Construction of enantioenriched polysubstituted hexahydropyridazines via a sequential multicatalytic process merging palladium catalysis and aminocatalysis

Article abstract of DOI:10.1039/c5ob02437d

An efficient multicatalytic strategy for the construction of nitrogen-containing heterocycles has been reported. The powerful combination of organic and metal catalysis in a single vessel allowed the formation of enantioenriched polysubstituted cyclic 6-membered hydrazines bearing a quaternary stereocenter in good yields and selectivities.

Full text of DOI:10.1039/c5ob02437d

Organic &
Biomolecular Chemistry
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Construction of enantioenriched polysubstituted
hexahydropyridazines via a sequential
multicatalytic process merging palladium catalysis
and aminocatalysis†
Cite this: DOI: 10.1039/c5ob02437d
Received 27th November 2015,
Accepted 8th February 2016
DOI: 10.1039/c5ob02437d
www.rsc.org/obc
A.-S. Marques, M. Giardinetti, J. Marrot, V. Coeffard,* X. Moreau* and C. Greck
An efficient multicatalytic strategy for the construction of
nitrogen-containing heterocycles has been reported. The powerful
combination of organic and metal catalysis in a single vessel
allowed the formation of enantioenriched polysubstituted cyclic
6-membered hydrazines bearing
good yields and selectivities.
a quaternary stereocenter in
Asymmetric catalysis remains a challenge to synthetic chemists
as the demand for enantiomerically enriched drug-like mole-
cules continues to increase.1 Inspired by the cooperative cata-
lysis in enzymatic processes, the combination of different
catalysts to reach an inaccessible synthetic efficiency and
stereoselectivity by a single catalyst has attracted increasing
attention over the past few years.2 The development of multi-
catalytic processes that merge the complementary activation
offered by a metal and an organocatalyst has allowed the con-
struction of enantioenriched complex structures from simple
starting materials.3 In the meantime, nitrogen-containing het-
erocycles are ubiquitous building blocks in natural products4
and pharmaceuticals.5 Among the wide variety of structures,
cyclic hydrazines represent an interesting class of compounds
owing to their presence in a myriad of molecules of biological
interest.6 Numerous efficient syntheses of hydrazine-contain-
ing heterocycles have been reported in the literature7 and the
main strategies to construct enantioenriched structures
include sequential multi-step sequences or one-pot processes
(Scheme 1). Electrophilic amination8 was generally chosen for
the stereoselective formation of the nitrogen-containing stereo-
center and the cyclization step involved ring-closure meta-
thesis,9 the Wittig reaction10 or SN2 reaction.11 Catalytic
asymmetric [4 + 2] cycloaddition with diazene compounds has
also been reported as a straightforward method to such
Scheme 1 Main strategies towards hexahydropyridazines.
motifs.12 Despite these elegant achievements, enantioselective
examples remain scarce and there is still a need for original
catalytic methods aiming at synthesizing chiral polyfunctiona-
lized structures. In connection with our ongoing program
devoted to the preparation of nitrogen-containing hetero-
cycles,13 we describe herein a multicatalytic approach for the
synthesis of enantioenriched cyclic 6-membered hydrazines.
The reaction sequence involves a stereoselective organocataly-
tic C–N bond formation followed by an unprecedented palla-
dium-catalyzed cyclization reaction of 4,5-allenylic hydrazine
with aryl halides14 to afford hexahydropyridazines bearing a
quaternary stereocenter (Scheme 1). Inspired by our previous
work providing enantioenriched α-hydrazino aldehydes,15 we
reasoned that the aminocatalyzed α-amination of aldehydes 1
could afford the key intermediates that would undergo cycliza-
tion under palladium catalysis. We also assumed that the
intramolecular formation of the second C–N bond could be
Institut Lavoisier Versailles, UMR CNRS 8180, Université de Versailles-St-Quentin-en-
Yvelines, 45 Avenue des États-Unis, 78035 Versailles cedex, France.
E-mail: vincent.coeffard@uvsq.fr, xavier.moreau@uvsq.fr
†Electronic supplementary information (ESI) available. CCDC 1438954. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c5ob02437d
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facilitated by a gem-disubstituent effect induced by the stereo- selective α-amination (aldehyde (1.5 equiv.), di-tert-butylazodi-
center formed in the first step.16
carboxylate (DtBAD, 1 equiv.), catalyst 5 (5 mol%), TFA
The starting aldehydes 1 were readily prepared according to (15 mol%) in CHCl3 ([DtBAD] = 0.5 M)) and a Pd catalyst used
the synthetic strategy depicted in Scheme 2. Benzyl bromide under the conditions described by Ma20 (hydrazine 6a
derivatives 2 were converted into the corresponding benzyl (1 equiv.), PhI (1.2 equiv.), Cs2CO3 (1.1 equiv.), and [Pd(PPh3)4]
cyanides 3 by treatment with trimethylsilyl cyanide under (5 mol%) in MeCN ([6a] = 0.08 M)) was efficient for a sequen-
basic conditions.17 After deprotonation of 3 with sodium tial process (Scheme 3, eqn (1)). The challenge was then to
hydride in N,N-dimethylformamide, the addition of 5-iodo-
penta-1,2-diene18 enabled the preparation of 4a and 4b in 33%
and 27% yields respectively. The nitrile moiety was finally
reduced by using diisobutylaluminium hydride in dichloro-
methane to provide the aldehydes 1.
With the substrate 1a in hand, the transformation was first
investigated as a two-step protocol. Preliminary studies19
revealed that a combination of 9-amino(9-deoxy)epi-quinine 5
used under the previously reported conditions for the enantio-
Scheme 2 Synthesis of 1: (step 1) TMSCN, K2CO3, MeCN, 60 °C, 16 h;
(step 2) (i) NaH, DMF, 0 °C, 1 h; (ii) 5-iodopenta-1,2-diene, 0 °C, 0.5 h,
r.t., 0.5 h; (step 3) DIBAL, CH2Cl2, −78 °C, 3 h.
Fig. 1 Scope of the one-pot sequence (major diastereomers are drawn;
yields of the isolated mixture of diastereomers; dr have been determined
by 1H NMR analysis of the crude product, see the ESI† for details).
Scheme 3 Optimization of the sequential multicatalysis.
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optimize these conditions toward a one-pot procedure. In aromatic ring could influence the efficiency and stereo-
order to circumvent the compatibility problems (acidic selectivity of the reaction. Starting from 4-, 3-, or 2-iodo-
medium of the first step and basic medium of the second one, toluene, the formation of the corresponding cyclic hydrazines
solvent systems), a sequential multicatalysis, which describes was accompanied by a continuous decrease in reactivity and
reactions that rely on the addition of another catalyst or/and diastereoselectivity in the following order: para (8, 55% yield,
reagents to initiate a subsequent catalytic cycle, was envisaged. 3/1 dr), meta (9, 49% yield, 2.5/1 dr), ortho (10, 21% yield, 2/1
We also accounted for the difference in concentration in the dr) showing that the second step of the sequence was influ-
two reaction media to homogenize the solvent system. Hence, enced by the steric hindrance of the iodoarene coupling
the reaction of 2-phenylhepta-5,6-dienal 1a with DtBAD in the partner. We then focused our attention on the influence of the
presence of aminocatalyst 5 (5 mol%) and TFA (15 mol%) in electronic nature of the substituent of the aromatic ring on the
CHCl3 was carried out under stirring overnight at room temp- outcome of the reaction. Employing an electron-rich aryl
erature and the mixture was diluted with MeCN. [Pd(PPh3)4] group like para-iodoanisole for the multicatalytic process
(5 mol%) and a slightly increased amount of iodobenzene and afforded 11 in 56% yield and 3/1 dr. Identical results as for 7
Cs2CO3 (1.4 instead of 1.2 equiv.) were then added and the (67% yield, 3/1 dr) were obtained when aromatics with elec-
reaction mixture was stirred at 75 °C for 24 h to ensure com- tron-withdrawing substituents such as an ester (compound 12)
pletion of the cyclization (Scheme 3, eqn (2)). The expected or a fluorine atom (compound 13) were used in the transform-
product 7 was obtained in 67% yield as a 3/1 mixture of dia- ation. A slight decrease in the reaction rate was observed when
stereomers and a high level of enantioselectivity (94% ee).
the sequence was performed with 1-iodo-4-nitrobenzene and
With the optimized conditions in hand, the scope of the the corresponding hexahydropyridazine 14 was synthesized in
sequence was surveyed using various iodoarenes (Fig. 1). We 49% yield and 3/1 dr. Finally, aldehyde 1b was employed in
first examined whether the position of a methyl group on the the sequence with iodobenzene as the coupling partner and
compound 15 was isolated in 61% yield and 3/1 dr. It is worth
noting that due to the high enantioselectivity reached during
the first step, compounds 7–14 were obtained in 94% ee and
compound 15 with 93% ee.
The absolute configuration of the stereocenter formed
during the electrophilic amination step, obviously S, if we
referred to our previous work, has been confirmed by X-ray
analysis of a single crystal of a minor diastereomer of com-
pound 13. Therefore, absolute and relative configurations of
all other products have been assigned by analogy to be (1S,4R)
for major diastereomers and (1S,4S) for the minor ones
(Fig. 2).
Fig. 2 X-Ray structure for compound 13 (minor diastereomer).
Scheme 4 Proposed mechanism for the sequential multicatalysis.
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Based on the above results related to the sequential multi-
catalysis, a plausible double catalytic cycle is proposed in
Scheme 4. The first catalytic cycle which corresponds to the
known organocatalytic α-amination would start by the for-
mation of the enamine A which would react with DtBAD to
afford the iminium intermediate B. A subsequent hydrolysis
would regenerate the primary amine catalyst 5 and would liber-
ate the α-hydrazino aldehyde 7. Based on a mechanistic study
published by Melchiorre in 2013,21 a postulated transition
state explaining the Si face selectivity of the addition was pro-
posed. The second catalytic cycle would start by the oxidative
addition of aryl iodide to palladium(0) followed by the inser-
tion of this complex to the allene moiety of the newly syn-
thesized compound 7. An intramolecular reaction to form
cyclic 6-membered heterocycles between hydrazine and π-allyl
species of intermediate C in the presence of a base would give
rise to hexahydropyridazines 7–15. The low diastereo-
selectivities could originate from the existence of different con-
formations for C which are in equilibrium. This would lead to
both diastereomers of the cyclization product.
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2-arylhepta-5,6-dienal. The overall protocol involves an organo-
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Acknowledgements
The authors thank the LabEx CHARM3AT for financial support
(A.-S.M.) and the University of Versailles-St-Quentin-en-Yve-
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