Copper-catalyzed decarboxylative cyclization: Via tandem C-P and C-N bond formation: Access to 2-phosphorylmethyl indoles

Article abstract of DOI:10.1039/c8cc00739j

A novel copper-catalyzed decarboxylative cyclization of ethynyl benzoxazinanones with P(O)H compounds has been developed. This protocol leads to a series of 2-phosphorylmethyl indoles with high efficiency and selectivity (up to 99% yield) through tandem C-P/C-N bond formation under mild conditions.

Full text of DOI:10.1039/c8cc00739j

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Copper-catalyzed decarboxylative cyclization via tandem C–P and
C–N bond formation: access to 2-phosphorylmethyl indoles
Bao-Cheng Wang,‡a Ya-Ni Wang,‡a Mao-Mao Zhang,a Wen-Jing Xiaoab and Liang-Qiu Lu*ac
3Received 00th April 20xx,
Accepted 00th May 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Following the pioneering works of Murahashi and Godfrey,5 Cu-
catalyzed propargylations through the key Cu-allenylidene
A novel copper-catalyzed decarboxylative cyclization of ethynyl
benzoxazinanones with P(O)H compounds has been developed.
This protocol leads to a series of 2-phosphorylmethyl indoles with intermediate have been established as an important tool for
carbon-carbon and carbon-heteroatom bond formations.6 Recently,
high efficiency and selectivity (up to 99% yield) through tandem C-
P/C-N bond formation under mild conditions.
mainly due to the substantial contributions from Hu and co-
workers,7 the Cu-allenylidene species was further utilized for
cascade reactions by exploiting its multiple reacting sites, including
electrophilic α~γ-positions to Cu atom (Scheme 1a, int. I). As a result,
a wide range of binucleophiles, such as cyclic enamines, hydrazines,
Phosphorus-containing aza-heterocyclic compounds are a kind
of important structural motifs that are widespread in
pharmaceutical agents1 and widely used in organic synthesis as
ligands2 and intermediates.3 Consequently, plenty of research
endeavours have been devoted to developing efficient methods to
produce these compounds.4 With phosphorated indoles as example,
in 2010 Yorimitsu and Oshima developed a Pd-catalyzed formal
[3+2] cycloaddition between 2-iodoanilines and 1-alkynylphosphine
oxides, affording 2-phospho-indoles with good reaction efficiency.4a
In 2014, Yang and co-workers disclosed
a
Cu-catalyzed
dehydrogenative cross-coupling reaction of electro-deficient
indoles with P(O)H compounds, producing 3-phospho-indoles with
high efficiency and atom economy.4b Recently, Tang’s group
reported an alternative route to 3-phospho-indoles through an
efficient Ag-mediated cycloaddition of N-Ts-2-alkynylanilines with
P(O)H compounds.4d Despite important advances, these protocols
are usually performed under heating conditions or with
stoichiometric AgOAc as oxidant. Therefore, inventions of novel
methods to catalytically synthesize phosphorus-containing indoles
under mild conditions are still highly desirable from the viewpoints
of diverse and sustainable synthesis.
Scheme 1 Tandem reactions based on the Cu-allenylidene species.
β-enamino esters, o-aminophenols, etc. were successfully applied
to the [3+3],7a [3+2]7b,c,e,f or [4+2]7d cycloadditions of propargylic
ester reagents.7 In 2016, our group designed and synthesized a new
ethynyl benzoxazinone reagent (1a), which can react with Cu
catalysts to generate a tosyl amide-containing Cu-allenylidene
intermediate (int. II) under mild conditions (Scheme 1b).8a Quickly,
this reagent was widely applied to many propargylation-initiated
cyclizations and related cascade reactions by us8 and other groups.9
Considering our research interests on the development of transition
metal-catalyzed cyclization reactions8,10 and the rich reactivity of
Cu-allenylidene species, herein we planned to develop a new Cu-
catalyzed decarboxylative cyclization of reagent 1a with P(O)H
a
CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticide &
Chemical Biology, Ministry of Education, College of Chemistry, Central
China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China.
Email: luliangqiu@mail.ccnu.edu.cn
b
Hubei Key Laboratory for Processing and Application of Catalytic
Materials, Huanggang Normal College, Huanggang 438000, China
c
State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou 730000, China
†
Electronic supplementary information (ESI) available. See DOI:
10.1039/0000000000
‡ These authors contributed equally to this work.
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compounds
Journal Name
2
(Scheme 1c). Different from previously well- precursor for the synthesis of natural product nostodione A, which
established processes initiated by the γ-propargylation of int. II, this shows important biological activities, such as acytotoxicity and anti-
transformation was expected to start with an α-addition of P(O)H invasion activity.12 In order to improve the yield of desired product
compounds to the same intermediate. If successful, a series of 3a, the ratio of 1a to 2a was firstly examined (Table 1, entries 1-4).
synthetically significantly 2-phosphorylmethyl indoles would be When 2.5 equivalent of 2a was used, product 3a could be obtained
achieved in high efficiency through tandem C-P/C-N bond formation in 89% yield (Table 1, entry 4). Then we investigated the solvent
under mild conditions with the use of cheap metal catalyst.
effect (Table 1, entries 4-8) and the protic solvent MeOH was still
To examine the hypothesis, we initially performed the the best choice. Importantly, we found that byproduct 3a’ could be
decarboxylative cyclization of ethynyl benzoxazinanone 1a with inhibited when phosphine ligand dppe was introduced, albeit with a
dimethyl phosphonate 2a at room temperature in the presence of reduced reaction efficiency (Table 1, entry 9: 77% yield). Inspired by
iPr2NEt and CuI in MeOH (Table 1, entry 1). To our delight, the this result, other ligands were tested to improve the result (Table 1,
reaction did occur and the 2-phosphorylmethyl indole 3a was entries 10 and 11)13 and nitrogen ligand pybox gave an improved
produced in 72% yield after one hour, accompanying with trace yield (Table 1, entry 11: 96% yield). Meanwhile, the replacement of
amount of 3-phosphoryl indole byproduct 3a’ (see the mechanism Cul with Cu(OAc)2 has no effect on the reaction (Table 1, entry 12).
part). Worthy to note that, product 3a has been used as a key
Table 1 Optimization of reaction conditionsa
Control experiments were performed and the results suggested
that both base and copper catalyst were necessary for present
transformation (Table 1, entries 13-14). Furthermore, this
cyclization reaction could still proceed very well when the loading
of dimethyl phosphonate 2a was reduced from 2.5 equiv. to 2.0
equiv. (Table 1, entry 15: 96% yield).
With the optimal conditions in hand, we started to probe
the generality of this Cu-catalyzed decarboxylative cyclization.
Firstly, we focused on investigating the scope of P(O)H
Entry
Cu cat.
Ligand
1a:2a
Solvent
Yield (%)b
d
Table 2 The scope of P(O)H compoundsa,b
1
2
CuI
CuI
_
1:1.2
1:1.5
1:2.0
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.0
MeOH
MeOH
MeOH
MeOH
EtOH
72c
77c
82c
89c
79
d
_
d
3
CuI
_
d
4
CuI
_
d
5
CuI
_
d
6
CuI
_
THF
69
d
7
CuI
_
CH3CN
Toleune
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
43
d
8
CuI
_
trace
77
9
CuI
dppe
dppp
10
11
12
13e
14f
15
CuI
89
CuI
pybox
pybox
pybox
pybox
pybox
96
Cu(OAc)2
none
CuI
96
0
0
CuI
96
a
Conditions: 1a (0.2 mmol), 2a (0.24-0.50 mmol), Cu cat. (5 mol%),
i
ligand (6 mol%), and Pr2NEt (2.0 equiv.) in 2 mL of solvent at rt for
b
c
1h.
Isolated yield.
Trace amount of 3a’ (<10% yield) was
determined by 1H NMR. d No ligand. e No copper salt. f No base. THF:
tetrahydrofuran; DCE: 1,2-dichloroethane.
O
O
Ph2P
PPh2
Ph2P
PPh2
N
N
N
a
Unless noted otherwise, reactions were performed under the
b
pybox
dppe
dppp
conditions as described in Table 1, entry 15 at 0.2 mmol scale.
Isolated yield. c EtOH as solvent. d DCE as solvent.
2 | J. Name., 2015, 00, 1-3
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compounds and generally, good to excellent reaction yields 8-position proceeded very well, too; the desired product 3s
were obtained. As summarized in Table 2, dialkyl was afforded in 99% yield. To our delight, the success of this
phosphonates, such as diethyl phosphonate (Table 2, 3b: 84% cyclization can be extended to ethynyl benzoxazinanones
yield) and dibutyl phosphonate (Table 2, 3c: 65% yield), were having substituents at the 4-position. For example, when 4-
successfully involved in this transformation by using EtOH as methyl-substituted substrate 1t was subjected to the optimal
the solvent. The reaction with diphenyl phosphonate also conditions, the 2,3-substituted indole product 3t was obtained
proceeded well by using DCE as the solvent (Table 2, 3d, 93% in a moderate yield (Table 3 3t: 40% yield). Furthermore, a
yield).14 In addition to phosphonates, this method was also gram-scale experiment with substrates 1a and 2e was performed
amenable to diphenylphosphine oxide, affording the desired under the standard conditions, producing the 2-phosphorylmethyl
product 3e in 94% yield.15 Then the variation of substitution indole 3e with the same reaction efficiency (equation 1: 94% yield).
position and electronic effect on the aromatic ring of
diphenylphosphine oxides were evaluated. It was found that,
substrates
2 bearing electron-donating groups (i.e., methyl-,
dimethyl-) and halogen groups (i.e., fluoro-, chloro-) can be
facilely converted into corresponding products 3f-3i in 93%-
99% yields. Furthermore, reactions with methylphenylphosphinate
2j and dibenzo[c,e][1,2] oxaposphinine 6-oxide 2k were also
performed, furnishing the desired products 3j and 3k in good
yields (Table 2, 3j: 72% yield, 3k: 98% yield).
Next, we proposed a possible mechanism to understand the
generation of 2-phosphorylmethyl indoles from ethynyl
benzoxazinanones and P(O)H compounds. As illustrated in
Scheme 2, ethynyl benzoxazinanone 1a initially reacts with copper
catalyst to generate the alkynyl copper immediate A assisted by
Afterwards, we turned our attention to the cyclization
reaction of dimethyl phosphonate 2a with various ethynyl
benzoxazinanones. As highlighted in Table 3, variation of
electronic effect of substituents, such as methoxyl-, methyl-,
chloro- and bromo-, at the 7-position of ethynyl
benzoxazinanones did not obviously affect the efficiency of
cyclization reactions (Table 3, 3l-3o: 84-99% yields). The
substrates possessing a fluoro or chloro atom at the 5- or 7-
position were well tolerated in this reaction, producing
i
organic base Pr2NEt. Then, a decarboxylation process undergoes
smoothly to form the key Cu-allenylidene intermediate (int. II).8,9
Next, according to the impressive mechanism investigation by Shen
and Han,16 we propose that an α-addition of dimethyl phosphonate
2a to int. II might occur to form the C-P bond and the possible
intermediate C could be transiently generated. Finally, the desired
product 3a is furnished through the subsequent Michael
addition/protolysis processes. The propagation reaction of P(O)H
compound 2a at the γ-position of int. II would result in the 3-
phospho-indole byproduct 3a’, which is a possible competitive
pathway but can be inhibited by ligand.
corresponding 2-phosphorylmethyl indoles 3p-3r in 93-97%
yields. Similarly, the cyclization reaction performed with the
ethynyl benzoxazinanone with a methyl group at the
Table 3 The scope of ethynyl benzoxazinanonesa,b
Scheme 2 A proposed mechanism.
In conclusion, we have developed
a copper-catalyzed
decarboxylative cyclization of ethynyl benzoxazinanones with P(O)H
compounds. This protocol enables the facile preparation of 2-
phosphorylmethyl indoles in high yields and with excellent
chemoselectivity. We believe that this new transformation will
attract the interests from synthetic community for its good
substrate scope and mild reaction conditions.
a
Unless noted otherwise, reactions were performed under the
b
condition as described in Table 1, entry 15 at 0.2 mmol scale.
Isolated yield. c 3h.
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18, 2734-2737; (f) L. Shao, Y.-H. Wang, D.-Y. Zhang, J. Xu and
X.-P. Hu, Angew. Chem., Int. Ed., 2016, 55, 1-6.
We are grateful to the National Natural Science Foundation
of China (NO. 21572074, 21772052 and 21772053), the
Program of Introducing Talents of Discipline to Universities of
China (111 Program, B17019), the Foundation for the Author
of National Excellent Doctoral Dissertation of PR China (NO.
201422) and the Natural Science Foundation of Hubei Province
(2015CFA033 and 2017AH047) for support of this research. We
also thank Prof. Jia-Rong Chen for helpful discussion and Prof.
Dr. Fang-Fang Pan for X-ray analysis.
8
9
(a) Q. Wang, T.-R. Li, L.-Q. Lu, M.-M. Li, K. Zhang and W.-J.
Xiao, J. Am. Chem. Soc., 2016, 138, 8360-8363; (b) T.-R. Li, B.-
Y. Cheng, Y.-N. Wang, M.-M. Zhang, L.-Q. Lu and W.-J. Xiao,
Angew. Chem., Int. Ed., 2016, 55, 12422-12426; (c) T.-R. Li,
L.-Q. Lu, Y.-N. Wang, B.-C. Wang and W.-J. Xiao, Org. Lett.,
2016, 19, 4098-4101.
(a) J. Song, Z.-J. Zhang and L.-Z. Gong, Angew. Chem., Int. Ed.,
2017, 56, 5212-5216; (b) X. Lu, L. Ge, C. Cheng, J. Chen, W.
Cao and X. Wu, Chem. Eur. J., 2017, 23, 7689-7693; (c) W.
Shao and S.-L. You, Chem. Eur. J., 2017, 23, 1-6; (d) Q. Lu, S.
Cembellín, S. Greßies, S. Singha, C. G. Daniliuc and F. Glorius,
Angew. Chem., Int. Ed., 2018, 57, 1399-1403.
Notes and references
10 For a related review, see: (a) L.-Q. Lu, T.-R. Li, Q. Wang and
W.-J. Xiao, Chem. Soc. Rev., 2017, 46, 4135-4149; for recent
examples, see: (b) Y. Wei, L.-Q. Lu, T.-R. Li, B. Feng, Q. Wang,
1
For a review, see: (a) L. Bialy and H. Waldmann, Angew.
Chem., Int. Ed., 2005, 44, 3814-3839; for recent examples,
see: (b) Q. Dang, Y. Liu and D. K. Cashion, J. Med. Chem.,
2011, 54, 153-165; (c) F. R. Alexandre, A. Amador and S. Bot,
J. Med. Chem., 2011, 54, 392-395; (d) X. Chen, D. J. Kopecky
and J. Mihalic, J. Med. Chem., 2012, 55, 3837-3851.
W.-J. Xiao and H. Alper, Angew. Chem., Int. Ed., 2016, 55
,
2200-2204; (c) T.-R Li, B.-Y. Cheng, S.-Q. Fan, Y.-N. Wang, L.-
Q. Lu and W.-J. Xiao, Chem. Eur. J., 2016, 22, 6243-6247; (d)
Y.-N. Wang, B.-C. Wang, M.-M. Zhang, X.-W. Gao, T.-R. Li, L.-
Q. Lu and W.-J. Xiao, Org. Lett., 2017, 19, 4094-4097; (e) M.-
M. Li, Y. Wei, J. Liu, H.-W. Chen, L.-Q. Lu and W.-J. Xiao, J. Am.
Chem. Soc., 2017, 139, 14707-14713.
2
3
For select reviews, see: (a) W. Tang and X. Zhang, Chem. Rev.,
2003, 103, 3029-3069; (b) H. A. McManus and P. J. Guiry,
Chem. Rev., 2004, 104, 4151-4202; (c) H. F. Perez, E. Pablo, P.
Armen and V. F. Anton, Chem. Rev., 2011, 111, 2119-2176; (d)
S.-F. Zhu and Q.-L. Zhou, Acc. Chem. Res., 2017, 50, 988-1001.
For select reviews, see: (a) K. Moonen, I. Laureyn and C. V.
Stevens, Chem. Rev., 2004, 104, 6177-6215; (b) L. Coudray
and J. Montchamp, Eur. J. Org. Chem., 2008, 21, 3601-3613;
11 Byproduct 3a’ was believed to be generated from the
competitive γ-propargylation pathway, which was similar
with one of our previous works in ref. 8b.
12 J. McNulty, K. Keskar, C. Bordón, R. Yolken and L. Jones-
Brando, Chem. Commun., 2014, 50, 8904-8907.
13 See the supporting information for the ligand evaluation and
other details of condition optimization.
14 When the reaction was performed with phosphonates 2b-2d,
(c) S. V. Jeught and C. V. Stevens, Chem. Rev., 2009, 109
,
2672-2702; (d) C. S. Demmer, N. K. Larsen and L. Bunch,
Chem. Rev., 2011, 111, 7981-8006.
4
For select examples, see: (a) A. Kondoh, H. Yorimitsu and K.
Oshima, Org. Lett., 2010, 12, 1476-1479; (b) A.-X. Zhou, L.-L.
complex reaction mixture or low yield was achieved.
15 The structure of product 3e was confirmed by x-ray
diffraction analysis. CCDC 1818277 contains the
crystallographic data of this product, which can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Mao, G.-W. Wang and S.-D. Yang, Chem. Commun., 2014, 50
,
8529-8532; (c) H.-Y. Zhang, L.-L. Mao, B. Yang and S.-D. Yang,
Chem. Commun., 2015, 51, 4101-4104; (d) Y. Gao, G. Lu, P.
Zhang, L. Zhang, G. Tang and Y. Zhao, Org. Lett., 2016, 18
,
1242-1245; (e) J. Zheng, Y. Zhang, D. Wang and S. Cui, Org.
Lett., 2016, 18, 1768-1771; (f) C.-X. Li, D.-S. Tu, R. Yao, H. Yan
and C.-S. Lu, Org. Lett., 2016, 18, 4928-4931; (g) H. Zhang, Z.
Gu, Z. Li, C. Pan, W. Li, H. Hu and C. Zhu, J. Org. Chem., 2016,
81, 2122-2127; (h) W. Wei, X. Li, M. Gu, H. Yao and A. Lin,
Org. Biomol. Chem., 2017, 15, 8458-8462; (i) H. Zhang, W. Li,
16 R. Shen, B. Luo, J. Yang, L. Zhang and L.-B. Han, Chem.
Commun., 2016, 52, 6451-6454.
and C. Zhu, J. Org. Chem., 2017, 82, 2199-2204；(j) W.-S.
Guo, Q. Dou, J. Hou, L.-R. Wen and M. Li, J. Org. Chem., 2017,
82, 7015-7022.
5
6
(a) Y. Imada, M. Yuasa, I. Nakamura and S. I. Murahashi, J.
Org. Chem., 1994, 59, 2282-2284; (b) J. D. Godfrey, R. H.
Mueller, T. C. Sedergran, N. Soundararajan and V. J.
Colandrea, Tetrahedron Lett., 1994, 35, 6405-6408.
(a) N. Ljungdahl and N. Kann, Angew. Chem., Int. Ed., 2009,
48, 642-644; (b) R. J. Detz, H. Hiemstra and J. H. van
Maarseveen, Eur. J. Org. Chem., 2009, 36, 6263-6276; (c) Y.
Miyake, S. Uemura and Y. Nishibayashi, ChemCatChem.,
2009, 1, 331-334; (d) C.-H. Ding and X.-L. Hou, Chem. Rev.,
2011, 111, 1914-1937; (e) Y. Nishibayashi, Synthesis, 2012,
44, 489-503; (f) E. B. Bauer, Synthesis, 2012, 44, 1131-1151;
(g) X.-H. Hu, Z.-T. Liu, H. Shao and X.-P. Hu, Synthesis, 2015,
47, 913-923; (h) D.-Y. Zhang and X.-P. Hu, Tetrahedron Lett.,
2015, 56, 283-295.
7
(a) C. Zhang, X.-H. Hu, Y.-H. Wang, Z. Zheng, J. Xu and X.-P.
Hu, J. Am. Chem. Soc., 2012, 134, 9585-9588; (b) D.-Y. Zhang,
L. Shao, J. Xu and X.-P. Hu, ACS Catal., 2015,
Q. Li, C.-J. Hou, Y.-Z. Hui, Y.-J. Liu, R.-F. Yang and X.-P. Hu, RSC
Adv., 2015, , 85879-85883; (d) Z.-T. Liu, Y.-H. Wang, F.-L.
5, 5026-5030; (c)
5
Zhu and X.-P. Hu, Org. Lett., 2016, 18, 1190-1193; (e) Y. Zhou,
F.-L. Zhu, Z.-T. Liu, X.-M. Zhou and X.-P. Hu, Org. Lett., 2016,
4 | J. Name., 2015, 00, 1-3
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Contents
Graphic Abstract:
A copper-catalyzed decarboxylative cyclization of ethynyl benzoxazinanones with P(O)H compounds
has been developed for the synthesis of 2-phosphorylmethyl indoles.