Olefin Preparation via Palladium-Catalyzed Oxidative De-Azotative and De-Sulfitative Internal Cross-Coupling of Sulfonylhydrazones

Article abstract of DOI:10.1021/acs.orglett.5b01494

A novel reactivity of sulfonylhydrazones under Pd catalysis is described, where SO₂ and N₂ are formally extruded to afford the product of an apparent internal coupling reaction. The reaction is effective with both carbocyclic and heterocyclic aromatic precursors.

Full text of DOI:10.1021/acs.orglett.5b01494

Letter
pubs.acs.org/OrgLett
Olefin Preparation via Palladium-Catalyzed Oxidative De-Azotative
and De-Sulfitative Internal Cross-Coupling of Sulfonylhydrazones
Hongyu Tan,†,§ Ioannis Houpis,*,‡ Renmao Liu,§ Youchu Wang,§ and Zhilong Chen*,†
†Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai 201600,
P. R. China
‡Janssen Pharmaceutica, API Development, Turnhoutseweg 30, 2340 Beerse, Belgium
§STA Pharmaceuticals, 288 Fute Zhong Road, Shanghai 200131, P. R. China
S
* Supporting Information
ABSTRACT: A novel reactivity of sulfonylhydrazones under
Pd catalysis is described, where SO2 and N2 are formally
extruded to afford the product of an apparent internal coupling
reaction. The reaction is effective with both carbocyclic and
heterocyclic aromatic precursors.
Scheme 1. Reaction of Sulfonylhydrazone 7 under Pd
Catalysis
he synthesis of highly substituted olefins from activated
ketone derivatives such as enol perfluoro-sulfonates and
T
boronic acids or sulfonyl hydrazones and aryl halides has
been used extensively in synthesis. During the preparation of an
active pharmaceutical ingredient, we reported an interesting
side reaction which was observed during our attempts to couple
sulfonylhydrazones with aryl bromides bearing α-amino groups.1
We reported that the reaction of 1 with the aryl bromide 3
(Ar1 = o-anilino derivative) produced the expected Barluenga
product2 4, albeit under modified reaction conditions (eq 1).
nucleophilic and electrophilic coupling partners, they would
both be contained in the same molecule (Scheme 1).4
Our investigation started with the tosyl hydrazone of aceto-
phenone (7, Scheme 1) which, when subjected to our optimized
reaction conditions Pd(OAc)2, [t-Bu2PMe]HBF4, K2CO3 in
dimethylacetamide at 100 °C, afforded a 25% yield of the
desired product 8. In addition, the sulfinic acid 9 was observed,
as expected (see companion paper), along with the intriguing
product 10 and diene 11. Our initial assumption was that 8
was formed by the combination of a vinyl Pd species (from
the decomposition of the diazo intermediate C, Scheme 2) and
sulfinate B (i.e., 9 in Scheme 1).5 However, when the reaction
was performed with 1 equiv of catalyst, a 90% yield of 8 was
isolated from the reaction mixture without a trace of 9−11.
This interesting result prompted us to speculate that a Pd(II)
species (Scheme 2) was responsible for the desired product 8,
while the impurities 9−11 were produced by side reactions of C
that may or may not involve Pd.6 Interestingly, no cyclopropane
However, in the presence of an electron-rich sulfonylhydrazone
(such as 1) significant amounts of the “internal” cross-coupled
product 5 were formed as well. The formation of the latter
could be suppressed, in order to meet our synthetic needs, by
employing electron-deficient substrates of the general structure
2. In that case none of the “internal” product 6 was observed
and 4 was obtained in high yield.
We found the formation of 5 intriguing and considered the
possibility of using this side reaction synthetically. We
envisioned using it as a more general and atom-economical
way to prepare olefins from ketones and various aryl or hetero-
arylsulfonylhydrazones.3 If we could force the two organic
moieties to couple intramolecularly, extruding SO2 and N2,
we may have an alternative to the more traditional, stepwise,
ketone activation by enol derivative formation followed by
transition-metal-catalyzed coupling with organometallic com-
pounds. In other words, instead of separately preparing the
Received: June 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01494
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Organic Letters
Letter
Scheme 2. Mechanistic Possibilities for the Formation of I
Table 1. Exploration of Oxidant, Solvent, and Ligand in the
Reaction of 7 under Pd-Catalysis
a
b
entry
L
oxidant
solv/add. 8, %
9, % 10, % 11, %
1
19
19
19
19
19
19
19
19
19
19
19
19
15
14
12
17
21
20
13
16
19
Cu(OAc)2
AgOAc
BQ
DCP
air
DMA
DMA
DMA
DMA
DMA
CH3CN
DCE
20
9
35
31
30
10
11
8
0
45
0
0
2
0
3
5
0
4
10
60
22
46
20
19
23
48
27
63
40
33
31
50
30
57
38
83
14
25
59
5
0
5
8
6
air
0.5
3
7
air
7
8
air
i-BuOH
PhCl
23
0
42
15
58
45
38
16
19
28
31
10
58
11
22
12
6
9
air
0.5
2
10
11
12
13
14
15
16
17
18
19
20
21
air
MEK
10
0
air
toluene
dioxane
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
Bu4NI
DMA
Bu4NI
DMA
Bu4NBr
DMA
Bu4NI
DMA
Bu4NI
1.5
air
19
17
17
16
18
42
15
21
34
0
10
air
7
6
air
air
8
air
10
22
14
16
9
air
air
air
air
c
air
6
or styrene by-products were observed in the reaction. As a
working hypothesis then, we assumed that the aryl sulfinate B
could displace one of the acetate groups at Pd(OAc)2, to
produce D, which would then insert the diazo intermediate C to
form the Pd(II) species E followed by loss of SO2 to give F. Aryl
migration as in the accepted Barluenga mechanism (resulting in
species G) would afford 8 and Pd(0), which, in a catalytic cycle
but not in a stoichiometric reaction, needs to be reoxidized
to Pd(II). It is the rate of this oxidation that, we believe, is the
key to the success of this process, and therefore we decided to
introduce a stoichiometric oxidant as well as investigate the other
reaction parameters in order to optimize this reaction (Table 1).
A number of practical oxidants7 were tested in the reaction, using
our Pd(OAc)2, t-Bu2PMeHBF4, K2CO3 conditions (Table 1,
entries 1−5), and atmospheric oxygen appears to be the
most effective, giving approximately 60% isolated yield of the
desired 8, although the byproduct 10 was also produced in 25%
yield. Other solvents (Table 1, entries 6−12) were significantly
less effective than DMA affording even higher yields of 10.
At this point it is not clear if this reactivity difference is due
to the solubility of oxygen in these solvents or just the inherent
reactivity of 7 in these solvents. Other metal precursors such
as Pd2dba3, Pd(O2CCF3)2, Pd(COD)Cl2, Cl2Pd(CH3CN)2 in
combination with t-Bu2PMeHBF4 gave similar results as the
Pd(OAc)2 precursor, and Pd−N-heterocyclic carbene complexes
were not useful catalysts. Non-carbonate bases such as t-BuOLi,
t-BuONa, or t-BuOK, in combination with or without
t-Bu2PMeHBF4, gave no 8 with the majority of the reaction
products (>60%) being a combination of 10 and 11.
22
23
24
25
18
19
air
air
air
air
82
73
57
46
0
8
8
18
9
2
7
18-O2
15
1
4
−
22
16
a
Pd(OAc)2 (S/C ratio = 10) was used as the metal precursor in the
specified solvent (7−10 mL/g of 7). M/L ratio is 1:2 for the mono-
b
c
dentate and 1:1 for the bidentate ligands. HPLC area %. Control
experiments under Ar atmosphere and degassed solvents showed only
10% conversion with 10 mol % of catalyst.
In order to assess the effect of the ligand (Figure 1), using
Pd(OAc)2 and K2CO3, under an air atmosphere, we examined a
variety of phosphines (Table 1, entries 13−20). To our surprise,
there does not appear to be a dramatic effect of the ligand
on product distribution, although there are some significant dif-
ferences between alkyl and ferrocene-based phosphines (for
example compare, in Table 1, entries 5 and 13 with entry 18).
A substantial increase in the yield of 8, and commensurate
decrease in the undesired products, occurred when Bu4NI
was added to the reaction mixture (Table 1, entries 21−25).
Figure 1. Ligands explored in Table 1.
B
DOI: 10.1021/acs.orglett.5b01494
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The isolated yield of 8 increased to 83% with 19 as the ligand,
while the cheaper and more stable ligand 18 gave an 82% yield
with a <10% combined yield of 9−11. Interestingly, Bu4NBr
does not perform as well as the iodide derivative (compare
entries 21 and 23 in Table 1). Although the role of the Bu4NI
is not understood at this time, it does not appear to be merely
stabilizing Pd nanoparticles, as has been shown elsewhere.8
The presence of a highly dative ligand affects the success of this
reaction, since the absence of ligand or its substitution by the
corresponding phosphine oxide reduced the efficiency of the
reaction (Table 1, entries 24−25).
Using the optimized conditions for this reaction (eq 2),
we investigated its scope (Table 2). In most cases substituents
on the ketone moiety do not markedly affect the reaction,
and fluoro, chloro, and cyano aromatics give a good yield of
the desired product (Table 2, entries 1, 3, 4). On the other
hand, the electronic nature of the sulfonylhydrazone is very
important and electron-deficient hydrazones do not couple well
intramolecularly (Table 2, entry 11). Heteroaromatics always
present a unique challenge in many Pd-catalyzed reactions, and we
were pleased to see that our reaction can be extended to hetero-
aromatic ketones (eq 3). A thorough assessment of this chemistry
Table 2. Scope of the Reaction under Optimized Conditions
(eq 2)
and its application to more heteroaromatic ketones and heteroaryl
sulfonylhydrazones is underway and will be reported shortly.
Finally, we have been able to take advantage of the fact that
electron-deficient sulfonylhydrazones do not perform well in
the intramolecular version of the reaction to develop an inter-
molecular version of this chemistry (eq 4). Indeed, when the
NO2-sulfonylhydrazone was reacted under our optimized reaction
conditions in the presence of an external sulfinic acid derivative, a
useful yield of the intermolecular coupling product was obtained.
This observation, which has mechanistic implications for the
intramolecular reaction discussed above, is being studied further,
and further applications will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, and spectral data for all new compounds.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01494.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yhoupis@its.jnj.com.
*E-mail: zhlchen@dhu.edu.cn.
C
DOI: 10.1021/acs.orglett.5b01494
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Organic Letters
Letter
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.5b01494
Org. Lett. XXXX, XXX, XXX−XXX