Deconstructive di-functionalization of unstrained, benzo cyclic amines by C-N bond cleavage using a recyclable tungsten catalyst

Article abstract of DOI:10.1039/c9ob00693a

With H₂WO₄ as the catalyst and H₂O₂ as the oxidant, we herein report a deconstructive difunctionalization of the C-N bond in unstrained, benzo cyclic amines to generate an ester group and nitro group simultaneously. The preliminary mechanistic studies suggested that the corresponding hydroxamic acid is the key intermediate for this transformation. Importantly, with the utilization of this transformation, we achieved an interesting approach for the ring contraction of quinoline to indole, an example of scaffold hopping in a hetero-aromatic system.

Full text of DOI:10.1039/c9ob00693a

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Deconstructive di-functionalization of unstrained, benzo cyclic
amines by C-N bond cleavage using a recyclable tungsten catalyst
Yujing Zhang,a,b Shuai Sun,b Yijin Su,*a Jian Zhao,b Yong-Hong Li,b Bo Han,a,b Feng Shi*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
With H2WO4 as catalyst and H2O2 as oxidant, we herein report a organic synthesis and widely exists in natural products and
deconstructive difunctionalization of C-N bond in unstrained, benzo bioactive molecules8 (Fig. 2A). On the basis of our recent studies
cyclic amines to generate ester group and nitro group for selective oxidation of amines9, we envisioned the
simulateously. The preliminary mechanistic studies suggested that deconstructive diversification of 1, 2, 3, 4-tetrahydro-
the corresponding hydroxamic acid is the key intermediate for this quninolines with C-N bond cleavage could provide an
transformation. Importantly, with the utilization of this opportunity to achieve the ring contraction of quinolines to
transformation, we achieved an interesting approach for the ring indoles (Fig. 2B). The deconstructive functionalization of 1, 2, 3,
contraction of quinoline to indole, an example of scaffold hopping 4-tetrahydroquinolines through the formation of hemi-aminal
in hetero-aromatic system.
should be much more challenging than that of piperidines
because of the following reasons: 1) tetrahydroisoquinoline-
derived hemi-aminal gave lower concentration of the reactive
aldehyde10; 2) the undesired aromatization pathway to
generate thermally stable quinolines.11 In order to conquer the
these challenges, a new activation mode is needed.
Skeletal diversification of bioactive molecules is a robust tool for
synthetic chemists in pharmaceutical industry.1 Recently, a
powerful synthetic strategy, deconstructive functionalization of
saturated cyclic amine2, has been developed to achieve some
interesting skeletal diversification reactions3 (Fig. 1).
Importantly, the formation of hemi-aminal are the key step for
these transformations. First, the oxidative cleavage of C(sp3)–
C(sp3) single bond of hemi-aminal and sequential
decarboxylative functionalization could install fluorine atom
(Fig. 1a). Second, C-O bond, C-N bond, C-Cl bond and C-Br bond
could be formed through the cleavage of C(sp3)–N single bond
of hemi-aminal by White, Sarpong and other groups (Fig. 1b).
Notably, on the basis of deconstructive diversification reaction,
the ring contraction of piperidines to pyrrolidines could be
accomplished efficiently by the Sarpong and co-workers3f (Fig.
1c), which is an example of scaffold hopping in medicinal
chemistry4. Inspired by this work, we wondered if this synthetic
strategy could be extended to aromatic system for achieving the
ring contraction of quinoline5 to indole6 (Fig. 1d). The scaffold
hopping between Pitavastatin and Fluvastatin is one of the most
famous examples for drug discovery.
Figure 1. Reported deconstructive mono-functionalization of piperidine and
further ring contraction.
With the formation of electrophilic tungsten peroxides from
H2O2 and Na2WO4, Marahashi and co-workers reported the
oxidation of 1, 2, 3, 4-tetrahydroquinolines to generate cyclic
hydroxamic acids.12 Inspired by their work, we believed that the
usage of tungsten catalyst possessing proper structure ([W])
could not only avoid the aromatization pathway, but also
further activate the C-N bond of hydroxamic acids13 to generate
ester and nitro group simultaneously (Fig. 2B). Moreover, this
newly formed 6 could be further transformed into indoles using
known methods including Baeyer-Emmerling indole synthesis.14
The reduction of quinolines could efficiently provide 1,2,3,4-
tetrahydroquinolines,7 which is an important moiety in modern
a. State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics (LICP), Chinese Academy of Sciences, No. 18, Tianshui Middle
Road, Lanzhou, P. R. China. E-mail: fshi@licp.cas.cn
b. University of Chinese Academy of Sciences, Beijing, 100049, China
† Electronic Supplementary Information (ESI) available: See DOI: XXXXXXXXX
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yield of 6aa decreased to 46%. We identified the optimized
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conditions shown in entries 10 and 11,DwOhI:ic10h.1u03s9e/dC98O0B0m0o69l 3%A
loading of H2WO4 at 65°C for 24 hours. The high loading of
H2WO4 (80 mol%) should be needed to generate high enough
concentration of H2[WO(O2)2(OH)2] for the selective formation
of 6aa. Both reaction temperature and the amount of H2O2
were crucial to the efficiency of this reaction (entries 13 and 14).
The recovery experiments were proceeded with several
steps using a NEt3-HNO3 method16 (for more details, please see
SI). The catalyst was reused for five times with 6aa as substrate
and the yields of the product were obtained in 94%, 91%, 83%,
81%, 82% respectively (Scheme 1).
Figure 2. Hypothetic deconstructive di-functionalization of 1, 2, 3, 4-
tetrahydroquinolines and further ring contraction.
100
80
60
40
20
0
We began our investigation by establishing the conditions for
the desired transformation using 1, 2, 3, 4-tetrahydroquinolines
and methanol as the starting materials. In preliminary
experiment, the desired product 6aa was obtained in 9% yield
altogether with the undesired aromatization products
(quinoline 3a in 31% yield and quinoline N-oxide 9a in 24%
yield), when Na2WO4 was used as catalyst and H2O2 (50%, w/w)
was used as oxidant (entry 1).
Table 1. Selected optimization experiments a,b
1
2
3
4
5
Catalyst recycling numbers
Scheme 1. Recyclability of H2WO4
Yield
(6aa)
9%
4%
39%
40%
Yield
(3a)
31%
50%
12%
14%
Yield
(9a)
24%
29%
24%
12%
With optimal conditions in hand, we examined the substrate
scope of alcohols in Table 2. Methanol, ethanol and propan-1-
ol were competitive partners for this deconstructive difunction-
alization reaction and provided 6aa in 82% yield, 6ab in 82%
yield and 6ac in 62% yield, respectively. Interestingly, when tert-
butanol was used, acid 6ad was obtained in 74% yield instead
of the corresponding ester. The product 6ad might be
generated from the further hydrolysis of the corresponding
tert-butyl ester in acidic conditions17.
Entry
1
2
3
[W]
Na2WO4
H4[SiO4(W3O9)]• x H2O
Na3PO4•12WO3• x H2O
Na2H5[P (W2O7)6]
H3PO4•12 WO3• x H2O
WO3
4
5
6
7
8
33%
11%
75%
trace
46%
83%
94%f
31%
65%
-
14%
23%
9%
48%
28%
3%
31%
14%
10%
17%
15%
2%
H2WO4
H3PO4
H2WO4
H2WO4
H2WO4
H2WO4
H2WO4
H2WO4
Table 2. Substrate scope of alcohols a
9c
10d
11d,e
12g
13h
14i
3%
2%
23%
14%
-
23%
15%
-
aReaction conditions: 0.2 mmol (W, Mo, P) catalyst, (entries 1-3, 0.2mmol W), 0.5
mmol 1,2,3,4-tetrahydroquinoline, 5 mmol H2O2 (50%, w/w), 2 mL CH3OH, 65 oC,
500 rps, 11 h. bThe yields were determined by GC-FID with external standard
c
f
method. 0.1 mmol catalyst. d0.4 mmol catalyst. e24 hours. Isolated yield = 83%.
aReaction conditions: 0.4 mmol (W) catalyst, 0.5 mmol 1,2,3,4-
tetrahydroquinoline, 5 mmol H2O2 (50%, w/w), 2 ml CH3OH, 65 oC, 500 rps, 24h,
isolated yields. b1.5 mmol H2WO4 and 15 ml tBuOH were used.
g50 oC. h3 mmol H2O2. iWithout H2O2.
The evaluation of tungsten catalysts showed that H2WO4
catalyzed the target transformation efficiently and 6aa was
obtained in 75% yield (entries 2-7). The good performance of
H2WO4 might be attributed to the in-situ generation of
H2[WO(O2)2(OH)2] in the presence of H2O2.15 Only trace amount
of 6aa were given, while H3PO4 was used as catalyst instead of
H2WO4 (entry 8). With 20 mol % loading of H2WO4 (entry 9), the
The data in Table 3 outlined the effects of varying the
structure of 1, 2, 3, 4-tetrahydroquinolines. First of all, the
potentially reactive CAr-Br bonds in different positions of
benzene ring were tolerated in this tungsten-catalyzed
deconstructive difunctionalization reaction, thus providing a
2 | J. Name., 2012, 00, 1-3
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handle for the derivatization of 6ba, 6ca and 6da. Moreover, the desired 6aa at all, while 1-hydroxy-3,4-dihydroquinolin-2-(1H)-
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substitution of fluorine atom and trifluoromethyl group, which one (5a) yielded 6aa with 99% conversion and > 95% selectivity.
plays a very important role in drug industry18, carried out the Importantly, without the utilization of H2WO4, only 24%
desired reaction effectively (6ea and 6fa). A variety of conversion was obtained, which indicated the H2WO4 could
electronically modified 1,2,3,4-tetrahydroquinolines still accelerate the ring opening process of 5a dramatically.
reacted efficiently (6ga, 6ha, and 6ia). Importantly, 4-methyl-
1,2,3,4-tetrahydroquinolines carried out this transformation
smoothly (6ja-6ka).
Table 3. Substrate scope of 1, 2, 3, 4-tetrahydroquinolinesa
Figure 3. Exploring the reaction intermediates.
Furthermore, we monitored the standard reaction by GC-FID
using external standard method. As shown in Figure 4, cyclic
hydroxamic acid 5a was observed and formed quickly in the first
3 hours. After 24 hours, compound 5a was totally transformed
into the desired product 6aa. This reaction kinetic profile
further illustrated that the cyclic hydroxamic acid 5a was the
key intermediate of the standard reaction.
aReaction conditions: 0.4 mmol H2WO4, 0.5 mmol 1, 2, 3, 4-tetrahydroquinoline, 5
mmol H2O2 (50%, w/w), 2 ml ROH, 65 oC, 500 rps, 24h, isolated yields.
On the other hand, we explored the substrate scope of other
unstrained, benzo cyclic amines without the competitive
aromatization pathway in Table 4. First, the 3,4-dihydro-2H-1,4-
benzoxazines, which could not be oxidized to form stable
aromatic rings, were also competent reaction partners, thus
affording 6la, 6lb, 6lc, 6ma, and 6na in moderate to excellent
yields. Second, the deconstructive difunctionalization of slightly
strained seven-membered substrates provided 3oa and 3pa in
good to excellent yields.
Table 4. Substrate scope of unstrained benzo cyclic amines without the
Figure 4. Monitoring the standard reaction: (a) 1a, (b) 6aa and (c) 5a.
competitive aromatization pathway a
Based on the above experimental results and reported
researches10, 12, 13, 15, a plausible mechanism for this reaction
was shown in Scheme 2. The active species H2[W(O2)2(OH)2]
formed in situ from the reaction of H2WO4 and H2O2. The
oxidation of 1, 2, 3, 4-tetrahydro-quinolines
1
by
H2[W(O2)2(OH)2] yielded the key cyclic hydroxamic acids 5.
Further oxidation of 5 gave the oxoammonium 10, which could
O
aReaction conditions: 0.4 mmol (W) catalyst, 0.5 mmol 1, 2, 3, 4-
tetrahydroquinoline, 5 mmol (2 equiv.) H2O2 (50%, w/w), 2 ml ROH, 65 oC, 500 rps,
24h, isolated yields.
O
H2WO4
H2O2
H2[W(O2)2(OH)2]
insoluble
soluble
H2[W(O2)2(OH)2]
OR
OR
N
O
NO2
6
11
ROH
In order to identify the key intermediate of this
transformation, quinoline (3a), quinoline N-oxide (9a), and 1-
hydroxy-3,4-dihydroquinolin-2-(1H)-one (5a) were used as
starting material in standard conditions. As shown in Figure 3,
quinoline (3a) and quinoline N-oxide (9a) could not provide the
H2[W(O2)2(OH)2]
H2[W(O2)2(OH)2]
N
OH
O
N
O
N
H
O
10
1
5
Scheme 2. Proposed Mechanism.
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Kaname, S. Yoshifuji and H. Sashida, Tetrahedron Lett., 2008,
49, 2786-2788; (e) T. J. Osberger, D. C.DROoI:g1n0e.1s0s3,V9Ji/e.CwT9.AOrKtBioc0lhe0rO6tn9,li3AnAe.
F. Stepan and M. C. White, Nature, 2016, 537, 214-219; (f) J.
B. Roque, Y. Kuroda, L. T. Göttemann and R. Sarpong, Nature,
2018, 564, 244-248; (g) J. B. Roque, Y. Kuroda, L. T. Göttemann
and R. Sarpong, Science, 2018, 361, 171-174.
(a) G. Schneider, W. Neidhart, T. Giller, G. Schmid, Angew.
Chem., Int. Ed. 1999, 38, 2894−2896; (b) Y. Hu, D. Stumpfe, J.
Bajorath, J. Med. Chem. 2016, 59, 4062−4076; (c) Y. Hu, D.
Stumpfe, J. Bajorath, J. Med. Chem. 2017, 60, 1238-1246.
(a) F. O’donnell, T. Smyth, V. Ramachandran and W. Smyth,
Int. J. Antimicrob. Ag., 2010, 35, 30-38; (b) O. Afzal, S. Kumar,
M. R. Haider, M. R. Ali, R. Kumar, M. Jaggi and S. Bawa, Eur. J.
Med. Chem., 2015, 97, 871-910; (c) P. Y. Chung, Z. X. Bian, H.
Y. Pun, D. Chan, A. S. C. Chan, C. H. Chui, J. C. O. Tang and K.
H. Lam, Future Med. Chem., 2015, 7, 947-967.
be attacked by alcohol to generate the ester 11. After further
oxidation, the desired product 6 could be produced finally.
Ring contraction, an example of molecule editing, plays an
important role in medicinal chemistry1, 4, 19. As shown in Scheme
3, the ring contraction of quinolines to indoles was
accomplished with the utilization of the reported reactions20
and the following two new transformations: 1) the bromination
of 6aa providing the 8aa in 73% yield; 2) Elimination of 8aa
yielding the key olefin 9aa in the presence of base. On the other
hand, 6aa has been reported as a versatile intermediate in
organic chemistry21. Moreover, the newly formed nitro group
could be further transformed into other functional groups22.
4
5
6
7
(a) S. Ali, N. Ali, B. Ahmad Dar, V. Pradhan and M. Farooqui,
M. Chem. Rev., 2013, 13, 1792-1800; (b) N. Kaushik, N.
Kaushik, P. Attri, N. Kumar, C. Kim, A. Verma and E. Choi,
Molecules, 2013, 18, 6620-6662; (c) S. Lancianesi, A. Palmieri
and M. Petrini, Chem. Rev., 2014, 114, 7108-7149.
(a) W.-B. Wang, S. M. Lu, P. Y. Yang, X. W. Han and Y. G. Zhou,
J. Am. Chem. Soc., 2003, 125, 10536-10537; (b) Y. G. Zhou,
Acc. Chem. Res., 2007, 40, 1357-1366; (c) D. W. Wang, X. B.
Wang, D. S. Wang, S. M. Lu, Y. G. Zhou and Y. X. Li, J. Org.
Chem., 2009, 74, 2780-2787; (d) F. R. Gou, W. Li, X. Zhang and
Y. M. Liang, Adv. Synth. Catal., 2010, 352, 2441-2444; (e) G. E.
Dobereiner, A. Nova, N. D. Schley, N. Hazari, S. J. Miller, O.
Eisenstein and R. H. Crabtree, J. Am. Chem. Soc., 2011, 133,
7547-7562.
Scheme 3. Scaffold Hopping: Ring contraction of quinolines to indoles.
In summary, we developed an unprecedented deconstructive
difunctionalization of the C−N bond in benzo cyclic amines to
generate ester group and nitro group, respectively. Moreover,
intermediates identification reactions and reaction kinetic
study indicated that generating hydroxamic acid is assumed to
be involved as a key step. Importantly, an interesting approach
for the ring contraction of quinoline to indole was
accomplished. Further development of this catalytic system is
ongoing on our laboratory.
8
9
V. Sridharan, P. A. Suryavanshi and J. C. Menéndez, Chem.
Rev., 2011, 111, 7157-7259.
(a) X. Cui, F. Shi and Y. Deng, Chem. Commun., 2012, 48, 7586-
7588; (b) X. Dai, J. Rabeah, H. Yuan, A. Brückner, X. Cui and F.
Shi, ChemSusChem, 2016, 9, 3133-3138; (c) Z. Ke, Y. Zhang, X.
Cui and F. Shi, Green Chem., 2016, 18, 808-816; (d) Y. Zhang,
S. Pang, Z. Wei, H. Jiao, X. Dai, H. Wang and F. Shi, Nat.
Commun., 2018, 9, 1465-1474.
10 S.-L. Shi, X.-F. Wei, Y. Shimizu, M. Kanai, J. Am. Chem. Soc.
2012, 134, 17019-17022.
Conflicts of interest
There are no conflicts to declare.
11 (a) K. Kamata, J. Kasai, K. Yamaguchi and N. Mizuno, Org. Lett.,
2004, 6, 3577-3580; (b) H. Choi and M. P. Doyle, Chem.
Commun., 2007, 745-747; (c) F. Li, J. Chen, Q. Zhang and Y.
Wang, Green Chem., 2008, 10, 553-562; (d) K. Yamaguchi, J.
W. Kim, J. He and N. Mizuno, J. Catal., 2009, 268, 343-349; (e)
D. Ge, L. Hu, J. Wang, X. Li, F. Qi, J. Lu, X. Cao and H. Gu,
ChemCatChem, 2013, 5, 2183-2186; (f) S. Furukawa, A. Suga
and T. Komatsu, Chem. Commun., 2014, 50, 3277-3280; (g) A.
E. Wendlandt and S. S. Stahl, J. Am. Chem. Soc., 2014, 136,
11910-11913; (h) X. Cui, Y. Li, S. Bachmann, M. Scalone, A.-E.
Surkus, K. Junge, C. Topf and M. Beller, J. Am. Chem. Soc.,
2015, 137, 10652-10658; (i) D. V. Jawale, E. Gravel, N. Shah, V.
Dauvois, H. Li, I. N. Namboothiri and E. Doris, Chem. Eur. J.,
2015, 21, 7039-7042.
Acknowledgements
Financial support from National Natural Science Foundation of
China (21602229), the National Key Research and Development
Program of China (2017YFA0403103), the Key Research
Program of Frontier Sciences of CAS (QYZDJ-SSW-SLH051), the
State Key Laboratory for Oxo Synthesis and Selective Oxidation
(OSSO), and Lanzhou Institute of Chemical Physics (LICP) are
gratefully acknowledged.
12 S. Murahashi, T. Oda, T. Sugahara and Y. Masui, J. Org. Chem.,
1990, 55, 1744-1749.
13 (a) S. Prabhakar, A. M. Lobo, M. M. Marques, M. R. Tavares, J.
Chem. Res. (S), 1985, 394-395; (b) R. Braslau J. Org. Chem.
1995, 60, 6191-6193; (c) H. Lu, L. Kopcho, K. Ghosh, M.
Witmer, M. Parker, S. Gupta, M. Paul, P. Krishnamurthy, B.
Laksmaiah, D. Xie, J. Tredup, L. Zhang, L. M. Abell, Anal.
Biochem. 2016, 501, 56-65; (d) C. Yuan, B. Du, M.-M. Xun, B.
Liu, Tetrahedron, 2017, 73, 3622-3628.
14 A. Baeyer and A. Emmerling, Ber Dtsch Chem Ges, 1869, 2,
679-682.
15 Y. Usui and K. Sato, Green Chem., 2003, 5, 373-375.
16 C. Ye, P. Jin, J. Liu, Y. Wen, H. Wei, X. Zheng, X. Wang and B. Li,
Ind. Eng. Chem. Res., 2013, 52, 3600-3606.
Notes and references
1
K. R. Campos, P. J. Coleman, J. C. Alvarez, S. D. Dreher, R. M.
Garbaccio, N. K. Terrett, R. D. Tillyer, M. D. Truppo and E. R.
Parmee, Science, 2019, 363, 244-252.
2
3
A. Henninot, J. C. Collins and J. M. Nuss, J. Med. Chem., 2017,
61, 1382-1414.
(a) A. Shawcross and S. Stanforth, J. Heterocycl. Chem., 1990,
27, 367-369; (b) G. Han, M. C. McIntosh and S. M. Weinreb,
Tetrahedron Lett., 1994, 35, 5813-5816; (c) R. Ito, N. Umezawa
and T. Higuchi, J. Am. Chem. Soc., 2005, 127, 834-835; (d) M.
4 | J. Name., 2012, 00, 1-3
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17 B. Li, M. Berliner, R. Buzon, C. K.-F. Chiu, S. T. Colgan, T.
Kaneko, N. Keene, W. Kissel, T. Le, K. R. Leeman, B. Marquez,
R. Morris, L. Newell, S. Wunderwald, M. Witt, J. Weaver, Z.
Zhang, Z. Zhang, J. Org. Chem., 2006, 71, 9045-9050.
View Article Online
DOI: 10.1039/C9OB00693A
18 (a) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E.
Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev.,
2014, 114, 2432-2506; (b) K. Müller, C. Faeh, F. Diederich,
Science 2007, 317, 1881−1886; (c) T. Furuya, A. S. Kamlet, T.
Ritter, Nature 2011, 473, 470−477.
19 Selected examples, see: (a) A. A. Nagel, J. Dibrino, L. A.
Vincent, J. A. Retsema, J. Med. Chem. 1982, 25, 881-884; (b)
M. E. Kuehne, L. He, P. A. Jokiel, C. J. Pace, M. W. Fleck, I. M.
Maisonneuve, S. D. Glick, J. M. Bidlack, J. Med. Chem. 2003,
46, 2716-2730; (c) W. H. Jung, C. Harrison, Y. Shin, J.-H.
Fournier, R. Balachandran, B. S. Raccor, R. P. Sikorski, A. Vogt,
D. P. Curran, B. W. Day, J. Med. Chem. 2007, 50, 2951-2966.
20 (a) H. Miyamura, A. Suzuki, T. Yasukawa and S. Kobayashi, J.
Am. Chem. Soc., 2018, 140, 11325-11334; (b) A. K.
Chakraborti, L. Sharma and M. K. Nayak, J. Org. Chem., 2002,
67, 2541-2547; (c) K. Yang, F. Zhou, Z. Kuang, G. Gao, T. G.
Driver and Q. Song, Org. Lett., 2016, 18, 4088-4091.
21 (a) R. Coutts, D. Noble and D. Wibberley, J. Pharm.
Pharmacol., 1964, 16, 773-778; (b) Y. Hashimoto, T. Ishizaki,
K. Shudo and T. Okamoto, Chem. Pharm. Bull., 1983, 31, 3891-
3896; (c) M. A. Cismesia, M. A. Ischay and T. P. Yoon,
Synthesis, 2013, 45, 2699-2705; (d) B. Egle, J. M. de Muñoz, N.
Alonso, W. M. De Borggraeve, A. de la Hoz, A. Díaz-Ortiz and
J. Alcázar, J. Flow Chem., 2014, 4, 22-25;
22 Selected synthetic utility of the nitro products, see: M. R.
Yadav, M. Nagaoka, M. Kashihara, R.-L. Zhong, T. Miyazaki, S.
Sakaki, Y. Nakao, J. Am. Chem. Soc. 2017, 139, 9423-9426.
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