Enantioselective Rhodium(I) Donor Carbenoid-Mediated Cascade Triggered by a Base-Free Decomposition of Arylsulfonyl Hydrazones

Article abstract of DOI:10.1002/chem.201502909

The reaction of diyne arylsulfonyl hydrazone substrates under rhodium(I)/BINAP catalysis gives access to sulfonated azacyclic frameworks in a highly enantioselective manner. This new cascade process considerably increases the molecular complexity by generating two C-C bonds, one C-S bond, and one C-H bond. Theoretical calculations, competitive experiments, and deuterium labeling have jointly been used to propose a mechanism that accounts for the reaction. The mechanism involves the formation of vinyl rhodium carbenoids, hydride migratory insertion, and intermolecular stereoselective nucleophilic attack. The last two steps are the key to the stereoselectivity of the process.

Full text of DOI:10.1002/chem.201502909

DOI: 10.1002/chem.201502909
Full Paper
&
Rhodium
Enantioselective Rhodium(I) Donor Carbenoid-Mediated Cascade
Triggered by a Base-Free Decomposition of Arylsulfonyl
Hydrazones
[a]
[b]
[a]
[a]
[a]
Òscar Torres, Teodor Parella, Miquel Solà, Anna Roglans, and Anna Pla-Quintana*
Abstract: The reaction of diyne arylsulfonyl hydrazone sub-
strates under rhodium(I)/BINAP catalysis gives access to sul-
fonated azacyclic frameworks in a highly enantioselective
manner. This new cascade process considerably increases
the molecular complexity by generating two CÀC bonds,
one CÀS bond, and one CÀH bond. Theoretical calculations,
competitive experiments, and deuterium labeling have joint-
ly been used to propose a mechanism that accounts for the
reaction. The mechanism involves the formation of vinyl rho-
dium carbenoids, hydride migratory insertion, and intermo-
lecular stereoselective nucleophilic attack. The last two steps
are the key to the stereoselectivity of the process.
[
2]
[3]
Introduction
selective transformations. Alternatively, N-tosylhydrazones
[
4]
[5]
and N-sulfonyl-1,2,3-triazoles, among other sources, can be
used to generate metal carbenoids in situ, which both circum-
vents the use of hazardous and potentially explosive diazo car-
bonyl compounds and broadens the range of possible synthet-
ic transformations.
Metal carbenoids are important reaction intermediates that are
capable of mediating numerous different reactions, such as cy-
clopropanation, cyclopropenation, CÀH insertion, CÀC cou-
[
1]
pling, ylide formation, metathesis, and migratory insertion.
Owing to their versatility and high reactivity, they have great
potential as participants in step-economic and waste-reducing
cascade processes, which are particularly desirable for the con-
struction of complex molecules.
Rhodium(I) has also been reported to catalyze a few interest-
ing reactions that involve carbenoid intermediates. The corre-
sponding carbenoids have been formed by transmetallation
[
6]
from a chromium alkenyl Fischer carbene, by oxidation of an
[
7]
[8]
The reactivity and stability of the metal carbenoids is highly
dependent on their substitution pattern. Following Davies’
classification, acceptor and acceptor/acceptor metal carbenoids
are extremely reactive and behave as highly electrophilic spe-
cies. On the other hand, donor/acceptor-substituted carbe-
noids facilitate highly chemoselective and stereoselective reac-
tions due to the ability of the donor group to moderate their
reactivity. Although the reactivity of these carbenoids is well
established, a major challenge is to develop reactions of metal
carbenoids without electron-withdrawing substituents, also
known as donor carbenoids.
ynamide, by decomposition of diazo compounds, and by
[
9]
decomposition of tosylhydrazones. However, rhodium(I) com-
plexes of donor carbenoids have only been achieved when
[
6]
[9]
chromium alkenyl Fischer carbenes and tosylhydrazones
were used as carbenoid sources.
Although rhodium(I) complexes are known to mediate vari-
[
10]
ous asymmetric reactions, the development of stereoselec-
tive processes that make use of rhodium(I)-carbene chemistry
has been little explored (Scheme 1).
In 2010, Hayashi et al. reported the use of a cationic chiral
I
diene–Rh complex for the asymmetric cyclopropanation of al-
[
8b]
Among the different metals, rhodium(II) carbenoids, which
can be formed by the decomposition of diazo compounds
with rhodium(II) dimers, have shown great potential in stereo-
kenes with dimethyl diazomalonate. Hu et al. also used a rho-
dium(I) complex with a chiral diene ligand to promote an
enantioselective three-component reaction, in which an inter-
mediate ylide was formed that was subsequently involved in
[
8c]
a Michael addition-type reaction. In 2014, Murakami et al. re-
ported the enantioselective insertion of cyclopentanols that
[
a] Ò. Torres, Prof. Dr. M. Solà, Prof. Dr. A. Roglans, Dr. A. Pla-Quintana
Institut de Química Computacional i Catàlisi (IQCC)
and Departament de Química
I
was promoted by a Rh–carbene complex, which was formed
upon decomposition of tosylhydrazones and was stabilized
Universitat de Girona
Campus de Montilivi, s/n, 17071 - Girona (Spain)
Fax: (+34)972-41-81-50
[
9]
with diphosphine ligands. Finally, Xu et al. very recently re-
ported the asymmetric carbene insertion into BÀH bonds to
give access to functionalized organoboranes, again by using
E-mail: anna.plaq@udg.edu
[
b] Dr. T. Parella
[8f]
a chiral diene rhodium(I) complex. It should be noted that
Servei de Ressonància Magn›tica Nuclear
Universitat Autònoma de Barcelona (Spain)
[
9]
only in the case of tosylhydrazones was an enantioselective
process achieved with carbenes that do not have an electron-
withdrawing group.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502909.
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Table 1. Optimization of the rhodium(I)-catalyzed cyclization of diyne
[a]
tosylhydrazone 1aa.
Entry
1
[Rh]
Biphosphine
Base
Yield
ee
[%]
[b]
[%]
[Rh(cod)
[Rh(cod)
[Rh(cod)
[Rh(cod)
[Rh(cod)
[Rh(cod)
[Rh(cod)
[Rh(cod)
[Rh(cod)
[Rh(cod)
[Rh(cod)
2
2
2
2
2
2
2
2
2
2
2
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
]BF
4
4
4
4
4
4
4
4
4
4
4
rac-BINAP
rac-BINAP
rac-BINAP
(R)-BINAP
(S)-BINAP
KOtBu
–
–
–
–
[c]
2
3
4
5
6
7
8
9
1
K
2
CO
3
47
46
58
45
–
>99
>99
–
[d]
(R)-DTBM-Segphos
BIPHEP
–
–
(R)-TolBINAP
(R)-TolBINAP
(R)-TolBINAP
(R)-TolBINAP
(R)-BINAP
–
55
43
48
51
–
>99
n.d.
n.d.
n.d.
–
[
e]
[
f]
0
[g]
11
Scheme 1. Rhodium(I)–carbene-mediated asymmetric transformations.
1
1
2
3
[RhCl(cod)
[Rh (OAc)
2
]
[h]
2
2
]
–
–
[
1
a] Reaction conditions: [Rh(cod)
aa (0.10 mmol, 0.03m), dichloroethane, heat at reflux, 1 h. [b] Yield of
2 4
]BF (10 mol%), (R)-BINAP (10 mol%),
Considering that the formation of vinyl carbenes through
the reaction of alkynes and rhodium(II) carbenoids (carbene–
alkyne metathesis) constitutes an attractive entry to a cascade
isolated product after column chromatography. [c] Reaction time: 1.5 h.
[d] The reaction forms the opposite enantiomer to the one obtained with
(R)-BINAP. [e] Reaction in chlorobenzene at 110 8C. [f] Reaction in chloro-
benzene at 110 8C under microwave heating for 10 min. [g] Reaction con-
centration: 0.01m. [h] Starting material was recovered.
[
11]
processes, we envisioned that the use of rhodium(I) could
afford a new enantioselective cascade process. Therefore,
herein, we aimed to develop a cascade process that was trig-
gered by the decomposition of arylsulfonyl hydrazones, which
are a much safer and more versatile source of donor carbe-
noids, in the presence of a rhodium(I) complex to form a rho-
dium(I) carbenoid that could react in an intramolecular fashion
with an alkyne. Accordingly, we report a cascade process that
is mediated by rhodium(I) vinyl carbenoid intermediates.
The use of a combination of BINAP with a cationic rhodium
source, such as [Rh(cod) ]BF , in the presence of potassium
2
4
tert-butoxide only led to the decomposition of the starting ma-
terial (Table 1, entry 1). Nevertheless, changing the base to po-
[
12]
tassium carbonate
effectively furnished a new cyclization
product 2aa after 1.5 h (entry 2). Careful structural analysis by
NMR spectroscopy (see the Supporting Information) showed
that two new CÀC bonds had formed by a carbocyclization re-
action, hydride migration had constructed a new CÀH bond,
and a tosyl migration led to the generation of a CÀS bond,
Results and Discussion
As a first step, we designed and synthesized a diyne tosylhy-
drazone model substrate 1aa with N-tosyl (NTs) groups as link-
ers (see the Supporting Information for details of the synthe-
sis). We then evaluated the substrate reactivity with a series of
rhodium catalysts (Table 1).
with the corresponding loss of N . To our delight, carrying the
2
reaction out in the absence of a base furnished the product
2aa in the same yield over a decreased reaction time (entry 3).
We then tested the process under enantioselective conditions;
accordingly, the use of either (R)- or (S)-BINAP in combination
with [Rh(cod) ]BF enabled the isolation of the two enantio-
2
4
mers of the cycloadduct 2aa, respectively, with very high enan-
tiomeric excesses (entries 4 and 5). No reaction took place
when the temperature was lowered to 658C, and the use of bi-
phosphines of different steric bulk resulted in a complete loss
of reactivity (entries 6 and 7). (R)-TolBINAP gave analogous re-
sults to those that were obtained with (R)-BINAP (entry 8). The
yield was not improved by increasing the reaction temperature
to 110 8C, by either conventional or microwave heating (en-
tries 9 and 10), or by changing the concentration of the reac-
tion mixture (entry 11). Degradation of the substrate 1aa was
observed when the cationic rhodium source was replaced by
Abstract in Catalan: La reacció catalitzada per rodi(I)/BINAP
de substrats contenint dos alquins i una sulfonilhidrazona
permet sintetitzar compostos nitrogenats amb un grup sulfona
de forma altament enantioselectiva. Aquest nou procØs en casca-
da augmenta considerablement la complexitat molecular ja que
genera dos enllaÅos CÀC, un enllaÅ CÀS i un enllaÅ CÀH. S’ha
proposat un mecanisme per al procØs desenvolupat en base als
resultats obtinguts mitjanÅant càlculs DFT, experiments de com-
petició i marcatge amb deuteri. El mecanisme involucra la forma-
ció d’un vinilcarbenoid de rodi, una inserció migratòria d’hidrur
i un atac nucleofílic intermolecular estereoselectiu. Els dos darrers
passos són claus per a l’enantioselectivitat del procØs.
a neutral one, such as [RhCl(cod) ] (entry 12). The use of
2
[
Rh(OH)(cod) ], either alone or in combination with bases, such
2
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as KOtBu, also led to decomposition of the substrate 1aa. In-
terestingly, no reaction took place when the rhodium(II) dimer
tial of this transformation. Initially, we focused our attention on
establishing whether the migration of the sulfonyl group oc-
curred by an intramolecular or intermolecular pathway. A
crossover experiment between equimolar amounts of reactants
1ab and 1ba, which differ in both the tethers and the aryl
group of the hydrazone, was conducted. The reaction yielded
equal amounts of all four possible products, which clearly indi-
cates that the migration proceeds in an intermolecular manner
(Scheme 2a). To verify the form in which the sulfonyl group
[
Rh (OAc) ], which was previously used in the cyclization of
2 4
[11b]
diazo alkynyl ketones,
was used as the catalyst, even when
the reaction time was prolonged to 24 h. A control reaction
without a transition-metal catalyst showed no reaction and
only recovery of the starting material.
Having developed an extremely interesting new process for
[
13]
the formation of a CÀS bond in an enantioselective manner,
we wished to examine how broadly this transformation could
be applied (Table 2).
I
Table 2. Scope of the Rh -catalysed cyclization of diyne aryl hydrazones
1.
[
a]
Entry
1
X
Y
R
2/2’
Yield
ee of 2
[%]
[
b]
[
%]
1
2
3
4
5
6
7
1aa
NTs
NTs
NTs
NTs
NTs
CH
H
OMe
NO
CH
CH
CH
3
>20:1 58
>99
>99
>99
>99
69
1ab NTs
1ac NTs
1ad NTs
1ba N(2-Ns) N(2-Ns)
1ca
1da
3.2:1 55
>20:1 33
1.4:1 34
>20:1 43
>20:1 45
>20:1 44
[
14]
Scheme 2. Competitive experiments.
2
3
NTs
O
C(CO
NTs
2
Et)
2
3
96
93
3
was transferred, we performed another competitive experi-
ment by adding sodium phenylsulfinate to the cyclization reac-
tion of 1aa, which has a tosylhydrazone group (Scheme 2b).
Analysis by mass spectrometry and NMR spectroscopy revealed
that the reaction afforded a mixture of the expected product
2aa and the competitive product 2ab. The competition of the
external sulfinate anion indicates that the decomposition of
the hydrazone generates a sulfinate anion in situ.
1
[
[
a] Determined by H NMR spectroscopy of the crude reaction mixture.
b] Yield of isolated product after column chromatography.
Changing the p-toluenesulfonyl ring of the hydrazone
moiety to a phenylsulfonyl group promoted the formation of
the two isomers 2 and 2’ in a 3.2:1 ratio, respectively, which
was due to a variation in the positions that the phenylsulfonyl
group migrated to (Table 2, entry 2). Switching to an electron-
donating substituent on the phenyl ring, such as OMe, ensured
that the reaction proceeded with high levels of regioselectivity
We then turned our attention to the CÀH bond that is
formed in the cyclization reaction. The working hypothesis for
this step was that the H atom on the tosylhydrazone was
transferred to the terminal alkyne. To confirm this theory, we
conducted deuterium-labeling experiments. By stirring the cor-
responding substrate 1 in anhydrous dichloroethane in the
(
entry 3). On the other hand, an electron-withdrawing substitu-
ent on the phenyl ring, such as NO , promoted the reaction at
2
the less hindered position and afforded a 1.4:1 ratio of re-
gioisomers 2 and 2’ (entry 4). Therefore, we can assume that
the regioselectivity would be high with electron-rich sulfonyl
substituents on the phenyl ring. The influence of the tether
group was then studied: changing the tosyl group to a 2-nitro-
phenylsulfonyl ring (N(2-Ns)) in the tether gave bicycle 2ba
with a slightly lower level of enantioselectivity (entry 5). The
cycloaddition of substrates 1ca and da, in which one of the ni-
trogenated tethers was substituted by either a malonate or
oxygen, respectively, also furnished the corresponding cycload-
ducts in a highly regioselective and enantioselective way (en-
tries 6 and 7).
presence of 6 equiv of D O, the NH was partially exchanged
2
1
(1:6.1 ratio of products 1 and 1-D, determined by H NMR
1
spectroscopy), which led to a deuterium-enriched sample. H
2
and H NMR spectroscopy revealed the stereoselective incorpo-
ration of the deuterium at the olefinic trans position during
the cyclization reaction under the optimized conditions
(Scheme 3, see the Supporting Information).
To establish a mechanism that could account for the whole
set of experimental results, DFT calculations were performed
[
15]
with the B3LYP functional. The calculations were carried out
on a model substrate, in which the N-tosyl tethers were re-
placed by N-mesyl tethers to reduce the computational cost.
The results are summarized in the Gibbs energy profile in
Scheme 4.
We were eager to gain a better understanding of the reac-
tion mechanism to obtain a greater appreciation for the poten-
Chem. Eur. J. 2015, 21, 16240 – 16245
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[
17]
tene complex. Transformation of intermediate B into C has
À1
a low Gibbs energy barrier of 4.9 kcalmol and releases
À1
2
1
8.5 kcalmol . The 16-electron complex C rearranges to the
8-electron complex D, in which the terminal alkyne group is
2
h -coordinated to the Rh atom. Intermediate D then reacts
with the terminal alkyne to form vinyl rhodium(I) carbene E.
The transformation of intermediate D into E follows the same
reaction pathway as the process that converts intermediate B
into C; it is exergonic by the same energy as in the conversion
À1
from B to C (28.5 kcalmol ), and it has to surmount a Gibbs
À1
energy barrier of 14.6 kcalmol . The conversion from inter-
mediate D to E is the rate-determining step (rds); accordingly,
complex D and the transition state that arises in its conversion
to complex E are the rate-determining intermediate and transi-
Scheme 3. Deuterium-labeling experiments.
[
18]
tion state, respectively. Subse-
quent metal–carbene migratory
insertion, in which the hydride
migrates from the metal to the
5
carbenic carbon, leads to a h -
pentadienyl rhodium intermedi-
ate F. Transformation of complex
E to F is thermodynamically very
À1
favorable (39.4 kcalmol ) and
takes place through an energy
À1
barrier of 11.7 kcalmol . In the
final part of the reaction mecha-
5
nism, the h -pentadienyl rhodi-
um intermediate G, which con-
stitutes complex F interacting
À
with Ts , is attacked by the p-
methylphenylsulfinate anion in
a stereoselective way to furnish
the final cyclized product 2 and
to regenerate the catalytically
active species. This last part of
the reaction is slightly endergon-
À1 [19]
ic (13.2 kcalmol ).
Overall, our data suggests that
the Rh-catalyzed cyclization pro-
ceeds by the mechanism that is
depicted in Scheme 5. The rho-
dium(I) carbenoid is formed
À1
I
Scheme 4. Gibbs energy profile (in kcalmol ) for the cascade reaction of substrate 1 catalyzed by Rh /BINAP to
form product 2.
The first step involves the reaction of the arylsulfonyl hydra-
through a [ 2 + 2 ] addition with the alkyne and subsequent
p s p a
I
zone moiety in substrate 1 with the rhodium catalyst Rh L2
L2 =biphosphine) to give the rhodium carbenoid complex A,
electrocyclic opening of the rhodacyclobutene to release N2
and arylsulfinate, which generates vinyl rhodium carbenes C
and E. A metal-to-carbene migratory insertion step then leads
(
which is stabilized by the coordination of one of the oxygen
[
16]
5
atoms of the sulfonamide moiety with the carbenic carbon.
This process, which releases N and the arylsulfinate, is exer-
to the h -pentadienyl rhodium intermediate F, which under-
goes an intermolecular, stereoselective reaction with the aryl-
sulfinate to furnish the final cyclization product 2 and to re-
generate the catalytically active species.
2
À1
2
gonic by 7.4 kcalmol . Subsequent h -coordination of the Rh
atom to the central alkyne group (Rh···C distances of 2.375 and
2
.639 Š) leads to the rhodium carbenoid B through a process
To further confirm the mechanism, we evaluated the reactivi-
ty of substrate 3 that featured a methyl substituent at the ter-
minal alkyne, in which b-hydride elimination could efficiently
compete after the metal-to-carbene migratory insertion. Sub-
strate 3 was reacted under the optimized conditions to afford
product 4, in which the sulfonyl group was not incorporated
(Scheme 6). Trienic product 4 arises from a b-hydride elimina-
À1
that is slightly exergonic by 2.4 kcalmol . The next step in-
volves a [ 2 + 2 ] addition of the central alkyne to the rhodi-
p
s
p a
um carbenoid double bond and subsequent electrocyclic
opening of the newly formed rhodacyclobutene to yield a new
vinyl rhodium(I) carbene C. A similar ring opening of the rho-
dacyclobutene has already been described in a cobaltacyclobu-
Chem. Eur. J. 2015, 21, 16240 – 16245
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Acknowledgements
This research was funded by the Spanish Ministry of Education
and Science (MINECO) (CTQ2014-54306-P and CTQ2012-32436)
and the DIUE of the Generalitat de Catalunya (2014SGR931,
ICREA Academia 2014 to M.S., and FI predoctoral grant to Ò.T.).
M.S. acknowledges funding through the European Union (EU)
FEDER fund (UNGI10-4E-801).
Keywords: carbenoids
· cascade · cyclization · density
functional calculations · rhodium
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Conclusion
We have described a new stereoselective cascade reaction that
affords a sulfonated azacyclic framework through a process in
which two CÀC bonds are formed and both a hydrogen atom
and a sulfonyl group migrate in a stereoselective manner. We
proposed, with the support of DFT calculations, that this mech-
anism, which has also been studied by competitive and iso-
tope-labeling experiments, takes place through rhodium(I)–car-
bene intermediates and involves a metal-to-carbene migratory
insertion step.
1
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Experimental Section
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1
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[
0
Rh(cod) ]BF (0.0040 g, 0.01 mmol) and (R)-BINAP (0.0068 g,
2 4
.01 mmol) were dissolved in dichloromethane (3 mL) under nitro-
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tion for 30 min, and the resulting mixture was concentrated in
vacuo. The residue was dissolved in 1,2-dichloroethane (1.5 mL),
and a solution of the substrate 1 (0.10 mmol) in dichloroethane
[
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1
1.5 mL) was added. The reaction mixture was heated at reflux for
h (monitoring by TLC). The solvent was evaporated in vacuo and
[
[
the residue was purified by column chromatography on silica gel
to afford the cyclization product 2.
Chem. Eur. J. 2015, 21, 16240 – 16245
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Full Paper
1
22, 7482–7485; c) X. Ma, J. Jiang, S. Lv, W. Yao, Y. Yang, S. Liu, F. Xia, W.
[15] Reported Gibbs energies are B3LYP/cc-pVDZ-PP electronic energies cor-
rected with ZPEs, thermal energies, entropy effects, and solvent effects
(dichloroethane solution). Further computational details are given in
the Supporting Information.
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[16] The hydride transfer from the amino group to the Rh atom can occur
at any step of the reaction mechanism prior to the formation of com-
plex E. In the Gibbs profile that is depicted in Scheme 4, the hydride is
already coordinated to the Rh atom in complex A. We have analyzed al-
ternative pathways in which the incorporation takes place later in the
reaction path (see the Supporting Information); all these alternatives
lead to profiles with higher energy barriers than those that are involved
in the profile shown in Scheme 4. Consequently, we have concluded
that the hydride transfer occurs at the beginning of the reaction mech-
anism, although a later transfer cannot be totally ruled out.
[
7
220.
[
[
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[
12] Treatment of 1aa in dioxane at 1108C in the presence of K
2
CO
3
and
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2
003, 68, 5381–5383; b) M. C. PØrez-Aguilar, C. ValdØs, Angew. Chem.
[19] As we found in deuterium-labeling experiments, the final product 2 in-
corporates the migrated H atom in the olefinic trans position. We have
calculated an alternative reaction pathway that leads to the same final
product 2, but with the transferred H atom in the olefinic cis position
(see the Supporting Information). The latter pathway has a higher
Int. Ed. 2013, 52, 7219–7223; Angew. Chem. 2013, 125, 7360–7364.
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Chem. Asian J. 2013, 8, 2546–2563. For selected recent examples on
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[
À1
energy barrier (25.6 kcalmol ), and its rate-determining step is the
4
202–4221; c) M. Ueda, J. F. Hartwig, Org. Lett. 2010, 12, 92–94; d) X.-S.
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transformation from intermediate E to F. Moreover, complex E, with the
H atom in the cis position, can be easily transformed into the isomeric
complex E with the H atom in the trans position. The latter, which is
1
À1
more stable than the cis conformer by 2.3 kcalmol , evolves rapidly to
1
2584; f) Q.-G. Wang, Q.-Q. Zhou, J.-G. Deng, Y.-C. Chen, Org. Lett. 2013,
the final product.
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2
014, 136, 12161–12165.
[
14] Reactions ran under optimized conditions: [Rh(cod)
BINAP (10 mol%), DCE, heated at reflux, 1 h.
2
]BF
4
(10 mol%), (R)-
Received: July 24, 2015
Published online on September 23, 2015
Chem. Eur. J. 2015, 21, 16240 – 16245
www.chemeurj.org
16245
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim