Copper-catalyzed cycloaddition between hydrogen phosphonates and activated alkenes: Synthesis of phosphonoisoquinolinediones

Article abstract of DOI:10.1039/c5ra22570a

A new, general method for the synthesis of phosphonoisoquinolinediones has been achieved via copper-catalyzed phosphonation-cyclization of various methacryloylbenzamides with P(O)H compounds. This transformation allows the direct formation of a P-C bond a

Full text of DOI:10.1039/c5ra22570a

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: G. Tang, J. Wu, Y.
Gao, X. Zhao, L. Zhang, W. Chen and Y. Zhao, RSC Adv., 2015, DOI: 10.1039/C5RA22570A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 5
RSC Advances
View Article Online
DOI: 10.1039/C5RA22570A
Journal Name
RSCPublishing
COMMUNICATION
Copper-Catalyzed Cycloaddition between Hydrogen
Phosphonates and Activated Alkenes: Synthesis of
Phosphonoisoquinolinediones
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Ju Wu,a Yuzhen Gao,a Xin Zhao,a Liangliang Zhang,a Weizhu Chen,a,b Guo Tang,a,*
and Yufen Zhaoa
DOI: 10.1039/x0xx00000x
www.rsc.org/
formation of a PꢀC bond and the construction of a heterocyclic ring
in one reaction.
A
new, general method for the synthesis of
phosphonoisoquinolinediones has been achieved via copper-
catalyzed phosphonation-cyclization of various
Nevado's work, only one example
methacryloylbenzamides with P(O)H compounds. This
transformation allows the direct formation of a P-C bond and
the construction of an isoquinolinedione ring in one reaction.
O
P
Ph
Ph
O
COOCH3
O
O
O
AgNO3 (10%)
S
H P Ph
Ph
(a)
(b)
CH3CN, 100 o
C
N
N
O
CH3
CH3
O
This work
O
P
R2
R3
O
As one of the most important heterocyclic compounds, substituted
isoquinolinedione derivatives are important scaffolds in a broad
array of biologically active compounds. Over the last 20 years, more
isoquinolinedioneꢀcontaining compounds as drug candidates have
increased greatly.1 Thus, the development of new methods for their
synthesis has been a major focus of study.2 Among the synthetic
O
O
O
Cu(OTf)2 (10%)
TBHP, CH3CN
H P R2
N
N
R1
R3
R1
O
methods
to
obtain
isoquinolinedione
derivatives,
the Scheme 1. Synthetic routes to phosphonoisoquinolinediones.
difunctionalization reaction of alkenes through a radical process is
well known, including direct intramolecular aryltrifluoromethylation
2d and arylphosphonylation 3 of activated alkenes.
This idea was first examined by using NꢀmethacryloylꢀNꢀ
methylbenzamide (1a) and diethyl Hꢀphosphonate (2a) as reaction
partners (table 1). It has been found that many salts such as copper,6
silver7 and manganese8 can work with R2P(O)H to form the
corresponding phosphonyl radical which promoted phosphonyl
radical addition chemistry. In the beginning, various silver and
manganese catalysts were tested and all gave moderate yields
(entries 1ꢀ4, Table 1). In these processes, manganese is used in
excess (3 equivalents), which is quite wasteful. For a practical
reaction, using readily available and lowꢀcost catalyst for this
transformation would be appealing. Gratifyingly, the combined use
of Cu(OAc)2 and TBHP (tertꢀbutylhydroperoxide) gave 3a in 40%
yield (entry 6). Subsequently, various Cu(II) salts were further
checked and the results showed that Cu(OTf)2 was more effective to
give the desired product (entries 5ꢀ9). However, the attempt to
decrease the amount of Cu(OTf)2 was failed (entry 10). Moreover,
the yield was reduced to 43% under air (entry 11). Low yield was
afforded without copper salt or TBHP (entries 12 and 13). Cu(I) salt
and Cu powder couldn’t execute this reaction efficiently (entries 14
and 15). After optimization of the reaction conditions, we
established an efficient route to the phosphonation–annulation of
methacryloylbenzamides (entry 9, table 1).
As we know, organophosphorus compounds have broad
applications in the fields of organic synthesis, pharmaceuticals and
agrochemicals owing to its unique properties.4 Heterocyclic
phosphonate compounds are ubiquitous and exhibit interesting
biological activities and potential pharmaceutical applications.5 If
both phosphonyl group and isoquinolinedione structural motif can be
simultaneously introduced into organic compounds, a series of new
isoquinolinedioneꢀcontaining organophosphorus compounds might
be expected, and might provide an opportunity to introduce
phosphonyl group into the original lead compounds or drugs to
adjust their bioactivity. However, the efficient synthesis of
molecules bearing both isoquinolinedione motif and phosphonyl
group is quite rare. In 2014, Nevado group reported that the reaction
of methyl 2ꢀ(NꢀmethacryloylꢀNꢀmethylsulfamoyl)benzoate with
diphenylphosphine oxide in the presence of silver salt led to
phosphonoisoquinolinedione.3 Only one example was provided
(Scheme 1 a). Herein, we report the successful realization of this
concept with the introduction of phosphonyl radicals for the flexible
synthesis of unprecedented phosphonoisoquinolinediones with a
quaternary carbon centre. This transformation allows the direct
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 1

RSC Advances
Page 2 of 5
COMMUNICATION
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5RA22570A
Table 1. Optimization of reaction conditions.a
Table 2. Reaction scope study.
Entry
1
Additive (equiv)
Solvent
HOAc
T (oC)
60
Yield(%)
63
O
P
O
O
P
OEt
OEt
OiPr
OiPr
Mn(OAc)3·2H2O (3)
OEt
OEt
P
2
Mn(OAc)3·2H2O (3)
HOAc
70
59
O
O
O
3
AgNO3(0.05)+Mg(NO3)2·6H2O(0.5)
AgNO3(0.1)+Mg(NO3)2·6H2O(0.5)
Cu(OAc)2 (0.1)+TBHP (3)
CuCl2 (0.1)+TBHP (3)
CuSO4·5H2O (0.1)+TBHP (3)
Cu(NO3)2·3H2O (0.1)+TBHP (3)
Cu(OTf)2 (0.1)+TBHP (3)
Cu(OTf)2 (0.05)+TBHP (3)
Cu(OTf)2 (0.1)+TBHP (3)
TBHP (3)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
100
100
60
62
N
N
N
4
65
O
O
O
5
40
3a 80%, 65%,a 50%b
3b 71%
3c 68%
6
60
15
O
O
O
OEt
OEt
7
60
20
OiPr
OiPr
OEt
OEt
P
P
P
8
60
48
Ph
O
F
O
t-Bu
O
9
60
83
N
N
N
10
11b
12
13
14
60
70
O
O
60
43
O
3f 51%
3e 67%
3d 50%
60
34
O
Cu(OTf)2 (0.2)
60
0
O
O
OEt
OEt
OEt
OEt
OEt
OEt
P
P
N
P
CuCl (0.1)+TBHP (3)
60
15
Cl
O
F3C
O
Br
O
15
a
Cu powder(0.1)+TBHP (3)
60
5
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), additive in solvent (2.0 mL)
stirring under nitrogen for 24 h. Oil bath temperature. Yields were determined by 31P
NMR based on Ph3PO as internal standard. b Unde air.
N
N
O
O
O
3g 67%
3h 62%
3i 45%
O
O
N
O
OiPr
OiPr
P
P(OEt)2
O
OEt
With this preliminary result in hand, the results of
MeO
O
P
O
+
phosphonation–annulation for methacryloylbenzamides
1 with
O
OEt
N
N
different H–phosphonates 2 can be summarized as follows. As
shown in Table 2, a variety of functional groups on the phenyl ring
of methacryloylbenzamides were compatible under this procedure,
affording the desired products in moderate to good yields. The alkyl
and phenyl substituted benzamide substrates, such as paraꢀmethyl,
orthoꢀmethyl, para-tert-butyl and paraꢀphenyl on the aryl ring,
reacted with 2a efficiently and gave the desired products 3b-3e in
good yields. Halogen atoms such as fluoro, chloro, and bromo on the
aromatic ring were unaffected under the present reaction conditions
to afford the corresponding products 3f-3h in moderate to good
yields, which could allow for further synthetic transformations.
Benzamide substrates bearing CF3 group reacted smoothly to give
the corresponding product in moderate yield (3i). When Nꢀ
methacryloylꢀ4ꢀmethoxyꢀNꢀmethylbenzamide reacted with 2a, we
acquired both the normal coupling product 3ja and the
dearomatization product 3jb as a 1:2 mixture in 96% total yield. The
product 3jb was formed by annulation of alkenyl radical with the
aryl ring at the carbon atom directly attached to the carbonyl atom to
form 1,3,8ꢀtrioxoꢀ2ꢀazaspiro compound.9 The reactivity of Nꢀalkyl
substituted substrates was further explored. More bulk alkyl groups
at the nitrogen atom such as ethyl and isopropyl groups react with
diethyl Hꢀphosphonate (2a) furnishing the corresponding
isoquinolinedione 3k and 3l in 68% and 71% yields, respectively. Nꢀ
Et
O
total yield: 96%
O
O
3ja 31%
3jb 65%
3k 68%
O
O
O
OiPr
OiPr
OEt
OEt
OMe
OMe
P
N
P
P
N
O
O
O
N
S
iPr
O
O
O
3l 71%
3m n.d.
3n 82%
O
O
P
OiPr
OiPr
P(OBn)2
N
O
O
O
N
N
O
P
OEt
OEt
3q 68%
O
O
3o 72%
3p 71%
O
P
O
Ph
Ph
OEt
Ph
P
N
O
O
N
O
O
MethacryloylꢀNꢀmethylthiopheneꢀ2ꢀcarboxamide
gave
a
3r 51%
3s 70%
complicated mixture, no 3m was obtained. Dimethyl, diisopropyl,
and dibenzyl H–phosphonates could be also used as substrates,
generating the corresponding products (3n-3p) in good yields. 1ꢀ
a
Reaction conditions: 1a (10 mmol), 2a (20 mmol), Cu(OTf)2 (1.0 mmol),
TBHP(30 mmol), CH3CN (30 mL) stirring under nitrogen for 30 h. b 1a (10 mmol),
2a (20 mmol), Cu(OTf)2 (0.5 mmol), TBHP(30 mmol), CH3CN (30 mL) stirring
under nitrogen for 30 h.
Methacryloylꢀ1,2,3,4ꢀtetrahydroquinoline was also
a
suitable
acceptor to extend the applicability of the current method, and led to
the formation of product (3q) in 68% yield. It is worth noting that
ethoxyphenylphosphine oxide and diphenylphosphine oxide can be
also applied in the preparation of the corresponding
phosphonoisoquinolinediones in moderate yields (3r and 3s).
In order to demonstrate the practical application of this method,
NꢀmethacryloylꢀNꢀmethylbenzamide (1a, 10 mmol) was employed
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 3 of 5
Journal Name
RSC Advances
View Article Online
COMMUNICATION
DOI: 10.1039/C5RA22570A
in a gramꢀscale reaction and delivered 3a in 65% yield (Table 2). Innovative Research Team in University.
When the loading of Cu(OTf)2 was reduced to 5 mol%, the reaction
also afforded 3a in 50% yield.
Notes and references
No desired product was obtained when 2.0 equiv of TEMPO was
added in the reaction of 1a with 2a under the optimal conditions.
This result indicates that the phosphonyl radicals may be intercepted
by TEMPO. According to our previous Cu(II)–TBHP catalytic
reaction mechanism study,[6a,c] a plausible mechanism is proposed as
shown in Scheme 2. Initially, the reaction of P(O)H 1 with Cu(II)
salt and TBHP generates phosphonyl radical A which then goes
through intermolecular addition onto the carbonꢀcarbon double bond
of 2 to produce alkyl radical B. Followed by intramolecular attack of
the radical B on the pendant aromatic ring subsequently provides
radical C. Subsequently, phosphonoisoquinolinedione 3ka is formed
through oxidationꢀdeprotonation reaction. Alternatively, alkyl
radical B attacks the aryl ring at the carbon atom directly attached to
the carbonyl group to form radical E. Cationic intermediate F is
formed through singleꢀelectron oxidation which could afford
resonance structure G. The intermediate G converts into the product
3kb via demethylation.
a Department of Chemistry, College of Chemistry and Chemical Engineering,
and the Key Laboratory for Chemical Biology of Fujian Province, Xiamen
University,
Xiamen,
Fujian
361005,
China
Fax: (86)592ꢀ2185780; Eꢀmail: t12g21@xmu.edu.cn
b
The Third Institute of Oceanography of the State Oceanic Administration,
Xiamen, Fujian 361005, China
Electronic Supplementary Information (ESI) available: Experimental
procedures for the synthesis, spectral data and NMR spectra of
compounds 3aꢀ3s. See DOI: 10.1039/c000000x/
1 (a) M. Paige, G. Kosturko, G. Bulut, M. Miessau, S. Rahim, J. A. Toretsky, M.
L. Brown and A. Uren, Bioorg. Med. Chem., 2014, 22, 478; (b) M. Billamboz,
V. Suchaud, F. Bailly, C. Lion, J. Demeulemeester, C. Calmels, M. L.
Andréola, F. Christ, Z. Debyser and P. Cotelle, ACS Med. Chem. Lett., 2013, 4,
606; (c) L. Chen, M. CondaꢀSheridan, P. V. N. Reddy, A. Morrell, E.ꢀJ. Park,
T. P. Kondratyuk, J. M. Pezzuto, R. B. van Breemen and M. Cushman, J. Med.
Chem., 2012, 55, 5965; (d) M. Billamboz, F. Bailly, C. Lion, N. Touati, H.
Vezin, C. Calmels, M. L. Andréola, F. Christ, Z. Debyser and P. Cotelle, J.
Med. Chem., 2011, 54, 1812; (e) A. Bolognese, G. Correale, M. Manfra, A.
Lavecchia, O. Mazzoni, E. Novellino, V. Barone, P. La Colla and R. Loddo, J.
Med. Chem., 2002, 45, 5217.
2 (a) M. Billamboz, F. Bailly, M. L. Barreca, L. De Luca, J.ꢀF. Mouscadet, C.
Calmels, M.ꢀL. Andréola, M. Witvrouw, F. Christ, Z. Debyser and P. Cotelle
J. Med. Chem., 2008, 51, 7717; (b) J. J. Medvedev, M. V. Meleshina, T. L.
Panikorovskii, C. Schneider, V. A. Nikolaev, Org. Biomol. Chem., 2015, 13,
9107; (c) M. C GarciaꢀGonzalez, E. HernandezꢀVazquez, , R. E. GordilloꢀCruz
and L. D. Miranda, Chem. Commun., 2015, 51, 11669; (d) L. Zheng, C. Yang,
Z. Z. Xu, F. Gao and W. Xia, J. Org. Chem., 2015, 80, 5730; (e) C. Yang, X.
Zhang, D. ZhangꢀNegrerie, Y. Du, K. Zhao, J. Org. Chem., 2015, 80, 5320; (f)
J. Shi, J. Zhou, Y. Yan, J. Jia, X. Liu, H. Song, H. E. Xu, W. Yi, Chem.
Commun., 2015, 51, 668.
3 W. Kong, E. Merino and C. Nevado, Angew. Chem. Int. Ed., 2014, 53, 5078.
4 (a) T. Baumgartner, R. Réau, Chem. Rev., 2006, 106, 4681; (b) H. A. McManus,
P. J. Guiry, Chem. Rev., 2004, 104, 4151; (c) M. N. Birkholz, Z. Freixa, P. W.
N. M. van Leeuwen, Chem. Soc. Rev., 2009, 38, 1099.
5 A. Arnone, P. Bravo, M. Frigerio, F. Viani and C. Zappalà, Synthesis, 1998,
1511; (b) H. Krawczyk, K. Wasek, J. Kedzia, J. Wojciechowski and W. M.
Wolf, Org. Biomol. Chem., 2008, 6, 308; (c) A. Arnone, P. Bravo, M. Frigerio,
A. Mele, B. Vergani and F. Viani, Eur. J. Org. Chem., 1999, 2149; (d) M.
Frings, I. Thomé, I. Schiffers, F. Pan and C. Bolm, Chem. Eur. J., 2014, 20,
1691; (e) A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I.
Livantsova and V. S. Petrosyan, Heteroatom Chemistry, 2008, 19, 418; (f) P.
Dauban and R. H. Dodd, J. Org. Chem., 1997, 62, 4277; (g) R. Mansueto, V.
Mallardo, F. M. Perna, A. Salomone and V. Capriati, Chem. Commun., 2013,
49, 10160.
6 (a) P. Zhang, L. Zhang, Y. Gao, J. Xu, H. Fang, G. Tang and Y. Zhao, Chem.
Commun., 2015, 51, 7839; (b) H. Y. Zhang, L. L. Mao, B. Yang and S. D.
Yang, Chem. Commun., 2015, 51, 4101; (c) Z. Zhao, W. Xue, Y. Gao, G.
Tang and Y. Zhao, Chem. Asian J., 2013, 8, 713; (d) B. Xiong, X. Feng, L.
Zhu, T. Chen, Y. Zhou, C. T. Au and S. F. Yin, ACS Catal., 2015, 5, 537; (e)
M. Zhou, M. Chen, Y. Zhou, K. Yang, J. Su, J. Du and Q. Song, Org. Lett.,
2015, 17, 1786.
Scheme 2. Proposed reaction mechanism.
In conclusion, we have successfully developed a facile catalytic
method for the preparation of phosphonoisoquinolinediones via
phosphonationꢀcyclization of various methacryloylbenzamides with
P(O)H compounds. This method provides a rapid access to a broad
spectrum of phosphonoisoquinolinediones in moderate to good 7 (a) Y. M. Li, M. Sun, H. L. Wang, Q. P. Tian and S. D. Yang, Angew. Chem. Int.
Ed., 2013, 52, 3972; (b) B. Zhang, C. G. Daniliuc and A. Studer, Org. Lett.,
2014, 16, 250; (c) M. C. Lamas and A. Studer, Org. Lett., 2011, 13, 2236;
(d) X. Chen, X. Li, X. L. Chen, L. B. Qu, J. Y. Chen, K. Sun, Z. D. Liu,W.
Z. Bi, Y. Y. Xia, H. T. Wu, and Y. F. Zhao, Chem. Commun., 2015, 51,
3846; (e) Z. Z. Zhou, D. P. Jin, L. H. Li, Y. T. He, P. X. Zhou, X. B. Yan, X.
Y. Liu and Y. M. Liang, Org. Lett., 2014, 16, 5616.
yields. Moreover, the use of inexpensive Cu(II) catalyst, using
readilyꢀprepared methacryloylbenzamides and P(O)H compounds
mean that this facile protocol will be attractive for academia and
industry.
8 (a) B. B. Snider, Chem. Rev., 1996, 96, 339; (b) W. Liu, D. Zell, M. John, L.
Ackermann, Angew. Chem., Int. Ed., 2015, 54, 13; (c) X. Li, J. Xu, Y. Gao, H.
Fang, G. Tang and Y. Zhao, J. Org. Chem., 2015, 80, 2621; (d) Y. Gao, J. Xu,
P. Zhang, H. Fang, G. Tang and Y. Zhao, RSC Adv., 2015, 5, 36167; (e) H. C.
Fisher, O. Berger, F. Gelat and J. L. Montchamp, Adv. Synth. Catal., 2014,
356, 1199; (f) D. P. Li, X. Q. Pan,L. T. An, J. P. Zou, and W. Zhang, J. Org.
Chem., 2014, 79, 1850; (g) X. H. Cao, X. Pan, P. J. Zhou, J. P. Zou and O. T.
Asekun, Chem. Commun., 2014, 50, 3359; (h) S. F. Zhou, D. P. Li, K. Liu, J.
Acknowledgements
We acknowledge financial support from the Chinese National
Natural Science Foundation (21173178, 21232005, 21375113),
J1310024, the National Basic Research Program of China
(2012CB821600), and the Program for Changjiang Scholars and
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3

RSC Advances
Page 4 of 5
COMMUNICATION
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5RA22570A
P. Zou, and O. T. Asekun, J. Org. Chem., 2015, 80, 1214; (i) Y. Gao, X. Li, J.
Xu, Y. Wu, W. Chen, G. Tang and Y. Zhao, Chem. Commun., 2015, 51, 1605.
9 (a) G. Han, Q. Wang, Y. Liu and Q. Wang，Org. Lett., 2014, 16, 5914; (b) G.
Han, Y. Liu and Q. Wang, Org. Lett., 2014, 16, 3188.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 5 of 5
RSC Advances
View Article Online
DOI: 10.1039/C5RA22570A
Copper-Catalyzed
Phosphonates and
Phosphonoisoquinolinediones
Cycloaddition
between
Hydrogen
of
Activated
Alkenes: Synthesis
Ju Wu,a Yuzhen Gao,a Xin Zhao,a Liangliang Zhang,a Weizhu Chen,a,b Guo Tang,a,* and
Yufen Zhaoa
A new and general method for the synthesis of phosphonoisoquinolinediones has been
achieved through copper-catalyzed phosphonation-cyclization of various
methacryloylbenzamides with P(O)H compounds.