Palladium-Catalyzed Asymmetric Hydrosulfonylation of 1,3-Dienes with Sulfonyl Hydrazides

Article abstract of DOI:10.1002/anie.202012485

A highly enantio- and regioselective hydrosulfonylation of 1,3-dienes with sulfonyl hydrazides has been realized by using a palladium catalyst containing a monodentate chiral spiro phosphoramidite ligand. The reaction provided an efficient approach to synthetically useful chiral allylic sulfones. Mechanistic studies suggest that the reaction proceeds through the formation of an allyl hydrazine intermediate and subsequent rearrangement to the chiral allylic sulfone product. The transformation of the allyl hydrazine intermediate to the product is the enantioselectivity-determining step.

Full text of DOI:10.1002/anie.202012485

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Accepted Article
Title: Palladium-Catalyzed Asymmetric Hydrosulfonylation of 1,3-
Dienes with Sulfonyl Hydrazides
Authors: Qi-Lin Zhou, Ming-Ming Li, Lei Cheng, Li-Jun Xiao, and Jian-
Hua Xie
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Palladium-Catalyzed Asymmetric Hydrosulfonylation of 1,3-
Dienes with Sulfonyl Hydrazides
Ming-Ming Li,[a] Lei Cheng,[a] Li-Jun Xiao,[a] Jian-Hua Xie,[a] and Qi-Lin Zhou*[a]
[a]
M.-M. Li, L. Cheng, Dr. L.-J. Xiao, Prof. J.-H. Xie, Prof. Q.-L. Zhou
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
E-mail: qlzhou@nankai.edu.cn
Supporting information for this article is given via a link at the end of the document
Abstract: A highly enantio- and regioselective hydrosulfonylation of
bisphosphine ligands have been evaluated, the hydrosulfonylation
product 3a was obtained in only moderate yield and up to 56% ee (for
details, see Supporting Information).It is delighted that when we use
palladium catalyst bearing monodentate chiral spiro phosphoramidite
ligand L4 the hydrosulfonylation product, 3,4-Markovnikov branched
allylic sulfone 3a, was obtained in 85%yield and 64% ee (Table 1,
entry 4). Other monodentate chiral spiro phosphorus ligands or
1,3-dienes with sulfonyl hydrazides has been realized by using
palladium
catalyst
containing
monodentate
chiral
spiro
phosphoramidite ligand. The reaction provided efficient approach to
the synthetically useful chiral allylic sulfones. Mechanistic studies
suggest that the reaction proceeds through a formation of allyl
hydrazine intermediate and subsequent rearrangement to the chiral
allylic sulfone product. The transformation of the allyl hydrazine
intermediate to the product is enantioselectivity-determining step.
Optically active organic sulfur compounds occur in various
natural and bio-active systems.[1] In particular, the chiral allylic
sulfones exhibit rich biological activities such as antibacterial, and
antiviral activities (Figure 1).[2] Many efforts have been devoted to
the development of the methodology for the synthesis of chiral
allylic sulfones. The asymmetric allylic substitution with sulfur
reagents[3] and asymmetric hydrogenation reaction[4] are
demonstrated to be efficient methods for the synthesis of chiral
allylic sulfones. Transition metal-catalyzed asymmetric
hydrofunctionalization reactions of 1,3-dienes, allenes, and
alkynes with different nucleophiles or electrophiles provided a
straightforward and atom-economical approach to the chiral allylic
compounds.[5] Among them, the hydrothiolation has been applied
in the enantioselective synthesis of chiral allylic sulfones, however
one oxidation step was required. For example, in 2014, Breit and
Figure 1. Examples of natural products and drugs containing chiral sulfone
motifs
co-workers developed
a
Rh-catalyzed enantioselective
hydrothiolation of allenes, followed by oxidation of the products,
giving chiral allylic sulfones (Scheme 1a).[6] In 2018, Dong et al.
reported an enantioselective hydrothiolation of 1,3-dienes,
affording 1,2-Markovnikov sulfide products, which could be
converted to chiral allylic sulfones by oxidation (Scheme 1b).[7]
However, in contrast, the synthesis of chiral allylic sulfone
compounds from direct enantioselective hydrosulfonylation of
dienes remains a challenge. As a part of our continuous research
interests in developing methods for the synthesis of chiral allylic
compounds through asymmetric hydrofunctionalization of
dienes,[8]
we
studied
Pd-catalyzed
enantioselective
hydrosulfonylation of 1,3-dienes with sulfonyl hydrazides and
obtained chiral allylic sulfones with perfect 3,4-Markovnikov
regioselectivity and high enantioselectivity (Scheme 1c).
Scheme 1. Enantioselective hydrofunctionalization of unsaturated
hydrocarbons for the synthesis of chiral allylic sulfones
We first studied the reaction of p-toluenesulfonyl hydrazide
(2a) (1.0 equiv) with 1-phenylbutadiene (1a) (2.0 equiv) using
nickel catalysts we developed in the hydroarylation of styrenes
and 1,3-dienes.[9] However, although various chiral mono- or
diphosphine ligand gave low enantioselectivity (entries 1–3 and
5). Solvent’s evaluation showed that the diglyme is the choice of
solvent, giving higher enantioselectivity (75% ee, entry 8). The
enantioselectivity of reaction was increased to 89% ee by adding
1
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p-toluenesulfonic acid (50 mol %) (entry 11),[10] and was further
enhanced to 93% ee at a lower temperature (60 °C) (entries 13
and 14).
aliphatic 1,3-dienes (1u and 1v) were investigated in the
hydrosulfonylation reaction with hydrazide 2a, however, a mixture
of 3,4- and 1,2-addition products was obtained.
Table 2 Enantioselective hydrosulfonylation with various dienes[a]
Table 1. Enantioselective hydrosulfonation of diene, Optimization of reaction
conditions[a]
Entry
Ligand
L1
additives
none
Solv.
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
yield (%)[b]
ee (%)[c]
2
1
2
95
41
93
85
64
81
85
84
85
89
91
90
73
92
L2
none
2
3
L3
none
37
64
5
4
L4
none
5
L5
none
6
L4
none
44
74
75
63
70
89
65
93
93
7
L4
none
THF
8
L4
none
diglyme
9
L4
PhCOOH
PhCH2COOH
TsOH
diglyme
10
11
12
13[d]
14[d],[e]
L4
diglyme
L4
diglyme
L4
(PhO)2P(O)OH
TsOH
diglyme
L4
diglyme
L4
TsOH
diglyme
[a] Reaction conditions: 1-phenylbutadiene (1a) (0.2 mmol), p-toluenesulfonyl
hydrazide (2a) (0.1 mmol), Pd(OAc)2 (0.01 mmol), ligand (0.01 mmol), additive
(0.05 mmol), solvent (0.5 mL) at 80 °C for 12 h. [b] Isolated yield. [c] Determined
by chiral HPLC. [d] At 60 °C , 24h. [e] Use 0.012 mmol ligand.
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.1 mmol), Pd(OAc)2 (0.01 mmol),
ligand L4 (0.012 mmol), p-toluenesulfonic acid (0.05 mmol), diglyme (0.5 mL)
at 60 °C for 24 h. Isolated yield. Regioselectivity of product was determined by
1H NMR. [b] E/Z configuration of aromatic dienes had no effect on the yield and
selectivity of the reaction. [c] Temperature: 80 °C. [d] Combined yield.
Having the optimized reaction conditions, we evaluated the
substrate scope of the reaction. Various 1,3-dienes can react with
p-toluenesulfonyl hydrazide (2a) to produce allylic sulfones (Table
2). The aromatic dienes showed perfect regioselectivity in the
reaction and only formed 3,4-Markovnikov addition product. It is
noteworthy that the E/Z mixture of 1,3-diene 1a gives the same
result as the pure E-isomer. The absolute configuration of the
product 3a was determined by X-ray diffraction analysis of single
crystal. Most of the tested para- and meta-substituted aromatic
dienes (1b–1g and 1j–1l) reacted with hydrazide 2a to afford
hydrosulfonylation products in good yield (71–86%) and high
enantioselectivity (86–94% ee), however the substrates
containing para-dimethylamino (1h) and para-methylthio (1i)
groups have slightly lower enantioselctivity (70% ee and 72% ee,
respectively). The ortho-substituted aromatic dienes 1m and 1n
have 89% ee and 78% ee of enantioselectivity. The dienes with
3,4-methylenedioxyphenyl (1o), 2-naphthyl (1p), thienyl (1q) and
furyl (1r) also showed good yield and high enantioselectivity. 1,2-
Disubstituted diene 1s also worked in high enantioselectivity
(94% ee), albeit with moderate yield. The internal diene 1t
afforded 79% ee of enantioselectivity, but with a poor yield (37%)
in the present reaction conditions. Besides aromatic dienes, the
We then studied the scope of sulfonyl hydrazides 2. As
shown in Table 3, variation of electronic effect of the phenyl
sulfonyl hydrazides had no influence on both yield and
enantioselectivity of hydrosulfonylation reaction (2a–2f). 1-
Naphthyl sulfonyl hydrazide (2g) showed moderate yield and
good enantioselectivity. In addition to aromatic sulfonyl
hydrazides, aliphatic sulfonyl hydrazides (2h–2l) can also be
efficient sulfonylation reagents, albeit the 3-chloropropyl sulfonyl
hydrazide (2l) gives a lower yield (51%).
To probe the reaction mechanism, we conducted several
control experiments (see Supporting Information). The reaction
was stopped at 1 hour and the racemic hydrazide intermediate 3′
was isolated as main product (see SI 6a). When the intermediate
3′ was treated under standard reaction conditions, sulfone
product 3a was obtained in 98% yield with 91% ee (see SI 6b).
These two experiments indicated that the enantioselectivity of the
reaction was determined during the conversion of hydrazide
intermediate 3′ to sulfone product 3a,[11] ruling out the process of
chirality transfer of the intermediate 3′.[12] A cross reaction of 4-
2
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methoxylphenyl buta-1,3-diene (1c) and the intermediate 3′
afforded a mixture of sulfones 3a (47%, 88% ee) and 3c (46%,
91% ee), indicating that the transformation of diene to the
intermediate 3′ is reversible (see SI 6c). Tracing the reaction
process showed that the intermediate 3′ was quickly accumulated
at about half an hour, and then was gradually transformed into the
product 3a (see SI 6d). It is worth noting that when the reaction
was performed without adding p-toluenesulfonic acid, the
intermediate 3′ was obtained with 67% yield and 78% ee after 5
hours (see SI 6e). This means that the addition of the acid
changes the reaction pathway, and accelerates the conversion of
the intermediate 3′ to product 3a.
dienes,[13] we proposed a mechanism for the enantio- and
regioselective hydrosulfonylation of 1,3-dienes with sulfonyl
hydrazides (Scheme 2). The reduction of Pd(II) complex by
hydrazide formed Pd(0) species I. Depending on adding TsOH or
not, there are two possible paths that generate intermediate 3′:
Path A, with TsOH. The Pd(0) underwent oxidative addition with
TsOH to yield Pd−H species II, which coordinated with diene 1a
followed by insertion of hidride into terminal double bond,
providing Pd-π-allyl complex IV. The nucleophilic attack of
sulfonyl hydrazide to the complex IV gave intermediate 3′ with low
enantioselectivity (see SI 6a); Path B, without TsOH. The Pd(0)
underwent oxidative addition with sulfonyl hydrazide to yield
Pd−H species II′, which coordinated with diene 1a to form
intermediate III′. The insertion of Pd−H of III′ into the terminal
double bond of diene generated Pd-π-allyl complex IV′, which
was attacked by sulfonyl hydrazide to form 3′ with 78% ee (see SI
6e). Since TsNHNH2 is more than TsOH in the beginning of
Table 3 Enantioselective hydrosulfonylation with various sulfonyl hydrazides[a]
reaction, the pathway
B was dominant. As the reaction
progresses, the TsNHNH2 was consumed and the pathway A
gradually became dominant, and the ee value of intermediate 3′
dropped (see SI 6d). The ligand exchange of Pd(II) species II with
intermediate 3′, followed by β-H elimination generated diazene
intermediate VI.[11] The oxidative addition of Pd(0) with VI and
releasing nitrogen produced the intermediate VII. Finally, the
reductive elimination of VII delivered the hydrosulfonylation
product 3a and regenerated Pd(0) species I.[14]
In summary, we developed
a
highly enantio- and
regioselective hydrosulfonylation of 1,3-dienes with sulfonyl
hydrazides catalyzed by palladium complex of monodentate chiral
spiro phosphoramidites. The reaction provides a new strategy for
the synthesis of chiral allylic sulfones in high enantioselectivity.
Mechanistic studies suggest that the reaction proceeds through a
formation of allyl hydrazine intermediate and subsequent
conversion of intermediate to chiral allylic sulfone product. The
enantioselectivity of the reaction was controlled at the reductive
elimination step.
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.1 mmol), Pd(OAc)2 (0.01 mmol),
ligand L4 (0.012 mmol), p-toluenesulfonic acid (0.05 mmol), diglyme (0.5 mL) at
60 °C for 24 h. Isolated yield.
Based on aforementioned experiments and previous reports
on the Pd-catalyzed hydrofunctionalization of conjugated
Scheme 2. Proposed mechanism
3
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[13] For reviews, see: a) B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103,
2921–2944; b) J. D. Weaver, A. Recio III, A. J. Grenning, J. A. Tunge, Chem.
Acknowledgements
Rev. 2011, 111, 1846–1913; c) G. Li, X. H. Huo, X. Y. Jiang, W. B. Zhang, Chem.
We thank the National Natural Science Foundation of China
(Nos. 21532003, 21790332, 21871152 and 91956000), the “111”
project (B06005) of the Ministry of Education of China and the
Fundamental Research Funds for the Central Universities
(Nankai University, 020-63191746) for financial support.
Soc. Rev. 2020, 49, 2060–2118.
[14] During the preparation of this manuscript, an enantioselective
hydrosulfonylation of internal 1,3-dienes with sulfinic acids using Pd/DTBM-
Segphos catalyst was reported by Zi et al.: 10.1021/jacs.0c05976. In that
research, the internal dienes performed well, and is complementary to this work.
Keywords: asymmetric hydrosulfonylation • 1,3-dienes • sulfonyl
hydrazides • palladium • chiral sulfone
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Table of Contents
5
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