Cobalt-Catalyzed Oxidative C(sp3)âH Phosphonylation for Î±

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Cobalt-Catalyzed Oxidative C(sp3)-H Phosphonylation for #-Aminophosphonates via C(sp3)–H/P(O)–H Coupling Binzhou Lin, Shanshan Shi, Rongcan Lin, Yiqun Cui, Meijuan Fang, Guo Tang, and YuFen Zhao J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00674 • Publication Date (Web): 22 May 2018 Downloaded from http://pubs.acs.org on May 22, 2018

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The Journal of Organic Chemistry

Cobalt-Catalyzed Oxidative C(sp3) -H Phosphonylation for α-Aminophosphonates via C(sp3)–H/P(O)–H Coupling Binzhou Lin,† Shanshan Shi,† Rongcan Lin,† Yiqun Cui,† Meijuan Fang,‡ Guo Tang,*,† and Yufen Zhao† †

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 ‡

Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen

University, Xiamen 361000, China

[email protected] RECEIVED DATE (will be automatically inserted after manuscript is accepted).

O 1 R H P R2

R4 +

R3

dialkyl H-phosphonates diaryl phosphine oxides

N

R5

Co(OAc)2, NHPI

R

4

2 R1 R P O

N R3 R5 air instead of pure oxygen and organic oxidants

CH3CN, air,16 h, 80 oC

tertiary aromatic amines tertiary aliphatic amines

The first oxidative C(sp3)-H phosphonylation of tertiary aliphatic amines has been developed. The use of cobalt acetate as catalyst, N-hydroxyphthalimide as co-catalyst, and air as oxidant enabled the conversion of tertiary aromatic and aliphatic amines into α-aminophosphonates in moderate to excellent yields under mild conditions via a cross dehydrogenative coupling reaction.

Carbon−phosphorus

bond

is

widely

found

in

many

biologically-active

compounds,

among

which

α-aminophosphonates (N−C−P bond) and related α-aminophosphonic acids possess a broad capability of influencing physiologic and pathologic processes, with applications ranging from inhibitors of enzymes to medicine.1 Consequently, the increasing demand for α-aminophosphonates has generated considerable interest in the development of efficient and flexible synthetic methods. The classical methods for their preparations are the Pudovik reaction2 and the Kabachnik−Fields reaction3 found in 1952 involving the condensation of H−phosphonates with aldehydes or imines [Scheme 1 (a)]. Since then great efforts have been made to develop the Lewis acid catalytic,4 and catalyst-free5 synthesis of α-aminophosphonates. Although these methods are effective, they need imines formed by the prefunctionalized aldehydes and amines.

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 19

Scheme 1. Synthetic Routes to α-Aminophosphonates (a) Classical methods imines or ketones or amides as starting material O R3 N O R4 R3 2 N R1 N R Cp2ZrHCl 1 2 1 2 R R R R H R3 (b) Oxidative C(sp3)-H phosphonylation for -aminophosphonates R1 R2

N

O 4 1 R C(sp3)-H/P(O)-H R H P + R3 coupling R5 R2 H P

Previous work: only tertiary arylamines

R3 R4

N P O

R5

This work: both tertiary aliphaticamines and tertiary arylamines

N

R1

P

R2

R3 N

The key intermidiates: stable conjugated imine intermidiates

P

The key intermidiates: both unstable and stable imine intermidiates R1

N

R2 Ph2P(O)H catalyzed by P the noble metal catalysts, such as Ir, Au etc.

N

R3

P Ph2P(O)H catalyzed by the cheap cobalt catalyst

In recent years, oxidative C(sp3)–H phosphonylation for the synthesis of α-aminophosphonates from amines by employing the atom efficient cross dehydrogenative coupling (CDC) method is of high relevance in organic synthesis, and has been the focus of recent research [Scheme 1 (b)]. Pioneered by Li,6 Koenigs,7 and König,8 the direct phosphonylation of sp3-hybridized carbon−hydrogen bonds adjacent to tertiary arylamines, in particular N-aryltetrahydroisoquinolines, has seen an explosion of interest.9 However, although these methods are very elegant, the range of starting materials is limited to tertiary arylamines,6-10 and a general method for the synthesis of α-aminophosphonates from tertiary aromatic and aliphatic amines has not yet been described. This is likely because tertiary aromatic amines have strong propensity toward dehydrogenation to form stable extended π−conjugated imine intermediates. Compared with tertiary arylamines, aliphatic amines form the unstable intermediates. On the other hand,


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P(O)H compounds can easily be oxidized to P(O)OH.11 Since CDC involves an oxidant, there is a fine line between oxidation of tertiary amines to imines versus direct oxidation of P(O)H compounds to the acids. As a continuation of our endeavour to develop step economical P−C formations,12 we reported a direct reductive phosphonylation of inert amide carbonyls promoted by Cp2ZrHCl for the preparation of α-aminophosphonates in 2013 [Scheme 1 (a)].13 Herein, we describe the use of the inexpensive cobalt acetate in combination with N-hydroxyphthalimide (NHPI), and air as a highly active catalytic system for the oxidative α-phosphonylation of tertiary aliphatic and aromatic amines. This dehydrogenative coupling process provides access to a host of α-aminophosphonates from a wide variety of amine substrates. The use of air instead of pure oxygen and organic oxidants is advantageous in terms of safety. Table 1. Reaction Conditions Optimizationa

Entry

Catalyst

Cocatalyst

T/oC

Solvent

Oxidant

Yield/%

1

FeCl2

no

rt-60

CH3CN

TBHP

0-15

2

CuBr

no

60

CH3OH

O2

10

3

CuBr2

no

60

CH3CN

O2

0

4

Co(OAc)2

-

80

CH3CN

O2

38

5

-

NHPI

60

CH3CN

O2

0

6

Co(OAc)2

NHPI

80

CH3CN

O2

80

7

Co(OAc)2

NHPI

rt-60

CH3CN

O2

25-50

8

CoCl2

NHPI

80

CH3CN

O2

80

9

Co(NO3)2

NHPI

80

CH3CN

O2

78

10

Co(OEt)2

NHPI

80

CH3CN

O2

77

11

Co(OAc)2

NHPI

80

footnote

O2

31-43b

12

Co(OAc)2

NHPI

80

-

O2

45

13

Co(OAc)2

NHPI

80

CH3CN

air

85(62c, 60d)

14

Co(OAc)2

HOSU

80

CH3CN

air

72

15

Co(OAc)2

HOBT

80

CH3CN

air

80



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a

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Reaction conditions: 1 (0.5 mmol), 2 (1.7 mmol), catalyst (0.05 mmol), co-catalyst (0.15 mmol), solvent (2.5 mL), were heated at the refluxing temperature under air for 16 h. Isolated yield. All catalysts are hydrated salts and used without further purification. b tetrahydrofuran, dichloroethane or 1,4-dioxane as solvent. c Co(OAc)2 (5 mol%) and NHPI (30 mol%). d Co(OAc)2 (10 mol%) and NHPI (10 mol%).

Initial investigations into the proposed cross dehydrogenative coupling focused on the reaction of diethyl H−phosphonate (1) with tri-n-butylamine (2) (Table 1). In the beginning, various copper, iron salts were tested, most of which behaved poorly(entries 1-3 in Table 1). We were delighted to find that the C−H phosphonylation in the presence of cobalt acetate (10 mol%) and molecular oxygen (1 atm, balloon) provided the desired α-aminophosphonate product in moderate yield (38%; entry 4 in Table 1). Although NHPI alone has been revealed to be efficient organocatalyst for free-radical processes and has found ample application in promoting the aerobic oxidation of a wide range of organic substrates,14 the reaction was inhibited in the absence of a cobalt salt (entry 5). A combination of cobalt acetate with NHPI furnished 3 in good yield (80%; entry 6 vs 4).15 The yield of product 3 decreased when the reaction was operated in the temperature range of rt−60 oC (entry 7). Subsequently, various cobalt salts were screened under similar conditions, all cobalt salts showed good efficacy (entries 8−10). The reaction performed best in acetonitrile (entries 10−12). Gratifyingly, air as an oxidant can further improve the reaction, giving 3 in 85% isolated yield (entry 13). To elucidate the respective importance of cobalt acetate and NHPI further, we carried out two experiments (entries 14b and 14c). We found that a combination of 0.1 equivalents of cobalt acetate with 0.3 equivalents of NHPI provided the best results (entry 13). Screening other co-catalysts, such as N−hydroxysuccinimide (HOSU), and 1-hydroxybenzotriazole (HOBT), revealed that NHPI was the best choice (entries 13−15). After a series of detailed investigations, we established an efficient route to substituted α-aminophosphonates via Co-catalyzed CDC reactions. The optimal reaction conditions are 1 (0.5 mmol), 2 (1.7 mmol), Co(OAc)2 (10 mol%), NHPI (30 mol%), and CH3CN (2.5 mL) at 80 °C for 16 h under aerobic conditions (entry13 in Table 1) . We next explored the substrate scope of the C−H phosphonation reaction using a wide range of tertiary aromatic or aliphatic amines (Table 2). Good to excellent yields were observed in most cases, illustrating the efficiency of the developed CDC method. For the tertiary aliphatic amines, tri-n-butylamine, tri-n-propylamine, tri-n-hexylamine, tri-n-octylamine, the steric hindrance has no influence on the formation of α-aminophosphonates. For example, tri-n-octylamine with three bulky octyl groups provided 6 in 70% yield. Triethylamine (7) gave a moderate yield. N,N-Dimethylaniline (8) and N,N-dimethyltetradecanamine (9) were quiet incompetent to do these transformations and P(O)H was oxidized to P(O)OH completely. This behavior could be explained by the oxidation potentials of tertiary amines, which decrease with increasing chain length (e.g., Me3N, +0.82 V; Et3N, +0.79 V; n-Bu3N, +0.62 V; measured vs SCE).16 In regard to the H−phosphonates, in addition to diethyl H−phosphonate (1), dimethyl, diisopropyl, dibutyl, and dibenzyl H−phosphonates all could be used as the substrates, generating the corresponding α-aminophosphonates (10−13) in good yields. Not surprisingly, reacting


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diphenylphosphine oxide (Ph2P(O)H) with tri-n-butylamine in the presence of Co catalyst in one pot gave the desired product 14 in merely 20% yield. The tautomeric equilibria of diphenylphosphine oxide is well-known and the tricoordinated phosphite can be easily oxidized to Ph2P(O)OH.17 Oxidation of the diphenylphosphine oxide with air will inhibit the C−H activation step.

Table 2. The Oxidative C(sp3)–H Phosphonylation for α-Aminophosphonates via C(sp3)–H/P(O)–H Coupling



O OR1 H P OR2

EtO

C2H5

+

R3

O

C5H11

Ph

EtO

O

C3H7

CH3CN (2.5 mL), air 16 h, 80 oC

R3

O C7H15

MeO

C3H7 C3H7

EtO P O OEt 16, quant.

N

Br


BnO P O OBn 23, 73%

N EtO P O OEt 27, 75% (25 hrs)

C3H7

11, 55%

P

N

O

N C3H7

EtO P O OEt 15, 90%

C3H7

N EtO P O CF3 OEt mixture 17 :17' = 90:10 17' 17 total yield: quant.

O P OEt OEt

Br N EtO P O OEt 18, quant.

CF3

N

N

N Br

MeO P O OMe

Br

21, quant.

Br

24, 68%

Ph P O Ph 25, 71%

N

C4H9

EtO P O OEt 28, 70% (25 hrs)

n-BuO P O OBu-n

Br

22, 75%

N

i-PrO P O OPr-i

i-PrO OPr-i P O N C3H7

Ph

Ph

C3H7

N Br

O

14, 20%


N

C3H7

C3H7

N OCH3

O

7, 37%

10, 75%

13, 67%

OEt P

N

OMe P

N

O

n-BuO OBu-n P O N C3H7 C3H7

N

O

6, 70%

C3H7

12, 65%

EtO

C7H15

9, trace

BnO OBn P O N C3H7

2 R1O OR P O N 5 R

OEt P

N

OEt P

4

EtO

C7H15

C5H11

N

C14H29

8, trace

C3H7

R

5, 70%

OEt P

Co(OAc)2 (10 mol%) NHPI (30 mol%)

OEt P

N

C2H5

N

EtO

C5H11

4, 65% EtO

R5

N

OEt P

N C2H5

R4

Page 6 of 19

N Br

Ph P O Ph 26, 85%

N EtO P O O OEt 29, trace

Different N−aryltetrahydroisoquinolines were coupled with diethyl H−phosphonate. They can uniformly afford the ACS Paragon Plus Environment

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desired products with almost quantitative yields (15−20). The reaction of diisopropyl H−phosphonate, dibutyl H−phosphonate, and dibenzyl H−phosphonate with 2-(4-bromophenyl)-1,2,3,4-tetrahydroisoquinoline gave slightly lower yields under the standard conditions (22−24 vs 15-21). This is likely due to the high steric sensitivity of the addition reaction of the bulky O,O-dialkyl phosphonyl anions with iminium cation intermediates. Although several methods have been developed for oxidative α-C−H phosphonation of N-aryltetrahydroisoquinolines, diaryl phosphine oxides as reaction partners are rarely reported. Kobayashi and Zhu reported the aerobic phosphonylation reaction of N-aryl tetrahydroisoquinolines with Ph2P(O)H catalyzed by the noble iridium-based and gold-based photocatalyst under visible light irradiation, independently.18 The base cobalt catalytic system could proceed smoothly to furnish the C−P coupling products 25 and 26 in good yields. N-Benzyl and N-butyl-tetrahydroisoquinolines could be used as the substrates, generating the corresponding α-aminophosphonates 27 and 28 in 75 and 70% yields, respectively. N-Acyl-tetrahydroisoquinolines was also examined. Unfortunately, only trace amount of the desired product was detected (29). In order to demonstrate the practical application of this method, diethyl H−phosphonate (1, 5 mmol) and tri-n-butylamine (2, 17 mmol) were employed in a gram-scale reaction and delivered 3 in 75% yield (Scheme 2). The excess amount of amine was recovered in 75% yield.

Scheme 2. Gram-Scale Preparation of 3

The reaction between 1 and 2 was inhibited obviously by adding 1.5 equiv of 2,2,6,6-tetra-methylpiperidinooxy (TEMPO) or butylated hydroxytoluene (BHT)(Scheme 3). Although the detailed mechanism remains ambiguous at present, a possible mechanism for this Co(II) complex-catalyzed α-aminophosphonylation of aliphatic tertiary amines with P(O)H compounds is described in Scheme 4. Co(II)-NHPI complex A is formed when Co(OAc)2 and NHPI are added into acetonitrile. Co(II) complex activates the molecular oxygen to produce oxidized Co(III)-phthalimide-N-oxyl (PINO) radical B and HOO−. Subsequent coordination of Lewis basic tertiary amine to complex B produces complex C. Single electron abstraction from the nitrogen atom produces aminyl radical D, which is facilitated by the coordination of electron-deficient PINO. Concerted



Page 8 of 19

α-C−H bond cleavage, an intramolecular 1,4-hydrogen transfer, by the N-oxyl radical produces iminium cation intermediate E while regenerating Co(II)-NHPI complex A. A further addition of anion F to iminium cation E gives the desired CDC product.

Scheme 3 Control Experiments

Scheme 4.

A Tentative Mechanistic Pathway

In conclusion, we have developed a Co(OAc)2/ NHPI-catalyzed α-aminophosphonylation of aliphatic and aromatic tertiary amines with P(O)H compounds, which is efficient for the synthesis of α-aminophosphonates. The protocol represents the first cross dehydrogenative coupling reaction between α-C−H bonds of tertiary aliphatic amines and phosphinylidenes. Furthermore, the use of air instead of pure oxygen and organic oxidants is advantageous in terms of safety.


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EXPERIMENTAL SECTION General: and

13

All reagents were obtained from commercial suppliers and used without further purification. 1H NMR (500 MHz)

C NMR (125 MHz) spectra were measured on Bruker AVⅢ 500M spectrometers with CDCl3 as solvent and

tetramethylsilane (TMS) as internal standard. Chemical shifts were reported in units (ppm) by assigning TMS resonance in the 1H spectrum as 0.00 ppm and CDCl3 resonance in the 13C spectrum as 77.23 ppm. All coupling constants (J values) were reported in Hertz (Hz). Chemical shifts of common trace 1H NMR impurities (ppm): H2O: 1.56, CHCl3: 7.26. Column chromatography was performed on silica gel 300-400 mesh. The unknown products were further characterized by HRMS (FT-ICR-MS) and electrospray ionization source in positive-ion mode .

General Procedure for the Synthesis of 1,2,3,4-Tetrahydroisoquinoline Derivatives.19 Copper(I) iodide (200 mg, 1.0 mmol) and anhydrous potassium phosphate (4.25 g, 20.0 mmol) were put into a Schlenk tube (No product was obtained when hydrated potassium phosphate was used). The tube was evacuated and refilled with nitrogen. 2-Propanol (10 mL), ethylene glycol (1.11 mL, 20.0 mmol), 1,2,3,4-tetrahydro-isoquinoline (2.0 mL, 15.0 mmol) and iodobenzene (1.12 mL, 10.0 mmol) were added successively using a syringe at room temperature. The reaction mixture was heated at 85-90 °C and kept for 24 h. The reaction mixture was allowed to cool to ambient temperature, and then transferred to a round-bottom flask. Silica gel (3.0 g) was added, and the solvent was removed under reduced pressure to afford a free-flowing powder. This powder was then dryloaded onto a silica gel column and purified by flash chromatography using a petroleum ether/AcOEt mixture [from 50:1 to 20:1 (v/v)] as the eluent to give the desired product in 60% isolated yield. Diethyl (1-(dibutylamino)butyl)phosphonate (3) (CAS no: 875228-32-3).3a Yield: 137 mg, 85%. Light yellow oil. 1H NMR (500 MHz, CDCl3) δ (ppm) 4.12 – 4.00 (m, 4H), 2.93 – 2.87 (m, 1H), 2.67 – 2.62 (m, 2H), 2.59 – 2.54 (m, 2H), 1.58 – 1.51 (m, 3H), 1.35 – 1.20 (m, 15H), 0.89 – 0.85 (m, 9H). 13C NMR (125 MHz, CDCl3) δ (ppm) 61.5 (d, J = 7.4 Hz), 60.9 (d, J = 7.6 Hz), 58.4 (d, J = 134.2 Hz), 51.7 (d, J = 3.5 Hz), 31.8 (s), 30.0 (d, J = 7.2 Hz), 20.5 (d, J = 12.7 Hz), 20.4 (s), 16.7 (d, J = 5.7 Hz), 16.65 (d, J = 5.9 Hz), 14.2 (s), 14.0 (s).

31

P NMR (202 MHz, CDCl3) δ (ppm) 29.8. HRMS Calcd for

C16H36NNaO3P+ [M+Na]+ 344.2325, found 344.2320. Diethyl (1-(dipropylamino)propyl)phosphonate (4). Yield: 91 mg, 65%. Light yellow oil. 1H NMR (500 MHz, CDCl3) δ (ppm) 4.09 – 4.00 (m, 4H), 2.79 – 2.73 (m, 1H), 2.65 – 2.59 (m, 2H), 2.53 – 2.47 (m, 2H), 1.67 – 1.56 (m, 2H), 1.41 – 1.30 (m, 4H), 1.27 – 1.25 (m, 5H), 0.97 (t, J = 7.7 Hz, 3H), 0.81 (t, J = 7.4 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ (ppm) 61.5 (d, J = 7.4 Hz), 60.9 (d, J = 7.5 Hz), 60.6 (d, J = 133.8 Hz), 53.9 (d, J = 3.4 Hz), 22.6 (s), 21.0 (d, J = 7.6 Hz), 16.68 (d, J = 5.8 Hz), 16.60(d, J = 5.6Hz), 12.3 (d, J = 13.0 Hz), 11.7 (s).

31




Page 10 of 19

C13H30NNaO3P+ [M+Na]+ 302.1856, found 302.1861. Diethyl (1-(dihexylamino)hexyl)phosphonate (5). Yield: 142 mg, 70%. Light yellow oil. 1H NMR (500 MHz, CDCl3) δ (ppm) 4.09 – 4.01 (m, 4H), 2.88 – 2.82 (m, 1H), 2.65 – 2.59 (m, 2H), 2.56 – 2.50 (m, 2H), 1.58 – 1.49 (m, 2H), 1.32 – 1.23 (m, 28H), 0.85 – 0.81 (m, 9H). 13C NMR (125 MHz, CDCl3) δ (ppm) 61.4 (d, J = 7.5 Hz), 60.9 (d, J = 7.6 Hz), 58.6 (d, J = 133.6 Hz), 51.9 (d, J = 3.3 Hz), 31.9 (s), 31.7 (s), 29.5 (s), 27.7 (d, J = 7.3 Hz), 26.967 (d, J = 12.3 Hz), 27.968 (s), 22.8 (s), 22.6 (s), 16.9 (d, J = 5.6 Hz), 16.60 (d, J = 5.8 Hz),14.09 (s), 14.06 (s). 31P NMR (202 MHz, CDCl3) δ (ppm) 29.8. HRMS Calcd for C22H48NNaO3P+ [M+Na]+ 428.3264, found 428.3264. Diethyl (1-(dioctylamino)octyl)phosphonate (6). Yield: 171 mg, 70%. Light yellow oil. 1H NMR (500 MHz, CDCl3) δ (ppm) 4.08 – 3.98 (m, 4H), 2.88 – 2.82 (m, 1H), 2.65 – 2.59 (m, 2H), 2.55 – 2.50 (m, 2H), 1.58 – 1.49 (m, 2H), 1.32 – 1.20 (m, 40H), 0.83 – 0.81 (m, 9H). 13C NMR (125 MHz, CDCl3) δ (ppm) 61.4 (d, J = 7.4 Hz), 60.9 (d, J = 7.5 Hz), 58.6 (d, J = 133.4 Hz), 51.8 (d, J = 2.9 Hz), 31.92 (s), 31.90 (s), 29.5 (s), 29.7 (s), 29.49 (s), 29.47 (s), 29.4 (s), 29.3 (s), 27.75 (s), 27.70 (s), 27.32 (s), 27.29 (s), 27.23 (s), 22.7 (s), 16.66 (d, J = 5.7 Hz), 16.59 (d, J = 5.7 Hz), 14.1 (s). 31P NMR (202 MHz, CDCl3) δ (ppm) 29.8. HRMS Calcd for C28H61NO3P+ [M+H]+ 490.4384, found 490.4383. Diethyl (1-(diethylamino)ethyl)phosphonate (7) (CAS no: 19097-67-7).3a Yield: 44 mg, 37%. Light yellow oil. 1H NMR (500 MHz, CDCl3) δ (ppm) 4.19 – 4.04 (m, 4H), 3.20 – 3.11 (m, 1H), 2.81 – 2.74 (m, 2H), 2.54 – 2.47 (m, 2H), 1.32 – 1.20 (m, 9H), 1.02 (t, J = 7.3 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ (ppm) 62.7 (d, J = 7.2 Hz), 61.1 (d, J = 7.3 Hz), 52.8 (d, J = 156.2 Hz), 44.8 (d, J = 7.3 Hz), 16.7 (d, J = 5.7 Hz), 16.6 (d, J = 5.6Hz), 14.3 (s), 9.9 (d, J = 5.1 Hz), 31P NMR (202 MHz, CDCl3) δ (ppm) 28.2. HRMS Calcd for C10H24NNaO3P+ [M+Na]+ 260.1386, found 260.1390. Dimethyl (1-(dibutylamino)butyl)phosphonate (10). Yield: 110 mg, 75%. Light yellow oil. 1H NMR (500 MHz, CDCl3) δ (ppm) 3.72 – 3.65 (m, 6H), 2.95 – 2.89 (m, 1H), 2.61 – 2.45 (m, 4H), 1.62 – 1.52 (m, 3H), 1.34 – 1.19 (m, 9H), 0.89 – 0.82 (m, 9H). 13C NMR (125 MHz, CDCl3) δ (ppm) 58.2 (d, J = 135.8 Hz), 52.4 (d, J = 7.6 Hz), 51.7 (s), 51.6 (d, J = 3.6 Hz), 31.7 (s), 29.9 (d, J = 7.0 Hz), 20.5 (d, J = 12.6 Hz), 20.4 (s), 14.1 (s), 13.9 (s). 31P NMR (202 MHz, CDCl3) δ (ppm) 32.2. HRMS Calcd for C14H33NO3P+ [M+H]+ 294.2193, found 294.2195. Diisopropyl (1-(dibutylamino)butyl)phosphonate (11). Yield: 96 mg, 55%. Light yellow oil. 1H NMR (500 MHz, CDCl3) δ (ppm) 4.69 – 4.63 (m, 2H), 2.83 – 2.77 (m, 1H), 2.69 – 2.63 (m, 2H), 2.59 – 2.53 (m, 2H), 1.56 – 1.49 (m, 3H), 1.36 – 1.19 (m, 21H), 0.90 – 0.83 (m, 9H). 13C NMR (125 MHz, CDCl3) δ (ppm) 69.8 (d, J = 7.7 Hz), 69.4 (d, J = 8.1 Hz), 58.9 (d, J = 134.1 Hz), 51.6 (d, J = 2,7 Hz), 31.8 (s), 30.0 (d, J = 7.2 Hz), 24.5 (d, J = 2.9 Hz), 24.3 (d, J = 3.1 Hz), 24.2 (d, J = 5.3 Hz), 20.5 (s), 20.4 (s), 20.36 (s), 14.2 (s), 14.0 (s).

31

P NMR (202 MHz, CDCl3) δ (ppm) 28.0. HRMS Calcd for C18H41NO3P+

[M+H]+ 350.2819, found 350.2821.


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The Journal of Organic Chemistry Dibenzyl (1-(dibutylamino)butyl)phosphonate (12). Yield: 145 mg, 65%. Light yellow oil. 1H NMR (500 MHz, CDCl3) δ

(ppm) 7.34 – 7.28 (m, 2H), 5.06 – 4.92 (m, 4H), 2.99 – 2.93 (m, 1H), 2.72 – 2.66 (m, 2H), 2.62 – 2.57 (m, 2H), 1.63 – 1.51 (m, 2H), 1.38 – 1.18 (m, 10H), 0.87 – 0.83 (m, 9H). 13C NMR (125 MHz, CDCl3) δ (ppm) 137.0 (s), 136.99 (s), 136.97 (s), 136.92 (s), 128.6 (s), 128.29 (s), 128.27 (s), 128.1 (s), 67.2 (d, J = 7.3 Hz), 66.5 (d, J = 7.7 Hz), 58.9 (d, J = 140.3 Hz), 51.7 (d, J = 3.2Hz), 31.8 (s), 30.0 (d, J = 7.2 Hz), 20.44 (d, J = 12.8 Hz), 20.43 (s), 14.2 (s), 14.0 (s). 31P NMR (202 MHz, CDCl3) δ (ppm) 30.7. HRMS Calcd for C26H41NO3P+ [M+H]+ 446.2819, found 446.2819. Dibutyl (1-(dibutylamino)butyl)phosphonate (13). Yield: 126 mg, 67%. Light yellow oil. 1H NMR (500 MHz, CDCl3) δ (ppm) 4.06 – 3.95 (m, 4H), 2.96 – 2.90 (m, 1H), 2.69 – 2.63 (m, 2H), 2.61 – 2.55 (m, 2H), 1.65 – 1.55 (m, 6H), 1.43 – 1.20 (m, 14H), 0.94 – 0.87 (m, 15H). 13C NMR (125 MHz, CDCl3) δ (ppm) 65.3 (d, J = 7.5 Hz), 64.7 (d, J = 7.6 Hz), 58.4 (d, J = 132.9 Hz), 51.7 (d, J = 3.0 Hz), 32.9 (s), 32.88 (s), 32.83 (s), 31.9 (s), 30.1 (d, J = 7.2 Hz), 20.6 (s), 20.47 (s), 20.45 (s), 19.0 (s), 14.2 (s), 14.0 (s), 13.7 (s). 31P NMR (202 MHz, CDCl3) δ (ppm) 30.0. HRMS Calcd for C20H45NO3P+ [M+H]+ 378.3132, found 378.3132. (1-(Dibutylamino)butyl)diphenylphosphine Oxide (14). Yield: 39 mg, 20%. White paste. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.86 – 7.80 (m,4H), 7.48 – 7.37 (m, 6H), 3.56 – 3.52 (m, 1H), 2.66 – 2.61 (m, 2H), 2.56 – 2.51 (m, 2H), 1.90 – 1.81 (m, 1H), 1.67 – 1.58 (m, 1H), 1.44 – 1.06 (m, 14H), 0.82 – 0.78 (m, 9H). 13C NMR (125 MHz, CDCl3) δ (ppm) 134.4 (d, J = 4.5 Hz), 133.7 (d, J = 5.1 Hz), 131.6 (d, J = 8.8 Hz), 131.4 (d, J = 2.5 Hz), 131.2 (d, J = 2.5 Hz ), 131.1 (d, J = 8.2 Hz), 128.6 (d, J = 10.3 Hz), 128.1 (d, J = 11.3 Hz), 61.5 (d, J = 78.0 Hz), 52.5 (d, J = 5.0 Hz), 31.7 (s), 28.2 (d, J = 6.8 Hz), 21.7 (d, J = 10.9 Hz), 20.4 (s), 14.2 (s), 14.1 (s).

31

P NMR (202 MHz, CDCl3) δ (ppm) 32.0. HRMS Calcd for C24H37NOP+ [M+H]+

386.2607, found 386.2610. Diethyl (2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (15) (CAS no: 87992-94-7).6 Yield: 155 mg, 90%. White solid, m.p. 62-64 oC.

1

H NMR (500 MHz, CDCl3) δ (ppm) 7.37 (t, J = 7.6 Hz, 1H), 7.25 – 7.22 (m, 2H), 7.19 – 7.13

(m, 3H), 6.97 (t, J = 8.3 Hz, 2H), 6.78 (t, J = 7.2 Hz, 1H), 5.18 (d, J = 20.0 Hz, 1H), 4.12 – 3.85 (m, 5H), 3.64 – 3.60 (m, 1H), 3.10 – 3.04 (m, 1H), 3.01 – 2.95 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 149.6 (d, J = 5.7 Hz), 136.5 (d, J = 5.5 Hz), 130.7 (s), 129.2 (s), 128.8 (d, J = 2.5 Hz), 128.2 (d, J = 4.6 Hz), 127.5 (d, J = 3.4 Hz ), 125.9 (d, J = 2.7 Hz), 118.5 (s), 114.9 (s), 63.4 (d, J = 7.2 Hz), 62.4 (d, J = 7.7 Hz), 58.9 (d, J = 159.2 Hz), 43.6 (s), 26.8 (s), 16.5 (d, J = 5.4 Hz), 16.4 (d, J = 5.7 Hz).

31


C19H25NO3P+ [M+H]+ 346.1567, found 346.1567. Diethyl (2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (16) (CAS no: 87992-95-8).6 Yield: 187 mg, 100%. Light yellow oil. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.39 (t, J = 6.2 Hz, 2H), 7.20 – 7.11 (m, 3H), 6.92 (d, J = 9.1 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 5.02 (d, J = 21.5 Hz, 1H), 4.12 – 3.92 (m, 5H), 3.74 (s, 3H), 3.56 – 3.51 (m, 1H), 2.93 (s, ACS Paragon Plus Environment


Page 12 of 19

2H), 1.26 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 153.2 (s), 144.2 (d, J = 8.2 Hz), 136.5 (d, J = 6.0 Hz), 130.6 (s), 129.0 (d, J = 2.1 Hz), 128.2 (d, J = 4.5 Hz), 127.3 (d, J = 3.4 Hz ), 125.8 (d, J = 2.9 Hz), 118.6 (s), 114.6 (s), 63.4 (d, J = 7.2 Hz), 62.3 (d, J = 7.5 Hz), 58.5 (d, J = 158.5 Hz), 55.7 (s), 44.7 (s), 26.2 (s), 16.5 (d, J = 5.4 Hz), 16.4 (d, J = 5.7 Hz). 31P NMR (202 MHz, CDCl3) δ (ppm) 22.2. HRMS Calcd for C20H27NO4P+ [M+H]+ 376.1672, found 376.1672. Diethyl (2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (17). Yield: 206 mg, 100%. Light yellow oil. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.47 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 6.8 Hz, 1H), 7.21 – 7.15 (m, 4H), 7.00 (d, J = 8.5 Hz, 2H), 5.23 (d, J = 18.2 Hz, 1H), 4.14 – 3.82 (m, 5H), 3.62 – 3.57 (m, 1H), 3.28 – 3.22 (m, 1H), 3.02 – 2.96 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 151.4 (s), 136.3 (d, JC-P = 5.1 Hz), 130.3 (s), 128.6 (d, JC-P = 2.6 Hz), 128.2 (d, JC-P = 4.7 Hz), 127.9 (d, JC-P = 3.5 Hz ), 126.4 (d, JC-F = 3.6 Hz), 126.2 (d, JC-P = 2.6 Hz), 124.9 (d, JC-F = 270.2 Hz), 119.5 (d, JC-F = 32.7 Hz), 113.2 (s), 63.5 (d, JC-P = 7.3 Hz), 62.8 (d, JC-P = 7.6 Hz), 58.4 (d, JC-P = 159.7 Hz), 43.5 (s), 27.3 (s), 16.5 (d, JC-P = 5.4 Hz), 16.4 (d, JC-P = 5.5 Hz). 31P NMR (202 MHz, CDCl3) δ (ppm) 21.8. HRMS Calcd for C20H23F3NNaO3P+ [M+Na]+ 436.1260, found 436.1263. Diethyl (2-(2-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (18). Light yellow oil. Yield: 212 mg, 100%. 1

H NMR (500 MHz, CDCl3) δ (ppm) 7.35 (t, J = 7.0 Hz, 1H), 7.22 – 7.14 (m, 3H), 7.11 – 7.07 (m, 2H), 6.89 – 6.87 (m, 2H),

5.14 (d, J = 18.7 Hz, 1H), 4.10 – 3.84 (m, 5H), 3.56 – 3.51 (m, 1H), 3.20 – 3.15 (m, 1H), 3.00 – 2.94 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 155.4 (d, J = 4.2 Hz), 136.3 (d, J = 5.4 Hz), 133.9 (s), 130.3 (s), 128.7 (d, J = 2.8 Hz), 128.2 (d, J = 5.3 Hz), 127.7 (d, J = 3.4 Hz ), 126.1 (d, J = 2.6 Hz), 123.3 (s), 121.0 (s), 117.2 (s), 112.9 (s), 63.4 (d, J = 7.3 Hz), 62.6 (d, J = 7.8 Hz), 58.8 (d, J = 159.6 Hz), 43.5 (s), 27.1 (s), 16.4 (d, J = 6.0 Hz), 16.4 (d, J = 6.0 Hz).

31

P NMR (202 MHz, CDCl3) δ (ppm) 21.7. HRMS Calcd for C19H23BrNaNO3P+ [M+Na]+ 446.0491, found

446.0488. Diethyl (2-(3-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (19). Yield: 211 mg, 100%. Light yellow oil. 1

H NMR (500 MHz, CDCl3) δ (ppm) 7.35 (t, J = 7.2 Hz, 1H), 7.23 – 7.15 (m, 3H), 7.11 – 7.07 (m, 2H), 6.90 – 6.87 (m, 2H),

5.13 (d, J = 18.5 Hz, 1H), 3.90 – 3.84 (m, 5H), 3.57 – 3.52 (m, 1H), 3.21 – 3.15 (m, 1H), 3.00 – 2.95 (m, 1H), 1.23 (t, J = 7.5 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 150.5 (d, J = 4.4 Hz), 136.4 (d, J = 5.4 Hz), 130.5 (s), 130.4 (s), 128.7 (d, J = 2.7 Hz), 128.2 (d, J = 4.6 Hz), 127.8 (d, J = 3.5 Hz ), 126.1 (d, J = 2.6 Hz), 123.4 (s), 121.0 (s), 117.2 (s), 112.9 (s), 63.3 (d, J = 7.3 Hz), 62.6 (d, J = 7.7 Hz), 58.8 (d, J = 159.2 Hz), 43.6 (s), 27.2 (s), 16.5 (d, J = 5.5 Hz), 16.4 (d, J = 6.0 Hz).

31


446.0486. Diethyl (2-(4-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (20) (CAS no: 1315275-83-2).7 Yield: 212 mg, ACS Paragon Plus Environment

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100%. White solid, m.p. 85-87 oC. Yield: quant. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.35 (d, J = 7.1 Hz, 1H), 7.33 – 7.29 (m, 2H), 7.22 – 7.14 (m, 3H), 6.85 – 6.82 (m, 2H), 5.10 (d, J = 19.1 Hz, 1H), 4.13 – 3.83 (m, 5H), 3.55 – 3.50 (m, 1H), 3.17 – 3.11 (m, 1H), 2.99 – 2.93 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 148.3 (d, J = 4.9 Hz), 136.3 (d, J = 5.4 Hz), 131.8 (s), 130.4 (s), 128.7 (d, J = 2.6 Hz), 128.2 (d, J = 4.7 Hz), 127.7 (d, J = 4.0 Hz ), 126.1 (d, J = 2.6 Hz), 116.2 (s), 110.3 (s), 63.4 (d, J = 7.3 Hz), 62.5 (d, J = 7.6 Hz), 58.8 (d, J = 159.0 Hz), 43.7 (s), 27.0 (s), 16.5 (d, J = 5.4 Hz), 16.4 (d, J = 5.6 Hz).

31


C19H23BrNaNO3P+ [M+Na]+ 446.0491, found 446.0490. Dimethyl (2-(4-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (21) (CAS no: 1435940-00-3).9f Yield: 197 mg, 100%. White solid, m.p. 159.5-161.5 oC. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.33 (d, J = 9.0 Hz, 3H), 7.24 – 7.16 (m, 3H), 6.84 (d, J = 9.8 Hz, 2H), 5.12 (d, J = 19.1 Hz, 1H), 3.98 – 3.93 (m, 1H), 3.64 (t, J = 10.9 Hz, 6H), 3.56 – 3.51 (m, 1H), 3.16 – 3.12 (m, 1H), 3.00 – 2.94 (m, 1H),. 13C NMR (125 MHz, CDCl3) δ (ppm) 148.2 (d, J = 5.0 Hz), 136.3 (d, J = 5.5 Hz), 132.0 (s), 130.2 (s), 128.8 (d, J = 2.6 Hz), 128.0 (d, J = 5.0 Hz), 127.8 (d, J = 3.4 Hz ), 126.3 (d, J = 2.7 Hz), 116.2 (s), 110.6 (s), 58.7 (d, J = 159.8 Hz), 53.9 (d, J = 8.0 Hz), 53.1 (d, J = 8.0 Hz), 43.8 (s), 26.9 (s). 31P NMR (202 MHz, CDCl3) δ (ppm) 24.0. HRMS Calcd for C17H19BrNaNO3P+ [M+Na]+ 418.0178, found 418.0175. Dibutyl (2-(4-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (22). Yield: 180 mg, 75%. White solid, m.p. 52-54 oC. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.35 (d, J = 7.3 Hz, 1H), 7.32 – 7.29 (m, 2H), 7.21 – 7.14 (m, 3H), 6.85 – 6.82 (m, 2H), 5.11 (d, J = 18.0 Hz, 1H), 4.02 – 3.92 (m, 3H), 3.88 – 3.82 (m, 1H), 3.79 – 3.73 (m, 1H), 3.56 – 3.51 (m, 1H), 1.57 – 1.51 (m, 2H), 1.47 – 1.42 (m, 2H), 1.34 – 1.28 (m, 2H), 1.26 – 1.20 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H), 0.82 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 148.4 (d, J = 4.8 Hz), 136.3 (d, J = 5.3 Hz), 131.9 (s), 130.6 (s), 128.8 (d, J = 2.6 Hz), 128.2 (d, J = 4.7 Hz), 127.7 (d, J = 3.4 Hz ), 126.1 (d, J = 2.7 Hz), 116.2 (s), 110.4 (s), 67.0 (d, J = 7.7 Hz), 66.2 (d, J = 8.1 Hz), 58.8 (d, J = 158.8 Hz), 43.7 (s), 32.7 (d, J = 5.5 Hz), 32.6 (d, J = 5.5 Hz), 27.1 (s), 18.8 (d, J = 5.6 Hz), 13.7 (d, J = 4.8 Hz).

31


502.1119. Dibenzyl (2-(4-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate(23) (CAS no: 1322668-09-6).8 Yield: 200 mg, 73%. White solid, m.p. 83-85 oC. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.35 – 7.33 (m, 4H), 7.30 – 7.28 (m, 4H), 7.24 – 7.22 (m, 2H), 7.20 – 7.16 (m, 2H), 7.14 – 7.12 (m, 2H), 6.82 (d, J = 10.9 Hz, 2H), 5.22 (d, J = 18.8 Hz), 5.01 – 4.97 (m, 1H), 4.96 – 4.87 (m, 2H), 4.80 – 4.76 (m, 1H), 3.99 – 3.94 (m, 1H), 3.56 – 3.52 (m, 1H), 3.16 – 3.13 (m, 1H), 3.01 – 2.96 (m, 1H). 13

C NMR (125 MHz, CDCl3) δ (ppm) 148.2 (d, J = 4.6 Hz), 136.4 (d, J = 5.4 Hz), 136.27 (s), 136.22 (s), 131.18 (s), 131.9

(s), 130.2 (s), 128.9 (d, J = 2.6 Hz), 128.6 (s), 128.50 (s), 128.48 (s), 128.42 (s), 128.3 (d, J = 4.9 Hz), 128.2 (d, J = 1.4 Hz), 127.9 (d, J = 3.7 Hz), 126.5 (,d, J = 2.7 Hz), 116.4 (s), 110.6 (s), 68.8 (d, J = 7.4 Hz), 68.0 (d, J = 7.6 Hz), 59.0 (d, J = 157.6



Page 14 of 19

Hz), 43.7 (s), 27.1 (s). 31P NMR (202 MHz, CDCl3) δ (ppm) 22.7. HRMS Calcd for C29H27BrNaNO3P+ [M+Na]+ 570.0804, found 570.0798. Diisopropyl (2-(4-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (24). Yield: 153 mg, 68%. White solid, m.p. 80-82 oC. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.37 (d, J = 7.1 Hz, 1H), 7.31 – 7.27

(m, 2H), 7.20 – 7.12 (m, 3H),

6.83 – 6.80 (m, 2H), 5.05 (d, J = 19.9 Hz, 1H), 4.63 – 4.55 (m, 2H), 4.00 – 3.95 (m, 1H), 3.57 – 3.52 (m, 1H), 3.13 – 3.07 (m, 1H), 2.97 – 2.91 (m, 1H), 1.28 (t, J = 6.0 Hz, 3H), 1.14 (d, J = 6.2 Hz, 2H), 0.94 (d, J = 6.3 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ (ppm) 148.5 (d, J = 5.5 Hz), 136.3 (d, J = 5.4 Hz), 131.7 (s), 130.7 (s), 128.7 (d, J = 2.6 Hz), 128.5 (d, J = 4.8 Hz), 127.6 (d, J = 3.4 Hz ), 125.6 (d, J = 2.6 Hz), 116.4 (s), 110.1 (s), 72.3 (d, J = 7.9 Hz), 71.1 (d, J = 8.2 Hz), 58.9 (d, J = 161.4 Hz), 43.7 (s), 26.8 (s), 24.5 (d, J = 2.7 Hz), 24.2 (d, J = 3.3 Hz), 23.8 (d, J = 5.5 Hz), 23.4 (d, J = 5.4 Hz). 31P NMR (202 MHz, CDCl3) δ (ppm) 20.5. HRMS Calcd for C21H27BrNaNO3P+ [M+Na]+ 474.0804, found 474.0797. (2-(4-Bromophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)diphenylphosphine oxide (25) (CAS no: 1382465-08-8).18c Yield: 173 mg, 71%. White solid, m.p. 147.5-149.5 oC. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.76 (t, J = 8.8 Hz, 2H), 7.69 (t, J = 8.9 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.47 – 7.44 (m, 3H), 7.39 – 7.33 (m, 2H), 7.21 – 7.14 (m, 3H), 7.08 (d, J = 7.7 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.66 – 6.61 (m, 3H), 5.48 (d, J = 9.9 Hz, 1H), 4.05 – 4.00 (m, 1H), 3.52 – 3.48 (m, 1H), 2.83 – 2.69 (m, 2H).

13

C NMR (125 MHz, CDCl3) δ (ppm) 149.0 (d, J = 7.1 Hz), 136.7 (d, J = 4.2 Hz), 132.4 (s), 132.3 (d, J = 8.4 Hz),

132.2 (d, J = 2.6 Hz), 132.0 (s), 131.7 (d, J = 8.8 Hz), 131.3 (s), 130.6 (s), 129.7 (s), 129.3 (d, J = 1.7 Hz), 128.6 (d, J = 11.2 Hz), 128.5 (d, J = 11.1 Hz), 127.8 (d, J = 3.2 Hz), 127.7 (d, J = 2.7 Hz), 125.7 (d, J = 2.7 Hz), 118.1 (s), 111.6 (s), 62.2 (d, J = 78.7 Hz), 45.2 (s), 25.9 (s).

31

P NMR (202 MHz, CDCl3) δ (ppm) 30.6. HRMS Calcd for C27H23BrNaNOP+ [M+Na]+

510.0593, found 510.0591. Diphenyl(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphine oxide (26) (CAS no: 1382465-02-2).18c Yield: 174 mg, 85%. White solid, m.p. 196.5-198.5 oC. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.80 (t, J = 8.6 Hz, 2H), 7.71 (t, J = 8.5 Hz, 2H), 7.71 (t, J = 5.4 Hz, 1H), 7.47 – 7.42 (m, 3H), 7.36 – 7.32 (m, 2H), 7.16 – 7.07 (m, 4H), 6.94 (t, J = 7.5 Hz, 1H), 6.81 – 6.76 (m, 3H), 6.65 (d, J = 7.7 Hz, 1H), 5.57 (d, J = 10.6 Hz, 1H), 4.07 – 4.01 (m, 1H), 3.60 – 3.56 (m, 1H), 2.86 – 2.82 (m, 1H), 2.70 – 2.66 (m, 1H).

13

C NMR (125 MHz, CDCl3) δ (ppm) 150.1 (d, J = 7.8 Hz), 137.0 (d, J = 4.0 Hz), 132.7 (s),

132.3 (d, J = 8.3 Hz), 132.0 (d, J = 2.7 Hz), 131.8 (d, J = 9.0 Hz), 131.76 (s), 131.1 (s), 130.0 (s), 129.3 (d, J = 1.7 Hz), 129.2 (s), 128.5 (d, J = 11.0 Hz), 128.4 (d, J = 11.1 Hz), 127.9 (d, J = 3.0 Hz), 127.5 (d, J = 2.7 Hz), 125.6 (d, J = 2.5 Hz), 119.6 (s), 116.9 (s), 62.1 (d, J = 79.7 Hz), 45.3 (s), 25.7 (s). 31P NMR (202 MHz, CDCl3) δ (ppm) 30.6. HRMS Calcd for C27H24NaNOP+ [M+Na]+ 432.1488, found 432.1487. 1

Diethyl (2-benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (27). Yield: 135 mg, 75%. H NMR (500 MHz, CDCl3)


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δ (ppm) 7.42 – 7.27 (m, 6H), 7.23 – 7.14 (m, 3H), 4.21 (d, J = 21.5 Hz, 1H), 4.10 – 3.95 (m, 6H), 3.72 – 3.66 (m, 1H), 2.98 – 2.84 (m, 2H), 2.73 (d, J = 17.6 Hz, 1H), 1.30 – 1.23 (m, 6H). 13C NMR (125 MHz, CDCl3) δ (ppm) 138.7 (s), 136.0 (d, J = 5.8 Hz), 129.7 (s), 129.3 (d, J = 4.2 Hz), 129.0 (d, J = 2.7 Hz), 128.3 (s ), 127.2 (s), 127.0 (d, J = 3.6 Hz), 125.6 (d, J = 3.2 Hz), 62.8 (d, J = 7.3 Hz), 62.3 (d, J = 7.4 Hz), 60.0 (d, J = 157.8 Hz), 59.5 (d, J = 12.4 Hz), 45.5 (d, J = 1.8 Hz), 25.1 (s), 16.5 (d, J = 2.8 Hz), 16.4 (d, J = 2.6 Hz). 31P NMR (202 MHz, CDCl3) δ (ppm) 23.3. HRMS Calcd for C20H27NO3P+ [M+H]+ 360.1723, found 360.1720. 1

Diethyl (2-butyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (28). Yield: 114 mg, 70%. H NMR (500 MHz, CDCl3)

δ (ppm) 7.31 (d, J = 7.2 Hz, 1H), 7.17 – 7.08 (m, 3H), 4.11 (d, J = 22.5 Hz, 1H), 4.09 – 3.97 (m, 4H), 3.66 – 3.61 (m, 1H), 2.89 – 2.80 (m, 2H), 2.69 – 2.65 (m, 3H), 1.53 – 1.48 (m, 2H), 1.36 – 1.31 (m, 2H), 1.28 – 1.21 (m, 6H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 136.4 (d, J = 6.3 Hz), 130.0 (s), 129.3 (d, J = 3.9 Hz), 129.0 (d, J = 2.1 Hz), 127.0 (d, J = 3.5 Hz), 125.6 (d, J = 2.9 Hz), 63.2 (d, J = 7.5 Hz), 62.3 (d, J = 7.6 Hz), 60.5 (d, J = 159.7 Hz), 55.3 (d, J = 12.6 Hz), 45.8 (s), 30.1 (s), 24.9 (s), 20.5 (s), 16.5505 (s), 16.5501 (d, J = 10.4 Hz), 14.2(s). 31P NMR (202 MHz, CDCl3) δ (ppm) 23.3. HRMS Calcd for C17H28NNaO3P+ [M+Na]+ 348.1699, found 348.1699.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: xxxxxxxxx.

1

H NMR, 31P

NMR and 13C NMR spectrum (PDF). AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We acknowledge financial support from the NSFC (21772163, 21778042, 21375113), NFFTBS (J1310024) and the



Page 16 of 19

Fundamental Research Funds for the Central Universities (20720160030). REFERENCES (1)

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