Metal-free oxidative cleavage of the C-C bond in α-hydroxy-β-oxophosphonates

Article abstract of DOI:10.1039/c5ob01615k

The potential of TBHP to promote oxidative hydroxylation of α-hydroxy-β-oxophosphonates (HOPs) through C(CO)-C bond cleavage is described. This cleavage, as depicted in the mechanism is expected through an isomer of HOP that reacts with TBHP to generate acids.

Full text of DOI:10.1039/c5ob01615k

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Metal-Free Oxidative Cleavage of C-C bond in α-Hydroxy-β-
oxophosphonates
Satyanarayana Battula, a,b Atul Kumar, a,b and Qazi Naveed Ahmeda,b
Received 00th January 20xx,
Accepted 00th January 20xx
٭
DOI: 10.1039/x0xx00000x
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The potential of TBHP to promote oxidative hydroxylation of α- ates (HOP) through 2-oxo promoted hydrophosphonylation of
hydroxy-β-oxophosphonates (HOP) through C(CO)–C bond H-phosphonates.4 The unique capability of α-hydroxy-β-
Cleavage is described. This cleavage, as depicted in mechanism is oxophosphonates was further exploited to synthesize 2-
expected through an isomer of HOP that reacts with TBHP to oxoesters under catalyst free condition (Scheme 1). As an
generate acids.
advancement in application of HOP, our further endeavours to
evaluate its features by its new linkage, helped to develop a
metal-free oxidative C(CO)-C bond cleavage in HOP. In 2012,
Jiang. X and his co-workers also reported cleavage of α-
hydroxyketones under transition metal-free condition.5 In
comparison to his work; we explored TBHP as a reagent of
choice for generation of acids through oxidative hydroxylation
of HOP.
The C-C bond cleavage is a challenging field and has immense
importance in modern organic chemistry owing to its high
thermodynamic stability and uncontrollable selectivity.1 In past
few decades, numerous unprecedented carbon–carbon bond
cleavage methods have been developed.1 Despite plethora of
methods have been accomplished in the oxidative cleavage of
C-C bonds, the use of toxic metals under harsh conditions in
combination with other additives may produce large amount
of byproducts which perhaps limits its applications.1,2
Therefore, the discovery of a metal-free method to achieve
unique C-C bond cleavage is still desirable for various synthetic
transformations.3 Recently, we described a novel approach for
generation of biologically valuable α-hydroxy-β-oxophosphon-
We commenced our studies by the reaction of diethyl (1-
hydroxy-2-oxo-2-phenylethyl)phosphonate 1a (1.0 mmol) with
o
1.2 mmol of TBHP in toluene at 80 C for 7 h. Fortunately, we
obtained benzoic acid 2a in low yield (10%), along with
α-
oxoester 3a (entry 1, Table 1). The outcome of the benzoic acid
2a was apparently caused by the oxidative cleavage of C-C
bond in 1a, and it ultimately prompted us to optimize the
reaction conditions for enrichment of the desired product 2a
.
For this we initially screened our reaction at different tempera-
Table 1. Optimization of the reactiona
entry
Oxidant
t (oC)
time
Yield (%)b
2a
3a
1.
2.
3.
4.
5.
6.
7.
8.
9.
TBHP (1.2 mmol)
TBHP (1.2 mmol)
TBHP (1.2 mmol)
TBHP (1.2 mmol)
TBHP (1.5 mmol)
TBHP (2 mmol)
TBHP (2.2 mmol)
IBX (2 mmol)
80
60
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
7 h
7 h
7 h
10
12
-
70
56
-
˂5
˂5
-
4 days
4 days
4 days
4 days
4 days
4 days
4 days
4 days
4 days
52
61
92
92
15
41
54
47
-
Scheme 1. Summary of this work
-
˂5
10
˂10
-
a.Medicinal Chemistry Division, Indian Institute of Integrative Medicine (IIIM),
Jammu, India-180001.
K2S2O8 (2 mmol)
Oxone (2 mmol)
H2O2 (2 mmol)
10.
11.
12.
b.Academey of Scientific and Innovative Research (AcSIR Fax: +91-1912569333), 2-
Rafi Marg, New Delhi, India.
NBS (2 mmol)
-
٭ naqazi@iiim.ac.in, IIIM/1831/2015.
aReaction conditions: HOP 1a (1.0 mmol), TBHP (2.0 mmol) and toluene (2 mL)
Electronic Supplementary Information (ESI) available: Experimental procedures,
analytical data for products, and NMR spectra of products. See
DOI: 10.1039/x0xx00000x
at room temperature for 4 days; b isolated yields are given
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tures/ time (entry 1-4). We were gratified to see that the initial result, we attempted optimization of the reaction at
concentration of benzoicacid was enhanced at room varied concentrations of TBHP at room temperature (entry 5-
temperature when stirred for 4 days (52%, entry 4). After this
7). We discovered 2a could be achieved exclusively in 92%
yield when the reaction was conducted at room temperature
between 1a (1.0 mmol) and TBHP (2.0 mmol) in 2 mL of
toluene for 4 days (entry 6). Furthermore, a series of reactions
were conducted with different oxidizing agents, including IBX,
K2S2O8, oxone, H2O2, NBS; but no one procured better yields
than TBHP (entry 8-12). Finally, as our observation, 1.0 mmol
of 1a in 2 mL of toluene, when treated with 2 mmol of TBHP
could produce best results for this oxidative C-C cleavage
reaction (entry 6).
Table 2. Scope of the oxidative C-C cleavage of HOP to acida
entry
Reactent
Product
Yield (%) of 2
A
B
C
R1 - methyl - 92%
ethyl - 90%
i-propyl - 85%
benzyl - 85%
With the optimized procedure in hand, we performed a series
of experiments (A-AB) to verify the substrate scope of the
reaction in terms of substitutions at aryl and phosphoryl
D
2a
2b
2c
E
F
G
R1 - methyl - 95%
ethyl - 89%
groups of HOP 1. As we observed, all these transformations
benzyl - 85%
were quite appreciable and obtained good to excellent yields.
Irrespective of the substitution at aryl group of HOP, all these
reactions could be smoothly converted to the required acids 2.
But various substitutions in phosphoryl group of HOP had
brought significant changes in the yield of reaction. In general,
we noticed bulkiness of phosphoryl group afforded lower
O
O
H
I
O
P
R1
R1- methyl - 82%
O
ethyl - 81%
OH
R1
Cl
J
K
R1- methyl - 90%
benzyl - 75%
2d
yields of product 2, for example methylated HOP’s produced
L
(reactions A, E, H, J, L, M, O, T, V, X and Y) higher yields than
the ethylated substrates (reactions B, F, I, N, P, R and W). The
same pattern was observed as a sequence in remaining HOP
substrates, viz., iso-propylated (reaction C) and benzylated
(reactions D, H, L, P, R and V) HOP’s. Along with mono
substituted HOP’s, disubstituted HOP’s also successfully
underwent oxdative C-C cleavages to their corresponding acids
82%
2e
M
N
R1- methyl - 85%
ethyl - 74%
2f
O
P
Q
R1- methyl - 93%
ethyl - 87%
benzyl - 80%
(2j, 2k and 2l). Along with these results, we successfully
conducted the reaction with thiophene, benzofuran based
HOP’s as well and isolated respective acids in good yields (92%
for 2n and 83% for 2o).
To interpret the reaction mechanism, we conducted few
controlled experiments (Scheme 2). In the experiment (a), HOP
1a on stirring in toluene at room temperature failed to
2g
2h
R
S
R1- ethyl - 78%
benzyl - 70%
T
U
R1- methyl - 85%
benzyl - 74%
produce 2a and/ 3a. This clearly indicates that room
2i
2j
temperature is neither favourable for self catalyzed aerobic
intermolecular nucleophilic displacement reaction to 2-
oxoesters nor promotes oxidative hydroxylation to acids.
Further to prove the nature of reaction in presence of TBHP, a
reaction (b) was conducted between 1a (1.0 mmol) and TBHP
V
W
R1- methyl - 71%
ethyl - 68%
X
Y
75%
72%
(2.0 mmol) with TEMPO (2.0 mmol) in
2 mL of toluene at room
temperature for 4 days. In this case we isolated trace amounts
of benzoicacid 2a. This obviously indicates the free radical
nature of the reaction. Experiment (c) indicated non
2k
2l
participation of
α-oxoester 3a towards the generation of
corresponding acid 2a. In addition, generation of comparable
yields in experiments (d), (e) and (f) highlighted the non
participation of air (oxygen)/ water in our reaction. Finally,
experiments (g), (h) and (i), wherein we failed to isolate
Z
87%
92%
2m
expected products
(2a)
with
acetophenone and methylbenzoate 6
β
-ketophosphonate 4,
respectively as
AA
5,
substrates, indicated the structural requirement of the α-
hydroxy-β-oxophosphoryl group to this reaction.
2n
2o
On the basis of controlled experiments and literature
a
AB
83%
reports,3d,4a
hydroxylation of HOP is described in Scheme 3. HOP , as
plausible reaction pathway for oxidative
1
described before has a tendency to exist in different resonance
structures. Under TBHP environment, isomer (I) as expected
reacts with radicals (OH., tBuO.) to produce a intermediate (II)
a Reaction conditions: HOP 1 (1.0 mmol), TBHP (2.0 mmol) and toluene (2 mL) at rt for
4 days.
2 | J. Name., 2012, 00, 1-3
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that ultimately on reaction with tertiarybutyl peroxy radical S. Battula, A. Kumar thanks CSIR and UGC respectively. We also
generates
2.
thank the analytical department of IIIM. Finally, we are
grateful to the CSIR network project (BSC-0108) for funding to
this work.
References
1. a) R. H. Crabtree, Chem. Rev., 1985, 85, 245-269; b) B.
Rybtchinski and D. Milstein, Angew. Chem. Int. Ed., 1999, 38,
870-883; c) C.-H. Jun, Chem. Soc. Rev., 2004, 33, 610-618; d)
M. Tobisu and N. Chatani, Chem. Soc. Rev., 2008, 37, 300-307;
e) Y. J. Park, J.-W. Park and C.-H. Jun, Acc. Chem. Res., 2008,
41, 222-234; f) F. Chen, T. Wang and N. Jiao, Chem. Rev., 2014,
114, 8613-8661; g) M. Murakami and T. Matsuda, Chem.
Commun., 2011, 47, 1100-1105.
2. a) C. He, S. Guo, L. Huang and A. Lei, J. Am. Chem. Soc., 2010,
132, 8273–8275; b) W. Zhou, W. Fan, Q. Jiang, Y.-F. Liang and
N. Jiao, Org. Lett., 2015, 17, 2542–2545; c) A. Wang and H.
Jiang, J. Am. Chem. Soc., 2008, 130, 5030-5031; d) A. P.
Dieskau, M. S. Holzwarth and B. Plietker, J. Am. Chem. Soc.,
2012, 134, 5048–5051; e) M. Murakami and Y. Ito, Topics in
Organometallic Chemistry, 1999, 3, 97-129; f) C. Tang and N.
Jiao, Angew. Chem. Int. Ed., 2014, 53, 6528-6532; g) Y. Terao,
H. Wakui, T. Satoh, M. Miura and M. Nomura, J. Am. Chem.
Soc., 2001, 123, 10407-10408; h) J. Li and K. Yoshizawa, Chem.
Eur. J., 2012, 18, 783-787.
3. a) R. Lin, F. Chen and N. Jiao, Org. Lett., 2012, 14, 4158-4161; b)
M. N. Kopylovich, K. T. Mahmudov, M. Haukka and A. J. L.
Pombeiro, New J. Chem., 2014, 38, 495-498; c) L. Liu, L. Du, D.
Zhang-Negrerie, Y. Du and K. Zhao, Org. Lett., 2014, 16, 5772-5775;
d) Q. Zhao, H. Li and L. Wang, Org. Biomol. Chem., 2013, 11, 6772-
6779; (e) F.-X. Luo, T.-G. Zhou, X. Li, Y.-L. Luo and Z.-J. Shi, Org.
Scheme 2. Controlled experiments.
Chem. Front., 2015, 2, 1066-1070.
4. a) S. Battula, N. Battini, D. Singhc and Q. N. Ahmed, Org.
Biomol. Chem., 2015, 13, 8637-8641; b) Z. Huang, K.-K. A.
Wang, J. Leea and W. A. v. d. Donk, Chem. Sci., 2015, 6, 1282–
1287.
5. H. Liu, C. Dong, Z. Zhang, P. Wu and X. Jiang, Angew. Chem.
Int. Ed., 2012, 51, 12570-12574.
Scheme 3. The plausible reaction mechanism for oxidative C-C cleavage of HOP.
In summary, we have established a metal-free oxidative C(CO)-
C cleavage in α-hydroxy-β-oxo phosphonates (HOP). Notably,
C-C cleavages on molecules bearing such linkages have never
been reported before. Furthermore, such cleavages were
successful in good yields with broad range of substrate scope.
This protocol, certainly can find applications of HOP as
synthons for generation of different valuable structures in
future.
Acknowledgement
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