Stereoselective Csp3-Csp2 Bond-Forming Reactions by Transition-Metal-Free Reductive Coupling of Cyclic Tosylhydrazones with Boronic Acids

Article abstract of DOI:10.1002/chem.201600837

The reactions between alkenylboronic acids and tosylhydrazones derived from substituted cyclohexanones lead to the construction of disubstituted cyclohexanes with total regio- and stereoselectivity. In these transition-metal-free processes, a Csp³-Csp² and Csp³-H bond are formed on the same carbon atom. The stereoselective reaction is general for 2-, 3-, and 4-substituted cyclohexanone tosylhydrazones, as well as for 2-substituted cyclopentanones. However, no stereoselectivity is observed for acyclic derivatives. DFT computational modeling suggests that the stereoselectivity of the reaction is determined by the approach of the boronic acid to the diazocyclohexane on its most stable chair conformation through an equatorial trajectory.

Full text of DOI:10.1002/chem.201600837

DOI: 10.1002/chem.201600837
Communication
&
Organic Chemistry
Stereoselective Csp3–Csp2 Bond-Forming Reactions by Transition-
Metal-Free Reductive Coupling of Cyclic Tosylhydrazones with
Boronic Acids
Manuel Plaza, M. Carmen PØrez-Aguilar, and Carlos ValdØs*[a]
Abstract: The reactions between alkenylboronic acids and
tosylhydrazones derived from substituted cyclohexanones
lead to the construction of disubstituted cyclohexanes
with total regio- and stereoselectivity. In these transition-
metal-free processes, a Csp3ÀCsp2 and Csp3ÀH bond are
formed on the same carbon atom. The stereoselective re-
action is general for 2-, 3-, and 4-substituted cyclohexa-
none tosylhydrazones, as well as for 2-substituted cyclo-
pentanones. However, no stereoselectivity is observed for
acyclic derivatives. DFT computational modeling suggests
that the stereoselectivity of the reaction is determined by
the approach of the boronic acid to the diazocyclohexane
Scheme 1. a) Metal-free Csp3–Csp2 bond-forming reactions from tosylhydra-
on its most stable chair conformation through an equato-
zones and boronic acids. b) This work.
rial trajectory.
selectivity leading to the reductive alkenylation product as
a single diasteroisomer. It is noteworthy that an important limi-
Sulfonylhydrazones are highly versatile intermediates for the
modification of carbonyl compounds. Noteworthy is the dis-
covery over the last fifteen years of a variety of new transition-
metal-catalyzed and also noncatalytic processes based on
these substrates, which has fostered a growing interest in
these intermediates.[1–4] In particular, the reductive cross-cou-
pling between boronic acids and sulfonylhydrazones repre-
sents a very versatile method for the modification of carbonyl
compounds through a transition-metal-free reductive Csp2À
Csp3 bond-forming reaction.[5,6] Since our initial report in 2009,
this transformation has shown considerable usefulness in me-
dicinal chemistry and diversity-oriented synthesis.[7–9]
tation of the reactions based on sulfonylhydrazones or diazo
compounds that proceed without the need of a metal catalyst
is their lack of stereocontrol;[11] therefore, this particular reac-
tion was indeed a rare example of a diastereoselective reaction
based on diazo compounds in the absence of a metal cata-
lyst.[12]
Taking into consideration the ample synthetic possibilities
that these reductive couplings offer, we decided to investigate
in more detail the stereoselectivity of these metal-free Csp3À
Csp2 bond-forming reactions. We envisioned that if a general
stereoselective reaction could be developed, it might represent
a very direct way to achieve a challenging transformation
from carbonyl compounds via their tosylhydrazones: the for-
mation of a Csp3ÀCsp2 bond and a Csp3ÀH bond on the same
carbon atom; therefore, a reductive coupling reaction, in a dia-
stereoselective manner, and in one single synthetic operation
(Scheme 1b).
In this context, the reaction between tosylhydrazones and
alkenylboronic acids is particularly appealing. In a previous
communication,[10] we showed that two different double bond
regioisomers—the olefination product A or the reductive alke-
nylation derivative B, respectively, can be obtained depending
on the nature of both coupling partners, and in a totally pre-
dictable manner (Scheme 1a). Interestingly, in a single particu-
lar example when a 4-substituted cyclohexanone was em-
ployed, the coupling reaction proceeded with total diastereo-
We started our investigation with the tosylhydrazone 1a de-
rived from the corresponding 2-aminomethylcyclohexanone
(Scheme 2). At the outset of this work we believed that this
might be a quite demanding reaction, as this particular mole-
cule consisted in a 2-substituted cyclohexanone featuring a po-
tentially reactive NH group. Our initial efforts were carried out
under the experimental conditions previously developed for
the tosylhydrazone of 4-phenylcyclohexanone, which had re-
sulted in a very high regio- and stereoselective reaction.
Indeed, with these new substrate, the reaction afforded the re-
ductive coupling product 3a as a single diastereoisomer, but
[a] M. Plaza, Dr. M. C. PØrez-Aguilar, Dr. C. ValdØs
Departamento de Química Orgµnica e Inorgµnica
and Instituto Universitario de Química Organometµlica “Enrique Moles”
Universidad de Oviedo, c/Juliµn Clavería 8, Oviedo, 33006 (Spain)
E-mail: acvg@uniovi.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600837.
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Table 1. Stereoselective synthesis of trans-1-aminomethyl-2-(1-alkenyl)cy-
clohexanes 3.
Compd.
R
X
Ar
Yield [%][a]
3a
3b
3c
3d
3e
3 f
Bn
Bn
Bn
Bn
Bn
n-C6H13
n-C4H9
CH2
NBn
NBoc
O
CH2
CH2
CH2
PMP
PMP
PMP
PMP
4-Tol
4-Tol
4-Tol
62
68
56
60
65
66
52
Scheme 2. Preliminary experiments on the reaction between tosylhydra-
zones 1 and boronic acid 2.
3g
was accompanied with a minor amount of the two Z/E isomers
of the olefination product 4; a 10:1 ratio was determined by
GCMS and 1H NMR spectroscopic analysis of the reaction
crude. However, the regioselectivity of the reaction was not re-
produced when the reductive coupling was attempted with
the tosylhydrazones 1b, 1c, and 1d derived from the N-pro-
tected 4-piperidones and 4-pyranone, respectively. In these
cases, the coupling took place with excellent conversion, but
a substantial amount of the regioisomers 4 were obtained in
the reaction crude (Scheme 2).
[a] Isolated yield after column chromatography. Boc=tert-butoxycarbon-
yl; PMP=p-methoxyphenyl.
Table 2. Stereoselective synthesis of trans-1,2-disubstituted cyclohexanes
3.
In an attempt to improve the regioselectivity of the reac-
tions and drive the coupling to the exclusive obtention of the
regioisomer 3, a large set of experiments was conducted for
tosylhydrazones 1a and 1b, with variations in the nature of
the base (Na2CO3, K2CO3, Cs2CO3, CsF, LiOtBu), the solvent (THF,
1,4-dioxane, MeOH, CH3CN), the temperature, and the heating
source. It was found that the regioselectivity could be im-
proved by reducing the temperature of the reaction. The best
results, without compromising the conversion of the coupling
reactions, were obtained by running the reactions at 1208C
under microwave heating, employing a combination of K2CO3
(2 equiv) and CsF (2 equiv), in 1,4-dioxane for 120 min. It must
be noted that the microwave heating turned out to be essen-
tial for the outcome of the reaction, as the results could not
be efficiently reproduced under conventional heating after
testing an array of temperatures and reaction times. Neverthe-
less, under the optimized reaction conditions, the reductive
coupling products 3 could be obtained as single diastereoiso-
mers, and with less than 5% of the olefination regioisomer 4
being detected in the reaction crude.
Compd.
R1
R2
X
Yield [%][a]
5a
5b
5c
5d
5e
5 f
5 g
5h
5i
CH3
CH3
CH3
Bn
Allyl
Allyl
Allyl
Allyl
Ph
Bn
n-Hexyl
ÀCH2À
ÀCH2À
ÀCH2À
ÀCH2À
NBoc
NBoc
NBoc
NBoc
ÀCH2À
ÀCH2À
ÀCH2À
52
56
60
56
58
50
50
65
55
51
63
À(CH2)2OTBDMS
Bn
Bn
n-Propyl
n-Hexyl
À(CH2)2OTBDMS
Bn
n-Propyl
Bn
5j
5k
Ph
CF3
[a] Isolated yield after column chromatography. TBDMS=tert-butyldi-
methylsilyl.
from the reductive coupling were obtained in moderate yield,
and as single regio- and diastereoisomers. Importantly, the re-
action could be applied to both cyclohexanone and 4-piperi-
done tosylhydrazones with similar results.
As depicted in Table 1, the reaction could be performed
with very similar results for tosylhydrazones derived from cy-
clohexanone, pyranone, and N-protected piperidone deriva-
tives with no variation on the regio- and stereoselectivity. Anal-
The same reaction was then explored with tosylhydrazones
derived from 3-substituted cyclohexanones 6. Again, the re-
ductive coupling proceeded with complete regio- and stereo-
selectivity leading to the 1,3-disubstituted cyclohexanes 7, that
featured both substituents at equatorial positions, and, there-
fore, in a cis relationship (Scheme 3). Additionally, under these
reaction conditions, the reductive alkylation of the tosylhydra-
zone derived from 4-phenylcyclohexanone 8 took place also
with complete regio- and stereoselectivity, providing the ex-
pected trans-1,4-disubstituted cyclohexanes 9.
1
ysis of the stereochemistry through H NMR, homonuclear de-
coupling, and bidimensional NMR spectroscopy experiments
revealed that compounds 3 feature both substituents in
a trans equatorial arrangement in the six-membered ring.
Next, we moved to evaluate the employment of other cyclo-
hexanone derivatives, featuring different classes of substituents
at the 2-position, including alkyl, aryl, allyl, and even a trifluoro-
methyl substitution. The main results are highlighted in
Table 2. In all cases, the disubstituted cyclohexanes 5 derived
To test if the diastereoselective reductive cross-coupling of
2-substituted tosylhydrazones 4 could take place with reten-
tion of the configuration on the potentially epimerizable a-
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Scheme 3. Stereoselective synthesis of cis-1,3-disubstituted cyclohexanes 7
and trans-1,4-disubstituted cyclohexanes 9.
Scheme 5. Scope of the stereoselective reductive coupling.
The mechanism proposed for the reactions between tosylhy-
drazones and alkenyl boronic acids involves: 1) the decomposi-
tion of the hydrazone to give a diazo compound I, 2) reaction
of the diazo compound I with the boronic acid II through the
boronate species III, to give the allylboronic acid IV,[16] and
3) protodeboronation of IV that provides the final alkene V
(Scheme 6). It has been previously observed that the protode-
Scheme 4. Synthesis of enantiomerically pure alkenes 12 from (À)-menthol.
carbon atom,[13] we selected the tosylhydrazone 11, that can
be readily obtained as a unique enantiomer from (À)-menthol
(Scheme 4). Both menthone and its tosylhydrazone 11 have
been reported to undergo easy partial epimerization of the a-
carbon atom,[14] but nevertheless 11 has been successfully em-
ployed for the synthesis of sterochemically pure menthol deriv-
atives through Shapiro reactions.[15] In our case, when freshly
prepared tosylhydrazone 11 was treated with the alkenyl bo-
ronic acid under our standard conditions, the reductive cou-
pling product was obtained as a unique enantiomer, showing
that the whole process from (À)-menthol, including the reduc-
tive coupling reaction had taken place without epimerization
(Scheme 4).
The reductive coupling reaction was also explored by em-
ploying tosylhydrazones derived from other cyclic and also
acyclic ketones, to establish the scope of the stereoselective
transformation. When the couplings were conducted with
tosylhydrazone 13, derived from 2-methylcyclopentanone, the
expected 1,2-disubstituted cyclopentanes 14 were obtained
again as single regio- and diastereoisomers (Scheme 5). There-
fore, according to this result, the stereoselective reductive cou-
pling is also useful for the modification of 2-substituted cyclo-
pentanones. However, when the same transformation was at-
tempted with cycloheptanone derivative 15, a 1:1 mixture of
the two diastereoisomers of cycloheptane 16 was detected in
the reaction crude.
Scheme 6. Mechanism proposed for the reductive alkenylation.
boronation of tertiary boronic esters takes place with retention
of the configuration under conditions quite similar to those
employed herein.[17] If a similar mechanism operates for the
protodeboronation of the allylboronic acids, the stereochemi-
cal control should come from the formation of the intermedi-
ate allylboronic acid IV. Thus, to explain the stereoselectivity
observed in the reductive alkenylation reactions, a DFT-based
computational study of the addition of the boronic acid to the
diazo compound was conducted.[18]
As a model reaction, the addition of E-1-propenylboronic
Finally, the coupling reaction with tosylhydrazone 17, as an
example of an acyclic system led to the expected alkene, but
again as a nearly 1:1 mixture of diastereoisomers 13. These
latter results clearly establish the need of a rigid cyclic system
to enable the stereoselective reaction.
acid II to 1-diazo-4-methylcyclohexane I was considered
(Scheme 7). In our initial studies, the starting geometries were
chosen by considering the methyl group in an equatorial posi-
tion. Interestingly, it was found that the boronate species typi-
cally proposed as an intermediate in these reactions (III in
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trajectory leads to allylboronic acid IVeq, and after the proto-
deboronation, to the cyclohexane that features both substitu-
ents in equatorial positions, in agreement with the experimen-
tal observations.
In summary, we have reported a general stereoselective re-
ductive alkenylation of substituted cyclohexanones and cyclo-
pentanones by their tosylhydrazones by a operationally simple
reaction that does not require the participation of any metal
catalyst. Noteworthy is that these are rare examples of uncata-
lyzed stereoselective reactions based on diazo compounds. A
rationale for the complete stereoselectivity observed can be
found in the asynchronus concerted transition state that leads
to the intermediate allyl boronic acid, which is notoriously fa-
vored through an equatorial trajectory. From a synthetic point
Scheme 7. DFT computational modelling of the reaction between 1-diazo-4-
methylcyclohexane I and 1-propenylboronic acid II at the M06-2X/6-
311+ +G**/PCM(1,4-dioxane) level.
Scheme 6) is not an intermediate but a transition state in the of view, the methodology introduced herein represents a very
potential energy surface. According to this result, the forma- powerful tool for the diastereoselective modification of substi-
tion of the allylboronic acid IV takes place through a very asyn- tuted cyclic ketones by the simultaneous formation of a Csp3À
chronous concerted process, in which the release of N2, the Csp2 and Csp3ÀH bond. Importantly, this is a transformation for
formation of the Csp3ÀB bond, the cleavage of the BÀCsp2 which no other simple alternative is available. Considering the
bond and the formation of the Csp3ÀCsp2 bond occurs in one wide availability of enantiomerically pure substituted cyclo-
single step (Scheme 7, Figure 1).[12,19]
hexanones and cyclopentanones from the chiral pool and also
through a variety of asymmetric catalytic reactions, we think
that this method will be highly useful in organic synthesis.
Acknowledgements
Financial support of this work by Ministerio de Economía y
Competitividad of Spain (Grant: MINECO-CTQ2013-41336-P),
a FICYT (Principado de Asturias) predoctoral fellowship to M.P.
and a FPI predoctoral fellowship (Ministerio de Economía y
Competitividad of Spain) to M.C.P.-A. are gratefully acknowl-
edged. We wish to thank Dr. Isabel Merino for assistance in
NMR stereochemical analysis.
Keywords: boronic acids · diazo compounds · reductive
coupling · stereoselectivity · tosylhydrazones
Figure 1. Transition states obtained for the reaction between diazo com-
pound I and 1-propenylboronic acid II (M06-2X/6-311+ +G**).
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[19] Exhaustive attempts to locate a boronate complex as an intermediate
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that indeed the proposed TS connects the reagents with the allylboron-
ic acid.
[20] Two additional saddle points (TSeq’ and TSax’) are expected consider-
ing the chair conformation that features the methyl group in an axial
position. TSeq’ features a Gibbs free energy 1.3 kcalmolÀ1 higher than
the analogous TSeq. This value is very close to the energy difference
calculated for the two chair conformers of 4-methyldiazocyclohexane.
Although the energy difference between TSeq and TSeq’ is not large in
this particular example, this value will depend on the specific substitu-
ents for other substituted diazocyclohexanes. Therefore, larger substitu-
ents are expected to feature larger energy differences between both
transition states (see the Supporting Information).
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Received: February 22, 2016
[13] For previous examples from our group of reactions of tosylhydrazones
that proceed without epimerization of the a-carbon atom, see: a) J. Bar-
Published online on March 21, 2016
Chem. Eur. J. 2016, 22, 6253 – 6257
www.chemeurj.org
6257
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