 4-FC6H4, 6e, 85%
R = 4-ClC6H4, 6f, 87%
R = 4-BrC6H4, 6g, 76%
R = 4-IC6H4, 6h, 78%
R = 4-MeC6H4, 6i, 84%
R = 4-MeOC6H4, 6j, 87%
R = 4-CF3C6H4, 6k, 81%
R = 3-BrC6H4, 6l, 85%
R = 3-Br, 4-MeC6H3, 6m, 84%
R = 3,5-diCF3C6H3, 6n, 83%
X = C(CO2Me)2, 4h
CO2Me
CO2Me
CN
CN
O
O
O
O
Br
PyH*Br3
DCM, rt
m-CPBA
DCM
O3, Me2S
TsN
TsN
N
Ph
N Ph
TsN
DCM, -78 o
C
X
O
Br
, 88%, 1:1 dr
O
O
6q, 80%
6r, 55%
X = NTs, 11a, 91%
X = C(CO2Me)2, 11h,
8% from 4h, 93% from 10 h
8
O
N Ph
TsN
4
O
9
, 84%, 6:1 dr
Scheme 4 Diverse synthetic transformations of 4a and 4h.
CN
CN
CO2Me
CO2Et
CO2Et
N
N
TsN
TsN
CN
CN
TsN
First, the palladium catalyzed diastereoselective
hydrogenation delivered the saturated azatricyclic 7 as a single
diastereomer in high yield. By treatment of suitable
CO2Me
6s, 81%
6t, 67%
6u, 95%
3
bromination reagent (PyH*Br ) in DCM, the dibrominated
aThe reactions were carried out on a 0.2 mmol scale of 1a with 1.0 equivalent of 5
in the presence of 0.5 mol% of [Rh(COD)Cl] and 1.0 mol% of DPEphos in THF (1.0
mL) at 80 °C for 20 h. For products 6s to 6u, the reactions were performed in DCE
1.0 mL) using 2.0 mol% of [Rh(COD)Cl] and 4.0 mol% of DPEphos and the
dienophiles were added after the first cycloisomerization step completed. All the
yields were isolated yields.
product 8 was obtained as a mixture of diastereomers.
Epoxidation with m-CPBA furnished the epoxide 9 as a single
diastereomer. A dihydroxylation yielded the vicinal diols 10a
and 10h as single diastereomers from 4a and 4h, respectively.
2
(
2
4
| J. Name., 2012, 00, 1-3
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3
Selected recent reviews: (a) Y. Hu, M. Bai, Y. YangViaewndArQtic.leZOhnolinue,
These diols could be oxidatively cleaved to give the ten-
membered diketones 11a and 11h. Alternatively, tricyclic
product 4h could be directly transformed into 11h via
ozonolysis. It is noteworthy, that such medium-sized fused
bicyclic structures are difficult to access by other methods,
highlighting the significance of this new method for potential
applications in natural product synthesis and medicinal
chemistry.
Org. Chem. Front., 2017, 4, 2256–2275; (b) R. Dorel and A. M.
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In conclusion, a novel regioselective cycloisomerization of 1,6-
allenenes was successfully developed to generate six-
2
membered ring exocyclic 1,3-dienes by using
a
Y. K. Chung, Angew. Chem. Int. Ed., 2009, 48, 4532–4535; (c)
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There are no conflicts to declare.
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Natural Science Foundation of China (no. 21602089) for
support. We thank Dr. D. Kratzert for the X-ray diffraction
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PleaseC dh oe mn oi ct a al dS cj ui es nt cme argins
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| J. Name., 2012, 00, 1-3
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Chemical Science
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DOI: 10.1039/C9SC00980A
·
[
Rh]
[Rh]
EWG
EWG
DPEphos
DPEphos
X
X
X
dienophiles
1
4 examples
36 examples
up to 95% yield
up to 86% yield
X = NR, C(CO R)2
2
A new rhodium catalyzed regioselective cycloisomerization of 1,6-allenenes was successfully
developed to prepare six-membered ring exocyclic 1,3-dienes. Moreover, one-pot tandem
Diels-Alder reaction with various dienophiles proved to be a high efficient construction of diverse
bicyclic and tricyclic nitrogen heterocycles. This methodology was distinguished by complete
atom and step economy, low catalyst loading of 0.5 mol%, excellent chemo-, regio-, and
diastereoselectivity.