Catalyst-free synthesis of α1-oxindole-α-hydroxyphosphonates: Via phospha-aldol reaction of isatins employing N-heterocyclic phosphine (NHP)-thiourea

Article abstract of DOI:10.1039/c6ob01608a

A highly efficient phospha-aldol reaction for the synthesis of α¹-oxindole-α-hydroxyphosphonates is developed utilizing N-heterocyclic phosphine (NHP)-thiourea as a phosphonylation reagent under catalyst, additive free conditions. This methodology encompasses a variety of isatin derivatives to provide α¹-oxindole- α-hydroxyphosphonates up to 99% yield.

Full text of DOI:10.1039/c6ob01608a

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Biomolecular Chemistry
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Catalyst-free synthesis of α -oxindole-
α-hydroxyphosphonates via phospha-aldol
reaction of isatins employing N-heterocyclic
phosphine (NHP)-thiourea†
Cite this: DOI: 10.1039/c6ob01608a
Received 28th July 2016,
Accepted 9th September 2016
DOI: 10.1039/c6ob01608a
www.rsc.org/obc
Nagaraju Molleti and Jun Yong Kang*
1
2
A highly efficient phospha-aldol reaction for the synthesis of (Scheme 1a) in the presence of additives such as alkali metal
1
13
14
15
16
α -oxindole-α-hydroxyphosphonates is developed utilizing alcoholates,
Cu,
β-cyclodextrin,
nano-rod ZnO,
1
7
18
19
N-heterocyclic phosphine (NHP)-thiourea as a phosphonylation Amberlyst-15, or magnetic nanoparticles (Fe O , γ-Fe O ).
3
4
2 3
reagent under catalyst, additive free conditions. This methodology On the other hand, there is one report using trialkyl phosphite
1
encompasses a variety of isatin derivatives to provide α -oxindole- with polyethylene glycol (PEG-400) as reaction medium
2
0
α-hydroxyphosphonates up to 99% yield.
(Scheme 1b). However, most of these approaches require the
use of catalysts or additives to establish the tautomeric equili-
brium (tetracoordinate phosphonate – a major tautomeric
Oxindoles and oxindole derivatives are important structural
motifs widely distributed in many natural products as well as
pharmaceuticals with a broad range of biological activities,
and they also serve as significant key intermediates in organic
form and tricoordinate phosphite – a minor form without
additives) shifted towards
Scheme 2) in which isatins rapidly undergo phospha-aldol
reaction with the phosphites to afford α -oxindole-
α-hydroxyphosphonates. In addition, these additives exhibit
toxicity of reagents, moisture sensitivity, and corrosiveness of
21
a reactive phosphite form
(
1
synthesis. Therefore, there are several reports on the synthetic
1
applications of oxindole derivatives in various organic reac-
tions, which mainly involve aldol reactions of isatins with
2
different carbon nucleophiles such as the metal-mediated 1,2-
13,14,16,17
acidic or basic reagents.
3
4
addition of boronic acids, Henry reaction, and decarboxyla-
To the best of our knowledge, there is no efficient method
5
tive 1,2-addition of acetic acids. Similarly, α-hydroxy-phospho-
1
available
for
the
synthesis
of
α -oxindole-
nates have received much attention because of their
wide range of biological and pharmaceutical activities.
They are also useful intermediates in the synthesis of
α-substituted phosphonyl compounds. The pioneering work
α-hydroxyphosphonates without catalysts or additives.
Recently, we have developed highly nucleophilic bifunctional
6
7
8
towards α-hydroxy-phosphonate synthesis presents Abramov
9
and Pudovik reactions in which aldehydes or ketones react
with dialkyl or trialky phosphites under acidic or basic
1
0
catalysts.
In view of the different impressive biological activities
associated with various oxindole derivatives and
1
α-hydroxyphosphonates, the synthesis of α -oxindole-
α-hydroxyphosphonates has gained considerable interest in
1
1
the synthetic community. Current synthetic protocols toward
1
α -oxindole-α-hydroxyphosphonates include phospha-aldol
reactions of isatins with dialkyl or diaryl phosphites
Department of Chemistry and Biochemistry, University of Nevada, Las Vegas,
4
505 S Maryland Parkway, Las Vegas, Nevada, 89154-4003, USA.
E-mail: junyong.kang@unlv.edu
Electronic supplementary information (ESI) available: Experimental pro-
†
1
cedures, characterization data for products, and NMR spectra of products. See
DOI: 10.1039/c6ob01608a
Scheme 1 Different types of phosphonylation reagents for α -ox-
indole-α-hydroxyphosphonates.
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phospha-aldol reaction with N-methyl isatin 1a. The parent
1
NHP-phenyl-thiourea
2a
provided
α -oxindole-
α-hydroxyphosphonate 3a in excellent yield 99% (Table 2,
entry 1). Different substituents on the phenyl group of thio-
ureas 2b (-4-OMe) and 2c (-3,5-CF ) did not show much effect
on the phospha-aldol reaction, providing the product 3a in
3
Scheme 2 Tautomeric equilibria of H-phosphonates.
89% and 71% yield, respectively (entries 2 and 3). The
N-methyl substituted NHP-thiourea 2d and NHP-amide 2e sig-
nificantly reduced the reactivity of this phospha-aldol reaction
and resulted in poor yields 35% and 15%, respectively (entries
4 and 5), probably due to the hampering of the intramolecular
nucleophilic substitution process. In addition, this phospha-
aldol reaction of N-methyl isatin 1a with NHP-ethanol 2f under
the optimized reaction conditions did not provide the desired
product (entry 6), presumably due to the absence of an intra-
molecular nucleophilic substitution reaction trigger of a
thiourea motif. These outcomes strongly support our hypoth-
esis of the bifunctional role of NHP-thioureas in this phospha-
aldol reaction. It should also be noted that triethyl or diethyl
phosphite, widely used in the additive-mediated synthesis of
phosphites of N-heterocyclic phosphine (NHP)-thioureas as
versatile phosphonylation reagents and successfully demon-
strated their synthetic utilities in the synthesis of vinyldiaza-
22
phosphonates, α-aminophosphonates, and γ-ketophosphonates.
Hence, we hypothesize that this highly nucleophilic bifunc-
tional NHP-thiourea (Scheme 1c) would facilitate a phospha-
aldol reaction of isatins through the synergetic hydrogen-bond
activation of the carbonyl group with a strongly nucleophilic
phosphine. Herein, we describe a catalyst, additive free
phospha-aldol reaction of isatins with NHP-thioureas for the
1
synthesis of α -oxindole-α-hydroxyphosphonates (Scheme 1c).
To test our hypothesis, a phospha-aldol reaction was per-
formed with N-methyl isatin 1a and NHP-thiourea 2a in 1,2-
dichloroethane (DCE) at 70 °C without additives. The desired
phospha-aldol product 3a was obtained in good yield (70%)
1
α -oxindole-α-hydroxyphosphonates, did not proceed to form
the phospha-aldol products under the standard reaction con-
ditions. After an exhaustive study of different NHPs, it was
found that NHP-phenyl thiourea 2a is the most efficient phos-
phonylation reagent for this phospha-aldol reaction.
We next explored the synthetic scope of this phospha-aldol
reaction using N-methyl isatin 1a with different NHP-thioureas
(Table 1, entry 1). Encouraged by this initial result, we initiated
a systematic optimization study. A slight excess of NHP-
thiourea (1.5 equiv.) 2a helped improve the product yield
(entry 2, 93%). After having the optimized ratio of reagents, we
studied the effect of different solvents on this phospha-aldol
reaction. The evaluation of different solvents revealed that the
phospha-aldol reaction is well tolerated under both non-polar
and polar solvent conditions (entries 2–7). Among the solvents
(
Table 3, 2g–2i). During the course of the examination of the
substrate scope, we observed that the electronic effects of the
NHP motif on this reaction were negligible (3b–3c), whereas
the steric effects of the NHP scaffold with a bulky 2,6-(i-Pr)-
substituent on this phospha-aldol reaction significantly influ-
enced the reactivity, not resulting in the desired product (3d).
Next, we explored the substrate scope of isatins with NHP-
thiourea 2a. This methodology showed a broad substrate scope
tested in this phospha-aldol reaction, CHCl was proven as an
3
optimal solvent and provided an excellent yield 99% (entry 7).
On the other hand, we observed that lowering the reaction temp-
erature to room temperature led to a reduced yield (entry 8).
With the optimized reaction conditions in hand, we investi-
gated the effect of Brønsted acids of different NHPs on this
1
encompassing a variety of isatin derivatives to provide α -oxi-
ndole-α-hydroxyphosphonates 3a–r with 45–99% yields. Isatins
with electron donating or withdrawing substituents on the aro-
1
a
matic ring were smoothly proceeded to form α -oxindole-
Table 1 Optimization study
α-hydroxyphosphonates (3f–o) in good to excellent yields. The
steric hindrance caused by substituted-isatin derivatives has a
significant influence on the phospha-aldol reaction. For
instance, isatins with 7-F or 4-Br-substituents (1m–n) provided
the product in lower yields with 73% (3m) and 56% (3n),
respectively. An isatin having multiple substituents on the aro-
matic ring proved to be a viable substrate and afforded the
corresponding product 3o in good yield (87%). Furthermore,
we also studied the reactivity of isatins with various substitu-
ents on the nitrogen atom (N-Me, N-Bn, N-Boc, and N-Ac), and
it was found that the electronic nature of the nitrogen atom
had a significant effect on this phospha-aldol reaction.
Electron-donating groups (1a, 1p) on the nitrogen atom of
isatin furnished the products in excellent yields (3a, 99% and
b
Entry
NHP (equiv.)
Solvent
Temp (°C)
Time
Yield (%)
1
2
3
4
5
6
7
8
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
DCE
DCE
Toluene
CH
CH
THF
CHCl
CHCl
70
70
70
70
40
66
61
rt
21 h
15 h
15 h
15 h
15 h
15 h
15 h
15 h
70
93
87
81
85
77
99
75
3
CN
Cl
2
2
3
3
3p, 93%, respectively) whereas isatins with electron-withdraw-
a
ing substituents (1q, 1r) provided the corresponding products
in moderate yields (3q, 60% and 3r, 45%, respectively). Finally,
Reaction conditions: 1a (0.05 mmol), 2a (0.075 mmol), solvent
b
(0.5 mL). Isolated yield.
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a
Table 2 Effects of different NHP reagents on phospha-aldol reaction
b
b
Entry
1
NHP
Yield
Entry
4
NHP
Yield
99%
35%
2
3
89%
71%
5
6
15%
0%
a
b
Reaction conditions: 1a (0.05 mmol), 2 (0.075 mmol), CHCl
3
(0.5 mL), temperature 61 °C, time 15 h. Isolated yield.
a
Table 3 Substrate scope of isatins for phospha-aldol reaction
Scheme 3 A probable reaction mechanism.
Scheme 3. The phospha-aldol reaction initiated by the hydro-
gen-bond activation of the carbonyl group with a thiourea
motif generates diazaphosphonium intermediate A. A sub-
sequent proton transfer affords an intermediate B, which after
the intramolecular nucleophilic substitution reaction fur-
nishes the desired product 3a and thiazolidine C as the
byproduct.
a
Conclusions
Reaction conditions: 1a (0.10 mmol), 2 (0.15 mmol), CHCl
3
(1.0 mL),
b
temperature 61 °C, time 15 h. Isolated yield.
In summary, we have developed a phospha-aldol reaction of
isatins with N-heterocyclic phosphine (NHP)-thioureas to gene-
1
rate α -oxindole-α-hydroxyphosphonates. Unlike most of the
it is noteworthy that a scale up of this reaction (2.25 mmol) reported methods for the phospha-aldol reaction, this
was performed without compromising the reactivity of this approach does not involve the use of catalysts or additives.
2
3
transformation (3a, 95%) and provided the byproduct C with This transformation has demonstrated the important role of
0% yield.
the Brønsted acid motif essential for the intramolecular
On the basis of the experimental observations and our pre- nucleophilic substitution reaction sequence to achieve additive
9
2
2
vious reports, a plausible reaction pathway is depicted in free reaction conditions. In addition, this method was well
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tolerated with electronically and sterically diverse isatin sub-
strates and afforded α -oxindole-α-hydroxyphosphonates in
good to excellent yields (up to 99%). Further application of
this transformation for the synthesis of biologically important
compounds and anti-cancer agents is in progress and will be
disclosed in due course.
6 (a) B. Stowasser, K.-H. Budt, L. Jian-Qi, A. Peyman and
D. Ruppert, Tetrahedron Lett., 1992, 33, 6625–6628;
(b) K. U. M. Rao, C. S. Sundar, S. S. Prasad, C. R. Rani and
C. S. Reddy, Bull. Korean Chem. Soc., 2011, 32, 3343–3347;
(c) G. S. Reddy, C. SyamaSundar, S. S. Prasad, E. Dadapeer,
C. N. Raju and C. S. Reddy, Der. Pharma. Chem., 2012, 4,
1
2208–2213; (d) Y.-H. Wang, Z.-Y. Cao and J. Zhou, J. Org.
Chem., 2016, 81, 7807–7816.
7
(a) T. Yokomatsu and S. Shibuya, Tetrahedron: Asymmetry,
Acknowledgements
1992, 3, 377–378; (b) L. Maier, Phosphorus, Sulfur Silicon
This work was financially supported by the University of
Nevada, Las Vegas (Star-up fund and Faculty Opportunity
Awards). Dr Katarzyna Lorenc-Kukula (SCAAC) is acknowledged
for mass spectra data.
Relat. Elem., 1993, 76, 119–122; (c) T. Yamagishi, T. Kusano,
B. Kaboudin, T. Yokomatsu, C. Sakuma and S. Shibuya,
Tetrahedron, 2003, 59, 767–772.
8 (a) V. S. Abramov, Dokl. Akad. Nauk SSSR, 1950, 73, 487–
4
9
89; (b) V. S. Abramov, Dokl. Akad. Nauk SSSR, 1954, 95,
91–992.
9
(a) A. N. Pudovik, Dokl. Akad. Nauk SSSR, 1950, 73, 499–
02; (b) A. N. Pudovik and Y. P. Kitaev, Zh. Obshch. Khim.,
1952, 22, 467–473.
007, 46, 8748–8758; (b) C. Marti and E. M. Carreira, 10 (a) A. Heydari, A. Arefi, S. Khaksar and M. Tajbakhsh,
Notes and references
5
1
(a) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed.,
2
Eur. J. Org. Chem., 2003, 2209–2219; (c) P. Satyamaheshwar,
Curr. Bioact. Compd., 2009, 5, 20–38; (d) H. Kobayashi,
K. Shin-Ya, K. Nagai, K. Suzuki, Y. Hayakawa, H. Seto,
B. S. Yun, I. J. Ryoo, J. S. Kim, C. J. Kim and I. D. Yoo,
J. Antibiot., 2001, 54, 1013–1018; (e) H. Suzuki, H. Morita,
M. Shiro and J. Kobayashi, Tetrahedron, 2004, 60, 2489–
Catal. Commun., 2006, 7, 982–984; (b) C. Liu, Y. Zhang,
Q. Qian, D. Yuan and Y. Yao, Org. Lett., 2014, 16, 6172–
6175; (c) Q. Wu, J. Zhou, Z. Yao, F. Xu and Q. Shen, J. Org.
Chem., 2010, 75, 7498–7501; (d) W. Goldeman and
M. Soroka, Synthesis, 2006, 3019–3024; (e) J. P. Abell and
H. Yamamoto, J. Am. Chem. Soc., 2008, 130, 10521–10523;
(f) A. H. Kategaonkar, R. U. Pokalwar, S. S. Sonar,
V. U. Gawali, B. B. Shingate and M. S. Shingare, Eur. J. Med.
Chem., 2010, 45, 1128–1132; (g) R. U. Pokalwar,
R. V. Hangarge, P. V. Maskeb and M. S. Shingare, ARKIVOC,
2006, 11, 196–204; (h) K. Suyama, Y. Sakai, K. Matsumoto,
B. Saito and T. Katsuki, Angew. Chem., Int. Ed., 2010, 49,
797–799.
2
495; (f) V. U. Khuzhaev, I. Zhalolov, K. K. Turgunov,
B. Tashkhodzhaev, M. G. Levkovich, S. F. Aripova and
A. S. Shashkov, Chem. Nat. Compd., 2004, 40, 269–272;
(
g) T. Kagata, S. Saito, H. Shigemori, A. Ohsaki,
H. Ishiyama, T. Kubota and J. Kobayashi, J. Nat. Prod.,
006, 69, 1517–1521; (h) F. Zhao, Y.-L. Liu and J. Zhou, Adv.
Synth. Catal., 2010, 352, 1381–1407.
2
2
(a) Q. Guo, M. Bhanushali and C.-G. Zhao, Angew. Chem., 11 L. I. Musin, A. V. Bogdanov and V. F. Mironov, Chem.
Int. Ed., 2010, 49, 9460–9464; (b) G. Luppi, P. G. Cozzi, Heterocycl. Compd., 2015, 51, 421–439.
M. Monari, B. Kaptein, Q. B. Broxterman and C. Tomasini, 12 A. Mustafa, M. M. Sidky and F. M. Spoliman, Tetrahedron,
J. Org. Chem., 2005, 70, 7418–7421; (c) S. Allu, N. Molleti, 1966, 22, 393–398.
R. Panem and V. K. Singh, Tetrahedron Lett., 2011, 52, 13 P. Gurevich, G. Akhmetova, A. Gubaidullin, V. Moskva and
080–4083. For catalyst-free synthesis of hydroxy oxindole I. Litvinov, Russ. J. Gen. Chem., 1998, 68, 1501–1506.
derivatives: (d) J.-S. Yu, Y.-L. Liu, J. Tang, X. Wang and 14 T. Deng, H. Wang and C. Cai, Org. Biomol. Chem., 2014, 12,
J. Zhou, Angew. Chem., Int. Ed., 2014, 53, 9512–9516; 5843–5846.
e) Y.-L. Liu, X.-P. Zeng and J. Zhou, Chem. – Asian J., 2012, 15 J. Shankar, K. Karnakar, B. Srinivas and Y. V. D. Nageswar,
4
(
7
, 1759–1763; (f) F.-M. Liao, Y.-L. Liu, J.-S. Yu, F. Zhou and
Tetrahedron Lett., 2010, 51, 3938–3939.
J. Zhou, Org. Biomol. Chem., 2015, 13, 8906–8911. For 16 M. Hosseini-Sarvari and M. Tavakolian, Can. J. Chem.,
addition reactions of other nucleophiles to isatins: 2012, 91, 1117–1122.
g) Y.-L. Liu, B.-L. Wang, J.-J. Cao, L. Chen, Y.-X. Zhang, 17 K. U. Maheswara Rao, G. D. Reddy and C.-M. Chung,
(
C. Wang and J. Zhou, J. Am. Chem. Soc., 2010, 132, 15176–
Phosphorus, Sulfur Silicon Relat. Elem., 2013, 188, 1104–
1
5178; (h) Y.-L. Liua and J. Zhou, Chem. Commun., 2012, 48,
1109.
1
919–1921; (i) Z.-Y. Cao, J.-S. Jiang and J. Zhou, Org. 18 X. J. Yang, Appl. Organomet. Chem., 2014, 28, 471–
476.
R. Shintani, M. Inoue and T. Hayashi, Angew. Chem., Int. 19 M. Nazish, S. Saravanan, N.-u. H. Khan, P. Kumari,
Biomol. Chem., 2016, 14, 5500–5504.
3
4
5
Ed., 2006, 45, 3353–3356.
R. I. Kureshy, S. H. R. Abdi and H. C. Bajaj, ChemPlusChem,
2014, 79, 1753–1760.
L. Liu, S. Zhang, F. Xue, G. Lou, H. Zhang, S. Ma, W. Duan
and W. Wang, Chem. – Eur. J., 2011, 17, 7791–7795.
Q. Ren, J. Huang, L. Wang, W. Li, H. Liu, X. Jiang and
J. Wang, ACS Catal., 2012, 2, 2622–2625.
20 L. Nagarapu, R. Mallepalli, U. Nikhil Kumar,
P. Venkateswarlu, R. Bantu and L. Yeramanchi, Tetrahedron
Lett., 2012, 53, 1699–1700.
Org. Biomol. Chem.
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2
1 (a) J. Stawinski and A. Kraszewski, Acc. Chem. Res., 2002, 22 (a) K. Mulla, K. L. Aleshire, P. M. Forster and J. Y. Kang,
3
2
1
5, 952–960; (b) A. Y. Rulev, RSC Adv., 2014, 4, 26002–
6012; (c) G. O. Doak and L. D. Freedman, Chem. Rev.,
961, 61, 31–44; (d) W. J. Pietro and W. J. Hehre, J. Am.
J. Org. Chem., 2016, 81, 77–88; (b) K. Mulla and J. Y. Kang,
J. Org. Chem., 2016, 81, 4550–4558; (c) H. Huang and
J. Y. Kang, Org. Lett., 2016, 18, 4372–4375.
1
Chem. Soc., 1982, 104, 3594–3595.
23 For the H spectrum of C, see the ESI.†
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