Practical Synthesis of 1,2,3,4-Tetrahydroisoquinoline-1-phosphonic and -1-phosphinic Acids through Kabachnik-Fields and Aza-Pudovik Reaction

Article abstract of DOI:10.1055/s-0039-1690755

We report here an alternative and practical method for the preparation of 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid and the first synthesis of 1,2,3,4-tetrahydroisoquinoline-1- H -phosphinic and 1,2,3,4-tetrahydroisoquinoline-1-phenylphosphinic aci

Full text of DOI:10.1055/s-0039-1690755

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–F
paper
A
en
J. T. Hernández-Moreno et al.
Paper
Synthesis
Practical Synthesis of 1,2,3,4-Tetrahydroisoquinoline-1-phosphonic
and -1-phosphinic Acids through Kabachnik–Fields and Aza-Pudovik
Reaction
Jesús Tadeo Hernández-Morenoa
(RO)3P
Ivan Romero-Estudilloa,b
Carlos Cativielac
Mario Ordóñez*a
O
X
H
P
0
0
0
0-
0
0
0
1-9
3
9
5-7
0
7
9
OEt
N
O
a Centro de Investigaciones Químicas-IICBA, Universidad Autónoma
del Estado de Morelos, Av. Universidad 1001,
Cuernavaca, Morelos 62209, Mexico
N
X = OEt, Ph
H
X
P
O
X
HO
palacios@uaem.mx
H
P
X = OH, H, Ph
b CONACyT-Centro de Investigaciones Químicas-IICBA, Universidad
Autónoma del Estado de Morelos, Av. Universidad 1001,
Cuernavaca, Morelos 62209, Mexico
OH
X = H, OH
c Departamento de Química Orgánica, Universidad de Zaragoza-
CSIC, ISQCH, Zaragoza 50009, Spain
Mild reaction conditions
Operational simplicity
No metals needed
Received: 20.10.2019
Accepted after revision: 07.11.2019
Published online: 26.11.2019
On the other hand, 1,2,3,4-tetrahydroisoquinoline-1-
phosphonic, -1-H-phosphinic, and -1-phenylphosphinic ac-
ids (2–4, respectively; Figure 1) are probably the most im-
portant analogues of 1-Tic (1), obtained by isosteric re-
placement of the planar carboxylic group (CO2H) by a tetra-
hedral and sterically more demanding phosphonic or
phosphinic acid functionality (PO3H2, PO2H2, or PO2HR).
These classes of compounds are currently attracting
much interest in medicinal chemistry due to their import-
ant pharmacological activities against many diseases,3 ren-
dering these as privileged structures in the development of
new therapeutic agents. Owing to the great importance of
these compounds, several interesting reviews on the syn-
thesis of -aminophosphonic4 and -aminophosphinic ac-
ids5 have been published. In this context, the Kabachnik–
Fields6 and Pudovik7 reactions are the most widely used
synthetic strategies for the preparation of -aminophos-
phonic and -aminophosphinic acids. Additionally, in re-
cent reports, a variety of cross-dehydrogenative coupling
(CDC)8 methods for the synthesis of N-aryl-substituted 1-
phosphonylated 1,2,3,4-tetrahydroisoquinolines (THIQs)
have been described, with significant limitations (Scheme
1a). Namely, the substrate scope is limited to N-aryl-substi-
tuted THIQs, the use of harsh oxidant conditions, or cataly-
sis by expensive or toxic metals, thus limiting the synthesis
and discovery of novel THIQs of biological importance.
On the other hand, we have recently described a three-
step method for the synthesis of 1-phosphonylated N-Cbz-
1,2,3,4-tetrahydroisoquinoline. In this method, benzyl chlo-
roformate is added to isoquinoline to generate N-Cbz-iso-
quinolinium chloride which, by addition of triethyl phos-
phite followed by reduction of the double bond with trieth-
ylsilane in the presence of trifluoroacetic acid, affords
diethyl N-Cbz-1,2,3,4-tetrahydroisoquinoline-1-phospho-
nate (Scheme 1b).9 In view of the importance of the THIQ
DOI: 10.1055/s-0039-1690755; Art ID: ss-2019-m0590-op
Abstract We report here an alternative and practical method for the
preparation of 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid and
the first synthesis of 1,2,3,4-tetrahydroisoquinoline-1-H-phosphinic
and 1,2,3,4-tetrahydroisoquinoline-1-phenylphosphinic acids through
Kabachnik–Fields and aza-Pudovik reaction. This methodology does not
require any metallic catalyst and proceeds under mild reaction condi-
tions.
Key words -aminophosphonic acids, -aminophosphinic acids, N-
acyliminium ions, Kabachnik–Fields reaction, aza-Pudovik reaction
1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acid (1-Tic,
1; Figure 1) has been identified in several peptide-based
drugs and constitutes the skeleton of various biologically
active compounds with wide-ranging therapeutic applica-
tions.1 1-Tic (1) is also important as a conformationally con-
strained phenylglycine (Phg) analogue, present in the struc-
ture of diverse biologically active peptides, providing great-
er bioavailability, stability, and selectivity.2
Isosteric
replacement
N
N
H
H
X
P
HO
1-Tic; 1
O
O
HO
2; X = OH
3; X = H
4; X = Ph
Figure 1 1-Tic (1) and phospho analogues
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. T. Hernández-Moreno et al.
Paper
Synthesis
(a) Recent reports: Cross-Dehydrogenative Coupling (CDC)8
O
CDC
+
H
P(OR)2
N
N
cat. [M+]
Ar
Ar
R = alkyl
(RO)2P
O
(b) Previous work (three steps): via N-acyliminium ion9
Cl
CbzCl
1. (EtO)3P
2. Et3SiH, TFA
N
N
N
Cbz
MeCN
Cbz
(EtO)2P
O
(c) This work (one step): Kabachnik–Fields and aza-Pudovik reactions
O
X
H
P
Br
R
H2N
O
OR
+
N
N
H
H
X
X
O
H
P
P
O
OR
RO
X = OR, H, Ph
R = Me, Et, H
- Mild reaction conditions
- Operational simplicity
- No metals needed
Scheme 1 Methods for the synthesis of 1-phosphonylated 1,2,3,4-tetrahydroisoquinolines
H2N Bn
Br
PhB(OH)2
(10 mol%)
moiety and as a part of our current efforts to develop sus-
N
H
+
tainable methodologies for P–C bond formation,10 we here-
in report an alternative and practical method for the prepa-
ration of 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid
(2) and, for first time, the synthesis of 1,2,3,4-tetrahy-
droisoquinoline-1-H-phosphinic acid (3) and 1,2,3,4-tetra-
hydroisoquinoline-1-phenylphosphinic acid (4) through
Kabachnik–Fields or aza-Pudovik methodology and under
metal- and oxidant-free conditions (Scheme 1c).
MeCN
85 °C, 1.0 h
Bn
O
(MeO)2P
O
O
H
P(OMe)2
5
6; 74%
Pd/C 20 mol%
H2 5 atm, MeOH
50 °C, 24.0 h
Based on our previous experience in the preparation of
acyclic -aminophosphonates via ‘one-pot’ three-compo-
nent reactions,11 initially we proposed the synthesis of
1,2,3,4-tetrahydroisoquinoline-1-phosphonate 6 using 2-
(2-bromoethyl)benzaldehyde (5) as starting material,
which was easily obtained from isochroman.12 Thus, the
Kabachnik–Fields reaction of benzaldehyde 5 with benzyl-
amine and dimethyl phosphite in the presence of phenylbo-
ronic acid (PhB(OH)2) as catalyst (MeCN, 85 °C, 1.0 h) gave
dimethyl 2-benzyl-1,2,3,4-tetrahydroisoquinoline-1-phos-
phonate (6) in 74% yield13,14 which, by hydrogenolysis of the
N–Bn bond with hydrogen (5 atm) using 20% Pd/C as cata-
lyst (MeOH, 50 °C, 24.0 h), afforded the cyclic -aminophos-
phonate 7 in 32% yield (Scheme 2).
N
H
(MeO)2P
O
7; 32%
Scheme 2 Synthesis of dimethyl 1,2,3,4-tetrahydroisoquinoline-1-
phosphonate (7) through Kabachnik–Fields reaction
phenylphosphonic acid (PhPO(OH)2) in MeCN at 60 °C for
24.0 hours produced diethyl 1,2,3,4-tetrahydroisoquino-
line-1-phosphonate (8) in 70% yield (Scheme 3).15
On the other hand, the aza-Pudovik reaction of 3,4-di-
hydroisoquinoline (9), easily obtained by oxidation of
1,2,3,4-tetrahydroisoquinoline,16 with triethyl phosphite,
benzyl chloroformate, and NaI in MeCN at 50 °C for 2.0
hours furnished diethyl 2-benzyloxycarbonyl-1,2,3,4-tetra-
hydroisoquinoline-1-phosphonate (10) in 94% yield
Considering these results, we decided to use ammonia
as an alternative nitrogen source to avoid N–Bn bond hy-
drogenolysis. In this context, the Kabachnik–Fields reaction
of benzaldehyde 5 with excess ammonium acetate and tri-
ethyl phosphite in the presence of catalytic amounts of
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–F

C
J. T. Hernández-Moreno et al.
Paper
Synthesis
hours furnished the target 1,2,3,4-tetrahydroisoquinoline-
1-phosphonic acid (2) in 53% yield. Furthermore, the reac-
tion of imine 9 with ethyl phenylphosphinate in the pres-
ence of catalytic amounts of PhPO(OH)2 in MeCN at 80 °C
for 6.0 hours gave the corresponding mixture of diastereo-
mers 11 in 84% yield (Scheme 5).
PhPO(OH)2
(10 mol%)
Br
AcONH4
(EtO)3P
H
+
N
MeCN
H
60 °C, 24.0 h
(EtO)2P
O
O
5
8; 70%
Finally, hydrolysis of the cyclic -aminophosphonates 7,
8, 10 and the cyclic -aminophosphinate 11 with a 33%
solution of hydrogen bromide in acetic acid, followed by
treatment with propylene oxide in ethanol at room tem-
perature for 12.0 hours, afforded the corresponding 1,2,3,4-
tetrahydroisoquinoline-1-phosphonic acid (2, 87–94%
yield) and 1,2,3,4-tetrahydroisoquinoline-1-phenylphos-
phinic acid (4) in 91% yield (Scheme 6).
Scheme 3 Synthesis of diethyl 1,2,3,4-tetrahydroisoquinoline-1-phos-
phonate (8) through Kabachnik–Fields reaction
(Scheme 4). Upon changing the order of reagent addition,
3,4-dihydroisoquinoline (9), benzyl chloroformate, and NaI
in MeCN followed by the addition of triethyl phosphite at
50 °C for 2.0 hours, the cyclic diethyl phosphonate 10 was
obtained in low yield. Taking this into account, and to mini-
mize the number of reaction steps in the synthesis of the
cyclic -aminophosphonates 7 and 8, we carried out the di-
rect addition8k of dimethyl or diethyl phosphite to 3,4-dihy-
droisoquinoline (9) in the presence of catalytic amounts of
PhB(OH)2 in MeCN at 80 °C for 5.0 hours to obtain phospho-
nates 7 and 8 in 73% and 91% yield, respectively (Scheme 4).
1. HBr/AcOH
N
N
Z
H
2.
, EtOH
HO
HO
O
RO
RO
P
P
r.t., 12.0 h
O
O
2
7; Z = H; R = Me
8; Z = H; R = Et
10; Z = Cbz; R = Et
87% (from 7)
93% (from 8)
94% (from 10)
7
O
(73%)
N
O
CbzCl, NaI
H
P(OR)2
1. HBr/AcOH
2.
Cbz
N
N
or
N
(EtO)2P
PhB(OH)2
(10 mol%), MeCN
80 °C, 5.0 h
(EtO)3P, MeCN
0 to 50 °C, 2.0 h
H
H
, EtOH
O
Ph
P
Ph
9
8
P
r.t., 12.0 h
10; 94%
O
O
HO
EtO
(91%)
11
4; 91%
Scheme 4 Synthesis of 1,2,3,4-tetrahydroisoquinoline-1-phospho-
nates 7, 8, and 10 through aza-Pudovik methodology
Scheme 6 Hydrolysis of cyclic -aminophosphonates 7, 8, 10 and cy-
clic -aminophosphinate 11
With the results described above, the direct hydrophos-
phonylation of 9 using different phosphorus nucleophilic
sources was examined. Thus, the aza-Pudovik reaction of
3,4-dihydroisoquinoline (9) with phosphinic acid (H3PO2)
in MeCN at 80 °C for 30 minutes gave the expected 1,2,3,4-
tetrahydroisoquinoline-1-H-phosphinic acid (3) in 84%
yield (Scheme 5). In similar way, the reaction of imine 9
with phosphorous acid (H3PO3) in MeCN at 80 °C for 36.0
In conclusion, we have developed an alternative and
practical method for the preparation of 1,2,3,4-tetrahy-
droisoquinoline-1-phosphonic acid (2) and the first synthe-
sis of 1,2,3,4-tetrahydroisoquinoline-1-H-phosphinic acid
(3) and 1,2,3,4-tetrahydroisoquinoline-1-phenylphosphinic
acid (4) through Kabachnik–Fields and aza-Pudovik reac-
tion, demonstrating once more that N-acyliminium ions
and imines are key intermediates for the synthesis of cyclic
O
Ph
P
H
OEt
H3PO2, MeCN
N
N
N
PhPO(OH)2
(10 mol%), MeCN
80 °C, 6.0 h
80 °C, 0.5 h
H
H
9
Ph
H
P
P
O
O
EtO
HO
H3PO3, MeCN
3; 84%
11; 84%
80 °C, 36.0 h
2
(53%)
Scheme 5 Direct hydrophosphonylation of 3,4-dihydroisoquinoline (9)
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–F

D
J. T. Hernández-Moreno et al.
Paper
Synthesis
-aminophosphonic and cyclic -aminophosphinic acids
and their derivatives. Due to the high potential pharmaco-
logical properties and the relevance of these kinds of com-
pounds, studies are currently underway to develop an en-
antioselective synthesis.
HRMS (ESI+): m/z [M + Na]+ calcd for C11H16NNaO3P: 264.0765; found:
264.0766.
Diethyl 1,2,3,4-Tetrahydroisoquinoline-1-phosphonate (8)
From 5: A mixture of benzaldehyde 5 (0.20 g, 0.94 mmol), ammonium
acetate (0.54 g, 7.05 mmol), phenylphosphonic acid (14 mg, 0.09
mmol), and anhydrous Na2SO4 (1.0 g, 7.05 mmol) in anhydrous MeCN
(5 mL) was stirred at r.t. for 15 min. After this time, triethyl phosphite
(0.17 g, 0.18 mL, 1.03 mmol) was added, and the reaction mixture
was stirred at 60 °C for 24.0 h. The crude product was purified by
flash chromatography (EtOAc:MeOH, 95:5), giving compound 8 (0.18
g, 70%) as a colorless oil. The spectroscopic 1H, 13C, and 31P NMR data
are similar to those reported previously.15
All commercial materials were of analytical grade and used as re-
ceived unless noted otherwise. Flash chromatography was performed
using 230–400 mesh Silica Flash 60. TLC was done on pre-coated TLC
sheets of silica gel 60 F254 (E. Merck, Germany), and two reagent al-
ternatives were used for visualization: (a) iodine, (b) KMnO4 in water.
1H, 13C, and 31P NMR spectra were recorded in CDCl3, DCl/D2O, or
NaOD/D2O on a Varian MERCURY (200 MHz), Varian MERCURY plus
(400 MHz) or Bruker AVANCE III HD (500 MHz) instrument using TMS
as internal reference and P(O)Ph3 for 31P NMR. Chemical shifts ()
were determined in parts per million and coupling constant (J) values
are given in hertz. Standard abbreviations are used for peak multiplic-
ities. High-resolution FAB+ mass spectra (HRMS) and Electrospray
Ionization Interface (ESI+) data of the new derivatives were obtained
on a JEOL MStation MS-700 mass spectrometer and Synapt G2-Si, Wa-
ters Acquity Class I Inc.
From 9: A solution of imine 9 (0.10 g, 0.76 mmol) in MeCN (3 mL) was
treated with phenylboronic acid (10 mg, 0.07 mmol) and diethyl
phosphite (0.12 g, 0.11 mL, 0.84 mmol). The reaction mixture was
stirred at r.t. for 5 min. After this time, the mixture was heated at
80 °C for 5.0 h. The crude product was purified by flash chromatogra-
phy (EtOAc:MeOH, 95:5), giving compound 8 (0.19 g, 91%) as a color-
less oil.
Diethyl 2-Benzyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-1-
phosphonate (10)
A solution of imine 9 (0.20 g, 1.52 mmol) and triethyl phosphite (0.28
g, 0.29 mL, 1.68 mmol) in anhydrous MeCN (2 mL) was cooled at 0 °C
and treated with benzyl chloroformate (0.29 g, 0.24 mL 1.68 mmol).
Then, NaI (0.342 g, 2.287 mmol) was slowly added. The reaction mix-
ture was stirred at 50 °C for 2.0 h. The crude product mixture was
poured into saturated aqueous NaHCO3 (5 mL) and extracted with
CH2Cl2 (3 × 10 mL). The organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography (EtOAc:hexane,
80:20), giving compound 10 (0.58 g, 94%) as a colorless oil. The spec-
troscopic 1H, 13C, and 31P NMR data are similar to those reported pre-
viously.9
Dimethyl 2-Benzyl-1,2,3,4-tetrahydroisoquinoline-1-phospho-
nate (6)
A solution of 2-(2-bromoethyl)benzaldehyde12 (5; 0.21 g, 1.0 mmol)
in MeCN (3 mL) at 0 °C was treated with benzylamine (0.11 g, 1.0
mmol), dimethyl phosphite (0.12 g, 0.1 mL, 1.1 mmol), and phenylbo-
ronic acid (10 mg, 0.1 mmol). The reaction mixture was stirred at
26 °C for 10 min. After this time, the mixture was heated at 85 °C for 1
h. The crude product was purified by flash chromatography
(EtOAc:hexane, 95:5), giving compound 6 (0.25 g, 74%) as a yellow oil.
The spectroscopic 1H, 13C, and 31P NMR data are similar to those re-
ported previously.13
Dimethyl 1,2,3,4-Tetrahydroisoquinoline-1-phosphonate (7)
Ethyl 1,2,3,4-Tetrahydroisoquinoline-1-phenylphosphinate (11)
From 6: A mixture of 6 (2.0 g, 6.04 mmol) and 20% Pd/C (0.4 g) in
MeOH (20 mL) was stirred under 5 atm pressure hydrogen gas at
50 °C for 24.0 h. The crude product was filtered over Celite and puri-
fied by flash chromatography (EtOAc:MeOH, 95:5), giving compound
7 (0.47 g, 32%) as a colorless oil.
A solution of imine 9 (0.20 g, 1.52 mmol) in MeCN (5 mL) was treated
with phenylphosphonic acid (20 mg, 0.15 mmol) and ethyl phenyl-
phosphinate (0.29 g, 0.25 mL, 1.68 mmol). The reaction mixture was
stirred at r.t. for 5 min. After this time, the mixture was heated at
80 °C for 6.0 h. The crude product was purified by flash chromatogra-
phy (EtOAc:MeOH, 99:1), giving a separable mixture of diastereo-
mers, less polar (0.19 g, 42%) and more polar (0.19 g, 42%), as colorless
oils.
From 9: A solution of 3,4-dihydroisoquinoline (9; 0.10 g, 0.76 mmol)
in MeCN (3 mL) was treated with phenylboronic acid (10 mg, 0.08
mmol) and dimethyl phosphite (0.09 g, 0.08 mL, 0.84 mmol). The re-
action mixture was stirred at r.t. for 5 min. After this time, the mix-
ture was heated at 80 °C for 5.0 h. The crude product was purified by
flash chromatography (EtOAc:MeOH, 95:5), giving compound 7 (0.13
g, 73%) as a colorless oil.
1H NMR (500 MHz, CDCl3):  = 7.50–7.45 (m, 1 H, Harom), 7.21–7.16
(m, 2 H, Harom), 7.16–7.11 (m, 1 H, Harom), 4.51 (d, J = 16.9 Hz, 1 H,
CHP), 3.73 (d, J = 10.4 Hz, 3 H, CH3O), 3.64 (d, J = 10.4 Hz, 3 H, CH3O),
3.40 (ddd, J = 12.1, 6.3, 2.1 Hz, 1 H, CH2N), 3.04 (ddd, J = 12.1, 5.3, 5.2
Hz, 1 H, CH2N), 2.87–2.82 (m, 2 H, CH2Ph), 2.19 (br, 1 H, NH).
Less Polar Diastereomer
1H NMR (500 MHz, CDCl3):  = 7.77–7.70 (m, 2 H, Harom), 7.54–7.47
(m, 2 H, Harom), 7.42–7.36 (m, 2 H, Harom), 7.16–7.09 (m, 2 H, Harom),
7.04–6.98 (m, 1 H, Harom), 4.58 (d, J = 14.5 Hz, 1 H, CHP), 4.22–4.11 (m,
1 H, OCH2CH3), 4.02–3.91 (m, 1 H, OCH2CH3), 3.40–3.34 (m, 1 H,
CH2N), 2.94–2.87 (m, 1 H, CH2N), 2.72–2.64 (m, 1 H, CH2Ph), 2.64–2.56
(m, 1 H, CH2Ph), 2.24 (br, 1 H, NH), 1.34 (t, J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (125 MHz, CDCl3):  = 136.3 (d, JC-P = 5.7 Hz), 132.9, 132.8,
132.4 (d, JC-P = 2.1 Hz), 130.1, 129.9 (d, JC-P = 3.3 Hz), 129.5, 129.1,
128.5, 128.4, 126.9 (d, JC-P = 2.7 Hz), 125.8 (d, JC-P = 2.5 Hz), 61.3 (d,
JC-P = 7.3 Hz, OCH2), 57.0 (d, JC-P = 106.0 Hz, CHP), 41.1 (d, JC-P = 5.9 Hz,
CH2N), 29.6 (CH2Ph), 16.8 (d, JC-P = 5.8 Hz, OCH2CH3).
13C NMR (125 MHz, CDCl3):  = 135.9 (d, JC-P = 6.8 Hz), 129.9 (d, JC-P
3.2 Hz), 129.8, 128.1 (d, JC-P = 3.9 Hz), 127.2 (d, JC-P = 2.9 Hz), 126.0 (d,
JC-P = 2.8 Hz), 54.3 (d, JC-P = 145.9 Hz, CHP), 53.8 (d, JC-P = 7.3 Hz, CH3O),
53.2 (d, JC-P = 7.5 Hz, CH3O), 41.1 (d, JC-P = 5.6 Hz, CH2N), 29.5 (CH2Ph).
=
31P NMR (202 MHz, CDCl3):  = 39.70.
HRMS (ESI+): m/z [M + Na]+ calcd for C17H20NNaO2P: 324.1129; found:
31P NMR (202 MHz, CDCl3):  = 26.70.
324.1139.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–F

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J. T. Hernández-Moreno et al.
Paper
Synthesis
More Polar Diastereomer
1,2,3,4-Tetrahydroisoquinoline-1-phosphonic Acid (2)
1H NMR (500 MHz, CDCl3):  = 7.53–7.45 (m, 3 H, Harom), 7.36–7.29
(m, 3 H, Harom), 7.18–7.09 (m, 2 H, Harom), 7.03–6.98 (m, 1 H, Harom),
4.58 (d, J = 15.1 Hz, 1 H, CHP), 4.10–4.01 (m, 1 H, OCH2CH3), 3.94–3.85
(m, 1 H, OCH2CH3), 3.22–3.16 (m, 1 H, CH2N), 2.96–2.89 (m, 1 H,
CH2N), 2.78–2.70 (m, 1 H, CH2Ph), 2.50–2.45 (m, 1 H, CH2Ph), 2.44–
2.24 (m, 1 H, NH), 1.29 (t, J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (125 MHz, CDCl3):  = 136.09 (d, JC-P = 5.7 Hz), 132.84,
132.77, 132.46 (d, JC-P = 2.0 Hz), 130.34, 130.17 (d, JC-P = 1.8 Hz),
129.48, 129.42, 128.50, 128.40, 127.10 (d, JC-P = 2.7 Hz), 125.70 (d,
JC-P = 2.4 Hz), 61.64 (d, JC-P = 7.6 Hz, OCH2), 57.26 (d, JC-P = 100 Hz,
CHP), 40.64 (d, JC-P = 4.5 Hz, CH2N), 29.26 (CH2Ph), 16.71 (d, JC-P = 6.0
Hz, OCH2CH3).
A solution of imine 9 (0.20 g, 1.52 mmol) in MeCN (5 mL) was treated
with phosphorous acid (0.08 mL, 1.68 mmol). The reaction mixture
was stirred at r.t. for 10 min. After this time, the mixture was heated
at 80 °C for 36 h. The solid formed was filtered and washed with EtOAc
and MeOH, giving compound 2 (0.17 g, 53%) as a white solid; mp
242–243 °C. The spectroscopic 1H, 13C, and 31P NMR data are similar
to those reported previously.9
1,2,3,4-Tetrahydroisoquinoline-1-phenylphosphinic Acid (4)
1H NMR (400 MHz, NaOD/D2O):  = 6.78–6.69 (m, 2 H, Harom), 6.68–
6.61 (m, 1 H, Harom), 6.42–6.31 (m, 3 H, Harom), 6.31–6.23 (m, 2 H, Harom),
6.17–6.09 (m, 1 H, Harom), 3.61 (d, J = 18.3 Hz, 1 H, CHP), 2.31–2.19 (m,
1 H, CH2N), 1.89–1.77 (m, 1 H, CH2N), 1.72–1.57 (m, 1 H, CH2Ph),
1.36–1.20 (m, 1 H, CH2Ph).
13C NMR (100 MHz, NaOD/D2O):  = 135.5, 134.8 (d, JC-P = 4.4 Hz),
134.3, 132.1, 131.6 (d, JC-P = 8.1 Hz), 130.0, 127.9, 127.6, 127.2, 127.1,
125.2, 124.8, 57.7 (d, JC-P = 93.3 Hz), 39.4, 28.3.
31P NMR (202 MHz, CDCl3):  = 39.55.
HRMS (ESI+): m/z [M + Na]+ calcd for C17H20NNaO2P: 324.1129; found:
324.1129.
1,2,3,4-Tetrahydroisoquinoline-1-H-phosphinic Acid (3)
31P NMR (202 MHz, NaOD/D2O):  = 29.44.
HRMS (FAB+): m/z [M + H]+ calcd for C15H17NO2P: 274.0997; found:
A solution of imine 9 (0.20 g, 1.52 mmol) in MeCN (5 mL) was treated
with a 60% solution of hypophosphorous acid in water (0.15 mL, 1.68
mmol). The reaction mixture was stirred at r.t. for 5 min. After this
time, the mixture was heated at 80 °C for 30 min. The precipitate
formed was filtered and washed with EtOAc and MeOH, giving com-
pound 3 (252 mg, 84%) as a white solid; mp 236–238 °C.
1H NMR (500 MHz, DCl/D2O):  = 7.13–7.06 (m, 3 H, Harom), 7.06–7.02
(m, 1 H, Harom), 6.73 (d, J = 549.6 Hz, 1 H, HP), 4.24 (d, J = 14.9 Hz, 1 H,
CHP), 3.42–3.35 (m, 1 H, CH2N), 3.31–3.24 (m, 1 H, CH2N), 2.93–2.79
(m, 2 H, CH2Ph).
13C NMR (125 MHz, DCl/D2O):  = 131.7 (d, JC-P = 4.6 Hz), 129.6 (d,
JC-P = 2.3 Hz), 128.4 (d, JC-P = 2.7 Hz), 127.3 (d, JC-P = 2.8 Hz), 127.2
(d, JC-P = 4.5 Hz), 125.7 (d, JC-P = 2.9 Hz), 55.7 (d, J = 83.7 Hz, CHP), 40.3
(d, J = 2.7 Hz, CH2N), 24.6 (CH2Ph).
274.0991.
Funding Information
The authors thank the Consejo Nacional de Ciencia y Tecnología
(CONACyT) for financial support through projects 286614, 807, and
Cátedra contract 942, and Gobierno de Aragón-FEDER (Grupo Amino-
ácidos y Péptidos E19_17R; FEDER 2014-2020 ‘Construyendo Europa
desde Aragón’). J.T.H.-M. also wishes to thank CONACyT for Graduate
Scholarship 335029.
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31P NMR (81 MHz, DCl/D2O):  = 20.61.
HRMS (FAB+): m/z [M + H]+ calcd for C9H13NO2P: 198.0684; found:
Acknowledgment
The authors thank Victoria Labastida and Juan Monribot for their
valuable technical support in obtaining mass spectrometric analyses.
198.0722.
1,2,3,4-Tetrahydroisoquinoline-1-phosphonic Acid (2) and 1,2,3,4-
Tetrahydroisoquinoline-1-phenylphosphinic Acid (4); General
Procedure
Supporting Information
Supporting information for this article is available online at
The appropriate cyclic phosphorus derivative (0.2 g, 1 equiv) was
treated with a 33% solution of hydrogen bromide in acetic acid (2 mL)
at 0 °C, and the reaction mixture was stirred at r.t. for 5 h. After this
time, the volatiles were evaporated under reduced pressure. The
crude product was dissolved in EtOH (0.5 mL), and the resulting solu-
tion was treated with propylene oxide (2 mL) and stirred at r.t. for
12.0 h. The precipitate formed was filtered, washed with EtOH, and
dried under reduced pressure, giving compound 2 or 4.
https://doi.org/10.1055/s-0039-1690755.
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References
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