Cobalt-Catalyzed Oxidative C(sp3)-H Phosphonylation for α-Aminophosphonates via C(sp3)-H/P(O)-H Coupling

Article abstract of DOI:10.1021/acs.joc.8b00674

The first oxidative C(sp³)-H phosphonylation of tertiary aliphatic amines has been developed. The use of cobalt acetate as a catalyst, N-hydroxyphthalimide as a cocatalyst, and air as an 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.

Full text of DOI:10.1021/acs.joc.8b00674

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Note
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
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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
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‡Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen
University, Xiamen 361000, China
t12g21@xmu.edu.cn
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
R2
O
R5
R4
R1
O
R1
R2
R4
R3
P
Co(OAc)2, NHPI
CH3CN, air,16 h, 80 oC
H P
+
R3
N
R5
N
dialkyl H-phosphonates
diaryl phosphine oxides
tertiary aromatic amines
tertiary aliphatic amines
air instead of pure oxygen
and organic oxidants
The first oxidative C(sp3)ꢀH phosphonylation of tertiary aliphatic amines has been developed. The use of cobalt acetate as
catalyst, Nꢀhydroxyphthalimide as coꢀcatalyst, and air as oxidant enabled the conversion of tertiary aromatic and aliphatic
amines into αꢀaminophosphonates in moderate to excellent yields under mild conditions via a cross dehydrogenative
coupling reaction.
Carbon−phosphorus bond is widely found in many biologicallyꢀactive compounds, among which
αꢀaminophosphonates (N−C−P bond) and related αꢀaminophosphonic 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 αꢀaminophosphonates 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 catalystꢀfree5 synthesis of αꢀaminophosphonates. Although these methods are effective,
they need imines formed by the prefunctionalized aldehydes and amines.
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Scheme 1. Synthetic Routes to αꢀAminophosphonates
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(a) Classical methods
imines or ketones or amides as starting material
R3
O
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R4 R3
O
N
R2
Cp2ZrHCl
R1
N
R3
N
H
R1
R2
R1
R2
(b) Oxidative C(sp3)-H phosphonylation for -aminophosphonates
R1
R1
R2
O
R3
P
R4
R5
C(sp3)-H/P(O)-H
coupling
R4
R5
H P
+
R2
N
R3
N
H P
O
Previous work:
This work:
both tertiary aliphaticamines
and tertiary arylamines
only tertiary arylamines
N
R1
R2
R3
N
P
P
The key intermidiates:
The key intermidiates:
both unstable and stable
imine intermidiates
stable
conjugated
imine intermidiates
R1
N
R3
R2
N
Ph2P(O)H catalyzed by
Ph2P(O)H catalyzed
by the cheap cobalt
catalyst
P
P
the
noble
metal
catalysts, such as Ir, Au
etc.
In recent years, oxidative C(sp3)–H phosphonylation for the synthesis of αꢀaminophosphonates 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 sp3ꢀhybridized carbon−hydrogen bonds adjacent to tertiary arylamines, in particular
Nꢀaryltetrahydroisoquinolines, has seen an explosion of interest.9 However, although these methods are very elegant,
the range of starting materials is limited to tertiary arylamines 6ꢀ10
and a general method for the synthesis of
,
αꢀaminophosphonates 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.
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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 αꢀaminophosphonates in 2013
[Scheme 1 (a)].13 Herein, we describe the use of the inexpensive cobalt acetate in combination with Nꢀhydroxyphthalimide
(NHPI), and air as a highly active catalytic system for the oxidative αꢀphosphonylation of tertiary aliphatic and aromatic
amines. This dehydrogenative coupling process provides access to a host of αꢀaminophosphonates from a wide variety of
amine substrates. The use of air instead of pure oxygen and organic oxidants is advantageous in terms of safety.
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Table 1. Reaction Conditions Optimizationa
Entry
Catalyst
FeCl2
Cocatalyst
no
T/oC
rtꢀ60
60
Solvent
CH3CN
CH3OH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Oxidant
TBHP
O2
Yield/%
0ꢀ15
10
1
2
3
4
5
6
7
8
9
10
CuBr
no
CuBr2
no
60
O2
0
Co(OAc)2
ꢀ
ꢀ
80
O2
38
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
60
O2
0
Co(OAc)2
Co(OAc)2
CoCl2
80
O2
80
rtꢀ60
80
O2
25ꢀ50
80
O2
Co(NO3)2
Co(OEt)2
80
O2
78
80
O2
77
11
12
Co(OAc)2
Co(OAc)2
NHPI
NHPI
80
80
footnote
ꢀ
O2
O2
31ꢀ43b
45
13
85(62c, 60d)
Co(OAc)2
NHPI
80
CH3CN
air
14
15
Co(OAc)2
Co(OAc)2
HOSU
HOBT
80
80
CH3CN
CH3CN
air
air
72
80
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a Reaction conditions: 1 (0.5 mmol), 2 (1.7 mmol), catalyst (0.05 mmol), coꢀcatalyst (0.15 mmol), solvent (2.5 mL), were
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heated at the refluxing temperature under air for 16 h. Isolated yield. All catalysts are hydrated salts and used without further
b
c
d
purification. tetrahydrofuran, dichloroethane or 1,4ꢀdioxane as solvent. Co(OAc)2 (5 mol%) and NHPI (30 mol%).
Co(OAc)2 (10 mol%) and NHPI (10 mol%).
5
6
7
8
9
Initial investigations into the proposed cross dehydrogenative coupling focused on the reaction of diethyl H−phosphonate
(1) with triꢀnꢀbutylamine (2) (Table 1). In the beginning, various copper, iron salts were tested, most of which behaved
poorly(entries 1ꢀ3 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 αꢀaminophosphonate product in moderate yield (38%;
entry 4 in Table 1). Although NHPI alone has been revealed to be efficient organocatalyst for freeꢀradical 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 coꢀcatalysts, such as N−hydroxysuccinimide
(HOSU), and 1ꢀhydroxybenzotriazole (HOBT), revealed that NHPI was the best choice (entries 13−15). After a series of
detailed investigations, we established an efficient route to substituted αꢀaminophosphonates via Coꢀcatalyzed 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) .
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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, triꢀnꢀbutylamine, triꢀnꢀpropylamine, triꢀnꢀhexylamine, triꢀnꢀoctylamine, the
steric hindrance has no influence on the formation of αꢀaminophosphonates. For example, triꢀnꢀoctylamine with three bulky
octyl groups provided 6 in 70% yield. Triethylamine (7) gave a moderate yield. N,NꢀDimethylaniline (8) and
N,Nꢀdimethyltetradecanamine (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; nꢀBu3N, +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 αꢀaminophosphonates (10−13) in good yields. Not surprisingly, reacting
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diphenylphosphine oxide (Ph2P(O)H) with triꢀnꢀbutylamine 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 wellꢀknown 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.
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Table 2. The Oxidative C(sp3)–H Phosphonylation for αꢀAminophosphonates via C(sp3)–H/P(O)–H Coupling
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OR2
O
R5
R1O
N
R4
1
2
3
4
O
Co(OAc)2 (10 mol%)
OR1
OR2
R4
R3
P
NHPI (30 mol%)
R5
H P
+
R3
N
CH3CN (2.5 mL), air
16 h, 80 oC
5
6
7
8
9
OEt
O
OEt
OEt
O
EtO
N
C2H5
C2H5
OEt
O
EtO
N
EtO
N
C5H11
C5H11
P
C7H15
C7H15
EtO
N
P
P
P
O
C2H5
C5H11
C7H15
10
11
12
13
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7, 37%
i-PrO
N
4, 65%
6, 70%
5, 70%
OPr-i
OMe
O
MeO
P
N
OEt
O
C3H7
C3H7
OEt
C3H7
C3H7
EtO
P
EtO
P
O
P
O
N
N
C3H7
C3H7
C14H29
Ph
9, trace
11, 55%
8, trace
10, 75%
OBu-n
O
OBn
n-BuO
N
BnO
N
Ph
Ph
C3H7
C3H7
C3H7
N
C3H7
C3H7
P
P
P
O
O
N
EtO P O
C3H7
C3H7
C3H7
C3H7
OEt
15, 90%
12, 65%
13, 67%
14, 20%
O
Br
P OEt
OEt
N
N
N
N
EtO P O
OEt
EtO P O
OEt
EtO P O
OEt
CF3
OCH3
CF3
mixture 17 :17' = 90:10
18, quant.
17'
16, quant.
17
:
total yield quant.
N
N
N
Br
N
n-BuO P O
MeO P O
OMe
EtO P O
OEt
19, quant.
EtO P O
OEt
Br
Br
Br
OBu-n
21, quant.
20, quant.
22, 75%
N
N
N
N
i-PrO P O
OPr-i
BnO P O
OBn
Ph P
O
Ph P
O
Br
Br
Br
Ph
Ph
26, 85%
23, 73%
24, 68%
25
, 71%
N
N
N
C4H9
EtO P O O
OEt
EtO P O
OEt
EtO P O
OEt
28, 70% (25 hrs)
29, trace
27, 75% (25 hrs)
Different N−aryltetrahydroisoquinolines were coupled with diethyl H−phosphonate. They can uniformly afford the
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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 2ꢀ(4ꢀbromophenyl)ꢀ1,2,3,4ꢀtetrahydroisoquinoline 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,Oꢀdialkyl phosphonyl anions with iminium cation intermediates. Although several methods have been
developed for oxidative αꢀC−H phosphonation of Nꢀaryltetrahydroisoquinolines, diaryl phosphine oxides as reaction partners
are rarely reported. Kobayashi and Zhu reported the aerobic phosphonylation reaction of Nꢀaryl tetrahydroisoquinolines with
Ph2P(O)H catalyzed by the noble iridiumꢀbased and goldꢀbased 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.
NꢀBenzyl and Nꢀbutylꢀtetrahydroisoquinolines could be used as the substrates, generating the corresponding
αꢀaminophosphonates 27 and 28 in 75 and 70% yields, respectively. NꢀAcylꢀtetrahydroisoquinolines was also examined.
Unfortunately, only trace amount of the desired product was detected (29).
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In order to demonstrate the practical application of this method, diethyl H−phosphonate (1, 5 mmol) and triꢀnꢀbutylamine
(2, 17 mmol) were employed in a gramꢀscale reaction and delivered 3 in 75% yield (Scheme 2). The excess amount of amine
was recovered in 75% yield.
Scheme 2. GramꢀScale Preparation of
3
The reaction between 1 and 2 was inhibited obviously by adding 1.5 equiv of 2,2,6,6ꢀtetraꢀmethylpiperidinooxy (TEMPO)
or butylated hydroxytoluene (BHT)(Scheme 3). Although the detailed mechanism remains ambiguous at present, a possible
mechanism for this Co(II) complexꢀcatalyzed αꢀaminophosphonylation 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)ꢀphthalimideꢀNꢀoxyl (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 electronꢀdeficient PINO. Concerted
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αꢀC−H bond cleavage, an intramolecular 1,4ꢀhydrogen transfer, by the Nꢀoxyl 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.
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Scheme 3 Control Experiments
Scheme 4. A Tentative Mechanistic Pathway
In conclusion, we have developed a Co(OAc)2/ NHPIꢀcatalyzed αꢀaminophosphonylation of aliphatic and aromatic tertiary
amines with P(O)H compounds, which is efficient for the synthesis of αꢀaminophosphonates. The protocol represents the first
cross dehydrogenative coupling reaction between αꢀC−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
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General: All reagents were obtained from commercial suppliers and used without further purification. H NMR (500 MHz)
and 13C NMR (125 MHz) spectra were measured on Bruker AV 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
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reported in Hertz (Hz). Chemical shifts of common trace H NMR impurities (ppm): H2O: 1.56, CHCl3: 7.26. Column
chromatography was performed on silica gel 300ꢀ400 mesh. The unknown products were further characterized by HRMS
(FTꢀICRꢀMS) and electrospray ionization source in positiveꢀion 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. 2ꢀPropanol (10 mL),
ethylene glycol (1.11 mL, 20.0 mmol), 1,2,3,4ꢀtetrahydroꢀisoquinoline (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 85ꢀ90 °C and kept
for 24 h. The reaction mixture was allowed to cool to ambient temperature, and then transferred to a roundꢀbottom flask.
Silica gel (3.0 g) was added, and the solvent was removed under reduced pressure to afford a freeꢀflowing 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). 31P NMR (202 MHz, CDCl3) δ (ppm) 29.8. HRMS Calcd for
C16H36NNaO3P+ [M+Na]+ 344.2325, found 344.2320.
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Diethyl (1-(dipropylamino)propyl)phosphonate (4). Yield: 91 mg, 65%. Light yellow oil. H 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). 31P NMR (202 MHz, CDCl3) δ (ppm) 29.6. HRMS Calcd for
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C13H30NNaO3P+ [M+Na]+ 302.1856, found 302.1861.
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Diethyl (1-(dihexylamino)hexyl)phosphonate (5). Yield: 142 mg, 70%. Light yellow oil. H 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.
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Diethyl (1-(dioctylamino)octyl)phosphonate (6). Yield: 171 mg, 70%. Light yellow oil. H 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. H NMR
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(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.
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Dimethyl (1-(dibutylamino)butyl)phosphonate (10). Yield: 110 mg, 75%. Light yellow oil. H 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). 31P NMR (202 MHz, CDCl3) δ (ppm) 28.0. HRMS Calcd for C18H41NO3P+
[M+H]+ 350.2819, found 350.2821.
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Dibenzyl (1-(dibutylamino)butyl)phosphonate (12). Yield: 145 mg, 65%. Light yellow oil. H 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.
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Dibutyl (1-(dibutylamino)butyl)phosphonate (13). Yield: 126 mg, 67%. Light yellow oil. H 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.
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(1-(Dibutylamino)butyl)diphenylphosphine Oxide (14). Yield: 39 mg, 20%. White paste. H 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). 31P 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. 62ꢀ64 oC. 1H 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). 31P NMR (202 MHz, CDCl3) δ (ppm) 22.2. HRMS Calcd for
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,
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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.
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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%.
1H 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). 31P 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.
1H 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). 31P NMR (202 MHz, CDCl3) δ (ppm) 21.7. HRMS Calcd for C19H23BrNaNO3P+ [M+Na]+ 446.0491, found
446.0486.
Diethyl (2-(4-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (20) (CAS no: 1315275-83-2).7 Yield: 212 mg,
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100%. White solid, m.p. 85ꢀ87 C. Yield: quant. H 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). 31P NMR (202 MHz, CDCl3) δ (ppm) 21.8. HRMS Calcd for
C19H23BrNaNO3P+ [M+Na]+ 446.0491, found 446.0490.
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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. 159.5ꢀ161.5 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.
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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). 31P NMR (202 MHz, CDCl3) δ (ppm) 22.0. HRMS Calcd for C23H31BrNaNO3P+ [M+Na]+ 502.1117, found
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. 83ꢀ85 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).
13C 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
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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.
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Diisopropyl (2-(4-bromophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (24). Yield: 153 mg, 68%. White solid,
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m.p. 80ꢀ82 C. H 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.
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(2-(4-Bromophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)diphenylphosphine oxide (25) (CAS no: 1382465-08-8).18c Yield:
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173 mg, 71%. White solid, m.p. 147.5ꢀ149.5 C. H 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). 13C 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). 31P 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,
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85%. White solid, m.p. 196.5ꢀ198.5 C. H 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). 13C 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.
Diethyl (2-benzyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (27). Yield: 135 mg, 75%. 1H 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.
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Diethyl (2-butyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phosphonate (28). Yield: 114 mg, 70%. 1H 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. 1H NMR, 31P
NMR and 13C NMR spectrum (PDF).
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: t12g21@xmu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge financial support from the NSFC (21772163, 21778042, 21375113), NFFTBS (J1310024) and the
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Fundamental Research Funds for the Central Universities (20720160030).
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