C-H bonds phosphorylation of ketene dithioacetals

Article abstract of DOI:10.1021/acs.orglett.5b00728

C-H bond phosphorylation of ketene dithioacetals was achieved under transition-metal-free or AgNO₃ mediated conditions. Synthetic transformations of the coupling product provided promising methods for the construction of highly functionalized p

Full text of DOI:10.1021/acs.orglett.5b00728

Letter
pubs.acs.org/OrgLett
C−H Bonds Phosphorylation of Ketene Dithioacetals
Liping Zhu,† Hongmei Yu,† Quanping Guo,† Qiao Chen,† Zhaoqing Xu,*,† and Rui Wang*,†,‡
†Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University,
Lanzhou 730000, China
‡State Key Laboratory of Chiroscience, Hong Kong, Polytechnic University, Hong Kong, China
S
* Supporting Information
ABSTRACT: C−H bond phosphorylation of ketene dithioacetals was
achieved under transition-metal-free or AgNO3 mediated conditions.
Synthetic transformations of the coupling product provided promising
methods for the construction of highly functionalized phosphorylated N-
heterocycles and tetrasubstituted alkenes.
Scheme 1. Phosphorylation Reaction
hosphonates and their derivatives attracted increasing
1
Pattention for their great importance in drug discovery,
organic synthesis,2 photoelectric materials,3 and catalysis.4 Since
the first report by Hirao and co-workers,5 a wide variety of
transition-metal-catalyzed cross-coupling reactions for the
construction of C−P bonds have been developed, including
the reaction of C(sp2)-halides/triflates/tosylates,6 aryl boronic
acids,7 aryl diazonium salts,8 alkenyl/alkynyl carboxyl acids,9 or
nucleophilic heteroarenes10 with H-phosphonates or H-
phosphine oxides (Scheme 1, eq 1). In previous decades,
transition-metal-catalyzed C−H functionalizations emerged as a
very efficient strategy for C−C and C−heteroatom formations.11
However, transition-metal-catalyzed direct C−H phosphoryla-
tion remains an enormous challenge. Both H-phosphonates and
H-phosphine oxides are in equilibrium with the corresponding
phosphinous acids and tend to form a P-bound phosphinous acid
complex in the presence of a late transition metal.12 Thus, the
metal catalyst binds to the existing phosphorus rather than to the
much less coordinative C−H bond, which inhibits the C−H
activation step.13 In 2013, Yu and co-workers reported a
pyridine-directed aromatic C−H phosphorylation, in which a
strategy involving slow addition of a H-phosphonate via a syringe
pump was employed to avoid the deactivation of the Pd catalyst
(eq 2).14 With the same substrates and catalyst, the Murakami
group recently reported another protocol for aryl C−H
phosphorylation. In that reaction, α-hydroxyalkylphosphonate
was used as a masked phosphonation agent which released H-
phosphonate gradually in the reaction, thereby avoiding its
coordination to Pd (eq 2).15
As a significant motif in organic chemistry, the C−H
functionalization of alkenes has been intensively studied over
the past years.11e−g Although the C−P coupling of aromatic C−
H has been developed, the C−H phosphorylation of the alkene
C−H bond has not yet been achieved due to the low reactivity of
the alkene C−H bond (especially for internal alkenes) and the
strong coordination of the phosphorus reagents to transition
metal catalysts. In recent years, remarkable results from
transition-metal-free C−H activation have been reported.16
Encouraged by those results, we envisioned transition-metal-free
conditions that could avoid the catalyst deactivation problem
since no transition metals were involved in the system. To
activate the inert C−H bond of the internal alkene, an electron-
donating dithioalkyl group is installed in the substrates, by which
Received: March 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00728
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Organic Letters
Letter
the olefin would be reactive enough for a direct functionaliza-
tion.17 In continuing with our research interest in C−H
functionalization,18 we disclose here the first example of
transition-metal-free C−H phosphorylation of internal alkenes
with diaryl phoshine oxides (eq 3). With modified conditions, H-
phosphonates were also successfully coupled with internal
alkenes in good yields (eq 4). Moreover, the phosphorylation
product was easily cross-coupled with aryl boronic acid through
Pd-catalyzed C−S cleavage and gave the tetrasubstituted alkene
in moderate yield. The synthetic utilities of current methodology
were further demonstrated by the synthesis of highly function-
alized phosphorylated N-heterocycle compounds through a
simple one-step operation from the C−H phosphorylation
product in excellent yields.
the amount of solvent, oxidant, or diphenylphosphine oxide 2
resulted in negative reaction effects (see the SI for details).
With the optimized reaction conditions in hand, we next
investigated the reaction generality by using various internal
alkene substrates (Scheme 2). The benzoyl alkenes with the
a b
,
Scheme 2. Transition-Metal-Free C−H Phosphorylation
Initially, we used alkene 1a as the model substrate and reacted
it with diphenylphosphine oxide 2 (2 equiv) in the presence of
K2S2O8 (3 equiv) in CH3CN at 60 °C. However, after 24 h, only
11% desired product was obtained (Table 1, entry 1).
a
Table 1. Optimization of Reaction Conditions
b
entry
oxidant
solvents (ratio)
CH3CN
t (°C)
yield (%)
c
1
K2S2O8
K2S2O8
MnO2
60
60
60
60
60
60
60
60
60
60
60
60
60
20
40
80
100
11
74
20
<10
22
14
85
3
2
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
DMF/H2O (1:1)
tol/H2O (1:1)
3
4
PhI(OAc)2
H2O2
5
6
TBHP
7
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
8
9
DCE/H2O (1:1)
dioxane/H2O (1:1)
DMSO/H2O (1:1)
DMF/H2O (2:1)
H2O
7
10
11
12
13
14
15
16
17
8
67
89
20
<5
12
DMF/H2O (2:1)
DMF/H2O (2:1)
DMF/H2O (2:1)
DMF/H2O (2:1)
a
All reactions were carried out by using 0.2 mmol of 1, 0.4 mmol of 2,
0.6 mmol of K2S2O8, 2 mL of solvent (DMF/H2O = 2/1,) and 80 °C
d
92
b
77
for 5 h. Isolated yields.
a
All reactions were carried out by using 0.2 mmol of 1a, 0.4 mmol of
2, 0.6 mmol of oxidant, 2 mL of mixed solvents, followed by stirring
b
for 5 h under aerobic conditions, except as noted. Yields were
detected by GC. Reacted for 24 h. Isolated yield of 3a is 90%.
c
d
methoxy or halogen substituent at the o-, m-, and p-position on
the aryl ring were well tolerated (3b−3h). The substrates with
the 2-naphthyl and 2-thienoyl moiety gave moderate yields (3i,
3j). Gratifyingly, we found that, under optimized conditions,
alkenes with other types of substituents such as alkyl acyl (3k, 3l),
ester (3m), amide (3n), cyano (3o), and phenyl (3p) were all
reactive and gave the desired products in good yields.
Furthermore, altering the dithioalkyl moiety to −S(CH2)3S−
(3q, 3r) or using acyclic alkylthio (3s, 3t) did not affect the
outcome of the C−H phosphorylation reaction. However, under
the standard conditions, the phosphorylation of diphenyl alkene
only afforded 3u in 42% yield.
In the study of using H-phosphonates as the coupling partners,
we found that the stated reaction conditions in Scheme 2 did not
work efficiently. In this context, we next explored another
protocol for alkene C−H bond phosphorylation (Scheme 3; for
reaction conditions optimization, see the SI). By using 3 equiv of
Astonishingly, a mixed solvent (CH3CN/H2O = 1:1) dramat-
ically improve the yield to 74% (entry 2). Several other oxidants
could also be used as an oxidant albeit less effectively compared
to K2S2O8 (entries 3−6). A solvent survey proved that high polar
solvents, such as DMF and DMSO, facilitated the reaction
(entries 7 and 11), whereas solvents with low polarity, namely
toluene, 1,2-dichloroethane, and 1,4-dioxane, completely in-
hibited the reaction (entries 8−10). The variation of the solvent
ratio revealed that DMF/H2O = 2:1 was optimal (entry 12; see
the Supporting Information (SI) for details) and H2O is less
efficient for this reaction (entry 13). It is worth noting that the
yield of 3a decreased significantly with reaction temperature
reduction (entries 14 and 15). 80 °C was determined to be the
best temperature for this reaction (entries 16 and 17). Changing
B
DOI: 10.1021/acs.orglett.5b00728
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Organic Letters
Letter
a b
,
Scheme 3. Alkene C−H Phosphorylation with H-
Table 2. KIE Exploration
a b
,
Phosphonates
yield
time
3a (%)
3a[D] (%)
kH/kD
5 min
10 min
15 min
2 h
31
67
81
86
89
32
70
81
87
89
1.0
4 h
a
b
a
Yields were detected by GC. All reactions were carried out by using
All reactions were carried out by using 0.2 mmol of 1, 0.4 mmol of 2,
b
1 (0.2 mmol), 2 (0.4 mmol), and K2S2O8 (0.6 mmol) in DMF/H2O
(2/1, 2 mL) at 80 °C for 5 h.
0.6 mmol of AgNO3, 2 mL of DMF, at 80 °C for 5 h. Isolated yields.
AgNO3 as a promoter, the reactions went smoothly for both H-
phosphine oxide (2) and H-phosphonate (4, 5) with good yields.
The pharmaceutical and biological utility of the phosphor-
ylation product was demonstrated for the synthesis of
phosphorylated tetrasubstituted alkenes.19 Under the typical
Liebeskind−Srogl cross-coupling reaction conditions,18d,20 3t
was treated with arylboronic acid in the presence of Pd(PPh3)4
and CuTC to give the alkenyl phosphine oxide 3u in 48% yield
(Scheme 4).
Scheme 6. Radical Trapping Study
Scheme 4. Synthesis of Tetrasubstituted Alkenes
of TEMPO or BHT. Moreover, the BHT adduct 10 was detected
by ESI-HRMS measurement of the crude reaction mixture.
These results indicated that a radical pathway might be involved
in the transformation.
Based on previous reports and the above-mentioned
experimental results, a plausible mechanism was proposed in
Scheme 7.13c,17a Initially, diphenylphosphine oxide 2 is in
Following the successful building of the C−H phosphorylation
reaction, its conversion into a valuable phosphorylated N-
heterocycle structure was also found to be straightforward
(Scheme 5). Compound 3t was reacted with hydrazine hydrate
Scheme 7. Proposed Mechanism
Scheme 5. Synthesis of Phosphorylated N-Heterocycles
smoothly and transformed into multifunctionalized pyrazole 8 in
99% yield. The six-membered N-heterocycle pyrimidine 9 was
successfully achieved in 92% yield as well.
equilibrium with the phosphinous acid, which is oxidized by
K2S2O8 to form a cation radical A.21 Then, the nucleophilic attack
of 1a to A leads to a thionium cation radical intermediate B. A
subsequent deprotonation followed by the second single-
electron-transfer process gives the intermediate D. The final
elimination of H+ results in the desired C−H phosphorylation
product 3a.
In summary, we have reported the first example of alkene C−
H phosphorylation under transition-metal-free conditions. A
variety of internal alkenes were coupled with H-phosphine oxides
To gain some mechanistic insight, we performed the kinetic
isotope effect (KIE) exploration by a deuterium labeling
experiment (Table 2). The experimental results suggested that
the rupture of the C−H bond in internal olefin was not involved
in the rate-determining step of the reaction. Radical trapping
experiments were also examined (Scheme 6). At the end of the
reaction, GC analysis of the reaction mixture revealed formation
of the target product 3a decreased dramatically with the addition
C
DOI: 10.1021/acs.orglett.5b00728
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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N-heterocycles (8, 9) and tetrasubstituted alkene (3u) in good
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, characterization data and NMR spectra.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zqxu@lzu.edu.cn.
*E-mail: wangrui@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
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We are grateful for the grants from the NSFC (Nos. 21202072,
21102141, and 21432003) and the Fundamental Research Funds
for the Central Universities (No. 860976)
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