Iron-catalyzed aerobic oxidative phosphonation of N-aryl tetrahydroisoquinolines

Article abstract of DOI:10.1080/10426507.2017.1330827

We report herein a novel and efficientmethod for iron-catalyzed aerobic oxidative phosphonation of N-aryl tetrahydroisoquinolines for the synthesis of biologically interesting α-aminophosphonates. This new C–P bond formation reaction features the employme

Full text of DOI:10.1080/10426507.2017.1330827

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Iron-catalyzed Aerobic Oxidative Phosphonation of
N-aryl Tetrahydroisoquinolines
Junjie Cai, Yingle Liu, Yan Jiang & Yi Yang
To cite this article: Junjie Cai, Yingle Liu, Yan Jiang & Yi Yang (2017): Iron-catalyzed Aerobic
Oxidative Phosphonation of N-aryl Tetrahydroisoquinolines, Phosphorus, Sulfur, and Silicon and
the Related Elements, DOI: 10.1080/10426507.2017.1330827
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1330827
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Iron-catalyzed Aerobic Oxidative Phosphonation of N-aryl Tetrahydroisoquinolines
Junjie Cai, Yingle Liu, Yan Jiang, and Yi Yang*
Key Laboratory of Green Catalysis of Higher Education Institutes of Sichuan, College of
Chemistry and Environmental Engineering, Sichuan University of Science & Engineering, 180
Xueyuan Street, Huixing Road, Zigong, Sichuan 643000, China
Correspondence author: E-mail: yangyiyoung@163.com
Abstract
We report herein a novel and efficient method for iron-catalyzed aerobic oxidative
phosphonation of N-aryl tetrahydroisoquinolines for the synthesis of biologically interesting
α-aminophosphonates. This new C-P bond formation reaction features the employment of a
sustainable and cost-effective iron salt [Fe(NO3)3·9H2O] as catalyst, the utilization of air as
environmental-benign oxidant, as well as the user-friendly open-flask reaction conditions.
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Keywords
Oxidative Phosphonation; Iron Catalysis; Coupling; α-Aminophosphonate.
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Introduction
Organophosphorus compounds are of great interest to synthetic chemists due to the broad
applications in the fields of organic synthesis, materials, agrochemicals and pharmaceuticals1.
α-Aminophosphonates and related α-aminophosphonic acids, containing amino and phosphonyl
groups, are privileged structure motifs in the organophosphorus family. As the analogues of
α-amino acids2, these compounds shows promising potential in the regulation of binding affinity
of target proteins which enables them to be good candidates for the discovery of potent enzyme
inhibitors3, antitumor4 and antifungal agents5. In addition, α-aminophosphonates have also been
served as useful precursors in Horner--Wadsworth--Emmons (HWE) reactions for the
construction of enamine moieties6. Therefore, the development of simple and efficient methods
to access the valuable α-aminophosphonate molecules is highly desirable.
Traditional operative methods to obtain α-aminophosphonates are using Kabachnik-Fields
reaction7 or Pudovik reaction8 which is characterized by the addition of dialkyl phosphite to an
imine intermediate. In contrast, the recent disclosed cross-dehydrogenative coupling (CDC)9
between the C(sp3)-H bond of tertiary amines and P-H bond of dialkyl phosphite represents an
appealing alternative strategy to produce α-aminophosphonates owing to bypassing the necessity
of prefunctionalization of the starting materials prior to the coupling event. Pioneered by Genies’
electrical oxidation method10, transition-metal-catalyzed chemical oxidative versions have
already become important techniques for the dehydrogenative coupling of tertiary amines and
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dialkyl phosphite (Scheme 1). Li and coworkers have established copper-catalyzed
α-phosphonation of N-phenyl tetrahydroisoquinoline under aerobic conditions by using oxygen
as sacrificial oxidant (Scheme 1a) 11. Further, the Ofial group has found that sustainable and
cost-effective iron catalysts are highly efficient for the construction of C-P bond in
N,N-dimethylaniline substrates (ArNMe2) (Scheme 1b) 12. It is worth noting that N-phenyl
tetrahydroisoquinoline substrates failed to produce the α-phosphonation products in Ofial’s iron
catalysis protocol, only delivering the corresponding lactam as an over-oxidation product
(Scheme 1c) 13. We speculate that the major challenges of desired transformation in Scheme 1c
lie in the proper regulation of iron-catalyzed oxidation process on the sensitive α-sites of
N-phenyl tetrahydroisoquinoline substrates and the cooperative interception of iminium ions by
the nucleophilic dialkyl phosphite.
In this context, choosing a suitable combination of iron catalyst and oxidant could be very
crucial to the success of oxidative phosphonation of N-phenyl tetrahydroisoquinoline substrates.
It is well known that air is a ubiquitous and environment-friendly oxidant source which has
versatile profiles in chemical oxidative transformations14. To take advantage of the joint
synthetic merits from iron catalysis15 and aerobic oxidation, we report herein our efforts to an
iron-catalyzed aerobic oxidative phosphonation of N-phenyl tetrahydroisoquinolines to access
biologically interesting α-aminophosphonate molecules.
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Result and Discussion
Initial studies were focused on the screening of effective iron catalysts with using N-phenyl
tetrahydroisoquinoline (1a) as the standard substrate and diethyl phosphite (2a) as the
phosphonate source (Table 1). The ferrous salts which had superior catalytic activities in Ofial’s
reports12,13 were found to be sluggish in our aerobic oxidation cases (entries 1-2). The ferric salts
displayed improved catalytic performance on this transformation (entries 3-5). For the iron(III)
nitrate nonahydrate [Fe(NO3)3·9H2O] (10 mol% catalyst loading), the desired product 3 can be
smoothly obtained in 93% yield (entry 5). In comparison, iron(III) chloride hexahydrate
[FeCl3·6H2O] and iron(III) sulfate [Fe2(SO4)3] gave inferior catalytic activities with prolonged

time and decreased yield. These results revealed that the oxidizing nitrate [NO3 ] played an
important role in accelerating this iron-catalyzed oxidation process16. Heterogeneous iron(III)
oxide (entry 6) and control experiment (entry 7) confirmed that iron(III) ionic species were
essential factors for the activation of α position of tertiary amines. Further investigation of
solvent effects indicated that ethanol are preferential solvent for this cross-dehydrogenative
coupling (entries 5, 9-11).
With the optimized conditions in hand, the substrate scope of this iron-catalyzed aerobic
oxidative phosphonation was examined (Table 2). A variety of dialkyl phosphites (including
diethyl phosphite 2a, diisopropyl phosphite 2b, dibutyl phosphite 2c and dibenzyl phosphite 2d)
were proved to be effective substrates to afford the corresponding coupling products in
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satisfactory yields (entries 1-4). Next, we continued to explore the variability of N-aryl
tetrahydroisoquinolines substrates. Gratifyingly, N-aryl tetrahydroisoquinolines (1a-1e) bearing
either electron-withdrawing or electron-donating substituents on the aryl ring could be smoothly
transformed into the desired phosphonation products (entries 5-8). For the substrate 1e, an
elevated temperature and oxygen atmosphere were required to obtain satisfactory conversion
(entry 8). The larger oxidation barrier in 1e was rationalized by the drastic decrease of electron
density of α C-H bond in light of the presence of a strong electron-withdrawing nitro group.
Additionally, the substrate 1f was found to be amenable to the established conditions to furnish
the corresponding products 13-15 (entries 11-13) which could allow further elaboration of the
chloro group on the quinoline ring through coupling chemistry.
Consistent with the previous reports of iron-catalyzed CDC reactions13,17, an analogous
putative mechanism involving radical and iminium intermediates was proposed (Scheme 2). It
was found that when one equivalent of radical scavenger 2,2,6,6-tetramethylpiperidinooxy
(TEMPO) was added in the reaction system of 1a and 2a (Scheme 3a), the reaction was partially
suppressed and the yield dropped to 37% (vs Table 2, entry 1). The interruption effect was
highly likely to be caused by TEMPO’s coordinative deactivation towards catalytic iron species.
This speculation was supported by the observation of [(TEMPO)Fe(NO3)3 + K+] peak (m/z 437.3)
in ESI-MS. In addition, the iminium intermediate and derivative species were also identified by
ESI-MS monitoring of the reaction mixture (see supplemental materials). Next, preliminary
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studies to examine the role of oxidizing nitrate in this catalysis were also conducted. We found
that nitric acid9k,16b exhibited catalytic activities in the oxdative coupling of 1a and 2a albeit
being lower than the optimal catalyst Fe(NO3)3·9H2O (Scheme 3b). This observation indicated
that the nitrate species (acidified) 9k could play important roles within the oxidative catalysis
process. Further, a mixed catalyst combination of FeCl3·6H2O and nitric acid displayed
improved catalytic efficiency which supported the synergistic effects of Fe(III) and nitrate on
this phosphonation reaction (Scheme 3c). Taken together, the innate and cooperative catalytic
roles exerted by Fe(NO3)3·9H2O were the key to achieve this aerobic oxidative phosphonation of
N-aryl tetrahydroisoquinolines.
Conclusion
In summary, we have demonstrated a facile and sustainable iron-catalyzed α-phosphonation
reaction of N-aryl tertrahydroisoquinoline derivatives. Various dialkyl phosphites and N-aryl
tertrahydroisoquinolines were effective substrates to access the biologically active
α-aminophosphonates under the mild ambient conditions. Further work to extend this
methodology to other nucleophiles and systematic mechanistic study are in progress, and the
result will be reported in due course.
Experimental
1H, 13C and 31P NMR spectra were recorded on a Bruker AM-400 spectrometer with CDCl3 as
solvent and tetramethylsilane (TMS) as an internal standard; J-values are in hertz. Mass spectra
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were recorded by EI methods, and high-resolution mass spectral analyses (HRMS) was measured
on a Waters Micromass GCT Premier mass spectrometer. Commercially obtained reagents were
used without further purification. All reactions were monitored by thin-layer chromatography
(TLC) with Huanghai GF 254 silica gel-coated plates. Flash column chromatography was carried
out using 300--400-mesh silica gel at increased pressure. The Supplemental Materials contain 1H,
13C and 31P NMR spectra of samples 3-15 (Figures S 1--S 47 are available online in
Supplemental Materials).
General Procedure for Iron-catalyzed Aerobic Oxidative Phosphonation of N-aryl
tetrahydroisoquinolines
To a solution of N-aryl tetrahydroisoquinoline 1 (0.4 mmol) in ethanol (2.0 mL) were added
dialkyl phosphite 2 (0.8 mmol) and then Fe(NO3)3•9H2O (16 mg, 0.04 mmol). The reaction
mixture was stirred vigorously under an open atmosphere at 30 C for 24−48 h until the N-aryl
tertrahydroisoquinoline substrate disappeared by TLC monitoring. After completion of the
reaction, the reaction mixture was poured into 5% aqueous NaHCO3 solution (20 mL), then was
extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with
saturated NaCl aqueous solution and then dried over sodium sulfate. After removing the solvent
in vacuo, the residue was purified by flash chromatography on silica gel to afford the
corresponding coupling products.
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Diethyl (6-Chloro- 2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (13)
Column chromatography (hexane: ethyl acetate = 3: 1) on silica gel gave a light yellow solid
(129 mg, 85%): 1H NMR (400 MHz, CDCl3): δ7.32 (dd, J = 8.9 Hz, 2.2 Hz, 1H), 7.28 -- 7.20
(m, 2H), 7.15 (d, J = 6.6 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H), 6.81 (t, J = 7.3 Hz, 1H), 5.13 (d, J =
20.7 Hz, 1H), 4.16 -- 3.98 (m, 4H), 3.92 (ddd, J = 17.2 Hz, 11.1 Hz, 7.1 Hz, 1H), 3.68 -- 3.59 (m,
1H), 3.06 -- 2.89 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); 31P NMR (162 MHz,
CDCl3) δ 21.54 (s, 1P).; 13C NMR (101 MHz, CDCl3) δ 149.40 (d, J = 6.3 Hz), 138.42 (d, J = 5.6
Hz,), 133.22 (d, J = 4.2 Hz), 129.57 (d, J = 4.5 Hz), 129.35 (s), 128.86 (d, J = 2.5 Hz), 119.04 (s,
2H), 115.21 (s), 63.57 (d, J = 7.3 Hz), 62.46 (d, J = 7.7 Hz), 58.47 (d, J = 159.9 Hz), 43.27 (s),
26.64 (s), 16.54 (dd, J = 9.2, 5.6 Hz); MS (EI) m/z 379 [M]+; HRMS (EI) m/z [M]+ calcd. for
C19H23ClNO3P, 379.1104; found 379.1101.
Diisopropyl (6-Chloro- 2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (14)
Column chromatography (hexane: ethyl acetate = 3: 1) on silica gel gave a light yellow solid
(127 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 7.9 Hz, 2.0 Hz, 1H), 7.28 -- 7.19
(m, 2H), 7.14 (d, J = 7.9 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 6.79 (t, J = 7.3 Hz, 1H), 5.07 (d, J =
22.0 Hz, 1H), 4.72 -- 4.57 (m, 2H), 4.12 -- 4.00 (m, 1H), 3.66 (dt, J = 13.0 Hz, 5.0 Hz, 1H), 2.94
(dt, J = 8.1 Hz, 4.1 Hz, 2H), 1.30 (dd, J = 8.7 Hz, 6.2 Hz, 6H), 1.18 (d, J = 6.2 Hz, 3H), 0.98 (d,
J = 6.2 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 20.15 (s, 1P); 13C NMR (101 MHz, CDCl3) δ
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149.57 (d, J = 7.2 Hz), 138.45 (d, J = 5.7 Hz), 133.06 (d, J = 4.2 Hz), 129.89 (d, J = 4.5 Hz),
129.67 (d, J = 1.5 Hz), 129.24 (s,), 128.82 (d, J = 2.5 Hz), 125.98 (d, J = 2.9 Hz), 118.90 (s),
115.49 (s), 72.52 (d, J = 7.8 Hz), 71.07 (d, J = 8.1 Hz), 58.46 (d, J = 161.9 Hz), 43.34 (s), 26.42
(s), 24.70 (d, J = 2.9 Hz), 24.25 (d, J = 3.3 Hz), 23.93 (d, J = 5.5 Hz), 23.52 (d, J = 5.5 Hz); MS
(EI) m/z 407 [M]+; HRMS (EI) m/z [M]+ calcd. for C21H27ClNO3P, 407.1417; found 407.1422.
Dibutyl (6-Chloro- 2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (15)
Column chromatography (hexane: ethyl acetate = 3: 1) on silica gel gave a light yellow solid
(131 mg, 75%): 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 8.9 Hz, 2.2 Hz, 1H), 7.28 -- 7.21
(m, 2H), 7.15 (d, J = 6.3 Hz, 2H), 6.95 (d, J = 8.2 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 5.14 (d, J =
20.6 Hz, 1H), 4.09 -- 3.77 (m, 5H), 3.71 -- 3.59 (m, 1H), 3.06 -- 2.89 (m, 2H), 1.57 (dd, J = 13.5,
6.7 Hz, 2H), 1.46 (td, J = 13.6 Hz, 6.7 Hz, 2H), 1.38 -- 1.21 (m, 4H), 0.89 (t, J = 7.4 Hz, 3H),
0.82 (t, J = 7.4 Hz, 3H); 31P NMR (162 MHz, CDCl3) δ 21.70 (s, 1P); 13C NMR (101 MHz,
CDCl3) δ 149.34 (d, J = 6.1 Hz), 138.39 (d, J = 5.6 Hz), 133.21 (d, J = 4.2 Hz), 129.64, 129.59,
129.57 (d, J = 0.86 Hz), 129.33 (s), 128.84 (d, J = 2.5 Hz), 126.20 (d, J = 2.8 Hz), 118.99 (s),
115.17 (s), 67.18 (d, J = 7.5 Hz), 66.12 (d, J = 7.9 Hz), 58.40 (d, J = 159.3 Hz), 43.23 (s), 32.69
(dd, J = 7.4, 5.6 Hz), 26.69 (s), 18.79 (d, J = 7.8 Hz), 13.65 (d, J = 4.8 Hz); MS (EI) m/z 435
[M]+; HRMS (EI) m/z [M]+ calcd. for C23H31ClNO3P, 435.1730; found 435.1738.
Complete experimental details are available online in the Supplemental Materials.
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Funding
The National Natural Science Foundation of China (21502131), Zigong Science and
Technology Bureau (2013  02, 2015SF02), Key Laboratory of Green Chemistry of Sichuan
Institutes of Higher Education (LZJ1401, LZJ1505) are greatly acknowledged for funding this
work.
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[16] (a) Namboodiri, V. V.; Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2007, 48,
8839--8842. (b) Ma, S.; Liu, J.; Li, S.; Chen, B.; Cheng, J.; Kuang, J.; Liu, Y.; Wan, B.; Wang,
Y.; Ye, J.; Yu, Q.; Yuan, W.; Yu, S. Adv. Synth. Catal. 2011, 353, 1005--1017. (c) Jiang, X.;
Zhang, J.; Ma, S. J. Am. Chem. Soc. 2016, 138, 8344--8347.
[17] Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem. Soc. 2012, 134, 5317--5325.
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Table 1. Optimization of Reaction Conditionsa
Entry
1.
Iron catalysts
FeCl2
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH2Cl2
DMF
Time
48 h
48 h
48 h
48 h
24 h
48 h
48 h
48 h
48 h
48 h
48 h
Yieldb
33%
31%
58%
45%
93%
nonec
nonec
19%
37%
24%
12%
Fe(OAc)2
2.
FeCl3·6H2O
Fe2(SO4)3
3.
4.
Fe(NO3)3·9H2O
Fe2O3
5.
6.
no catalyst
7.
Fe(NO3)3·9H2Od
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
Fe(NO3)3·9H2O
8.
9.
10.
11.
THF
aGeneral conditions: 1a (0.2 mmol, 1.0 eq) and 2a (0.4 mmol, 2.0 eq) was dissolved in solvent
(1.0 mL), then added iron catalysts (0.02 mmol, 0.1 eq), stirring at ambient condition (open-flask,
30 C).
bIsolated yield by column chromatography.
cNo formation of 3.
dThe reaction was run under nitrogen atmosphere (O2 free condition).
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Table 2. Iron-catalyzed aerobic oxidative phosphonation of N-aryl tetrahydroisoquinolines a
Entry
R1
R2
R3
Product
Yieldb
1.
2.
Ph (1a)
Ph (1a)
H(1a)
H(1a)
Et (2a)
iPr (2b)
Bu (2c)
Bn (2d)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
iPr (2b)
iPr (2b)
Et (2b)
iPr (2b)
Bu (2c)
3 d
4d
93%
88%
82%
84%
80%
76%
82%
55%
77%
74%
85%
78%
75%
3.
Ph (1a)
H(1a)
5d
4.
Ph (1a)
H(1a)
6d
5.
4-MeOC6H4 (1b)
2-MeOC6H4 (1c)
4-ClC6H4 (1d)
3-O2NC6H4 (1e)
4-MeOC6H4 (1b)
4-ClC6H4 (1c)
Ph (1f)
H(1b)
H(1c)
7d
6.
8d
7.
H(1d)
H(1e)
9d
8. c
9.
10d
11d
12d
13
14
15
H(1b)
H(1c)
10.
11.
12.
13.
6-Cl(1f)
6-Cl(1f)
6-Cl(1f)
Ph (1f)
Ph (1f)
aGeneral conditions: 1 (0.4 mmol, 1.0 eq) and 2 (0.8 mmol, 2.0 eq) was dissolved in EtOH (2.0
mL), then added iron catalysts (0.04 mmol, 0.1 eq), stirring at ambient condition (open-flask, 30
C) for 24-48 h.
bIsolated yield by column chromatography.
cThe reaction was performed under the condition of O2 (1atm) atmosphere and 60 C.
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dThe NMR spectra of compounds 3-12 was consistent with the reference 9.
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Scheme 1. Representative Base Metal Catalyzed Methods for the Oxidative Phosphonation of
Tertiary Amines.
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Scheme 2. Plausible Mechanism for Iron-catalyzed aerobic oxidative phosphonation
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Scheme 3. Preliminary Mechanistic Investigations
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