Rhodium-catalysed tetradehydro-Diels-Alder reactions of enediynes: Via a rhodium-stabilized cyclic allene

Article abstract of DOI:10.1039/d0sc04390g

Efficient methods for the synthesis of fused-aromatic rings is a critical endeavour in the creation of new pharmaceuticals and materials. A direct method for preparing these systems is the tetradehydro-Diels-Alder reaction, however this is limited by the need for harsh reaction conditions. A potential, but underdeveloped, route to these systems is via transition metal-catalysed cycloaromatisation of ene-diynes. Herein, tethered unconjugated enediynes have been shown to undergo a facile room-temperature RhI-catalysed intramolecular tetradehydro-Diels-Alder reaction to produce highly substituted isobenzofurans, isoindolines and an indane. Furthermore, experimental and computational studies suggest a novel mechanism involving an unprecedented and complex RhI/RhIII/RhI/RhIII redox cycle involving the formation of an unusual strained 7-membered rhodacyclic allene intermediate and a RhIII-stabilized 6-membered ring allene complex.

Full text of DOI:10.1039/d0sc04390g

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DOI: 10.1039/D0SC04390G
ARTICLE
Rhodium-Catalyzed Tetradehydro-Diels–Alder Reactions of
Enediynes via a Rhodium-stabilized Cyclic Allene
Srinivas Thadkapally,[a] Keveh Farshadfar,[b] Melanie A. Drew,[a] Christopher Richardson[a], Alireza
Received 00th January 20xx,
Accepted 00th January 20xx
Ariafard,*[b] Stephen G. Pyne,*[a] and Christopher J. T. Hyland *[a]
DOI: 10.1039/x0xx00000x
Efficient methods for the synthesis of fused-aromatic rings is a critical endeavour in the creation of new pharmaceuticals
and materials. A direct method for preparing these systems is the tetradehydro-Diels–Alder reaction, however this is limited
by the need for harsh reaction conditions. A potential, but underdeveloped, route to these systems is via transition metal-
catalysed cycloaromatisation of ene-diynes. Herein, tethered unconjugated (Z)-enediynes have been shown to undergo a
facile room-temperature RhI-catalyzed intramolecular tetradehydro-Diels–Alder reactions to produce highly substituted
isobenzofurans, isoindolines and an indane. Furthermore, experimental and computational studies suggest a novel
mechanism involving an unprecedented and complex RhI/RhIII/RhI/RhIII redox cycle involving the formation of an unusual
strained 7-membered rhodacyclic allene intermediate and a RhIII-stabilized 6-membered ring allene complex.
a
Thermal tetradehydro-Diels-Alder (TDDA) Reaction v. high temp needed, restricted
scope
•
Introduction

New methods for the construction of functionalized aromatic
rings is an important area of research due to their wide
occurrence in bioactive molecules and materials. An advanced
strategy for preparing functionalized aromatic rings is
cycloaromatization of polyunsaturated acyclic building blocks,
including, enediynes, enyne-allenes and dienynes.1 The
tetradehydro-Diels–Alder (TDDA) reaction of polyunsaturated
enediyne systems is of particular note as it allows for the direct
formation of a benzenoid ring in a single step, via an intriguing
high energy cyclic allene intermediate, which typically
aromatises via a hydride shift (Scheme 1a).2, 3 The thermal mode
of this reaction has been investigated for many years, but its
synthetic applications are severely limited by the requirement
of the process for very forcing reaction conditions and particular
substitution patterns on the starting materials.3 The transition
metal-catalysed variant of the reaction has demonstrated
potential for unveiling tetradehydro-Diels–Alder reactions of
enediynes that proceed under milder conditions for a greater
range of substrates. For example, several recent reports have
harnessed dual gold-catalysts in cycloaromatisations via TDDA
reactions of enediynes.3-7 In these cases the enediyne is not fully
conjugated but has the alkyne and enyne units linked via a
heteroatom tether leading to a diverse range of fused
heterocyclic benzenoid structures of biological significance
(Scheme 1b).
cyclic allene
b
Gold-catalysed TDDA processes
via
BnN
R
BnN
O
R
R
[(Ph3PAu)3O]BF4
•
Au
BnN
Our previous work
R'
•
O
Au
O
(ref 5)
allenyl-gold
heat required
H
via
[(RuPhos)Au]NTf2
Gagosz (ref 6)
AuL
•
n
n
N
N
n
or
N
SO2Ar
ArO2S
DIPEA/IPrAuNTf2
Zi (ref 4)
ArO2S
AuL
Rhodium-catalysed cycloisomerisation of 1,6-enynes
c
CH3
RhIII
CH3
-hydride
oxidative
L
X
Rh(I)Ln
R
X
X
addition
elimination
R
R
X = N-PG, O
This work - a rhodium-catalyzed TDDA reaction via cyclic allenyl intermediates
d
R
R
no heating required
LRhI
H
H
•
•
RhLIII
X
R
RhL*
Rh(I)Ln
X
X
X
R
C
B
A
1-Rh
rhodium-stabilised
cyclic allene
cyclic allenyl-rhodium
L = BINAP
O
CN
O
O
N
X
HN
N
O
R
NH2
X = N-PG, O, CR2
Lenalidomide
(anticancer, multiple myeloma)
Escitalopram
F
antidepressant drug
2
a. School of Chemistry and Molecular Bioscience, University of Wollongong,
Wollongong, NSW 2522, Australia..
b. School of Physical Sciences, University of Tasmania, Hobart, TAS 7018, Australia.
Scheme 1. Type III tetradehydro-Diels–Alder reactions of enediynes.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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In the case of our previous work,5 the key reaction intermediate
incorporated a vinylidene gold8 intermediate and a rare allenyl
gold species (Scheme 1c).
DOI: 10.1039/D0SC04390G
Chart 1: Substrate scope for Rh-catalyzed tetradehydro-Diels–Alder reactions of
enediynes 1.[a]
[RhCl(COD)]2 (5 mol%)
R3
R1
Curiously, there have been no investigations of rhodium-
catalyzed cycloaromatization reactions of tethered non-
conjugated enediynes – and just a single report of a
cycloaromatization reaction of a conjugated enediyne.9 We
hypothesized that a rhodium-catalyzed cycloaromatization
reaction could be realized by harnessing the well-known
oxidative cyclization process observed in Rh-catalysed 1,6-
enyne reactions (Scheme 1c).10-16 The triple bond of an
enediyne opens up the possibility of forming a cyclic vinyl-
rhodium species A via oxidative cyclization of ene-diyne 1-Rh.
Isomerization of the oxidative cyclization product A should form
B – providing a direct route to the intriguing allenyl-rhodium
intermediate B and an alternative route to a cyclic allene cf the
thermal TDDA reaction (Scheme 1d). A reductive elimination to
the same cyclic allene proposed in the thermal TDDA reaction
could then be envisaged en-route to the final fused-aromatic
products 2 via a potential final hydride shift. Herein, we report
the successful implementation of this proposed pathway and
provide experimental and computational evidence for a
rhodium-catalyzed TDDA reaction that proceeds via an
unprecedented cyclic allenyl-rhodium species B and a rhodium-
stabilised 6-membered cyclic allene C involving a complex
AgSbF6 (20 mol%),
rac-BINAP (12 mol%)
X
X
R1
R3
DCE, rt, 1-12h
R2
R2
2
1
X
= NTs, NNs, O and C(CO2Me)2
H3C
TsN
X = NTs substrates:
TsN
2a
2b,
, 79%
71%*
H3C
TsN
H3C
TsN
H3C
TsN
F
O
2c,
2d
2e,
83%
80%
, 78%
H3C
TsN
H3C
H3C
TsN
Ns
N
SiMe3
H3C
2f,
2g,
81%
2h,
81%
55%
H3C
O
O
X = O and C(CO2Me)2
2k
, 65%
2l
, 66 %
H3C
O
H3C
O
H3C
RhI/RhIII/RhI/RhIII redox cycle. The resulting isobenzofuran,17
19
isoindoline,18,
isoindolinone20 and indane21 products are
O
F
important heterocycles that are found in an array of important
bioactive and medicinally important compounds.
O
2m
2n
, 70%
, 66 %
2o
, 75%
Ph
O
O
Results and Discussion
O
2r
, 70%
To examine our hypothesis the NTs-tethered (Z)-enediyne 1a
was synthesized (see SI) as a model substrate and treated with
[RhCl(COD)]2/AgSbF6 and (rac)-BINAP at rt in DCE – a general
system that has previously proved successful in catalyzing the
cycloisomerization of 1,6-enynes.16 Gratifyingly, this proved a
highly efficient catalyst for the cycloaromatization of 1a to give
isoindoline 2a in high yield (Scheme 2a – structure determined
unambiguously by X-ray crystallography).22 Replacing the ligand
BINAP with dppb, which has a similar bite angle, had a
deleterious effect on the yield (Scheme 2b). Starting material
was recovered when 1a was heated at reflux in DCE in the
absence of catalyst, indicating that there is no competing non-
catalyzed TDDA reaction occurring (Scheme 2c).
2q
, 0%
2p, 70%
CH3
H3C
O
MeO2C
MeO2C
O
Ph
2s
2t
, 81%
,70%
2u,
77%
[a] The starting material for 2d and 2f were a mixture of E/Z isomers. *2.5 mol%
of the Rh-catalyst gave the product in 10% yield (17% conversion) or 19% yield
(38% conversion) at 80 C
The presence of AgSbF6 was essential as the reaction with
[RhCl(COD)]2 alone resulting in no conversion. Replacing AgSbF6
with AgBF4 also proved detrimental giving only a 60% yield of
isoindoline 2a (80% conversion). Furthermore, lowering the Rh-
catalyst loading to 2.5 mol% resulted in a significantly reduced
conversion (75%) and yield (44%) over 12 h. This is even more
striking for substrate 1b to give 2b (see Chart 1), where 2.5
mol% of the Rh-catalyst gave the product in 10% yield (17%
conversion) or 19% yield (38% conversion) at 80 C. Finally,
changing the solvent to DCM reduced the yield to 62%.
[RhCl(COD)]2 (5 mol%)
AgSbF6 (20 mol%),
L (12 mol%)
H3C
TsN
Ph
NTs
1a
a) L = (rac)-BINAP,
H3C
Ph
DCE, rt, 12 h
2a
79% yield/100% conv.
With an effective catalyst system identified for the Rh-
catalyzed TDDA reaction, the substrate scope was established
with a range of N- and O-tethered enediynes 1, as shown in
Chart 1. For both the N- and O-tethered enediynes, aryl
(products 2a-d, 2g-h, 2k-n, 2p and 2s-2u), alkyl (products 2e and
49% yield/100% conv.
no reaction
no reaction
-
b) L = dppb,
c) heat only -
d) AgSbF6
Scheme 2: Initial cycloaromatization reaction discovery.
2 | J. Name., 2012, 00, 1-3
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2o) and silyl (product 2f) groups at R1 could be accommodated. With this set of key experimental results in place, we turned
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Both R1 and R5 could be simultaneously substituted to provide attention to DFT calculations for further mechanistic insight,
DOI: 10.1039/D0SC04390G
more densely functionalised isoindolines and isobenzofurans 2g considering our proposed cyclic allenyl-Rh intermediate B
and 2t, respectively. The R3 position could be unsubstituted (Figure 1d).28 In contrast to simple 1,6-enynes, the initial
(products 2b and 2k) or accommodate an n-propyl group in rhodium-catalyzed oxidative cyclization has two coordination
place of the methyl group (product 2p). However, branched possibilities – coordination between the enyne double bond
substituents or a phenyl ring (to give predicted products 2q and and the triple bond of the propargyl sulfonamide (1aRh), or
2r) were not tolerated, presumably for steric reasons – in these between the two triple bonds of the enediyne (1a'Rh). While
cases only decomposition of starting material was observed. oxidative cyclization via 1a'Rh would directly afford the
The dimethyl substituted O-tethered enediyne 1s was also well proposed allenyl-RhIII intermediate B, the barrier for this
tolerated under the cycloaromatisation reaction conditions to process was significantly higher than that for the oxidative
give trisubstituted isobenzofuran 2s in good yield. Isoindoline cyclization via 1aRh to provide RhIII metallacyclopentene A.
2h formed smoothly from nosyl-protected enediyne 1h. Other Following this exergonic process, an endergonic ring-expansion
protecting groups on N were not investigated due to the transformation into the key RhIII intermediate B occurs. This
established instability of isoindolines without an electron- unusual intermediate can be represented by two resonance
withdrawing N group.23-27 Finally, a carbon-tethered enediyne contributors: an allenyl-RhIII intermediate B' and a propargyl
1u was prepared and found to undergo smooth RhIII B'' and its hybrid structure (top corner of Figure 1) is
cycloaromatization to trisubstituted indane 2u.
indicative of a bent allenyl rhodium species. The ensuing allenyl-
Our attention then turned to experimentally and Rh intermediate is a branching point for two different reaction
computationally investigating the reaction mechanism (Scheme channels: (a) C–H elimination via transition structure TSB-F
3 and Figure 1). The C3-position in the ene-diyne starting affording F and (b) C–C reductive elimination via transition
material 1 (X = O or NTs) is key to understanding the reaction structure TSB-C yielding strained RhI-stabilised cyclic allene C.
mechanism as it becomes one of the carbons (C7a) fusing the
Surprisingly, the C–C reductive elimination process is
two rings of the product 2 via migration of the attached computed to be significantly more favourable than the C–H
hydrogen. For the thermal TDDA reaction this typically occurs elimination. This is because the allenyl Rh resonance
via one or more hydride shifts. To understand this process for contributor B' makes a significant contribution to the overall
the current system, a C3-deuterated analogue 1i and a C3- structure B and this means that there is significant -bond
methylated analogue 1j were prepared (Scheme 3). To character between the Rh and C1, thus promoting reductive
determine the fate of the C3-hydrogen, deuterated substrate 1i elimination. The intermediate resulting from the reductive
was subjected to the reaction conditions, leading to elimination can be considered as a stabilized version of the
predominant deuterium incorporation at the C6-position of the cyclic allene invoked in the thermal TDDA reactions of
isoindoline benzenoid ring of 2i. The partial loss of deuterium at enediynes – thereby playing a key role in making the rhodium
the C6-position of the product pointed away from a hydride catalyzed variant so facile (Scheme 1a). The catalytic cycle
shift in intermediate B or C to yield the aromatic product and continues with the allene-bound RhI intermediate C undergoing
hinted at the potential formation of a rhodium-hydride species. oxidative addition to the C–H bond to form RhIII-hydride D, with
A substrate (1j) with a methyl group on the enyne double bond the rhodium being bound to one face of the aromatic ring,
stopped the reaction completely – again suggesting a key role having the formal anion at C6. This result explains the failure of
for this position in the reaction. The sensitivity of the substrate 1j in the reaction due to the low propensity of C–C
cycloaromatization reaction towards the double bond bonds to undergo oxidative addition compared with C–H
geometry was also probed by utilizing (E)-enediyne 1l', which bonds.29 This is also an interesting mechanistic point of
led to the formation of the isobenzofuran 2l in comparable yield difference to the thermal TDDA reaction, wherein formation of
to its corresponding (Z)-enediyne starting material 1l.
the final aromatic ring typically occurs via hydride-migration. In
the current case, coordination of Rh to the -system of
intermediate C directs reactivity away from such a hydride
migration and towards a C–H insertion.
H
4
(87%)
D
H
7
(72%)
D
H3C
[RhCl(COD)]2
1
7a
6
5
3
(rac)-BINAP, AgSbF6
2
2
TsN
Ph
H3C
H3C
NTs
1i
3a
DCE, RT, 12 h
Ph
3
4
2i
, 81%
[RhCl(COD)]2
(rac)-BINAP, AgSbF6
NTs
no reaction
DCE, RT, 24 h
1j
H3C
O
H3C
O
Ph
[RhCl(COD)]2
(rac)-BINAP, AgSbF6
DCE, RT, 24 h
2l,
68%
(E)-1l'
(E)-isomer
Scheme 3: Experiments carried out to probe the reaction mechanism
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J. Name., 2013, 00, 1-3 | 3
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DOI: 10.1039/D0SC04390G
P
Ph
P
P
P
Rh
Ph
Ph
:
Ph
P
P
TsN
TS1'aRh-B
24.8 (26.3)
P
P
P
H
P
Rh
Rh
TsN
P
TSB-F
TS1aRh-A
TsN
P
11.8 (13.2)
11.4 (9.0)
P
P
Rh
Rh
6
TsN
P
P
1
TsN
TSA-B
2
Rh
3
H
-0.7 (-4.2)
TsN
TSB-C
-3.5 (-7.0)
0.6 (1.9)
0.0 (0.0)
TSC-D
B
C
P
-8.2 (-9.2)
P
I
-7.1 (-6.8)
P
-7.0 (-7.4)
P
Rh
I
P
Rh
H
P
III
Rh
Ts
III
NTs
1aRh
6
Rh
P
N
TsN
P
1a'Rh
H
1
2
3
B'
F
-19.3 (-23.4)
TsN
-20.3 (-22.4)
P
P
P
P
B
I
H
Rh
III
Rh
= vacant site
H
-27.4 (-30.4)
TsN
H
TsN
P
Rh
P
P
TsN
III
Rh
P
P
C
P
III
H
Rh
A
H
TSE-2aRh
-54.3 (-55.6)
TsN
TsN
B"
D
Ts
N
-56.3 (-59.5)
1a
H
TsN
+ 1a/1a'R
-81.7 (-83.5)
TsN
III
Rh
TsN
P
P
2a
I
Rh
E
-96.6 (-98.9)
P
P
2aRh
Figure 1: Free energy profile for Rh-catalyzed tetradehydro-Diels– Alder reaction of an (E)-enediyne. Free energies (potential energies) are given in kcal/mol
The hydride complex D undergoes rearrangement to E, which
is primed for a highly favourable H–C6 reductive elimination.
Once this has taken place, the organic product 2a is formed
and the RhI catalyst re-enters the catalytic cycle. This
mechanism explains the incorporation of deuterium at C6,
with some scrambling likely occurring between rhodium
hydrides D/E and solvent/adventitious water. These
calculations and the experimental studies enable the catalytic
cycle in Figure 2 to be proposed. Attempts to trap cyclic allene
(derived from ene-diyne 1a or 1j) intermediate C via Diels–
Alder reactions with furan were not successful, which is due
to the favorable oxidative addition towards intermediate D –
which is a fast intramolecular process – as well as the
coordination of Rh to the resulting cyclic allene.
P
Ph
Ph
P
:
Ph
Ph
I
P
P
P
P
Rh
Ts
N
1a'Rh
TsN
P
2a
oxidative
cyclization
I
Rh
H2
P
Ts
N
P
P
NTs
1a
III
1aRh
Rh
H
TsN
TsN
I
Rh
A
P
P
2aRh
C-H reductive
elimination
Synthetic transformations were performed on the isoindoline
and isobenzofuran products to demonstrate their utility
(Scheme 4). Initially, 2a and 2i were converted to biologically
important isoindolinone scaffolds 3 and isobenzofuranone
P
TsN
H
III
Rh
P
III
Rh
H
P
P
TsN
E
B
4:4' respectively, using sodium chlorite as a mild and green
P
30
P
oxidizing reagent.
Gratifyingly, the N-Ts group could be
C-C reductive
elimination
P
P
I
Rh
readily removed from 2a upon sonication in the presence of
Mg/MeOH to produce 1-methyl-5-phenylisoindoline 5 in
excellent yield – it should be noted, however, that this
product is unstable and cannot be purified by
chromatography.31
III
H
H
Rh
TsN
TsN
C
D
C-H oxidative
addition
Figure 2: Proposed mechanism for the transformation 1a  2a catalysed by a Rh
complex involving RhI/RhIII/RhI/RhIII cycle and allenic-intermediate C.
4 | J. Name., 2012, 00, 1-3
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O
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DCE:H2O (4:1)
65 °C, 24 h
Ph
Ph
5.
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3, 60%
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NaClO2
7.
O
O
+
O
Ph
Ph
DCE:H2O (4:1)
65 °C, 3.5 h
Ph
4:4’
O
8.
B. M. Trost and A. McClory, Chem. Asian. J., 2008, 3, 164-
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(1:1.6
87%)
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CH3
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40 min
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11.
12.
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H
N
Ts
Ph
Ph
5
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2a
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Conclusions
In conclusion, a mild and versatile rhodium-catalyzed
tetradehydro-Diels–Alder reaction of (E)-enediynes has been
developed allowing the synthesis of substituted, biologically 15.
important isoindolines, isobenzofurans and indanes. DFT
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Acknowledgements
The authors thank the Australian Research Council (grant
number DP180101332) for the generous funding for this
research. ST thanks the University of Wollongong for a PhD
scholarship.
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This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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6 | J. Name., 2012, 00, 1-3
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