Donor Rhodium Carbenes by Retro-Buchner Reaction

Article abstract of DOI:10.1002/anie.201813512

Rhodium carbenes are key intermediates in a range of cycloadditions and insertion reactions. Herein, we report the first generation of donor Rh^II carbenes by decarbenation of 7-substituted 1,3,5-cycloheptatrienes. This discovery unlocks an improved retro-Buchner-cyclopropanation sequence, a Si?H insertion reaction for a broad-scope synthesis of allylsilanes, and a new method for the vinylogation of aldehydes. The last strategy led to the development of an iterative synthesis of E-polyenes, and to the total synthesis of navenones B and C.

Full text of DOI:10.1002/anie.201813512

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Accepted Article
Title: Donor Rhodium Carbenes by Retro-Buchner Reaction
Authors: Antonio M. Echavarren and Mauro Mato
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10.1002/anie.201813512
Angewandte Chemie International Edition
Donor Rhodium Carbenes by Retro-Buchner Reaction
Mauro Mato and Antonio M. Echavarren*
7-Styryl-1,3,5-trimethyl-1,3,5-cyclohepatrienes undergo a retro-
Buchner reaction under mild conditions in the presence of
[Rh(TFA)2]2, to generate carbenes upon release of mesitylene,
which can cyclopropanate a wide range of alkenes,[16] covering and
improving both the complementary scopes previously developed
with AuI and ZnII analogs.[14] While AuI carbenes generated by this
method do not react with silanes, the new generated donor RhII
carbenes react in an intermolecular Si–H insertion process to give
allyl silanes.[17] Finally, we found that the resulting carbenes can be
efficiently trapped by a mild oxidant to give aldehydes. This
strategy allowed developing a method for the vinylogation of
aldehydes, an iterative synthesis of conjugated E-polyenes, and a
total synthesis of navenones B and C (Scheme 1-III).
Abstract: Rhodium carbenes are key intermediates in a range of
cycloadditions and insertion reactions. Herein, we report the first
generation of donor RhII carbenes by decarbenation of 7-substituted
1,3,5-cycloheptatrienes. This discovery unlocks an improved retro-
Buchner–cyclopropanation sequence, a Si–H insertion reaction for a
broad-scope synthesis of allylsilanes, and a new method for the
vinylogation of aldehydes. The last strategy led to the development of
an iterative synthesis of E-polyenes, and to the total synthesis of
navenones B and C.
Throughout the past decades, rhodium carbenes have been
proposed as intermediates that can engage in an extensive range
of transformations, which include cyclopropanations[1] or C–H[2] and
C–X[3] insertion reactions, among others.[4] Rhodium carbenes are
traditionally generated by decomposition of diazo compounds or
direct precursors, such as tosylhydrazones (Scheme 1-I).[5] Some
of these intermediates have been characterized recently, both
spectroscopically and in solid state.[6] Diazo compounds bearing a
stabilizing (i.e. electron-withdrawing) group are generally
employed for the generation of carbenes, since they are safer and
easier to handle, but this limits most methodologies to the use of
acceptor rhodium carbenes. Although procedures are available for
the synthesis of non-stabilized diazo compounds with aryl, vinyl or
even alkyl substituents (which are precursors for donor carbenes),7
they are usually challenging to prepare, inherently unstable,
explosive in pure form, cannot be stored for long periods of time,[8]
and are especially prone to diazo dimerization.[9] Encouraged by
the fact that alternatives to diazo compounds for the safe
generation of RhII carbenes are scarce,[10] we decided to explore
the use of 7-substitued 1,3,5-cycloheptatrienes to generate these
intermediates through a RhII-catalyzed retro-Buchner reaction
(decarbenation). The gold(I)-catalyzed decarbenation was first
reported by our group in 2010,[11] and emerged as a powerful
alternative for the generation of gold(I) carbenes, which can
engage in cyclopropanation reactions,[12] and take part in a range
of intramolecular transformations.[13] More recently, we showed
that through the design of a new generation of more reactive
cycloheptatrienes, a retro-Buchner–cyclopropanation sequence
could be carried out at very mild conditions and using ZnII salts as
substitutes of AuI phosphine or NHC (N-heterocyclic carbene)
complexes.[ 14 ] These findings, backed up by an early report
I.
Generation of Rh(II) carbenes from diazo compounds or direct precursors:
R2
[Rh]
-N2
R2
• R1 and/or R2 = EWG: Safe, widely explored
R1 • Without EWG: Explosive, much less explored
R1
N2
[Rh]
• R1, R2 = EWG: acceptor carbene; R1, R2 = alkyl, aryl, vinyl, H: donor carbene
II.
Generation of donor Rh(II) carbenes from 7-substituted 1,3,5-cycloheptatrienes:
[Rh]
• No stabilizing groups required
• Non-explosive reagents
Ar
[Rh]
-Mesitylene
Ar
Cyclopropanation of olefins
• Improved selectivity
III.
• Broad-scope cyclopropanation
R
Ar
R
Si–H insertion for the synthesis of allylsilanes
Ar
HSi(iPr)3
H
with [Au]: n/d
with [Rh]: 69%
(iPr)3Si
Ph
[Rh]
Ph
2S
O
Oxidation: iterative vinylogation of aldehydes
Natural
polyenes
Ar
n Ar
O
O
Scheme 1. (I) Traditional approach: generation of rhodium carbenes from diazo
compounds or direct precursors. EWG = electron-withdrawing group (CO2R,
CONR2, COR, CHO). (II) This approach: safe generation of donor rhodium
carbenes by decarbenation of cycloheptatrienes. (III) New reactivity unlocked
through this concept.
Our investigation commenced by exploring the reaction of
cycloheptatriene 3a with styrene, in the presence of [Rh(TFA)2]2.
We found that at 60 ºC, the generation and trapping of the RhII
carbene proceeded cleanly with only 3 mol% of the catalyst, giving
the corresponding cis-cyclopropane (5a) in 72% yield and 12:1 dr.
describing
a rhodium-promoted retro-cyclopropanation of a
polymethylated tricyclic structure,[15] led us to the discovery of the
generation of RhII carbenes from cycloheptatrienes (Scheme 1-II).
These
7-styryl-1,3,5-trimethyl-1,3,5-cycloheptatrienes
were
synthesized with excellent yields in gram scale by Julia-Kocienski
olefination of aldehydes using sulfone 2, which is a stable and
easy-to-handle white solid that can be prepared in decagram scale
by a sequence involving a RhII-catalyzed Buchner ring expansion
of mesitylene with ethyl diazoacetate (EDA), reduction of the ester,
Mitsunobu reaction with 1-phenyl-1H-tetrazole-5-thiol, and
oxidation (Scheme 2).[14] It is important to remark that very low
catalyst loadings (0.1 mol%) are required for the Buchner reaction
of mesitylene.
[*] M. Mato, Prof. A. M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute
of Science and Technology
Av. Països Catalans 16, 43007 Tarragona (Spain)
Departament de Química Analítica i Química Orgànica, Universitat
Rovira i Virgili, C/ Marcel·li Domingo s/n, 43007 Tarragona (Spain)
E-mail: aechavarren@iciq.es
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
This article is protected by copyright. All rights reserved.

10.1002/anie.201813512
Angewandte Chemie International Edition
first example of an intermolecular Si–H insertion reaction of a metal
OH 1. 1-phenyl-1-H-
1. EDA,
[Rh]
(0.1 mol%)
tetrazole-5-thiol,
DIAD, P(nBu)3
Ph
O
O
S
carbene generated via retro-Buchner reaction (Scheme 4). Using
N
only
2
mol% of [Rh(TFA)2]2, 7-styryl-1,3,5-trimethyl-1,3,5-
N
2. LiAlH4
2. H2O2, [Mo] (cat)
N
N
cycloheptatriene 3a reacted with triisopropylsilane to give 7a in
69% yield.[18] Gold(I) complexes failed to promote this
transformation, highlighting the difference in reactivity between
both AuI and RhII carbenes. This synthetic methodology turned out
to be very general (Scheme 4), affording the corresponding
allylsilanes in good yields across a wide range of cycloheptatrienes,
bearing both electron-poor and electron-rich substituents in
different positions of the aromatic ring (7a–e). Halides, from
fluoride to iodide, were tolerated (7f–h, 7v), and it was possible to
transfer polyarene units such as naphthalene and phenanthrene
(7q–r). Dienyl silane 7z was also obtained in 67% yield using the
same reaction conditions. The scope of the reaction is also broad
in terms of the silane group, allowing to perform the Si–H insertion
in substrates as bulky as (TMS)3SiH (7m). Selective mono-
insertion could also be carried out in a primary silane, PhSiH3 (7y).
1 (66%)
1. LiHMDS
2. RCHO
Excellent yields
Gram-scale
R
3
2 (53%, 18 grams)
Scheme 2: Decagram-scale preparation of Julia-Kocienski reagent 2 and
synthesis of starting materials. [Rh] = [Rh(OAc)2]2, DIAD
azodicarboxylate, [Mo] = ammonium molybdate tetrahydrate.
= diisopropyl
The retro-Buchner–cyclopropanation from 3a could be carried
out at 25 ºC, but longer times were required, and slightly lower
yields were obtained than by performing the reaction at 60 ºC for
18 h in 1,2-DCE (1,2-dichloroethane), which were selected as
standard conditions.[ 18 ] We compared this novel RhII-catalyzed
retro-Buchner–cyclopropanation protocol to the ones previously
reported based on AuI or ZnII catalysis (Scheme 3).[14]
R
3 R4
R3
[Rh(TFA)2]2 (2 mol%)[a]
[Rh(TFA)2]2 (3 mol%)[a]
1,2-DCE, 60 ºC, 18 h
Ar
SiR3
+
R3SiH
R1
R2
R1
1,2-DCE, 60 ºC, 18 h
Ar
R4
+
3
6
7
Ar
Ar
R2
3
4
5
R
Cl
R
O
Si(iPr)3
Si(iPr)3
Si(iPr)3
N
Ph
Ph
Ph
Cl
Ar
7g, R = 3-bromo (68%)
7h, R = 2-iodo (57%)
7a R = H (69%)
7f (71%)
7b R = Me (65%)
7c R = MeO (59%)
7d R = CF3 (63%)
7e R = Ph (70%)
5c (Ar = phenyl)
[Rh]: 89% (20:1)[d]
[Au]: 23%[b]
[Zn]: 63% (6:1)[c]
5a
5b
O
[Rh]: 72% (12:1)
[Au]: 80% (>20:1)[b]
[Zn]: 51% (>20:1)[c]
[Rh]: 70% (>20:1)
[Au]: 68% (>20:1)[b]
[Zn]: n/d[c]
Ar
SiMePh2
[Si]
7i Ar = 3-bromophenyl (68%)
7j Ar = 2-naphtyl (69%)
R
5d (Ar = 2-iodophenyl)
[Rh]: 71% (12:1)
7l [Si] = SiMe2(tBu) (73%)
7m [Si] = Si(TMS)3 (37%)
7n [Si] = SiMePh2 (66%)
[Si]
Ar
Ph
Ar
Si(iPr)3
CF3
[Si] = SiEt3:
5e
Ar
5f (Ar = 3-methylphenyl)
[Rh]: 90% (15:1)
[Au]: 57% (>20:1)[b]
[Rh]: 85% (9:1)[d]
[Au]: 12%[b]
[Zn]: 55% (5:1)[c]
7o R = Me (40%)
7p R = CF3 (45%)
7q Ar = 2-naphtyl (69%)
7r Ar = 9-phenanthrenyl (54%)
OMe
[Si] = SiMe2Bn
:
5g (Ar = 3-methylphenyl)
[Rh]: 71% (20:1)
[Au]: 40% (14:1)[b]
7k R = Me (74%)
Ar
SiMe2Ph
Br
O
O
F
O
O
7s Ar = 3-bromophenyl (86%)
7t Ar = phenyl (82%)
nC6H13
Ph
Ph
[Si]
F
F
F
5h
7u Ar = 2-naphtyl (78%)
Ph
Br
[Rh]: 35% (2:1)
[Au]: traces[b]
[Zn]: 48% (3:1)[c]
Si(iPr)3
7w [Si] = Si(iPr)3 (62%)
7x [Si] = SiMePh2 (68%)
5i
5j
F
7v (66%)
[Rh]: 58% (>20:1)
[Rh]: 90% (11:1)
Me
Scheme 3: Reactivity comparison of the new RhII carbenes with analogous AuI
and ZnII intermediates and scope of the cis-cyclopropanation reaction. Yields are
for isolated products. The cis or endo product is the major one in all cases, the
obtained ratio is shown in brackets. [a]New [Rh] conditions: 3 (0.1 M in 1,2-DCE)
with 4 equiv of 4, 3 mol% of [Rh(TFA)2]2 at 60 ºC for 16 h. [b] Previously reported
H2
Si
Ph
Si(iPr)3
Ph
7u (X-ray)
7y (51%)
7z (67%)
Scheme 4: Synthesis of allylsilanes by Si–H insertion of donor RhII carbenes.
Yields are for isolated products. [a] Reaction of 3 (0.1 M in 1,2-DCE) with 4 equiv
of 6, 2 mol% of [Rh(TFA)2]2 at 60 ºC for 16 h.
[Au] conditions:[14]
3 (0.1 M in EtOAc) with 1.5 equiv of 4, 5 mol% of
[(JohnPhos)Au(MeCN)]SbF6 at 25 ºC for 24 h. [c] Previously reported [Zn]
conditions:[14] 3 (0.1 M in 1,2-DCE) with 4 equiv of 4, 10 mol% of ZnBr2 at 65 ºC
for 40 h. [d] At 50 ºC for 20 h.
We also discovered that the reaction of 7-styryl-1,3,5-trimethyl-
1,3,5-cycloheptatriene with diphenylsulfoxide, in the presence of
[Rh(TFA)2]2, led cleanly to cinnamaldehyde (9a). This finding
allowed developing a two-step vinylogation of aldehydes. Thus, an
E-diastereoselective Julia-Kocienski olefination of aldehydes 8a–e
with sulfone 2 gives cycloheptatrienes (3), which were treated with
1.5 equiv of Ph2SO in the presence of 3 mol% of [Rh(TFA)2]2 to
assemble vinylogous aldehydes 9a–e (Scheme 5).
The AuI-based system shines on the cyclopropanation of
styrenes or related activated alkenes (5a–b), but performs poorly
with unactivated alkenes (5c–e) (Scheme 3). The ZnII-based
system complemented
AuI by allowing
an
efficient
cyclopropanation of these simple alkenes, but failed when
substrates bearing coordinating atoms were employed (5b). The
new RhII-based system often performed better, both in terms of
yield and selectivity, across all the different types of substrates,
resulting in
a
more general method for the cis-
vinylcyclopropanation of alkenes. Interestingly, electron-rich
carbenes (5g, 5i), which are the most problematic using AuI,[12b]
give remarkable levels of diastereoselectivity.
We found that the styryl rhodium carbenes could be efficiently
trapped with silanes R3SiH to give allylsilanes. This represents the
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10.1002/anie.201813512
Angewandte Chemie International Edition
intense yellow solid, in 70% yield with excellent diastereoselectivity.
Similarly, submitting 4-methoxycinnamaldehyde 9b to two
vinylogation iterations, gave trienal 13b, which after reaction with
the same ylide (14) gave methyl-navenone C (16) in 65% yield.
Treatment with BBr3 allowed demethylation of 16, affording
navenone C (17) in 74% yield. Finally, we decided to merge this
iterative process with the other two new methodologies based on
RhII carbenes: cyclopropanation (Scheme 3) and Si–H insertion
(Scheme 4). Following this idea, we showed how this strategy can
be used for the synthesis of E-polyenes bearing not only aldehyde
groups, but also silanes, and cyclopropanes. Thus, 7-polyenyl-
1,3,5-trimethyl-1,3,5-cycloheptatrienes 10a and 10b provided
polyenyl cis-cyclopropane (11b) or polyenyl silanes 11a and 11c in
good yield and moderate to good diastereoselectivity (Scheme 6).
Ph
O
O
S
N
O
Ph2SO (1.5 equiv)
[Rh(TFA)2]2 (3 mol%)
N
O
N
Li+
N
Ar
1,2-DCE, 80 ºC, 16 h
Ar
2-Li, THF, -78–25 ºC
8
Ar
3
9
O
O
O
O
O
R
Br
9a: R = H (80%, E/Z >20:1)
9b: R = OMe (92%, E/Z >20:1)
9c: R = CF3 (50%, E/Z >20:1)
9e (77%, E/Z >20:1)
9d (77%, E/Z >20:1)
Scheme 5: Vinylogation of aldehydes via Julia-Kocienski olefination and RhII-
catalyzed oxidative retro-Buchner reaction sequence. Yields are for isolated
products.
Given that both the starting material and the product of this
protocol are aldehydes, we envisioned that this sequence could be
applied in an iterative manner. This iterative chain growth would
deliver conjugated E-polyenes, a prevalent motif in Nature, present
in hundreds of compounds which are relevant across a variety of
biosynthetic pathways.[19] We decided to apply our iterative chain
growth to the total synthesis of the navenones, a family of trail-
breaking pheromones from the marine opisthobranch Navanax
inermis.[ 20 ] We prepared navenone B (15) in 5 steps from
cinnamaldehyde, after two iterations of the same Julia–Kocienski
olefination and retro-Buchner–oxidation sequence (Scheme 6).
This process afforded trienal 13a in 26% overall yield (4 steps) as
the all-E diastereoisomer. The reaction of 13a with 1.5 equiv of
stabilized ylide 14 in toluene at 100 ºC gave navenone B, as an
In order to gain mechanistic insight on these three new
transformations, we performed different control and competition
experiments (Scheme 7). Although cycloheptatriene 3a undergoes
the retro-Buchner and Si–H insertion sequence even at room
temperature, performing the reaction with non-methylated analog
3aH7 did not deliver a significant amount of product in the range
between 25 and 100 ºC (Scheme 7-I). The reaction of 3a with an
equimolar mixture of iPr3SiH and iPr3SiD gave the corresponding
non-deuterated and deuterated allylsilane in
a 1.3 ratio,
respectively (Scheme 7-II), which is consistent with previously
reported values for concerted metal carbene insertions in Si–H
bonds.[17d,21]
O
O
Me3CHT =
Me
BBr3
Me
R
O
R = MeO
17 (Navenone C, 74%)
OH
15 R = H (Navenone B, 70%, >20:1 E/Z)
PPh3
Me
16 R = MeO, (65%, >20:1 E/Z)
14 (1.5 equiv)
2-Li[a]
2-Li[a]
O
O
O
[O][b]
[Rh]
[O][b]
[Rh]
R
9a R = H
9b R = MeO
R
R
12a R = H (60%, 2 steps, >20:1 E/Z)
12b R = MeO (47%, 2 steps, >20:1 E/Z)
gram scale
13a R = H (44%, 2 steps, 20:1 E/Z)
13b R = MeO (51%, 2 steps, 20:1 E/Z)
Me3CHT
Me3CHT
10a (8:1 E/Z)
OMe
Ar
10b (4:1 E/Z)
OMe
2-Li
(iPr)3SiH
[Rh]
(iPr)3SiH
O
O
[Rh]
[Rh]
Li+
S
Ar = p-AcO-phenyl
Ph
N
N
(iPr)3Si
(iPr)3Si
Ar
N
N
11b 72% (5:1 dr)
OMe
11a 65% (10:1 E/Z)
OMe
OMe
11c 64% (5:1 E/Z)
Scheme 6. Iterative chain growth via Julia-Kocienski olefination and Rh-catalyzed oxidative retro-Buchner reaction for the synthesis of conjugated all-E polyenes, total
synthesis of navenones B and C, and diversification of intermediates. Yields are for isolated products. [a] Julia-Kocienski olefination, with 1.2 equiv of 2-Li in THF (0.1 M),
from -78 ºC to 25 ºC over 12 h. [b] Retro-Buchner–oxidation sequence, 1.5 equiv of Ph2SO and 3 mol% of [Rh(TFA)2]2 in 1,2-DCE (0.1 M), at 80 ºC for 16 h.
Then, we compared the reactivity of a RhII carbene with the
three studied nucleophiles: an alkene, a silane, and an oxidant
(Scheme 7-III). For this purpose, three reaction mixtures were
prepared, each one with a combination of two nucleophiles, and 1
equiv of cycloheptatriene 3a. We observed that the affinity of the
carbene towards styrene and triisopropylsilane was identical.
Mixing styrene with Ph2SO, a 4:1 distribution was obtained,
favoring the product of oxidative trapping over the cyclopropane.
Finally, we studied the competition for the three reactions between
3b and 3c, beaing electron-rich and an electron-poor substituents
at the para position of the styryl group (Scheme 7-IV). Significant
differences were only observed in the oxidative trapping (2:1 ratio
favoring the electron rich carbene). These results highlight the
similar reactivity of carbenes with different electronic properties,
accounting for the wide scope of these transformations.
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10.1002/anie.201813512
Angewandte Chemie International Edition
I.
In conclusion, we have developed a new method for the
rhodium(II)-catalyzed decarbenation of 7-substituted 1,3,5-
cycloheptatrienes, generating intermediates which display the
typical reactivity of donor RhII carbenes. It is remarkable how, by
tuning the substituents on the RhII carbene (from an acetate with
EDA to a vinyl group with 3), it is possible to achieve an opposite
reactivity (from a Buchner ring expansion to a retro-Buchner–
cyclopropanation) using exactly the same catalytic system,
[Rh(TFA)2]2. These RhII carbenes react with a broad range of
alkenes, resulting in an improved retro-Buchner–cyclopropanation
sequence. The same intermediates also react with silanes, which
represents the first example of an intermolecular insertion reaction
of a metal carbene generated via retro-Buchner. Finally, we
showed that it is possible to oxidatively trap these carbenes to give
aldehydes, leading to the development of an iterative protocol for
the vinylogation of aldehydes. This was applied to the preparation
of conjugated E-polyenes and to the total synthesis of navenones
B and C.
R
Ph
Si(iPr)3
[Rh]a
Temp
R
(iPr)3SiH
+
7a
6a
Ph
R = Me; 25 ºC: 47%, 60 ºC: 64%
R = H; 25 ºC: n/d, 60 ºC: n/d
R
3a/3aH7
II.
[Rh]a
Ph
Si(iPr)3
H/D
(iPr)3SiH/D
6a/6a-d1
+
Ph
Ph
7a/7a-d1 (1.3 ratio)
3a
4a
4a + 6a 4a + 18 6a + 18
III.
26%
25%
-
11%
-
-
Ph
Ph
Ph
[Rh]a
(iPr)3SiH
trace
trace
3a
+
6a
18
Si(iPr)3
mixture of
two nucleophiles
(2+2 equiv)
47%
Ph2SO
Ph
O
IV.
OMe
CF3
Me3CHT
3b (1 equiv)
30%
28%
Acknowledgements
Ar
Ar
Ar
OMe
[Rh]a
+
32%
27%
29%
14%
Si(iPr)3
We thank the Agencia Estatal de Investigación (AEI)/FEDER,
UE (CTQ2016-75960-P and FPI predoctoral fellowship to M.M.),
the AGAUR (2017 SGR 1257), and CERCA Program/Generalitat
de Catalunya for financial support. We also thank the ICIQ X-ray
diffraction unit and the CELLEX-ICIQ HTE laboratory.
nucleophile
(2 equiv)
Me3CHT
Ar
O
3c (1 equiv)
CF3
Scheme 7. Mechanistic investigations. (I) Comparison between first and second
generation of cycloheptatrienes. (II) Deuteration experiments and kinetic isotope
effect. (III) Competition experiments between each pair of nucleophiles. (IV)
Competition experiments between 3b and 3c. [a] Unless otherwise stated, 1 equiv
of cycloheptatriene with 4 equiv of nucleophile were stirred in 1,2-DCE (0.1 M) at
60 ºC for 16 h. Yields and ratios determined by 1H NMR using Ph2CH2 as internal
standard.
Keywords: rhodium catalysis · carbenes · retro-Buchner reaction
· silanes · total synthesis
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